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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 103-107

Membranous nephropathy and malignancy


1 Renal Service, Darling Downs Hospital and Health Service; Renal Service, Darling Downs Hospital and Health Service, Toowoomba, Queensland Rural School of Medicine, University of Queensland, Toowoomba, Queensland, Australia
2 Renal Service, Darling Downs Hospital and Health Service, Toowoomba, Queensland, Australia

Date of Submission14-Aug-2019
Date of Decision03-Feb-2021
Date of Acceptance03-Feb-2021
Date of Web Publication17-Jul-2021

Correspondence Address:
Vinod Khelgi
Renal Unit, Royal Adelaide Hospital, Adelaide - SA 5000
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCSR.JCSR_95_19

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  Abstract 


Background: There is variable association of membranous nephropathy (MN) with malignancy predominantly of solid organ tumours. There is debate as to how to screen and or investigate for evidence of malignancy in this group.
Methods: Retrospective analysis of kidney biopsies performed between 2006 and 2016. Patients with MN were identified and clinical course including age, degree of proteinuria, histology details, treatment and rates of remission documented. Evidence of malignancy and its temporal association with MN noted.
Results: Over ten-year period 216 biopsies were performed of which 20 patients (10.8%) had MN [mean age 48.5 years (range 20-82 years); there were to males]. Of these, eight patients (40%) had evidence of malignancy. Four patients were diagnosed with malignancy prior to the biopsy (mean duration 39.7 months) whereas, 4 patients were diagnosed after the biopsy (mean duration 6.7 months). Patients with MN and malignancy were older compared to those without malignancy (63.0 Vs 38.2 years) (P = 0.0054). There was no statistical difference in degree of proteinuria, focal segmental glomerulosclerosis lesions, and number of inflammatory cells in the study population.
Conclusions: Higher prevalence (40%) of malignancy was associated with biopsy proven MN from Darling Downs which was statistically significant. Although age appropriate investigations are indicated in these patients, it may be prudent to actively look for evidence of underlying malignancy especially in elderly population given the concerns associated with immunosuppressive therapies.

Keywords: Membranous nephropathy, malignancy, antiphospholipase A2 receptor


How to cite this article:
Khelgi V, Stack P, Venuthurupalli SK. Membranous nephropathy and malignancy. J Clin Sci Res 2021;10:103-7

How to cite this URL:
Khelgi V, Stack P, Venuthurupalli SK. Membranous nephropathy and malignancy. J Clin Sci Res [serial online] 2021 [cited 2021 Aug 3];10:103-7. Available from: https://www.jcsr.co.in/text.asp?2021/10/2/103/321704




  Introduction Top


Membranous nephropathy (MN) is histological diagnosis characterised by glomerular basement membrane thickening due to immune complex deposits in sub-epithelial location, beneath the foot process caused by multiple aetiologies.[1] Idiopathic or primary MN accounts for 80% of the cases, while the remaining 20% are associated with secondary causes such as infections, autoimmune diseases, drugs/toxins and malignancy.[2] An association of MN with malignancy is well noted in the literature (6%–22%) and debated extensively in the past.[1],[3],[4],[5],[6],[7] In adults, irrespective of age, malignancy is an important secondary cause of MN that needs to be ruled out. Common organs involved are solid organs not restricting to lung, gastrointestinal tract, and prostate. Tumour-antigen deposition at the basement membrane is considered pivotal in the pathogenesis; however, only few tumour antigens have been identified and demonstrated.[8] There is debate on how to screen and/or investigate for evidence of malignancy in this group. Currently, there are no definite guidelines and age-appropriate screening is warranted and recommended.[9] Hence, we report our experience with biopsy-proven MN and their temporal association with malignancy over 10-year period


  Material and Methods Top


We retrospectively reviewed the temporal relationship between MN and malignancy at Darling Downs Hospital and Health Service (DDHHS), Toowoomba for a duration of 10 years from 2006 to 2016. The institutional Human Research Ethics Committee approval was obtained.

All patients who had renal biopsy between January 2006 and December 2016 were identified from the records at the Department of Pathology, DDHHS region, Queensland, Australia. After reviewing their histology, patients with biopsy-proven MN were included in the study. Their baseline characteristics including age, sex, renal function (creatinine and estimated glomerular filtration rate) at the time of diagnosis, presence or absence of associated haematuria and degree of proteinuria at the time of biopsy were collected. Testing for phospholipase A2 receptor antibodies (PLA2R) was not done in most patients as this was not available at that time.

The pathology slides were reviewed and reported by pathologists from Royal Brisbane Women's and Children's Hospital. After the diagnosis was confirmed histologically, stage of MN, number of inflammatory cells/glomerulus, associated focal segmental glomerulosclerosis (FSGS) lesions, and the degree of interstitial fibrosis and tubular atrophy (IFTA) were documented.

Systematic review of clinical records was done to confirm the presence or absence of underlying malignancy. Once the patients were identified their clinical course including treatment, immunosuppressive medications, rate of remission was documented and followed up for 10 years. The evidence of malignancy and its temporal association with the diagnosis of MN was also documented.

Statistical analysis

Data were entered in a structured proforma. All entries were double-checked for possible errors. Continuous variables are summarised as mean, median (range). Mann–Whitney U test (2-tailed) was used for statistical analysis assuming median of the two groups are identical.


  Results Top


Over a 10-year period 216 biopsies were performed at DDHHS of which 20 patients (10.8%) had biopsy-proven MN. Secondary causes of MN were ruled out through careful drug history, viral infections (hepatitis B and C), and immunological disorders in all the patients. The mean age of the patients was 48.5 years (20–82 years). Baseline clinical and laboratory data at the time of kidney biopsy is shown in [Table 1].
Table 1: Baseline clinical and laboratory data at the time of kidney biopsy

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Eight patients (40%) had evidence of malignancy during the course of investigation. Comparison of renal biopsies in MN patients with and without associated malignancy is shown in [Table 2]. Out of these 2 had haematological malignancy, 3 solid organ (colon, lung and breast), 2 unknown primary and 1 invasive BCC [Table 3]. Four patients were diagnosed with malignancy before the biopsy (average duration 39.7 months) and four patients were diagnosed after the biopsy (average duration 6.7 months).
Table 2: Comparison of renal biopsies in MN patients with and without associated malignancy

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Table 3: Types of cancer and outcome of malignancy and nephrotic proteinuria among 8 patients with cancer-associated MN

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Patients with MN and malignancy were older compared to those without malignancy (63.0 Vs 38.2 years) (P = 0.0054). There was no statistical difference in the degree of proteinuria, FSGS lesions, number of inflammatory cells and degree of IFTA on biopsy between MN patients with and without malignancy.

Treatment details and renal outcome at the time of diagnosis is shown in [Table 4]. Four achieved complete remission (3 standard therapy including surgery in 1, steroids only in 1). Two had partial remission (1 cyclophosphamide + corticosteroids followed by rituximab and 1 only rituximab). Two nonresponders died due to malignancy-related complications.
Table 4: Treatment details and renal outcome at the time of diagnosis

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  Discussion Top


MN is known to be associated with malignancies for almost 100 years, being posthumously described by Galloway in association with Hodgkin's lymphoma in 1922.[10] The association between the MN and malignancy was further described over 50 years ago.[11] There appears to be a diverse spectrum of malignancy associated with MN, though solid organ malignancies such as lung, prostate and gastric origin cancers are much more commonly found than haematological malignancies.[12]

The pathogenesis of MN associated with malignancy remains uncertain. Tumour-antigen deposition at the basement membrane is considered pivotal in the pathogenesis; however, only few tumour antigens have been identified and demonstrated.[8] Suggested mechanisms include immune complex depositions, due to circulating antigens such as prostate-specific antigen or carcinoembryonic antigen; or a yet unidentified antigen formation may be present in the kidney attracting such deposition.[4] It has been argued that it is also possible that no causal relationship exists as both MN and malignancy increase in prevalence with age; and the association may be coincidental rather than the actual cause.[3] Another factor confounding the association between the MN and malignancy is argued to be the potential oncogenesis of immunosuppression; particularly should the diagnosis of MN precede that of the associated malignancy.[13]

The exact prevalence of MN at the population level is unknown but based on the meta-analysis the estimate is around 1.2/100,000/year.[14] In our small retrospective case series, the point prevalence of MN was 10.8% (population of 540,000).[15],[16] Moreover, our study also noted an almost twofold increased risk of malignancy following the diagnosis of MN as compared to other studies.[17],[18]

M-type PLA2R is the dominant antigen located on the podocytes. IgG type autoantibodies against these antigens (anti-PLA2R) account for 75%–80% of primary MN. The detection of antibodies in serum rules out a secondary form of MN with >90% specificity.[19] Hence, the ability to screen and measure anti-PLA2R levels has allowed distinguishing between primary and secondary forms of MN.

In older patients of >60 years the prevalence of malignancy in MN is 20%–30%. In our study, patients with malignancy (mean 63 years) were significantly older compared to those without malignancy (mean 38 years), which is consistent with prior studies.[3],[8],[18] Four patients with MN were previously diagnosed with malignancy before kidney biopsy and four others were subsequently diagnosed with a malignancy, the time to diagnosis varied between 1 and 14 months with an average of 6.75 months to the diagnosis of malignancy following biopsy-proven MN.

The overall association of malignancy associated with MN in our cohort was 40% which is high compared to other population studies. There are major limitations of our study. The higher prevalence could be related to selection bias and anchoring bias. Our study only captured patients referred to the public system. As the treating Nephrologist is aware of MN, there is a possibility of over investigation to identify occult malignancies. We also could argue whether monoclonal gammopathy of undetermined significance (MGUS) is malignancy or just a precursor. Given the very small sample size and retrospective analysis, these results cannot be compared at the population level. Patients with sub-nephrotic range proteinuria and clinically nonnephrotic might not have been referred to Nephrology services for evaluation.

Several further confounding factors that may diminish the significance of the association between malignancy and MN have been described; these include detection bias, increased prevalence of both conditions with age, and the potential oncogenic treatment of glomerular disease.[20] In our cohort of patients whose MN diagnosis preceded the cancer diagnosis, age may remain a confounding factor, and possibly detection bias, however, it is unlikely that oncogenesis from treatment was a significant factor given the short duration between diagnosis and the malignancy being diagnosed in patients treated conservatively for MN.

A similar negative association with oncogenesis has been reported where none of the patients with malignancy-associated MN (5 of 82) had been neither administered steroids nor cytotoxic agents before the diagnosis of MN.[7] Further studies following patients with MN to the development of subsequent cancer had a median of 60 months from diagnosis of MN to diagnosis of a malignancy.[18] Although the range of 0–157 months from the diagnosis of MN to diagnosis of a malignancy is large and suggests that at the longer extremity malignancy may have developed entirely independently of MN.

Given the high rates of association of malignancy with MN, It seems prudent to screen patients diagnosed with MN for malignancy, particularly as treatments for both MN and associated malignancies have improved since the association was first described. The number needed to screen to detect malignancy is unable to be precisely quantified, as the prevalence of MN and malignancies varies across several studies. However, given the range of published prevalence of malignancy within biopsy-proven MN, the number needed to screen is likely to be relatively low, being in the range of approximately 5–100, a targeted screening programme may be of benefit. Furthermore in the era of PLA2R testing, positive results will rule out secondary forms with >90% specificity. The prospective diagnosis of malignancy in half of the patients in our cohort may suggest that though oncogenesis from immunosuppression may be a factor in the development of some malignancies, that it is not the sole factor. For malignancy-associated MN, treatment of underlying cancer may result in resolution of the MN.

Malignancy is an important secondary/associated cause of MN in the older population. In the current era, PLA2R testing is readily available and could be used to distinguish between primary and secondary causes. Although age-appropriate screening has been recommended and practiced it is worth considering more intensive screening of patients with MN, especially with PLA2R-negative patients. In our cohort incidence of malignancy was higher and the major limitation was the small sample size. Further studies into the pathogenesis of malignancy-associated MN may identify novel biomarkers to allow for improved screening and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Cattran DC, Feehally J, Cook HT, Liu ZH, Fervenza FC, Mezzano SA, et al. Kidney disease: Improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139-274.  Back to cited text no. 9
    
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Galloway J. Remarks on Hodgkin's disease. Br Med J 1922;2:1201-8.  Back to cited text no. 10
    
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McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: A systematic review of the literature. Nephrol Dial Transplant 2011;26:414-30.  Back to cited text no. 14
    
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Cattran DC, Brenchley PE. Membranous nephropathy: Integrating basic science into improved clinical management. Kidney Int 2017;91:566-74.  Back to cited text no. 15
    
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Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: An update. Semin Immunopathol 2014;36:381-97.  Back to cited text no. 16
    
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Alnasrallah B, Collins JF, Zwi LJ. Malignancy in membranous nephropathy: Evaluation of incidence. Int J Nephrol 2017;2017:8409829.  Back to cited text no. 17
    
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Bjørneklett R, Vikse BE, Svarstad E, Aasarød K, Bostad L, Langmark F, et al. Long-term risk of cancer in membranous nephropathy patients. Am J Kidney Dis 2007;50:396-403.  Back to cited text no. 18
    
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Bomback AS. Management of membranous nephropathy in the PLAR Era. Clin J Am Soc Nephrol 2018;13:784-6.  Back to cited text no. 19
    
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Pani A, Porta C, Cosmai L, Melis P, Floris M, Piras D, et al. Glomerular diseases and cancer: Evaluation of underlying malignancy. J Nephrol 2016;29:143-52.  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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