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Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

Abstract

Diabetic kidney disease is the leading cause of kidney failure worldwide; in the USA, it accounts for over 50% of individuals entering dialysis or transplant programmes. Unlike other complications of diabetes, the prevalence of diabetic kidney disease has failed to decline over the past 30 years. Hyperglycaemia is the primary aetiological factor responsible for the development of diabetic kidney disease. Once hyperglycaemia becomes established, multiple pathophysiological disturbances, including hypertension, altered tubuloglomerular feedback, renal hypoxia, lipotoxicity, podocyte injury, inflammation, mitochondrial dysfunction, impaired autophagy and increased activity of the sodium–hydrogen exchanger, contribute to progressive glomerular sclerosis and the decline in glomerular filtration rate. The quantitative contribution of each of these abnormalities to the progression of diabetic kidney disease, as well as their role in type 1 and type 2 diabetes mellitus, remains to be determined. Sodium–glucose co-transporter 2 (SGLT2) inhibitors have a beneficial impact on many of these pathophysiological abnormalities; however, as several pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease, multiple agents used in combination will likely be required to slow the progression of disease effectively.

Key points

  • Multiple pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease (DKD); from a clinical standpoint, this multifactorial pathogenic process implies that the use of multiple agents in combination will be required to treat the disease.

  • Hyperglycaemia and hypertension are the key factors responsible for the development of DKD, but, once established, even tight glycaemic and/or hypertension control may not be able to halt or slow disease progression.

  • Other pathogenic processes underlying the development and progression of DKD include alterations in tubuloglomerular feedback, tubule hypertrophy, hypoxia, podocyte injury, albuminuria and lipotoxicity.

  • Inflammation, endothelial dysfunction, mitochondrial injury, fibrosis and impaired autophagy also contribute to the progressive nature of DKD, but these defects are most likely to be secondary events that follow the primary events described above. Sodium–glucose co-transporter 2 (SGLT2) inhibitors correct or improve many of the pathological processes involved in the development of and progression of DKD and are likely to underlie the ability of these agents to slow progression of established DKD in large prospective clinical trials; of these mechanisms, restoration of normal tubuloglomerular feedback and reduced interglomerular pressure are especially pertinent.

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Fig. 1: The pathophysiology of diabetic kidney disease.
Fig. 2: Effect of hyperglycaemia on the kidney.
Fig. 3: The effect of diabetes mellitus and SGLT2 inhibitors on tubuloglomerular feedback.
Fig. 4: The effect of diabetes and SGLT2 inhibitors on kidney oxygen delivery and demand.
Fig. 5: Podocyte injury in diabetic kidney disease.

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Acknowledgements

The authors wish to thank Lorrie Albarado (UT Health, San Antonio, Texas) for assistance in the preparation of the manuscript before submission.

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A.S.A. and R.A.D. wrote the first draft of the manuscript, which was subsequently revised by all authors. The final version of the manuscript was reviewed by all authors.

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Correspondence to Ralph A. DeFronzo.

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R.A.D. is a member of the Speakers Bureau for AstraZeneca and Novo Nordisk, a member of the Advisory Board of AstraZeneca, Janssen, Intarcia and Boehringer-Ingelheim, and has received research grants from AstraZeneca, Janssen and Merck. The other authors declare no competing interests.

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Glossary

Angiotensin escape

The inability of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers to reduce circulating angiotensin II concentrations to undetectable levels.

Aldosterone escape

The inability of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers to reduce circulating aldosterone concentrations to undetectable levels.

BOLD-MRI

Blood oxygen level-dependent (BOLD)-MRI represents a non-invasive technique for assessing renal hypoxia by measuring tissue oxygen bioavailability through measurements of relative changes in deoxyhaemoglobin.

Mitochondrial fission

The splitting of mitochondria into two, which, together with mitochondrial fusion, is required for mitochondrial homeostasis.

Mitochondrial fusion

The combining of two mitochondria, which, together with mitochondrial fission, is required for mitochondrial homeostasis.

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DeFronzo, R.A., Reeves, W.B. & Awad, A.S. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol 17, 319–334 (2021). https://doi.org/10.1038/s41581-021-00393-8

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