The role of renin angiotensin system inhibition in kidney repair

Abstract

Chronic kidney diseases share common pathogenic mechanisms that, independently from the initial injury, lead to glomerular hyperfiltration, proteinuria, and progressive renal scarring and function loss. Inhibition of the renin angiotensin system (RAS) has been consistently found to reduce or halt the progressive deterioration of renal function through reduction of blood pressure and proteinuria, the two main determinants of renal function decline. In few instances, RAS inhibition may even promote amelioration of the glomerular filtration rate. Animal data suggest that chronic therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor type I blockers promotes regression of glomerulosclerosis, even in later phases of the disease. In humans, studies investigating the effect of angiotensin II inhibition on renal structural changes have shown inconsistent results, possibly due to small numbers and/or short duration of follow-up. Whether regression of glomerulosclerosis relies on a direct regenerative effect of RAS inhibition or on spontaneous kidney self-repair after the injury has been removed is still unknown. Improved understanding of mechanisms that promote renal regeneration may help in designing specific therapies to prevent the development of end-stage renal disease. This is a desirable goal, considering the economic burden of chronic kidney diseases and their effect on morbidity and mortality.

Figure 1

GFR time-dependent changes over time in the 26 patients on prolonged ramipril therapy in the Ramipril Efficacy in Nephropathy (REIN) study. The breakpoint analysis found that GFR time-dependent changes could not be described by one single first-degree equation, but rather by two different equations describing randomization to 36 months and from 36 to 54 months, respectively. Y₁ and Y₂ equations describe the interpolating curves before and after the breakpoint, respectively.

Figure 2

Regression of glomerulosclerosis by ACE inhibition in an experimental model for progressive kidney disease. Distribution of nonsclerosed capillary tissue as estimated by serial section reconstruction of the entire capillary tuft in Munich Wistar-Frömter rats at 50 weeks of age (in red), in untreated rats at 60 weeks of age, (in brown) and in animals treated with the ACE inhibitor lisinopril from 50-60 weeks of age (in yellow). In total, 100 glomeruli have been completely reconstructed in each animal group. Numbers in the abscissa represent reconstructed glomerular capillary tufts.