Pathophysiology

A causal link between neoplasia and PNGN remains ill defined, but there are several purported pathogenetic mechanisms. In a study of three patients with gastric cancer presenting with NS, glomerular eluates reacted specifically with the surface of the cancer cells from the same host seen under immunofixation (IF). Thus one hypothesis is that there is deposition of circulating tumor antigen-antibody complexes in the glomeruli with subsequent activation of inflammatory pathways, which eventually produces glomerular disease. In addition, antibodies could be directed toward specific endogenous glomerular antigens. Couser et al. report a case of a patient with MN who was found to have elevated carcinoembryonic antigen following the diagnosis of NS. The patient was subsequently diagnosed with colon cancer and underwent colon resection. The authors of the report demonstrated that an antibody in the serum of the patient reacted with an antigen on the glomerular basement membrane (GBM). This antibody was removed by adsorption of serum with homogenates of the patient’s serum but not by the homogenates of normal colon, liver, or spleen.

Another possible pathogenetic mechanism is that tumors elaborate cytokines and/or permeability factors, which triggers glomerular injury. In a study on a patient with rectal adenocarcinoma associated minimal change disease (MCD), Taniguchi et al. demonstrated high levels of vascular endothelial growth factor (VEGF) in the tumor. After resection of the tumor, VEGF levels returned to normal and the proteinuria resolved. The authors hypothesized that the overexpression of VEGF by certain tumor cells was linked to the onset of proteinuria, and thus when the VEGF levels decreased after tumor resection, the proteinuria resolved. ^{, ,}

Intrinsic viral oncogenic activity has been offered as an additional pathogenetic mechanism for PNGN. Viral activity may interfere with the renal clearance of the prooncogenic biological mediators released from the body. Alternatively, viral infections could lead to both malignancy and a PNGN through a common pathway. ^, The possible role of viral oncogenic activity and PNGN is discussed in more detail in the chapter on Paraneoplastic Glomerulopathy in Hematologic Malignancies.

The cellular and humoral immune systems may also have a role in the pathogenesis of PNGN. In an animal study that was performed by injecting rat colon cancer cells into immunocompetent and T-cell deficient F344 rats, the T-cell deficient rat’s kidneys did not show any morphologic abnormalities and did not have any immunoglobulin (Ig)G deposition. Thus it can be hypothesized that the presence of an intact cellular and humoral immunity is required for development of PNGN.

The various histologic patterns of PNGN may be dependent on several factors, including: (1) the duration of the neoplasm; (2) degree of tumor differentiation, which may dictate the elaboration of specific and nonspecific antigens; (3) type of tumor antigen and other products expressed; (4) type and extent of host response to these antigens via cell-mediated and antibody-mediated mechanisms; and/or (5) physiochemical characteristics of the circulating IC that render them pathogenic or nephritogenic.

Histopathology

On light microscopy (LM), the GBMs in MN appear thickened. On electron microscopy (EM), subepithelial deposits are evident. The presence of subendothelial or mesangial deposits should raise concern for a secondary or paraneoplastic process. There are several features on histopathology that have been associated with a paraneoplastic MN. Patients with paraneoplastic MN have an increased number of infiltrating inflammatory cells in the glomeruli (> 8 cells per glomeruli). Also, whereas IgG4 is the predominant subclass found in idiopathic MN, IgG1, IgG2, and IgG3 are predominantly found in cases of secondary MN. Circulating antiphospholipase A2 receptor is seen in up to 89% cases of idiopathic membranous nephropathy. It is worth noting that circulating antiphospholipase A2 receptor is occasionally present with secondary, including paraneoplastic membranous. ^,

Pathogenetic mechanism

Heymann nephritis is an experimental rat model for active and passive immune-mediated nephritis. Megalin, which is the target antigen, localizes to the podocytes in the rat model. However, in humans, megalin is found in the proximal tubule and not in podocytes. Hence investigators have sought to find an equivalent antigen present in the podocytes to explain paraneoplastic membranous glomerulonephritis (MGN). The finding of thrombospondin type-1 domain-containing 7A (THSD7A) antibody in a patient with MGN with a neoplasm, and the disappearance of the antibody and urinary protein after the malignancy was treated, suggests a potential causal relationship between THSD7A expression and MGN. Other factors may exist, but they have yet to be fully defined. There are a number of isolated case reports in which eluates from the glomeruli of patients with known malignancy showed reactivity with the patient’s serum and the tumor homogenates, but not with normal kidney.

Histopathology

Patients with IgAN have increased levels of abnormally galactosylated IgA1 subtype. On LM, IgAN is characterized by mesangial expansion with cellular proliferation and increased mesangial matrix. There can also be segmental or global endocapillary proliferation, presence of crescents, and segmental sclerosis. Immunofixation (IF) study is required for the diagnosis of IgAN because optically normal glomeruli on LM will have IgA as the principal and sole Ig on IF. It is not known whether IgA in the deposits is the antigen or the antibody that fixes C3. On the EM reveals granular electron dense mesangial and paramesangial deposits.

Pathogenetic mechanism

There are major differences between mice and human IgA systems. Therefore a good animal model for IgAN is lacking. One hypothesis is that the invasion of the mucosa by the malignancy leads to increased circulating IgA, leading to mesangial IgA deposits. In human models of RCC, elevated levels of interleukin-6 (IL-6) have been found in the serum and cell lines on cancer patients. In murine models, it has been shown that IgA production is stimulated by IL-6. Therefore one postulate is that elevated levels of IL-6 in RCC stimulates IgA production, leading to increased circulating levels of IgA, which in turn deposit in the mesangium. Alternatively, it is possible that tumors could stimulate secretion of abnormal IgA1-like particles that could then induce an IgG response in the host, which in turn could lead to formation of ICs that deposit in the mesangium.

Histopathology

MCD is characterized by normal looking glomeruli on LM with abundant proximal tubular protein reabsorption droplets. Staining for complement and Ig is negative on IF. The distinct histopathologic finding diffuse foot process effacement is seen on EM.

Pathogenetic mechanism

It has long been postulated that acquired podocytopathies are the consequence of immune factors, specifically a dysregulation of T-cell regulation. The Buffalo/Mna rat, which is a spontaneous model for thymoma and myasthenia gravis, has been studied for MCD-like glomerular disease. In these rats, NS presents at 1 month of age and the renal biopsy shows typical MCD features. In a retrospective study of 21 patients with thymoma, all patients with type B2 grade of malignant thymoma had MCD. Sixty-seven percent (14 out of 21) of the cases of thymoma had MCD on renal biopsy. Various T-cell related cytokines, such as IL-2, IL-4, and IL-13 may act as permeability factors and contribute to nephrotic range proteinuria. IL-13 levels are increased in the serum and T-cells of patients with MCD. Wistar rats that transfected with a vector, which resulted in overexpression of IL-13, developed significant proteinuria, hypoalbuminemia, and hypercholesterolemia when compared with control rats. The glomeruli of the transfected rats were optically normal on LM and had diffuse foot process fusion on EM. Further analysis revealed that there was downregulation of the proteins necessary to maintain the integrity of the GBM (nephrin, podocin, and dystroglycan), and upregulation of expression of IL-13 receptors. VEGF may also act as a permeability factor in patients with MCD. Increased secretion of VEGF has been observed in RCC.

Histopathology

Histologically, on LM, the lesion is characterized by segmental obliteration of the glomerular capillary, glomerular sclerosis, capsular adhesion, and hyaline deposition. As a result of proteinuria, increased proximal tubular reabsorption droplets can be found. On EM, there is extensive effacement of epithelial foot processes and absence of electron dense immune deposits. IF typically shows coarsely granular staining for IgM and C3 in the mesangial areas. These findings are generally caused by nonspecific trapping of IgM and C3, particularly in areas of sclerosis.

Pathogenetic mechanism

As is the case with MCD, a potential paraneoplastic link between thymoma and podocyte dysfunction in FSGS was studied in the Buffalo/Mna rat model because of their association with spontaneous thymoma. Data showed that the thymic disease did not cause proteinuria, because thymectomy had no effect on proteinuria. In the Buffalo/Mna rats, two autosomal recessive genes were located on chromosome 13, which seems to confer susceptibility to glomerulosclerosis. This chromosome corresponds to the long arm of human chromosome 1, where the Nephs2 gene coding for podocin has been located. This gene colocalization suggests that perhaps there is a genetic predisposition to paraneoplastic FSGS. As is the case with MCD, the cytokine milieu of malignancy may produce the ultrastructural changes seen in paraneoplastic FSGS. Increased production of macrophage associated cytokines, particularly tumor necrosis factor alpha (TNF-α) and cytokines associated with Th2-cells, have also been shown to produce an FSGS pattern of glomerular injury.