Kidney

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk

of Chronic Kidney Disease in Subjects With Hypertension
Nationwide Longitudinal Cohort Study
Chih-Cheng Hsu, Hongjian Wang, Yueh-Han Hsu, Shao-Yuan Chuang, Ya-Wen Huang,
Yu-Kang Chang, Jia-Sin Liu, Chao A. Hsiung, Hui-Ju Tsai
AbstractLimited studies have examined the effects of nonsteroidal anti-inflammatory drug (NSAID) use on the risk of
chronic kidney disease (CKD), especially in subjects with hypertension. Using National Health Insurance claims data in
Taiwan, we conducted a propensity scorematched cohort study to investigate the relationship between NSAID use and
CKD in subjects with hypertension. A total of 31976 subjects were included in this study: subjects not taking any NSAIDs
in 2007 (n=10782); subjects taking NSAIDs for 1 to 89 days in 2007 (n=10605); and subjects taking NSAIDs for 90
days in 2007 (n=10589). We performed multivariable proportional hazard models to determine the relationship between
NSAID use and CKD. The results showed that NSAID use was associated with a 1.18-fold increased risk of CKD in
subjects taking NSAIDs for 1 to 89 days; and a 1.32-fold increased risk of CKD in hypertension subjects taking NSAIDs
for 90 days, compared with subjects not taking any NSAIDs, after controlling for the confounding factors. In subgroup
analyses, subjects taking NSAIDs for 90 days, >1 defined daily dose per day or taking NSAIDs >15 cumulative defined
daily doses had a greater risk of CKD than subjects not taking any NSAID, but not for congestive heart failure, stroke,
cancer, osteoarthritis, or rheumatoid arthritis. These results provide supportive evidence that NSAID use is associated
with increased risk of CKD in subjects with hypertension. It is important to closely monitor the effects of NSAID
use, particularly in patients with hypertension, a susceptible population for CKD.(Hypertension. 2015;66:524-533.
DOI: 10.1161/HYPERTENSIONAHA.114.05105.) Online Data Supplement

Key Words: chronic kidney disease

epidemiology

he rising prevalence of chronic kidney disease (CKD) has

led to a substantial public health burden around the world,
including in Taiwan.1,2 Moreover, clinically unrecognized CKD
can lead to the progression to end-stage renal disease, which
usually requires dialysis therapy or renal transplantation and
poses a considerable healthcare burden.3 Therefore, it is of significant importance to determine CKD-related risk factors for
slowing or preventing progression to end-stage renal disease.
It has been known that various epidemiological factors
such as age, sex, race, medication use, and comorbidity (ie,
diabetes mellitus (DM), cardiovascular disease, and hypertension) are associated with the development of CKD.2,46
In addition, previous studies have reported that the use of
nonsteroidal anti-inflammatory drugs (NSAIDs), one of the

hypertension

nonsteroidal anti-inflammatory agent

most commonly used medications in the world, is associated

with adverse effects on renal function.79 For example, previous findings have suggested that short-term NSAID use has
adverse effects on renal function, including sodium retention, estimated glomerular filtration rate (eGFR) alteration,
and blood pressure elevation.1012 But the association between
NSAID use and CKD risk has remained inconclusive.1315
Moreover, little is known about the effects of NSAID use on
CKD among subjects with hypertension, even though they
represent one of the most vulnerable populations predisposed
to the development of CKD or end-stage renal disease.16,17
At present, limited studies have been conducted to investigate the association of NSAID use with CKD among subjects
with hypertension.3,18 Therefore, in this study we examined the

Received March 9, 2015; first decision March 24, 2015; revision accepted June 15, 2015.
From the Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan (C.-C.H., S.-Y.C., Y.-W.H., Y.-K.C., J.-S.L.,
C.A.H., H.-J.T.); Departments of Health Services Administration (C.-C.H., Y.-H.H.) and Public Health (H.-J.T.), China Medical University, Taichuang
City, Taiwan; Department of Cardiovascular Internal Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Beijing, China (H.W.);
National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (H.W.); Division
of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City, Taiwan (Y.-H.H.); Department
of Nursing, Min-Hwei College of Health Care Management, Tainan City, Taiwan (Y.-H.H.); and Department of Pediatrics, Feinberg School of Medicine,
Northwestern University, Chicago, IL (H.-J.T.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
114.05105/-/DC1.
Reprint requests to Hui-Ju Tsai, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes,
Zhunan, Miaoli County, Taiwan. E-mail tsaihj@nhri.org.tw
2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.114.05105

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by guest on September 9, 2015
524

Hsu et al NSAID Use on Chronic Kidney Disease 525

effects of NSAID use on the development of CKD among subjects with hypertension using a nationwide propensity score
matched cohort.

Patients and Methods

Data Source
The single-payer National Health Insurance (NHI) program has been
at the core of the healthcare system in Taiwan since 1995. Over the
years, >98% of the total Taiwanese population has been covered by
the NHI program.19 The National Health Insurance Research Database
(NHIRD), derived from the NHI reimbursement claims data, was created for research purposes in 1996. Data used for this study were
obtained from the Longitudinal Health Insurance Database for the
year 2005 (LHID2005), which was derived from the NHIRD of 2005
and included 1000000 individuals (roughly 5% of the total population of Taiwan) randomly sampled from the 2005 NHI Registry for
Beneficiaries, and were representative of the original NHIRD (http://
w3.nhri.org.tw/nhird/date_01.html). In detail, the LIHD2005 contains data on subjects demographic characteristics, disease diagnoses, and prescription records (including types of medication, time of
prescription, duration of drug supply, and dosage). This study was
approved by the Institutional Review Board of the National Health
Research Institutes in Taiwan.

Study Cohort
We identified individuals with hypertension from the LHID2005.
In detail, the selection criteria were described as follows: (1) subjects aged 20 years in 2006; (2) subjects who had at least 1 hospital
admission or 2 outpatient visits within 1 year for hypertension-related
illnesses (International Classification of Diseases Ninth Revision
[ICD-9]-CM code:401405) between 2001 and 2006; (3) subjects free
of CKD (based on ICD-9-CM codes: 250.4, 274.1, 403.x1, 404.x2,
440.1, 442.1, 453.3, 572.4, 580587, 593, 753.0, 753.1, 753.3, 791.0,

and 866) during the period of 2005 to 2007;20 and (4) subjects registered as NHI beneficiaries in 2006; and the exclusion criteria were
(1) subjects aged <20 years in 2006; (2) subjects with CKD diagnosis
before 2007; (3) subjects developing CKD, but taking erythropoiesisstimulating agents or phosphate binders; or with dialysis during the
entire study period. As a result, a total of 94541 CKD-free subjects
with hypertension in 2007 were identified from the LHID2005 for
the study. All study subjects were followed-up through December 31,
2011 to record any incident CKD. Figure1 presents the detailed flow
diagram related to the selection of study subjects for this longitudinal
cohort study.

Exposure to NSAIDs
Each prescription record in the NHIRD (including the LHID2005)
contains types of medication prescribed, time of prescription, and
duration of drug supply and dosage. In this study, we defined the
length of exposure to NSAIDs use in 2007 based on the date of the
prescription plus the duration of the drug supply (total prescription
days) in 2007. The total prescription days for any NSAIDs use in
2007 were summed together to represent NSAID exposure time in
2007. We then classified study subjects into 3 groups based on their
NSAID exposure time in 2007: (1) subjects taking NSAIDs for 90
days; (2) subjects taking NSAIDs for at least 1 day, but <90 days; and
(3) subjects not taking any NSAIDs. In addition, we also computed
the cumulative defined daily dose (DDD) of NSAID use in 2007;
and the average daily dosage of NSAID use (defined as dividing the
cumulative DDD by 365), respectively, for further analyses. In particular, the NSAIDs investigated in this study were as follows: (1) selective cyclooxygenase (COX)-2 inhibitors: celecoxib, and etoricoxib;
(2) propionic acid derivatives: ibuprofen, ketoprofen, naproxen, flurbiporfen, tiaprofenic acid, fenoprofen, and fenbufen; (3) acetic acid
derivatives: ketorolac, indomethacin, tolmetin, sulindac, etodolac,
diclofenac, aceclofenac, and acemetacin; (4) fenamic acid derivatives: mefenamic acid; (5) enolic acid derivatives: piroxicam, meloxicam, and tenoxicam; and (6) others: difunisal, nabumetone, nefopam,
and nimesulide.

LHID 2005
(n=1,000,000)
Exclude:
Subjects aged <20 in 2006 (n=240,149)
Subjects age 20 and
CKD-free in 2006
(n=759,851)

HT patients in 2007
(n=94,541)

Exclude:
Subjects with CKD diagnosis before 2007
(n=48,226)
Subjects developing CKD, but taking
erythropoiesis-stimulating agents or
phosphate binders; or with dialysis during the
entire study period (n=40,873).

Propensity score matching

No NSAIDs use in 2007

(n=10,782)

Short-term NSAIDs use

(1-89 days) in 2007
(n=10,605)

Long-term NSAIDs use

(90 days) in 2007
(n=10,589)

CKD develop in 2008-2011

No
(n=9,859)

Yes
(n=923)

No
(n=9,513)

Yes
(n=1,092)

No
(n=9,312)

Yes
(n=1,277)

Figure 1. Flow chart for study subject selection, 2006 to 2011. CKD indicates chronic kidney disease; HT, hypertension; LHID,
Longitudinal Health Insurance Database; and NSAID, nonsteroidal anti-inflammatory drugs.

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526HypertensionSeptember 2015

Study Cohort Matched Using Propensity Score

To control for the effects of potential confounding factors associated
with NSAID use, we applied the propensity score method in this
study. We computed the propensity score, the predicted probability
of a subject taking NSAIDs conditional on his/her observed baseline
characteristics, to identify a nonuser group matched with an NSAID
user group with a similar demographic and clinical profile.21,22 For
each NSAID user in the group of subjects taking NSAIDs for 90
days, 1 control was adaptively matched for propensity score, within
strata defined by age, sex, enrollee category (EC), geographical area,
and the Charlson comorbidity index (CCI) score.23 We took similar steps to match subjects in the group of subjects taking NSAIDs
ranging from 1 to 89 days. As described above, a total of 94541
CKD-free subjects with hypertension in 2007 were identified from
the LHID2005 for the study. After matching subjects for propensity
score, 31976 CKD-free subjects with hypertension in 2007 were
included for the subsequent analyses.

Definition of Subjects With CKD

The definition for newly diagnosed CKD subjects was determined
to be those who had a diagnosis that included the following ICD9-CM codes in inpatient or outpatient medical claims data from 2008
to 201120: 250.4 (diabetes with renal manifestation), 274.1 (gouty
nephropathy), 403.x1 (hypertensive renal disease), 404.x2 (hypertensive heart and renal disease), 440.1 (atherosclerosis of renal artery),
442.1 (other aneurysm of renal artery), 453.3 (venous embolism and
thrombosis, renal vein), 572.4 (hepatorenal syndrome), 580 (acute
glomerulonephritis), 581 (nephrotic syndrome), 582 (chronic glomerulonephritis), 583 (nephritis and nephropathy, acute/chronic NOS),
584 (acute renal failure), 585 (chronic renal failure), 586 (renal failure, unspecified), 587 (renal sclerosis, unspecified), 593 (other disorders of kidney and ureter), 753.0 (renal agenesis and dysgenesis),
753.1 (cystic kidney disease), 753.3 (other specified anomalies of
kidney), 791.0 (proteinuria), and 866 (injury to kidney).

Statistical Analysis
We calculated and compared the distributions of demographic and
clinical characteristics of our study subjects across 3 different NSAID
exposure groups using the 2 test for categorical variables and F-test
for continuous variables, respectively. The examined demographic
characteristics included age (<40, 4064, and 65 years), sex, EC
(IIV), and geographical area (northern, central, southern, and eastern). Of note, we used EC as a proxy measure to represent the study
subjects socioeconomic status. A detailed description of EC classification is described elsewhere.24 The clinical characteristics of medical comorbidities (ie, myocardial infarction [MI], congestive heart
failure [CHF], stroke, DM, cancer, systemic lupus erythematosus
[SLE], rheumatoid arthritis [RA], osteoarthritis, gout, and calculus
of kidney and ureter); medication use in the past year (ie, antihypertensive drugs, statin, aspirin, urate-lowering drugs, and proton pump
inhibitors); and the CCI score (=0, 12, and 3) were also examined
in this study. Because the primary outcome of interest was incident
CKD in patients with hypertension, moderate or severe renal disease
was not included in the CCI score calculation.
Next, we applied Cox proportional hazard models to investigate
the relationship of incident CKD with NSAID use and various CKDrelated risk factors (such as MI, CHF, stroke, DM, cancer, SLE, RA,
osteoarthritis, gout, calculus of kidney and ureter, past-year medication use of statin and aspirin, and CCI score) in subjects with hypertension. In addition, Cox proportional hazard models were also
performed to investigate the relationship between the effects of
NSAID use (including number of NSAID use days, average DDD
of NSAID use, and cumulative DDD of NSAID use, separately)
and the risk of developing incident CKD, with and without adjustment of covariates. The included covariates were MI, CHF, stroke,
DM, cancer, SLE, osteoarthritis, RA, gout, calculus of kidney and
ureter, hypertension duration, CCI score, number of antihypertension drugs, past-year use of statin, aspirin, calcium channel blockers,
-blockers, reninangiotensinaldosterone system blocking agents,
thiazide diuretics, urate-lowering drugs, and proton pump inhibitors,

respectively. The group of subjects who did not take any NSAIDs was
treated as the reference group. To account for the effect of time-varying NSAID use, we calculated total NSAID prescription days from
2007 until either the development of CKD or the end of the study
period for each study subject, which was treated as a time-varying
covariate and adjusted in analytic models, accordingly. We further
performed subgroup analyses to assess whether the NSAID effects
were modified by various demographic or clinical characteristics of
the study subjects, stratified by MI, CHF, stroke, DM, cancer, osteoarthritis, RA, gout, calculus of kidney and ureter, CCI score, and pastyear medication use of statin, aspirin, reninangiotensinaldosterone
system blocking agents, urate-lowering drugs and proton pump inhibitors, respectively. Finally, we tested whether the effects of NSAID
use interacted with each of the examined demographic or clinical
characteristics by adding a product term in the analytic models.
All the analyses were performed using STATA 11.0 software (Stata
Corp, College Station, TX) and SAS version 8.2 (SAS institute, Cary,
NC). P<0.05 were declared to be statistically significant.

Results
Demographic and Clinical Characteristics of the
Study Subjects
The study cohort was composed of 94541 subjects with
hypertension. After subjects were matched for propensity
score, a total of 31976 CKD-free subjects with hypertension
in 2007 were included for the subsequent analyses. Table1
depicts the demographic and clinical characteristics of the
31976 CKD-free study subjects. The distributions of age,
sex, EC, geographical area, and CCI score were not different
across the 3 NSAID exposure groups because of propensity
score matching. In terms of clinical characteristics, the distributions of stroke, DM, osteoarthritis, RA, SLE, gout, and calculus of kidney and ureter were significantly different across
the 3 groups (all P<103). Among those, the percentages of
SLE, RA, osteoarthritis, gout, and calculus of kidney and ureter were the highest in the group of subjects taking NSAIDs
for 90 days compared with the other 2 groups. Similarly, a
significant difference was observed for past-year medication
use of all examined drugs (all P<103).

Association of CKD With Various CKD-Related

Risk Factors
Table2 shows the association of CKD with various CKDrelated risk factors, including NSAIDs use, comorbidity of
MI, CHF, stroke, DM, cancer, SLE, osteoarthritis, RA, gout,
calculus of kidney and ureter, past-year medication use of
statin and aspirin, and CCI score in subjects with hypertension. The results in Table2 suggest that CKD development is
significantly associated with NSAID use, comorbidity of MI
(adjusted hazard ratio [AHR], 1.29; 95% confidence interval
[CI], 1.051.58), stroke (AHR, 1.17; 95% CI, 1.051.30), DM
(AHR, 1.72; 95% CI, 1.571.89), RA (AHR, 1.14; 95% CI,
1.051.23), gout (AHR, 1.14; 95% CI, 1.011.30), calculus of
kidney and ureter (AHR, 1.38; 95% CI, 1.171.64), past-year
medication use of statin (AHR, 1.09; 95% CI, 1.031.15) and
aspirin (AHR, 1.06; 95% CI, 1.001.13), hypertension duration (AHR, 1.05; 95% CI, 1.041.07), and CCI score (AHR,
1.04; 95% CI: 1.021.06).
In addition to 3 study groups, we have further classified
subjects into a fourth group (subjects not taking any NSAIDs,
subjects taking NSAIDs for 129 days, subjects taking

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Hsu et al NSAID Use on Chronic Kidney Disease 527

Table 1. Demographic and Clinical Characteristics of NSAID Use in Subjects With Hypertension
Match by Propensity Score
Characteristic

Total Study Subjects

(n=31976)

Subjects Taking NSAIDs

90 d (n=10589)

Subjects Taking NSAIDs for

189 d (n=10605)

Subjects Not Taking Any

NSAIDs (n=10782)

P Value

Demographic characteristics
Age (y; n, %)

<40

249 (2.35)

252 (2.38)

235 (2.18)


4064

13125 (41.05)

736 (2.30)

4347 (41.05)

4350 (41.02)

4428 (41.07)


65

18115 (56.65)

5993 (56.60)

6003 (56.61)

6119 (56.75)


Male

14156 (44.27)

4677 (44.17)

4690 (44.22)

4789 (44.42)


Female

17820 (55.73)

5912 (55.83)

5915 (55.78)

5993 (55.58)

0.89

Sex (n, %)
0.93

EC (n, %)

I

2299 (7.19)

765 (7.22)

755 (7.12)

779 (7.23)


II

6777 (21.19)

2251 (21.26)

2248 (21.20)

2278 (21.13)


III

14938 (46.72)

4928 (46.54)

4970 (46.86)

5040 (46.74)


IV

7962 (24.90)

2645 (24.98)

2632 (24.82)

2685 (24.90)

0.99

Geographical area (n, %)


Northern

13717 (42.90)

4562 (43.08)

4520 (42.62)

4635 (42.99)


Central

8146 (25.48)

2697 (25.47)

2717 (25.62)

2732 (25.34)


Southern

7494 (23.44)

2469 (23.32)

2501 (23.58)

2524 (23.41)


Eastern

2619 (8.19)

861 (8.13)

867 (8.18)

891 (8.26)

0.99

Clinical characteristics
Medical comorbidities (n, %)

MI

634 (1.98)

220 (2.08)

221 (2.08)

193 (1.79)


CHF

9671 (30.24)

3108 (29.35)

3266 (30.80)

3297 (30.58)

0.05*


Stroke

4851 (15.17)

1523 (14.38)

1386 (13.07)

1942 (18.01)

<0.001*


DM

7723 (24.15)

2311 (21.82)

2655 (25.04)

2757 (25.57)

<0.001*


CA

1607 (5.03)

511 (4.83)

521 (4.91)

575 (5.33)


SLE

45 (0.14)

32 (0.30)

9 (0.08)

4 (0.04)

<0.001*


RA

485 (1.52)

352 (3.32)

95 (0.90)

38 (0.35)

<0.001*


OA

7726 (24.16)

4331 (40.90)

2201 (20.75)

1194 (11.07)

<0.001*


SLE/RA/OA

8006 (25.04)

4516 (42.65)

2266 (21.37)

1224 (11.35)

<0.001*


Gout

3338 (10.44)

1735 (16.38)

955 (9.01)

648 (6.01)

<0.001*

911 (2.85)

375 (3.54)

353 (3.33)

183 (1.70)

<0.001*


0

5144 (16.09)

1218 (11.50)

1706 (16.09)

2220 (20.59)

<0.001*


1

10123 (31.66)

3394 (32.05)

3368 (31.76)

3361 (31.17)


2

10638 (33.27)

3610 (34.09)

3548 (33.46)

3480 (32.28)


3

6071 (18.99)

2367 (22.35)

1983 (18.70)

1721 (15.96)


0

7802 (24.40)

2174 (20.53)

2596 (24.48)

3032 (28.12)


1

7931 (24.80)

2656 (25.08)

2703 (25.49)

2572 (23.85)


2

8893 (27.81)

2969 (28.04)

2980 (28.10)

2944 (27.30)


3

7350 (22.99)

2790 (26.35)

2326 (21.93)

2234 (20.72)


ACEI/ARB

12224 (38.23)

4194 (39.61)

4025 (37.95)

4005 (37.15)

<0.001*


CCB

16348 (51.13)

5870 (55.43)

5325 (50.21)

5153 (47.79)

<0.001*

Calculus of kidney
and ureter

0.21

0.19

Medication use in past year (n, %)

No. of drugs

No. of anti-HT drugs

<0.001*

Anti-HT drugs

(Continued)

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528HypertensionSeptember 2015
Table 1. Continued
Match by Propensity Score
Characteristic

Total Study Subjects

(n=31976)


-Blocker

Subjects Taking NSAIDs

90 d (n=10589)

Subjects Taking NSAIDs for

189 d (n=10605)

Subjects Not Taking Any

NSAIDs (n=10782)

P Value

10999 (34.40)

3859 (36.44)

3636 (34.29)

3504 (32.50)

<0.001*


Diuretics

8914 (27.88)

3328 (31.43)

2873 (27.09)

2713 (25.16)

<0.001*


Thiazide diuretics

8101 (25.33)

3022 (28.54)

2641 (24.90)

2438 (22.61)

<0.001*


Loop diuretics

1178 (3.68)

479 (4.52)

332 (3.13)

367 (3.40)

<0.001*


Potassium-sparing
diuretics

1271 (3.97)

481 (4.54)

396 (3.73)

394 (3.65)

<0.001*


Statin

12508 (39.12)

4376 (41.33)

4176 (39.38)

3956 (36.69)

<0.001*


Aspirin

9362 (29.28)

3233 (30.53)

3156 (29.76)

2973 (27.57)

<0.001*


Urate-lowering drugs

2749 (8.60)

1428 (13.49)

801 (7.55)

520 (4.82)

<0.001*

Proton pump inhibitors

1727 (5.40)

684 (6.46)

563 (5.31)

480 (4.45)

<0.001*
0.99

CCI score

0

12

3
HT duration (y; meanSD)
CKD development in
20082011
Observed person-year
CKD incidence density
per 1000 (95% CI)

8775 (27.44)

2896 (27.35)

2915 (27.49)

2964 (27.49)

13703 (42.85)

4554 (43.04)

4546 (42.87)

4603 (42.69)

9498 (29.70)

3139 (29.64)

3144 (29.65)

3215 (29.82)

4.201.86
3292
90927
36.20 (34.9737.44)

4.271.84
1277

4.151.86

4.171.87

1092

0.31

923

29816

30178

30933

42.83 (40.4845.18)

36.19 (34.0438.33)

29.84 (27.9131.76)

ACEI/ARB indicates angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers; CA, cancer; CCB, calcium channel blockers; CCI, Charlson comorbidity
index; CHF, congestive heart failure; CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; EC, enrollee category; HT, hypertension; MI, myocardial
infarction; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; RA, rheumatoid arthritis; and SLE, systemic lupus erythematosus.
*P<0.05.

NSAIDs for 3089 days, and subjects taking NSAIDs for 90

days) and a fifth group (subjects not taking any NSAIDs, subjects taking NSAIDs for 129 days, subjects taking NSAIDs
for 3089 days, subjects taking NSAIDs for 90119 days,
and subjects taking NSAIDs for 120 days), respectively.
The results in Table S1 in the online-only Data Supplement
show that subjects exposed to longer periods of NSAID use
tend to have an increased risk of developing CKD. Moreover,
similar results were observed when we treated a time-varying
variable, defined as total NSAID prescription days from 2007
until either the development of CKD or the end of the study
period, as an additional covariate in the model (Table S1).

Relationship Between NSAID Use and Risk of CKD

In addition to length of NSAID use, we next investigated the
relationship between dose of NSAID use and risk of CKD.
The results in Table3 indicate that compared with nonusers,
subjects with NSAID use for 90 days had a 32% increased
risk of CKD (AHR, 1.32; 95% CI, 1.211.44), and subjects
with NSAID use for 1 to 89 days had a 18% increased risk
of CKD (AHR, 1.18; 95% CI, 1.081.29), respectively. When
examining the NSAID exposure dose, the risk of CKD development increased by 23% in the group of subjects taking
NSAIDs >1 DDD per day, compared with nonusers (AHR,
1.23; 95% CI, 1.131.34 for NSAID use >1 DDD per day).
Similar results were found when we examined the cumulative

DDD of NSAID use in this propensity scorematched study

cohort (Table3).

Subgroup Analyses of the Effects of NSAID Use on

CKD
Figure2 depicts the results of the subgroup analyses (stratified by MI, CHF, stroke, DM, cancer, osteoarthritis, RA, gout,
calculus of kidney and ureter, CCI score and past-year medication use of reninangiotensinaldosterone system blocking
agents, statin, aspirin, urate-lowering drugs, and proton pump
inhibitors, individually). Similar to the findings presented in
Table2, using nonusers as the reference group, hypertensive
patients taking NSAIDs for 90 days in 2007 had a greater
risk of CKD than subjects taking NSAIDs for 1 to 89 days
in 2007 in most examined factors, except for stroke and RA
(Figure2A). Likewise, the results also show that subjects
taking NSAIDs over 1 DDD per day or taking NSAIDs >15
cumulative DDDs tended to have a greater risk of CKD than
their counterparts (Figures S1 and S2). Furthermore, the interactive effects of NSAID use and each of the examined factors
were also investigated, but no significant interactive effect was
found.

Discussion
Our results demonstrated that the use of NSAIDs significantly
elevated the risk of CKD among subjects with hypertension

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Hsu et al NSAID Use on Chronic Kidney Disease 529

Table 2. Association Between CKD and Various CKD-Related Risk Factors in Subjects With
Hypertension
Duration/Variable

Crude HR (95% CI)*

Adjusted HR (95% CI)

Adjusted HR (95% CI)

NSAID use
None

Ref

Ref

Ref

189 d

1.21 (1.111.32)

1.18 (1.081.29)

1.28 (1.171.40)


90 d

1.44 (1.321.56)

1.32 (1.211.44)

2.07 (1.882.28)

MI

1.61 (1.321.97)

1.29 (1.051.58)

1.28 (1.041.56)

CHF

1.25 (1.161.34)

1.03 (0.951.12)

1.02 (0.941.11)

Stroke

1.39 (1.271.51)

1.17 (1.051.30)

1.14 (1.031.27)

DM

2.00 (1.872.15)

1.72 (1.571.89)

1.70 (1.551.86)

CA

1.18 (1.021.36)

0.98 (0.821.16)

0.95 (0.801.13)

SLE

0.64 (0.212.00)

0.64 (0.212.00)

0.82 (0.272.56)

OA

1.12 (0.861.46)

0.93 (0.711.22)

1.19 (0.911.56)

RA

1.33 (1.231.43)

1.14 (1.051.23)

1.26 (1.161.36)

Gout

1.52 (1.381.68)

1.14 (1.011.30)

1.20 (1.051.36)

Calculus of kidney and ureter

1.53 (1.291.81)

1.38 (1.171.64)

1.40 (1.181.66)

Past-year medication use of statin

1.34 (1.271.42)

1.09 (1.031.15)

1.10 (1.041.17)

Past-year medication use of aspirin

1.31 (1.241.39)

1.06 (1.001.13)

1.07 (1.011.14)

HT duration

1.09 (1.071.11)

1.05 (1.041.07)

1.06 (1.041.08)

CCI score

1.12 (1.111.13)

1.04 (1.021.06)

1.04 (1.021.06)

Comorbidity

Medication

CA indicates cancer; CCB, calcium channel blockers; CCI, Charlson comorbidity index; CHF, congestive heart failure;
CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; HR, hazard ratio; HT, hypertension; MI,
myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; RA, rheumatoid arthritis; RAAS,
reninangiotensinaldosterone system; and SLE, systemic lupus erythematosus.
*Crude HR.
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter,
HT duration, CCI score, number of anti-HT drugs, past-year use of statin, aspirin, CCB, -blockers, RAAS blocking agents,
thiazide diuretics, urate-lowering drugs, and proton pump inhibitors.
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter,
HT duration, CCI score, number of anti-HT drugs, past-year use of statin, aspirin, CCB, -blockers, RAAS blocking agents,
thiazide diuretics, urate-lowering drugs, and proton pump inhibitors, and total NSAID prescription days from 2007 until
either the development of CKD or the end of the study period.
Subjects not taking any NSAIDs were used as the reference group.
P<0.05.

in this propensity scorematched study cohort. Our findings

also suggested that both the NSAID exposing dose and the
duration play a role in CKD. In addition to NSAID use, several risk factors (including MI, stroke, DM, RA, gout, calculus
of kidney and ureter, past-year medication use of statin and
aspirin, hypertension duration and CCI score) were found to
be associated with the risk of CKD in this study. Moreover,
to increase comparability among the different study groups,
we carried out the analyses using propensity score matching,
which might reduce the probability that the findings were due
to confounding by factors related to the use of NSAIDs. To
the best of our knowledge, this is one of the few nationwide
longitudinal cohort studies attempting to determine the effects
of NSAID use on the increased risk of CKD in patients with
hypertension, a vulnerable population predisposed to develop
nephropathy.
The results from this study are in line with those reported
from previous studies, suggesting an association between
NSAID use and an increased risk for CKD.7,13,14,17,25 For

example, Gooch et al17 investigated the effects of NSAID use

on the risk for CKD progression in a study cohort of subjects
aged >65 years, and showed that high cumulative NSAID use
was significantly associated with elevated risk for rapid CKD
progression in an elderly community-based cohort. In addition, the results from our subgroup analyses, that is, subjects
taking higher dose of NSAIDs tended to have a greater risk
of CKD than their counterparts, support the findings reported
in a recent meta-analysis study.13 Moreover, numerous studies
have demonstrated that subjects with CKD increase the risk
of developing cardiovascular events and highlighted the clinical and public health importance, particularly, the relationship
between CKD and future cardiovascular events may lead to
an increased population health burden.2628 For example, Go
et al29 investigated the association between the eGFR and
the risks of death, cardiovascular events, and hospitalization.
They found that reduced eGFR was significantly associated
with the development of death, cardiovascular events, and
hospitalization.

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530HypertensionSeptember 2015
Table 3. Relationship Between Use of NSAIDs and Risk of Developing CKD in Subjects With
Hypertension
Duration/Dosage

Crude HR (95% CI)*

Adjusted HR (95% CI)

Adjusted HR (95% CI)

No. of NSAID use days during 1 y

Subjects not taking any NSAIDs

Ref

Ref

Ref

Subjects taking NSAIDs for 189 d

1.21 (1.111.32)

1.18 (1.081.29)

1.28 (1.171.40)

Subjects taking NSAIDs for 90 d

1.44 (1.321.56)

1.32 (1.211.44)

2.07 (1.882.28)

Ref

Ref

Ref

DDD/d >0 and 1

1.37 (1.241.51)

1.26 (1.141.40)

1.51 (1.371.68)

DDD/d >1

1.30 (1.201.41)

1.23 (1.131.34)

1.51 (1.381.64)

Ref

Ref

Ref

Cumulative DDDs >0 and 15

1.16 (1.021.33)

1.14 (1.001.30)

1.16 (1.021.32)

Cumulative DDDs >15

1.35 (1.251.46)

1.26 (1.161.37)

1.62 (1.491.76)

Average DDD of NSAID use (DDD per d)

DDD/d=0

Cumulative DDD of NSAID use during 1 year (cumulative DDDs)

Cumulative DDDs=0

CA indicates cancer; CCB, calcium channel blockers; CCI, Charlson comorbidity index; CHF, congestive heart failure;
CI, confidence interval; CKD, chronic kidney disease; DDD, defined daily dose; DM, diabetes mellitus; HR, hazard ratio; HT,
hypertension; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; RA, rheumatoid arthritis;
RAAS, reninangiotensinaldosterone system; and SLE, systemic lupus erythematosus.
*Crude HR.
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT
duration, CCI score, number of anti-HT drugs, past-year use of statin, aspirin, CCB, -blockers, RAAS blocking agents, thiazide
diuretics, urate lowering drugs, and proton pump inhibitors.
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT
duration, CCI score, number of anti-HT drugs, past-year use of statin, aspirin, CCB, -blockers, RAAS blocking agents, thiazide
diuretics, urate lowering drugs and proton pump inhibitors, and total NSAID prescription days from 2007 until either the
development of CKD or the end of the study period.
Subjects not taking any NSAIDs were used as the reference group.
P<0.05.

However, some observational studies have reported conflicting results.30,31 Using 1999 to 2002 National Health and
Nutrition Examination Survey (NHANES) data, Agodoa et al31
evaluated the association between analgesic use and reduced
eGFR, an indicator for classifying CKD clinical stages, in an
adult population, and suggested that there was no association between analgesic use and reduced eGFR. Mller et al32
examined the impact of NSAID exposure on renal function
in a prospective cohort of subjects with RA. They found that
NSAIDs had negative impact on renal function decline only
in subjects with advanced renal impairment, specifically, CKD
clinical stage >4 at baseline. Conflicting results across various
observational studies might logically be because of differences
in study populations, study designs or study sample sizes, etc.
In our subgroup analyses, an increased risk of CKD
attributable to NSAID use was observed across most
examined factors. Of note, subjects with a longer period
of NSAID use (90 days in 1 year), or who were exposed
to more DDDs or cumulative doses (DDDs per day >1 or
cumulative DDDs >15) tended to have a greater risk of
CKD, compared with the counter groups (subjects with
NSAID use for 189 days, DDDs per day 1 or cumulative
DDDs 15, respectively). In addition, given the increase
in mortality associated with the development of CKD in
this high-risk study population, mortality might represent
a competing outcome. Thus, we have treated mortality as
an outcome and examined the relationship between use of
NSAIDs and risk of mortality. The results have suggested

that use of NSAIDs may increase risk of mortality in subjects with hypertension (Table S2).
Several plausible explanations might help to elucidate the
observed adverse effect of NSAID use on CKD in patients
with hypertension. First, it has been reported that NSAIDs
inhibit the activity of the COX isozymes (COX-1 and COX2), have an influence on decreasing total renal perfusion,
and lead to changes in renal blood flow, all of which may
worsen edema and elevate blood pressure, particularly in
treated hypertensive patients.33,34 Second, some studies have
reported that NSAIDs play a role in elevating systemic vascular resistance and decreasing glomerular filtration rate in
predisposed populations, that is, patients with hypertension
or osteoarthritis.35,36 Third, previous reports have provided
supportive evidence that COX-2 plays a role in modulating harmful actions of angiotensin II, consequently impacting the regulation of renal function and blood pressure.37,38
Fourth, previous studies have demonstrated that NSAIDs
could increase plasma asymmetrical dimethylarginine level,
indicating NSAIDs impacts on inhibition of renal COX-2
and consequent cardiovascular dysfunction and renal disease
progression.38,39 For example, Kielstein et al39 documented
that systemic infusion of asymmetrical dimethylarginine
reduced renal plasma flow and had considerable effects on
systemic vascular resistance. In addition, Ahmetaj-Shala
et al40 reported that asymmetrical dimethylarginine was a
potential biomarker involved in inhibition of COX-2 in the
kidney and elevating cardiovascular risk.

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Hsu et al NSAID Use on Chronic Kidney Disease 531

A
MI
MI at risk
CHF
CHF at risk
Stroke
Stroke at risk
DM
DM at risk
Cancer
Cancer at risk
Osteoarthritis
Osteoarthritis at risk
Rheumatoid arthritis
Rheumatoid arthritis
at risk
Gout
Gout at risk
Calculus
Calculus at risk
CCI1
CCI=0

1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90
1-89
90

n
221
220
10,384
10,369
3,266
3,108
7,339
7,481
1,386
1,523
9,219
9,066
2,655
2,311
7,950
8,278
521
511
10,084
10,078
2,201
4,331
8,404
6,258
95
352
10,510
10,237
955
1,735
9,650
8,854
353
375
10,252
10,214
7,690
7,693
2,915
2,896

RAAS blocking agents 1-89 4,025

user
90 4,194
RAAS blocking agents 1-89 6,580
non-user
90 6,395
1-89 4,176
Statin user
90 4,376
1-89 6,429
Statin non-user
90 6,213
1-89 3,156
Aspirin user
90 3,233
1-89 7,449
Aspirin non-user
90 7,356
Urate lowering drugs 1-89
801
user
90 1,428
Urate lowering drugs 1-89 9,804
non-user
90 9,161
Proton pump inhibitors 1-89
563
user
684
90
Proton pump inhibitors 1-89 10,042
non-user
90 9,905

CKD Person year

35
609
46
585
1,057
29,570
1,231
29,231
382
9,219
425
8,675
710
20,959
852
21,142
199
3,853
231
4,214
893
26,325
1,046
25,602
435
7,316
424
6,266
657
22,862
853
23,550
64
1,468
71
1,415
1,028
28,711
1,206
28,401
262
6,195
573
12,096
830
23,983
704
17,720
12
267
40
1,010
1,080
29,911
1,237
28,806
128
2,666
283
4,753
964
27,512
994
25,063
63
964
62
1,024
1,029
29,214
1,215
28,792
904
21,705
1,031
21,499
188
8,474
246
8,317

HR
1.63
1.80
1.17
1.32
1.09
1.20
1.23
1.40
1.22
1.21
1.17
1.36
1.15
1.27
1.20
1.37
1.21
1.23
1.18
1.34
1.07
1.21
1.20
1.37
1.30
1.17
1.18
1.33
1.15
1.42
1.18
1.31
2.73
2.48
1.15
1.32
1.17
1.30
1.19
1.47

95% CI
(0.93 - 2.87)
(1.01 - 3.22)
(1.07 - 1.28)
(1.21 - 1.45)
(0.94 - 1.27)
(1.03 - 1.40)
(1.10 - 1.38)
(1.25 - 1.57)
(1.01 - 1.49)
(0.99 - 1.48)
(1.06 - 1.29)
(1.23 - 1.51)
(1.00 - 1.32)
(1.09 - 1.47)
(1.07 - 1.35)
(1.22 - 1.54)
(0.84 - 1.74)
(0.84 - 1.78)
(1.08 - 1.29)
(1.22 - 1.47)
(0.87 - 1.32)
(1.00 - 1.46)
(1.09 - 1.32)
(1.23 - 1.51)
(0.41 - 4.15)
(0.41 - 3.35)
(1.08 - 1.29)
(1.22 - 1.46)
(0.86 - 1.54)
(1.09 - 1.86)
(1.08 - 1.30)
(1.19 - 1.45)
(1.47 - 5.08)
(1.32 - 4.67)
(1.05 - 1.26)
(1.20 - 1.44)
(1.07 - 1.29)
(1.18 - 1.44)
(0.96 - 1.48)
(1.19 - 1.82)

482
592
610
685
450
602
642
675
385
439
707
838
104
261
988
1,016
63
107
1,029
1,170

1.12
1.27
1.23
1.38
1.10
1.38
1.24
1.29
1.07
1.16
1.24
1.44
0.80
1.18
1.23
1.33
1.13
1.53
1.19
1.32

(0.98
(1.11
(1.09
(1.22
(0.96
(1.21
(1.11
(1.15
(0.92
(0.99
(1.11
(1.28
(0.60
(0.91
(1.12
(1.21
(0.77
(1.06
(1.08
(1.20

11,340
11,671
18,838
18,145
11,865
12,203
18,313
17,613
8,909
9,039
21,270
20,778
2,239
3,887
27,939
25,929
1,593
1,881
28,585
27,935

1.28)
1.45)
1.39)
1.56)
1.26)
1.59)
1.40)
1.46)
1.24)
1.34)
1.39)
1.61)
1.07)
1.52)
1.35)
1.47)
1.66)
2.20)
1.30)
1.45)

Figure 2. A, Nonsteroidal anti-inflammatory drug (NSAID) use on risk of chronic kidney disease (CKD) in subjects with hypertension (HT),
stratified by myocardial infarction (MI), congestive heart failure (CHF), stroke, diabetes mellitus (DM), cancer, osteoarthritis, rheumatoid
arthritis, gout, calculus, and Charlson comorbidity index (CCI) score, respectively. B, NSAID use on risk of CKD in subjects with HT,
stratified by past-year medication use of reninangiotensinaldosterone system (RAAS) blocking agents, statin, aspirin, urate-lowering
drugs, and proton pump inhibitors, respectively.

Of note, the results should be interpreted within the context of the following limitations. First, detailed information
on clinical or laboratory data such as serum eGFR or severity

of CKD is not available in the NHIRD. In addition, it was

likely that some CKD subjects may not have been identified
because of a lack of clinical or laboratory data. As such, we

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532HypertensionSeptember 2015
identified CKD subjects using various definitions. In addition
to the definition described above, first, we only included study
subjects with medical records from outpatient visits, which
was indicated stable CKD subjects; second, we restricted the
ICD-9-CM codes to NSAID-related renal disease, specifically,
582, 583, 585, 586, 587 (chronic renal failure), 250.4, 250.40,
250.41, 250.42, 250.43 (diabetic nephropathy), 403.xx, 404.
xx (hypertensive nephropathy), and 572.4, 580.xx, 584.xx,
580.0, 580.4, 580.89, 580.9, 582.4, 791.2, 791.3 (acute renal
failure). Similar results were found according to the 2 different CKD definitions (Table S3). However, the misclassification of CKD diagnosis might be undifferentiated across
different groups of NSAID use. Second, exposure bias may
exist because we did not consider over-the-counter (OTC)
NSAID use. Similar to many countries, some NSAIDs can be
obtained OTC in Taiwan. The ingredients of OTC NSAIDs
that subjects can obtain in Taiwan include aspirin, ibuprofen
and naproxen. Currently, >98% of total Taiwanese population
has been covered by the National Health Insurance program;
and the cost of obtaining OTC NSAIDs without prescription
is usually higher than the copayment of an outpatient visit.
As the result, most people obtain NSAIDs through prescriptions unless under an urgent condition. Among those OTC
NSAIDs, aspirin is not examined in this study because of different therapeutic purposes from most other NSAIDs. For the
rare cases of OTC NSAID use, we think this misclassification is undifferentiated across all of the examined NSAIDs
groups and may have potentially reduced the estimated risk
observed in the study. Third, it was likely that subjects might
be taking NSAIDs because of other diseases/symptoms,
which could have had a direct influence on their kidney function or renal disease itself, for example, more chances to be
diagnosed CKD earlier. Even though we included relevant
comorbid medical conditions as covariates in the analyses, we
could not fully exclude potential confounding by indication.
Moreover, some potential confounding laboratory data, such
as serum albuminuria and eGFR levels, were not available in
the NHIRD, and it is likely that the observed increased risk
might be partially explained by those unmeasured confounders. Fourth, the underlying pathophysiology of NSAID effects
on kidney function remains unclear, and further investigation
is merited. Fifth, several studies have suggested that vitamin D
deficiency or lack of calcium intake might be associated with
CKD development and progression as well as cardiovascular
events.4144 However, the information about vitamin supplements is not available in this study. Further investigation will
be merited to evaluate the association between use of vitamin
supplements and CKD development and progression (or with
cardiovascular events).
Taken together, the results demonstrate that NSAID use
increases the risk of CKD among subjects with hypertension, a
high-risk population for CKD, in a propensity scorematched
study cohort. These findings underscore the importance of
closely monitoring renal function in patients with HT taking
NSAIDs. NSAID use should be based on a careful clinical
evaluation of benefits and risks, particularly in patients with
hypertension. Physicians should take caution when administering NSAIDs to subjects with hypertension or subjects
at high risk for CKD. Further investigation is warranted to

better understand the underlying mechanisms in relation to

the effects of NSAID use on CKD development in vulnerable
groups.

Sources of Funding
This study is supported by grants from the National Health Research
Institutes, Taiwan (PI: Tsai, PH-099-PP-56, PH-103-PP-14, PH103-SP-05, and PH-103-SP-17) and the National Science Council,
Taiwan (PI: Hsu, NSC 101-2314-B-400-002). We thank Tami R.
Bartell, Stanley Manne Childrens Research Institute for English
editing, and Wen-Ling Liu for her assistance on this work. This
study is based, in part, on data from the National Health Insurance
Research Database (NHIRD) provided by the National Health
Insurance Administration, and managed by the National Health
Research Institutes, Taiwan (Registered numbers: 99081, 99136,
99287, 101014, NHRID-101-548, NHIRD-103-042). The interpretation and conclusions contained herein do not represent those of
the National Health Insurance Administration, or National Health
Research Institutes.

Disclosures
None.

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Novelty and Significance

What Is New?

Summary

This is one of the few nationwide longitudinal cohort studies attempting

The findings underscore the importance of closely monitoring renal

function in patients with hypertension taking NSAIDs. NSAID use
should be based on a careful clinical evaluation of benefits and
risks, particularly in patients with hypertension. Physicians should
take caution when administering NSAIDs to subjects with hypertension or subjects at high risk for chronic kidney disease.

to determine the effects of nonsteroidal anti-inflammatory drug (NSAID)

use on the increased risk of chronic kidney disease in patients with hypertension, a vulnerable population predisposed to develop nephropathy.

What Is Relevant?

The results from this propensity scorematched cohort study provide

supportive evidence that NSAID use is associated with increased risk of
chronic kidney disease in subjects with hypertension.

Downloaded from http://hyper.ahajournals.org/ by guest on September 9, 2015

Use of non-steroidal anti-inflammatory drugs and risk of chronic kidney

disease in subjects with hypertension, a nationwide longitudinal cohort
study
Chih-Cheng Hsu, , MD, PhD1,2, Hongjian Wang, MD, PhD3, Yueh-Han Hsu, MD4,5,6,
Shao-Yuan Chuang, PhD1, Ya-Wen Huang, MS1, Yu-Kang Chang, PhD1, Jia-Sin Liu,
MS1, Chao A Hsiung, PhD1, Hui-Ju Tsai, MPH, PhD1,7,8
1

Institute of Population Health Sciences, National Health Research Institutes, Zhunan,

Taiwan.
2
Department of Health Services Administration, China Medical University, Taichuang City,
Taiwan.
3
Department of Cardiovascular Internal Medicine, State Key Laboratory of Cardiovascular
Disease, Fuwai Hospital; National Center for Cardiovascular Disease, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing, China.
4
Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation
Chia-Yi Christian Hospital, Chia-Yi City, Taiwan.
5
Department of Nursing, Min-Hwei College of Health Care Management, Tainan City,
Taiwan.
6
Department of Health Services Administration, China Medical University, Taichung City,
Taiwan.
7
Department of Public Health, China Medical University, Taichung City, Taiwan.
8
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago,
IL, USA.

Correspondence and reprint requests should be addressed to:

Hui-Ju Tsai, MPH, PhD
Division of Biostatistics and Bioinformatics
Institute of Population Health Sciences
National Health Research Institutes
Zhunan, Miaoli County, Taiwan
Tel: 886-37-246166 ext 36150
Fax: 886-37-586467
Email: tsaihj@nhri.org.tw; h-tsai@northwestern.edu

List of supplemental materials

Supplemental Table S1. Association between various periods of NSAID use and
chronic kidney disease (CKD) in subjects with hypertension.

Supplemental Table S2. Relationship between use of NSAIDs and risk of mortality in
subjects with hypertension.

Supplemental Table S3. Relationship between use of NSAIDs and risk of developing
chronic kidney disease in subjects with hypertension.

Supplemental Figure S1. NSAID use on risk of chronic kidney disease in subjects with HT,
stratified by MI, CHF, stroke, DM, CA, osteoarthritis, rheumatoid arthritis, gout, calculus,
CCI score and past-year medication use of RAAS blocking agents, statin, aspirin, urate
lowering drugs and proton pump inhibitors, respectively.

Supplemental Figure S2. NSAID use on risk of chronic kidney disease in subjects with HT,
stratified by MI, CHF, stroke, DM, CA, osteoarthritis, rheumatoid arthritis, gout, calculus,
CCI score and past-year medication use of RAAS blocking agents, statin, aspirin, urate
lowering drugs and proton pump inhibitors, respectively.

Supplemental Table S1. Association between various periods of NSAID use and chronic kidney disease (CKD) in subjects with hypertension.
NSAID use

Crude HR (95% CI)

Adjusted HR I (95%CI)

Adjusted HR II (95%CI)||

None*
1-89 days
>=90 days

Ref
1.21 (1.11-1.32)
1.44 (1.32-1.56)

Ref
1.18 (1.08-1.29)
1.32 (1.21-1.44)

Ref
1.28 (1.17-1.40)
2.07 (1.88-2.28)

None*
1-29 days
30-89 days
>=90 days

Ref
1.15 (1.04-1.27)
1.33 (1.18-1.49)
1.44 (1.32-1.56)

Ref
1.14 (1.03-1.26)
1.24 (1.11-1.40)
1.32 (1.21-1.45)

Ref
1.19 (1.08-1.32)
1.46 (1.30-1.64)
2.09 (1.90-2.30)

None*
1-29 days
30-89 days
90-119 days
>=120 days

Ref
1.15 (1.04-1.27)
1.33 (1.18-1.49)
1.31 (1.16-1.48)
1.49 (1.36-1.63)

Ref
1.14 (1.03-1.26)
1.25 (1.11-1.40)
1.24 (1.09-1.40)
1.36 (1.23-1.50)

Ref
1.19 (1.08-1.32)
1.47 (1.31-1.66)
1.66 (1.46-1.89)
2.39 (2.15-2.66)

Note:
*
Subjects not taking any NSAIDs were used as the reference group.

p value < 0.05 is in bold.

Crude hazard ratio.

Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT duration, CCI score, number of anti-HT drugs,
past-year use of statin, aspirin, CCB, beta-blockers, RAAS blocking agents, thiazide diuretics, urate lowering drugs and proton pump inhibitors.
||
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT duration, CCI score, number of anti-HT drugs,
past-year use of statin, aspirin, CCB, beta-blockers, RAAS blocking agents, thiazide diuretics, urate lowering drugs and proton pump inhibitors, and total NSAID prescription
days from 2007 until either the development of CKD or the end of the study period.

Supplemental Table S2. Relationship between use of NSAIDs and risk of mortality in subjects with hypertension.
Duration/Dosage

Crude HR (95% CI)

Number of NSAID use days during one year

Subjects not taking any NSAIDs*
Ref

0.90
(0.84-0.97)
Subjects taking NSAIDs for 1-89 days
1.07 (0.99-1.14)
Subjects taking NSAIDs for 90 days
Average defined daily dose (DDD) of NSAID use (DDD per day)
DDD/day = 0*
Ref
1.05 (0.97-1.13)
DDD/day >0 and 1
0.96 (0.90-1.02)
DDD/day > 1
Cumulative DDD of NSAID use during one year (cumulative DDDs)
Cumulative DDDs = 0*
Ref
0.89
(0.80-0.99)
Cumulative DDDs >0 and 15
1.00 (0.94-1.06)
Cumulative DDDs >15

Adjusted HR (95% CI)

Ref
1.00 (0.93-1.07)
1.85 (1.71-2.00)
Ref
1.27 (1.17-1.38)
1.22 (1.14-1.30)
Ref
0.91 (0.82-1.01)
1.33 (1.25-1.43)

Note:
*
Subjects not taking any NSAIDs were used as the reference group.

p value < 0.05 is in bold.

Crude hazard ratio.

Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT duration, CCI score, number of anti-HT drugs,
past-year use of statin, aspirin, CCB, beta-blockers, RAAS blocking agents, thiazide diuretics, urate lowering drugs and proton pump inhibitors, and total NSAID prescription
days from 2007 until either the development of mortality or the end of the study period.

Supplemental Table S3. Relationship between use of NSAIDs and risk of developing chronic kidney disease in subjects with hypertension.
Duration/Dosage
Crude HR (95% CI)
Adjusted HR (95% CI)
Adjusted HR (95% CI)||
CKD subjects identified from outpatient medical records
Number of NSAID use days during one year
Subjects not taking any NSAIDs*
Ref
Ref
Ref

1.32 (1.19-1.46)
1.25 (1.13-1.39)
1.36 (1.23-1.51)
Subjects taking NSAIDs for 1-89 days
Subjects taking NSAIDs for 90 days
1.56 (1.42-1.72)
1.38 (1.25-1.53)
2.13 (1.91-2.38)
Average defined daily dose (DDD) of NSAID use (DDD per day)
DDD/day = 0*
Ref
Ref
Ref
1.39 (1.24-1.55)
1.26 (1.12-1.41)
1.51 (1.34-1.70)
DDD/day >0 and 1
1.46 (1.34-1.60)
1.34 (1.21-1.47)
1.63 (1.48-1.80)
DDD/day > 1
Cumulative DDD of NSAID use during one year (cumulative DDDs)
Cumulative DDDs = 0*
Ref
Ref
Ref
1.18 (1.02-1.37)
1.17 (1.00-1.36)
1.19 (1.02-1.39)
Cumulative DDDs >0 and 15
Cumulative DDDs >15
1.48 (1.36-1.62)
1.34 (1.22-1.47)
1.71 (1.55-1.88)

CKD subjects indentified using restrict ICD-9-CM codes

Number of NSAID use days during one year
Subjects not taking any NSAIDs*
Ref
1.19 (1.08-1.30)
Subjects taking NSAIDs for 1-89 days
1.42 (1.29-1.55)
Subjects taking NSAIDs for 90 days
Average defined daily dose (DDD) of NSAID use (DDD per day)
DDD/day = 0*
Ref
1.30 (1.17-1.45)
DDD/day >0 and 1
1.30 (1.20-1.42)
DDD/day > 1
Cumulative DDD of NSAID use during one year (cumulative DDDs)

Ref
1.16 (1.06-1.28)
1.30 (1.18-1.43)

Ref
1.26 (1.14-1.38)
2.05 (1.84-2.27)

Ref
1.20 (1.08-1.34)
1.24 (1.13-1.35)

Ref
1.43 (1.29-1.60)
1.51 (1.38-1.66)

Cumulative DDDs = 0*
Cumulative DDDs >0 and 15
Cumulative DDDs >15

Ref
1.05 (0.91-1.22)
1.34 (1.24-1.46)

Ref
1.04 (0.90-1.20)
1.26 (1.16-1.38)

Ref
1.06 (0.92-1.22)
1.62 (1.48-1.77)

Note:
*
Subjects not taking any NSAIDs were used as the reference group.

p value < 0.05 is in bold.

Crude hazard ratio.

Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT duration, CCI score, number of anti-HT drugs,
past-year use of statin, aspirin, CCB, beta-blockers, RAAS blocking agents, thiazide diuretics, urate lowering drugs and proton pump inhibitors.
||
Adjusted variables included: NSAID use, MI, CHF, stroke, DM, CA, SLE, OA, RA, gout, calculus of kidney and ureter, HT duration, CCI score, number of anti-HT drugs,
past-year use of statin, aspirin, CCB, beta-blockers, RAAS blocking agents, thiazide diuretics, urate lowering drugs and proton pump inhibitors, and total NSAID prescription
days from 2007 until either the development of CKD or the end of the study period.

Restrict ICD-9-CM codes are listed as follows: 582, 583, 585, 586 and 587 for chronic renal failure; 250.4, 250.40, 250.41, 250.42, 250.43 for diabetic nephropathy; 403.xx,
404.xx for hypertensive nephropathy; 572.4, 580.xx, 584.xx, 580.0, 580.4, 580.89, 580.9, 582.4, 791.2, 791.3 for acute renal failure.

Supplemental Figure S1. NSAID use on risk of chronic kidney disease in subjects with HT,
stratified by MI, CHF, stroke, DM, CA, osteoarthritis, rheumatoid arthritis, gout, calculus,
CCI score and past-year medication use of RAAS blocking agents, statin, aspirin, urate
lowering drugs and proton pump inhibitors, respectively.
n

CKD
20
61

Person year
311
883

HR
1.59
1.75

95% CI
(0.84 - 3.03)
(1.02 - 3.01)

5,826

666

16,475

1.27

14,923

1,621

42,314

1.23

(1.14 - 1.40)
(1.13 - 1.33)

245
562

5,113
12,778

1.20
1.12

(1.02 - 1.42)
(0.97 - 1.28)

4,113

441

11,672

1.31

10,704

1,120

30,420

1.30

(1.16 - 1.49)
(1.18 - 1.45)

2,745

1.14

5,322

1.26

14,040

1.31

MI

0< DDD/day 1
DDD/day >1

114
327

MI at risk

0< DDD/day 1
DDD/day >1

CHF

0< DDD/day 1
DDD/day >1

1,827
4,546

CHF at risk

0< DDD/day 1
DDD/day >1

Stroke

0< DDD/day 1
DDD/day >1

985

137

1,924

293

Stroke at risk

0< DDD/day 1
DDD/day >1

4,955

549

13,326

1,389

37,876

1.23

DM

0< DDD/day 1
DDD/day >1

1,506

258

4,113

1.19

3,459

600

9,467

1.20

DM at risk

0< DDD/day 1
DDD/day >1

Cancer

0< DDD/day 1
DDD/day >1

Cancer at risk

0< DDD/day 1
DDD/day >1

Osteoarthritis

4,434

428

12,673

1.33

11,791

1,082

33,730

1.26

317

46

873

1.43

715

89

2,010

1.13

(0.92 - 1.42)
(1.05 - 1.51)
(1.17 - 1.47)
(1.12 - 1.35)
(1.01 - 1.40)
(1.05 - 1.37)
(1.17 - 1.51)
(1.14 - 1.41)
(0.96 - 2.13)
(0.80 - 1.60)

5,623

640

15,912

1.26

14,535

1,593

41,187

1.24

(1.14 - 1.40)
(1.14 - 1.35)

0< DDD/day 1
DDD/day >1

1,846

231

5,169

1.12

4,686

604

13,122

1.17

(0.90 - 1.39)
(0.97 - 1.42)

Osteoarthritis at risk

0< DDD/day 1
DDD/day >1

4,094
10,564

455
1,078

11,616
30,076

1.33
1.24

(1.18 - 1.49)
(1.13 - 1.36)

Rheumatoid arthritis

0< DDD/day 1
DDD/day >1

103
344

10
42

296
982

0.99
1.26

(0.30 - 3.25)
(0.44 - 3.60)

Rheumatoid arthritis
at risk

0< DDD/day 1
DDD/day >1

5,837
14,906

676
1,640

16,490
42,216

1.28
1.23

(1.15 - 1.41)
(1.13 - 1.34)

Gout

0< DDD/day 1
DDD/day >1

639
2,050

99
311

1,757
5,659

1.30
1.30

(0.96 - 1.77)
(1.00 - 1.68)

Gout at risk

0< DDD/day 1
DDD/day >1

5,301
13,200

587
1,371

15,029
37,538

1.27
1.23

(1.14 - 1.42)
(1.12 - 1.34)

Calculus

0< DDD/day 1
DDD/day >1

177
551

24
101

491
1,497

2.03
2.81

(1.01 - 4.08)
(1.53 - 5.15)

Calculus at risk

0< DDD/day 1
DDD/day >1

5,763
14,699

662
1,581

16,295
41,700

1.26
1.21

(1.14 - 1.40)
(1.11 - 1.32)

CCI1

0< DDD/day 1
DDD/day >1

4,381
10,999

562
1,372

12,270
30,926

1.24
1.22

(1.11 - 1.39)
(1.12 - 1.34)

CCI=0

0< DDD/day 1
DDD/day >1

1,559
4,251

124
310

4,516
12,272

1.41
1.29

(1.10 - 1.79)
(1.06 - 1.57)

RAAS blocking agents

user

0< DDD/day 1
DDD/day >1

2,361
5,856

313
760

6,598
16,407

1.21
1.18

(1.04 - 1.40)
(1.04 - 1.34)

RAAS blocking agents

non-user

0< DDD/day 1
DDD/day >1

3,579

373

10,187

1.33

9,394

922

26,790

1.29

(1.16 - 1.52)
(1.15 - 1.44)

Statin user

0< DDD/day 1
DDD/day >1

2,417

317

6,763

1.32

6,134

734

17,303

1.19

Statin non-user

0< DDD/day 1
DDD/day >1

3,523

369

10,022

1.24

9,116

948

25,895

1.28

Aspirin user

0< DDD/day 1
DDD/day >1

1,815

226

5,116

1.06

4,573

597

12,829

1.13

Aspirin non-user

0< DDD/day 1
DDD/day >1

4,125

460

11,670

1.40

10,677

1,085

30,369

1.30

Urate lowering drugs

user

0< DDD/day 1
DDD/day >1

554

89

1,525

0.97

1,674

275

4,598

1.02

Urate lowering drugs

non-user

0< DDD/day 1
DDD/day >1

5,386

597

15,260

1.31

13,576

1,407

38,599

1.26

Proton pump inhibitors

user

0< DDD/day 1
DDD/day >1

355

45

995

1.19

892

125

2,480

1.39

(0.78 - 1.81)
(0.98 - 1.97)

Proton pump inhibitors

non-user

0< DDD/day 1
DDD/day >1

5,585
14,358

641
1,557

15,790
40,718

1.28
1.23

(1.16 - 1.42)
(1.13 - 1.34)

(1.13 - 1.54)
(1.04 - 1.35)
(1.08 - 1.41)
(1.15 - 1.43)
(0.89 - 1.26)
(0.98 - 1.29)
(1.24 - 1.59)
(1.17 - 1.44)
(0.72 - 1.32)
(0.79 - 1.32)
(1.18 - 1.46)
(1.15 - 1.37)

Note: Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; MI, myocardial infarction; CHF,
congestive heart failure; DM, diabetes mellitus; calculus, calculus of kidney and ureter; CCI, Charlson
comorbidity index; RAAS, renin-angiotensin-aldosterone system. NSAID use was classified by
average defined daily dose (DDD) of NSAID use (DDD per day).

Supplemental Figure S2. NSAID use on risk of chronic kidney disease in subjects with HT,
stratified by MI, CHF, stroke, DM, CA, osteoarthritis, rheumatoid arthritis, gout, calculus,
CCI score and past-year medication use of RAAS blocking agents, statin, aspirin, urate
lowering drugs and proton pump inhibitors, respectively.
MI

0<DDDs15
15<DDDs

n
53
388

CKD
9
72

Person year HR
144 2.02
1,050 1.66

95% CI
(0.91 - 4.52)
(0.98 - 2.83)

MI at risk

0<DDDs15
15<DDDs

2,937
17,813

287
2,001

8,390
50,401

1.12
1.26

(0.98 - 1.28)
(1.16 - 1.37)

CHF

0<DDDs15
15<DDDs

894
5,479

96
711

2,538
15,352

0.99
1.17

(0.79 - 1.24)
(1.02 - 1.34)

CHF at risk

0<DDDs15
15<DDDs

2,096

200

5,995

1.23

12,722

1,362

36,100

1.33

(1.04 - 1.44)
(1.20 - 1.47)

Stroke

0<DDDs15
15<DDDs

433

58

1,208

1.15

2,476

372

6,859

1.23

Stroke at risk

0<DDDs15
15<DDDs

2,557

238

7,326

1.14

15,725

1,701

44,593

1.28

DM

0<DDDs15
15<DDDs

798

129

2,194

1.14

4,168

730

11,389

1.22

DM at risk

0<DDDs15
15<DDDs

2,192

167

6,340

1.13

14,033

1,343

40,063

1.31

(0.95 - 1.35)
(1.18 - 1.45)

Cancer

0<DDDs15
15<DDDs

158
874

20
115

442
2,442

1.31
1.20

(0.78 - 2.18)
(0.86 - 1.68)

Cancer at risk

0<DDDs15
15<DDDs

2,832
17,327

276
1,958

8,092
49,010

1.13
1.27

(0.99 - 1.29)
(1.17 - 1.39)

Osteoarthritis

0<DDDs15
15<DDDs

466
6,066

48
787

1,318
16,973

0.93
1.18

(0.67 - 1.30)
(0.98 - 1.42)

Osteoarthritis at risk

0<DDDs15
15<DDDs

2,524
12,135

248
1,286

7,216
34,479

1.18
1.29

(1.02 - 1.36)
(1.18 - 1.41)

Rheumatoid arthritis

0<DDDs15
15<DDDs

17
430

1
51

50
1,227

0.60
1.23

(0.07 - 5.49)
(0.43 - 3.49)

Rheumatoid arthritis
at risk

0<DDDs15
15<DDDs

2,973
17,771

295
2,022

8,484
50,224

1.14
1.27

(1.00 - 1.30)
(1.17 - 1.38)

Gout

0<DDDs15
15<DDDs

201
2,489

23
388

566
6,853

0.96
1.35

(0.60 - 1.54)
(1.05 - 1.75)

Gout at risk

0<DDDs15
15<DDDs

2,789

273

7,968

1.15

15,712

1,685

44,599

1.26

(1.01 - 1.32)
(1.16 - 1.37)

Calculus

0<DDDs15
15<DDDs

103

18

282

2.53

625

107

1,706

2.63

Calculus at risk

0<DDDs15
15<DDDs

2,887

278

8,252

1.11

17,576

1,966

49,746

1.25

CCI1

0<DDDs15
15<DDDs

2,098

239

5,926

1.13

13,283

1,696

37,272

1.25

CCI=0

0<DDDs15
15<DDDs

892

57

2,608

1.18

4,918

377

14,179

1.35

RAAS blocking agents 0<DDDs15

user
15<DDDs

1,110

127

3,131

1.07

7,108

947

19,877

1.21

(0.88 - 1.31)
(1.07 - 1.37)

RAAS blocking agents 0<DDDs15

non-user
15<DDDs

1,880
11,093

169
1,126

5,403
31,575

1.19
1.32

(1.00 - 1.42)
(1.18 - 1.47)

Statin user

0<DDDs15
15<DDDs

1,131
7,421

112
940

3,235
20,834

1.01
1.27

(0.82 - 1.25)
(1.12 - 1.44)

Statin non-user

0<DDDs15
15<DDDs

1,859

184

5,299

1.23

10,780

1,133

30,618

1.27

(1.04 - 1.46)
(1.14 - 1.42)

865

95

2,460

0.94

(0.86 - 1.54)
(1.03 - 1.47)
(0.98 - 1.32)
(1.17 - 1.40)
(0.93 - 1.39)
(1.07 - 1.38)

(1.21 - 5.28)
(1.44 - 4.82)
(0.97 - 1.27)
(1.15 - 1.36)
(0.98 - 1.31)
(1.14 - 1.37)
(0.87 - 1.60)
(1.11 - 1.64)

Aspirin user

0<DDDs15
15<DDDs

5,524

729

15,487

1.14

(0.75 - 1.19)
(1.00 - 1.31)

Aspirin non-user

0<DDDs15
15<DDDs

2,125
12,677

201
1,344

6,074
35,965

1.26
1.34

(1.07 - 1.47)
(1.22 - 1.49)

Urate lowering drugs

user

0<DDDs15
15<DDDs

197
2,032

23
342

554
5,573

0.71
1.06

(0.45 - 1.13)
(0.83 - 1.36)

Urate lowering drugs

non-user

0<DDDs15
15<DDDs

2,793

273

7,980

1.19

16,169

1,731

45,879

1.29

(1.04 - 1.37)
(1.19 - 1.41)

Proton pump inhibitors 0<DDDs15

user
15<DDDs

144

15

411

1.09

1,103

155

3,064

1.36

Proton pump inhibitors 0<DDDs15

non-user
15<DDDs

2,846

281

8,123

1.14

17,098

1,918

48,388

1.27

(0.61 - 1.95)
(0.97 - 1.92)
(1.00 - 1.31)
(1.17 - 1.38)

Note: Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; MI, myocardial infarction; CHF,
congestive heart failure; DM, diabetes mellitus; calculus, calculus of kidney and ureter; CCI, Charlson
comorbidity index; RAAS, renin-angiotensin-aldosterone system. NSAID use was classified by
cumulative DDD of NSAID use during one year (cumulative DDDs).

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Chronic Kidney Disease in

Subjects With Hypertension: Nationwide Longitudinal Cohort Study
Chih-Cheng Hsu, Hongjian Wang, Yueh-Han Hsu, Shao-Yuan Chuang, Ya-Wen Huang,
Yu-Kang Chang, Jia-Sin Liu, Chao A. Hsiung and Hui-Ju Tsai
Hypertension. 2015;66:524-533; originally published online July 13, 2015;
doi: 10.1161/HYPERTENSIONAHA.114.05105
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563

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http://hyper.ahajournals.org/content/suppl/2015/07/13/HYPERTENSIONAHA.114.05105.DC1.html

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