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

AimsCONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.Methods and resultsPatients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.ConclusionsThis is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

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Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P 0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

Purpose: Diabetes and obesity, components of the metabolic syndrome (MetS), are risk factors for urinary incontinence (UI) and chronic kidney disease (CKD). We interrogated US population-based data to explore independent, sex-specific associations between nondiabetic MetS, with and without obesity, and UI and/or CKD. Materials and Methods: We analyzed data from 8586 males and 8420 females -20 years from the National Health and Nutrition Examination Survey. Multivariable logistic regression models were used to examine associations of UI or CKD with diabetes and 4 nondiabetic obesity/metabolic phenotypes: non-MetS/nonobese, MetS/nonobese, non-MetS/obese, and MetS/obese. Multinominal logistic regression models were used to assess associations of co-occurring UI/CKD with obesity/metabolic phenotypes. Results: Male MetS/obese participants had increased odds of any UI (1.25; 95% CI 1.00-1.57) and urgency UI (1.36; 1.03-1.80), compared with non-MetS/nonobese participants. Female MetS/obese participants had increased odds of any UI (2.16; 95% CI 1.76-2.66), stress UI (1.51; 1.21-1.87), and mixed UI (1.66; 1.31-2.11) compared with non-MetS/nonobese participants. The odds of cooccurring UI/CKD were increased relative to either condition alone in persons with diabetes, and in males with MetS/obese phenotypes and females with MetS phenotypes as compared to same sex participants with neither obesity nor MetS. Conclusions: We found novel associations between MetS/obese and urgency UI in males without diabetes, and between SUI and both MetS and obesity in females without diabetes. Odds estimates for UI/CKD were increased by existing obesity or MetS as compared to those for UI or CKD alone. Improved understanding of modifiable factors associated with UI will inform prevention and treatment opportunities. [ABSTRACT FROM AUTHOR]

The document is a reply to an article titled "Association of Obesity, Metabolic Syndrome, and Diabetes With Urinary Incontinence and Chronic Kidney Disease: Analysis of the National Health and Nutrition Examination Survey, 2003-2020." The authors thank the readers for their interest and suggestions for future studies. They clarify that their study focused on sex-specific associations, not gender disparities, and analyzed men and women separately. They acknowledge the limitations of their study design and suggest further investigations to explore potential confounding factors and to use varied study designs and populations. The authors provide their contact information for further inquiries. [Extracted from the article]

Introduction: Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU).Objective: This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU.Discussion: All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies.Conclusion: MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED. [ABSTRACT FROM AUTHOR]