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Laura Palau,1,* Steven Menez,1,* Javier Rodriguez-Sanchez,1 Tessa Novick,1 Marco Delsante,2 Blaithin A McMahon,1 Mohamed G Atta1 1Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Department of Pathology, Johns Hopkins University, Baltimore, MD, USA *These authors contributed equally to this work Abstract: Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in APOL1 gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin–angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended. Keywords: HIVAN, HIV, APOL1 polymorphism, ESRD, kidney transplant

Background: Accurate diagnosis of acute tubulointerstitial nephritis (AIN) often requires a kidney biopsy. We previously developed a diagnostic statistical model for predicting biopsy-confirmed AIN by combining four laboratory tests after evaluating over 150 potential predictors from the electronic health record. Here, we validate this diagnostic model in two biopsy-based cohorts at Johns Hopkins Hospital (JHH) and Yale, which were geographically and temporally distinct from the development cohort, respectively., Methods: We analyzed patients who underwent kidney biopsy at JHH and Yale University (2019-2023). We assessed discrimination (AUC) and calibration using previously derived model coefficients and recalibrated the model using an intercept correction factor that accounted for differences in baseline prevalence of AIN between development and validation cohorts., Results: We included 1982 participants: 1454 at JHH and 528 at Yale. JHH (5%) and Yale (17%) had lower proportions of biopsies with AIN than the development set (23%). The AUC was 0.73 (0.66-0.79) at JHH and 0.73 (0.67-0.78) at Yale, similar to the development set (0.73 (0.64-0.81)). Calibration was imperfect in validation cohorts, particularly at JHH, but improved with application of an intercept correction factor. The model increased AUC of clinicians' prebiopsy suspicion for AIN by 0.10 to 0.77 (0.71-0.82)., Conclusions: An AIN diagnostic model retained discrimination in two validation cohorts but needed recalibration to account for local AIN prevalence. The model improved clinicians' ability to predict AIN., (Copyright © 2024 by the American Society of Nephrology.)

Importance: Acute kidney injury (AKI) is a common complication during hospitalization and is associated with adverse outcomes., Objective: To evaluate whether diagnostic and therapeutic recommendations sent by a kidney action team through the electronic health record improve outcomes among patients hospitalized with AKI compared with usual care., Design, Setting, and Participants: Randomized clinical trial conducted at 7 hospitals in 2 health systems: in New Haven, Bridgeport, New London, and Waterbury, Connecticut, and Westerly, Rhode Island; and in Baltimore, Maryland. Hospitalized patients with AKI were randomized between October 29, 2021, and February 8, 2024. Final follow-up occurred February 22, 2024., Intervention: An alert about AKI was sent to the kidney action team, consisting of a study physician and study pharmacist, which sent personalized recommendations through the electronic health record in 5 major categories (diagnostic testing, volume, potassium, acid base, and medications) within 1 hour of AKI detection. The note was immediately visible to anyone with access to the electronic health record. Randomization to the intervention or usual care occurred after the recommendations were generated, but the note was only delivered to clinicians of patients randomized to the intervention group., Main Outcomes and Measures: The primary outcome was a composite outcome consisting of AKI progression to a higher stage of AKI, dialysis, or mortality occurring while the patient remained hospitalized and within 14 days from randomization., Results: Of the 4003 patients randomized (median age, 72 years [IQR, 61-81 years), 1874 (47%) were female and 931 (23%) were Black patients. The kidney action team made 14 539 recommendations, with a median of 3 (IQR, 2-5) per patient. The primary outcome occurred in 19.8% of the intervention group and in 18.4% in the usual care group (difference, 1.4%, 95% CI, -1.1% to 3.8,% P = .28). Of 6 secondary outcomes, only 1 secondary outcome, rates of recommendation implementation, significantly differed between the 2 groups: 2459 of 7270 recommendations (33.8%) were implemented in the intervention group and 1766 of 7269 undelivered recommendations (24.3%) were implemented in the usual care group within 24 hours (difference, 9.5%; 95% CI, 8.1% to 11.0%)., Conclusions and Relevance: Among patients hospitalized with AKI, recommendations from a kidney action team did not significantly reduce the composite outcome of worsening AKI stage, dialysis, or mortality, despite a higher rate of recommendation implementation in the intervention group than in the usual care group., Trial Registration: ClinicalTrials.gov Identifier: NCT04040296.

Rationale & Objective: The prevalence of community-acquired acute kidney injury (CA-AKI) in the United States and its clinical consequences are not well described. Our objective was to describe the epidemiology of CA-AKI and the associated clinical outcomes., Study Design: Retrospective cohort study., Setting & Participants: 178,927 encounters by 139,632 adults at 5 US emergency departments (EDs) between July 1, 2017, and December 31, 2022., Predictors: CA-AKI identified using KDIGO (Kidney Disease: Improving Global Outcomes) serum creatinine (Scr)-based criteria., Outcomes: For encounters resulting in hospitalization, the in-hospital trajectory of AKI severity, dialysis initiation, intensive care unit (ICU) admission, and death. For all encounters, occurrence over 180 days of hospitalization, ICU admission, new or progressive chronic kidney disease, dialysis initiation, and death., Analytical Approach: Multivariable logistic regression analysis to test the association between CA-AKI and measured outcomes., Results: For all encounters, 10.4% of patients met the criteria for any stage of AKI on arrival to the ED. 16.6% of patients admitted to the hospital from the ED had CA-AKI on arrival to the ED. The likelihood of AKI recovery was inversely related to CA-AKI stage on arrival to the ED. Among encounters for hospitalized patients, CA-AKI was associated with in-hospital dialysis initiation (OR, 6.2; 95% CI, 5.1-7.5), ICU admission (OR, 1.9; 95% CI, 1.7-2.0), and death (OR, 2.2; 95% CI, 2.0-2.5) compared with patients without CA-AKI. Among all encounters, CA-AKI was associated with new or progressive chronic kidney disease (OR, 6.0; 95% CI, 5.6-6.4), dialysis initiation (OR, 5.1; 95% CI, 4.5-5.7), subsequent hospitalization (OR, 1.1; 95% CI, 1.1-1.2) including ICU admission (OR, 1.2; 95% CI, 1.1-1.4), and death (OR, 1.6; 95% CI, 1.5-1.7) during the subsequent 180 days., Limitations: Residual confounding. Study implemented at a single university-based health system. Potential selection bias related to exclusion of patients without an available baseline Scr measurement. Potential ascertainment bias related to limited repeat Scr data during follow-up after an ED visit., Conclusions: CA-AKI is a common and important entity that is associated with serious adverse clinical consequences during the 6-month period after diagnosis., Plain-Language Summary: Acute kidney injury (AKI) is a condition characterized by a rapid decline in kidney function. There are many causes of AKI, but few studies have examined how often AKI is already present when patients first arrive to an emergency department seeking medical attention for any reason. We analyzed approximately 175,000 visits to Johns Hopkins emergency departments and found that AKI is common on presentation to the emergency department and that patients with AKI have increased risks of hospitalization, intensive care unit admission, development of chronic kidney disease, requirement of dialysis, and death in the first 6 months after diagnosis. AKI is an important condition for health care professionals to recognize and is associated with serious adverse outcomes., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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.

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: Limited data exist on patient perspectives of the implications of kidney biopsies. We explored patients' perspectives alongside those of clinicians to better understand how kidney biopsies affect patients' viewpoints and the clinical utility of biopsies., Study Design: Prospective Cohort Study., Setting & Participants: Patient participants and clinicians in the Kidney Precision Medicine Project, a prospective cohort study of patients who undergo a research protocol biopsy, at 9 recruitment sites across the United States. Surveys were completed at enrollment before biopsy and additional timepoints after biopsy (participants: 28 days, 6 months; clinicians: 2 weeks)., Analytical Approach: Kappa statistics assessed prebiopsy etiology concordance between clinicians and participants. Participant perspectives after biopsy were analyzed using a thematic approach. Clinician ratings of clinical management value were compared to prebiopsy ratings with Wilcoxon matched-pairs signed-rank tests and paired t tests., Results: A total of 167 participants undergoing biopsy (124 participants with chronic kidney disease [CKD], 43 participants with acute kidney injury [AKI]) and 58 clinicians were included in this study. CKD participants and clinicians had low etiology concordance for the 2 leading causes of CKD: diabetes (k = 0.358) and hypertension (k = 0.081). At 28 days postbiopsy, 46 (84%) participants reported that the biopsy affected their understanding of their diagnosis, and 21 (38%) participants reported that the results of the biopsy affected their medications. Participants also shared biopsy impressions in free-text responses, including impacts on lifestyle and concurrent condition management. The biopsy positively shifted clinician perceptions of the procedure's clinical management benefits, while perceptions of prognostic value decreased and diagnostic ratings remained unchanged., Limitations: Our study did not have demographic data of clinicians and could not provide insight into postbiopsy experiences for participants who did not respond to follow-up surveys., Conclusions: Participant perspectives of the personal implications of kidney biopsy can be integrated into shared decision-making between clinicians and patients. Enhanced biopsy reports and interactions between nephrologists and pathologists could augment the management and prognostic value of kidney biopsies., Plain-Language Summary: The utility of kidney biopsy is debated among clinicians, and patients' perspectives are even less explored. To address these gaps, we synthesized perspectives from clinicians and patient participants of the Kidney Precision Medicine Project (KPMP). Both before and after biopsy, clinicians were surveyed on how the procedure affected their clinical management, diagnosis, and prognosis. After biopsy, participants shared how the procedure affected their diagnosis, medication, and lifestyle changes. Clinicians and patients shared an appreciation for the biopsy's impact on medical management but diverged in their takeaways on diagnosis and prognosis. These findings highlight the need for greater collaboration between patients and clinicians, particularly as they navigate shared decision-making when considering kidney biopsy., (© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Introduction: Although studies have examined the utility of clinical decision support tools in improving acute kidney injury (AKI) outcomes, no study has evaluated the effect of real-time, personalised AKI recommendations. This study aims to assess the impact of individualised AKI-specific recommendations delivered by trained clinicians and pharmacists immediately after AKI detection in hospitalised patients., Methods and Analysis: KAT-AKI is a multicentre randomised investigator-blinded trial being conducted across eight hospitals at two major US hospital systems planning to enrol 4000 patients over 3 years (between 1 November 2021 and 1 November 2024). A real-time electronic AKI alert system informs a dedicated team composed of a physician and pharmacist who independently review the chart in real time, screen for eligibility and provide combined recommendations across the following domains: diagnostics, volume, potassium, acid-base and medications. Recommendations are delivered to the primary team in the alert arm or logged for future analysis in the usual care arm. The planned primary outcome is a composite of AKI progression, dialysis and mortality within 14 days from randomisation. A key secondary outcome is the percentage of recommendations implemented by the primary team within 24 hours from randomisation. The study has enrolled 500 individuals over 8.5 months. Two-thirds were on a medical floor at the time of the alert and 17.8% were in an intensive care unit. Virtually all participants were recommended for at least one diagnostic intervention. More than half (51.6%) had recommendations to discontinue or dose-adjust a medication. The median time from AKI alert to randomisation was 28 (IQR 15.8-51.5) min., Ethics and Dissemination: The study was approved by the ethics committee of each study site (Yale University and Johns Hopkins institutional review board (IRB) and a central IRB (BRANY, Biomedical Research Alliance of New York). We are committed to open dissemination of the data through clinicaltrials.gov and sharing of data on an open repository as well as publication in a peer-reviewed journal on completion., Trial Registration Number: NCT04040296., Competing Interests: Competing interests: FPW reports research funding unrelated to this project from AstraZeneca, Boehringer-Ingelheim, Vifor Pharma and Whoop, Inc. CP is a member of the advisory board of and owns equity in RenalytixAI. He also serves as a consultant for Genfit and Novartis. All other authors have no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 Aims: The contribution of kidney dysfunction, especially at mild-to-moderate stages, and bone-mineral metabolism (BMM) markers to vascular calcification remains controversial or unclear. We comprehensively evaluated the association of kidney and BMM markers with coronary artery calcification (CAC) and extra-coronary calcification (ECC)., Methods: In 1931 ARIC participants (age 73-95 years) without coronary heart disease at visit 7 (2018-19), we investigated the associations of estimated glomerular filtration rate (eGFR) (with creatinine, cystatin C, and both) and five serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) with high CAC and ECC (sex-race specific ≥75th vs. <75th percentile Agatston score) or any vs. zero CAC and ECC using multivariable logistic regression. For eGFR and BMM markers, we took their weighted cumulative averages from visit 1 (1987-89) to visit 5 (2011-13)., Results: Lower eGFR, regardless of equations used, was not robustly associated with high CAC or ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed robust associations with high CAC (only when modeled continuously) and ECC, independently of kidney function (e.g., odds ratio 1.94 [95%CI 1.38-2.73] for high aortic valve calcification, in the highest vs. lowest quartile). Results were generally consistent when analyzing any CAC or ECC, although cystatin C-based eGFR <60 mL/min/1.73 m 2 became significantly associated with mitral valve calcification (odds ratio 1.69 [1.10-2.60])., Conclusions: Among kidney and BMM measures tested, only serum phosphorus demonstrated robust associations with both CAC and ECC, supporting a key role of phosphorus in the pathophysiology of vascular calcification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Evidence of an association between intravenous contrast media (CM) and persistent renal dysfunction is lacking for patients with pre-existing acute kidney injury (AKI). This study was designed to determine the association between intravenous CM administration and persistent AKI in patients with pre-existing AKI., Methods: A retrospective propensity-weighted and entropy-balanced observational cohort analysis of consecutive hospitalized patients ≥ 18 years old meeting Kidney Disease Improving Global Outcomes (KDIGO) creatinine-based criteria for AKI at time of arrival to one of three emergency departments between 7/1/2017 and 6/30/2021 who did or did not receive intravenous CM. Outcomes included persistent AKI at hospital discharge and initiation of dialysis within 180 days of index encounter., Results: Our analysis included 14,449 patient encounters, with 12.8% admitted to the intensive care unit (ICU). CM was administered in 18.4% of all encounters. AKI resolved prior to hospital discharge for 69.1%. No association between intravenous CM administration and persistent AKI was observed after unadjusted multivariable logistic regression modeling (OR 1; 95% CI 0.89-1.11), propensity weighting (OR 0.93; 95% CI 0.83-1.05), and entropy balancing (OR 0.94; 95% CI 0.83-1.05). Sub-group analysis in those admitted to the ICU yielded similar results. Initiation of dialysis within 180 days was observed in 5.4% of the cohort. An association between CM administration and increased risk of dialysis within 180 days was not observed., Conclusion: Among patients with pre-existing AKI, contrast administration was not associated with either persistent AKI at hospital discharge or initiation of dialysis within 180 days. Current consensus recommendations for use of intravenous CM in patients with stable renal disease may also be applied to patients with pre-existing AKI., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected patients with kidney disease, causing significant challenges in disease management, kidney research and trainee education. For patients, increased infection risk and disease severity, often complicated by acute kidney injury, have contributed to high mortality. Clinicians were faced with high clinical demands, resource shortages and novel ethical dilemmas in providing patient care. In this review, we address the impact of COVID-19 on the entire spectrum of kidney care, including acute kidney injury, chronic kidney disease, dialysis and transplantation, trainee education, disparities in health care, changes in health care policies, moral distress and the patient perspective. Based on current evidence, we provide a framework for the management and support of patients with kidney disease, infection mitigation strategies, resource allocation and support systems for the nephrology workforce., (© 2022. Springer Nature Limited.)

Background: Sensitive and specific biomarkers are needed to provide better biologic insight into the risk of incident and progressive CKD. However, studies have been limited by sample size and design heterogeneity., Methods: In this assessment of the prognostic value of preclinical plasma and urine biomarkers for CKD outcomes, we searched Embase (Ovid), MEDLINE ALL (Ovid), and Scopus up to November 30, 2020, for studies exploring the association between baseline kidney biomarkers and CKD outcomes (incident CKD, CKD progression, or incident ESKD). We used random-effects meta-analysis., Results: After screening 26,456 abstracts and 352 full-text articles, we included 129 studies in the meta-analysis for the most frequently studied plasma biomarkers (TNFR1, FGF23, TNFR2, KIM-1, suPAR, and others) and urine biomarkers (KIM-1, NGAL, and others). For the most frequently studied plasma biomarkers, pooled RRs for CKD outcomes were 2.17 (95% confidence interval [95% CI], 1.91 to 2.47) for TNFR1 (31 studies); 1.21 (95% CI, 1.15 to 1.28) for FGF-23 (30 studies); 2.07 (95% CI, 1.82 to 2.34) for TNFR2 (23 studies); 1.51 (95% CI, 1.38 to 1.66) for KIM-1 (18 studies); and 1.42 (95% CI, 1.30 to 1.55) for suPAR (12 studies). For the most frequently studied urine biomarkers, pooled RRs were 1.10 (95% CI, 1.05 to 1.16) for KIM-1 (19 studies) and 1.12 (95% CI, 1.06 to 1.19) for NGAL (19 studies)., Conclusions: Studies of preclinical biomarkers for CKD outcomes have considerable heterogeneity across study cohorts and designs, limiting comparisons of prognostic performance across studies. Plasma TNFR1, FGF23, TNFR2, KIM-1, and suPAR were among the most frequently investigated in the setting of CKD outcomes., (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.)

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.)

Background: Kidney involvement is common in patients with systemic lupus erythematosus (SLE). This study investigates the clinical and prognostic characteristics of thrombotic microangiopathy (TMA) compared to class IV lupus nephritis in SLE patients., Methods: A retrospective review of patients who underwent kidney biopsy, with a primary diagnosis of SLE and TMA between June 2006 and September 2018 was conducted. Those patients were subsequently compared to patients with class IV lupus nephritis between January 2018 and December 2018. Demographics, laboratory, and serological data at the time of biopsy were abstracted., Results: Among 214 SLE patients records screened, 27 were included in the final analysis. Eight patients had lupus-related TMA without evidence of active lupus nephritis, while 19 patients had class IV lupus nephritis without evidence of TMA. TMA patients had significantly higher lactate dehydrogenase levels (718 ± 499 vs. 264 ± 107.7 U/L, p = 0.009), serum C3 (100.6 ± 39.3 vs. 65.8 ± 27 mg/dL, p = 0.049), white blood cell count (14743.8 ± 7933.3 vs. 5807.9 ± 2053.2 × 10E3/uL, p < 0.001), and total bilirubin (0.8 ± 0.5 vs. 0.3 ± 0.1 mg/dL, p = 0.007) in addition to significantly lower platelet counts (158.4 ± 88.6 vs. 240.3 ± 100.3 × 10E3/uL, p = 0.03), and haptoglobin (68.8 ± 116.1 vs. 166.8 ± 95.4 mg/dL, p = 0.03). After a median follow-up time of 53 weeks, 3 patients with TMA were dialysis-dependent (37.5%), compared with none in class IV lupus nephritis patients (p = 0.002)., Conclusions: TMA-associated SLE has worse prognosis compared to class IV lupus nephritis. An array of laboratory and pathological findings may be of value in discriminating between those two entities., (© 2021. Italian Society of Nephrology.)

Since the start of the COVID-19 pandemic, several manifestations of kidney involvement associated with infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been described, including proteinuria, hematuria, and acute kidney injury. A growing body of literature has explored the risk factors and pathogenesis of COVID-19-associated acute kidney injury (AKI), including direct and indirect mechanisms, as well as early postdischarge outcomes that may result from various manifestations of kidney involvement. In this review, we explore the current state of knowledge of the epidemiology of COVID-19-associated AKI, potential mechanisms and pathogenesis of AKI, and various management strategies for patients in the acute setting. We highlight how kidney replacement therapy for patients with COVID-19-associated AKI has been affected by the increasing demand for dialysis and how the postacute management of patients, including outpatient follow-up, is vitally important. We also review what is presently known about long-term kidney outcomes after the initial recovery from COVID-19. We provide some guidance as to the management of patients hospitalized with COVID-19 who are at risk for AKI as well as for future clinical research in the setting of COVID-19 and the significance of early identification of patients at highest risk for adverse kidney outcomes.

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.

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m 2 , we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m 2 , we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT)., Objective: The purpose of this study was to assess the nature of TCP in patients receiving CRRT., Methods: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria., Results: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32-3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU., Conclusion: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care., (© 2021 S. Karger AG, Basel.)

Competing Interests: All authors have nothing to disclose.

Background: Few studies have investigated the association of magnesium levels with incident peripheral artery disease (PAD) despite emerging evidence of magnesium contributing to vascular calcification. Moreover, no data are available on whether the magnesium-PAD relationship is independent of or modified by kidney function., Methods: A cohort of 11 839 participants free of PAD in the Atherosclerosis Risk in Communities Study at Visit 2 (1990-92) was studied. We investigated the association of serum magnesium and other bone-mineral metabolism markers [calcium, phosphorus, intact parathyroid hormone (iPTH) and intact fibroblast growth factor-23] with incident PAD using multivariable Cox proportional hazards regression., Results: Over a median of 23 years, there were 471 cases of incident PAD. The hazard ratio for incident PAD in Quartile 1 (<1.5 mEq/L) versus Quartile 4 (>1.7 mEq/L) of magnesium was 1.96 (95% confidence interval 1.40-2.74) after adjustment for potential confounders. Lower magnesium levels were associated with greater incidence of PAD, particularly in those with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (n = 11 606). In contrast, the association was largely flat in those with eGFR <60 mL/min/1.73 m2 (n = 233) with P-for-interaction 0.03. Among bone-mineral metabolism markers, only higher iPTH showed an interaction with kidney function (P-for-interaction 0.01) and iPTH >65 pg/mL was significantly related to PAD only in those with eGFR <60 mL/min/1.73 m2., Conclusions: Lower magnesium was independently associated with incident PAD, but this association was significantly weaker in those with reduced kidney function. In contrast, higher iPTH levels were particularly related to PAD risk in this clinical population., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Study Objective: Acute kidney injury occurs commonly and is a leading cause of prolonged hospitalization, development and progression of chronic kidney disease, and death. Early acute kidney injury treatment can improve outcomes. However, current decision support is not able to detect patients at the highest risk of developing acute kidney injury. We analyzed routinely collected emergency department (ED) data and developed prediction models with capacity for early identification of ED patients at high risk for acute kidney injury., Methods: A multisite, retrospective, cross-sectional study was performed at 3 EDs between January 2014 and July 2017. All adult ED visits in which patients were hospitalized and serum creatinine level was measured both on arrival and again with 72 hours were included. We built machine-learning-based classifiers that rely on vital signs, chief complaints, medical history and active medical visits, and laboratory results to predict the development of acute kidney injury stage 1 and 2 in the next 24 to 72 hours, according to creatinine-based international consensus criteria. Predictive performance was evaluated out of sample by Monte Carlo cross validation., Results: The final cohort included 91,258 visits by 59,792 unique patients. Seventy-two-hour incidence of acute kidney injury was 7.9% for stages greater than or equal to 1 and 1.0% for stages greater than or equal to 2. The area under the receiver operating characteristic curve for acute kidney injury prediction ranged from 0.81 (95% confidence interval 0.80 to 0.82) to 0.74 (95% confidence interval 0.74 to 0.75), with a median time from ED arrival to prediction of 1.7 hours (interquartile range 1.3 to 2.5 hours)., Conclusion: Machine learning applied to routinely collected ED data identified ED patients at high risk for acute kidney injury up to 72 hours before they met diagnostic criteria. Further prospective evaluation is necessary., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: In patients with systemic lupus erythematosus (SLE) without concurrent active urinary sediment or unexplained acute kidney injury (AKI), current guidelines recommend performing a kidney biopsy in those with at least 500 mg/24-hour (European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association [EULAR/ERA-EDTA]) or 1000 mg/24-hour (American College of Rheumatology [ACR]) proteinuria. To evaluate the relevance of these indications, we studied histopathologic findings in patients with SLE with proteinuria below these cutoffs., Methods: We retrospectively reviewed the clinical, laboratory and histological characteristics of patients with SLE with <1000 mg/24-hour proteinuria (or mg/g urinary protein-to-creatinine ratio [UPCR]) who underwent their first kidney biopsy between 2003 and 2018., Results: We identified 87 patients with SLE with proteinuria less than 1000 mg/24-hour (or mg/g UPCR); 52 of 87 (60%) with isolated proteinuria, that is, without AKI or active urinary sediment (hematuria). Histologic evidence of lupus nephritis (LN) was present in 40 of 52 (76%). Of the 40 patients with LN, 12 had class I or II, 14 had class III or IV, 8 had class V, 6 had a combined proliferative and membranous LN. Non-lupus diagnoses included focal segmental glomerulosclerosis, acute interstitial nephritis, and others. Patient's age, low C3, low C4, and positivity for anti-double-stranded DNA (anti-dsDNA) antibodies predicted the histological diagnosis of LN on univariate logistic regression; however, a multivariate model including these parameters as independent covariates failed to predict LN., Conclusions: Patients with SLE with low-level proteinuria may have significant lupus- or non-lupus-related kidney disease with management implications. There was a significant burden of severe forms of LN. The presence of LN was not predicted by laboratory abnormalities. Based on our findings, we suggest current guidelines be revised to expand kidney biopsy indications to include isolated proteinuria of any grade., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Ankle-brachial index (ABI), the first-line diagnostic test for peripheral artery disease, can be falsely elevated when ankle arteries are incompressible, showing a J-shaped association with mortality. In this situation, toe-brachial index (TBI) is the recommended test. However, whether TBI provides additional prognostic information beyond ABI in patients on hemodialysis is unknown., Methods: In this retrospective cohort study of 247 Japanese prevalent hemodialysis patients (mean age 66.8 [SD 11.6] years), we evaluated mortality (116 deaths over a median follow-up of 5.2 years) related to quartiles of ABI and TBI, as well as three categories of low ABI (≤0.9), normal/high ABI (> 0.9) + low TBI (≤0.6), and normal/high ABI + normal TBI (> 0.6) using multivariable Cox models., Results: ABI showed a J-shaped association with mortality (adjusted hazard ratio 2.72 [95% CI, 1.52-4.88] in the lowest quartile and 1.59 [95% CI, 0.87-2.90] in the highest quartile vs. the second highest). Lower TBI showed a potentially dose-response association with mortality (e.g., adjusted hazard ratios 2.63 [95% CI, 1.36-5.12] and 2.89 [95% CI, 1.49-5.61] in the lowest two quartiles vs. the highest). When three categories by both ABI and TBI were analyzed, those with low ABI (≤0.9) experienced the highest risk followed by normal/high ABI (> 0.9) + low TBI (≤0.6). Among patients with normal/high ABI (> 0.9), the increased mortality risk in individuals with low TBI (≤0.6) compared to those with normal TBI (> 0.6) were significant (adjusted hazard ratio 1.84 [95% CI, 1.12-3.02])., Conclusions: Lower TBI was independently associated with mortality in patients on hemodialysis and has the potential to classify mortality risk in patients with normal/high ABI. Our results support the importance of evaluating TBI in addition to ABI in this clinical population.

Background: Sodium bicarbonate, in the form of baking soda, is widely used as a home remedy, and as an additive for personal and household cleaning products. Its toxicity has previously been reported following oral ingestion in the setting of dyspepsia. However, its use as a non-ingested agent, like a toothpaste additive, has not been reported as a potential cause of toxicity., Case Presentation: We are reporting a case of an 80-year-old woman who presented with chronic metabolic alkalosis and hypokalemia secondary to exogenous alkali exposure from baking soda as a toothpaste additive, which might have represented an underreported ingestion of the substance., Conclusions: Considering that one teaspoon of baking soda provides approximately 59 m-equivalents (mEq) of bicarbonate, specific questioning on its general use should be pursued in similar cases of chloride resistant metabolic alkalosis.

Competing Interests: All authors have nothing to disclose.

Background: Acceptance of organs from acute chemical intoxicated donors remains controversial and outcomes are insufficiently explored., Methods: This is a single-center retrospective cohort analysis of 484 patients undergoing deceased donor kidney transplantation (DDKT). We assessed the association of positive urine drug screen before transplantation with cohort statistics, delayed graft function (DGF), and graft outcomes at 2 years. Multiple logistical regression (MLR) analysis was used to assess the odds ratio for DGF., Results: Of 484 random DDKTs performed at our institution between January 2010 and October 2015, 280 deceased kidney donors were current drug users. Mean age was 35.4 (15) years, 39% male, 61% were African Americans, and 38.2% had more than one test positive. The main chemical toxins detectable in donor urine were alcohol, heroin, opioid/methadone, cocaine, marijuana, benzodiazepines, methamphetamine, ecstasy, and LSD. Single and multiple urine chemical toxicology of kidney donors did not have a significant effect on KT outcomes of DGF and graft failure during a median follow-up (P for odds ratios > 0.05)., Conclusions: The use of deceased donor kidney grafts from donors with positive urine chemical toxicology may be a worthwhile method of increasing the availability of scarce donor kidney organs as such exposure to illicit drug(s) is not associated with major adverse transplant outcomes.

Purpose of Review: Serum creatinine and urine output continue to be the mainstays of diagnosis of acute kidney injury, though both of these measures have significant limitations, especially in acutely hospitalized patients. Biomarkers in both blood and urine have been studied extensively in the research setting and are on the verge of clinical practice to improve diagnosis of AKI., Recent Findings: Blood and urine biomarkers can be localized to specific areas or functions within the nephron. Biomarkers can help to characterize glomerular or tubular function; glomerular, tubular, or interstitial injury; inflammation; or repair. Further, biomarkers can improve diagnosis of AKI in various clinical settings including acute interstitial nephritis, acute tubular injury, and hepatorenal syndrome, and cardiorenal syndrome., Summary: Biomarkers are becoming more prevalent in both research and getting close to clinical use. Both blood and urine biomarkers can help to localize impairment in nephron health by either location or function within the nephron and among various causes of AKI.

Point-of-care ultrasound (POCUS) is rapidly emerging as a bedside diagnostic tool that can enhance physical diagnosis and facilitate clinical decision making. Although ultrasound is widely used by nephrologists for vascular access and kidney imaging, diagnostic POCUS skills in other anatomic areas are not part of routine nephrology training. In this narrative review, we will provide an overview of selected POCUS techniques, highlight potential uses of POCUS in routine nephrology practice, and describe a new curriculum implemented at Johns Hopkins University School of Medicine to teach diagnostic POCUS skills to nephrology fellows., (© 2018 Wiley Periodicals, Inc.)

Objectives and Methods: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant., Results: On an adjusted multiple logistic regression, a single 100 mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6 h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6 h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of <600 mls at 6 h with a sensitivity of and a specificity of 83% and 74%, respectively., Conclusions: The FST is a predictor of DGF post kidney transplant and has the potential to identify patients requiring RRT early after KT.