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AKI is a complex clinical syndrome associated with an increased risk of morbidity and mortality, particularly in critically ill and perioperative patient populations. Most AKI clinical trials have been inconclusive, failing to detect clinically important treatment effects at predetermined statistical thresholds. Heterogeneity in the pathobiology, etiology, presentation, and clinical course of AKI remains a key challenge in successfully testing new approaches for AKI prevention and treatment. This article, derived from the ?AKI? session of the ?Kidney Disease Clinical Trialists? virtual workshop held in October 2021, reviews barriers to and strategies for improving the design and implementation of clinical trials in patients with, or at risk of, developing AKI. The novel approaches to trial design included in this review span adaptive trial designs that increase the knowledge gained from each trial participant; pragmatic trial designs that allow for the efficient enrollment of sufficiently large numbers of patients to detect small, but clinically significant, treatment effects; and platform trial designs that use one trial infrastructure to answer multiple clinical questions simultaneously. This review also covers novel approaches to clinical trial analysis, such as Bayesian analysis and assessing heterogeneity in the response to therapies among trial participants. We also propose a road map and actionable recommendations to facilitate the adoption of the reviewed approaches. We hope that the resulting road map will help guide future clinical trial planning, maximize learning from AKI trials, and reduce the risk of missing important signals of benefit (or harm) from trial interventions.

Differences in survival between Black and White patients with childhood-onset kidney failure are recognized, but the impact of lifelong racial disparities in kidney transplantation on survival is not well characterized. In a 30-year observational cohort study of 28,337 children that extends into young adulthood, Black patients had a 45% higher risk of death, a 31% lower rate of first transplant, and a 39% lower rate of second transplant. Black patients had fewer living donor transplants than White patients. Children and young adults are likely to require more than one transplant during their lifetime, yet even after their first transplant Black patients received 11% fewer total lifetime transplants than White patients. Transplants failed earlier for Black patients after the first and second transplant. These combined disparities resulted in Black patients spending 24% less time being treated for kidney failure with a transplant than White patients. We estimate that 35% of excess deaths in Black patients with ESKD beginning in childhood would be prevented if their time with a transplant was the same as among White patients. Increasing kidney transplant rates and improving allograft survival for Black children and young adults has the potential to help close the survival gap.

Acute kidney injury (AKI) carries high rates of morbidity and mortality. This study quantified various short- and long-term outcomes after hospitalization with AKI.

Introduction:Endothelial dysfunction underlies the pathophysiology of cardiovascular disease (CVD) in patients with diabetes mellitus (DM), but no known effective therapies exist. The randomized, double-blind ACESO clinical trial evaluated the safety and efficacy of allogeneic human mesenchymal stem cells (allo-MSCs) infusion to target endothelial dysfunction in Type 2 DM subjects.Methods:An open label pilot phase (n=6) was followed by a blinded, randomized phase (n=10) study. DM subjects with endothelial dysfunction received a single peripheral intravenous infusion of either 20 or 100 million allo-MSCs (obtained from 3 healthy bone marrow donors) and followed for 1 yr. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAE) within 1-month post-infusion. Secondary endpoints assessed endothelial function via endothelial progenitor cell-colony forming units (EPC-CFUs) and flow-mediated dilation (FMD%).Results:Participants had well-controlled DM, blood pressure, and kidney function (GFR ≥50 ml/min), and most were taking statins. The 6 pilot-phase participants were men (1 Asian, 5 non-Hispanic white) with mean (±SD) age of 69.3 (9.6) years. The 10 randomized participants were 5 men and 5 women (5 Hispanic, 3 non-Hispanic Black), with mean age of 60.9 (10.6) years. No TE-SAEs were reported. None of the patients in the pilot phase developed Panel Reactive Antibodies (PRAs). One randomized subject had a moderate increase in PRAs after infusion. Both treatment groups (20 and 100M allo-MSCs) in the pilot and randomized phases showed increased EPC-CFUs over time, particularly at 14 and 28 days post-infusion, that was sustained at 6-12 months. FMD data followed a trend rising above baseline and peaking at days 7 to 14, and then subsided to pre-infusion levels by 1 yr.Conclusion:Peripheral infusion of allo-MSCs for patients with DM and endothelial dysfunction is safe. Allo-MSCs improve EPCs and FMD within 14 to 28 days post-infusion, and the effect is sustained for 6 to 12 months. Larger clinical trials are warranted to assess the efficacy of allo-MSC therapy for cardiovascular outcomes in diabetic patients.Clinical Trial Registration:URL: https://www.clinicaltrials.gov.; Unique ID: NCT02886884

A bidirectional relationship between depression and renal dysfunction has been posited, however, a paucity of longitudinal data exists in individuals with major depression disorder (MDD). As depression may contribute to the progression of chronic kidney disease (CKD), we sought to determine whether effective depression treatment was associated with improvement in renal function.

Inclusion of women and minorities in clinical research is critical to fully assess the safety and efficacy of innovative therapies. With inadequate representation of demography, generalizability is impaired since pharmacokinetics and pharmacodynamics differ in these patient populations. This study was designed to analyze the voluntary participation rates of different demographic groups in cell-based therapy clinical trials conducted by the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami, Miller School of Medicine. ISCI conducted eight clinical trials between 2007 and 2017. The trials enrolled patients with ischemic and non-ischemic cardiomyopathy, idiopathic pulmonary fibrosis (IPF), aging-frailty, and Type-2 Diabetes. Participants received cell-based therapy (n = 218) or placebo (n = 33). Among the 251 participants, 29.5% were Hispanic and 20% were women. The proportion of individuals participating in each trial was compared to that of the respective disease populations attending University of Miami Health System clinics to calculate the participation to prevalence ratio (PPR). Distribution of women accurately reflected the population attending the University of Miami Health System in trials for dilated cardiomyopathy (DCM) and aging-frailty but was under-represented in others. Similarly, Hispanics and whites were accurately represented in three of the five disease fields, with Hispanics under-represented in frailty and diabetes, and whites over-represented in DCM and IPF. Black patients were accurately represented in the diabetes trial but were under-represented in all others. This study provides insight into challenges of achieving representative inclusion in research. Novel community engagement strategies are necessary to improve inclusion of women and under-represented minorities in clinical research of cell-based therapy.

Introduction:Myocardial ischemia (MI) is a leading cause of morbidity and mortality worldwide. Mesenchymalstemcell(MSC) treatment of MI reduces scar size and improves perfusion and heart function. While few MSCs are retained, improvements followingMSC-based therapies have been attributed to paracrine effects, in whichexosomes(Exos) may play a major role.HYPOTHESIS:The effectiveness ofby MSC-derived exosomes (MSC-Exos) is sex-dependent.Methods:MSC-Exos were isolated from conditioned medium via ultracentrifu-gation. Flow cytometry analysis, transmission electron microscopy, and nanosight were used to identify and quantifyexosomes. Human inducedpluripotentstemcells (hiPSCs) and human-MSCs (hMSCs) were co-cultured under hypoxic (1% O2) conditions. We evaluated the effects of male and female MSC-Exos on differentiation and proliferation of hiPSCs by qPCR and MTT assays, respectively. Exosomal microRNAs (miRs) were subjected to microarray profiling analysis and WNT signaling was assessed by Western blot.Results:Most MSC-Exos were ~50-150 nm in diameter and expressed CD9, CD63, and CD81. Female MSC-Exos increased hiPSC expression of NKX2.5 and WNT signaling compared to treatment with male MSC-Exos. Similarly, hiPSCs proliferation was stimulated by both female and male MSC-Exos, with female MSC-Exos exerting a greater effect. Expression of miR302b and miR181b were significantly different in female compared to male MSC-Exos .Conclusions:We demonstrated that female MSC-Exos have a greater effect on hiPSC differentiation and proliferation than male MSC-Exos. We predict that miR302b promotes differentiation of hiPSCs into cardiac progenitor cells in a sex-specific manner and that miR181b enhances proliferation through activating the WNT signaling pathway of hiPSCs, potentially increasing cardiomyocyte proliferation.