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The tubular hypothesis of nephron filtration and diabetic kidney disease

Nature Reviews Nephrology volume 16, pages 317–336 (2020)Cite this article

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Abstract

Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium–glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium–glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium–glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.

Key points

  • Rising blood glucose levels drive increased delivery of glucose into the Bowman’s space by glomerular filtration and cause increased reabsorption of glucose and sodium by the proximal tubule sodium–glucose cotransporters, SGLT2 and SGLT1, up to a transport maximum.

  • Diabetes mellitus causes the kidney tubule to grow and increase its capacity for transport; most of this growth occurs in the proximal tubule, which increases glucose reabsorption and contributes to hyperglycaemia, and induces abnormally high reabsorption of filtered sodium chloride (NaCl).

  • The increase in proximal reabsorption reduces NaCl and fluid delivery to the macula densa and induces glomerular hyperfiltration through tubuloglomerular feedback and a decline in tubular back pressure, which helps to normalize renal NaCl and fluid excretion.

  • Glomerular hyperfiltration places physical stress on the filtration barrier and increases the demand for oxygen to reabsorb the filtered load; hypertrophic tubular cells exhibit a senescence-like phenotype, with pro-inflammatory and pro-fibrotic consequences that might promote the development of diabetic kidney disease (DKD).

  • Not all patients with diabetes develop DKD, suggesting that the tubular growth and hyperreabsorption response must be subject to genetic or environmental influences; one such environmental factor is dietary NaCl, which mitigates hyperfiltration in diabetes by suppressing proximal reabsorption and thereby increasing the tubuloglomerular feedback signal.

  • The clinical relevance of increased proximal reabsorption and hyperfiltration in diabetes is demonstrated by the ability of SGLT2 to improve renal outcomes in patients with diabetes, which has been verified in large-scale clinical trials.

  • SGLT1 is a positive regulator of NOS1 in the macula densa, and acts as a glucose sensor to stimulate hyperfiltration and potentially regulate tubule growth in the diabetic kidney.

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Fig. 1: Tubular hypothesis of glomerular filtration and nephropathy in diabetes mellitus.
Fig. 2: Primary tubular hyperreabsorption drives hyperfiltration in diabetes.
Fig. 3: Renal glucose reabsorption in the proximal tubule.
Fig. 4: Diabetes induces the hyperreabsorption of glucose and sodium in the proximal tubule.
Fig. 5: Mechanisms of kidney protection in response to SGLT2 inhibition.
Fig. 6: The role of SGLT1 in the diabetic kidney.
Fig. 7: Mechanisms and consequences of tubular growth in diabetes.

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Acknowledgements

The authors are supported by NIH grants R01DK112042 (V.V., S.C.T.), R01DK106102, R01HL142814, RF1AG061296 (V.V.), the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337 (V.V., S.C.T.) and the Department of Veterans Affairs (V.V., S.C.T.).

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  1. Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA, USA

    Volker Vallon & Scott C. Thomson

  2. Department of Pharmacology, University of California San Diego, La Jolla, CA, USA

    Volker Vallon

  3. VA San Diego Healthcare System, San Diego, CA, USA

    Volker Vallon & Scott C. Thomson

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Correspondence to Volker Vallon.

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V.V. declares that he has served as a consultant and received honoraria from Astra-Zeneca, Bayer, Boehringer Ingelheim, Janssen Pharmaceutical, Eli Lilly, Merck and Retrophin, and has received grant support for investigator-initiated research from Astra-Zeneca, Bayer, Boehringer Ingelheim, Fresenius and Janssen. S.C.T. declares that he has received grant support for investigator-initiated research from Merck.

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Glossary

Glomerular ultrafiltration coefficient

A measure of the glomerular capillary membrane’s permeability to water; specifically, the volume of fluid filtered in unit time through a unit area of glomerular capillary membrane per unit pressure difference.

Tubuloglomerular feedback

A mechanism that inversely relates single nephron glomerular filtration rate to the NaCl concentration at the macula densa of the same nephron.

Tubular back pressure

The hydrostatic pressure in the Bowman’s space.

Filtration fraction

The fraction of renal plasma flow that is filtered by the glomeruli.

Gibbs free energy

The thermodynamic potential (or available energy) associated with a chemical reaction that can be used to do reversible work at a constant temperature and pressure.

Electrogenic

A type of transport process that leads to the translocation of net charge across the membrane and produces a change in the electrical potential of a cell.

Facilitated diffusion

The process of spontaneous passive transport of molecules or ions across a biological membrane along their electrochemical gradient, usually via a transmembrane integral protein.

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Vallon, V., Thomson, S.C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol 16, 317–336 (2020). https://doi.org/10.1038/s41581-020-0256-y

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