Biologic Use May Be Linked to Kidney Function Decline in IBD Patients

Among patients with new onset inflammatory bowel disease (IBD), exposure to anti-tumor necrosis factor (TNF)-biologic therapy was associated with higher risk for kidney function decline, but not higher all-cause mortality, in an observational study involving U.S. veterans.

Incident use of TNF inhibitors was found to be independently linked to higher progressive kidney function decline, compared to non-use (adjusted hazard ratio, 1.34; 95% CI, 1.18-1.52) in the large, nationwide cohort study.

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, is widely known to impact chronic kidney disease progression and has been associated with premature death in patients with both conditions. According to Kovesdy and colleagues, studies examining the impact of biologic therapy on kidney function in non-IBD populations have reported mixed findings.

In an effort to examine the impact of incidence TNF inhibitor use on kidney decline in patients with IBD, the researchers conducted an analysis of data on 10,689 veterans with new-onset IBD who were participants in the nationwide, retrospective, cohort Therapeutic Interventions to Assess Outcomes and Disparities study.

The study originally included more than 3.5 million U.S. veterans, but the analysis was restricted to those with an estimated glomerular filtration rate (eGRF) of 60 mL/min/1.73 m² or greater between October 2004 and September 2006, with follow-up through September 2019. The main study outcome was eGFR decline of at least 30% and all-cause mortality during follow-up.

The mean age of the patients was 67.4 years, 93.5% were male. 84% were White, and 31.4% had diabetes. Meean baseline eGFR was 77.2 mL/min/1.73 m², and 14.2% had just initiated anti-TNF therapy. The most commonly prescribed TNF inhibitor was adalimumab (52.4% of prescriptions), followed by infliximab (45.2%), certolizumab (2.2%), and golimumab (0.2%).

A total of 3,367 patients—including 607 users of TNF inhibitors and 2,760 nonusers—experienced a decline in eGFR of 30% or more over a median follow-up of 4.1 years, and 2,502 patients died over a median 5-year follow-up, "including 262 (crude rate, 32.6 [95% CI, 28.9-36.8] per 1,000 PYs) deaths in patients with TNF inhibitor use and 2240 (crude rate, 43.8 [95% CI, 42.1-45.7] per 1,000 PYs) deaths in patients without TNF inhibitor use."

"After multivariable adjustments, incident use (vs non-use) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21])," the researchers wrote.

The findings were similar in selected subgroups and were "robust to sensitivity analyses accounting for missing data, confounding by indication in the propensity- matched cohort, and potential multicollinearity," Kovesdy et al noted.

Upon subgroup analysis, they also found the following:

• The association of TNF inhibitor use to the risk of decline in eGFR was most evident in subgroups of patients aged 70 years and older (HR, 1.89; 95% CI, 1.54-2.33) and those without corticosteroid use (HR, 1.44; 95% CI, 1.24-1.67) than in their counterparts, with statistically significant interactions.
• The use of TNF inhibitors was significantly associated with lower all-mortality in corticosteroid users in the sub-study analysis, with an HR of 0.76 (95% CI, 0.60-0.96) compared with 1.23 (95% CI, 0.99-1.51) in non-corticosteroids users.

"The precise mechanism underlying (the corticosteroid) observation remains unclear," Kovesdy and colleagues wrote. "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."

Study limitations included the largely homologous population of mostly male, mostly White patients and the restriction of biologic use to TNF inhibitors.

Kovesdy and colleagues also noted that the low number of incident kidney failure requiring kidney replacement in this cohort precluded examination of the association of incident TNF inhibitor use with a tangible kidney outcome. Likewise, the small number of patients with serum cystatin-C measurements available precluded assessment of cystatin-C–based eGFR.

"As with all observational studies, we cannot eliminate the possibility of unmeasured (e.g., IBD severity and proteinuria) and residual (eg, doses of immunomodulators) confounders that might have affected the association between incident TNF inhibitor use and outcomes," they wrote.

The researchers concluded that "future studies are needed to confirm findings and to examine potentially distinct pathophysiologic contributions of incident TNF inhibitor use to kidney and non-kidney outcomes in patients with IBD."

This research was funded by a grant from the US Department of VA Affairs and the VA Memphis and Long Beach Medical Centers.

Kovesdy reported receiving personal fees from Abbott, Akebia, AstraZeneca, Bayer, Boehringer Ingelheim, Cara Therapeutics, CSL Vifor, GSK, Pharmacosmos, ProKidney, and Takeda outside the submitted work.

Sumida K, et al "Anti-tumor necrosis factor therapy and risk of kidney function decline and mortality in inflammatory bowel disease" JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2024.6822.