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Clinical Epidemiology
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Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD

Yan Xie, Benjamin Bowe, Tingting Li, Hong Xian, Sumitra Balasubramanian and Ziyad Al-Aly
JASN October 2016, 27 (10) 3153-3163; DOI: https://doi.org/10.1681/ASN.2015121377
Yan Xie
*Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System,
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Benjamin Bowe
*Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System,
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Tingting Li
†Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri;
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Hong Xian
*Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System,
‡Department of Biostatistics, College for Public Health and Social Justice, Saint Louis University,
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Sumitra Balasubramanian
*Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System,
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Ziyad Al-Aly
*Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System,
†Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri;
§Division of Nephrology, Department of Medicine, Veterans Affairs Saint Louis Health Care System, Saint Louis, Missouri
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    Figure 1.

    Flow diagram of cohort assembly of primary cohort of new users of PPI (n=173,321) and new users of H2 blockers (20,270).

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    Figure 2.

    Duration of PPI exposure and risk of renal outcomes among PPI users (n=173,321).

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    Table 1.

    Baseline characteristics of a cohort of new users of H2 blockers, and new users of PPI

    Baseline CharacteristicsH2 Blockers (n=20,270)PPI (n=173,321)P Value
    Age (SD)55.40 (12.81)56.85 (11.85)P<0.001
    Baseline eGFR in ml/min per 1.73 m2 (SD)86.98 (15.88)86.56 (15.67)P<0.001
    RaceWhite (%)15,937 (78.62)137,174 (79.14)P=0.01
    Black (%)3,784 (18.67)32,018 (18.47)
    Other (%)549 (2.71)4,129 (2.38)
    SexMale (%)18,929 (93.38)161,259 (93.04)P=0.07
    Female (%)1,341 (6.62)12,062 (6.96)
    Diabetes mellitus (%)8,923 (44.02)72,309 (41.72)P<0.001
    Hypertension (%)15,814 (78.02)136,782 (78.92)P<0.01
    Chronic lung disease (%)7,951 (39.23)66,955 (38.63)P=0.10
    Peripheral artery disease (%)5,009 (24.71)31,311 (18.07)P<0.001
    Cardiovascular disease (%)8,459 (41.73)71,807 (41.43)P=0.41
    Cerebrovascular disease (%)4,596 (22.67)26,457 (15.26)P<0.001
    Dementia (%)5,058 (24.95)32,380 (18.68)P<0.001
    Hyperlipidemia (%)14,785 (72.94)127,463 (73.54)P=0.07
    Hepatitis C (%)1,198 (5.91)14,892 (8.59)P<0.001
    HIV (%)55 (0.27)678 (0.39)P<0.01
    Gastroesophageal reflux disease (%)3,767 (18.58)86,804 (50.08)P<0.001
    Upper gastrointestinal tract bleeding (%)246 (1.21)7,898 (4.56)P<0.001
    Ulcer disease (%)666 (3.29)26,228 (15.13)P<0.001
    H. pylori infection (%)22 (0.11)4,052 (2.34)P<0.001
    Barrett esophagus (%)15 (0.07)3,207 (1.85)P<0.001
    Achalasia (%)1 (0.00)214 (0.12)P<0.001
    Stricture (%)33 (0.16)2,299 (1.33)P<0.001
    Esophageal adenocarcinoma (%)3 (0.01)291 (0.17)P<0.001
    Years of follow-up (IQR)5.00 (5.00, 5.00)5.00 (5.00, 5.00)P<0.001
    Days of having related prescription during follow-up (IQR)90 (30, 270)450 (90, 1260)P<0.001
    • IQR, interquartile range.

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    Table 2.

    Association between PPI and risk of eGFR<60 ml/min per 1.73 m2, and risk of CKD

    OutcomeH2 Blockers (n=20,270)PPI (n=173,321)
    Incident eGFR<60 ml/min per 1.73 m2Number of events (%)4,429 (21.85)48,171 (27.79)
    Incident rate (95% CI)5408.24 (5248.96 to 5567.52)7241.27 (7176.61 to 7305.94)
    HR (95% CI)1.01.22 (1.18 to 1.26)
    Incident chronic kidney diseaseNumber of events (%)2,234 (11.02)26,193 (15.11)
    Incident rate (95% CI)2569.86 (2463.30 to 2676.43)3683.12 (3638.52 to 3727.72)
    HR (95% CI)1.01.28 (1.23 to 1.34)
    • Incident rate as incident per 100,000 person-years.

    • HRs were obtained from Cox models adjusted for baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

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    Table 3.

    Association between PPI and risk of kidney disease progression and risk of ESRD

    OutcomeH2 Blockers (n=20,270)PPI (n=173,321)
    Doubling of serum creatinineNumber of events (%)759 (3.74)10,766 (6.21)
    Incident rate (95% CI)816.98 (758.86 to 875.10)1387.02 (1360.81 to 1413.22)
    HR (95% CI)1.01.53 (1.42 to 1.65)
    >30% decline in eGFRNumber of events (%)3,949 (19.48)43,842 (25.30)
    Incident rate (95% CI)4533.25 (4391.86 to 4674.64)6170.27 (6112.51 to 6228.03)
    HR (95% CI)1.01.32 (1.28 to 1.37)
    ESRDNumber of events (%)25 (0.12)329 (0.19)
    Incident rate (95% CI)26.50 (16.11 to 36.88)41.25 (36.79 to 45.70)
    HR (95% CI)1.01.96 (1.21 to 3.18)
    ESRD or >50% decline in eGFRNumber of events (%)947 (4.67)12,952 (7.47)
    Incident rate (95% CI)1024.27 (959.03 to 1089.51)1679.40 (1650.48 to 1708.32)
    HR (95% CI)1.01.47 (1.38 to 1.57)
    • Incident rate as incident per 100,000 person-years.

    • HRs were obtained from Cox models adjusted for baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

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    Table 4.

    Duration of exposure to PPI and risk of renal outcomes among new users of PPI (n=173,321)

    DurationLess or Equal to 30 Days31–90 Days91–180 Days181–360 Days361–720 Days>720 days
    Incident eGFR<60 ml/min per 1.73 m2n (%)25,912 (14.95)31,192 (18.00)18,889 (10.90)20,770 (11.98)23,446 (13.53)53,112 (30.64)
    HR (95% CI)11.94 (1.88 to 2.00)2.30 (2.22 to 2.39)2.65 (2.56 to 2.74)2.75 (2.66 to 2.85)1.95 (1.87 to 2.02)
    Incident CKDn (%)23,621 (13.63)29,886 (17.24)18,338 (10.58)20,148 (11.62)23,293 (13.44)58,035 (33.48)
    HR (95% CI)11.82 (1.74 to 1.89)2.00 (1.91 to 2.10)2.16 (2.06 to 2.26)1.96 (1.87 to 2.06)0.84 (0.79 to 0.89)
    Doubling of serum creatininen (%)19,602 (11.31)27,234 (15.71)16,989 (9.80)19,116 (11.03)23,603 (13.62)66,777 (38.53)
    HR (95% CI)11.22 (1.13 to 1.30)1.50 (1.39 to 1.62)1.74 (1.61 to 1.87)1.99 (1.85 to 2.14)1.47 (1.37 to 1.59)
    >30% decline in eGFRn (%)22,751 (13.13)29,291 (16.90)18,209 (10.51)20,444 (11.80)24,371 (14.06)58,255 (33.61)
    HR (95% CI)11.76 (1.70 to 1.83)2.31 (2.22 to 2.40)2.87 (2.76 to 2.99)3.48 (3.34 to 3.61)3.29 (3.17 to 3.42)
    ESRDn (%)18,529 (10.69)26,469 (15.27)16,649 (9.61)18,792 (10.84)23,500 (13.56)69,382 (40.03)
    HR (95% CI)11.04 (0.70 to 1.56)1.80 (1.18 to 2.75)2.04 (1.33 to 3.12)3.12 (2.07 to 4.71)2.25 (1.46 to 3.47)
    ESRD or >50% decline in eGFRn (%)19,799 (11.42)27,349 (15.78)17,105 (9.87)19,248 (11.11)23,695 (13.67)66,125 (38.15)
    HR (95% CI)11.23 (1.16 to 1.31)1.57 (1.47 to 1.69)1.85 (1.72 to 1.98)2.13 (1.99 to 2.28)1.58(1.47 to 1.69)
    • HRs were obtained from Cox models adjusted for PPI duration, baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

    • Beginning of follow up (T0) was defined as the date of last use of PPI before event occurrence.

    • PPI duration was computed between first PPI prescription date and T0.

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    Table 5.

    Risk of renal events in a 1:1 propensity score-matched cohort of new users of PPI (n=20,270) and new users of H2 blockers (n=20,270)

    OutcomeH2 Blockers (n=20,270)PPI (n=20,270)
    Incident eGFR<60 ml/min per 1.73 m2Number of events (%)4,429 (21.85)5,204 (25.67)
    Incident rate (95% CI)5408.24 (5249.96 to 5567.52)6563.33 (6385.01 to 6741.65)
    HR (95% CI)1.01.23 (1.17 to 1.30)
    Incident CKDNumber of events (%)2,234 (11.02)2,776 (13.70)
    Incident rate (95% CI)2569.86 (2463.30 to 2676.43)3294.88 (3172.31 to 3417.44)
    HR (95% CI)1.01.28 (1.18 to 1.38)
    Doubling of serum creatinineNumber of events (%)759 (3.74)1,185 (5.85)
    Incident rate (95% CI)816.98 (758.86 to 875.10)1300.96 (1226.89 to 1375.03)
    HR (95% CI)1.01.63 (1.47 to 1.81)
    >30% decline in eGFRNumber of events (%)3,949 (19.48)4,762 (23.49)
    Incident rate (95% CI)4533.25 (4391.86 to 4674.64)5669.45 (5508.42 to 5830.47)
    HR (95% CI)1.01.32 (1.25 to 1.39)
    ESRDNumber of events (%)25 (0.12)38 (0.19)
    Incident rate (95% CI)26.50 (16.11 to 36.88)40.69 (27.75 to 53.63)
    HR (95% CI)1.01.48 (0.49 to 4.50)
    ESRD or >50% decline in eGFRNumber of events (%)947 (4.67)1433 (7.07)
    Incident rate (95% CI)1024.27 (959.03 to 1089.51)1582.80 (1500.85 to 1664.75)
    HR (95% CI)1.01.59 (1.45 to 1.74)
    • Incident rate as incident per 100,000 person-years.

    • HRs were obtained from Cox models adjusted for baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper GI tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

    • View popup
    Table 6.

    Risk of renal events in a 1:1 propensity matched cohort of new PPI users (173,321) and a control group (n=173,321)

    OutcomeControl (n=173,321)PPI (n=173,321)
    Incident eGFR<60 ml/min per 1.73 m2Number (%)35,759 (20.63)48,171 (27.79)
    Incident rate (95% CI)5105.97 (5053.05 to 5158.90)7241.27 (7176.61 to 7305.93)
    HR (95% CI)1.01.57 (1.54 to 1.60)
    Incident CKDNumber (%)17,426 (10.05)26,193 (15.11)
    Incident rate (95% CI)2359.99 (2323.96 to 2394.01)3683.12 (3638.52 to 3727.72)
    HR (95% CI)1.01.81 (1.76 to 1.86)
    Doubling of serum creatinineNumber (%)6,039 (3.48)10,766 (6.21)
    Incident rate (95% CI)770.38 (750.95 to 789.81)1387.02 (1360.81 to 1413.22)
    HR (95% CI)1.01.86 (1.80 to 1.93)
    >30% decline in eGFRNumber (%)31,781 (18.34)43,842 (25.30)
    Incident rate (95% CI)4255.67 (4208.88 to 4302.46)6170.27 (6112.51 to 6228.03)
    HR (95% CI)1.01.67 (1.64 to 1.70)
    ESRDNumber (%)219 (0.13)329 (0.19)
    Incident rate (95% CI)27.60 (23.94 to 31.25)41.25 (36.79 to 45.70)
    HR (95% CI)1.01.61 (1.26 to 2.04)
    ESRD or >50% decline in eGFRNumber (%)7,410 (4.28)12,952 (7.47)
    Incident rate (95% CI)949.13 (927.52 to 970.74)1679.40 (1650.48 to 1708.32)
    HR (95% CI)1.01.83 (1.77 to 1.89)
    • Incident rate as incident per 100,000 person-years.

    • HRs were obtained from Cox models adjusted for baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

    • View popup
    Table 7.

    Risk of renal events in models additionally adjusted for AKI during exposure to acid-suppression therapy

    OutcomeH2 Blockers (n=20,270)PPI (n=173,321)
    Incident eGFR<60 ml/min per 1.73 m2Number of patients with AKI during exposure to acid-suppression therapy (%)690 (3.40)10,903 (6.29)
    HR (95% CI)11.20 (1.16 to 1.24)
    Incident CKDNumber of patients with AKI during exposure to acid-suppression therapy (%)710 (3.50)12,170 (7.02)
    HR (95% CI)11.28 (1.22 to 1.34)
    Doubling of serum creatinineNumber of patients with AKI during exposure to acid-suppression therapy (%)749 (3.70)14,620 (8.44)
    HR (95% CI)11.42 (1.32 to 1.54)
    >30% decline in eGFRNumber of patients with AKI during exposure to acid-suppression therapy (%)720 (3.55)11,797 (6.81)
    H R (95% CI)11.28 (1.24 to 1.33)
    ESRDNumber of patients with AKI during exposure to acid-suppression therapy (%)760 (3.75)16,063 (9.27)
    HR (95% CI)11.79 (1.10 to 2.89)
    ESRD or >50% decline in eGFRNumber of patients with AKI during exposure to acid-suppression therapy (%)748 (3.69)14,293 (8.25)
    HR (95% CI)11.38 (1.29 to 1.47)
    • HRs were obtained from Cox models adjusted for AKI during exposure to acid-suppression therapy, baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection, Barrett esophagus, achalasia, stricture, and esophageal adenocarcinoma.

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Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD
Yan Xie, Benjamin Bowe, Tingting Li, Hong Xian, Sumitra Balasubramanian, Ziyad Al-Aly
JASN Oct 2016, 27 (10) 3153-3163; DOI: 10.1681/ASN.2015121377

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Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD
Yan Xie, Benjamin Bowe, Tingting Li, Hong Xian, Sumitra Balasubramanian, Ziyad Al-Aly
JASN Oct 2016, 27 (10) 3153-3163; DOI: 10.1681/ASN.2015121377
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