Certain immune system biomarkers could be clinically useful in the management of patients with chronic kidney disease (CKD) attributed to hypertension.
In a study involving Black patients, these biomarkers — serum soluble tumor necrosis factor (TNF) receptor 1 (sTNFR1), TNF receptor 2 (sTNFR2), and tumor necrosis factor alpha (TNF-α) — were associated with incident kidney failure with replacement therapy (KFRT) and mortality, investigators reported in the American Journal of Kidney Diseases.
The findings are from a study involving 500 participants in the African American Study of Kidney Disease and Hypertension (AASK), of whom 333 had available genotyping for the APOL1 risk variants. AASK was a double-blinded, randomized, controlled trial that enrolled 1,094 Black patients with CKD attributed to hypertension. Among the 500 participants included in the present study, 37% were female and mean age was 54.1 years at baseline. KFRT developed in 161 participants over a median follow-up of 8.5 years.
Each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was significantly associated with a 3.7-, 2.3-, and 1.4-fold increased risk for KFRT, respectively, and up to 2.2-fold increased risk for death, the investigators reported. Interferon gamma was not associated with either KFRT or death.
“Our findings suggest that biomarkers of the tumor necrosis factor pathway are particularly promising and could perhaps be used to enrich recruitment of high-risk individuals for clinical trials,” said lead study author Teresa K. Chen, MD, MHS, of Johns Hopkins University School of Medicine in Baltimore, Maryland. “In clinical practice, nephrologists might consider intensifying available CKD treatments among African-American patients with higher levels of these biomarkers.”
She also observed, “Prior studies have shown that higher levels of sTNFR1 and sTNFR2 are associated with worse kidney outcomes. These studies, however, included mostly patients with diabetes and few African Americans. We conducted this study because we wanted to better understand CKD progression in African Americans.”
The new findings have potential implications in the research arena because sTNFR1, sTNFR2, and/or TNF-α could be used to identify individuals with CKD who are more likely to experience KFRT, CKD progression, or mortality, thus potentially reducing the number of participants needed for a clinical trial or shorten a trial’s duration.
Among the 333 participants with APOL1 genotyping, 87 (26%) had APOL1 high-risk status and 246 (74%) had low-risk status. Those with APOL1 high-risk status were younger and had lower mean systolic blood pressure and GFR. They also had a higher median urine protein-to-creatinine ratio and serum sTNFR1, sTNFR2, and suPAR levels compared with those of low-risk status. The study showed that baseline sTNFR1, sTNFR2, TNF-α, or IFN-γ did not modify the association of APOL1 high-risk status with KFRT or CKD progression.
The investigators had hypothesized that higher levels of these biomarkers would enhance the association of APOL1 risk variants and KFRT, but this was not the case, Dr. Chen related.
The authors acknowledged that their study has limited generalizability to other ethnic groups or other CKD etiologies, but they noted their investigation was among the few studies to examine the clinical significance of sTNFR1 and sTNFR2 in nondiabetic kidney disease.
Nephrologist Sandeep Padala, MD, of the Medical College of Georgia and Augusta University Health System in Augusta, Georgia, said the new study is well-designed and may have significant clinical implications, additional research in a larger and more diverse population is needed.
Katalin Susztak, MD, PhD, professor of medicine and genetics in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said genetic variants in APOL1 explain most excess kidney disease risk among Black patients. Not all individuals with APOL1 kidney disease risk variants develop kidney failure, however. “About 20% of people with these genetic variants develop renal failure, Dr Susztak said. “There are new therapies on the horizon for APOL1-associated kidney disease. Understanding who is at risk is very important.”
Chen TK, Estrella MM, Appel LJ, et al. Biomarkers of immune activation and incident kidney failure with replacement therapy: Findings from the African American Study of Kidney Disease and Hypertension. Published online December 31, 2020. Am J Kidney Dis. doi:10.1053/j.ajkd.2020.11.014.