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Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.e8525 (Published 08 January 2013) Cite this as: BMJ 2013;346:e8525

Re: Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study

We read with great interest the recent report by Lapi et al on the impact of NSAIDs use on nephrotoxicity associated with the concurrent use of diuretics, ACE inhibitors and ARBs (1). This United Kingdom study was carried out using the Clinical Practice Research Datalink (CPRD), the world’s largest computerized database of longitudinal records from primary care (1). Given the large number (487 372 patients), the relatively long follow up of 5.9 years, and thus generating 3 047 813 person years of follow-up, this was a very commendable study. The investigators had identified 2215 cases of acute kidney injury (AKI) during follow-up, yielding an overall incidence rate of 7/10 000 (95% confidence interval 7/10 000 to 8/10 000) person years (2). Just recently, Hsu et al had reported a rapidly increasing rise in the incidence of serious AKI requiring dialysis in the United States of America (2). Hsu et al demonstrated that from 2000 to 2009, the incidence of dialysis-requiring AKI in the USA had increased from 222 to 533 cases per million person-years, averaging a 10% increase per year (incidence rate ratio=1.10, 95% CI=1.10–1.11 per year) (2). The authors while noting that the number of deaths associated with dialysis-requiring AKI had more than doubled during the period had concluded that they were unable to entirely explain the rising incidence of dialysis-requiring AKI (2). Clearly, from the foregoing, the impact of AKI on patient and renal outcomes cannot be overemphasized. Moreover, despite the availability of renal replacement therapy in so-called developed countries, AKI remains a formidable foe and more preventative efforts to reduce the incidence of AKI are warranted (3).

In our 2008 report of AKI on CKD occurring in a 100-patient cohort followed prospectively for several years at the Mayo Clinic Health System in Eau Claire, Wisconsin, USA, of the 100 patients recruited into the study with increasing baseline serum creatinine, while concurrently on an ACEI, an ARB or both, 10 (10%) of them had a clear association with concurrent use of NSAIDs or cox II inhibitors (3-5). As early as 2000, Thomas in an Australian report had described the potential nephrotoxic harm from the combined use of diuretics, ACE inhibitors and NSAIDs, and had introduced the so-called “triple whammy” into the medical literature (6).

Finally, while congratulating Lapi et al for an excellent study, this should be a call to all physicians and healthcare providers around the world to be more aware of the potential nephrotoxicities of these agents, used singly or worse still in combination (3-6). There is this overarching need for us all to make every effort to limit the use of medications, always picking and choosing the ones that would cause the least harm to our patients (3-6). Indefinite monitoring of kidney function, especially in our older patients must be the norm and physicians must be willing and ready to discontinue such medications at any time when unexplained AKI is diagnosed (3).

REFERENCES
1. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013; 346: e8525. Published online 2013 January 8. doi: 10.1136/bmj.e8525
2. Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu C. Temporal Changes in Incidence of Dialysis-Requiring AKI. J Am Soc Nephrol 2012 vol. 24 no. 1:37-42.
3. Onuigbo MAC. 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. South African Excerpts Edition. 2009; 8(3):169-181.
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. Epub 2008 Jan 15. PMID:18196471. DOI:10.1007/s11255-007-9299-2.
5. 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(1):73-80. PMID:18197547. DOI:10.1080/08860220701742161.
6. Thomas MC. Diuretics, ACE inhibitors and NSAIDs--the triple whammy. Med J Aust. 2000 Feb 21;172(4):184-5.

Competing interests: No competing interests

17 January 2013
Macaulay A. Onuigbo
Nephrologist & Hypertension Specialist
Mayo Clinic, Rochester, MN, USA & Mayo Clinic Health System, Eau Claire, WI, USA
1221 Whipple Street, Eau Claire, WI 54702
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