Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study

Background: Focal segmental glomerulosclerosis (FSGS) is an important cause of non-diabetic chronic kidney disease (CKD). Sodium glucose cotransporter-2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in non-diabetic CKD such as FSGS. Objective: The primary aim of this pilot study was to determine the effect of 8 weeks of dapagliflozin on GFR in humans and in experimental FSGS. Secondary endpoints were related to changes in renal hemodynamic function, proteinuria and blood pressure (BP). Methods and Results: GFR (inulin) and renal plasma flow (para-aminohippurate), proteinuria and BP were measured in patients with FSGS (n=10) and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow and 24-hour urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196±26 vs. 165±33 mmHg, p<0.001), whereas changes were not statistically significant in humans (SBP 112.7±8.5 to 112.8±11.2 mmHg, diastolic BP 71.8±6.5 to 69.6±8.4 mmHg, p=NS), while hematocrit increased (0.40±0.05% to 0.42±0.05%, p=0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared to controls. Conclusions: Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of non-diabetic CKD are needed.