Next to GI adverse events, most patients (and many doctors) worry about the impact of NSAIDs on the kidneys. Some studies estimate that 25% of patients experience transient renal adverse events on starting NSAIDs – typically salt and fluid retention and elevations of blood pressure – but these return to baseline after 3-7 days. Only 5% of patients receiving NSAIDs experience persistent serious renal adverse events. It is impossible to rank NSAIDs based on their renal side effects because comparative data are scarce if not existent. 1
Most major prostanoids (PGD2, PGE2, PGF2a, PGI2 and thromboxane A2) are expressed in the kidneys. PGE2 is a renal vasodilator and has a major role in salt and water excretion in the kidneys. PGI2 likewise behaves as a renal vasodilator. Both PGE2 and PGI2 are affected by the action of NSAIDs on COX enzymes. Some renal AEs are PGE2 mediated like sodium retention, hypertension and fluid retention (which may lead to peripheral edema and congestive heart failure in predisposed individuals). Hyperkalemia and acute renal failure are mediated by NSAID action on PGI2. Other rare renal AEs include interstitial nephritis, renal papillary necrosis and chronic renal failure.
Based on the review of Harirforoosh (2013)1 acute declines of renal function were higher among patients with hypertension, diabetes mellitus, heart failure and those concomitantly using ACE inhibitors, ARBs, diuretics and aminoglycosides.
Whelton (2006)2 performed a subanalysis of the Celecoxib Long Term Arthritis Safety Study (CLASS) – looking into the renal adverse events among arthritis patients receiving celecoxib 400 mg twice daily (which is 2x the usual dose given to osteoarthritis patients), diclofenac 75 mg twice daily and ibuprofen 800 mg thrice daily (usual doses given to osteoarthritis patients). Patients on ibuprofen had higher rates of peripheral edema and hypertension compared to those who took celecoxib and diclofenac. However, more patients who took diclofenac had declines in renal function compared to celecoxib and ibuprofen users. Interestingly, among azotemic patients (or those with elevated serum creatinine at baseline) more patients on diclofenac and ibuprofen had clinically significant declines in renal function (i.e. serum Crea increase of >0.5mg/dl from baseline, absolute serum crea >1.5mg/dl or decline of renal function >30ml/min relative to baseline) compared to celecoxib (7.3% vs. 7.3% vs. 3.7%, p<0.05).
Zhang (2006)3 performed a meta-analysis of randomized trials to evaluate renal adverse events (hypertension, edema and renal dysfunction) among coxib users. 114 randomized double blind trials enrolling 116,094 participants were included. The coxib studies included 40 for rofecoxib, 37 for celecoxib, 29 for valdecoxib + parecoxib, 15 for etoricoxib and 6 for lumiracoxib. Compared to placebo or traditional (non-selective) NSAID users (the two were not separated so we can’t say if tNSAIDS likewise increased renal AEs or not), patients on rofecoxib had increased risks for peripheral edema (RR 1.43; 95% CI 1.23-1.66), hypertension (RR 1.55; 95% CI 1.29-1.85) and renal dysfunction (RR 2.31; 95% CI 1.05-5.07). In contrast, celecoxib users had lower risks for both renal dysfunction (RR 0.61; 95% CI 0.40-0.94) and hypertension (RR 0.83; 95% CI 0.71-0.97). Other agents were not associated with significantly risk for renal adverse events. Based on Zhang’s study, a class effect among coxibs was not evident.
Nderitu (2013)4 recently published an interesting paper on NSAIDs and progression of chronic kidney disease (CKD). He performed a systematic review of 7 studies (5 cohorts, 1 case-control and 1 cross-sectional studies) but only three of these were included in a meta-analysis. Regular doses of NSAIDs (dose were not properly defined) did not accelerate the progression of CKD (OR 0.96; 95% CI 0.86-1.07) but higher doses of NSAIDs did (OR 1.26; 95% CI 1.06-1.50). Patients included in the meta-analysis had moderate to severe CKD (defined as Crea clearance <60ml/min). It concluded that avoidance of NSAIDs in the medium term among moderate-to-severe CKD is unnecessary, unless otherwise contraindicated. As the definition for high dose NSAIDs were unclear, the lowest effective doses of NSAIDs should be prescribed when indicated.
So, how do we prescribe NSAIDs when there are concerns over renal safety? Patients who are candidates for NSAID therapy should be profiled in terms of their risk for renal adverse events. An NSAID that poses the lowest risk for the patient given his specific renal risk profile should be prescribed at the lowest effective dose for the shortest duration needed. Monitoring for renal adverse events should be done – particularly if NSAID therapy is prolonged.
- Harirforoosh S, Asghar W, Jamali F. Adverse effects of non-steroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 2013; 16 (5): 821-47.
- Whelton A, Lefkowith JL, West CR, et al. Cardiorenal effects of celecoxib as compared with the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen. Kidney Int 2006; 70:1495-1502.
- Zhang J, et al. Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhtyhmia Events. JAMA 2006; 296:1619-32.
- Nderitu P, et al. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Fam Prac 2013; 30: 247-55.
- Weir MR. Renal effects of non-selective NSAIDs and coxibs. Cleveland Clinic J Med 2002; 69(SI):53-58.