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1.  Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review 
Nephrology Dialysis Transplantation  2012;27(8):3305-3314.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1093/ndt/gfr806
PMCID: PMC3716303  PMID: 22498916
biomarkers; deceased donors; delayed graft function; kidney transplantation
2.  Predicting Acute Kidney Injury Following Cardiac Surgery: A Systematic Review 
The Annals of Thoracic Surgery  2012;93(1):337-347.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.athoracsur.2011.09.010
PMCID: PMC3286599  PMID: 22186469
Statistics; risk analysis/modeling; kidney Ischemia/reperfusion injury; cardiac surgery; CABG
3.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3851/IMP2677
PMCID: PMC3933452  PMID: 23970313
4.  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.
doi:10.1371/journal.pone.0090419
PMCID: PMC3953079  PMID: 24625747
5.  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.
Background
Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.
Design
Retrospective cohort analysis.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1097/QAD.0b013e328362e874
PMCID: PMC3919542  PMID: 23669156
Creatinine; Cystatin C; Glomerular Filtration Rate; HIV; Mortality; Kidney; Women
6.  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.
doi:10.1016/j.bbmt.2007.12.492
PMCID: PMC3909878  PMID: 18275897
renal dysfunction; acute kidney injury; bone marrow transplant; prognosis
7.  Serum Cystatin C– Versus Creatinine-Based Definitions of Acute Kidney Injury Following Cardiac Surgery: A Prospective Cohort Study 
Background
The primary aim of this study was to compare the sensitivity and rapidity of AKI detection by cystatin C relative to creatinine following cardiac surgery.
Study Design
Prospective cohort study
Settings and Participants
1,150 high-risk, adult cardiac surgery patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium.
Predictor
Changes in serum creatinine and cystatin C
Outcome
Post-surgical incidence of AKI
Measurements
Serum creatinine and cystatin C were measured at the preoperative visit and daily on postoperative days 1–5. To allow comparisons between changes in creatinine and cystatin C, AKI endpoints were defined by the relative increases in each marker from baseline (25, 50 and 100%) and the incidence of AKI was compared based upon each marker. Secondary aims were to compare clinical outcomes among patients defined as having AKI by cystatin C and/or creatinine.
Results
Overall, serum creatinine detected more cases of AKI than cystatin C: 35% developed a ≥25% increase in serum creatinine, whereas only 23% had ≥25% increase in cystatin C (p < 0.001). Creatinine also had higher proportions meeting the 50% (14% and 8%, p<0.001) and 100% (4% and 2%, p=0.005) thresholds for AKI diagnosis. Clinical outcomes were generally not statistically different for AKI cases detected by creatinine or cystatin C. However, for each AKI threshold, patients with AKI confirmed by both markers had significantly higher risk of the combined mortality/dialysis outcome compared with patients with AKI detected by creatinine alone (p=0.002).
Limitations
There were few adverse clinical outcomes, limiting our ability to detect differences in outcomes between subgroups of patients based upon their definitions of AKI.
Conclusion
In this large multicenter study, we found that cystatin C was less sensitive for AKI detection compared with creatinine. However, confirmation by cystatin C appeared to identify a subset of AKI patients with substantially higher risk of adverse outcomes.
doi:10.1053/j.ajkd.2012.06.002
PMCID: PMC3496012  PMID: 22809763
8.  Duration of Acute Kidney Injury Impacts Long-term Survival Following Cardiac Surgery 
The Annals of thoracic surgery  2010;90(4):10.1016/j.athoracsur.2010.04.039.
Background
Acute kidney injury (AKI) following cardiac surgery is associated with worse outcomes. However, it is not known how adverse long-term consequences vary according to the duration of AKI. We sought to determine the association between duration of AKI and survival.
Methods
4,987 cardiac surgery patients from 2002 through 2007 with serum creatinine (SCr) collection at a medical center in northern New England. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline and further classified into AKI network stages. Duration of AKI was defined by the number of days AKI was present and categorized by: no AKI, AKI for 1–2, 3–6 and ≥7 days.
Results
39% of patients developed AKI. Long-term survival was significantly different by AKI duration (p < 0.001). The proportion of patients with AKI duration, adjusted hazard ratios (HR) and 95% confidence intervals for mortality (no AKI as referent), were: 1–2 days (18%, HR 1.66; 1.32–2.09), 3–6 days (11%, HR 1.94; 1.51–2.49), ≥7 days (9%, HR 3.40; 2.73–4.25). This graded relationship of duration of AKI with long-term mortality persisted when patients who died during hospitalization were excluded from analysis (p < 0.001). Propensity matched analysis confirmed results.
Conclusion
The duration of AKI after cardiac surgery is directly proportional to long-term mortality. This AKI dose-dependent effect on long-term mortality helps to close the gap between association and causation, whereby AKI stages and AKI duration have important implications for patient care and can aid clinicians in evaluating the risk of in-hospital and post discharge death.
doi:10.1016/j.athoracsur.2010.04.039
PMCID: PMC3819730  PMID: 20868804
acute kidney injury; acute renal failure; clinical epidemiology; epidemiology and outcomes; survival; coronary artery disease
9.  Chronic Kidney Disease after Acute Kidney Injury: A Systematic Review and Meta-analysis 
Kidney international  2011;81(5):442-448.
Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk of CKD, ESRD and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8/100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks of developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0) and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) than patients without AKI. The relationship between AKI and CKD or ESRD was graded depending on the severity of AKI and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, and death and other important non-renal outcomes.
doi:10.1038/ki.2011.379
PMCID: PMC3788581  PMID: 22113526
10.  Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool 
The Annals of thoracic surgery  2011;93(2):570-576.
Background
Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival.
Methods
We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau.
Results
AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort.
Conclusion
We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI.
doi:10.1016/j.athoracsur.2011.11.004
PMCID: PMC3761881  PMID: 22206952
acute kidney injury; cardiac surgery; risk model; risk prediction; Statistics; risk analysis/modeling; Surgery; complications; Kidney; CABG; Heart Valve surgery
11.  Prevention of Chronic Kidney Disease and Subsequent Effect on Mortality: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e71784.
Objectives
To perform a systematic review of randomized controlled trials to determine whether prevention or slowing of progression of chronic kidney disease would translate into improved mortality, and if so, the attributable risk due to CKD itself on mortality.
Background
CKD is associated with increased mortality. This association is largely based on evidence from the observational studies and evidence from randomized controlled trials is lacking.
Methods
We searched Ovid, Medline and Embase for RCTs in which an intervention was given to prevent or slow the progression of CKD and mortality was reported as primary, secondary or adverse outcomes were eligible and selected. For the first phase, pooled relative risks for renal endpoints were assessed. For the second phase, we assessed the effect on mortality in trials of interventions that definitively reduced CKD endpoints.
Results
Among 52 studies selected in first phase, only renin-angiotensin-aldosterone-system blockade vs. placebo (n = 18 trials, 32,557 participants) met the efficacy criteria for further analysis in the second phase by reducing renal endpoints 15 to 27% compared to placebo. There was no difference in all-cause mortality (RR 0.99, 95% CI 0.92 to 1.08) or CV death (RR 0.97, 95% CI 0.78 to 1.21) between the treatment and control groups in these trials. There was sufficient statistical power to detect a 9% relative risk reduction in all-cause mortality and a 14% relative risk reduction in cardiovascular mortality.
Conclusions
Firm evidence is lacking that prevention of CKD translates into reductions in mortality. Larger trials with longer follow-up time are needed to determine the benefit of CKD prevention on survival.
doi:10.1371/journal.pone.0071784
PMCID: PMC3756976  PMID: 24009665
12.  Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: Data from the Veterans Aging Cohort Study 
Introduction
Approximately 15% of HIV-infected individuals have comorbid diabetes. Studies suggest that HIV and diabetes have an additive effect on chronic kidney (CKD) progression; however, this observation may be confounded by differences in traditional CKD risk factors.
Methods
We studied a national cohort of HIV-infected and matched HIV-uninfected individuals who received care through the Veterans Healthcare Administration. Subjects were divided into four groups based on baseline HIV and diabetes status, and the rate of progression to an estimated glomerular filtration rate (eGFR) < 45ml/min/1.73m2 was compared using Cox-proportional hazards modeling to adjust for CKD risk factors.
Results
31,072 veterans with baseline eGFR ≥ 45ml/min/1.73m2 (10,626 with HIV only, 5,088 with diabetes only, and 1,796 with both) were followed for a median of 5 years. Mean baseline eGFR was 94ml/min/1.73m2, and 7% progressed to an eGFR < 45ml/min/1.73m2. Compared to those without HIV or diabetes, the relative rate of progression was increased in individuals with diabetes only [adjusted hazard ratio (HR) 2.48; 95% confidence interval (CI) 2.19–2.80], HIV only [HR 2.80, 95% CI 2.50–3.15], and both HIV and diabetes [HR 4.47, 95% CI 3.87–5.17].
Discussion
Compared to patients with only HIV or diabetes, patients with both diagnoses are at significantly increased risk of progressive CKD even after adjusting for traditional CKD risk factors. Future studies should evaluate the relative contribution of complex comorbidities and accompanying polypharmacy to the risk of CKD in HIV-infected individuals, and prospectively investigate the use of cART, glycemic control, and adjunctive therapy to delay CKD progression.
doi:10.1097/QAI.0b013e31825b70d9
PMCID: PMC3392432  PMID: 22592587
non-AIDS complications; HIV; chronic kidney disease; diabetes; risk factors
13.  Role of Intensive Glucose Control in Development of Renal Endpoints in Type 2 Diabetes: Systematic Review and Meta-analysis 
Archives of internal medicine  2012;172(10):761-769.
Background
Aggressive glycemic control has been hypothesized to prevent renal disease in type 2 diabetics. A systematic review was conducted to summarize the benefits of intensive versus conventional glucose control on kidney-related outcomes for adults with type 2 diabetes.
Methods
Three databases were systematically searched (January 1950 to December 2010) with no language restrictions to identify randomized trials that compared surrogate renal endpoints (micro and macroalbuminuria) and clinical renal endpoints (doubling of serum creatinine, End Stage Renal Disease [ESRD] and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control versus receiving conventional glucose control.
Results
Seven trials involving 28,065 adults who were followed-up for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio [RR], 0.86 [95% CI, 0.76 to 0.96]) and macroalbuminuria (RR 0.74 [95% CI, 0.65–0.85]), but not doubling of serum creatinine (RR 1.06 [95% CI, 0.92 to 1.22]), ESRD (RR 0.69 [95% CI, 0.46–1.05]), or death from renal disease (RR 0.99 [95% CI 0.55–1.79]). Meta-regression revealed that larger differences in HbA1C between intensive and conventional therapy at the study level were associated with greater benefit for both micro- and macroalbuminuria. The pooled cumulative incidence of doubling of creatinine, ESRD, and death from renal disease was low (< 4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal endpoints of micro- (23%) and macroalbuminuria (5%).
Conclusion
Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes such as doubling of creatinine, ESRD or death from renal disease during the years of follow-up of the trials.
doi:10.1001/archinternmed.2011.2230
PMCID: PMC3688081  PMID: 22636820
Proteinuria; creatinine; chronic kidney disease; end-stage renal disease; prognosis
14.  Chronic kidney disease is associated with adverse outcomes among elderly patients taking clopidogrel after hospitalization for acute coronary syndrome 
BMC Nephrology  2013;14:107.
Background
Chronic kidney disease (CKD) is associated with worse outcomes among patients with acute coronary syndrome (ACS). Less is known about the impact of CKD on longitudinal outcomes among clopidogrel treated patients following ACS.
Methods
Using a retrospective cohort design, we identified patients hospitalized with ACS between 10/1/2005 and 1/10/10 at Department of Veterans Affairs (VA) facilities and who were discharged on clopidogrel. Using outpatient serum creatinine values, estimated glomerular filtration rate [eGFR (1.73 ml/min/m2)] was calculated using the CKD-EPI equation. The association between eGFR and mortality, hospitalization for acute myocardial infarction (AMI), and major bleeding were examined using Cox proportional hazards models.
Results
Among 7413 patients hospitalized with ACS and discharged taking clopidogrel, 34.5% had eGFR 30–60 and 11.6% had eGFR < 30. During 1-year follow-up after hospital discharge, 10% of the cohort died, 18% were hospitalized for AMI, and 4% had a major bleeding event. Compared to those with eGFR > =60, individuals with eGFR 30–60 (HR 1.45; 95% CI: 1.18-1.76) and < 30 (HR 2.48; 95% CI: 1.97-3.13) had a significantly higher risk of death. A progressive increased risk of AMI hospitalization was associated with declining eGFR: HR 1.20; 95% CI: 1.04-1.37 for eGFR 30–60 and HR 1.47; 95% CI: 1.22-1.78 for eGFR < 30. eGFR < 30 was independently associated with over a 2-fold increased risk in major bleeding (HR 2.09; 95% CI: 1.40-3.12) compared with eGFR > = 60.
Conclusion
Lower levels of kidney function were associated with higher rates of death, AMI hospitalization, and major bleeding among patients taking clopidogrel after hospitalization for ACS.
doi:10.1186/1471-2369-14-107
PMCID: PMC3668174  PMID: 23688069
Kidney disease; Myocardial infarction; Hospitalization; Bleeding
15.  Pre-Operative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury after Cardiac Surgery 
Circulation  2012;125(11):1347-1355.
Background
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes and is difficult to predict. We conducted a prospective study to evaluate whether pre-operative brain natriuretic peptide (BNP) levels predict postoperative AKI among patients undergoing cardiac surgery.
Methods and Results
The TRIBE-AKI Consortium enrolled 1,139 adults undergoing cardiac surgery at six hospitals from 2007–2009, who were selected for high AKI risk. Pre-operative BNP was categorized into quintiles. AKI was common using Acute Kidney Injury Network definitions; at least mild AKI was a ≥0.3mg/dL or 50% rise in creatinine, n=407 (36%), and severe AKI was either a doubling of creatinine or the requirement of acute renal replacement therapy, n=58 (5.1%). In analyses adjusted for pre-operative characteristics, pre-operative BNP was a strong and independent predictor of mild and severe AKI. Compared with the lowest BNP quintile the highest quintile had significantly higher risk of at least mild AKI (risk ratio [RR] 1.87; 1.40–2.49) and severe AKI (RR 3.17; 1.06–9.48). After adjustment for clinical predictors, addition of BNP improved the area under the curve to predict at least mild AKI (0.67 to 0.69, p=0.02) and severe AKI (0.73 to 0.75, p=0.11). Compared with clinical parameters alone, BNP modestly improved risk prediction of AKI cases into lower and higher risk (continuous net reclassification index at least mild AKI 0.183; 0.061, 0.314; severe AKI 0.231; 0.067, 0.506).
Conclusions
Pre-operative BNP level is associated with post-operative AKI in high-risk patients undergoing cardiac surgery. If confirmed in other types of patients and surgeries, pre-operative BNP may be a valuable component of future efforts to improve pre-operative risk stratification and discrimination among surgical candidates.
doi:10.1161/CIRCULATIONAHA.111.029686
PMCID: PMC3312808  PMID: 22322531
brain natriuretic peptide; cardiac surgery; acute renal failure; creatinine
16.  Chronic Kidney Disease After Hematopoietic Cell Transplantation: a Systematic Review 
Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD), however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts, and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9,317 adults and children underwent HCT and 7,317 (79%) survived to at least 100 days, permitting inclusion of 5,337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in ml/min/1.73m2) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (ΔeGFR = −40.0 versus −18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease, and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common, however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.
doi:10.1111/j.1600-6143.2008.02408.x
PMCID: PMC3564956  PMID: 18925905
chronic kidney disease (CKD); hematopoietic stem cell transplantation; bone marrow transplantation; renal failure; meta-analysis; systematic review; risk factor; complications
17.  Evaluation of urine biomarkers of kidney injury in Polycystic Kidney Disease 
Kidney International  2012;81(8):784-790.
Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of ADPKD. Here we evaluated the effect of these processes on the expression of NGAL and IL-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated which resulted in early or adult onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated GFR (eGFR) by the MDRD equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4 /year and the mean decline in eGFR 2.4 mL/min/year. The trend of increased mean urine NGAL and IL-18 over three years was statistically significant; however, there was no association of tertiles of IL-18 or quartiles of NGAL and the change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion are mildly and stably elevated in ADPKD, but do not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.
doi:10.1038/ki.2011.465
PMCID: PMC3319327  PMID: 22258321
surrogate; NGAL; IL-18; biomarker
18.  Presurgical Serum Cystatin C and Risk of Acute Kidney Injury After Cardiac Surgery 
Background
Acute kidney injury (AKI) following cardiac surgery is associated with poor outcomes, but is challenging to predict from information available prior to surgery.
Study Design
Prospective cohort study
Setting & Participants
The TRIBE-AKI Consortium enrolled 1,147 adults undergoing cardiac surgery at six hospitals from 2007–2009; participants were selected for high AKI risk.
Predictors
Pre-surgical cystatin C, creatinine, and creatinine-based estimated glomerular filtration rate (eGFR) were categorized into quintiles and grouped as ‘Best’ (quintiles 1–2), ‘Intermediate’ (quintiles 3–4), and ‘Worst’ (quintile 5) kidney function.
Outcomes
The primary outcome was AKI Network (Acute Kidney Injury Network) Stage 1 or higher; ≥0.3mg/dL or 50% rise in creatinine.
Measurements
Analyses were adjusted for characteristics used clinically for pre-surgical risk stratification.
Results
The average age and kidney function were: 71±10 years (mean ± standard deviation), serum creatinine 1.1±0.3 mg/dL, eGFR-Cr, 74±9 mL/min/1.73m2, and cystatin C, 0.9 ±0.3 mg/L. A total of 407 (36%) participants developed AKI during hospitalization. Adjusted odds ratios for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4–2.7) and 4.8 (95% CI, 2.9–7.7) compared with 1.2 (95% CI, 0.9–1.7) and 1.8 (95% CI, 1.2–2.6) for creatinine and 1.0 (95% CI, 0.7–1.4) and 1.7 (95% CI, 1.1–2.3) for eGFR-Cr categories, respectively. After adjustment for clinical predictors, the C statistic to predict AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C also substantially improved AKI risk classification compared to creatinine, based on a net reclassification index of 0.21 (p<0.001).
Limitations
The ability of these kidney biomarkers to predict risk for dialysis-requiring AKI or death could not be reliably assessed in our study due to a small number of patients with either outcome.
Conclusions
Pre-surgical cystatin C is better than creatinine or creatinine-based eGFR at forecasting the risk of AKI after cardiac surgery.
doi:10.1053/j.ajkd.2011.03.015
PMCID: PMC3159705  PMID: 21601336
acute renal failure; creatinine; prognosis
19.  Secular trends in acute dialysis after elective major surgery — 1995 to 2009 
Background:
Acute kidney injury is a serious complication of elective major surgery. Acute dialysis is used to support life in the most severe cases. We examined whether rates and outcomes of acute dialysis after elective major surgery have changed over time.
Methods:
We used data from Ontario’s universal health care databases to study all consecutive patients who had elective major surgery at 118 hospitals between 1995 and 2009. Our primary outcomes were acute dialysis within 14 days of surgery, death within 90 days of surgery and chronic dialysis for patients who did not recover kidney function.
Results:
A total of 552 672 patients underwent elective major surgery during the study period, 2231 of whom received acute dialysis. The incidence of acute dialysis increased steadily from 0.2% in 1995 (95% confidence interval [CI] 0.15–0.2) to 0.6% in 2009 (95% CI 0.6–0.7). This increase was primarily in cardiac and vascular surgeries. Among patients who received acute dialysis, 937 died within 90 days of surgery (42.0%, 95% CI 40.0–44.1), with no change in 90-day survival over time. Among the 1294 patients who received acute dialysis and survived beyond 90 days, 352 required chronic dialysis (27.2%, 95% CI 24.8–29.7), with no change over time.
Interpretation:
The use of acute dialysis after cardiac and vascular surgery has increased substantially since 1995. Studies focusing on interventions to better prevent and treat perioperative acute kidney injury are needed.
doi:10.1503/cmaj.110895
PMCID: PMC3414596  PMID: 22733671
20.  Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery – a prospective multicenter study 
Critical Care Medicine  2011;39(6):1493-1499.
Objective
To determine the incidence, severity and risk-factors of AKI in children undergoing cardiac surgery for congenital heart defects.
Design
Prospective observational multicenter cohort study
Setting
Three pediatric intensive care units at academic centers.
Patients
311 children between the ages of 1 month and 18 years undergoing pediatric cardiac surgery.
Interventions
None.
Measurements and Main Results
AKI was defined as a ≥ 50% increase in serum creatinine from the pre-operative value. Secondary outcomes were length of mechanical ventilation, length of ICU and hospital stays, acute dialysis, and in-hospital mortality. The cohort had an average age of 3.8 years with 45% females and was mostly white (82%). One third had prior cardiothoracic surgery, 91% of the surgeries were elective, and almost all patients required cardiopulmonary bypass (CPB). AKI occurred in 42% (130 patients) within 3 days after surgery. Children ≥ 2 years old and less than 13 years old had 72% lower likelihood of AKI (adjusted OR: 0.28, 95% CI: 0.16, 0.48), and patients 13 years and older had 70% lower likelihood of AKI (adjusted OR: 0.30, 95% CI: 0.10, 0.88) compared to patients less than 2 years old. Longer CPB time was linearly and independently associated with AKI. Development of AKI was independently associated with prolonged ventilation and with increased length of hospital stay.
Conclusions
AKI is common after pediatric cardiac surgery and is associated with prolonged mechanical ventilation and increased hospital stay. CPB time and age were independently associated with AKI risk. CPB time may be a marker for case complexity.
doi:10.1097/CCM.0b013e31821201d3
PMCID: PMC3286600  PMID: 21336114
Renal Insufficiency, Acute; Heart Defects, Congenital; Cardiac Surgical Procedures; Intensive Care Units, Pediatric; Cardiopulmonary Bypass; Risk Factors
21.  Urine Cystatin C as a Biomarker of Proximal Tubular Function Immediately after Kidney Transplantation 
American Journal of Nephrology  2011;33(5):407-413.
Background/Aims
Clinical methods to predict allograft function soon after kidney transplantation are ineffective.
Methods
We analyzed urine cystatin C (CyC) in a prospective multicenter observational cohort study of deceased-donor kidney transplants to determine its peritransplant excretion pattern, utility for predicting delayed graft function (DGF) and association with 3-month graft function. Serial urine samples were collected for 2 days following transplant and analyzed blindly for CyC. We defined DGF as any hemodialysis in the first week after transplant, slow graft function (SGF) as a serum creatinine reduction <70% by the first week and immediate graft function (IGF) as a reduction ≥70%.
Results
Of 91 recipients, 33 had DGF, 34 had SGF and 24 had IGF. Urine CyC/urine creatinine was highest in DGF for all time-points. The area under the curve (95% CI) for predicting DGF at 6 h was 0.69 (0.57–0.81) for urine CyC, 0.74 (0.62–0.86) for urine CyC/urine creatinine and 0.60 (0.45–0.75) for percent change in urine CyC. On the first postoperative day, urine CyC/urine creatinine and percent change in urine CyC were associated with 3-month graft function.
Conclusion
Urine CyC on the day after transplant differs between degrees of perioperative graft function and modestly corresponds with 3-month function.
doi:10.1159/000326753
PMCID: PMC3100377  PMID: 21494031
Transplantation; Biomarkers; Ischemia/reperfusion; Outcomes
22.  ACUTE KIDNEY INJURY IN PATIENTS WITH SYSTEMIC SCLEROSIS PARTICIPATING IN HEMATOPOIETIC CELL TRANSPLANTATION TRIALS IN THE UNITED STATES 
Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury and this risk may increase in patients who undergo transplantation for severe systemic sclerosis due to underlying scleroderma renal disease. Acute kidney injury after transplantation can increase transplant related mortality. To better define these risks, we analyzed 91 patients with systemic sclerosis who were enrolled in three clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation. Eleven (12%) of the 91 scleroderma patients in these studies (8 autologous, 1 allogeneic, 1 pre-transplant, 1 given intravenous cyclophosphamide on transplant trial) experienced acute kidney injury of whom eight required dialysis and/or total plasma exchange. Acute kidney injury in the 9 transplant recipients developed a median of 35 (range, 0–90) days after transplantation. Ten of 11 patients with acute kidney injury received angiotensin converting enzyme-inhibitors (ACE-I) treatment. The etiology of acute kidney injury was attributed to scleroderma renal crisis in 6 patients (including two with normotensive renal crisis), acute kidney injury of uncertain etiology in 2 patients and acute kidney injury superimposed on scleroderma kidney disease in 3 patients. Eight of the 11 patients died: causes of death included progression of SSc (1), multiorgan failure (1), gastrointestinal and pulmonary bleeding (1), pericardial tamponade and pulmonary complications (1), diffuse alveolar hemorrhage (1), pulmonary embolism (1), graft-versus-host disease (1) and malignancy (1). Limiting nephrotoxins, cautious use of corticosteroids, renal shielding during total body irradiation, strict control of blood pressure and aggressive use of ACE-I may be of importance in preventing renal complications after hematopoietic cell transplantation for systemic sclerosis.
doi:10.1016/j.bbmt.2010.08.003
PMCID: PMC3012135  PMID: 20708086
Acute kidney injury; systemic sclerosis; scleroderma; hematopoietic cell transplant
23.  Pre-operative Proteinuria predicts Acute Kidney Injury in Patients Undergoing Cardiac Surgery 
Objective
To examine the utility of using proteinuria in pre-operative risk stratification for acute kidney injury (AKI). AKI is a common and important complication for patients undergoing cardiac surgery. Proteinuria, which reflects structural damage to the glomeruli or renal tubules, may aid the prediction of AKI.
Methods
The ratio of urine albumin to creatinine (UACR) and dipstick proteinuria concentration were prospectively measured in 1159 patients undergoing cardiac surgery. The cohort was organized into four clinical risk categories based on the pre-operative UACR: UACR ≤ 10 mg/g (≤ 1.1 mg/mmol), 11–29 mg/g (1.2–3.3 mg/mmol), 30–299 mg/g (3.4–33.8 mg/mmol), and ≥ 300 mg/g (≥ 33.9 mg/mmol). The primary outcome was post-operative AKI, defined by the AKIN stage I criterion (serum creatinine rise by ≥50% or ≥ 0.3 mg/dL (26.5 μmol/L)).
Results
An increase in the incidence of AKI was noted across the UACR categories. Adding UACR to the clinical model to predict AKI improved the AUC from 0.64 to 0.67 (p < 0.001) and the continuous net reclassification improvement (NRI) was 30% (p < 0.001). UACR was also independently associated with risk of in-hospital dialysis, and ICU and hospital length of stay. Surgery status and pre-operative GFR were effect modifiers; the association was stronger amongst those undergoing elective surgery and those with eGFR ≥ 45 mL/min per 1.73 m2.
Conclusions
Pre-operative proteinuria provides graded stratification risk for AKI and is an independent predictor of other outcomes in patients undergoing cardiac surgery.
doi:10.1016/j.jtcvs.2011.09.023
PMCID: PMC3341084  PMID: 22050987
24.  Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial 
BMJ Open  2012;2(2):e001080.
Introduction
CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump. Compared with on-pump, off-pump surgery may prevent acute kidney injury (AKI) in the short term and may better preserve kidney function 1 year following surgery. Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function.
Methods and analysis
With respect to the study schedule, the last of 4752 patients from 79 sites in 19 countries were randomised in November 2011 to cardiac surgery performed with an on-pump or off-pump procedure. The authors will use regression models to compare the groups in the outcome of peri-operative AKI (per cent change in serum creatinine, ≥50% increase in serum creatinine) and 1-year kidney function (per cent change in estimated glomerular filtration rate (eGFR), ≥20% eGFR loss 1 year after surgery). The authors will use interaction terms in regression models to determine if there is a differential impact of the intervention in those with and without pre-existing chronic kidney disease. The authors will use regression-based tests to determine the proportion of the total effect of surgery type (off-pump vs on-pump CABG) on 1-year eGFR that is mediated by peri-operative AKI.
Ethics and dissemination
In the year 2009, the authors were competitively awarded a grant from the Canadian Institutes of Health Research to answer these kidney questions in CORONARY. Ethics approval was obtained for additional renal data collection in centres that agreed to study participation (>90% of participating centres). This collection began for patients enrolled after 1 January 2010. Remaining 1-year renal outcome data will be collected throughout 2012. Results will be reported in 2013.
Clinical trial registration number
NCT 00463294.
Article summary
Article focus
CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump.
Compared with on-pump, off-pump surgery may prevent AKI in the short term and may better preserve kidney function 1 year after surgery.
Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function.
Key messages
Presented is this pre-specified CORONARY kidney substudy analytic protocol.
Data collection and analysis will be completed in 2013.
Understanding the degree to which avoiding AKI preserves longer term kidney function has broader implications for the acceptability of side effects and costs of interventions which prevent AKI.
Strengths and limitations of this study
This will be largest AKI prevention trial conducted to date.
It will be one of the first trials to consider the impact of a peri-operative intervention on longer term kidney function.
International recruitment across 19 countries will provide generalisable estimates of the treatment effect.
doi:10.1136/bmjopen-2012-001080
PMCID: PMC3332245  PMID: 22514244
25.  An eUtils toolset and its use for creating a pipeline to link genomics and proteomics analyses to domain-specific biomedical literature 
Background
Numerous biomedical software applications access databases maintained by the US National Center for Biotechnology Information (NCBI). To ease software automation, NCBI provides a powerful but complex Web-service-based programming interface, eUtils. This paper describes a toolset that simplifies eUtils use through a graphical front-end that can be used by non-programmers to construct data-extraction pipelines. The front-end relies on a code library that provides high-level wrappers around eUtils functions, and which is distributed as open-source, allowing customization and enhancement by individuals with programming skills.
Methods
We initially created an application that queried eUtils to retrieve nephrology-specific biomedical literature citations for a user-definable set of genes. We later augmented the application code to create a general-purpose library that accesses eUtils capability as individual functions that could be combined into user-defined pipelines.
Results
The toolset’s use is illustrated with an application that serves as a front-end to the library and can be used by non-programmers to construct user-defined pipelines. The operation of the library is illustrated for the literature-surveillance application, which serves as a case-study. An overview of the library is also provided.
Conclusions
The library simplifies use of the eUtils service by operating at a higher level, and also transparently addresses robustness issues that would need to be individually implemented otherwise, such as error recovery and prevention of overloading of the eUtils service.
doi:10.1186/2043-9113-2-9
PMCID: PMC3422171  PMID: 22507626
Entrez Programming Utilities; Proteomics Analysis; Pubmed filters

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