Increased Risk of Chronic Kidney Disease in Rheumatoid Arthritis Associated with Cardiovascular Complications - A National Population-Based Cohort Study

Increased Risk of Chronic Kidney Disease in

Rheumatoid Arthritis Associated with

Cardiovascular Complications – A National

Population-Based Cohort Study

Hsien-Yi Chiu

, Hui-Ling Huang

, Chien-Hsun Li

, Hung-An Chen

,

Chia-Lun Yeh

_{, Shih-Hsiang Chiu}

_{, Wei-Chun Lin}

_{, Yu-Pin Cheng}

_{, Tsen-Fang Tsai}

_*,

Shinn-Ying Ho

*

1 Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan, 2 Department of Dermatology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan, 3 Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, 4 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, 5 Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, 6 Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, 7 Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan, 8 Department of Dermatology, Cathay General Hospital, Taipei, Taiwan ☯ These authors contributed equally to this work.

*tftsai@yahoo.com(T-FT);syho@mail.nctu.edu.tw(S-YH)

Abstract

Background and Objectives

There have been few large population-based studies of the association between

rheuma-toid arthritis (RA) and chronic kidney disease (CKD) and glomerulonephritis. This

nation-wide cohort study investigated the risks of developing CKD and glomerulonephritis in

patients with RA, and the associated risks for cardiovascular complications.

Methods

From the Taiwan National Health Insurance Research Database, we identified a study

cohort of 12,579 patients with RA and randomly selected 37,737 subjects without RA as a

control cohort. Each subject was individually followed for up for 5 years, and the risk of CKD

was analyzed using Cox proportional hazards regression models.

Results

During the follow-up period, after adjusting for traditional cardiovascular risk factors RA was

independently associated with a significantly increased risk of CKD (adjusted hazard ratio

[aHR] 1.31; 95% confidence interval [CI] 1.23

–1.40) and glomerulonephritis (aHR 1.55;

95% CI 1.37

–1.76). Increased risk of CKD was also associated with the use of non-steroidal

anti-inflammatory drugs, cyclosporine, glucocorticoids, mycophenolate mofetil, and

cyclo-phosphamide. Patients with comorbidities had even greater increased risk of CKD.

a11111

OPEN ACCESS

Citation: Chiu H-Y, Huang H-L, Li C-H, Chen H-A, Yeh C-L, Chiu S-H, et al. (2015) Increased Risk of Chronic Kidney Disease in Rheumatoid Arthritis Associated with Cardiovascular Complications_{– A} National Population-Based Cohort Study. PLoS ONE 10(9): e0136508. doi:10.1371/journal.pone.0136508 Editor: Emmanuel A Burdmann, University of Sao Paulo Medical School, BRAZIL

Received: June 1, 2015 Accepted: August 4, 2015 Published: September 25, 2015

Copyright: © 2015 Chiu et al. This is an open access article distributed under the terms of the

Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability Statement: All relevant data are within the paper.

Funding: This work was funded by the Cathay General Hospital (Grant number: MR-A10324;http:// www.cgh.org.tw/index.html), the National Science Council of Taiwan under contract number MOST-103-2221-E-009-117-, and the Center forBioinformatics Research of Aiming for the Top University Program of the National Chiao Tung University and Ministry of Education, Taiwan, R.O.C. for the project 104W962. This work was also supported in part by UST-UCSD International Center of Excellence in Advanced

Moreover, RA patients with concurrent CKD had significantly higher likelihood of developing

ischemic heart disease and stroke.

Conclusions

RA patients had higher risk of developing CKD and glomerulonephritis, independent of

tra-ditional cardiovascular risk factors. Their increased risk of CKD may be attributed to

glomer-ulonephritis, chronic inflammation, comorbidities, and renal toxicity of antirheumatic drugs.

Careful monitoring of renal function in RA patients and tight control of their comorbid

dis-eases and cardiovascular risk factors are warranted.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects many

body tissues and leads to joint destruction and other major morbidity and mortality. In

partic-ular, previous reports have indicated that patients with RA also have considerable incidence of

renal disease. Specifically, there is accruing evidence that a substantial proportion of patients

with early RA have proteinuria, hematuria and renal dysfunction [

1

,

2

].

Renal disease in RA is clinically important because it not only restricts the management of

primary disease, but also increases mortality. In one study, RA patients with renal disease had

significantly increased mortality compared to those with normal renal function, with a hazard

ratio (HR) of 2.77

–4.45 [

3

]. Other investigators have shown that subjects hospitalized for RA

were significantly more likely to die from renal failure than the general population: HR 3.1

(95% confidence interval [CI]: 2.5

–3.9) for males, and HR 3.5 (95% CI: 3.0–4.0) for females

[

2

,

4

]. Autopsy findings in patients with RA have shown that renal failure is a major cause of

death in 3

–20% of cases [

5

,

6

].

However, previous studies evaluated a variety of kidney disorders or used different criteria

to define renal abnormality in RA. Further major limitations were small sample sizes,

cross-sectional design, sampling frame at consecutive times from a single rheumatology clinic, lack

of a comparison group, and short follow-up, all of which make it difficult to determine the true

magnitude of risk and potentially limit the generalizability of their results. Few studies have

specifically investigated the chronic kidney disease (CKD) in patients with RA and despite

evi-dence that Asians have higher prevalence of CKD than Caucasians, such research focusing on

Asian subjects is lacking [

7

]. Furthermore, as treatment patterns for RA have changed over the

years, the true incidence of CKD may be different nowadays and remains unclear. This study

was conducted to determine the risk of CKD and glomerulonephritis (GN) and the associated

risk for cardiovascular (CV) complications in a nationally-representative cohort of patients

with RA from Taiwan.

Materials and Methods

Dataset

This retrospective cohort study used data from the Taiwan Longitudinal Health Insurance

Database (LHID) 2005, which is a subset of the National Health Insurance Research Database

(NHIRD). NHIRD data are compiled from the Taiwan National Health Insurance (NHI)

sys-tem, which was launched in 1995 to finance health care for all citizens and provides care for

approximately 99% of the Taiwanese population of more than 23 million. In the LHID 2005,

Bioengineering, sponsored by the Ministry of Science and Technology with I-RiCE Program under Grant Number: MOST 103-2911-I-009-101. 2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: Dr. Tsai has conducted clinical trials or received honoraria for serving as a consultant for Pfizer Pharmaceuticals, Serono International SA (now Merck Serono International), UniPharma/Biogen Idec, Novartis Pharmaceuticals and Janssen-Cilag Pharmaceutical and has received speaking fees from AbbVie. Other authors have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

approximately 1,000,000 representative individuals were randomly sampled from among all of

those in NHIRD that year. The database includes inpatient care, outpatient care, ambulatory

care and prescription drugs from 1 January 2000 through 31 December 2010. A multistage

stratified systematic sampling design was used and there were no statistically significant

differ-ences in gender, age, or average insured payroll-related amount, between the LHID sample and

the whole NHIRD population [

8

]. The disease diagnoses used in our study were coded using

the International Classification of Diseases, 9

Revision, Clinical Modification (ICD-9-CM).

The local Investigational Research Bureau approved the study (HCH 103-024-E).

Study Population

The RA study cohort comprised 12,579 patients newly diagnosed with RA (ICD-9-CM 714.0,

714.2, and 720.0) between 1 January 2001, and 31 December 2005. The initial diagnosis date

was defined as the index date of entry into the RA cohort. Patients who were younger than 18

or who had CKD within 1 year before the index date were excluded. A control cohort of 37,737

subjects who had not been diagnosed with RA from year 2000 through 2010, were selected to

match each RA patient for gender and age.

Study Outcomes

The primary study outcomes were new-onset CKD (ICD-9-CM 580, 581, 582, 583, 584, 585,

586, 587, 588, 589, 753, 403, 404, 2504, 2741, 4401, 4421, 4473, 5724, 6421, 6462) and GN

(ICD-9-CM codes: 580.0, 580.1, 580.2, 580.3, 580.4, 580.9, 590.81, 582.0, 582.1, 582.4, 582.81,

582.89, 582.9, 583.0, 583.1, 583.2, 583.4, and 583.9); final-stage CKD (end-stage renal disease

[ESRD]) (ICD-9-CM 585) was the secondary outcome. Patients were followed-up for 5 years

from the index date or until the development of CKD (

Fig 1

). Comorbidities included diabetes

mellitus (ICD-9-CM 250.xx), hypertension (ICD-9-CM 362.11, 401–405, and 437.2),

hyperlip-idemia (ICD-9-CM 272.x), CV disease (ICD-9-CM 410–429), and obesity (ICD-9-CM 278.0x).

Statistical Analysis

SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. A

two-sided p-value

<0.05 determined statistical significance. Microsoft SQL Server 2008

soft-ware was used for data management and analysis.

Pearson

’s chi-square was used to compare the distributions of demographic characteristics

between patients with and without RA, and for evaluating differences between categorical

vari-ables. Cox proportional hazard regression was performed to estimate the HR and 95% CI of

RA associated with CKD. The covariate-adjusted HR was analyzed after adjusting for

signifi-cant factors (p-value

<0.05).

Results

Table 1

shows the baseline distributions of demographic characteristics and clinical features,

such as comorbidities and medication use, that occurred throughout the study period among

patients with and without RA. There were no significant differences between RA patients and

controls in gender or age. However, several comorbidities were significantly more prevalent

among RA patients than controls; these included diabetes, hypertension, hyperlipidemia, CV

disease, and obesity (all p

<0.001). Compared with RA patients, a significantly lower

propor-tion of controls were prescribed glucocorticoids, disease modifying antirheumatic drugs

(DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs) and biologics; however, some

control patients also received short-term and infrequent glucocorticoids or NSAIDs for

common ailments, such as upper respiratory infections, lower back pain and skin allergy (

S1

Table

).

Table 2

shows the incidence and HRs of CKD, GN and ESRD among patients with RA and

without. Of 12,759 patients with RA, 1442 (11.5%), 166 (1.3%) and 379 (3.0%) patients

respec-tively, developed CKD, ESRD and GN during the 5 year follow-up period. After adjusting for

monthly income, age, gender, urbanization, medication, geography, and comorbidities, the

adjusted HR (aHR) among patients with RA versus controls was 1.31 (95% CI 1.23–1.40, p

<0.001) for CKD, 1.08 (95% CI 0.90–1.29, p = 0.43) for final- stage CKD (ESRD) and 1.55

(95% CI, 1.37–1.76, p <0.001) for GN.

Fig 2

shows Kaplan-Meier survival curves for time to

CKD occurrence for RA versus controls. Stratified by age, the aHRs for CKD, GN and ESRD

increased with age and were highest in the oldest adults among both RA patients and controls.

Moreover, the aHRs for CKD were higher in subjects with comorbidities than those without.

Table 3

shows the risks of CKD among RA patients treated with various medications.

Adjusted for gender, age, comorbidities, and every other drug listed that showed significant

crude HR, patients who received glucocorticoids (p<0.001), mycophenolate mofetil (p<0.05),

cyclophosphamide (p

<0.05) or NSAIDs (p<0.05) had significantly increased risk of CKD. The

overall OR for risk of CKD conferred by DMARDs was 1.22 (p<0.05). Moreover, frequent

Fig 1. Study cohort. Subject flow for study cohort. doi:10.1371/journal.pone.0136508.g001

Table 1. Gender, age, urbanization, geography comorbidity, and medications distributions among individuals with and without rheumatoid arthritis.

Variable Numbers (proportions) of individuals P-value

Patients with RA(N = 12579) Patients without RA(N = 37737)

Sex 1.00 Female 7580 (60.3%) 22740 (60.3%) Male 4999 (39.7%) 14997 (39.7%) Age (years) 1 18_–29 1693 (13.5%) 5079 (13.5%) 30–39 1982 (15.8%) 5946 (15.8%) 40–49 2889 (23.0%) 8667 (23.0%) 50–59 2535 (20.2%) 7605 (20.2%) 60_–69 1901 (15.1%) 5703 (15.1%) 70 1579 (12.6%) 4737 (12.6%) Incomea <0.001 <18,000 5269 (41.9%) 16923 (44.8%) 18,000_–34,000 5465 (43.4%) 15567 (41.3%) 35,000 1845 (14.7%) 5247 (13.9%) Urbanization 0.22 Provinces 3232 (25.7%) 10024 (26.6%) Counties 998 (7.9%) 2975 (7.9%) Districts 3255 (25.9%) 9770 (25.9%) Urban villages 5094 (40.5%) 14968 (39.7%) Geography <0.001 North 6510 (51.8%) 18787 (49.8%) Central 2161 (17.2%) 6686 (17.7%) South 3488 (27.7%) 11357 (30.1%) East 420 (3.3%) 907 (2.4%) Comorbidity Hypertension 4756 (37.8%) 12197 (32.3%) <0.001 Diabetes 2441 (19.4%) 5863 (15.5%) <0.001 Cardiovascular disease 3999 (31.8%) 8581 (22.7%) <0.001 Hyperlipidemia 3683 (29.3%) 8530 (22.6%) <0.001 Obesity 166 (1.3%) 296 (0.8%) <0.001 Drug Glucocorticoids 6055 (48.1%) 10639 (28.2%) <0.001 Methotrexate 615 (4.9%) 74 (0.2%) <0.001 Cyclosporine 99 (0.8%) 13 (0.0%) <0.001 Azathioprine 105 (0.8%) 29 (0.1%) <0.001 Mycophenolate Mofetil 7 (0.1%) 7 (0.0%) <0.05 Hydroxyurea 3 (0.0%) 15 (0.0%) 0.41 Cyclophosphamide 49 (0.4%) 90 (0.2%) <0.05 Sulfasalazine 1453 (11.6%) 81 (0.2%) <0.001 Leflunomide 53 (0.4%) 4 (0.0%) <0.001 Penicillamine 34 (0.3%) 8 (0.0%) <0.001 Hydroxychloroquine 1181 (9.4%) 160 (0.4%) <0.001 NSAIDs 12007 (95.5%) 28583 (75.7%) <0.001 Etanercept 33 (0.3%) 1 (0.0%) <0.001 (Continued)

Table 1. (Continued)

Variable Numbers (proportions) of individuals P-value

Patients with RA(N = 12579) Patients without RA(N = 37737)

Adalimumab 12 (0.1%) 0 (0.0%) _<0.001

NSAIDs, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis. a_{New Taiwan dollars}

doi:10.1371/journal.pone.0136508.t001

Table 2. Incidence rates and hazard ratios for CKD, ESRD, and GN in patients with rheumatoid arthritis.

Variable CKD ESRD GN Crude HR (95% CI) Adjusted HR_{* (95%} CI) Crude HR (95% CI) Adjusted HR_{* (95%} CI) Crude HR (95% CI) Adjusted HR_{* (95%} CI) Rheumatoid arthritis 1.50 (1.41– 1.60)‡ 1.31 (1.23 to 1.4)‡ 1.22 (1.02– 1.46)† 1.08(0.90–1.29) 1.74 (1.53– 1.974)‡ 1.55(1.37–1.76)‡ Incidence ratea _{18.34 2.44 4.38} Gender Female 1.00 ND 1.00 1.00 1.00 1.00 Male 1.01 (0.95–1.07) ND 1.23 (1.05– 1.45)† 1.47(1.25–1.74)‡ 0.87 (0.77– 0.99)† 1.01(0.89–1.15) Age (years) 18_–29 1.00 1.00 1.00 1.00 1.00 1.00 30–39 1.45 (1.19– 1.76)‡ 1.27(1.05–1.54)† 1.85 (0.96–3.58) 1.75(0.91–3.40) 1.24 (0.87–1.77) 1.15(0.80–1.63) 40–49 2.44 (2.06– 2.89)‡ 1.57(1.32–1.87)‡ 3.03 (1.67–5.5)‡ 2.23(1.22–4.07)‡ 2.08 (1.52– 2.82)‡ 1.55(1.13–2.12)† 50–59 4.09 (3.47– 4.82)‡ 1.83(1.54–2.17)‡ 5.82 (3.27– 10.34)‡ 3.15(1.74–5.69)‡ 3.10 (2.30– 4.19)‡ 1.76(1.29–2.42)‡ 60–69 6.24 (5.3–7.35)‡ 2.12(1.78–2.52)‡ 11.1 (6.3– 19.56)‡ 4.49(2.48–8.10)‡ 4.45 (3.30– 6.00)‡ 2.03(1.47–2.80)‡ 70 8.8 (7.48– 10.36)‡ 2.82(2.37–3.37)‡ 19.6 (11.2– 34.31)‡ 7.08(3.93–12.75)‡ 5.82 (4.32– 7.83)‡ 2.53(1.83–3.50)‡ Comorbidity Hypertension 4.37 (4.1–4.66)‡ 1.81(1.68–1.96)‡ 5.11 (4.28– 6.11)‡ 1.73(1.40–2.15)‡ 3.02 (2.67– 3.42)‡ 1.34(1.15–1.56)‡ Diabetes 4.23 (3.98– 4.49)‡ 2.04(1.91–2.18)‡ 4.57 (3.88– 5.38)‡ 2.16(1.81–2.59)‡ 2.86 (2.52– 3.26)‡ 1.47(1.28–1.69)‡ Cardiovascular disease 3.51 (3.31– 3.72)‡ 1.60(1.50–1.71)‡ 4.1 (3.48–4.83)‡ 1.70(1.42–2.05)‡ 3.19 (2.83– 3.60)‡ 1.74(1.52–2.00)‡ Hyperlipidemia 3.3 (3.11–3.5)‡ 1.57(1.47–1.68)‡ 2.82 (2.39– 3.31)‡ 1.28(1.07–1.53)‡ 2.87 (2.54– 3.23)‡ 1.63(1.42–1.87)‡ Obesity 1.81 (1.43–2.3)‡ 1.16(0.91–1.47) 1.76 (0.91– 3.39)† 1.39(0.71–2.69)‡ 1.40 (0.81–2.43) N/A * Each variable was adjusted for every other variable listed for which crude HR was significant (p <0.05), and also for income

†_{p<0.05 for comparison between patients with versus without rheumatoid arthritis.} ‡_{p<0.001 for comparison between patients with versus without rheumatoid arthritis.} a_{Incidence rate: per 1000 person-years.}

CI, confidence interval; CKD, chronic kidney disease; ESRD, end-stage renal disease; GN, glomerulonephritis; HR, hazard ratio; N/A, not applicable; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; ND, not done.

NSAID users had significantly higher likelihood of developing CKD than infrequent users and

non-users.

Table 4

shows the comparative risks of CV complications in RA patients with and without

CKD. Adjusted for gender, age, diabetes, hypertension, and hyperlipidemia, RA patients with

versus without CKD had significantly increased risks of ischemic heart disease (p

<0.001) and

stroke (p<0.05).

Discussion

This national population-based cohort study of more than 12, 000 RA patients who were

fol-lowed for up to 5 years, not only affords generalizability in comparing the incidence of CKD in

patients with versus without RA, but also makes it possible to assess the temporal relationship

between RA and CKD.

The reported prevalence of kidney disease in patients with RA ranges from 5

–50%,

reflect-ing wide variations in the diagnostic criteria and definitions of renal disease, and different

study designs [

1

,

5

,

9

,

10

]. In a cross-sectional population-based cohort study of 604 Finnish

patients with RA, 17% had evidence of nephropathy (defined as hematuria, proteinuria, or

kid-ney failure) [

11

]. The prevalence of kidney disease among 129 consecutive RA patients in a

more recent study was 46.3% as measured by the Modification of Diet in Renal Disease

Fig 2. Kaplan-Meier survival curves. Kaplan-Meier survival curves for time to occurrence of chronic kidney disease among patients with and without rheumatoid arthritis.

Table 3. Risks of CKD among rheumatoid arthritis patients treated with medications.

Medication* RA with CKD RA without CKD Crude OR (95% CI) Adjusted OR**(95% CI)

Glucocorticoids 888 5167 1.85 (1.66_–2.07)‡ 1.49 (1.32_–1.68)‡ Non-users 554 5967 1 1.00 (ND) Infrequent usersa 650 4137 1.64 (1.47–1.84)‡ 1.40 (1.25–1.57)‡ Frequent usersb 238 1033 2.33 (2.01–2.72)‡ 1.75 (1.47–2.07)‡ DMARDs 264 1924 1.07 (0.93_–1.24) 1.22 (1.02_–1.45)† Methotrexate 73 542 1.04 (0.81–1.34)† 1.07 (0.82–1.41) Azathioprine 20 85 2.81 (1.48–5.30)† 1.74 (0.99–3.05) Mycophenolate mofetil 4 3 1.83 (1.12–2.99)† 10.58 (2.13–52.54)† Hydroxyurea 2 1 10.32 (2.31–46.17)† 13.16 (0.96–180.65) Cyclophosphamide 13 36 15.47 (1.40–170.68) 2.57 (1.27–5.20)† Sulfasalazine 164 1289 0.98 (0.83–1.17) 1.23 (0.99–1.51) Leflunomide 10 43 1.80 (0.90–3.59) 1.87 (0.88–399.00) Penicillamine 5 29 1.33 (0.52–3.45) 0.97 (0.35–2.65) Hydroxychloroquine 155 1026 1.19 (0.99–1.42) 1.15 (0.93–1.43)

Gold 0 0 N/A N/A

Cyclosporine 17 82 1.61 (0.95–2.72) 1.54 (0.84–2.82) Non-users 1425 11055 1.00 1.00 (ND) Infrequent usersa _{7 19 2.86 (1.20–6.81)}† _{3.01(1.18–7.71)}† Frequent usersb 10 63 1.23 (0.63–2.41) 1.09 (0.51–2.35) NSAIDs 1418 10589 3.06 (2.02–4.62)‡ 1.68 (1.10–2.56)† Non-users 24 548 1.00 1.00 (ND) Infrequent usersa _{444 5678 1.79 (1.17–2.72)}† _{1.45 (0.95–2.22)} Frequent usersb 974 4911 4.53 (2.99–6.85)‡ 2.01 (1.31–3.09)‡ Biologics 5 40 0.97 (0.38–2.45) 0.86 (0.32–2.34)

†_{p<0.05 for comparison between patients with rheumatoid arthritis and without rheumatoid arthritis.} ‡_{p<0.001 for comparison between patients with rheumatoid arthritis and without rheumatoid arthritis.} * Rheumatoid arthritis patients with one or more drug prescription during 5-year follow-up

** Adjusted for gender, age group, comorbidities and every other listed drug for which crude hazard ratio was significant (p <0.05).

CI, con_{fidence interval; CKD, chronic kidney disease; N/A, not applicable; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; RA, rheumatoid} arthritis; ND, not done.

a_{Prescribed<90 days.} b_{Prescribed90 days.} doi:10.1371/journal.pone.0136508.t003

Table 4. The risk of cardiovascular complications in rheumatoid arthritis patients with versus without CKD.

Variable RA with CKD RA without CKD Crude HR Adjusted HR_*

Ischemic heart disease 590 2119 2.95 (2.63–3.31)‡ 1.57 (1.38–1.79)‡

Stroke 351 1274 2.49 (2.18–2.85)‡ 1.24 (1.06–1.43)†

†_{p<0.05 for comparison between rheumatoid arthritis patients with versus without.} ‡_{p<0.001 for comparison between rheumatoid arthritis patients with versus without.} *Adjusted for gender, age group, diabetes, hypertension, and hyperlipidemia.

CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; RA, Rheumatoid arthritis. doi:10.1371/journal.pone.0136508.t004

formula, and 57% according to Cockcroft-Gault formula [

2

]. Another recent study of 350

con-secutive RA patients in England found that 53% had mild renal impairment, with glomerular

filtration rate (GFR) of 60

–90 mL/min/1.73 m

, and 13% had moderate renal impairment, with

GFR below 60 mL/min/1.73m

[

12

]. Among another 400 RA patients, 11.5% had GFR below

60, and only four had severe renal impairment (GFR

<30) [

13

]. However, specific data on the

incidence of CKD in Asian patients with RA are lacking.

The cause of renal disease in RA patients is contentious, and may be attributable to

nephro-toxic pharmacotherapies, secondary renal diseases induced by amyloidosis and/or GN, and

associated comorbidities [

5

,

13

]. The etiologic role of chronic inflammation has also been

highlighted [

14

,

15

,

16

,

17

]. Accumulating data reveal that CKD is more prevalent in patients

with chronic inflammatory disorders, such as psoriasis [

17

,

18

] and ankylosing spondylitis [

19

],

compared to the general population. Systemic inflammation may contribute to progressive loss

of kidney function and anti-inflammatory drugs, such as TNF-

α antagonists, have therapeutic

potential in preventing CKD progression in RA [

20

,

21

,

22

]. Concerning comorbidities in CKD,

Daoussis and coworkers showed renal dysfunction to be strongly associated with classic CV

risk factors [

13

]. Likewise, our analysis found that diabetes, hypertension, hyperlipidemia, and

CV disease were associated with the development of CKD in RA. Moreover, our results

demon-strate that RA is associated with increased risk of CKD independently of traditional CV risk

factors. In a recent study, excess weight rather than hypertension and diabetes appeared to be

more strongly associated with CKD in RA [

9

]; however, we did not find a significant

associa-tion between obesity and CKD after adjustment, probably due to ethnic differences or relatively

lower prevalence of obesity in Asian populations.

Previous reports suggested that RA may be complicated by renal disease secondary to GN.

Renal biopsies in 158 Japanese and 110 Finnish RA patients with clinical renal diseases,

sug-gested that mesangial GN is the most frequent type of GN (34

–36%), followed by membranous

GN [

23

,

24

]. Other types of GN, including rapidly progressive GN, minimal change

glomerulo-pathy, and immunoglobulin A nephropathy have also been reported in RA [

1

,

2

,

23

,

24

]. Since

GN may progress to CKD and CKD is diagnosed based on abnormal urinalysis and GFR

results, irrespective of the specific cause, we further investigated the relationship among GN,

ESRD and RA. Our patients with RA were at higher risk of both GN and ESRD than controls.

The increased risk of CKD may be partly attributed to higher incidence of GN in patients with

RA.

Anti-inflammatory drugs have also been implicated in causing renal disease in RA patients

[

1

,

9

,

25

,

26

]. Likewise, we found that use of NSAIDs was associated with the development of

CKD in patients with RA in a dose-dependent manner. Also consistent with earlier studies,

cyclosporine [

26

,

27

] and cyclophosphamide [

28

,

29

] were associated with nephrotoxicity that

would lead to CKD in patients with RA. However, our data showed a higher likelihood of

developing CKD in infrequent versus frequent cyclosporine users. Further analysis showed

that infrequent users are older than frequent users, and the probable explanation for our result

is that physicians may avoid prescribing frequent cyclosporine in elderly patients with RA who

tend to be more likely to progress to CKD (

S2 Table

). Our observation that glucocorticoids,

mycophenolate mofetil and cyclophosphamide were associated with increased risk of CKD

might be because prescription of these drugs indicates higher disease activity or presence of

comorbidity, resulting in rapidly declining renal function. Similarly, Hickson and coworkers

found corticosteroids to be associated with increased risk of estimated GFR (eGFR)

<45 mL/

min/1.73 m

in RA [

9

]. Nevertheless, the small sample size in the mycophenolate mofetil and

cyclophosphamide subgroups may be confounding.

Patients with RA have higher CV mortality than non-RA controls, independent of

tradi-tional CV risk factors, has been underestimated [

30

]. Moreover, hematuria, proteinuria, or

CKD are associated with three- to four-fold higher mortality in patients with RA [

3

]. A recent

study showed that in RA, renal dysfunction is associated with a higher risk of CV disease,

inde-pendently of traditional CV risk factors [

31

]. However, the small number of CV events,

con-founding variables, and the lack of healthy control subjects limited the generalizability of these

results [

32

].

Study Strengths and Limitations

NHIRD data are generally accurate and reliable because the Taiwan NHI Bureau performs

reg-ular cross-checks and imposes heavy fines for false claims, overcharging, or malpractice. Earlier

reports have affirmed the reliability of performing epidemiological research using the NHIRD

LHID [

33

,

34

,

35

], and also that of the specific ICD-9-CM codes used to assess CKD outcomes

[

36

,

37

,

38

].

By using a large national cohort with a longitudinal design and adjusting for several

con-founders, we have been able to affirm that CKD in RA patients is significantly associated with

increased risk of ischemic heart disease and stroke, independent of traditional CV risk factors.

Our findings concur with others which showed that CKD was independently associated with

atherosclerosis and endothelial activation in RA, suggesting that endothelial dysfunction is

cen-tral to the pathogenesis of CV complications in RA patients with CKD [

39

].

Our study had limitations. First, diagnoses of CKD, GN and ESRD were based entirely on

secondary claim data, rather than eGFR. Thus, we were unable to stratify the risk of CKD in

RA by CKD stage. However, others have documented the similarity of CKD diagnosis based on

large administrative data sets and on eGFR [

18

,

36

]. Second, we have no renal biopsy pathology

data. Third, because NHIRD lacks a reliable severity index for RA, we did not correlate disease

activity with the prevalence of CKD. Although we were unable to adjust for potential

unmea-sured confounders, previous research suggests that such factors contribute far less to CKD

than traditional risk factors, namely aging, diabetes, and hypertension [

40

], which were

included in our analysis.

Conclusions

This national cohort study demonstrates that the risks of CKD, GN and ESRD are significantly

higher in patients with RA than the general population. The development of CKD in patients

with RA is multifactorial and may result from several ongoing processes, including primary or

secondary renal involvement associated with RA (eg, GN), chronic inflammation,

comorbidi-ties, and nephrotoxic antirheumatic drugs. Moreover, concurrent CKD disease predicts CV

complications in RA patients, independent of other risk factors. Physicians should monitor the

renal function of patients with RA regularly and intervene to tightly control CV risk factors

and the progression of CKD, particularly in patients who are older, NSAID users, or have

comorbidities.

Supporting Information

S1 Table. Frequency of glucocorticoids and NSAIDs use between patients with versus

with-out RA.

(DOCX)

S2 Table. Distribution of age, comorbidity and medication between RA patients with

fre-quent versus infrefre-quent cyclosporine use.

Acknowledgments

This study is based in part on data from the Taiwan National Health Insurance Research

Data-base, which is provided by the National Health Insurance Administration, Ministry of Health

and Welfare, and managed by National Health Research Institutes. The interpretation and

con-clusions contained herein do not represent those of the National Health Insurance

Administra-tion, Ministry of Health and Welfare, or National Health Research Institutes. This work was

funded by Cathay General Hospital (Gant number:MR-A10324), National Science Council of

Taiwan under the contract number MOST-103-2221-E-009-117-, and "Center for

Bioinfor-matics Research of Aiming for the Top University Program" of the National Chiao Tung

Uni-versity and Ministry of Education, Taiwan, R.O.C. for the project 104W962. This work was

also supported in part by UST-UCSD International Center of Excellence in Advanced

Bioengi-neering sponsored by the Ministry of Science and Technology with I-RiCE Program under

Grant Number: MOST 103-2911-I-009-101.-The funders had no role in study design, data

col-lection and analysis, decision to publish, or preparation of the manuscript. We thank Dr.

David Neil (PhD), of Content Ed Net Taiwan Ltd., for professional medical editing services.

Author Contributions

Conceived and designed the experiments: HYC HLH CHL YPC TFT SYH. Performed the

experiments: HYC HLH CHL HAC CLY SHC WCL YPC TFT SYH. Analyzed the data: HLH

HAC CLY SHC WCL SYH. Contributed reagents/materials/analysis tools: HLH CHL HAC

CLY SHC WCL YPC SYH. Wrote the paper: HYC HLH CHL HAC CLY SHC WCL YPC TFT

SYH.

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