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Limitations of angiotensin inhibition

Nature Reviews Nephrology volume 7, pages 356–359 (2011)Cite this article

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Abstract

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have beneficial effects in patients with cardiovascular disease and in those with diabetes-related and diabetes-independent chronic kidney diseases. These beneficial effects are independent of the antihypertensive properties of these drugs. However, ACE inhibitors, ARBs, and combinations of agents in these two classes are limited in the extent to which they inhibit the activity of the renin–angiotensin–aldosterone system (RAAS). Angiotensin breakthrough and aldosterone breakthrough may be important mechanisms involved in limiting the effects of ACE inhibitors and ARBs. Whether direct renin inhibitors will overcome some of the limitations of ACE-inhibitor and ARB therapy by blocking the deleterious effects of the RAAS remains to be proven. This important area is, however, in need of further investigation.

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Figure 1: Role of NFκB in mediating the effects of aldosterone in cardiovascular and kidney disease.
Figure 2: The pathways through which direct renin inhibitors, ACE inhibitors, ARBs and aldosterone-receptor antagonists inhibit the renin–angiotensin–aldosterone system are shown by the dashed lines.

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References

  1. Gerstein, H. C. et al. Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes: the MICRO-HOPE study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation. Diabetes Care 19, 1225–1228 (1996).

    Article  CAS  Google Scholar 

  2. McPherson, E. A. et al. Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 15, 493–500 (2004).

    Article  CAS  Google Scholar 

  3. Chapman, A. B., Johnson, A., Gabow, P. A. & Schrier, R. W. The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N. Engl. J. Med. 323, 1091–1096 (1990).

    Article  CAS  Google Scholar 

  4. Loghman-Adham, M., Soto, C. E., Inagami, T. & Cassis, L. The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney disease. Am. J. Physiol. Renal Physiol. 287, 755–768 (2004).

    Article  Google Scholar 

  5. Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).

    Article  CAS  Google Scholar 

  6. Brenner, B. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    Article  CAS  Google Scholar 

  7. Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N. Engl. J. Med. 329, 1456–1462 (1993).

    Article  CAS  Google Scholar 

  8. Wolf, G. & Ritz, E. Combinatin therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int. 67, 799–812 (2005).

    Article  CAS  Google Scholar 

  9. Nakao, N. et al. Combination treatment of angiotensin-II receptor blocker and angiotensin converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361, 117–124 (2003). Retraction in: Lancet 374, 1226 (2009).

    Article  CAS  Google Scholar 

  10. Pfeffer, M. A. et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362, 759–766 (2003).

    Article  CAS  Google Scholar 

  11. Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med. 358, 1547–1559 (2008).

    Article  CAS  Google Scholar 

  12. Cohn, J. N. et al. Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valslartan Heart Failure Trial. Circulation 108, 1306–1309 (2003).

    Article  CAS  Google Scholar 

  13. Yusuf, S. et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342, 145–153 (2000).

    Article  CAS  Google Scholar 

  14. Staessen, J., Lijnen, P., Fagard, R., Verschueren, L. J. & Amery, A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J. Endocrinol. 91, 457–465 (1981).

    Article  CAS  Google Scholar 

  15. Bomback, A. S. & Klemmer, P. J. The incidence and implications of aldosterone breakthrough. Nat. Clin. Pract. Nephrol. 3, 486–492 (2007).

    Article  CAS  Google Scholar 

  16. Schjoedt, K. J., Anderson, S., Rossing, P., Tarnow, L. & Parving, H. H. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 47, 1936–1939 (2004).

    Article  CAS  Google Scholar 

  17. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study investigators. N. Engl. J. Med. 341, 709–717 (1999).

    Article  CAS  Google Scholar 

  18. Pitt, B., Bakris, G., Ruilope, L. M., DiCarlo, L. & Mukherjee, R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 118, 1643–1650 (2008).

    Article  CAS  Google Scholar 

  19. Schrier, R. W., Masoumi, A. & Elhassan, E. Aldosterone: role in edematous disorders, hypertension, chronic renal failure, and metabolic syndrome. Clin. J. Am. Soc. Nephrol. 5, 1132–1140 (2010).

    Article  CAS  Google Scholar 

  20. Schrier, R. W. Aldosterone 'escape' vs 'breakthrough.' Nat. Rev. Nephrol. 6, 61 (2010).

    Article  Google Scholar 

  21. Battenburg, W. W. & Jan Danser, A. H. The (pro)renin receptor: a new addition to the renin-angiotensin system? Eur. J. Pharmacol. 585, 320–324 (2008).

    Article  Google Scholar 

  22. Lindenmeyer, M. T. et al. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J. Am. Soc. Nephrol. 18, 1765–1776 (2007).

    Article  CAS  Google Scholar 

  23. Kang, J. J. et al. The collecting duct is the major source of prorenin in diabetes. Hypertension 51, 1597–1604 (2008).

    Article  CAS  Google Scholar 

  24. Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).

    Article  CAS  Google Scholar 

  25. Riccioni, O., Vitulano, N., D'Orazio, N. & Bellocci, F. Aliskiren, the first approved renin inhibitor: clinical application and safety in the treatment of hypertension. Adv. Ther. 26, 700–710 (2009).

    Article  CAS  Google Scholar 

  26. Parving, H. H. et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 358, 2433–2446 (2008).

    Article  CAS  Google Scholar 

  27. Parving, H. H. et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol. Dial. Transplant. 24, 1663–1671 (2009).

    Article  CAS  Google Scholar 

  28. McMurray, J. J. et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ. Heart Fail. 1, 17–24 (2008).

    Article  CAS  Google Scholar 

  29. Sanoski, C. A. Aliskiren: an oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 29, 193–212 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Jan Darling for her editorial assistance.

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Authors and Affiliations

  1. Division of Nephrology, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 565-59, Los Angeles, 90095, CA, USA

    Niloofar Nobakht, Mohammad Kamgar & Anjay Rastogi

  2. Division of Renal Diseases & Hypertension, University of Colorado Denver, Box C281, 12700 East 19th Avenue, Aurora, 80045, CO, USA

    Robert W. Schrier

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All authors researched the data for the article, provided a substantial contribution to discussion of content, and contributed to the review and/or editing of the manuscript before submission. R. W. Schrier and N. Nobakht contributed equally to writing the article.

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Correspondence to Robert W. Schrier.

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Nobakht, N., Kamgar, M., Rastogi, A. et al. Limitations of angiotensin inhibition. Nat Rev Nephrol 7, 356–359 (2011). https://doi.org/10.1038/nrneph.2011.29

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