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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 4  |  Page : 821-827
Role of light and immunofluorescence microscopy to differentiate primary and secondary membranous nephropathy


1 Department of Pathology, Institute of Postgraduate Medical Education and Research, Health University, Kolkata, West Bengal, India
2 Department of Nephrology, Institute of Postgraduate Medical Education and Research, Health University, Kolkata, West Bengal, India

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Date of Submission07-Jan-2021
Date of Decision24-May-2021
Date of Acceptance28-Jul-2021
Date of Web Publication21-Oct-2022
 

   Abstract 


Context: Membranous nephropathy (MN) causes nephrotic syndrome, mostly primary but may be associated with SLE, infections, cancer, or drug. Aims: To estimate clinical, serological, light microscopic, and direct immunofluorescence (DIF) findings to differentiate primary and secondary MN. Settings and Design: Prospective, cross-sectional, single-center study in a tertiary care hospital. Methods and Material: Total 51 cases from September 2019 to February 2020. Laboratory Data: Blood glucose, urine analysis, urea, creatinine, albumin, cholesterol, HBsAg, Anti HCV, ASO, ANA, MPO ANCA, PR3 ANCA, dsDNA, PLA2R, C3, and C4. Clinical parameters: age, sex, BP, skin lesions, arthralgia, edema, obesity. Renal biopsies examined with H and E, PAS, silver methanamine, MT stains. DIF done with IgG, IgM, IgA, C3c, C1q, kappa, and lambda. Statistical Analysis Used: Statistical software (Graph Pad PRISM 6) and Chi-square test). Results: Among 51 cases, 25 are primary and 26 are secondary MN with 22 being lupus nephritis, with 2 being post-infectious and the remaining 2 being proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMIDD) with kappa chain restriction. Mean age was 37 ± 12.18 and 30.69 ± 13.92 years for primary and secondary MN, respectively. Significant male preponderance in primary MN. Serum C4 significantly low in secondary MN (15.34 ± 9.59). Microscopic hematuria present in secondary MN. Mesangial and endocapillary hypercellularity are significant in secondary MN. IgG and kappa are significantly intense in primary whereas IgA, C3c, and C1q are significantly intense in secondary MN. Conclusions: Reliable differentiation between primary and secondary MN has important therapeutic implications.

Keywords: Immunofluorescence, lupus nephritis, membranous nephropathy, secondary

How to cite this article:
Basu K, Sengupta M, Mukherjee S, Karmakar S, Roychowdhury A, Bandopadhyay M. Role of light and immunofluorescence microscopy to differentiate primary and secondary membranous nephropathy. Indian J Pathol Microbiol 2022;65:821-7

How to cite this URL:
Basu K, Sengupta M, Mukherjee S, Karmakar S, Roychowdhury A, Bandopadhyay M. Role of light and immunofluorescence microscopy to differentiate primary and secondary membranous nephropathy. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Nov 30];65:821-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/4/821/359315





   Introduction Top


In membranous pattern of glomerular injury, there is widespread immune complex deposition in the subepithelial location. When one of the known etiologies present the disease is termed secondary MN (SMN). Cases with no systemic diseases have traditionally been termed “primary” or “idiopathic” MN (PMN). PMN is a kidney-specific, autoimmune glomerular disease causing nearly one-third of idiopathic nephrotic syndrome in adults with high incidence in patients above 60 years of age.[1],[2],[3] Children are rarely affected (1%–7% of biopsies).[3] Almost 85% of PMN is mediated by antibodies to the M-type phospholipase A2 receptor (anti-PLA2R), whereas thrombospondin type 1 domain-containing 7A (THSD7A) is involved in 3%–5%. Some unidentified mechanisms are involved in the rest 10%.[1],[2], [3,[4],[5],[6],[7] PMN patients are classified as immunologically active and inactive diseases according to the positivity of antibodies in serum and glomerular basement membrane (GBM). Anti-PLA2R–reactive epitopes are conformation-dependent and have been identified in different domains of PLA2R[1],[4]: cysteine-rich (Ricin B) domain and a tandem repeat of 8 C type lectin domains (CDLD 1–8), particularly CTLD1 and CTLD7.[8],[9]

Conditions associated with SMN are chronic infections, neoplasms, autoimmune diseases, drugs, toxins, and sarcoidosis. Neoplasms commonly associated with MN are carcinomas, lymphomas, leukemia, mesothelioma, and melanoma. Infections such as viruses, parasites, spirochetes, rarely tuberculosis[10], etc., cause MN. Autoimmune diseases, graft-versus-host disease, transplantation, IgG4 disease, etc., are associated with MN. Drugs and toxins may also cause secondary MN.

Aims and objectives

  1. To estimate the clinical features, biochemical parameters, and serological features of membranous pattern of glomerular injury
  2. To estimate light microscopic and immunofluorescence microscopic findings of membranous pattern of glomerular injury
  3. To differentiate between primary and secondary MN cases on the basis of the abovementioned findings.



   Subjects and Methods Top


Patient and public involvement

Patients attending the Nephrology department who undergo renal biopsy with the diagnosis of membranous pattern of injury are included in this study after taking proper informed consent.

Study design

Prospective, cross-sectional, single-center study in a tertiary care hospital.

Ultrasonography-guided percutaneous needle biopsies with two core of renal biopsies obtained from each patient are taken. Biopsies are collected in prone position with a pillow below the abdomen under local anesthesia. Biopsy specimens for light microscopic (LM) examination are fixed in 10% formalin. Sections of 2–3-μm thickness from paraffin-embedded material are stained routinely with Haematoxylin and Eosin (H and E), Periodic Acid Schiff (PAS) stain, Masson Trichrome, and silver methanamine stain. Specimens for DIF microscopy are received in normal saline and immediately frozen and embedded in Optimal Cutting Temperature compound. The sections are stained with FITC conjugated anti-sera against human IgM, IgG, IgA, C3c, C1q, kappa, and lambda light chain and stored in a cool dark place until viewed. For light microscopy, 6–10 glomeruli are considered adequate for evaluation.[1] For DIF biopsy containing even 1 glomerulus is adequate. In this study, we have evaluated the profile of renal biopsies diagnosed with membranous pattern of glomerular injury received in 6 months' period and correlated the findings of LM and DIF staining to differentiate between primary and secondary MN. All the primary and secondary MN cases are finally confirmed by electron microscopy done from outside.

Ethical issues

This study is approved by the institutional ethics committee and research advisory committee of our institute. All the patients gave informed consent before participating in this study.

Statistical analysis

We performed the Kruskal–Wallis test for comparisons between multiple groups, succeeded by an analysis by using Pearson's Chi-square test for categorical evaluation. χ2 test Correlations were evaluated using Spear man's rank correlation. P < 0.05 was considered as significant. We used statistical software (Graph Pad PRISM 6) for analysis.


   Results Top


A total of 51 patients with MN are identified from the consecutive renal biopsy cases from September 2019 to February 2020 at our hospital. Among these, 22 patients are lupus nephritis (LN) with serological evidence of ANA and dsDNA positivity. Two cases are post-infectious MN, one with HBsAg positivity and the other with both HBsAg and HCV positivity. Two are diagnosed with PGNMIDD [Nasr Disease][11] due to kappa light chain restriction in immunofluorescence staining along with IgG positivity in one case and IgA positivity in the other. Total 26 cases are diagnosed as secondary MN. Rest 25 cases are diagnosed as primary MN due to increased serum PLA2R level in 23 cases [Figure 1]. Range of serum PLA2R level in PMN cases is 2.0–620.4 RU/mL, of which 23 cases reveal serum PLA2R positivity (>20 RU/mL. All the cases are confirmed by electron microscopy done outside. On electron microscopy, PMN cases showed subepithelial electron-dense deposits (EDD), whereas SMN cases showed subendothelial, mesangial, and intramembranous EDD. Serum PLA2R estimation is not done in SMN cases.
Figure 1: Distribution of membranous nephropathy

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Demographics, including average age, are 33.82 ± 13.3 years for MN. It is 37 ± 12.18 years for PMN cases and 30.69 ± 13.92 years for SMN cases, and the difference is statistically insignificant. Overall male: female ratio is 1:1.22. Male gender distribution is prevalent in PMN as opposed to female preponderance in SMN, and this difference is statistically significant [Table 1]. Hypertension is present in 27.5% cases of MN and edema is present in 38.74% cases. Almost 84% patients of PMN presented with edema, whereas for SMN cases, it was 65.3%.
Table 1: Baseline clinical and serological characteristics

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Most of the patients presented with nephrotic syndrome with an average 24-h urinary protein of 3.6 ± 1.9 g and an average serum albumin of 2.68 ± 1.2 g/dL. Average serum creatinine is 1.26 ± 0.96 μg/dL. Comorbidities, such as edema, hypertension, diabetes, infection, embolism, and nephrotic syndrome, are comparable in primary and secondary MN cases, except microscopic hematuria, which is significantly associated with SMN. All the other serum and urine test results such as fibrinogen, serum albumin, complement 3, serum creatinine, and proteinuria are comparable in the two groups but serum complement 4 level (15.34 ± 9.59) is diminished in highly significant concentration in SMN cases [Table 1].

All MN patients are diagnosed on light microscopy on the basis of diffuse and global GBM thickening except in 3 cases of PMN where glomeruli appear normal. Silver Methanamine stain showed prominent spikes along the GBM [Figure 2]. Associated findings such as mesangial hypercellularity, mesangial matrix expansion, and endocapillary hypercellularity are statistically significantly found in secondary MN [Figure 3]. Rest of the parameters such as segmental sclerosis, global sclerosis, crescent, inflammatory cell infiltration, interstitial fibrosis, and tubular atrophy (IFTA) are comparable in both. Arteriolar hyperplasia is also found equally in both types, but arteriolar hyalinosis was associated with SMN more than PMN [Table 2].
Figure 2: Primary membranous nephropathy Upper left: Diffuse global membrane thickening (H and E X 400) Upper right: Foam cells in interstitium (H and E X 400) Lower left: Spikes in SM stain (JMS X 400) Lower right: Thick glomerular basement membrane (PAS X 400)

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Figure 3: Secondary membranous nephropathy (Lupus nephritis) Upper left: Spike and splitting of glomerular basement membrane (JMS X 400) Upper right: Segmental crescent formation (PAS X 400) Lower left: Wire loop lesion with intramembranous fuschcinophilic deposits (MT X 400) Lower right: Mesangial proliferation with thickening of glomerular basement membrane (H and E X 400)

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Table 2: Baseline histopathological examination and fluorescence immunohistochemical staining of renal biopsies

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In DIF microscopy, 96% of MN cases show positivity for IgG (100% of PMN vs. 92% of SMN). PMN cases showed fine granular positivity of IgG along the GBM with significantly higher intensity (3+ to 4+) than SMN [Figure 4]. LN class V showed full house positivity of antibodies and complements along the GBM as well as in mesangium [Figure 5]. Post-infectious MN cases show prominent positivity of antibodies and complements along the peripheral capillary wall. Two cases are IgG negative for IgG deposit-diagnosed as PGNMIDD and LN combined class III+Vrespectively. Next frequent immunoglobulins are IgM and IgA followed by complements C3c and C1q. SMN, particularly LN cases, are associated with mesangial immunoglobulin and complement deposition in addition to the deposition along the GBM. Kappa and lambda light chain depositions are identified in similar patterns and locations except in one PGNMIDD and another 3 LN cases where kappa chain is absent. Lambda light chain is absent in 1 LN case. Intensity and frequency of occurrence of IgG and kappa (positive in 100% of PMN vs. 84% of SMN) staining are statistically significantly high in PMN than in SMN, whereas intensities and frequency of occurrence of IgA (positive in 59% of SMN vs. 40% of PMN), IgM (positive in 84% SMN vs. 48% PMN) and C1q (positive in 77% of SMN vs. 32% of PMN) stains are significantly high in SMN in comparison with PMN. The staining intensity and frequency of occurrence for C3c (positive in 73% of SMN vs. 28% of PMN) is highly significant in SMN. Lambda light chain stain (positive in 100% of PMN vs. 96% of SMN) is comparable in intensity and frequency of occurrence in both groups [Table 2] and [Table 3].
Figure 4: Direct immunofluorescence positivity in Primary membranous nephropathy Upper left: IgG 3+ fine granular positivity along glomerular basement membrane (DIF X 400) Upper middle: C3c 3+ fine granular positivity along glomerular basement membrane (DIF X400) Upper right: Kappa 1+ fine granular positivity along glomerular basement membrane (DIF X 400) Lower left: IgA negative (DIF X 400) Lower middle: C1q negative (DIF X 400) Lower right: Lambda 2+ fine granular positivity along glomerular basement membrane (DIF X 400)

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Figure 5: Direct immunofluorescence positivity in Secondary membranous nephropathy Upper left: IgG 2+ fine granular positivity along GBM (DIF X 400) Upper middle: IgA 2+ fine granular positivity along GBM (DIF X 400) Upper right: C1q 2+ fine granular positivity along GBM (DIF X 400) Lower left: C3c 1+ fine granular positivity along GBM (DIF X 400) Lower middle: Kappa 2+ fine granular positivity along GBM (DIF X 400) Lower right: Lambda 1+ fine granular positivity along GBM (DIF X 400)

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Table 3: Histopathologic differences between primary and secondary MN, as reported in different studies

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   Discussion Top


Though differentiation between PMN and SMN is very important for the proper management of patients with membranous pattern of injury, literature regarding differentiation between the two varieties is sparse. We have done this study to estimate the clinical, histological, and immunofluorescence characteristics of PMN and SMN. Patients with PMN are managed by close follow-up during the first 6 months since diagnosis, with careful monitoring (monthly or bimonthly) of renal function, proteinuria, and anti-PLA2R titer. Changes in the abovementioned parameters will help the clinician to identify those patients in the favorable prognostic group, i.e., more likely to develop spontaneous remission and those with a bad prognosis in whom prompt initiation of immunosuppression may be warranted. Immunosuppression regimens are frequently associated with significant treatment complications. Patients with secondary MN are mostly managed by taking care of the underlying disease.[17] This distinction between the two groups is ultimately determined on clinical grounds after a thorough evaluation. However, there are findings on the renal biopsy that, while not specific, are suggestive of one over the other and play important role in this process of differentiation.

As a noninflammatory autoimmune disease, MN affects the kidney glomerulus, resulting in the formation of immune deposits on the subepithelial aspect of the GBM.[18] The mechanism behind most forms of adult MN is the binding of circulating antibodies specific for an intrinsic antigen presented on the basal surface of the podocytes.[19] Similar structural and biochemical properties are present in PLA2R and THSD7A.[20],[21],[22] Autoantibodies against these two antigens are predominantly classified into the IgG4 subclass.[20],[21],[22],[23]

Based on the current report and that of Qin et al.[24], it is clear that PLA2R positive MN can occur in the setting of SMN as well. This stands in contrast to the data of Hoxha et al.[25], who reported no secondary etiologies in cases with PLA2R staining. It should be noted, however, that Hoxha et al. did not provide details regarding the secondary etiologies that were excluded. Although Larsen et al.[26] recognized that secondary etiologies in the setting of PLA2R positive MN most likely represent the chance occurrence of two diseases, it is premature at this point to draw any definitive conclusion.

This new understanding of PLA2R antibody-mediated pathogenesis of PMN is in the process of changing the way the disease is diagnosed. Direct immunofluorescence assay of PLA2R antigen can be done in renal biopsies utilizing a commercially available antibody. SMN with positive PLA2R showed IgG4-predominant staining while analyzing IgG subclass in DIF. On the contrary, IgG4 is typically associated with PMN.[27] This IgG4 predominance raises the possibility that these cases are more pathogenically related to PMN rather than SMN.

Perhaps the inflammatory milieu which is present due to underlying disease triggers the onset of MN in susceptible individuals with risk alleles.[12] It is also possible that PLA2R autoantibodies are the result of an aberrant expression of PLA2R epitopes by the tumor cells in neoplasm-associated membranous glomerulopathy or by the granulomas in sarcoidosis-associated membranous glomerulopathy. More studies are needed to determine the clinical significance of PLA2R antibodies in the setting of secondary membranous glomerulopathy, particularly whether or not secondary membranous glomerulopathy cases with positive staining are less likely to resolve after treatment of the underlying disease than PLA2R negative cases.

Apart from PLA2R, another serological marker that is significantly reduced in SMN is serum complement 4 level in our study. Preliminary studies report that affinity-purified anti-PLA2R antibodies could bind mannose-binding lectin and promote C4 deposition.[13] Complement activation products in the serum of patients are commonly estimated as serum C3 and C4 levels. The complement activation may occur through lectin pathway in the patients who are anti-PLA2R antibody positive. Whereas in patients who are anti-PLA2R antibody-negative complement activation occurs through an alternative pathway. These complement-related mechanisms may provide potential therapeutic targets in patients with MN.

[Table 3] shows the comparison of our cases with the studies of Ohtani et al.,[14] Qu et al.,[15] Huang et al.,[16] Larsen et al.,[26] and Lonnbro Widgren et al.[28] All these studies, including our study, show that although anti PLA2R positivity in serum and predominant fine granular positivity of IgG and C3c along the GBM in a case of nephrotic syndrome indicate PMN, no single parameter can establish the diagnosis. On the contrary, SMN is diagnosed by the presence of nephritic syndrome along with endocapillary hypercellularity, mesangial cell proliferation, and mesangial matrix expansion in LM and more common occurrence of IgA, C3c, and C1q in DIF microscopy in a proper clinical setup. Confirmatory diagnosis requires electron microscopy, which shows exclusive subepithelial EDD in PMN, whereas SMN shows subendothelial, mesangial, and intramembranous EDD. The majority of cases of membranous glomerulopathy show near equal staining intensity for kappa and lambda light chains. However, there are rare cases with light chain restriction, lambda light chain restriction in three cases, and kappa light chain restriction in a single case. Among the cases that are showing light chain restriction, two cases have been included within the spectrum of PGNMIDD. The majority of the reported cases are idiopathic in nature without a known secondary lymphoproliferative disorder.[29] There is, however, one report of this form of membranous glomerulopathy in the setting of lymphoma.[30]


   Conclusion Top


The findings of “full house” staining with both antibodies and complements and serum PLA2R negativity are highly specific for SMN with a known secondary etiology. PMN shows positive PLA2R along with fine granular deposits of IgG along the GBM. Hence, DIF can substantially differentiate between PMN and SMN, and this reliable differentiation between the two has significant therapeutic implications.

Limitations

An important limitations is that we have not estimated serum PLA2R in secondary MN cases.

Ethics

This study is approved by the institute's ethical committee. All the participants gave informed consent in writing at the beginning of the study.

Data availability statement

All data relevant to the study are included in the Article.

Data sharing statement

No additional data available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA (2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med 2011;364:616-26.  Back to cited text no. 12
    
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Yang Y, Wang C, Jin L, He F, Li C, Gao Q, et al. IgG4 anti-phospholipase A2 receptor might activate lectin and alternative complement pathway meanwhile in idiopathic membranous nephropathy: An inspiration from a cross-sectional study. Immunol Res 2016;64:919–30.  Back to cited text no. 13
    
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Evans DJ, Macanovic M, Dunn MJ, Pusey CD. Membranous glomerulonephritis associated with follicular B-cell lymphoma and subepithelial deposition of IgG1-kappa paraprotein. Nephron Clin Pract 2003;93:c112-8. doi: 10.1159/000069548.  Back to cited text no. 30
    

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Correspondence Address:
Keya Basu
244. A. J. C. Bose Road, Institute of Postgraduate Medical Education and Research, Kolkata - 700020, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_22_21

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