Syphilis-related Membranous Nephropathy in a 35-year-old Woman

Abstract

A 35-year-old woman was admitted for the examination of lower leg edema and proteinuria. A kidney biopsy showed membranous nephropathy (MN) with fine granular deposits of IgG along the glomerular capillary and poor spike formation, differing from primary MN in the presence of positive IgG3 and C1q. Lupus nephritis was excluded because serum complement and anti-dsDNA antibody, anti-Smith antibody, and anti-cardiolipin antibody tests were negative. The serological test for syphilis was positive, as was the Treponema pallidum hemagglutination test. The patient was diagnosed with syphilis, and the proteinuria disappeared with antibiotic treatment. In MN with positive IgG3 and C1q, syphilis nephropathy may be a differential diagnosis.

Introduction

Primary membranous nephropathy (MN) is most commonly seen in people 50-60 years old, and its frequency is extremely low in people ≤40 years old. MN that develops in these relatively young patients is often secondary MN (1,2). Although complications of MN with viral diseases, such as hepatitis B and C virus and human immunodeficiency virus (HIV), are known to occur (2-4), the only reported case of MN associated with bacterial infection was related to syphilis.

We herein report a case of MN caused by syphilis in a patient in her 30s.

Case Report

A 35-year-old woman presented to our hospital with the chief complaint of facial and lower leg edema. On admission, the patient was 150 cm tall and weighed 56.0 kg. Her blood pressure was 116/93 mmHg, and her body temperature was 36.5°C. Heart and breath sounds were normal, but pitting edema was present in the lower extremities. Laboratory findings were as follows: white blood cell count, 6,000/μL; serum albumin, 2.0 g/dL; estimated glomerular filtration rate, 53.4 mL/min/1.73 m²; C-reactive protein, 1.98 mg/dL; IgG, 1,181 mg/dL; IgA, 361 mg/dL; IgM, 144.0 mg/dL; 50% haemolytic complement (CH50), 84 U/mL (normal value, ＞30 U/mL); C3, 148 mg/dL (normal value, 86-160 mg/dL); and C4, 53 mg/dL (normal value, 17-45 mg/dL). Tests for antinuclear antibody were positive, with a ratio of 1:80 (normal ratio, 1:＜40), but tests for double-stranded DNA (ds-DNA) antibody, anti-U1 ribonucleoprotein antibody, anti-Smith antibody, anti-cardiolipin antibody, and anti-cardiolipin beta-2-glycoprotein I antibody were negative. Urinary protein excretion was 1.15 g/day, and the urinary sediment contained ＜1 erythrocyte per high-power field. A renal biopsy was performed.

Kidney biopsy

A light microscopic examination of a biopsy specimen containing 30 glomeruli showed no sclerotic glomeruli. The tubulointerstitium was intact, and no spike formation was observed in the glomerular capillary (Figure). Immunofluorescence showed fine granular deposits of IgG, C3, and C1q along the glomerular basement membrane, which were negative for IgA and IgM. IgG subclass tests were positive for IgG, IgG1, IgG3 and IgG4 and negative for IgG2. Electron microscopy showed prominent foot process effacement but only a few subepithelial deposits (Figure).

Figure.

Kidney biopsy findings. Periodic acid methenamine silver (PAM) staining did not show spike formation on the glomerular capillary; original magnification ×400. Immunofluorescence (IF) showed fine granular deposits of immunoglobulin (Ig) G, IgG1, IgG3, C3, C1q and phospholipase A₂ receptor; original magnification ×200). Electron microscopy (EM) showed prominent foot process effacement but only a few subepithelial deposits (arrow).

Reasoning for the diagnosis of MN due to syphilis

The renal biopsy led to the diagnosis of MN. The patient was only 35 years old, and at this young age, MN was more likely to be secondary than primary MN. The biopsy findings supported secondary MN because the sample was characterized by a high degree of foot process effacement, with only a few deposits. Positive IgG3 staining in the IgG subclass test and positive C1q staining were similar to the findings in lupus nephritis. However, the patient did not have lupus nephritis because the complement was normal, and tests for ds-DNA, Smith, anticardiolipin, and anticardiolipin beta-2-glycoprotein I antibodies were negative. Other autoantibodies associated with autoimmune diseases and tests for hepatitis B antigen, hepatitis C, and HIV antibodies were also negative. The test for serum phospholipase A₂ receptor antibody was positive (5.5 RU/mL; normal value, ＜5.0 RU/mL), but tests for serum thrombospondin type-I domain-containing 7A were negative.

In the past, we have experienced cases in which MN with renal biopsy results similar to those in the present patient were actually MN related to syphilis (5). Consequently, we performed syphilis tests in the patient: the serologic test for syphilis (STS) was positive (8.8 U; normal value, ＜1.0 U), as was the Treponema pallidum hemagglutination test (829 U; normal value, ＜1.0 U). Therefore, we hypothesized that MN was associated with syphilis. We checked the patient again for rashes or ulcers but found none. Further inquiries revealed that she had had sexual intercourse with several other men.

In addition, tests for serum phospholipase A₂ receptor antibody were positive, and the phospholipase A₂ receptor was also confirmed by an immunofluorescence examination of the kidney biopsy specimen, yielding a positive finding.

Clinical course

We administered cefalexin 750 mg/day for 7 days but did not deliver immunosuppressive therapy. Two weeks later, the urine proteinuria had decreased markedly from 1.2 g/day to 0.04 g/day, the lower extremity pitting edema had subsided, and the patient was doing well.

Discussion

Lupus has been known to be associated with a positive serum reaction to syphilis, and attention to this shared antigenicity may lead to a diagnosis of MN due to syphilis after lupus nephritis has been ruled out. Syphilis infection produces IgG and IgM antibodies against cardiolipin lecithin (phospholipid). This method corresponds to the STS, a qualitative screening test for syphilis. However, it may deliver false-positive results because it can be positive for other diseases that involve antiphospholipid antibodies (6). The T. pallidum hemagglutination test is a quantitative test that measures the presence of syphilis, which is diagnosed if the result is positive. The assay was negative for lupus nephritis without syphilis. This test not only differentiates lupus nephritis from syphilis but also confirms the diagnosis of syphilis (7).

Lupus nephritis is characterized by positivity for not only C1q, but also IgG3 as well as IgG1 and IgG4 among IgG subclasses. This is because IgG3 binds strongly to C1q and activates the classical active pathway of complement starting from C1q, which not only decreases serum CH50, C3, and C4 but also attracts inflammatory cells into the glomerulus, leading to lupus nephritis (8). However, in the present case of syphilis nephropathy, not only C1q but also IgG1, IgG3, and IgG4 among the IgG subclasses were positive, and similar positive results for C1q and IgG3 were also reported by Ishiwatari et al. (9). There have been other reports of positive results for C1q, although no analysis focusing on IgG subclasses has been performed (5). In view of these reports, IgG3 and C1q positivity may be a feature of syphilis nephropathy.

Lupus nephritis and syphilis nephropathy do share some similarities but are fundamentally different. Syphilitic nephropathy, as in the present case, is an MN with subepithelial deposits, no decrease in serum CH50, C3, or C4, no inflammatory cell infiltration of the glomerulus, and no changes in the endothelial or mesangial cells. In contrast, in lupus nephritis, serum CH50, C3, and C4 values are clearly decreased, and the patient's condition is characterized by endocapillary proliferative nephritic changes, including mesangial and endothelial cell injury, although MN is also present. Nephropathy associated with syphilis is predominantly MN. In addition, electron microscopy shows a variety of subepithelial deposits, ranging from large to small, but the basement membrane covering the deposits is poorly elongated. The lack of spike formation is a common feature in light microscopy. Since the onset of leg edema and proteinuria often occurs within one week to three months after syphilis infection, it may take more time for the glomerular basement membrane to elongate over the subepithelial deposits, which may not result in spike formation (5,9). This may explain why MN with spike formation has a long chronic course before the diagnosis is confirmed, whereas MN caused by syphilitic nephropathy has a short, acute course before the diagnosis is confirmed.

In our case, the anti-phospholipase A₂ receptor antibody was positive at a low titer, and kidney biopsy tissue showed evidence of the phospholipase A₂ receptor. Anti-phospholipase A₂ receptor antibody was reported as a feature of primary MN (10,11), but it is also reported to be positive in cases of secondary MN, such as lupus nephritis, although less frequently. Although the relationship between syphilitic nephropathy and anti-phospholipase A₂ receptor antibody has not yet been reported, we suggest that the relationship between syphilitic nephropathy and anti-phospholipase A₂ receptor antibody should be examined in the future, even if the titer of anti-phospholipase A₂ receptor antibody is low.

An attempt to determine the presence of anti-treponemal IgG antibodies in the tissue of the kidney biopsy was reported by Gamble et al. in 1975. However, no further attempts were made to stain kidney biopsy tissue with anti-treponemal IgG antibodies in similar cases. Unfortunately, we could not attempt staining in our clinical hospital for the present case (12).

In summary, we reported a case of MN related to syphilis in which IgG3 and C1q were positive, serum anti-phospholipase A₂ receptor antibody was positive (although at low titer), and phospholipase A₂ receptor was confirmed on a kidney biopsy.

The present study adhered to the Declaration of Helsinki, and the patient provided her consent for the publication of the case report.

The authors state that they have no Conflict of Interest (COI).