Viral Infection Associated Membranous Nephropathy: Clinical Presentation and Outcomes

Introduction

Membranous nephropathy (MN) linked to infections has been extensively documented in individuals with human immunodeficiency virus (HIV), as well as hepatitis B (HBV) and C (HCV) infections.^1-4 Although the pathophysiology of post-viral MN remains unclear, initial findings indicate that MN might be triggered by viral infection-induced immunomodulation.⁵ In recent years, a notable transformation in the treatment landscape of viral infections, particularly in the case of Hepatitis C is seen. We anticipate that the successful treatment outcomes may contribute to reducing the incidence of MN associated with these infections.

The molecular categorization of MN has brought about a transformative impact on the disease’s management. Circulating autoantibodies targeting the phospholipase A2 receptor (PLA2R) antigen range between 70% and 80% among individuals with primary MN (PMN).^6-9 Initially, the concept of anti-PLA2R antibodies was introduced to differentiate primary MN from secondary forms.^10-11 Nevertheless, recent data indicate the presence of anti-PLA2R antibodies in individuals with MN and concurrent viral infections.^2,11-15 Despite numerous reports linking viral infections to MN, the question remains unanswered regarding whether remission can be achieved solely through antiviral therapy or if immunosuppressive treatment is also necessary. This manuscript shares our firsthand experiences and presents a case-based review of MN in patients with hepatitis B/C and HIV infection in the post-PLA2R era.

Materials and Methods

Two separate reviewers, PK and AP, conducted literature search across four databases—PubMed, Scopus, Embase, and Web of Science. The aim was to identify all documented cases of MN associated with HBV/HCV/HIV infections between 2010 and February 2023, commonly referred to as the PLA2R era. The inclusion criteria encompassed patients aged 18 years and above who underwent PLA2R testing in either their serum or kidney biopsy. The search utilized specific terms such as ‘Hepatitis virus,’ ‘Hepatitis B,’ ‘HBsAg,’ ‘Hepatitis C,’ ‘HCV,’ ‘Human immunodeficiency virus,’ ‘HIV,’ ‘Viruses,’ ‘Membranous glomerulonephritis,’ ‘MN,’ and ‘Primary membranous nephropathy.’ Further refinement involved additional criteria, including the presence of PLA2R in the title, keywords, or abstract. Including cases that required individual clinical details, investigative findings, and follow-up information. Cohorts and randomized trials that lacked specific patient details were excluded from the analysis. Reviewers independently assessed relevant studies and agreed on including studies that met the specified criteria.

The data are expressed as mean ± standard deviation (SD) and median with interquartile range (IQR) for normally distributed and skewed data, respectively. Categorical data are presented as frequencies or proportions. The data analysis was performed using the Statistical Package for the Social Sciences (SPSS) for Macintosh, version 26.0.0.0, developed by IBM Corp., Armonk, NY, USA. The study was approved by the institutional ethics committee and appropriate patient consent was obtained.

All patients at our center were treated with supportive care, which included angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEi), statins, and anticoagulants (if indicated), along with antiviral therapy (in case of active viral infection).

Patients with inactive infection and persistent proteinuria were offered cyclical cyclophosphamide and corticosteroids in accordance with the KDIGO guidelines (2012).¹⁶ For those with contraindications such as diabetes mellitus (DM) or suspected intolerance to the therapy, rituximab therapy was administered, ensuring alignment with the current guidelines set forth by KDIGO (2021).¹⁷

Results

The exploration of PubMed, EMBASE, Medline, and Web of Science databases produced 50,531 records, as illustrated in Figure 1. Including seven patients from our centre contributed to the analysis of 63 cases in this review.^{1-4,13-14 18-25}

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Figure 1:

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram. The diagram illustrates the systematic process of incorporating papers identified through our search. PLA2R: Phospholipase A2 receptor.

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The mean age was 47.0 years (SD of 15.40). The male-to-female ratio was 2:1.

The mean proteinuria, serum albumin, and creatinine were 7.5 g/day (38 cases), 2.3 g/dl (40 cases), and 1.4 mg/dl (44 cases), respectively. A total of 27 cases were associated with HIV (43%), 18 with HBV (28.5%), 11 with HCV (17.5%), 4 with both HCV and HIV (6%), and 3 with both HBV and HIV (5%). Among the 63 cases, 39% had underlying comorbidities, including hypertension, diabetes, dyslipidemia, and hypothyroidism, among others. Two cases involved liver disease (cases 32 and 45), and two were associated with malignancies (cases 42 and 60). Notably, in the case series by Ma et al., four patients (cases 16-19) were diagnosed with both syphilis and HIV infection at the time of MN diagnosis.⁴

At the time of MN diagnosis, one patient (case 25) was pregnant. Antinuclear antibody (ANA) positivity was observed in three patients: two with HIV (cases 44 and 45) and one with HCV (case 34). Case #63, a kidney transplant recipient diagnosed with MN 16 years post-transplant, had an HCV infection. Clinical remission was achieved by 15 patients (24%) through antiviral treatment alone, while 25 patients (40%) required immunosuppressive therapy either independently or in conjunction with antiviral treatment. Upon stratification based on PLA2R positivity, no significant difference was observed for remission rate with antiviral treatment alone and immunosuppressive with and without antivirals between both PLA2R-related and unrelated patients (p = 0.089). Also, no statistically significant difference was observed for the patients who received only antiviral therapy with positive and negative PLA2R antibodies (p = 0.55). The comprehensive details of individual studies’ clinical, biopsy, and treatment aspects can be found in Table 1, and additional in-depth information is available in Supplemental Tables 1 and 2.

Discussion

We highlight the close link netween MN and prevalent viral infections. Over a third of the patients exhibited active viral replication during the diagnosis, and the PLA2R association was identified in two-thirds of the cases. The administration of antiviral therapy, with or without concurrent immunosuppressive treatment, led to remission in over three-fourths of the cases. Overall, individuals with MN associated with viral diseases demonstrated a favorable prognosis.

MN is traditionally categorized into primary and secondary MN. Cases lacking associations with drugs, infections, or other systemic diseases are termed primary MN. Identifying the PLA2R antigen has enhanced our comprehension of MN and has been utilized as a tool to distinguish between primary and secondary MN. However, recent reports have indicated that PLA2R is linked to autoimmune diseases such as lupus nephritis, sarcoidosis, infections, and malignancies.^1-4,15,26-29 According to the present analysis, approximately two-thirds of viral-associated MN cases were found to be PLA2R-related, displaying a heightened association with hepatitis B/C infection (exceeding 80%). This challenges our conventional understanding of primary and secondary MN, raising uncertainties about whether viral infection acts as a trigger or merely assumes a coincidental role.

Viruses can potentially contribute to the predisposition of MN through various mechanisms. The investigation conducted by Xie and colleagues uncovered the existence of anti-PLA2R antibodies and observed an overlap between PLA2R and HbsAg along capillary walls.¹² A recent study found that introducing the Hepatitis B virus into human podocytes induced PLA2R antigen expression.³⁰ Indirect pathways involve the disturbance of host defense mechanisms by pathogen-associated molecular patterns (PAMPs) and the entrapment of circulating immunoglobulin complexes, resulting in inflammation. A sustained inflammatory response can further activate non-specific auto-reactive lymphocyte clones. Additionally, the release of interferon I by NLR family pyrin domain-containing protein 3 (NLRP3) may contribute to podocyte loss.⁵ Hence, it is plausible that both direct and indirect mechanisms generate anti-PLA2R (or other autoantibodies) antibodies during viral infections. The persistence of clinical symptoms despite viral replication suppression implies the involvement of multiple mechanisms in the pathogenesis of virus-associated MN. The double-hit hypothesis may contribute to disease pathogenesis, involving genetic susceptibility as the first hit, followed by the direct or indirect impact of the virus on antibody production.³¹ In the current review, only a quarter of patients with active MN attained remission with antiviral therapy, supporting the double-hit hypothesis.

As indicated in Supplemental Table 3, the initial parameters of the current study, including proteinuria, serum creatinine and albumin levels, and anti-PLA2R status, closely resemble those observed in prior studies such as MENTOR, STARMEN, and RI-CYCLO.^32-34 More than half of the individuals with viral disease-associated MN exhibited mesangial proliferation and intramembranous deposits, features not typical of primary MN. This may be partly attributed to the viral infection inducing proliferative changes. Compared to the other two groups, two-thirds of patients with MN associated with HCV infection required immunosuppressive treatment. This is partly because direct-acting antiviral agents (DAAs) generally yield a sustained virological response without the risk of viral reactivation upon treatment discontinuation, making the addition of immunosuppressive agents convenient. Patients with HBV/HCV-associated MN demonstrated higher remission rates than those with HIV or combined infections.

The treatment approach for viral-associated MN lacks clarity, specifically regarding the use of immunosuppressive therapy, the timing of its administration, and the appropriate dosage. In the current study, no significant difference in remission rates was observed between patients undergoing antiviral therapy and those receiving immunosuppressive therapy. However, it’s important to note that a direct comparison between these groups is challenging, as patients who did not respond to antiviral therapy might have subsequently received additional immunosuppressive treatments. It has been previously suggested that patients with viral disease-associated MN may benefit from an extended course of antiviral therapy.¹ The findings from this analysis indicate that immunosuppressive therapy is safe and effective for individuals with viral-associated MN. This is especially when employed in conjunction with antiviral treatments for cases involving HBV and HIV or post-sustained virological response (with DAAs) in patients infected with HCV.

To the best of our knowledge, this is the first series that thoroughly examines data from all documented instances of membranous nephropathy associated with hepatitis B/C and HIV. However, it is essential to acknowledge certain limitations in this study, including a relatively small sample size, the absence of a standardized approach in managing cases, and some missing data in a few instances.

Conclusion

The findings of the present study indicate that two-thirds of MN linked to common viral diseases are PLA2R-associated and combination of antiviral therapy, with or without immunosuppressive therapy, achieves remission in three-quarters of the cases.