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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Forbes, Josephine M
McCarthy, Domenica A
Kassianos, Andrew J
Baskerville, Tracey
Fotheringham, Amelia K
Giuliani, Kurt TK
Grivei, Anca
Murphy, Andrew J
Flynn, Michelle C
Sullivan, Mitchell A
Chandrashekar, Preeti
Whiddett, Rani
Radford, Kristen J
Flemming, Nicole
Beard, Sam S
et al.
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Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) 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 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with 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 defined by area under the curve (AUC; uACRAUC0–10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; 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 sodium–glucose cotransporter 2 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.

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Forbes, JM; McCarthy, DA; Kassianos, AJ; Baskerville, T; Fotheringham, AK; Giuliani, KTK; Grivei, A; Murphy, AJ; Flynn, MC; Sullivan, MA; Chandrashekar, P; Whiddett, R; Radford, KJ; Flemming, N; Beard, SS; D’Silva, N; Nisbet, J; Morton, A; Teasdale, S; Russell, A; Isbel, N; Jones, T; Couper, J; Healy, H; Harris, M; Donaghue, K; Johnson, DW; Cotterill, A; Barrett, HL; O’Moore-Sullivan, T, T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes, Diabetes, 2021, 70 (8), pp. 1754-1766