This application claims the benefit of U.S. Provisional Application No. 62/066,310 filed Oct. 20, 2014; and of U.S. Provisional Application No. 62/066,313 filed Oct. 20, 2014; and of U.S. Provisional Application No. 62/066,316 filed Oct. 20, 2014; each of which is hereby incorporated in its entirety including all tables, figures, and claims.
BACKGROUND OF THE INVENTION
The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The kidney is responsible for water and solute excretion from the body. Its functions include maintenance of acid-base balance, regulation of electrolyte concentrations, control of blood volume, and regulation of blood pressure. As such, loss of kidney function through injury and/or disease results in substantial morbidity and mortality. A detailed discussion of renal injuries is provided in Harrison's Principles of Internal Medicine, 17th Ed., McGraw Hill, New York, pages 1741-1830, which are hereby incorporated by reference in their entirety. Renal disease and/or injury may be acute or chronic. Acute and chronic kidney disease are described as follows (from Current Medical Diagnosis & Treatment 2008, 47th Ed, McGraw Hill, New York, pages 785-815, which are hereby incorporated by reference in their entirety): “Acute renal failure is worsening of renal function over hours to days, resulting in the retention of nitrogenous wastes (such as urea nitrogen) and creatinine in the blood. Retention of these substances is called azotemia. Chronic renal failure (chronic kidney disease) results from an abnormal loss of renal function over months to years”.
Acute renal failure (ARF, also known as acute kidney injury, or AKI) is an abrupt (typically detected within about 48 hours to 1 week) reduction in glomerular filtration. This loss of filtration capacity results in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidney, a reduction in urine output, or both. It is reported that ARF complicates about 5% of hospital admissions, 4-15% of cardiopulmonary bypass surgeries, and up to 30% of intensive care admissions. ARF may be categorized as prerenal, intrinsic renal, or postrenal in causation. Intrinsic renal disease can be further divided into glomerular, tubular, interstitial, and vascular abnormalities. Major causes of ARF are described in the following table, which is adapted from the Merck Manual, 17th ed., Chapter 222, and which is hereby incorporated by reference in their entirety:
Type Risk Factors
Prerenal
ECF volume depletion Excessive diuresis, hemorrhage, GI losses, loss of
intravascular fluid into the extravascular space (due to
ascites, peritonitis, pancreatitis, or burns), loss of skin
and mucus membranes, renal salt- and water-wasting states
Low cardiac output Cardiomyopathy, MI, cardiac tamponade, pulmonary embolism,
pulmonary hypertension, positive-pressure mechanical ventilation
Low systemic vascular Septic shock, liver failure, antihypertensive drugs
resistance
Increased renal vascular NSAIDs, cyclosporines, tacrolimus, hypercalcemia,
resistance anaphylaxis, anesthetics, renal artery obstruction, renal
vein thrombosis, sepsis, hepatorenal syndrome
Decreased efferent ACE inhibitors or angiotensin II receptor blockers
arteriolar tone (leading to
decreased GFR from
reduced glomerular
transcapillary pressure,
especially in patients with
bilateral renal artery
stenosis)
Intrinsic Renal
Acute tubular injury Ischemia (prolonged or severe prerenal state): surgery,
hemorrhage, arterial or venous obstruction; Toxins:
NSAIDs, cyclosporines, tacrolimus, aminoglycosides,
foscarnet, ethylene glycol, hemoglobin, myoglobin,
ifosfamide, heavy metals, methotrexate, radiopaque
contrast agents, streptozotocin
Acute glomerulonephritis ANCA-associated: Crescentic glomerulonephritis,
polyarteritis nodosa, Wegener's granulomatosis; Anti-
GBM glomerulonephritis: Goodpasture's syndrome;
Immune-complex: Lupus glomerulonephritis,
postinfectious glomerulonephritis, cryoglobulinemic
glomerulonephritis
Acute tubulointerstitial Drug reaction (eg, β-lactams, NSAIDs, sulfonamides,
nephritis ciprofloxacin, thiazide diuretics, furosemide, phenytoin,
allopurinol, pyelonephritis, papillary necrosis
Acute vascular Vasculitis, malignant hypertension, thrombotic
nephropathy microangiopathies, scleroderma, atheroembolism
Infiltrative diseases Lymphoma, sarcoidosis, leukemia
Postrenal
Tubular precipitation Uric acid (tumor lysis), sulfonamides, triamterene,
acyclovir, indinavir, methotrexate, ethylene glycol
ingestion, myeloma protein, myoglobin
Ureteral obstruction Intrinsic: Calculi, clots, sloughed renal tissue, fungus
ball, edema, malignancy, congenital defects; Extrinsic:
Malignancy, retroperitoneal fibrosis, ureteral trauma
during surgery or high impact injury
Bladder obstruction Mechanical: Benign prostatic hyperplasia, prostate
cancer, bladder cancer, urethral strictures, phimosis,
paraphimosis, urethral valves, obstructed indwelling
urinary catheter; Neurogenic: Anticholinergic drugs,
upper or lower motor neuron lesion
In the case of ischemic ARF, the course of the disease may be divided into four phases. During an initiation phase, which lasts hours to days, reduced perfusion of the kidney is evolving into injury. Glomerular ultrafiltration reduces, the flow of filtrate is reduced due to debris within the tubules, and back leakage of filtrate through injured epithelium occurs. Renal injury can be mediated during this phase by reperfusion of the kidney. Initiation is followed by an extension phase which is characterized by continued ischemic injury and inflammation and may involve endothelial damage and vascular congestion. During the maintenance phase, lasting from 1 to 2 weeks, renal cell injury occurs, and glomerular filtration and urine output reaches a minimum. A recovery phase can follow in which the renal epithelium is repaired and GFR gradually recovers. Despite this, the survival rate of subjects with ARF may be as low as about 60%.
Acute kidney injury caused by radiocontrast agents (also called contrast media) and other nephrotoxins such as cyclosporine, antibiotics including aminoglycosides and anticancer drugs such as cisplatin manifests over a period of days to about a week. Contrast induced nephropathy (CIN, which is AKI caused by radiocontrast agents) is thought to be caused by intrarenal vasoconstriction (leading to ischemic injury) and from the generation of reactive oxygen species that are directly toxic to renal tubular epithelial cells. CIN classically presents as an acute (onset within 24-48 h) but reversible (peak 3-5 days, resolution within 1 week) rise in blood urea nitrogen and serum creatinine.
A commonly reported criteria for defining and detecting AKI is an abrupt (typically within about 2-7 days or within a period of hospitalization) elevation of serum creatinine. Although the use of serum creatinine elevation to define and detect AKI is well established, the magnitude of the serum creatinine elevation and the time over which it is measured to define AKI varies considerably among publications. Traditionally, relatively large increases in serum creatinine such as 100%, 200%, an increase of at least 100% to a value over 2 mg/dL and other definitions were used to define AKI. However, the recent trend has been towards using smaller serum creatinine rises to define AKI. The relationship between serum creatinine rise, AKI and the associated health risks are reviewed in Praught and Shlipak, Curr Opin Nephrol Hypertens 14:265-270, 2005 and Chertow et al, J Am Soc Nephrol 16: 3365-3370, 2005, which, with the references listed therein, are hereby incorporated by reference in their entirety. As described in these publications, acute worsening renal function (AKI) and increased risk of death and other detrimental outcomes are now known to be associated with very small increases in serum creatinine. These increases may be determined as a relative (percent) value or a nominal value. Relative increases in serum creatinine as small as 20% from the pre-injury value have been reported to indicate acutely worsening renal function (AKI) and increased health risk, but the more commonly reported value to define AKI and increased health risk is a relative increase of at least 25%. Nominal increases as small as 0.3 mg/dL, 0.2 mg/dL or even 0.1 mg/dL have been reported to indicate worsening renal function and increased risk of death. Various time periods for the serum creatinine to rise to these threshold values have been used to define AKI, for example, ranging from 2 days, 3 days, 7 days, or a variable period defined as the time the patient is in the hospital or intensive care unit. These studies indicate there is not a particular threshold serum creatinine rise (or time period for the rise) for worsening renal function or AKI, but rather a continuous increase in risk with increasing magnitude of serum creatinine rise.
One study (Lassnigg et all, J Am Soc Nephrol 15:1597-1605, 2004, hereby incorporated by reference in its entirety) investigated both increases and decreases in serum creatinine. Patients with a mild fall in serum creatinine of −0.1 to −0.3 mg/dL following heart surgery had the lowest mortality rate. Patients with a larger fall in serum creatinine (more than or equal to −0.4 mg/dL) or any increase in serum creatinine had a larger mortality rate. These findings caused the authors to conclude that even very subtle changes in renal function (as detected by small creatinine changes within 48 hours of surgery) seriously effect patient's outcomes. In an effort to reach consensus on a unified classification system for using serum creatinine to define AKI in clinical trials and in clinical practice, Bellomo et al., Crit Care. 8(4):R204-12, 2004, which is hereby incorporated by reference in its entirety, proposes the following classifications for stratifying AKI patients:
-
- “Risk”: serum creatinine increased 1.5 fold from baseline OR urine production of <0.5 ml/kg body weight/hr for 6 hours;
- “Injury”: serum creatinine increased 2.0 fold from baseline OR urine production <0.5 ml/kg/hr for 12 h;
- “Failure”: serum creatinine increased 3.0 fold from baseline OR creatinine >355 μmol/l (with a rise of >44) or urine output below 0.3 ml/kg/hr for 24 h or anuria for at least 12 hours;
And included two clinical outcomes: - “Loss”: persistent need for renal replacement therapy for more than four weeks.
- “ESRD”: end stage renal disease—the need for dialysis for more than 3 months.
These criteria are called the RIFLE criteria, which provide a useful clinical tool to classify renal status. As discussed in Kellum, Crit. Care Med. 36: S141-45, 2008 and Ricci et al., Kidney Int. 73, 538-546, 2008, each hereby incorporated by reference in its entirety, the RIFLE criteria provide a uniform definition of AKI which has been validated in numerous studies.
More recently, Mehta et al., Crit. Care 11:R31 (doi:10.1186.cc5713), 2007, hereby incorporated by reference in its entirety, proposes the following similar classifications for stratifying AKI patients, which have been modified from RIFLE:
-
- “Stage I”: increase in serum creatinine of more than or equal to 0.3 mg/dL (≥26.4 μmol/L) or increase to more than or equal to 150% (1.5-fold) from baseline OR urine output less than 0.5 mL/kg per hour for more than 6 hours;
- “Stage II”: increase in serum creatinine to more than 200% (>2-fold) from baseline OR urine output less than 0.5 mL/kg per hour for more than 12 hours;
- “Stage III”: increase in serum creatinine to more than 300% (>3-fold) from baseline OR serum creatinine ≥354 μmol/L accompanied by an acute increase of at least 44 μmol/L OR urine output less than 0.3 mL/kg per hour for 24 hours or anuria for 12 hours.
The CIN Consensus Working Panel (McCollough et al, Rev Cardiovasc Med. 2006; 7(4):177-197, hereby incorporated by reference in its entirety) uses a serum creatinine rise of 25% to define Contrast induced nephropathy (which is a type of AKI). Although various groups propose slightly different criteria for using serum creatinine to detect AKI, the consensus is that small changes in serum creatinine, such as 0.3 mg/dL or 25%, are sufficient to detect AKI (worsening renal function) and that the magnitude of the serum creatinine change is an indicator of the severity of the AKI and mortality risk.
Although serial measurement of serum creatinine over a period of days is an accepted method of detecting and diagnosing AKI and is considered one of the most important tools to evaluate AKI patients, serum creatinine is generally regarded to have several limitations in the diagnosis, assessment and monitoring of AKI patients. The time period for serum creatinine to rise to values (e.g., a 0.3 mg/dL or 25% rise) considered diagnostic for AKI can be 48 hours or longer depending on the definition used. Since cellular injury in AKI can occur over a period of hours, serum creatinine elevations detected at 48 hours or longer can be a late indicator of injury, and relying on serum creatinine can thus delay diagnosis of AKI. Furthermore, serum creatinine is not a good indicator of the exact kidney status and treatment needs during the most acute phases of AKI when kidney function is changing rapidly. Some patients with AKI will recover fully, some will need dialysis (either short term or long term) and some will have other detrimental outcomes including death, major adverse cardiac events and chronic kidney disease. Because serum creatinine is a marker of filtration rate, it does not differentiate between the causes of AKI (pre-renal, intrinsic renal, post-renal obstruction, atheroembolic, etc) or the category or location of injury in intrinsic renal disease (for example, tubular, glomerular or interstitial in origin). Urine output is similarly limited, Knowing these things can be of vital importance in managing and treating patients with AKI.
These limitations underscore the need for better methods to detect and assess AKI, particularly in the early and subclinical stages, but also in later stages when recovery and repair of the kidney can occur. Furthermore, there is a need to better identify patients who are at risk of having an AKI.
BRIEF SUMMARY OF THE INVENTION
It is an object of the invention to provide methods and compositions for evaluating renal function in a subject. As described herein, measurement of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and Tyrosine-protein kinase receptor UFO (collectively referred to herein as “kidney injury markers, and individually as a “kidney injury marker”) can be used for diagnosis, prognosis, risk stratification, staging, monitoring, categorizing and determination of further diagnosis and treatment regimens in subjects suffering or at risk of suffering from an injury to renal function, reduced renal function, and/or acute renal failure (also called acute kidney injury).
These kidney injury markers may be used, individually or in panels comprising a plurality of kidney injury markers, for risk stratification (that is, to identify subjects at risk for a future injury to renal function, for future progression to reduced renal function, for future progression to ARF, for future improvement in renal function, etc.); for diagnosis of existing disease (that is, to identify subjects who have suffered an injury to renal function, who have progressed to reduced renal function, who have progressed to ARF, etc.); for monitoring for deterioration or improvement of renal function; and for predicting a future medical outcome, such as improved or worsening renal function, a decreased or increased mortality risk, a decreased or increased risk that a subject will require renal replacement therapy (i.e., hemodialysis, peritoneal dialysis, hemofiltration, and/or renal transplantation, a decreased or increased risk that a subject will recover from an injury to renal function, a decreased or increased risk that a subject will recover from ARF, a decreased or increased risk that a subject will progress to end stage renal disease, a decreased or increased risk that a subject will progress to chronic renal failure, a decreased or increased risk that a subject will suffer rejection of a transplanted kidney, etc.
In a first aspect, the present invention relates to methods for evaluating renal status in a subject. These methods comprise performing an assay method that is configured to detect one or more kidney injury markers of the present invention in a body fluid sample obtained from the subject. The assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are then correlated to the renal status of the subject. This correlation to renal status may include correlating the assay result(s) to one or more of risk stratification, diagnosis, prognosis, staging, classifying and monitoring of the subject as described herein. Thus, the present invention utilizes one or more kidney injury markers of the present invention for the evaluation of renal injury.
In certain embodiments, the methods for evaluating renal status described herein are methods for risk stratification of the subject; that is, assigning a likelihood of one or more future changes in renal status to the subject. In these embodiments, the assay result(s) is/are correlated to one or more such future changes. The following are preferred risk stratification embodiments.
In preferred risk stratification embodiments, these methods comprise determining a subject's risk for a future injury to renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a likelihood of such a future injury to renal function. For example, the measured concentration(s) may each be compared to a threshold value. For a “positive going” kidney injury marker, an increased likelihood of suffering a future injury to renal function is assigned to the subject when the measured concentration is above the threshold, relative to a likelihood assigned when the measured concentration is below the threshold. For a “negative going” kidney injury marker, an increased likelihood of suffering a future injury to renal function is assigned to the subject when the measured concentration is below the threshold, relative to a likelihood assigned when the measured concentration is above the threshold.
In other preferred risk stratification embodiments, these methods comprise determining a subject's risk for future reduced renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a likelihood of such reduced renal function. For example, the measured concentrations may each be compared to a threshold value. For a “positive going” kidney injury marker, an increased likelihood of suffering a future reduced renal function is assigned to the subject when the measured concentration is above the threshold, relative to a likelihood assigned when the measured concentration is below the threshold. For a “negative going” kidney injury marker, an increased likelihood of future reduced renal function is assigned to the subject when the measured concentration is below the threshold, relative to a likelihood assigned when the measured concentration is above the threshold.
In still other preferred risk stratification embodiments, these methods comprise determining a subject's likelihood for a future improvement in renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a likelihood of such a future improvement in renal function. For example, the measured concentration(s) may each be compared to a threshold value. For a “positive going” kidney injury marker, an increased likelihood of a future improvement in renal function is assigned to the subject when the measured concentration is below the threshold, relative to a likelihood assigned when the measured concentration is above the threshold. For a “negative going” kidney injury marker, an increased likelihood of a future improvement in renal function is assigned to the subject when the measured concentration is above the threshold, relative to a likelihood assigned when the measured concentration is below the threshold.
In yet other preferred risk stratification embodiments, these methods comprise determining a subject's risk for progression to ARF, and the result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a likelihood of such progression to ARF. For example, the measured concentration(s) may each be compared to a threshold value. For a “positive going” kidney injury marker, an increased likelihood of progression to ARF is assigned to the subject when the measured concentration is above the threshold, relative to a likelihood assigned when the measured concentration is below the threshold. For a “negative going” kidney injury marker, an increased likelihood of progression to ARF is assigned to the subject when the measured concentration is below the threshold, relative to a likelihood assigned when the measured concentration is above the threshold.
And in other preferred risk stratification embodiments, these methods comprise determining a subject's outcome risk, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a likelihood of the occurrence of a clinical outcome related to a renal injury suffered by the subject. For example, the measured concentration(s) may each be compared to a threshold value. For a “positive going” kidney injury marker, an increased likelihood of one or more of: acute kidney injury, progression to a worsening stage of AKI, mortality, a requirement for renal replacement therapy, a requirement for withdrawal of renal toxins, end stage renal disease, heart failure, stroke, myocardial infarction, progression to chronic kidney disease, etc., is assigned to the subject when the measured concentration is above the threshold, relative to a likelihood assigned when the measured concentration is below the threshold. For a “negative going” kidney injury marker, an increased likelihood of one or more of: acute kidney injury, progression to a worsening stage of AKI, mortality, a requirement for renal replacement therapy, a requirement for withdrawal of renal toxins, end stage renal disease, heart failure, stroke, myocardial infarction, progression to chronic kidney disease, etc., is assigned to the subject when the measured concentration is below the threshold, relative to a likelihood assigned when the measured concentration is above the threshold.
In such risk stratification embodiments, preferably the likelihood or risk assigned is that an event of interest is more or less likely to occur within 180 days of the time at which the body fluid sample is obtained from the subject. In particularly preferred embodiments, the likelihood or risk assigned relates to an event of interest occurring within a shorter time period such as 18 months, 120 days, 90 days, 60 days, 45 days, 30 days, 21 days, 14 days, 7 days, 5 days, 96 hours, 72 hours, 48 hours, 36 hours, 24 hours, 12 hours, or less. A risk at 0 hours of the time at which the body fluid sample is obtained from the subject is equivalent to diagnosis of a current condition.
In preferred risk stratification embodiments, the subject is selected for risk stratification based on the pre-existence in the subject of one or more known risk factors for prerenal, intrinsic renal, or postrenal ARF. For example, a subject undergoing or having undergone major vascular surgery, coronary artery bypass, or other cardiac surgery; a subject having pre-existing congestive heart failure, preeclampsia, eclampsia, diabetes mellitus, hypertension, coronary artery disease, proteinuria, renal insufficiency, glomerular filtration below the normal range, cirrhosis, serum creatinine above the normal range, or sepsis; or a subject exposed to NSAIDs, cyclosporines, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin are all preferred subjects for monitoring risks according to the methods described herein. This list is not meant to be limiting. By “pre-existence” in this context is meant that the risk factor exists at the time the body fluid sample is obtained from the subject. In particularly preferred embodiments, a subject is chosen for risk stratification based on an existing diagnosis of injury to renal function, reduced renal function, or ARF.
In other embodiments, the methods for evaluating renal status described herein are methods for diagnosing a renal injury in the subject; that is, assessing whether or not a subject has suffered from an injury to renal function, reduced renal function, or ARF. In these embodiments, the assay result(s) is/are correlated to the occurrence or nonoccurrence of a change in renal status. The following are preferred diagnostic embodiments.
In preferred diagnostic embodiments, these methods comprise diagnosing the occurrence or nonoccurrence of an injury to renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of such an injury. For example, each of the measured concentration(s) may be compared to a threshold value. For a positive going marker, an increased likelihood of the occurrence of an injury to renal function is assigned to the subject when the measured concentration is above the threshold (relative to the likelihood assigned when the measured concentration is below the threshold); alternatively, when the measured concentration is below the threshold, an increased likelihood of the nonoccurrence of an injury to renal function may be assigned to the subject (relative to the likelihood assigned when the measured concentration is above the threshold). For a negative going marker, an increased likelihood of the occurrence of an injury to renal function is assigned to the subject when the measured concentration is below the threshold (relative to the likelihood assigned when the measured concentration is above the threshold); alternatively, when the measured concentration is above the threshold, an increased likelihood of the nonoccurrence of an injury to renal function may be assigned to the subject (relative to the likelihood assigned when the measured concentration is below the threshold).
In other preferred diagnostic embodiments, these methods comprise diagnosing the occurrence or nonoccurrence of reduced renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of an injury causing reduced renal function. For example, each of the measured concentration(s) may be compared to a threshold value. For a positive going marker, an increased likelihood of the occurrence of an injury causing reduced renal function is assigned to the subject when the measured concentration is above the threshold (relative to the likelihood assigned when the measured concentration is below the threshold); alternatively, when the measured concentration is below the threshold, an increased likelihood of the nonoccurrence of an injury causing reduced renal function may be assigned to the subject (relative to the likelihood assigned when the measured concentration is above the threshold). For a negative going marker, an increased likelihood of the occurrence of an injury causing reduced renal function is assigned to the subject when the measured concentration is below the threshold (relative to the likelihood assigned when the measured concentration is above the threshold); alternatively, when the measured concentration is above the threshold, an increased likelihood of the nonoccurrence of an injury causing reduced renal function may be assigned to the subject (relative to the likelihood assigned when the measured concentration is below the threshold).
In yet other preferred diagnostic embodiments, these methods comprise diagnosing the occurrence or nonoccurrence of ARF, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of an injury causing ARF. For example, each of the measured concentration(s) may be compared to a threshold value. For a positive going marker, an increased likelihood of the occurrence of ARF is assigned to the subject when the measured concentration is above the threshold (relative to the likelihood assigned when the measured concentration is below the threshold); alternatively, when the measured concentration is below the threshold, an increased likelihood of the nonoccurrence of ARF may be assigned to the subject (relative to the likelihood assigned when the measured concentration is above the threshold). For a negative going marker, an increased likelihood of the occurrence of ARF is assigned to the subject when the measured concentration is below the threshold (relative to the likelihood assigned when the measured concentration is above the threshold); alternatively, when the measured concentration is above the threshold, an increased likelihood of the nonoccurrence of ARF may be assigned to the subject (relative to the likelihood assigned when the measured concentration is below the threshold).
In still other preferred diagnostic embodiments, these methods comprise diagnosing a subject as being in need of renal replacement therapy, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a need for renal replacement therapy. For example, each of the measured concentration(s) may be compared to a threshold value. For a positive going marker, an increased likelihood of the occurrence of an injury creating a need for renal replacement therapy is assigned to the subject when the measured concentration is above the threshold (relative to the likelihood assigned when the measured concentration is below the threshold); alternatively, when the measured concentration is below the threshold, an increased likelihood of the nonoccurrence of an injury creating a need for renal replacement therapy may be assigned to the subject (relative to the likelihood assigned when the measured concentration is above the threshold). For a negative going marker, an increased likelihood of the occurrence of an injury creating a need for renal replacement therapy is assigned to the subject when the measured concentration is below the threshold (relative to the likelihood assigned when the measured concentration is above the threshold); alternatively, when the measured concentration is above the threshold, an increased likelihood of the nonoccurrence of an injury creating a need for renal replacement therapy may be assigned to the subject (relative to the likelihood assigned when the measured concentration is below the threshold).
In still other preferred diagnostic embodiments, these methods comprise diagnosing a subject as being in need of renal transplantation, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a need for renal transplantation. For example, each of the measured concentration(s) may be compared to a threshold value. For a positive going marker, an increased likelihood of the occurrence of an injury creating a need for renal transplantation is assigned to the subject when the measured concentration is above the threshold (relative to the likelihood assigned when the measured concentration is below the threshold); alternatively, when the measured concentration is below the threshold, an increased likelihood of the nonoccurrence of an injury creating a need for renal transplantation may be assigned to the subject (relative to the likelihood assigned when the measured concentration is above the threshold). For a negative going marker, an increased likelihood of the occurrence of an injury creating a need for renal transplantation is assigned to the subject when the measured concentration is below the threshold (relative to the likelihood assigned when the measured concentration is above the threshold); alternatively, when the measured concentration is above the threshold, an increased likelihood of the nonoccurrence of an injury creating a need for renal transplantation may be assigned to the subject (relative to the likelihood assigned when the measured concentration is below the threshold).
In still other embodiments, the methods for evaluating renal status described herein are methods for monitoring a renal injury in the subject; that is, assessing whether or not renal function is improving or worsening in a subject who has suffered from an injury to renal function, reduced renal function, or ARF. In these embodiments, the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of a change in renal status. The following are preferred monitoring embodiments.
In preferred monitoring embodiments, these methods comprise monitoring renal status in a subject suffering from an injury to renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of a change in renal status in the subject. For example, the measured concentration(s) may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is below the threshold, an improvement of renal function may be assigned to the subject. For a negative going marker, when the measured concentration is below the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is above the threshold, an improvement of renal function may be assigned to the subject.
In other preferred monitoring embodiments, these methods comprise monitoring renal status in a subject suffering from reduced renal function, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of a change in renal status in the subject. For example, the measured concentration(s) may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is below the threshold, an improvement of renal function may be assigned to the subject. For a negative going marker, when the measured concentration is below the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is above the threshold, an improvement of renal function may be assigned to the subject.
In yet other preferred monitoring embodiments, these methods comprise monitoring renal status in a subject suffering from acute renal failure, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of a change in renal status in the subject. For example, the measured concentration(s) may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is below the threshold, an improvement of renal function may be assigned to the subject. For a negative going marker, when the measured concentration is below the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is above the threshold, an improvement of renal function may be assigned to the subject.
In other additional preferred monitoring embodiments, these methods comprise monitoring renal status in a subject at risk of an injury to renal function due to the pre-existence of one or more known risk factors for prerenal, intrinsic renal, or postrenal ARF, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the occurrence or nonoccurrence of a change in renal status in the subject. For example, the measured concentration(s) may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is below the threshold, an improvement of renal function may be assigned to the subject. For a negative going marker, when the measured concentration is below the threshold, a worsening of renal function may be assigned to the subject; alternatively, when the measured concentration is above the threshold, an improvement of renal function may be assigned to the subject.
In yet other preferred monitoring embodiments, these methods comprise monitoring renal status in a subject having, or at risk of, an injury to renal function for future persistence of acute kidney injury. “Future persistence” as used herein refers to an existing acute renal injury that will continue for a period selected from the group consisting of 21 days, 14 days, 7 days, 5 days, 96 hours, 72 hours, 48 hours, 36 hours, 24 hours, and 12 hours. In certain embodiments the subject has an acute kidney injury at the time the sample is obtained. This is not meant to imply that the subject must have an acute kidney injury at the time the sample is obtained, but rather that the subject, upon onset of an acute kidney injury, suffers from an acute kidney injury that will persist. In various embodiments, the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the future persistence of the acute kidney injury in the subject. For example, the measured concentration(s) may be compared to a threshold value. For a positive going marker, when the measured concentration is above the threshold, a future persistence of acute kidney injury may be assigned to the subject; alternatively, when the measured concentration is below the threshold, a future improvement of renal function may be assigned to the subject. For a negative going marker, when the measured concentration is below the threshold, a future persistence of acute kidney injury may be assigned to the subject; alternatively, when the measured concentration is above the threshold, a future improvement of renal function may be assigned to the subject.
In still other embodiments, the methods for evaluating renal status described herein are methods for classifying a renal injury in the subject; that is, determining whether a renal injury in a subject is prerenal, intrinsic renal, or postrenal; and/or further subdividing these classes into subclasses such as acute tubular injury, acute glomerulonephritis acute tubulointerstitial nephritis, acute vascular nephropathy, or infiltrative disease; and/or assigning a likelihood that a subject will progress to a particular RIFLE stage. In these embodiments, the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to a particular class and/or subclass. The following are preferred classification embodiments.
In preferred classification embodiments, these methods comprise determining whether a renal injury in a subject is prerenal, intrinsic renal, or postrenal; and/or further subdividing these classes into subclasses such as acute tubular injury, acute glomerulonephritis acute tubulointerstitial nephritis, acute vascular nephropathy, or infiltrative disease; and/or assigning a likelihood that a subject will progress to a particular RIFLE stage, and the assay result(s), for example a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and/or Tyrosine-protein kinase receptor UFO, is/are correlated to the injury classification for the subject. For example, the measured concentration may be compared to a threshold value, and when the measured concentration is above the threshold, a particular classification is assigned; alternatively, when the measured concentration is below the threshold, a different classification may be assigned to the subject.
A variety of methods may be used by the skilled artisan to arrive at a desired threshold value for use in these methods. For example, the threshold value may be determined from a population of normal subjects by selecting a concentration representing the 75th, 85th, 90th, 95th, or 99th percentile of a kidney injury marker measured in such normal subjects. Alternatively, the threshold value may be determined from a “diseased” population of subjects, e.g., those suffering from an injury or having a predisposition for an injury (e.g., progression to ARF or some other clinical outcome such as death, dialysis, renal transplantation, etc.), by selecting a concentration representing the 75th, 85th, 90th, 95th, or 99th percentile of a kidney injury marker measured in such subjects. In another alternative, the threshold value may be determined from a prior measurement of a kidney injury marker in the same subject; that is, a temporal change in the level of a kidney injury marker in the subject may be used to assign risk to the subject.
The foregoing discussion is not meant to imply, however, that the kidney injury markers of the present invention must be compared to corresponding individual thresholds. Methods for combining assay results can comprise the use of multivariate logistical regression, loglinear modeling, neural network analysis, n-of-m analysis, decision tree analysis, calculating ratios of markers, etc. This list is not meant to be limiting. In these methods, a composite result which is determined by combining individual markers may be treated as if it is itself a marker; that is, a threshold may be determined for the composite result as described herein for individual markers, and the composite result for an individual patient compared to this threshold.
The ability of a particular test to distinguish two populations can be established using ROC analysis. For example, ROC curves established from a “first” subpopulation which is predisposed to one or more future changes in renal status, and a “second” subpopulation which is not so predisposed can be used to calculate a ROC curve, and the area under the curve provides a measure of the quality of the test. Preferably, the tests described herein provide a ROC curve area greater than 0.5, preferably at least 0.6, more preferably 0.7, still more preferably at least 0.8, even more preferably at least 0.9, and most preferably at least 0.95.
In certain aspects, the measured concentration of one or more kidney injury markers, or a composite of such markers, may be treated as continuous variables. For example, any particular concentration can be converted into a corresponding probability of a future reduction in renal function for the subject, the occurrence of an injury, a classification, etc. In yet another alternative, a threshold that can provide an acceptable level of specificity and sensitivity in separating a population of subjects into “bins” such as a “first” subpopulation (e.g., which is predisposed to one or more future changes in renal status, the occurrence of an injury, a classification, etc.) and a “second” subpopulation which is not so predisposed. A threshold value is selected to separate this first and second population by one or more of the following measures of test accuracy:
-
- an odds ratio greater than 1, preferably at least about 2 or more or about 0.5 or less, more preferably at least about 3 or more or about 0.33 or less, still more preferably at least about 4 or more or about 0.25 or less, even more preferably at least about 5 or more or about 0.2 or less, and most preferably at least about 10 or more or about 0.1 or less;
- a specificity of greater than 0.5, preferably at least about 0.6, more preferably at least about 0.7, still more preferably at least about 0.8, even more preferably at least about 0.9 and most preferably at least about 0.95, with a corresponding sensitivity greater than 0.2, preferably greater than about 0.3, more preferably greater than about 0.4, still more preferably at least about 0.5, even more preferably about 0.6, yet more preferably greater than about 0.7, still more preferably greater than about 0.8, more preferably greater than about 0.9, and most preferably greater than about 0.95;
- a sensitivity of greater than 0.5, preferably at least about 0.6, more preferably at least about 0.7, still more preferably at least about 0.8, even more preferably at least about 0.9 and most preferably at least about 0.95, with a corresponding specificity greater than 0.2, preferably greater than about 0.3, more preferably greater than about 0.4, still more preferably at least about 0.5, even more preferably about 0.6, yet more preferably greater than about 0.7, still more preferably greater than about 0.8, more preferably greater than about 0.9, and most preferably greater than about 0.95;
- at least about 75% sensitivity, combined with at least about 75% specificity;
- a positive likelihood ratio (calculated as sensitivity/(1-specificity)) of greater than 1, at least about 2, more preferably at least about 3, still more preferably at least about 5, and most preferably at least about 10; or
- a negative likelihood ratio (calculated as (1-sensitivity)/specificity) of less than 1, less than or equal to about 0.5, more preferably less than or equal to about 0.3, and most preferably less than or equal to about 0.1.
The term “about” in the context of any of the above measurements refers to +/−5% of a given measurement.
Multiple thresholds may also be used to assess renal status in a subject. For example, a “first” subpopulation which is predisposed to one or more future changes in renal status, the occurrence of an injury, a classification, etc., and a “second” subpopulation which is not so predisposed can be combined into a single group. This group is then subdivided into three or more equal parts (known as tertiles, quartiles, quintiles, etc., depending on the number of subdivisions). An odds ratio is assigned to subjects based on which subdivision they fall into. If one considers a tertile, the lowest or highest tertile can be used as a reference for comparison of the other subdivisions. This reference subdivision is assigned an odds ratio of 1. The second tertile is assigned an odds ratio that is relative to that first tertile. That is, someone in the second tertile might be 3 times more likely to suffer one or more future changes in renal status in comparison to someone in the first tertile. The third tertile is also assigned an odds ratio that is relative to that first tertile.
In certain embodiments, the assay method is an immunoassay. Antibodies for use in such assays will specifically bind a full length kidney injury marker of interest, and may also bind one or more polypeptides that are “related” thereto, as that term is defined hereinafter. Numerous immunoassay formats are known to those of skill in the art. Preferred body fluid samples are selected from the group consisting of urine, blood, serum, saliva, tears, and plasma.
The foregoing method steps should not be interpreted to mean that the kidney injury marker assay result(s) is/are used in isolation in the methods described herein. Rather, additional variables or other clinical indicia may be included in the methods described herein. For example, a risk stratification, diagnostic, classification, monitoring, etc. method may combine the assay result(s) with one or more variables measured for the subject selected from the group consisting of demographic information (e.g., weight, sex, age, race), medical history (e.g., family history, type of surgery, pre-existing disease such as aneurism, congestive heart failure, preeclampsia, eclampsia, diabetes mellitus, hypertension, coronary artery disease, proteinuria, renal insufficiency, or sepsis, type of toxin exposure such as NSAIDs, cyclosporines, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin), clinical variables (e.g., blood pressure, temperature, respiration rate), risk scores (APACHE score, PREDICT score, TIMI Risk Score for UA/NSTEMI, Framingham Risk Score), a glomerular filtration rate, an estimated glomerular filtration rate, a urine production rate, a serum or plasma creatinine concentration, a urine creatinine concentration, a fractional excretion of sodium, a urine sodium concentration, a urine creatinine to serum or plasma creatinine ratio, a urine specific gravity, a urine osmolality, a urine urea nitrogen to plasma urea nitrogen ratio, a plasma BUN to creatinine ratio, a renal failure index calculated as urine sodium/(urine creatinine/plasma creatinine), a serum or plasma neutrophil gelatinase (NGAL) concentration, a urine NGAL concentration, a serum or plasma cystatin C concentration, a serum or plasma cardiac troponin concentration, a serum or plasma BNP concentration, a serum or plasma NTproBNP concentration, and a serum or plasma proBNP concentration. Other measures of renal function which may be combined with one or more kidney injury marker assay result(s) are described hereinafter and in Harrison's Principles of Internal Medicine, 17th Ed., McGraw Hill, New York, pages 1741-1830, and Current Medical Diagnosis & Treatment 2008, 47th Ed, McGraw Hill, New York, pages 785-815, each of which are hereby incorporated by reference in their entirety.
When more than one marker is measured, the individual markers may be measured in samples obtained at the same time, or may be determined from samples obtained at different (e.g., an earlier or later) times. The individual markers may also be measured on the same or different body fluid samples. For example, one kidney injury marker may be measured in a serum or plasma sample and another kidney injury marker may be measured in a urine sample. In addition, assignment of a likelihood may combine an individual kidney injury marker assay result with temporal changes in one or more additional variables.
In various related aspects, the present invention also relates to devices and kits for performing the methods described herein. Suitable kits comprise reagents sufficient for performing an assay for at least one of the described kidney injury markers, together with instructions for performing the described threshold comparisons.
In certain embodiments, reagents for performing such assays are provided in an assay device, and such assay devices may be included in such a kit. Preferred reagents can comprise one or more solid phase antibodies, the solid phase antibody comprising antibody that detects the intended biomarker target(s) bound to a solid support. In the case of sandwich immunoassays, such reagents can also include one or more detectably labeled antibodies, the detectably labeled antibody comprising antibody that detects the intended biomarker target(s) bound to a detectable label. Additional optional elements that may be provided as part of an assay device are described hereinafter.
Detectable labels may include molecules that are themselves detectable (e.g., fluorescent moieties, electrochemical labels, ecl (electrochemical luminescence) labels, metal chelates, colloidal metal particles, etc.) as well as molecules that may be indirectly detected by production of a detectable reaction product (e.g., enzymes such as horseradish peroxidase, alkaline phosphatase, etc.) or through the use of a specific binding molecule which itself may be detectable (e.g., a labeled antibody that binds to the second antibody, biotin, digoxigenin, maltose, oligohistidine, 2,4-dintrobenzene, phenylarsenate, ssDNA, dsDNA, etc.).
Generation of a signal from the signal development element can be performed using various optical, acoustical, and electrochemical methods well known in the art. Examples of detection modes include fluorescence, radiochemical detection, reflectance, absorbance, amperometry, conductance, impedance, interferometry, ellipsometry, etc. In certain of these methods, the solid phase antibody is coupled to a transducer (e.g., a diffraction grating, electrochemical sensor, etc) for generation of a signal, while in others, a signal is generated by a transducer that is spatially separate from the solid phase antibody (e.g., a fluorometer that employs an excitation light source and an optical detector). This list is not meant to be limiting. Antibody-based biosensors may also be employed to determine the presence or amount of analytes that optionally eliminate the need for a labeled molecule.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods and compositions for diagnosis, differential diagnosis, risk stratification, monitoring, classifying and determination of treatment regimens in subjects suffering or at risk of suffering from injury to renal function, reduced renal function and/or acute renal failure through measurement of one or more kidney injury markers. In various embodiments, a measured concentration of one or more markers selected from the group consisting of C-C motif chemokine 16, C-C motif chemokine 14, and Tyrosine-protein kinase receptor UFO or one or more markers related thereto, and optionally one or more additional kidney injury markers known in the art, are correlated to the renal status of the subject.
For purposes of this document, the following definitions apply:
As used herein, an “injury to renal function” is an abrupt (within 14 days, preferably within 7 days, more preferably within 72 hours, and still more preferably within 48 hours) measurable reduction in a measure of renal function. Such an injury may be identified, for example, by a decrease in glomerular filtration rate or estimated GFR, a reduction in urine output, an increase in serum creatinine, an increase in serum cystatin C, a requirement for renal replacement therapy, etc. “Improvement in Renal Function” is an abrupt (within 14 days, preferably within 7 days, more preferably within 72 hours, and still more preferably within 48 hours) measurable increase in a measure of renal function. Preferred methods for measuring and/or estimating GFR are described hereinafter.
As used herein, “reduced renal function” is an abrupt (within 14 days, preferably within 7 days, more preferably within 72 hours, and still more preferably within 48 hours) reduction in kidney function identified by an absolute increase in serum creatinine of greater than or equal to 0.1 mg/dL (≥8.8 μmol/L), a percentage increase in serum creatinine of greater than or equal to 20% (1.2-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 ml/kg per hour).
As used herein, “acute renal failure” or “ARF” is an abrupt (within 14 days, preferably within 7 days, more preferably within 72 hours, and still more preferably within 48 hours) reduction in kidney function identified by an absolute increase in serum creatinine of greater than or equal to 0.3 mg/dl (≥26.4 μmol/l), a percentage increase in serum creatinine of greater than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 ml/kg per hour for at least 6 hours). This term is synonymous with “acute kidney injury” or “AKI.”
In this regard, the skilled artisan will understand that the signals obtained from an immunoassay are a direct result of complexes formed between one or more antibodies and the target biomolecule (i.e., the analyte) and polypeptides containing the necessary epitope(s) to which the antibodies bind. While such assays may detect the full length biomarker and the assay result be expressed as a concentration of a biomarker of interest, the signal from the assay is actually a result of all such “immunoreactive” polypeptides present in the sample. Expression of biomarkers may also be determined by means other than immunoassays, including protein measurements (such as dot blots, western blots, chromatographic methods, mass spectrometry, etc.) and nucleic acid measurements (mRNA quatitation). This list is not meant to be limiting.
As used herein, the term “C-C motif chemokine 16” refers to one or more polypeptides present in a biological sample that are derived from the C-C motif chemokine 16 precursor (human sequence: Swiss-Prot 015467 (SEQ ID NO: 1)):
MKVSEAALSL LVLILIITSA SRSQPKVPEW VNTPSTCCLK YYEKVLPRRL 50
VVGYRKALNC HLPAIIFVTK RNREVCTNPN DDWVQEYIKD PNLPLLPTRN 100
LSTVKIITAK NGQPQLLNSQ 120
The following domains have been identified in C-C motif chemokine 16:
Residues Length Domain ID
1-23 23 Signal peptide
24-120 97 C-C motif chemokine 16
As used herein, the term “C-C motif chemokine 14” refers to one or more polypeptides present in a biological sample that are derived from the C-C motif chemokine 14 precursor (human sequence: Swiss-Prot Q16627 (SEQ ID NO: 1)):
MKISVAAIPE FLLITIALGT KTESSSRGPY HPSECCFTYT TYKIPRQRIM 50
DYYETNSQCS KPGIVFITKR GHSVCTNPSD KWVQDYIKDM KEN 93
The following domains have been identified in C-C motif chemokine 14:
Residues Length Domain ID
1-19 19 Signal peptide
20-93 74 C-C motif chemokine 14
22-93 72 HCC-1(3-74)
23-93 71 HCC-1(4-74)
28-93 66 HCC-1(9-74)
27 R → QTGGKPKVVKIQLKLVG
(SEQ ID NO: 2) in isoform 2
As used herein, the term “Tyrosine-protein kinase receptor UFO” refers to one or more polypeptides present in a biological sample that are derived from the Tyrosine-protein kinase receptor UFO precursor (human sequence: Swiss-Prot P30530 (SEQ ID NO: 1)):
MAWRCPRMGR VPLAWCLALC GWACMAPRGT QAEESPFVGN PGNITGARGL 50
TGTLRCQLQV QGEPPEVHWL RDGQILELAD STQTQVPLGE DEQDDWIVVS 100
QLRITSLQLS DTGQYQCLVF LGHQTFVSQP GYVGLEGLPY FLEEPEDRTV 150
AANTPFNLSC QAQGPPEPVD LLWLQDAVPL ATAPGHGPQR SLHVPGLNKT 200
SSFSCEAHNA KGVTTSRTAT ITVLPQQPRN LHLVSRQPTE LEVAWTPGLS 250
GIYPLTHCTL QAVLSNDGMG IQAGEPDPPE EPLTSQASVP PHQLRLGSLH 300
PHTPYHIRVA CTSSQGPSSW THWLPVETPE GVPLGPPENI SATRNGSQAF 350
VHWQEPRAPL QGTLLGYRLA YQGQDTPEVL MDIGLRQEVT LELQGDGSVS 400
NLTVCVAAYT AAGDGPWSLP VPLEAWRPGQ AQPVHQLVKE PSTPAFSWPW 450
WYVLLGAVVA AACVLILALF LVHRRKKETR YGEVFEPTVE RGELVVRYRV 500
RKSYSRRTTE ATLNSLGISE ELKEKLRDVM VDRHKVALGK TLGEGEFGAV 550
MEGQLNQDDS ILKVAVKTMK IAICTRSELE DFLSEAVCMK EFDHPNVMRL 600
IGVCFQGSER ESFPAPVVIL PFMKHGDLHS FLLYSRLGDQ PVYLPTQMLV 650
KFMADIASGM EYLSTKRFIH RDLAARNCML NENMSVCVAD FGLSKKIYNG 700
DYYRQGRIAK MPVKWIAIES LADRVYTSKS DVWSFGVTMW EIATRGQTPY 750
PGVENSEIYD YLRQGNRLKQ PADCLDGLYA LMSRCWELNP QDRPSFTELR 800
EDLENTLKAL PPAQEPDEIL YVNMDEGGGY PEPPGAAGGA DPPTQPDPKD 850
SCSCLTAAEV HPAGRYVLCP STTPSPAQPA DRGSPAAPGQ EDGA 894
In certain embodiments, the Tyrosine-protein kinase receptor UFO assay detects one or more soluble forms of Tyrosine-protein kinase receptor UFO. Tyrosine-protein kinase receptor UFO is a single-pass membrane protein having an extracellular domain which may be found in Tyrosine-protein kinase receptor UFO forms of Tyrosine-protein kinase receptor UFO generated by proteolysis of the membrane-bound form or by alternative splicing. In the case of an immunoassay, one or more antibodies that bind to epitopes within an extracellular domain may be used to detect these Tyrosine-protein kinase receptor UFO form(s). The following domains have been identified in Tyrosine-protein kinase receptor UFO:
Residues Length Domain ID
1-25 25 Signal peptide
26-894 869 Tyrosine-protein kinase receptor UFO
473-894 422 cytoplasmic domain
452-472 21 transmembrane domain
26-451 426 extracellular domain
429-437 Missing in isoform 2
As used herein, the term “relating a signal to the presence or amount” of an analyte reflects this understanding. Assay signals are typically related to the presence or amount of an analyte through the use of a standard curve calculated using known concentrations of the analyte of interest. As the term is used herein, an assay is “configured to detect” an analyte if an assay can generate a detectable signal indicative of the presence or amount of a physiologically relevant concentration of the analyte. Because an antibody epitope is on the order of 8 amino acids, an immunoassay configured to detect a marker of interest will also detect polypeptides related to the marker sequence, so long as those polypeptides contain the epitope(s) necessary to bind to the antibody or antibodies used in the assay.
The term “related marker” as used herein with regard to a biomarker such as one of the kidney injury markers described herein refers to one or more fragments, variants, etc., of a particular marker or its biosynthetic parent that may be detected as a surrogate for the marker itself or as independent biomarkers. The term also refers to one or more polypeptides present in a biological sample that are derived from the biomarker precursor complexed to additional species, such as binding proteins, receptors, heparin, lipids, sugars, etc.
The term “positive going” marker as that term is used herein refer to a marker that is determined to be elevated in subjects suffering from a disease or condition, relative to subjects not suffering from that disease or condition. The term “negative going” marker as that term is used herein refer to a marker that is determined to be reduced in subjects suffering from a disease or condition, relative to subjects not suffering from that disease or condition.
The term “subject” as used herein refers to a human or non-human organism. Thus, the methods and compositions described herein are applicable to both human and veterinary disease. Further, while a subject is preferably a living organism, the invention described herein may be used in post-mortem analysis as well. Preferred subjects are humans, and most preferably “patients,” which as used herein refers to living humans that are receiving medical care for a disease or condition. This includes persons with no defined illness who are being investigated for signs of pathology.
Preferably, an analyte is measured in a sample. Such a sample may be obtained from a subject, or may be obtained from biological materials intended to be provided to the subject. For example, a sample may be obtained from a kidney being evaluated for possible transplantation into a subject, and an analyte measurement used to evaluate the kidney for preexisting damage. Preferred samples are body fluid samples.
The term “body fluid sample” as used herein refers to a sample of bodily fluid obtained for the purpose of diagnosis, prognosis, classification or evaluation of a subject of interest, such as a patient or transplant donor. In certain embodiments, such a sample may be obtained for the purpose of determining the outcome of an ongoing condition or the effect of a treatment regimen on a condition. Preferred body fluid samples include blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, and pleural effusions. In addition, one of skill in the art would realize that certain body fluid samples would be more readily analyzed following a fractionation or purification procedure, for example, separation of whole blood into serum or plasma components.
The term “diagnosis” as used herein refers to methods by which the skilled artisan can estimate and/or determine the probability (“a likelihood”) of whether or not a patient is suffering from a given disease or condition. In the case of the present invention, “diagnosis” includes using the results of an assay, most preferably an immunoassay, for a kidney injury marker of the present invention, optionally together with other clinical characteristics, to arrive at a diagnosis (that is, the occurrence or nonoccurrence) of an acute renal injury or ARF for the subject from which a sample was obtained and assayed. That such a diagnosis is “determined” is not meant to imply that the diagnosis is 100% accurate. Many biomarkers are indicative of multiple conditions. The skilled clinician does not use biomarker results in an informational vacuum, but rather test results are used together with other clinical indicia to arrive at a diagnosis. Thus, a measured biomarker level on one side of a predetermined diagnostic threshold indicates a greater likelihood of the occurrence of disease in the subject relative to a measured level on the other side of the predetermined diagnostic threshold.
Similarly, a prognostic risk signals a probability (“a likelihood”) that a given course or outcome will occur. A level or a change in level of a prognostic indicator, which in turn is associated with an increased probability of morbidity (e.g., worsening renal function, future ARF, or death) is referred to as being “indicative of an increased likelihood” of an adverse outcome in a patient.
Marker Assays
In general, immunoassays involve contacting a sample containing or suspected of containing a biomarker of interest with at least one antibody that specifically binds to the biomarker. A signal is then generated indicative of the presence or amount of complexes formed by the binding of polypeptides in the sample to the antibody. The signal is then related to the presence or amount of the biomarker in the sample. Numerous methods and devices are well known to the skilled artisan for the detection and analysis of biomarkers. See, e.g., U.S. Pat. Nos. 6,143,576; 6,113,855; 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; 5,885,527; 5,851,776; 5,824,799; 5,679,526; 5,525,524; and 5,480,792, and The Immunoassay Handbook, David Wild, ed. Stockton Press, New York, 1994, each of which is hereby incorporated by reference in its entirety, including all tables, figures and claims.
The assay devices and methods known in the art can utilize labeled molecules in various sandwich, competitive, or non-competitive assay formats, to generate a signal that is related to the presence or amount of the biomarker of interest. Suitable assay formats also include chromatographic, mass spectrographic, and protein “blotting” methods. Additionally, certain methods and devices, such as biosensors and optical immunoassays, may be employed to determine the presence or amount of analytes without the need for a labeled molecule. See, e.g., U.S. Pat. Nos. 5,631,171; and 5,955,377, each of which is hereby incorporated by reference in its entirety, including all tables, figures and claims. One skilled in the art also recognizes that robotic instrumentation including but not limited to Beckman ACCESS®, Abbott AXSYM®, Roche ELECSYS®, Dade Behring STRATUS® systems are among the immunoassay analyzers that are capable of performing immunoassays. But any suitable immunoassay may be utilized, for example, enzyme-linked immunoassays (ELISA), radioimmunoassays (RIAs), competitive binding assays, and the like.
Antibodies or other polypeptides may be immobilized onto a variety of solid supports for use in assays. Solid phases that may be used to immobilize specific binding members include those developed and/or used as solid phases in solid phase binding assays. Examples of suitable solid phases include membrane filters, cellulose-based papers, beads (including polymeric, latex and paramagnetic particles), glass, silicon wafers, microparticles, nanoparticles, TentaGels, AgroGels, PEGA gels, SPOCC gels, and multiple-well plates. An assay strip could be prepared by coating the antibody or a plurality of antibodies in an array on solid support. This strip could then be dipped into the test sample and then processed quickly through washes and detection steps to generate a measurable signal, such as a colored spot. Antibodies or other polypeptides may be bound to specific zones of assay devices either by conjugating directly to an assay device surface, or by indirect binding. In an example of the later case, antibodies or other polypeptides may be immobilized on particles or other solid supports, and that solid support immobilized to the device surface.
Biological assays require methods for detection, and one of the most common methods for quantitation of results is to conjugate a detectable label to a protein or nucleic acid that has affinity for one of the components in the biological system being studied. Detectable labels may include molecules that are themselves detectable (e.g., fluorescent moieties, electrochemical labels, metal chelates, etc.) as well as molecules that may be indirectly detected by production of a detectable reaction product (e.g., enzymes such as horseradish peroxidase, alkaline phosphatase, etc.) or by a specific binding molecule which itself may be detectable (e.g., biotin, digoxigenin, maltose, oligohistidine, 2,4-dintrobenzene, phenylarsenate, ssDNA, dsDNA, etc.).
Preparation of solid phases and detectable label conjugates often comprise the use of chemical cross-linkers. Cross-linking reagents contain at least two reactive groups, and are divided generally into homofunctional cross-linkers (containing identical reactive groups) and heterofunctional cross-linkers (containing non-identical reactive groups). Homobifunctional cross-linkers that couple through amines, sulfhydryls or react non-specifically are available from many commercial sources. Maleimides, alkyl and aryl halides, alpha-haloacyls and pyridyl disulfides are thiol reactive groups. Maleimides, alkyl and aryl halides, and alpha-haloacyls react with sulfhydryls to form thiol ether bonds, while pyridyl disulfides react with sulfhydryls to produce mixed disulfides. The pyridyl disulfide product is cleavable. Imidoesters are also very useful for protein-protein cross-links. A variety of heterobifunctional cross-linkers, each combining different attributes for successful conjugation, are commercially available.
In certain aspects, the present invention provides kits for the analysis of the described kidney injury markers. The kit comprises reagents for the analysis of at least one test sample which comprise at least one antibody that a kidney injury marker. The kit can also include devices and instructions for performing one or more of the diagnostic and/or prognostic correlations described herein. Preferred kits will comprise an antibody pair for performing a sandwich assay, or a labeled species for performing a competitive assay, for the analyte. Preferably, an antibody pair comprises a first antibody conjugated to a solid phase and a second antibody conjugated to a detectable label, wherein each of the first and second antibodies that bind a kidney injury marker. Most preferably each of the antibodies are monoclonal antibodies. The instructions for use of the kit and performing the correlations can be in the form of labeling, which refers to any written or recorded material that is attached to, or otherwise accompanies a kit at any time during its manufacture, transport, sale or use. For example, the term labeling encompasses advertising leaflets and brochures, packaging materials, instructions, audio or video cassettes, computer discs, as well as writing imprinted directly on kits.
Antibodies
The term “antibody” as used herein refers to a peptide or polypeptide derived from, modeled after or substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, capable of specifically binding an antigen or epitope. See, e.g. Fundamental Immunology, 3rd Edition, W. E. Paul, ed., Raven Press, N.Y. (1993); Wilson (1994; J. Immunol. Methods 175:267-273; Yarmush (1992) J. Biochem. Biophys. Methods 25:85-97. The term antibody includes antigen-binding portions, i.e., “antigen binding sites,” (e.g., fragments, subsequences, complementarity determining regions (CDRs)) that retain capacity to bind antigen, including (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Single chain antibodies are also included by reference in the term “antibody.”
Antibodies used in the immunoassays described herein preferably specifically bind to a kidney injury marker of the present invention. The term “specifically binds” is not intended to indicate that an antibody binds exclusively to its intended target since, as noted above, an antibody binds to any polypeptide displaying the epitope(s) to which the antibody binds. Rather, an antibody “specifically binds” if its affinity for its intended target is about 5-fold greater when compared to its affinity for a non-target molecule which does not display the appropriate epitope(s). Preferably the affinity of the antibody will be at least about 5 fold, preferably 10 fold, more preferably 25-fold, even more preferably 50-fold, and most preferably 100-fold or more, greater for a target molecule than its affinity for a non-target molecule. In preferred embodiments, Preferred antibodies bind with affinities of at least about 107 M−1, and preferably between about 108 M−1 to about 109 M−1, about 109 M−1 to about 1010 M−1, or about 1010 M−1 to about 1012 M−1.
Affinity is calculated as Kd=koff/kon (koff is the dissociation rate constant, Kon is the association rate constant and Kd is the equilibrium constant). Affinity can be determined at equilibrium by measuring the fraction bound (r) of labeled ligand at various concentrations (c). The data are graphed using the Scatchard equation: r/c=K(n−r): where r=moles of bound ligand/mole of receptor at equilibrium; c=free ligand concentration at equilibrium; K=equilibrium association constant; and n=number of ligand binding sites per receptor molecule. By graphical analysis, r/c is plotted on the Y-axis versus r on the X-axis, thus producing a Scatchard plot. Antibody affinity measurement by Scatchard analysis is well known in the art. See, e.g., van Erp et al., J. Immunoassay 12: 425-43, 1991; Nelson and Griswold, Comput. Methods Programs Biomed. 27: 65-8, 1988.
The term “epitope” refers to an antigenic determinant capable of specific binding to an antibody. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
Numerous publications discuss the use of phage display technology to produce and screen libraries of polypeptides for binding to a selected analyte. See, e.g, Cwirla et al., Proc. Natl. Acad. Sci. USA 87, 6378-82, 1990; Devlin et al., Science 249, 404-6, 1990, Scott and Smith, Science 249, 386-88, 1990; and Ladner et al., U.S. Pat. No. 5,571,698. A basic concept of phage display methods is the establishment of a physical association between DNA encoding a polypeptide to be screened and the polypeptide. This physical association is provided by the phage particle, which displays a polypeptide as part of a capsid enclosing the phage genome which encodes the polypeptide. The establishment of a physical association between polypeptides and their genetic material allows simultaneous mass screening of very large numbers of phage bearing different polypeptides. Phage displaying a polypeptide with affinity to a target bind to the target and these phage are enriched by affinity screening to the target. The identity of polypeptides displayed from these phage can be determined from their respective genomes. Using these methods a polypeptide identified as having a binding affinity for a desired target can then be synthesized in bulk by conventional means. See, e.g., U.S. Pat. No. 6,057,098, which is hereby incorporated in its entirety, including all tables, figures, and claims.
The antibodies that are generated by these methods may then be selected by first screening for affinity and specificity with the purified polypeptide of interest and, if required, comparing the results to the affinity and specificity of the antibodies with polypeptides that are desired to be excluded from binding. The screening procedure can involve immobilization of the purified polypeptides in separate wells of microtiter plates. The solution containing a potential antibody or groups of antibodies is then placed into the respective microtiter wells and incubated for about 30 min to 2 h. The microtiter wells are then washed and a labeled secondary antibody (for example, an anti-mouse antibody conjugated to alkaline phosphatase if the raised antibodies are mouse antibodies) is added to the wells and incubated for about 30 min and then washed. Substrate is added to the wells and a color reaction will appear where antibody to the immobilized polypeptide(s) are present.
The antibodies so identified may then be further analyzed for affinity and specificity in the assay design selected. In the development of immunoassays for a target protein, the purified target protein acts as a standard with which to judge the sensitivity and specificity of the immunoassay using the antibodies that have been selected. Because the binding affinity of various antibodies may differ; certain antibody pairs (e.g., in sandwich assays) may interfere with one another sterically, etc., assay performance of an antibody may be a more important measure than absolute affinity and specificity of an antibody.
Assay Correlations
The term “correlating” as used herein in reference to the use of biomarkers refers to comparing the presence or amount of the biomarker(s) in a patient to its presence or amount in persons known to suffer from, or known to be at risk of, a given condition; or in persons known to be free of a given condition. Often, this takes the form of comparing an assay result in the form of a biomarker concentration to a predetermined threshold selected to be indicative of the occurrence or nonoccurrence of a disease or the likelihood of some future outcome.
Selecting a diagnostic threshold involves, among other things, consideration of the probability of disease, distribution of true and false diagnoses at different test thresholds, and estimates of the consequences of treatment (or a failure to treat) based on the diagnosis. For example, when considering administering a specific therapy which is highly efficacious and has a low level of risk, few tests are needed because clinicians can accept substantial diagnostic uncertainty. On the other hand, in situations where treatment options are less effective and more risky, clinicians often need a higher degree of diagnostic certainty. Thus, cost/benefit analysis is involved in selecting a diagnostic threshold.
Suitable thresholds may be determined in a variety of ways. For example, one recommended diagnostic threshold for the diagnosis of acute myocardial infarction using cardiac troponin is the 97.5th percentile of the concentration seen in a normal population. Another method may be to look at serial samples from the same patient, where a prior “baseline” result is used to monitor for temporal changes in a biomarker level.
Population studies may also be used to select a decision threshold. Reciever Operating Characteristic (“ROC”) arose from the field of signal dectection theory developed during World War II for the analysis of radar images, and ROC analysis is often used to select a threshold able to best distinguish a “diseased” subpopulation from a “nondiseased” subpopulation. A false positive in this case occurs when the person tests positive, but actually does not have the disease. A false negative, on the other hand, occurs when the person tests negative, suggesting they are healthy, when they actually do have the disease. To draw a ROC curve, the true positive rate (TPR) and false positive rate (FPR) are determined as the decision threshold is varied continuously. Since TPR is equivalent with sensitivity and FPR is equal to 1-specificity, the ROC graph is sometimes called the sensitivity vs (1-specificity) plot. A perfect test will have an area under the ROC curve of 1.0; a random test will have an area of 0.5. A threshold is selected to provide an acceptable level of specificity and sensitivity.
In this context, “diseased” is meant to refer to a population having one characteristic (the presence of a disease or condition or the occurrence of some outcome) and “nondiseased” is meant to refer to a population lacking the characteristic. While a single decision threshold is the simplest application of such a method, multiple decision thresholds may be used. For example, below a first threshold, the absence of disease may be assigned with relatively high confidence, and above a second threshold the presence of disease may also be assigned with relatively high confidence. Between the two thresholds may be considered indeterminate. This is meant to be exemplary in nature only.
In addition to threshold comparisons, other methods for correlating assay results to a patient classification (occurrence or nonoccurrence of disease, likelihood of an outcome, etc.) include decision trees, rule sets, Bayesian methods, and neural network methods. These methods can produce probability values representing the degree to which a subject belongs to one classification out of a plurality of classifications.
Measures of test accuracy may be obtained as described in Fischer et al., Intensive Care Med. 29: 1043-51, 2003, and used to determine the effectiveness of a given biomarker. These measures include sensitivity and specificity, predictive values, likelihood ratios, diagnostic odds ratios, and ROC curve areas. The area under the curve (“AUC”) of a ROC plot is equal to the probability that a classifier will rank a randomly chosen positive instance higher than a randomly chosen negative one. The area under the ROC curve may be thought of as equivalent to the Mann-Whitney U test, which tests for the median difference between scores obtained in the two groups considered if the groups are of continuous data, or to the Wilcoxon test of ranks.
As discussed above, suitable tests may exhibit one or more of the following results on these various measures: a specificity of greater than 0.5, preferably at least 0.6, more preferably at least 0.7, still more preferably at least 0.8, even more preferably at least 0.9 and most preferably at least 0.95, with a corresponding sensitivity greater than 0.2, preferably greater than 0.3, more preferably greater than 0.4, still more preferably at least 0.5, even more preferably 0.6, yet more preferably greater than 0.7, still more preferably greater than 0.8, more preferably greater than 0.9, and most preferably greater than 0.95; a sensitivity of greater than 0.5, preferably at least 0.6, more preferably at least 0.7, still more preferably at least 0.8, even more preferably at least 0.9 and most preferably at least 0.95, with a corresponding specificity greater than 0.2, preferably greater than 0.3, more preferably greater than 0.4, still more preferably at least 0.5, even more preferably 0.6, yet more preferably greater than 0.7, still more preferably greater than 0.8, more preferably greater than 0.9, and most preferably greater than 0.95; at least 75% sensitivity, combined with at least 75% specificity; a ROC curve area of greater than 0.5, preferably at least 0.6, more preferably 0.7, still more preferably at least 0.8, even more preferably at least 0.9, and most preferably at least 0.95; an odds ratio different from 1, preferably at least about 2 or more or about 0.5 or less, more preferably at least about 3 or more or about 0.33 or less, still more preferably at least about 4 or more or about 0.25 or less, even more preferably at least about 5 or more or about 0.2 or less, and most preferably at least about 10 or more or about 0.1 or less; a positive likelihood ratio (calculated as sensitivity/(1-specificity)) of greater than 1, at least 2, more preferably at least 3, still more preferably at least 5, and most preferably at least 10; and or a negative likelihood ratio (calculated as (1-sensitivity)/specificity) of less than 1, less than or equal to 0.5, more preferably less than or equal to 0.3, and most preferably less than or equal to 0.1
Additional clinical indicia may be combined with the kidney injury marker assay result(s) of the present invention. These include other biomarkers related to renal status. Examples include the following, which recite the common biomarker name, followed by the Swiss-Prot entry number for that biomarker or its parent: Actin (P68133); Adenosine deaminase binding protein (DPP4, P27487); Alpha-1-acid glycoprotein 1 (P02763); Alpha-1-microglobulin (P02760); Albumin (P02768); Angiotensinogenase (Renin, P00797); Annexin A2 (P07355); Beta-glucuronidase (P08236); B-2-microglobulin (P61769); Beta-galactosidase (P16278); BMP-7 (P18075); Brain natriuretic peptide (proBNP, BNP-32, NTproBNP; P16860); Calcium-binding protein Beta (S100-beta, P04271); Carbonic anhydrase 9 (Q16790); Casein Kinase 2 (P68400); Clusterin (P10909); Complement C3 (P01024); Cysteine-rich protein (CYR61, O00622); Cytochrome C (P99999); Epidermal growth factor (EGF, P01133); Endothelin-1 (P05305); Exosomal Fetuin-A (P02765); Fatty acid-binding protein, heart (FABP3, P05413); Fatty acid-binding protein, liver (P07148); Ferritin (light chain, P02792; heavy chain P02794); Fructose-1,6-biphosphatase (P09467); GRO-alpha (CXCL1, (P09341); Growth Hormone (P01241); Hepatocyte growth factor (P14210); Insulin-like growth factor I (P05019); Immunoglobulin G; Immunoglobulin Light Chains (Kappa and Lambda); Interferon gamma (P01308); Lysozyme (P61626); Interleukin-1alpha (P01583); Interleukin-2 (P60568); Interleukin-4 (P05112); Interleukin-9 (P15248); Interleukin-12p40 (P29460); Interleukin-13 (P35225); Interleukin-16 (Q14005); L1 cell adhesion molecule (P32004); Lactate dehydrogenase (P00338); Leucine Aminopeptidase (P28838); Meprin A-alpha subunit (Q16819); Meprin A-beta subunit (Q16820); Midkine (P21741); MIP2-alpha (CXCL2, P19875); MMP-2 (P08253); MMP-9 (P14780); Netrin-1 (O95631); Neutral endopeptidase (P08473); Osteopontin (O14788); Renal papillary antigen 1 (RPA1); Renal papillary antigen 2 (RPA2); Retinol binding protein (P09455); Ribonuclease; S100 calcium-binding protein A6 (P06703); Serum Amyloid P Component (P02743); Sodium/Hydrogen exchanger isoform (NHE3, P48764); Spermidine/spermine N1-acetyltransferase (P21673); TGF-Beta1 (P01137); Transferrin (P02787); Trefoil factor 3 (TFF3, Q07654); Toll-Like protein 4 (O00206); Total protein; Tubulointerstitial nephritis antigen (Q9UJW2); Uromodulin (Tamm-Horsfall protein, P07911).
For purposes of risk stratification, Adiponectin (Q15848); Alkaline phosphatase (P05186); Aminopeptidase N (P15144); CalbindinD28k (P05937); Cystatin C (P01034); 8 subunit of FIFO ATPase (P03928); Gamma-glutamyltransferase (P19440); GSTa (alpha-glutathione-S-transferase, P08263); GSTpi (Glutathione-S-transferase P; GST class-pi; P09211); IGFBP-1 (P08833); IGFBP-2 (P18065); IGFBP-6 (P24592); Integral membrane protein 1 (Itm1, P46977); Interleukin-6 (P05231); Interleukin-8 (P10145); Interleukin-18 (Q14116); IP-10 (10 kDa interferon-gamma-induced protein, P02778); IRPR (IFRD1, O00458); Isovaleryl-CoA dehydrogenase (IVD, P26440); I-TAC/CXCL11 (O14625); Keratin 19 (P08727); Kim-1 (Hepatitis A virus cellular receptor 1, 043656); L-arginine:glycine amidinotransferase (P50440); Leptin (P41159); Lipocalin2 (NGAL, P80188); MCP-1 (P13500); MIG (Gamma-interferon-induced monokine Q07325); MIP-la (P10147); MIP-3a (P78556); MIP-1beta (P13236); MIP-1d (Q16663); NAG (N-acetyl-beta-D-glucosaminidase, P54802); Organic ion transporter (OCT2, O15244); Osteoprotegerin (O14788); P8 protein (O60356); Plasminogen activator inhibitor 1 (PAI-1, P05121); ProANP (1-98) (P01160); Protein phosphatase 1-beta (PPI-beta, P62140); Rab GDI-beta (P50395); Renal kallikrein (P06870); RT1.B-1 (alpha) chain of the integral membrane protein (Q5Y7A8); soluble tumor necrosis factor receptor superfamily member 1A (sTNFR-I, P19438); soluble tumor necrosis factor receptor superfamily member 1B (sTNFR-II, P20333); Tissue inhibitor of metalloproteinases 3 (TIMP-3, P35625); uPAR (Q03405) may be combined with the kidney injury marker assay result(s) of the present invention.
Other clinical indicia which may be combined with the kidney injury marker assay result(s) of the present invention includes demographic information (e.g., weight, sex, age, race), medical history (e.g., family history, type of surgery, pre-existing disease such as aneurism, congestive heart failure, preeclampsia, eclampsia, diabetes mellitus, hypertension, coronary artery disease, proteinuria, renal insufficiency, or sepsis, type of toxin exposure such as NSAIDs, cyclosporines, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin), clinical variables (e.g., blood pressure, temperature, respiration rate), risk scores (APACHE score, PREDICT score, TIMI Risk Score for UA/NSTEMI, Framingham Risk Score), a urine total protein measurement, a glomerular filtration rate, an estimated glomerular filtration rate, a urine production rate, a serum or plasma creatinine concentration, a renal papillary antigen 1 (RPA1) measurement; a renal papillary antigen 2 (RPA2) measurement; a urine creatinine concentration, a fractional excretion of sodium, a urine sodium concentration, a urine creatinine to serum or plasma creatinine ratio, a urine specific gravity, a urine osmolality, a urine urea nitrogen to plasma urea nitrogen ratio, a plasma BUN to creatnine ratio, and/or a renal failure index calculated as urine sodium/(urine creatinine/plasma creatinine). Other measures of renal function which may be combined with the kidney injury marker assay result(s) are described hereinafter and in Harrison's Principles of Internal Medicine, 17th Ed., McGraw Hill, New York, pages 1741-1830, and Current Medical Diagnosis & Treatment 2008, 47th Ed, McGraw Hill, New York, pages 785-815, each of which are hereby incorporated by reference in their entirety.
Combining assay results/clinical indicia in this manner can comprise the use of multivariate logistical regression, loglinear modeling, neural network analysis, n-of-m analysis, decision tree analysis, etc. This list is not meant to be limiting.
Diagnosis of Acute Renal Failure
As noted above, the terms “acute renal (or kidney) injury” and “acute renal (or kidney) failure” as used herein are defined in part in terms of changes in serum creatinine from a baseline value. Most definitions of ARF have common elements, including the use of serum creatinine and, often, urine output. Patients may present with renal dysfunction without an available baseline measure of renal function for use in this comparison. In such an event, one may estimate a baseline serum creatinine value by assuming the patient initially had a normal GFR. Glomerular filtration rate (GFR) is the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys. GFR is typically expressed in units of ml/min:
By normalizing the GFR to the body surface area, a GFR of approximately 75-100 ml/min per 1.73 m2 can be assumed. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood.
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). In clinical practice, however, creatinine clearance is used to measure GFR. Creatinine is produced naturally by the body (creatinine is a metabolite of creatine, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the renal tubules in very small amounts such that creatinine clearance overestimates actual GFR by 10-20%. This margin of error is acceptable considering the ease with which creatinine clearance is measured.
Creatinine clearance (CCr) can be calculated if values for creatinine's urine concentration (UCr), urine flow rate (V), and creatinine's plasma concentration (PCr) are known. Since the product of urine concentration and urine flow rate yields creatinine's excretion rate, creatinine clearance is also said to be its excretion rate (UCr×V) divided by its plasma concentration. This is commonly represented mathematically as:
Commonly a 24 hour urine collection is undertaken, from empty-bladder one morning to the contents of the bladder the following morning, with a comparative blood test then taken:
To allow comparison of results between people of different sizes, the CCr is often corrected for the body surface area (BSA) and expressed compared to the average sized man as ml/min/1.73 m2. While most adults have a BSA that approaches 1.7 (1.6-1.9), extremely obese or slim patients should have their CCr corrected for their actual BSA:
The accuracy of a creatinine clearance measurement (even when collection is complete) is limited because as glomerular filtration rate (GFR) falls creatinine secretion is increased, and thus the rise in serum creatinine is less. Thus, creatinine excretion is much greater than the filtered load, resulting in a potentially large overestimation of the GFR (as much as a twofold difference). However, for clinical purposes it is important to determine whether renal function is stable or getting worse or better. This is often determined by monitoring serum creatinine alone. Like creatinine clearance, the serum creatinine will not be an accurate reflection of GFR in the non-steady-state condition of ARF. Nonetheless, the degree to which serum creatinine changes from baseline will reflect the change in GFR. Serum creatinine is readily and easily measured and it is specific for renal function.
For purposes of determining urine output on a Urine output on a mL/kg/hr basis, hourly urine collection and measurement is adequate. In the case where, for example, only a cumulative 24-h output was available and no patient weights are provided, minor modifications of the RIFLE urine output criteria have been described. For example, Bagshaw et al., Nephrol. Dial. Transplant. 23: 1203-1210, 2008, assumes an average patient weight of 70 kg, and patients are assigned a RIFLE classification based on the following: <35 mL/h (Risk), <21 mL/h (Injury) or <4 mL/h (Failure).
Selecting a Treatment Regimen
Once a diagnosis is obtained, the clinician can readily select a treatment regimen that is compatible with the diagnosis, such as initiating renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, kidney transplantation, delaying or avoiding procedures that are known to be damaging to the kidney, modifying diuretic administration, initiating goal directed therapy, etc. The skilled artisan is aware of appropriate treatments for numerous diseases discussed in relation to the methods of diagnosis described herein. See, e.g., Merck Manual of Diagnosis and Therapy, 17th Ed. Merck Research Laboratories, Whitehouse Station, N J, 1999. In addition, since the methods and compositions described herein provide prognostic information, the markers of the present invention may be used to monitor a course of treatment. For example, improved or worsened prognostic state may indicate that a particular treatment is or is not efficacious.
One skilled in the art readily appreciates that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The examples provided herein are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention.
Example 1: Contrast-Induced Nephropathy Sample Collection
The objective of this sample collection study is to collect samples of plasma and urine and clinical data from patients before and after receiving intravascular contrast media. Approximately 250 adults undergoing radiographic/angiographic procedures involving intravascular administration of iodinated contrast media are enrolled. To be enrolled in the study, each patient must meet all of the following inclusion criteria and none of the following exclusion criteria:
Inclusion Criteria
-
- males and females 18 years of age or older;
- undergoing a radiographic/angiographic procedure (such as a CT scan or coronary intervention) involving the intravascular administration of contrast media;
- expected to be hospitalized for at least 48 hours after contrast administration.
- able and willing to provide written informed consent for study participation and to comply with all study procedures.
Exclusion Criteria - renal transplant recipients;
- acutely worsening renal function prior to the contrast procedure;
- already receiving dialysis (either acute or chronic) or in imminent need of dialysis at enrollment;
- expected to undergo a major surgical procedure (such as involving cardiopulmonary bypass) or an additional imaging procedure with contrast media with significant risk for further renal insult within the 48 hrs following contrast administration;
- participation in an interventional clinical study with an experimental therapy within the previous 30 days;
- known infection with human immunodeficiency virus (HIV) or a hepatitis virus.
Immediately prior to the first contrast administration (and after any pre-procedure hydration), an EDTA anti-coagulated blood sample (10 mL) and a urine sample (10 mL) are collected from each patient. Blood and urine samples are then collected at 4 (±0.5), 8 (±1), 24 (±2) 48 (±2), and 72 (±2) hrs following the last administration of contrast media during the index contrast procedure. Blood is collected via direct venipuncture or via other available venous access, such as an existing femoral sheath, central venous line, peripheral intravenous line or hep-lock. These study blood samples are processed to plasma at the clinical site, frozen and shipped to Astute Medical, Inc., San Diego, CA. The study urine samples are frozen and shipped to Astute Medical, Inc.
Serum creatinine is assessed at the site immediately prior to the first contrast administration (after any pre-procedure hydration) and at 4 (±0.5), 8 (±1), 24 (±2) and 48 (±2)), and 72 (±2) hours following the last administration of contrast (ideally at the same time as the study samples are obtained). In addition, each patient's status is evaluated through day 30 with regard to additional serum and urine creatinine measurements, a need for dialysis, hospitalization status, and adverse clinical outcomes (including mortality).
Prior to contrast administration, each patient is assigned a risk based on the following assessment: systolic blood pressure <80 mm Hg=5 points; intra-arterial balloon pump=5 points; congestive heart failure (Class III-IV or history of pulmonary edema)=5 points; age >75 yrs=4 points; hematocrit level <39% for men, <35% for women=3 points; diabetes=3 points; contrast media volume=1 point for each 100 mL; serum creatinine level >1.5 g/dL=4 points OR estimated GFR 40-60 mL/min/1.73 m2=2 points, 20-40 mL/min/1.73 m2=4 points, <20 mL/min/1.73 m2=6 points. The risks assigned are as follows: risk for CIN and dialysis: 5 or less total points=risk of CIN—7.5%, risk of dialysis—0.04%; 6-10 total points=risk of CIN—14%, risk of dialysis—0.12%; 11-16 total points=risk of CIN—26.1%, risk of dialysis—1.09%; >16 total points=risk of CIN—57.3%, risk of dialysis—12.8%.
Example 2: Cardiac Surgery Sample Collection
The objective of this sample collection study is to collect samples of plasma and urine and clinical data from patients before and after undergoing cardiovascular surgery, a procedure known to be potentially damaging to kidney function. Approximately 900 adults undergoing such surgery are enrolled. To be enrolled in the study, each patient must meet all of the following inclusion criteria and none of the following exclusion criteria:
Inclusion Criteria
-
- males and females 18 years of age or older;
- undergoing cardiovascular surgery;
- Toronto/Ottawa Predictive Risk Index for Renal Replacement risk score of at least 2 (Wijeysundera et al., JAMA 297: 1801-9, 2007); and
- able and willing to provide written informed consent for study participation and to comply with all study procedures.
Exclusion Criteria - known pregnancy;
- previous renal transplantation;
- acutely worsening renal function prior to enrollment (e.g., any category of RIFLE criteria);
- already receiving dialysis (either acute or chronic) or in imminent need of dialysis at enrollment;
- currently enrolled in another clinical study or expected to be enrolled in another clinical study within 7 days of cardiac surgery that involves drug infusion or a therapeutic intervention for AKI;
- known infection with human immunodeficiency virus (HIV) or a hepatitis virus.
Within 3 hours prior to the first incision (and after any pre-procedure hydration), an EDTA anti-coagulated blood sample (10 mL), whole blood (3 mL), and a urine sample (35 mL) are collected from each patient. Blood and urine samples are then collected at 3 (±0.5), 6 (±0.5), 12 (±1), 24 (±2) and 48 (±2) hrs following the procedure and then daily on days 3 through 7 if the subject remains in the hospital. Blood is collected via direct venipuncture or via other available venous access, such as an existing femoral sheath, central venous line, peripheral intravenous line or hep-lock. These study blood samples are frozen and shipped to Astute Medical, Inc., San Diego, CA. The study urine samples are frozen and shipped to Astute Medical, Inc.
Example 3: Acutely Ill Subject Sample Collection
The objective of this study is to collect samples from acutely ill patients. Approximately 900 adults expected to be in the ICU for at least 48 hours will be enrolled. To be enrolled in the study, each patient must meet all of the following inclusion criteria and none of the following exclusion criteria:
Inclusion Criteria
-
- males and females 18 years of age or older;
- Study population 1: approximately 300 patients that have at least one of:
- shock (SBP <90 mmHg and/or need for vasopressor support to maintain MAP >60 mmHg and/or documented drop in SBP of at least 40 mmHg); and
- sepsis;
Study population 2: approximately 300 patients that have at least one of: - IV antibiotics ordered in computerized physician order entry (CPOE) within 24 hours of enrollment;
- contrast media exposure within 24 hours of enrollment;
- increased Intra-Abdominal Pressure with acute decompensated heart failure; and
- severe trauma as the primary reason for ICU admission and likely to be hospitalized in the ICU for 48 hours after enrollment;
Study population 3: approximately 300 patients - expected to be hospitalized through acute care setting (ICU or ED) with a known risk factor for acute renal injury (e.g. sepsis, hypotension/shock (Shock=systolic BP<90 mmHg and/or the need for vasopressor support to maintain a MAP >60 mmHg and/or a documented drop in SBP >40 mmHg), major trauma, hemorrhage, or major surgery); and/or expected to be hospitalized to the ICU for at least 24 hours after enrollment.
Exclusion Criteria - known pregnancy;
- institutionalized individuals;
- previous renal transplantation;
- known acutely worsening renal function prior to enrollment (e.g., any category of RIFLE criteria);
- received dialysis (either acute or chronic) within 5 days prior to enrollment or in imminent need of dialysis at the time of enrollment;
- known infection with human immunodeficiency virus (HIV) or a hepatitis virus;
- meets only the SBP <90 mmHg inclusion criterion set forth above, and does not have shock in the attending physician's or principal investigator's opinion.
After providing informed consent, an EDTA anti-coagulated blood sample (10 mL) and a urine sample (25-30 mL) are collected from each patient. Blood and urine samples are then collected at 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. Blood is collected via direct venipuncture or via other available venous access, such as an existing femoral sheath, central venous line, peripheral intravenous line or hep-lock. These study blood samples are processed to plasma at the clinical site, frozen and shipped to Astute Medical, Inc., San Diego, CA. The study urine samples are frozen and shipped to Astute Medical, Inc.
Example 4. Immunoassay Format
Analytes are measured using standard sandwich enzyme immunoassay techniques. A first antibody which binds the analyte is immobilized in wells of a 96 well polystyrene microplate. Analyte standards and test samples are pipetted into the appropriate wells and any analyte present is bound by the immobilized antibody. After washing away any unbound substances, a horseradish peroxidase-conjugated second antibody which binds the analyte is added to the wells, thereby forming sandwich complexes with the analyte (if present) and the first antibody. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution comprising tetramethylbenzidine and hydrogen peroxide is added to the wells. Color develops in proportion to the amount of analyte present in the sample. The color development is stopped and the intensity of the color is measured at 540 nm or 570 nm. An analyte concentration is assigned to the test sample by comparison to a standard curve determined from the analyte standards. Units for C-C motif chemokine 16 reported herein are ng/mL. Units for C-C motif chemokine 14 reported herein are ng/mL. Units for soluble Tyrosine-protein kinase receptor UFO reported herein are ng/mL.
Example 5. Apparently Healthy Donor and Chronic Disease Patient Samples
Human urine samples from donors with no known chronic or acute disease (“Apparently Healthy Donors”) were purchased from two vendors (Golden West Biologicals, Inc., 27625 Commerce Center Dr., Temecula, CA. 92590 and Virginia Medical Research, Inc., 915 First Colonial Rd., Virginia Beach, VA 23454). The urine samples were shipped and stored frozen at less than −20° C. The vendors supplied demographic information for the individual donors including gender, race (Black/White), smoking status and age.
Human urine samples from donors with various chronic diseases (“Chronic Disease Patients”) including congestive heart failure, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus and hypertension were purchased from Virginia Medical Research, Inc., 915 First Colonial Rd., Virginia Beach, VA 23454. The urine samples were shipped and stored frozen at less than −20 degrees centigrade. The vendor provided a case report form for each individual donor with age, gender, race (Black/White), smoking status and alcohol use, height, weight, chronic disease(s) diagnosis, current medications and previous surgeries.
Example 6. Use of C-C Motif Chemokine 14 for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. C-C motif chemokine 14 is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is risk of injury (R), injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 6.1
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 12 hours after sample collection and renal status is assessed by
serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
Recovery Period Duration (hr)
24 48 72
Non- Non- Non-
Recovered recovered Recovered recovered Recovered recovered
Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.475 1.19 0.547 1.15 0.805 1.04
Average 0.567 2.10 0.625 2.06 0.744 2.02
Stdev 0.332 2.12 0.365 2.11 0.384 2.10
p (t-test) 6.1E−7 1.9E−5 0.0017
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 1.16 7.86 1.16 7.86 1.16 7.86
n (Patient) 8 73 6 75 4 77
sCr only
Median 0.551 1.58 0.557 1.38 0.611 1.20
Average 0.964 2.53 1.01 2.45 1.04 2.38
Stdev 0.898 2.32 0.916 2.31 0.939 2.30
p (t-test) 6.0E−5 1.7E−4 4.4E−4
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 3.52 7.86 3.52 7.86 3.52 7.86
n (Patient) 30 51 28 53 26 55
UO only
Median 0.640 1.33 0.838 1.26 1.04 1.19
Average 1.21 2.18 1.30 2.15 1.42 2.09
Stdev 1.33 2.13 1.36 2.13 1.38 2.13
p (t-test) 0.068 0.13 0.25
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 4.74 7.86 4.74 7.86 4.74 7.86
n (Patient) 11 61 10 62 9 64
sCr sCr UO sCr sCr UO sCr sCr UO
or UO only only or UO only only or UO only only
AUC 0.75 0.71 0.65 0.71 0.68 0.61 0.65 0.67 0.56
SE 0.076 0.057 0.084 0.094 0.060 0.091 0.13 0.062 0.100
p Value 8.8E−4 2.0E−4 0.076 0.024 0.0022 0.24 0.24 0.0070 0.57
nCohort Recovered 8 30 11 6 28 10 4 26 9
nCohort Non-recovered 73 51 61 75 53 62 77 55 64
Cutoff Quartile 2 0.460 0.460 0.525 0.460 0.460 0.502 0.460 0.460 0.474
Sensitivity 77% 80% 77% 75% 77% 74% 74% 78% 72%
Specificity 50% 37% 36% 33% 32% 20% 25% 35% 11%
Cutoff Quartile 3 1.04 1.04 1.15 1.04 1.04 1.15 1.04 1.04 1.15
Sensitivity 52% 57% 54% 51% 55% 53% 49% 53% 52%
Specificity 75% 63% 73% 67% 61% 70% 50% 58% 67%
Cutoff Quartile 4 2.87 2.87 2.94 2.87 2.87 2.94 2.87 2.87 2.91
Sensitivity 27% 35% 28% 27% 34% 27% 26% 33% 27%
Specificity 100% 93% 91% 100% 93% 90% 100% 92% 89%
OR Quartile 2 3.29 2.37 1.92 1.47 1.62 0.719 0.950 1.90 0.319
p Value 0.12 0.095 0.35 0.67 0.36 0.69 0.97 0.22 0.30
Lower limit of 95% CI 0.744 0.861 0.490 0.250 0.583 0.138 0.0934 0.677 0.0372
Upper limit of 95% CI 14.6 6.55 7.52 8.70 4.49 3.74 9.67 5.32 2.74
OR Quartile 3 3.26 2.28 3.14 2.05 1.87 2.66 0.974 1.52 2.13
p Value 0.16 0.082 0.11 0.42 0.19 0.18 0.98 0.38 0.31
Lower limit of 95% CI 0.616 0.901 0.760 0.355 0.736 0.628 0.131 0.594 0.489
Upper limit of 95% CI 17.2 5.75 13.0 11.9 4.74 11.2 7.27 3.90 9.26
OR Quartile 4 6.51 7.64 3.86 4.80 6.69 3.40 3.21 5.84 2.89
p Value 0.20 0.0099 0.21 0.29 0.016 0.26 0.44 0.026 0.33
Lower limit of 95% CI 0.359 1.63 0.459 0.259 1.42 0.400 0.165 1.24 0.337
Upper limit of 95% CI 118 35.8 32.5 89.1 31.4 28.9 62.2 27.5 24.9
TABLE 6.2
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 24 hours after sample collection and renal status is assessed by
serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
Recovery Period Duration (hr)
24 48 72
Non- Non- Non-
Recovered recovered Recovered recovered Recovered recovered
Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.545 1.19 1.04 1.09 1.05 1.03
Average 0.882 2.14 1.06 2.07 1.17 2.05
Stdev 0.714 2.16 0.765 2.14 0.748 2.14
p (t-test) 7.0E−4 0.015 0.042
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 2.75 7.86 2.75 7.86 2.75 7.86
n (Patient) 11 69 8 72 7 73
sCr only
Median 0.556 1.60 0.651 1.48 0.651 1.48
Average 0.967 2.61 1.02 2.48 1.02 2.48
Stdev 0.884 2.34 0.914 2.32 0.914 2.32
p (t-test) 4.3E−5 1.8E−4 1.8E−4
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 3.52 7.86 3.52 7.86 3.52 7.86
n (Patient) 31 49 28 52 28 52
UO only
Median 1.04 1.19 1.05 1.19 1.11 1.15
Average 1.34 2.16 1.42 2.12 1.51 2.05
Stdev 1.21 2.10 1.22 2.10 1.22 2.09
p (t-test) 0.073 0.13 0.26
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 4.74 6.66 4.74 6.66 4.74 6.66
n (Patient) 14 54 13 55 12 57
sCr sCr UO sCr sCr UO sCr sCr UO
or UO only only or UO only only or UO only only
AUC 0.67 0.72 0.59 0.60 0.69 0.55 0.54 0.69 0.50
SE 0.080 0.057 0.083 0.10 0.060 0.087 0.11 0.060 0.092
p Value 0.036 1.5E−4 0.29 0.33 0.0019 0.58 0.71 0.0019 1.0
nCohort Recovered 11 31 14 8 28 13 7 28 12
nCohort Non-recovered 69 49 54 72 52 55 73 52 57
Cutoff Quartile 2 0.457 0.457 0.525 0.457 0.457 0.502 0.457 0.457 0.474
Sensitivity 77% 82% 76% 75% 81% 73% 74% 81% 70%
Specificity 36% 35% 29% 25% 36% 15% 14% 36% 8%
Cutoff Quartile 3 1.04 1.04 1.15 1.04 1.04 1.15 1.04 1.04 1.15
Sensitivity 52% 59% 52% 50% 56% 51% 49% 56% 49%
Specificity 64% 65% 57% 50% 61% 54% 43% 61% 50%
Cutoff Quartile 4 2.88 2.88 2.94 2.88 2.88 2.94 2.88 2.88 2.91
Sensitivity 29% 37% 30% 28% 35% 29% 27% 35% 28%
Specificity 100% 94% 93% 100% 93% 92% 100% 93% 92%
OR Quartile 2 1.89 2.44 1.26 1.00 2.33 0.485 0.474 2.33 0.214
p Value 0.35 0.089 0.73 1.0 0.11 0.38 0.50 0.11 0.15
Lower limit of 95% CI 0.491 0.871 0.338 0.185 0.828 0.0960 0.0535 0.828 0.0256
Upper limit of 95% CI 7.30 6.86 4.71 5.40 6.57 2.45 4.19 6.57 1.79
OR Quartile 3 1.91 2.64 1.44 1.00 1.95 1.21 0.730 1.95 0.966
p Value 0.34 0.041 0.55 1.0 0.16 0.76 0.69 0.16 0.96
Lower limit of 95% CI 0.512 1.04 0.439 0.232 0.765 0.360 0.152 0.765 0.278
Upper limit of 95% CI 7.12 6.69 4.70 4.31 4.96 4.06 3.49 4.96 3.35
OR Quartile 4 9.53 8.42 5.47 6.64 6.88 4.92 5.75 6.88 4.29
p Value 0.12 0.0069 0.12 0.20 0.015 0.14 0.24 0.015 0.18
Lower limit of 95% CI 0.536 1.79 0.660 0.366 1.46 0.590 0.314 1.46 0.512
Upper limit of 95% CI 169 39.5 45.4 120 32.3 41.1 105 32.3 36.0
TABLE 6.3
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 1.04 1.19 1.05 1.03 1.05 1.03
Average 1.18 2.29 1.27 2.22 1.27 2.22
Stdev 0.991 2.30 0.993 2.29 0.993 2.29
p (t-test) 0.0038 0.012 0.012
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 3.52 7.86 3.52 7.86 3.52 7.86
n (Patient) 23 57 21 59 21 59
sCr only
Median 0.653 1.58 0.640 1.48 0.640 1.48
Average 1.17 2.50 1.16 2.47 1.16 2.47
Stdev 1.27 2.32 1.29 2.30 1.29 2.30
p (t-test) 0.0020 0.0022 0.0022
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 6.43 7.86 6.43 7.86 6.43 7.86
n (Patient) 34 45 33 46 33 46
UO only
Median 1.10 1.33 1.24 1.19 1.24 1.19
Average 1.47 2.48 1.58 2.32 1.58 2.32
Stdev 1.23 2.32 1.24 2.30 1.24 2.30
p (t-test) 0.036 0.12 0.12
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 4.74 6.66 4.74 6.66 4.74 6.66
n (Patient) 22 37 20 40 20 40
24 48 72
Recovery Period sCr or sCr UO sCr or sCr UO sCr or sCr UO
Duration (hr) UO only only UO only only UO only only
AUC 0.61 0.68 0.58 0.56 0.69 0.52 0.56 0.69 0.52
SE 0.067 0.060 0.076 0.072 0.059 0.079 0.072 0.059 0.079
p Value 0.099 0.0028 0.29 0.38 0.0018 0.80 0.38 0.0018 0.80
nCohort 23 34 22 21 33 20 21 33 20
Recovered
nCohort Non- 57 45 37 59 46 40 59 46 40
recovered
Cutoff Quartile 2 0.457 0.454 0.520 0.457 0.454 0.502 0.457 0.454 0.502
Sensitivity 75% 82% 73% 73% 83% 68% 73% 83% 68%
Specificity 26% 35% 23% 19% 36% 10% 19% 36% 10%
Cutoff Quartile 3 1.04 1.04 1.20 1.04 1.04 1.19 1.04 1.04 1.19
Sensitivity 51% 56% 51% 49% 57% 50% 49% 57% 50%
Specificity 52% 59% 55% 48% 61% 50% 48% 61% 50%
Cutoff Quartile 4 2.88 2.82 2.98 2.88 2.82 2.94 2.88 2.82 2.94
Sensitivity 32% 38% 32% 31% 37% 30% 31% 37% 30%
Specificity 91% 91% 86% 90% 91% 85% 90% 91% 85%
OR Quartile 2 1.08 2.52 0.794 0.632 2.71 0.231 0.632 2.71 0.231
p Value 0.89 0.081 0.71 0.47 0.060 0.073 0.47 0.060 0.073
Lower limit of 0.358 0.893 0.231 0.185 0.958 0.0464 0.185 0.958 0.0464
95% CI
Upper limit of 3.29 7.13 2.73 2.17 7.69 1.15 2.17 7.69 1.15
95% CI
OR Quartile 3 1.13 1.79 1.27 0.879 2.00 1.00 0.879 2.00 1.00
p Value 0.80 0.21 0.66 0.80 0.14 1.0 0.80 0.14 1.0
Lower limit of 0.429 0.725 0.440 0.324 0.805 0.342 0.324 0.805 0.342
95% CI
Upper limit of 2.98 4.40 3.65 2.38 4.97 2.93 2.38 4.97 2.93
95% CI
OR Quartile 4 4.85 6.27 3.04 4.17 5.86 2.43 4.17 5.86 2.43
p Value 0.047 0.0068 0.12 0.073 0.0091 0.21 0.073 0.0091 0.21
Lower limit of 1.02 1.66 0.751 0.877 1.55 0.598 0.877 1.55 0.598
95% CI
Upper limit of 22.9 23.7 12.3 19.8 22.1 9.86 19.8 22.1 9.86
95% CI
TABLE 6.4
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.838 1.19 1.04 1.11 1.04 1.11
Average 1.11 2.37 1.14 2.33 1.14 2.33
Stdev 0.912 2.35 0.915 2.34 0.915 2.34
p (t-test) 0.0012 0.0020 0.0020
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 3.52 7.86 3.52 7.86 3.52 7.86
n (Patient) 26 53 25 54 25 54
sCr only
Median 0.665 1.19 0.653 1.20 0.848 1.19
Average 1.36 2.33 1.25 2.40 1.31 2.31
Stdev 1.58 2.29 1.46 2.31 1.49 2.30
p (t-test) 0.034 0.010 0.025
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 6.43 7.86 6.43 7.86 6.43 7.86
n (Patient) 35 42 34 43 32 45
UO only
Median 1.05 1.33 1.10 1.26 1.10 1.26
Average 1.80 2.43 1.89 2.38 1.89 2.38
Stdev 1.74 2.27 1.75 2.26 1.75 2.26
p (t-test) 0.28 0.42 0.42
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 6.26 6.66 6.26 6.66 6.26 6.66
n (Patient) 17 35 16 36 16 36
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.63 0.64 0.57 0.61 0.66 0.53 0.61 0.62 0.53
SE 0.064 0.063 0.084 0.066 0.062 0.087 0.066 0.064 0.087
p Value 0.038 0.025 0.43 0.089 0.0091 0.70 0.089 0.055 0.70
nCohort Recovered 26 35 17 25 34 16 25 32 16
nCohort Non- 53 42 35 54 43 36 54 45 36
recovered
Cutoff Quartile 2 0.454 0.448 0.525 0.454 0.448 0.525 0.454 0.448 0.525
Sensitivity 77% 81% 74% 76% 81% 72% 76% 78% 72%
Specificity 31% 34% 24% 28% 35% 19% 28% 31% 19%
Cutoff Quartile 3 1.04 1.03 1.19 1.04 1.03 1.19 1.04 1.03 1.19
Sensitivity 51% 52% 54% 50% 53% 53% 50% 51% 53%
Specificity 54% 54% 59% 52% 56% 56% 52% 53% 56%
Cutoff Quartile 4 2.82 2.75 3.17 2.82 2.75 3.17 2.82 2.75 3.17
Sensitivity 34% 36% 26% 33% 37% 25% 33% 36% 25%
Specificity 92% 89% 76% 92% 91% 75% 92% 91% 75%
OR Quartile 2 1.52 2.22 0.889 1.23 2.39 0.600 1.23 1.59 0.600
p Value 0.44 0.13 0.86 0.71 0.10 0.49 0.71 0.38 0.49
Lower limit of 0.530 0.784 0.230 0.419 0.842 0.140 0.419 0.570 0.140
95% CI
Upper limit of 4.35 6.27 3.44 3.59 6.76 2.56 3.59 4.44 2.56
95% CI
OR Quartile 3 1.21 1.31 1.70 1.08 1.46 1.44 1.08 1.18 1.44
p Value 0.69 0.56 0.38 0.87 0.41 0.55 0.87 0.71 0.55
Lower limit of 0.473 0.531 0.525 0.419 0.590 0.439 0.419 0.478 0.439
95% CI
Upper limit of 3.10 3.21 5.48 2.80 3.60 4.70 2.80 2.94 4.70
95% CI
OR Quartile 4 6.17 4.31 1.12 5.75 6.12 1.00 5.75 5.33 1.00
p Value 0.021 0.019 0.86 0.027 0.0079 1.0 0.027 0.014 1.0
Lower limit of 1.31 1.27 0.291 1.22 1.61 0.257 1.22 1.40 0.257
95% CI
Upper limit of 29.1 14.5 4.35 27.1 23.3 3.90 27.1 20.3 3.90
95% CI
TABLE 6.5
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts
within 7 days after sample collection and renal status is assessed by serum creatinine
(sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.620 1.26 0.637 1.19 0.640 1.16
Average 1.44 2.41 1.43 2.33 1.49 2.25
Stdev 1.70 2.24 1.68 2.22 1.71 2.21
p (t-test) 0.030 0.040 0.085
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 41 42 37 46 35 48
sCr only
Median 0.848 1.20 0.848 1.20 1.03 1.19
Average 1.66 2.37 1.62 2.38 1.71 2.21
Stdev 1.88 2.24 1.86 2.24 1.92 2.18
p (t-test) 0.15 0.11 0.29
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 48 33 46 35 42 39
UO only
Median 1.04 1.08 1.04 1.08 1.04 1.03
Average 1.86 2.01 1.60 2.10 1.65 2.07
Stdev 2.29 2.00 1.84 2.09 1.85 2.09
p (t-test) 0.77 0.27 0.36
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 8.44 6.66 7.86 6.66 7.86 6.66
n (Patient) 31 48 31 48 30 49
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.66 0.62 0.55 0.64 0.62 0.57 0.60 0.58 0.55
SE 0.060 0.064 0.066 0.061 0.064 0.065 0.062 0.064 0.066
p Value 0.0088 0.070 0.42 0.023 0.070 0.26 0.100 0.20 0.44
nCohort Recovered 41 48 31 37 46 31 35 42 30
nCohort Non- 42 33 48 46 35 48 48 39 49
recovered
Cutoff Quartile 2 0.467 0.460 0.493 0.467 0.460 0.493 0.467 0.460 0.493
Sensitivity 81% 79% 77% 80% 77% 77% 77% 77% 76%
Specificity 32% 29% 29% 32% 28% 29% 29% 29% 27%
Cutoff Quartile 3 1.04 1.04 1.04 1.04 1.04 1.04 1.04 1.04 1.04
Sensitivity 57% 55% 50% 54% 54% 50% 52% 51% 49%
Specificity 59% 54% 52% 57% 54% 52% 54% 52% 50%
Cutoff Quartile 4 2.82 2.87 2.82 2.82 2.87 2.82 2.82 2.87 2.82
Sensitivity 33% 30% 27% 33% 31% 29% 31% 28% 29%
Specificity 83% 79% 77% 84% 80% 81% 83% 79% 80%
OR Quartile 2 1.97 1.53 1.38 1.97 1.33 1.38 1.35 1.33 1.12
p Value 0.19 0.42 0.54 0.18 0.58 0.54 0.56 0.57 0.83
Lower limit of 0.717 0.540 0.493 0.724 0.481 0.493 0.497 0.490 0.397
95% CI
Upper limit of 5.43 4.33 3.84 5.38 3.68 3.84 3.64 3.63 3.17
95% CI
OR Quartile 3 1.88 1.42 1.07 1.56 1.41 1.07 1.29 1.16 0.960
p Value 0.15 0.44 0.89 0.32 0.44 0.89 0.57 0.74 0.93
Lower limit of 0.787 0.582 0.432 0.654 0.585 0.432 0.539 0.484 0.387
95% CI
Upper limit of 4.50 3.45 2.63 3.74 3.42 2.63 3.09 2.77 2.38
95% CI
OR Quartile 4 2.43 1.65 1.27 2.50 1.88 1.72 2.20 1.44 1.60
p Value 0.093 0.33 0.65 0.093 0.22 0.33 0.15 0.48 0.40
Lower limit of 0.862 0.597 0.443 0.858 0.680 0.579 0.753 0.522 0.539
95% CI
Upper limit of 6.84 4.57 3.66 7.29 5.22 5.09 6.41 3.97 4.75
95% CI
TABLE 6.6
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 125 258 108 255 111 254
Average 149 277 107 275 116 272
Stdev 59.3 120 20.2 119 12.5 120
p (t-test) 2.9E−4 1.8E−10 6.9E−13
Min 73.7 89.8 73.7 89.8 105 73.7
Max 255 651 137 651 137 651
n (Patient) 8 74 5 77 4 78
sCr only
Median 182 285 182 283 171 283
Average 206 301 205 298 201 297
Stdev 89.8 126 92.3 125 93.2 123
p (t-test) 1.9E−4 3.3E−4 2.8E−4
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 446 651 446 651 446 651
n (Patient) 31 50 29 52 27 54
UO only
Median 243 253 265 251 289 249
Average 232 278 233 277 253 273
Stdev 112 125 118 124 110 125
p (t-test) 0.28 0.35 0.66
Min 73.7 110 73.7 110 108 73.7
Max 395 651 395 651 395 651
n (Patient) 10 61 9 62 8 64
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.84 0.73 0.59 0.97 0.73 0.59 0.95 0.74 0.53
SE 0.057 0.055 0.093 0.021 0.056 0.097 0.033 0.055 0.11
p Value 2.6E−9 2.9E−5 0.31 0 4.3E−5 0.35 0 1.4E−5 0.78
nCohort Recovered 8 31 10 5 29 9 4 27 8
nCohort Non-recovered 74 50 61 77 52 62 78 54 64
Cutoff Quartile 2 172 171 174 172 171 174 172 171 175
Sensitivity 78% 86% 77% 79% 87% 77% 78% 87% 77%
Specificity 62% 45% 40% 100% 48% 44% 100% 52% 38%
Cutoff Quartile 3 249 249 253 249 249 253 249 249 251
Sensitivity 54% 62% 49% 53% 62% 48% 53% 61% 48%
Specificity 88% 71% 50% 100% 72% 44% 100% 74% 38%
Cutoff Quartile 4 331 331 339 331 331 339 331 331 337
Sensitivity 28% 34% 26% 27% 33% 26% 27% 31% 25%
Specificity 100% 90% 80% 100% 90% 78% 100% 89% 75%
OR Quartile 2 6.04 5.06 2.24 41.0 6.00 2.74 31.6 7.23 1.96
p Value 0.022 0.0029 0.26 0.013 0.0011 0.17 0.023 4.0E-4 0.39
Lower limit of 95% CI 1.30 1.74 0.553 2.16 2.04 0.648 1.62 2.42 0.419
Upper limit of 95% CI 28.0 14.7 9.07 780 17.7 11.6 616 21.6 9.18
OR Quartile 3 8.24 3.99 0.968 12.5 4.20 0.750 9.96 4.49 0.564
p Value 0.054 0.0049 0.96 0.091 0.0044 0.69 0.13 0.0039 0.46
Lower limit of 95% CI 0.964 1.52 0.254 0.668 1.56 0.184 0.519 1.62 0.124
Upper limit of 95% CI 70.3 10.4 3.69 234 11.3 3.06 191 12.5 2.56
OR Quartile 4 6.83 4.81 1.42 4.19 4.21 1.22 3.37 3.68 1.00
p Value 0.19 0.020 0.68 0.34 0.034 0.82 0.42 0.055 1.0
Lower limit of 95% CI 0.377 1.28 0.273 0.222 1.12 0.229 0.174 0.972 0.183
Upper limit of 95% CI 124 18.1 7.41 79.0 15.9 6.48 65.2 13.9 5.46
TABLE 6.7
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 179 255 132 254 132 254
Average 196 279 186 278 183 276
Stdev 90.2 121 97.7 119 88.7 120
p (t-test) 0.027 0.044 0.068
Min 73.7 103 73.7 103 108 73.7
Max 329 651 329 651 329 651
n (Patient) 10 70 8 72 6 74
sCr only
Median 204 293 193 283 187 285
Average 213 306 211 303 208 303
Stdev 88.7 126 91.4 124 90.8 123
p (t-test) 2.9E−4 4.5E−4 2.6E−4
Min 73.7 103 73.7 103 73.7 103
Max 446 651 446 651 446 651
n (Patient) 31 48 29 50 28 51
UO only
Median 314 239 321 235 328 235
Average 265 275 268 273 283 270
Stdev 102 129 105 129 93.9 129
p (t-test) 0.76 0.87 0.69
Min 73.7 110 73.7 110 108 73.7
Max 395 651 395 651 395 651
n (Patient) 15 54 14 55 13 57
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.70 0.72 0.48 0.73 0.72 0.47 0.75 0.74 0.41
SE 0.079 0.057 0.084 0.081 0.057 0.086 0.088 0.056 0.085
p Value 0.013 8.0E−5 0.77 0.0046 1.0E−4 0.69 0.0051 2.4E−5 0.31
nCohort Recovered 10 31 15 8 29 14 6 28 13
nCohort Non- 70 48 54 72 50 55 74 51 57
recovered
Cutoff Quartile 2 176 175 177 176 175 177 176 175 178
Sensitivity 79% 85% 74% 79% 86% 75% 78% 86% 74%
Specificity 50% 42% 27% 62% 45% 29% 67% 46% 23%
Cutoff Quartile 3 251 249 253 251 249 253 251 249 251
Sensitivity 51% 60% 44% 51% 60% 44% 51% 61% 44%
Specificity 60% 68% 33% 62% 69% 29% 67% 71% 23%
Cutoff Quartile 4 332 333 335 332 333 335 332 333 334
Sensitivity 29% 35% 26% 28% 34% 25% 27% 33% 25%
Specificity 100% 90% 80% 100% 90% 79% 100% 89% 69%
OR Quartile 2 3.67 4.23 1.04 6.33 4.99 1.17 7.25 5.45 0.840
p Value 0.062 0.0084 0.95 0.019 0.0036 0.81 0.030 0.0023 0.81
Lower limit of 0.937 1.45 0.284 1.36 1.69 0.316 1.22 1.83 0.203
95% CI
Upper limit of 14.4 12.4 3.80 29.5 14.7 4.34 43.2 16.2 3.47
95% CI
OR Quartile 3 1.59 3.21 0.400 1.76 3.33 0.310 2.11 3.88 0.234
p Value 0.50 0.016 0.13 0.46 0.015 0.072 0.40 0.0076 0.041
Lower limit of 0.412 1.24 0.120 0.392 1.26 0.0864 0.364 1.43 0.0582
95% CI
Upper limit of 6.12 8.28 1.33 7.93 8.78 1.11 12.2 10.5 0.943
95% CI
OR Quartile 4 8.52 5.12 1.40 6.64 4.46 1.25 4.89 4.17 0.733
p Value 0.15 0.016 0.64 0.20 0.028 0.76 0.29 0.036 0.64
Lower limit of 0.477 1.35 0.344 0.366 1.18 0.305 0.263 1.10 0.195
95% CI
Upper limit of 152 19.3 5.70 120 16.9 5.15 90.8 15.8 2.75
95% CI
TABLE 6.8
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 235 256 223 255 223 255
Average 233 283 237 280 237 280
Stdev 100 127 99.5 127 99.5 127
p (t-test) 0.082 0.15 0.15
Min 73.7 103 108 73.7 108 73.7
Max 446 651 446 651 446 651
n (Patient) 21 56 18 59 18 59
sCr only
Median 210 283 210 285 210 285
Average 220 305 217 305 217 305
Stdev 91.8 131 91.7 129 91.7 129
p (t-test) 0.0015 9.6E−4 9.6E−4
Min 73.7 103 73.7 103 73.7 103
Max 446 651 446 651 446 651
n (Patient) 32 44 31 45 31 45
UO only
Median 301 231 320 227 320 227
Average 280 280 296 272 296 272
Stdev 89.4 139 77.1 138 77.1 138
p (t-test) 1.00 0.42 0.42
Min 73.7 114 108 73.7 108 73.7
Max 429 651 429 651 429 651
n (Patient) 20 37 18 40 18 40
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.60 0.69 0.41 0.59 0.70 0.35 0.59 0.70 0.35
SE 0.070 0.060 0.078 0.074 0.059 0.075 0.074 0.059 0.075
p Value 0.16 0.0015 0.28 0.24 5.7E−4 0.048 0.24 5.7E−4 0.048
nCohort Recovered 21 32 20 18 31 18 18 31 18
nCohort Non-recovered 56 44 37 59 45 40 59 45 40
Cutoff Quartile 2 174 173 185 174 173 187 174 173 187
Sensitivity 79% 86% 68% 78% 87% 68% 78% 87% 68%
Specificity 38% 41% 15% 39% 42% 11% 39% 42% 11%
Cutoff Quartile 3 249 249 257 249 249 255 249 249 255
Sensitivity 52% 61% 41% 51% 62% 40% 51% 62% 40%
Specificity 57% 66% 35% 56% 68% 28% 56% 68% 28%
Cutoff Quartile 4 335 334 335 335 334 334 335 334 334
Sensitivity 29% 34% 24% 27% 33% 22% 27% 33% 22%
Specificity 86% 88% 75% 83% 87% 67% 83% 87% 67%
OR Quartile 2 2.26 4.33 0.368 2.25 4.69 0.260 2.25 4.69 0.260
p Value 0.14 0.0098 0.16 0.16 0.0067 0.10 0.16 0.0067 0.10
Lower limit of 95% CI 0.760 1.42 0.0900 0.727 1.54 0.0518 0.727 1.54 0.0518
Upper limit of 95% CI 6.70 13.2 1.50 6.97 14.3 1.30 6.97 14.3 1.30
OR Quartile 3 1.43 3.03 0.367 1.29 3.46 0.256 1.29 3.46 0.256
p Value 0.49 0.022 0.082 0.63 0.012 0.027 0.63 0.012 0.027
Lower limit of 95% CI 0.521 1.17 0.119 0.448 1.32 0.0765 0.448 1.32 0.0765
Upper limit of 95% CI 3.94 7.83 1.14 3.73 9.07 0.860 3.73 9.07 0.860
OR Quartile 4 2.40 3.62 0.964 1.86 3.38 0.581 1.86 3.38 0.581
p Value 0.20 0.039 0.95 0.37 0.051 0.39 0.37 0.051 0.39
Lower limit of 95% CI 0.620 1.07 0.273 0.475 0.997 0.170 0.475 0.997 0.170
Upper limit of 95% CI 9.28 12.3 3.40 7.29 11.4 1.99 7.29 11.4 1.99
TABLE 6.9
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 210 267 210 267 210 267
Average 220 289 220 289 220 289
Stdev 87.3 129 87.3 129 87.3 129
p (t-test) 0.011 0.011 0.011
Min 108 73.7 108 73.7 108 73.7
Max 395 651 395 651 395 651
n (Patient) 22 52 22 52 22 52
sCr only
Median 221 279 211 283 211 279
Average 238 290 228 295 230 291
Stdev 119 119 112 121 115 121
p (t-test) 0.070 0.017 0.035
Min 73.7 103 73.7 103 73.7 103
Max 651 592 651 592 651 592
n (Patient) 33 40 31 42 29 44
UO only
Median 308 240 308 240 308 240
Average 287 287 287 287 287 287
Stdev 72.0 142 72.0 142 72.0 142
p (t-test) 0.99 0.99 0.99
Min 140 73.7 140 73.7 140 73.7
Max 395 651 395 651 395 651
n (Patient) 14 34 14 34 14 34
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.65 0.64 0.41 0.65 0.67 0.41 0.65 0.66 0.41
SE 0.067 0.064 0.089 0.067 0.063 0.089 0.067 0.064 0.089
p Value 0.021 0.031 0.32 0.021 0.0055 0.32 0.021 0.014 0.32
nCohort Recovered 22 33 14 22 31 14 22 29 14
nCohort Non-recovered 52 40 34 52 42 34 52 44 34
Cutoff Quartile 2 175 174 201 175 174 201 175 174 201
Sensitivity 81% 82% 71% 81% 83% 71% 81% 82% 71%
Specificity 41% 36% 14% 41% 39% 14% 41% 38% 14%
Cutoff Quartile 3 249 249 261 249 249 261 249 249 261
Sensitivity 56% 57% 41% 56% 60% 41% 56% 57% 41%
Specificity 64% 61% 29% 64% 65% 29% 64% 62% 29%
Cutoff Quartile 4 331 329 345 331 329 345 331 329 345
Sensitivity 29% 30% 26% 29% 31% 26% 29% 30% 26%
Specificity 82% 82% 79% 82% 84% 79% 82% 83% 79%
OR Quartile 2 2.91 2.69 0.400 2.91 3.16 0.400 2.91 2.75 0.400
p Value 0.056 0.072 0.28 0.056 0.038 0.28 0.056 0.064 0.28
Lower limit of 95% CI 0.973 0.914 0.0754 0.973 1.07 0.0754 0.973 0.941 0.0754
Upper limit of 95% CI 8.69 7.94 2.12 8.69 9.36 2.12 8.69 8.03 2.12
OR Quartile 3 2.21 2.08 0.280 2.21 2.67 0.280 2.21 2.15 0.280
p Value 0.13 0.13 0.064 0.13 0.045 0.064 0.13 0.12 0.064
Lower limit of 95% CI 0.790 0.814 0.0729 0.790 1.02 0.0729 0.790 0.826 0.0729
Upper limit of 95% CI 6.16 5.32 1.08 6.16 6.98 1.08 6.16 5.61 1.08
OR Quartile 4 1.82 1.93 1.32 1.82 2.33 1.32 1.82 2.01 1.32
p Value 0.34 0.25 0.71 0.34 0.15 0.71 0.34 0.24 0.71
Lower limit of 95% CI 0.529 0.633 0.298 0.529 0.731 0.298 0.529 0.630 0.298
Upper limit of 95% CI 6.29 5.87 5.84 6.29 7.43 5.84 6.29 6.43 5.84
TABLE 6.10
Comparison of marker levels and the area under the ROC curve
(AUC) in EDTA samples for the “recovered” and “non-recovered” cohorts where
recovery starts within 7 days after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE
criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 246 255 246 255 246 252
Average 243 292 239 290 243 285
Stdev 101 141 101 137 100 138
p (t-test) 0.076 0.055 0.11
Min 73.7 89.8 73.7 89.8 103 73.7
Max 446 651 446 651 446 651
n (Patient) 44 40 40 44 38 46
sCr only
Median 246 249 246 249 239 255
Average 254 280 254 280 246 285
Stdev 121 124 122 122 119 123
p (t-test) 0.36 0.35 0.15
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 651 592 651 592 651 592
n (Patient) 48 33 46 35 42 39
UO only
Median 273 238 265 231 273 227
Average 266 274 259 274 265 270
Stdev 105 140 90.5 142 85.3 143
p (t-test) 0.77 0.56 0.84
Min 73.7 105 73.7 105 108 73.7
Max 559 651 429 651 429 651
n (Patient) 30 48 31 47 30 48
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.58 0.56 0.47 0.59 0.56 0.48 0.57 0.59 0.45
SE 0.063 0.066 0.067 0.062 0.065 0.067 0.063 0.063 0.067
p Value 0.21 0.39 0.69 0.14 0.35 0.76 0.27 0.14 0.48
nCohort Recovered 44 48 30 40 46 31 38 42 30
nCohort Non-recovered 40 33 48 44 35 47 46 39 48
Cutoff Quartile 2 169 171 172 169 171 172 169 171 172
Sensitivity 80% 82% 73% 82% 83% 72% 80% 85% 71%
Specificity 30% 31% 23% 32% 33% 23% 32% 36% 20%
Cutoff Quartile 3 249 249 249 249 249 249 249 249 249
Sensitivity 52% 52% 46% 52% 51% 45% 52% 54% 44%
Specificity 52% 52% 43% 52% 52% 42% 53% 55% 40%
Cutoff Quartile 4 332 331 334 332 331 334 332 331 334
Sensitivity 28% 24% 27% 30% 26% 28% 28% 28% 27%
Specificity 77% 75% 77% 80% 76% 77% 79% 79% 77%
OR Quartile 2 1.68 2.05 0.819 2.17 2.34 0.763 1.90 3.06 0.607
p Value 0.32 0.19 0.71 0.13 0.12 0.62 0.21 0.042 0.37
Lower limit of 95% CI 0.611 0.698 0.284 0.787 0.799 0.265 0.699 1.04 0.204
Upper limit of 95% CI 4.60 5.99 2.36 5.96 6.84 2.20 5.15 8.95 1.81
OR Quartile 3 1.21 1.15 0.647 1.21 1.16 0.583 1.21 1.41 0.519
p Value 0.66 0.75 0.35 0.66 0.75 0.25 0.66 0.44 0.16
Lower limit of 95% CI 0.514 0.476 0.258 0.514 0.479 0.233 0.513 0.589 0.205
Upper limit of 95% CI 2.85 2.80 1.62 2.85 2.78 1.46 2.87 3.39 1.31
OR Quartile 4 1.29 0.960 1.22 1.68 1.10 1.31 1.48 1.44 1.22
p Value 0.61 0.94 0.71 0.32 0.85 0.62 0.45 0.48 0.71
Lower limit of 95% CI 0.480 0.343 0.423 0.611 0.398 0.456 0.538 0.522 0.423
Upper limit of 95% CI 3.47 2.69 3.52 4.60 3.04 3.77 4.06 3.97 3.52
Example 7. Use of C-C Motif Chemokine 14 for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 and R from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. C-C motif chemokine 14 is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0) or risk of injury (R). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 7.1
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.474 1.33 0.506 1.33 0.537 1.26
Average 1.07 2.22 1.11 2.19 1.15 2.17
Stdev 1.70 2.09 1.74 2.09 1.78 2.08
p (t-test) 0.023 0.038 0.060
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 19 62 18 63 17 64
sCr only
Median 0.640 2.07 0.640 1.78 0.640 1.78
Average 1.44 2.67 1.48 2.55 1.48 2.55
Stdev 1.75 2.25 1.77 2.24 1.77 2.24
p (t-test) 0.011 0.024 0.024
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 47 34 45 36 45 36
UO only
Median 0.589 1.33 0.537 1.33 0.589 1.33
Average 1.53 2.23 1.48 2.26 1.52 2.19
Stdev 1.89 2.09 1.86 2.10 1.90 2.09
p (t-test) 0.19 0.14 0.21
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 7.86 6.66 7.86 6.66 7.86 6.66
n (Patient) 20 52 21 51 20 53
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.72 0.69 0.64 0.71 0.66 0.65 0.70 0.66 0.64
SE 0.061 0.061 0.070 0.063 0.061 0.068 0.065 0.061 0.070
p Value 2.4E−4 0.0022 0.047 0.0010 0.0080 0.026 0.0023 0.0080 0.051
nCohort Recovered 19 47 20 18 45 21 17 45 20
nCohort Non-recovered 62 34 52 63 36 51 64 36 53
Cutoff Quartile 2 0.460 0.460 0.525 0.460 0.460 0.502 0.460 0.460 0.474
Sensitivity 81% 82% 83% 79% 81% 82% 80% 81% 79%
Specificity 47% 32% 45% 44% 31% 43% 47% 31% 40%
Cutoff Quartile 3 1.04 1.04 1.15 1.04 1.04 1.15 1.04 1.04 1.15
Sensitivity 56% 62% 56% 56% 58% 57% 55% 58% 55%
Specificity 74% 60% 65% 72% 58% 67% 71% 58% 65%
Cutoff Quartile 4 2.87 2.87 2.94 2.87 2.87 2.94 2.87 2.87 2.91
Sensitivity 31% 38% 29% 30% 36% 29% 30% 36% 28%
Specificity 95% 85% 85% 94% 84% 86% 94% 84% 85%
OR Quartile 2 3.75 2.19 3.91 3.08 1.87 3.50 3.49 1.87 2.55
p Value 0.018 0.15 0.019 0.048 0.24 0.029 0.030 0.24 0.10
Lower limit of 95% CI 1.25 0.747 1.25 1.01 0.662 1.14 1.13 0.662 0.836
Upper limit of 95% CI 11.3 6.40 12.2 9.36 5.29 10.8 10.8 5.29 7.75
OR Quartile 3 3.63 2.38 2.34 3.25 1.92 2.64 2.90 1.92 2.24
p Value 0.026 0.060 0.12 0.044 0.15 0.074 0.071 0.15 0.14
Lower limit of 95% CI 1.16 0.964 0.804 1.03 0.788 0.911 0.914 0.788 0.773
Upper limit of 95% CI 11.3 5.88 6.82 10.2 4.66 7.63 9.18 4.66 6.52
OR Quartile 4 7.95 3.54 2.30 7.34 3.07 2.50 6.76 3.07 2.24
p Value 0.051 0.019 0.23 0.061 0.037 0.19 0.073 0.037 0.25
Lower limit of 95% CI 0.989 1.23 0.586 0.910 1.07 0.640 0.835 1.07 0.571
Upper limit of 95% CI 64.0 10.2 9.01 59.2 8.81 9.77 54.6 8.81 8.76
TABLE 7.2
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.541 1.33 0.545 1.33 0.551 1.26
Average 1.12 2.33 1.16 2.30 1.19 2.27
Stdev 1.57 2.15 1.60 2.15 1.62 2.14
p (t-test) 0.0076 0.013 0.021
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 24 56 23 57 22 58
sCr only
Median 0.640 1.99 0.653 1.78 0.640 1.99
Average 1.47 2.61 1.50 2.55 1.46 2.56
Stdev 1.78 2.24 1.79 2.24 1.79 2.21
p (t-test) 0.018 0.027 0.019
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 45 35 44 36 43 37
UO only
Median 0.598 1.33 0.556 1.33 0.598 1.33
Average 1.20 2.36 1.16 2.40 1.19 2.32
Stdev 1.17 2.16 1.16 2.17 1.18 2.16
p (t-test) 0.0063 0.0037 0.0078
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 4.74 6.66 4.74 6.66 4.74 6.66
n (Patient) 22 46 23 45 22 47
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.70 0.68 0.67 0.69 0.66 0.68 0.68 0.67 0.66
SE 0.060 0.061 0.067 0.062 0.062 0.066 0.063 0.061 0.067
p Value 6.9E−4 0.0036 0.013 0.0023 0.0095 0.0065 0.0047 0.0043 0.017
nCohort Recovered 24 45 22 23 44 23 22 43 22
nCohort Non-recovered 56 35 46 57 36 45 58 37 47
Cutoff Quartile 2 0.457 0.457 0.525 0.457 0.457 0.502 0.457 0.457 0.474
Sensitivity 82% 86% 83% 81% 83% 82% 81% 84% 79%
Specificity 42% 33% 41% 39% 32% 39% 41% 33% 36%
Cutoff Quartile 3 1.04 1.04 1.15 1.04 1.04 1.15 1.04 1.04 1.15
Sensitivity 57% 60% 57% 56% 58% 58% 55% 59% 55%
Specificity 67% 58% 64% 65% 57% 65% 64% 58% 64%
Cutoff Quartile 4 2.88 2.88 2.94 2.88 2.88 2.94 2.88 2.88 2.91
Sensitivity 34% 37% 33% 33% 36% 33% 33% 38% 32%
Specificity 96% 84% 91% 96% 84% 91% 95% 86% 91%
OR Quartile 2 3.29 3.00 3.29 2.69 2.33 2.97 2.96 2.49 2.11
p Value 0.028 0.057 0.041 0.069 0.12 0.060 0.048 0.098 0.19
Lower limit of 95% CI 1.14 0.968 1.05 0.927 0.791 0.957 1.01 0.845 0.694
Upper limit of 95% CI 9.50 9.30 10.3 7.80 6.88 9.24 8.66 7.36 6.45
OR Quartile 3 2.67 2.05 2.28 2.40 1.84 2.57 2.15 2.04 2.17
p Value 0.055 0.12 0.12 0.088 0.18 0.076 0.14 0.12 0.15
Lower limit of 95% CI 0.981 0.836 0.799 0.879 0.755 0.905 0.784 0.834 0.764
Upper limit of 95% CI 7.25 5.04 6.48 6.56 4.49 7.28 5.92 4.98 6.14
OR Quartile 4 11.8 3.21 4.84 11.0 2.99 5.25 10.2 3.75 4.69
p Value 0.020 0.031 0.050 0.024 0.042 0.039 0.028 0.017 0.055
Lower limit of 95% CI 1.48 1.11 0.998 1.38 1.04 1.08 1.28 1.26 0.968
Upper limit of 95% CI 94.3 9.24 23.5 87.9 8.59 25.4 81.9 11.2 22.7
TABLE 7.3
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and ″non-recovered″ cohorts where recovery starts at
48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.653 1.29 0.838 1.19 1.04 1.19
Average 1.34 2.54 1.42 2.38 1.45 2.33
Stdev 1.52 2.33 1.58 2.29 1.59 2.28
p (t-test) 0.0085 0.032 0.048
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 7.86 6.79 7.86
n (Patient) 38 42 34 46 33 47
sCr only
Median 1.03 1.19 0.848 1.20 0.848 1.20
Average 1.60 2.41 1.57 2.43 1.57 2.43
Stdev 1.80 2.27 1.81 2.24 1.81 2.24
p (t-test) 0.10 0.077 0.077
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 47 32 46 33 46 33
UO only
Median 1.04 2.07 1.05 1.33 1.10 1.26
Average 1.44 2.74 1.56 2.44 1.61 2.38
Stdev 1.46 2.31 1.54 2.27 1.55 2.26
p (t-test) 0.015 0.085 0.13
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 6.26 6.66 6.26 6.66 6.26 6.66
n (Patient) 29 30 25 35 24 36
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.64 0.62 0.65 0.61 0.63 0.60 0.60 0.63 0.57
SE 0.062 0.065 0.071 0.063 0.064 0.074 0.064 0.064 0.075
p Value 0.021 0.075 0.031 0.072 0.043 0.20 0.13 0.043 0.33
nCohort Recovered 38 47 29 34 46 25 33 46 24
nCohort Non-recovered 42 32 30 46 33 35 47 33 36
Cutoff Quartile 2 0.457 0.454 0.520 0.457 0.454 0.502 0.457 0.454 0.502
Sensitivity 79% 81% 80% 78% 82% 74% 77% 82% 72%
Specificity 29% 30% 31% 29% 30% 24% 27% 30% 21%
Cutoff Quartile 3 1.04 1.04 1.20 1.04 1.04 1.19 1.04 1.04 1.19
Sensitivity 55% 53% 57% 52% 55% 54% 51% 55% 53%
Specificity 55% 53% 59% 53% 54% 56% 52% 54% 54%
Cutoff Quartile 4 2.88 2.82 2.98 2.88 2.82 2.94 2.88 2.82 2.94
Sensitivity 36% 34% 37% 33% 36% 31% 32% 36% 31%
Specificity 87% 81% 86% 85% 83% 84% 85% 83% 83%
OR Quartile 2 1.49 1.84 1.80 1.50 1.97 0.912 1.23 1.97 0.684
p Value 0.44 0.27 0.33 0.43 0.22 0.88 0.69 0.22 0.54
Lower limit of 95% CI 0.540 0.621 0.547 0.542 0.665 0.277 0.442 0.665 0.201
Upper limit of 95% CI 4.13 5.44 5.92 4.15 5.83 3.00 3.41 5.83 2.33
OR Quartile 3 1.50 1.29 1.85 1.23 1.43 1.51 1.11 1.43 1.32
p Value 0.37 0.58 0.24 0.65 0.44 0.43 0.82 0.44 0.60
Lower limit of 95% CI 0.619 0.524 0.659 0.505 0.582 0.538 0.455 0.582 0.469
Upper limit of 95% CI 3.61 3.17 5.21 2.98 3.51 4.24 2.70 3.51 3.72
OR Quartile 4 3.67 2.21 3.62 2.81 2.71 2.41 2.62 2.71 2.20
p Value 0.025 0.13 0.051 0.074 0.060 0.18 0.095 0.060 0.23
Lower limit of 95% CI 1.18 0.790 0.996 0.905 0.958 0.665 0.846 0.958 0.608
Upper limit of 95% CI 11.4 6.19 13.2 8.70 7.69 8.70 8.14 7.69 7.97
TABLE 7.4
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.629 1.33 0.637 1.26 0.637 1.26
Average 1.31 2.55 1.33 2.50 1.33 2.50
Stdev 1.52 2.33 1.53 2.33 1.53 2.33
p (t-test) 0.0069 0.011 0.011
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 38 41 37 42 37 42
sCr only
Median 0.653 1.20 0.653 1.20 0.653 1.20
Average 1.51 2.46 1.51 2.46 1.51 2.46
Stdev 1.80 2.28 1.80 2.28 1.80 2.28
p (t-test) 0.062 0.062 0.062
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 46 31 46 31 46 31
UO only
Median 0.838 1.68 1.04 1.38 1.04 1.38
Average 1.57 2.64 1.63 2.57 1.63 2.57
Stdev 1.69 2.27 1.71 2.27 1.71 2.27
p (t-test) 0.064 0.11 0.11
Min 0.212 0.121 0.212 0.121 0.212 0.121
Max 6.26 6.66 6.26 6.66 6.26 6.66
n (Patient) 20 32 19 33 19 33
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.67 0.64 0.66 0.65 0.64 0.63 0.65 0.64 0.63
SE 0.060 0.065 0.076 0.061 0.065 0.078 0.061 0.065 0.078
p Value 0.0045 0.034 0.036 0.012 0.034 0.089 0.012 0.034 0.089
nCohort Recovered 38 46 20 37 46 19 37 46 19
nCohort Non-recovered 41 31 32 42 31 33 42 31 33
Cutoff Quartile 2 0.454 0.448 0.525 0.454 0.448 0.525 0.454 0.448 0.525
Sensitivity 83% 81% 81% 81% 81% 79% 81% 81% 79%
Specificity 34% 30% 35% 32% 30% 32% 32% 30% 32%
Cutoff Quartile 3 1.04 1.03 1.19 1.04 1.03 1.19 1.04 1.03 1.19
Sensitivity 56% 55% 59% 55% 55% 58% 55% 55% 58%
Specificity 58% 54% 65% 57% 54% 63% 57% 54% 63%
Cutoff Quartile 4 2.82 2.75 3.17 2.82 2.75 3.17 2.82 2.75 3.17
Sensitivity 37% 39% 28% 36% 39% 27% 36% 39% 27%
Specificity 87% 85% 80% 86% 85% 79% 86% 85% 79%
OR Quartile 2 2.53 1.82 2.33 2.04 1.82 1.71 2.04 1.82 1.71
p Value 0.085 0.28 0.19 0.18 0.28 0.41 0.18 0.28 0.41
Lower limit of 95% CI 0.880 0.613 0.650 0.726 0.613 0.478 0.726 0.613 0.478
Upper limit of 95% CI 7.25 5.42 8.37 5.73 5.42 6.15 5.73 5.42 6.15
OR Quartile 3 1.76 1.45 2.71 1.59 1.45 2.33 1.59 1.45 2.33
p Value 0.22 0.43 0.091 0.31 0.43 0.15 0.31 0.43 0.15
Lower limit of 95% CI 0.720 0.579 0.852 0.652 0.579 0.729 0.652 0.579 0.729
Upper limit of 95% CI 4.29 3.61 8.64 3.87 3.61 7.42 3.87 3.61 7.42
OR Quartile 4 3.81 3.52 1.57 3.56 3.52 1.41 3.56 3.52 1.41
p Value 0.021 0.023 0.51 0.028 0.023 0.62 0.028 0.023 0.62
Lower limit of 95% CI 1.22 1.19 0.410 1.14 1.19 0.367 1.14 1.19 0.367
Upper limit of 95% CI 11.8 10.4 5.97 11.1 10.4 5.39 11.1 10.4 5.39
TABLE 7.5
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts
within 7 days after sample collection and renal status is assessed by serum creatinine
(sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.665 1.68 0.639 1.38 0.639 1.38
Average 1.54 2.54 1.47 2.55 1.47 2.55
Stdev 1.85 2.19 1.76 2.24 1.76 2.24
p (t-test) 0.038 0.022 0.022
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 51 32 48 35 48 35
sCr only
Median 0.911 1.20 0.911 1.20 0.911 1.20
Average 1.74 2.48 1.72 2.47 1.72 2.47
Stdev 1.89 2.36 1.90 2.31 1.90 2.31
p (t-test) 0.20 0.17 0.17
Min 0.194 0.121 0.194 0.121 0.194 0.121
Max 7.86 6.79 7.86 6.79 7.86 6.79
n (Patient) 58 23 56 25 56 25
UO only
Median 0.727 1.19 0.665 1.29 0.653 1.20
Average 1.69 2.23 1.43 2.43 1.44 2.38
Stdev 2.09 2.11 1.68 2.20 1.70 2.19
p (t-test) 0.27 0.029 0.039
Min 0.208 0.121 0.208 0.121 0.208 0.121
Max 8.44 6.66 7.86 6.66 7.86 6.66
n (Patient) 40 39 41 38 40 39
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.66 0.59 0.59 0.67 0.60 0.64 0.67 0.60 0.64
SE 0.063 0.072 0.064 0.061 0.070 0.063 0.061 0.070 0.062
p Value 0.014 0.22 0.16 0.0064 0.15 0.026 0.0064 0.15 0.026
nCohort 51 58 40 48 56 41 48 56 40
Recovered
nCohort 32 23 39 35 25 38 35 25 39
Non-recovered
Cutoff Quartile 2 0.467 0.460 0.493 0.467 0.460 0.493 0.467 0.460 0.493
Sensitivity 81% 74% 79% 83% 76% 82% 83% 76% 82%
Specificity 29% 26% 30% 31% 27% 32% 31% 27% 32%
Cutoff Quartile 3 1.04 1.04 1.04 1.04 1.04 1.04 1.04 1.04 1.04
Sensitivity 62% 57% 54% 60% 56% 58% 60% 56% 56%
Specificity 59% 53% 55% 58% 54% 59% 58% 54% 57%
Cutoff Quartile 4 2.82 2.87 2.82 2.82 2.87 2.82 2.82 2.87 2.82
Sensitivity 38% 30% 31% 37% 32% 34% 37% 32% 33%
Specificity 82% 78% 80% 83% 79% 83% 83% 79% 82%
OR Quartile 2 1.81 0.988 1.66 2.20 1.16 2.06 2.20 1.16 2.20
p Value 0.28 0.98 0.33 0.15 0.79 0.18 0.15 0.79 0.14
Lower limit of 0.618 0.329 0.593 0.753 0.389 0.719 0.753 0.389 0.769
95% CI
Upper limit of 5.28 2.97 4.65 6.41 3.45 5.88 6.41 3.45 6.30
95% CI
OR Quartile 3 2.38 1.49 1.43 2.10 1.47 1.94 2.10 1.47 1.75
p Value 0.061 0.42 0.43 0.10 0.43 0.15 0.10 0.43 0.22
Lower limit of 0.961 0.564 0.588 0.865 0.569 0.793 0.865 0.569 0.718
95% CI
Upper limit of 5.90 3.95 3.46 5.10 3.79 4.75 5.10 3.79 4.27
95% CI
OR Quartile 4 2.80 1.51 1.78 2.95 1.73 2.53 2.95 1.73 2.36
p Value 0.047 0.45 0.27 0.038 0.31 0.085 0.038 0.31 0.11
Lower limit of 1.01 0.513 0.634 1.06 0.601 0.880 1.06 0.601 0.823
95% CI
Upper limit of 7.73 4.47 4.98 8.22 4.96 7.25 8.22 4.96 6.76
95% CI
TABLE 7.6
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 207 268 211 260 216 258
Average 205 284 207 282 207 281
Stdev 82.7 126 84.7 126 87.0 125
p (t-test) 0.0028 0.0050 0.0076
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 360 651 360 651 360 651
n (Patient) 20 62 19 63 18 64
sCr only
Median 239 281 239 276 239 276
Average 240 297 241 294 241 294
Stdev 108 133 110 131 110 131
p (t-test) 0.044 0.057 0.057
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 651 592 651 592 651 592
n (Patient) 46 35 44 37 44 37
UO only
Median 221 258 216 260 249 257
Average 237 286 234 288 239 284
Stdev 106 128 104 129 106 128
p (t-test) 0.10 0.073 0.13
Min 73.7 110 73.7 110 73.7 110
Max 421 651 421 651 421 651
n (Patient) 21 50 22 49 21 51
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.68 0.62 0.60 0.67 0.61 0.62 0.67 0.61 0.59
SE 0.064 0.063 0.071 0.066 0.063 0.070 0.067 0.063 0.072
p Value 0.0044 0.055 0.15 0.0080 0.072 0.098 0.011 0.072 0.20
nCohort Recovered 20 46 21 19 44 22 18 44 21
nCohort Non-recovered 62 35 50 63 37 49 64 37 51
Cutoff Quartile 2 172 171 174 172 171 174 172 171 175
Sensitivity 79% 83% 80% 79% 84% 80% 80% 84% 80%
Specificity 40% 33% 38% 42% 34% 36% 44% 34% 38%
Cutoff Quartile 3 249 249 253 249 249 253 249 249 251
Sensitivity 55% 54% 52% 54% 54% 53% 53% 54% 51%
Specificity 65% 54% 57% 63% 55% 59% 61% 55% 52%
Cutoff Quartile 4 331 331 339 331 331 339 331 331 337
Sensitivity 29% 34% 28% 29% 32% 29% 28% 32% 27%
Specificity 85% 83% 81% 84% 82% 82% 83% 82% 81%
OR Quartile 2 2.51 2.34 2.46 2.80 2.67 2.23 3.14 2.67 2.52
p Value 0.096 0.12 0.12 0.066 0.073 0.16 0.044 0.073 0.11
Lower limit of 95% CI 0.850 0.799 0.803 0.935 0.913 0.733 1.03 0.913 0.824
Upper limit of 95% CI 7.43 6.84 7.55 8.37 7.82 6.78 9.54 7.82 7.73
OR Quartile 3 2.26 1.41 1.44 2.01 1.41 1.63 1.78 1.41 1.14
p Value 0.13 0.44 0.48 0.19 0.44 0.35 0.29 0.44 0.80
Lower limit of 95% CI 0.792 0.585 0.517 0.699 0.587 0.590 0.613 0.587 0.414
Upper limit of 95% CI 6.42 3.42 4.03 5.78 3.40 4.52 5.18 3.40 3.16
OR Quartile 4 2.32 2.48 1.65 2.13 2.16 1.80 1.96 2.16 1.61
p Value 0.22 0.085 0.43 0.27 0.14 0.36 0.33 0.14 0.46
Lower limit of 95% CI 0.604 0.882 0.473 0.554 0.771 0.517 0.505 0.771 0.460
Upper limit of 95% CI 8.89 6.97 5.78 8.22 6.05 6.27 7.58 6.05 5.62
TABLE 7.7
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 216 277 221 260 235 258
Average 217 294 221 288 221 287
Stdev 84.9 127 88.3 126 90.2 126
p (t-test) 0.0023 0.0095 0.014
Min 73.7 110 73.7 110 73.7 110
Max 360 651 360 651 360 651
n (Patient) 26 54 23 57 22 58
sCr only
Median 239 281 243 279 239 281
Average 245 302 247 299 245 299
Stdev 115 122 116 122 117 120
p (t-test) 0.042 0.061 0.053
Min 73.7 123 73.7 123 73.7 123
Max 651 592 651 592 651 592
n (Patient) 46 33 45 34 44 35
UO only
Median 243 258 237 257 253 249
Average 241 291 242 288 247 284
Stdev 99.6 133 100 133 101 131
p (t-test) 0.088 0.12 0.21
Min 73.7 110 73.7 110 73.7 110
Max 421 651 421 651 421 651
n (Patient) 25 44 24 45 23 47
Recovery Period 24 48 72
Duration (hr) sCr or sCr or sCr or
UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.67 0.64 0.59 0.65 0.62 0.58 0.64 0.63 0.56
SE 0.061 0.064 0.070 0.065 0.064 0.071 0.066 0.064 0.072
p Value 0.0047 0.032 0.19 0.025 0.052 0.25 0.035 0.039 0.43
nCohort 26 46 25 23 45 24 22 44 23
Recovered
nCohort Non- 54 33 44 57 34 45 58 35 47
recovered
Cutoff Quartile 2 176 175 177 176 175 177 176 175 178
Sensitivity 81% 85% 80% 81% 85% 78% 81% 86% 79%
Specificity 38% 33% 36% 39% 33% 33% 41% 34% 35%
Cutoff Quartile 3 251 249 253 251 249 253 251 249 251
Sensitivity 56% 55% 52% 53% 53% 51% 52% 54% 49%
Specificity 62% 54% 56% 57% 53% 54% 55% 55% 48%
Cutoff Quartile 4 332 333 335 332 333 335 332 333 334
Sensitivity 31% 33% 30% 30% 32% 29% 29% 31% 28%
Specificity 88% 80% 84% 87% 80% 83% 86% 80% 78%
OR Quartile 2 2.75 2.71 2.19 2.69 2.90 1.75 2.96 3.10 1.97
p Value 0.058 0.085 0.16 0.069 0.066 0.32 0.048 0.050 0.23
Lower limit of 0.965 0.872 0.730 0.927 0.933 0.581 1.01 0.999 0.653
95% CI
Upper limit of 7.83 8.42 6.55 7.80 9.01 5.27 8.66 9.64 5.97
95% CI
OR Quartile 3 2.00 1.43 1.39 1.44 1.29 1.24 1.29 1.42 0.878
p Value 0.15 0.44 0.51 0.46 0.58 0.68 0.62 0.44 0.80
Lower limit of 0.769 0.582 0.520 0.545 0.527 0.458 0.480 0.584 0.324
95% CI
Upper limit of 5.20 3.51 3.74 3.83 3.14 3.34 3.44 3.47 2.38
95% CI
OR Quartile 4 3.52 2.06 2.20 2.83 1.91 2.03 2.63 1.78 1.38
p Value 0.064 0.17 0.22 0.13 0.21 0.27 0.16 0.27 0.60
Lower limit of 0.929 0.736 0.631 0.742 0.687 0.581 0.686 0.641 0.423
95% CI
Upper limit of 13.4 5.74 7.69 10.8 5.33 7.11 10.1 4.96 4.48
95% CI
TABLE 7.8
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 242 257 251 249 253 248
Average 243 293 244 288 248 285
Stdev 99.5 136 100 133 100 134
p (t-test) 0.072 0.11 0.18
Min 73.7 114 73.7 114 73.7 114
Max 446 651 446 651 446 651
n (Patient) 36 41 32 45 31 46
sCr only
Median 246 263 243 276 243 276
Average 251 297 250 297 250 297
Stdev 117 127 118 125 118 125
p (t-test) 0.12 0.11 0.11
Min 73.7 123 73.7 123 73.7 123
Max 651 592 651 592 651 592
n (Patient) 46 30 45 31 45 31
UO only
Median 281 246 288 231 295 227
Average 266 293 275 283 281 279
Stdev 90.7 146 87.4 141 85.0 141
p (t-test) 0.41 0.79 0.96
Min 73.7 114 73.7 114 73.7 114
Max 429 651 429 651 429 651
n (Patient) 27 30 23 35 22 36
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.59 0.60 0.49 0.57 0.61 0.43 0.55 0.61 0.40
SE 0.065 0.067 0.077 0.066 0.067 0.077 0.067 0.067 0.076
p Value 0.18 0.13 0.92 0.29 0.11 0.39 0.44 0.11 0.20
nCohort Recovered 36 46 27 32 45 23 31 45 22
nCohort Non-recovered 41 30 30 45 31 35 46 31 36
Cutoff Quartile 2 174 173 185 174 173 187 174 173 187
Sensitivity 80% 87% 70% 80% 87% 69% 78% 87% 67%
Specificity 33% 33% 22% 34% 33% 17% 32% 33% 14%
Cutoff Quartile 3 249 249 257 249 249 255 249 249 255
Sensitivity 51% 53% 43% 49% 55% 43% 48% 55% 42%
Specificity 53% 52% 44% 50% 53% 39% 48% 53% 36%
Cutoff Quartile 4 335 334 335 335 334 334 335 334 334
Sensitivity 27% 30% 27% 27% 29% 26% 26% 29% 25%
Specificity 78% 78% 78% 78% 78% 74% 77% 78% 73%
OR Quartile 2 2.06 3.15 0.667 2.10 3.38 0.459 1.71 3.38 0.316
p Value 0.17 0.066 0.51 0.16 0.051 0.24 0.30 0.051 0.11
Lower limit of 95% CI 0.731 0.929 0.201 0.746 0.997 0.126 0.613 0.997 0.0778
Upper limit of 95% CI 5.82 10.7 2.21 5.88 11.4 1.67 4.79 11.4 1.28
OR Quartile 3 1.17 1.25 0.612 0.957 1.39 0.482 0.859 1.39 0.408
p Value 0.73 0.64 0.36 0.92 0.48 0.18 0.74 0.48 0.11
Lower limit of 95% CI 0.479 0.496 0.215 0.386 0.554 0.165 0.345 0.554 0.137
Upper limit of 95% CI 2.88 3.13 1.74 2.37 3.48 1.41 2.14 3.48 1.22
OR Quartile 4 1.28 1.54 1.27 1.30 1.43 0.981 1.21 1.43 0.889
p Value 0.64 0.42 0.70 0.63 0.50 0.97 0.73 0.50 0.85
Lower limit of 95% CI 0.451 0.540 0.377 0.447 0.503 0.295 0.416 0.503 0.267
Upper limit of 95% CI 3.65 4.41 4.29 3.78 4.08 3.26 3.52 4.08 2.96
TABLE 7.9
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 239 267 243 257 243 257
Average 235 300 237 296 237 296
Stdev 95.7 135 95.9 135 95.9 135
p (t-test) 0.020 0.034 0.034
Min 73.7 123 73.7 123 73.7 123
Max 421 651 421 651 421 651
n (Patient) 36 38 35 39 35 39
sCr only
Median 246 249 246 249 246 249
Average 249 293 249 293 249 293
Stdev 115 127 115 127 115 127
p (t-test) 0.15 0.15 0.15
Min 73.7 123 73.7 123 73.7 123
Max 651 592 651 592 651 592
n (Patient) 44 29 44 29 44 29
UO only
Median 273 253 281 249 281 249
Average 262 302 269 297 269 297
Stdev 85.6 143 83.3 143 83.3 143
p (t-test) 0.24 0.39 0.39
Min 73.7 149 73.7 148 73.7 148
Max 395 651 395 651 395 651
n (Patient) 18 30 17 31 17 31
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.63 0.59 0.52 0.61 0.59 0.48 0.61 0.59 0.48
SE 0.065 0.069 0.087 0.065 0.069 0.088 0.065 0.069 0.088
p Value 0.048 0.17 0.80 0.096 0.17 0.84 0.096 0.17 0.84
nCohort Recovered 36 44 18 35 44 17 35 44 17
nCohort Non-recovered 38 29 30 39 29 31 39 29 31
Cutoff Quartile 2 175 174 201 175 174 201 175 174 201
Sensitivity 84% 83% 73% 82% 83% 71% 82% 83% 71%
Specificity 36% 32% 22% 34% 32% 18% 34% 32% 18%
Cutoff Quartile 3 249 249 261 249 249 261 249 249 261
Sensitivity 55% 52% 47% 54% 52% 45% 54% 52% 45%
Specificity 56% 52% 44% 54% 52% 41% 54% 52% 41%
Cutoff Quartile 4 331 329 345 331 329 345 331 329 345
Sensitivity 29% 28% 30% 28% 28% 29% 28% 28% 29%
Specificity 78% 77% 83% 77% 77% 82% 77% 77% 82%
OR Quartile 2 3.01 2.24 0.786 2.39 2.24 0.524 2.39 2.24 0.524
p Value 0.050 0.17 0.73 0.11 0.17 0.39 0.11 0.17 0.39
Lower limit of 95% CI 0.998 0.707 0.199 0.814 0.707 0.121 0.814 0.707 0.121
Upper limit of 95% CI 9.11 7.10 3.11 6.99 7.10 2.27 6.99 7.10 2.27
OR Quartile 3 1.54 1.17 0.700 1.39 1.17 0.576 1.39 1.17 0.576
p Value 0.35 0.74 0.55 0.49 0.74 0.37 0.49 0.74 0.37
Lower limit of 95% CI 0.617 0.459 0.216 0.554 0.459 0.174 0.554 0.459 0.174
Upper limit of 95% CI 3.86 3.00 2.26 3.46 3.00 1.91 3.46 3.00 1.91
OR Quartile 4 1.43 1.30 2.14 1.33 1.30 1.91 1.33 1.30 1.91
p Value 0.51 0.64 0.31 0.60 0.64 0.39 0.60 0.64 0.39
Lower limit of 95% CI 0.497 0.441 0.495 0.463 0.441 0.440 0.463 0.441 0.440
Upper limit of 95% CI 4.09 3.80 9.27 3.80 3.80 8.29 3.80 3.80 8.29
TABLE 7.10
Comparison of marker levels and the area under the ROC curve
(AUC) in EDTA samples for the “recovered” and “non-recovered” cohorts where
recovery starts within 7 days after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE
criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 247 255 246 255 246 255
Average 249 296 249 294 249 294
Stdev 108 144 110 140 110 140
p (t-test) 0.14 0.14 0.14
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 592 651 592 651 592 651
n (Patient) 54 30 52 32 52 32
sCr only
Median 255 221 256 224 256 224
Average 263 271 263 270 263 270
Stdev 120 129 121 127 121 127
p (t-test) 0.81 0.84 0.84
Min 73.7 89.8 73.7 89.8 73.7 89.8
Max 651 590 651 590 651 590
n (Patient) 59 22 58 23 58 23
UO only
Median 248 249 248 249 249 249
Average 253 290 247 293 248 291
Stdev 107 145 94.9 147 95.4 146
p (t-test) 0.21 0.11 0.14
Min 73.7 105 73.7 105 73.7 105
Max 559 651 429 651 429 651
n (Patient) 40 38 42 36 41 37
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.58 0.50 0.55 0.58 0.50 0.56 0.58 0.50 0.56
SE 0.066 0.073 0.065 0.065 0.072 0.066 0.065 0.072 0.065
p Value 0.25 0.96 0.43 0.24 0.97 0.33 0.24 0.97 0.38
nCohort Recovered 54 59 40 52 58 42 52 58 41
nCohort Non-recovered 30 22 38 32 23 36 32 23 37
Cutoff Quartile 2 169 171 172 169 171 172 169 171 172
Sensitivity 80% 77% 79% 81% 78% 78% 81% 78% 78%
Specificity 28% 27% 30% 29% 28% 29% 29% 28% 29%
Cutoff Quartile 3 249 249 249 249 249 249 249 249 249
Sensitivity 53% 41% 50% 53% 39% 50% 53% 39% 51%
Specificity 52% 47% 50% 52% 47% 50% 52% 47% 51%
Cutoff Quartile 4 332 331 334 332 331 334 332 331 334
Sensitivity 30% 27% 29% 28% 26% 31% 28% 26% 30%
Specificity 78% 76% 78% 77% 76% 79% 77% 76% 78%
OR Quartile 2 1.54 1.27 1.61 1.76 1.37 1.40 1.76 1.37 1.50
p Value 0.43 0.69 0.37 0.30 0.59 0.52 0.30 0.59 0.44
Lower limit of 95% CI 0.525 0.400 0.572 0.602 0.436 0.499 0.602 0.436 0.534
Upper limit of 95% CI 4.51 4.00 4.51 5.13 4.31 3.93 5.13 4.31 4.21
OR Quartile 3 1.23 0.625 1.00 1.22 0.560 1.00 1.22 0.560 1.11
p Value 0.65 0.35 1.0 0.65 0.25 1.0 0.65 0.25 0.82
Lower limit of 95% CI 0.503 0.232 0.411 0.507 0.209 0.411 0.507 0.209 0.456
Upper limit of 95% CI 3.01 1.69 2.43 2.96 1.50 2.44 2.96 1.50 2.70
OR Quartile 4 1.50 1.21 1.40 1.30 1.11 1.61 1.30 1.11 1.50
p Value 0.43 0.74 0.52 0.60 0.85 0.36 0.60 0.85 0.43
Lower limit of 95% CI 0.546 0.396 0.506 0.477 0.366 0.580 0.477 0.366 0.542
Upper limit of 95% CI 4.12 3.67 3.90 3.56 3.36 4.49 3.56 3.36 4.18
Example 8. Use of C-C Motif Chemokine 16 for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. C-C motif chemokine 16 is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is risk of injury (R), injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 8.1
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.00821 0.0173 0.0120 0.0157 0.0120 0.0157
Average 0.0135 0.0735 0.0153 0.0717 0.0167 0.0702
Stdev 0.0140 0.346 0.0158 0.342 0.0171 0.338
p (t-test) 0.15 0.17 0.18
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 7.74E−6 4.13E−6
Max 0.0427 2.98 0.0427 2.98 0.0427 2.98
n (Patient) 8 73 6 75 4 77
sCr only
Median 0.00821 0.0225 0.00715 0.0208 0.0122 0.0182
Average 0.0157 0.0981 0.0162 0.0947 0.0173 0.0913
Stdev 0.0223 0.412 0.0230 0.404 0.0236 0.397
p (t-test) 0.16 0.17 0.18
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 30 51 28 53 26 55
UO only
Median 0.0213 0.0181 0.0231 0.0177 0.0213 0.0177
Average 0.0368 0.0809 0.0405 0.0797 0.0422 0.0776
Stdev 0.0475 0.378 0.0483 0.375 0.0506 0.369
p (t-test) 0.39 0.44 0.48
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 11 61 10 62 9 64
24 48 72
Recovery Period sCr or sCr UO sCr or sCr UO sCr or sCr UO
Duration (hr) UO only only UO only only UO only only
AUC 0.61 0.68 0.49 0.59 0.67 0.45 0.56 0.64 0.44
SE 0.098 0.060 0.095 0.11 0.061 0.096 0.14 0.064 0.100
p Value 0.26 0.0033 0.94 0.41 0.0067 0.57 0.70 0.030 0.57
nCohort Recovered 8 30 11 6 28 10 4 26 9
nCohort Non- 73 51 61 75 53 62 77 55 64
recovered
Cutoff Quartile 2 0.00202 0.00202 0.00161 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 71% 78% 74% 72% 79% 71% 71% 78% 70%
Specificity 25% 40% 18% 33% 43% 10% 25% 42% 11%
Cutoff Quartile 3 0.0157 0.0157 0.0193 0.0157 0.0157 0.0193 0.0157 0.0157 0.0181
Sensitivity 51% 59% 49% 49% 57% 48% 49% 55% 48%
Specificity 62% 67% 45% 50% 64% 40% 50% 62% 44%
Cutoff Quartile 4 0.0427 0.0427 0.0464 0.0427 0.0427 0.0464 0.0427 0.0427 0.0460
Sensitivity 27% 35% 26% 27% 34% 26% 26% 33% 25%
Specificity 100% 93% 82% 100% 93% 80% 100% 92% 78%
OR Quartile 2 0.825 2.42 0.625 1.29 2.86 0.272 0.833 2.63 0.296
p Value 0.82 0.079 0.57 0.78 0.039 0.23 0.88 0.060 0.27
Lower limit of 0.154 0.901 0.122 0.219 1.05 0.0320 0.0822 0.960 0.0346
95% CI
Upper limit of 4.42 6.52 3.21 7.55 7.79 2.30 8.45 7.20 2.53
95% CI
OR Quartile 3 1.71 2.86 0.806 0.974 2.35 0.625 0.974 1.92 0.752
p Value 0.48 0.029 0.74 0.97 0.077 0.50 0.98 0.18 0.69
Lower limit of 0.381 1.11 0.222 0.185 0.913 0.160 0.131 0.741 0.185
95% CI
Upper limit of 7.70 7.33 2.93 5.14 6.04 2.43 7.27 4.97 3.06
95% CI
OR Quartile 4 6.51 7.64 1.60 4.80 6.69 1.39 3.21 5.84 1.17
p Value 0.20 0.0099 0.57 0.29 0.016 0.69 0.44 0.026 0.86
Lower limit of 0.359 1.63 0.312 0.259 1.42 0.267 0.165 1.24 0.220
95% CI
Upper limit of 118 35.8 8.21 89.1 31.4 7.25 62.2 27.5 6.20
95% CI
TABLE 8.2
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0151 0.0173 0.0209 0.0155 0.0206 0.0157
Average 0.0159 0.0768 0.0207 0.0737 0.0201 0.0730
Stdev 0.0128 0.356 0.0115 0.349 0.0122 0.347
p (t-test) 0.16 0.21 0.20
Min 6.68E−6 4.13E−6 0.00279 4.13E−6 0.00279 4.13E−6
Max 0.0427 2.98 0.0427 2.98 0.0427 2.98
n (Patient) 11 69 8 72 7 73
sCr only
Median 0.00908 0.0225 0.0122 0.0195 0.0122 0.0195
Average 0.0159 0.102
Stdev 0.0222 0.420 0.0231 0.408 0.0231 0.408
p (t-test) 0.16 0.17 0.17
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 31 49 28 52 28 52
UO only
Median 0.0209 0.0190 0.0213 0.0173 0.0209 0.0173
Average 0.0366 0.0881 0.0395 0.0866 0.0407 0.0840
Stdev 0.0417 0.401 0.0419 0.398 0.0434 0.391
p (t-test) 0.36 0.40 0.42
Min 6.68E−6 4.13E−6 0.00856 4.13E−6 0.00856 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 14 54 13 55 12 57
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.58 0.69 0.44 0.47 0.65 0.40 0.48 0.65 0.39
SE 0.090 0.059 0.084 0.11 0.062 0.084 0.11 0.062 0.085
p Value 0.40 0.0016 0.49 0.76 0.013 0.23 0.85 0.013 0.20
nCohort 11 31 14 8 28 13 7 28 12
Recovered
nCohort Non- 69 49 54 72 52 55 73 52 57
recovered
Cutoff Quartile 2 0.00202 0.00202 0.00161 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 71% 82% 70% 69% 81% 67% 70% 81% 67%
Specificity 18% 42% 7% 0% 43% 0% 0% 43% 0%
Cutoff Quartile 3 0.0165 0.0165 0.0207 0.0165 0.0165 0.0207 0.0165 0.0165 0.0206
Sensitivity 51% 59% 50% 49% 56% 49% 49% 56% 49%
Specificity 55% 65% 50% 38% 61% 46% 43% 61% 50%
Cutoff Quartile 4 0.0435 0.0435 0.0464 0.0435 0.0435 0.0464 0.0435 0.0435 0.0460
Sensitivity 29% 37% 26% 28% 35% 25% 27% 35% 25%
Specificity 100% 94% 79% 100% 93% 77% 100% 93% 75%
OR Quartile 2 0.544 3.21 0.183 0.132 3.15 0.0751 0.153 3.15 0.0790
p Value 0.46 0.024 0.12 0.17 0.027 0.078 0.20 0.027 0.084
Lower limit of 0.108 1.16 0.0220 0.00730 1.14 0.00423 0.00835 1.14 0.00444
95% CI
Upper limit of 2.75 8.86 1.52 2.39 8.72 1.33 2.79 8.72 1.41
95% CI
OR Quartile 3 1.24 2.64 1.00 0.568 1.95 0.827 0.730 1.95 0.966
p Value 0.75 0.041 1.0 0.46 0.16 0.76 0.69 0.16 0.96
Lower limit of 0.344 1.04 0.309 0.126 0.765 0.246 0.152 0.765 0.278
95% CI
Upper limit of 4.43 6.69 3.24 2.55 4.96 2.78 3.49 4.96 3.35
95% CI
OR Quartile 4 9.53 8.42 1.28 6.64 6.88 1.14 5.75 6.88 0.977
p Value 0.12 0.0069 0.73 0.20 0.015 0.86 0.24 0.015 0.97
Lower limit of 0.536 1.79 0.312 0.366 1.46 0.274 0.314 1.46 0.232
95% CI
Upper limit of 169 39.5 5.28 120 32.3 4.74 105 32.3 4.12
95% CI
TABLE 8.3
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Recovery Non- Non- Non-
Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0157 0.0173 0.0157 0.0173 0.0157 0.0173
Average 0.0210 0.0875 0.0218 0.0850 0.0218 0.0850
Stdev 0.0231 0.391 0.0237 0.384 0.0237 0.384
p (t-test) 0.21 0.22 0.22
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 23 57 21 59 21 59
sCr only
Median 0.0146 0.0208 0.0142 0.0217 0.0142 0.0217
Average 0.0183 0.106 0.0174 0.105 0.0174 0.105
Stdev 0.0227 0.438 0.0224 0.433 0.0224 0.433
p (t-test) 0.19 0.18 0.18
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 34 45 33 46 33 46
UO only
Median 0.0227 0.0208 0.0227 0.0190 0.0227 0.0190
Average 0.0348 0.116 0.0368 0.108 0.0368 0.108
Stdev 0.0385 0.481 0.0397 0.464 0.0397 0.464
p (t-test) 0.32 0.34 0.34
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 22 37 20 40 20 40
Recovery 24 48 72
Period sCr or sCr UO sCr or sCr UO sCr or sCr UO
Duration (hr) UO only only UO only only UO only only
AUC 0.54 0.63 0.46 0.52 0.65 0.43 0.52 0.65 0.43
SE 0.071 0.062 0.078 0.073 0.062 0.078 0.073 0.062 0.078
p Value 0.58 0.032 0.60 0.77 0.016 0.38 0.77 0.016 0.38
nCohort 23 34 22 21 33 20 21 33 20
Recovered
nCohort Non- 57 45 37 59 46 40 59 46 40
recovered
Cutoff Quar- 0.00202 0.00202 0.00393 0.00202 0.00202 0.00260 0.00202 0.00202 0.00260
tile 2
Sensitivity 70% 80% 65% 69% 80% 68% 69% 80% 68%
Specificity 22% 38% 9% 19% 39% 10% 19% 39% 10%
Cutoff Quar- 0.0165 0.0157 0.0208 0.0165 0.0157 0.0207 0.0165 0.0157 0.0207
tile 3
Sensitivity 51% 56% 49% 51% 57% 50% 51% 57% 50%
Specificity 52% 59% 50% 52% 61% 50% 52% 61% 50%
Cutoff Quar- 0.0435 0.0427 0.0467 0.0435 0.0427 0.0464 0.0435 0.0427 0.0464
tile 4
Sensitivity 32% 33% 27% 31% 35% 25% 31% 35% 25%
Specificity 91% 88% 77% 90% 91% 75% 90% 91% 75%
OR Quartile 2 0.654 2.48 0.185 0.536 2.67 0.231 0.536 2.67 0.231
p Value 0.47 0.077 0.039 0.32 0.056 0.073 0.32 0.056 0.073
Lower limit 0.209 0.906 0.0372 0.158 0.974 0.0464 0.158 0.974 0.0464
of 95% CI
Upper limit 2.05 6.77 0.917 1.82 7.33 1.15 1.82 7.33 1.15
of 95% CI
OR Quartile 3 1.13 1.79 0.947 1.14 2.00 1.00 1.14 2.00 1.00
p Value 0.80 0.21 0.92 0.80 0.14 1.0 0.80 0.14 1.0
Lower limit 0.429 0.725 0.330 0.420 0.805 0.342 0.420 0.805 0.342
of 95% CI
Upper limit 2.98 4.40 2.72 3.08 4.97 2.93 3.08 4.97 2.93
of 95% CI
OR Quartile 4 4.85 3.75 1.26 4.17 5.33 1.00 4.17 5.33 1.00
p Value 0.047 0.033 0.71 0.073 0.014 1.0 0.073 0.014 1.0
Lower limit 1.02 1.11 0.367 0.877 1.41 0.289 0.877 1.41 0.289
of 95% CI
Upper limit 22.9 12.6 4.32 19.8 20.2 3.45 19.8 20.2 3.45
of 95% CI
TABLE 8.4
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0152 0.0182 0.0153 0.0177 0.0153 0.0177
Average 0.0216 0.0915 0.0225 0.0898 0.0225 0.0898
Stdev 0.0287 0.405 0.0290 0.401 0.0290 0.401
p (t-test) 0.22 0.23 0.23
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.113 2.98 0.113 2.98 0.113 2.98
n (Patient) 26 53 25 54 25 54
sCr only
Median 0.0151 0.0177 0.0146 0.0182 0.0152 0.0173
Average 0.0191 0.108 0.0179 0.107 0.0190 0.102
Stdev 0.0229 0.453 0.0220 0.448 0.0222 0.438
p (t-test) 0.22 0.20 0.21
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 35 42 34 43 32 45
UO only
Median 0.0293 0.0225 0.0296 0.0217 0.0296 0.0217
Average 0.0427 0.122 0.0453 0.118 0.0453 0.118
Stdev 0.0434 0.494 0.0434 0.488 0.0434 0.488
p (t-test) 0.36 0.39 0.39
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 17 35 16 36 16 36
24 48 72
Recovery Period sCr or sCr UO sCr or sCr UO sCr or sCr UO
Duration (hr) UO only only UO only only UO only only
AUC 0.58 0.60 0.45 0.56 0.62 0.41 0.56 0.58 0.41
SE 0.067 0.064 0.085 0.069 0.064 0.084 0.069 0.066 0.084
p Value 0.21 0.11 0.55 0.37 0.056 0.29 0.37 0.23 0.29
nCohort 26 35 17 25 34 16 25 32 16
Recovered
nCohort Non- 53 42 35 54 43 36 54 45 36
recovered
Cutoff Quartile 2 0.00202 0.00202 0.00449 0.00202 0.00202 0.00449 0.00202 0.00202 0.00449
Sensitivity 74% 79% 71% 72% 79% 69% 72% 76% 69%
Specificity 31% 37% 18% 28% 38% 12% 28% 34% 12%
Cutoff Quartile 3 0.0157 0.0153 0.0237 0.0157 0.0153 0.0237 0.0157 0.0153 0.0237
Sensitivity 53% 52% 49% 52% 53% 47% 52% 51% 47%
Specificity 58% 54% 47% 56% 56% 44% 56% 53% 44%
Cutoff Quartile 4 0.0427 0.0411 0.0494 0.0427 0.0411 0.0494 0.0427 0.0411 0.0494
Sensitivity 30% 31% 23% 30% 33% 22% 30% 31% 22%
Specificity 88% 83% 71% 88% 85% 69% 88% 84% 69%
OR Quartile 2 1.24 2.17 0.536 1.01 2.34 0.325 1.01 1.62 0.325
p Value 0.69 0.13 0.40 0.98 0.099 0.18 0.98 0.34 0.18
Lower limit of 0.441 0.792 0.126 0.351 0.853 0.0628 0.351 0.597 0.0628
95% CI
Upper limit of 3.48 5.93 2.28 2.91 6.42 1.68 2.91 4.39 1.68
95% CI
OR Quartile 3 1.53 1.31 0.840 1.37 1.46 0.696 1.37 1.18 0.696
p Value 0.38 0.56 0.77 0.52 0.41 0.55 0.52 0.71 0.55
Lower limit of 0.593 0.531 0.263 0.528 0.590 0.213 0.528 0.478 0.213
95% CI
Upper limit of 3.94 3.21 2.68 3.56 3.60 2.28 3.56 2.94 2.28
95% CI
OR Quartile 4 3.32 2.17 0.711 3.09 2.80 0.629 3.09 2.44 0.629
p Value 0.079 0.17 0.61 0.099 0.078 0.49 0.099 0.13 0.49
Lower limit of 0.869 0.724 0.192 0.808 0.892 0.168 0.808 0.777 0.168
95% CI
Upper limit of 12.6 6.48 2.63 11.8 8.79 2.35 11.8 7.66 2.35
95% CI
TABLE 8.5
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts
within 7 days after sample collection and renal status is assessed by serum creatinine
(sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Recovery Non- Non- Non-
Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0151 0.0177 0.0153 0.0171 0.0153 0.0171
Average 0.0265 0.105 0.0250 0.0996 0.0254 0.0961
Stdev 0.0352 0.453 0.0302 0.434 0.0309 0.425
p (t-test) 0.27 0.26 0.26
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.113 2.98 0.113 2.98
n (Patient) 41 42 37 46 35 48
sCr only
Median 0.0152 0.0182 0.0152 0.0182 0.0155 0.0173
Average 0.0268 0.127 0.0245 0.124 0.0254 0.113
Stdev 0.0341 0.509 0.0294 0.494 0.0301 0.469
p (t-test) 0.27 0.25 0.26
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.113 2.98 0.113 2.98
n (Patient) 48 33 46 35 42 39
UO only
Median 0.0206 0.0150 0.0181 0.0150 0.0169 0.0151
Average 0.0322 0.0925 0.0297 0.0933 0.0299 0.0919
Stdev 0.0413 0.425 0.0365 0.425 0.0371 0.421
p (t-test) 0.34 0.31 0.31
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.191 2.98 0.151 2.98 0.151 2.98
n (Patient) 31 48 31 48 30 49
Recovery 24 48 72
Period sCr or sCr UO sCr or sCr UO sCr or sCr UO
Duration (hr) UO only only UO only only UO only only
AUC 0.57 0.57 0.47 0.55 0.58 0.49 0.55 0.56 0.50
SE 0.063 0.066 0.067 0.063 0.065 0.067 0.064 0.064 0.067
p Value 0.27 0.31 0.67 0.39 0.21 0.88 0.39 0.37 0.94
nCohort 41 48 31 37 46 31 35 42 30
Recovered
nCohort Non- 42 33 48 46 35 48 48 39 49
recovered
Cutoff Quar- 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
tile 2
Sensitivity 76% 79% 69% 76% 80% 69% 77% 79% 69%
Specificity 32% 33% 23% 32% 35% 23% 34% 36% 23%
Cutoff Quar- 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157
tile 3
Sensitivity 55% 55% 46% 52% 54% 48% 52% 51% 49%
Specificity 56% 54% 45% 54% 54% 48% 54% 52% 50%
Cutoff Quar- 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427
tile 4
Sensitivity 26% 27% 23% 26% 29% 25% 25% 28% 24%
Specificity 78% 77% 74% 78% 78% 77% 77% 79% 77%
OR Quar- 1.49 1.86 0.642 1.53 2.13 0.642 1.75 2.15 0.690
tile 2
p Value 0.42 0.24 0.40 0.39 0.15 0.40 0.26 0.13 0.48
Lower limit 0.564 0.664 0.227 0.581 0.764 0.227 0.666 0.791 0.243
of 95% CI
Upper limit 3.91 5.19 1.82 4.01 5.96 1.82 4.63 5.86 1.95
of 95% CI
OR Quar- 1.55 1.42 0.697 1.28 1.41 0.862 1.29 1.16 0.960
tile 3
p Value 0.32 0.44 0.44 0.57 0.44 0.75 0.57 0.74 0.93
Lower limit 0.651 0.582 0.281 0.539 0.585 0.349 0.539 0.484 0.387
of 95% CI
Upper limit 3.68 3.45 1.73 3.06 3.42 2.13 3.09 2.77 2.38
of 95% CI
OR Quar- 1.26 1.26 0.855 1.28 1.44 1.14 1.12 1.44 1.07
tile 4
p Value 0.65 0.66 0.77 0.64 0.48 0.81 0.82 0.48 0.91
Lower limit 0.460 0.455 0.299 0.460 0.522 0.394 0.404 0.522 0.366
of 95% CI
Upper limit 3.46 3.50 2.44 3.56 3.97 3.32 3.13 3.97 3.10
of 95% CI
TABLE 8.6
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 8.48 9.96 8.41 10.0 8.48 9.96
Average 8.83 12.4 6.73 12.4 8.01 12.3
Stdev 4.38 8.96 2.95 8.82 1.64 8.85
p (t-test) 0.090 0.012 0.0088
Min 1.62 1.32 1.62 1.32 5.31 1.32
Max 15.9 38.9 9.75 38.9 9.75 38.9
n (Patient) 8 74 5 77 4 78
sCr only
Median 7.90 10.6 7.72 10.9 7.90 10.6
Average 9.48 13.8 9.08 13.8 9.33 13.5
Stdev 5.27 9.94 5.22 9.75 5.29 9.70
p (t-test) 0.014 0.0061 0.015
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 22.8 38.9 22.8 38.9 22.8 38.9
n (Patient) 31 50 29 52 27 54
UO only
Median 8.48 9.53 8.56 9.28 10.8 8.94
Average 12.3 11.8 12.9 11.8 14.3 11.6
Stdev 8.63 8.65 8.87 8.62 8.41 8.59
p (t-test) 0.88 0.75 0.43
Min 1.62 1.32 1.62 1.32 5.31 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 10 61 9 62 8 64
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.58 0.62 0.48 0.69 0.64 0.46 0.61 0.62 0.38
SE 0.10 0.063 0.098 0.11 0.062 0.10 0.13 0.064 0.098
p Value 0.40 0.065 0.83 0.074 0.020 0.66 0.40 0.057 0.22
nCohort Recovered 8 31 10 5 29 9 4 27 8
nCohort Non-recovered 74 50 61 77 52 62 78 54 64
Cutoff Quartile 2 6.18 6.19 6.19 6.18 6.19 6.19 6.18 6.19 6.19
Sensitivity 74% 78% 74% 75% 79% 74% 74% 78% 73%
Specificity 25% 32% 20% 40% 34% 22% 25% 33% 12%
Cutoff Quartile 3 9.66 9.75 9.00 9.66 9.75 9.00 9.66 9.75 8.94
Sensitivity 51% 58% 51% 52% 60% 50% 51% 57% 50%
Specificity 62% 65% 60% 80% 69% 56% 75% 67% 50%
Cutoff Quartile 4 15.6 15.9 14.3 15.6 15.9 14.6 15.6 15.9 14.6
Sensitivity 27% 32% 25% 27% 31% 24% 27% 30% 23%
Specificity 88% 87% 70% 100% 86% 67% 100% 85% 62%
OR Quartile 2 0.965 1.69 0.703 2.04 1.96 0.821 0.967 1.75 0.395
p Value 0.97 0.31 0.68 0.45 0.19 0.82 0.98 0.28 0.40
Lower limit of 95% CI 0.179 0.617 0.135 0.316 0.711 0.154 0.0950 0.628 0.0452
Upper limit of 95% CI 5.19 4.62 3.67 13.1 5.41 4.37 9.83 4.88 3.45
OR Quartile 3 1.76 2.51 1.55 4.32 3.28 1.25 3.16 2.70 1.00
p Value 0.46 0.051 0.53 0.20 0.016 0.76 0.33 0.044 1.0
Lower limit of 95% CI 0.392 0.995 0.397 0.462 1.25 0.306 0.315 1.03 0.230
Upper limit of 95% CI 7.90 6.34 6.05 40.5 8.59 5.10 31.7 7.08 4.35
OR Quartile 4 2.59 3.18 0.761 4.19 2.78 0.638 3.37 2.42 0.510
p Value 0.39 0.060 0.72 0.34 0.098 0.56 0.42 0.15 0.39
Lower limit of 95% CI 0.300 0.950 0.174 0.222 0.829 0.142 0.174 0.721 0.109
Upper limit of 95% CI 22.4 10.6 3.32 79.0 9.30 2.87 65.2 8.13 2.39
TABLE 8.7
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 6.35 10.2 5.75 10.2 7.30 9.96
Average 9.04 12.5 8.67 12.5 10.7 12.2
Stdev 7.82 8.84 8.47 8.74 8.89 8.77
p (t-test) 0.24 0.29 0.72
Min 1.62 1.32 1.62 1.32 5.31 1.32
Max 30.3 38.9 30.3 38.9 30.3 38.9
n (Patient) 10 70 8 72 6 74
sCr only
Median 7.72 10.9 7.38 10.9 7.64 10.7
Average 9.80 13.7 9.71 13.6 9.92 13.4
Stdev 6.40 9.78 6.54 9.62 6.56 9.62
p (t-test) 0.037 0.038 0.064
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.3 38.9 30.3 38.9 30.3 38.9
n (Patient) 31 48 29 50 28 51
UO only
Median 7.94 9.74 8.17 9.91 8.41 9.56
Average 10.2 12.4 10.4 12.4 11.1 12.1
Stdev 7.79 8.93 8.00 8.89 7.91 8.87
p (t-test) 0.36 0.44 0.69
Min 1.62 1.32 1.62 1.32 3.20 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 15 54 14 55 13 57
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.65 0.62 0.59 0.69 0.63 0.58 0.59 0.61 0.53
SE 0.085 0.063 0.081 0.088 0.063 0.083 0.11 0.065 0.088
p Value 0.076 0.053 0.28 0.031 0.038 0.36 0.42 0.082 0.72
nCohort Recovered 10 31 15 8 29 14 6 28 13
nCohort Non-recovered 70 48 54 72 50 55 74 51 57
Cutoff Quartile 2 6.16 6.19 6.18 6.16 6.19 6.18 6.16 6.19 6.19
Sensitivity 77% 79% 76% 78% 80% 76% 76% 78% 75%
Specificity 40% 32% 33% 50% 34% 36% 33% 32% 31%
Cutoff Quartile 3 9.28 9.56 9.00 9.28 9.56 9.00 9.28 9.56 8.94
Sensitivity 54% 58% 54% 54% 58% 53% 53% 57% 53%
Specificity 80% 65% 67% 88% 66% 64% 83% 64% 62%
Cutoff Quartile 4 16.0 16.1 14.5 16.0 16.1 14.7 16.0 16.1 14.7
Sensitivity 27% 31% 26% 26% 30% 25% 26% 29% 26%
Specificity 90% 84% 80% 88% 83% 79% 83% 82% 77%
OR Quartile 2 2.25 1.81 1.58 3.50 2.11 1.79 1.56 1.72 1.37
p Value 0.25 0.26 0.47 0.10 0.16 0.36 0.63 0.30 0.64
Lower limit of 95% CI 0.565 0.649 0.456 0.786 0.750 0.510 0.263 0.611 0.363
Upper limit of 95% CI 8.97 5.05 5.46 15.6 5.91 6.31 9.21 4.86 5.13
OR Quartile 3 4.75 2.55 2.32 8.27 2.62 2.01 5.57 2.37 1.78
p Value 0.059 0.050 0.17 0.054 0.046 0.26 0.13 0.075 0.36
Lower limit of 95% CI 0.941 1.00 0.699 0.968 1.02 0.596 0.620 0.917 0.518
Upper limit of 95% CI 24.0 6.47 7.70 70.7 6.78 6.76 50.0 6.14 6.10
OR Quartile 4 3.35 2.36 1.40 2.51 2.06 1.25 1.73 1.92 1.19
p Value 0.27 0.14 0.64 0.40 0.21 0.76 0.63 0.26 0.81
Lower limit of 95% CI 0.398 0.760 0.344 0.289 0.659 0.305 0.190 0.613 0.288
Upper limit of 95% CI 28.3 7.35 5.70 21.8 6.42 5.15 15.7 5.99 4.92
TABLE 8.8
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 7.11 10.6 8.15 10.3 8.15 10.3
Average 9.28 13.1 10.1 12.7 10.1 12.7
Stdev 6.82 8.98 6.94 8.98 6.94 8.98
p (t-test) 0.055 0.23 0.23
Min 1.62 1.32 3.20 1.32 3.20 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 21 56 18 59 18 59
sCr only
Median 7.25 11.5 7.38 11.0 7.38 11.0
Average 8.89 14.0 9.06 13.7 9.06 13.7
Stdev 5.17 9.57 5.16 9.58 5.16 9.58
p (t-test) 0.0046 0.0085 0.0085
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 22.8 38.9 22.8 38.9 22.8 38.9
n (Patient) 32 44 31 45 31 45
UO only
Median 8.41 10.0 9.39 9.74 9.39 9.74
Average 11.6 13.0 12.4 12.4 12.4 12.4
Stdev 7.66 9.86 7.63 9.71 7.63 9.71
p (t-test) 0.57 0.99 0.99
Min 1.62 1.32 3.20 1.32 3.20 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 20 37 18 40 18 40
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.65 0.67 0.52 0.59 0.65 0.47 0.59 0.65 0.47
SE 0.067 0.062 0.080 0.074 0.063 0.082 0.074 0.063 0.082
p Value 0.023 0.0061 0.78 0.21 0.017 0.73 0.21 0.017 0.73
nCohort Recovered 21 32 20 18 31 18 18 31 18
nCohort Non-recovered 56 44 37 59 45 40 59 45 40
Cutoff Quartile 2 6.19 6.19 6.24 6.19 6.19 6.29 6.19 6.19 6.29
Sensitivity 80% 82% 76% 78% 80% 75% 78% 80% 75%
Specificity 43% 34% 30% 39% 32% 28% 39% 32% 28%
Cutoff Quartile 3 9.56 9.28 9.91 9.56 9.28 9.74 9.56 9.28 9.74
Sensitivity 57% 61% 51% 54% 60% 50% 54% 60% 50%
Specificity 71% 66% 55% 67% 65% 50% 67% 65% 50%
Cutoff Quartile 4 15.9 15.0 15.9 15.9 15.0 15.6 15.9 15.0 15.6
Sensitivity 29% 34% 24% 27% 33% 25% 27% 33% 25%
Specificity 86% 88% 75% 83% 87% 72% 83% 87% 72%
OR Quartile 2 3.07 2.36 1.33 2.25 1.90 1.15 2.25 1.90 1.15
p Value 0.043 0.11 0.64 0.16 0.23 0.82 0.16 0.23 0.82
Lower limit of 95% CI 1.03 0.818 0.395 0.727 0.667 0.329 0.727 0.667 0.329
Upper limit of 95% CI 9.10 6.79 4.50 6.97 5.44 4.05 6.97 5.44 4.05
OR Quartile 3 3.33 3.03 1.29 2.37 2.73 1.00 2.37 2.73 1.00
p Value 0.030 0.022 0.65 0.13 0.038 1.0 0.13 0.038 1.0
Lower limit of 95% CI 1.13 1.17 0.433 0.784 1.06 0.329 0.784 1.06 0.329
Upper limit of 95% CI 9.86 7.83 3.84 7.16 7.03 3.04 7.16 7.03 3.04
OR Quartile 4 2.40 3.62 0.964 1.86 3.38 0.867 1.86 3.38 0.867
p Value 0.20 0.039 0.95 0.37 0.051 0.82 0.37 0.051 0.82
Lower limit of 95% CI 0.620 1.07 0.273 0.475 0.997 0.247 0.475 0.997 0.247
Upper limit of 95% CI 9.28 12.3 3.40 7.29 11.4 3.04 7.29 11.4 3.04
TABLE 8.9
Comparison of marker levels and the area under the ROC curve (AUC)
in EDTA samples for the “recovered” and “non-recovered” cohorts where recovery starts
at 72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 8.17 10.6 8.17 10.6 8.17 10.6
Average 9.65 12.8 9.65 12.8 9.65 12.8
Stdev 5.94 9.17 5.94 9.17 5.94 9.17
p (t-test) 0.094 0.094 0.094
Min 3.20 1.32 3.20 1.32 3.20 1.32
Max 24.1 38.9 24.1 38.9 24.1 38.9
n (Patient) 22 52 22 52 22 52
sCr only
Median 7.90 10.9 7.90 10.9 7.94 10.6
Average 10.4 12.7 9.67 13.1 9.84 12.9
Stdev 8.00 8.57 6.69 9.18 6.88 9.05
p (t-test) 0.26 0.071 0.12
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 36.8 38.9 34.6 38.9 34.6 38.9
n (Patient) 33 40 31 42 29 44
UO only
Median 10.2 9.46 10.2 9.46 10.2 9.46
Average 11.9 12.8 11.9 12.8 11.9 12.8
Stdev 5.52 10.2 5.52 10.2 5.52 10.2
p (t-test) 0.69 0.69 0.69
Min 5.31 1.32 5.31 1.32 5.31 1.32
Max 24.1 38.9 24.1 38.9 24.1 38.9
n (Patient) 14 34 14 34 14 34
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.60 0.60 0.45 0.60 0.63 0.45 0.60 0.61 0.45
SE 0.070 0.066 0.091 0.070 0.065 0.091 0.070 0.066 0.091
p Value 0.16 0.12 0.58 0.16 0.055 0.58 0.16 0.10 0.58
nCohort Recovered 22 33 14 22 31 14 22 29 14
nCohort Non-recovered 52 40 34 52 42 34 52 44 34
Cutoff Quartile 2 6.19 6.18 6.96 6.19 6.18 6.96 6.19 6.18 6.96
Sensitivity 79% 78% 71% 79% 79% 71% 79% 80% 71%
Specificity 36% 30% 14% 36% 32% 14% 36% 34% 14%
Cutoff Quartile 3 9.28 9.00 9.96 9.28 9.00 9.96 9.28 9.00 9.96
Sensitivity 56% 60% 47% 56% 60% 47% 56% 57% 47%
Specificity 64% 64% 43% 64% 65% 43% 64% 62% 43%
Cutoff Quartile 4 14.7 14.6 14.9 14.7 14.6 14.9 14.7 14.6 14.9
Sensitivity 31% 32% 26% 31% 33% 26% 31% 32% 26%
Specificity 86% 85% 79% 86% 87% 79% 86% 86% 79%
OR Quartile 2 2.13 1.50 0.400 2.13 1.75 0.400 2.13 2.05 0.400
p Value 0.18 0.45 0.28 0.18 0.30 0.28 0.18 0.19 0.28
Lower limit of 95% CI 0.713 0.524 0.0754 0.713 0.609 0.0754 0.713 0.709 0.0754
Upper limit of 95% CI 6.36 4.28 2.12 6.36 5.01 2.12 6.36 5.91 2.12
OR Quartile 3 2.21 2.62 0.667 2.21 2.67 0.667 2.21 2.15 0.667
p Value 0.13 0.047 0.53 0.13 0.045 0.53 0.13 0.12 0.53
Lower limit of 95% CI 0.790 1.01 0.190 0.790 1.02 0.190 0.790 0.826 0.190
Upper limit of 95% CI 6.16 6.79 2.34 6.16 6.98 2.34 6.16 5.61 2.34
OR Quartile 4 2.81 2.70 1.32 2.81 3.38 1.32 2.81 2.92 1.32
p Value 0.13 0.093 0.71 0.13 0.053 0.71 0.13 0.088 0.71
Lower limit of 95% CI 0.728 0.846 0.298 0.728 0.986 0.298 0.728 0.851 0.298
Upper limit of 95% CI 10.9 8.59 5.84 10.9 11.6 5.84 10.9 9.99 5.84
TABLE 8.10
Comparison of marker levels and the area under the ROC curve
(AUC) in EDTA samples for the “recovered” and “non-recovered” cohorts where
recovery starts within 7 days after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE citeria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 9.06 10.2 8.48 10.5 8.48 10.5
Average 11.3 12.9 11.1 13.0 11.2 12.8
Stdev 7.16 9.92 7.39 9.52 7.40 9.46
p (t-test) 0.41 0.32 0.42
Min 1.62 1.32 1.62 1.32 3.20 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 22 52 22 52 22 52
sCr only
Median 8.48 10.4 8.41 10.5 8.41 10.5
Average 11.6 12.9 11.4 13.1 11.4 12.9
Stdev 7.97 9.65 8.08 9.40 8.39 8.99
p (t-test) 0.54 0.41 0.46
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 36.8 38.9 36.8 38.9 36.8 38.9
n (Patient) 48 33 46 35 42 39
UO only
Median 8.48 10.2 8.41 10.4 8.48 10.2
Average 11.1 13.1 10.4 13.2 10.7 13.0
Stdev 7.72 9.28 6.57 9.30 6.48 9.36
p (t-test) 0.33 0.12 0.21
Min 1.62 1.32 1.62 1.32 3.20 1.32
Max 33.3 38.9 30.8 38.9 30.8 38.9
n (Patient) 30 48 31 47 30 48
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.53 0.53 0.55 0.56 0.55 0.58 0.54 0.56 0.55
SE 0.063 0.066 0.067 0.063 0.065 0.066 0.063 0.064 0.067
p Value 0.69 0.65 0.44 0.38 0.40 0.24 0.49 0.31 0.43
nCohort Recovered 44 48 30 40 46 31 38 42 30
nCohort Non-recovered 40 33 48 44 35 47 46 39 48
Cutoff Quartile 2 6.19 6.19 6.24 6.19 6.19 6.24 6.19 6.19 6.24
Sensitivity 75% 76% 75% 77% 77% 77% 76% 79% 75%
Specificity 25% 27% 30% 28% 28% 32% 26% 31% 30%
Cutoff Quartile 3 9.66 9.75 9.66 9.66 9.75 9.66 9.66 9.75 9.66
Sensitivity 52% 55% 54% 55% 57% 55% 54% 56% 54%
Specificity 52% 54% 57% 55% 57% 58% 55% 57% 57%
Cutoff Quartile 4 16.0 15.9 15.6 16.0 15.9 15.6 16.0 15.9 15.6
Sensitivity 30% 30% 31% 30% 31% 32% 28% 28% 31%
Specificity 80% 79% 83% 80% 80% 84% 79% 79% 83%
OR Quartile 2 1.00 1.16 1.29 1.29 1.33 1.56 1.14 1.74 1.29
p Value 1.0 0.77 0.63 0.61 0.58 0.39 0.80 0.29 0.63
Lower limit of 95% CI 0.372 0.419 0.464 0.480 0.481 0.567 0.422 0.629 0.464
Upper limit of 95% CI 2.69 3.22 3.56 3.47 3.68 4.29 3.06 4.80 3.56
OR Quartile 3 1.21 1.42 1.55 1.47 1.73 1.71 1.47 1.73 1.55
p Value 0.66 0.44 0.35 0.38 0.22 0.25 0.38 0.22 0.35
Lower limit of 95% CI 0.514 0.582 0.617 0.620 0.713 0.686 0.620 0.716 0.617
Upper limit of 95% CI 2.85 3.45 3.87 3.47 4.21 4.29 3.49 4.16 3.87
OR Quartile 4 1.67 1.65 2.27 1.68 1.88 2.44 1.48 1.44 2.27
p Value 0.32 0.33 0.16 0.32 0.22 0.12 0.45 0.48 0.16
Lower limit of 95% CI 0.615 0.597 0.728 0.611 0.680 0.782 0.538 0.522 0.728
Upper limit of 95% CI 4.52 4.57 7.09 4.60 5.22 7.60 4.06 3.97 7.09
Example 9. Use of C-C Motif Chemokine 16 for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 and R from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. C-C motif chemokine 16 is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0) or risk of injury (R). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 9.1
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.00734 0.0207 0.00738 0.0206 0.00908 0.0194
Average 0.0126 0.0844 0.0129 0.0832 0.0134 0.0819
Stdev 0.0148 0.375 0.0151 0.372 0.0154 0.369
p (t-test) 0.14 0.14 0.15
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.0518 2.98 0.0518 2.98 0.0518 2.98
n (Patient) 19 62 18 63 17 64
sCr only
Median 0.0108 0.0262 0.0142 0.0217 0.0142 0.0217
Average 0.0190 0.135 0.0197 0.127 0.0197 0.127
Stdev 0.0228 0.500 0.0230 0.487 0.0230 0.487
p (t-test) 0.19 0.20 0.20
Min 4.13E−6 6.68E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 47 34 45 36 45 36
UO only
Median 0.0125 0.0217 0.0108 0.0225 0.0125 0.0208
Average 0.0293 0.0914 0.0282 0.0932 0.0290 0.0899
Stdev 0.0407 0.408 0.0400 0.412 0.0409 0.405
p (t-test) 0.29 0.28 0.29
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 20 52 21 51 20 53
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.67 0.68 0.55 0.67 0.64 0.57 0.66 0.64 0.56
SE 0.066 0.061 0.075 0.068 0.062 0.073 0.069 0.062 0.074
p Value 0.0095 0.0039 0.48 0.014 0.023 0.37 0.021 0.023 0.40
nCohort Recovered 19 47 20 18 45 21 17 45 20
nCohort Non-recovered 62 34 52 63 36 51 64 36 53
Cutoff Quartile 2 0.00202 0.00202 0.00161 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 73% 82% 73% 73% 81% 73% 73% 81% 74%
Specificity 32% 36% 20% 33% 36% 24% 35% 36% 30%
Cutoff Quartile 3 0.0157 0.0157 0.0193 0.0157 0.0157 0.0193 0.0157 0.0157 0.0181
Sensitivity 56% 62% 54% 56% 58% 55% 55% 58% 53%
Specificity 74% 60% 60% 72% 58% 62% 71% 58% 60%
Cutoff Quartile 4 0.0427 0.0427 0.0464 0.0427 0.0427 0.0464 0.0427 0.0427 0.0460
Sensitivity 31% 38% 27% 30% 36% 27% 30% 36% 26%
Specificity 95% 85% 80% 94% 84% 81% 94% 84% 80%
OR Quartile 2 1.22 2.64 0.679 1.35 2.29 0.826 1.51 2.29 1.19
p Value 0.73 0.073 0.54 0.60 0.11 0.75 0.48 0.11 0.76
Lower limit of 95% CI 0.400 0.913 0.193 0.438 0.819 0.254 0.483 0.819 0.384
Upper limit of 95% CI 3.73 7.66 2.38 4.18 6.38 2.68 4.71 6.38 3.71
OR Quartile 3 3.63 2.38 1.75 3.25 1.92 1.98 2.90 1.92 1.68
p Value 0.026 0.060 0.30 0.044 0.15 0.20 0.071 0.15 0.33
Lower limit of 95% CI 1.16 0.964 0.614 1.03 0.788 0.700 0.914 0.788 0.591
Upper limit of 95% CI 11.3 5.88 4.99 10.2 4.66 5.59 9.18 4.66 4.78
OR Quartile 4 7.95 3.54 1.47 7.34 3.07 1.61 6.76 3.07 1.44
p Value 0.051 0.019 0.54 0.061 0.037 0.46 0.073 0.037 0.57
Lower limit of 95% CI 0.989 1.23 0.420 0.910 1.07 0.460 0.835 1.07 0.410
Upper limit of 95% CI 64.0 10.2 5.17 59.2 8.81 5.62 54.6 8.81 5.03
TABLE 9.2
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0125 0.0217 0.0142 0.0208 0.0146 0.0195
Average 0.0158 0.0909 0.0162 0.0895 0.0167 0.0880
Stdev 0.0150 0.394 0.0152 0.390 0.0154 0.387
p (t-test) 0.16 0.17 0.17
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.0518 2.98 0.0518 2.98 0.0518 2.98
n (Patient) 24 56 23 57 22 58
sCr only
Median 0.0142 0.0225 0.0146 0.0217 0.0142 0.0225
Average 0.0199 0.131 0.0202 0.127 0.0197 0.125
Stdev 0.0229 0.493 0.0231 0.487 0.0231 0.480
p (t-test) 0.20 0.20 0.20
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.106 2.98 0.106 2.98 0.106 2.98
n (Patient) 45 35 44 36 43 37
UO only
Median 0.0167 0.0237 0.0153 0.0249 0.0167 0.0225
Average 0.0298 0.100 0.0288 0.103 0.0296 0.0985
Stdev 0.0382 0.433 0.0376 0.438 0.0384 0.429
p (t-test) 0.28 0.27 0.29
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 22 46 23 45 22 47
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.61 0.65 0.52 0.61 0.64 0.54 0.60 0.65 0.53
SE 0.066 0.063 0.075 0.068 0.063 0.074 0.069 0.062 0.074
p Value 0.086 0.021 0.76 0.11 0.030 0.61 0.16 0.018 0.69
nCohort Recovered 24 45 22 23 44 23 22 43 22
nCohort Non-recovered 56 35 46 57 36 45 58 37 47
Cutoff Quartile 2 0.00202 0.00202 0.00161 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 70% 80% 70% 70% 81% 69% 71% 81% 70%
Specificity 21% 33% 14% 22% 34% 17% 23% 35% 23%
Cutoff Quartile 3 0.0165 0.0165 0.0207 0.0165 0.0165 0.0207 0.0165 0.0165 0.0206
Sensitivity 55% 60% 54% 54% 58% 56% 53% 59% 53%
Specificity 62% 58% 59% 61% 57% 61% 59% 58% 59%
Cutoff Quartile 4 0.0435 0.0435 0.0464 0.0435 0.0435 0.0464 0.0435 0.0435 0.0460
Sensitivity 32% 37% 28% 32% 36% 29% 31% 35% 28%
Specificity 92% 84% 82% 91% 84% 83% 91% 84% 82%
OR Quartile 2 0.604 2.00 0.361 0.654 2.14 0.466 0.709 2.30 0.693
p Value 0.38 0.19 0.14 0.47 0.15 0.23 0.56 0.12 0.54
Lower limit of 95% CI 0.193 0.711 0.0917 0.209 0.762 0.134 0.225 0.816 0.214
Upper limit of 95% CI 1.88 5.63 1.42 2.05 6.03 1.63 2.23 6.46 2.25
OR Quartile 3 2.07 2.05 1.72 1.85 1.84 1.94 1.66 2.04 1.64
p Value 0.15 0.12 0.30 0.22 0.18 0.20 0.32 0.12 0.34
Lower limit of 95% CI 0.776 0.836 0.614 0.692 0.755 0.699 0.614 0.834 0.589
Upper limit of 95% CI 5.51 5.04 4.81 4.97 4.49 5.41 4.48 4.98 4.57
OR Quartile 4 5.21 3.21 1.77 4.85 2.99 1.93 4.50 2.79 1.72
p Value 0.037 0.031 0.37 0.047 0.042 0.31 0.058 0.057 0.40
Lower limit of 95% CI 1.10 1.11 0.503 1.02 1.04 0.549 0.949 0.971 0.489
Upper limit of 95% CI 24.6 9.24 6.25 22.9 8.59 6.78 21.3 7.99 6.05
TABLE 9.3
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
48 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0129 0.0262 0.0152 0.0195 0.0153 0.0182
Average 0.0232 0.109 0.0257 0.0999 0.0265 0.0978
Stdev 0.0336 0.452 0.0347 0.433 0.0349 0.429
p (t-test) 0.23 0.26 0.27
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 24 56 23 57 22 58
sCr only
Median 0.0151 0.0195 0.0146 0.0208 0.0146 0.0208
Average 0.0248 0.132 0.0244 0.129 0.0244 0.129
Stdev 0.0321 0.516 0.0323 0.508 0.0323 0.508
p (t-test) 0.26 0.25 0.25
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 47 32 46 33 46 33
UO only
Median 0.0157 0.0315 0.0206 0.0208 0.0227 0.0190
Average 0.0295 0.141 0.0336 0.121 0.0350 0.118
Stdev 0.0373 0.532 0.0386 0.495 0.0388 0.488
p (t-test) 0.27 0.31 0.33
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 29 30 25 35 24 36
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.61 0.65 0.52 0.61 0.64 0.54 0.60 0.65 0.53
SE 0.066 0.063 0.075 0.068 0.063 0.074 0.069 0.062 0.074
p Value 0.086 0.021 0.76 0.11 0.030 0.61 0.16 0.018 0.69
nCohort Recovered 24 45 22 23 44 23 22 43 22
nCohort Non-recovered 56 35 46 57 36 45 58 37 47
Cutoff Quartile 2 0.00202 0.00202 0.00161 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 70% 80% 70% 70% 81% 69% 71% 81% 70%
Specificity 21% 33% 14% 22% 34% 17% 23% 35% 23%
Cutoff Quartile 3 0.0165 0.0165 0.0207 0.0165 0.0165 0.0207 0.0165 0.0165 0.0206
Sensitivity 55% 60% 54% 54% 58% 56% 53% 59% 53%
Specificity 62% 58% 59% 61% 57% 61% 59% 58% 59%
Cutoff Quartile 4 0.0435 0.0435 0.0464 0.0435 0.0435 0.0464 0.0435 0.0435 0.0460
Sensitivity 32% 37% 28% 32% 36% 29% 31% 35% 28%
Specificity 92% 84% 82% 91% 84% 83% 91% 84% 82%
OR Quartile 2 0.604 2.00 0.361 0.654 2.14 0.466 0.709 2.30 0.693
p Value 0.38 0.19 0.14 0.47 0.15 0.23 0.56 0.12 0.54
Lower limit of 95% CI 0.193 0.711 0.0917 0.209 0.762 0.134 0.225 0.816 0.214
Upper limit of 95% CI 1.88 5.63 1.42 2.05 6.03 1.63 2.23 6.46 2.25
OR Quartile 3 2.07 2.05 1.72 1.85 1.84 1.94 1.66 2.04 1.64
p Value 0.15 0.12 0.30 0.22 0.18 0.20 0.32 0.12 0.34
Lower limit of 95% CI 0.776 0.836 0.614 0.692 0.755 0.699 0.614 0.834 0.589
Upper limit of 95% CI 5.51 5.04 4.81 4.97 4.49 5.41 4.48 4.98 4.57
OR Quartile 4 5.21 3.21 1.77 4.85 2.99 1.93 4.50 2.79 1.72
p Value 0.037 0.031 0.37 0.047 0.042 0.31 0.058 0.057 0.40
Lower limit of 95% CI 1.10 1.11 0.503 1.02 1.04 0.549 0.949 0.971 0.489
Upper limit of 95% CI 24.6 9.24 6.25 22.9 8.59 6.78 21.3 7.99 6.05
TABLE 9.4
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
72 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0146 0.0208 0.0151 0.0195 0.0151 0.0195
Average 0.0251 0.109 0.0258 0.106 0.0258 0.106
Stdev 0.0349 0.458 0.0351 0.453 0.0351 0.453
p (t-test) 0.26 0.26 0.26
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 38 41 37 42 37 42
sCr only
Median 0.0146 0.0182 0.0146 0.0182 0.0146 0.0182
Average 0.0237 0.133 0.0237 0.133 0.0237 0.133
Stdev 0.0308 0.524 0.0308 0.524 0.0308 0.524
p (t-test) 0.26 0.26 0.26
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 46 31 46 31 46 31
UO only
Median 0.0227 0.0265 0.0249 0.0225 0.0249 0.0225
Average 0.0375 0.132 0.0395 0.128 0.0395 0.128
Stdev 0.0421 0.516 0.0423 0.508 0.0423 0.508
p (t-test) 0.32 0.33 0.33
Min 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 20 32 19 33 19 33
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.59 0.58 0.52 0.57 0.58 0.49 0.57 0.58 0.49
SE 0.064 0.067 0.083 0.064 0.067 0.084 0.064 0.067 0.084
p Value 0.14 0.25 0.81 0.25 0.25 0.86 0.25 0.25 0.86
nCohort Recovered 38 46 20 37 46 19 37 46 19
nCohort Non-recovered 41 31 32 42 31 33 42 31 33
Cutoff Quartile 2 0.00202 0.00202 0.00449 0.00202 0.00202 0.00449 0.00202 0.00202 0.00449
Sensitivity 76% 77% 75% 74% 77% 73% 74% 77% 73%
Specificity 32% 33% 25% 30% 33% 21% 30% 33% 21%
Cutoff Quartile 3 0.0157 0.0153 0.0237 0.0157 0.0153 0.0237 0.0157 0.0153 0.0237
Sensitivity 56% 55% 50% 55% 55% 48% 55% 55% 48%
Specificity 58% 54% 50% 57% 54% 47% 57% 54% 47%
Cutoff Quartile 4 0.0427 0.0411 0.0494 0.0427 0.0411 0.0494 0.0427 0.0411 0.0494
Sensitivity 29% 26% 25% 29% 26% 24% 29% 26% 24%
Specificity 82% 76% 75% 81% 76% 74% 81% 76% 74%
OR Quartile 2 1.43 1.66 1.00 1.19 1.66 0.711 1.19 1.66 0.711
p Value 0.48 0.34 1.0 0.73 0.34 0.62 0.73 0.34 0.62
Lower limit of 95% CI 0.533 0.584 0.275 0.445 0.584 0.186 0.445 0.584 0.186
Upper limit of 95% CI 3.84 4.71 3.63 3.19 4.71 2.72 3.19 4.71 2.72
OR Quartile 3 1.76 1.45 1.00 1.59 1.45 0.847 1.59 1.45 0.847
p Value 0.22 0.43 1.0 0.31 0.43 0.77 0.31 0.43 0.77
Lower limit of 95% CI 0.720 0.579 0.327 0.652 0.579 0.274 0.652 0.579 0.274
Upper limit of 95% CI 4.29 3.61 3.06 3.87 3.61 2.62 3.87 3.61 2.62
OR Quartile 4 1.83 1.11 1.00 1.71 1.11 0.896 1.71 1.11 0.896
p Value 0.26 0.85 1.0 0.32 0.85 0.87 0.32 0.85 0.87
Lower limit of 95% CI 0.634 0.387 0.275 0.594 0.387 0.245 0.594 0.387 0.245
Upper limit of 95% CI 5.29 3.17 3.63 4.95 3.17 3.27 4.95 3.17 3.27
TABLE 9.5
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
within 7 days after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 0.0108 0.0262 0.0112 0.0225 0.0112 0.0225
Average 0.0243 0.133 0.0245 0.124 0.0245 0.124
Stdev 0.0335 0.515 0.0340 0.494 0.0340 0.494
p (t-test) 0.25 0.25 0.25
Min 4.13E−6 6.68E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 51 32 48 35 48 35
sCr only
Median 0.0152 0.0182 0.0152 0.0182 0.0152 0.0182
Average 0.0265 0.171 0.0267 0.159 0.0267 0.159
Stdev 0.0323 0.604 0.0328 0.581 0.0328 0.581
p (t−test) 0.27 0.28 0.28
Min 4.13E−6 6.68E−6 4.13E−6 6.68E−6 4.13E−6 6.68E−6
Max 0.151 2.98 0.151 2.98 0.151 2.98
n (Patient) 58 23 56 25 56 25
UO only
Median 0.0155 0.0170 0.0142 0.0190 0.0147 0.0173
Average 0.0285 0.110 0.0257 0.114 0.0262 0.112
Stdev 0.0391 0.470 0.0349 0.475 0.0352 0.469
p (t−test) 0.29 0.26 0.27
Min 6.68E−6 4.13E−6 4.13E−6 6.68E−6 6.68E−6 4.13E−6
Max 0.191 2.98 0.151 2.98 0.151 2.98
n (Patient) 40 39 41 38 40 39
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.64 0.57 0.53 0.63 0.57 0.58 0.63 0.57 0.56
SE 0.064 0.072 0.065 0.063 0.070 0.065 0.063 0.070 0.065
p Value 0.023 0.33 0.68 0.044 0.31 0.23 0.044 0.31 0.32
nCohort Recovered 51 58 40 48 56 41 48 56 40
nCohort Non−recovered 32 23 39 35 25 38 35 25 39
Cutoff Quartile 2 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202 0.00202
Sensitivity 84% 78% 74% 83% 80% 76% 83% 80% 77%
Specificity 35% 31% 30% 35% 32% 32% 35% 32% 32%
Cutoff Quartile 3 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157 0.0157
Sensitivity 66% 57% 51% 63% 56% 55% 63% 56% 54%
Specificity 61% 53% 52% 60% 54% 56% 60% 54% 55%
Cutoff Quartile 4 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427 0.0427
Sensitivity 28% 30% 26% 29% 28% 29% 29% 28% 28%
Specificity 78% 78% 78% 79% 77% 80% 79% 77% 80%
OR Quartile 2 2.95 1.62 1.24 2.65 1.89 1.50 2.65 1.89 1.60
p Value 0.057 0.41 0.67 0.071 0.27 0.43 0.071 0.27 0.35
Lower limit of 95% CI 0.967 0.520 0.463 0.919 0.613 0.553 0.919 0.613 0.593
Upper limit of 95% CI 8.97 5.05 3.33 7.65 5.86 4.05 7.65 5.86 4.35
OR Quartile 3 2.96 1.49 1.16 2.58 1.47 1.58 2.58 1.47 1.43
p Value 0.021 0.42 0.74 0.038 0.43 0.31 0.038 0.43 0.43
Lower limit of 95% CI 1.18 0.564 0.481 1.05 0.569 0.649 1.05 0.569 0.588
Upper limit of 95% CI 7.43 3.95 2.81 6.33 3.79 3.84 6.33 3.79 3.46
OR Quartile 4 1.42 1.51 1.19 1.52 1.29 1.68 1.52 1.29 1.57
p Value 0.50 0.45 0.74 0.42 0.64 0.33 0.42 0.64 0.40
Lower limit of 95% CI 0.513 0.513 0.423 0.553 0.441 0.592 0.553 0.441 0.554
Upper limit of 95% CI 3.94 4.47 3.34 4.18 3.75 4.77 4.18 3.75 4.46
TABLE 9.6
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
12 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 7.55 10.4 7.38 10.4 7.25 10.4
Average 9.81 12.8 9.49 12.8 9.59 12.7
Stdev 7.72 8.86 7.79 8.80 7.99 8.75
p (t-test) 0.17 0.13 0.17
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 20 62 19 63 18 64
sCr only
Median 8.41 10.5 8.41 10.5 8.41 10.5
Average 11.8 12.6 11.9 12.4 11.9 12.4
Stdev 9.26 7.92 9.35 7.89 9.35 7.89
p (t−test) 0.70 0.81 0.81
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 38.9 37.2 38.9 37.2 38.9 37.2
n (Patient) 46 35 44 37 44 37
UO only
Median 7.72 10.2 7.83 10.3 7.56 10.3
Average 9.64 12.8 9.93 12.8 9.61 12.8
Stdev 6.85 9.15 6.82 9.23 6.86 9.08
p (t−test) 0.13 0.15 0.12
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 21 50 22 49 21 51
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.62 0.56 0.61 0.64 0.55 0.59 0.64 0.55 0.61
SE 0.069 0.065 0.071 0.068 0.065 0.071 0.070 0.065 0.071
p Value 0.080 0.33 0.13 0.038 0.41 0.21 0.044 0.41 0.12
nCohort Recovered 20 46 21 19 44 22 18 44 21
nCohort Non−recovered 62 35 50 63 37 49 64 37 51
Cutoff Quartile 2 6.18 6.19 6.19 6.18 6.19 6.19 6.18 6.19 6.19
Sensitivity 76% 80% 76% 76% 78% 76% 77% 78% 76%
Specificity 30% 30% 29% 32% 30% 27% 33% 30% 29%
Cutoff Quartile 3 9.66 9.75 9.00 9.66 9.75 9.00 9.66 9.75 8.94
Sensitivity 56% 57% 58% 57% 57% 57% 56% 57% 59%
Specificity 70% 57% 71% 74% 57% 68% 72% 57% 71%
Cutoff Quartile 4 15.6 15.9 14.3 15.6 15.9 14.6 15.6 15.9 14.6
Sensitivity 29% 31% 30% 30% 30% 29% 30% 30% 29%
Specificity 85% 80% 86% 89% 80% 82% 89% 80% 86%
OR Quartile 2 1.34 1.75 1.27 1.48 1.52 1.16 1.63 1.52 1.30
p Value 0.61 0.29 0.69 0.50 0.42 0.80 0.40 0.42 0.65
Lower limit of 95% CI 0.439 0.619 0.402 0.478 0.550 0.369 0.523 0.550 0.413
Upper limit of 95% CI 4.11 4.95 3.99 4.56 4.20 3.62 5.10 4.20 4.09
OR Quartile 3 3.02 1.73 3.45 3.73 1.73 2.86 3.34 1.73 3.57
p Value 0.045 0.22 0.027 0.023 0.22 0.052 0.039 0.22 0.023
Lower limit of 95% CI 1.03 0.713 1.15 1.20 0.714 0.989 1.07 0.714 1.19
Upper limit of 95% CI 8.91 4.21 10.4 11.6 4.17 8.25 10.5 4.17 10.7
OR Quartile 4 2.32 1.88 2.57 3.67 1.65 1.80 3.38 1.65 2.50
p Value 0.22 0.22 0.17 0.10 0.34 0.36 0.13 0.34 0.19
Lower limit of 95% CI 0.604 0.680 0.658 0.771 0.595 0.517 0.706 0.595 0.640
Upper limit of 95% CI 8.89 5.22 10.1 17.5 4.55 6.27 16.2 4.55 9.77
TABLE 9.7
Comparison of marker levels and the area under the ROC curve (AUC)
in urine samples for the “recovered” and “non-recovered” cohorts where recovery starts at
24 hours after sample collection and renal status is assessed by serum creatinine (sCr)
only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
24 48 72
Non- Non- Non-
Recovery Period Recovered recovered Recovered recovered Recovered recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
sCr or UO
Median 7.55 10.6 7.11 10.6 6.81 10.5
Average 9.74 13.2 9.43 13.2 9.51 13.1
Stdev 7.47 9.15 7.83 8.93 8.00 8.88
p (t-test) 0.078 0.074 0.097
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 26 54 23 57 22 58
sCr only
Median 8.17 10.7 7.94 11.4 7.92 12.0
Average 11.8 12.7 11.7 12.8 11.1 13.6
Stdev 9.25 8.16 9.33 8.05 8.47 9.05
p (t−test) 0.65 0.58 0.23
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 38.9 37.2 38.9 37.2 36.8 38.9
n (Patient) 46 33 45 34 44 35
UO only
Median 7.94 10.2 7.83 10.3 7.56 10.3
Average 9.91 13.1 10.1 13.0 9.86 13.0
Stdev 6.93 9.44 7.17 9.34 7.23 9.18
p (t−test) 0.12 0.16 0.13
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 25 44 24 45 23 47
24 48 72
Recovery Period sCr or sCr or sCr or
Duration (hr) UO sCr only UO only UO sCr only UO only UO sCr only UO only
AUC 0.63 0.56 0.60 0.66 0.58 0.60 0.66 0.60 0.62
SE 0.064 0.066 0.070 0.064 0.066 0.070 0.065 0.065 0.069
p Value 0.042 0.33 0.14 0.013 0.24 0.16 0.015 0.12 0.088
nCohort Recovered 26 46 25 23 45 24 22 44 23
nCohort Non−recovered 54 33 44 57 34 45 58 35 47
Cutoff Quartile 2 6.16 6.19 6.18 6.16 6.19 6.18 6.16 6.19 6.19
Sensitivity 80% 79% 77% 81% 79% 78% 81% 80% 79%
Specificity 35% 28% 32% 39% 29% 33% 41% 30% 35%
Cutoff Quartile 3 9.28 9.56 9.00 9.28 9.56 9.00 9.28 9.56 8.94
Sensitivity 57% 58% 57% 60% 59% 58% 59% 60% 60%
Specificity 65% 57% 64% 74% 58% 67% 73% 59% 70%
Cutoff Quartile 4 16.0 16.1 14.5 16.0 16.1 14.7 16.0 16.1 14.7
Sensitivity 31% 33% 30% 30% 32% 27% 29% 34% 30%
Specificity 88% 80% 84% 87% 80% 79% 86% 82% 83%
OR Quartile 2 2.07 1.46 1.60 2.69 1.57 1.75 2.96 1.68 1.97
p Value 0.17 0.48 0.40 0.069 0.40 0.32 0.048 0.33 0.23
Lower limit of 95% CI 0.728 0.511 0.534 0.927 0.547 0.581 1.01 0.586 0.653
Upper limit of 95% CI 5.88 4.19 4.79 7.80 4.49 5.27 8.66 4.80 5.97
OR Quartile 3 2.55 1.76 2.34 4.19 1.95 2.74 3.78 2.17 3.37
p Value 0.059 0.22 0.100 0.0087 0.15 0.056 0.015 0.094 0.025
Lower limit of 95% CI 0.964 0.715 0.851 1.44 0.792 0.973 1.29 0.877 1.16
Upper limit of 95% CI 6.73 4.35 6.43 12.2 4.83 7.70 11.1 5.35 9.74
OR Quartile 4 3.52 2.06 2.20 2.83 1.91 1.38 2.63 2.35 2.02
p Value 0.064 0.17 0.22 0.13 0.21 0.59 0.16 0.11 0.27
Lower limit of 95% CI 0.929 0.736 0.631 0.742 0.687 0.422 0.686 0.833 0.579
Upper limit of 95% CI 13.4 5.74 7.69 10.8 5.33 4.52 10.1 6.62 7.01
TABLE 9.8
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 48 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 7.81 10.7 7.92 10.4 7.94 10.4
Average 9.91 14.0 10.2 13.4 10.3 13.3
Stdev 6.55 9.69 6.86 9.44 6.95 9.38
p (t-test) 0.035 0.089 0.11
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 36 41 32 45 31 46
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.17 10.6 7.94 10.7 7.94 10.7
Average 11.5 12.4 10.9 13.2 10.9 13.2
Stdev 8.68 7.90 7.74 9.08 7.74 9.08
p (t-test) 0.64 0.24 0.24
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 38.9 37.2 36.8 38.9 36.8 38.9
n (Patient) 46 30 45 31 45 31
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.41 10.4 8.41 10.3 8.41 10.2
Average 10.9 13.9 11.1 13.3 11.3 13.1
Stdev 6.91 10.6 7.29 10.0 7.41 9.95
p (t-test) 0.21 0.35 0.43
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 27 30 23 35 22 36
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.63 0.57 0.56 0.61 0.59 0.55 0.60 0.59 0.54
SE 0.063 0.068 0.076 0.065 0.067 0.077 0.065 0.067 0.078
p Value 0.041 0.34 0.43 0.099 0.17 0.51 0.13 0.17 0.61
nCohort Recovered 36 46 27 32 45 23 31 45 22
nCohort Non-recovered 41 30 30 45 31 35 46 31 36
Cutoff Quartile 2 6.19 6.19 6.24 6.19 6.19 6.29 6.19 6.19 6.29
Sensitivity 80% 80% 77% 80% 81% 74% 80% 81% 75%
Specificity 33% 28% 30% 34% 29% 26% 35% 29% 27%
Cutoff Quartile 3 9.56 9.28 9.91 9.56 9.28 9.74 9.56 9.28 9.74
Sensitivity 61% 60% 57% 58% 61% 57% 57% 61% 56%
Specificity 64% 57% 59% 62% 58% 61% 61% 58% 59%
Cutoff Quartile 4 15.9 15.0 15.9 15.9 15.0 15.6 15.9 15.0 15.6
Sensitivity 32% 30% 30% 29% 32% 29% 28% 32% 28%
Specificity 83% 78% 81% 81% 80% 78% 81% 80% 77%
OR Quartile 2 2.06 1.58 1.38 2.10 1.69 1.02 2.26 1.69 1.12
p Value 0.17 0.42 0.59 0.16 0.35 0.97 0.12 0.35 0.85
Lower limit of 95% CI 0.731 0.524 0.424 0.746 0.564 0.307 0.803 0.564 0.338
Upper limit of 95% CI 5.82 4.74 4.51 5.88 5.08 3.39 6.37 5.08 3.75
OR Quartile 3 2.76 1.95 1.90 2.28 2.17 2.07 2.06 2.17 1.81
p Value 0.031 0.16 0.23 0.082 0.10 0.18 0.13 0.10 0.28
Lower limit of 95% CI 1.10 0.766 0.663 0.901 0.851 0.710 0.813 0.851 0.617
Upper limit of 95% CI 6.97 4.96 5.46 5.77 5.51 6.06 5.21 5.51 5.29
OR Quartile 4 2.32 1.54 1.89 1.76 1.90 1.44 1.64 1.90 1.31
p Value 0.13 0.42 0.32 0.31 0.23 0.56 0.38 0.23 0.67
Lower limit of 95% CI 0.776 0.540 0.542 0.588 0.667 0.420 0.547 0.667 0.380
Upper limit of 95% CI 6.95 4.41 6.56 5.27 5.44 4.94 4.92 5.44 4.50
TABLE 9.9
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 72 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.17 10.6 8.41 10.4 8.41 10.4
Average 9.99 13.6 10.1 13.4 10.1 13.4
Stdev 6.20 9.83 6.28 9.75 6.28 9.75
p (t-test) 0.068 0.086 0.086
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 24.1 38.9 24.1 38.9 24.1 38.9
n (Patient) 36 38 35 39 35 39
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.17 10.4 8.17 10.4 8.17 10.4
Average 10.8 12.9 10.8 12.9 10.8 12.9
Stdev 7.69 9.22 7.69 9.22 7.69 9.22
p (t-test) 0.33 0.33 0.33
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 36.8 38.9 36.8 38.9 36.8 38.9
n (Patient) 44 29 44 29 44 29
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.99 10.6 9.56 10.4 9.56 10.4
Average 10.5 13.8 10.7 13.5 10.7 13.5
Stdev 5.62 10.4 5.73 10.3 5.73 10.3
p (t-test) 0.17 0.23 0.23
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 24.1 38.9 24.1 38.9 24.1 38.9
n (Patient) 18 30 17 31 17 31
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.60 0.57 0.56 0.60 0.57 0.54 0.60 0.57 0.54
SE 0.066 0.069 0.085 0.066 0.069 0.087 0.066 0.069 0.087
p Value 0.11 0.29 0.49 0.15 0.29 0.62 0.15 0.29 0.62
nCohort Recovered 36 44 18 35 44 17 35 44 17
nCohort Non-recovered 38 29 30 39 29 31 39 29 31
Cutoff Quartile 2 6.19 6.18 6.96 6.19 6.18 6.96 6.19 6.18 6.96
Sensitivity 82% 79% 73% 82% 79% 74% 82% 79% 74%
Specificity 33% 30% 22% 34% 30% 24% 34% 30% 24%
Cutoff Quartile 3 9.28 9.00 9.96 9.28 9.00 9.96 9.28 9.00 9.96
Sensitivity 58% 59% 53% 56% 59% 52% 56% 59% 52%
Specificity 58% 57% 56% 57% 57% 53% 57% 57% 53%
Cutoff Quartile 4 14.7 14.6 14.9 14.7 14.6 14.9 14.7 14.6 14.9
Sensitivity 32% 31% 30% 31% 31% 29% 31% 31% 29%
Specificity 81% 80% 83% 80% 80% 82% 80% 80% 82%
OR Quartile 2 2.21 1.61 0.786 2.39 1.61 0.885 2.39 1.61 0.885
p Value 0.15 0.40 0.73 0.11 0.40 0.86 0.11 0.40 0.86
Lower limit of 95% CI 0.757 0.531 0.199 0.814 0.531 0.223 0.814 0.531 0.223
Upper limit of 95% CI 6.48 4.87 3.11 6.99 4.87 3.51 6.99 4.87 3.51
OR Quartile 3 1.92 1.86 1.43 1.73 1.86 1.20 1.73 1.86 1.20
p Value 0.16 0.20 0.55 0.25 0.20 0.76 0.25 0.20 0.76
Lower limit of 95% CI 0.764 0.721 0.442 0.687 0.721 0.367 0.687 0.721 0.367
Upper limit of 95% CI 4.85 4.82 4.62 4.34 4.82 3.92 4.34 4.82 3.92
OR Quartile 4 1.91 1.75 2.14 1.78 1.75 1.91 1.78 1.75 1.91
p Value 0.24 0.31 0.31 0.29 0.31 0.39 0.29 0.31 0.39
Lower limit of 95% CI 0.655 0.597 0.495 0.609 0.597 0.440 0.609 0.597 0.440
Upper limit of 95% CI 5.59 5.13 9.27 5.19 5.13 8.29 5.19 5.13 8.29
TABLE 9.10
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts within 7 days after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 9.06 10.2 9.06 10.2 9.06 10.2
Average 11.4 13.3 11.4 13.1 11.4 13.1
Stdev 7.18 10.6 7.17 10.5 7.17 10.5
p (t-test) 0.39 0.44 0.44
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 30.8 38.9 30.8 38.9 30.8 38.9
n (Patient) 54 30 52 32 52 32
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 9.75 9.74 9.16 9.91 9.16 9.91
Average 12.6 10.8 12.5 11.1 12.5 11.1
Stdev 8.99 7.79 9.04 7.73 9.04 7.73
p (t-test) 0.38 0.47 0.47
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 38.9 37.2 38.9 37.2 38.9 37.2
n (Patient) 59 22 58 23 58 23
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 8.48 10.6 8.48 10.6 8.41 10.7
Average 11.0 13.7 10.5 13.9 10.5 13.9
Stdev 7.48 9.75 6.64 9.84 6.58 9.82
p (t-test) 0.19 0.089 0.089
Min 1.62 1.32 1.62 1.32 1.62 1.32
Max 33.3 38.9 30.8 38.9 30.8 38.9
n (Patient) 40 38 42 36 41 37
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.53 0.46 0.57 0.52 0.48 0.59 0.52 0.48 0.59
SE 0.066 0.073 0.065 0.065 0.072 0.065 0.065 0.072 0.065
p Value 0.68 0.62 0.26 0.78 0.79 0.17 0.78 0.79 0.17
nCohort Recovered 54 59 40 52 58 42 52 58 41
nCohort Non-recovered 30 22 38 32 23 36 32 23 37
Cutoff Quartile 2 6.19 6.19 6.24 6.19 6.19 6.24 6.19 6.19 6.24
Sensitivity 77% 77% 79% 75% 78% 81% 75% 78% 78%
Specificity 26% 27% 32% 25% 28% 33% 25% 28% 32%
Cutoff Quartile 3 9.66 9.75 9.66 9.66 9.75 9.66 9.66 9.75 9.66
Sensitivity 53% 50% 58% 53% 52% 58% 53% 52% 59%
Specificity 52% 51% 57% 52% 52% 57% 52% 52% 59%
Cutoff Quartile 4 16.0 15.9 15.6 16.0 15.9 15.6 16.0 15.9 15.6
Sensitivity 27% 14% 34% 28% 17% 33% 28% 17% 35%
Specificity 76% 71% 82% 77% 72% 81% 77% 72% 83%
OR Quartile 2 1.15 1.27 1.81 1.00 1.37 2.07 1.00 1.37 1.68
p Value 0.79 0.69 0.26 1.0 0.59 0.17 1.0 0.59 0.32
Lower limit of 95% CI 0.406 0.400 0.649 0.362 0.436 0.728 0.362 0.436 0.605
Upper limit of 95% CI 3.26 4.00 5.02 2.76 4.31 5.89 2.76 4.31 4.68
OR Quartile 3 1.23 1.03 1.86 1.22 1.17 1.87 1.22 1.17 2.07
p Value 0.65 0.95 0.18 0.65 0.75 0.17 0.65 0.75 0.11
Lower limit of 95% CI 0.503 0.389 0.757 0.507 0.445 0.758 0.507 0.445 0.839
Upper limit of 95% CI 3.01 2.75 4.57 2.96 3.07 4.60 2.96 3.07 5.11
OR Quartile 4 1.15 0.390 2.45 1.30 0.553 2.12 1.30 0.553 2.63
p Value 0.79 0.17 0.096 0.60 0.34 0.15 0.60 0.34 0.073
Lower limit of 95% CI 0.413 0.102 0.853 0.477 0.163 0.754 0.477 0.163 0.914
Upper limit of 95% CI 3.19 1.49 7.04 3.56 1.88 5.99 3.56 1.88 7.57
Example 10. Use of Tyrosine-Protein Kinase Receptor UFO for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. Tyrosine-protein kinase receptor UFO is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is risk of injury (R), injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 10.1
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 12 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 6.03 3.67 5.42 3.71 6.03 3.71
Average 6.95 4.61 5.98 4.75 6.82 4.74
Stdev 2.51 4.17 2.14 4.21 2.09 4.15
p (t-test) 0.051 0.29 0.18
Min 3.44 0.276 3.44 0.276 4.88 0.276
Max 10.3 20.6 10.3 20.6 10.3 20.6
n (Patient) 8 73 6 75 4 77
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 7.53 2.44 6.87 2.51 6.87 2.51
Average 8.09 2.93 7.97 3.20 7.89 3.40
Stdev 4.48 2.25 4.61 2.57 4.52 2.94
p (t-test) 1.1E−6 1.5E−5 6.4E−5
Min 0.696 0.276 0.696 0.276 0.696 0.276
Max 20.6 11.5 20.6 11.5 20.6 14.5
n (Patient) 30 51 28 53 26 55
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 3.44 4.42 4.16 4.30 3.44 4.30
Average 3.86 5.21 4.05 5.21 3.93 5.17
Stdev 2.86 4.32 2.94 4.35 3.07 4.29
p (t-test) 0.22 0.32 0.33
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 10.3 20.6 10.3 20.6 10.3 20.6
n (Patient) 11 61 10 62 9 64
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.24 0.12 0.58 0.31 0.15 0.56 0.24 0.16 0.58
SE 0.076 0.037 0.090 0.099 0.041 0.095 0.10 0.043 0.098
p Value 6.7E−4 0 0.38 0.053 0 0.54 0.0097 1.6E−15 0.44
nCohort Recovered 8 30 11 6 28 10 4 26 9
nCohort Non-recovered 73 51 61 75 53 62 77 55 64
Cutoff Quartile 2 1.99 1.99 2.09 1.99 1.99 2.09 1.99 1.99 2.12
Sensitivity 71% 61% 77% 72% 62% 76% 73% 64% 77%
Specificity 0% 3% 36% 0% 4% 30% 0% 4% 44%
Cutoff Quartile 3 3.81 3.81 4.30 3.81 3.81 4.30 3.81 3.81 4.18
Sensitivity 45% 27% 51% 47% 30% 50% 47% 31% 50%
Specificity 12% 13% 55% 17% 14% 50% 0% 12% 56%
Cutoff Quartile 4 6.29 6.29 6.33 6.29 6.29 6.33 6.29 6.29 6.32
Sensitivity 22% 4% 26% 24% 8% 26% 23% 9% 25%
Specificity 50% 40% 82% 67% 43% 80% 50% 42% 78%
OR Quartile 2 0.144 0.0534 1.92 0.195 0.0611 1.34 0.292 0.0700 2.61
p Value 0.19 0.0056 0.35 0.27 0.0082 0.69 0.42 0.012 0.19
Lower limit of 95% CI 0.00793 0.00674 0.490 0.0105 0.00770 0.308 0.0151 0.00881 0.621
Upper limit of 95% CI 2.60 0.424 7.52 3.61 0.485 5.85 5.66 0.556 11.0
OR Quartile 3 0.118 0.0582 1.24 0.175 0.0721 1.00 0.0977 0.0584 1.25
p Value 0.051 4.8E−6 0.74 0.12 2.0E−5 1.0 0.12 2.9E−5 0.76
Lower limit of 95% CI 0.0138 0.0172 0.342 0.0195 0.0215 0.263 0.00509 0.0154 0.307
Upper limit of 95% CI 1.01 0.197 4.50 1.57 0.242 3.80 1.88 0.221 5.08
OR Quartile 4 0.281 0.0272 1.60 0.632 0.0612 1.39 0.305 0.0733 1.17
p Value 0.095 9.0E−6 0.57 0.61 1.5E−5 0.69 0.25 2.1E−5 0.86
Lower limit of 95% CI 0.0631 0.00554 0.312 0.107 0.0173 0.267 0.0401 0.0220 0.220
Upper limit of 95% CI 1.25 0.134 8.21 3.74 0.217 7.25 2.32 0.245 6.20
TABLE 10.2
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 24 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 6.38 3.60 6.87 3.52 7.36 3.60
Average 6.96 4.50 7.71 4.51 8.08 4.52
Stdev 3.14 4.16 2.76 4.13 2.76 4.10
p (t-test) 0.042 0.019 0.019
Min 1.99 0.276 4.88 0.276 4.88 0.276
Max 13.5 20.6 13.5 20.6 13.5 20.6
n (Patient) 11 69 8 72 7 73
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 6.38 2.44 6.35 2.51 6.35 2.51
Average 7.72 3.01 7.58 3.36 7.58 3.36
Stdev 4.54 2.47 4.52 2.99 4.52 2.99
p (t-test) 5.4E−6 8.7E−5 8.7E−5
Min 0.696 0.276 0.696 0.276 0.696 0.276
Max 20.6 11.5 20.6 14.5 20.6 14.5
n (Patient) 31 49 28 52 28 52
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 4.30 4.30 4.88 4.18 4.30 4.18
Average 3.90 5.11 4.05 5.11 3.96 5.07
Stdev 2.62 4.35 2.67 4.38 2.76 4.32
p (t-test) 0.21 0.28 0.28
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 8.32 20.6 8.32 20.6 8.32 20.6
n (Patient) 14 54 13 55 12 57
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.26 0.14 0.55 0.19 0.17 0.53 0.17 0.17 0.55
SE 0.070 0.041 0.085 0.065 0.045 0.088 0.064 0.045 0.090
p Value 5.2E−4 0 0.55 1.7E−6 3.6E−13 0.71 3.1E−7 3.6E−13 0.61
nCohort Recovered 11 31 14 8 28 13 7 28 12
nCohort Non-recovered 69 49 54 72 52 55 73 52 57
Cutoff Quartile 2 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.99
Sensitivity 71% 61% 76% 72% 63% 76% 73% 63% 75%
Specificity 0% 3% 29% 0% 4% 31% 0% 4% 33%
Cutoff Quartile 3 3.77 3.77 4.30 3.77 3.77 4.30 3.77 3.77 4.18
Sensitivity 45% 27% 50% 44% 29% 49% 45% 29% 49%
Specificity 18% 13% 50% 0% 11% 46% 0% 11% 50%
Cutoff Quartile 4 6.30 6.30 6.30 6.30 6.30 6.30 6.30 6.30 6.29
Sensitivity 20% 6% 26% 21% 10% 25% 21% 10% 25%
Specificity 45% 45% 79% 38% 46% 77% 29% 46% 75%
OR Quartile 2 0.105 0.0526 1.26 0.151 0.0643 1.44 0.174 0.0643 1.54
p Value 0.12 0.0054 0.73 0.20 0.0095 0.59 0.24 0.0095 0.53
Lower limit of 95% CI 0.00591 0.00662 0.338 0.00831 0.00808 0.379 0.00950 0.00808 0.401
Upper limit of 95% CI 1.87 0.419 4.71 2.73 0.512 5.44 3.19 0.512 5.88
OR Quartile 3 0.181 0.0535 1.00 0.0472 0.0486 0.827 0.0551 0.0486 0.966
p Value 0.037 2.9E−6 1.0 0.038 9.7E−6 0.76 0.050 9.7E−6 0.96
Lower limit of 95% CI 0.0365 0.0157 0.309 0.00263 0.0127 0.246 0.00304 0.0127 0.278
Upper limit of 95% CI 0.901 0.182 3.24 0.849 0.186 2.78 1.00 0.186 3.35
OR Quartile 4 0.212 0.0537 1.28 0.158 0.0922 1.14 0.103 0.0922 0.977
p Value 0.022 2.7E−5 0.73 0.019 7.9E−5 0.86 0.010 7.9E−5 0.97
Lower limit of 95% CI 0.0564 0.0137 0.312 0.0338 0.0282 0.274 0.0182 0.0282 0.232
Upper limit of 95% CI 0.797 0.210 5.28 0.737 0.301 4.74 0.587 0.301 4.12
TABLE 10.3
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 48 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 6.01 2.51 6.32 2.77 6.32 2.77
Average 7.12 3.91 7.42 3.91 7.42 3.91
Stdev 3.85 3.87 3.88 3.81 3.88 3.81
p (t-test) 0.0020 0.0013 0.0013
Min 2.12 0.276 2.12 0.276 2.12 0.276
Max 20.6 20.5 20.6 20.5 20.6 20.5
n (Patient) 23 57 21 59 21 59
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.77 2.51 5.79 2.47 5.79 2.47
Average 6.84 3.39 7.02 3.34 7.02 3.34
Stdev 4.45 3.15 4.40 3.13 4.40 3.13
p (t-test) 3.6E−4 1.6E−4 1.6E−4
Min 0.696 0.276 0.696 0.276 0.696 0.276
Max 20.6 14.5 20.6 14.5 20.6 14.5
n (Patient) 34 45 33 46 33 46
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.32 3.03 5.19 3.15 5.19 3.15
Average 5.34 4.26 4.90 4.50 4.90 4.50
Stdev 3.35 4.07 2.83 4.24 2.83 4.24
p (t-test) 0.28 0.67 0.67
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 14.5 20.5 9.65 20.5 9.65 20.5
n (Patient) 22 37 20 40 20 40
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.20 0.22 0.37 0.19 0.20 0.40 0.19 0.20 0.40
SE 0.050 0.051 0.073 0.048 0.049 0.076 0.048 0.049 0.076
p Value 1.9E−9 3.4E−8 0.070 7.1E−11 5.2E−10 0.21 7.1E−11 5.2E−10 0.21
nCohort Recovered 23 34 22 21 33 20 21 33 20
nCohort Non-recovered 57 45 37 59 46 40 59 46 40
Cutoff Quartile 2 1.90 2.05 1.62 1.90 2.05 1.63 1.90 2.05 1.63
Sensitivity 65% 62% 68% 66% 61% 70% 66% 61% 70%
Specificity 0% 9% 14% 0% 6% 15% 0% 6% 15%
Cutoff Quartile 3 3.77 3.81 3.81 3.77 3.81 3.77 3.77 3.81 3.77
Sensitivity 35% 29% 41% 36% 28% 42% 36% 28% 42%
Specificity 13% 24% 36% 10% 21% 35% 10% 21% 35%
Cutoff Quartile 4 6.30 6.30 6.15 6.30 6.30 6.08 6.30 6.30 6.08
Sensitivity 16% 11% 22% 15% 11% 22% 15% 11% 22%
Specificity 52% 56% 68% 48% 55% 70% 48% 55% 70%
OR Quartile 2 0.0389 0.159 0.329 0.0448 0.100 0.412 0.0448 0.100 0.412
p Value 0.026 0.068 0.12 0.033 0.0036 0.21 0.033 0.0036 0.21
Lower limit of 95% CI 0.00225 0.0422 0.0812 0.00258 0.0214 0.101 0.00258 0.0214 0.101
Upper limit of 95% CI 0.675 0.602 1.33 0.778 0.472 1.67 0.778 0.472 1.67
OR Quartile 3 0.0811 0.125 0.390 0.0582 0.106 0.398 0.0582 0.106 0.398
p Value 2.1E−4 6.6E−5 0.090 3.3E−4 3.0E−5 0.10 3.3E−4 3.0E−5 0.10
Lower limit of 95% CI 0.0214 0.0450 0.131 0.0123 0.0370 0.131 0.0123 0.0370 0.131
Upper limit of 95% CI 0.307 0.347 1.16 0.274 0.304 1.21 0.274 0.304 1.21
OR Quartile 4 0.205 0.158 0.591 0.164 0.146 0.677 0.164 0.146 0.677
p Value 0.0041 0.0017 0.39 0.0014 0.0011 0.53 0.0014 0.0011 0.53
Lower limit of 95% CI 0.0691 0.0501 0.180 0.0538 0.0462 0.202 0.0538 0.0462 0.202
Upper limit of 95% CI 0.605 0.500 1.94 0.498 0.464 2.27 0.498 0.464 2.27
TABLE 10.4
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 72 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.90 2.77 6.01 2.64 6.01 2.64
Average 6.65 3.65 6.83 3.62 6.83 3.62
Stdev 3.99 3.19 3.96 3.16 3.96 3.16
p (t-test) 0.0021 0.0012 0.0012
Min 0.502 0.276 0.502 0.276 0.502 0.276
Max 20.5 14.5 20.5 14.5 20.5 14.5
n (Patient) 26 53 25 54 25 54
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.58 2.65 5.67 2.51 5.67 2.77
Average 6.10 3.56 6.24 3.50 6.27 3.60
Stdev 3.92 3.19 3.89 3.17 3.94 3.20
p (t-test) 0.0034 0.0017 0.0029
Min 0.502 0.276 0.502 0.276 0.502 0.276
Max 20.5 14.5 20.5 14.5 20.5 14.5
n (Patient) 35 42 34 43 32 45
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 3.72 3.03 4.09 2.91 4.09 2.91
Average 4.05 4.06 4.18 4.00 4.18 4.00
Stdev 2.71 3.51 2.74 3.48 2.74 3.48
p (t-test) 0.99 0.85 0.85
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 9.53 14.5 9.53 14.5 9.53 14.5
n (Patient) 17 35 16 36 16 36
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.24 0.27 0.46 0.22 0.25 0.44 0.22 0.26 0.44
SE 0.054 0.057 0.085 0.052 0.055 0.086 0.052 0.056 0.086
p Value 1.1E−6 6.3E−5 0.64 5.5E−8 8.5E−6 0.50 5.5E−8 2.0E−5 0.50
nCohort Recovered 26 35 17 25 34 16 25 32 16
nCohort Non-recovered 53 42 35 54 43 36 54 45 36
Cutoff Quartile 2 1.81 2.12 1.56 1.81 2.12 1.56 1.81 2.12 1.56
Sensitivity 66% 67% 71% 67% 65% 72% 67% 67% 72%
Specificity 8% 17% 18% 8% 15% 19% 8% 16% 19%
Cutoff Quartile 3 3.72 3.81 3.36 3.72 3.81 3.36 3.72 3.81 3.36
Sensitivity 34% 31% 46% 33% 30% 44% 33% 31% 44%
Specificity 19% 29% 41% 16% 26% 38% 16% 25% 38%
Cutoff Quartile 4 6.15 6.29 5.39 6.15 6.29 5.39 6.15 6.29 5.39
Sensitivity 15% 12% 20% 15% 12% 19% 15% 13% 19%
Specificity 54% 60% 65% 52% 59% 62% 52% 59% 62%
OR Quartile 2 0.162 0.414 0.536 0.174 0.322 0.600 0.174 0.370 0.600
p Value 0.021 0.11 0.40 0.027 0.051 0.49 0.027 0.087 0.49
Lower limit of 95% CI 0.0344 0.139 0.126 0.0368 0.103 0.140 0.0368 0.119 0.140
Upper limit of 95% CI 0.764 1.23 2.28 0.821 1.00 2.56 0.821 1.16 2.56
OR Quartile 3 0.122 0.179 0.589 0.0952 0.156 0.480 0.0952 0.151 0.480
p Value 2.7E−4 6.1E−4 0.38 1.4E−4 2.8E−4 0.23 1.4E−4 2.7E−4 0.23
Lower limit of 95% CI 0.0396 0.0671 0.182 0.0284 0.0573 0.144 0.0284 0.0543 0.144
Upper limit of 95% CI 0.379 0.479 1.90 0.319 0.425 1.60 0.319 0.417 1.60
OR Quartile 4 0.207 0.203 0.458 0.188 0.188 0.402 0.188 0.225 0.402
p Value 0.0042 0.0067 0.24 0.0026 0.0046 0.17 0.0026 0.0085 0.17
Lower limit of 95% CI 0.0706 0.0640 0.126 0.0636 0.0592 0.109 0.0636 0.0740 0.109
Upper limit of 95% CI 0.609 0.642 1.67 0.558 0.597 1.49 0.558 0.684 1.49
TABLE 10.5
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts within 7 days after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.58 2.51 5.58 2.51 5.58 2.65
Average 6.47 3.34 6.43 3.65 6.38 3.80
Stdev 4.50 2.83 4.34 3.34 4.43 3.38
p (t-test) 4.0E−4 0.0024 0.0060
Min 0.366 0.276 0.502 0.276 0.502 0.276
Max 20.6 11.5 20.6 14.5 20.6 14.5
n (Patient) 41 42 37 46 35 48
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.32 2.51 5.32 2.51 5.32 2.51
Average 6.07 3.07 6.10 3.20 6.03 3.56
Stdev 4.53 2.46 4.51 2.72 4.40 3.30
p (t-test) 3.0E−4 6.8E−4 0.0059
Min 0.366 0.276 0.502 0.276 0.502 0.276
Max 20.6 11.5 20.6 11.5 20.6 14.5
n (Patient) 48 33 46 35 42 39
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.16 3.52 5.16 3.52 5.19 3.60
Average 5.76 4.53 5.74 4.56 5.76 4.57
Stdev 4.17 4.00 4.17 4.00 4.23 3.96
p (t-test) 0.21 0.22 0.23
Min 0.0344 0.398 0.366 0.398 0.366 0.398
Max 20.5 20.6 20.5 20.6 20.5 20.6
n (Patient) 31 48 31 48 30 49
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.26 0.27 0.39 0.26 0.27 0.39 0.28 0.29 0.39
SE 0.054 0.059 0.064 0.054 0.058 0.064 0.056 0.058 0.064
p Value 6.4E−6 1.2E−4 0.073 1.2E−5 9.7E−5 0.087 1.1E−4 3.2E−4 0.10
nCohort Recovered 41 48 31 37 46 31 35 42 30
nCohort Non-recovered 42 33 48 46 35 48 48 39 49
Cutoff Quartile 2 2.05 1.99 2.05 2.05 1.99 2.05 2.05 1.99 2.05
Sensitivity 60% 64% 69% 61% 63% 69% 62% 64% 69%
Specificity 10% 19% 16% 8% 17% 16% 9% 17% 17%
Cutoff Quartile 3 4.01 3.81 4.42 4.01 3.81 4.42 4.01 3.81 4.42
Sensitivity 31% 27% 40% 33% 29% 42% 35% 31% 43%
Specificity 32% 35% 35% 30% 35% 39% 31% 33% 40%
Cutoff Quartile 4 6.30 6.29 6.35 6.30 6.29 6.35 6.30 6.29 6.35
Sensitivity 12% 6% 21% 15% 9% 21% 17% 13% 20%
Specificity 61% 62% 68% 62% 63% 68% 63% 64% 67%
OR Quartile 2 0.159 0.404 0.423 0.137 0.356 0.423 0.156 0.357 0.453
p Value 0.0027 0.080 0.14 0.0032 0.049 0.14 0.0058 0.053 0.17
Lower limit of 95% CI 0.0478 0.146 0.136 0.0366 0.128 0.136 0.0417 0.126 0.146
Upper limit of 95% CI 0.529 1.11 1.32 0.514 0.993 1.32 0.585 1.01 1.41
OR Quartile 3 0.208 0.206 0.360 0.205 0.213 0.451 0.251 0.222 0.500
p Value 9.1E−4 0.0014 0.033 9.0E−4 0.0015 0.091 0.0035 0.0016 0.14
Lower limit of 95% CI 0.0823 0.0781 0.141 0.0802 0.0824 0.179 0.0995 0.0873 0.198
Upper limit of 95% CI 0.526 0.541 0.919 0.522 0.553 1.14 0.635 0.566 1.26
OR Quartile 4 0.211 0.108 0.553 0.295 0.160 0.553 0.338 0.265 0.513
p Value 0.0067 0.0047 0.26 0.022 0.0068 0.26 0.038 0.021 0.20
Lower limit of 95% CI 0.0685 0.0229 0.198 0.104 0.0425 0.198 0.122 0.0854 0.183
Upper limit of 95% CI 0.650 0.504 1.54 0.837 0.602 1.54 0.941 0.820 1.44
TABLE 10.6
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 12 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.706 0.614 0.468 0.636 0.373 0.640
Average 0.685 0.887 0.537 0.889 0.434 0.890
Stdev 0.369 0.875 0.329 0.859 0.288 0.854
p (t-test) 0.26 0.11 0.061
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 1.22 4.86 0.948 4.86 0.881 4.86
n (Patient) 8 74 5 77 4 78
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.522 0.737 0.484 0.737 0.484 0.690
Average 0.615 1.04 0.603 1.03 0.612 1.01
Stdev 0.410 0.990 0.416 0.973 0.428 0.961
p (t-test) 0.010 0.0087 0.014
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.35 4.86 2.35 4.86 2.35 4.86
n (Patient) 31 50 29 52 27 54
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.915 0.575 0.881 0.571 0.817 0.571
Average 0.880 0.870 0.842 0.872 0.829 0.863
Stdev 0.451 0.921 0.460 0.915 0.487 0.905
p (t-test) 0.96 0.88 0.88
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 1.47 4.86 1.47 4.86 1.47 4.86
n (Patient) 10 61 9 62 8 64
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.52 0.63 0.38 0.64 0.64 0.42 0.72 0.63 0.43
SE 0.11 0.062 0.090 0.12 0.062 0.098 0.11 0.064 0.10
p Value 0.87 0.039 0.19 0.23 0.022 0.39 0.046 0.041 0.52
nCohort Recovered 8 31 10 5 29 9 4 27 8
nCohort Non-recovered 74 50 61 77 52 62 78 54 64
Cutoff Quartile 2 0.374 0.374 0.375 0.374 0.374 0.375 0.374 0.374 0.374
Sensitivity 74% 78% 74% 75% 79% 74% 76% 78% 75%
Specificity 25% 32% 20% 40% 34% 22% 50% 33% 25%
Cutoff Quartile 3 0.614 0.636 0.636 0.614 0.636 0.593 0.614 0.636 0.584
Sensitivity 50% 56% 46% 51% 56% 47% 51% 54% 48%
Specificity 50% 61% 30% 60% 62% 33% 75% 59% 38%
Cutoff Quartile 4 1.04 1.04 0.990 1.04 1.04 0.990 1.04 1.04 0.984
Sensitivity 26% 36% 23% 27% 35% 24% 27% 33% 23%
Specificity 75% 94% 60% 100% 93% 67% 100% 93% 62%
OR Quartile 2 0.965 1.69 0.703 2.04 1.96 0.821 3.11 1.75 1.00
p Value 0.97 0.31 0.68 0.45 0.19 0.82 0.27 0.28 1.0
Lower limit of 95% CI 0.179 0.617 0.135 0.316 0.711 0.154 0.409 0.628 0.183
Upper limit of 95% CI 5.19 4.62 3.67 13.1 5.41 4.37 23.6 4.88 5.46
OR Quartile 3 1.00 2.02 0.364 1.54 2.06 0.439 3.16 1.69 0.564
p Value 1.0 0.13 0.17 0.65 0.13 0.27 0.33 0.27 0.46
Lower limit of 95% CI 0.232 0.808 0.0859 0.243 0.815 0.101 0.315 0.662 0.124
Upper limit of 95% CI 4.30 5.02 1.54 9.73 5.22 1.92 31.7 4.30 2.56
OR Quartile 4 1.04 8.16 0.447 4.19 7.15 0.638 3.37 6.25 0.510
p Value 0.97 0.0078 0.26 0.34 0.013 0.56 0.42 0.020 0.39
Lower limit of 95% CI 0.193 1.74 0.110 0.222 1.52 0.142 0.174 1.33 0.109
Upper limit of 95% CI 5.58 38.2 1.81 79.0 33.5 2.87 65.2 29.4 2.39
TABLE 10.7
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 24 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.724 0.614 0.517 0.640 0.517 0.640
Average 0.809 0.881 0.728 0.888 0.755 0.881
Stdev 0.557 0.882 0.594 0.871 0.661 0.861
p (t-test) 0.74 0.53 0.70
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.14 4.86 2.14 4.86 2.14 4.86
n (Patient) 10 70 8 72 6 74
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.567 0.644 0.522 0.644 0.545 0.643
Average 0.685 1.01 0.675 0.999 0.687 0.986
Stdev 0.486 1.000 0.498 0.981 0.502 0.975
p (t-test) 0.065 0.058 0.079
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.35 4.86 2.35 4.86 2.35 4.86
n (Patient) 31 48 29 50 28 51
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.754 0.640 0.673 0.636 0.593 0.636
Average 0.923 0.874 0.902 0.877 0.898 0.866
Stdev 0.685 0.925 0.704 0.919 0.730 0.907
p (t-test) 0.83 0.91 0.90
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 15 54 14 55 13 57
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.48 0.58 0.42 0.56 0.59 0.44 0.56 0.58 0.45
SE 0.097 0.065 0.081 0.10 0.065 0.084 0.12 0.066 0.087
p Value 0.87 0.23 0.32 0.55 0.15 0.50 0.61 0.24 0.59
nCohort Recovered 10 31 15 8 29 14 6 28 13
nCohort Non-recovered 70 48 54 72 50 55 74 51 57
Cutoff Quartile 2 0.374 0.375 0.376 0.374 0.375 0.376 0.374 0.375 0.375
Sensitivity 76% 77% 72% 76% 78% 73% 76% 76% 74%
Specificity 30% 29% 20% 38% 31% 21% 33% 29% 23%
Cutoff Quartile 3 0.614 0.636 0.643 0.614 0.636 0.636 0.614 0.636 0.614
Sensitivity 50% 52% 48% 51% 52% 49% 51% 51% 51%
Specificity 50% 55% 47% 62% 55% 50% 67% 54% 54%
Cutoff Quartile 4 1.04 1.04 1.00 1.04 1.04 1.00 1.04 1.04 0.995
Sensitivity 24% 33% 22% 26% 34% 24% 26% 33% 25%
Specificity 70% 87% 67% 88% 90% 71% 83% 89% 69%
OR Quartile 2 1.34 1.38 0.650 1.94 1.60 0.727 1.56 1.30 0.840
p Value 0.70 0.54 0.55 0.40 0.38 0.66 0.63 0.62 0.81
Lower limit of 95% CI 0.311 0.493 0.161 0.420 0.568 0.178 0.263 0.457 0.203
Upper limit of 95% CI 5.75 3.84 2.63 8.98 4.48 2.97 9.21 3.69 3.47
OR Quartile 3 1.00 1.32 0.812 1.76 1.33 0.964 2.11 1.20 1.21
p Value 1.0 0.55 0.72 0.46 0.54 0.95 0.40 0.70 0.76
Lower limit of 95% CI 0.266 0.533 0.258 0.392 0.532 0.298 0.364 0.477 0.361
Upper limit of 95% CI 3.76 3.27 2.56 7.93 3.34 3.12 12.2 3.02 4.04
OR Quartile 4 0.748 3.38 0.571 2.51 4.46 0.774 1.73 4.17 0.733
p Value 0.70 0.049 0.38 0.40 0.028 0.70 0.63 0.036 0.64
Lower limit of 95% CI 0.174 1.01 0.164 0.289 1.18 0.208 0.190 1.10 0.195
Upper limit of 95% CI 3.22 11.3 2.00 21.8 16.9 2.88 15.7 15.8 2.75
TABLE 10.8
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 48 hours after sample collection and renal status is assessed by serum
creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.567 0.614 0.625 0.593 0.625 0.593
Average 0.692 0.915 0.725 0.894 0.725 0.894
Stdev 0.563 0.923 0.587 0.907 0.587 0.907
p (t-test) 0.21 0.37 0.37
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 21 56 18 59 18 59
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.503 0.644 0.522 0.643 0.522 0.643
Average 0.674 0.988 0.685 0.973 0.685 0.973
Stdev 0.578 0.983 0.584 0.977 0.584 0.977
p (t-test) 0.090 0.12 0.12
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 32 44 31 45 31 45
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.718 0.532 0.718 0.553 0.718 0.553
Average 0.857 0.880 0.865 0.859 0.865 0.859
Stdev 0.604 0.879 0.634 0.853 0.634 0.853
p (t-test) 0.91 0.98 0.98
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.60 2.99 4.60 2.99 4.60
n (Patient) 20 37 18 40 18 40
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.55 0.61 0.43 0.51 0.59 0.43 0.51 0.59 0.43
SE 0.073 0.065 0.079 0.078 0.066 0.080 0.078 0.066 0.080
p Value 0.53 0.094 0.34 0.89 0.16 0.36 0.89 0.16 0.36
nCohort Recovered 21 32 20 18 31 18 18 31 18
nCohort Non-recovered 56 44 37 59 45 40 59 45 40
Cutoff Quartile 2 0.374 0.374 0.389 0.374 0.374 0.379 0.374 0.374 0.379
Sensitivity 73% 80% 68% 71% 78% 70% 71% 78% 70%
Specificity 24% 31% 15% 17% 29% 17% 17% 29% 17%
Cutoff Quartile 3 0.593 0.584 0.636 0.593 0.584 0.614 0.593 0.584 0.614
Sensitivity 50% 57% 46% 49% 56% 48% 49% 56% 48%
Specificity 52% 59% 45% 50% 58% 44% 50% 58% 44%
Cutoff Quartile 4 1.00 1.01 1.07 1.00 1.01 1.06 1.00 1.01 1.06
Sensitivity 32% 36% 24% 31% 36% 25% 31% 36% 25%
Specificity 95% 91% 75% 94% 90% 72% 94% 90% 72%
OR Quartile 2 0.854 1.77 0.368 0.494 1.43 0.467 0.494 1.43 0.467
p Value 0.79 0.29 0.16 0.31 0.50 0.29 0.31 0.50 0.29
Lower limit of 95% CI 0.266 0.621 0.0900 0.127 0.503 0.114 0.127 0.503 0.114
Upper limit of 95% CI 2.74 5.03 1.50 1.93 4.08 1.92 1.93 4.08 1.92
OR Quartile 3 1.10 1.92 0.695 0.967 1.73 0.724 0.967 1.73 0.724
p Value 0.85 0.17 0.51 0.95 0.24 0.57 0.95 0.24 0.57
Lower limit of 95% CI 0.403 0.763 0.233 0.336 0.687 0.237 0.336 0.687 0.237
Upper limit of 95% CI 3.00 4.84 2.07 2.78 4.36 2.21 2.78 4.36 2.21
OR Quartile 4 9.47 5.52 0.964 7.46 5.15 0.867 7.46 5.15 0.867
p Value 0.035 0.012 0.95 0.060 0.016 0.82 0.060 0.016 0.82
Lower limit of 95% CI 1.18 1.45 0.273 0.922 1.35 0.247 0.922 1.35 0.247
Upper limit of 95% CI 76.2 21.1 3.40 60.4 19.6 3.04 60.4 19.6 3.04
TABLE 10.9
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 72 hours after sample collection and renal status is assessed by
serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.669 0.584 0.669 0.584 0.669 0.584
Average 0.832 0.883 0.832 0.883 0.832 0.883
Stdev 0.672 0.927 0.672 0.927 0.672 0.927
p (t-test) 0.80 0.80 0.80
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 22 52 22 52 22 52
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.567 0.614 0.567 0.614 0.656 0.584
Average 0.779 0.927 0.782 0.917 0.818 0.888
Stdev 0.650 0.999 0.663 0.980 0.671 0.967
p (t-test) 0.46 0.49 0.72
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 33 40 31 42 29 44
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.625 0.605 0.625 0.605 0.625 0.605
Average 0.752 0.880 0.752 0.880 0.752 0.880
Stdev 0.372 0.871 0.372 0.871 0.372 0.871
p (t-test) 0.49 0.49 0.49
Min 0.279 0.172 0.279 0.172 0.279 0.172
Max 1.47 4.60 1.47 4.60 1.47 4.60
n (Patient) 14 34 14 34 14 34
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.48 0.53 0.45 0.48 0.53 0.45 0.48 0.48 0.45
SE 0.073 0.068 0.091 0.073 0.069 0.091 0.073 0.069 0.091
p Value 0.78 0.67 0.59 0.78 0.69 0.59 0.78 0.82 0.59
nCohort Recovered 22 33 14 22 31 14 22 29 14
nCohort Non-recovered 52 40 34 52 42 34 52 44 34
Cutoff Quartile 2 0.375 0.374 0.397 0.375 0.374 0.397 0.375 0.374 0.397
Sensitivity 73% 75% 71% 73% 74% 71% 73% 70% 71%
Specificity 23% 27% 14% 23% 26% 14% 23% 21% 14%
Cutoff Quartile 3 0.614 0.593 0.614 0.614 0.593 0.614 0.614 0.593 0.614
Sensitivity 48% 50% 50% 48% 50% 50% 48% 48% 50%
Specificity 45% 52% 50% 45% 52% 50% 45% 48% 50%
Cutoff Quartile 4 1.03 1.00 1.05 1.03 1.00 1.05 1.03 1.00 1.05
Sensitivity 29% 30% 26% 29% 31% 26% 29% 30% 26%
Specificity 82% 82% 79% 82% 84% 79% 82% 83% 79%
OR Quartile 2 0.798 1.12 0.400 0.798 0.980 0.400 0.798 0.622 0.400
p Value 0.71 0.83 0.28 0.71 0.97 0.28 0.71 0.40 0.28
Lower limit of 95% CI 0.248 0.394 0.0754 0.248 0.340 0.0754 0.248 0.206 0.0754
Upper limit of 95% CI 2.57 3.21 2.12 2.57 2.83 2.12 2.57 1.88 2.12
OR Quartile 3 0.772 1.06 1.00 0.772 1.07 1.00 0.772 0.852 1.00
p Value 0.61 0.90 1.0 0.61 0.89 1.0 0.61 0.74 1.0
Lower limit of 95% CI 0.284 0.423 0.288 0.284 0.421 0.288 0.284 0.333 0.288
Upper limit of 95% CI 2.10 2.67 3.47 2.10 2.70 3.47 2.10 2.18 3.47
OR Quartile 4 1.82 1.93 1.32 1.82 2.33 1.32 1.82 2.01 1.32
p Value 0.34 0.25 0.71 0.34 0.15 0.71 0.34 0.24 0.71
Lower limit of 95% CI 0.529 0.633 0.298 0.529 0.731 0.298 0.529 0.630 0.298
Upper limit of 95% CI 6.29 5.87 5.84 6.29 7.43 5.84 6.29 6.43 5.84
TABLE 10.10
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts within 7 days after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.602 0.618 0.612 0.614 0.561 0.640
Average 0.845 0.874 0.875 0.844 0.869 0.851
Stdev 0.838 0.827 0.872 0.796 0.894 0.779
p (t-test) 0.88 0.87 0.92
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 4.86 4.60 4.86 4.60 4.86 4.60
n (Patient) 44 40 40 44 38 46
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.561 0.644 0.602 0.643 0.539 0.644
Average 0.845 0.919 0.865 0.889 0.862 0.889
Stdev 0.847 0.836 0.860 0.821 0.897 0.781
p (t-test) 0.71 0.90 0.89
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 4.86 4.60 4.86 4.60 4.86 4.60
n (Patient) 48 33 46 35 42 39
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.580 0.609 0.593 0.575 0.580 0.609
Average 0.753 0.906 0.746 0.909 0.739 0.910
Stdev 0.537 0.979 0.533 0.989 0.541 0.979
p (t-test) 0.38 0.35 0.33
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 30 48 31 47 30 48
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.51 0.56 0.47 0.49 0.53 0.47 0.51 0.56 0.49
SE 0.063 0.066 0.067 0.063 0.065 0.067 0.064 0.064 0.067
p Value 0.94 0.39 0.67 0.86 0.61 0.71 0.87 0.32 0.84
nCohort Recovered 44 48 30 40 46 31 38 42 30
nCohort Non-recovered 40 33 48 44 35 47 46 39 48
Cutoff Quartile 2 0.372 0.374 0.375 0.372 0.374 0.374 0.372 0.374 0.374
Sensitivity 72% 79% 69% 73% 77% 70% 74% 79% 71%
Specificity 23% 29% 17% 22% 28% 19% 24% 31% 20%
Cutoff Quartile 3 0.614 0.636 0.584 0.614 0.636 0.584 0.614 0.636 0.584
Sensitivity 50% 55% 50% 50% 51% 49% 52% 54% 50%
Specificity 50% 54% 50% 50% 52% 48% 53% 55% 50%
Cutoff Quartile 4 1.04 1.04 0.995 1.04 1.04 0.995 1.04 1.04 0.995
Sensitivity 30% 30% 29% 27% 29% 30% 28% 28% 29%
Specificity 80% 79% 80% 78% 78% 81% 79% 79% 80%
OR Quartile 2 0.775 1.53 0.440 0.774 1.33 0.566 0.879 1.74 0.607
p Value 0.61 0.42 0.16 0.61 0.58 0.30 0.80 0.29 0.37
Lower limit of 95% CI 0.288 0.540 0.141 0.286 0.481 0.190 0.325 0.629 0.204
Upper limit of 95% CI 2.09 4.33 1.37 2.09 3.68 1.68 2.38 4.80 1.81
OR Quartile 3 1.00 1.42 1.00 1.00 1.16 0.898 1.21 1.41 1.00
p Value 1.0 0.44 1.0 1.0 0.75 0.82 0.66 0.44 1.0
Lower limit of 95% CI 0.425 0.582 0.402 0.425 0.479 0.363 0.513 0.589 0.402
Upper limit of 95% CI 2.35 3.45 2.49 2.35 2.78 2.23 2.87 3.39 2.49
OR Quartile 4 1.67 1.65 1.65 1.29 1.44 1.77 1.48 1.44 1.65
p Value 0.32 0.33 0.37 0.61 0.48 0.30 0.45 0.48 0.37
Lower limit of 95% CI 0.615 0.597 0.554 0.477 0.522 0.595 0.538 0.522 0.554
Upper limit of 95% CI 4.52 4.57 4.90 3.50 3.97 5.25 4.06 3.97 4.90
Example 11. Use of Tyrosine-Protein Kinase Receptor UFO for Evaluating Renal Status in Patients Admitted to the ICU: Recovery to RIFLE 0 and R from RIFLE I and F
Patients from the intensive care unit (ICU) are enrolled in the following study. EDTA anti-coagulated blood samples (10 mL) and a urine samples (25-30 mL) are collected from each patient at enrollment, 4 (±0.5) and 8 (±1) hours after contrast administration (if applicable); at 12 (±1), 24 (±2), and 48 (±2) hours after enrollment, and thereafter daily up to day 7 to day 14 while the subject is hospitalized. Tyrosine-protein kinase receptor UFO is measured in the earliest samples collected while the patients were in RIFLE I or F by standard immunoassay methods using commercially available assay reagents.
Kidney status is assessed by RIFLE criteria based on serum creatinine, urine output, or both serum creatinine and urine output during a period starting at 12, 24, 48, or 72 hours after sample collection or at any time within 7 days after sample collection. Two cohorts are defined to represent a “recovered” and a “non-recovered” population. “Recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is non-injury (RIFLE 0) or risk of injury (R). “Non-recovered” indicates those patients whose maximum RIFLE stage during a period of 24, 48 or 72 hours is injury (I) or failure (F). If a patient dies or is placed on renal replacement therapy (RRT) within 9 days of enrollment, the patient is considered “non-recovered”.
The ability to distinguish the “recovered” and “non-recovered” cohorts is determined using receiver operating characteristic (ROC) analysis.
TABLE 11.1
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 12 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.79 3.52 5.74 3.60 5.69 3.64
Average 6.19 4.43 5.96 4.53 5.46 4.68
Stdev 3.26 4.24 3.19 4.27 2.51 4.41
p (t-test) 0.070 0.14 0.36
Min 1.99 0.276 1.99 0.276 1.99 0.276
Max 14.5 20.6 14.5 20.6 10.3 20.6
n (Patient) 19 62 18 63 17 64
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.58 2.32 5.58 2.47 5.58 2.47
Average 6.33 2.79 6.31 3.02 6.31 3.02
Stdev 4.42 2.41 4.45 2.65 4.45 2.65
p (t-test) 2.0E−5 1.1E−4 1.1E−4
Min 0.502 0.276 0.502 0.276 0.502 0.276
Max 20.6 11.5 20.6 11.5 20.6 11.5
n (Patient) 47 34 45 36 45 36
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 4.74 4.09 4.88 4.01 4.21 4.18
Average 4.87 5.05 5.13 5.01 4.29 5.29
Stdev 3.50 4.39 3.61 4.42 2.74 4.58
p (t-test) 0.86 0.91 0.27
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 14.5 20.6 14.5 20.6 10.3 20.6
n (Patient) 20 52 21 51 20 53
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.30 0.21 0.48 0.33 0.23 0.46 0.35 0.23 0.53
SE 0.064 0.053 0.076 0.067 0.054 0.074 0.071 0.054 0.076
p Value 0.0021 6.9E−8 0.83 0.0094 9.1E−7 0.58 0.039 9.1E−7 0.73
nCohort Recovered 19 47 20 18 45 21 17 45 20
nCohort Non-recovered 62 34 52 63 36 51 64 36 53
Cutoff Quartile 2 1.99 1.99 2.09 1.99 1.99 2.09 1.99 1.99 2.12
Sensitivity 68% 56% 75% 68% 58% 75% 69% 58% 75%
Specificity 5% 13% 25% 6% 13% 24% 6% 13% 30%
Cutoff Quartile 3 3.81 3.81 4.30 3.81 3.81 4.30 3.81 3.81 4.18
Sensitivity 44% 24% 48% 44% 25% 47% 45% 25% 49%
Specificity 32% 32% 45% 33% 31% 43% 35% 31% 50%
Cutoff Quartile 4 6.29 6.29 6.33 6.29 6.29 6.33 6.29 6.29 6.32
Sensitivity 21% 6% 25% 22% 8% 24% 23% 8% 26%
Specificity 63% 62% 75% 67% 62% 71% 71% 62% 80%
OR Quartile 2 0.117 0.185 1.00 0.126 0.215 0.913 0.138 0.215 1.32
p Value 0.043 0.0025 1.0 0.052 0.0056 0.88 0.063 0.0056 0.64
Lower limit of 95% CI 0.0145 0.0622 0.304 0.0157 0.0728 0.279 0.0170 0.0728 0.421
Upper limit of 95% CI 0.937 0.552 3.29 1.02 0.638 2.99 1.11 0.638 4.14
OR Quartile 3 0.356 0.144 0.758 0.400 0.151 0.667 0.452 0.151 0.963
p Value 0.063 1.5E−4 0.60 0.10 1.6E−4 0.44 0.16 1.6E−4 0.94
Lower limit of 95% CI 0.120 0.0530 0.269 0.133 0.0563 0.239 0.149 0.0563 0.344
Upper limit of 95% CI 1.06 0.393 2.13 1.20 0.403 1.86 1.37 0.403 2.69
OR Quartile 4 0.455 0.101 1.00 0.571 0.150 0.769 0.735 0.150 1.44
p Value 0.17 0.0036 1.0 0.34 0.0050 0.65 0.61 0.0050 0.57
Lower limit of 95% CI 0.149 0.0215 0.304 0.182 0.0397 0.244 0.223 0.0397 0.410
Upper limit of 95% CI 1.39 0.472 3.29 1.80 0.564 2.42 2.42 0.564 5.03
TABLE 11.2
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 24 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.90 3.15 5.79 3.28 5.79 3.36
Average 6.37 4.17 6.20 4.28 5.83 4.46
Stdev 3.54 4.18 3.52 4.22 3.11 4.39
p (t-test) 0.022 0.046 0.13
Min 0.502 0.276 0.502 0.276 0.502 0.276
Max 14.5 20.6 14.5 20.6 13.5 20.6
n (Patient) 24 56 23 57 22 58
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.58 2.44 5.54 2.47 5.58 2.51
Average 6.41 2.81 6.32 3.02 6.34 3.08
Stdev 4.49 2.38 4.50 2.65 4.55 2.65
p (t-test) 2.1E−5 1.4E−4 1.9E−4
Min 0.502 0.276 0.502 0.276 0.502 0.276
Max 20.6 11.5 20.6 11.5 20.6 11.5
n (Patient) 45 35 44 36 43 37
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.02 3.84 5.16 3.67 4.74 4.01
Average 4.96 4.82 5.19 4.77 4.42 5.09
Stdev 3.39 4.38 3.49 4.42 2.70 4.61
p (t-test) 0.89 0.67 0.46
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 14.5 20.6 14.5 20.6 8.84 20.6
n (Patient) 22 46 23 45 22 47
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.28 0.21 0.45 0.30 0.24 0.43 0.33 0.25 0.49
SE 0.059 0.053 0.074 0.061 0.055 0.072 0.064 0.055 0.075
p Value 2.4E−4 6.3E−8 0.49 0.0014 1.4E−6 0.31 0.0071 3.8E−6 0.91
nCohort Recovered 24 45 22 23 44 23 22 43 22
nCohort Non-recovered 56 35 46 57 36 45 58 37 47
Cutoff Quartile 2 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.90 1.99
Sensitivity 66% 57% 74% 67% 58% 73% 67% 59% 74%
Specificity 4% 11% 23% 4% 11% 22% 5% 12% 27%
Cutoff Quartile 3 3.77 3.77 4.30 3.77 3.77 4.30 3.77 3.77 4.18
Sensitivity 41% 23% 46% 42% 25% 44% 43% 27% 47%
Specificity 29% 29% 41% 30% 30% 39% 32% 30% 45%
Cutoff Quartile 4 6.30 6.30 6.30 6.30 6.30 6.30 6.30 6.30 6.29
Sensitivity 16% 6% 22% 18% 8% 20% 19% 8% 23%
Specificity 54% 60% 68% 57% 61% 65% 59% 60% 73%
OR Quartile 2 0.0847 0.167 0.833 0.0909 0.179 0.764 0.0977 0.193 1.09
p Value 0.020 0.0022 0.76 0.024 0.0032 0.66 0.028 0.0047 0.88
Lower limit of 95% CI 0.0106 0.0530 0.252 0.0114 0.0572 0.232 0.0122 0.0617 0.348
Upper limit of 95% CI 0.676 0.524 2.75 0.726 0.563 2.51 0.782 0.604 3.44
OR Quartile 3 0.287 0.120 0.582 0.318 0.140 0.514 0.354 0.160 0.733
p Value 0.017 4.6E−5 0.30 0.030 1.0E−4 0.20 0.049 2.3E−4 0.55
Lower limit of 95% CI 0.103 0.0435 0.208 0.113 0.0517 0.185 0.125 0.0606 0.265
Upper limit of 95% CI 0.803 0.333 1.63 0.893 0.378 1.43 0.997 0.425 2.03
OR Quartile 4 0.226 0.0909 0.595 0.277 0.144 0.469 0.338 0.135 0.815
p Value 0.0067 0.0024 0.37 0.019 0.0043 0.19 0.048 0.0031 0.73
Lower limit of 95% CI 0.0773 0.0194 0.191 0.0948 0.0382 0.152 0.116 0.0357 0.256
Upper limit of 95% CI 0.662 0.427 1.86 0.807 0.545 1.45 0.989 0.510 2.59
TABLE 11.3
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 48 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.67 2.65 5.67 2.91 5.58 3.03
Average 6.19 3.61 5.96 4.00 5.88 4.10
Stdev 4.10 3.75 3.96 4.05 3.99 4.06
p (t-test) 0.0051 0.036 0.059
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.6 20.5 20.6 20.5 20.6 20.5
n (Patient) 38 42 34 46 33 47
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.36 2.65 5.32 2.78 5.32 2.78
Average 6.01 3.20 6.03 3.27 6.03 3.27
Stdev 4.52 2.75 4.57 2.73 4.57 2.73
p (t-test) 0.0011 0.0014 0.0014
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.6 11.5 20.6 11.5 20.6 11.5
n (Patient) 47 32 46 33 46 33
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.16 2.91 4.88 3.28 4.67 3.36
Average 5.49 3.87 4.76 4.54 4.59 4.66
Stdev 3.43 4.07 2.79 4.42 2.72 4.42
p (t-test) 0.11 0.81 0.95
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 14.5 20.5 9.65 20.5 9.65 20.5
n (Patient) 29 30 25 35 24 36
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.27 0.28 0.32 0.30 0.29 0.41 0.32 0.29 0.44
SE 0.056 0.060 0.070 0.058 0.060 0.074 0.059 0.060 0.075
p Value 2.3E−5 2.7E−4 0.0095 7.0E−4 5.3E−4 0.23 0.0023 5.3E−4 0.39
nCohort Recovered 38 47 29 34 46 25 33 46 21
nCohort Non-recovered 42 32 30 46 33 35 47 33 36
Cutoff Quartile 2 1.90 2.05 1.62 1.90 2.05 1.63 1.90 2.05 1.63
Sensitivity 60% 62% 60% 63% 64% 66% 64% 64% 67%
Specificity 8% 17% 10% 9% 17% 12% 9% 17% 12%
Cutoff Quartile 3 3.77 3.81 3.81 3.77 3.81 3.77 3.77 3.81 3.77
Sensitivity 33% 28% 37% 37% 30% 43% 38% 30% 44%
Specificity 32% 36% 38% 32% 37% 40% 33% 37% 42%
Cutoff Quartile 4 6.30 6.30 6.15 6.30 6.30 6.08 6.30 6.30 6.08
Sensitivity 12% 9% 17% 15% 9% 23% 17% 9% 25%
Specificity 61% 64% 66% 62% 63% 72% 64% 63% 75%
OR Quartile 2 0.126 0.342 0.173 0.165 0.368 0.261 0.176 0.368 0.286
p Value 0.0023 0.044 0.014 0.0078 0.060 0.059 0.010 0.060 0.078
Lower limit of 95% CI 0.0333 0.120 0.0427 0.0438 0.130 0.0649 0.0468 0.130 0.0709
Upper limit of 95% CI 0.477 0.972 0.702 0.623 1.04 1.05 0.666 1.04 1.15
OR Quartile 3 0.231 0.222 0.354 0.280 0.255 0.500 0.310 0.255 0.571
p Value 0.0022 0.0024 0.054 0.0077 0.0050 0.19 0.014 0.0050 0.29
Lower limit of 95% CI 0.0903 0.0838 0.123 0.110 0.0982 0.176 0.122 0.0982 0.201
Upper limit of 95% CI 0.589 0.587 1.02 0.714 0.661 1.42 0.789 0.661 1.62
OR Quartile 4 0.207 0.183 0.380 0.290 0.171 0.762 0.359 0.171 1.00
p Value 0.0067 0.012 0.12 0.022 0.0091 0.65 0.054 0.0091 1.0
Lower limit of 95% CI 0.0664 0.0483 0.111 0.100 0.0451 0.235 0.127 0.0451 0.303
Upper limit of 95% CI 0.647 0.690 1.30 0.838 0.645 2.47 1.02 0.645 3.30
TABLE 11.4
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 72 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.54 2.44 5.49 2.47 5.49 2.47
Average 5.89 3.47 5.81 3.60 5.81 3.60
Stdev 3.78 3.32 3.79 3.38 3.79 3.38
p (t-test) 0.0039 0.0090 0.0090
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.5 14.5 20.5 14.5 20.5 14.5
n (Patient) 38 41 37 42 37 42
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.02 2.51 5.02 2.51 5.02 2.51
Average 5.72 3.21 5.72 3.21 5.72 3.21
Stdev 3.98 2.80 3.98 2.80 3.98 2.80
p (t-test) 0.0020 0.0020 0.0020
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.5 11.5 20.5 11.5 20.5 11.5
n (Patient) 46 31 46 31 46 31
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 4.09 2.91 3.72 3.03 3.72 3.03
Average 4.28 3.92 4.04 4.06 4.04 4.06
Stdev 2.74 3.56 2.59 3.60 2.59 3.60
p (t-test) 0.69 0.98 0.98
Min 0.366 0.398 0.366 0.398 0.366 0.398
Max 9.53 14.5 9.53 14.5 9.53 14.5
n (Patient) 20 32 19 33 19 33
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.27 0.28 0.42 0.29 0.28 0.45 0.29 0.28 0.45
SE 0.056 0.061 0.081 0.057 0.061 0.083 0.057 0.061 0.083
p Value 3.8E−5 4.3E−4 0.32 1.9E−4 4.3E−4 0.54 1.9E−4 4.3E−4 0.54
nCohort Recovered 38 46 20 37 46 19 37 46 19
nCohort Non-recovered 41 31 32 42 31 33 42 31 33
Cutoff Quartile 2 1.81 2.12 1.56 1.81 2.12 1.56 1.81 2.12 1.56
Sensitivity 59% 61% 69% 60% 61% 70% 60% 61% 70%
Specificity 8% 17% 15% 8% 17% 16% 8% 17% 16%
Cutoff Quartile 3 3.72 3.81 3.36 3.72 3.81 3.36 3.72 3.81 3.36
Sensitivity 32% 29% 44% 33% 29% 45% 33% 29% 45%
Specificity 32% 37% 40% 32% 37% 42% 32% 37% 42%
Cutoff Quartile 4 6.15 6.29 5.39 6.15 6.29 5.39 6.15 6.29 5.39
Sensitivity 15% 10% 19% 17% 10% 21% 17% 10% 21%
Specificity 63% 65% 65% 65% 65% 68% 65% 65% 68%
OR Quartile 2 0.121 0.333 0.388 0.130 0.333 0.431 0.130 0.333 0.431
p Value 0.0019 0.040 0.20 0.0026 0.040 0.25 0.0026 0.040 0.25
Lower limit of 95% CI 0.0319 0.117 0.0922 0.0343 0.117 0.102 0.0343 0.117 0.102
Upper limit of 95% CI 0.459 0.953 1.63 0.491 0.953 1.82 0.491 0.953 1.82
OR Quartile 3 0.214 0.240 0.519 0.240 0.240 0.606 0.240 0.240 0.606
p Value 0.0015 0.0043 0.26 0.0030 0.0043 0.39 0.0030 0.0043 0.39
Lower limit of 95% CI 0.0830 0.0900 0.167 0.0937 0.0900 0.194 0.0937 0.0900 0.194
Upper limit of 95% CI 0.554 0.639 1.61 0.615 0.639 1.89 0.615 0.639 1.89
OR Quartile 4 0.294 0.201 0.429 0.369 0.201 0.583 0.369 0.201 0.583
p Value 0.027 0.019 0.19 0.064 0.019 0.41 0.064 0.019 0.41
Lower limit of 95% CI 0.0990 0.0528 0.119 0.128 0.0528 0.163 0.128 0.0528 0.163
Upper limit of 95% CI 0.873 0.764 1.54 1.06 0.764 2.09 1.06 0.764 2.09
TABLE 11.5
Comparison of marker levels and the area under the ROC curve (AUC) in urine samples for the “recovered” and
“non-recovered” cohorts where recovery starts within 7 days after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.16 2.35 5.54 2.51 5.54 2.51
Average 6.00 3.11 6.18 3.11 6.18 3.11
Stdev 4.39 2.63 4.45 2.55 4.45 2.55
p (t-test) 3.8E−4 1.9E−4 1.9E−4
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.6 11.5 20.6 11.5 20.6 11.5
n (Patient) 51 32 48 35 48 35
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 4.87 2.44 4.88 2.44 4.88 2.44
Average 5.57 3.02 5.66 3.01 5.66 3.01
Stdev 4.33 2.71 4.37 2.63 4.37 2.63
p (t-test) 0.0027 0.0014 0.0014
Min 0.366 0.276 0.366 0.276 0.366 0.276
Max 20.6 11.5 20.6 11.5 20.6 11.5
n (Patient) 58 23 56 25 56 25
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 5.02 3.28 5.16 3.23 5.02 3.43
Average 5.61 4.41 5.69 4.29 5.56 4.46
Stdev 3.99 4.15 4.02 4.08 4.01 4.14
p (t-test) 0.20 0.14 0.24
Min 0.0344 0.398 0.366 0.398 0.366 0.398
Max 20.5 20.6 20.5 20.6 20.5 20.6
n (Patient) 40 39 41 38 40 39
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.27 0.29 0.38 0.26 0.29 0.36 0.26 0.29 0.39
SE 0.059 0.068 0.063 0.057 0.065 0.063 0.057 0.065 0.063
p Value 8.5E−5 0.0020 0.050 1.9E−5 9.8E−4 0.029 1.9E−5 9.8E−4 0.073
nCohort Recovered 51 58 40 48 56 41 48 56 40
nCohort Non-recovered 32 23 39 35 25 38 35 25 39
Cutoff Quartile 2 2.05 1.99 2.05 2.05 1.99 2.05 2.05 1.99 2.05
Sensitivity 56% 61% 67% 57% 60% 66% 57% 60% 67%
Specificity 14% 21% 18% 12% 20% 17% 12% 20% 18%
Cutoff Quartile 3 4.01 3.81 4.42 4.01 3.81 4.42 4.01 3.81 4.42
Sensitivity 28% 22% 36% 29% 24% 37% 29% 24% 38%
Specificity 37% 40% 38% 35% 39% 39% 35% 39% 40%
Cutoff Quartile 4 6.30 6.29 6.35 6.30 6.29 6.35 6.30 6.29 6.35
Sensitivity 9% 9% 18% 9% 8% 16% 9% 8% 18%
Specificity 65% 69% 68% 62% 68% 66% 62% 68% 68%
OR Quartile 2 0.205 0.406 0.424 0.190 0.367 0.396 0.190 0.367 0.424
p Value 0.0033 0.093 0.11 0.0028 0.058 0.085 0.0028 0.058 0.11
Lower limit of 95% CI 0.0709 0.142 0.148 0.0643 0.130 0.138 0.0643 0.130 0.148
Upper limit of 95% CI 0.590 1.16 1.22 0.564 1.03 1.14 0.564 1.03 1.22
OR Quartile 3 0.232 0.183 0.336 0.219 0.204 0.373 0.219 0.204 0.417
p Value 0.0028 0.0030 0.020 0.0016 0.0034 0.034 0.0016 0.0034 0.058
Lower limit of 95% CI 0.0892 0.0594 0.135 0.0855 0.0706 0.150 0.0855 0.0706 0.169
Upper limit of 95% CI 0.605 0.560 0.839 0.563 0.592 0.928 0.563 0.592 1.03
OR Quartile 4 0.190 0.212 0.454 0.156 0.184 0.362 0.156 0.184 0.454
p Value 0.014 0.050 0.14 0.0058 0.032 0.066 0.0058 0.032 0.14
Lower limit of 95% CI 0.0507 0.0448 0.159 0.0417 0.0390 0.122 0.0417 0.0390 0.159
Upper limit of 95% CI 0.710 1.00 1.30 0.585 0.865 1.07 0.585 0.865 1.30
TABLE 11.6
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 12 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.659 0.584 0.682 0.575 0.718 0.584
Average 0.828 0.881 0.843 0.875 0.855 0.871
Stdev 0.681 0.886 0.695 0.880 0.712 0.874
p (t-test) 0.78 0.87 0.94
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 20 62 19 63 18 64
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.527 0.979 0.539 0.738 0.539 0.738
Average 0.724 1.07 0.734 1.04 0.734 1.04
Stdev 0.611 1.04 0.623 1.02 0.623 1.02
p (t-test) 0.087 0.12 0.12
Min 0.108 0.204 0.108 0.204 0.108 0.204
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 46 35 44 37 44 37
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.682 0.571 0.659 0.567 0.682 0.567
Average 1.01 0.814 0.988 0.815 0.989 0.806
Stdev 1.06 0.771 1.04 0.778 1.07 0.764
p (t-test) 0.46 0.50 0.49
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 4.86 4.60 4.86 4.60 4.86 4.60
n (Patient) 21 50 22 49 21 51
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.50 0.63 0.45 0.50 0.62 0.45 0.50 0.62 0.47
SE 0.075 0.063 0.074 0.076 0.063 0.073 0.077 0.063 0.074
p Value 0.97 0.045 0.46 1.00 0.063 0.48 1.0 0.063 0.66
nCohort Recovered 20 46 21 19 44 22 18 44 21
nCohort Non-recovered 62 35 50 63 37 49 64 37 51
Cutoff Quartile 2 0.374 0.374 0.375 0.374 0.374 0.375 0.374 0.374 0.374
Sensitivity 76% 80% 76% 76% 81% 76% 77% 81% 76%
Specificity 30% 30% 29% 32% 32% 27% 33% 32% 29%
Cutoff Quartile 3 0.614 0.636 0.636 0.614 0.636 0.593 0.614 0.636 0.584
Sensitivity 48% 60% 48% 48% 57% 47% 48% 57% 47%
Specificity 45% 59% 48% 42% 57% 45% 44% 57% 43%
Cutoff Quartile 4 1.04 1.04 0.990 1.04 1.04 0.990 1.04 1.04 0.984
Sensitivity 26% 40% 24% 25% 38% 24% 25% 38% 24%
Specificity 75% 87% 71% 74% 86% 73% 72% 86% 71%
OR Quartile 2 1.34 1.75 1.27 1.48 2.00 1.16 1.63 2.00 1.30
p Value 0.61 0.29 0.69 0.50 0.19 0.80 0.40 0.19 0.65
Lower limit of 95% CI 0.439 0.619 0.402 0.478 0.708 0.369 0.523 0.708 0.413
Upper limit of 95% CI 4.11 4.95 3.99 4.56 5.65 3.62 5.10 5.65 4.09
OR Quartile 3 0.767 2.13 0.839 0.661 1.73 0.737 0.752 1.73 0.667
p Value 0.61 0.098 0.74 0.43 0.22 0.55 0.59 0.22 0.44
Lower limit of 95% CI 0.279 0.871 0.302 0.235 0.714 0.269 0.263 0.714 0.239
Upper limit of 95% CI 2.11 5.22 2.33 1.86 4.17 2.02 2.15 4.17 1.86
OR Quartile 4 1.04 4.44 0.789 0.953 3.86 0.865 0.867 3.86 0.769
p Value 0.94 0.0075 0.69 0.94 0.015 0.80 0.81 0.015 0.65
Lower limit of 95% CI 0.327 1.49 0.251 0.296 1.30 0.276 0.267 1.30 0.244
Upper limit of 95% CI 3.33 13.3 2.49 3.07 11.4 2.71 2.81 11.4 2.42
TABLE 11.7
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 24 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.602 0.618 0.636 0.593 0.625 0.614
Average 0.763 0.924 0.795 0.903 0.802 0.899
Stdev 0.616 0.936 0.647 0.916 0.660 0.908
p (t-test) 0.37 0.56 0.61
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 26 54 23 57 22 58
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.544 0.738 0.555 0.691 0.561 0.644
Average 0.736 1.08 0.741 1.06 0.754 1.04
Stdev 0.614 1.07 0.620 1.06 0.621 1.05
p (t-test) 0.11 0.12 0.17
Min 0.108 0.217 0.108 0.217 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 46 33 45 34 44 35
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.656 0.609 0.659 0.575 0.682 0.575
Average 0.950 0.848 0.969 0.835 0.969 0.825
Stdev 0.981 0.813 0.996 0.807 1.02 0.791
p (t-test) 0.67 0.58 0.56
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 4.86 4.60 4.86 4.60 4.86 4.60
n (Patient) 25 44 24 45 23 47
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.53 0.61 0.46 0.52 0.61 0.44 0.52 0.59 0.46
SE 0.069 0.065 0.072 0.071 0.065 0.072 0.072 0.065 0.073
p Value 0.66 0.078 0.58 0.83 0.088 0.43 0.82 0.19 0.57
nCohort Recovered 26 46 25 23 45 24 22 44 23
nCohort Non-recovered 54 33 44 57 34 45 58 35 47
Cutoff Quartile 2 0.374 0.375 0.376 0.374 0.375 0.376 0374 0.375 0.375
Sensitivity 78% 82% 75% 77% 82% 73% 78% 80% 77%
Specificity 31% 30% 28% 30% 31% 25% 32% 30% 30%
Cutoff Quartile 3 0.614 0.636 0.643 0.614 0.636 0.636 0.614 0.636 0.614
Sensitivity 50% 58% 48% 49% 56% 49% 50% 54% 49%
Specificity 50% 57% 48% 48% 56% 50% 50% 55% 48%
Cutoff Quartile 4 1.04 1.04 1.00 1.04 1.04 1.00 1.04 1.04 0.995
Sensitivity 28% 36% 25% 26% 35% 24% 26% 34% 26%
Specificity 81% 83% 76% 78% 82% 75% 77% 82% 74%
OR Quartile 2 1.56 1.97 1.17 1.48 2.11 0.917 1.62 1.68 1.43
p Value 0.41 0.22 0.79 0.48 0.18 0.88 0.39 0.33 0.53
Lower limit of 95% CI 0.544 0.665 0.385 0.502 0.713 0.294 0.544 0.586 0.469
Upper limit of 95% CI 4.45 5.83 3.53 4.37 6.23 2.85 4.80 4.80 4.37
OR Quartile 3 1.00 1.76 0.843 0.885 1.58 0.957 1.00 1.42 0.878
p Value 1.0 0.22 0.73 0.80 0.32 0.93 1.0 0.44 0.80
Lower limit of 95% CI 0.392 0.715 0.315 0.336 0.646 0.355 0.375 0.584 0.324
Upper limit of 95% CI 2.55 4.35 2.25 2.33 3.88 2.58 2.67 3.47 2.38
OR Quartile 4 1.62 2.71 1.06 1.29 2.52 0.971 1.19 2.35 0.971
p Value 0.41 0.060 0.93 0.67 0.081 0.96 0.77 0.11 0.96
Lower limit of 95% CI 0.515 0.958 0.336 0.406 0.893 0.308 0.373 0.833 0.311
Upper limit of 95% CI 5.06 7.69 3.31 4.07 7.13 3.06 3.77 6.62 3.03
TABLE 11.8
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 48 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.539 0.644 0.561 0.636 0.567 0.614
Average 0.668 1.02 0.698 0.966 0.710 0.952
Stdev 0.511 1.03 0.531 0.997 0.536 0.990
p (t-test) 0.062 0.14 0.17
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 36 41 32 45 31 46
sCr only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.503 0.691 0.522 0.644 0.522 0.644
Average 0.706 1.09 0.718 1.06 0.718 1.06
Stdev 0.594 1.10 0.595 1.09 0.595 1.09
p (t-test) 0.096 0.13 0.13
Min 0.108 0.217 0.108 0172 0.108 0.172
Max 2.99 4.86 2.99 4.86 2.99 4.86
n (Patient) 46 30 45 31 45 31
UO only
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median 0.593 0.644 0.682 0.575 0.718 0.553
Average 0.771 0.963 0.816 0.890 0.838 0.875
Stdev 0.561 0.946 0.596 0.896 0.600 0.888
p (t-test) 0.36 0.71 0.85
Min 0.108 0.172 0.108 0.172 0.108 0.172
Max 2.99 4.60 2.99 4.60 2.99 4.60
n (Patient) 27 30 23 35 22 36
Recovery Period 24 48 72
Duration (hr) sCr or UO sCr only UO only sCr or UO sCr only UO only sCr or UO sCr only UO only
AUC 0.60 0.64 0.50 0.56 0.61 0.46 0.55 0.61 0.44
SE 0.065 0.066 0.077 0.066 0.067 0.077 0.067 0.067 0.077
p Value 0.13 0.034 0.97 0.34 0.090 0.59 0.49 0.090 0.40
nCohort Recovered 36 46 27 32 45 23 31 45 22
nCohort Non-recovered 41 30 30 45 31 35 46 31 36
Cutoff Quartile 2 0.374 0.374 0.389 0.374 0.374 0.379 0.374 0.374 0.379
Sensitivity 78% 90% 67% 78% 87% 71% 76% 87% 69%
Specificity 31% 35% 19% 31% 33% 22% 29% 33% 18%
Cutoff Quartile 3 0.593 0.584 0.636 0.593 0.584 0.614 0.593 0.584 0.614
Sensitivity 54% 60% 53% 51% 58% 49% 50% 58% 47%
Specificity 56% 57% 56% 53% 56% 48% 52% 56% 45%
Cutoff Quartile 4 1.00 1.01 1.07 1.00 1.01 1.06 1.00 1.01 1.06
Sensitivity 34% 37% 27% 31% 35% 26% 30% 35% 25%
Specificity 86% 83% 78% 84% 82% 74% 84% 82% 73%
OR Quartile 2 1.56 4.80 0.455 1.59 3.38 0.694 1.30 3.38 0.505
p Value 0.39 0.022 0.21 0.38 0.051 0.56 0.62 0.051 0.30
Lower limit of 95% CI 0.562 1.26 0.133 0.570 0.997 0.202 0.465 0.997 0.138
Upper limit of 95% CI 4.36 18.3 1.56 4.44 11.4 2.38 3.65 11.4 1.84
OR Quartile 3 1.45 1.95 1.43 1.18 1.73 0.866 1.07 1.73 0.746
p Value 0.42 0.16 0.50 0.71 0.24 0.79 0.89 0.24 0.59
Lower limit of 95% CI 0.589 0.766 0.503 0.478 0.687 0.302 0.429 0.687 0.257
Upper limit of 95% CI 3.56 4.96 4.06 2.94 4.36 2.48 2.65 4.36 2.16
OR Quartile 4 3.21 2.75 1.27 2.44 2.54 0.981 2.28 2.54 0.889
p Value 0.045 0.062 0.70 0.13 0.085 0.97 0.16 0.085 0.85
Lower limit of 95% CI 1.02 0.949 0.377 0.777 0.881 0.295 0.724 0.881 0.267
Upper limit of 95% CI 10.1 7.97 4.29 7.66 7.35 3.26 7.15 7.35 2.96
TABLLE 11.9
Comparison of marker levels and the area under the ROC curve (AUC) in EDTA samples for the “recovered” and
“non-recovered” cohorts where recovery starts at 72 hours after sample collection and renal status is assessed
by serum creatinine (sCr) only, urine output (UO) only, or serum creatinine or urine output RIFLE criteria.
sCr or UO
24 48 72
Recovery Period Recovered Non-recovered Recovered Non-recovered Recovered Non-recovered
Duration (hr) Cohort Cohort Cohort Cohort Cohort Cohort
Median