Renal Toxicity Associated with Salsalate in Elderly Adults with Anemia (2016)

We are writing to caution the geriatrics community about the possibility of serious adverse renal toxicity occurring with the use of salsalate in older individuals. Salsalate, a nonsteroidal anti-inflammatory nonacetylated form of salicylate, is one of the oldest drugs available to clinicians and has been used to treat inflammatory conditions such as rheumatological disorders. 1 Although not as widely used as aspirin (the acetylated form), it has had a recent renaissance in use, in part because of its relative lack of cyclooxygenase-2 inhibition and resultant fewer gastrointestinal (GI) side effects.1, 2 In particular, because of its ability to regulate the nuclear factor kappa beta pathway,3 it has been studied in a number of recent clinical trials using doses of 3.0 to 4.5 g/d for the management of type 2 diabetes mellitus.1, 4 Its potential to reduce insulin resistance and other risk factors for diabetes mellitus has been demonstrated, and it has been found to do so with “few if any side effects,”1, 5, 6 but these trials have included few elderly participants. For example, in one trial, the mean age of subjects was 56.2 A number of subjects, more in the salsalate than the placebo arm, had mild decreases in renal function, but no serious adverse renal toxicities were noted. Recently, as part of the work of a consortium supported by the National Institute on Aging, The Partnership for Anemia: Clinical and Translation Trials in the Elderly (PACTTE),7 a Phase II trial of salsalate to treat unexplained anemia in elderly adults (www.clinicaltrials.gov, NCT01506726) was initiated based on the hypothesis that an anti-inflammatory agent could improve hemoglobin levels because of its effect on the putative contribution of chronic age-related inflammation to unexplained anemia in elderly adults. We chose salsalate because of its reputed advantageous side effect profile. The target enrollment was 32 in each group. Subjects aged 65 and older with unexplained anemia with interleukin-6 levels greater than 1.0 pg/mL, 6-minute walk times less than the expected range for median age, and an estimated glomerular filtration rate greater than 30 mL/min (4-variable Modified Diet in Renal Disease) were randomized one to one to salsalate or placebo; hemoglobin levels and walking speed at 6 months were the primary outcome measures. The initial dose was 1.5 g/d, if tolerated, increasing to 3.0 g/d. As has been the case for other trials of unexplained anemia in elderly adults,7 it was difficult to recruit for this study. The observation of adverse events early in the study, which was ultimately terminated early on the advice of the Data and Safety Monitoring Board, after enrollment of only 11 subjects further complicated this. One subject (baseline creatinine 1.3 mg/dL) treated with the initial dose for 2 weeks had diarrhea associated with nausea, abdominal pain, dehydration, and acute renal failure (creatinine 5.7 mg/dL), which partially resolved after vigorous hydration. Another subject (baseline creatinine 0.8 mg/dL) had diarrhea and a decrease in renal function (peak creatinine 1.5 mg/dL) after being treated with the initial dose for 1 month and was taken off the drug. Diarrhea recurred after readministration, so the drug was discontinued again, and the individual received intravenous fluids, with no recurrence of the renal dysfunction. Although diarrhea (1/5) and nausea (2/5) were also seen in the placebo group, no decreases in renal function were noted. Attributable adverse events are shown in Table 1. Although the number of subjects reported here is too small to draw definitive conclusions, this experience suggests that, if salsalate is to be used in older individuals, especially those who may be frail or prefrail, practitioners should be especially alert to the possibility of renal failure especially in the context of diarrhea and dehydration. An additional concern is that these adverse events occurred at a dose half that used in reported trials. Given that older adults are frequently underrepresented in clinical trials, these observations highlight the importance of having sufficient numbers of older adults in trials of agents likely to be used in that population. Conflict of Interest: The authors declare no competing interests. Author Contributions: All authors contributed to this paper. Sponsor's Role: None.