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1.  First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort 
PLoS ONE  2016;11(8):e0161098.
We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation.
We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0–6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1–2, 3–6, ≥7 days).
Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1–2 days, 118 (28.9%) had duration 3–6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13–1.32; KIM-1: 1.36, 1.21–1.52; albumin 1.20, 1.09–1.32; L-FABP 1.11, 1.04–1.19; NGAL 1.06, 1.00–1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years.
There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI.
PMCID: PMC4990204  PMID: 27537050
2.  Association between Organ Procurement Organization Social Network Centrality and Kidney Discard and Transplant Outcomes1 
Transplantation  2015;99(12):2617-2624.
Given growth in kidney transplant waitlists and discard rates, donor kidney acceptance is an important problem. We used network analysis to examine whether organ procurement organization (OPO) network centrality affects discard and outcomes.
We identified 106,160 deceased-donor kidneys recovered for transplant from 2000–2010 in SRTR. We constructed the transplant network by year with each OPO representing a node and each kidney-sharing relationship between OPOs representing a directed tie between nodes. Primary exposures were the number of different OPOs to which an OPO has given a kidney or from which an OPO has received a kidney in year preceding procurement year. Primary outcomes were discard, cold-ischemia time, delayed graft function, and 1-year graft loss. We used multivariable regression, restricting analysis to the 50% of OPOs with highest discard and stratifying remaining OPOs by kidney volume. Models controlled for kidney donor risk index, waitlist time, and kidney pumping.
An increase in one additional OPO to which a kidney was given by a procuring OPO in a year was associated with 1.4% lower likelihood of discard for a given kidney (odds ratio, 0.986; 95% confidence interval, 0.974-0.998) among OPOs procuring high kidney volume, but 2% higher likelihood of discard (OR:1.021, CI:1.006, 1.037) among OPOs procuring low kidney volume, with mixed associations with recipient outcomes.
Our study highlights the value of network analysis in revealing how broader kidney sharing is associated with levels of organ acceptance. We conclude interventions to promote broader inter-OPO sharing could be developed to reduce discard for a subset of OPOs.
PMCID: PMC4668206  PMID: 26102610
3.  Amino-terminal Pro B-Type Natriuretic Peptide for Diagnosis and Prognosis in Patients with Renal Dysfunction: A Systematic Review and Meta-Analysis 
JACC. Heart failure  2015;3(12):977-989.
Structured Abstract
To determine if Amino-terminal Pro B-type Natriuretic Peptide (NT-proBNP) has different diagnostic and prognostic utility in patients with renal dysfunction.
Patients with renal dysfunction have higher NT-proBNP, which may complicate interpretation for diagnosis of acute decompensated heart failure (ADHF) or prognosis.
We searched MEDLINE and EMBASE through August 2014 for studies with a subgroup analysis by renal function of the diagnostic or prognostic ability of NT-proBNP.
For diagnosis, nine studies were included with 4,287 patients and 1,325 ADHF events. Patients were mostly divided into sub-groups with and without renal dysfunction by an estimated glomerular filtration rate of 60 ml/min/1.73m2. In patients with renal dysfunction, the area under the curve (AUC) for NT-proBNP ranged from 0.66 to 0.89 with a median cut-point of 1980 pg/ml, while the AUC ranged from 0.72 to 0.95 with a cut-point of 450 pg/ml in patients with preserved renal function. For prognosis, 30 studies with 32,203 patients were included, and mortality in patients with renal dysfunction (25.4%) was twice that of patients with preserved renal function (12.2%). The unadjusted pooled risk ratio (RR) for NT-proBNP and mortality was 3.01 (95% CI, 2.53-3.58) in patients with preserved renal function and was similar in patients with renal dysfunction (3.25 [CI, 2.45-4.30]). Upon meta-regression, heterogeneity was partially explained if patients with heart failure or coronary artery disease were enrolled.
NT-proBNP retains utility for diagnosis of ADHF in patients with renal dysfunction with higher cut-points. Elevated NT-proBNP confers a worse prognosis regardless of renal function.
PMCID: PMC4683413  PMID: 26671676
Amino-terminal Pro B-type Natriuretic Peptide; Renal Dysfunction; Diagnosis; Prognosis
4.  Storage Time and Urine Biomarker Levels in the ASSESS-AKI Study 
PLoS ONE  2016;11(10):e0164832.
Although stored urine samples are often used in biomarker studies focused on acute and chronic kidney disease, how storage time impacts biomarker levels is not well understood.
866 subjects enrolled in the NIDDK-sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study were included. Samples were processed under standard conditions and stored at -70°C until analyzed. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and liver fatty acid binding protein (L-FABP) were measured in urine samples collected during the index hospitalization or an outpatient visit 3 months later. Mixed effects models were used to determine the effect of storage time on biomarker levels and stratified by visit.
Median storage was 17.8 months (25–75% IQR 10.6–23.7) for samples from the index hospitalization and 14.6 months (IQR 7.3–20.4) for outpatient samples. In the mixed effects models, the only significant association between storage time and biomarker concentration was for KIM-1 in outpatient samples, where each month of storage was associated with a 1.7% decrease (95% CI -3% to -0.3%). There was no relationship between storage time and KIM-1 levels in samples from the index hospitalization.
There was no significant impact of storage time over a median of 18 months on urine KIM-1, NGAL, IL-18 or L-FABP in hospitalized samples; a statistically significant effect towards a decrease over time was noted for KIM-1 in outpatient samples. Additional studies are needed to determine whether longer periods of storage at -70°C systematically impact levels of these analytes.
PMCID: PMC5082822  PMID: 27788160
5.  Urine Stability Studies for Novel Biomarkers of Acute Kidney Injury 
The study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect measurement of urine biomarkers.
Cross-sectional, prospective.
Hospitalized patients from two sites: Yale New Haven Hospital (n= 52) and University of California, San Francisco Medical Center (n=36)
We tested the impact of 3 urine processing conditions on these biomarkers: a) centrifugation and storage at 4°C for 48 hours before freezing at −80°C, b) centrifugation and storage at 25°C for 48 hours before freezing at −80°C, and c) uncentrifuged samples immediately frozen at −80°C.
Urine concentration of five biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), liver-type fatty acid–binding protein (L-FABP) and cystatin C
We measured urine biomarkers by an established ELISA method. Biomarker values were log-transformed, and agreement with a reference standard of immediate centrifugation and storage at −80°C was compared using concordance correlation coefficients (CCCs).
Neither storing samples at 4°C for 48 hours nor centrifugation had a significant effect on measured levels, with CCCs above 0.9 for all biomarkers tested. For samples stored at 25°C for 48 hours, excellent CCC values (>0.9) were also noted between the test sample and the reference standard for NGAL, cystatin C, L-FABP and KIM-1. However, the CCC for IL-18 between samples stored at 25°C for 48 hours and the reference standard was 0.81 (95% CI, 0.66–0.96).
No comparisons to fresh “unfrozen” samples, no evaluation of the effect of protease inhibitors.
All candidate markers tested using the specified assays showed high stability with both short-term storage at 4°C and without centrifugation prior to freezing. For optimal fidelity, urine for IL-18 measurement should not be stored at 25°C before long-term storage or analysis.
PMCID: PMC3969397  PMID: 24200462
proteins; storage; handling; concordance; urine biomarker; AKI; acute renal failure (ARF); protein stability; biospecimen handling
6.  Development of a Targeted Urine Proteome Assay for Kidney Diseases 
Human urine is the least invasive and most readily available bio fluid whose proteome has been shown to change in response to disease or drug treatment. Urine is thus very amenable to quantitative proteomics and is a logical sample choice for identifying protein biomarkers for kidney diseases. In this study potential biomarkers were identified initially by using a multi-proteomics workflow to compare urine proteomes of kidney transplant patients who exhibited immediate versus delayed graft function. To comprehensively interrogate the urine proteome two “bottom up”, mass spectrometric-based discovery approaches, iTRAQ and Label Free Quantitation (LFQ), were complemented by Differential Fluorescence Gel Electrophoresis (DIGE) analyses of intact urine proteins from kidney transplant recipients who received a deceased donor kidney. Differentially expressed proteins in the two patient groups were identified, and corresponding stable isotope–labeled internal peptide standard (SIS) peptides were synthesized for scheduled multiple reaction monitoring (MRM). The Targeted Urine Proteome Assay (TUPA) was then developed by identifying those peptides for which there were at least 2 transitions for which interference in a urine matrix across 156 MRM runs was less than 30%. This resulted in a final assay that monitors 224 peptides corresponding to 167 quantifiable proteins.
PMCID: PMC5003777  PMID: 26220717
Chronic kidney disease; Polycystic kidney disease; Targeted Proteomics; Urine
7.  Methodological issues in current practice may lead to bias in the development of biomarker combinations for predicting acute kidney injury 
Kidney international  2016;89(2):429-438.
Individual biomarkers of renal injury are only modestly predictive of acute kidney injury (AKI). Using multiple biomarkers has the potential to improve predictive capacity. In this systematic review, statistical methods of articles developing biomarker combinations to predict acute kidney injury were assessed. We identified and described three potential sources of bias (resubstitution bias, model selection bias and bias due to center differences) that may compromise the development of biomarker combinations. Fifteen studies reported developing kidney injury biomarker combinations for the prediction of AKI after cardiac surgery (8 articles), in the intensive care unit (4 articles) or other settings (3 articles). All studies were susceptible to at least one source of bias and did not account for or acknowledge the bias. Inadequate reporting often hindered our assessment of the articles. We then evaluated, when possible (7 articles), the performance of published biomarker combinations in the TRIBE-AKI cardiac surgery cohort. Predictive performance was markedly attenuated in six out of seven cases. Thus, deficiencies in analysis and reporting are avoidable and care should be taken to provide accurate estimates of risk prediction model performance. Hence, rigorous design, analysis and reporting of biomarker combination studies are essential to realizing the promise of biomarkers in clinical practice.
PMCID: PMC4805513  PMID: 26398494
acute kidney injury; cardiovascular disease
8.  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
9.  Biomarkers of acute kidney injury and associations with short- and long-term outcomes 
F1000Research  2016;5:F1000 Faculty Rev-986.
Acute kidney injury is strongly associated with increased mortality and other adverse outcomes. Medical researchers have intensively investigated novel biomarkers to predict short- and long-term outcomes of acute kidney injury in many patient care settings, such as cardiac surgery, intensive care units, heart failure, and transplant. Future research should focus on leveraging this relationship to improve enrollment for clinical trials of acute kidney injury.
PMCID: PMC4879936  PMID: 27239295
acute kidney injury; AKI; biomarkers; chronic kidney disease; CKD
10.  Cardiac Biomarkers and Acute Kidney Injury After Cardiac Surgery 
Pediatrics  2015;135(4):e945-e956.
To examine the relationship of cardiac biomarkers with postoperative acute kidney injury (AKI) among pediatric patients undergoing cardiac surgery.
Data from TRIBE-AKI, a prospective study of children undergoing cardiac surgery, were used to examine the association of cardiac biomarkers (N-type pro–B-type natriuretic peptide, creatine kinase-MB [CK-MB], heart-type fatty acid binding protein [h-FABP], and troponins I and T) with the development of postoperative AKI. Cardiac biomarkers were collected before and 0 to 6 hours after surgery. AKI was defined as a ≥50% or 0.3 mg/dL increase in serum creatinine, within 7 days of surgery.
Of the 106 patients included in this study, 55 (52%) developed AKI after cardiac surgery. Patients who developed AKI had higher median levels of pre- and postoperative cardiac biomarkers compared with patients without AKI (all P < .01). Preoperatively, higher levels of CK-MB and h-FABP were associated with increased odds of developing AKI (CK-MB: adjusted odds ratio 4.58, 95% confidence interval [CI] 1.56–13.41; h-FABP: adjusted odds ratio 2.76, 95% CI 1.27–6.03). When combined with clinical models, both preoperative CK-MB and h-FABP provided good discrimination (area under the curve 0.77, 95% CI 0.68–0.87, and 0.78, 95% CI 0.68–0.87, respectively) and improved reclassification indices. Cardiac biomarkers collected postoperatively did not significantly improve the prediction of AKI beyond clinical models.
Preoperative CK-MB and h-FABP are associated with increased risk of postoperative AKI and provide good discrimination of patients who develop AKI. These biomarkers may be useful for risk stratifying patients undergoing cardiac surgery.
PMCID: PMC4379461  PMID: 25755241
biological markers; acute kidney injury; postoperative complications; pediatrics; thoracic surgery; creatine kinase; brain natriuretic peptide; troponin; fatty acid-binding proteins
11.  Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery 
Kidney international  2015;88(3):576-583.
Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery.
PMCID: PMC4556547  PMID: 25830762
Heart-type fatty acid binding protein; Acute Kidney Injury; Mortality; Cardiac Surgery
12.  Associations of deceased donor kidney injury with kidney discard and function after transplantation 
Deceased-donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing admission-to-terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08–1.52), 1.82 (1.45–2.30) and 2.74 (2.0–3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09–1.49), 1.70 (1.37–2.12) and 2.25 (1.74–2.91), respectively. Six-month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 [interquartile range: 31–61] vs. 58 [45–75] ml/min/1.73m2 for no DGF, P<0.001). There was significant favorable interaction between donor AKI and DGF such that 6-month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 [29–60], 49 [32–64], 52 [36–59] and 58 [39–71] ml/min/1.73m2 for no AKI, stage 1, 2 and 3, respectively; interaction P=0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6-month allograft function, clinicians should consider cautious expansion into this donor pool.
PMCID: PMC4563988  PMID: 25762442
Kidney transplantation; deceased donor; acute kidney injury; organ discard; delayed graft function; allograft function
13.  Association of Serum Erythropoietin with Cardiovascular Events, Kidney Function Decline and Mortality: The Health ABC Study 
Circulation. Heart failure  2016;9(1):e002124.
Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No studies have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community living older adults.
Methods and Results
Erythropoietin concentration was measured in 2,488 participants aged 70–79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease (CHD), stroke, mortality, and ≥30% decline in estimated glomerular filtration rate (eGFR) were examined using Cox proportional hazards and logistic regression over 10.7 years of follow up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% CI 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease (CVD), CVD risk factors, kidney function and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (p>0.50). There were 330 incident CHD events, 161 strokes, 1,112 deaths and 698 outcomes of ≥ 30% decline in eGFR. Serum erythropoietin was not significantly associated with these outcomes.
Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.
PMCID: PMC4698899  PMID: 26721912
erythropoietin; heart failure; chronic kidney disease; cardiovascular outcomes; death
14.  Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure 
Circulation. Heart failure  2016;9(1):e002370.
Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure (ADHF) and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed.
Methods and Results
Based on well-established renal physiologic principles an equation was derived to predict net sodium output using a spot urine sample obtained one or two hours following loop diuretic administration. This equation was then prospectively validated in 50 ADHF patients using meticulously obtained timed 6-hour urine collections to quantitate loop diuretic induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91, p<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (AUC=0.95, 95% CI 0.89–1.0, p<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66, p<0.001) and lesser ability to predict poor natriuretic response (AUC=0.76, 95% CI 0.63–0.89, p=0.002).
In patients being treated for ADHF, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.
PMCID: PMC4741370  PMID: 26721915
diuretics; heart failure; sodium; diuretic resistance; poor natriuretic response
15.  Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure 
Circulation. Heart failure  2015;9(1):e002333.
Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure (ADHF) is strongly and independently associated with worsening renal function (WRF). Our objective was to determine if SBP reduction or titration of oral neurohormonal antagonists during ADHF treatment negatively influences diuresis and decongestion.
Methods and Results
SBP reduction was evaluated from admission to discharge in consecutive ADHF admissions (n=656). Diuresis and decongestion was examined across a range of parameters such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4 ± 19.4 mmHg and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with WRF (OR=1.9, 95% CI: 1.2-2.9, p=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (OR=2.0, 95% CI: 1.3-3.2, p=0.002). However, SBP reduction did not negatively impact diuresis or decongestion (p≥0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in over 50% of admissions and was associated with a modest additional reduction in blood pressure (≤ 5.6 mmHg). Notably, WRF was not increased and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists.
Despite a higher rate of WRF, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline recommended titration of chronic oral medication during ADHF hospitalization may not be antagonistic to the short-term goal of decongestion.
PMCID: PMC4741376  PMID: 26699390
renal function; acute heart failure; diuretics; blood pressure
16.  Association of Definition of Acute Kidney Injury by Cystatin C Rise With Biomarkers and Clinical Outcomes in Children Undergoing Cardiac Surgery 
JAMA pediatrics  2015;169(6):583-591.
Research has identified improved biomarkers of acute kidney injury (AKI). Cystatin C (CysC) is a better glomerular filtration rate marker than serum creatinine (SCr) and may improve AKI definition.
To determine if defining clinical AKI by increases in CysC vs SCr alters associations with biomarkers and clinical outcomes.
Three-center prospective cohort study of intensive care units in New Haven, Connecticut, Cincinnati, Ohio, and Montreal, Quebec, Canada. Participants were 287 patients 18 years or younger without preoperative AKI or end-stage renal disease who were undergoing cardiac surgery. The study dates were July 1, 2007, through December 31, 2009.
For biomarker vs clinical AKI associations, the exposures were first postoperative (0–6 hours after surgery) urine interleukin 18, neutrophil gelatinase – associated lipocalin, kidney injury molecule 1, and liver fatty acid–binding protein. For clinical AKI outcome associations, the exposure was Kidney Disease: Improving Global Outcomes AKI definition (based on SCr or CysC).
Clinical AKI, length of stay, and length of mechanical ventilation. We determined areas under the receiver operating characteristic curve and odds ratios for first postoperative biomarkers to predict AKI.
The SCr-defined vs CysC-defined AKI incidence differed substantially (43.6% vs 20.6%). Percentage agreement was 71% (κ = 0.38); stage 2 or worse AKI percentage agreement was 95%. Interleukin 18 and kidney injury molecule 1 discriminated for CysC-defined AKI better than for SCr-defined AKI. For interleukin 18 and kidney injury molecule 1, the areas under the receiver operating characteristic curve were 0.74 and 0.65, respectively, for CysC-defined AKI, and 0.66 and 0.58, respectively, for SCr-defined AKI. Fifth (vs first) quintile concentrations of both biomarkers were more strongly associated with CysC-defined AKI. For interleukin 18 and kidney injury molecule 1, the odds ratios were 16.19 (95% CI, 3.55–73.93) and 6.93 (95% CI, 1.88–25.59), respectively, for CysC-defined AKI vs 6.60 (95% CI, 2.76–15.76) and 2.04 (95% CI, 0.94–4.38), respectively, for SCr-defined AKI. Neutrophil gelatinase–associated lipocalin and liver fatty acid–binding protein associations with both definitions were similar. The CysC definitions and SCr definitions were similarly associated with clinical outcomes of resource use.
Compared with the SCr-based definition, the CysC-based definition is more strongly associated with urine interleukin 18 and kidney injury molecule 1 in children undergoing cardiac surgery. Consideration should be made for defining AKI based on CysC in clinical care and future studies.
PMCID: PMC4506750  PMID: 25844892
17.  Association of Perioperative Plasma Neutrophil Gelatinase-Associated Lipocalin Levels with 3-Year Mortality after Cardiac Surgery: A Prospective Observational Cohort Study 
PLoS ONE  2015;10(6):e0129619.
Higher levels of plasma neutrophil gelatinase-associated lipocalin (pNGAL) are an early marker of acute kidney injury and are associated with increased risk of short-term adverse outcomes. The independent association between pNGAL and long-term mortality is unknown.
In this prospective observational cohort study, we studied 1191 adults who underwent cardiac surgery between 2007 and 2009 at 6 centers in the TRIBE-AKI cohort. We measured the pNGAL on the pre-operative and first 3 post-operative days and assessed the relationship of peri-operative pNGAL concentrations with all-cause mortality.
During a median follow-up of 3.0 years, 139 participants died (50/1000 person-years). Pre-operative levels of pNGAL were associated with 3-year mortality (unadjusted HR 1.96, 95% CI 1.34,2.85) and the association persisted after adjustment for pre-operative variables including estimated glomerular filtration rate (adjusted HR 1.48, 95% CI 1.04–2.12). After adjustment for pre- and intra-operative variables, including pre-operative NGAL levels, the highest tertiles of first post-operative and peak post-operative pNGAL were also independently associated with 3-year mortality risk (adjusted HR 1.31, 95% CI 1.0–1.7 and adjusted HR 1.78, 95% CI 1.2–2.7, respectively). However, after adjustment for peri-operative changes in serum creatinine, there was no longer an independent association between the first post-operative and peak post-operative pNGAL and long-term mortality (adjusted HR 0.98,95% CI 0.79–1.2 for first pNGAL and adjusted HR 1.19, 95% CI 0.87–1.61 for peak pNGAL).
Pre-operative pNGAL levels were independently associated with 3-year mortality after cardiac surgery. While post-operative pNGAL levels were also associated with 3-year mortality, this relationship was not independent of changes in serum creatinine. These findings suggest that while pre-operative pNGAL adds prognostic value for mortality beyond routinely available serum creatinine, post-operative pNGAL measurements may not be as useful for this purpose.
PMCID: PMC4460181  PMID: 26053382
18.  Association between preoperative statin use and acute kidney injury biomarkers in cardiac surgery 
The Annals of thoracic surgery  2014;97(6):2081-2087.
Acute kidney injury is a serious complication of cardiac surgery for which there remains no specific therapy. Animal data and several observational studies suggest that statins prevent acute kidney injury, but the results are not conclusive, and many studies are retrospective in nature.
We conducted a multi-center prospective cohort study of 625 adult patients undergoing elective cardiac surgery. All patients were on statins and were grouped on whether statins were continued or held in the 24 hours prior to surgery. The primary outcome was acute kidney injury defined by a doubling of serum creatinine or dialysis. The secondary outcome was the peak level of several kidney injury biomarkers. Results were adjusted for demographic and clinical factors.
Continuing (vs. holding) a statin prior to surgery was not associated with a lower risk of acute kidney injury defined by a doubling of serum creatinine or dialysis, [adjusted relative risk (RR) 1.09 (95% confidence interval (CI) 0.44, 2.70)]. However, continuing a statin was associated with a lower risk of elevation of the following AKI biomarkers: urine interleukin-18, urine neutrophil gelatinase-associated lipocalin, urine kidney injury molecule-1, and plasma neutrophil gelatinase-associated lipocalin [adjusted RR 0.34 (95% CI 0.18, 0.62), adjusted RR 0.41 (95% CI 0.22, 0.76), adjusted RR 0.37 (95% CI 0.20, 0.76), adjusted RR 0.62 (95% CI 0.39, 0.98), respectively].
Statins may prevent kidney injury after cardiac surgery as evidenced by lower levels of kidney injury biomarkers.
PMCID: PMC4068122  PMID: 24725831
CABG; kidney; renal failure
19.  Urine Biomarkers and Perioperative Acute Kidney Injury: The Impact of Preoperative Estimated GFR 
The interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear.
Study Design
Post-hoc analysis of prospective cohort study.
Setting & Participants
The 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants.
Unadjusted post-operative urinary biomarkers of AKI measured within 6 hours of surgery.
AKI was defined as greater than or equal to AKI Network stage 1 (any AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for emergent dialysis (severe AKI).
Stratified analyses by a pre-operative eGFR ≤ 60 ml/min/1.73 m2 vs. > 60 ml/min/1.73 m2.
180 (42%) patients with a pre-operative eGFR ≤ 60 ml/min/1.73m2 developed clinical AKI compared to 246 (31%) in those with an eGFR >60 ml/min//1.73m2 (p<0.001). For log2-transformed biomarker concentrations there was a significant interaction between any AKI and baseline eGFR for interleukin 18 (IL-18; p=0.007) and borderline significance for liver-type fatty acid binding protein (p=0.06). For all biomarkers, the adjusted relative risk (RR) point estimates for the risk of any AKI were higher in those with elevated baseline eGFRs compared to those with an eGFR ≤ 60 ml/min/1.73m2. However the difference in magnitude of these risks were quite low (adjusted RRs were 1.04 [95% CI, 0.99–1.09] and 1.11 [95% CI, 1.07–1.15] for those with a pre-operative eGFR ≤ 60 ml/min/1.73 m2 and those with higher eGFRs, respectively). Although no biomarker displayed an interaction for baseline eGFR and severe AKI, log2-transformed IL-18 and kidney injury molecule 1 (KIM-1) had significant adjusted RRs for severe AKI in those with and without baseline eGFR ≤ 60 ml/min/1.73 m2.
Limited numbers of patients with severe AKI and emergent dialysis.
The association between early post-operative AKI urinary biomarkers and AKI is modified by preoperative eGFR. The degree of this modification and its impact on the biomarker-AKI association is small across biomarkers. Our findings suggest that distinct biomarker cut-offs for those with and without a pre-operative eGFR ≤ 60 ml/min/1.73 m2 is not necessary.
PMCID: PMC4658239  PMID: 26386737
urine biomarkers; interleukin 18 (IL-18); liver-type fatty acid binding protein (L-FABP); Acute Renal Failure (ARF); acute kidney injury (AKI); perioperative AKI; effect modification; estimated glomerular filtration rate (eGFR); prognosis; cardiac surgery; surgical complication
20.  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
21.  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
22.  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
23.  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
24.  Interleukin-6 and Interleukin-10 as Acute Kidney Injury Biomarkers after Pediatric Cardiac Surgery 
Children undergoing cardiac surgery may exhibit a pronounced inflammatory response to cardiopulmonary bypass (CPB). Inflammation is recognized as an important pathophysiologic process leading to acute kidney injury (AKI). The aim of this study was to evaluate the association of two inflammatory cytokines interleukin (IL)-6 and IL-10 with AKI and other adverse outcomes in children after CPB surgery.
This is a sub-study of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) cohort, including 106 children from 1 month to 18 years old undergoing CPB. Plasma IL-6 and IL-10 were measured preoperatively and postoperatively on days 1 (within 6 hours after surgery) and 3.
Stage 2/3 AKI, defined by atleast a doubling of baseline serum creatinine or dialysis, was diagnosed in 24 (23%) patients. Preoperative IL-6 was significantly higher in patients with stage 2/3 AKI vs. without stage 2/3 AKI (median (IQR), 2.6 (0.6-4.9) vs. 0.6 (0.6-2.2), p=0.03). After adjustment for clinical and demographic variables, the highest preoperative IL-6 tertile was associated with a six-fold increased risk for stage 2/3 AKI compared with the lowest tertile (adjusted OR 6.41 (CI: 1.16-35.35)). IL-6 and IL-10 increased significantly after surgery, peaking postoperatively on day 1. First postoperative IL-6 and IL-10 did not significantly differ between patients with vs. without stage 2/3 AKI. Elevated IL-6 on day 3 was associated with longer hospital stay (p=0.0001).
Preoperative plasma IL-6 is associated with development of stage 2/3 AKI and may be prognostic of resource utilization.
PMCID: PMC4537680  PMID: 25877915
IL-6; IL-10; inflammatory; cardiopulmonary bypass; CPB; children
25.  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

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