J FORBES1,2,3,4, D MCCARTHY1, A KASSIANOS5, A FOTHERINGHAM1,3, K GIULIANI5, A GRIVEI5,11, A MURPHY6, M FLYNN6, M SULLIVAN1,3, P CHANDRASHEKAR1, R WHIDDETT1, N FLEMMING1,3, N ISBEL3,8, T JONES9, J COUPER10, H HEALY3,11, K DONAGHUE12, D JOHNSON3,8, H BARRETT2,3, T O’MOORE-SULLIVAN2,3
1Mater Research Institute – The University of Queensland, TRI, Brisbane, Australia, 2Mater Young Adults Health Centre, Mater Misericordiae Ltd, Brisbane, Australia, 3Faculty of Medicine, The University of Queensland, St Lucia, Australia, 4Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia, 5Conjoint Kidney Research Laboratory, Chemical Pathology, Pathology Queensland, Brisbane , Australia, 6Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Australia, 7Diabetes and Endocrinology, Metro South Health, Brisbane, Australia, 8The Metro South Integrated Nephrology and Transplant Service (MINTS), Princess Alexandra Hospital, Brisbane, Australia, 9Telethon Kid’s Institute, Perth, Australia, 10Robinson Research Institute, University of Adelaide, Adelaide, Australia, 11Kidney Health Service, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 12Children’s Hospital at Westmead, Sydney, Australia
Aim: To examine a potential early mechanistic link between glucose variations, T cell KIM-1 expression, and increased risk for kidney disease (DKD) in youth with type 1 diabetes (T1DM).
Background: DKD develops early in T1DM, with youth in the highest tertile of uACR, even within a normal range, at greatest risk. The factors responsible for this early increase in uACR are unknown. We postulated that T cell production of the immunomodulator KIM-1 was one such factor.
Methods: Youth with T1DM, without DKD, were recruited [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/m²]. Participants blood, urine and current and historical clinical characteristics (including blood glucose, HbA1c, and uACR) were collected. T cells were isolated from PBMCs and KIM-1 expression on T cells was quantified using flow cytometry.
Results: Participants were divided into tertiles for DKD risk according to uACR (low risk uACR≤0.66; 33 subjects, medium risk uACR=0.67-1.16; 33 subjects or high risk uACR≥1.17; 34 subjects). High risk individuals had elevations in uACR from diagnosis, higher eGFR (P<0.031 vs low risk; age, sex, diabetes duration adjusted) and elevated plasma KIM-1 (P<0.034 vs low risk). High risk individuals had greater glycemic variability and increased T cell surface expression of KIM-1, particularly on CD8+ Treg and Tconv näive subsets. Cultured kidney cells exposed to plasma from high risk individuals had elevations in collagen IV and SGLT2, which KIM-1 blockade alleviated. In non-diabetic mice, simulating glycemic variability via glucose injections also increased T cell KIM-1 expression and uACR.
Conclusions: Youth with T1DM at high risk for DKD have increased CD8+ T cell production of KIM-1 in response to glucose variations, which contributes to their elevation in uACR.
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