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Background: The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown., Study Design: Cross-sectional analysis from multicenter prospective cohort., Settings & Participants: Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation., Predictors: (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement., Outcome: Histologic acute tubular injury., Results: Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1., Limitations: The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population., Conclusions: Concentrations of Scr and kidney injury biomarkers (L-FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest., (Published by Elsevier Inc.)

Clinical guidelines recommend prophylactic hydration to reduce the risk of contrast-induced nephropathy in high-risk patients, including those with chronic kidney disease. A recent single-center randomized trial showed no significant difference in the incidence of contrast-induced nephropathy in ambulatory patients with stage 3 chronic kidney disease who were randomized to no prophylactic hydration versus normal saline hydration. While these results may identify patients who are less likely to benefit from prophylactic hydration, nephrologists and interventionalists should carefully consider the generalizability of these results to individual patients., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies., Methods and Results: We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001)., Conclusion: The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Objectives: Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome., Design, Setting, Participants, & Measurements: We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with ≥40% sustained eGFR decline over the 5-year follow-up period to 190 participants with ≤10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 μg/mg, and baseline eGFR within 10 ml/min per 1.73 m(2)), with ≤10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression., Results: Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-to-creatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio., Conclusions: Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2 diabetes with preserved renal function., (Copyright © 2016 by the American Society of Nephrology.)

Observational studies have shown that acute change in kidney function (specifically, AKI) is a strong risk factor for poor outcomes. Thus, the outcome of acute change in serum creatinine level, regardless of underlying biology or etiology, is frequently used in clinical trials as both efficacy and safety end points. We performed a meta-analysis of clinical trials to quantify the relationship between positive or negative short-term effects of interventions on change in serum creatinine level and more meaningful clinical outcomes. After a thorough literature search, we included 14 randomized trials of interventions that altered risk for an acute increase in serum creatinine level and had reported between-group differences in CKD and/or mortality rate ≥3 months after randomization. Seven trials assessed interventions that, compared with placebo, increased risk of acute elevation in serum creatinine level (pooled relative risk, 1.52; 95% confidence interval, 1.22 to 1.89), and seven trials assessed interventions that, compared with placebo, reduced risk of acute elevation in serum creatinine level (pooled relative risk, 0.57; 95% confidence interval, 0.44 to 0.74). However, pooled risks for CKD and mortality associated with interventions did not differ from those with placebo in either group. In conclusion, several interventions that affect risk of acute, mild to moderate, often temporary elevation in serum creatinine level in placebo-controlled randomized trials showed no appreciable effect on CKD or mortality months later, raising questions about the value of using small to moderate changes in serum creatinine level as end points in clinical trials., (Copyright © 2016 by the American Society of Nephrology.)

The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials., (Published by Elsevier Inc.)

Background: Acute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described., Methods: This is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site., Results: During the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47)., Conclusions: Elevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Hepatorenal syndrome is a severe complication of cirrhosis and associates with significant mortality. Vasoconstrictor medications improve renal function in patients with hepatorenal syndrome. However, it is unclear to what extent changes in serum creatinine during treatment may act as a surrogate for changes in mortality. We have performed a meta-analysis of randomized trials of vasoconstrictors assessing the association between changes in serum creatinine, taken as a continuous variable, and mortality, both while on treatment and during the follow-up period for survivors., Methods: The electronic databases of PubMed, Web of Science and Embase were searched for randomized trials evaluating the efficacy of vasoconstrictor therapy for treatment of HRS type 1 or 2. The relative risk (RR) for mortality was calculated against delta creatinine. The proportion of treatment effect explained (PTE) was calculated for delta creatinine., Results: Seven trials enrolling 345 patients were included. The correlation between delta creatinine and ln (RR) was moderately good (R2 = 0.61). The intercept and parameter estimate indicated a fall in creatinine while on treatment of 1 mg/dL resulted in a 27% reduction in RR for mortality compared to the control arm. In patients surviving the treatment period, a fall in creatinine while on treatment of 1 mg/dL resulted in a 16% reduction in RR for post-treatment mortality during follow-up. The PTE of delta creatinine for overall mortality was 0.91 and 0.26 for post-treatment mortality., Conclusions: Changes in serum creatinine in response to vasoconstrictor therapy appear to be a valid surrogate for mortality, even in the period following the completion of treatment.

Background: Identifying reversible renal dysfunction (RD) in the setting of heart failure is challenging. The goal of this study was to evaluate whether elevated admission blood urea nitrogen/creatinine ratio (BUN/Cr) could identify decompensated heart failure patients likely to experience improvement in renal function (IRF) with treatment., Methods and Results: Consecutive hospitalizations with a discharge diagnosis of heart failure were reviewed. IRF was defined as ≥20% increase and worsening renal function as ≥20% decrease in estimated glomerular filtration rate. IRF occurred in 31% of the 896 patients meeting eligibility criteria. Higher admission BUN/Cr was associated with in-hospital IRF (odds ratio, 1.5 per 10 increase; 95% confidence interval [CI], 1.3-1.8; P<0.001), an association persisting after adjustment for baseline characteristics (odds ratio, 1.4; 95% CI, 1.1-1.8; P=0.004). However, higher admission BUN/Cr was also associated with post-discharge worsening renal function (odds ratio, 1.4; 95% CI, 1.1-1.8; P=0.011). Notably, in patients with an elevated admission BUN/Cr, the risk of death associated with RD (estimated glomerular filtration rate <45) was substantial (hazard ratio, 2.2; 95% CI, 1.6-3.1; P<0.001). However, in patients with a normal admission BUN/Cr, RD was not associated with increased mortality (hazard ratio, 1.2; 95% CI, 0.67-2.0; P=0.59; p interaction=0.03)., Conclusions: An elevated admission BUN/Cr identifies decompensated patients with heart failure likely to experience IRF with treatment, providing proof of concept that reversible RD may be a discernible entity. However, this improvement seems to be largely transient, and RD, in the setting of an elevated BUN/Cr, remains strongly associated with death. Further research is warranted to develop strategies for the optimal detection and treatment of these high-risk patients.

Background and Objectives: This study determined if preoperative and postoperative urine albumin/creatinine ratios (ACRs) predict postoperative AKI in children undergoing cardiac surgery (CS)., Design, Setting, Participants, & Measurements: This was a three-center, prospective study (2007-2009) of 294 children undergoing CS (n=145 aged <2 years). Urine ACR was measured preoperatively and 0-6 hours after intensive care unit arrival. AKI outcomes were based on the Acute Kidney Injury Network serum creatinine (SCr) criteria (stage 1 AKI, ≥50% or 0.3 mg/dl SCr rise from baseline; and stage 2 or worse AKI, ≥SCr doubling or dialysis). AKI was predicted using preoperative and postoperative ACRs and postoperative ACR performance was compared with other AKI biomarkers., Results: Preoperative ACR did not predict AKI in younger or older children. In children aged <2 years, first postoperative ACR ≥908 mg/g (103 mg/mmol) predicted stage 2 AKI development (adjusted relative risk, 3.4; 95% confidence interval, 1.2-9.4). In children aged ≥2 years, postoperative ACR ≥169 mg/g (19.1 mg/mmol) predicted stage 1 AKI (adjusted relative risk, 2.1; 95% confidence interval, 1.1-4.1). In children aged ≥2 years, first postoperative ACR improved AKI prediction from other biomarker and clinical prediction models, estimated by net reclassification improvement (P≤0.03), but only when serum cystatin C was also included in the model., Conclusions: Postoperative ACR is a readily available early diagnostic test for AKI after pediatric CS that performs similarly to other AKI biomarkers; however, its use is enhanced in children aged ≥2 years and in combination with serum cystatin C.

Background: Recently, acute kidney injury defined by small changes in serum creatinine levels was associated with worse short-term outcomes; however, the precision and variability of this association was not fully explored., Study Design: Systematic review and meta-analysis., Setting & Participants: Hospitalized patients., Selection Criteria for Studies: MEDLINE and EMBASE databases were searched for observational cohort studies and randomized controlled trials published from 1990 through February 2007 that provided information for small changes in serum creatinine levels., Predictor: Small acute changes in serum creatinine levels by absolute and percentage of changes in serum creatinine levels (lower threshold for increase in serum creatinine <0.5 mg/dL or <25%)., Outcome: Short-term mortality (or=50%) had the greatest RR of death (RR, 6.9; 95% CI, 2.0 to 24.5). Results were similar when absolute changes in creatinine levels were considered and when pooled estimates of adjusted RR were used., Limitations: Individual patient data were unavailable; thus, only group-level data were pooled for meta-analysis. Results showed a significant degree of statistical heterogeneity that was only partially ameliorated by separating studies into subsets based on clinical setting., Conclusions: Short-term mortality and acute decreases in renal function are associated through a graded relationship such that even mild changes in serum creatinine levels portend worse outcome in a variety of clinical settings and patient-types.

Rationale & objectiveThe process of angiogenesis after kidney injury may determine recovery and long-term outcomes. We evaluated the association of angiogenesis markers with acute kidney injury (AKI) and mortality after cardiac surgery.Study designProspective cohort.Setting & participants1,444 adults undergoing cardiac surgery in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) cohort.ExposuresPlasma concentrations of 2 proangiogenic markers (vascular endothelial growth factor A [VEGF] and placental growth factor [PGF]) and 1 antiangiogenic marker (soluble VEGF receptor 1 [VEGFR1]), measured pre- and postoperatively within 6 hours after surgery.OutcomesAKI, long AKI duration (≥7 days), and 1-year all-cause mortality.Analytical approachMultivariable logistic regression.ResultsFollowing cardiac surgery, plasma VEGF concentrations decreased 2-fold, and PGF and VEGFR1 concentrations increased 1.5- and 8-fold, respectively. There were no meaningful associations of preoperative concentrations of angiogenic markers with outcomes of AKI and mortality. Higher postoperative VEGF and PGF concentrations were independently associated with lower odds of AKI (adjusted ORs of 0.89 [95% CI, 0.82-0.98] and 0.69 [95% CI, 0.55-0.87], respectively), long AKI duration (0.65 [95% CI, 0.49-0.87] and 0.48 [95% CI, 0.28-0.82], respectively), and mortality (0.74 [95% CI, 0.62-0.89] and 0.46 [95% CI, 0.31-0.68], respectively). In contrast, higher postoperative VEGFR1 concentrations were independently associated with higher odds of AKI (1.56; 95% CI, 1.31-1.87), long AKI duration (1.75; 95% CI, 1.09-2.82), and mortality (2.28; 95% CI, 1.61-3.22).LimitationsAngiogenesis markers were not measured after hospital discharge, so we were unable to determine long-term trajectories of angiogenesis marker levels during recovery and follow-up.ConclusionsHigher levels of postoperative proangiogenic markers, VEGF and PGF, were associated with lower AKI and mortality risk, whereas higher postoperative antiangiogenic VEGFR1 levels were associated with higher risk for AKI and mortality.

BackgroundThe interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear.Study designPost hoc analysis of prospective cohort study.Setting & participantsThe 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants.PredictorUnadjusted postoperative urinary biomarkers of AKI measured within 6 hours of surgery.OutcomeAKI was defined as AKI Network stage 1 (any AKI) or higher, as well as a doubling of serum creatinine level from the preoperative value or the need for post-operative dialysis (severe AKI).MeasurementsStratified analyses by preoperative estimated glomerular filtration rate (eGFR) ≤ 60 versus > 60mL/min/1.73m(2).Results180 (42%) patients with preoperative eGFRs≤60mL/min/1.73m(2) developed clinical AKI compared with 246 (31%) of those with eGFRs>60mL/min/1.73m(2) (P

Acute kidney injury (AKI) has been implicated as an independent risk factor for the development of CKD in recent observational studies. The presumption in the nephrology community is that this association represents a causal relationship. However, because of potential problems related to residual confounding (shared risk factors), ascertainment bias (sicker patients have more follow-up assessments), misclassification of exposure (problems with defining baseline kidney function and AKI representing a discrete event versus progression of renal disease), and misclassification of outcome (de novo CKD versus CKD progression), it is difficult to conclude with certainty that AKI is truly causal for CKD. In this review we highlight several of the Hill causality criteria to examine the existing evidence and point out the missing elements that preclude defining AKI as a cause of CKD in the general population. Only well-designed studies with rigorous assessment of kidney function in all participants (AKI and non-AKI) before and after the episode or hospitalization or randomized, controlled trials demonstrating that prevention or treatment of AKI reduces the incidence of subsequent CKD can clarify the causal nature of the AKI-CKD relationship.

Patients with kidney disease (KD) are at increased risk for cerebrovascular disease (CVD) and CVD patients with KD have worse outcomes. We aimed to determine the representation of KD patients in major randomized controlled trials (RCTs) of CVD interventions. We searched MEDLINE for reports of major CVD trials published through February 9, 2017. We excluded trials that did not report mortality outcomes, enrolled fewer than 100 participants, or were subgroup, follow-up, or post-hoc analyses. Two independent reviewers performed study selection and data extraction. We included 135 RCTs randomizing 194,977 participants. KD patients were excluded in 48 (35.6%) trials, but were less likely to be excluded from trials of class I/II recommended interventions (n = 7; 15.9%; p = 0.001) and more likely to be excluded in trials with registered protocols (45.5% vs. 22.4%; p = 0.007). Exclusion was lower in trials supported by academic or governmental grants compared to industry or combined funding (21.2% vs. 42.0% and 47.8%; p = 0.033 and 0.028, respectively). Among trials excluding KD patients, 24 (50.0%) used serum creatinine, 7 (14.6%) used estimated glomerular filtration rate or creatinine clearance, 7 (14.6%) used renal replacement therapy, and 19 (39.6%) used non-specific kidney-related criteria. Only 4 (3.0%) trials reported baseline renal function. No trials prespecified or reported subgroup analyses by baseline renal function. Although 19 (14.1%) trials reported the incidence of acute kidney injury, no trial examined adverse event rates according to renal function. In summary, more than one third of major CVD trials excluded patients with KD, primarily based on serum creatinine or non-specific criteria, and outcomes were not stratified by renal parameters. Therefore, purposeful efforts to increase inclusion of KD patients in CVD trials and evaluate the impact of renal function on efficacy and safety are needed to improve the quality of evidence for interventions in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

IMPORTANCE Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function. OBJECTIVES To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later. DESIGN, SETTING, AND PARTICIPANTS The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011,2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18,2013. MAIN OUTCOMES AND MEASURES Acute kidney injury within 30 days of surgery (>50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (>20% loss in estimated glomerular filtration rate from prerandomization level). RESULTS Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease. CONCLUSIONS AND relevance Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00463294 [ABSTRACT FROM AUTHOR]

Background Using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) the morning of surgery may lead to ‘functional’ postoperative acute kidney injury (AKI), measured by an abrupt increase in serum creatinine. Whether the same is true for ‘structural’ AKI, measured with new urinary biomarkers, is unknown. Methods The TRIBE-AKI study was a prospective cohort study of 1594 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2010. We classified the degree of exposure to ACEi/ARB into three categories: ‘none’ (no exposure prior to surgery), ‘held’ (on chronic ACEi/ARB but held on the morning of surgery) or ‘continued’ (on chronic ACEi/ARB and taken the morning of surgery). The co-primary outcomes were ‘functional’ AKI based upon changes in pre- to postoperative serum creatinine, and ‘structural AKI’, based upon peak postoperative levels of four urinary biomarkers of kidney injury. Results Across the three levels (none, held and continued) of ACEi/ARB exposure there was a graded increase in functional AKI, as defined by AKI stage 1 or worse; (31, 34 and 42%, P for trend 0.03) and by percentage change in serum creatinine from pre- to postoperative (25, 26 and 30%, P for trend 0.03). In contrast, there were no differences in structural AKI across the strata of ACEi/ARB exposure, as assessed by four structural AKI biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18 or liver-fatty acid-binding protein). Conclusions Preoperative ACEi/ARB usage was associated with functional but not structural acute kidney injury. As AKI from ACEi/ARB in this setting is unclear, interventional studies testing different strategies of perioperative ACEi/ARB use are warranted. [ABSTRACT FROM PUBLISHER]

Objective: The study objective was to examine the utility of using proteinuria in preoperative risk stratification for acute kidney injury. Acute kidney injury 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 acute kidney injury. Methods: The urine albumin to creatinine ratio and dipstick proteinuria concentration were prospectively measured in 1159 patients undergoing cardiac surgery. The cohort was organized into 4 clinical risk categories based on the preoperative urine albumin to creatinine ratio: 10 mg/g or less (≤1.1 mg/mmol), 11 to 29 mg/g (1.2–3.3 mg/mmol), 30 to 299 mg/g (3.4–33.8 mg/mmol), and 300 mg/g or greater (≥33.9 mg/mmol). The primary outcome was postoperative acute kidney injury, defined by the Acute Kidney Injury Network stage I criterion (serum creatinine increase ≥ 50% or ≥ 0.3 mg/dL; 26.5 μmol/L). Results: An increase in the incidence of acute kidney injury was noted across the urine albumin to creatinine ratio categories. Adding the urine albumin to creatinine ratio to the clinical model to predict acute kidney injury improved the area under the curve from 0.67 to 0.70 (P < .001), and the continuous net reclassification improvement was 29% (P < .001). The urine albumin to creatinine ratio was also independently associated with the risk of in-hospital dialysis and intensive care unit and hospital lengths of stay. Surgery status and preoperative glomerular filtration rate were effect modifiers; the association was stronger among those undergoing elective surgery and those with an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater. Conclusions: Preoperative proteinuria provides graded stratification risk for acute kidney injury and is an independent predictor of other outcomes in patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) duration after cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what perioperative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify perioperative 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. Acute kidney injury was defined as a 0.3 or greater (mg/dL) or 50% or greater increase in serum creatinine from baseline. Duration of AKI was defined by the number of days AKI was present. Stepwise multivariable negative binomial regression analysis was conducted using perioperative risk factors for AKI duration. The c-index was estimated by Kendall''s tau. Results: Acute kidney injury 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 a duration of 0 days. Independent predictors of AKI duration included baseline patient and disease characteristics, and operative and postoperative 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 (Translational Research Investigating Biomarker Endpoints-AKI). The c-index was 0.65 (p < 0.001) for the derivation cohort and 0.62 (p < 0.001) for the validation cohort. Conclusions: We identified and externally validated perioperative 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 levels 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. [Copyright &y& Elsevier]

Acute kidney injury (AKI) is primarily defined and staged according to the magnitude of the rise in serum creatinine. Here we sought to determine if the duration of AKI adds additional prognostic information above that from the magnitude of injury alone. We prospectively studied 35,302 diabetic patients from 123 Veterans Affairs Medical Centers undergoing their first noncardiac surgery. The main outcome was long-term mortality in those who survived the index hospitalization. AKI was stratified by magnitude according to AKI Network stages and by the duration (short (less than 2 days), medium (3-6 days) or long (7 days or more)). Overall, 17.8% of patients experienced at least stage 1 AKI or greater following surgery. Both the magnitude and duration of AKI were significantly associated with long-term survival in a dose-dependent manner. Within each stage, longer duration of AKI was significantly associated with a graded higher rate of mortality. However, within each of the duration categories, the stage was not associated with mortality. When considered separately in multivariate analyses, both a higher stage and duration were independently associated with increased risk of long-term mortality. Hence, the duration of AKI adds additional information to predict long-term mortality. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI), as defined by peak increase in serum creatinine, is independently associated with increased risk of mortality and length of stay. Studies have suggested that the duration of AKI may be an important additional or independent prognostic marker of increased mortality in patients with AKI across clinical settings. We performed a systematic review and meta-analysis of published studies to assess the impact of duration of AKI on outcomes.Methods: Various bibliographic databases (MEDLINE, Embase, Cochrane Library, CINAHL and Web of Science) were searched through database inception to December 2015. Human, longitudinal studies with patients aged 18 or above describing outcomes of duration of AKI were included. Duration of AKI categorized as "Short" if AKI duration was ≤2 days or labeled as "transient AKI"; "Medium" for AKI durations 3-6 days and "Long" for AKI duration of ≥7 days or "non-recovered". Various outcomes looked at were Long term mortality, cardiovascular events, chronic kidney disease (CKD).Results: Eighteen studies were deemed eligible for the systematic review. The outcome of long-term mortality with duration of AKI was reported in 8 studies. The pooled Risk Ratio (RR) for long-term mortality generally was higher for longer duration of AKI: short duration of AKI (n = 8 studies, RR 1.42, 95% CI 1.21-1.66), medium duration (n = 4 studies, RR 1.92, 95% CI 1.34-2.75), and long duration (n = 8 studies, RR 2.28, 95% CI 1.77-2.94) duration of AKI. Further, Duration of AKI was independently associated with higher risk of cardiovascular outcomes and incident CKD Stage 3 when stratified within each stage of AKI.Conclusion: Duration of AKI was independently associated with long term mortality, cardiovascular(CV) events, and development of incident CKD Stage 3. [ABSTRACT FROM AUTHOR]

BACKGROUND The development of drug-induced acute interstitial nephritis (AIN) is usually managed by withdrawal of the precipitating agent; however, renal function does not always return to normal afterwards. OBJECTIVE To determine the effect of steroid treatment on long-term renal function in patients with drug-induced AIN. DESIGN AND INTERVENTION The medical records of patients with biopsy-proven drug-induced AIN who had been admitted to 1 of 10 hospitals in Madrid, Spain during the period 1975-2006 were retrospectively reviewed. Suspected systemic disease was an exclusion criterion. The presence of urinary tract obstruction or infection was excluded by radiological examination and urinalysis. OUTCOME MEASURE The outcome measure was serum creatinine level. RESULTS The 61 patients included in the analysis had a mean serum creatinine level of 1.1 ± 0.39 mg/dl (97±34 µmol/l; range 0.4-2.3mg/dl [35-203 µmol/l]) at baseline (0.5-16 months before the onset of AIN). The causative agent (an antibiotic in 34 [56%] patients; an NSAID in 23 [37%] patients; other drugs in 4 [7%] patients) was withdrawn in all cases, and steroid treatment was initiated a mean of 23 ± 17 days (range 2-68 days) afterwards, in 52 patients. The 52 patients who received steroids and the 9 who did not were similar in terms of demographic characteristics, baseline serum creatinine level and cause of interstitial nephritis (i.e. drug type). The most commonly used steroid regimen comprised intravenous pulse methylprednisolone 250-500mg/day for 3-4 days, followed by oral prednisone (starting dose 1 mg/kg/day) for 8-12 weeks. Six months after withdrawal of the causative agent, the steroid-treated group had a significantly lower mean serum creatinine level than the untreated group (2.1 ± 2.1mg/dl [186 ± 186 µmol/l] vs 3.7 ± 2.9mg/dl [327+256 ± µmol/l]; P<0.05), and fewer of the steroid-treated patients required chronic dialysis (2 [3.8%] vs 4 [44.4%]; P<0.001). The steroid-treated group was then subdivided into patients who experienced complete renal recovery (n =28) and those who experienced incomplete renal recovery (i.e. serum creatinine level remained ≥25% higher than baseline at 6 months after withdrawal of the causative agent; n=24). There was no significant difference in the duration of steroid treatment between the subgroups, but the patients who experienced incomplete renal recovery had a significantly longer interval between withdrawal of the causative agent and start of steroid treatment (34 ± 10 days.; P <0.0001). Multivariate regression analysis revealed that an interval of >7 days was associated with a more than 6 times increased risk of experiencing incomplete recovery of renal function (odds ratio 6.6, 95% CI 1.3-33.6; P=0.02). No steroid-related adverse events occurred. CONCLUSION Steroid treatment seems to be associated with improved renal outcome in patients with drug-induced AIN, especially when initiated soon after withdrawal of the offending agent. [ABSTRACT FROM AUTHOR]

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis.Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C.Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001).Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury. [ABSTRACT FROM AUTHOR]

Background--Acute kidney injury (AKI) after cardiac surgery is associated with poor outcomes and is difficult to predict. We conducted a prospective study to evaluate whether preoperative brain natriuretic peptide (BNP) levels predict postoperative AKI among patients undergoing cardiac surgery. ethods and Results--The Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury (TRIBE-AKI) study enrolled 1139 adults undergoing cardiac surgery at 6 hospitals from 2007 to 2009 who were selected for high AKI risk. Preoperative BNP was categorized into quintiles. AKI was common with the use of Acute Kidney Injury Network definitions; at least mild AKI was a >0.3-mg/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 preoperative characteristics, preoperative 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, 1.87; 95% confidence interval, 1.40-2.49) and severe AKI (risk ratio, 3.17; 95% confidence interval, 1.06-9.48). After adjustment for clinical predictors, the addition of BNP improved the area under the curve to predict at least mild AKI (0.67-0.69; P=0.02) and severe AKI (0.73-0.75; 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: risk ratio, 0.183; 95% confidence interval, 0.061-0.314; severe AKI: risk ratio, 0.231; 95% confidence interval, 0.067-0.506). onclusions--Preoperative BNP level is associated with postoperative AKI in high-risk patients undergoing cardiac-surgery. If confirmed in other types of patients and surgeries, preoperative BNP may be a valuable component of future efforts to improve preoperative risk stratification and discrimination among surgical candidates. [ABSTRACT FROM AUTHOR]