What are the causes of acute kidney injury (AKI) in patients with Rheumatoid Arthritis (RA)?

From the Guidelines

Acute kidney injury (AKI) in rheumatoid arthritis (RA) is most commonly caused by medication-related nephrotoxicity, particularly from nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs), as well as RA-related amyloidosis and glomerulonephritis. The causes of AKI in RA can be multifactorial, but generally, they can be categorized into prerenal, renal, and postrenal causes [ 1 ]. Prerenal factors include impaired blood flow from any cause, including hypotension, hypovolemia, decreased cardiac output, or renal artery occlusion. Renal causes include any disease that damages renal parenchyma, such as vasculitis, acute tubular necrosis, glomerulonephritis, interstitial nephritis, renal infection or infiltration, drugs, and toxins [ 1 ].

Common Causes of AKI in RA

• Medication-related nephrotoxicity, particularly from NSAIDs like ibuprofen, naproxen, and diclofenac, which can reduce renal blood flow and cause acute tubular necrosis
• Disease-modifying antirheumatic drugs (DMARDs) like methotrexate, which can cause direct tubular toxicity, especially at higher doses or with impaired kidney function
• Cyclosporine and tacrolimus, which may cause vasoconstriction leading to AKI
• RA-related amyloidosis, where inflammatory proteins deposit in kidney tissue, can develop in long-standing, poorly controlled disease
• Glomerulonephritis, which may occur as an extra-articular manifestation of RA or as a complication of medications
• Interstitial nephritis, which can result from medications like NSAIDs, antibiotics, or proton pump inhibitors commonly used in RA patients
• Hemodynamic instability from systemic inflammation, vasculitis affecting renal vessels, and infections secondary to immunosuppression are additional potential causes

Prevention Strategies

• Regular monitoring of kidney function, especially when using nephrotoxic medications
• Maintaining adequate hydration
• Promptly treating infections or RA flares that could compromise kidney function
• Using the lowest effective dose of nephrotoxic medications and avoiding combinations of nephrotoxic agents when possible
• Considering alternative medications with less nephrotoxic potential when feasible

According to the most recent evidence [ 1 ], people with diabetes are at higher risk of AKI than those without diabetes, and other risk factors for AKI include preexisting chronic kidney disease (CKD), the use of medications that cause kidney injury, and the use of medications that alter renal blood flow and intrarenal hemodynamics. However, in the context of RA, the primary concern remains the direct and indirect effects of the disease and its treatment on kidney function. Therefore, it is crucial to carefully manage RA patients to prevent AKI, focusing on medication safety, monitoring, and prompt intervention for any signs of kidney dysfunction.

From the FDA Drug Label

Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.

The causes of acute kidney injury in rheumatoid arthritis patients taking methotrexate include:

• Impaired renal function: Methotrexate elimination is reduced in patients with impaired renal functions.
• Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs): Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate and some NSAIDs. No other direct causes of acute kidney injury are mentioned in the provided drug labels 2 2.

From the Research

Causes of Acute Kidney Injury in Rheumatoid Arthritis

• Rheumatoid arthritis (RA) can lead to kidney damage, including acute kidney injury, due to various factors such as secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs, and nephropathies as extra-articular manifestations 3.
• The use of proton pump inhibitors has been associated with an increased risk of acute kidney injury among patients with rheumatoid arthritis, with a hazard ratio of 2.30 and an absolute risk difference of 40 events per 100,000 episodes of use 4.
• Non-steroidal anti-inflammatory drugs (NSAIDs) can also increase the risk of acute kidney injury, particularly in patients with preexisting renal impairment, with a hazard ratio of 1.38 5.
• Other factors that can contribute to acute kidney injury in RA patients include the use of certain disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and biologic medications, as well as uncontrolled systemic inflammation and chronic NSAID use 3, 6.
• Biologic agents, such as tumor necrosis factor (TNF)-alpha inhibitors, can also increase the risk of infections and other side effects, including infusion and injection site reactions 7.

Renal Manifestations of Rheumatoid Arthritis

• Renal manifestations in RA have evolved over time, with a decrease in renal manifestations due to improved RA management and the use of newer medications 6.
• Chronic kidney disease in RA is now more likely to be caused by cardiovascular risk factors than uncontrolled RA disease severity 6.
• Patients with renal dysfunction may need to adjust or avoid certain medications, such as NSAIDs, methotrexate, and tofacitinib, to prevent adverse events 6.

Medication-Related Risks

• The use of certain medications, such as proton pump inhibitors and NSAIDs, can increase the risk of acute kidney injury in RA patients 4, 5.
• Biologic agents can also increase the risk of infections and other side effects, and patients should be screened annually for tuberculosis and receive pneumococcal, influenza, and hepatitis B vaccinations 7.