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  • Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRÉ Study

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Clinical and epidemiological research
Extended report
Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRÉ Study
  1. A M van Sijl1,2,3,
  2. I A M van den Oever1,
  3. M J L Peters3,
  4. M Boers1,4,
  5. B A C Dijkmans1,2,5,
  6. V P van Halm6,
  7. Y M Smulders3,5,
  8. A E Voskuyl2,
  9. M T Nurmohamed1,2,3
  1. 1Department of Rheumatology, Jan van Breemen Research Institute/Reade, Amsterdam, The Netherlands
  2. 2Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands
  3. 3Department of Internal Medicine and Institute for Cardiovascular Research (ICaR), VU University Medical centre, Amsterdam, The Netherlands
  4. 4Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands
  5. 5Rheumatology, Free University Hospital, Amsterdam, The Netherlands
  6. 6Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands
  1. Correspondence to Dr M T Nurmohamed, Departments of Internal Medicine and Rheumatology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands; mt.nurmohamed{at}vumc.nl

Abstract

Background Patients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) disease, largely independently of traditional CV risk factors. Renal dysfunction is associated with CV morbidity and mortality in the general population, but data on this association in RA are lacking.

Objective To investigate the association between renal function and CV events in RA.

Methods The CARRÉ Study is an ongoing prospective cohort study of Dutch patients with RA, which records CV events. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease formula. Logistic regression determined the association between estimated GFR and the occurrence of CV events.

Results 353 patients were followed for 3 years, and 23 (7%) had a CV event. Patients who had an event had a significantly lower baseline GFR than those who did not (59 vs 79 ml/min, p=0.001). This association remained significant after adjustment for traditional risk factors: in this analysis, a decrease in GFR of 5 ml/min was associated with a 30% (95% CI 7% to 59%) increase in the occurrence of CV events. During follow-up, an unfavourable change in GFR was noted in patients who later had a CV event compared with those who did not.

Conclusion These data confirm that, in RA, renal dysfunction is associated with a higher risk of CV disease independently of traditional CV risk factors.

https://doi.org/10.1136/annrheumdis-2011-200051

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    Introduction

    In recent years, rheumatoid arthritis (RA) has been linked with increased cardiovascular (CV) disease morbidity and mortality, an association that persists after adjustment for traditional CV disease risk factors such as age, gender, smoking, blood pressure and hypercholesterolaemia.1 Epidemiological evidence suggests that other risk factors may be responsible for the excess CV risk.2 3 However, the causative mechanism behind this increased CV disease risk is still mostly unknown.

    A recent meta-analysis clearly illustrates that renal dysfunction is a strong and independent CV risk factor in the general population,4 but data on the association between renal dysfunction and CV disease in RA is lacking. Renal dysfunction is also common among patients with RA,5 and this may be attributable to use of anti-inflammatory medication,6 extra-articular manifestations (including amyloidosis and/or glomerulonephritis),7 a higher prevalence of either diabetes mellitus (DM) or hypertension in RA,6 8 or chronic inflammation.9 A necropsy study found that 90% of patients with RA had benign nephrosclerosis, which correlated with arteriosclerosis.10

    In the present study, we investigate the association between renal dysfunction and CV disease in patients with RA using data from the prospective CARRÉ Study, in the context of known traditional risk factors.

    Methods

    CarrÉ Study

    The CARRÉ Study is a prospective cohort of patients with RA, in whom CV events and concurrent risk factors were investigated. For this study, we used data from the 3-year follow-up period.11 A total of 353 patients aged 50–75 years who fulfilled the American College of Rheumatology criteria of 1987 for RA 12 were enrolled. Follow-up duration was calculated as time from enrolment in the study until follow-up measurement or occurrence of a (non-) fatal CV event. During the follow-up period, all CV events were recorded. Adjudication of CV events was performed on the basis of standardised criteria by an independent trained person according to the ICD-9 codes for myocardial infarction (410.0-9), stroke (436) or transient ischaemic attack (435.9), a history of peripheral arterial reconstruction, carotid endarterectomy, percutaneous coronary intervention (PCI) (8036), coronary artery by-pass surgery (CABG) (8038) and sudden death, cause unknown (798). The local ethics committee approved the study protocol, and all participants gave written informed consent.

    Baseline characteristics

    Blood pressure, length, weight, waist and hip circumference, presence of subcutaneous nodules, smoking habits, medication use, comorbidity, previous CV disease, Disease Activity Score of 28 joints (DAS28) and functional (disability) status were all assessed according to the protocol during admission and physical examination. Hypertension was defined as blood pressure >140/90 mm Hg and/or use of antihypertensive medication. In addition, rheumatoid factor positivity, inflammatory markers, serum creatinine and lipid concentrations were determined in fasting blood samples, and urinary protein excretion was determined from a second void urine sample.11 Atherogenic index was calculated as the ratio between total cholesterol and high-density lipoprotein cholesterol. The 10-year CV risk was calculated using the Systematic Coronary Risk Evaluation (SCORE) formula.13

    Renal function

    Serum creatinine was measured in 349 patients at baseline and 261 patients at follow-up. Two methods were used to estimate renal function: the Cockcroft–Gault formula for creatinine clearance in ml/min ((140 − age in years) × body weight in kg/(serum creatinine in µmol/l × 0.81) × 0.85 if female); and the abbreviated Modification of Diet in Renal Disease (MDRD) formula for glomerular filtration rate (GFR) in ml/min/1.73 m2 (186.3 × (age in years(−0.203)) × serum creatinine in µmol/l / (88.4(−1.154)) × 0.742 if female and/or × 1.212 if ethnic black).14 15 We chose the abbreviated MDRD formula as the primary measure, as it is the most reliable in patients with decreased renal function and is currently the most widely used formula for estimating renal function in clinical settings.16

    Statistical analysis

    Baseline characteristics of the patients are presented as mean ± SD, median (interquartile range) or percentage. Baseline characteristics were compared between patients with and without a CV event, using parametric or non-parametric tests where appropriate. Logistic regression analyses evaluated the association between renal function and CV events. Multivariate logistic regression analysis assessed whether this association was independent of: (1) demographic factors; (2) CV risk factors (including cardioprotective medication); (3) RA-related factors (including anti-inflammatory medication). Results are described as OR with 95% CI expressing the incremental risk of a CV event per 5 ml/min decrease in GFR. Two-sided p values <0.05 were considered significant. All analyses were performed using SPSS V.17.0.

    Results

    Baseline characteristics

    Baseline characteristics are shown in table 1 for the total study population and stratified for patients with and without a CV event. Patients with a CV event were significantly older, more often male, more often a smoker, and more often had hypertension, hypercholesterolaemia and previous CV disease. In addition, they more commonly used statins and antihypertensive medication.

    View this table:
    Table 1

    Baseline characteristics

    Follow-up and CV events

    Mean follow-up duration was 2.7±0.8 years. Nineteen of the 349 participants were lost to follow-up because of moving away from the area or because they stopped participating in the study. Of the remaining 330 participants, 23 had a single CV disease event (7%). Of these, eight patients were diagnosed as having a myocardial infarction (all non-fatal) for which most received PCI or CABG, three patients underwent elective PCI and two patients underwent elective CABG, two patients were diagnosed as having ischaemic stroke (all non-fatal) and four patients as having a transient ischaemic attack, two patients underwent peripheral arterial reconstruction, and two patients died suddenly, cause unknown.

    Estimates of renal function and CV events

    Patients who had a CV event had substantially and significantly higher serum levels of creatinine and lower GFR at baseline (measured with the Cockcroft–Gault and MDRD formulas) compared with patients who did not have a CV event (table 1). The mean difference in estimated GFR between the two groups was 19 ml/min/1.73 m2. Half of the patients with a subsequent CV event had a GFR below the threshold of 60 ml/min/1.73 m2, which is an indication of moderate renal dysfunction.17 Also, 17% (n=15/87) of patients below this threshold had a CV event compared with 3% (n=8/243) above this threshold (p<0.001). The difference in renal function between the two groups increased during follow-up (online supplementary table S1).

    Logistic regression analyses

    Logistic regression analyses showed that a lower estimated renal function (GFR calculated with the MDRD formula) was associated with an increased risk of a CV event, OR (95% CI) 1.30 (1.14 to 1.49), per 5 ml/min/1.73 m2 decrease in GFR (table 2). In other words, a decrease in the estimated GFR of 5 ml/min was associated with a 30% increase in risk of a CV event over the 3-year follow-up, which corresponds to a yearly risk increase of 11%. Similar results were found when the Cockroft–Gault formula for creatinine clearance was used (data not shown). Additional adjustment for (1) age and gender, (2) age, gender and traditional CV risk factors, (3) age, gender and RA-related factors did not significantly change the association between estimates of renal function and CV disease events. Subgroup analyses with exclusion of patients with a CV disease before inclusion in the cohort showed similar results, OR (95% CI) 1.33 (1.13 to 1.56), per 5 ml/min/1.73 m2 decrease in GFR. Furthermore, we evaluated which changes in traditional risk factors had a similar risk increase to a 5 ml/min/1.73 m2 decrease in GFR (table 3). It appeared that this was comparable to (1) an increment in age of ∼5 years, (2) an absolute increase in 10-year CV risk (according to SCORE) of ∼5%, and (3) an increase in systolic blood pressure of 10 mm Hg.

    View this table:
    Table 2

    Multivariate regression analyses of estimated renal function and incident CV disease

    View this table:
    Table 3

    Comparison of crude CV risk between renal function and other traditional risk factors

    Discussion

    This is the first prospective study that clearly shows a clinically relevant association between moderate renal dysfunction and an increased risk of CV events in RA. An 11% increased yearly risk of developing a CV event for every decrease in GFR of 5 ml/min, independent of traditional risk factors, is substantial. Thus far, only one cross-sectional study has shown an association between renal dysfunction and CV disease risk factors, such as total cholesterol, hypertension and previous CV disease, in patients with RA.18

    In the last two decades it has become clear that patients with RA are at increased risk of developing CV disease, largely independently of traditional CV risk factors.1 RA could even be seen as a CV risk factor for CV disease, similar to DM.19 In addition, recent reports suggest that CV disease risk assessment tools designed for the general population, such as the SCORE and Framingham formulas, may not accurately estimate CV risk for individual patients with RA, as other underlying pathological processes may explain the excess CV risk.20–22 It is not yet known what the exact underlying cause of this excess CV risk is, but non-traditional CV risk factors, such as inflammation and moderate renal dysfunction, may play a pivotal role in atherosclerosis in RA.2

    Recently, a meta-analysis of observational studies showed that an estimated renal function of less than 60 ml/min/1.73 m2 (MDRD formula) is associated with an increased HR for CV disease mortality: 1.18 (1.05 to 1.32), independent of traditional CV risk factors.4

    Compared with a study investigating the association between renal function (calculated with the Cockcroft–Gault estimate) and CV events in patients with DM23, a disease with a high CV risk, our population of patients with RA showed a similar association between renal function and CV disease, independently of traditional CV risk factors (19% vs 20% higher risk of an incident CV disease per 5 ml/min decrease in renal function, calculated with the Cockroft–Gault estimate) (data not shown). Thus, not only is a decrease in renal function independently associated with incident CV disease in RA, but the effect size also appears stronger than in the general population and is comparable to that in DM.

    As the association we found was independent of other risk factors, this suggests a causal role for the chronic inflammatory state present in both diseases. Other possibilities include renal dysfunction itself causing CV disease or other underlying pathological processes affecting both renal function and CV disease. In our data, concomitant use of anti-inflammatory medication (especially non-steroidal anti-inflammatory drugs, but also glucocorticosteroids, etc) did not appear to explain our findings.

    Strengths of our study include the prospective design, with low rates of loss to follow-up. Also, we were able to test several factors one by one as confounders by studying the change in β coefficient of GFR before and after inclusion of the potential confounder. In the end, only age, sex, systolic blood pressure, use of antihypertensive medication and/or statins, RA disease duration, Health Assessment Questionnaire and presence of nodules proved to be confounders in our dataset and were thus included in the adjusted models. In addition, we performed subgroup analyses to investigate whether exclusion of previous CV disease changed the association between GFR and CV events in RA. Furthermore, we found a strong association between CV disease and both estimates of renal function (the Cockcroft–Gault and MDRD formulas). Several limitations merit attention. First, we were not able to adjust for residual confounding by recently discovered markers of both renal dysfunction and CV disease in patients with RA. One of these is uric acid, which is a predictor of CV disease in patients with RA24 and has been linked with renal dysfunction in such patients.25 Second, we did not use a control population of healthy subjects and therefore were not able to compare the present findings in RA patients with matched non-RA patients. Third, the small number of incident cases and soft events (elective PCI or CABG) may have resulted in relatively low power. Therefore we restricted confounding analyses to a minimum of variables.

    In conclusion, this study suggests that subclinical renal dysfunction is an independent risk factor for CV events in RA. A relatively minor decrease in estimated GFR may be associated with a substantial increase in CV morbidity. Therefore clinicians should be aware that patients with RA with decreased renal function are more prone to CV events.

    Acknowledgments

    We would like to express our gratitude to I M Visman and J W R Twisk for their statistical help.

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    Footnotes

    • Patient consent Obtained.

    • Ethics approval Ethics Committee of the Slotervaart Hospital and Read.

    • Provenance and peer review Not commissioned; externally peer reviewed.