*Purpose: Calcineurin Inhibitors (CNIs) prevent transplant rejection but cause significant nephrotoxicity. Biomarkers of CNI nephrotoxicity could help drug dosing and improve long-term graft outcomes. As CNIs impair mitochondrial homeostasis, and Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC 1 alpha) regulates mitochondrial biogenesis and is increased by metformin, we hypothesised that CNI nephrotoxicity could be ameliorated using metformin.

*Methods: Rodent model of subclinical CNI nephrotoxicity was developed using daily gavage with 25mg/kg cyclosporine for 14 days. Urinary kidney damage biomarker levels were assessed at regular intervals in cyclosporine treated and controls rats, and in kidney tissue from day 14. Label-free quantitative proteomic analysis was used to identify novel urine biomarkers of CNI nephrotoxicity. Metformin 200mg/kg combined with cyclosporin was compared with cyclosporin alone, metformin alone and control.

*Results: Subclinical CNI nephrotoxicity occurred in the model with increased urinary KIM-1 levels in cyclosporine treated rats without change in serum creatinine. Urinary Clusterin increased while urinary calbindin reduced compared to control rats. Proteomic analysis identified changes in urinary Epidermal Growth Factor (EGF) and e-Cadherin levels as potential novel biomarkers of CNI nephrotoxicity. Cyclosporin significantly reduced tissue expression and nuclear localisation of PGC 1 alpha. Urinary Clusterin and KIM-1 levels were reduced in urine from rats treated with cyclosporin combined with metformin compared to cyclosporin alone.

*Conclusions: Urinary KIM 1, Clusterin, Calbindin, EGF and e-Cadherin are potential biomarkers of CNI nephrotoxicity. Reduction in PGC 1 alpha is a possible mechanism of CNI nephrotoxicity. Metformin may be a useful preventive treatment strategy.

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