Paraneoplastic glomerulopathy remains a rare clinical entity. Please refer to Chapters 22 and 23 for a more detailed discussion on the reported prevalence and some of the purported mechanisms for paraneoplastic glomerular diseases. Arguably, the data supporting the relationship between neoplasia and paraneoplastic glomerulopathy are most convincing for membranous nephropathy with solid tumors, and minimal change disease with Hodgkin lymphoma. Nonetheless, diverse patterns of glomerular diseases have been reported in association with a number of malignancies. Because glomerular disease can be the initial clinical manifestation of an underlying malignancy, the nephrologist may have a crucial role in initiating the evaluation for an underlying malignancy, and in doing so, avoid delays in the proper identification and treatment of a neoplasia. If paraneoplastic glomerulopathy is properly identified and treated, treatment of the tumor should lead to remission of the renal disease and thus spare the patient exposure to unnecessary immunosuppressive therapy for an incorrect diagnosis of a primary glomerular disease. Moreover, if an antecedent occult tumor is not properly identified, the development of that tumor may be subsequently ascribed to the immunosuppressive therapy that was used to treat the initial presenting glomerular disease.
As detailed in Chapters 22 and 23 , a number of reports support an increased prevalence in cancer among patients with primary glomerular diseases. Tumors of the lung, colorectal system, prostate, breast, and the hematologic and lymphatic tissue have been most frequently reported in association with paraneoplastic glomerulopathy. Paraneoplastic glomerular disease can present before, after, or concurrent with the detection of an associated neoplasia. Based on analysis of Danish registry data, the risk of cancer was 2.5 and 3.5 times higher than in the general population at 1 and 2 years, respectively, after diagnosis of the glomerular disease. In another case series of 24 patients with paraneoplastic membranous nephropathy, in 21 cases the cancer was detected at the time of the renal biopsy, and in the remaining three, within 1 year after the renal biopsy. Given the lack of any clear pattern or time course between detecting the paraneoplastic glomerular disease and malignancy, the clinician should maintain a constant level of suspicion for this underlying, albeit rare, clinical entity.
There is no clear consensus on whether all patients who present with a glomerular disease should be screened for an underlying malignancy. In addition, there are no clear guidelines on what an appropriate cancer screening program should entail. Moreover, the duration of cancer screening after the glomerular disease is recognized as uncertain. Based on prospective and retrospective reports, populations who may be at risk for paraneoplastic glomerulopathy include older patients, those with a history of heavy tobacco use, unexplained proteinuria, those exposed to immunosuppressive medications, , and patients with membranous nephropathy on the renal biopsy. In addition, there are specific findings on the renal biopsy that may serve as a signal for underlying malignancy. ,
Unexplained microalbuminuria, especially in a patient with other risk factors for bladder and lung cancer, may be a hint to an underlying paraneoplastic glomerulopathy. In a prospective analysis of 5425 Norwegians with no underlying history of diabetes, cancer, or macroalbuminuria, when compared with individuals with the lowest quintile of albumin to creatinine ratio, those with a ratio at the highest quintile were 8.3 times more likely to develop bladder cancer, and 5.4 times more likely to develop lung cancer. Risk factors for bladder cancer include age older than 65 years, smoking history, male gender, Caucasian race, cyclophosphamide exposure, and occupational exposures (rubber, textiles, paint).
Individuals exposed to some of the immunosuppressive therapies used to treat primary glomerular diseases, autoimmune diseases, and for protection against renal transplant rejection are at increased risk for later development of specific malignancies and may warrant additional scrutiny for an underlying cancer. Cyclophosphamide exposure is linked to the bladder tumors and hematologic malignancies. Cyclophosphamide itself and acrolein, an inactive metabolite of cyclophosphamide, may have oncogenic effects on the bladder urothelium. The risk of malignancy is dose related. Individuals who had received greater than 36 grams of cyclophosphamide had a standardized incidence ratio (SIR) of bladder cancer of 9.6 when compared with those who received lower doses of the drug or no drug at all. Patients with lupus who were treated with cyclophosphamide had a higher risk of lymphoma and those with granulomatous polyangiitis who had received greater than 36 grams of cyclophosphamide had a SIR of 59 for acute myeloid leukemia when compared with the general population. Long-term use of chlorambucil for treatment of polycythemia vera and ovarian cancer is associated with an increased risk for acute leukemia. It is not known if the increased risk of acute leukemia is related to cumulative dose of the drug. Long-term exposure to azathioprine in organ transplant recipients is linked to increased risk for skin cancer, lymphoma, and urinary tract cancers. In patients with multiple sclerosis, the risk of cancer correlated with cumulative doses of greater than 600 grams of azathioprine and treatment duration of greater than 10 years. Azathioprine has been largely replaced by the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, for prevention of graft rejection in transplant recipients and for treatment of some primary glomerular diseases. When compared with azathioprine, the CNIs are associated with earlier development of cancers. As is the case with azathioprine, the risk of cancer increases with increased total dose and duration of CNI exposure. Recipients of solid organ transplants are exposed to CNIs, in addition to other classes of immunosuppressants. When compared with the general population, the SIR for virus related cancer in recipients of solid organ transplants is 7.54 for non-Hodgkin lymphoma (NHL), 3.58 for Hodgkin lymphoma (HL), 6.15 for Kaposi sarcoma, up to 7.6 for human papilloma virus–related cancers, 4.65 for kidney, and 1.97 for lung cancer. The SIR for nonmelanoma skin cancer in this group is 50 at 4 years posttransplant and increases greater than 100-fold at 10 years from transplant.
There are several specific findings on the renal biopsy in patients with membranous nephropathy that may serve as a clue for a paraneoplastic process. Because idiopathic membranous nephropathy is not associated with electron dense deposits in the mesangium and subendothelium, the presence of such deposits should raise concern for a secondary or paraneoplastic process. In addition, inflammatory cells are rarely seen in idiopathic membranous nephropathy. In one report, the presence of more than eight leukocytes per glomerulus had a sensitivity and specificity of 75% and 92%, respectively, for identifying a paraneoplastic glomerulopathy. Idiopathic membranous nephropathy is most often associated with immunoglobulin (Ig)G4 deposits, whereas IgG1, IgG2, and IgG3 are seen more frequently with secondary membranous nephropathy. Circulating antiphospholipase A2 receptor is seen in up to 89% cases of idiopathic membranous nephropathy. Nonetheless, in patients who are not responding appropriately to directed therapy against membranous nephropathy, it is noteworthy that circulating antiphospholipase A2 receptor is occasionally present with secondary, including paraneoplastic, membranous nephropathy. , Furthermore, there are some clinical findings in patients with membranous nephropathy that should raise the suspicion for a paraneoplastic process. Membranous nephropathy and cancer are both associated with increased risk for thromboembolic events, and the risk of thromboembolic events increases in the presence of cancer. Up to 25% of patients with cancer associated membranous nephropathy developed a thromboembolic event in one report. Along with patients with membranous nephropathy, another population that may warrant closer scrutiny are those with mixed cryoglobulinemia without evidence for hepatitis C viral infection, because studies have revealed a fourfold increased risk of developing B-cell and NHL.
None of the national or international nephrology groups have offered or endorsed any cancer screening guidelines in patients with suspected paraneoplastic glomerulopathy. Screening guidelines require data from large randomized controlled trials, and it is unlikely that such data can be obtained in the population under consideration. In general, cancer screening is performed with the intent of early detection and early treatment of cancers to improve life expectancy. Any such benefit for cancer screening in patients with paraneoplastic glomerulopathy is unknown. Additional unknown factors include the financial cost of cancer screening in this population, potential complications of cancer screening, test performance (sensitivity, specificity, positive predictive value), or whether there is any benefit of early detection of cancers that have no mortality benefit when detected early. Because paraneoplastic glomerulopathy can predate the discovery of a tumor, it is unclear if a paraneoplastic glomerulopathy associates with early (in situ) or advanced malignancies. If one finds an in situ cervical cancer as part of the workup for a paraneoplastic glomerulopathy, there is no way of being certain that this early lesion is linked to the glomerular abnormality or if ongoing screening is required. With these cautions and limitations in mind, the general recommendations that follow are thus opinion based.
At a minimum, all patients with glomerular disease should have a complete personal history, family history, physical examination, smoking history, medication history (with attention to chemotherapy, radiation treatment, and immunosuppressive drugs), and routine serum chemistry and a urinalysis. If a hematologic malignancy is suspected, testing of the serum, urine bone marrow, and peripheral blood are essential for confirmation. Patients with age and other specific risk factors for malignancy should have appropriate screening. In a patient who was previously treated with cyclophosphamide or who has a history of tobacco use, it may be reasonable to check a urinalysis to evaluate for hematuria. Table 24.1 lists the current recommendations for cancer screening from the U.S. Preventive Services Task Force. For patients who have been treated with azathioprine and for recipients of solid organ transplants, it may be prudent to screen for skin cancers, because these cancers can be very aggressive in these populations. For recipients of solid organ transplants, a recent review article summarized the recommendations from national and international transplantation societies. Some of those findings are presented in Table 24.2 . Screening for malignancy may also be considered in those individuals who fail to respond appropriately to the standard therapy for their primary glomerulopathy. In a study where eight out of 21 patients had minimal change disease diagnosed months before the diagnosis of HL, two of eight were resistant to steroid therapy or cyclosporine. The minimal change disease responded to treatment for their HL.
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