Circulating proteins linked to apoptosis processes and  fast development of end stage kidney disease in diabetes.
Background: Many circulating proteins are associated with risk of ESKD but their source and the biological pathways/disease processes they represent are unclear. Methods: Using OLINK proteomics platform, concentrations of 455 proteins were measured in plasma specimens obtained at baseline from 399 individuals with diabetes. Results: Elevated concentrations of 46 circulating proteins were associated (p <10-5) with development of ESKD (n=149) during 7-15 years of follow-up. Twenty of these proteins enriched apoptosis/TNF receptors signaling pathways. A subset (5-7), summarized as an apoptosis score, together with clinical variables accurately predicted risk of ESKD. Expression of genes encoding the 46 proteins in peripheral white blood cells showed no difference between cells from individuals who did or did not develop ESKD. In contrast, plasma concentration of many of the 46 proteins differed by this outcome. In snRNA-seq analysis of kidney biopsies, the majority of genes encoding for the 20 apoptosis/TNF receptors proteins were overexpressed in injured versus healthy proximal tubule cells. Expression of these 20 genes also correlated with the overall index of apoptosis in these cells. Conclusion: Elevated levels of circulating proteins flagging apoptotic processes/TNF receptors signaling pathways, and likely originating from injured/apoptotic proximal tubular cells, preceded the development of ESKD. Overall design: RNAseq was performed in mRNA from peripheral blood (collected in PAXgene tubes) from 72 individuals with diabetes (23 T1D, 49 T2D) to examine the expression of 46 genes encoding end-stage kidney disease risk associated proteins.  71 individuals were included in the analysis (18992X7 was excluded from the analysis), including who 16 developed end-stage kidney disease during 7-15 years of follow-up. Please note that differential expression analysis was performed among individuals with ESKD versus those non-ESKD (not by diabetes type). Therefore diabetes type information is not provided.