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Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFR Cr-CysC , N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m 2 . MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (β = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (β = 0.430, SE = 0.073; p = 4.2E-9), and V (β = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale & Objective: Urinary biomarkers of injury, inflammation, and repair may help phenotype acute kidney injury (AKI) observed in clinical trials. We evaluated the differences in biomarkers between participants randomized to monotherapy or to combination renin-angiotensin-aldosterone system (RAAS) blockade in VA NEPHRON-D, where an increased proportion of observed AKI was acknowledged in the combination arm., Study Design: Longitudinal analysis., Setting & Participants: A substudy of the VA NEPHRON-D trial., Predictor: Primary exposure was the treatment arm (combination [RAAS inhibitor] vs monotherapy). AKI is used as a stratifying variable., Outcome: Urinary biomarkers, including albumin, EGF (epidermal growth factor), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3-like protein 1), and KIM-1 (kidney injury molecule-1)., Analytical Approach: Biomarkers measured at baseline and at 12 months in trial participants were compared between treatment groups and by AKI. AKI events occurring during hospitalization were predefined safety end points in the original trial. The results were included in a meta-analysis with other large chronic kidney disease trials to assess global trends in biomarker changes., Results: In 707 participants followed for a median of 2.2 years, AKI incidence was higher in the combination (20.7%) versus the monotherapy group (12.7%; relative risk [RR], 1.64 [95% CI, 1.16-2.30]). Compared with the monotherapy arm, in the combination arm the urine biomarkers at 12 months were either unchanged (MCP-1: RR, -3% [95% CI, -13% to 9%], P adj =0.8; KIM-1: RR, -10% [95% CI, -20% to 1%], P adj =0.2; EGF, RR-7% [95% CI, -12% to-1%], P adj =0.08) or lower (albuminuria: RR, -24% [95% CI, -37% to-8%], P adj =0.02; YKL: RR, -40% to-44% [95% CI, -58% to-25%], P adj <0.001). Pooled meta-analysis demonstrated reduced albuminuria in the intervention arm across 3 trials and similar trajectories in other biomarkers., Limitations: Biomarker measurement was limited to 2 time points independent of AKI events., Conclusions: Despite the increased risk of serum creatinine-defined AKI, combination RAAS inhibitor therapy was associated with unchanged or decreased urinary biomarkers at 12 months. This suggests a possible role for kidney biomarkers to further characterize kidney injury in clinical trials., Plain-Language Summary: The VA NEPHRON-D trial investigated inhibition of the renin-angiotensin-aldosterone system (RAAS) hormonal axis on kidney outcomes in a large population of diabetic chronic kidney disease patients. The trial was stopped early due to increased events of serum creatinine-defined acute kidney injury in the combination therapy arm. Urine biomarkers can serve as an adjunct to serum creatinine in identifying kidney injury. We found that urinary biomarkers in the combination therapy group were not associated with a pattern of harm and damage to the kidney, despite the increased number of kidney injury events in that group. This suggests that serum creatinine alone may be insufficient for defining kidney injury and supports further exploration of how other biomarkers might improve identification of kidney injury in clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is common during hospitalization and is associated with long-term risk of readmissions and chronic kidney disease (CKD). Preclinical studies and novel urine biomarkers have demonstrated that subclinical inflammation and repair continue for several months after AKI. We conducted three clinical and translational studies to alleviate long-term sequelae after AKI. First, we assessed repair in deceased donor kidneys which can assist with organ allocation and reduce discard. In an ongoing study, organ procurement organizations are measuring repair biomarkers via lateral flow devices to assess organ quality and adding it to their workflow. Second, we performed research biopsies during AKI to interrogate kidney tissue with novel transcriptomic and proteomic techniques to advance therapeutic development. Third, we initiated pragmatic clinical trials to reduce readmissions after an episode of AKI by providing nurse navigator and pharmacist support to optimize blood pressure, fluid, and medication management., (© 2024 The American Clinical and Climatological Association.)

Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor-β2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.

Background: People with HIV (PWH) generally have worse ambulatory levels of kidney injury biomarkers and excess risk of acute kidney injury (AKI) compared to persons without HIV. We evaluated whether ambulatory measures of subclinical kidney injury among PWH are associated with subsequent AKI., Methods: In the Predictors of Acute Renal Injury Study (PARIS), which enrolled 468 PWH from April 2016 to August 2019, we measured 10 urine biomarkers of kidney health (albumin, a1m, b2M, NGAL, IL18, KIM-1, EGF, UMOD, MCP-1, YKL40) at baseline and annually during follow-up. Using multivariable Cox regression models, we evaluated baseline and time-updated biomarker associations with the primary outcome of AKI (≥0.3 mg/dl or ≥1.5-times increase in serum creatinine from baseline) and secondary outcome of all-cause hospitalization., Results: At baseline, the mean age was 53 years old, and 45% self-identified as female. In time-updated models adjusting for sociodemographic factors, comorbidities, albuminuria, estimated glomerular filtration rate, and HIV-associated factors, higher KIM-1 [hazard ratio (HR) = 1.30 per twofold higher; 95% confidence interval (CI) 1.03-1.63] and NGAL concentrations (HR = 1.24, 95% CI 1.06-1.44) were associated with higher risk of hospitalized AKI. Additionally, in multivariable, time-updated models, higher levels of KIM-1 (HR = 1.19, 95% CI 1.00, 1.41), NGAL (HR = 1.13, 95% CI 1.01-1.26), and MCP-1 (HR = 1.20, 95% CI 1.00, 1.45) were associated with higher risk of hospitalization., Conclusions: Urine biomarkers of kidney tubular injury, such as KIM-1 and NGAL, are strongly associated with AKI among PWH, and may hold potential for risk stratification of future AKI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Patients hospitalized with COVID-19 are at increased risk for major adverse kidney events (MAKE). We sought to identify plasma biomarkers predictive of MAKE in patients hospitalized with COVID-19., Study Design: Prospective cohort study., Setting & Participants: A total of 576 patients hospitalized with COVID-19 between March 2020 and January 2021 across 3 academic medical centers., Exposure: Twenty-six plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization., Outcome: MAKE, defined as KDIGO stage 3 acute kidney injury (AKI), dialysis-requiring AKI, or mortality up to 60 days., Analytical Approach: Cox proportional hazards regression to associate biomarker level with MAKE. We additionally applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and estimated model discrimination with time-varying C index., Results: The median length of stay for COVID-19 hospitalization was 9 (IQR, 5-16) days. In total, 95 patients (16%) experienced MAKE. Each 1 SD increase in soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 was significantly associated with an increased risk of MAKE (adjusted HR [AHR], 2.30 [95% CI, 1.86-2.85], and AHR, 2.26 [95% CI, 1.73-2.95], respectively). The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84), and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). LASSO and random forest regression modeling using all biomarkers yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively., Limitations: No control group of hospitalized patients without COVID-19., Conclusions: We found that sTNFR1 and sTNFR2 are independently associated with MAKE in patients hospitalized with COVID-19 and can both also serve as predictors for adverse kidney outcomes., Plain-Language Summary: Patients hospitalized with COVID-19 are at increased risk for long-term adverse health outcomes, but not all patients suffer long-term kidney dysfunction. Identification of patients with COVID-19 who are at high risk for adverse kidney events may have important implications in terms of nephrology follow-up and patient counseling. In this study, we found that the plasma biomarkers soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 measured in hospitalized patients with COVID-19 were associated with a greater risk of adverse kidney outcomes. Along with clinical variables previously shown to predict adverse kidney events in patients with COVID-19, both sTNFR1 and sTNFR2 are also strong predictors of adverse kidney outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes., Study Design: Multicenter cohort study., Setting & Participants: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study., Predictors: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes., Outcome: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years., Analytical Approach: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models., Results: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P=0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes., Limitations: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable., Conclusions: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI., Plain-Language Summary: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline., Methods: We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years., Results: Of the 117 children enrolled, 30 (24%) had cyanotic heart disease. During 48 months of follow-up, the median eGFR in the subgroup of children with cyanotic heart disease was lower at all study visits as compared with children with acyanotic heart disease (p = 0.01). In the overall cohort, lower levels of both urine uromodulin and IL-18 after discharge were associated with eGFR decline. After adjustment for age, RACHS-1 surgical complexity score, proteinuria, and eGFR at the 3-month study visit, lower concentrations of urine uromodulin and IL-18 were associated with a monthly decline in eGFR (uromodulin β = 0.04 (95% CI: 0.00-0.09; p = 0.07) IL-18 β = 0.07 (95% CI: 0.01-0.13; p = 0.04), ml/min/1.73 m 2 per month)., Conclusions: At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. A higher-resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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&#95;08&#95;08&#95;CJN0000000000000192.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients., Objective: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting., Methods: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s)., Results: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration., Conclusions: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 - 1.14, p = 0.0003). The primary outcome - a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 - 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977., (© 2023. The Author(s).)

BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

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.)

Rationale & Objective: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown., Study Design: Prospective cohort., Setting & Participants: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements., Predictors: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge., Outcomes: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated., Analytical Approach: Cox proportional hazard models., Results: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes., Limitations: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups., Conclusions: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation., Study Design: Prospective cohort., Setting & Participants: 862 deceased donors for 1,137 kidney recipients at 13 centers., Exposures: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI., Outcomes: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year., Analytical Approach: Multivariable Fine-Gray models with death as a competing risk., Results: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA., Limitations: BPAR was ascertained through for-cause biopsies, not surveillance biopsies., Conclusions: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: See Disclosures at the end of the article.

Background: Soluble tumor necrosis factor receptor (sTNFR)1, sTNFR2, and plasma kidney injury molecule-1 (KIM-1) are associated with kidney events in patients with and without diabetes. However, their associations with clinical outcomes when obtained pre-operatively have not been explored., Methods: The TRIBE-AKI cohort study is a prospective, multicenter, cohort study of high-risk adults undergoing cardiac surgery. We assessed the associations between pre-operative concentrations of plasma sTNFR1, sTNFR2, and KIM-1 and post-operative long-term outcomes including mortality, cardiovascular events, and chronic kidney disease (CKD) incidence or progression after discharge., Results: Among 1378 participants included in the analysis with a median follow-up period of 6.7 (IQR 4.0-7.9) years, 434 (31%) patients died, 256 (19%) experienced cardiovascular events and out of 837 with available long-term kidney function data, 30% developed CKD. After adjustment for clinical covariates, each log increase in biomarker concentration was independently associated with mortality with 95% CI adjusted hazard ratios (aHRs) of 3.0 (2.3-4.0), 2.3 (1.8-2.9), and 2.0 (1.6-2.4) for sTNFR1, sTNFR2, and KIM-1, respectively. For cardiovascular events, the 95% CI aHRs were 2.1 (1.5-3.1), 1.9 (1.4-2.6) and 1.6 (1.2-2.1) for sTNFR1, sTNFR2 and KIM-1, respectively. For CKD events, the aHRs were 2.2 (1.5-3.1) for sTNFR1, 1.9 (1.3-2.7) for sTNFR2, and 1.7 (1.3-2.3) for KIM-1. Despite the associations, each of the biomarkers alone or in combination failed to result in robust discrimination on an absolute basis or compared to a clinical model., Conclusion: sTNFR1, sTNFR2, and KIM-1 were independently associated with longitudinal outcomes after discharge from a cardiac surgery hospitalization including death, cardiovascular, and CKD events when obtained pre-operatively in high-risk individuals. Pre-operative plasma biomarkers could serve to assist during the evaluation of patients in whom cardiac surgery is planned., (© 2022. The Author(s).)

Background: Acute kidney injury (AKI) is common in deceased organ donors and is associated with high rates of kidney discard by transplant centers. High discard rates may consequently drive nonprocurement of these kidneys by organ procurement organizations. We aimed to study the relationship between donor AKI and kidney nonprocurement., Methods: Using U.S. registry data, we identified donors with at least one organ recovered from 2008 to 2018. We compared characteristics of donors with no kidneys procured across AKI stages, and used multivariable logistic regression to evaluate the relationship between AKI severity and kidney nonprocurement., Results: Overall 14 543 kidneys from 7620 donors were not procured, among which 93% were from donors with AKI. For 6945 donors with no kidneys procured but an extrarenal organ recovered, most had stage 3 (51%), followed by stage 1 (27%) and stage 2 AKI (15%). Nonprocured stage 3 donors were the youngest and had the lowest Kidney Donor Risk Index of all nonprocured donors. Adjusted odds of kidney nonprocurement were 1.14 (95%CI 1.02-1.27) for stage 1, 1.25 (95%CI 1.12-1.41) for stage 2, and 10.37 (95%CI 9.30-11.56) for stage 3 donors, compared to non-AKI donors. Among donors with minimum creatinine <1.5 mg/dl, stage 2 and 3 AKI were still associated with significantly higher odds of nonprocurement., Conclusions: AKI severity is a strong risk factor for kidney nonprocurement. Efforts to address the organ shortage should focus on encouraging procurement and utilization of kidneys from deceased donors with severe AKI, given the large and rising prevalence of donor AKI and excellent transplant outcomes with these kidneys., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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: Mechanisms by which AKI leads to CKD progression remain unclear. Several urine biomarkers have been identified as independent predictors of progressive CKD. It is unknown whether AKI may result in long-term changes in these urine biomarkers, which may mediate the effect of AKI on CKD progression., Methods: We selected 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥ 1.5) among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. We matched the best non-AKI hospitalization (unique patients) for each AKI hospitalization using pre-hospitalization characteristics including eGFR and urine protein/creatinine ratio. Biomarkers were measured in banked urine samples collected at annual CRIC study visits., Results: Urine biomarker measurements occurred a median of 7 months before and 5 months after hospitalization. There were no significant differences in the change in urine biomarker-to-creatinine ratio between the AKI and non-AKI groups: KIM-1/Cr + 9% vs + 7%, MCP-1/Cr + 4% vs + 1%, YKL-40/Cr + 7% vs -20%, EGF/Cr -11% vs -8%, UMOD/Cr -2% vs -7% and albumin/Cr + 17% vs + 13% (all p > 0.05)., Conclusion: In this cohort of adults with CKD, AKI did not associate with long-term changes in urine biomarkers., (© 2022. The Author(s).)

Objectives: The epidemiology of hospitalized acute kidney injury (AKI) among people living with HIV (PLWH) in the era of modern antiretroviral therapy (ART) for all PLWH is not well characterized. We evaluated the incidence of and risk factors for hospitalized AKI from 2005 to 2015 among PLWH on ART., Methods: We conducted a retrospective analysis of PLWH from the Johns Hopkins HIV Clinical Cohort. We defined hospitalized AKI as a rise of ≥ 0.3 mg/dL in serum creatinine (SCr) within any 48-h period or a 50% increase in SCr from baseline and assessed associations of risk factors with incident AKI using multivariate Cox regression models., Results: Most participants (75%) were black, 34% were female, and the mean age was 43 years. The incidence of AKI fluctuated annually, peaking at 40 per 1000 person-years (PY) [95% confidence interval (CI) 22-69 per 1000 PY] in 2007, and reached a nadir of 20 per 1000 PY (95% CI 11-34 per 1000 PY) in 2010. There was no significant temporal trend (-3.3% change per year; 95% CI -8.6 to 2.3%; P = 0.24). After multivariable adjustment, characteristics independently associated with AKI included black race [hazard ratio (HR) 2.44; 95% CI 1.42-4.20], hypertension (HR 1.62; 95% CI 1.09-2.38), dipstick proteinuria > 1 (HR 1.86; 95% CI 1.07-3.23), a history of AIDS (HR 1.82; 95% CI 1.29-2.56), CD4 count < 200 cells/µL (HR 1.46; 95% CI 1.02-2.07), and lower serum albumin (HR 1.73 per 1 g/dL decrease; 95% CI 1.02-2.07)., Conclusions: In this contemporary cohort of PLWH, the annual incidence of first AKI fluctuated during the study period. Attention to modifiable AKI risk factors and social determinants of health may further reduce AKI incidence among PLWH., (© 2021 British HIV Association.)

Background: Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown., Methods: Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization)., Results: In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P <0.01), TNFR2 (10% versus 3%, P <0.01), and KIM-1 (13% versus -2%, P <0.01)., Conclusions: Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult., (Copyright © 2022 by the American Society of Nephrology.)

Kidney involvement is common in coronavirus disease-2019 (COVID-19), and our understanding of the effects of COVID-19 on short- and long-term kidney outcomes has evolved over the course of the pandemic. Initial key questions centered on the spectrum and degree of acute kidney injury (AKI) in patients hospitalized with severe COVID-19. Investigators worldwide have explored the association between COVID-19-associated AKI and short-term outcomes, including inpatient mortality and disease severity. Even as treatments evolved, vaccinations were developed, and newer viral variants arose, subsets of patients were identified as at continued high risk for major adverse kidney outcomes. In this review, we explore key topics of continued relevance including the following: (1) a comparison of COVID-19-associated AKI with AKI developing in other clinical settings; (2) the ongoing controversy over kidney tropism in the setting of COVID-19 and the potential for competitive binding of the severe acute respiratory syndrome coronavirus 2 virus with angiotensin converting enzyme-2 to prevent viral cell entry; and (3) the identification of high-risk patients for adverse outcomes to inform long-term outpatient management. Patients at particularly high risk for adverse kidney outcomes include those with APOL1 high-risk genotype status. Biomarkers of injury, inflammation, tubular health, and repair measured in both the blood and urine may hold prognostic significance., (Copyright © 2022. Published by Elsevier Inc.)

Background: Acute kidney injury (AKI) in deceased donors is not associated with graft failure (GF). We hypothesize that hemodynamic AKI (hAKI) comprises the majority of donor AKI and may explain this lack of association., Methods: In this ancillary analysis of the Deceased Donor Study, 428 donors with available charts were selected to identify those with and without AKI. AKI cases were classified as hAKI, intrinsic (iAKI), or mixed (mAKI) based on majority adjudication by three nephrologists. We evaluated the associations between AKI phenotypes and delayed graft function (DGF), 1-year eGFR and GF. We also evaluated differences in urine biomarkers among AKI phenotypes., Results: Of the 291 (68%) donors with AKI, 106 (36%) were adjudicated as hAKI, 84 (29%) as iAKI and 101 (35%) as mAKI. Of the 856 potential kidneys, 669 were transplanted with 32% developing DGF and 5% experiencing GF. Median 1-year eGFR was 53 (IQR: 41-70) ml/min/1.73m2. Compared to non-AKI, donors with iAKI had higher odds DGF [aOR (95%CI); 4.83 (2.29, 10.22)] and had lower 1-year eGFR [adjusted B coefficient (95% CI): -11 (-19, -3) mL/min/1.73 m2]. hAKI and mAKI were not associated with DGF or 1-year eGFR. Rates of GF were not different among AKI phenotypes and non-AKI. Urine biomarkers such as NGAL, LFABP, MCP-1, YKL-40, cystatin-C and albumin were higher in iAKI., Conclusion: iAKI was associated with higher DGF and lower 1-year eGFR but not with GF. Clinically phenotyped donor AKI is biologically different based on biomarkers and may help inform decisions regarding organ utilization., Competing Interests: The authors have declared that no competing interests exist.

Kidney allocation trends from deceased donors with acute kidney injury (AKI) have not been characterized since initial Kidney Donor Profile Index reporting in 2012 and its use under the revised Kidney Allocation System (KAS) in 2014. We conducted a retrospective analysis of US registry data to characterize kidney procurement and discard trends in deceased donors with AKI, defined by ≥50% or ≥0.3 mg/dl (≥4.0 mg/dl or ≥200% for stage 3) increase in terminal serum creatinine from admission. From 2010 to 2020, 172 410 kidneys were procured from 93 341 deceased donors 16 years or older; 34 984 kidneys were discarded (17 559 from AKI donors). The proportion of stage 3 AKI donors doubled from 6% (412/6841) in 2010 to 12% (1365/11493) in 2020. Procurement of stage 3 AKI kidneys increased from 51% (423/824) to 80% (2183/2730). While discard of stage 3 AKI kidneys increased from 41% (175/423) in 2010 to 44% (960/2183) in 2020, this increase was not statistically significant in interrupted time-series analysis following KAS implementation (slope difference -0.41 [-3.22, 2.4], and level change 3.09 [-6.4, 12.6]). In conclusion, the absolute number of stage 3 AKI kidneys transplanted has increased. Ongoing high discard rates of these kidneys suggest opportunities for improved utilization., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In patients receiving immune checkpoint inhibitor (ICI) therapy, acute kidney injury (AKI) is common, and can occur either from kidney injury unrelated to ICI use or from immune activation resulting in acute interstitial nephritis (AIN). In this study, we test the hypothesis that occurrence of AIN indicates a favorable treatment response to ICI therapy and therefore among patients who develop AKI while on ICI therapy, those with AIN will demonstrate greater survival compared with others with AKI., Methods: In this observational cohort study, we included participants initiated on ICI therapy between 2013 and 2019. We tested the independent association of AKI and estimated AIN (eAIN) with mortality up to 1 year after therapy initiation as compared with those without AKI using time-varying Cox proportional hazard models controlling for demographics, comorbidities, cancer type, stage, and therapy, and baseline laboratory values. We defined eAIN as those with a predicted probability of AIN >90th percentile derived from a recently validated diagnostic model., Results: Of 2207 patients initiated on ICIs, 617 (28%) died at 1 year and 549 (25%) developed AKI. AKI was independently associated with higher mortality (adjusted HR, 2.28 (95% CI 1.90 to 2.72)). Those AKI patients with eAIN had more severe AKI as reflected by a higher peak serum creatinine (3.3 (IQR 2.1-6.1) vs 1.4 (1.2-1.9) mg/dL, p<0.001) but exhibited lower mortality than those without eAIN in univariable analysis (HR 0.43 (95% CI 0.21 to 0.89)) and after adjusting for demographics, comorbidities, and cancer type and severity (adjusted HR 0.44 (95% CI 0.21 to 0.93))., Conclusion: In patients treated with ICI, mortality was higher in those with AKI unrelated to ICI but lower in those where the underlying etiology was AIN. Future studies could evaluate the association of biopsy-proven or biomarker-proven AIN with mortality in those receiving ICI therapy., Competing Interests: Competing interests: DGM and CRP are coinventors of the pending patent application 'Methods and Systems for Diagnosis of Acute Interstitial Nephritis' that is subject to an option for a license agreement with Renalytix AI., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure., Methods: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later., Results: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression., Conclusions: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI., (Copyright © 2022 by the American Society of Nephrology.)

Rationale & Objective: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19., Study Design: Prospective cohort study., Setting & Participants: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020., Exposure: 19 urinary biomarkers of injury, inflammation, and repair., Outcome: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings., Analytical Approach: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome., Results: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine., Limitations: Small sample size with low number of composite outcome events., Conclusions: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (r s ) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median r s was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater r s in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (r s > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Current methods of processing and storing urine samples have not been compared systematically to determine optimal conditions for advancing research on urinary biomarkers. Often, preanalytical handling is nonideal, especially considering the COVID-19 pandemic; consequently, we compared the effects of different short-term storage and processing methods on urinary biomarker measurements., Methods: Spot urine samples were collected via a Foley catheter from 20 hospitalized patients from the Yale New Haven Hospital within 48 hours postcardiac surgery. The effects of 3 urine storage and processing methods on biomarkers were tested: (a) 48-hour temporary storage at 4 °C prior to freezing at -80 °C, (b) 48-hour temporary storage at 25 °C prior to freezing at -80 °C, and (c) no centrifugation and immediate storage at -80 °C. Established Meso-Scale Device assay methods were used to measure the urine concentrations of 18 biomarkers: interferon gamma (IFN-ɣ), interleukin (IL)-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-18, tumor necrosis factor alpha (TNF-α), epidermal growth factor (EGF), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), uromodulin (UMOD), kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), and chitinase-3-like protein 1 (YKL-40)., Results: Measurements of most biomarkers investigated remained stable after temporary storage at 4 °C. IL-6, IL-8, KIM-1, MCP-1, YKL-40, EGF, and NGAL were stable across all 3 processing conditions. IL-12p70 and IL-4 demonstrated significant differences in all tested conditions compared to the reference standard., Conclusions: We identified several notable biomarkers that are robust to variations in preanalytical techniques and can be reliably investigated with nonideal handling conditions., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Acute kidney injury (AKI) is a sudden episode of kidney damage or failure affecting up to 15% of hospitalized patients and is associated with serious short- and long-term complications, mortality, and health care costs. Current practices to diagnose and stage AKI are variable and do not factor in our improved understanding of the biological and analytical variability of creatinine. In addition, the emergence of biomarkers, for example, cystatin C, insulin-like growth factor binding protein 7, and tissue inhibitor of metalloproteinases 2, and electronic notification tools for earlier detection of AKI, highlights the need for updated recommendations to address these developments., Content: This AACC Academy guidance document is intended to provide laboratorians and clinicians up-to-date information regarding current best practices for the laboratory investigation of AKI. Topics covered include: clinical indications for further investigating potential AKI, analytical considerations for creatinine assays, the impact of biological variability on diagnostic thresholds, defining "baseline" creatinine, role of traditional markers (urine sodium, fractional excretion of sodium, fractional excretion of urea, and blood urea-to-creatinine ratio), urinary microscopic examination, new biomarkers, improving AKI-associated test utilization, and the utility of automated AKI alerts., Summary: The previous decade brought us a significant number of new studies characterizing the performance of existing and new biomarkers, as well as potential new tools for early detection and notification of AKI. This guidance document is intended to inform clinicians and laboratorians on the best practices for the laboratory investigation of AKI, based on expert recommendations where the preponderance of evidence is available., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite advancements in standardizing the criteria for acute kidney injury (AKI), its definition remains based on changes in serum creatinine and urinary output that do not specifically represent tubular function or injury and that have significant limitations in the acute hospital setting. Much effort in nephrology has centered on identifying biomarkers of AKI to address these limitations. This review summarizes recent advances in our knowledge of biomarkers involved in pathophysiological processes during AKI and describes their potential clinical implications. Blood and urine biomarkers are released via various mechanisms during renal tubular injury. Urinary kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), insulin-like growth factor-binding protein-7 (IGFBP-7), and tissue inhibitor of metalloprotease-2 (TIMP-2) are released from the proximal tubule while uromodulin (UMOD) is secreted from the loop of Henle and neutrophil gelatinase-associated lipocalin (NGAL) is released from the distal tubule. These biomarkers could therefore be used to localize specific segments of injured tubules. Biomarkers also have diverse roles in pathophysiological processes in AKI, including inflammation, repair, and fibrosis. Current evidence suggests that these biomarkers could be used to predict the transition to chronic kidney disease (CKD), decrease discard of AKI kidneys, differentiate between kidney dysfunction and injury, guide AKI management, and improve diagnosis of diseases such as acute interstitial nephritis (AIN). They could differentiate between disease phenotypes, facilitate the inclusion of a homogenous patient population in future trials of AKI, and shed light on therapeutic pathways to prevent the transition from AKI to CKD. However, a major limitation of current biomarker research in AKI is the lack of tissue correlation. The Kidney Precision Medicine Project, a large-scale national effort, is currently underway to construct a kidney tissue atlas and expand the use of biomarkers to assess nephron health. Numerous biomarkers are involved in distinct pathophysiological processes after kidney injury and have demonstrated potential to improve diagnosis and risk stratification as well as provide a prognosis for patients with AKI. Some biomarkers are ready for use in clinical trials of AKI and could guide management in various clinical settings. Further investigation of these biomarkers will provide insight that can be applied to develop novel therapeutic agents for AKI.

Background: There has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations., Methods: We quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization., Results: Among 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes., Conclusions: Contrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations., (© 2021. The Author(s).)

BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting long-term kidney outcomes after cardiac surgery.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1's associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O'Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.

Background: Children undergoing cardiac surgery are at risk of high blood pressure (BP), a risk factor for cardiovascular and kidney disease. Twenty-four-hour ambulatory BP monitoring (ABPM) is a reference standard hypertension (HTN) test. Little data exist on ABPM abnormalities in children several years post cardiac surgery. This study aimed to (a) determine ABPM feasibility; (b) describe and compare ABPM measures and abnormalities (percent load, masked HTN [MH]; non-dipping, mean systolic/diastolic BP > 95th percentile; pre-HTN (ABPM); white-coat HTN [WCH]) to casual BP; and (c) compare BP in patients with and without acute kidney injury (AKI)., Methods: Prospective, follow-up pilot study of children (0-18 years) who underwent cardiac surgery from 2007 to 2009 at Montreal Children's Hospital. We recorded if participants had post-operative AKI and assessed the following outcomes at 9-year follow-up: casual BP classified by three single-visit measures (normal; elevated BP [eBP SingleVisit ]; HTN SingleVisit ); ABPM. Bivariable analyses were used to compare characteristics between groups., Results: Twenty-three patients (median [interquartile range], 8.6 [8.0, 9.0] years post cardiac surgery) were included; 16 (70%) male. Six participants (26%) had eBP SingleVisit or higher. On ABPM, 11 (48%) had ≥ 1 abnormality: 9 (39%) had non-dipping; 3 (13%) had pre-HTN; 3 (13%) had WCH; none had HTN or MH. There were no differences in ABPM according to AKI status., Conclusion: Our pilot study determined that ABPM was feasible in children years after cardiac surgery and frequently identified ABPM abnormalities. Future research in larger populations is needed to define specific risk factors for HTN in children after cardiac surgery.

Background: Acute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI., Methods: This prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size., Results: The cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m 2 , 56.4 per 1000-person-years with BMI 25-29.9 kg/m 2 , and 72.6 per 1000-person-years with BMI 20-24.9 kg/m 2 . AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87-3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76-2.92) and similarly, there was no detectable effect of BMI modifying this risk., Conclusions: In this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.

AKI frequently occurs in patients with COVID-19, and kidney injury severe enough to require RRT is a common complication among patients who are critically ill. During the surge of the pandemic, there was a high demand for dialysate for continuous RRT, and this increase in demand, coupled with vulnerabilities in the supply chain, necessitated alternative approaches, including internal production of dialysate. Using a standard hemodialysis machine and off-the-shelf supplies, as per Food and Drug Administration guidelines, we developed a method for on-site dialysate production that is adaptable and can be used to fill multiple bags at once. The use of a central reverse osmosis unit, dedicated hemodialysis machine, sterile bags with separate ports for fill and use, and frequent testing will ensure stability, sterility, and-therefore-safety of the produced dialysate. The dialysate made in house was tested and it showed both stability and sterility for at least 30 hours. This detailed description of our process for generating dialysate can serve as a guide for other programs experiencing similar vulnerabilities in the demand versus supply of dialysate., Competing Interests: C.R. Parikh reports having consultancy agreements with Genfit Biopharmaceutical Company; serving as a scientific advisor for, or member of, Genfit Biopharmaceutical Company and RenalytixAI; having ownership interest in RenalytixAI; and receiving research funding from the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). D. Fine reports serving on the medical advisory board for Fresenius Medical Corporation, and having consultancy agreements with GlaxoSmithKline (data and safety monitoring board). S. Mohan reports serving as a member of the Angion Pharma scientific advisory board, as deputy editor for Kidney International Reports (International Society of Nephrology), receiving research funding from Angion Biomedica; receiving research funding from NIH (National Institute of Biomedical Imaging and Bioengineering, National Institute on Minority Health and Health Disparities, and NIDDK). All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

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.)