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Little Warning of CKD Progression in Veterans Using Proton Pump Inhibitors

by U.S. Medicine

June 13, 2017

By Brenda L. Mooney

ST. LOUIS — While renal symptoms are a known side effect of proton pump inhibitors, the assumption always has been that the drugs could be discontinued before any lasting damage was done.

A new VA study has determined that is not the case and, in patients using PPIs, chronic kidney issues often occur without the warning of an acute presentation.1

The damage occurs so silently, according to the report published recently in the journal Kidney International, prescribers might not realize the need to discontinue the drugs. PPIs are marketed under brand names such as Prevacid, Prilosec, Nexium and Protonix, as well as generics and over-the-counter formulations.

When the popular heartburn medications are used for prolonged periods, serious renal damage can occur, even in patients who show no signs of kidney problems, pointed out researchers at the VA St. Louis Health Care System and Washington University School of Medicine in St. Louis.

The new study of 125,000 VA patients suggested that more than half of those who develop chronic kidney damage on PPIs never presented with acute kidney problems beforehand. Because of that, the researchers urged VA clinicians to be more vigilant in monitoring use of the medications.

“Our results indicate kidney problems can develop silently and gradually over time, eroding kidney function and leading to long-term kidney damage or even renal failure,” explained senior author Ziyad Al-Aly, MD. “Patients should be cautioned to tell their doctors if they’re taking PPIs and only use the drugs when necessary.”

For the study, researchers analyzed data from the VA databases on 125,596 new users of PPIs and 18,436 new users of H2 blockers. Over five years of follow-up, results indicated that more than 80% of PPI users did not develop acute kidney problems, which usually are reversible issues with symptoms such as fatigue and swelling in the legs and ankles.

Still, more than half of the cases of chronic kidney damage and end-stage renal disease associated with PPI use occurred in veterans who had not previously been found to have acute kidney problems, study authors cautioned.

Among new users of H2 blockers, on the other hand, only 7.67% developed chronic kidney disease in the absence of acute kidney problems, and 1.27% developed end-stage renal disease.

End-stage renal disease occurs when the kidneys can no longer effectively remove waste from the body. In such cases, dialysis or a kidney transplant is needed to keep patients alive.

Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m2 (hazard ratio 1.19), incident CKD (HR 1.26), eGFR decline over 30% (HR 1.22) and end stage renal disease (ESRD) or eGFR decline over 50% (HR 1.30).

The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m2, incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively, according to the study, which adds, “Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.”

Multivariate logistic regression models of the association between PPI use and the odds of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) where the last eGFR before the first occurrence of AKI, ESRD, death, or end of follow-up was used to define outcomes (N = 144,032)
  No. (%) of eventsa Univariate ORb

(95% CI)
Multivariate ORb,c

(95% CI)
H2 blockers PPIs
eGFR <60 ml/min per 1.73 m2 2041 (11.07) 17,463 (13.90) 1.30 (1.24–1.36) 1.26 (1.19–1.32)
>30% decrease in eGFR 1342 (7.28) 11,493 (9.15) 1.28 (1.21–1.36) 1.24 (1.17–1.31)
>50% decrease in eGFR 292 (1.58) 2272 (2.21) 1.40 (1.24–1.58) 1.34 (1.19–1.52)

AKI, acute kidney disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; OR, odds ratio; PPIs, proton pump inhibitors.

aBased on a comparison of the first and last eGFRs, in which the last eGFR was the eGFR before and closest to first occurrence of AKI, ESRD, death, or end of follow-up.
bH2 blockers serve as the reference group.
cMultivariate model controlling for first eGFR, age, race, sex, smoking, body mass index, diastolic and systolic blood pressure, nonsteroidal anti-inflammatory drug; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, number of outpatient serum creatinine measurements, number of hospitalizations, diabetes mellitus, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, cancer, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, Helicobacter pylori infection, Barrett’s esophagus, achalasia, stricture, and esophageal adenocarcinoma.

 

Monitor Kidney Function

“Doctors must pay careful attention to kidney function in their patients who use PPIs, even when there are no signs of problems,” warned Al-Aly, who also is the VA’s associate chief of staff for research and education and co-director of the VA’s Clinical Epidemiology Center. “In general, we always advise clinicians to evaluate whether PPI use is medically necessary in the first place, because the drugs carry significant risks, including a deterioration of kidney function.”

Up to now, the supposition has been that users of PPI would develop AKI before developing chronic injury would “(i) offer a warning sign and induce avoidance of PPIs as acid suppressants and (ii) identify those at risk and who are susceptible to (or with a predilection for) chronic renal outcomes associated with PPI use,” study authors pointed out.

 

“Our study was designed to address this knowledge gap and answer this clinically relevant question; the results suggest that a significant association exists between PPI use and CKD outcomes without an intervening AKI,” they wrote. “The finding that PPI use is associated with adverse chronic renal outcomes independent of the occurrence of AKI suggests that monitoring for AKI or acute interstitial nephritis among PPI users is not sufficient to guard against the development of CKD and ESRD.”

The researchers also said they conducted a PubMed search and found no published animal studies on PPI-induced acute or chronic renal injury. “The conspicuous absence of published literature evaluating possible mechanisms of PPI-related renal injury suggests a significant knowledge gap and highlights the pressing need for experimental work to further enhance our understanding of the effect of PPIs on the kidney,” they suggested.

“In sum, our results show a significant association of PPI use and the risk of CKD and progression to ESRD in the absence of intervening AKI,” study authors concluded. “Reliance on antecedent AKI as warning sign to guard against the risk of the development of CKD and progression to ESRD among PPI users is not sufficient as a sole risk mitigation strategy. Exercising vigilance in PPI use, even in the absence of AKI, and careful attention to kidney function in PPI users may be a reasonable approach.”

 

Survival models of the association of PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants included those with no AKI before onset of chronic renal outcome (excluded from cohort entry those participants with AKI between the time of cohort entry time 0 and before chronic renal outcome)
  Incident ratea

(95% CI)
Univariate hazard ratiob (95% CI) Multivariate hazard ratiob,c (95% CI)
H2 blockers PPIs
Incident eGFR <60 ml/min per 1.73 m2, N = 124,788 44.78 (43.22–46.39) 57.27 (56.57–57.99) 1.27 (1.22–1.32) 1.22 (1.17–1.27)
Incident chronic kidney disease, N = 121,478 19.76 (18.76–20.80) 26.62(26.16–27.10) 1.35 (1.28–1.42) 1.29 (1.22–1.36)
>30% decrease in eGFR, N = 122,337 23.82 (22.72–24.97) 30.46 (29.96–30.96) 1.28 (1.22–1.34) 1.26 (1.19–1.32)
ESRD or >50% decrease in eGFR, N = 119,578 3.51 (3.10–3.95) 4.83 (4.64–5.03) 1.38 (1.21–1.56) 1.35 (1.19–1.53)

AKI, acute kidney injury; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; OR, odds ratio; PPIs, proton pump inhibitors.

aIncident rate as incident kidney outcome occurrence per 1000 person-years.
bH2 blockers serve as the reference group.
cMultivariate model controlling for first eGFR, age, race, sex, smoking, body mass index, diastolic blood pressure, systolic blood pressure, nonsteroidal anti-inflammatory drug, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, number of outpatient serum creatinine measurements, number of hospitalizations, diabetes mellitus, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, cancer, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, Helicobacter pylori infection, Barrett’s esophagus, achalasia, stricture, and esophageal adenocarcinoma.
  1. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017 Feb 20. pii: S0085-2538(17)30005-4. doi: 10.1016/j.kint.2016.12.021. [Epub ahead of print] PubMed PMID: 28237709.

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