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

作者：Rajasekeran Harindra; Reich Heather N; Hladunewich Michelle A; Cattran Daniel; Lovshin Julie A; Lytvyn Yuliya; Bjornstad Petter; Lai Vesta; Tse Josephine; Cham Leslie; Majumder Syamantak; Bowskill Bridgit B; Kabir M Golam; Advani Suzanne L; Gibson Ian W; Sood Manish M; Advani Andrew; Cherney David Z I^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2018, 314(3): F412-F422.

DOI：10.1152/ajprenal.00445.2017

• FSGS
• nondiabetic CKD
• SGLT2 inhibition

Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic 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 nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). 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-h 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 = not significant), although 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 with controls. 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 nondiabetic CKD are needed.

• 出版日期2018-3