TNF Inhibitors Linked to Greater Risk of Progressive eGFR Decline in Patients with IBD

Keiichi Sumida, MD, MPH, PhD

Credit: University of Tennessee Health Science Center

Incident use of tumor necrosis factor (TNF) inhibitors may be independently associated with an increased risk of progressive kidney function decline in patients with inflammatory bowel disease (IBD), according to findings from a retrospective cohort study published in JAMA Network Open.¹

The results suggest potentially distinct pathophysiologic contributions of TNF inhibitor use associated with kidney outcomes in patients with IBD and the need for careful monitoring of kidney function when initiating anti-TNF therapy in these patients.¹

An estimated 3.1 million adults in the United States have been diagnosed with IBD and are more likely to have other chronic conditions than those without IBD.2 Among these complications are renal manifestations such as chronic kidney disease (CKD), although little is known about the impact of anti-TNF therapy on disease progression and outcomes in these patients.¹

“To date, a number of studies have reported favorable effects of anti-TNF therapy on the extraintestinal manifestations of IBD,” Keiichi Sumida, MD, MPH, PhD, associate professor in the division of nephrology in the department of medicine at the University of Tennessee Health Science Center, and colleagues wrote.¹ “Despite this, studies investigating the effect of anti-TNF therapy on survival for patients with IBD are limited, and to our knowledge, no prior studies have assessed its effect on the risk of CKD progression, a well-known extraintestinal manifestation of IBD and an established risk factor for mortality, in these patients.”

To determine the associations of TNF inhibitor use with kidney and survival outcomes in IBD, investigators examined longitudinal data from the Therapeutic Interventions to Assess Outcomes and Disparities in CKD study, a nationwide retrospective cohort study of more than 3 million US veterans with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 recorded between October 1, 2004, and September 30, 2006, with follow-up through September 30, 2019. Participants were US veterans with new-onset IBD, defined as ≥2 IBD diagnoses based on ICD-9 or ICD-10 after cohort entry with ≥1 diagnosis being made at an outpatient setting.¹

A total of 10,689 patients were included in the final analytical cohort. The mean age was 67.4 (Standard deviation [SD], 12.3) years, the majority (93.5%) of participants were male, 84.3% were White, and 14.2% were newly initiated on anti-TNF therapy. The most frequently prescribed TNF inhibitor was adalimumab (52.4%), followed by infliximab (45.2%).¹

Investigators used an intention-to-treat–like approach, where patients with de novo TNF inhibitor use were considered part of the treated group until the end of follow-up, irrespective of subsequent treatment status. The study follow-up in treated patients began on the date of receiving the first de novo prescription of TNF inhibitors. To mitigate differential start of follow-up bias, untreated patients were enrolled on a randomly assigned date that was computer-generated based on the start dates in the treated group.¹

The main outcomes were ≥ 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Patients free of death were censored at the date of the last VA encounter, incident ESKD, or September 30, 2019, whichever occurred first.¹

A total of 3367 patients (crude rate, 66.1; 95% CI, 63.9-68.4 per 1000 patient-years), including 607 users (crude rate, 92.7; 95% CI, 85.6-100.4 per 1000 patient-years) and 2760 nonusers (crude rate, 62.2; 95% CI, 59.9-64.6 per 1000 patient-years) of TNF inhibitors, experienced ≥ 30% decline in eGFR over a median follow-up of 4.1 (Interquartile range [IQR], 1.9-7.0) years. Compared to patients without anti-TNF therapy, those who newly initiated TNF inhibitors had a greater cumulative incidence of 30% decline in eGFR (log-rank P <.001).¹

After multivariable adjustments, incident use of TNF inhibitors was significantly associated with an increased risk of decline in eGFR (adjusted hazard ratio [aHR], 1.34; 95% CI, 1.18-1.52). Investigators noted 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.¹

During a median follow-up of 5.0 (IQR, 2.5-8.0) years, a total of 2502 all-cause deaths occurred (crude rate, 42.3; 95% CI, 40.3-44.0 per 1000 patient-years), including 262 (crude rate, 32.6; 95% CI, 28.9-36.8 per 1000 patient-years) deaths in patients with TNF inhibitor use and 2240 (crude rate, 43.8; 95% CI, 42.1-45.7 per 1000 patient-years) deaths in patients without TNF inhibitor use. Further analysis revealed patients with TNF inhibitor use had a greater cumulative incidence of all-cause mortality (log-rank P <.001), although this association was attenuated after incremental multivariable adjustment and was no longer significant in the fully adjusted model (aHR, 1.02; 95% CI, 0.86-1.21).¹

Investigators highlighted several potential limitations to these findings, some of which included the predominance of male participants, the potential lack of generalizability to biologics beyond TNF inhibitors, and the inability to examine the association of incident TNF inhibitor use with a tangible kidney outcome.¹

“We found that incident use of TNF inhibitors was independently associated with higher risk of progressive kidney function decline but was not associated with risk of all-cause mortality. Further studies are needed to confirm findings and to examine potentially distinct pathophysiologic contributions of incident TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD,” investigators concluded.¹

References:

1. ^{Sumida K, Shrestha P, Mallisetty Y, et al. Anti–Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease. JAMA Netw Open. 2024;7(4):e246822. doi:10.1001/jamanetworkopen.2024.6822}
2. ^{US Centers for Disease Control and Prevention. People with IBD Have More Chronic Diseases. Inflammatory bowel disease (IBD). April 15, 2022. Accessed April 16, 2024. https://www.cdc.gov/ibd/features/IBD-more-chronic-diseases.html}