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Rationale & Objective: We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD)., Study Design: Prespecified subcohort analysis of a randomized controlled trial., Setting & Participants: A substudy of the STOP Gout Trial in participants with CKD. CKD was defined as an estimated glomerular filtration rate (eGFR) 30-59mL/min/1.73m 2 at baseline., Exposure: Trial participants with CKD and gout and serum urate (SUA) concentration of≥6.8mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate-lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal SUA of<6.0mg/dL (<5.0mg/dL with tophi) (phase 1) and maintained during weeks 25-48 (phase 2). Gout flare was assessed between weeks 49-72 (phase 3)., Outcome: Gout flare between weeks 49-72 (phase 3) was the primary outcome. Secondary outcomes included SUA goal achievement and ULT dosing at end of phase 2, and serious adverse events., Analytical Approach: Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm., Results: CKD was present in 351 of 940 participants; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; P=0.02) despite similar attainment of the SUA goal (79% vs 81%; P=0.6) by the end of phase 2. Acute kidney injury was more common in participants with stage 3 CKD randomized to allopurinol compared with febuxostat., Limitations: Limited power to assess infrequent safety events, largely male, older population., Conclusions: Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen with lower incidence of gout flares in participants randomized to allopurinol., Plain-Language Summary: The STOP Gout Trial was a multicenter, randomized, double-blind, noninferiority, comparative effectiveness trial, which found that allopurinol was noninferior to febuxostat in gout flare prevention and that both medications were similarly efficacious in reaching a serum urate goal when used as part of a treat-to-target approach. A significant proportion of patients with chronic kidney disease (CKD) are afflicted by gout, yet there is a lack of high-quality comparative effectiveness data comparing allopurinol and febuxostat in these patients. We evaluated the efficacy and safety of allopurinol and febuxostat in the subgroup of STOP Gout Trial participants with stage 3 CKD and found that allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen, with lower incidence of gout flares in participants randomized to allopurinol., (Published by Elsevier Inc.)

Objective: Initiating urate-lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat-to-target strategy with optimal anti-inflammatory prophylaxis., Methods: This was a post-hoc analysis of a 72-week randomized, double-blind, placebo-controlled, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression., Results: Study participants (n = 940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti-inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (hazard ratio [HR] 1.17; febuxostat vs allopurinol), ULT-dose escalation (HR 1.18 vs no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT-dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi., Conclusion: These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat-to-target strategy using gradual ULT-dose titration and best practice gout flare prophylaxis., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Continuous kidney replacement therapy (CKRT) is commonly used to manage critically ill patients with severe acute kidney injury. While recent trials focused on the correct dosing and timing of CKRT, our understanding regarding the optimum dose of net ultrafiltration is limited to retrospective data. The Restrictive versus Liberal Rate of Extracorporeal Volume Removal Evaluation in Acute Kidney Injury (RELIEVE-AKI) trial has been conducted to assess the feasibility of a prospective randomized trial in determining the optimum net ultrafiltration rate. This paper outlines the relevant challenges and solutions in implementing this complex ICU-based trial. Several difficulties were encountered, starting with clinical issues related to conducting a trial on patients with rapidly changing hemodynamics, low patient recruitment rates, increased nursing workload, and the enormous volume of data generated by patients undergoing prolonged CKRT. Following several brainstorming sessions, several points were highlighted to be considered, including the need to streamline the intervention, add more flexibility in the trial protocols, ensure comprehensive a priori planning, particularly regarding nursing roles and their compensation, and enhance data management systems. These insights are critical for guiding future ICU-based dynamically titrated intervention trials, leading to more efficient trial management, improved data quality, and enhanced patient safety., Competing Interests: Declaration of competing interest RM, KK, and PMP filed an international patent application for the method of fluid removal described herein (Patent no. PCT/US2023/012204). RM received research grants from NIDDK and consulting fees from Baxter Inc., AM Pharma Inc., Bioporto Inc., and La Jolla Inc., which are unrelated to this study. KK received research grants NIDDK and from, Philips Research North America, and Google, a speaker honorarium from Nikkiso Critical Care Medical Supplies (Shanghai) Co., Ltd., and consulting fees to Mayo Clinic and from Baxter Inc.; PMP received consulting fees and advisory committee fees from Durect, Health-Span Dx, and Novartis; served on a Data and Safety Monitoring Board for Baxter; served as a member of an endpoint adjudication committee for GE Healthcare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Advanced kidney disease is a progressive life-limiting illness associated with high symptom burden, disability, and highly intensive care near the end of life. There is growing interest in integrating palliative care principles into the care of patients with advanced kidney disease to improve care and outcomes for these patients. The United States (US) Department of Veterans Affairs (VA) has been a leader in advancing palliative care initiatives across its health system and whose experience and approach may be instructive to other health systems seeking to develop kidney palliative care (KPC) services. Herein, we review current KPC programs in the VA and highlight the different models of care that programs have been adopted and how key components of goals of care conversations and advance care planning, symptom management, multidisciplinary care, patient selection, and quality improvement have been implemented across programs. VA KPC programs have adopted "parallel", "merged", and "embedded" models of KPC that reflect the different configurations of partnerships between nephrology and palliative care providers to deliver KPC. A primary service of VA KPC programs is providing goals of care conversations and advance care planning to referred patients and systematically documenting the outcomes of these discussions in standardized note templates in the electronic medical record. Symptom management is delivered by KPC providers through regular shared or sequential visits with patients' nephrology providers and is guided by patient responses to validated symptom surveys. Programs are staffed by allied health professionals, such as chaplains, pharmacists, social workers, and dieticians, to provide whole-person care and regularly huddle with nephrology staff to reach a shared understanding of each patient's care needs and plan. KPC programs implement champions who select patients in greatest need of KPC using a combination of clinical events that trigger referral for KPC and validated mortality risk prediction scores that are automatically generated in each patient's medical record. KPC programs also routinely collect clinical, patient-reported, process, and care quality measures to assess its services. The experiences of the VA highlight novel approaches that strive to close the care gaps in meeting the KPC needs of patients with advanced kidney disease.

Objective: Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement., Methods: Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence., Results: Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence., Conclusions: Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout., (© 2023 American College of Rheumatology.)

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: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI)., Methods: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization., Results: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94)., Conclusions: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale & Objective: Creatinine-based GFR estimating (eGFRcr) equations may be inaccurate in populations with acute or chronic illness. The accuracy of GFR equations that use cystatin C (eGFRcys) or creatinine-cystatin C (eGFRcr-cys) is not well studied in these populations., Study Design: A systematic review of original articles identified from PubMed and expert sources. Two reviewers screened articles independently and identified those meeting inclusion criteria., Setting & Study Populations: Adults and children with acute or chronic illness., Selection Criteria for Studies: Studies published since 2011 that compared performance of eGFRcr, eGFRcys, and eGFRcr-cys relative to measured GFR (mGFR), used standardized assays for creatinine or cystatin C, and used eGFR equations developed using such assays. Studies of ambulatory clinical populations or research studies in populations with only CKD, kidney transplant recipients, only diabetes, kidney donor candidates, and community-based cohorts were excluded., Data Extraction: Data extracted from full text., Analytical Approach: Bias and percentages of estimates within 30% of mGFR (P 30 ) of eGFR compared with mGFR were evaluated., Results: Of the 179 citations, 26 studies met the inclusion criteria: 24 in adults and 2 in children in clinical populations with cancer (n=5), HIV (n=5), cirrhosis (n=3), liver transplant (n=3), heart failure (n=2), neuromuscular diseases (n=1) critical illness (n=5), and obesity (n=2). In general, eGFRcr-cys had greater accuracy than eGFRcr or eGFRcys equations among study populations with cancer, HIV, and obesity, but did not perform consistently better in cirrhosis, liver transplant, heart failure, neuromuscular disease, and critical illness., Limitations: Participants were selected because of concern for inaccurate eGFRcr, which may bias results. Most studies had small sample sizes, limiting generalizability., Conclusions: eGFRcr-cys improves GFR estimation in populations with a variety of acute and chronic illnesses, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent mGFR., Plain-Language Summary: Kidney function, specifically glomerular filtration rate (GFR), estimated using creatinine (eGFRcr) is often inaccurate in people with acute and chronic illness. The accuracy of estimates using cystatin C alone (eGFRcys) or together with creatinine (eGFRcr-cys) is not well studied in these populations. We conducted a systematic review to address the knowledge gap. Of the 179 papers reviewed, we identified 26 studies in clinical populations with cancer (n=5); HIV (n=5); cirrhosis (n=3); liver transplant (n=3); heart failure (n=2); neuromuscular disease (n=1); critical illness (n=5); and obesity (n=2). In general, eGFRcr-cys improved the GFR estimation in HIV, cancer, and obesity, providing indications for cystatin C measurement. Performance was poor in many studies, suggesting the need for more frequent measured GFR., (© 2023 The Authors.)

Kidney health advocacy organizations and leaders in the nephrology community have repeatedly emphasized the need to increase home dialysis utilization in the United States. Limited awareness and understanding of options for the management of kidney failure among patients living with advanced CKD is a significant barrier to increasing the selection and use of home dialysis. Studies have shown that providing targeted comprehensive patient education before the onset of kidney failure can improve patients' awareness of kidney disease and substantially increase the informed utilization of home dialysis. Unfortunately, in the absence of validated evidence-based education protocols, outcomes associated with home dialysis use vary widely among published studies, potentially affecting the routine implementation and reporting of these services among patients with advanced CKD. This review provides pragmatic guidance on establishing effective patient-centered education programs to empower patients to make informed decisions about their KRT and, in turn, increase home dialysis use., (Copyright © 2023 by the American Society of Nephrology.)

Background: Contrast-associated acute kidney injury (CA-AKI) has been associated with a higher risk of cardiovascular (CV) events. We studied the risk of CV events in chronic kidney disease (CKD) patients undergoing angiography and whether biomarkers can predict such events. We also explored whether CA-AKI mediates the association of pre-angiography estimated glomerular filtration rate (eGFR) on CV events., Methods: We analysed participants from the Prevention of Serious Adverse Events following the Angiography (PRESERVE) trial. Urinary tissue inhibitor of matrix metalloproteinase [TIMP]-2 and insulin growth factor binding protein [IGFBP]-7, plasma brain-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hs-CRP), and serum cardiac troponin-I (Tn-I) were assayed before and after angiography. We assessed the composite risk of CV events by day 90., Results: Of the 922 participants, 119 (12.9%) developed CV events, and 73 (7.9%) developed CA-AKI. Most cases of CA-AKI (90%) were stage 1. There were no differences in urinary [TIMP-2]•[IGFBP7] concentrations or the proportion of patients with CA-AKI among those with and without CV events. Higher BNP, Tn-I, and hs-CRP were associated with CV events, but their discriminatory capacity was modest (AUROC <0.7). CA-AKI did not mediate the association of the pre-angiography eGFR on CV events., Conclusions: Most episodes of CA-AKI are stage 1 AKI and are not associated with CV events. Less severe CA-AKI episodes also did not mediate the risk of pre-angiography eGFR on CV events. Our findings suggest that most CV events after contrast procedures are due to underlying CKD and CV risk factors rather than less severe CA-AKI episodes and should help enhance the utilization of clinically indicated contrast procedures among high-risk patients with CKD. Further research is required to examine whether moderate-to-severe CA-AKI episodes are associated with CV events., Competing Interests: R.M. reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases and consulting fees from Baxter Inc unrelated to this study. P.M.P. received consulting fees and advisory committee fees from Durect, Health-Span Dx, and Novartis; served on a Data and Safety Monitoring Board for Baxter; served as a member of an endpoint adjudication committee for GE Healthcare; and reports receiving grants from BioPorto and Dascena outside the submitted work. S.W. has received consulting fees and advisory fees from Durect and Saghmos Therapeutics and reports receiving personal fees from Cytokinetics and Saghmos Therapeutics outside the submitted work. J.A.K. has received grant support and/or consulting fees from Astute Medical/BioMerieux, and GE Healthcare outside the submitted work. M. Kelly has nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated. Co-expression network analysis of the endothelial genes yielded three gene set modules as significantly associated with arteriolar hyalinosis. Pathway analysis of these modules showed enrichment of transforming growth factor beta / bone morphogenetic protein (TGFβ / BMP) and vascular endothelial growth factor (VEGF) signaling pathways in the endothelial cell signatures. Ligand-receptor analysis identified multiple integrins and cell adhesion receptors as over-expressed in arteriolar hyalinosis, suggesting a potential role of integrin-mediated TGFβ signaling. Further analysis of arteriolar hyalinosis associated endothelial module genes identified focal segmental glomerular sclerosis as an enriched term. On validation in gene expression profiles from the Nephrotic Syndrome Study Network cohort, one of the three modules was significantly associated with the composite endpoint (> 40% reduction in estimated glomerular filtration rate (eGFR) or kidney failure) independent of age, sex, race, and baseline eGFR, suggesting poor prognosis with elevated expression of genes in this module. Thus, integration of structural and single cell molecular features yielded biologically relevant gene sets, signaling pathways and ligand-receptor interactions, underlying arteriolar hyalinosis and putative targets for therapeutic intervention.

Introduction: Observational studies have linked slower and faster net ultrafiltration (UF NET ) rates during kidney replacement therapy (KRT) with mortality in critically ill patients with acute kidney injury (AKI) and fluid overload. To inform the design of a larger randomised trial of patient-centered outcomes, we conduct a feasibility study to examine restrictive and liberal approaches to UF NET during continuous KRT (CKRT)., Methods and Analysis: This study is an investigator-initiated, unblinded, 2-arm, comparative-effectiveness, stepped-wedged, cluster randomised trial among 112 critically ill patients with AKI treated with CKRT in 10 intensive care units (ICUs) across 2 hospital systems. In the first 6 months, all ICUs started with a liberal UF NET rate strategy. Thereafter, one ICU is randomised to the restrictive UF NET rate strategy every 2 months. In the liberal group, the UF NET rate is maintained between 2.0 and 5.0 mL/kg/hour; in the restrictive group, the UF NET rate is maintained between 0.5 and 1.5 mL/kg/hour. The three coprimary feasibility outcomes are (1) between-group separation in mean delivered UF NET rates; (2) protocol adherence; and (3) patient recruitment rate. Secondary outcomes include daily and cumulative fluid balance, KRT and mechanical ventilation duration, organ failure-free days, ICU and hospital length of stay, hospital mortality and KRT dependence at hospital discharge. Safety endpoints include haemodynamics, electrolyte imbalance, CKRT circuit issues, organ dysfunction related to fluid overload, secondary infections and thrombotic and haematological complications., Ethics and Dissemination: The University of Pittsburgh Human Research Protection Office approved the study, and an independent Data and Safety Monitoring Board monitors the study. A grant from the United States National Institute of Diabetes and Digestive and Kidney Diseases sponsors the study. The trial results will be submitted for publication in peer-reviewed journals and presented at scientific conferences., Trial Registration Number: This trial has been prospectively registered with clinicaltrials.gov (NCT05306964). Protocol version identifier and date: 1.5; 13 June 2023., Competing Interests: Competing interests: RM received research grants from NIDDK, consulting fees from Baxter, AM Pharma, Bioporto and La Jolla unrelated to this study; DTH received grants from NIH. KK received research grants NIDDK and from Philips Research North America and Google, speaker honorarium from Nikkiso Critical Care Medical Supplies (Shanghai) and consulting fees to Mayo Clinic and from Baxter; PMP received consulting fees and advisory committee fees from Durect, Health-Span Dx and Novartis; served on a Data and Safety Monitoring Board for Baxter; served as a member of an endpoint adjudication committee for GE Healthcare; and CCH, MR and NN has nothing to disclose., (© 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.)

Background: Kidney disease (KD) is an important health equity issue with Black, Hispanic, and socioeconomically disadvantaged individuals experiencing a disproportionate disease burden. Prior to 2021, the commonly used estimated glomerular filtration rate (eGFR) equations incorporated coefficients for Black race that conferred higher GFR estimates for Black individuals compared to non-Black individuals of the same sex, age, and blood creatinine concentration. With a recognition that race does not delineate distinct biological categories, a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the CKD-EPI 2021 race-agnostic equations., Content: This document provides guidance on implementation of the CKD-EPI 2021 equations. It describes recommendations for KD biomarker testing, and opportunities for collaboration between clinical laboratories and providers to improve KD detection in high-risk populations. Further, the document provides guidance on the use of cystatin C, and eGFR reporting and interpretation in gender-diverse populations., Summary: Implementation of the CKD-EPI 2021 eGFR equations represents progress toward health equity in the management of KD. Ongoing efforts by multidisciplinary teams, including clinical laboratorians, should focus on improved disease detection in clinically and socially high-risk populations. Routine use of cystatin C is recommended to improve the accuracy of eGFR, particularly in patients whose blood creatinine concentrations are confounded by processes other than glomerular filtration. When managing gender-diverse individuals, eGFR should be calculated and reported with both male and female coefficients. Gender-diverse individuals can benefit from a more holistic management approach, particularly at important clinical decision points., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations., (© 2023. The Author(s).)

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.)

The selection of modality of kidney replacement therapy (KRT) has been debated for decades. Although the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury considers intermittent hemodialysis and continuous KRT (CKRT) to be complementary therapies, with a recommendation to preferably use CKRT in hemodynamically unstable patients, there is a vocal cadre of practitioners and investigators who argue that CKRT is the only modality that should be used to support critically ill patients with AKI, relying on observational data to argue that intermittent hemodialysis is associated with impaired recovery of kidney function. In this issue of CJASN , we have provided a virtual debate allowing advocates for and against the use of intermittent hemodialysis to make their best cases. In the end, their arguments converge, with a call for more data and a pragmatic, patient-focused approach to the delivery of KRT to critically ill patients with AKI., (Copyright © 2023 by the American Society of Nephrology.)

Significance Statement: Of studies reporting an association of CKD with lower use of invasive cardiac care to treat acute coronary syndrome (ACS), just one accounted for the appropriateness of such care. However, its findings in patients hospitalized nearly 30 years ago may not apply to current practice. In a more recent cohort of 64,695 veterans hospitalized with ACS, CKD was associated with a 32% lower likelihood of receiving invasive care determined to be clinically indicated. Among patients with CKD, not receiving such care was associated with a 1.39-fold higher risk of 6-month mortality. Efforts to elucidate the reasons for this disparity in invasive care in patients with ACS and CKD and implement tailored interventions to enhance its use in this population may offer the potential to improve clinical outcomes., Background: Previous studies have shown that patients with CKD are less likely than those without CKD to receive invasive care to treat acute coronary syndrome (ACS). However, few studies have accounted for whether such care was clinically indicated or assessed whether nonuse of such care was associated with adverse health outcomes., Methods: We conducted a retrospective cohort study of US veterans who were hospitalized at Veterans Affairs Medical Centers from January 2013 through December 2017 and received a discharge diagnosis of ACS. We used multivariable logistic regression to investigate the association of CKD with use of invasive care (coronary angiography, with or without revascularization; coronary artery bypass graft surgery; or both) deemed clinically indicated based on Global Registry of Acute Coronary Events 2.0 risk scores that denoted a 6-month predicted all-cause mortality ≥5%. Using propensity scoring and inverse probability weighting, we examined the association of nonuse of clinically indicated invasive care with 6-month all-cause mortality., Results: Among 34,430 patients with a clinical indication for invasive care, the 18,780 patients with CKD were less likely than the 15,650 without CKD to receive such care (adjusted odds ratio, 0.68; 95% confidence interval, 0.65 to 0.72). Among patients with CKD, nonuse of invasive care was associated with higher risk of 6-month all-cause mortality (absolute risk, 21.5% versus 15.5%; absolute risk difference 6.0%; adjusted risk ratio, 1.39; 95% confidence interval, 1.29 to 1.49). Findings were consistent across multiple sensitivity analyses., Conclusions: In contemporary practice, veterans with CKD who experience ACS are less likely than those without CKD to receive clinically indicated invasive cardiac care. Nonuse of such care is associated with increased mortality., (Copyright © 2023 by the American Society of Nephrology.)

Rationale & Objective: Recent studies in patients with chronic kidney disease (CKD) indicate that most cases of contrast-associated acute kidney injury (CA-AKI) are mild and are not associated with elevation in kidney injury biomarkers. We used highly sensitive kidney cell cycle arrest and cardiac biomarkers to assess the risk of CA-AKI and major adverse kidney events in patients with CKD undergoing angiography., Study Design: A retrospective study., Setting & Participants: A subset of 922 participants from the Prevention of Serious Adverse Events following Angiography trial., Predictors: Pre- and postangiography urinary tissue inhibitor of matrix metalloproteinase [TIMP]-2 and insulin growth factor binding protein [IGFBP]-7 were measured in 742 subjects, and plasma β natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP), and serum troponin (Tn) in 854 participants using samples obtained 1-2 hours before and 2-4 hours after angiography., Outcomes: CA-AKI and major adverse kidney events., Analytical Approach: We fitted logistic regression to examine association and area under the receiver operating characteristic curves for risk prediction., Results: There were no differences in postangiography urinary [TIMP-2]•[IGFBP7], plasma BNP, serum Tn, and hs-CRP concentrations among patients with and without CA-AKI and major adverse kidney events. However, higher pre- and postangiography median plasma BNP (pre: 200.0 vs 71.5, pg/mL, P   =  0.05; post: 165.0 vs 81 pg/mL, P   =  0.02); serum Tn (pre: 0.03 vs 0.01, ng/mL, P  < 0.001; post, 0.04 vs 0.02, ng/mL, P   =  0.01); and hs-CRP (pre: 9.55 vs 3.40 mg/L, P   =  0.01; post: 9.90 vs 3.20 mg/L, P   =  0.002) concentrations were associated with major adverse kidney events, although their discriminatory capacity was only modest (area under the receiver operating characteristic curves <0.7)., Limitations: Most participants were men., Conclusions: Most mild CA-AKI cases are not associated with urinary cell cycle arrest biomarker elevation. Significant elevation in preangiography cardiac biomarkers may reflect patients with more significant cardiovascular disease that may predispose to poor long-term outcomes independent of CA-AKI status., (© 2022 The Authors.)

Background: Among critically ill patients with acute kidney injury (AKI), earlier initiation of renal replacement therapy (RRT) may mitigate fluid accumulation and confer better outcomes among individuals with greater fluid overload at randomization., Methods: We conducted a pre-planned post hoc analysis of the STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. We evaluated the effect of accelerated RRT initiation on cumulative fluid balance over the course of 14 days following randomization using mixed models after censoring for death and ICU discharge. We assessed the modifying effect of baseline fluid balance on the impact of RRT initiation strategy on key clinical outcomes. Patients were categorized in quartiles of baseline fluid balance, and the effect of accelerated versus standard RRT initiation on clinical outcomes was assessed in each quartile using risk ratios (95% CI) for categorical variables and mean differences (95% CI) for continuous variables., Results: Among 2927 patients in the modified intention-to-treat analysis, 2738 had available data on baseline fluid balance and 2716 (92.8%) had at least one day of fluid balance data following randomization. Over the subsequent 14 days, participants allocated to the accelerated strategy had a lower cumulative fluid balance compared to those in the standard strategy (4509 (- 728 to 11,698) versus 5646 (0 to 13,151) mL, p = 0.03). Accelerated RRT initiation did not confer greater 90-day survival in any of the baseline fluid balance quartiles (quartile 1: RR 1.11 (95% CI 0.92 to 1.34), quartile 2: RR 1.03 (0.87 to 1.21); quartile 3: RR 1.08 (95% CI 0.91 to 1.27) and quartile 4: RR 0.87 (95% CI 0.73 to 1.03), p value for trend 0.08)., Conclusions: Earlier RRT initiation in critically ill patients with AKI conferred a modest attenuation of cumulative fluid balance. Nonetheless, among patients with greater fluid accumulation at randomization, accelerated RRT initiation did not have an impact on all-cause mortality., Trial Registration: ClinicalTrials.gov number, https://clinicaltrials.gov/ct2/show/NCT02568722 , registered October 6, 2015., (© 2022. The Author(s).)

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: General severity of illness scores are not well calibrated to predict mortality among patients receiving renal replacement therapy (RRT) for acute kidney injury (AKI). We developed machine learning models to make mortality prediction and compared their performance to that of the Sequential Organ Failure Assessment (SOFA) and HEpatic failure, LactatE, NorepInephrine, medical Condition, and Creatinine (HELENICC) scores. Methods: We extracted routinely collected clinical data for AKI patients requiring RRT in the MIMIC and eICU databases. The development models were trained in 80% of the pooled dataset and tested in the rest of the pooled dataset. We compared the area under the receiver operating characteristic curves (AUCs) of four machine learning models (multilayer perceptron [MLP], logistic regression, XGBoost, and random forest [RF]) to that of the SOFA, nonrenal SOFA, and HELENICC scores and assessed calibration, sensitivity, specificity, positive (PPV) and negative (NPV) predicted values, and accuracy. Results: The mortality AUC of machine learning models was highest for XGBoost (0.823; 95% confidence interval [CI], 0.791−0.854) in the testing dataset, and it had the highest accuracy (0.758). The XGBoost model showed no evidence of lack of fit with the Hosmer−Lemeshow test (p > 0.05). Conclusion: XGBoost provided the highest performance of mortality prediction for patients with AKI requiring RRT compared with previous scoring systems.

Patients with chronic kidney disease (CKD) are at an increased risk of developing cardiovascular disease (CVD), whereas those with established CVD are at risk of incident or progressive CKD. Compared with individuals with normal or near normal kidney function, there are fewer data to guide the management of patients with CVD and CKD. As a joint effort between the National Kidney Foundation and the Society for Cardiovascular Angiography and Interventions, a workshop and subsequent review of the published literature was held. The present document summarizes the best practice recommendations of the working group and highlights areas for further investigation.