Introduction
The expression is paraneoplastic syndrome defined by clinical manifestations that are not directly related to tumor burden, tumor metastasis or invasion, but as a result of the tumor cells secretions produced, such as cytokines, tumor antigens, hormones and growth factors. (1 -2) The tumor producing these substances can damage the kidney, generating paraneoplastic glomerulopathies. The prevalence of cancer in patients with nephrotic syndrome is 11-13%, but this percentage varies according to the patient’s age , especially those with more than 50 years, the sex male , which is more prevalent, the type of glomerulonephritis (GN), whose highest incidence occurs in membranous nephropathy, with the type of malignancy and the use of alkylating agents to treat glomerular disease , which may subsequently influence the development of malignancies. (3)
The tumors that are most associated with this type of paraneoplastic syndrome are carcinomas, mainly pulmonary and gastrointestinal tract, and those of hematopoietic origin, such as Hodgkin’s lymphoma. Among the most common paraneoplastic glomerulopathy found: GN membranous, GN minimal injuries, focal and segmental glomerulosclerosis (FSGS), GN membranopoliferative, IgA nephropathy, and GN rapidly progressive, with the first four are manifested clinically as nephrotic syndrome. The NS is characterized by presenting clinical -laboratorial of: proteinuria greater than or equal to 3,5 g / 24h, hypoalbuminemia, hyperlipidemia and edema, with patients with this disease have a tendency to develop combination of hypertension and microscopic hematuria. (1, 4)
The diagnosis of paraneoplastic glomerulopathy is based on the following criteria: lack of an alternative etiology associated with the syndrome, remission of clinical and histological manifestations after complete treatment of the neoplasia, whether performed by surgical removal of the tumor or chemotherapy, recurrence of neoplasia is accompanied by recurrence of glomerulopathy and there must be an association of pathophysiology between the two diseases. These criteria suggest the occurrence of paraneoplastic glomerulopathy, but confirmation of the diagnosis is acquired by renal biopsy, which also helps determine the patient’s prognosis and treatment. (1,2,3,5)
The occurrence of glomerulonephritis may occur before, concurrent or after the diagnosis of cancer and a temporal relationship is suspected when proteinuria occurs six months before or after the diagnosis of malignancy, but emergence of the risk the cancer persists for more than 10 years after Diagnostic confirmation of glomerulopathy. (1, 2,5,6) Therefore, it is extremely important to research neoplasms in patients with idiopathic nephrotic syndrome, especially in those over 50 years of age. And assessment should be directed according to history, physical examination, personal and family history of cancer. We also consider neoplasms related frequently nephrotic syndrome and invested initial should be carried out screening of radiography or computed tomography, colonoscopy, prostate specific antigen, mammography, among others. Even if these tests are unchanged, the patient should often be followed for a long time, due to the long period of risk of cancer. (1, 7)
Paraneoplastic membranous nephropathy (MN) is the most common form of nephrotic syndrome in adults, with males accounting for 70% of cases. Its prevalence in malignancies is from 2 to 11% and in patients over 60 years and this rate can reach 22%, in smokers (20 packs / year) this prevalence is also increased. (1, 2, 8, 9)Studies have shown evidence showing differences in the pathophysiology of primary paraneoplastic membranous nephropathy. The phospholipase A2 receptor (PLA2R) was identified as the primary target antigens involved in most primary MN adult, producing self - antibodies anti-PLA2R and immune deposits glomerular mainly consist of IgG4 subclass, the MN paraneoplastic these Anti-PLA2R autoantibodies are rarely observed, immune deposits in the glomerulus are particularly characterized by IgG1 and IgG2 subclasses, and the presence of more than eight inflammatory cells infiltrating the glomerulus increases the likelihood of being a paraneoplastic MN with 92% sensitivity and 75% specificity. Complete tumor resolution through surgery, chemotherapy and/or radiotherapy promotes NM remission with proteinuria remission. (7 ,10)
There are other less frequent associations of para-neoplastic syndrome with glomerular changes. Among these is the minimal change disease, the membranopoliferative glomerulonephritis, rapidly progressive glomerulonephritis paraneoplastic, Iga nephropathy and focal and segmental glomerulosclerosis (FSGS).
Paraneoplastic minimal lesion disease is more associated with Hodking’s lymphoma, but there are also reported cases of leukemia and carcinomas (lung, kidney, gastrointestinal tract, ovarian, mesothelioma), in which in most cases it is diagnosed concomitantly with the diagnosis of malignancy. This disease is histologically defined by normal light microscopy, negative immunofluorescence and electron microscopy, which diffuses the foot processes diffusely. (4, 11 ) Its pathophysiology can be explained by an intense inflammatory reaction in response to the tumor, evolving to formation of granulomas with production of cytokines and growth factors (mainly VEGF - vascular endothelial growth factor) which may promote increased permeability of the glomerular basement membrane, allowing the passage of proteins. In addition to treating malignancy, the use of corticosteroids is very effective in resolving this type of glomerulopathy. (10,12)
The membranoproliferative GN paraneoplastic occurs primarily in lymphoproliferative malignancies but can also occur in carcinomas such as smalls cells. It is histologically characterized by mesangial proliferation, thickening of the capillary wall due to enlargement of the subendothelial mesangium and cellular enlargement consisting of mesangial cells and infiltrating leukocytes. (3) There are three types of histological classification, types I and III derive from changes in the immune complex, and type II derive from modifications in the complement pathways. The pathogenesis of this disease is not well understood, several studies have shown glomerular deposits containing specific tumor antigens and their antibodies and cryoglobulins appear to originate membranoproliferative glomerulonephritis-like glomerular lesions. (13)
Paraneoplastic rapidly progressive glomerulonephritis is present in 7 to 9% of cancer patients, with a prevalence of up to 20% in patients over 40 years of age. The most related tumors are prostate, bladder, lung, gastric adenocarcinoma, renal cell carcinoma, myelodysplastic and myeloproliferative syndrome and leukemia. It is a serious disease that presents an acute and severe evolution that deteriorates renal function in days or weeks. It is histologically manifested by extracapillary proliferation with crescent formation, and crescent production is stimulated by fibrin accumulation in the Bowman space. (1, 3) Several studies relating its pathophysiology to malignancy have been performed, including unregulated T cell responses, cytokine production and uteroglobin suppression. Uteroglobin is a protein that under normal conditions is expressed in most epithelia, and it has been shown that in many carcinomas its presence is reduced, experiments with rats have shown that uteroglobin suppression promotes glomerular lesions with fibrin and IgA deposition in these rats. The treatment of rapidly progressive paraneoplastic glomerulonephritis is the immediate use of immunosuppressants. (1, 14)
Paraneoplastic IgA nephropathy has a cancer prevalence of 3%, the tumors most commonly associated with it being those of the respiratory tract, oral cavity, and nasopharynx, where this relationship can be reinforced by the presence of alcoholism, the association has also been described with renal cell carcinoma and lymphoma. It is characterized by microscopic/macroscopic hematuria and / or proteinuria and mesangial proliferation and diffuse IgA deposition in the glomerular mesangium. Light microscopy also helps to reveal an increase in extracellular matrix and hypercellularity in mesangium. (1, 3, 5, 15) Its pathophysiology is not well known, but we know that there is a strong link between IgA nephropathy and HLA-DR4, and studies indicate that invasion of the intestinal mucosa by malignancy promotes increased levels. IgA nephropathy may be limited to the kidneys or may be associated with a type of vasculitis, Henoch-Schonlein Purpura (HSP), which is defined by the presence of necrotic skin lesions in the skin. In the absence of cryoglobulins, patients with PHS have an increased risk of malignancy of 5.2%. (1, 3, 16)
And finally, the focal segmental glomerulosclerosis (FSGS) paraneoplastic, which is rarer with few case reports in the literature about its association with cancer . It is associated with lymphoma (particularly Hodking’s disease), leukemia, thymoma, hematologic malignancies and non-small cell lung carcinoma. Cancer cells have the ability to synthesize growth factors, and the factor’s growth of fibroblasts and transformer beta have been associated with the emergence of FSGS in experimental animal models. (17, 18) FSGS is defined as involvement of only a few glomerulus (focal) and only one segment of the glomerulus is injured (segmental), with areas of glomerular sclerosis, tubular atrophy and interstitial fibrosis. extracellular matrix containing different types of collagen and laminin, and IgM and C3 deposits are present in a few cases. Treatment can be done with corticosteroids, but this therapy is effective in less than 50% of patients, so the use of immunosuppressants is also indicated. Immunosuppression should be given as soon as possible, as this condition may progress to renal failure if inadequate treatment is obtained.