An absolute, supraphysiologic elevation in GFR is observed early in the natural history in 10%-67% and 6%-73% of patients with type 1 and type 2 diabetes, respectively. Moreover, at the single-nephron level, diabetes-related renal hemodynamic alterations-as an adaptation to reduction in functional nephron mass and/or in response to prevailing metabolic and (neuro)hormonal stimuli-increase glomerular hydraulic pressure and transcapillary convective flux of ultrafiltrate and macromolecules. This phenomenon, known as glomerular hyperfiltration, classically has been hypothesized to predispose to irreversible nephron damage, thereby contributing to initiation and progression of kidney disease in diabetes. However, dedicated studies with appropriate diagnostic measures and clinically relevant end points are warranted to confirm this assumption. In this review, we summarize the hitherto proposed mechanisms involved in diabetic hyperfiltration, focusing on ultrastructural, vascular, and tubular factors. Furthermore, we review available evidence on the clinical significance of hyperfiltration in diabetes and discuss currently available and emerging interventions that may attenuate this renal hemodynamic abnormality. The revived interest in glomerular hyperfiltration as a prognostic and pathophysiologic factor in diabetes may lead to improved and timely detection of (progressive) kidney disease, and could provide new therapeutic opportunities in alleviating the renal burden in this population.

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) improve hard renal outcomes in type 2 diabetes (T2D) patients. An acute and reversible drop in eGFR that stabilizes over time, as with RAS inhibitors, suggests involvement of a beneficial renal hemodynamic mechanism. In hyperfiltering T1D patients, SGLT2i lowered GFR by increasing afferent arteriolar resistance, possibly by activating tubuloglomerular feedback. We studied the renal hemodynamic effects of SGLT2i dapagliflozin in T2D patients like those included in recent outcome trials. Methods: Forty-four T2D patients on metformin monotherapy, (62.9±7.0 years, HbA1c 7.38±0.63%, GFR 113±19 mL/min) were randomized to 12 weeks dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD to achieve glycemic equipoise. At baseline and week 12, GFR and renal plasma flow (RPF) were measured by gold-standard inulin and para-aminohippurate clearances. The measurements were performed 1) in the fasting state, 2) during clamped euglycemia (90 mg/dL) and 3) hyperglycemia (270 mg/dL). Renal vascular resistance (RVR) and filtration fraction (FF) were calculated using GFR, RPF, Ht and MAP. Afferent and efferent arteriolar resistances were estimated by Gomez’ equations. Results: HbA1C decreased similarly (0.47% with DAPA and 0.65% with GLIC; p=ns), while only DAPA significantly reduced MAP by approximately 6 mmHg. DAPA reduced GFR during all three conditions by 8.9 (p<0.01), 9.0 (p=0.01) and 13.4 mL/min (p<0.001), respectively, without altering RPF, thus also reducing FF. Importantly, DAPA lowered RVR and efferent arteriolar resistance. GLIC did not alter any renal hemodynamic variables. Conclusion: We confirm that SGLT2i induces beneficial renal hemodynamic changes in T2D beyond glycemic control that are characterized by reduced GFR and FF. However, in contrast to standing opinion, this is mediated by efferent arteriolar dilation rather than afferent arteriolar constriction. Disclosure E.J. van Bommel: None. M.A. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. J.A. Joles: None. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Funding AstraZeneca Nederland BV

In adults with type 2 diabetes, men had higher markers of hyperfiltration, which could potentially explain the accelerated progression of diabetic kidney disease in men compared with women.

Objective Diabetic kidney disease is a microvascular complication of diabetes. Here, we assessed the association between skin microvascular function and renal hemodynamic function in a cohort of well‐phenotyped adults with type 2 diabetes (T2D). Methods We included 81 overweight/obese adults (age: 62 ± 8 years; BMI: 32 ± 4 kg/m2) with well‐controlled T2D and no renal impairment. Skin microvascular function was assessed by nailfold capillary density in rest and after arterial occlusion (ie, peak capillary density). Renal hemodynamic functions (ie, measured glomerular filtration rate [mGFR], effective renal blood flow [ERBF], filtration fraction [FF], and effective renal vascular resistance [ERVR]) were assessed by combined inulin and para‐aminohippurate clearances and blood pressure measurements. Results Skin capillary density was 45 ± 10 capillaries/mm2 at baseline and 57 ± 11 capillaries/mm2 during post‐occlusive peak; mGFR averaged 108 ± 20 ml/min. In multivariable regression analyses, positive associations between capillary density during post‐occlusive peak and mGFR (β = 0.224; p = 0.022) and ERBF (β = 0.203; p = 0.020) and a positive trend for hyperemia and mGFR (β = 0.391; p = 0.053) were observed, while a negative association for post‐occlusive capillary density with ERVR (β = −0.196; p = 0.027) was found. Conclusion These findings indicate that microvascular dysfunction in overweight adults with T2D is associated with lower mGFR and ERPF and higher ERVR. We hypothesize that increased renal vascular resistance may contribute to glomerular dysfunction due to impaired renal perfusion.

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