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.