Phase I/II study and long-term follow-up of Adipose-derived Mesenchymal stromal cell infusion in critically ill patients with concomitant acute LUng and KIdney failure (AM-LU-KI study)

Acute Respiratory Distress Syndrome (ARDS) is the leading cause of Intensive Care Unit admission. Acute Kidney Injury (AKI) is a frequent complication of ARDS. Lung and kidney damage share pathogenic mechanisms leading to long-term dysfunction. Current therapeutic strategies are only supportive and without any impact on mortality. Adipose Mesenchymal Stromal Cells (AMSCs) may promote tissue regeneration in ARDS/AKI and are under evaluation in clinical trials. AMSC-induced repair is mainly ascribed to paracrine factors such as Extracellular Vesicles (EVs). Aims of the study: 1. Safety and efficacy of AMSC infusion in patients with ARDS and AKI (including COVID-19); 2. Long-term follow-up of lung/kidney function in comparison to a control cohort; 3. Identification of intracellular pathways by which AMSCs and EVs enhance lung/kidney repair. Project development in Work Packages (WPs): WP1: Isolation, characterization of AMSCs and related EVs: AMSCs isolated from adipose tissue will be characterized for phenotypic and immunologic profiling following cGMP guidelines. EVs will be characterized for size, concentration and protein/RNA content. WP2: Evaluation of the protective effects of AMSCs and derived EVs in vitro on human endothelial and epithelial cells isolated from lung (LUEnd, LUEp) and kidney (KIEnd, KIEp) cultured in inflammatory conditions mimicking ARDS/AKI. Injured cells will be challenged with AMSCs or EVs and tested for viability, apoptosis, mitochondrial function, senescence, complement activation, modulation of intracellular pathways. WP3: Safety and efficacy of AMSC infusion in patients with ARDS and AKI: Phase I/II clinical trial based on AMSC infusion in 30 patients with ARDS according to Berlin definition and AKI stage 2/3 (KDIGO criteria). A single dose of AMSC will be i.v. injected: safety (Adverse Events occurring after AMSC infusion) and efficacy (lung/kidney function, mortality at 28, 60 and 90 days from ICU entry) will be evaluated. WP4: Follow-up of lung function. Quantification of lung morphological and functional classes by computed tomography and follow-up of cardio-respiratory function through a bio-engineering approach based on continuous monitoring by wearable devices. WP5: Follow-up of kidney function. Standard (eGFR, urine test) and second level assays such as Renal Functional Reserve (RFR) and urinary biomarkers of CKD progression (NGAL, Nephrocheck, DDK-3, CCL14, exosomal CD133) coupled to imaging techniques (elastosonography). Expected results and future developments Creation of AMSC biobank for cell therapy in patients with ARDS and AKI including COVID-19. Potential decrease of mortality associated with ARDS and AKI. Long-term follow-up of lung/kidney function in survivors. Exploration of AMSC-derived EV role in lung/kidney regeneration. Identification of intracellular pathways involved in lung/kidney injury (new therapeutic targets).