Angiotensin-converting enzyme inhibition and angiotensin II antagonism in nondiabetic chronic nephropathies.

Angiotensin II (A II), the main effector of the renin angiotensin system (RAS), plays a central role in the hemodynamic and nonhemodynamic mechanisms of chronic renal disease and is currently the main target of interventions aimed to prevent the onset and progression of chronic nephropathies to end-stage renal disease (ESRD). In addition, to ameliorate glomerular hyperfiltration and size selectivity, reduce protein traffic and prevent glomerular and tubulointerstitial toxicity of ultrafiltered proteins, RAS inhibitors also limit the direct nephrotoxic effects of A II. Thus, both angiotension-converting enzyme (ACE) inhibitors (ACEi) and A II antagonists (ATA) exert a specific nephroprotective effect in both experimental and human chronic renal disease. This effect is time-dependent and is observed across degrees of renal insufficiency. Forced ACEi or ATA uptitration above doses recommended to control arterial hypertension and combined treatment with both agents allow optimization of A II inhibition and maximization of renoprotection. Multifactorial interventions combining RAS inhibition to treatments targeted also to non-RAS mechanisms could even achieve regression of glomerulosclerosis and chronic tubulointerstitial injury. Studies are needed to assess whether renal damage can be reverted to such a point that renal function could be fully prevented from worsening, and possibly improvement. The economic impact of even a partial improvement would be enormous. Moreover, chronic renal insufficiency is an independent risk factor for cardiovascular disease, and effective nephroprotection could also decrease the excess cardiovascular morbidity and mortality associated with chronic nephropathies. In patients with renal insufficiency, ACEi are even more cardioprotective than in those without and are well tolerated. Thus, RAS inhibitor therapy should be offered to all renal patients without specific contraindications, including those closer to renal replacement therapy.