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.

Introduction

The lymphatic system consists of an extensive network of high-capacity vessels that drain extravasated fluid and macromolecules from nearly every part of the body. Historically, the lymphatics have been overlooked in the study of anatomy, in large part owing to difficulty in visualizing these typically small, sparse, and nearly invisible vessels.¹ Although modern visualization techniques have advanced our understanding of vascular anatomy, the lymphatic system remains far less understood than its neighboring blood circulatory system. In clinical practice today, the lymphatic system remains largely overlooked outside of the context of malignancy staging.

Far from merely a passive conduit for fluid removal as its anatomy might suggest, the lymphatic system also plays a critical role in immune surveillance and immune response modulation through the drainage of fluid and macromolecules through regional draining lymph nodes (DLNs) before their return to the systemic circulation. These DLNs contain cells that are poised to detect immune activation in the respective organ and respond by providing a rapid adaptive immune response. The potential implications this system may have in numerous disease states both within and outside of the kidney are increasingly being explored for their therapeutic potential.

In this focused review, we will provide an overview of the general functions of the lymphatic system as well as its specific functions in the kidney. With its normal physiologic roles in mind, we will subsequently provide an overview of our current understanding of the role of the lymphatic system in several kidney disease states.

Structure and Function of the Lymphatic System

With the exception of bone marrow, lymphatic capillaries exist in virtually all vascularized tissues, including the central nervous system.^2–4 Embryologically, the lymphatic system originates from the early venous endothelium and expands through developmental lymphangiogenesis.⁵ In healthy adulthood, further lymphangiogenesis, or expansion of lymphatics, decreases to very low levels.⁶

Within peripheral tissues, lymphatic vessels (LVs) begin as blind-ended capillaries, often running adjacent to blood capillaries. In contrast to blood vessels, lymphatic capillaries maintain a discontinuous basal lamina and are fenestrated with button junctions connecting adjacent lymphatic endothelial cells (LECs), allowing open communication with adjacent connective tissues (Figure 1). Capillary LECs have anchoring filaments connecting to the pericellular matrix, which cause intercellular fenestrations between button junctions to be pulled further open by interstitial edema, allowing more fluid to enter vessels.⁷

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.

Once fluid enters lymphatic capillaries, this fluid (now lymph) drains to precollector and collector lymphatics. Functioning in lymph transport rather than uptake, collecting LVs have zipper junctions without fenestrations to prevent free fluid flow, smooth muscle to contract vessels and propel lymph forward, and valves to prevent backward flow (Figure 1).⁸ Increases in transmural pressure as well as vasoactive signals activated in response to increasing demands for lymphatic drainage promote greater pulsatile vascular contraction and lymphatic flow.⁸ Collector lymphatics drain to DLNs and subsequently to the thoracic duct or right lymphatic duct before drainage into the subclavian vein. This lymphatic network serves three critical functions: fluid reabsorption, cholesterol handling, and immune cell trafficking and immunomodulation.

With their highly permeable, valved, and contractile structure, the lymphatics are uniquely poised to reabsorb fluid and macromolecules extravasated from blood vessels and secreted by tissues and return this mixture back to the circulation to limit edema formation. In a healthy adult, lymphatics are estimated to return 8–12 L of fluid per day to the circulation and have a capacity of 1–2 L.^9–11 With congestive heart failure and increased central venous pressure, lymphatics fail to prevent tissue edema as return of fluid to the circulation relies on a favorable hydrostatic gradient, and LVs become dilated to accommodate a higher volume of lymph.^12–15 LV dilation is additionally believed to lead to compromised lymphatic function through poor valvular coaptation and impaired vessel contractility.¹⁵ A related but less understood role of LVs is in modulating blood pressure and sodium balance, potentially through limiting accumulation of sodium in the interstitium and by augmenting nitric oxide release in response to the states of positive sodium balance and hypertension.¹⁶

While outside the scope of this review, LVs play a major role in the absorption and transport of dietary lipids from the intestinal lumen to the liver.¹⁷ LVs are also the route of reverse cholesterol transport, where cholesterol and lipids are trafficked from cells back to the systemic circulation.¹⁷ Animal and human studies suggest that augmentation of reverse cholesterol transport attenuates atherosclerosis, making this a topic of active cardiovascular research.^18,19

The focus of this review is the role of the lymphatic system in modulating immune responses. Both fluid and macromolecules, including soluble antigens and cytokines, are absorbed from tissues into LVs (Figure 2). Unlike the passive and indolent uptake of fluid and macromolecules into lymphatics, antigen presenting cells (APCs) and lymphocytes are specifically recruited into LVs through the interaction of C-C motif chemokine receptor 7 (CCR7) on APCs and lymphocytes with C-C motif chemokine ligand 21 (CCL21), constitutively secreted by LECs.²⁰ In response to inflammatory stimuli, such as TNFα, CCL21 release by LECs is significantly increased, through both increased transcriptional upregulation and release of intracellular stores.²¹ In addition, numerous adhesion molecules critical for lymphocyte and APC trafficking to and within DLNs, including intracellular adhesion molecule 1 and vascular cell adhesion molecule 1, are upregulated on LECs in response to inflammatory mediators.^22–26 Both changes in chemokine and adhesion molecule expression in the setting of inflammatory stimuli facilitate increased antigen presentation and leukocyte trafficking to DLNs in the states of inflammation.^26–28

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.^{26, 93} 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.²⁶ 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.

In DLNs, lymphocytes arriving from both tissue and the circulation come in close contact with antigens and APCs draining from tissues. Extranodal LECs are phenotypically and functionally distinct from intranodal LECs, which project into interfollicular ridges to create both a highly compartmentalized environment for multiple specialized LEC functions as well as a lattice which directs APC trafficking (Figure 3).^29,30 Although peripheral LECs secrete CCL21 to facilitate dendritic cell migration into LVs to reach lymph nodes (LNs), within the LNs themselves, fibroblastic reticular cells in the medulla secrete C-C chemokine receptor-like 1 while LECs lining the external layer of the LN express a decoy receptor for CCL21 and C-C chemokine receptor-like 1 This arrangement creates a CCL21 gradient for facilitating migration of dendritic cells into the LN medulla.²⁰ LECs in the LN medulla express self-antigens and T-cell inhibitory programmed-death ligand 1 to promote alloreactive CD8+ T-cell deletion.²⁰ Subcapsular sinus LECs transcytose immunoglobulin G from draining lymph into the medulla, where it is used by LECs for soluble antigen acquisition and LEC presentation to CD8+ T cells to mediate deletional tolerance and to allow extremely rare populations of naive lymphocytes specific for a given antigen to detect the presence of their target antigen anywhere in the body.²⁰

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.

In addition to directly participating in antigen presentation, LECs themselves serve as a reservoir of antigens from their upstream tissue.^31,32 Intranodal LECs have also been demonstrated to directly suppress the local immune response, for example, by expressing checkpoint proteins in response to IFNγ to limit accumulation of CD8+ T cells.^33,34 Finally, intranodal LECs also express sphingosine 1 phosphate, which is sensed by various immune cell populations to mediate egress into efferent LV and promotes lymphocyte survival.²⁰ Overall, this system facilitates both cross-tolerance against innocuous circulating and tissue-derived antigens as well as continuous lymphocyte surveillance for potentially harmful antigens.³⁴

In the kidney of healthy adults, fluid reuptake and immune surveillance and modulation by the lymphatic system are predicted to be important for maintaining normal fluid and oncotic balance and in facilitating balanced immune responses to circulating and kidney-derived antigens.

Lymphatic System within the Kidney

Consistent with its highly stereotypic tubular and capillary architecture, the kidney's LVs follow a highly preserved organizational structure, well-described and illustrated in a recent review by Donnan et al.⁵ Lymph drains from kidney tissue along two connecting systems. The first, intraparenchymal system, begins as cortical intralobular lymphatic capillaries running adjacent to tubules and arterioles near glomeruli. Capillaries drain to a hierarchical network of collecting lymphatics mirroring blood vascular drainage in interlobular, interlobar, arcuate, and hilar regions. Notably, there are no LVs in the medulla.³⁵ A second, superficial capsular lymphatic system drains the kidney capsule and has connections to the outermost cortical tissue and intraparenchymal lymphatic system. Both systems drain into hilar lymphatics and subsequently into DLNs, with LVs from the left kidney entering periaortic DLNs and from the right kidney pericaval DLNs. Lymph exiting DLNs continues along LVs to the thoracic duct and subsequently re-enters the circulation.

The function of the lymphatics within the kidney mirrors their role in other tissues, but with several special considerations. Capillaries in the cortical interstitium drain excess fluid and macromolecules along hydrostatic and oncotic pressure gradients. This is particularly important in the kidney, where albumin is reabsorbed from the glomerular filtrate by the proximal tubule and also transudates from highly permeable and fenestrated peritubular blood capillaries. Drainage of albumin and other transudate proteins which would otherwise accumulate at the interface between tubules and peritubular capillaries is thus a primary function of the lymphatics, helping to maintain a favorable oncotic pressure gradient in the cortex for fluid and electrolyte uptake from tubules to peritubular capillaries.^36,37 Lymphatic drainage from the kidney also increases when barriers to drainage through the venous system or urinary system arise, such as in the cases of hydronephrosis or renal vein occlusion.^38,39 After the discovery of the role LVs play in modulating blood pressure through modulating interstitial sodium retention throughout the body, the importance of kidney lymphatics in the control of natriuresis and blood pressure has also recently been considered. Kidney-specific augmentation of LV growth in mice with nitric oxide synthase inhibitor-induced hypertension resulted in significant attenuation of hypertension as compared with controls, and kidney LV augmentation also resulted in improved natriuresis and blood pressure control when mice were fed a high salt diet.⁴⁰ Finally, in polycystic kidney disease, inadequate polycystin 1 or 2 expression in LECs is believed to result in diminished lymphatic drainage and may contribute to cyst expansion through diminished clearance of interstitial fluid.^41,42

Of course, the lymphatic system also functions in immune surveillance and immune response modulation in the kidney. Kidney-derived antigens, including small, filtered proteins reabsorbed by tubules into the interstitium, are passively collected by cortical lymphatic capillaries and carried to DLNs. At the same time, APCs and lymphocytes are trafficked to the DLN through a dynamic and coordinated system of adhesion molecules, cytokines, and chemokines as previously outlined.

The degree of inflammation, specific immune response, and resolution of that immune response are likely determinants of prognosis in AKI, including acute tubulointerstitial nephritis, CKD, and kidney transplant rejection. Given its role in both training the adaptive immune system in response to exposure to tissue antigens as well as in the drainage of interstitial fluid and potential proinflammatory mediators, the lymphatic system has become an area of interest as a potential therapeutic target in many disease states, including kidney diseases. The discovery of pathological lymphangiogenesis, or growth of new lymphatics vessels due to pathogenic, nondevelopmental stimuli, in countless inflammatory disease states, including the kidney, has furthered the interest in this system as a potential therapeutic target.^5,20,43

Lymphatics in Kidney Disease

Pathologic lymphangiogenesis is found at the sites of tissue injury, interstitial fluid overload, inflammation, and metastasizing tumors and is pervasive in kidney diseases.^{16, 44–46} It has been demonstrated in both AKI and CKD irrespective of etiology, both in kidney tissue and kidney DLNs, and is also a common feature of kidney allograft rejection.^47–50 Although the expansion of lymphatics within the cortex has been a focus of most studies, expansion into the medulla where lymphatics are usually absent has also been suggested to occur in some settings.^47,51

Under the conditions of tissue damage and inflammation, the demand for efficient lymphatic drainage increases, as noxious antigens and debris need to be cleared and excessive interstitial fluid needs to be drained. In these settings, resident and infiltrating macrophages and tubular epithelial cells secrete vascular endothelial growth factor–C (VEGF-C) in response to the injury itself and resulting inflammatory cytokines.^44,52 VEGF-C activates VEGF receptor 3 (VEGFR3) on LECs.^53,54 VEGF-C signaling through VEGFR3 results in an expansion of lymphatic vasculature, primarily through division of existing LECs. Pathologic lymphangiogenesis has also been postulated to occur to a small extent through recruitment and differentiation of yet unidentified circulating precursor cells.^44,55 With resolution of prolymphangiogenic signaling, some regression of newly formed lymphatics is possible in a tissue-dependent and context-dependent manner; however, this is not well understood.⁵⁶

In line with the multifaceted role of the lymphatic system, the available literature examining whether lymphangiogenesis has a positive or negative effect in specific kidney disease states suggests that the answer is complex and highly context dependent. Within injured kidney tissue, an enhanced lymphatic network could not only result in increased clearance of interstitial fluid, signaling molecules, debris, and macrophages but also increased transport of antigens, lymphocytes, and APCs from the site of injury to surrounding DLNs to initiate an immune response. Within DLNs, lymphangiogenesis results in a greatly expanded lymphatic endothelial infrastructure for immune cell trafficking and positioning, which may support further immune cell activation. Interestingly, studies of productive immune responses to vaccination have demonstrated that persistence of antigen presentation by LECs within DLNs is dependent on lymphangiogenesis.³¹ LECs “archive” antigens against which a robust, lymphangiogenesis-producing response has been initiated well after the peak of the normal immune response, resulting in a memory CD8+ T-cell pool with increased effector function and protective capacity. This carries potential implications for inflammatory disease states.

In the following sections, we will explore the literature to date on the role of the lymphatics and lymphangiogenesis in several kidney disease states.

AKI

In AKI, cellular injury results in the development of both intrarenal and systemic inflammation. Capillary vascular permeability increases leading to extravasation of fluid and migration of cellular infiltrates into the kidney interstitium. Inflammatory cytokines, including IFNγ, TNFα, and TGFβ, stimulate macrophages and proximal tubule epithelial cells to secrete nitric oxide, proinflammatory cytokines (IL-1, IL-6, IL-12, IL-23), connective tissue growth factor, VEGF-C, and VEGF-D.⁵ VEGF-C subsequently promotes expansion and remodeling of the lymphatic capillary network through activation of VEGFR3 on existing LECs, resulting in lymphangiogenesis in both the kidney and the DLN.^5,49

Numerous animal models of AKI have demonstrated the induction of lymphangiogenesis in kidney tissue and kidney DLN after injury.⁴⁹ However, the functional significance of this remains an unanswered question, with theoretical mechanisms to explain both positive and negative effects of lymphangiogenesis on AKI outcomes. An expanded lymphatic network can lead to the production of more CCL21 and adhesion molecules in response to inflammatory signals, recruiting more APCs to traffic to DLNs, and activating lymphocytes in response to antigens coming from the kidney. This activated lymphocyte population can then return to the circulation and eventually the kidney, perpetuating the cycle with more renal damage.^49,57 Kidney fibrosis is the final common pathway for almost all forms of kidney disease that progress to ESKD and occurs to varying degrees after AKI. Infiltration of activated leukocytes into the interstitium can trigger kidney fibrosis either by direct injury of kidney parenchymal cells or by secretion of cytokines that promote myofibroblast activation.^57,58 On the other hand, an expanded lymphatic network may aid in clearing noxious stimuli, macrophages, and excessive extravasated fluid in tissues after injury and improve outcomes after AKI.^43,59

In some animal models, disruption of lymphangiogenesis does seem to improve AKI. In an animal model of antiglomerular basement membrane crescentic GN, one study found that either removal of bilateral kidney DLN or administration of an antibody against LECs to reduce the number of LECs resulted in a reduction in kidney injury after GN induction as compared with control mice.⁶⁰ Another study using unilateral ureteral obstruction and ischemia reperfusion injury models of kidney injury suggested that disruption of lymphangiogenesis using inducible diphtheria toxin receptor expression to partially deplete LECs improved AKI outcomes, with fewer infiltrating lymphocytes and macrophages in injured kidneys, fewer tubular casts, and less histologic evidence of fibrosis at day 14.⁴⁹

Other animal studies offer contrasting conclusions regarding the effect of lymphangiogenesis on AKI prognosis. A frequent approach to induce lymphangiogenesis involves the administration of VEGF-C to animals to stimulate LEC proliferation. In one study, VEGF-C induced lymphangiogenesis after unilateral ureteral obstruction and ischemia reperfusion injury resulted in reduced profibrotic markers in the injured kidney and diminished interstitial fibrosis.⁵⁹ One drawback to this study design is that macrophages also express VEGFR3, and VEGFR3 signaling in macrophages may be protective against injury on the basis of studies in other organ systems.^61–64 In addition, VEGF-C may exert protective effects in podocytes independent of its effect on lymphatics.^65,66 These findings make interpretation of the beneficial effects of VEGF-C administration after AKI challenging to interpret, as the effect may not be mediated by lymphangiogenesis but by another VEGF-C–mediated process. Regardless, administration of VEGF-C or augmentation of VEGFR3 signaling has been suggested as a possible treatment strategy in numerous disease states, both within and outside of the kidney.^67–72 Another study design aimed at investigating the role of lymphatics in AKI involves the complete ligation of the kidney lymphatics, which consistently results in exacerbated injury and worsened fibrosis.^73,74 These studies demonstrate that lymphatic drainage is beneficial in AKI as complete disruption of the system is harmful; however, they do not address what effect pathologic lymphangiogenesis might have.

Further animal studies with targeted partial disruption or augmentation of the lymphatic system after kidney injury are needed to better understand the role this process may play in AKI. The inclusion of available lymphatic markers in analyses of human kidney tissues will also be of value in furthering our understanding of how lymphatic function affects repair and fibrosis after AKI.

CKD

Irrespective of how lymphangiogenesis is induced, an expanded lymphatic vascular system within kidney tissue strongly correlates with the severity of tubulointerstitial fibrosis in human and animal studies of CKD.⁴⁹ In a study investigating kidney biopsies from 289 patients with CKD, increased density of kidney LVs corresponded with more severe proteinuria, lower eGFR, greater interstitial inflammation, and more severe fibrosis.⁴⁹ In mouse models of proteinuric CKD, kidney lymphangiogenesis occurs before the development of fibrosis, and lymphangiogenesis and fibrosis occur primarily in the regions of inflammatory cell infiltration.⁷⁵ Although a correlational relationship between lymphangiogenesis and fibrosis is fairly well established, demonstration of any causative relationship remains a challenge. Multiple theories exist for how an expanded lymphatic network may contribute to fibrosis. Chronic inflammation in other tissues has been tied to the development of enlarged, hyperpermeable, “leaky” lymphatics, which in the kidney could impair clearance of fluid and proinflammatory stimuli in the interstitium.⁷⁶ A disorganized arrangement of newly formed lymphatics that may be less effective at drainage has also been proposed.⁷⁷ Finally, an expanded network of LVs with upregulated CCL21 and leukocyte adhesion molecule expression in response to a proinflammatory landscape could result in increased antigen presentation and archival and leukocyte activation. However, the appearance of lymphatics in response to inflammation does not necessarily imply causation and may even be protective by improving antigen and immune cell clearance.

Animal models of diabetic nephropathy and human kidney tissue samples with diabetic nephropathy show increased expression of proinflammatory cytokines and VEGF-C concomitant with increased LV density throughout the kidney.⁴⁷ However, a study of 121 human renal biopsy specimens, including 20 with diabetic nephropathy, demonstrated that, unlike other kidney diseases, the increase in lymphatic density in diabetic nephropathy does not seem to significantly correlate with the markers of fibrosis and macrophage infiltration.⁴⁷ Glucose, as well as advanced glycation end products, stimulates macrophages to make VEGF-C, uncoupling lymphangiogenesis from inflammation and injury, and possibly explaining this finding.⁴⁷ While it remains uncertain whether lymphangiogenesis is directly or indirectly affecting CKD progression and fibrosis, a particularly increased propensity for lymphangiogenesis in diabetic nephropathy may have implications for responses to AKI.

Interstitial nephritis, particularly chronic interstitial nephritis, is also associated with significantly increased LV density.^47,78 As a form of kidney injury driven predominantly by an overzealous adaptive immune response rather than an innate immune response, enhancement of antigen presentation and lymphocyte trafficking with lymphangiogenesis would be predicted to more clearly have a negative role and potentially predict progression to CKD. In the absence of clear animal models, the data available on the role of lymphatic responses during interstitial nephritis unfortunately remain limited.

Several studies have been aimed at augmenting lymphangiogenesis in animal CKD models on the basis of the expectation that increased lymphatic clearance of activated immune cells would prevent fibrotic remodeling. Although some have shown positive results,⁷⁹ many of these studies have relied on VEGF-C or VEGF-D signaling, making it unclear whether the benefit is derived from their effects on lymphatics versus other off-target cells.

Kidney Transplant and Transplant Rejection

In addition to the renal artery and renal vein being transected in kidney transplantation, hilar lymphatic drainage is also transected and is not reconnected on implantation. Correspondingly, donor leukocytes are rarely observed in host DLNs in the first week after transplant in animal models.^80,81 Immediately after transplant, allograft size can increase from interstitial edema and lymphoceles can form.^38,82 In animal models, this edema can be relieved by draining the lymphatics.⁸³ Soon after transplant, lymphatic flow is restored by lymphangiogenesis occurring from a combination of growth of donor kidney lymphatics as well as circulating lymphatic progenitor cells.^54,55 In mice, evidence for re-establishment of lymphatic drainage to DLNs begins at around 1 week after transplant.⁸⁴ The patterns of LV reconnection are understudied; however, iliac lymph nodes and mesenteric lymph nodes are suggested to be the primary draining nodes on the basis of animal studies.⁸⁵ Although guidance cues for LV tip migration have been proposed for developmental and pathological lymphangiogenesis, the existence of any unique mechanism by which LVs reconnect to host DLNs after transplantation remains unknown.^44,54

In addition to attenuating interstitial edema, restoration of lymphatic efflux from the allograft shortly after transplantation provides a route for migration of transplanted kidney antigens and APCs to host DLNs, potentially facilitating alloimmune responses and the formation of donor-specific antibodies. Allograft rejection is associated with increased tissue lymphangiogenesis in kidney transplant recipients and animal models of transplant rejection as well as in other organ allografts.^48,86–90 In animal models of kidney transplant rejection, inhibition of the lymphatic response by severing the lymphatic connection to DLN, performing LEC knockdown, or inhibition of CCL21-CCR7 signaling has been demonstrated to be beneficial.⁸⁴ Disruption of lymphangiogenesis has been demonstrated to be effective in preventing transplant rejection in heart transplants; however, in lung transplants, lymphangiogenesis seems to serve a beneficial role.^91,92 Therapies to inhibit lymphangiogenesis may represent a future strategy to improve outcomes in kidney allografts, but clearly further investigation is needed.⁸⁶

Conclusions

In the kidneys, the lymphatics play a critical role in fluid and macromolecule removal, in shaping kidney immunity, and likely in balancing physiological pathways that promote healthy organ maintenance and systemic homeostasis as well as responses to injury. However, the available literature informing our understanding of how dynamic changes in the lymphatic system can affect kidney disease states are limited by confounding explanations for findings performed in many animal models in which lymphatic growth is inhibited and by a lack of human studies. In addition to this, the disparate hats the lymphatic system wears—namely as a primary instrument of interstitial fluid drainage and regulator of sodium balance, as well as an immunomodulator and trafficker of immune cells—make the possibility of an either wholly “positive” or “negative” effect of disruption of this system seem unlikely, and studies aimed at understanding more specific lymphatic targets (i.e., CCR7-CCL21 interactions in inflammatory kidney diseases) should provide deeper and more promising insights. In many states of kidney disease, including AKI, the demand on the preexisting lymphatic network increases to enable clearance of injury-related tissue edema and inflammatory infiltrates. Renal lymphangiogenesis, stimulated by macrophages, injured resident cells, and potentially other drivers (e.g., glucose), is pervasive in the settings of AKI, CKD, and transplantation. Accumulating evidence suggests that lymphangiogenesis may be detrimental in AKI and kidney allograft rejection, which would position lymphatics as another target for novel therapies to improve outcomes. However, the diverse forms of kidney insults that comprise AKI and CKD, as well as the complexity of the structural and immune responses to those insults, make it imperative that we better understand the mechanistic underpinnings of the lymphatic response to injury and how that response affects both kidney physiology and the immune cell–structural cell crosstalk that are so fundamental to both injury and repair.

Disclosures

L. Cantley reports the following: Consultancy: Drug Farm, Johnson and Johnson, and Vivace Therapeutics. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Megan L. Baker.

Writing – original draft: Megan L. Baker.

Writing – review & editing: Lloyd G. Cantley.