Marcel H.A. Muskiet^1,2,3, Michaël J.B. van Baar¹, Daan J Touw⁴, Jaap A. Joles⁵, Merle M. Krebber⁵, David Z.I. Cherney³, Petter Bjornstad⁶, Daniël H. van Raalte¹

¹Amsterdam UMC, Amsterdam, Netherlands; ²Leiden University Medical Center, Leiden, Netherlands. ³University Health Network, Toronto, Ontario, Canada. ⁴University Medical Center Groningen, Groningen, Netherlands, ⁵UMC, Utrecht, Netherlands, ⁶University of Washington, Seattle, WA, USA.

ma.muskiet@amsterdamumc.nl

Background: Glomerular hyperfiltration is common in type 2 diabetes (T2D) and may reflect reduced nephron number and/or perturbed intrarenal hemodynamics. Renal functional reserve (RFR), the kidney’s capacity to increase GFR upon physiological stimulation (e.g., a meal), can help identify single-nephron hyperfiltration in patients with preserved baseline whole-kidney GFR. We assessed whether postprandial RFR predicts the acute GFR-response to the SGLT2-inhibitor empagliflozin, the DPP-4-inhibitor linagliptin, or a sulfonylurea.

Methods: This analysis pooled data from two 8-week randomized, double-blind, parallel-group mechanistic trials, encompassing 71 T2D patients with preserved whole-kidney GFR (mean±SD age 65±7 years, BMI 30.4±3.9 kg/m², HbA1c 7.8±1.0%, GFR 86.5±17.6 mL/min/1.73m²). Patients received empagliflozin (10mg; N=20), linagliptin (5mg; N=27) or sulfonylurea (glimepiride 1mg or gliclazide 30mg; N=24), in addition to metformin. Measured (m)GFR and effective renal plasma flow (ERPF) were determined by inulin/iohexol and PAH-clearance, respectively, based on timed urine-sampling in fasting and post-protein-rich meal conditions. Intrarenal-hemodynamics were calculated using Gomez-equations; fractional sodium-excretion (FE_Na) and systemic hemodynamics were evaluated.

Results: The meal increased mGFR (+7.3±1.7 mL/min/1.73m²; p<0.001) and ERPF (+44.3±14.9 mL/min/1.73m²; p=0.005), with a concomitant decrease in renal vascular resistance (RVR; −0.02±0.01 mmHg/L/min; p<0.001), primarily driven by reduced afferent arteriolar resistance (−1068±241 dyne/sec/cm^-5; p<0.001) and lower FE_Na (−0.21±0.05; p<0.001). Postprandial mGFR-changes did not correlate with baseline mGFR, but did correlate with postprandial RVR-change (r −0.57; p<0.001). After 8 weeks, mGFR tended to decrease with sulfonylurea (p=0.054) and decreased with empagliflozin (−9.1±3.2 mL/min/1.73m²; p=0.016), with no effect of linagliptin. Baseline meal-induced mGFR-changes correlated with 8-week treatment-induced mGFR-changes with empagliflozin (r:0.88; p<0.001), but not with linagliptin or sulfonylurea.

Discussion/Conclusion: Baseline RFR predicts GFR-dipping with empagliflozin after 8-weeks. As GFR-dipping is associated with long-term kidney-benefit, RFR warrants further evaluation as a biomarker to personalize SGLT2-inhibitor therapy.