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1.  Glutathione S-transferase iso-enzymes in perfusate from pumped kidneys are associated with delayed graft function 
Accurate and reliable assessment tools are needed in transplantation. The objective of this prospective, multicenter study was to determine the associations of the alpha and pi iso-enzymes of glutathione S-transferase (GST), measured from perfusate solution at the start and end (base and post) of kidney allograft machine perfusion, with subsequent delayed graft function (DGF). We also compared GST iso-enzyme perfusate levels from discarded versus transplanted kidneys. A total of 428 kidneys were linked to outcomes as recorded by the United Network of Organ Sharing. DGF, defined as any dialysis in the first week of transplant, occurred in 141 recipients (32%). Alpha and pi-GST levels significantly increased during machine perfusion. The adjusted relative risks (95% confidence interval) of DGF with each log-unit increase in base and post pi-GST were 1.14 (1.0-1.28) and 1.33 (1.02-1.72), respectively. Alpha-GST was not independently associated with DGF. There were no significant differences in GST values between discarded and transplanted kidneys, though renal resistance was significantly higher in discarded kidneys. We found pi-GST at the end of machine perfusion to be independently associated with DGF. Further studies should elucidate the utility of GST for identifying injured kidneys with regard to organ allocation, discard and recipient management decisions.
PMCID: PMC4051136  PMID: 24612768
Perfusion pumping; kidney injury; ischemia; biomarker
2.  Urinary Cystatin C and Acute Kidney Injury After Cardiac Surgery 
Acute Kidney Injury (AKI) is common following cardiac surgery and is associated with adverse patient outcomes. Urinary cystatin C (CysC) is a biomarker of proximal tubule function and may rise earlier in AKI than serum creatinine.
Study Design
Prospective cohort study
Settings & Participants
The TRIBE AKI (Translational Research Investigating Biomarker Endpoints in AKI) Consortium prospectively enrolled 1,203 adults and 299 children at 8 institutions from 2007–2009.
Index Test
Urinary CysC (mg/L) within the first 12 hours after surgery
Serum Creatinine based AKI was defined as AKI Network stage 1 (Mild AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for dialysis during hospitalization (Severe AKI).
Other Measurements
Analyses were adjusted for characteristics used clinically for AKI risk stratification including age, sex, race, eGFR, diabetes, hypertension, heart failure, non-elective surgery, cardiac catheterization within 72 hours, type of surgery, myocardial infarction, and cardiopulmonary bypass time greater than 120 minutes.
Urinary CysC measured in the early post-operative period (0–6 and 6–12 hours postoperatively) correlated with both mild and severe AKI in adults and children. However after analyses were adjusted for other factors the effect was attenuated for both forms of AKI in both cohorts.
Limited numbers of patients with severe AKI and short-term dialysis
Urinary CysC values are not significantly associated with the development of AKI following cardiac surgery in adults and children.
PMCID: PMC3627833  PMID: 23332602
Acute kidney injury Biomarkers; Cystatin C; Dialysis; Peri-operative
3.  Early Trends in Cystatin C and Outcomes in Patients with Cirrhosis and Acute Kidney Injury 
Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr−/CysC−); only cystatin increased 25 (24%) (Scr−/CysC+); only creatinine increased 15 (14%) (Scr+/CysC−); and both increased 28 (26%) (Scr+/CysC+). With Scr−/CysC− as the reference, in both instances where cystatin rose, Scr−/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes.
PMCID: PMC3976933  PMID: 24757564
4.  Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review 
Nephrology Dialysis Transplantation  2012;27(8):3305-3314.
Accurate and reliable assessment of kidney quality before transplantation is needed to predict recipient outcomes and to optimize management and allocation of the allograft. The aim of this study was to systematically review the published literature on biomarkers in two mediums (the perfusate from deceased-donor kidneys receiving machine perfusion and deceased-donor urine) that were evaluated for their possible association with outcomes after kidney transplantation.
We searched the Ovid Medline and Scopus databases using broad keywords related to deceased-donor biomarkers in kidney transplantation (limited to humans and the English language). Studies were included if they involved deceased-donor kidneys, measured perfusate or urine biomarkers and studied a possible relationship between biomarker concentrations and kidney allograft outcomes. Each included article was assessed for methodological quality.
Of 1430 abstracts screened, 29 studies met the inclusion criteria. Of these, 23 were studies of perfusate (16 biomarkers examined) and 6 were studies of urine (18 biomarkers examined). Only 3 studies (two perfusate) met the criteria of ‘good’ quality and only 12 were published since 2000. Perfusate lactate dehydrogenase, glutathione-S-transferase (GST) and aspartate transaminase were all found to be significantly associated with delayed graft function in a majority of their respective studies (6/9, 4/6 and 2/2 studies, respectively). Urine neutrophil gelatinase-associated lipocalin, GST, Trolox-equivalent antioxidant capacity and kidney injury molecule-1 were found to be significantly associated with allograft outcomes in single studies that examined diverse end points.
Higher quality studies are needed to investigate modern kidney injury biomarkers, to validate novel biomarkers in larger donor populations and to determine the incremental predictive value of biomarkers over traditional clinical variables.
PMCID: PMC3716303  PMID: 22498916
biomarkers; deceased donors; delayed graft function; kidney transplantation
5.  Predicting Acute Kidney Injury Following Cardiac Surgery: A Systematic Review 
The Annals of Thoracic Surgery  2012;93(1):337-347.
Acute kidney injury (AKI) after cardiac surgery confers a significant increased risk of mortality. Several risk models have been developed to predict postoperative kidney failure after cardiac surgery. The objective of this systematic review is to evaluate the available risk models for AKI after cardiac surgery.
Literature searches were performed in the Web of Science/Knowledge, Scopus, and MEDLINE databases for articles reporting the primary development of a risk model and articles reporting validation of existing risk models for AKI after cardiac surgery. Data on model variables, internal and/or external validation, measures of discrimination, and measures of calibration were extracted.
Seven articles with a primary development of a prediction score for AKI after cardiac surgery and 8 articles with external validation of established models were included in the systematic review. The models for AKI requiring dialysis are the most robust and externally validated. Among the prediction rules for AKI requiring dialysis after cardiac surgery, the Cleveland Clinic model has been the most widely tested thus far and has shown high discrimination in most of the tested populations. A validated score to predict non-dialysis requiring AKI is lacking.
Further studies are required to develop risk models to predict milder, non-dialysis requiring AKI after cardiac surgery. Standardizing risk factor and AKI definitions will facilitate both the development and validation of risk models predicting AKI.
PMCID: PMC3286599  PMID: 22186469
Statistics; risk analysis/modeling; kidney Ischemia/reperfusion injury; cardiac surgery; CABG
6.  Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery 
Kidney International  2011;80(6):655-662.
In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI.
PMCID: PMC3312809  PMID: 21525851
acute renal failure; cardiovascular; creatinine; epidemiology and outcomes; renal function
7.  RiGoR: reporting guidelines to address common sources of bias in risk model development 
Biomarker Research  2015;3(1):2.
Reviewing the literature in many fields on proposed risk models reveals problems with the way many risk models are developed. Furthermore, papers reporting new risk models do not always provide sufficient information to allow readers to assess the merits of the model. In this review, we discuss sources of bias that can arise in risk model development. We focus on two biases that can be introduced during data analysis. These two sources of bias are sometimes conflated in the literature and we recommend the terms resubstitution bias and model-selection bias to delineate them. We also propose the RiGoR reporting standard to improve transparency and clarity of published papers proposing new risk models.
PMCID: PMC4312434  PMID: 25642328
Risk prediction; Reporting standards; Research design; Statistical bias
8.  Influence of Age-Related Versus Non-Age-Related Renal Dysfunctionon Survival in Patients with Left Ventricular Dysfunction 
The American journal of cardiology  2013;113(1):127-131.
Normal aging results in a predictable decline in glomerular filtration rate (GFR) and low GFR is associated with worsened survival. If this survival disadvantage is directly caused by the low GFR, as opposed to the disease causing the low GFR, the risk should be similar regardless of the underlying mechanism. Our objective was to determine if age related declines in estimated GFR (eGFR) carry the same prognostic importance as disease attributable losses in patients with ventricular dysfunction. We analyzed the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337). The primary analysis focused on determining if the eGFR mortality relationship differed by the extent the eGFR was consistent with normal ageing. Mean eGFR was 65.7 ± 19.0ml/min/1.73m2. Across the range of age in the population (27 to 80 years), baseline eGFR decreased by 0.67 ml/min/1.73m2 per year (95% CI 0.63 to 0.71). The risk of death associated with eGFR was strongly modified by the degree to which the low eGFR could be explained by aging (p interaction <0.0001). For example, in a model incorporating the interaction, uncorrected eGFR was no longer significantly related to mortality (adjusted HR=1.0 per 10 ml/min/1.73m2, 95% CI 0.97–1.1, p=0.53) whereas a disease attributable decrease in eGFR above the median carried significant risk (adjusted HR=2.8, 95% CI 1.6–4.7, p<0.001). In conclusion, in the setting of LV dysfunction, renal dysfunction attributable to normal aging had a limited risk for mortality, suggesting that the mechanism underlying renal dysfunction is critical in determining prognosis.
PMCID: PMC3915785  PMID: 24216124
Cardio-renal syndrome; Age related renal dysfunction; Prognosis; Heart failure
9.  Impact of Peri-Operative Acute Kidney Injury as a Severity Index for 30-day Readmission After Cardiac Surgery 
The Annals of thoracic surgery  2013;97(1):111-117.
Of patients undergoing cardiac surgery in the United States, 15–20% are re-hospitalized within 30-days. Current models to predict readmission have not evaluated the association between severity of post-operative acute kidney injury (AKI) and 30-day readmissions.
We collected data from 2,209 consecutive patients who underwent either coronary artery bypass (CABG) or valve surgery at seven member hospitals of the Northern New England Cardiovascular Disease Study Group Cardiac Surgery Registry (NNE) between July 2008 and December 2010. Administrative data at each hospital was searched to identify all patients readmitted to the index hospital within 30 days of discharge. We defined AKI Stages by the AKI Network definition of 0.3 or 50% increase (Stage 1), 2-fold increase (stage 2) and a 3-fold or 0.5 increase if the baseline serum creatinine was at least 4.0 (mg/dL) or new dialysis (stage 3). We evaluate the association between stages of AKI and 30-day readmission using multivariate logistic regression.
There were 260 patients readmitted within 30-days (12.1%). The median time to readmission was 9 (IQR 4–16) days. Patients not developing AKI following cardiac surgery had a 30-day readmission rate of 9.3% compared to patients developing AKI stage 1 (16.1%), AKI stage 2 (21.8%) and AKI stage 3 (28.6%, p <0.001). Adjusted odds ratios for AKI stage 1 (1.81; 1.35, 2.44), stage 2 (2.39; 1.38, 4.14) and stage 3 (3.47; 1.85–6.50). Models to predict readmission were significantly improved with the addition of AKI stage (c-statistic 0.65, p = 0.001) and net reclassification rate of 14.6% (95%CI: 5.05% to 24.14%, p = .003).
In addition to more traditional patient characteristics, the severity of post-operative AKI should be used when assessing a patient’s risk for readmission.
PMCID: PMC4009924  PMID: 24119985
Coronary artery bypass grafts; CABG; Kidney; renal function; failure; dialysis; Outcomes (incl mortality, morbidity, survival, etc.); Surgery; complications; Readmission
10.  Acute Kidney Injury in Patients with Cirrhosis: Perils and Promise 
Case Vignette
A 62-year-old man with cirrhosis secondary to hepatitis C and chronic alcohol abuse is admitted to the intensive care unit with hematemesis and mental status changes. Physical examination reveals ascites and stigmata of chronic liver disease. Blood pressure is noted as 87/42 mm Hg while laboratory studies show serum creatinine level of 0.8 mg/dL, estimated glomerular filtration rate (GFR) 84 ml/min/1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) Study equation, serum sodium 123 mEq/L, total serum bilirubin 4.3 mg/dL and international normalization ratio (INR) 1.6. The patient is resuscitated with packed red blood cells and fresh frozen plasma and bleeding is controlled. However, on the third day of admission, creatinine rises to 1.5 mg/dL. Examination of urine sediment reveals 1–5 bilirubin stained granular casts per high powered field and a few renal tubular epithelial cells. Urine sodium is 21 mEq/L and fractional excretion of sodium (FENa) is 0.43%.
PMCID: PMC3840046  PMID: 23583467
11.  Long-term risk of chronic kidney disease and mortality in children after acute kidney injury: a systematic review 
BMC Nephrology  2014;15(1):184.
Acute kidney injury (AKI) is associated with significant short-term morbidity and mortality in children. However, the risk for long-term outcomes after AKI is largely unknown.
We performed a systematic review and meta-analysis to determine the cumulative incidence rate of proteinuria, hypertension, decline in glomerular filtration rate (GFR), and mortality after an episode of AKI. After screening 1934 published articles from 1985–2013, we included 10 cohort studies that reported long-term outcomes after AKI in children.
A total of 346 patients were included in these studies with a mean follow-up of 6.5 years (range 2–16) after AKI. The studies were of variable quality and had differing definitions of AKI with five studies only including patients who required dialysis during an AKI episode. There was a substantial discrepancy in the outcomes across these studies, most likely due to study size, disparate outcome definitions, and methodological differences. In addition, there was no non-AKI comparator group in any of the published studies. The cumulative incidence rates for proteinuria, hypertension, abnormal GFR (<90 ml/min/1.73 m2), GFR < 60 ml/min/1.73 m2, end stage renal disease, and mortality per 100 patient-years were 3.1 (95% CI 2.1-4.1), 1.4 (0.9-2.1), 6.3 (5.1-7.5), 0.8 (0.4 -1.4), 0.9 (0.6-1.4), and 3.7 (2.8-4.5) respectively.
AKI appears to be associated with a high risk of long-term renal outcomes in children. These findings may have implications for care after an episode of AKI in children. Future prospective studies with appropriate non-AKI comparator groups will be required to confirm these results.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-184) contains supplementary material, which is available to authorized users.
PMCID: PMC4251927  PMID: 25416588
Pediatrics; Acute kidney injury; Progression; Proteinuria; Hypertension; Chronic kidney disease; Long-term survival
12.  Biochemical Evidence of Mild Hepatic Dysfunction Identifies Decompensated Heart Failure Patients with Reversible Renal Dysfunction 
Journal of cardiac failure  2013;19(11):10.1016/j.cardfail.2013.10.005.
Differentiation of HF-induced renal dysfunction (RD) from irreversible intrinsic kidney disease is challenging, likely related to the multifactorial pathophysiology underlying HF-induced RD. To the contrary, HF-induced liver dysfunction results in characteristic laboratory abnormalities. Given similar pathophysiologic factors are thought to underlie both conditions, and that the liver and kidneys share a common circulatory environment, patients with laboratory evidence of HF-induced liver dysfunction may also have a high incidence of potentially reversible HF-induced RD.
Methods and Results
Hospitalized patients with a discharge diagnosis of HF were reviewed (n=823). IRF was defined as a 20% improvement in estimated glomerular filtration rate (eGFR). An elevated international normalized ratio (INR) (OR=2.8, p<0.001), bilirubin (BIL) (OR=2.2, p<0.001), aspartate aminotransferase (AST) (OR=1.8, p=0.004), and alanine aminotransferase (ALT) (OR=2.1, p=0.001) were all significantly associated with IRF. Amongst patients with baseline RD (eGFR≤ 45 ml/min/1.73m2), associations between liver dysfunction and IRF were particularly strong (INR OR=5.7, p<0.001; BIL OR=5.1, p<0.001; AST OR=2.9, p=0.005; ALT OR=4.8, p<0.001).
Biochemical evidence of mild liver dysfunction is associated with reversible RD in decompensated HF patients. In the absence of methodology to directly identify HF-induced RD, signs of HF-induced dysfunction of other organs may serve as an accessible method by which HF-induced RD is recognized.
PMCID: PMC3884639  PMID: 24263117
Cardio-renal syndrome; congestive hepatopathy; improved renal function; decompensated heart failure
13.  Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and acute kidney injury in patients undergoing cardiac surgery 
Nephrology Dialysis Transplantation  2013;28(11):2787-2799.
Using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) the morning of surgery may lead to ‘functional’ postoperative acute kidney injury (AKI), measured by an abrupt increase in serum creatinine. Whether the same is true for ‘structural’ AKI, measured with new urinary biomarkers, is unknown.
The TRIBE-AKI study was a prospective cohort study of 1594 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2010. We classified the degree of exposure to ACEi/ARB into three categories: ‘none’ (no exposure prior to surgery), ‘held’ (on chronic ACEi/ARB but held on the morning of surgery) or ‘continued’ (on chronic ACEi/ARB and taken the morning of surgery). The co-primary outcomes were ‘functional’ AKI based upon changes in pre- to postoperative serum creatinine, and ‘structural AKI’, based upon peak postoperative levels of four urinary biomarkers of kidney injury.
Across the three levels (none, held and continued) of ACEi/ARB exposure there was a graded increase in functional AKI, as defined by AKI stage 1 or worse; (31, 34 and 42%, P for trend 0.03) and by percentage change in serum creatinine from pre- to postoperative (25, 26 and 30%, P for trend 0.03). In contrast, there were no differences in structural AKI across the strata of ACEi/ARB exposure, as assessed by four structural AKI biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18 or liver-fatty acid-binding protein).
Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted.
PMCID: PMC3811062  PMID: 24081864
acute renal failure; biomarkers; serum creatinine
14.  Assessing the agreement of biomarker data in the presence of left-censoring 
BMC Nephrology  2014;15:144.
In many clinical biomarker studies, Lin’s concordance correlation coefficient (CCC) is commonly used to assess the level of agreement of a biomarker measured under two different conditions. However, measurement of a specific biomarker typically cannot provide accurate numerical values below the lower limit of detection (LLD) of the assay, which results in left-censored data. Most researchers discard the data below the LLD or apply simple data imputation methods in the presence of left-censored data, such as replacing values below the LLD with a fixed number less than or equal to the LLD. This is not statistically optimal, because it often leads to biased estimates and overestimates the precision.
We describe a simple method using a bivariate normal distribution in this situation and apply SAS statistical software to arrive at the maximum likelihood (ML) estimate of the parameters and construct the estimate of the CCC. We conduct a computer simulation study to investigate the statistical properties of the ML method versus the data deletion and simple data imputation method. We also contrast the methods with real data using two urine biomarkers, Interleukin 18 and Cystatin C.
The computer simulation studies confirm that the ML procedure is superior to the data deletion and simple data imputation procedures. In all of the simulated scenarios, the ML method yields the smallest relative bias and the highest percentage of the 95% confidence intervals that include the true value of the CCC. In the first simulation scenario (sample size of 100 paired data points, 25% left-censoring for both members of the pair, true CCC of 0.238), the relative bias is −1.43% for the ML method, −40.97% for the data deletion method, and it ranges between −12.94% and −21.72% for the simple data imputation methods. Similarly, when the left-censoring for one of the members of the data pairs increases from 25% to 40%, the relative bias displays the same pattern for all methods.
When estimating the CCC from paired biomarker data in the presence of left-censored values, the ML method works better than data deletion and simple data imputation methods.
PMCID: PMC4236661  PMID: 25186769
15.  Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2 
Cell reports  2013;4(4):830-841.
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
PMCID: PMC3988532  PMID: 23972995
16.  Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients 
BMC Nephrology  2014;15:133.
A translational study in renal transplantation suggested YKL-40, a chitinase 3-like-1 gene product, plays an important role in acute kidney injury (AKI) and repair, but data are lacking about this protein in urine from native human kidneys.
This is an ancillary study to a single-center, prospective observational cohort of patients with clinically-defined AKI according to AKI Network serum creatinine criteria. We determined the association of YKL -40 ≥ 5 ng/ml, alone or combined with neutrophil gelatinase-associated lipocalin (NGAL), in urine collected on the first day of AKI with a clinically important composite outcome (progression to higher AKI stage and/or in-hospital death).
YKL-40 was detectable in all 249 patients, but urinary concentrations were considerably lower than in previously measured deceased-donor kidney transplant recipients. Seventy-two patients (29%) progressed or died in-hospital, and YKL-40 ≥ 5 ng/ml had an adjusted odds ratio (95% confidence interval) for the outcome of 3.4 (1.5-7.7). The addition of YKL-40 to a clinical model for predicting the outcome resulted in a continuous net reclassification improvement of 29% (P = 0.04). In patients at high risk for the outcome based on NGAL concentrations in the upper quartile, YKL-40 further partitioned the cohort into moderate-risk and very high-risk groups.
Urine YKL-40 is associated with AKI progression and/or death in hospitalized patients and improves clinically determined risk reclassification. Combining YKL-40 with other AKI biomarkers like NGAL may further delineate progression risk, though additional studies are needed to determine whether YKL-40 has general applicability and to define its association with longer-term outcomes in AKI.
PMCID: PMC4144686  PMID: 25128003
Acute kidney injury; Biomarker; BRP-39; Chitinase 3-like-1; Net reclassification improvement; YKL-40
17.  Timing of Hemoconcentration during Treatment of Acute Decompensated Heart Failure and Subsequent Survival: Importance of sustained decongestion 
We sought to determine if the timing of hemoconcentration influences the associated survival.
Indicating a reduction in intravascular volume, hemoconcentration during the treatment of decompensated heart failure (HF) has been associated with reduced mortality. However, it is unclear if this survival advantage stems from the improved intravascular volume or if healthier patients are simply more responsive to diuretics. Rapid diuresis early in the hospitalization should similarly identify diuretic responsiveness, but hemoconcentration this early would not indicate euvolemia if extravascular fluid has not yet equilibrated.
Consecutive admissions at a single center with a primary discharge diagnosis of HF were reviewed (n=845). Hemoconcentration was defined as an increase in both hemoglobin and hematocrit, then further dichotomized into Early or Late using the midway point of the hospitalization.
Hemoconcentration occurred in 422 (49.9%) patients; 41.5% Early and 58.5% Late. Patients with Late vs. Early hemoconcentration had similar baseline characteristics, cumulative in-hospital loop diuretic administered, and worsening of renal function. However, patients with Late vs. Early hemoconcentration had higher average daily loop diuretic doses (p=0.001), greater weight loss (p<0.001), later transition to oral diuretics (p=0.03), and shorter length of stay (p<0.001). Late hemoconcentration conferred a significant survival advantage (HR=0.74, 95% CI 0.59–0.93, p=0.009) whereas Early hemoconcentration offered no significant mortality benefit (HR=1.0, 95% CI 0.80–1.3, p=0.93) over no hemoconcentration.
Only hemoconcentration occurring late in the hospitalization was associated with improved survival. These results provide further support for the importance of achieving sustained decongestion during treatment of decompensated heart failure.
PMCID: PMC3892152  PMID: 23747773
Hemoconcentration; Mortality; Decompensated Heart Failure
18.  Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study 
BMC Nephrology  2014;15:105.
Adjudication of patient outcomes is a common practice in medical research and clinical trials. However minimal data exists on the adjudication process in the setting of Acute Kidney Injury (AKI) as well as the ability to judge different etiologies (e.g. Acute Tubular Necrosis (ATN), Pre-renal Azotemia (PRA)).
We enrolled 475 consecutive patients undergoing cardiac surgery at four sites of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study. Three expert nephrologists performed independent chart review, utilizing clinical variables and retrospective case report forms with pre intra and post-operative data, and then adjudicated all cases of AKI (n = 67). AKI was defined as a > 50% increase in serum creatinine for baseline (RIFLE Risk). We examined the patterns of AKI diagnoses made by the adjudication panel as well as association of these diagnoses with pre and postoperative kidney injury biomarkers.
There was poor agreement across the panel of reviewers with their adjudicated diagnoses being independent of each other (Fleiss’ Kappa = 0.046). Based on the agreement of the two out of three reviewers, ATN was the adjudicated diagnosis in 41 cases (61%) while PRA occurred in 13 (19%). Neither serum creatinine or any other biomarker of AKI (urine or serum), was associated with an adjudicated diagnosis of ATN within the first 24 post-operative hours.
The etiology of AKI after cardiac surgery is probably multi-factorial and pure forms of AKI etiologies, such as ATN and PRA may not exist. Biomarkers did not appear to correlate with the adjudicated etiology of AKI; however the lack of agreement among the adjudicators impacted these results.
Trial registration NCT00774137
PMCID: PMC4091753  PMID: 24996668
Acute kidney injury; Acute tubular necrosis; Cardio-thoracic surgery; Adjudication
19.  Prevalence and Prognostic Importance of Changes in Renal Function After Mechanical Circulatory Support 
Circulation. Heart failure  2013;7(1):68-75.
The long-term durability and prognostic significance of improvement in renal function after mechanical circulatory support (MCS) has yet to be characterized in a large multicenter population. The primary goals of this analysis were to describe serial post-MCS changes in estimated glomerular filtration rate (eGFR) and determine their association with all-cause mortality.
Methods and Results
Adult patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with serial creatinine levels available (n=3363) were studied. Early post-MCS, eGFR improved substantially (median improvement, 48.9%; P<0.001) with 22.3% of the population improving their eGFR by ≥100% within the first few weeks. However, in the majority of patients, this improvement was transient, and by 1 year, eGFR was only 6.7% above the pre-MCS value (P<0.001). This pattern of early improvement followed by deterioration in eGFR was observed with both pulsatile and continuous-flow devices. Interestingly, poor survival was associated with both marked improvement (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.19–2.26; P=0.002) and worsening in eGFR (adjusted HR, 1.63; 95% CI, 1.15–2.13; P=0.004).
Post-MCS, early improvement in renal function is common but seems to be largely transient and not necessarily indicative of an improved prognosis. This pattern was observed with both pulsatile and continuous-flow devices. Additional research is necessary to better understand the mechanistic basis for these complex post-MCS changes in renal function and their associated survival disadvantage.
Clinical Trial Registration
URL: Unique identifier: NCT00119834.
PMCID: PMC4067252  PMID: 24214901
cardio-renal syndrome; heart failure; heart-assist devices; transplantation
20.  Is Delayed Graft Function Causally Associated with Long-Term Outcomes after Kidney Transplantation? Instrumental Variable Analysis1 
Transplantation  2013;95(8):1008-1014.
While some studies have found an association between delayed graft function (DGF) after kidney transplantation and worse long-term outcomes, a causal relationship remains controversial. We investigated this relationship using an instrumental variables model (IVM), a quasi-randomization technique for drawing causal inferences.
We identified 80,690 adult, deceased-donor, kidney-only transplant recipients from the Scientific Registry of Transplant Recipients between 1997 and 2010. We used cold ischemia time (CIT) as an instrument to test the hypothesis that DGF causes death-censored graft loss and mortality at 1 and 5 years post-transplant, controlling for an array of characteristics known to affect patient and graft survival. We compared our IVM results to a multivariable linear probability model (LPM).
DGF occurred in 27% of our sample. Graft loss rates at 1 and 5 years were 6% and 22%, respectively, and 1-year and 5-year mortality rates were 5% and 20%, respectively. In the LPM, DGF was associated with increased risk of both graft loss and mortality at 1 and 5 years (p<0.001). In the IVM, we found evidence suggesting a causal relationship between DGF and death-censored graft loss at both 1 year (13.5% increase; p<0.001) and 5 years (16.2% increase; p<0.001), and between DGF and mortality at both 1 year (7.1% increase; p<0.001) and 5 years (11.0% increase; p<0.01). Results were robust to exclusion of lower-quality as well as pumped kidneys and use of a creatinine-based definition for DGF.
Instrumental variables analysis supports a causal relationship between DGF and both graft loss and mortality.
PMCID: PMC3629374  PMID: 23591726
delayed graft function; kidney transplantation; outcomes; cold ischemia time; allograft failure
21.  Association between angiotensin converting enzyme inhibitor or angiotensin receptor blocker use prior to major elective surgery and the risk of acute dialysis 
BMC Nephrology  2014;15:53.
Some studies but not others suggest angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use prior to major surgery associates with a higher risk of postoperative acute kidney injury (AKI) and death.
We conducted a large population-based retrospective cohort study of patients aged 66 years or older who received major elective surgery in 118 hospitals in Ontario, Canada from 1995 to 2010 (n = 237,208). We grouped the cohort into ACEi/ARB users (n = 101,494) and non-users (n = 135,714) according to whether the patient filled at least one prescription for an ACEi or ARB (or not) in the 120 days prior to surgery. Our study outcomes were acute kidney injury treated with dialysis (AKI-D) within 14 days of surgery and all-cause mortality within 90 days of surgery.
After adjusting for potential confounders, preoperative ACEi/ARB use versus non-use was associated with 17% lower risk of post-operative AKI-D (adjusted relative risk (RR): 0.83; 95% confidence interval (CI): 0.71 to 0.98) and 9% lower risk of all-cause mortality (adjusted RR: 0.91; 95% CI: 0.87 to 0.95). Propensity score matched analyses provided similar results. The association between ACEi/ARB and AKI-D was significantly modified by the presence of preoperative chronic kidney disease (CKD) (P value for interaction < 0.001) with the observed association evident only in patients with CKD (CKD - adjusted RR: 0.62; 95% CI: 0.50 to 0.78 versus No CKD: adjusted RR: 1.00; 95% CI: 0.81 to 1.24).
In this cohort study, preoperative ACEi/ARB use versus non-use was associated with a lower risk of AKI-D, and the association was primarily evident in patients with CKD. Large, multi-centre randomized trials are needed to inform optimal ACEi/ARB use in the peri-operative setting.
PMCID: PMC4021413  PMID: 24694072
Acute dialysis; Angiotensin converting enzyme inhibitor; Angiotensin receptor blocker; Major elective surgery
22.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
PMCID: PMC3933452  PMID: 23970313
23.  Risk Factors and Outcomes Stratified by Severity of Acute Kidney Injury in Malaria 
PLoS ONE  2014;9(3):e90419.
Severe acute kidney injury (AKI) is known to have prognostic value for in-hospital outcomes in malaria. However, little is known about the association of AKI of lesser severity with malarial risk factors and outcomes – and such a gap is becoming increasingly relevant with the upsurge in the incidence of AKI due to Plasmodium falciparum malaria and Plasmodium vivax malaria over the last decade. We aimed to identify risk factors of AKI in malaria and assessed in-hospital outcomes stratified by severity of AKI. We performed an observational study of 1,191 hospitalized malaria patients enrolled between 2007 and 2011 in a tertiary care academic center in India. Patients were categorized based on peak serum creatinine into one of three groups: no AKI (<1.6 mg/dL), mild AKI (1.6–3.0 mg/dL), and severe AKI (>3 mg/dL). Plasmodium vivax was the predominant species (61.41%), followed by Plasmodium falciparum (36.41%) and mixed infections with both the species (2.18%). Mild and severe AKI were detected in 12% and 5.6% of patients, respectively. Mild AKI due to Plasmodium vivax (49%) and Plasmodium falciparum (48.5%) was distributed relatively equally within the sample population; however, cases of severe AKI due to Plasmodium falciparum (80%) and Plasmodium vivax (13%) was significantly different (P<0.001). On history and physical examination, risk factors for AKI were age, absence of fever, higher heart rate, lower diastolic blood pressure, icterus, and hepatomegaly. The only laboratory parameter associated with risk of AKI on multivariate analysis was direct bilirubin. Patients with mild and severe AKI had greater organ complications, supportive requirements, longer duration of hospital stay and in-hospital mortality in a dose-dependent relationship, than patients with no AKI. Mild AKI is associated with significant (P<0.05) morbidity compared to no AKI, and future studies should assess strategies for early diagnosis of AKI and prevent AKI progression.
PMCID: PMC3953079  PMID: 24625747
24.  Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women 
AIDS (London, England)  2013;27(14):2291-2299.
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Retrospective cohort analysis.
Cystatin C and creatinine were measured from specimens taken and stored during the 1999–2000 exam among 908 HIV-infected participants in the Women’s Interagency HIV study (WIHS). Mean follow-up was 10.2 years. The associations of baseline categories (<60, 60–90, and >90 mL/min/1.73m2) of creatinine eGFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.
The prevalence of CKD (eGFR<60) at baseline was higher with eGFRcys (10.1%) compared to eGFRcr (6.7%, p=0.0006) and eGFRcr-cys (7.5%, p=0.011). Relative to eGFR >90, the eGFR <60 category by eGFRcys (Adjusted HR: 2.56; 95% CI: 1.63, 4.02), eGFRcr-cys (3.11; 1.94–5.00), and eGFRcr (2.34; 1.44–3.79) was associated with increased mortality risk. However, the eGFR 60–90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28–2.53) and eGFRcr-cys (1.91; 1.38–2.66) but not eGFRcr (1.20; 0.85–1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (p<0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (p<0.001).
Cystatin C detected a higher prevalence of CKD relative to creatinine and improves CKD staging relative to creatinine by reclassifying individuals at the highest mortality risk to lower eGFR categories.
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
25.  Impact of Acute Kidney Injury on Long Term Mortality after Nonmyeloablative Hematopoietic Cell Transplantation 
Acute kidney injury (AKI) occurs frequently after nonmyeloablative hematopoetic cell transplantation (HCT). The severity of AKI after nonmyeloablative HCT has association with short term mortality. However, the long term effect of AKI on survival after nonmyeloablative HCT is not known. We performed a retrospective analysis of patients who underwent a HLA matched nonmyeloablative HCT between 1997–2006. Patients were followed for a median of 36 (range 3–99) months. AKI occurring upto day 100 was defined as a greater than 2 fold increase in serum creatinine or requirement of dialysis. Of the 358 patients who were included in the analysis, 200 (56%) had AKI, 158 (44 %) had no AKI. Overall 158 patients (43 %) died during follow up. After controlling for potential confounders, the adjusted hazard ratio for overall mortality associated with AKI was 1.57 (95 % CI 1.2–2.3; p=0.0006). The adjusted hazards ratio of non relapse mortality associated with AKI was 1.72 (95 %0.9–3.1; p=0.07).
AKI is an independent predictor of overall mortality after nonmyeloablative HCT. This finding reiterates the importance of identifying preventative strategies in nonmyeloablative HCT for attenuating incidence and severity of AKI.
PMCID: PMC3909878  PMID: 18275897
renal dysfunction; acute kidney injury; bone marrow transplant; prognosis

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