Back to the future: glomerular hyperfiltration and the diabetic kidney

Abstract

Observations that early changes in renal hemodynamics beget later kidney damage was a seminal scientific discovery that ultimately led to development of the only class of agents, inhibitors of the renin-angiotensin system (ACE inhibitors and angiotensin receptor blockers), approved by regulatory agencies for the treatment of diabetic kidney disease (DKD) (1,2). The first drugs in this class were approved more than two decades ago, and the concept of glomerular hyperfiltration as a targetable mechanism for DKD goes back almost four decades. It is rather ironic that looking backward in this direction may move the field forward in the future. Despite tremendous efforts of the clinical and translational research community and enormous amounts of scientific evidence discovered about various disease mechanisms, no others have successfully translated to a new treatment for DKD. Processes like fibrosis and inflammation undoubtedly contribute in major ways to the pathogenesis of DKD, but many attempts to translate these mechanisms to therapeutic targets have not yet succeeded (3–7). This consequence is likely due to a number of issues in the design and conduct of clinical trials, lack of validated DKD biomarkers, and barriers in the regulatory and business domains (8). Interest has resurged in renal hemodynamics because this DKD mechanism is targetable by strategies already in hand. In addition to the effects of renin-angiotensin system inhibition to decompress the glomerulus by releasing efferent arteriolar vasoconstriction, the sodium–glucose cotransporter 2 inhibitor class of oral hypoglycemic agents may reduce glomerular hyperfiltration by another mechanism. These agents increase distal tubular delivery of solute, specifically sodium chloride to the macula densa, and thereby reduce afferent arteriolar vasodilation via tubuloglomerular feedback (Fig. 1) (9 …