A Mechanism for Cancer-Associated Membranous Nephropathy

Abstract

To the Editor: An association between mem-branous nephropathy and malignant tumors has been known for decades. 1 It was hypothesized that circulating, preformed immune complexes containing tumor antigens deposit in the glom-eruli and induce membranous nephropathy; however , this hypothesis no longer appears to explain how subepithelial immune deposition occurs. 2 The in situ binding of antibodies to endogenous antigens, which is strongly supported Figure 1. Clinical and Morphologic Characterization of the Patient. Panel A shows that thrombospondin type-1 domain-containing 7A (THSD7A) antibody levels were elevated and proteinuria was present at the time membranous nephropathy was diagnosed. Two weeks after the start of chemotherapy with gemcitabine and cisplatin, THSD7A antibody levels decreased, followed by a decrease in urinary protein excretion. At 18 weeks after the start of chemotherapy, THSD7A anti-body levels were not detectable, and urinary protein excretion was reduced to 0.7 g of protein per gram of creatinine (protein-to-creatinine ratio). THSD7A antibody levels are expressed in a semiquantitative measurement according to the serum dilution that resulted positive for THSD7A antibody; the higher a dilution with still detectable antibody, the higher the concentration of the antibody in the serum. CT denotes computed tomography. Panels B through D are immunohistologic stains for THSD7A. Panel E is also an immunohistologic stain but against THSD7A, CD21, and DNA. Panel B shows a strong enhancement of the glomerular THSD7A expression on immunohisto-chemical analysis of the renal-biopsy specimen. Panel C shows mixed adenoneuroendocrine carcinoma of the gallbladder. The carcinoma cells were positive for THSD7A on immunohistochemical analyses (right half), whereas the dysplastic gallbladder cells showed a markedly lower degree of positivity for THSD7A (left half). Panel D shows that the metastatic cells (lower right) as well as the follicular dendritic cells (upper left) were positive for THSD7A on immunohistochemical staining of the lymph nodes infiltrated by the metastatic gallbladder carcinoma. Panel E shows that the cells expressing THSD7A (green) were also positive for CD21 (red) on confocal microscopy, confirming that these are follicular dendritic cells (yellow) (blue indicates staining for DNA to depict the accumulation of THSD7A and CD21 in relation to the cells).