TNF Inhibitors for IBD Linked to Kidney Function Declines

Anti-tumor necrosis factor (TNF) therapy for new-onset inflammatory bowel disease (IBD) was independently associated with progressive kidney function decline but not survival, a VA cohort study found.

Multivariable analysis revealed that newly initiated use of TNF inhibitors was associated with significantly higher risk of at least a 30% decline in estimated glomerular filtration rate (eGFR) versus nonuse (adjusted hazard ratio [aHR] 1.34, 95% CI 1.18-1.52), reported Csaba Kovesdy, MD, of the Memphis VA Medical Center in Tennessee, and coauthors.

Results were generally consistent across subgroups, including whether patients were diagnosed with ulcerative colitis (aHR 1.25, 95% CI 1.02-1.53) or Crohn’s disease (aHR 1.40, 95% CI 1.19-1.65), though no association was seen among the veterans also on corticosteroids.

However, that same analysis in JAMA Network Open found that use of TNF inhibitors was ultimately not associated with a higher risk for all-cause mortality (aHR 1.02, 95% CI 0.86-1.21).

Although the observational study could not conclude any causal relationships, the findings line up with a 2022 expert consensus to “suggest the need for careful assessment and monitoring of kidney function when initiating anti-TNF therapy in patients with IBD,” Kovesdy’s group concluded.

Prior research has shown associations between IBD and increased risks for chronic kidney disease and mortality, and while biologic agents like TNF inhibitors have “revolutionized the management of IBD” with their tolerability and efficacy, concerns about the long-term safety of the treatment remain.

Autoimmune-mediated phenomena are well-known adverse events with biologic use in IBD, including anti-TNF-induced lupus, which affects various organs, including the kidneys.

Another cause of eGFR decline in these IBD patients could be due to an increase in serum creatinine generation as a consequence of gaining muscle mass, the researchers noted. “Albeit speculative, it is … possible that the gain of muscle mass associated with improvement of IBD symptoms following anti-TNF therapy and resultant amelioration of nutritional deficiency led to an apparent decline in eGFR among patients with incident TNF inhibitor use.”

Data for their analysis was taken from the Therapeutic Interventions to Assess Outcomes and Disparities in CKD study, a nationwide study of veterans spanning October 2004 through September 2006, with follow-up through September 2019.

As expected with a VA population, the patient cohort was overwhelmingly male (93.5%), with an average age of 67.4 years. The patients included were 84.3% white, 11.3% African American, 4.3% of another race, and 4.1% were of Hispanic ethnicity. Mean patient BMI was 28.8, while the mean eGFR was 77.2 mL/min/1.73 m² at baseline. Ischemic heart disease was the most common comorbidity present in the patient population at 32.2%, followed by diabetes at 31.4%, and chronic lung disease at 30.8%. A large portion, 44.6%, of patients were on statins, 38.9% were on proton pump inhibitors, 34.7% were on renin-angiotensin-aldosterone system inhibitors, 20.1% were on calcium channel blockers, and 12.3% were on corticosteroids.

Ulcerative colitis was diagnosed in 60% while Crohn’s disease was diagnosed in 40%. Adalimumab (Humira) was the most commonly prescribed TNF inhibitor among the 1,515 patients on anti-TNF therapy, used for 52.4% of patients, followed by infliximab (Remicade) for 45.2%, certolizumab (Cimzia) for 2.2%, and golimumab (Simponi) for 0.2%.

Over a median 4.1 years of follow-up after diagnosis with new-onset IBD, 3,367 of 10,689 patients experienced at least a 30% decline in eGFR, with a crude rate of 92.7 per 1,000 patient-years in the anti-TNF-treated group and 62.2 per 1,000 among nonusers. Subgroup analyses of eGFR decline with anti-TNF therapy showed significant interactions by age (aHR 1.89 for those 70 and older, 95% CI 1.54-2.33) and corticosteroid use (aHR 1.44 for no use, 95% 1.24-1.67).

Overall, 2,502 of the IBD patients died over a median of 5 years.

“Notably, in the subgroup analysis, we observed a significantly lower risk of all-cause mortality associated with anti-TNF therapy in patients with corticosteroid use,” wrote Kovesdy and colleagues. “The precise mechanisms underlying this observation remain unclear. Given the well-known corticosteroid-sparing effects of biologics in IBD, the observed survival benefit might be owing at least in part to corticosteroid-sparing effects following the administration of biologic therapy.”

The researchers acknowledged that the retrospective nature of the study was a limitation. Also, the study population of largely white, male veterans could limit generalizability, they noted, while characteristics that made patients eligible for anti-TNF therapy could have differed from those who were ultimately not eligible.

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