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Recent progress with specific markers of lymphatic vessel endothelium allowed recognition of lymphangiogenic events in various disease states; however, there is little information concerning this process in human chronic renal diseases. To determine this we measured expression of the lymphatic marker D2-40 and vascular endothelial growth factor-C (VEGF-C), a major growth factor in lymphangiogenesis, in 124 human renal biopsy specimens. In the kidneys of control subjects and in uninjured areas of pathologic specimens, lymphatic vessels were detected only around the arcuate and interlobular arteries. An increase in the number of lymphatic vessels was found at the site of tubulointerstitial lesions correlating with the degree of tissue damage and more strongly correlating with areas of fibrosis than inflammation. On serial sections, lymphatic vessel proliferation was found in the tubulointerstitial area at the site of tuft adhesions to Bowman's capsule. Lymphatic growth was associated with VEGF-C expression in inflammatory mononuclear cells and tubular epithelial cells, mainly of proximal tubules. Lymphangiogenesis and VEGF-C expression was elevated in diabetic nephropathy in comparison to other renal diseases. Our results indicate that lymphangiogenesis is a common feature in the progression of the tubulointerstitial fibrosis.