Reduced Kidney Function in Rheumatoid Arthritis
Reduced Kidney Function in Rheumatoid Arthritis
The study population included 813 patients with RA and 813 non-RA individuals. The 2 cohorts had similar characteristics (Table 1). Average age at RA incidence (index date for the non-RA cohort) was 56 ± 16 (SD) years, and 556 (68%) were women. There was a statistically significant difference between smoking status in patients with RA (45% never smokers) compared with individuals in the non-RA cohort (54%). There was no difference in the presence of reduced kidney function at RA incidence/index date (P = 0.9), but mean eGFR was higher in the RA cohort compared to the non-RA cohort (86 ± 20 vs 83 ± 20 mL/min/1.73 m; P = 0.008). There were no end-stage renal disease events.
During follow-up (among patients without prior eGFR < 60 mL/min/1.73 m), 111 and 88 people in the RA and non-RA cohorts, respectively, developed eGFR < 60 mL/min/1.73 m. The cumulative incidence of eGFR < 60 mL/min/1.73 m was higher in patients with RA compared to the non-RA cohort (25% ± 2.5% vs 20% ± 2.3% at 20 years in the RA and non-RA cohorts, respectively; P = 0.03; Table 2). As illustrated in Fig 1, patients with RA were more likely to develop eGFR < 60 mL/min/1.73 m during follow-up (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.23–2.16; analysis adjusted for age, sex, and calendar year). This difference between RA and non-RA cohorts persisted after adjustment for smoking and baseline eGFR (HR, 1.95; 95% CI, 1.45–2.62).
(Enlarge Image)
Figure 1.
Cumulative incidence of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m in individuals with rheumatoid arthritis (RA; solid line) versus non-RA (dashed line; P = 0.03).
The rate of creatinine testing was higher during follow-up in the RA cohort (20,363 tests/7,827.7 person-years = 2.6 tests per patient per year) than in the non-RA cohort (13,887 tests/8,886.3 person-years = 1.6 per patient per year). To examine the possibility that the differences in testing rates influenced results, a sensitivity analysis was performed. More frequent testing in patients with RA may have led to earlier dates of meeting reduced kidney function definitions. The time between consecutive abnormal test results at least 90 days apart was compared and was found to be shorter in the RA cohort compared to the non-RA cohort (mean, 255 ± 183 vs 322 ± 223 days; P = 0.01). In sensitivity analyses, the date of reduced kidney function was defined to be exactly 90 days after the first abnormal creatinine test result instead of the actual date of the second abnormal test result, and results comparing cumulative incidence of reduced kidney function in the RA versus non-RA cohort did not change. Patients with RA remained more likely to develop eGFR < 60 mL/min/1.73 m during follow-up after adjustment for number of serum creatinine measures (HR, 1.53; 95% CI, 1.14–2.05).
There was no difference in the development of eGFR < 45 mL/min/1.73 m between the RA cohort and non-RA cohort (HR, 1.13; 95% CI, 0.76–1.70; P = 0.6; analysis adjusted for age, sex, and calendar year). The cumulative incidence of eGFR < 45 mL/min/1.73 m at 20 years of follow-up was not different in the RA compared to the non-RA group (9% ± 1.6% vs 10% ± 1.6%; P = 0.8).
The potential association of both RA disease characteristics and CV risk factors with the development of reduced kidney function in patients with RA also was examined (Table 3). An elevation in the inflammatory marker erythrocyte sedimentation rate (highest value in the first year after RA diagnosis) was associated with eGFR < 60 mL/min/1.73 m (HR per 10-mm/h greater, 1.08; 95% CI, 1.00–1.16; P = 0.05). The presence of CVD was associated with a nearly 2-fold increased risk of eGFR < 60 mL/min/1.73 m (HR, 1.77; 95% CI, 1.14–2.73; P = 0.01). Patients with obesity (body mass index ≥30 kg/m) and dyslipidemia also were more likely to develop eGFR < 60 mL/min/1.73 m. Erythrocyte sedimentation rate (highest value in the first year), CVD, severe extra-articular manifestations, and use of corticosteroids were each associated with the development of eGFR < 45 mL/min/1.73 m in patients with RA.
Some characteristics were "protective" for the development of reduced kidney function, including body mass index < 20 kg/m and use of NSAIDs. NSAID use was common in patients with RA during the study period. Nearly all patients with RA used NSAIDs, with 588 of 813 (72%) using them at the time of RA diagnosis and another 149 (18%) using NSAIDs during follow-up. Additionally, we found no association between NSAID exposure and the development of CVD, hypertension, or diabetes mellitus during follow-up (P = 0.9 for all). Given the extensive NSAID use, there was no difference in eGFRs at baseline between patients with RA who did and did not use NSAIDs at baseline (mean, 85.5 ± 19.6 vs 86.4 ± 20.1 mL/min/1.73 m; P = 0.5).
During follow-up, 392 patients (RA, 229; non-RA, 163) died. eGFR < 60 mL/min/1.73 m was associated with increased risk of mortality in the non-RA (HR, 1.59; 95% CI, 1.13–2.24) and RA (HR, 1.25; 95% CI, 0.92–1.68) cohorts, but the effect of eGFR < 60 mL/min/1.73 m on mortality was significantly less in patients with RA compared to non-RA individuals (HR for interaction, 0.66; 95% CI, 0.43–0.97; P = 0.04). Results were similar for eGFR < 45 mL/min/1.73 m (HRs of 2.06 [95% CI, 1.41–2.99] and 1.62 [95% CI, 1.15–2.28] for the RA and non-RA cohorts, respectively [HR for interaction, 0.66; 95% CI, 0.41–1.06; P = 0.09]).
During follow-up, 245 patients (RA, 137; non-RA, 108) developed CVD. eGFR < 60 mL/min/1.73 m was not associated significantly with increased risk of CVD in the non-RA (HR, 1.37; 95% CI, 0.83–2.24; P = 0.2) or RA (HR, 0.99; 95% CI, 0.63–1.57; P = 0.9) cohorts, and the effect of eGFR < 60 mL/min/1.73 m on mortality was not different between the RA and non-RA cohorts (HR for interaction, 0.71; 95% CI, 0.39–1.29; P = 0.3). For patients with RA, eGFR < 45 mL/min/1.73 m was associated with increased risk of CVD development (HR, 1.93; 95% CI, 1.04–3.58; P = 0.04). Results were similar, but not statistically significant, for the non-RA cohort (HR, 1.41; 95% CI, 0.67–2.98; P = 0.4 [HR for interaction, 1.25; 95% CI, 0.50–3.16; P = 0.6]).
Results
Study Participants
The study population included 813 patients with RA and 813 non-RA individuals. The 2 cohorts had similar characteristics (Table 1). Average age at RA incidence (index date for the non-RA cohort) was 56 ± 16 (SD) years, and 556 (68%) were women. There was a statistically significant difference between smoking status in patients with RA (45% never smokers) compared with individuals in the non-RA cohort (54%). There was no difference in the presence of reduced kidney function at RA incidence/index date (P = 0.9), but mean eGFR was higher in the RA cohort compared to the non-RA cohort (86 ± 20 vs 83 ± 20 mL/min/1.73 m; P = 0.008). There were no end-stage renal disease events.
eGFR < 60 mL/min/1.73 m
During follow-up (among patients without prior eGFR < 60 mL/min/1.73 m), 111 and 88 people in the RA and non-RA cohorts, respectively, developed eGFR < 60 mL/min/1.73 m. The cumulative incidence of eGFR < 60 mL/min/1.73 m was higher in patients with RA compared to the non-RA cohort (25% ± 2.5% vs 20% ± 2.3% at 20 years in the RA and non-RA cohorts, respectively; P = 0.03; Table 2). As illustrated in Fig 1, patients with RA were more likely to develop eGFR < 60 mL/min/1.73 m during follow-up (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.23–2.16; analysis adjusted for age, sex, and calendar year). This difference between RA and non-RA cohorts persisted after adjustment for smoking and baseline eGFR (HR, 1.95; 95% CI, 1.45–2.62).
(Enlarge Image)
Figure 1.
Cumulative incidence of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m in individuals with rheumatoid arthritis (RA; solid line) versus non-RA (dashed line; P = 0.03).
The rate of creatinine testing was higher during follow-up in the RA cohort (20,363 tests/7,827.7 person-years = 2.6 tests per patient per year) than in the non-RA cohort (13,887 tests/8,886.3 person-years = 1.6 per patient per year). To examine the possibility that the differences in testing rates influenced results, a sensitivity analysis was performed. More frequent testing in patients with RA may have led to earlier dates of meeting reduced kidney function definitions. The time between consecutive abnormal test results at least 90 days apart was compared and was found to be shorter in the RA cohort compared to the non-RA cohort (mean, 255 ± 183 vs 322 ± 223 days; P = 0.01). In sensitivity analyses, the date of reduced kidney function was defined to be exactly 90 days after the first abnormal creatinine test result instead of the actual date of the second abnormal test result, and results comparing cumulative incidence of reduced kidney function in the RA versus non-RA cohort did not change. Patients with RA remained more likely to develop eGFR < 60 mL/min/1.73 m during follow-up after adjustment for number of serum creatinine measures (HR, 1.53; 95% CI, 1.14–2.05).
eGFR < 45 mL/min/1.73 m
There was no difference in the development of eGFR < 45 mL/min/1.73 m between the RA cohort and non-RA cohort (HR, 1.13; 95% CI, 0.76–1.70; P = 0.6; analysis adjusted for age, sex, and calendar year). The cumulative incidence of eGFR < 45 mL/min/1.73 m at 20 years of follow-up was not different in the RA compared to the non-RA group (9% ± 1.6% vs 10% ± 1.6%; P = 0.8).
Risk Factors for Reduced Kidney Function in RA
The potential association of both RA disease characteristics and CV risk factors with the development of reduced kidney function in patients with RA also was examined (Table 3). An elevation in the inflammatory marker erythrocyte sedimentation rate (highest value in the first year after RA diagnosis) was associated with eGFR < 60 mL/min/1.73 m (HR per 10-mm/h greater, 1.08; 95% CI, 1.00–1.16; P = 0.05). The presence of CVD was associated with a nearly 2-fold increased risk of eGFR < 60 mL/min/1.73 m (HR, 1.77; 95% CI, 1.14–2.73; P = 0.01). Patients with obesity (body mass index ≥30 kg/m) and dyslipidemia also were more likely to develop eGFR < 60 mL/min/1.73 m. Erythrocyte sedimentation rate (highest value in the first year), CVD, severe extra-articular manifestations, and use of corticosteroids were each associated with the development of eGFR < 45 mL/min/1.73 m in patients with RA.
Some characteristics were "protective" for the development of reduced kidney function, including body mass index < 20 kg/m and use of NSAIDs. NSAID use was common in patients with RA during the study period. Nearly all patients with RA used NSAIDs, with 588 of 813 (72%) using them at the time of RA diagnosis and another 149 (18%) using NSAIDs during follow-up. Additionally, we found no association between NSAID exposure and the development of CVD, hypertension, or diabetes mellitus during follow-up (P = 0.9 for all). Given the extensive NSAID use, there was no difference in eGFRs at baseline between patients with RA who did and did not use NSAIDs at baseline (mean, 85.5 ± 19.6 vs 86.4 ± 20.1 mL/min/1.73 m; P = 0.5).
Reduced Kidney Function Outcomes
During follow-up, 392 patients (RA, 229; non-RA, 163) died. eGFR < 60 mL/min/1.73 m was associated with increased risk of mortality in the non-RA (HR, 1.59; 95% CI, 1.13–2.24) and RA (HR, 1.25; 95% CI, 0.92–1.68) cohorts, but the effect of eGFR < 60 mL/min/1.73 m on mortality was significantly less in patients with RA compared to non-RA individuals (HR for interaction, 0.66; 95% CI, 0.43–0.97; P = 0.04). Results were similar for eGFR < 45 mL/min/1.73 m (HRs of 2.06 [95% CI, 1.41–2.99] and 1.62 [95% CI, 1.15–2.28] for the RA and non-RA cohorts, respectively [HR for interaction, 0.66; 95% CI, 0.41–1.06; P = 0.09]).
During follow-up, 245 patients (RA, 137; non-RA, 108) developed CVD. eGFR < 60 mL/min/1.73 m was not associated significantly with increased risk of CVD in the non-RA (HR, 1.37; 95% CI, 0.83–2.24; P = 0.2) or RA (HR, 0.99; 95% CI, 0.63–1.57; P = 0.9) cohorts, and the effect of eGFR < 60 mL/min/1.73 m on mortality was not different between the RA and non-RA cohorts (HR for interaction, 0.71; 95% CI, 0.39–1.29; P = 0.3). For patients with RA, eGFR < 45 mL/min/1.73 m was associated with increased risk of CVD development (HR, 1.93; 95% CI, 1.04–3.58; P = 0.04). Results were similar, but not statistically significant, for the non-RA cohort (HR, 1.41; 95% CI, 0.67–2.98; P = 0.4 [HR for interaction, 1.25; 95% CI, 0.50–3.16; P = 0.6]).
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