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T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

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posted on 2021-03-18, 21:22 authored by Josephine M. Forbes, Domenica A. McCarthy, Andrew J. Kassianos, Tracey Baskerville, Amelia J. Fotheringham, Kurt T.K. Giuliani, Anca Grivei, Andrew J. Murphy, Michelle C. Flynn, Mitchell A. Sullivan, Preeti Chandrashekar, Rani Whiddett, Kristen J. Radford, Nicole Flemming, Sam S. Beard, Neisha D’Silva, Janelle Nisbet, Adam Morton, Stephanie Teasdale, Anthony Russell, Nicole Isbel, Timothy Jones, Jennifer Couper, Helen Healy, Mark Harris, Kim Donaghue, David W. Johnson, Andrew Cotterill, Helen L. Barrett, Trisha O’Moore-Sullivan

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk.

DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA_1C-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, HbA_1C 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 (uACR_AUC0-10yrs, 29.7±8.8 vs 4.5±0.5; P<0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min^-1.1.73m^-2 higher estimated glomerular filtration rates (eGFR_SCHWARTZ; P_adj <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.