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Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-β1 (TGF-β1). The expression of both TGF-β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-β type I receptor inhibitor LY364947. Thus, TGF-β1 induces VEGF-C expression, which leads to lymphangiogenesis.

Lymphangiogenesis is correlated with the degree of renal interstitial fibrosis. Pro-fibrotic transforming growth factor β induces VEGF-C production, the main driver of lymphangiogenesis. Connective tissue growth factor (CTGF) is an important determinant of fibrotic tissue remodeling, but its possible involvement in lymphangiogenesis has not been explored. We found prominent lymphangiogenesis during tubulointerstitial fibrosis to be associated with increased expression of CTGF and VEGF-C in human obstructed nephropathy as well as in diabetic kidney disease. Using CTGF knockout mice, we investigated the involvement of CTGF in development of fibrosis and associated lymphangiogenesis in obstructive nephropathy. The increase of lymphatic vessels and VEGF-C in obstructed kidneys was significantly reduced in CTGF knockout compared to wild-type mice. Also in mouse kidneys subjected to ischemia-reperfusion injury, CTGF knockdown was associated with reduced lymphangiogenesis. In vitro, CTGF induced VEGF-C production in HK-2 cells, while CTGF siRNA suppressed transforming growth factor β1-induced VEGF-C upregulation. Furthermore, surface plasmon resonance analysis showed that CTGF and VEGF-C directly interact. Interestingly, VEGF-C-induced capillary-like tube formation by human lymphatic endothelial cells was suppressed by full-length CTGF but not by naturally occurring proteolytic CTGF fragments. Thus, CTGF is significantly involved in fibrosis-associated renal lymphangiogenesis through regulation of, and direct interaction with, VEGF-C.

Lymphatic vessels drain excess tissue fluids to maintain the interstitial environment. Lymphatic capillaries develop during the progression of tissue fibrosis in various clinical and pathological situations, such as chronic kidney disease, peritoneal injury during peritoneal dialysis, tissue inflammation, and tumor progression. The role of fibrosis-related lymphangiogenesis appears to vary based on organ specificity and etiology. Signaling via vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor (VEGFR)-3 is a central molecular mechanism for lymphangiogenesis. Transforming growth factor-β (TGF-β) is a key player in tissue fibrosis. TGF-β induces peritoneal fibrosis in association with peritoneal dialysis, and also induces peritoneal neoangiogenesis through interaction with VEGF-A. On the other hand, TGF-β has a direct inhibitory effect on lymphatic endothelial cell growth. We proposed a possible mechanism of the TGF-β–VEGF-C pathway in which TGF-β promotes VEGF-C production in tubular epithelial cells, macrophages, and mesothelial cells, leading to lymphangiogenesis in renal and peritoneal fibrosis. Connective tissue growth factor (CTGF) is also involved in fibrosis-associated renal lymphangiogenesis through interaction with VEGF-C, in part by mediating TGF-β signaling. Further clarification of the mechanism might lead to the development of new therapeutic strategies to treat fibrotic diseases.

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Peritonitis is an important complication of peritoneal dialysis. Several animal peritonitis models have been described, including bacterial and fungal models that are useful for studying inflammation in peritonitis. However, these models have limitations for investigating peritoneal fibrosis induced by acute inflammation and present difficulties in handling the infected animals. Animal models of peritonitis which induced peritoneal fibrosis are important for establishing new therapies to improve peritoneal damage induced by peritonitis. Here, we present an overview of representative animal models of peritoneal dialysis-associated infectious and non-infectious peritonitis, including our novel animal models (scraping and zymosan models) that mimic peritoneal injury associated with fibrosis and neoangiogenesis caused by bacterial or fungal peritonitis.

Introduction Albeit uncommon, hydrothorax is an important complication of peritoneal dialysis (PD). Due to paucity of evidence for optimal treatment, this study aimed to evaluate the effectiveness and safety of computed tomographic (CT) peritoneography and surgical intervention involving video-assisted thoracic surgery (VATS) for hydrothorax in a retrospective cohort of patients who underwent PD in Japan. Methods Of the 982 patients who underwent PD from six centers in Japan between 2007 and 2019, 25 (2.5%) with diagnosed hydrothorax were enrolled in this study. PD withdrawal rates were compared between patients who underwent VATS for diaphragm repair (surgical group) and those who did not (non-surgical group) using the Kaplan-Meier method and log-rank test. Results The surgical and non-surgical groups comprised a total of 11 (44%) and 14 (56%) patients, respectively. Following hydrothorax diagnosis by thoracentesis and detection of penetrated sites on the diaphragm using CT peritoneography, VATS was performed at a median time of 31 days (interquartile range [IQR], 20-96 days). During follow-up (median, 26 months; IQR, 10-51 months), 9 (64.3%) and 2 (18.2%) patients in the non-surgical and surgical groups,