No Association between Vascular Inflammation and Estimated Glomerular Filtration Rate in Patients with Rheumatoid Arthritis: Secondary Analysis of TARGET Trial

To the editor:

Kidney dysfunction is a common complication in patients with rheumatoid arthritis (RA). [1] More severe RA disease activity is associated with a larger decline in the estimated glomerular filtration rate (eGFR) and development of chronic kidney disease (CKD).[2] Active RA presents with systemic vascular inflammation and a higher risk of cardiovascular events.[3] Vascular inflammation is closely associated with atherosclerosis, endothelial dysfunction, and hypertension,[4] potentially leading to nephrosclerosis in patients with RA.[5] Hence, we hypothesized that vascular inflammation in RA may underpin kidney dysfunction, and reductions in vascular inflammation may improve kidney function.

We performed a secondary analysis of the TARGET trial, [3] a randomized controlled trial examining the effect of tumor necrosis factor inhibitors vs triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) on vascular inflammation in patients with RA. The trial included patients with moderate-to-high RA disease activity despite methotrexate whose creatinine-based eGFR (eGFRcr) was ≥50 mL/min/1.73m². Study participants underwent fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) at baseline and week 24. Vascular inflammation was assessed with the target-to-background ratio (TBR) and standardized uptake value (SUV) of the most diseased segment in the aorta or carotid arteries. The trial revealed that both treatment strategies equally improved vascular inflammation. [3] Other study details were published previously. [3] Written informed consent was obtained from all participants, and the study was approved by the Mass General Brigham Human Research Committee. This secondary analysis included participants whose FDG-PET/CT results and cystatin C-based eGFR (eGFRcys) were available at baseline and week 24. Multivariable linear regression evaluated the cross-sectional association between baseline TBR and baseline eGFRcys. Then, the association between TBR change and eGFRcys change over 24 weeks was assessed. In multivariable analyses, we adjusted for baseline covariates, including age, sex, race, body mass index, smoking status, non-steroidal anti-inflammatory drugs, glucocorticoid dose, methotrexate dose, hypertension, diabetes, and hyperlipidemia. The eGFR change analysis additionally adjusted for baseline TBR and baseline eGFR. Multiple subgroup analyses were conducted. Additional sensitivity analyses utilized a) eGFRcr instead of eGFRcys, and b) SUV in place of TBR. We used Stata Version 17.1 for all analyses and reported point estimates with 95% confidence intervals (95%CI).

We identified 108 eligible patients (Supplemental Figure 1). At baseline, the median age was 58.5 years (IQR: 53.0, 65.5), 77 (71.3%) were female, and the median eGFRcys was 60.3 mL/min/1.73m² (IQR: 49.6, 75.7) (Supplemental Table 1). Baseline vascular inflammation (TBR) was not associated with baseline eGFRcys (adjusted β coefficient [95%CI] of TBR: 1.36 [−6.11, 8.83]) (Figure 1). During the follow-up, the mean TBR decreased from 2.63 to 2.43, but changes in vascular inflammation were not associated with eGFRcys changes (adjusted β coefficient [95%CI] of TBR change: 2.91 [−3.93, 9.76]) (Figure 1). Stratified subgroup analyses were similar to the primary analysis result (Figure 2). Results were consistent in the other sensitivity analyses using eGFRcr or SUV (Supplemental Figures 2 and 3).

Figure 1. Relationship between vascular inflammation (TBR) and eGFRcys.

Baseline relationship between vascular inflammation and eGFRcys (A) and between vascular inflammation change and eGFRcys change over 24 weeks (B). Multivariable models adjusted for age, sex, race, body mass index, smoking status, non-steroidal anti-inflammatory drugs, glucocorticoid dose, methotrexate dose, hypertension, diabetes, and hyperlipidemia. eGFRcys, estimated glomerular filtration rate based on cystatin C; TBR, target-to-background ratio

Figure 2. Subgroup analyses of Relationships between vascular inflammation (TBR) and eGFRcys.

Baseline relationship between vascular inflammation and eGFRcys (A) and between vascular inflammation change and eGFRcys change over 24 weeks (B). Multivariable models adjusted for age, sex, race, body mass index, smoking status, NSAIDs, glucocorticoid dose, methotrexate dose, hypertension, diabetes, and hyperlipidemia.

eGFRcys, estimated glomerular filtration rate based on cystatin C; TBR, target-to-background ratio; TNFi, tumor necrosis factor inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs

To our knowledge, this is the first study examining the association between vascular inflammation by PET/CT and eGFR in patients with RA. In the TARGET trial, immunomodulatory treatment for RA reduced vascular inflammation. [3] Methotrexate and biological therapy showed renoprotective effects of preserving eGFR in previous studies. [6, 7] However, the current set of analyses identified no relevant associations between vascular inflammation changes and eGFR changes over 6 months in patients with RA. The results suggested vascular inflammation reduction may not be strongly associated with temporal eGFR improvement. With repeated PET/CT results, we could evaluate the association between changes in vascular inflammation and eGFR changes. PET/CT was conducted using the standardized protocol and assessed by experienced specialists in the trial setting. [3] However, the non-significant results of this study can be due to a limited number of patients and/or a relatively short follow-up period. Patients with prevalent kidney dysfunction (eGFRcr <50 mL/min/1.73m²) were excluded from the TARGET trial. Additionally, we assessed vascular inflammation in the aorta and carotid vasculature because the method to directly measure inflammation in renal arteries and kidneys has not been established.

In conclusion, this study did not find a significant association between aortic or carotid vascular inflammation and eGFR in patients with active RA. Over the 6-month follow-up, reduction in vascular inflammation was not associated with temporal eGFR improvement. Future studies should investigate the association between chronic vascular inflammation and long-term kidney dysfunction in a larger population.

Access to Data statement:

SF had full access to all the data in the study and was responsible for its integrity and accuracy.