The Case for Cautious Consumption: NSAIDs in Chronic Kidney Disease

Sriram Sriperumbuduri; Swapnil Hiremath

Disclosures

Curr Opin Nephrol Hypertens. 2019;28(2):163-170. 

In This Article

NSAIDs and Chronic Kidney Disease

There is very little doubt that combination NSAID use, particularly including two NSAIDs and with caffeine, barbiturates and/or codeine, were responsible for CKD and end stage kidney disease (ESKD) in the past. In the modern era, that is since withdrawal of phenacetin, and decreased availability of the offending combinations, the question is whether NSAIDs should still be broadly castigated and vilified? High-quality large epidemiological studies do suggest a slightly higher risk of more rapid progression of CKD, albeit with several caveats.

In a study of over 10 000 community dwelling elderly (>65 years), a higher risk of rapid progression of CKD [defined as a glomerular filtration rate (GFR) decrease >15 ml/min/1.73 m2 over the period of study] was seen in NSAID users.[13] However, the increased risk was on the order of 25–30% higher risk, and observed only in those with GFR 60–89, and not in those with GFR less than 60. Moreover, this risk was isolated to those with high cumulative exposure to NSAIDs (e.g. 700 mg daily for ibuprofen for over 3 years, without a break). Such an increased risk was, however, not reported in all other epidemiological studies. In the Physicians Health Study, including about 4500 men, analgesic use was not associated with incident CKD, rapid progression or absolute change in creatinine, over a period of study of 14 years.[14,15] Similarly, in the Nurses Health Study, including ~1700 women, an increased risk of decreased kidney function (GFR decrease of >30 ml/min/1.73 m2 over 11 years) was not seen with self-reported aspirin or NSAID use.[16] Significantly, an increased risk was reported with higher acetaminophen use (adjusted odds ratio of 2.2) only in those who consumed over 3 kg of acetaminophen over a lifetime. Such an increased risk for albuminuria or decreased GFR (<60 ml/min/1.73 m2) was not seen in the 8000 participants of the 1999–2002 National Health and Nutrition Examination Survey for either habitual acetaminophen, ibuprofen or aspirin use.[17]

Most importantly, a common feature of all these epidemiological studies is that the profile of NSAID users was different from non-NSAID users. The toxicity of NSAIDs is now well known, unlike in the 1950–1980s. So individuals using NSAIDs are very likely using NSAIDs despite this well known and well publicized adverse effect profile. Is it possible that uncontrolled pain, underlying inflammatory diseases and higher chronic disease burden, which cause one to use NSAIDs at higher doses for longer periods of time, are associated with CKD and faster progression? The differential effect of acetaminophen compared with other NSAIDs seen in the Nurses Health Study might explain a rational shift in usage based on perceived risk by a population aware of the risk of NSAIDs. This selection bias (also labelled as 'protopathic bias') cannot be controlled away even with high-quality statistical adjustment.[18] Conversely, the paradoxical lower risk of progressive CKD reported in individuals with GFR less than 60 could reflect cautious and prudent use of NSAIDs in this population more than a genuinely protective effect.

One method of adjusting for confounding is to restrict the population to those who need an anti-inflammatory medication, as was done in this well conducted prospective cohort study including 4101 patients with rheumatoid arthritis (RA).[19] They reported no difference in GFR change between patients using an NSAID versus not using an NSAID, and the analysis did not change after adjusting for covariates, nor was a dose–response gradient observed. Even in this study, there were baseline differences between NSAID users and nonusers, an issue which can only be clarified in a sufficiently powered randomized trial. One such trial was performed, albeit comparing three different NSAIDs (celecoxib, naproxen and ibuprofen) in 24 222 patients with either osteoarthritis or RA and at high cardiovascular risk.[20] The renal outcomes, which was a composite of acute as well as long-term decrease in kidney function, was seen in only about 1% of all participants at the end of 3 years of follow-up. This is despite the high-risk patient profile: mean age was more than 60 years, they were mostly obese, 35% had diabetes, and more than 75% had hypertension. Moreover, the risk seemed to be lower with 200-mg celecoxib a day (0.7%) than 2400 mg ibuprofen daily (1.1%). Lastly, most patients did not need to take the NSAIDs for the entire follow-up of the study, almost 70% discontinued the study drug during follow-up, suggesting that most patients, even those with confirmed arthritis, do not need lifelong NSAIDs. Overall, even a systematic review of the literature around this topic concludes that the avoidance of NSAIDs is unnecessary in moderate to severe CKD.[21] There is a nonnegligible risk, but it is low and seems to be dependent partly on acute effects (see below) and on cumulative toxicity.

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