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Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j791 (Published 09 March 2017) Cite this as: BMJ 2017;356:j791

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Re: Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

Schmidt et al in this article report on the limitations of ACEI/ARB therapy when used as antihypertensive therapy especially as it applies to the potential nephrotoxicity of these agents 1. They demonstrated that increases in creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment 1. Furthermore, they showed that that creatinine increases after the start of ACEI/ARB treatment were associated with cardiorenal risks in a “dose-response” relation, with no distinct cut-off at 30%, as previously suggested 1. We very responsibly share these concerns.

In 2005, we described, for the first time, the previously unknown syndrome of late-onset renal failure from angiotensin blockade (LORFFAB) 2. Subsequently over the last ten years, we have variously described the features of this syndrome in various journal publications, book chapters and editorial pieces as well as in professional academic intellectual forums 3-8. It was indeed our work at the Mayo Clinic Health System in Northwestern Wisconsin that spurred the work of El Nahas and his group from the Sheffield Kidney Institute, Sheffield, in the United Kingdom 9. And the final result is that now we will have a RCT to determine whether withdrawal of ACEI/ARB in patients with advanced chronic kidney disease would result in improved cardiorenal outcomes - the ongoing STOP ACEi Trial 10,11. While we support the use of ACEI/ARB in the various pharmaceutical indications, we will continue to call for caution in the use of these agents, more so in older (>65-year old) patients with advanced stages of chronic kidney disease 12.

REFERENCES
1. Schmidt M, Mansfield KE, Bhaskaran K, Nitsch D, Sørensen HT, Smeeth L, Tomlinson LA. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ 2017;356:j791.
2. Onuigbo MA, Onuigbo NT. Late onset renal failure from angiotensin blockade (LORFFAB): a prospective thirty-month Mayo Health System clinic experience. Med Sci Monit. 2005 Oct;11(10):CR462-9. Epub 2005 Sep 26.
3. Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008;30:73-80.
4. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol. 2008;40(1):233-9. doi: 10.1007/s11255-007-9299-2. Epub 2008 Jan 15.
5. Onuigbo MA. Reno-prevention vs. reno-protection: a critical re-appraisal of the evidence-base from the large RAAS blockade trials after ONTARGET—a call for more circumspection. QJM 2009;102:155-167.
6. Onuigbo MA. Analytical review of the evidence for renoprotection by renin-angiotensin-aldosterone system blockade in chronic kidney disease - a call for caution. Nephron Clin Pract. 2009;113(2):c63-9, discussion c70. doi: 10.1159/000228536. Epub 2009 Jul 14.
7. Onuigbo MA. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2010 Apr;25(4):1344-5. doi: 10.1093/ndt/gfp678. Epub 2009 Dec 27.
8. Onuigbo MA. Can ACE inhibitors and angiotensin receptor blockers be detrimental in CKD patients? Nephron Clin Pract. 2011;118(4):c407-19. doi: 10.1159/000324164. Epub 2011 Mar 7.
9. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010;25:3977-82. doi:10.1093/ndt/gfp511.
10. Bhandari S, Ives N, Brettell EA, Valente M, Cockwell P, et al. Multicentre Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Withdrawal in Advanced Renal Disease. Nephrol Dial Transplant. 2016;31(2):255-261.
11. Onuigbo MA. The STOP-ACEi Trial - Apt timing for this long awaited randomised controlled trial - Validation of the syndrome of late-onset renal failure from angiotensin blockade (LORFFAB)? Int J Clin Pract. 2017 Jan;71(1). doi: 10.1111/ijcp.12916. Epub 2016 Dec 9.
12. Oh YJ, Kim SM, Shin BC, Kim HL, Chung JH, Kim AJ et al. The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease. PLoS One. 2017 Jan 25;12(1):e0170874. doi: 10.1371/journal.pone.0170874. eCollection 2017.

Competing interests: No competing interests

19 March 2017
MACAULAY A ONUIGBO
Physician - Nephrologist/Hypertension Specialist
Mayo Clinic, Rochester
Mayo Clinic Health System, 1221 Whipple Street, Eau Claire, WI 54702