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The RAAS in the pathogenesis and treatment of diabetic nephropathy

Abstract

Angiotensin II and other components of the renin–angiotensin–aldosterone system (RAAS) have a central role in the pathogenesis and progression of diabetic renal disease. A study in patients with type 1 diabetes and overt nephropathy found that RAAS inhibition with angiotensin-converting-enzyme (ACE) inhibitors was associated with a reduced risk of progression to end-stage renal disease and mortality compared with non-RAAS-inhibiting drugs. Blood-pressure control was similar between groups and proteinuria reduction was responsible for a large part of the renoprotective and cardioprotective effect. ACE inhibitors can also prevent microalbuminuria in patients with type 2 diabetes who are hypertensive and normoalbuminuric; in addition, ACE inhibitors are cardioprotective even in the early stages of diabetic renal disease. Angiotensin-II-receptor blockers (ARBs) are renoprotective (but not cardioprotective) in patients with type 2 diabetes and overt nephropathy or microalbuminuria. Studies have evaluated the renoprotective effect of other RAAS inhibitors, such as aldosterone antagonists and renin inhibitors, administered either alone or in combination with ACE inhibitors or ARBs. An important task for the future will be identifying which combination of agents achieves the best renoprotection (and cardioprotection) at the lowest cost. Such findings will have major implications, particularly in settings where money and facilities are limited and in settings where renal replacement therapy is not available and the prevention of kidney failure is life saving.

Key Points

  • Angiotensin II has a major role in the pathogenesis and progression of diabetic renal disease, and inhibition of angiotensin II production or activity using angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-II-receptor blockers (ARBs) is renoprotective in patients with diabetes

  • ACE inhibitors have a cardioprotective effect in patients with diabetes and renal disease that is not seen with ARBs

  • Early intervention with ACE inhibitors may prevent the onset of microalbuminuria, which is an early sign of renal involvement and a marker of cardiovascular disease in individuals with diabetes.

  • Late intervention with ACE inhibitors or ARBs in patients who have type 2 diabetes, renal insufficiency and nephrotic-range proteinuria is not very effective, which highlights the importance of early intervention and the urgent need for novel treatments in this population

  • Increasing the dosage of ACE inhibitors and ARBs above the recommended antihypertensive doses and combined therapy with both classes of drug are the most effective ways of reducing albuminuria and, conceivably, of maximizing renoprotection

  • Aldosterone-receptor antagonists and direct renin inhibitors may also reduce albuminuria in patients with diabetes; long-term clinical trials are needed to assess whether these medications offer advantages over ACE inhibitors and ARBs, alone or in combination

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Figure 1: The RAAS and examples of RAAS inhibitors that are available for oral treatment.

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Acknowledgements

The authors would like to thank Manuela Passera, secretary of the Mario Negri Institute for Pharmacological Research, Bergamo, Italy, for her editorial assistance in the preparation of this manuscript.

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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Correspondence to Giuseppe Remuzzi.

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Ruggenenti, P., Cravedi, P. & Remuzzi, G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol 6, 319–330 (2010). https://doi.org/10.1038/nrneph.2010.58

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