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

In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development., (© 2022. The Author(s).)

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients., (Published by Elsevier Inc.)

Background: Genetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury., Methods: Using liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology., Results: In human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1., Conclusions: These results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: We appreciate receiving BAC/APOL1 mice from Merck, Kenilworth, NJ. We appreciate receiving APOL1 antibodies from Genentech, South San Francisco, CA. Dr. Ian de Boer reports consulting fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Cyclerion Therapeutics, George Clinical, Gilead, Goldfinch Bio, and Ironwood. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Interested researchers are able to obtain BAC/APOL1 mice from Merck (contact is Lisa Gentile), APOL1 antibodies from Genentech (contact is Suzie Scales, PhD), and Alb/APOL1 transgenic mice from NIDDK, NIH (contact is Jeffrey Kopp, MD), under an appropriate material transfer agreement.

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of the kidney following its physiological functions and link cell subtypes to genes, proteins, metabolites, and pathways. They further show that messenger RNA levels along the nephron are congruent with the subsegmental physiological activity. This reference atlas provides a framework for the classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

Nephrotoxicity testing is an important step in preclinical development of new molecular entities (NMEs) and has traditionally been performed in 2-D cell culture systems and animal models. However, 2-D culture systems fail to replicate complex in vivo microenvironment and animal models face interspecies differences including the overexpression of drug transporters. In the last decade, 3-D microphysiological systems (MPS) have been developed to address these concerns. Here, we review recent advancements in kidney MPS and their application in drug-induced toxicity testing and kidney disease research. We find that current research is making significant progress addressing MPS limitations such as throughput, incorporating various regions of the nephron such as the glomerulus, and successfully modeling and predicting clinically relevant nephrotoxicity of current and new drugs., Competing Interests: Declaration of interests Edward J. Kelly & Catherine K. Yeung are consultants for Nortis, Inc., Woodinville, WA.

Background: Portable hemodialysis has the potential to improve health outcomes and quality of life for patients with kidney failure at reduced costs. Urea removal, required for dialysate regeneration, is a central function of any existing/potential portable dialysis device. Urea in the spent dialysate coexists with non-urea uremic toxins, nutrients, and electrolytes, all of which will interfere with the urea removal efficiency, regardless of whether the underlying urea removal mechanism is based on urease conversion, direct urea adsorption, or oxidation. The aim of the current review is to identify the amount of the most prevalent chemicals being removed during a single dialysis session and evaluate the potential benefits of an urea-selective membrane for portable dialysis., Methods: We have performed a literature search using Web of Science and PubMed databases to find available articles reporting (or be able to calculate from blood plasma concentration) > 5 mg of individually quantified solutes removed during thrice-weekly hemodialysis sessions. If multiple reports of the same solute were available, the reported values were averaged, and the geometric mean of standard deviations was taken. Further critical literature analysis of reported dialysate regeneration methods was performed using Web of Science and PubMed databases., Results: On average, 46.0 g uremic retention solutes are removed in a single conventional dialysis session, out of which urea is only 23.6 g. For both urease- and sorbent-based urea removal mechanisms, amino acids, with 7.7 g removal per session, could potentially interfere with urea removal efficiency. Additionally for the oxidation-based urea removal system, plentiful nutrients such as glucose (24.0 g) will interfere with urea removal by competition. Using a nanofiltration membrane between dialysate and oxidation unit with a molecular weight cutoff (MWCO) of ~200 Da, 67.6 g of non-electrolyte species will be removed in a single dialysis session, out of which 44.0 g are non-urea molecules. If the membrane MWCO is further decreased to 120 Da, the mass of non-electrolyte non-urea species will drop to 9.3 g. Reverse osmosis membranes have been shown to be both effective at blocking the transport of non-urea species (creatinine for example with ~90% rejection ratio), and permissive for urea transport (~20% rejection ratio), making them a promising urea selective membrane to increase the efficiency of the oxidative urea removal system., Conclusions: Compiled are quantified solute removal amounts greater than 5 mg per session during conventional hemodialysis treatments, to act as a guide for portable dialysis system design. Analysis shows that multiple chemical species in the dialysate interfere with all proposed portable urea removal systems. This suggests the need for an additional protective dialysate loop coupled to urea removal system and an urea-selective membrane., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: The kidneys efficiently filter waste products while retaining serum proteins in the circulation. However, numerous diseases compromise this barrier function, resulting in spillage of serum proteins into the urine (proteinuria). Some studies of glomerular filtration suggest that tubules may be physiologically exposed to nephrotic-range protein levels. Therefore, whether serum components can directly injure the downstream tubular portions of the kidney, which in turn can lead to inflammation and fibrosis, remains controversial., Methods: We tested the effects of serum protein exposure in human kidney tubule microphysiologic systems and with orthogonal epigenomic approaches since animal models cannot directly assess the effect of serum components on tubules., Results: Serum, but not its major protein component albumin, induced tubular injury and secretion of proinflammatory cytokines. Epigenomic comparison of serum-injured tubules and intact kidney tissue revealed canonical stress-inducible regulation of injury-induced genes. Concordant transcriptional changes in microdissected tubulointerstitium were also observed in an independent cohort of patients with proteinuric kidney disease., Conclusions: Our results demonstrate a causal role for serum proteins in tubular injury and identify regulatory mechanisms and novel pathways for intervention., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: Biomarkers of acute kidney injury (AKI) are often indexed to urine creatinine (UCr) or urine osmolarity (UOsm) to control for urine concentration. We evaluated how these approaches affect the biomarker-outcome association in patients with AKI., Methods: The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Study was a cohort of hospitalized patients with and without AKI between 2009 and 2015. Using Cox proportional hazards regression, we assessed the associations and predictions (C-statistics) of urine biomarkers with a composite outcome of incident chronic kidney disease (CKD) and CKD progression. We used 4 approaches to account for urine concentration: indexing and adjusting for UCr and UOsm., Results: Among 1538 participants, 769 (50%) had AKI and 300 (19.5%) developed composite CKD outcome at median follow-up of 4.7 years. UCr and UOsm during hospitalization were inversely associated with the composite CKD outcome. The associations and predictions with CKD were significantly strengthened after indexing or adjusting for UCr or UOsm for urine kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) in patients with AKI. There was no significant improvement with indexing or adjusting UCr or UOsm for albumin, neutrophil gelatinase-associated lipocalin (NGAL), and chitinase 3-like 1 (YKL-40). Uromodulin's (UMOD) inverse association with the outcome was significantly blunted after indexing but not adjusting for UCr or UOsm., Conclusion: UCr and UOsm during hospitalization are inversely associated with development and progression of CKD. Indexing or adjusting for UCr or UOsm strengthened associations and improved predictions for CKD for only some biomarkers. Incorporating urinary concentration should be individualized for each biomarker in research and clinical applications., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

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

The use of cyclosporine A (CsA) in transplantation is frequently associated with nephrotoxicity, characterized by renal vascular injury, thrombotic microangiopathy, and striped interstitial fibrosis. Here, using human kidney-specific microvascular endothelial cells (HKMECs), we showed that CsA inhibited NFAT1 activation and impaired VEGF signaling in these ECs in a dose- and time-dependent manner. Integrated genome regulatory analyses identified key distinctions in the landscapes of HKMECs compared to human umbilical vein endothelial cells, particularly around genes related to the formation and maintenance of fenestrae. Using a bioengineered flow-directed 3D kidney microphysiological system, we revealed that CsA-induced kidney microvascular injury was associated with fenestrae and cell adhesion impairment, membrane swelling, and erythrocyte adhesion and extravasation into the interstitial space. Our data provide novel insights into kidney-specific molecular and structural mechanisms of CsA-induced microvascular injury. Our results also suggest VEGF-related pathways as potential targets for therapy during CsA treatment and emphasize the importance of leveraging species and organ-specific cells to better reflect human pathophysiology and the response to injury.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) may induce systemic inflammation, a common condition in chronic kidney disease (CKD), by acting as a damage-associated molecular pattern. We hypothesized that in patients with moderate to severe CKD, aerobic exercise would reduce ccf-mtDNA levels. We performed a post hoc analysis of a multicenter randomized trial (NCT01150851) measuring plasma concentrations of ccf-mtDNA at baseline and 2 and 4 mo after aerobic exercise and caloric restriction. A total of 99 participants had baseline ccf-mtDNA, and 92 participants completed the study. The median age of the participants was 57 yr, 44% were female and 55% were male, 23% had diabetes, and 92% had hypertension. After adjusting for demographics, blood pressure, body mass index, diabetes, and estimated glomerular filtration rate, median ccf-mtDNA concentrations at baseline, 2 mo, and 4 mo were 3.62, 3.08, and 2.78 pM for the usual activity group and 2.01, 2.20, and 2.67 pM for the aerobic exercise group, respectively. A 16.1% greater increase per month in ccf-mtDNA was seen in aerobic exercise versus usual activity ( P = 0.024), which was more pronounced with the combination of aerobic exercise and caloric restriction (29.5% greater increase per month). After 4 mo of intervention, ccf-mtDNA increased in the aerobic exercise group by 81.6% (95% confidence interval: 8.2-204.8, P = 0.024) compared with the usual activity group and was more marked in the aerobic exercise and caloric restriction group (181.7% increase, 95% confidence interval: 41.1-462.2, P = 0.003). There was no statistically significant correlation between markers of oxidative stress and inflammation with ccf-mtDNA. Our data indicate that aerobic exercise increased ccf-mtDNA levels in patients with moderate to severe CKD. NEW & NOTEWORTHY The effects of prolonged exercise on circulating cell-free mitochondrial DNA (ccf-mtDNA) have not been explored in patients with chronic kidney disease (CKD). We showed that 4-mo aerobic exercise is associated with an increase in plasma ccf-mtDNA levels in patients with stages 3 or 4 CKD. These changes were not associated with markers of systemic inflammation. Future studies should determine the mechanisms by which healthy lifestyle interventions influence biomarkers of inflammation and oxidative stress in patients with CKD.

The use of microphysiological systems (MPS) to support absorption, distribution, metabolism, and elimination (ADME) sciences has grown substantially in the last decade, in part driven by regulatory demands to move away from traditional animal-based safety assessment studies and industry desires to develop methodologies to efficiently screen and characterize drugs in the development pipeline. The past decade of MPS development has yielded great user-driven technological advances with the collective fine-tuning of cell culture techniques, fluid delivery systems, materials engineering, and performance enhancing modifications. The rapid advances in MPS technology have now made it feasible to evaluate critical ADME parameters within a stand-alone organ system or through interconnected organ systems. This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug ADME. Whereas some systems are more suitable for ADME type research than others, not all system designs were intended to meet the recently published desired performance criteria and are reported as a summary of initial proof-of-concept studies., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.

Unmet needs for small diameter, non-biologic vascular grafts and the less-than-ideal performance of medium diameter grafts suggest opportunities for major improvements. Biomaterials that are mechanically matched to native blood vessels, reduce the foreign body capsule (FBC) and demonstrate improved integration and healing are expected to improve graft performance. In this study, we developed biostable, crosslinked polyurethane formulations and used them to fabricate scaffolds with precision-engineered 40 μm pores. We matched the scaffold mechanical properties with those of native blood vessels by optimizing the polyurethane compositions. We hypothesized that such scaffolds promote healing and mitigate the FBC. To test our hypothesis, polyurethanes with 40 μm pores, 100 μm pores, and non-porous slabs were implanted subcutaneously in mice for 3 weeks, and then were examined histologically. Our results show that 40 μm porous scaffolds elicit the highest level of angiogenesis, cellularization, and the least severe foreign body capsule (based on a refined assessment method). This study presents the first biomaterial with tuned mechanical properties and a precision engineered porous structure optimized for healing, thus can be ideal for pro-healing vascular grafts and in situ vascular engineering. In addition, these scaffolds may have wide applications in tissue engineering, drug delivery, and implantable device., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned., Objective: To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study., Design, Setting, and Participants: The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants., Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation., Main Outcomes and Measures: In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis., Results: Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications., Conclusions and Relevance: The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CL r ) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CL r and systemic disposition of morphine and M6G, resulting in successful prediction of CL r and the plasma concentration-time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects., (© 2021. The Author(s).)

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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

Rationale & Objective: Apolipoprotein L1 ( APOL1 ) high-risk variants are associated with an increased risk for chronic kidney disease (CKD) among African Americans. Less is known regarding the risk for the development of CKD and kidney failure (end-stage kidney disease [ESKD]) among African Americans with only 1 APOL1 risk variant or whether the risk is modified by sickle cell trait., Study Design: The Jackson Heart Study is a community-based longitudinal cohort study., Setting & Participants: Self-reported African Americans in the Jackson Heart Study (n = 5,306)., Exposures: APOL1 G1 and G2 genotypes and sickle cell trait., Outcomes: Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 ), albuminuria (urinary albumin-creatinine ratio ≥ 30 mg/g), continuous and rapid kidney function decline (≥30% decline), and incident ESKD., Analytical Approach: Multivariable linear and logistic regression, and Cox proportional hazards models adjusted for age, sex, hypertension, diabetes, ancestry informative markers, and sickle cell trait., Results: Of 2,300 participants, 41.3% had zero, 45.1% had 1, and 13.6% had 2 APOL1 risk variants. Sickle cell trait was present in 8.5%. Compared with participants with zero APOL1 risk variants, those with 2 alleles had an increased risk for incident albuminuria (adjusted HR [aHR], 1.88; 95% CI, 1.04 to 3.40), ESKD (aHR, 9.05; 95% CI, 1.79 to 45.85), incident CKD (aHR, 1.65; 95% CI, 1.06 to 2.57), continuous decline (β = -1.90; 95% CI, -3.35 to -0.45), and rapid kidney function decline (OR, 2.21; 95% CI, 1.22 to 4.00) after adjustment for sickle cell trait, with similar results after adjustment for ancestry informative markers. Having 1 APOL1 risk variant was not associated with CKD outcomes and there was no interaction of APOL1 with sickle cell trait., Limitations: Single-site recruitment of African American individuals with APOL1 and sickle cell trait., Conclusions: The presence of 1 APOL1 risk allele was not associated with increased risk for CKD outcomes, whereas 2 risk alleles were associated with incident albuminuria, CKD, ESKD, and rapid and continuous kidney function decline. Additional studies are needed to determine factors that might alter the risk for adverse kidney outcomes among individuals with high-risk APOL1 genotypes., (© 2021 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development., Competing Interests: JG, MO, AR, NC, JF, KJ, KF, JH, BF, JS No competing interests declared, (© 2021, Gopalan et al.)

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

BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were lower in critically ill patients compared with healthy individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each SD higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% to 38% lower) independent of severity of illness, SCr, and tubular injury markers. Higher urine-to-plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing.CONCLUSIONAmong critically ill adults, tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential ICU medications.FUNDINGGrants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH) K23DK116967, the University of Washington Diabetes Research Center P30DK017047, an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers, and the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Engineering functional human tissues in vitro is currently limited by difficulty replicating the small caliber, complex connectivity, cellularity, and 3D curvature of the native microvasculature. Multiphoton ablation has emerged as a promising technique for fabrication of microvascular structures with high resolution and full 3D control, but cellularization and perfusion of complex capillary-scale structures has remained challenging. Here, multiphoton ablation combined with guided endothelial cell growth from pre-formed microvessels is used to successfully create perfusable and cellularized organ-specific microvascular structures at anatomic scale within collagen hydrogels. Fabrication and perfusion of model 3D pulmonary and renal microvascular beds is demonstrated, as is replication and perfusion of a brain microvascular unit derived from in vivo data. Successful endothelialization and blood perfusion of a kidney-specific microvascular structure is achieved, using laser-guided angiogenesis. Finally, proof-of-concept hierarchical blood vessels and complex multicellular models are created, using multistep patterning with multiphoton ablation techniques. These successes open new doors for the creation of engineered tissues and organ-on-a-chip devices., (© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Background and Objectives: The population of patients with kidney failure in the United States using home dialysis modalities is growing rapidly. Unlike for in-center hemodialysis, there is no patient-reported experience measure for assessment of patient experience of care for peritoneal dialysis or home hemodialysis. We sought to develop and establish content validity of a patient-reported experience measure for patients undergoing home dialysis using a mixed methods multiple stakeholder approach., Design, Setting, Participants, & Measurements: We conducted a structured literature review, followed by concept elicitation focus groups and interviews among 65 participants, including 21 patients on home dialysis, 33 home dialysis nurses, three patient care partners, and eight nephrologists. We generated a list of candidate items for possible measure inclusion and conducted a national prioritization exercise among 91 patients on home dialysis and 39 providers using a web-based platform. We drafted the Home Dialysis Care Experience instrument and conducted cognitive debriefing interviews to evaluate item interpretability, order, and structure. We iteratively refined the measure on the basis of interview findings., Results: The literature review and concept elicitation phases supported 15 domains of home dialysis care experience in six areas: communication and education of patients, concern and helpfulness of the care team, proficiency of the care team, patient-centered care, care coordination, and amenities and environment. Focus groups results showed that domains of highest importance for measure inclusion were patient education and communication, care coordination, and personalization of care. Prioritization exercise results confirmed focus group findings. Cognitive debriefing indicated that the final measure was easily understood and supported content validity., Conclusions: The Home Dialysis Care Experience instrument is a 26-item patient-reported experience measure for use in peritoneal dialysis and home hemodialysis. The Home Dialysis Care Experience instrument represents the first rigorously developed and content-valid English-language instrument for assessment of patient-reported experience of care in home dialysis., (Copyright © 2021 by the American Society of Nephrology.)

The Kidney Precision Medicine Project (KPMP) is a multisite study designed to improve understanding of CKD attributed to diabetes or hypertension and AKI by performing protocol-driven kidney biopsies. Study participants and their kidney tissue samples undergo state-of-the-art deep phenotyping using advanced molecular, imaging, and data analytical methods. Few patients participate in research design or concepts for discovery science. A major goal of the KPMP is to include patients as equal partners to inform the research for clinically relevant benefit. The purpose of this report is to describe patient and community engagement and the value they bring to the KPMP. Patients with CKD and AKI and clinicians from the study sites are members of the Community Engagement Committee, with representation on other KPMP committees. They participate in KPMP deliberations to address scientific, clinical, logistic, analytic, ethical, and community engagement issues. The Community Engagement Committee guides KPMP research priorities from perspectives of patients and clinicians. Patients led development of essential study components, including the informed consent process, no-fault harm insurance coverage, the ethics statement, return of results plan, a "Patient Primer" for scientists and the public, and Community Advisory Boards. As members across other KPMP committees, the Community Engagement Committee assures that the science is developed and conducted in a manner relevant to study participants and the clinical community. Patients have guided the KPMP to produce research aligned with their priorities. The Community Engagement Committee partnership has set new benchmarks for patient leadership in precision medicine research., (Copyright © 2021 by the American Society of Nephrology.)

CYP3A5 is the primary CYP3A subfamily enzyme expressed in the human kidney and its aberrant expression may contribute to a broad spectrum of renal disorders. Pharmacogenetic studies have reported inconsistent linkages between CYP3A5 expression and hypertension, however, most investigators have considered CYP3A5*1 as active and CYP3A5*3 as an inactive allele. Observations of gender specific differences in CYP3A5*3/*3 protein expression suggest additional complexity in gene regulation that may underpin an environmentally responsive role for CYP3A5 in renal function. Reconciliation of the molecular mechanism driving conditional restoration of functional CYP3A5*3 expression from alternatively spliced transcripts, and validation of a morpholino-based approach for selectively suppressing renal CYP3A5 expression, is the focus of this work. Morpholinos targeting a cryptic splice acceptor created by the CYP3A5*3 mutation in intron 3 rescued functional CYP3A5 expression in vitro, and salt-sensitive cellular mechanisms regulating splicing and conditional expression of CYP3A5*3 transcripts are reported. The potential for a G-quadruplex (G4) in intron 3 to mediate restored splicing to exon 4 in CYP3A5*3 transcripts was also investigated. Finally, a proximal tubule microphysiological system (PT-MPS) was used to evaluate the safety profile of morpholinos in proximal tubule epithelial cells, highlighting their potential as a therapeutic platform for the treatment of renal disease.

Rationale & Objective: Bioelectrical impedance analysis (BIA) provides a noninvasive assessment of body composition. BIA measures of nutritional (phase angle) and hydration (vector length) status are associated with survival among individuals with chronic kidney disease (CKD), including those receiving maintenance dialysis. However, little is known regarding changes in these parameters with CKD following the high-risk transition to maintenance dialysis., Study Design: Observational study., Settings & Participants: 427 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, with BIA measurements performed within 1 year before and after initiation of maintenance dialysis., Exposures: We calculated the changes in vector length and phase angle for patients with CKD transitioning to maintenance dialysis., Outcomes: We examined the association of changes in vector length and phase angle during the transition to maintenance dialysis with risk for all-cause mortality or nonfatal myocardial infarction, stroke, or heart failure, adjusting for demographics, comorbid conditions, and nutritional parameters., Results: Mean age was 58 ± 12 years and mean estimated glomerular filtration rate using the CKD Epidemiology Collaboration equation before dialysis initiation was 17.0 ± 8.7 mL/min/1.73 m 2 . After covariate adjustment, mean changes in vector length and phase angle were 18 (95% CI, 7 to 30) Ω/m and -0.6  (95% CI, -1.3  to 0.1 ), respectively. Changes in both BIA parameters were not associated with risk for heart failure, stroke, myocardial infarction, or all-cause mortality: HR, 1.02 (95% CI, 0.91-1.14) per 1-SD increment in change for vector length and HR, 1.11 (95% CI, 0.88-1.41) per 1-SD increment in change for phase angle., Limitations: Observational study, relatively small sample size., Conclusions: In a multicenter cohort of patients with CKD who progressed to kidney failure, the transition to maintenance dialysis was associated with changes in body composition reflecting poorer cellular integrity and improved volume control. However, these longitudinal changes were not associated with adverse clinical events after dialysis initiation., (© 2021 The Authors.)

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes., (Copyright © 2020 International Society of Nephrology. All rights reserved.)

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.

Background: Although proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR., Methods: In a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m 2 . After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances., Results: Median iGFR of the 54 participants was 73 ml/min per 1.73 m 2 . The kidney furosemide clearance correlated with iGFR ( r =0.84) and the summary secretion score ( r =0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR ( r =0.83) and with the summary secretion score ( r =0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir., Conclusions: Secretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients., (Copyright © 2021 by the American Society of Nephrology.)

Background: The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD., Methods: We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling., Results: A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition ( P <0.001 by UniFrac distances) and metabolomic composition ( P <0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances ( P =0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident., Conclusions: The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies., Clinical Trial Registry Name and Registration Number: Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882., Competing Interests: D.M. Charytan reports receiving personal fees from AstraZeneca, Douglas and London, Fresenius, GSK, Merck, PLC Medical, and Zoll; grants and personal fees from Amgen, Gilead, Medtronic, and NovoNordisk; grants from Bioporto; other from Daichi-Sankyo; and personal fees and other from Janssen, outside the submitted work. L.M. Dember receives consulting fees from GlaxoSmithKline and Merck, and compensation from the National Kidney Foundation for her role as deputy editor of American Journal of Kidney Diseases, outside of the submitted work. J. Himmelfarb reports being a founder of AKTIV-X Technologies, Inc., with equity; and has received fees for acting as a consultant or scientific advisory board member for Akebia, Chinook Therapeutics, Maze Therapeutics, Pfizer, Renalytix AI, and Seattle Genetics. T.A. Ikizler received personal fees from Abbott Renal Care and Fresenius Kabi, during the conduct of the study. P.L. Kimmel is a coeditor of Chronic Renal Disease (Academic Press, San Diego, CA), and a member of the board of directors of the Washington Academy of Medicine. A.S. Kliger receives income from the American Society of Nephrology, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Yale New Haven Hospital. H. Li receives consulting fees from Eli Lily, outside the submitted work. R. Mehrotra receives consulting fees from Baxter Healthcare, outside the submitted work. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

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

Alterations in hemodialysis patients' serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients' chromium and antimony levels exceeded established accepted upper limits of normal.

Contemporary dialysis treatment for chronic kidney failure is complex, is associated with poor clinical outcomes, and leads to high health costs, all of which pose substantial policy challenges. Despite similar policy goals and universal access for their kidney failure programs, the United States and Canada have taken very different approaches to dealing with these challenges. While US dialysis care is primarily government funded and delivered predominantly by private for-profit providers, Canadian dialysis care is also government funded but delivered almost exclusively in public facilities. Differences also exist for regulatory mechanisms and the policy incentives that may influence the behavior of providers and facilities. These differences in health policy are associated with significant variation in clinical outcomes: mortality among patients on dialysis is consistently lower in Canada than in the United States, although the gap has narrowed in recent years. The observed heterogeneity in policy and outcomes offers important potential opportunities for each health system to learn from the other. This article compares and contrasts transnational dialysis-related health policies, focusing on key levers including payment, finance, regulation, and organization. We also describe how policy levers can incentivize favorable practice patterns to support high-quality/high-value, person-centered care and to catalyze the emergence of transformative technologies for alternative kidney replacement strategies., (Copyright © 2020 by the American Society of Nephrology.)

Background: Laboratory measures of glomerular function such as the glomerular filtration rate (GFR) contribute toward clinical evaluation of chronic kidney disease (CKD). However, diverse CKD etiologies have distinct pathological mechanisms that may differentially impact the kidney tubules. Little is known regarding how tubular function changes with varying kidney disease types., Methods: We used targeted mass spectrometry to quantify paired serum and urine concentration of 11 solutes of proximal tubular secretion in 223 patients from an outpatient CKD cohort. We reviewed clinic notes to ascertain the primary CKD diagnosis and categorized these as vascular, diabetic, glomerular or tubulointerstitial. We used one-way analysis of variance to compare secretory solute clearance across diagnoses setting a false discovery threshold of ≤5% and used linear regression to compare differences after adjustments for estimated GFR, age, race, sex, body mass index and urine albumin excretion., Results: After full adjustment, glomerular disease was associated with higher clearances of three tubular secretory solutes compared with vascular disease: 48% higher isovalerylglycine clearance [95% confidence interval (CI) 18-87%], 28% higher kynurenic acid clearance (95% CI 3-59%) and 33% higher tiglylglycine clearance (95% CI 7-67%). Diabetic kidney disease (DKD) was associated with 39% higher isovalerylglycine clearance compared with vascular disease (95% CI 13-72%)., Conclusion: Glomerular disorders and DKD are associated with higher net clearances of several secretory solutes compared with vascular causes of kidney disease. These findings suggest that different underlying etiologies of CKD may differentially impact proximal tubular secretory pathways., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Ochratoxin A (OTA) is one of the most abundant mycotoxin contaminants in food stuffs and possesses carcinogenic, nephrotoxic, teratogenic, and immunotoxic properties. Specifically, a major concern is severe nephrotoxicity, which is characterized by degeneration of epithelial cells of the proximal tubules and interstitial fibrosis. However, the mechanism of OTA toxicity, as well as the genetic risk factors contributing to its toxicity in humans has been elusive due to the lack of adequate models that fully recapitulate human kidney function in vitro. The present study attempts to evaluate dose-response relationships, identify the contribution of active transport proteins that govern the renal disposition of OTA, and determine the role of metabolism in the bioactivation and detoxification of OTA using a 3D human kidney proximal tubule microphysiological system (kidney MPS). We demonstrated that LC 50 values of OTA in kidney MPS culture (0.375-1.21 μM) were in agreement with clinically relevant toxic concentrations of OTA in urine. Surprisingly, no enhancement of kidney injury biomarkers was evident in the effluent of the kidney MPS after OTA exposure despite significant toxicity observed by LIVE/DEAD staining. Instead, these biomarkers decreased in an OTA concentration-dependent manner. Furthermore, the effect of 1-aminobenzotriazole (ABT) and 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), pan-inhibitors of P450 and glutathione S-transferase (GST) enzymes, respectively, on OTA-induced toxicity in kidney MPS was examined. These studies revealed significant enhancement of OTA-induced toxicity by NBDHEX (3 μM) treatment, whereas ABT (1 mM) treatment decreased OTA-induced toxicity, suggesting roles for GSTs and P450 enzymes in the detoxification and bioactivation of OTA, respectively. Analysis of transcriptional changes using RNA-sequencing of kidney MPS treated with different concentrations of OTA revealed downregulation of several nuclear factor (erythroid derived-2)-like 2 (NRF2)-regulated genes by OTA treatment, including GSTs. The transcriptional repression of GSTs is likely playing a key role in OTA toxicity via attenuation of glutathione conjugation/detoxification. The sequential molecular events may explain the mechanism of toxicity associated with OTA. Additionally, OTA transport studies using kidney MPS in the presence and absence of probenecid (1 mM) suggested a role for organic anionic membrane transporter(s) in the kidney specific disposition of OTA. Our findings provide a clearer understanding of the mechanism of OTA-induced kidney injury, which may support changes in risk assessment, regulatory agency policies on allowable exposure levels, and determination of the role of genetic factors in populations at risk for OTA nephrotoxicity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.

The development of dialysis by early pioneers such as Willem Kolff and Belding Scribner set in motion several dramatic changes in the epidemiology, economics and ethical frameworks for the treatment of kidney failure. However, despite a rapid expansion in the provision of dialysis - particularly haemodialysis and most notably in high-income countries (HICs) - the rate of true patient-centred innovation has slowed. Current trends are particularly concerning from a global perspective: current costs are not sustainable, even for HICs, and globally, most people who develop kidney failure forego treatment, resulting in millions of deaths every year. Thus, there is an urgent need to develop new approaches and dialysis modalities that are cost-effective, accessible and offer improved patient outcomes. Nephrology researchers are increasingly engaging with patients to determine their priorities for meaningful outcomes that should be used to measure progress. The overarching message from this engagement is that while patients value longevity, reducing symptom burden and achieving maximal functional and social rehabilitation are prioritized more highly. In response, patients, payors, regulators and health-care systems are increasingly demanding improved value, which can only come about through true patient-centred innovation that supports high-quality, high-value care. Substantial efforts are now underway to support requisite transformative changes. These efforts need to be catalysed, promoted and fostered through international collaboration and harmonization.

Protein and cell interactions on implanted, blood-contacting medical device surfaces can lead to adverse biological reactions. Medical-grade poly(vinyl chloride) (PVC) materials have been used for decades, particularly as blood-contacting tubes and containers. However, there are numerous concerns with their performance including platelet activation, complement activation, and thrombin generation and also leaching of plasticizers, particularly in clinical applications. Here, we report a surface modification method that can dramatically prevent blood protein adsorption, human platelet activation, and complement activation on commercial medical-grade PVC materials under various test conditions. The surface modification can be accomplished through simple dip-coating followed by light illumination utilizing biocompatible polymers comprising zwitterionic carboxybetaine (CB) moieties and photosensitive cross-linking moieties. This surface treatment can be manufactured routinely at small or large scales and can impart to commercial PVC materials superhydrophilicity and nonfouling capability. Furthermore, the polymer effectively prevented leaching of plasticizers out from commercial medical-grade PVC materials. This coating technique is readily applicable to many other polymers and medical devices requiring surfaces that will enhance performance in clinical settings.