A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

There is limited knowledge about the involvement of inflammation in the progression of diabetic kidney disease (DKD) to end stage renal disease (ESRD). Using the SOMAscan platform, we searched for circulating inflammatory proteins associated with risk of progression to ESRD in Caucasians from Joslin with late DKD and either T1D (n=219) or T2D (n= 144) and in Pima Indians with early DKD and T2D (n=167); all participants were followed for 7-15 years. A Kidney Risk Inflammatory Signature (KRIS) comprising 17 proteins, out of 194 inflammatory proteins examined at baseline, was strongly associated with high risk of ESRD in all cohorts but not with severity of diabetic eye complications. The KRIS was enriched for members of the TNF Receptor Superfamily, including TNFRSF1A, TNFRSF1B, TNFRSF19, TNFRSF19L, TNFRSF21 and TNFRSF27. Other KRIS proteins included IL15RA, IL17F, DAF, CLM6, TNFSF15, CCL14, CCL15, CSF1, TIMD3, IL1R1 and IL18R1. Urine proteomics profiling and kidney tissue expression analysis suggested a systemic non-kidney source of the KRIS proteins. Our findings indicate that a specific inflammatory process flagged by the KRIS proteins contribute to the progression of DKD to ESRD and this process is similar in different races, in either T1D or T2D, and at different stages of DKD. While the vast majority of current research utilizing high throughput technologies focuses on the kidney, our findings highlight the importance of non-renal factors as important potential etiological drivers of DKD.