Protecting the Kidney's Proximal Tubules From Platinum-Based Chemotherapy Toxicity

Platinum-based chemotherapy agents such as cisplatin and carboplatin are widely used in the treatment of various solid tumors due to their efficacy. However, their clinical utility is frequently limited by nephrotoxicity, predominantly targeting the proximal tubular epithelium. This can lead to acute kidney injury (AKI), electrolyte imbalances (notably hypomagnesemia, hyponatremia, and hypophosphatemia), and progression to chronic kidney disease (CKD). Current preventive strategies are largely supportive and include aggressive hydration, mannitol-induced diuresis, and magnesium supplementation, none of which offer specific cellular protection. Recent evidence suggests that inhibitors of the sodium-glucose cotransporter type 2 (SGLT2 inhibitors or iSGLT2s), such as dapagliflozin, may confer renal protective effects beyond their original indication for type 2 diabetes mellitus. Mechanistically, SGLT2 inhibition reduces proximal tubular reabsorption of sodium and glucose, leading to improved tubular oxygenation and reduced inflammatory and oxidative stress signaling. This has been associated with reduced progression of CKD and favorable modulation of tubular injury markers in both diabetic and non-diabetic populations. The present study, DAPA-ARMOR, is a randomized, double-blind, placebo-controlled clinical trial designed to assess the nephroprotective effects of dapagliflozin in adult patients with solid tumors undergoing platinum-based chemotherapy. The hypothesis is that short-term prophylactic administration of dapagliflozin can reduce proximal tubular injury, as evidenced by changes in urinary biomarkers. The primary endpoint is the difference in urinary levels of Kidney Injury Molecule-1 (KIM-1) 72 hours after platinum administration, between the intervention (dapagliflozin) and control (placebo) arms. Secondary endpoints include changes in additional urinary biomarkers associated with tubular injury and repair: uEGF (urinary Epidermal Growth Factor) uNAG (N-acetyl-β-D-glucosaminidase) uAlb (urinary albumin) uβ2-microglobulin These biomarkers will be measured at baseline, 72 hours (±3 days), and 168 hours (±7 days) after chemotherapy administration. Additional secondary endpoints include: Incidence of AKI at 72 hours and 7 days post-chemotherapy (defined per KDIGO criteria), Changes in estimated glomerular filtration rate (eGFR) using the CKD-EPI 2021 equation (Cystatin C and creatinine-based), Incidence of chemotherapy-related electrolyte disturbances (Na, Mg, P), Frequency and severity of adverse events graded according to the CTCAE (Common Terminology Criteria for Adverse Events). Exploratory outcomes will assess: Cancer response rate using RECIST 1.1 criteria at the first post-randomization imaging evaluation, Tolerability of dapagliflozin during chemotherapy. The study drug (dapagliflozin) or placebo will be administered starting 24 hours prior to platinum chemotherapy and continued for a total of 4 days, covering the period of expected peak tubular exposure and injury. Participants will be stratified by type of platinum agent used. Urine and blood samples will be collected at pre-specified timepoints for biomarker analysis and laboratory monitoring. The study design aims to ensure high internal validity while capturing clinically relevant endpoints that could inform future strategies to mitigate chemotherapy-induced nephrotoxicity without compromising oncologic efficacy.