Abstract
Acute kidney injury (AKI) affects up to half of critically ill intensive care unit (ICU) patients and remains associated with high mortality despite advances in renal replacement therapy (RRT). Current management is largely supportive and does not modify the underlying biological mechanisms driving inflammation, microvascular dysfunction, and maladaptive repair. Regenerative approaches using mesenchymal stromal cells (MSCs) and extracellular vesicles (EVs) have emerged as potential adjunctive therapies aimed at promoting renal recovery beyond organ support. Preclinical studies consistently demonstrate that MSCs and MSC-derived EVs reduce inflammation, attenuate oxidative stress, preserve tubular integrity, and enhance microvascular repair through paracrine signaling. However, early clinical trials in post-operative, sepsis-associated AKI populations have shown safety but limited efficacy signals. These neutral outcomes likely reflect AKI heterogeneity, delayed intervention timing, non-enriched patient selection, and reliance on insensitive endpoints such as serum creatinine. EV-based therapies offer practical advantages over whole-cell approaches, including scalable manufacturing, off-the-shelf availability, and easier integration into ICU workflows. Future progress requires phenotype-enriched enrollment strategies, biomarker-guided therapeutic windows, harmonized EV dosing and potency assays, and kidney-specific endpoints such as dialysis-free days.