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Mechanisms of diabetic kidney disease and established and emerging treatments

Nature Reviews Endocrinology volume 22, pages 21–35 (2026)Cite this article

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An Author Correction to this article was published on 10 October 2025

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Abstract

Kidney disease is one of the leading causes of mortality in persons with diabetes mellitus. Diabetic kidney disease (DKD) typically presents with a reduced estimated glomerular filtration rate and, in many but not all cases, with marked proteinuria. Strict glycaemic control and blood pressure control remain foundational in managing DKD, and advances in the understanding of disease mechanisms have redefined the therapeutic landscape. Large outcome trials, such as EMPA-KIDNEY, DAPA-CKD and CREDENCE, have demonstrated that sodium–glucose cotransporter 2 inhibitors slow chronic kidney disease progression and improve cardiovascular outcomes. Glucagon-like peptide 1 receptor agonists reduce albuminuria and preserve estimated glomerular filtration rate, as shown most recently in the FLOW trial. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, lowered renal and cardiovascular risk in the FIDELIO-DKD and FIGARO-DKD trials. Combination approaches (for example, sodium–glucose cotransporter 2 inhibition plus endothelin receptor type A blockade in ZENITH-CKD), aldosterone synthase inhibition, and targeted anti-inflammatory or complement-modifying agents offer additional promise. We summarize the key pathophysiological drivers (glomerular hyperfiltration, podocyte injury, tubulointerstitial inflammation and fibrosis), review established treatments and highlight emerging strategies to prevent or halt DKD.

Key points

  • Diabetic kidney disease (DKD) is diagnosed by an estimated glomerular filtration rate <60 ml/min/1.73 m² for more than 3 months with or without albuminuria >300 mg/day or an albumin-to-creatinine ratio >0.3 in individuals with diabetes mellitus.

  • DKD is the leading cause of chronic kidney disease and end-stage kidney disease and is associated with high 10-year all-cause mortality among people with diabetes mellitus and chronic kidney disease.

  • Key mechanisms driving DKD include glomerular hyperfiltration, podocyte injury, tubulointerstitial inflammation and fibrosis.

  • Although landmark clinical trials have shaped current treatment guidelines, several potential therapeutic targets involved in DKD pathophysiology remain unexplored.

  • Established treatments include renin–angiotensin system blockers, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists, which can slow disease progression; however, strict blood pressure control and glycaemic control remain essential for managing DKD.

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Fig. 1: Effects of hyperglycaemia on glucose metabolism and mitochondrial function in DKD.
Fig. 2: The metabolic effects of hyperglycaemia in the proximal tubular cell.
Fig. 3: Hyperglycaemia induces glomerular hyperfiltration.
Fig. 4: Glomerular structure and intercellular crosstalk between glomerular cells.

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Acknowledgements

K.S. is supported by the NIH grant numbers R01DK076077, R01DK087635, P50DK114786, R01DK105821 and R01DK132630. The Susztak lab is also supported by Boehringer Ingelheim, Bayer, Novo Nordisk, Novartis, Calico, Maze, Ventus, GSK, Gilead, Regeneron and ONO Pharma for studies not related to this manuscript.

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Authors and Affiliations

  1. Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Victor Martinez Leon, Rachel Hilburg & Katalin Susztak

  2. Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, PA, USA

    Victor Martinez Leon, Rachel Hilburg & Katalin Susztak

  3. Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA

    Victor Martinez Leon & Katalin Susztak

  4. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Victor Martinez Leon & Katalin Susztak

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  1. Victor Martinez Leon
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  2. Rachel Hilburg
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All authors researched data for the article. All authors contributed substantially to discussion of the content. K.S. and V.M.L. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Katalin Susztak.

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Martinez Leon, V., Hilburg, R. & Susztak, K. Mechanisms of diabetic kidney disease and established and emerging treatments. Nat Rev Endocrinol 22, 21–35 (2026). https://doi.org/10.1038/s41574-025-01171-3

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