P1839GLOMERULAR HYPERFILTRATION: THEORY AND APPLICATIONS
Authors: Mohamed Ali Moustafa Shendi 
Published: June 2020

Abstract

Background and Aims
The role of glomerular hyperfiltration in the development and progression of diabetic and non-diabetic chronic kidney disease (CKD) was established during the 80’s of the last century and represented a paradigm shift in current nephrology practice.

Method
A web-based review of relevant bibliography: articles and textbooks, reporting the development of hyperfiltration theory and its clinical applications was conducted.

Results
In 1982, after a series of animal studies, Brenner and colleagues proposed that glomerular hyperfiltration, in diabetic and other glomerulopathies, contributes to intrarenal hypertension and predispose to progressive glomerular sclerosis and deterioration of renal function. Clinical trials during late 80’s and early 90’s then focused on inhibition of Renin Angiotensin Aldosteron system (RAAS) to reverse glomerular hyperfiltration, and suggested that ACE inhibitors can be anti-proteinuric independent of their blood pressure-lowering effect in non-diabetic and diabetic nephropathies. In 1993, a randomized controlled trial (RCT) by Lewis and colleagues proved a beneficial effect of captopril in patients with nephropathy caused by type 1 diabetes. Few years later, the results of Ramipril Efficacy in Nephropathy (REIN) study proved the renoprotective role of ACE inhibition in patients with non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria in 2 Lancet articles in 1997 and 1999 respectively. The renoprotective role of RAAS inhibition with ARBs in patients with type 2 diabetes was proven in 3 RCTs published in the New England Journal of Medicine in 2001: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study, Irbesartan Diabetic Nephropathy Trial (IDNT), and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Dual blockade with an ACE inhibitor and an ARB was then attempted to further ameliorate glomerular hyperfiltration. Yet this approach was faced by an increased risk of hyperkalemia and acute kidney injury in 2 RCTs: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in 2008 and The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study in 2013.
It was until 2014 when evidence appeared for a potential role of SGLT2 inhibition in attenuating glomerular hyperfiltration. The 1st clinical evidence of renoprotective effect of SGLT2i appeared in 2016 when the results of the EMPA-REG OUTCOME study found that empagliflozin was associated with lower rates of renal events. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program trials and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found similar reductions in composite renal endpoints. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial published in 2019 was the first study designed to assess the effects of a SGLT2i, canagliflozin, on renal outcomes in patients with type 2 diabetes and albuminuric CKD, and proved significant reduction in the composite renal outcome with canagliflozin.
The potentiality for renoprotective role of SGLT2i in patients with non-diabetic CKD has stimulated a number of ongoing clinical trials: DIAMOND and Dapa-CKD using Dapagliflozin and EMPATHY and EMPA-KIDNEY using Empagliflozin.

Conclusion
The hyperfiltration theory represents the basis for current therapeutic interventions in diabetic and non-diabetic CKD. Current guidelines recommend using RAAS blockers in diabetic and non-diabetic proteinuric CKD and SGLT2i in patients with type 2 diabetes and CKD. Whether SGLT2i could be considered in patients with CKD independent of the diabetic state awaits the results of ongoing studies which might change the management practice of CKD.