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  • Review Article
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The effect of RAAS blockade on the progression of diabetic nephropathy

Nature Reviews Nephrology volume 10, pages 77–87 (2014)Cite this article

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A Correction to this article was published on 11 March 2014

This article has been updated

Key Points

  • Renin–angiotensin–aldosterone system (RAAS) blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, which have antihypertensive and antialbuminuric properties, has become the cornerstone of treatment of diabetic renal disease

  • As single-agent RAAS blockade does not completely block RAAS activation the residual renal risk of treated patients is high

  • Data from clinical trials of dual RAAS blockade (including the use of aldosterone blockers or renin inhibitors) are contradictory and safety remains a concern

  • Possible alternatives to dual RAAS blockade include restricting dietary sodium, increasing drug doses or using novel drugs to block the deleterious effects of RAAS activation whilst preserving its physiological role

  • Novel omic techniques might enable the identification of patients who are most likely to benefit from RAAS blockade and the individual tailoring of interventions

Abstract

The renin–angiotensin–aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy.

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Figure 1: Current and potential targets for therapeutic interventions in the RAAS cascade.
Figure 2: Randomized controlled trials that have investigated the effects of RAAS blockade at the various stages of progression of diabetic nephropathy.
Figure 3: The effect of enalapril versus metoprolol on surrogate outcomes in patients with type 1 diabetes (n = 40).
Figure 4: Residual risk of ESRD in patients with hypertension and diabetic nephropathy receiving angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker therapy (n = 1,428).
Figure 5: The addition of spironolactone (25 mg per day) to renin–angiotensin–aldosterone system blockade in diabetic patients with proteinuria (n = 87) resulted in an initial acute fall in eGFR and a sustained reduction in proteinuria.64

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Change history

  • 11 March 2014

    In the February 2014 issue of Nature Reviews Nephrology, the key in Figure 4 of this article was labelled incorrectly. The correct labelling is as follows: pale green <1; dark green 1–2, blue 2–3; purple >3.5. This error has been corrected online.

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  1. Department of Clinical Pharmacology, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713, AV, Netherlands

    Sara S. Roscioni, Hiddo J. Lambers Heerspink & Dick de Zeeuw

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  1. Sara S. Roscioni
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  2. Hiddo J. Lambers Heerspink
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  3. Dick de Zeeuw
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Contributions

S. S. Roscioni and H. J. Lambers Heerspink contributed equally to researching the data for the article and writing the manuscript. D. de Zeeuw reviewed and/or edited the manuscript before submission. All authors made a substantial contribution to discussions of the content.

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Correspondence to Dick de Zeeuw.

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Competing interests

S. S. Roscioni declares no competing interests. H. J. Lambers Heerspink has consulted for AbbVie, Astellas, Johnson & Johnson, Reata Pharmaceuticals, and Vitae. D. de Zeeuw has consulted for AbbVie, Astellas, Chemocentryx, Johnson & Johnson, Novartis, Reata Pharmaceutical, Takeda, and VITAE.

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Roscioni, S., Heerspink, H. & de Zeeuw, D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephrol 10, 77–87 (2014). https://doi.org/10.1038/nrneph.2013.251

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