A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders

This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive renal decline (PRD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes (T1D). The Macro-Albuminuria Study comprised of 198 individuals, and the Micro-Albuminuria Study consisted of 148 individuals. All individuals had normal renal function and were followed for 7–15 years to determine estimate glomerular filtration rate (eGFR) slopes and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PRD, determined as eGFR loss greater or equal to 3 ml/min/1.73m2/year, was associated with elevated circulating levels of 13 TNF receptors out of 19 examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PRD. In contrast, none of the 6 measured TNF ligands showed association with risk of early PRD. The disease process that underlies PRD which leads to ESKD in T1D is enriched with up-regulated levels of multiple TNF receptors, a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PRD in T1D and must be investigated further. Some of these receptors may be used as new predictors of risk of ESKD.