PPIs and chronic kidney dz

an article just came out looking at the relationship between PPI (proton-pump inhibitor) use and chronic kidney disease (CKD) (see ppi and ckd jamaintmed2015 in dropbox, or doi:10.1001/jamainternmed.2015.7193). details:

--10,482 patients in the ARIC study (Atherosclerosis Risk In Communities, in 4 US communities) who had baseline GFR of >60 ml/min/1.73 m² in 1996-9 were followed until 2011, mean 13.9 years

    --mean age 63, 44% male, 80% white, 80% with education >=12th grade, mean eGFR 88, urinary albumin/creatinine ratio 4, 12% smokers, BMI 29, systolic BP 127, 50% hypertensive, 15% diabetic, 30% on NSAIDs, 15% on ACE inhibitors, 60% on aspirin

--replication study in the Geisinger Health System database with 248,751 patients followed mean of 6.2 years

    --mean age 50, 43% male, 95% white, mean eGFR 95, 25% smokers, BMI 30, systolic BP 127, 33% hypertensive, 10% diabetic, 12% on NSAIDs, 30% on ACE inhibitors, 11% on aspirin

--assessed the occurrence of a diagnostic code for CKD in the ARIC study, and sustained GFR <60 in the Geisinger group, comparing PPI users, nonusers, and H2-blocker users

--results:

    --ARIC: 

        --56 incident CKD events among 322 baseline PPI users (14.2/1000 person-years) vs 1382 among 10,160 baseline nonusers (10.7/1000 person-years)

        --unadjusted incidence of CKD in PPI users: HR 1.45 (1.11-1.90, p=0.006)

        --adjusted for demographic (age, sex, race), socioeconomic (health insurance, education level) and clinical variables (baseline eGFR, urinary albumin/creatinine ratio, smoking, systolic BP, BMI, diabetes, cardiovasc disease, use of antihypertensives or anticoagulants): HR 1.50 (1.14-1.96, p=0.0013). they also considered annual household income, use of NSAIDs, aspirin, diuretics, statins, but these did not affect the adjusted HR results, so were not formally included.

        --given that PPI use escalated dramatically after the baseline in years of 1996-9, they did an analysis of PPIs ever-used as a time-varying variable, with HR=1.35 (1.17-1.55, p<0.001)

        --in comparing PPI use vs H2-blocker use: HR 1.39 (1.01-1.91, p=0.05)  [also, no association found between H2 blocker use vs non H2-blocker use and CKD]

        --in comparing PPI use to propensity-score matched non-users: HR 1.76 (1.13-2.74)

        --10-year absolute risk of CKD among the 322 baseline PPI users was 11.8% vs 8.5% in nonusers

    --Geisinger:

        --1921 incident CKD events among 16,900 baseline PPI users (20.1/1000 person-years), vs 28,226 events among 231,851 nonusers (18.3/1000 person-years)

        --unadjusted incidence of CKD in PPI users: HR 1.20 (1.15-1.26, p<0.001)

        --for adjusted analysis HR 1.17 (1.12-1.23, p<0.001) (adjusted for age, sex, race, baseline eGFR, smoking, BMI, systolic BP, diabetes, history cardiovac disease, antihypertensive med use, anticoagulatnts, statins, aspirin and NSAIDs)

        ​--for time-varying ever-use model HR 1.22 (1.19-1.25, p<0.001)

        --once-daily PPI use HR 1.15 (1.09-1.21, p<0.001)

        --twice-daily PPI use HR 1.46 (1.28-1.67, p<0.001)

        --in comparing PPI use vs H2-blocker use: HR 1.29 (1.19-1.40, p<0.001=0.05) [again, no association between H2 blocker use vs non H2-blocker use and CKD)]

    --also, the incidence of acute kidney injusry (AKI) was somewhat higher than CKD in both cohorts

so, a few points;

--CKD is really common in the US (13.6% of adults, and increasing over time); not only is CKD associated with end-stage renal disease but also with increased risk of cardiovascular disease and death; there are clear relationships with many meds and CKD, an issue in the setting of increasing polypharmacy; PPIs are one of the most prescribed meds in the US (>15 million Americans had scripts in 2013) and are available OTC; they are increasingly prescribed to kids; and estimates are that 25-70% overall are not for appropriate indications, and that 25% of those on long-term PPIs could discontinue them without getting any symptoms.
--this was a large observational study from 2 databases, with consistent results and even a dose-response relationship (at Geisinger, the more PPI taken, the more CKD). but, as an observational study, one cannot conclude that there is a causal relationship. although mathematical attempts were made to control for many of the suspect variables (eg, in the ARIC study, PPI users were more often white, obese and on antihypertensives), there still may be unknown or unaccounted variables (eg, were those on twice-daily PPIs sicker in other ways which predispose them to CKD?, does this modeling really apply to patients very under-represented in the cohort, such as non-whites?).

--this study adds to the list of potential adverse effects associated with chronic PPIs: hip fracture, community-acqured pneumonia, c diff invections, acute interstitial nephritis, etc

--and, as mentioned in several prior blogs, the issue is that PPIs are often used as first-line therapy for gastritis or GERD (since they work so well, and not only make patients more reliably happier with their therapy but also give us a better diagnostic sense of what is going on), stepping-down therapy to an H2-blocker or antacid doesn't happen often (much easier to continue the PPI and move on to dealing with the patient's other concerns, easier to avoid a prolonged discussion and potentially ineffective move to the less powerful therapies...), and if the patient ever makes it to the ER or to a GI appointment, in my experience, they pretty much inevitably are given PPIs, often at maximal doses (which also makes it more difficult for the primary care provider to talk the patient into a less aggressive therapy). but, as mentioned in prior blogs and reinforced in the above study, although the short-term effectiveness of PPIs is pretty dramatic, they are really overused and the long-term sequelae may well be profound...

for other possible adverse events associated with PPI use, see

--http://gmodestmedblogs.blogspot.com/2015/06/ppis-associated-with-mis.html  reviews the possible association between PPIs and MIs

--http://gmodestmedblogs.blogspot.com/2015/11/troubling-microbiome-changes.html reviews some profound microbiome changes which might predisopose people to c diff

--http://gmodestmedblogs.blogspot.com/2014/11/gastric-acid-suppression-and-microbiome_23.html  reviews a sstudy in kids finding that PPIs create profound changes in both the lung and gut microbiomes, but also brings up issues of PPI use and community-acquired pneumonia, c difficile infections, gastroenteritis esp associated with campylobacter and salmonella, atrophic gastritis especially in the setting of H pylori infection, decreased absorption of Mg, vit B12, iron, calcium, some data on osteoporosis and fractures. 

--the editorial associated with the above paper also goes through some of the data on these PPI complications (see ppi and overview adverse effects jamaintmed2015 in dropbox, or doi:10.1001/jamainternmed.2015.7927.)