Abstract
BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and it affects 30% of patients with type 1 diabetes mellitus (DM) and 20% of patients with type 2 DM. Clinical features in both types of DM are similar and are characterized by an underlying abnormality of the microcirculation, manifested by both retinopathy and nephropathy. Clinical hallmarks of DN include elevated blood pressure (BP) and elevated urinary protein excretion. Treatment consists of maintaining BP at <130/85 mm Hg in patients without proteinuria and <125/75 mm Hg in patients with microalbuminuria or overt DN. In addition, agents that inhibit the renin-angiotensin-aldosterone system (RAAS) have been found to be effective in reducing the risk of progression to DN, a result independent of their antihypertensive effect. SUMMARY: The earlier Collaborative Study Group (CGS) trial demonstrated that the angiotensin-converting enzyme (ACE) inhibitor captopril lowered BP and provided renal protection in type 1 diabetic kidney disease beyond that attributable to the BP change. The Irbesartan Diabetic Nephropathy Trial (IDNT) studied the effect of the angiotensin receptor blocker (ARB) irbesartan on the reduction of BP, urinary protein excretion, and progression to DN. The study end points in the IDNT demonstrated that ARB therapy reduced BP, reduced urinary protein excretion, and provided renal protection against progression to DN. The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) trial demonstrated that the ARB losartan, when combined with conventional antihypertensive agents, decreased urinary protein excretion by 35%. Losartan both lowered BP and provided renal protection against DN. In a study comparing an ACE inhibitor (trandolapril), an ARB (losartan), and a combination of the 2 agents (trandolapril and losartan), data showed that all 3 arms reduced BP to the same degree. However, a combination of the ARB plus the ACE inhibitor produced both a significant reduction in urinary protein excretion beyond that seen with either agent alone and a significantly greater protection against progression to doubling of serum creatinine or ESRD. The reduction in urinary protein excretion and renal progression seen with individual agents were not statistically different from each other. CONCLUSION: These studies demonstrated that the combination blockade of the RAAS axis with an ARB plus an ACE inhibitor may play an important role in the prevention and treatment of DN and may turn the tide of increasing kidney disease due to DM, improve the overall quality of life of patients