Intestinal Lymphatic Dysfunction in Kidney Disease

**Background:** Kidney disease is a global epidemic that adversely affects multiple organs beyond the kidneys, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies have identified the intestinal lymphatic network as a key participant in mediating these distant organ complications. The intestinal lymphatics are uniquely suited to absorb and transport large macromolecules, including dietary lipids and intestinally generated lipoproteins, making them a potentially significant route for disseminating gut-borne disease-associated factors. This review examines the novel paradigm of a vicious cycle of detrimental organ cross talk by which kidney injury-induced modulation of intestinal lymphatics contributes to systemic organ disease progression.

**Methods:** This is a narrative review that synthesizes findings from recent experimental studies, primarily using animal models of proteinuric kidney injury, as well as human data where available. The authors discuss the structure and function of the lymphatic system, with a focus on intestinal lymphatics, and summarize evidence on how kidney disease modifies gut lymphatics. They also explore potential mechanisms, including disruption of the intestinal epithelial barrier, dysbiosis and toxin production, dyslipidemia, inflammation, and sodium accumulation. The review includes data from studies using transgenic mice, antibiotic-treated animals, germ-free mice, and cell culture experiments.

**Key Results:** Proteinuric kidney injury causes significant expansion of intestinal lymphatics, increased mesenteric lymph flow, and altered pumping dynamics. Mesenteric lymphatic vessels from kidney-injured animals showed a significant increase in ejection fraction and a marked decrease in contraction amplitude and end-diastolic diameter compared with vessels from uninjured kidneys. Mesenteric lymph of proteinuric rats had reduced albumin output but increased output of cholesterol, triglycerides, and apoAI. The lymph was enriched in lipid peroxides, specifically isolevuglandin (IsoLG), which cross-links apoAI. The number of Th17 cells and cytokines including IL-6, IL-10, and IL-17 was increased in mesenteric lymph from kidney-injured animals. S1P and VEGFC also increased. Proteinuric kidney injury altered the transcriptome of intestinal LECs, affecting genes involved in lymphangiogenesis, vasodilation, and immune cell chemoattraction (e.g., CCL21, eNOS, SPHK2, SPNS2). Kidney disease causes dysbiosis with lower colonization of Bifidobacteriaceae, Lactobacillaceae, Bacteroidaceae, and Prevotellaceae and higher levels of Enterobacteriaceae, Enterobacter, Klebsiella, Enterococci, and Clostridium perfringens. Depletion of gut microbiota by antibiotics reduced lacteal length and impaired lipid transport. Oxidized LDL (oxLDL) inhibited lymphangiogenesis, while normal LDL stimulated it. IsoLG-apoAI directly affected lymphatic growth and contractility, increasing NOS3 in cultured LECs and blunting vasoactivity. Treatment to scavenge IsoLGs significantly reduced intestinal lymphangiogenesis, albuminuria, and interstitial fibrosis. High-sodium environment decreased lymphatic vessel contraction amplitude and ejection fraction, reduced phosphorylated NKCC1, SPAK, and eNOS, and blunted lymphatic response in injured kidneys.

**Clinical Implications:** The findings highlight a novel paradigm in which kidney injury-induced intestinal lymphatic dysfunction creates a vicious cycle of organ cross talk, contributing to systemic complications such as cardiovascular disease, hypertension, bone disease, and cognitive dysfunction. The intestinal lymphatic network emerges as a potential therapeutic target. Currently, no drugs specifically target lymphatics, but several FDA-approved drugs have recognized effects on lymphatic vessel number or function. These include VEGFC modulators (e.g., lymphactin in phase II trial for lymphedema), retinoic acid, dexamethasone, ROCK inhibitors, PDE3 inhibitors (cilostazol), diuretics (furosemide), ATP-gated potassium channel modulators (glibenclamide), and anti-inflammatory agents (doxycycline, bestatin). Drug delivery strategies targeting gastrointestinal lymphatics can bypass first-pass metabolism in the liver, increasing bioavailability and reducing off-target effects. For example, drug-containing nanoparticles delivered to the intestines showed >20-fold increase in drug bioavailability and 30-fold increase in elimination half-life. Lymph-targeted celecoxib prodrug was more effective in reversing mesenteric lymphatic vessel branching and lymph leakage, reducing visceral obesity and inflammation, and restoring glycemic control in obese mice. Future therapies may target the absorptive capacity, contractile dynamics, and clearance competence of intestinal lymphatics to lessen the adverse consequences of kidney disease.