Renal Complications in Rheumatoid Arthritis: Evolution and Management

Before the use of methotrexate and targeted biologic disease-modifying antirheumatic drugs (DMARDs) became standard practice in rheumatoid arthritis (RA) treatment, renal complications were common in RA, with a 37% to 57% prevalence of chronic kidney disease (CKD) previously noted in this population.¹ Such issues have decreased considerably as use of the older DMARDs and the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) have fallen out of favor.  The shift to a treat-to-target strategy in RA management has also helped lessen the incidence of CKD.¹

Some of the more common renal manifestations observed in RA are described below.¹

• Mesangial glomerulonephritis affects an estimated 35% to 78% of patients with RA with known nephropathy, typically those with long-standing RA (12.9 ± 10.4 years). Interleukin-6 has been implicated as a growth factor for mesangial cells in limited animal and human studies. The course of mesangial glomerulonephritis is usually mild and rarely associated with renal failure.
• Membranous glomerulonephritis can result from immune-complex deposition, in a segmental or diffuse pattern, in the glomerular basement membrane. In patients with RA, membranous glomerulonephritis has been linked with a shorter disease duration (3.8 ± 2.9 years) and primarily affects those taking DMARDs such as penicillamine, gold, and bucillamine. Discontinuation of the causative agent is the standard treatment approach in these cases. 
• Immunoglobulin A (IgA) glomerulonephritis has a reported prevalence of 12% in RA, similar to the general population, and is “histologically indistinguishable between patients with and without RA.”¹ IgA nephropathy is often treated with angiotensin-converting enzyme inhibitors, and severe cases have been treated with glucocorticoids.
• Secondary amyloidosis commonly affected patients with RA before the introduction of biologic DMARDs and represented a major cause of death in this population compared with controls. It is associated with longer RA disease duration (17.2 ± 7.3 years) and is the result of defective metabolism of serum amyloid A acute-phase reactant precursor protein. The concentration of this protein is associated with inflammatory disease activity. Patients generally have proteinuria and elevated serum creatinine levels, which can progress to renal failure.

Since methotrexate and biologic DMARDs have replaced the older RA therapies, chronic CKD in RA is now more often associated with cardiovascular disease (CVD) and CV risk factors, similar to the pattern observed in the general population. A cross-sectional study of 1908 patients with RA showed a higher prevalence of diabetes mellitus (17.2% vs 8.6%; P <.001), hypertension (60.1% vs 26.3%; odds ratio[OR], 3.05; P <.001), and older age (73.1 years vs 61.0 years; OR, 5.19; P <.001) in those with vs without CKD.² Substantially greater mortality rates (2- to 4-fold) have been found in patients with RA with vs without CKD (hazard ratios, 2.77-4.45).¹

For certain medications, dose adjustments may be required in patients with RA with CKD or end-stage renal disease. Although there is no need for dose adjustments with biologics, leflunomide, sulfasalazine, and hydroxychloroquine, the following medications may need to be adjusted as noted to minimize the risk for adverse events.¹

• NSAIDs: Use of NSAIDs is contraindicated in patients with creatine clearance (CrCl) ≤30 mL/min. They should be used with caution in those with CrCl 30 to 59 mL/min and should generally be avoided in patients receiving hemodialysis.
• Methotrexate: No adjustment is needed with CrCl >50 mL/min. A 50% reduction is recommended for CrCl 31 to 50 mL/min and its use is contraindicated for patients with CrCl ≤30 mL/min and those receiving hemodialysis or peritoneal dialysis.
• Tofacitinib: No adjustment is needed with CrCl>50 mL/min. Reduction to 5 mg once daily is recommended for patients with CrCl ≤50 mL/min and for those receiving hemodialysis or peritoneal dialysis.

For additional discussion of prevalent renal issues in RA, Rheumatology Advisor checked in with Rebecca L. Manno, MD, MHS, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins University School of Medicine and assistant director of the Johns Hopkins Vasculitis Center in Baltimore, Maryland, and Susan M. Goodman, MD, rheumatologist at Hospital for Special Surgery and associate professor of medicine at Weill Cornell Medical College, New York.

Rheumatology Advisor: What are examples of common renal manifestations in RA?

Dr Manno: Renal disease that is directly attributed to RA is rare. Although glomerulonephritis and renal vasculitis has been described in the literature, especially in the prebiologic DMARD era, it is exceedingly rare. Secondary amyloidosis attributed to RA is also quite rare today with the availability of very good RA therapies. But this should be a consideration in a patient with RA who has long-standing, poorly controlled disease.

Drug-related toxicities are a more common cause of renal insufficiency in [patients with RA] than the disease itself. NSAID-associated interstitial nephritis and TNF-induced lupus — which can cause a glomerulonephritis — are common culprits. With the known association between CVD and RA, other common causes of renal insufficiency such as hypertension and atherosclerotic renovascular disease should also be considered.

Dr Goodman: Patients with RA are at increased risk for renal disease, usually related to other comorbidities like age and hypertension. Previously, complications such as renal amyloid or RA-associated vasculitis were implicated in RA renal disease, but those are rare today. Medications remain a risk for renal damage, and while gold-induced nephrotic syndrome is no longer seen, case reports have described glomerulonephritis associated with TNF inhibitor use. Chronic use of NSAIDs is another well-described cause of renal disease. 

Rheumatology Advisor: What steps should be taken to minimize the risk for adverse renal events in these patients?

Dr Manno: A careful and thorough review of medication lists at every visit can help minimize the risk for renal events in [patients with RA]. It is best to try and minimize NSAID exposure, if possible, especially for older patients with long-standing disease.

Dr Goodman: It is important to carefully dose adjust for medications such as methotrexate, 90% of which is excreted through the kidney in a “first pass.” For those with advanced renal disease, careful attention to dose adjustment and avoiding nephrotoxic agents such as cyclosporine or long-term maintenance with NSAIDs is important. Reduced renal function is associated with CVD risk factors such as age and hypertension and does not seem to be linked to disease duration or severity.

Rheumatology Advisor: What are remaining research needs pertaining to this topic?

Dr Manno: As the associations between CVD, RA, and inflammation are further elucidated, we will understand more about how renal insufficiency fits into this picture.

Dr Goodman: Further epidemiologic studies are needed to understand the risk factors associated with the increased prevalence of renal disease in patients with RA.

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References

1. Kapoor T, Bathon J. Renal manifestations of rheumatoid arthritis.Rheum Dis Clin North Am. 2018;44(4):571-584.
2. Mori S, Yoshitama T, Hirakata N, Ueki Y. Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals. Clin Rheumatol. 2017;36(12):2673-2682.