Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D. Issue 5 (May 2022)

• Record Type: Journal Article
• Authors: Chen, Teresa K.; Coca, Steven G.; Estrella, Michelle M.; Appel, Lawrence J.; Coresh, Josef; Thiessen Philbrook, Heather; Obeid, Wassim; Fried, Linda F.; Heerspink, Hiddo J.L.; Ix, Joachim H.; Shlipak, Michael G.; Kimmel, Paul L.; Parikh, Chirag R.; Grams, Morgan E.
• Other Names: author non-byline.; Ramachandran Vasan S. author non-byline.; Massaro Joseph author non-byline.; Clish Clary author non-byline.; Schelling Jeffrey author non-byline.; Denburg Michelle author non-byline.; Furth Susan author non-byline.; Warady Bradley author non-byline.; Bonventre Joseph author non-byline.; Waikar Sushrut author non-byline.; McMahon Gearoid author non-byline.; Sabbisetti Venkata author non-byline.; Coresh Josef author non-byline.; Grams Morgan author non-byline.; Rebholz Casey author non-byline.; Abraham Alison author non-byline.; Tin Adrienne author non-byline.; Parikh Chirag author non-byline.; Klein Jon author non-byline.; Coca Steven author non-byline.; Ferket Bart S author non-byline.; Nadkarni Girish N. author non-byline.; Rhee Eugene author non-byline.; Kimmel Paul L. author non-byline.; Gossett Daniel author non-byline.; Rovin Brad author non-byline.; Shlipak Michael G. author non-byline.; Sarnak M author non-byline.; Levey Andrew S. author non-byline.; Inker Lesley A. author non-byline.; Foster Meredith author non-byline.; Gutiérrez Orlando M. author non-byline.; Ix Joachim author non-byline.; Dubin Ruth author non-byline.; Seegmiller Jesse author non-byline.; Hostetter Tom author non-byline.; Deo Rajat author non-byline.; Feldman Harold I. author non-byline.; Anderson Amanda author non-byline.; Mifflin Theodore author non-byline.; Xie Dawei author non-byline.; Shou Haochang author non-byline.; Ballard Shawn author non-byline.; Whitehead Krista author non-byline.; Collins Heather author non-byline.; Greenberg Jason author non-byline.; Ganz Peter author non-byline.;
• Is Part Of: Journal of the American Society of Nephrology. Volume 33:Issue 5(2022)
• Page Start: 996
• Page End: 1010
• Publication Date: 2022-05
• Subjects: AASK (African American Study of Kidney Disease and Hypertension) -- chronic kidney disease -- diabetes mellitus -- end-stage kidney disease -- renal function decline -- chronic inflammation
• DOI: 10.1681/ASN.2021060735
• Languages: English
• ISSNs: 1046-6673

Abstract

Significance Statement: Recent research suggests that biomarkers of the TNF pathway (TNFR1 and TNFR2) are associated with worse kidney outcomes. Most of these studies, however, evaluated baseline levels rather than longitudinal changes. In two cohorts (AASK, which enrolled Black people with CKD attributed to hypertension, and VA NEPHRON-D, which enrolled veterans with albuminuric CKD and type 2 diabetes), greater longitudinal increases in serum or plasma TNFR1 and TNFR2 were associated with higher risks of ESKD in AASK and subsequent kidney function decline in VA NEPHRON-D. These associations were independent of baseline biomarker level and kidney function. Longitudinal trajectories in TNFR1 and TNFR2 may ultimately allow improved risk assessment for kidney failure in persons with CKD. Abstract : Background: Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. Methods: We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m 2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m 2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. Results: There were 129 ESKD events over a median of 7.0 years in AASK ( n =418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D ( n =754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. Conclusions: Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.