Inflammation, Lymphatics, And Cardiovascular Disease: Amplification By Chronic Kidney Disease Ⅱ

Congenital Heart Disease Can Lead to Lymphatic Abnormalities—Pressure gradients dictate interstitial fluid formation as well as lymphatic-mediated fluid return to the cardiovascular system. Congenital heart disease often increases central venous pressure, which can inhibit lymphatic drainage from the thoracic duct. These structural anomalies can also give rise to abnormal hemodynamics that result in increased hydrostatic pressure in the vascular network that in turn can increase interstitial fluid accumulation in an already impaired drainage system. Consequently, patients with congenital heart defects, particularly those with single ventricle defects can develop lymphatic complications that profoundly affect their short- and long-term outcomes [31]. Notably, approximately 13% of patients with congenital heart diseases undergoing palliative procedures, e.g., Fontan, develop protein-losing enteropathy (PLE), a life-threatening condition characterized by leakage of lymphatic fluid and protein into the intestine [32]. It is hypothesized that elevated central venous pressure increases lymph production and impairs intrathoracic lymphatic drainage, leading to dilation of intestinal lymphatics and leakage of lymphatic fluid and protein into the intestinal lumen [33]. Interestingly, the majority of Fontan patients who develop PLE have elevated levels of IFN-γ and TNF-α, cytokines known to disrupt tight junctions in the intestinal epithelium and contribute to protein leakage [34]. Similarly, plastic bronchitis, a rare but significant complication in Fontan patients, features dilated pulmonary lymphatic vessels and inappropriate accumulation of protein-rich lymph in the lungs, which solidifies, forming plastic-like casts that plug airway lumens. Inflammation may also contribute to the progression of this disease, as it is speculated that inflammatory mediators could disrupt the pulmonary epithelium, making it easier for lymphatic fluid to leak into the bronchial tree [32]. 

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Lymphatic Regulation of Inflammation and CVD—As above, chronic inflammation is a major risk factor for CVD. Lymphangiogenesis and vessel remodeling are reactivated in response to inflammation [30], and the lymphatic system has an integral role in mediating the inflammatory response by regulating interstitial fluid drainage and trafficking of macromolecules including cytokines, tissue fragments, hormones, and foreign antigens [35]. Thus, the lymphatic system is a major influencer of the progression of CVD and may be an untapped therapeutic target. Lymphatic vessels play an integral role in the progression of atherosclerosis as demonstrated in animal studies, which showed that mice with impaired lymphatic function crossed with atherosclerotic mice had elevated levels of atherogenic lipoproteins and accelerated atherosclerosis, compared to hypercholesterolemic controls with functional lymphatics [36]. Plaque destabilization and cessation of disease progression involve removal and excretion of cholesterol from macrophage stores within the arterial wall, a process termed reverse cholesterol transport. Cholesterol is first hydrolyzed and then mobilized to lipoprotein acceptors such as apoAI, which results in the formation of HDL. Lymphatic vessels are then required to facilitate the transport of HDL from the arterial wall to the bloodstream where it flows to the liver and is excreted [37, 38]. Although different approaches to disrupt the growth and function of lymphatics accelerate atherosclerosis, the exact role of ineffective reverse cholesterol transport remains to be determined.

Lymphatic vessels are also abundant throughout the myocardium, subendocardial space, and even in the atrioventricular and semilunar valves, and significant lymphangiogenesis follows MI in regions adjacent to the infarct as well as in uninjured areas [39]. The lymphatic contribution to the inflammatory response following injury involves the removal of dead cardiomyocytes and initiation of tissue repair and remodeling [40]. This appears to be a critical step for tissue repair as demonstrated in animal studies where lymphangiogenesis was amplified. In these studies, mice with increased cardiac lymphangiogenesis had reduced scar formation and improved cardiac function compared to control mice [41]. Moreover, in mouse models where lymphangiogenesis was inhibited, cardiac injury and dysfunction were exacerbated after myocardial ischemia-reperfusion [42]. Based on the interplay of lymphatic vessels and myocardial infarction, targeted induction of lymphangiogenesis has been proposed as a novel therapeutic strategy for this form of CVD [43]. 

Hypertension is a major CVD risk factor that clusters with other risk factors such as increased age, BMI, and diabetes. Studies have shown that lymphangiogenesis in the skin and muscle is initiated in response to salt-induced hypertension and involves macrophage secretion of vascular endothelial growth factor-C (VEGF-C) and that blocking lymphangiogenesis results in increased blood pressure in response to salt loading [44]. Interestingly, recent studies showed that selective upregulation of lymphangiogenesis in the kidney protected against salt- and angiotensin II-induced hypertension [45, 46]. Together, these observations underscore the critical role of the lymphatics in cardiac and extracardiac tissues in promoting CVD. 

Role of Inflammation and Lymphatics in Amplifying CVD in Chronic Kidney Disease 

Kidney Disease Accelerates CVD—Chronic kidney disease (CKD), defined by the Kidney Disease: Improving Global Outcomes (KDIGO) as abnormalities in kidney structure or function that persist for more than three months, affects 15–20% of the world population [47]. The overarching consequence of CKD is CVD. CKD patients are more likely to die from CVD than to progress to end-stage CKD [48]. In the last five years, both the American College of Cardiology/American Heart Association (ACC/AHA) and the National Kidney Foundation (NKF) have recommended that CKD be considered equivalent to preexisting coronary artery disease (CAD) as a risk predictor. The increased cardiovascular risk is apparent with even modest kidney impairment, and measurable increases in risk have been identified when GFR falls to < 60 mL/min/1.73m2 [49]. CVD risk continues to increase as kidney function declines, becoming especially pronounced in patients requiring dialysis who are at >15 times greater risk of dying from CVD than the general population without CKD [50]. The exaggerated prevalence of CVD in the CKD population is further complicated by the fact that the predictive value of traditional risk factors, including hyperlipidemia, hypertension, diabetes, smoking, and obesity, become attenuated with declining kidney function, and some established risks, such as BMI and hyperlipidemia, may reverse [51]. Moreover, lipid-lowering therapies have shown little to no benefit in several large clinical trials of advanced CKD, including patients on dialysis, despite robust reductions in serum LDL cholesterol [52]. Further complicating the approach to CVD in CKD patients is the fact that as kidney function deteriorates, the type of CVD changes, with non-atherosclerotic disease becoming more important. Thus, in contrast to myocardial infarction and stroke, which are central events of atherosclerotic CVD, arterial calcification, heart failure, left-ventricular hypertrophy, arrhythmias, peripheral artery disease, and sudden cardiac death are more common in individuals with severe kidney impairment compared to patients with modest renal dysfunction or individuals with intact kidneys [53]. Thus, the CKD population presents a unique human circumstance of remarkable excess of CVD with limited responsiveness to lipid-lowering treatment that offers the opportunity and challenge to develop more comprehensive concepts of mechanisms and innovative therapeutic approaches for CVD.

Inflammation in Kidney Disease Reflects Disrupted Intestinal Integrity and the Microbiome—Although CVD is the major consequence of CKD, traditional risk cardiovascular factors, e.g., dyslipidemia, diabetes, obesity, may be more or less important at different stages of CKD. In contrast, inflammation and oxidative stress are consistently increased across the entire spectrum of renal dysfunction are likely key in the pathogenesis of CKD-associated CVD [54, 55]. A sub-analysis of the CANTOS trial that included 1875 patients with GFR < 60 ml/min followed for 48 months found that Canakinumab significantly lowered cardiovascular events compared to placebo in patients with CKD [56]. This benefit was observed in the absence of any effects on atherogenic lipids. As in the main CANTOS study, the beneficial effects on CKD-associated CVD paralleled reduced hsCRP underscoring that inflammation characterizing CKD may be especially relevant to the role of the “inflammatory hypothesis of atherosclerotic CVD” in the setting of kidney disease. Interestingly, post hoc analysis of two randomized clinical trials, IL-1 trap in patients with moderate CKD and IL-1 receptor antagonist in patients on maintenance hemodialysis, showed IL-1 blockade improved HDL functionality including its anti-inflammatory activity, e.g., blockade of IL-6, TNFα and NLRP3, and antioxidant function, e.g., lessening superoxide production, which may contribute to the benefits of this therapeutic intervention [57]. 

The pro-inflammatory and high oxidative state prevailing across the spectrum of renal disease is, at least in part, related to abnormalities in the integrity of the intestinal barrier and unaltered microbiome [58]. Several factors prevailing in CKD contribute to the barrier dysfunction, including gut dysbiosis, slow intestinal transit time, low dietary fiber intake, metabolic acidosis, gut ischemia and edema, iron therapy, and frequent exposure to antibiotics. The resulting increase in permeability promotes translocation of gut-derived factors such as bacterial components, endotoxins, intestinal metabolites that leak into the circulation, and then initiate immune activation and proinflammatory signaling. Endotoxin stimulation of TNF and NF-kB involves Toll-like receptor 4, which activates an inflammatory response in endothelial cells, transforms macrophages into foam cells and promotes procoagulant activity. Impaired intestinal integrity promotes leakage of gut metabolites including metabolites of carbohydrates, e.g., short-chain free fatty acids and proteins, e.g., trimethylamine N-oxide, p-cresol sulfate, and indoxyl sulfate and lipid peroxidation products. Each of these metabolites can directly disrupt cholesterol metabolism and increase the expression of scavenger receptors, which promotes foam cell formation. Together, these observations indicate that the intestines are an important source for inflammatory and oxidative factors and that kidney disease augments the generation of these potentially harmful compounds. 

Kidney Disease Stimulates Intestinal Lymphangiogenesis—Traditionally, blood vessels and nerves have been considered the primary conduits by which bacterial components and endotoxins initiate systemic immune activation and proinflammatory signaling. Little attention has been given to lymphatics, whose main function is the transport of fluid, solutes, macromolecules, lipids, and cells. Inflammatory injuries and disease increase lymphatic growth and lymph flow in the affected organ. Our groups found that kidney injury not only causes intrarenal lymphangiogenesis but also stimulates lymphangiogenesis in the gut [59]. Using two models of renal damage, we demonstrated that proteinuric kidney injury in mice as well as a proteinuric model in rats augments intestinal lymphangiogenesis, evidenced by increased mRNA and immunostaining for podoplanin, LYVE-1, and VEGF receptor 3. The intestinal lymphangiogenesis was accompanied by macrophage infiltration, which colocalized with VEGF-C protein, suggesting that intestinal macrophages are sources of the increased VEGF-C levels that have been documented in the intestinal lymphatics of proteinuric animals. Since kidney injury is known to stimulate VEGF-C production by the proximal tubules, the kidney may be an additional source for VEGF-C in this setting. The expanded lymphatic network showed an increased rate of lymph flow and lymph volume was > threefold higher in mesenteric lymphatics of proteinuric rats compared to normal controls. These findings support the idea that intestinal lymphatics are a pathway that delivers gut-generated metabolites into the circulation and distant organs. 

IsoLG Originating in Gut is a Mediator of Mesenteric Lymphatic Dysfunction and Activation of Lymphatic Endothelial Cells—Aside from lymphangiogenesis and increase in lymph flow, kidney injury also modifies the composition of the mesenteric lymph. Our study showed that cytokines, including IL-6, IL-10, and IL-17, were elevated in mesenteric lymph of proteinuric animals compared to lymph of uninjured rats. The proteinuric injury also increased the intestinal generation of the reactive peroxidation product IsoLG. These observations complement other studies documenting IsoLG along the gastrointestinal tract. For example, increased IsoLG adducts were reported in gastric epithelial cells of patients with gastritis, precancerous intestinal metaplasia, colitis-associated dysplasia, and colitis-associated carcinoma, as well as in mice with colitis-associated carcinoma [60]. Demonstration of IsoLG adducts in human gastric organoids infected with H. pylori supports the idea that intestinal epithelial cells can generate IsoLG. Animals with kidney injury showed increased IsoLG adducts in mesenteric lymph but not in concurrently collected plasma, suggesting that the intestines are the source of these potentially harmful particles. Further, cultured intestinal epithelial cells exposed to myeloperoxidase (MPO), a peroxidase enzyme elevated in many chronic diseases, including CKD, and shown to be enriched in the intestinal wall of proteinuric rats, stimulated the production of IsoLG. It is notable that in addition to gastrointestinal epithelial cells, immune cells infiltrating the intestinal wall can form IsoLG adducts as demonstrated in the intestines of mice fed a high-salt diet [61]. Thus, both parenchymal intestinal epithelial cells and infiltrating immune cells can augment IsoLG synthesis in the intestines. Interestingly, IsoLG can directly modulate lymphatic vessel dynamics and activate lymphatic endothelial cells. Lymphatic endothelial cells exposed to IsoLG have significantly increased production of ROS Nos3. Isolated mesenteric lymphatic vessels exposed to IsoLG manifest altered functionality, including blunted vasoactivity but greater contraction frequency. The pathophysiologic impact of these lymphatic changes is supported by in vivo studies, showing that inhibition of IsoLG by small molecule scavengers significantly lessens injury-induced intestinal lymphangiogenesis in proteinuric mice [59]. 

Conclusion and Future Perspectives Recent studies suggest that mesenteric lymphatics are a novel pathway linking intestinally generated inflammatory and oxidative metabolites with cardiovascular diseases. Kidney injury amplifies this pathway by stimulating intestinal lymphangiogenesis and increasing lymphatic flow via mechanisms involving intestinally generated IsoLG (Fig. 1). The net effect is greater delivery of intestinally derived molecules such as IsoLG that may contribute to the adverse systemic effects of kidney injury. More research is needed to investigate the specific mechanisms by which kidney disease causes intestinal lymphangiogenesis and IsoLG generation. Blocking intestinally generated IsoLG could become a future therapeutic target to reduce the CVD burden of individuals with renal disease. 

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