or agent. Secondary MN arises because of autoimmune response in the setting of systemic infections, malignancy, or drug exposure.
to overexpression of THSD7A in tumors. The autoimmune response toward the autoantigens causes MN. Strong THSD7A staining has also been seen in prostate, breast, kidney, and colorectal cancers.9 Autoantibodies to neural epidermal growth factor-like 1 (NELL-1) protein is another recent addition to the list of antigens implicated in MN. NELL-1-associated MN was identified in approximately 16% of PLA2R-negative MN cases without any identifiable secondary cause. The current literature suggests a connection between NELL-1 associated MN and malignancy.10 Yet another antigen, semaphorin-3B, was identified in infants and children, and deposits were in a segmental pattern in the glomerular tuft and in the tubular basement membrane (TBM).11 Of all the biopsies with diagnosis of MN, 30% are most likely associated with secondary causes. The precise pathology and antigens have not been clearly defined.12
FIGURE 19.2: Proposed mechanism of paraneoplastic glomerulonephritis (GN). Membranous nephropathy: The T-helper (TH-1) cells produce interferon-alpha (IFN-α), interleukin-2 (IL-2), and tumor necrosis factor-beta (TNF-β), which cause proliferative forms of GN, whereas the TH-2 cells produce IL-4, IL-5, IL-10, and IL-13, which cause membranous GN.11 There have been four proposed mechanisms to explain the pathogenesis of membranous nephropathy: (A) Tumor antigens mimicking endogenous podocyte antigens lead to antigen-antibody complex formation, which deposit in the subepithelial space; (B) circulating tumor antigens may get entrapped in the glomerular capillary wall attracting circulating antibodies, forming immune-complex deposits; (C) the antigen-antibody complexes formed in circulation may get trapped in subepithelial space; and (D) external trigger such as infections may cause direct development of MN in patients with malignancy.36 Minimal change disease: Studies have shown the role of vascular endothelial growth factor (VEGF) in minimal change disease, collapsing variant of focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA).11 The overexpression of VEGF leads to FSGS and underexpression leads to TMA.37 (Created with BioRender.com.)
monoclonal antibody that inhibits terminal complement activation by binding to complement C5 and preventing formation of the terminal membrane attack complex.22,23
TABLE 19.1 Paraproteinemia-Related Glomerular Renal Diseases
TABLE 19.2 Dysproteinemia-Associated Kidney Diseases, Incidence, Pathology, and Clinical Presentations