A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics

Abstract

A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects.

Keywords: GFR; RASi; SGLT2i; chronic kidney disease; vaptans.

Figure 1

Timeline of the renal reserve concept and the discovery of nephroprotective drugs. The observation of an increase in glomerular filtration rate (GFR) after a meat meal and in diabetes led to the hypothesis of intrarenal hypertension. The MDRD study introduced a new equation to estimate GFR and showed it is not sufficient to avoid meat meals. With the advent of RASi it has been possible to slow down chronic kidney disease (CKD) and hence a new staging system for CKD was designed. Two additional drug classes were then found to slow down CKD.

Figure 2

The extent of the initial drop in eGFR predicts the long term eGFR decline in patients treated with SGLT2i, Tolvaptan (a VRA), or ACEi. Negative values represent an eGFR loss over time. The horizontal axis reports the extent of acute fall in eGFR; the vertical axis reports the long-term effect on eGFR decline. Since these drugs are not reverting kidney damage, a long-term decrease of eGFR (negative values) should be expected, though at a lower rate than controls (values closer to zero). To allow comparisons among different trials, the eGFR loss has been divided by the weeks of observation. The more significant the initial drop in eGFR (horizontal axis), the greater the drug’s nephroprotective effect (vertical axis). ACEi data are elaborated from [39,40,50,51,52,53]. Tolvaptan data were elaborated from [7,10,54,55,56,57]. SGLT2i data were elaborated from [8,41,45,46,47,48,49]. Circles represent placebo effect.

Figure 3

Hypothesis on the shared nephroprotective property of RASi, SGLT2i, and VRA.