Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension.

Abstract Rationale & Objective Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with non-diabetic kidney disease is unclear. Study Design Prospective cohort Setting & Participants: African American Study of Kidney Disease and Hypertension participants with available baseline serum samples for biomarker measurement. Predictors Baseline serum soluble tumor necrosis factor receptor 1 and 2 (sTNFR1; sTNFR2), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) levels. Outcomes Incident KFRT, all-cause mortality. Analytic Approach Cox proportional hazards models. Results Among 500 participants with available samples, mean glomerular filtration rate was 44.7 ml/min/1.73 m2 and median urine protein-to-creatinine ratio was 0.09 g/g at baseline. Over a median follow-up 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each two-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66 (95% CI: 2.31,5.80), 2.29 (95% CI: 1.60,3.29), and 1.35-fold (95% CI: 1.07,1.71) greater risks of KFRT, respectively; in comparison, the association between suPAR and KFRT was 1.39 (95% CI: 1.04,1.86). These three biomarkers were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline level; p≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (p-interaction>0.05). Limitations Limited generalizability to other ethnic groups or CKD etiologies. Conclusions Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.