Kidney hyperfiltration and mitochondrial changes are associated with eGFR decline in young people with type 1 diabetes

Uyen N Pham; Alison Pryke; Tracey Baskerville; Alison Griffin; Rani O Whiddett; Amelia K Fotheringham; Mitchell A Sullivan; Janelle Nisbet; Liza Phillips; Ross S Francis; Elizabeth Davis; Timothy W Jones; Fergus Cameron; Jennifer Couper; Paul Benitez-Aguirre; Maria Craig; David W Johnson; R Neil Dalton; M Loredana Marcovecchio; Andrew Cotterill; Helen L Barrett; Kim C Donaghue; Josephine M Forbes

doi:10.1210/clinem/dgae787

Kidney hyperfiltration and mitochondrial changes are associated with eGFR decline in young people with type 1 diabetes

J Clin Endocrinol Metab. 2024 Nov 11:dgae787. doi: 10.1210/clinem/dgae787. Online ahead of print.

Authors

Uyen N Pham^{1

2

3}, Alison Pryke⁴, Tracey Baskerville¹, Alison Griffin⁵, Rani O Whiddett¹, Amelia K Fotheringham^{1

3}, Mitchell A Sullivan^{1

3}, Janelle Nisbet², Liza Phillips^{2

3}, Ross S Francis^{3

6}, Elizabeth Davis⁷, Timothy W Jones⁷, Fergus Cameron⁸, Jennifer Couper⁹, Paul Benitez-Aguirre⁴, Maria Craig⁴, David W Johnson^{3

6}, R Neil Dalton¹⁰, M Loredana Marcovecchio¹¹, Andrew Cotterill¹², Helen L Barrett^{1

13

14}, Kim C Donaghue⁴, Josephine M Forbes^{1

3}

Affiliations

¹ Mater Research Institute - The University of Queensland, TRI, Brisbane, Australia.
² Mater Hospital, Mater Misericordiae Ltd, Brisbane, Australia.
³ Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, Australia.
⁴ Children's Hospital at Westmead, University of Sydney, Sydney, Australia.
⁵ Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁶ Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁷ Department of Diabetes and Endocrinology, Perth Children's Hospital, Nedlands, Western Australia, Australia.
⁸ Department of Endocrinology and Diabetes, Royal Children's Hospital, Melbourne, Australia.
⁹ Robinson Research Institute, University of Adelaide, South Australia, Australia.
¹⁰ The WellChild Laboratory, Evelina London Children's Hospital, Guy's and St. Thomas' Hospital.
¹¹ Department of Paediatrics, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹² Children's Health Queensland, Brisbane, Australia.
¹³ Department of Obstetric Medicine, Royal Hospital for Women, Sydney, Australia.
¹⁴ Faculty of Medicine, University of New South Wales.

PMID: 39527041
DOI: 10.1210/clinem/dgae787

Abstract

Objectives: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA:nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function.

Methods: Eighty adolescents were studied at baseline [mean (SD) age 14.2 (1.5) years; mean diabetes duration 6.7 (3.0) years] and followed up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR (qPCR).

Results: Overall, 4.2% of participants had diabetic kidney disease (DKD) at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration and HbA1c [hyperfiltration -1.46 (3.07) mL/min/1.73 m2/year vs non-hyperfiltration -0.51 (2.48) mL/min/1.73m2/year, P=0.02]. Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73m2/year) compared to those without hyperfiltration [OR 14.11, 95% CI (2.30-86.60), P=0.004]. Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modelling.

Conclusion: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function.

Keywords: Type 1 diabetes; biomarkers; diabetes complications; diabetes in youth; early diabetic kidney disease; mitochondrial function.

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