Renin–angiotensin system blockade in diabetic nephropathy

SummaryDiabetes nephropathy (DN) is a clinical syndrome characterized by a relentless decline in GFR, persistent albuminuria, arterial hypertension and highly elevated risk for cardiovascular morbidity and mortality. Increased urinary albumin excretion rate (UAER) in the range of microalbuminuria (20–200 μg/min) predicts overt nephropathy in patients with type 1 and type 2 diabetes. The renin–angiotensin aldosterone (RAAS) system has been implicated in the patho-physiology of diabetic renal disease, based mainly upon the ability of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers to reduce proteinuria and the progression of diabetic glomerulosclerosis. The RAAS is a co-ordinated cascade of proteins and peptide hormones, the principal effector of which is angiotensin II. The RASS is a key player in the progression of diabetic renal disease. The systemic RAAS is generally suppressed in DN, whereas the intrarenal RAAS may be activated even early in the course of diabetes. All of the components of the RAAS are present within the kidney. Together with the observations that angiotensin II receptors are localized to renal arterioles, glomerular mesangial cells and the basolateral and apical membranes of proximal tubule cells, these findings are consistent with a primary role for ANG II as a paracrine substance in the control of renal function. Renal ANG II is therefore, a strong determinant of glomerular haemodynamics and intraglomerular pressure and stimulates mesential cell proliferation by increased expression of TGF-β and other cytokines and growth factors independent of blood pressure. Furthermore, prosclerotic effects of high glucose concentrations are most likely mediated by interaction with angiotensin II and autocrine production of TGF-β.Several studies have clearly shown that both in type 1 and type 2 diabetic patients who already have microalbuminuria, ACE inhibition is effective in reducing renal progression. It has been proposed that the benefit is independent of blood pressure. Therefore, inhibition of RAAS plays an essential role in the treatment of hypertension and diabetes related complications. Studies focusing on renal end-points suggest that ACE are more effective than other traditional agents in reducing the onset of clinical proteinuria in both type 1 and type 2 diabetic patients with incipient nephropathy, mainly in normotensive ones (secondary prevention). However, several small trials in type 2 diabetic patients with overt nephropathy (tertiary prevention) failed to demonstrate a specific renoprotective role for ACE inhibitors, at variance with type 1 diabetes. Three recent large trials addressed the question of whether ARB prevented the development of clinical proteinuria or delayed the progression of nephropathy in type 2 diabetes. The IRMA study showed that irbesartan is more effective than conventional therapy in preventing the development of clinical proteinuria and favouring the regression to normoalbuminuria for comparable BP control in patients with incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more effective than traditional antihypertensive therapies in reducing progression towards end-stage renal failure in type 2 diabetic patients with overt nephropathy independently of changes in BP. Moreover, a reduction in hospitalization for heart failure was demonstrated by ARB-treated patients compared with placebo. The time course of antihypertensive and antialbuminuric effects after initiation of ARB treatment shows that the maximal antialbuminuric effect is seen within 7 days and therefore, primarily consequence of systemic and renal haemodynamic changes. However, non-haemodynamic effects such as reduced renal expression of TGF-β and other cytokines are likely to contribute to the long-term reno-protective effect. Furthermore, elevated levels of sVCAM-1 are independently associated with increased cardiovascular mortality in type 2 diabetes and blockade of RAAS may have an antiatherogenic effect in diabetic patients with elevated albumin excretion as evaluated by a reduction in concentrations of circulating adhesion molecules.A number of studies in diabetic renal disease have found an increased risk for renal function loss in patients homozygous for the D allele of the ACE/ID polymorphism compared to II patients, even during ACE inhibition. ARB treatment in hypertensive type 1 diabetic patients with DN homozygous for I or D allele of the ACE/ID polymorphism conferred similar beneficial effect on changes in urinary albumin excretion and rate of decline in GFR in patients with different genotypes. A large-scale trial comparing the effects of ARB treatment and ACE inhibition should be performed to further investigate the pharmacogenetic possibilities of ACE/ID polymorphism in treatment of diabetic renal disease.Preliminary studies have suggested that dual blockade of the RAAS by combined treatment with ACE inhibition and ARBs is well tolerated and reduces albuminuria and blood pressure in patients with type 2 diabetes and DN responding insufficiently to antihypertensive combination therapy, including the recommended dose of ACE inhibitor. However, long-term studies of dual blockade in incipient and overt DN should be initiated. Increasing evidence suggest an implication of aldosterone in the pathogenesis of progressive renal disease, which may suggest a beneficial effect of aldosterone blockade. Therefore, selective and non-selective aldosterone blockers are being investigated as future treatment options in DN. The increased expression of renal TGF-β and other cytokines in diabetic glomerulopathy may be lowered by RAAS blockade, but probably not completely abolished even by high-dose treatment. Therefore, agents that modulate other pathogenic pathways are being evaluated as potential treatment modalities in diabetic renal disease. These studies include agents that interfere in formation of advanced glycation end products, compounds targeting the activity of protein kinase C and antibodies/receptor blockers to cytokines such as TGF-β.After establishing the concept of renin uptake as the underlying cause of tissue angiotensin generation, focus is now on the mechanism that mediates this uptake process. Several renin receptors have already been described. These receptors also bind prorenin, and such binding results in prorenin activation, either proteolytically or non-proteotytically. This is important in view of earlier observations that prorenin levels in diabetic subjects are an indication of microvascular complications. Now that renin inhibitors will soon be clinically available, it will be of great interest to investigate how these drugs affect these mechanisms in comparison with other RAAS blockers. Eventually a new class of drugs might emerge, the renin receptor blockers, which selectively block angiotensin generation at tissue sites and/or renin receptor-mediated effects.