Blog entry by Meguid El Nahas

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by Meguid El Nahas - Monday, 17 October 2016, 4:15 PM
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PPI and CKD: an association… but is it causality?

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease.

JAMA Intern Med. 2016 Feb;176(2):238-46. doi: 10.1001/jamainternmed.2015.7193.

Lazarus B1Chen Y2Wilson FP3Sang Y2Chang AR4Coresh J5Grams ME5.


Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD).


To quantify the association between PPI use and incident CKD in a population-based cohort.


In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System.


Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator.


Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort.


Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21).


Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.

J Am Soc Nephrol. 2016 Oct;27(10):3153-3163. Epub 2016 Apr 14.

Xie Y1Bowe B1Li T2Xian H3Balasubramanian S1Al-Aly Z4.


The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.


These two epidemiological studies found a higher significant risk of CKD in patients treated with PPI, notably in comparison with antiH2. It is the merit of the authors to have analyzed large databases of patients with modern, advanced and especially various statistical models. Contrary to other epidemiological studies, the CKD definition is relatively more consistent, especially in the JASN study. Indeed, even if based on eGFR, the authors have also considered CKD as confirmed decreased GFR. Even if the unique threshold at 60 mL/min/1.73 m² can be criticized, it must be underlined that hard endpoints such as 30 or 50% decline of GFR and ESRD have been considered. Also, it is of some interest to see that the risk is very similar between the two studies whereas populations are different.

Having underlined the interest of these studies, we have to discuss the limitations, as well (some of the limitations being discussed by the authors themselves). First, baseline characteristics between patients treated by PPI and antiH2 are very different, and so, adjustment for these different parameters are needed and, as usual, it is always quite difficult to be sure that residual adjustment has not been forgotten. Second, the physiopathological basis to explain this potential higher risk remains actually very speculative. PPI-induced low magnesium level is advanced to explain this risk but hypomagnesemia is actually relatively rare in PPI treated patients. AKI and especially interstitial nephritis is a well, or at least a better, known consequence of PPI therapy, with a probable immune-allergic explanation (such as several other drugs like penicillin etc). For sure these epidemiological results will promote clinical and basic research to explain the risk. Until then, the PPI higher risk remains an epidemiological risk and so, remains hypothetical. As stated by the authors of the JASN paper, the risk remains relatively low especially when hard endpoints and “the number needed to be harm” are considered. Right now, there is still no reason to stop this efficient therapy in CKD when the indication is clear and justified. The fact that PPI is too frequently prescribed beyond indication is a problem in itself.




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