T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes
DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA1C-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m-2] and 10 year historical uACR, HbA1C and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in Apolipoprotein E-/- mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease.
Individuals at high risk for DKD had
persistent elevations in uACR (uACRAUC0-10yrs, 29.7±8.8 vs
vs low risk) and early kidney dysfunction including ~8.3ml.min-1.1.73m-2
higher estimated glomerular filtration rates (eGFRSCHWARTZ; Padj <0.031 vs low risk)
and plasma KIM-1 concentrations (~15% higher vs low risk; P<0.034). High risk individuals had greater glycemic
variability and increased peripheral blood T cell KIM-1 expression, particularly
on CD8+ T cells. These findings were confirmed in a murine model of glycemic
variability both in the presence and absence of diabetes. KIM-1+ T cells were
also infiltrating kidney biopsies from individuals with DKD. Healthy primary human
proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes
showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1
blockade. Taken together, these studies suggest that glycemic variations confer
risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.