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The lymphatics in kidney health and disease

Abstract

The mammalian vascular system consists of two networks: the blood vascular system and the lymphatic vascular system. Throughout the body, the lymphatic system contributes to homeostatic mechanisms by draining extravasated interstitial fluid and facilitating the trafficking and activation of immune cells. In the kidney, lymphatic vessels exist mainly in the kidney cortex. In the medulla, the ascending vasa recta represent a hybrid lymphatic-like vessel that performs lymphatic-like roles in interstitial fluid reabsorption. Although the lymphatic network is mainly derived from the venous system, evidence supports the existence of lymphatic beds that are of non-venous origin. Following their development and maturation, lymphatic vessel density remains relatively stable; however, these vessels undergo dynamic functional changes to meet tissue demands. Additionally, new lymphatic growth, or lymphangiogenesis, can be induced by pathological conditions such as tissue injury, interstitial fluid overload, hyperglycaemia and inflammation. Lymphangiogenesis is also associated with conditions such as polycystic kidney disease, hypertension, ultrafiltration failure and transplant rejection. Although lymphangiogenesis has protective functions in clearing accumulated fluid and immune cells, the kidney lymphatics may also propagate an inflammatory feedback loop, exacerbating inflammation and fibrosis. Greater understanding of lymphatic biology, including the developmental origin and function of the lymphatics and their response to pathogenic stimuli, may aid the development of new therapeutic agents that target the lymphatic system.

Key points

  • Advances in imaging and genetics technologies have furthered our understanding of the role of lymphatic vascular systems in both homeostasis and disease.

  • Key advances include the discovery of hybrid lymphatic-like vessels in multiple tissues including in the kidney, where the ascending vasa recta express a combination of both blood and lymphatic endothelial markers and perform a lymphatic-like role in reabsorbing interstitial fluid in the medulla.

  • Kidney lymphangiogenesis is strongly associated with injury, inflammation and the progression of fibrosis.

  • Lymphangiogenesis can perform a protective role in clearing the accumulated fluid and immune cells associated with inflammation from the interstitial space; however, the kidney lymphatics also function to propagate an inflammatory feedback loop in coordination with the draining lymph nodes, which may exacerbate inflammation and fibrosis. In addition, chronic inflammation can result in the disorganized growth of leaky, poorly functioning lymphatic vessels, further contributing to tissue injury.

  • Targeting the lymphatic system is a potential future direction for new therapeutics for kidney disease, and several therapies are undergoing investigation in preclinical models.

  • Better understanding of the context-dependent consequences of kidney lymphangiogenesis, as well as the mechanisms of action and potential off-target consequences of targeting the proposed molecular pathways are needed prior to their clinical use.

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Fig. 1: Lymphatic structure and development.
Fig. 2: Structure and development of kidney lymphatics.
Fig. 3: Hybrid lymphatic structures.
Fig. 4: Lymphatic patterning and signalling in acute kidney injury.
Fig. 5: Peritoneal lymphatics and ultrafiltration failure.
Fig. 6: Lymphatic regulation of hypertension.

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Acknowledgements

M.D.D. was supported by the National Institutes of Health (T32DK108738) and is currently supported by the American Society of Nephrology Ben J. Lipps Research Fellowship. S.E.Q is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK114857) and National Eye Institute (R01EY025799).

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All authors made substantial contributions to the drafting, researching and writing of this article. All authors reviewed and/or edited this manuscript prior to submission.

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Correspondence to Susan E. Quaggin.

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S.E.Q. has applied for patents related to therapeutic targeting of the ANGPT–TEK pathway in ocular hypertension, glaucoma and kidney disease, receives research support, owns stocks in and is a director of Mannin Research, is an external advisory board member of AstraZeneca and receives consulting and advisory board fees from Roche, Janssen, Genentech and AstraZeneca. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks A. Phillips, who co-reviewed with P. Russell; J. Rutkowski; and J. Titze for their contribution to the peer review of this work.

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Glossary

Hypotrichosis–lymphoedema–telangiectasia

(HLT). A rare genetic syndrome characterized by lymphoedema in the lower limbs and eyelids, cutaneous telangiectasia and dilatations of superficial vasculature, and defects in hair follicle development.

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The accumulation of lipid-rich lymph in the peritoneal cavity as a result of lymphatic vessel dysfunction.

Lymphocele

A post-surgical complication in which lymphatic fluid collects in the body.

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Donnan, M.D., Kenig-Kozlovsky, Y. & Quaggin, S.E. The lymphatics in kidney health and disease. Nat Rev Nephrol (2021). https://doi.org/10.1038/s41581-021-00438-y

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