Proton pump inhibitor therapy is associated with an increased risk of chronic kidney disease compared to H2 receptor antagonist therapy in patients who did not first have an episode of acute kidney injury after starting acid suppression therapy

EBM Focus - Volume 12, Issue 23

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Reference – Kidney Int 2017 Jun;91(6):1482

  • Observational studies suggest that proton pump inhibitor (PPI) use may be associated with acute kidney injury (AKI) and chronic kidney disease (CKD). However, it is unknown whether there is an increased risk for CKD without first having an episode of AKI after starting PPI therapy.
  • In a retrospective cohort, 144,032 adults without kidney disease taking PPIs (in 87%) or histamine-2 (H2) receptor antagonists (in 13%) were assessed for renal outcomes over 5 years. The incidence of CKD without an intervening episode of AKI was investigated.
  • Compared to H2 receptor antagonist use, PPI use was associated with an increased risk of incident CKD occurring without an intervening episode of AKI (adjusted hazard ratio 1.26, 95% CI 1.2-1.33). Monitoring of renal function may be prudent in patients treated with PPIs.

Observational studies indicate that PPI use is associated with an increased risk of AKI and CKD compared to nonuse (JAMA Intern Med 2016 Feb;176(2):238). In addition, PPI use has been shown to be associated with an increased risk of CKD compared to H2 receptor antagonist use (J Am Soc Nephrol 2016 Oct;27(10):3153). To investigate whether there is an association between PPI use and CKD without an intervening AKI episode, a retrospective cohort study was conducted. The study included 144,032 United States veterans (mean age 58 years, 93% male) with first-time use of acid suppression therapy (87% took PPIs and 13% took H2 receptor antagonists). The patients had an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m2 within 90 days before their prescription and were assessed for renal outcomes over 5 years. In the analysis reported here, the patients were censored at the time of AKI occurrence if AKI occurred between the time of prescription for acid suppression therapy and occurrence of a chronic renal event. AKI was defined as an increase in serum creatinine by > 50% or by > 0.3 mg/dL (26.5 mcmol/L) within 90 days. The majority (82.5%) of patients did not have AKI during the time from prescription of acid suppression therapy to the end of follow-up.

The incidence of CKD occurring without an intervening episode of AKI was 24.8 per 1,000 person-years with PPIs vs. 18.8 per 1,000 person-years with H2 receptor antagonists (adjusted hazard ratio [HR] 1.26, 95% CI 1.2-1.33). The incidence of a > 30% decline in GFR was 28.4 vs. 22.8 per 1,000 person-years (adjusted HR 1.22, 95% CI 1.16-1.28) and incidence of a > 50% decline in eGFR was 4.5 vs. 3.3 per 1,000 person-years (adjusted HR 1.3, 95% CI 1.15-1.48). Consistent results were obtained in analyses excluding patients with AKI either before prescription or at any time after prescription to the end of follow-up and in several sensitivity analyses including those with different definitions of AKI.

This retrospective cohort study suggests that PPI use may increase the risk of developing CKD compared to H2 receptor antagonist use among patients without a preceding diagnosis of AKI. A potential limitation of this study is that some episodes of AKI may have gone undetected, as not all patients had frequent serum creatinine measurements (mean 4.6 outpatient measurements with a standard deviation of 5.6 measurements). This concern is somewhat mitigated by the expectation that both groups would have had similar rates of undetected AKI and that medication-induced AKI would be expected to persist with continued medication use, increasing the chance of AKI detection. Another concern is that the generalizability of the results is limited, as the cohort included mostly white males. Finally, although adjustment for potential confounding was extensive, residual confounding is still possible and as in all observational studies, inferences regarding causality should not be made. With these caveats in mind, these results indicate that PPIs may increase risk for the development of CKD compared to H2 receptor antagonists even in patients who do not develop AKI. It is worth noting that an American Gastroenterological Association Clinical Practice Update (Gastroenterology 2017 Mar;152(4):706) found an absence of evidence for or against screening patients on PPIs with serum creatinine. They suggested testing could be offered but the effectiveness of such testing was unproven. This new study should not alter this recommendation. While it may seem logical that screening could identify early signs of kidney impairment, which could be prevented from progressing by stopping the medications, proof of that would require a prospective study with sufficiently long follow up. Until then, periodic monitoring of renal function in patients treated with PPIs may be prudent.

For more information, see the Risk factors for chronic kidney disease topic in DynaMed plus. DynaMed users click here.