Antiproteinuric Therapies in Diabetic Nephropathy

Mechanistic experimental studies support that proteinuria is a risk factor but growth factor cytokines that are present in proteinuric glomerular ultrafiltrate are culprits in entertaining tubulo-interstitial fibrogenesis. Thus, the goal is to reduce glomerular macromolecule filtration. To this end angiotensin-converting enzyme (ACE) inhibitors have become the standard of care in DN. Substantial reductions in proteinuria can also be achieved with angiotensin receptor blockers (ARBs). In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, the level of proteinuria in type 2 diabetic patients with nephropathy who were treated with losartan decreased, on an average by 35% (58). Losartan has also been shown to reduce urinary TGF-P excretion without affecting TGF-P serum levels (59). With irbesartan, proteinuria can be reduced by approx 60% in type 2 diabetics with nephropathy and microalbuminuria as demonstrated in the Irbesartan in Microalbuminuria (IRMA)-2 study (60). A review of multiple clinical trials indicates that ACE inhibitors or ARBs are beneficial in patients with DN and reduce the rates of proteinuria as well as of the progression of renal failure (61).

ACE inhibitors, even at maximum dosages, do not completely block angiotensin II generation. Some angiotensin II persists, perhaps through parallel, ACE-independent pathways. Thus, theoretically, combination therapies with an ACE inhibitor and an ARB may provide additive benefits. This question has undergone only very limited clinical study thus far. Further reductions in proteinuria and urinary excretion of TGF-P with combined therapy using ramipril or candesartan in comparison with ramipril alone was demonstrated in a small trial in patients with IgA-nephropathy, but this benefit was not achieved in patients with DN (33). The COOPERATE trial demonstrated added benefit of combination therapy with losartan and trandolapril in patients with nondiabetic renal diseases but similar studies in DN are presently not available (62). Moreover, combinations of ACE inhibitors and ARBs may increase the risk for serious complications such as symptomatic hyperkalemia.

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