Advertisement
American Journal of Kidney Diseases

The Association of Disease Activity and Estimated GFR in Patients With Rheumatoid Arthritis: Findings From the ANSWER Study

      To the Editor:
      Patients with rheumatoid arthritis (RA) are more likely to develop reduced estimated glomerular filtration rate (eGFR) than the general population.
      • Hickson L.J.
      • Crowson C.S.
      • Gabriel S.E.
      • McCarthy J.T.
      • Matteson E.L.
      Development of reduced kidney function in rheumatoid arthritis.
      Decreased eGFR is associated with a higher risk of cardiovascular disease and mortality independent of traditional cardiovascular risk factors in RA.
      • van Sijl A.M.
      • van den Oever I.A.
      • Peters M.J.
      • et al.
      Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRE Study.
      ,
      • Al-Aly Z.
      • Zeringue A.
      • Fu J.
      • et al.
      Rate of kidney function decline associates with mortality.
      Because there is evidence that the inflammatory process might contribute to decreased kidney function,
      • Ramseyer V.D.
      • Garvin J.L.
      Tumor necrosis factor-alpha: regulation of renal function and blood pressure.
      ,
      • Zhang W.
      • Wang W.
      • Yu H.
      • et al.
      Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage.
      chronic inflammation might cause kidney damage in patients with RA. Thus, we aimed to identify the associations of disease activity with eGFR in patients with RA.
      This longitudinal cohort study used data derived from a multicenter registry of patients with RA in Japan. Patients with RA, eGFR ≥ 15 mL/min/1.73 m2 at baseline, and ≥2 assessments of eGFR were included. We excluded patients who used cyclosporine, gold compounds, or d-penicillamine during the follow-up period because few patients were treated with these drugs.
      The DAS28-CRP (disease activity score in 28 joints using C-reactive protein) was used as a continuous exposure variable for the primary analysis.
      • Inoue E.
      • Yamanaka H.
      • Hara M.
      • Tomatsu T.
      • Kamatani N.
      Comparison of Disease Activity Score (DAS)28-erythrocyte sedimentation rate and DAS28-C-reactive protein threshold values.
      eGFR, calculated using an equation approved by the Japanese Society of Nephrology,
      • Matsuo S.
      • Imai E.
      • Horio M.
      • et al.
      Revised equations for estimated GFR from serum creatinine in Japan.
      was the primary outcome. We considered age, sex, disease duration, rheumatoid factor (RF), anticitrullinated peptide antibodies (ACPA), disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroid as a priori confounders. Linear mixed-effect models were used to evaluate patients’ eGFR trajectories. Disease activity and medications were handled as time-varying variables. Detailed methods are in Item S1.
      Of 2,692 patients included, 2,269 (78.4% women; mean age, 61.4 years) met the research criteria (Table S1, Fig S1). The median follow-up time was 15.2 (interquartile range [IQR], 7.2-32.7) months and 29,254 data points were obtained with an interval between measurements of 1.4 (IQR, 0.9-2.1) months. The median number of eGFR assessments per patient was 9 (IQR, 5-18) and baseline eGFR was 78.5 ± 21.3 mL/min/1.73 m2 (Table S2, Fig S2-4). No patients died or needed kidney replacement therapy during the follow-up period. Patients with low disease activity or remission had longer disease duration than patients with high or moderate disease activity. Corticosteroid and NSAID use was less frequent in patients with low disease activity or remission.
      Although patients with higher DAS28-CRP had better eGFR at baseline (by 1.698 mL/min/1.73 m2), they had a significantly worse longitudinal eGFR trajectory (difference in slopes per 1 unit greater DAS28-CRP, 0.167 [95% CI, 0.062-0.272] mL/min/1.73 m2 per year; P = 0.002). Although as expected, RA patients in general had progressive eGFR decreases as they got older, patients who achieved remission or low disease activity had a slower rate of eGFR loss compared to patients with moderate or high disease activity (−0.817 vs −1.283 mL/min/1.73 m2 per year; P < 0.001; Fig 1A). The association of DAS28-CRP with the eGFR trajectory was dose-dependent (−0.723, −0.821, −1.041, and −1.386 mL/min/1.73 m2 per year for remission and low, moderate, and high disease activity, respectively; Fig 1B). Analyses of secondary outcomes and sensitivity analyses showed similar findings (Table S3). Subgroup analyses suggested that baseline elderly age, better eGFR at baseline, and shorter disease duration had stronger associations of disease activity with eGFR trajectory (Fig 2).
      Figure thumbnail gr1
      Figure 1Evolution of mean eGFR from baseline, with DAS28-CRP–determined disease activity in (A) 2 or (B) 4 categories. Trajectories were adjusted for age, sex, disease duration, RF, ACPA, methotrexate, sulfasalazine, other conventional synthetic DMARDs, biologic DMARDs, tofacitinib, NSAIDs, and corticosteroid. DAS28-CRP and medications were handled as time-varying variables. Error bars denote 95% CI.
      Figure thumbnail gr2
      Figure 2The association of DAS28-CRP on annual change in eGFR slope in the overall population and in subgroups.
      We showed that patients with higher disease activity had a significantly worse longitudinal eGFR trajectory in a dose-dependent manner. To put this finding in context, a meta-analysis found that for sufficiently large studies (sample size ~1,900), a mean difference of ~0.5 mL/min/1.73 m2 per year in eGFR slope over 1 and 2 years predicted benefits for clinical end points such as doubling of serum creatinine, eGFR < 15 mL/min/1.73 m2, or kidney failure with relatively high positive predictive values of 0.94 and 0.97, respectively.
      • Inker L.A.
      • Heerspink H.J.L.
      • Tighiouart H.
      • et al.
      GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.
      Two previous studies showed that disease activity was not associated with eGFR in patients with RA.
      • Daoussis D.
      • Panoulas V.F.
      • Antonopoulos I.
      • et al.
      Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis.
      ,
      • Couderc M.
      • Tatar Z.
      • Pereira B.
      • et al.
      Prevalence of renal impairment in patients with rheumatoid arthritis: results from a cross-sectional multicenter study.
      Both, however, were cross-sectional studies with a small sample size, and were not able to examine trend or causality. Also, because our study showed that the association of disease activity with eGFR trajectory was more prominent in patients with a shorter disease duration and the disease duration in both previous studies was about 10 years, it may have been difficult to examine the association in patients with longer disease duration.
      Our study also has several limitations, including use of creatinine to estimate GFR; no examination of kidney disease etiology; relatively short study duration and modest change in eGFR between groups; no assessment of urine protein and albumin; no examination of the mechanistic link between disease activity and eGFR; no assessment of use of over-the-counter NSAIDs; and unmeasured confounding (Item S1).
      In conclusion, lower disease activity was associated with a slower rate of eGFR decline, but clinicians must recognize that even RA patients in remission have progressive eGFR decline as they get older. Considering additional measures to protect kidney function, such as avoiding nephrotoxic medications and treating cardiovascular risk factors, is thus also important.

      Article Information

      Authors’ Contributions

      Research idea and study design: AO; data acquisition: AO, KA, WY, KM, MK, RH, KN, TH, KE, HA, YS, KY, MH, AM; data analysis/interpretation: AO, KA, WY, KM, MK, RH, KN, TH, KE, HA, YS, KY, MH, AM; statistical analysis: AO; supervision or mentorship: AO. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      This study used data from ANSWER Cohort Association supported by grants from 8 pharmaceutical companies ( AbbVie G.K., Asahi Kasei Pharma, AYUMI Pharmaceutical Co, Chugai Pharmaceutical Co, Ltd, Eisai Co, Ltd, Janssen Pharmaceutical K.K., Ono Pharmaceutical Co, UCB Japan Co Ltd, Teijin Healthcare Limited, and Sanofi ) and an information technology services company ( CAC ). This study was conducted as an investigator-initiated study. These companies had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

      Financial Disclosure

      Dr Onishi received grants from Advantest and a speaker fee from Chugai, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Asahi-Kasei, and Takeda. Dr Ebina is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho; has received research grants from Abbie, Asahi-Kasei, Astellas, Chugai, Eisai, Ono Pharmaceutical, and UCB Japan; and has received payments for lectures from Abbie, Asahi-Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Sanofi, and UCB Japan. Drs Murata and Hashimoto belong to a department that is financially supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan and 5 pharmaceutical companies (Tanabe-Mitsubishi, Chugai, UCB Japan, Ayumi, and Asahi-Kasei). Dr Hashimoto has received a research and/or speaker fee from Brystol-Myers, Eisai, Ely Lilly, and Tanabe-Mitsubishi. Dr Hirano received a speaker fee from GlaxoSmithKline, Chugai, Eisai, Eli Lilly, and NIPPON SHINYAKU. Dr Hara received a speaker fee from AbbVie. The remaining authors have no relevant financial interests.

      Acknowledgements

      We are grateful to the rheumatologists and patients that participated in the ANSWER cohort study and thereby made this study possible.

      Data Sharing

      The datasets generated and/or analyzed during the current study are not publicly available. Patients did not provide consent to raw data sharing during data collection. All aggregated data relevant to the study are included in the article or supplementary material.

      Peer Review

      Received October 8, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form February 25, 2021.

      Supplementary Material

      References

        • Hickson L.J.
        • Crowson C.S.
        • Gabriel S.E.
        • McCarthy J.T.
        • Matteson E.L.
        Development of reduced kidney function in rheumatoid arthritis.
        Am J Kidney Dis. 2014; 63: 206-213
        • van Sijl A.M.
        • van den Oever I.A.
        • Peters M.J.
        • et al.
        Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRE Study.
        Ann Rheum Dis. 2012; 71: 341-344
        • Al-Aly Z.
        • Zeringue A.
        • Fu J.
        • et al.
        Rate of kidney function decline associates with mortality.
        J Am Soc Nephrol. 2010; 21: 1961-1969
        • Ramseyer V.D.
        • Garvin J.L.
        Tumor necrosis factor-alpha: regulation of renal function and blood pressure.
        Am J Physiol Renal Physiol. 2013; 304: F1231-F1242
        • Zhang W.
        • Wang W.
        • Yu H.
        • et al.
        Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage.
        Hypertension. 2012; 59: 136-144
        • Inoue E.
        • Yamanaka H.
        • Hara M.
        • Tomatsu T.
        • Kamatani N.
        Comparison of Disease Activity Score (DAS)28-erythrocyte sedimentation rate and DAS28-C-reactive protein threshold values.
        Ann Rheum Dis. 2007; 66: 407-409
        • Matsuo S.
        • Imai E.
        • Horio M.
        • et al.
        Revised equations for estimated GFR from serum creatinine in Japan.
        Am J Kidney Dis. 2009; 53: 982-992
        • Inker L.A.
        • Heerspink H.J.L.
        • Tighiouart H.
        • et al.
        GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.
        J Am Soc Nephrol. 2019; 30: 1735-1745
        • Daoussis D.
        • Panoulas V.F.
        • Antonopoulos I.
        • et al.
        Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis.
        Ann Rheum Dis. 2010; 69: 517-521
        • Couderc M.
        • Tatar Z.
        • Pereira B.
        • et al.
        Prevalence of renal impairment in patients with rheumatoid arthritis: results from a cross-sectional multicenter study.
        Arthritis Care Res (Hoboken). 2016; 68: 638-644