Search

Background: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied., Methods: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022. AKI was determined with serum creatinine and diagnosis codes. Time was divided into 16-week periods (P1-6) and geographical regions into Northeast, Midwest, South, and West. Multivariable models were used to analyze the risk factors for AKI or mortality., Results: Of a total cohort of 336,473, 129,176 (38%) patients had AKI. Fifty-six thousand three hundred and twenty-two (17%) lacked a diagnosis code but had AKI based on the change in serum creatinine. Similar to patients coded for AKI, these patients had higher mortality compared with those without AKI. The incidence of AKI was highest in P1 (47%; 23,097/48,947), lower in P2 (37%; 12,102/32,513), and relatively stable thereafter. Compared with the Midwest, the Northeast, South, and West had higher adjusted odds of AKI in P1. Subsequently, the South and West regions continued to have the highest relative AKI odds. In multivariable models, AKI defined by either serum creatinine or diagnostic code and the severity of AKI was associated with mortality., Conclusions: The incidence and distribution of COVID-19-associated AKI changed since the first wave of the pandemic in the United States., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_08_08_CJN0000000000000192.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Background: AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition., Methods: We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models., Results: We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 ( N =181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 ( N =250) had the highest levels of uromodulin. AKI subphenotype 3 ( N =159) comprised patients with markedly high pro-brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase-associated lipocalin. Finally, patients with subphenotype 4 ( N =158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase-associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% confidence interval, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events., Conclusions: We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes., (Copyright © 2023 by the American Society of Nephrology.)

The major goals of the Kidney Precision Medicine Project (KPMPP) are to establish a molecular atlas of the kidney in health and disease and improve our understanding of the molecular drivers of CKD and AKI. In this clinical-pathologic-molecular correlation, we describe the case of a 38-year-old woman without any history of CKD who underwent a research kidney biopsy in the setting of AKI suspected to be due to nonsteroidal anti-inflammatory use after cesarean section delivery. The participant's histopathology was consistent with mild acute tubular injury, without significant interstitial fibrosis or tubular atrophy. This diagnosis was supported by analysis of the glomerular and tubulointerstitial proteomes. The proteomic interrogation revealed a molecular landscape that demonstrated differences in kidney prostaglandin synthesis that may be in response to nonsteroidal anti-inflammatory drugs and signs of intrarenal inflammation and fibrosis that were not evident by histopathology alone., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Contrast-associated AKI may result in higher morbidity and mortality. Intravenous fluid administration remains the mainstay for prevention. There is a lack of consensus on the optimal administration strategy. We studied the association of periprocedure fluid administration with contrast-associated AKI, defined as an increase in serum creatinine of at least 25% or 0.5 mg/dl from baseline at 3-5 days after angiography, and 90-day need for dialysis, death, or a 50% increase in serum creatinine., Design, Setting, Participants, & Measurements: We conducted a secondary analysis of 4671 PRESERVE participants who underwent angiographic procedures. Although fluid type was randomized, strategy of administration was at the discretion of the clinician. We divided the study cohort into quartiles by total fluid volume. We performed multivariable logistic regression, adjusting for clinically important covariates. We tested for the interaction between fluid volume and duration of fluid administration, categorized as <6 or ≥6 hours., Results: The mean (SD) age was 70 (8) years, 94% of participants were male, and median (interquartile range) eGFR was 60 (41-60) ml/min per 1.73 m 2 . The range of fluid administered was 89-882 ml in quartile 1 and 1258-2790 ml in quartile 4. Compared with the highest quartile (quartile 4) of fluid volume, we found a significantly higher risk of the primary outcome in quartile 1 (adjusted odds ratio, 1.58; 95% confidence interval, 1.06 to 2.38) but not in quartiles 2 and 3 compared with quartile 4. There was no difference in the incidence of contrast-associated AKI across the quartiles. The interaction between volume and duration was not significant for any of the outcomes., Conclusions: We found that administration of a total volume of 1000 ml, starting at least 1 hour before contrast injection and continuing postcontrast for a total of 6 hours, is associated with a similar risk of adverse outcomes as larger volumes of intravenous fluids administered for periods >6 hours. Mean fluid volumes <964 ml may be associated with a higher risk for the primary outcome, although residual confounding cannot be excluded., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice., Design, Setting, Participants, & Measurements: We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair., Results: We found urine uromodulin to be correlated with serum creatinine (rho=-0.43; P <0.001), bicarbonate (0.20; P <0.001), and hemoglobin (0.11; P =0.03) at the time of biopsy but not with urine albumin (-0.07; P =0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models., Conclusions: Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;08&#95;10&#95;CJN04360422.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Novel aptamer-based technologies can identify >7000 analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD., Design, Setting, Participants, & Measurements: We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality., Results: Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations ( r =0.94, 0.93, 0.89, 0.85, 0.46, and 0.23, respectively) between SOMAscan and immunoassay measurements, and three (IL-10, IFN- γ , and TNF- α ) were uncorrelated ( r =0.08, 0.07, and 0.02, respectively). Of the six biomarkers with non-negligible correlations, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were negatively correlated with measured GFR and associated with higher risk of kidney failure. IL-8, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were associated with a higher risk of mortality via both methods. On average, immunoassay measurements were more strongly associated with adverse outcomes than their SOMAscan counterparts., Conclusions: SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;02&#95;23&#95;CJN11700921.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria., Design, Setting, Participants, & Measurements: TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates., Results: In patients with normoalbuminuria ( n =2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8-6.4) years (event rate, 3.5; 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2; 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3; 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles., Conclusions: TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria., Clinical Trial Registry Name and Registration Number: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Moderate coffee consumption has been associated with lower risk of CKD; however, the exact biologic mechanisms underlying this association are unknown. Metabolomic profiling may identify metabolic pathways that explain the association between coffee and CKD. The goal of this study was to identify serum metabolites associated with coffee consumption and examine the association between these coffee-associated metabolites and incident CKD., Design, Setting, Participants, & Measurements: Using multivariable linear regression, we identified coffee-associated metabolites among 372 serum metabolites available in two subsamples of the Atherosclerosis Risk in Communities study (ARIC; n =3811). Fixed effects meta-analysis was used to pool the results from the two ARIC study subsamples. Associations between coffee and metabolites were replicated in the Bogalusa Heart Study ( n =1043). Metabolites with significant associations with coffee in both cohorts were then evaluated for their prospective associations with incident CKD in the ARIC study using Cox proportional hazards regression., Results: In the ARIC study, mean (SD) age was 54 (6) years, 56% were daily coffee drinkers, and 32% drank >2 cups per day. In the Bogalusa Heart Study, mean (SD) age was 48 (5) years, 57% were daily coffee drinkers, and 38% drank >2 cups per day. In a meta-analysis of two subsamples of the ARIC study, 41 metabolites were associated with coffee consumption, of which 20 metabolites replicated in the Bogalusa Heart Study. Three of these 20 coffee-associated metabolites were associated with incident CKD in the ARIC study., Conclusions: We detected 20 unique serum metabolites associated with coffee consumption in both the ARIC study and the Bogalusa Heart Study, and three of these 20 candidate biomarkers of coffee consumption were associated with incident CKD. One metabolite (glycochenodeoxycholate), a lipid involved in primary bile acid metabolism, may contribute to the favorable kidney health outcomes associated with coffee consumption. Two metabolites ( O -methylcatechol sulfate and 3-methyl catechol sulfate), both of which are xenobiotics involved in benzoate metabolism, may represent potential harmful aspects of coffee on kidney health., (Copyright © 2021 by the American Society of Nephrology.)

Objectives: Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019., Design: This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration., Setting: Sixty-eight U.S. ICUs., Patients: Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020., Interventions: None., Measurements and Main Results: The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao 2 /Fio 2 ratio were the most important predictors in the eXtreme Gradient Boosting model., Conclusions: eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment., Competing Interests: Dr. Churpek is supported by an R01 from National Institute of General Medical Sciences (NIGMS) (R01 GM123193), has a patent pending (ARCD. P0535US.P2) for risk stratification algorithms for hospitalized patients, and has received research support from EarlySense (Tel Aviv, Israel). Dr. Gupta is a scientific coordinator for the A Study of Cardiovascular Events in Diabetes trial (GlaxoSmithKline). Dr. Shaefi is supported by a K08 from NIGMS (K08GM134220) and an R03 from National Institute of Aging (R03AG060179). Dr. Leaf is supported by an R01 from National Heart, Lung, and Blood Institute (R01HL144566). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background and Objectives: BK polyomavirus (BKV) infection commonly complicates kidney transplantation, contributing to morbidity and allograft failure. The virus is often donor-derived and influenced by ischemia-reperfusion processes and disruption of structural allograft integrity. We hypothesized that deceased-donor AKI associates with BKV infection in recipients., Design, Setting, Participants, & Measurements: We studied 1025 kidney recipients from 801 deceased donors transplanted between 2010 and 2013, at 13 academic centers. We fitted Cox proportional-hazards models for BKV DNAemia (detectable in recipient blood by clinical PCR testing) within 1 year post-transplantation, adjusting for donor AKI and other donor- and recipient-related factors. We validated findings from this prospective cohort with analyses for graft failure attributed to BKV within the Organ Procurement and Transplantation Network (OPTN) database., Results: The multicenter cohort mean kidney donor profile index was 49±27%, and 26% of donors had AKI. Mean recipient age was 54±13 years, and 25% developed BKV DNAemia. Donor AKI was associated with lower risk for BKV DNAemia (adjusted hazard ratio, 0.53; 95% confidence interval, 0.36 to 0.79). In the OPTN database, 22,537 (25%) patients received donor AKI kidneys, and 272 (0.3%) developed graft failure from BKV. The adjusted hazard ratio for the outcome with donor AKI was 0.7 (95% confidence interval, 0.52 to 0.95)., Conclusions: In a well-characterized, multicenter cohort, contrary to our hypothesis, deceased-donor AKI independently associated with lower risk for BKV DNAemia. Within the OPTN database, donor AKI was also associated with lower risk for graft failure attributed to BKV., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021&#95;03&#95;10&#95;CJN18101120&#95;final.mp3., (Copyright © 2021 by the American Society of Nephrology.)

Background and Objectives: The risk-benefit ratio of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy after AKI may be altered due to concerns regarding recurrent AKI. We evaluated, in a prospective cohort, the association between use (versus nonuse) of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the subsequent risk of AKI and other adverse outcomes after hospitalizations with and without AKI., Design, Setting, Participants, & Measurements: We studied 1538 patients recently discharged from the hospital who enrolled in the multicenter, prospective ASSESS-AKI study, with approximately half of patients experiencing AKI during the index hospitalization. All participants were seen at a baseline visit 3 months after their index hospitalization and were categorized at that time on whether they were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or not. We used multivariable Cox regression, adjusting for demographics, comorbidities, eGFR, urine protein-creatinine ratio, and use of other medications, to examine the association between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and subsequent risks of AKI, death, kidney disease progression, and adjudicated heart-failure events., Results: The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 50% (386/769) among those with AKI during the index hospitalization and 47% (362/769) among those without. Among those with AKI during the index hospitalization, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was not associated with a higher risk of recurrent hospitalized AKI (adjusted hazard ratio, 0.88; 95% confidence interval, 0.69 to 1.13). Associations between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and death, kidney disease progression, and adjudicated heart-failure events appeared similar in study participants who did and did not experience AKI during the index hospitalization (all interaction P values >0.05)., Conclusions: The risk-benefit ratio of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy after hospital discharge appears to be similar regardless of whether AKI occurred during the hospitalization., (Copyright © 2021 by the American Society of Nephrology.)

The American Society of Nephrology has established a new initiative, AKI!Now , with the goal of promoting excellence in the prevention and treatment of AKI by building a foundational program that transforms education and delivery of AKI care, aiming to reduce morbidity and associated mortality and to improve long-term outcomes. In this article, we describe our current efforts to improve early recognition and management involving inclusive interdisciplinary collaboration between providers, patients, and their families; discuss the ongoing need to change some of our current AKI paradigms and diagnostic methods; and provide specific recommendations to improve AKI recognition and care. In the hospital and the community, AKI is a common and increasingly frequent condition that generates risks of adverse events and high costs. Unfortunately, patients with AKI may frequently have received less than optimal quality of care. New classifications have facilitated understanding of AKI incidence and its impact on outcomes, but they are not always well aligned with AKI pathophysiology. Despite ongoing research efforts, treatments to promote or hasten kidney recovery remain ineffective. To avoid progression, the current approach to AKI emphasizes the promotion of early recognition and timely response. However, a lack of awareness of the importance of early recognition and treatment among health care team members and the heterogeneity of approaches within the health care teams assessing the patient remains a major challenge. Early identification is further complicated by differences in settings where AKI occurs (the community or the hospital), and by differences in patient populations and cultures between the intensive care unit and ward environments. To address these obstacles, we discuss the need to improve education at all levels of care and to generate specific guidance on AKI evaluation and management, including the development of a widely applicable education and an AKI management toolkit, engaging hospital administrators to incorporate AKI as a quality initiative, and raising awareness of AKI as a complication of other disease processes., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: The association of AKI after pediatric cardiac surgery with long-term CKD and hypertension development is unclear. The study objectives were to determine whether AKI after pediatric cardiac surgery is associated with incident CKD and hypertension., Design, Setting, Participants, & Measurements: This was a prospective cohort study of children of 1 month to 18 years old who were undergoing cardiac surgery at two tertiary care centers (Canada, United States). Participants were recruited before cardiac surgery and were followed during hospitalization and at 3, 12, 24, 36, and 48 months after discharge. Exposures were postoperative AKI, based on the Kidney Disease Improving Global Outcomes (KDIGO) definition, and age <2 years old at surgery. Outcomes and measures were CKD (low eGFR or albuminuria for age) and hypertension (per the 2017 American Academy of Pediatrics guidelines) at follow-up, with the composite outcome of CKD or hypertension., Results: Among 124 participants, 57 (46%) developed AKI. AKI versus non-AKI participants had a median (interquartile range) age of 8 (4.8-40.8) versus 46 (6.0-158.4) months, respectively, and higher preoperative eGFR. From the 3- to 48-month follow-up, the cohort prevalence of CKD was high (17%-20%); hypertension prevalence was also high (22%-30%). AKI was not significantly associated with the development of CKD throughout follow-up. AKI was associated with hypertension development at 12 months after discharge (adjusted relative risk, 2.16; 95% confidence interval, 1.18 to 3.95), but not at subsequent visits. Children aged <2 years old at surgery had a significantly higher prevalence of hypertension during follow-up than older children (40% versus 21% at 3-month follow-up; 32% versus 13% at 48-month follow-up)., Conclusions: CKD and hypertension burden in the 4 years after pediatric cardiac surgery is high. Young age at surgery, but not AKI, is associated with their development., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: It is unknown whether iodinated contrast causes kidney parenchymal damage. Biomarkers that are more specific to nephron injury than serum creatinine may provide insight into whether contrast-associated AKI reflects tubular damage. We assessed the association between biomarker changes after contrast angiography with contrast-associated AKI and 90-day major adverse kidney events and death., Design, Setting, Participants, & Measurements: We conducted a longitudinal analysis of participants from the biomarker substudy of the Prevention of Serious Adverse Events following Angiography trial. We measured injury (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, IL-18) and repair (monocyte chemoattractant protein-1, uromodulin, YKL-40) proteins from plasma and urine samples at baseline and 2-4 hours postangiography. We assessed the associations between absolute changes and relative ratios of biomarkers with contrast-associated AKI and 90-day major adverse kidney events and death., Results: Participants ( n =922) were predominately men (97%) with diabetes (82%). Mean age was 70±8 years, and eGFR was 48±13 ml/min per 1.73 m 2 ; 73 (8%) and 60 (7%) participants experienced contrast-associated AKI and 90-day major adverse kidney events and death, respectively. No postangiography urine biomarkers were associated with contrast-associated AKI. Postangiography plasma kidney injury molecule-1 and IL-18 were significantly higher in participants with contrast-associated AKI compared with those who did not develop contrast-associated AKI: 428 (248, 745) versus 306 (179, 567) mg/dl; P =0.04 and 325 (247, 422) versus 280 (212, 366) mg/dl; P =0.009, respectively. The majority of patients did not experience an increase in urine or plasma biomarkers. Absolute changes in plasma IL-18 were comparable in participants with contrast-associated AKI (-30 [-71, -9] mg/dl) and those without contrast-associated AKI (-27 [-53, -10] mg/dl; P =0.62). Relative ratios of plasma IL-18 were also comparable in participants with contrast-associated AKI (0.91; 0.86, 0.97) and those without contrast-associated AKI (0.91; 0.85, 0.96; P =0.54)., Conclusions: The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: In kidney transplantation, the relative contribution of donor versus other factors on clinical outcomes is unknown. We sought to quantify overall donor effects on transplant outcomes for kidney donations from deceased donors., Design, Setting, Participants, & Measurements: For paired donations from deceased donors resulting in transplants to different recipients, the magnitude of donor effects can be quantified by examining the excess of concordant outcomes within kidney pairs beyond chance concordance. Using data from the Organ Procurement and Transplantation Network between the years 2013 and 2017, we examined concordance measures for delayed graft function, death-censored 1-year graft failure, and death-censored 3-year graft failure. The concordance measures were excess relative risk, excess absolute risk, and the fixation index (where zero is no concordance and one is perfect concordance). We further examined concordance in strata of kidneys with similar values of the Kidney Donor Profile Index, a common metric of organ quality., Results: If the transplant of the kidney mate resulted in delayed graft function, risk for delayed graft function was 19% higher (95% confidence interval [95% CI], 18% to 20%), or 1.76-fold higher (95% CI, 1.73- to 1.80-fold), than baseline. If a kidney graft failed within 1 year, then the kidney mate's risk of failure was 6% higher (95% CI, 4% to 9%), or 2.85-fold higher (95% CI, 2.25- to 3.48-fold), than baseline. For 3-year graft failure, the excess absolute risk was 7% (95% CI, 4% to 10%) but excess relative risk was smaller, 1.91-fold (95% CI, 1.56- to 2.28-fold). Fixation indices were 0.25 for delayed graft function (95% CI, 0.24 to 0.27), 0.07 for 1-year graft failure (95% CI, 0.04 to 0.09), and 0.07 for 3-year graft failure (95% CI, 0.04 to 0.10). Results were similar in strata of kidneys with a similar Kidney Donor Profile Index., Conclusions: Overall results indicated that the donor constitution has small or moderate effect on post-transplant clinical outcomes., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Survival after surgical repair for congenital heart disease has markedly improved; however, there are limited data on long-term ESKD and mortality during childhood., Design, Setting, Participants, & Measurements: We conducted an observational, population-based cohort study of children who had their first surgery for congenital heart disease within 10 years of birth. The study was conducted in Ontario, Canada, where residents have universal access to health care services. Each child who underwent surgical repair was matched to ten children from the general population who were similar in age, sex, index date, rurality, and neighborhood income. Primary outcomes of all-cause mortality and ESKD were reported until March 2015., Results: We followed 3600 children with congenital heart disease for a median of 5.9 (interquartile range, 2.9-9.0) years after their surgical repair. Median age at first surgery was 150 (interquartile range, 40-252) days and 22% were low birth weight (<2500 g). During follow-up, 140 (4%) children who had surgery for congenital heart disease died and 52 (1%) reached ESKD. The cumulative incidence of death and ESKD at 1, 5, and 10 years was higher in children with surgical repair of congenital heart disease (death: 3%, 4%, and 5%, respectively; ESKD: 1%, 2%, and 2%, respectively) compared with the matched control population without any congenital heart disease (death: 0.06%, 0.10%, and 0.13%, respectively; ESKD: 0.00%, 0.02%, and 0.02%, respectively). The risk of ESKD and death increased with severity of congenital heart disease, with the highest risk in children with hypoplastic left heart syndrome and increased in children who had surgical repair of congenital heart disease compared with those without surgical repair., Conclusions: The risk of mortality and ESKD is high in children who undergo surgical repair for congenital heart disease compared to the general population., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Marathon runners develop transient AKI with urine sediments and injury biomarkers suggesting nephron damage., Design, Setting, Participants, & Measurements: To investigate the etiology, we examined volume and thermoregulatory responses as possible mechanisms in runners' AKI using a prospective cohort of runners in the 2017 Hartford Marathon. Vitals, blood, and urine samples were collected in 23 runners 1 day premarathon and immediately and 1 day postmarathon. We measured copeptin at each time point. Continuous core body temperature, sweat sodium, and volume were assessed during the race. The primary outcome of interest was AKI, defined by AKIN criteria., Results: Runners ranged from 22 to 63 years old; 43% were men. Runners lost a median (range) of 2.34 (0.50-7.21) g of sodium and 2.47 (0.36-6.81) L of volume via sweat. After accounting for intake, they had a net negative sodium and volume balance at the end of the race. The majority of runners had increases in core body temperature to 38.4 (35.8-41)°C during the race from their baseline. Fifty-five percent of runners developed AKI, yet 74% had positive urine microscopy for acute tubular injury. Runners with more running experience and increased participation in prior marathons developed a rise in creatinine as compared with those with lesser experience. Sweat sodium losses were higher in runners with AKI versus non-AKI (median, 3.41 [interquartile range (IQR), 1.7-4.8] versus median, 1.4 [IQR, 0.97-2.8] g; P =0.06, respectively). Sweat volume losses were higher in runners with AKI versus non-AKI (median, 3.89 [IQR, 1.49-5.09] versus median, 1.66 [IQR, 0.72-2.84] L; P =0.03, respectively). Copeptin was significantly higher in runners with AKI versus those without (median, 79.9 [IQR, 25.2-104.4] versus median, 11.3 [IQR, 6.6-43.7]; P =0.02, respectively). Estimated temperature was not significantly different., Conclusions: All runners experienced a substantial rise in copeptin and body temperature along with salt and water loss due to sweating. Sodium and volume loss via sweat as well as plasma copeptin concentrations were associated with AKI in runners., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019&#95;08&#95;13&#95;CJASNPodcast&#95;19&#95;09&#95;.mp3., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Regulatory agencies warn about the risk of AKI with levetiracetam use on the basis of information from case reports. We conducted this study to determine whether new levetiracetam use versus nonuse is associated with a higher risk of AKI., Design, Setting, Participants, & Measurements: This was a population-based retrospective cohort study of adults with epilepsy in Ontario, Canada. Patients who received a new outpatient prescription for levetiracetam between January 1, 2004 and March 1, 2017 were matched to two nonusers on stage of CKD, recorded seizure in the prior 90 days, and logit of a propensity score for levetiracetam use. The primary outcome was a hospital encounter (emergency department visit or hospitalization) with AKI within 30 days of cohort entry. Secondary outcomes were AKI within 180 days and change in the concentration of serum creatinine. We assessed the primary outcome using health care diagnosis codes. We evaluated the change in the concentration of serum creatinine in a subpopulation with laboratory measurements., Results: We matched 3980 levetiracetam users to 7960 nonusers (mean age 55 years, 51% women). Levetiracetam use was not significantly associated with a higher risk of AKI within 30 days (13 [0.33%] events in levetiracetam users and 21 [0.26%] events in nonusers [odds ratio, 1.24; 95% confidence interval, 0.62 to 2.47]). Similarly, there was no significant association with AKI within 180 days (odds ratio, 0.70; 95% confidence interval, 0.43 to 1.13). The change in the concentration of serum creatinine did not significantly differ between levetiracetam users and nonusers., Conclusions: In this population-based study levetiracetam use was not associated with a higher risk of AKI., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018&#95;12&#95;11&#95;Yau&#95;Podcast.mp3., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Patients are informed of the risk of kidney biopsy-related complications using data from nonhospitalized patients, which may underestimate the risk for hospitalized patients. We evaluated the rate and risk factors of kidney biopsy-related complications in hospitalized patients with acute kidney disease (AKD) to better estimate the risk in this population., Design, Setting, Participants, & Measurements: We used data from the Yale biopsy cohort to evaluate rates of kidney biopsy-related complications including adjudicated procedure-related bleeding requiring blood transfusions or angiographic interventions, medium- or large-sized hematomas, reimaging after biopsy including abdominal ultrasonography or computed tomography, and death in hospitalized patients with AKD (including AKI). We evaluated univariable and multivariable association of risk factors with transfusions. We compared rates of complications between hospitalized and nonhospitalized patients., Results: Between 2015 and 2017, 159 hospitalized patients underwent a kidney biopsy for AKD evaluation, of which 80 (51%) had stage 1 AKI, 42 (27%) had stage 2 (or higher) AKI, and 27 (17%) had AKD (without AKI). Of these, 12 (8%; 95% confidence interval [95% CI], 5% to 15%) required a transfusion, three (2%; 95% CI, 1% to 5%) required an intervention, 11 (7%; 95% CI, 4% to 12%) had hematoma, and 31 (20%; 95% CI, 14% to 26%) required reimaging after biopsy. Of the four (3%; 95% CI, 1% to 6%) deaths during hospitalization, none were related to the biopsy. Female sex, lower platelet count, and higher BUN were associated with postbiopsy transfusions on univariable and multivariable analyses. Trainee as proceduralist and larger needle gauge were associated with transfusions in univariable, but not multivariable, analysis. Nonhospitalized patients had lower rates of transfusion than hospitalized patients, although the latter also had lower prebiopsy hemoglobin and greater surveillance after biopsy., Conclusions: Hospitalized patients experience higher risk of postbiopsy complications than previously reported and several factors, such as lower platelet count, female sex, and higher BUN, are associated with this risk., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Tenofovir disoproxil fumarate (tenofovir) is associated with elevated concentrations of biomarkers of kidney damage and dysfunction in individuals with HIV. The relationship of these kidney biomarkers with longitudinal kidney function decline is unknown., Design, Setting, Participants, & Measurements: We evaluated associations of 14 urinary biomarkers of kidney injury with changes in eGFR among 198 men and women with HIV who initiated tenofovir between 2009 and 2015 in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Urinary biomarkers included albumin-to-creatinine ratio, α -1-microglobulin, β -2-microglobulin, cystatin C, kidney injury molecule-1 (KIM-1), IL-18, neutrophil gelatinase-associated lipocalin (NGAL), clusterin, osteopontin, uromodulin, monocyte chemoattractant protein-1, EGF, trefoil factor 3, and chitinase 3-like protein 1. We used multivariable linear mixed-effect models controlling for demographics, traditional kidney disease risk factors, and HIV-related risk factors to evaluate associations of baseline biomarkers with first-year changes in eGFR, and associations of year 1 and first-year change in biomarkers with changes in eGFR from year 1 to year 3. We used the least absolute shrinkage and selection operator method to identify a parsimonious set of biomarkers jointly associated with changes in eGFR., Results: Median eGFR before tenofovir initiation was 103 (interquartile range, 88-116) ml/min per 1.73 m 2 . During the first year of tenofovir use, eGFR decreased on average by 9.2 (95% confidence interval, 6.5 to 11.9) ml/min per 1.73 m 2 and was stable afterward (decrease of 0.62; 95% confidence interval, -0.85 to 2.1 ml/min per 1.73 m 2 per year). After multivariable adjustment, higher baseline β -2-microglobulin, KIM-1, and clusterin were associated with larger first-year eGFR declines, whereas higher baseline uromodulin was associated with a smaller eGFR decline. First-year increase in urinary cystatin C and higher year 1 IL-18 were associated with larger annual eGFR declines from year 1 to year 3. The parsimonious models identified higher pre-tenofovir clusterin and KIM-1, lower pre-tenofovir uromodulin, and higher year 1 IL-18 as jointly associated with larger eGFR declines., Conclusions: Urinary biomarkers of kidney injury measured before and after tenofovir initiation are associated with subsequent changes in eGFR in individuals with HIV., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018&#95;08&#95;28&#95;CJASNPodcast&#95;18&#95;9&#95;S.mp3., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: Electronic alerts for heterogenous conditions such as AKI may not provide benefit for all eligible patients and can lead to alert fatigue, suggesting that personalized alert targeting may be useful. Uplift-based alert targeting may be superior to purely prognostic-targeting of interventions because uplift models assess marginal treatment effect rather than likelihood of outcome., Design, Setting, Participants, & Measurements: This is a secondary analysis of a clinical trial of 2278 adult patients with AKI randomized to an automated, electronic alert system versus usual care. We used three uplift algorithms and one purely prognostic algorithm, trained in 70% of the data, and evaluated the effect of targeting alerts to patients with higher scores in the held-out 30% of the data. The performance of the targeting strategy was assessed as the interaction between the model prediction of likelihood to benefit from alerts and randomization status. The outcome of interest was maximum relative change in creatinine from the time of randomization to 3 days after randomization., Results: The three uplift score algorithms all gave rise to a significant interaction term, suggesting that a strategy of targeting individuals with higher uplift scores would lead to a beneficial effect of AKI alerting, in contrast to the null effect seen in the overall study. The prognostic model did not successfully stratify patients with regards to benefit of the intervention. Among individuals in the high uplift group, alerting was associated with a median reduction in change in creatinine of -5.3% ( P =0.03). In the low uplift group, alerting was associated with a median increase in change in creatinine of +5.3% ( P =0.005). Older individuals, women, and those with a lower randomization creatinine were more likely to receive high uplift scores, suggesting that alerts may benefit those with more slowly developing AKI., Conclusions: Uplift modeling, which accounts for treatment effect, can successfully target electronic alerts for AKI to those most likely to benefit, whereas purely prognostic targeting cannot., (Copyright © 2018 by the American Society of Nephrology.)

Pediatric AKI has become a significant health concern due to its rising incidence and association with adverse outcomes. Because of the limitations of serum creatinine, ongoing research has evaluated multiple novel biomarkers for the early detection of AKI. Identifying biomarkers that precede changes in serum creatinine is vital, because these biomarkers provide opportunities to improve outcomes through early diagnosis and timely disease management. In this review, we discuss salient findings on 16 candidate biomarkers and their association with AKI. We explore the differences in biomarker distribution by age and discuss why adult biomarker research findings cannot be directly extrapolated to children. With future research, more consideration needs to be given to how the maturing kidney affects biomarker levels and how we interpret biomarker performance in children. A comprehensive approach using age-specific biomarker reference ranges is required to develop pediatric biomarkers and improve outcomes for children with kidney disease., (Copyright © 2017 by the American Society of Nephrology.)

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.)

Background and Objectives: Data reported to the Organ Procurement and Transplantation Network (OPTN) are used in kidney transplant research, policy development, and assessment of center quality, but the accuracy of early post-transplant outcome measures is unknown., Design, Setting, Participants, & Measurements: The Deceased Donor Study (DDS) is a prospective cohort study at five transplant centers. Research coordinators manually abstracted data from electronic records for 557 adults who underwent deceased donor kidney transplantation between April of 2010 and November of 2013. We compared the post-transplant outcomes of delayed graft function (DGF; defined as dialysis in the first post-transplant week), acute rejection, and post-transplant serum creatinine reported to the OPTN with data collected for the DDS., Results: Median kidney donor risk index was 1.22 (interquartile range [IQR], 0.97-1.53). Median recipient age was 55 (IQR, 46-63) years old, 63% were men, and 47% were black; 93% had received dialysis before transplant. Using DDS data as the gold standard, we found that pretransplant dialysis was not reported to the OPTN in only 11 (2%) instances. DGF in OPTN data had a sensitivity of 89% (95% confidence interval [95% CI], 84% to 93%) and specificity of 98% (95% CI, 96% to 99%). Surprisingly, the OPTN data accurately identified acute allograft rejection in only 20 of 47 instances (n=488; sensitivity of 43%; 95% CI, 17% to 73%). Across participating centers, sensitivity of acute rejection varied widely from 23% to 100%, whereas specificity was uniformly high (92%-100%). Six-month serum creatinine values in DDS and OPTN data had high concordance (n=490; Lin concordance correlation =0.90; 95% CI, 0.88 to 0.92)., Conclusions: OPTN outcomes for recipients of deceased donor kidney transplants have high validity for DGF and 6-month allograft function but lack sensitivity in detecting rejection. Future studies using OPTN data may consider focusing on allograft function at 6 months as a useful outcome., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false-positive rates because of inherent laboratory and biologic variabilities of creatinine., Design, Setting, Participants, & Measurements: We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false-positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patient's true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria., Results: Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false-positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%-8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false-positive AKI diagnosis rate of 30.5% (interquartile range =30.1%-30.9%) versus 2.0% (interquartile range =1.9%-2.1%) in patients with true serum creatinine values <1.5 mg/dl (P<0.001)., Conclusions: Use of small serum creatinine changes to diagnose AKI is limited by high false-positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies., (Copyright © 2015 by the American Society of Nephrology.)

Background and Objectives: Despite advances in therapy, HIV-infected individuals remain at higher risk for kidney dysfunction than uninfected individuals. It was hypothesized that urine levels of α1-microglobulin, a biomarker of proximal tubular dysfunction, would predict kidney function decline and mortality risk in HIV-infected and uninfected women., Design, Setting, Participants, & Measurements: In the Women's Interagency HIV Study, urine α1-microglobulin and creatinine concentrations were measured in 903 HIV-infected and 287 uninfected women using stored urine from 1999 to 2000, when prevalence of tenofovir use was <1%. Participants were categorized into three categories by level of α1-microglobulin-to-creatinine ratio, and associations with kidney decline and all-cause mortality over 8 years were evaluated., Results: Urine α1-microglobulin was detectable in 60% of HIV-infected and 40% of uninfected women (P<0.001). Among HIV-infected women, there were 177 (22%), 61 (7%), and 128 (14%) patients with incident CKD, with 10% annual eGFR decline, and who died, respectively. Compared with HIV-infected women in the lowest α1-microglobulin category, HIV-infected women in the highest α1-microglobulin category had a 2.1-fold risk of incident CKD (95% confidence interval, 1.3 to 3.4), 2.7-fold risk of 10% annual eGFR decline (95% confidence interval, 1.2 to 5.9), and 1.6-fold mortality risk (95% confidence interval, 1.0 to 2.6) in models adjusting for kidney risk factors, baseline eGFR, and albuminuria. Among uninfected women, the highest α1-microglobulin category was associated with 3% (relative risk, 2.2; 95% confidence interval, 1.4 to 3.5) and 5% (relative risk, 2.2; 95% confidence interval, 1.1 to 4.3) annual eGFR decline relative to the lowest α1-microglobulin category., Conclusions: Proximal tubular dysfunction, indicated by urine α1-microglobulin, was independently associated with kidney function decline in HIV-infected and uninfected women and mortality risk among HIV-infected women., (Copyright © 2015 by the American Society of Nephrology.)

Background and Objectives: AKI is a common and severe complication in patients with cirrhosis. AKI progression was previously shown to correlate with in-hospital mortality. Therefore, accurately predicting which patients are at highest risk for AKI progression may allow more rapid and targeted treatment. Urinary biomarkers of structural kidney injury associate with AKI progression and mortality in multiple settings of AKI but their prognostic performance in patients with liver cirrhosis is not well known., Design, Setting, Participants, & Measurements: A multicenter, prospective cohort study was conducted at four tertiary care United States medical centers between 2009 and 2011. The study comprised patients with cirrhosis and AKI defined by the AKI Network criteria evaluating structural (neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], and albuminuria) and functional (fractional excretion of sodium [FENa]) urinary biomarkers as predictors of AKI progression and in-hospital mortality., Results: Of 188 patients in the study, 44 (23%) experienced AKI progression alone and 39 (21%) suffered both progression and death during their hospitalization. Neutrophil gelatinase-associated lipocalin, IL-18, KIM-1, L-FABP, and albuminuria were significantly higher in patients with AKI progression and death. These biomarkers were independently associated with this outcome after adjusting for key clinical variables including model of end stage liver disease score, IL-18 (relative risk [RR], 4.09; 95% confidence interval [95% CI], 1.56 to 10.70), KIM-1 (RR, 3.13; 95% CI, 1.20 to 8.17), L-FABP (RR, 3.43; 95% CI, 1.54 to 7.64), and albuminuria (RR, 2.07; 95% CI, 1.05-4.10) per log change. No biomarkers were independently associated with progression without mortality. FENa demonstrated no association with worsening of AKI. When added to a robust clinical model, only IL-18 independently improved risk stratification on a net reclassification index., Conclusions: Multiple structural biomarkers of kidney injury, but not FENa, are independently associated with progression of AKI and mortality in patients with cirrhosis. Injury marker levels were similar between those without progression and those with progression alone., (Copyright © 2014 by the American Society of Nephrology.)

The field of nephrology is actively involved in developing biomarkers and improving models for predicting patients' risks of AKI and CKD and their outcomes. However, some important aspects of evaluating biomarkers and risk models are not widely appreciated, and statistical methods are still evolving. This review describes some of the most important statistical concepts for this area of research and identifies common pitfalls. Particular attention is paid to metrics proposed within the last 5 years for quantifying the incremental predictive value of a new biomarker., (Copyright © 2014 by the American Society of Nephrology.)

Background and Objectives: The influence of deceased-donor AKI on post-transplant outcomes is poorly understood. The few published studies about deceased-donor preimplant biopsy have reported conflicting results regarding associations between AKI and recipient outcomes., Design, Setting, Participants, & Measurements: This multicenter study aimed to evaluate associations between deceased-donor biopsy reports of acute tubular necrosis (ATN) and delayed graft function (DGF), and secondarily for death-censored graft failure, first adjusting for the kidney donor risk index and then stratifying by donation after cardiac death (DCD) status., Results: Between March 2010 and April 2012, 651 kidneys (369 donors, 4 organ procurement organizations) were biopsied and subsequently transplanted, with ATN reported in 110 (17%). There were 262 recipients (40%) who experienced DGF and 38 (6%) who experienced graft failure. DGF occurred in 45% of kidneys with reported ATN compared with 39% without ATN (P=0.31) resulting in a relative risk (RR) of 1.13 (95% confidence interval [95% CI], 0.9 to 1.43) and a kidney donor risk index-adjusted RR of 1.11 (95% CI, 0.88 to 1.41). There was no significant difference in graft failure for kidneys with versus without ATN (8% versus 5%). In stratified analyses, the adjusted RR for DGF with ATN was 0.97 (95% CI, 0.7 to 1.34) for non-DCD kidneys and 1.59 (95% CI, 1.23 to 2.06) for DCD kidneys (P=0.02 for the interaction between ATN and DCD on the development of DGF)., Conclusions: Despite a modest association with DGF for DCD kidneys, this study reveals no significant associations overall between preimplant biopsy-reported ATN and the outcomes of DGF or graft failure. The potential benefit of more rigorous ATN reporting is unclear, but these findings provide little evidence to suggest that current ATN reports are useful for predicting graft outcomes or deciding to accept or reject allograft offers.

Contrast-induced AKI (CI-AKI) is a common condition associated with serious, adverse outcomes. CI-AKI may be preventable because its risk factors are well characterized and the timing of renal insult is commonly known in advance. Intravenous (IV) fluids and N-acetylcysteine (NAC) are two of the most widely studied preventive measures for CI-AKI. Despite a multitude of clinical trials and meta-analyses, the most effective type of IV fluid (sodium bicarbonate versus sodium chloride) and the benefit of NAC remain unclear. Careful review of published trials of these interventions reveals design limitations that contributed to their inconclusive findings. Such design limitations include the enrollment of small numbers of patients, increasing the risk for type I and type II statistical errors; the use of surrogate primary endpoints defined by small increments in serum creatinine, which are associated with, but not necessarily causally related to serious, adverse, patient-centered outcomes; and the inclusion of low-risk patients with intact baseline kidney function, yielding low event rates and reduced generalizability to a higher-risk population. The Prevention of Serious Adverse Events following Angiography (PRESERVE) trial is a randomized, double-blind, multicenter trial that will enroll 8680 high-risk patients undergoing coronary or noncoronary angiography to compare the effectiveness of IV isotonic sodium bicarbonate versus IV isotonic sodium chloride and oral NAC versus oral placebo for the prevention of serious, adverse outcomes associated with CI-AKI. This article discusses key methodological issues of past trials investigating IV fluids and NAC and how they informed the design of the PRESERVE trial.

Background and Objectives: AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period., Design, Setting, Participants, & Measurements: This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis., Results: KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinase-associated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2., Conclusions: Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.

AKI is a common and serious complication that is associated with several adverse outcomes in hospitalized patients. The past several years have seen a large number of multicenter investigations of biomarkers of AKI in the setting of cardiac surgery and critical illness. This review summarizes these biomarker results to identify applications for clinical use. The Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study showed that blood and urine biomarkers measured preoperatively, immediately postoperatively, and at the time of the clinical increase in serum creatinine in the setting of cardiac surgery all had the ability to improve patient risk stratification for a variety of important clinical end points. Analyses of biomarkers concentrations from the Acute Respiratory Distress Syndrome Network, EARLY ARF, and other studies of critically ill subjects have similarly shown that biomarkers measured early in the clinical course can forecast the development of AKI and need for renal replacement therapy as well as inpatient mortality. Although biomarkers have informed the diagnosis, prognosis, and treatment of AKI and are inching closer to clinical application, large multicenter interventional clinical trials to prevent AKI using biomarkers should continue to be an active area of clinical investigation.

Background and Objectives: Preoperative proteinuria is associated with a higher incidence of postoperative AKI. Whether the same is true for postoperative proteinuria is uncertain. This study tested the hypothesis that increased proteinuria after cardiac surgery is associated with an increased risk for AKI., Design, Setting, Participants, & Measurements: This prospective cohort study included 1198 adults undergoing cardiac surgery at six hospitals between July 2007 and December 2009. Albuminuria, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria were measured 0-6 hours after surgery. The primary outcome was AKI, defined as a doubling in serum creatinine or receipt of acute dialysis during the hospital stay. Analyses were adjusted for patient characteristics, including preoperative albuminuria., Results: Compared with the lowest quintile, the highest quintile of albuminuria and highest grouping of dipstick proteinuria were associated with greatest risk for AKI (adjusted relative risks [RRs], 2.97 [95% confidence interval (CI), 1.20-6.91] and 2.46 [95% CI, 1.16-4.97], respectively). Higher ACR was not associated with AKI risk (highest quintile RR, 1.66 [95% CI, 0.68-3.90]). Of the three proteinuria measures, early postoperative albuminuria improved the prediction of AKI to the greatest degree (clinical model area under the curve, 0.75; 0.81 with albuminuria). Similar improvements with albuminuria were seen for net reclassification index (0.55; P<0.001) and integrated discrimination index (0.036; P<0.001)., Conclusions: Higher levels of proteinuria after cardiac surgery identify patients at increased risk for AKI during their hospital stay.

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 and Objectives: Current tools to predict outcomes after kidney transplantation are inadequate. The objective of this study was to determine the association of perioperative urine neutrophil gelatinase-associated lipocalin and IL-18 with poor 1-year allograft function (return to dialysis or estimated GFR<30 ml/min per 1.73 m(2))., Design, Setting, Participants, & Measurements: Neutrophil gelatinase-associated lipocalin and IL-18 from early post-transplant urine was measured in this prospective, multicenter study of deceased-donor kidney transplant recipients. The outcome of poor allograft function at 1 year relative to these biomarkers using multivariable logistic regression and net reclassification improvement was examined. Also, the interaction between delayed graft function and the biomarkers on the outcome were evaluated, and the change in biomarkers over consecutive days related to the outcome using trend tests was examined., Results: Mean age for the 153 recipients was 54 ± 13 years. Delayed graft function occurred in 42%, and 24 (16%) recipients had the 1-year outcome. Upper median values for neutrophil gelatinase-associated lipocalin and IL-18 on the first postoperative day had adjusted odds ratios (95% confidence interval) of 6.0 (1.5-24.0) and 5.5 (1.4-21.5), respectively. Net reclassification improvement (95% confidence interval) was significant for neutrophil gelatinase-associated lipocalin and IL-18 at 36% (1%-71%) and 45% (8%-83%), respectively. There was no significant interaction between biomarkers and delayed graft function on the outcome. Change in biomarkers moderately trended with the outcome., Conclusions: Perioperative urine neutrophil gelatinase-associated lipocalin and IL-18 are associated with poor 1-year allograft function, suggesting their potential for identifying patients for therapies that minimize the risk of additional injury.

Background and Objectives: Studies have evaluated acute kidney injury (AKI) using biomarkers in various settings, but their prognostic utility within current practice is unclear. Thus, we sought to determine the prognostic utility of newer biomarkers or traditional markers (fractional excretion of sodium [FeNa] and urea [FeUrea] and microscopy) over clinical assessment alone., Design, Setting, Participants, & Measurements: This is a prospective cohort study of adults on the first day of meeting AKI criteria. We measured urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and IL-18 and determined FeNa, FeUrea, and microscopy score for casts and tubular cells. Primary outcome was worsened AKI stage from enrollment to peak serum creatinine or in-hospital death., Results: In 249 recipients, 57% were ≥65 years old, 48% were from intensive care, and mean baseline GFR was 69 ± 30 ml/min per 1.73 m(2). AKI was considered prerenal in 164 (66%), acute tubular necrosis (ATN) in 51 (20%), and "other" in 34 (14%). All mean protein biomarker concentrations, FeNa, FeUrea, and microscopy scores were statistically different between prerenal and ATN. Seventy-two patients (29%) developed the primary outcome. There was an approximate three-fold increase in adjusted risk for the outcome for upper versus lower values of NGAL, KIM-1, IL-18, and microscopy score (P values <0.05). Net reclassification improved after adding these to baseline clinical assessment. FeNa and FeUrea were not useful., Conclusions: On the first day of AKI, urine protein biomarkers and microscopy significantly improve upon clinical determination of prognosis, indicating their potential utility in current practice.

Background and Objectives: Urine IL-18 (uIL-18) has demonstrated moderate capacity to predict acute kidney injury (AKI) and adverse outcomes in defined settings. Its ability to predict AKI and provide prognostic information in broadly selected, critically ill adults remains unknown., Design, Setting, Participants, & Measurements: The study prospectively evaluated the capacity of uIL-18 measured within 24 hours of intensive care unit (ICU) admission to predict AKI, death, and receipt of acute dialysis in a large mixed-adult ICU population., Results: Of 451 patients, 86 developed AKI within 48 hours of enrollment and had higher median uIL-18 levels [426 (interquartile range [IQR]: 152 to 1183) pg/mg creatinine] compared with those without AKI [248 (IQR: 120 to 559) pg/mg]. The area under the receiver operating characteristic curve for uIL-18 predicting subsequent AKI within 24 hours was 0.62 (95% CI: 0.54 to 0.69) and improved modestly to 0.67 (95% CI: 0.53 to 0.81) in patients whose enrollment eGFR was >or=75 ml/min per 1.73 m(2). The highest median uIL-18 levels were observed in patients with sepsis at enrollment [508 (IQR: 230 to 1281) pg/mg], those receiving acute dialysis [571 (IQR: 161 to 1614) pg/mg] or dying [532 (IQR: 210 to 1614) pg/mg] within 28 days of ascertainment. After adjustment for a priori selected clinical predictors, uIL-18 remained independently predictive of composite outcome of death or acute dialysis within 28 days of ascertainment (odds ratio, 1.86 [95% CI: 1.31 to 2.64])., Conclusions: uIL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in a broadly selected, critically ill adult population.

Background and Objectives: Ensuring follow-up of living kidney donors (LKDs) is essential to long-term preventive care. We sought information on health insurance status of US LKDs, with particular attention to age, gender, and ethnicity., Design, Setting, Participants, & Measurements: The United Network for Organ Sharing/Organ Procurement Transplantation Network database was queried for associations among age at donation, race, gender, and health insurance status. We studied all US LKDs between July 2004 and September 2006., Results: A total of 10,021 LKDs with known health insurance status were studied, 1765 (18%) of whom lacked health insurance at donation. There were 4852 donors without health insurance information. Younger kidney donors had higher rates of being uninsured (age 18 to 34: 26.2%; age 35 to 49: 15.2%; age 50 to 64: 11.2%; age >65: 3.8%; P < 0.0001), as did men (19.5 versus 16.3% for women; P < 0.0001), and ethnic minorities (white 13.4%, black 21%, Hispanic 35.6%, Asian 26.7%; P < 0.0001)., Conclusions: This study confirms that younger patients, ethnic minorities, and men are less likely to have health insurance when donating a kidney, which could negatively affect adherence to long-term follow-up.

Background and Objectives: Serum creatinine concentration at the time of nephrology consultation is not necessarily indicative of the severity of acute kidney injury (AKI). Although urine microscopy is useful to differentiate AKI, its role in predicting adverse clinical outcomes has not been well described., Design, Setting, Participants, & Measurements: The relationship between urine microscopy findings at the time of nephrology consultation for AKI and clinical outcomes was evaluated prospectively. A urinary sediment scoring system was created on the basis of the number of renal tubular epithelial cells and granular casts. The primary outcome was worsening of AKI (progressing to higher AKI Network stage, dialysis, or death) during hospitalization., Results: Of 249 patients consulted for AKI, 197 had acute tubular necrosis or prerenal AKI and were included in the analysis. At consultation, 80 (40%) had stage 1, 53 (27%) had stage 2, and 66 (33%) had stage 3 AKI. The urinary sediment combined scores were lowest in those with stage 1 and highest in stage 3 AKI. Seventy-nine patients (40%) experienced worsening of AKI from the time of consultation. The urinary scoring system was significantly associated with increased risk of worsening AKI (adjusted relative risk: 7.3; 95% confidence interval: 4.5 to 9.7 for worsening with score of > or =3 versus score of 0) and was more predictive than AKI Network stage at the time of consultation., Conclusions: The urinary sediment score may be a useful tool to predict worsening of AKI due to either acute tubular necrosis or prerenal AKI during hospitalization.

Background and Objectives: Identifying patients who may develop acute kidney injury (AKI) remains challenging, as clinical determinants explain only a portion of individual risk. Another factor that likely affects risk is intrinsic genetic variability. Therefore, a systematic review of studies was performed that related the development or prognosis of AKI to genetic variation., Design, Setting, Participants, and Measurements: MEDLINE, EMBASE, HuGEnet, SCOPUS, and Web of Science were searched for articles from 1950 to Dec 2007. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality via an aggregate scoring system., Results: The 16 included studies were of cohort or case-cohort design and investigated 35 polymorphisms in 21 genes in association with AKI. Fifteen gene-gene interactions were also investigated in four separate studies. Study populations were primarily premature infants or adults who were critically ill or postcardiac bypass patients. Among the studies, five different definitions of AKI were used. Only one polymorphism, APO E e2/e3/e4, had greater than one study showing a significant impact (P < 0.05) on AKI incidence. The mean quality score of 5.8/10 (range four to nine), heterogeneity in the studies, and the dearth of studies precluded additional meta-analysis of the results., Conclusions: Current association studies are unable to provide definitive evidence linking genetic variation to AKI. Future success will require a narrow consensus definition of AKI, rigorous epidemiologic techniques, and a shift from a priori hypothesis-driven to genome-wide association studies.