The Lymphatic System in Kidney Disease

Abstract

The high-capacity vessels of the lymphatic system drain extravasated fluid and macromolecules from nearly every part of the body. However, far from merely a passive conduit for fluid removal, the lymphatic system also plays a critical and active role in immune surveillance and immune response modulation through the presentation of fluid, macromolecules, and trafficking immune cells to surveillance cells in regional draining lymph nodes before their return to the systemic circulation. The potential effect of this system in numerous disease states both within and outside of the kidney is increasingly being explored for their therapeutic potential. In the kidneys, the lymphatics play a critical role in both fluid and macromolecule removal to maintain oncotic and hydrostatic pressure gradients for normal kidney function, as well as in shaping kidney immunity, and potentially in balancing physiological pathways that promote healthy organ maintenance and responses to injury. In many states of kidney disease, including AKI, the demand on the preexisting lymphatic network increases for clearance of injury-related tissue edema and inflammatory infiltrates. Lymphangiogenesis, stimulated by macrophages, injured resident cells, and other drivers in kidney tissue, is highly prevalent in settings of AKI, CKD, and transplantation. Accumulating evidence points toward lymphangiogenesis being possibly harmful in AKI and kidney allograft rejection, which would potentially position lymphatics as another target for novel therapies to improve outcomes. However, the extent to which lymphangiogenesis is protective rather than maladaptive in the kidney in various settings remains poorly understood and thus an area of active research.

Figure 1

Anatomy of lymphatic vessels (LVs). Lymphatic capillary vessels are comprised of LECs joined by button junctions resulting in large intercellular openings into the vessel, which can be further widened in states of tissue edema due to LEC anchoring to the extracellular matrix. Upstream collecting LVs have zipper junctions which do not allow free uptake of fluid and prevent leakage of lymphatic fluid from vessels into tissues. Collecting vessels also have smooth muscle and internal valves which function together to propel lymph forward and prevent backward flow. LEC, lymphatic endothelial cell.

Figure 2

Basic interactions between lymphatic vessels and leukocytes. Tissue injury and inflammatory states result in the release of various inflammatory stimuli, including TNFα and IL-1, from injured tissues and from resident and infiltrating macrophages. CCL21 expression by LECs and CCR7 expression by APCs is increased in response to these inflammatory stimuli as well as VEGF-C and transmural flow.^, CCL21 acts as a chemokine to attract CCR7-expressing leukocytes into LVs. TNFα and IL-1 also upregulate LEC expression of VCAM-1 and ICAM-1, directing leukocyte adhesion and trafficking within LVs. APC, antigen-presenting cell; CCL21, C-C motif chemokine ligand 21; CCR7, C-C motif chemokine receptor 7; ICAM-1, intracellular adhesion molecule 1; LEC, lymphatic endothelial cell; VCAM-1, vascular cell adhesion molecule 1; VEGF-C, vascular endothelial growth factor–C.

Figure 3

Lymph node structure before and after exposure to lymphangiogenic stimuli. As with lymphatic endothelium in resident tissues, LECs within lymph nodes proliferate in response to lymphangiogenic stimuli, such as VEGF-C. In the DLN, lymphangiogenesis results in the expansion of lymphatic trabeculae and internodal connections on which lymphocytes are trafficking. Lymphangiogenesis also results in increased antigen presentation and archival by LECs. Additionally shown are several characteristic features of intranodal LECs of various regions, including S1P release by LECs to mediate egress into efferent LVs, C-C chemokine receptor-like 1 decoy CCL21 receptor expression by subcapsular LECs, and CCL21 expression by fibroblastic reticular cells in the medulla mediating lymphocyte chemotaxis. CCL21, C-C motif chemokine ligand 21; DLN, draining lymph node; LEC, lymphatic endothelial cell; S1P, sphingosine 1 phosphate; VEGF-C, vascular endothelial growth factor–C.