"Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury, Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD"

1. Journal Club
Saroj Poudel, Pharm.D Candidate 2017-2018
Yan Xie, Long-term kidney outcomes among users of proton pump inhibitors without
intervening acute kidney injury, Proton Pump Inhibitors and Risk of Incident CKD and
Progression to ESRD.
Background and
Overview
Background/
Introduction
Numerouspriorobservationshave suggestedarelationshipbetweenexposure to
protonpumpinhibitors(PPI) andacute kidneyinjuryandacute interstitial nephritis.
Protonpumpinhibitors(PPI)are one of the mostcommonlyprescribedmedications
inthe US, and ithas beenestimatedthatbetween25% and 70% of prescriptions
have no appropriate indication.Patientswhotake proton-pumpinhibitorsare more
likelytodevelopchronickidneydisease andendstage renal disease thanthose
takinghistamine H2-receptorantagonists,studyfinds.The researchersused
informationfromUSDepartmentof VeteransAffairsdatabasestocreate acohort
studyinvolvingnew usersof PPIsandnew usersof H2 blockers.
Overfive years, those inthe PPIgroupwere 28% more likelytodevelopCKDand
96% more likelytodevelopESRDthanpatientsinthe H2-blockergroup,the
researchersreportinthe Journalof the American Society of Nephrology (online,14
April 2016).
The researchersalso usedlaboratoryparameterstolookat the riskof CKD
progression;theyfoundthatpatientsinthe PPIgroupwere 53% more likelyto
experience adoublingof serumcreatinine and32% more likelytohave aneGFR
decline of more than30% comparedwithpatientsinthe H2-blockergroup.
Funding Fundingforthistrial was notdiscussedatany pointinthe article.
Objective The researchers’objectivewasto quantifythe associationbetweenPPIuse and
incidentCKDina populationbasedcohort.
Methods
Studydesign The researchesutilizedaprospective cohort studydesignforthistrial.
Inclusion&
Exclusion
Exclusion Criteria:
 we excludedcohortparticipantswhoexperiencedAKIbefore chronicrenal
outcomes
 we excludedcohortparticipantsinwhomAKI developedduringthe time in
the cohort (fromT0 until the endof follow-up,eitherbefore orafterthe
occurrence of chronic renal outcomes)

2. Outcomes The primaryOutcomesfor the studyincludedanincidenteGFR <60ml/minper1.73
m2, Outcome to capture kidneydisesesprogressionincluded>30% decrease in
eGFR,and >50% decrease ineGFRor ESRD, doublingof serumcreatinine.Outcomes
were ascertainedfor5 yearsdurationfromtime of cohort entry(where baseline
eGFR wascaptured)
TreatmentPlan By usingVeteransaffairsdatabases,ZiyadAl-Aly,MD,of the VA St.LouisHealthcare
systemidentifiedanational cohortof 193,591 firsttime consumersof acid
suppressiontherapy.Of these,173,321 receivedanew prescriptionforaPPI(e.g.,
esomeprazole,lansoprazole,omeprazole,pantoprazole,orrabeprazole) and20,270
receivedaprescriptionforaH2 blockersreceptorantagonist(e.g.Ranitidine,
cimetidine,andfamotidine).All of the veteranshadnormal kidneyfunctionatthe
start.
To evaluate PPI use andchronicrenal outcomesinthe absence of AKI,the
investigatorscreatedsurvival modelsandalternatelycensored anyone withan
episode of AKI within5yearsof the studyor before developmentof CKD.
ComparedwithpatientswhotookanH2 blocker, PPIusershada 28% to experience
CKD progression.All findingswerestatisticallysignificant.The riskof CKDincreased
alongwithdurationof PPIuse.
Data Handling AuthorsusedDepartmentof VeteransAffairsdatabase includinginpatientsand
outpatientsmedical SASdatasets(include datawithinthe VA system),andUSRenal
database system(providesinformationaboutoccurrence of ESRD).
Statistical
Analysis
Authorsexaminedthe riskof renal outcomesina1:1 propensityscore-matched
cohort of newusersof PPI(n=20,270) and new usersof H2 blockers(n=20,270). The
standardizeddifference forage,race,sex distribution,clinical comorbidconditions,
and heathcharacteristicswas,0.1, indicatingbalance betweenthe twogroups.
Results
Baseline
Characteristics
Total participants193,591 were involvedinthisstudy.Outof which173,321 were
PPIgroupsand 20,270 were H2 blockers. Over5years of follow-upinsurvival
models,cohortparticipantswere censoredatthe time of AKIoccurrence.Compared
withincidentusersof H2 blockers,incidentusersof PPIshadanincreasedriskof an
estimatedglomerularfiltrationrate (eGFR) under60 ml/min/1.73m2(hazardratio
1.19; 95% confidence interval 1.15-1.24),incidentCKD(1.26; 1.20-1.33), eGFR
decline over30%(1.22; 1.16-1.28), andESRD or eGFRdecline over50% (1.30; 1.15-
1.48).
The demographicandhealthcharacteristicsare giveninTable 1;
Baseline characteristics H2 Blockers (n=20,270) PPI (n=173,321)
Sex; Male
Female
18,929 (93.38)
1,341 (6.62)
161,259 (93.04)
12,062 (6.96)
Diabetes mellitus (%) 8,923 (44.02) 72,309 (41.72)

3. Hypertension (%) 15,814 (78.02) 136,782 (78.92)
Gastroesophageal reflux disease
(%)
3,767 (18.58) 86,804 (50.08)
Upper GIT bleeding (%) 246 (1.21) 7,898 (4.56)
Association between PPI and Risk of eGFR<60 ml/min per 1.73 m2, and
Risk of CKD
Outcome H2 Blockers (n=20,270) PPI (n=173,321)
Incident eGFR<60 ml/min
per 1.73 m2, HR
5408.24, 1.0 7241.27, 1.22
Incident chronic kidney
disease, HR
2569.86, 1.0 3683.12, 1.28
Risk Incident eGFR<60 ml/min per 1.73 m2 was compared with h2 blockers
users, the PPI group showed an increased in HR of 1.22, similarly for the
incident rate for CKD, PPI users showed increased in HR of 1.28 than H2
blockers users
Association between PPI and risk of kidney disease progression and risk
of ESRD
Outcome H2 Blockers (n=20,270) PPI (n=173,321)
Doubling of serum
creatinine, HR
816.98, 1.0 1387.02, 1.53
>30% decline in eGFR, HR 4533.25, 1.0 6170.27, 1.32
ESRD, HR 26.50, 1.0 41.25, 1.96
ESRD or >50% decline in
eGFR, HR
1024.27, 1.0 1679.40, 1.47
Risk of doubling of serum creatinine and eGFR decline >30% was
significantly elevated in those with PPI (HR, 1.53;95% CI and HR, 1.32; 95%
CI respectively). Incident rate for the outcome of ESRD was significantly
higher among those treated with PPI compared with H2 blockers.
Duration Of PPI use and Risk of Renal Outcomes
Researchers evaluated the association between duration of exposure and risk
of renal outcomes among new users of PPI (n=173,321) and compared with
those exposed groups for less than or equals to 30 days, there was graded
association between duration of exposure and risk of renal outcomes among
those exposed for 31-90, 91-180, 181-360, and 361-720 days. The association
seems to diminish with exposure exceeding 720 days.
Author’s
Conclusion
The authors have shown the exposure of PPI is associated with increased risk
of development of CKD, progression of kidney disease, and risk of ESRD.
The results also suggest a graded relationship between duration of exposure of
PPI and risk of renal outcomes. Furthermore, we detected a graded

4. Basedon
Results
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.
DISCUSSION
Journal/Author Afterresearchingthe authors,All of themwere highlyqualifiedintheirrespective
fields,Some wereMDor Professorindepartmentof clinical science,somewere
Biostatistician atClinical EpidemiologyCenter. Iwasable tofindthat the majorityof
the authors specialize innephrologyandhave large numbersof publications.The
article waspublishedinbehalf of International Societyof Nephrologyandwas
fundedbya grant fromthe US Departmentof veteransAffairs.Basedonmyfindings
I have come to the conclusionthatthe authors are likelytobe well-qualifiedand
theirfindingsare thoroughandorganizedenoughtobe publishedinawell-known
medical journal.
Title/Abstract The title of thisarticle is appropriate initsway,but necessarilyoutlinesthe objective
of the trial withoutintroducingabiastowardsanyoutcomes.Ifelt thatthe abstract
was havingall itsnecessarybackgroundinformationand presentedthe resultsand
conclusionsof the study ina well explainedandthoroughmanner.The results
sectionwasable to contain outcomes of the results alongwithPvaluesand
confidence intervalswithoutgettingtoolengthy.
Study Subjects The selectionof testsubjectswasdone inaprospective mannerwhichallowedthe
authorsto target a group of patientsthatwas easyto obtaindatafrom and builda
simple andwell-organizedtrial around.There were twiceasmanymeninthisstudy
as women,butthe statistical analysisthe authorsconductedshowedthatthismade
no statistical difference.
Methodology
and Design
AuthorsidentifieduserswhohadnoPPIprescriptionbetweenoct1, 1999 and Sept
30,2006. Patientswere thenfurtherselectedintoPPI-treatmentandH2 blockers
groups.The PPI groupshad at leastone PPI Prescription betweenoct1, 2006 & sept
30, 2008. PPItreatmentgroupwere furtherrestrictedtothose withabaselineeGFR
>60ml/minper1.73m2 within90 days,Similarly
H2 blockersgroupswere alsoincludedwhodon’thave PPIPrescriptionbetweenoct-
1, 1999 until the endof follow uponsept30, 2013. And hadno H2 blockers
prescriptionsbetweenoct1,1999 & sept30,2006. The H2 blockersgroupwas
restrictedtothose withnew usersof H2 blockersbetweenoct1,2006 and sept30,
2008. Theywere alsorestrictedtothose withabaseline eGFR>60ml/minper
1.73m2 within90 days.
Patientsincohortwere followedfor5yearsfromtheirbaselineeGFRmeasurement
or until death.
Statistics The authors providedanextremelyclearandunderstandableexplanationof their
statistical analysis.The authorssetclearandacceptable levelsof significance and

5. providedaP value foreverysingle variable analyzedorcomparisonmade. T-testwas
usedto detectmeandifference forparametriccontinuous variables;Kruskal–Wallis
testwas usedto detectdifferencefornonparametriccontinuousvariablesandchi-
squaredtestwasusedto detectproportionsdifference betweenH2blockersandPPI
treatment.
Results I was particularlyimpressedwiththe presentationof the resultsof thisstudy.I
thoughtthe measuredoutcomeswere appropriate toapplytointerventionsafety,
tolerability,andefficacy.Furthermore,the authorsexplainedthe rationale behind
choosingeachtype of measurementandlaidoutclearscalesforthe categorical data
before presentingit.Eachof the resultswere presentedwithaPvalue that made it
extremelyeasytopickoutwhichoutcomeshada statistical significance,making
interpretation of the resultsverysimple. Itwasfoundthat patientswhotookproton-
pumpinhibitorswere more likelytodevelopchronickidneydisease andendstage
renal disease thanthose takinghistamine H2-receptorantagonists, The authors
were sure to use everyaspectof theirresultsto conclude thatlongtermexposure of
PPIleadsto chronickidneydisease,ESRDanddoublingof serumcreatinine.
Strengths and
Weaknesses
Strengths
Studyexaminedthe riskof renal outcomesinbothusersof PPI& H2 blockers
generallyprescribedforsimilarmedical indicationswhichmayreduce confounding
by indicationsbias.
The study issufficientlylarge,andthe outcome isnotparticularlyrare.
Weaknesses:
Study defineddrugexposure ashavingaprescription,PPIs(andH2blockers) are also
available withoutprescription.itispossiblethatsome participantsinthiscohortmay
have acquiredPPIswithoutprescription.Itwouldhave biasedandresultedinan
underestimationof risk.
Clinical
Application
and Conclusion
Overall,Ibelieve thatthe authorsprovided astudythatisa goodstart. The study
can be usedbycliniciansindecidingthe appropriate therapyforthe patients.
References AntoniouT,MacdonaldEM, HollandsS,GomesT, Mamdani MM, Garg AX,Paterson
JM, JuurlinkDN:Protonpumpinhibitorsandthe riskof acute kidneyinjuryinolder
patients:apopulation-basedcohortstudy.CMAJOpen3:E166–E171, 2015