Membranoproliferative glomerulonephritis with syphilis involvement and possible Hepatitis B virus contribution: a case report

Abstract

Background

Syphilis, a sexually transmitted disease, presents with a wide range of clinical manifestations. As the global rate of syphilis infection continues to rise, so does the incidence of syphilis-associated nephritis. Characterized by diverse clinical and pathological features, the disease shows a good response to penicillin treatment. This article presents the case of a 46-year-old Chinese male patient exhibiting edema, hematuria, proteinuria, and a tendency towards rapidly progressive glomerulonephritis (RPGN). The patient was diagnosed with membranoproliferative glomerulonephritis (MPGN), with syphilis being a likely etiology and co-infection with Hepatitis B virus (HBV). He was treated with benzathine penicillin for three weeks, followed by low-dose glucocorticoids and mycophenolate mofetil (MMF) for subsequent treatment, leading to a significant improvement in his condition.

Conclusion

Highlighting the significance of syphilis as a cause of nephritis and emphasizing the importance of timely diagnosis and treatment can greatly alleviate the patient’s condition. Additionally, the role of Hepatitis B virus as a contributing factor in the development of nephritis should not be overlooked.

Clinical trial number

Not applicable.

Background

MPGN is characterized by hematuria, proteinuria, and serum creatinine levels that may be normal or elevated. Pathologically, MPGN is characterized by mesangial hypercellularity, capillary endothelial hyperplasia, and double contours in the glomerular basement membranes. Based on immunofluorescence classification, MPGN is often a result of immune complex deposition following infection, with viral hepatitis such as Hepatitis B and C being the most common. In contrast, syphilis-associated MPGN is rare [1,2,3]. In this paper, we report a case of MPGN associated with both syphilis and hepatitis B.

Case presentation

Clinical presentation

A 46-year-old Han Chinese male freelance worker presented to the nephrology department with a six-month history of eyelid and lower limb edema. He had a past medical history of chronic viral Hepatitis B for six years, managed with oral adefovir dipivoxil 10 mg qd, with unknown quantitative control of Hepatitis B virus. He had a two-year history of hypertension, controlled with oral nifedipine and telmisartan. He denied any history of mental or eye disease, smoking, alcohol abuse, or family history of hereditary disease. On physical examination, his blood pressure was 170/110 mmHg, with mild edema of both lower limbs, no generalized rash, and no enlarged lymph nodes in the groin.

Laboratory data

The 24-hour urine protein quantification was 7.62 g, urine routine showed RBC 186/µL, serum creatinine was 137 µmol/L, albumin was 27.2 g/L, and no abnormal blood tests were observed. The patient was screened for secondary causes, and the results showed positivity for Hepatitis B surface antigen (HBsAg), Hepatitis B e antigen (HBeAg), and hepatitis B core antibody (HBcAb), with quantitative Hepatitis B virus DNA (HBV-DNA) at 1.3 × 10^6 copies/mL; enzyme immunoassay (EIA) was positive, and Treponema pallidum particle agglutination assay (TPPA) was positive. The IgG level was 6.61 g/L. Complement/anti-Glomerular Basement Membrane (GBM) antibody, Myeloperoxidase (MPO), Proteinase 3 (RP3), anti-nuclear antibody (ANA), tumor markers [AFP (Alpha-Fetoprotein), CEA (Carcinoembryonic Antigen), PSA (Prostate-Specific Antigen), CA199 (Carbohydrate Antigen 19 − 9)], Hepatitis C, and Human Immunodeficiency Virus (HIV) serology were all negative, and cryoglobulinemia testing was not performed. Ultrasound of the liver revealed a high level of fat accumulation. The patient presented with hematuria, massive proteinuria, hypoproteinemia, and elevated creatinine, with secondary factors of Hepatitis B and syphilis, indicating a need for renal biopsy after obtaining the patient’s consent. Specific laboratory results are shown in Table 1.

Table 1 Relevant Laboratory Data

Renal pathologyLight

Renal pathology: Light microscopy revealed 23 glomeruli, 12 of which were globally sclerosed, and the remaining 11 showed lobar changes with increased cellularity, including inflammatory cells, in the capillary loops. One small fibrocellular crescent and two small cellular crescents were also observed. The study observed thickening of the glomerular basement membrane, hyperplasia of mesangial cells, proliferation of mesangial matrix, and formation of double contours, with no evidence of mesangiolysis. Focal tubular atrophy (approximately 20–25% of the area) with diffuse interstitial inflammatory cell infiltration was observed, along with intimal thickening and luminal narrowing of the small arteries of the interstitial vessels of the kidney. See Fig. 1. Immunofluorescence showed diffuse deposition of IgG (3+), C3 (3+), and C1q (+); HBcAg and HBeAg were negative, while HBsAg was weakly positive. IgA, IgM, HBcAg, and HBeAg were all negative, while HBsAg showed weak positive expression. Kappa (++) showed no differential expression of lambda (+++). See Fig. 2. Mesangial cells and matrix proliferated in the glomerular mesangial area, with occasional mesangial insertion into the subendothelial space of the glomerular basement membrane. Electron microscopy suggested the presence of electron-dense deposits in the subendothelial and subepithelial regions of the glomeruli. See Fig. 3. These findings are consistent with membranoproliferative glomerulonephritis.

Fig. 1

A: Diffuse inflammatory cell infiltration in the renal interstitium, predominantly lymphocytes and monocytes, with focal plasma cells and a few neutrophils. B: Proliferation of the parietal layer of the renal capsule, with the presence of one crescent. C: Thickening of the glomerular basement membrane, with mesangial matrix insertion, double contour formation, partial loop segmentation, and intraluminal infiltration of mononuclear cells. D: Mesangial area, segmental capillary loop subendothelial, and intracapillary loop hemosiderin deposition.

Fig. 2

Direct Immunofluorescence (DIF) shows glomerular IgG (3+), C3 (3+), Clq (+), and HBsAg (±) staining;Deposition site: Glomerulus; Deposition pattern: Diffuse, global, and petal-like along the capillary loops and Mesangial areas

Fig. 3

Electron microscopic observation of the glomerulus reveals segmental mesangial insertions into the subendothelial space of the basement membrane, as well as newly formed basement membrane. Additionally, multiple sites of electron-dense deposits within the glomerulus were observed, with large deposits of electron-dense material in the mesangial area and the subendothelial space of the basement membrane of the capillary loops. Small deposits of electron-dense material were also seen within the basement membrane and the subepithelial space of the segmental glomeruli

Diagnosis

After excluding autoimmune, hematologic disorders, complement abnormalities, and bacterial infections, the patient tested positive for syphilis indicators and had positive renal pathology immunofluorescence test results for IgG, C3, and C1q, with weakly positive expression of Hepatitis B antigen. Light microscopy revealed diffuse infiltration of inflammatory cells in the renal interstitium, along with focal plasma cells and a few neutrophils. The patient’s secondary factors were considered to be syphilis and hepatitis B. However, the renal immunofluorescence test results suggest that Hepatitis B may be involved. Therefore, while the primary consideration is that the patient’s nephritis is caused by syphilis, the influence of Hepatitis B cannot be ruled out.

Treatment and follow-up

Based on previous case studies, penicillin-based antibiotics are effective in treating syphilis-associated glomerular disease, including membranous nephropathy [4, 5], RPGN [6, 7], and FSGS [8]. The treatment regimen included restricting protein (0.8 g/kg), salt (3 g/24 h), and water (1.5 L/24 h) intake, and the application of an Angiotensin Receptor Blocker (ARB) drug (olmesartan 40 mg qd). At the same time, on the advice of the dermatologist, the patient underwent intramuscular injection of penicillin G benzathine 2.4 million units per week for 3 weeks. Entecavir (0.5 mg qd) was adjusted to control Hepatitis B virus replication. After 3 weeks of treatment, the patient’s serum creatinine increased (Scr 100 → 148 µmol/L), but proteinuria and albumin improved significantly (UTP [Urine Total Protein] 7.62→5.27 g; albumin 27.2→35.3 g/L). Considering the patient’s elevated creatinine, we referred to a literature on syphilis-associated glomerulonephritis (RPGN) [9], which reports successful cases treated with penicillin (PCN) and immunosuppressive therapy. Therefore, we administered small doses of methylprednisolone (20 mg qd), MMF (0.75 g bid), and olmesartan (40 mg qd) along with dietary and lifestyle modifications. During the follow-up period, we observed gradual improvement in the patient’s proteinuria and creatinine, with urine output maintained at 1500–2000 mL per day. The specific treatment is shown in Fig. 4. For syphilis treatment, regular visits were recommended by the dermatological venereal disease clinician, and no further penicillin was applied. As of 26 April 2023, rechecked, toluidine red unheated serum test (TRUST) was negative, but TPPA was positive. No additional treatment was given. In terms of liver disease treatment, the liver clinician advised continuing the medication. A gradual decrease in viral quantification was observed, with HBV-DNA quantification at 300 copies/mL (< 500 copies/mL) as of 21 March 2023, and no cirrhosis or diffuse liver damage was detected on review of the hepatobiliary, pancreatic, and splenic ultrasound.

Fig. 4

Changes in laboratory indicators during follow-up

Discussion

Diagnosis and treatment of syphilitic nephritis

The term “syphilis” was first coined by Hieronymus Fracastorius in 1530, and it was not until 1905 that Schaudinn and Hoffmann demonstrated its association with Treponema pallidum in smears of syphilitic lesion secretions [10]. Syphilis is a bacterial infection caused by the pale spirochete that usually progresses through three stages: the initial, secondary, and tertiary stages. Of these, the secondary stage is characterized by multisystem involvement, including the liver, eyes, kidneys, nervous system (early meningeal vascular syphilis), and skin [11, 12]. Previous studies support the concept of syphilis causing glomerulonephritis, where antibodies obtained from kidney biopsy tests can identify spirochetes by fluorescent dense spirochete antibodies and indirect immunofluorescence detection [9]. Syphilis involves the kidneys and most commonly presents clinically as nephrotic-range proteinuria but can also manifest as nephritis with active urinary sediment and acute kidney injury. Membranous nephropathy is the most common histological manifestation, followed by minimal change disease, membranoproliferative glomerulonephritis, IgA-dominant post-infectious glomerulonephritis, and diffuse capillary endothelial GN (with or without crescent formation) [13,14,15].

Syphilis-associated nephrotic syndrome usually responds well to penicillin therapy [16]. Prior to 2000, few cases were reported, but the prevalence of syphilis-associated nephritis in patients diagnosed with stage II syphilis ranged from 0.3 to 10% [17]. However, the number of reported cases associated with syphilitic nephropathy has been increasing since 2000, although the exact incidence of syphilitic nephropathy has yet to be assessed. The pathogenesis of syphilis-associated nephritis is still unclear. It has been suggested that syphilis in the latent phase may directly damage the glomeruli or that prolonged exposure to Treponema pallidum leads to the formation and deposition of immune complexes in the glomeruli. It is also possible that the intense antigenemia that occurs during secondary syphilis induces acute immune complex formation and deposition, leading to glomerular injury [18, 19].Currently, penicillin G remains the antibiotic of choice for the treatment of syphilis infection. It is highly effective against Treponema pallidum and is the treatment of choice for primary, secondary, and tertiary syphilis, with intramuscular benzathine penicillin G (2.4 million units per week) remaining the preferred treatment. Available cases have reported syphilis-associated membranous nephropathy [20], syphilis-associated RPGN [6, 21], and IgA-dominant post-infectious glomerulonephritis [14], with significant remission following penicillin application in patients with these pathological types. Additionally, nephrotic syndrome associated with syphilis has been shown to have good efficacy [16]. In conjunction with the advice of the dermatologist, we inferred that the patient had latent syphilis, considering that he presented positive results in a serological test for syphilis (including two different types of syphilis tests, namely immunoglobulin M and immunoglobulin G), but the patient had no signs of infection or history of treatment [22]. Therefore, we administered benzathine penicillin G intramuscularly at 2.4 million units per week for 3 weeks to treat secondary syphilis, in accordance with the experience of previous studies. After 3 weeks of observation, the patient’s proteinuria resolved, and albumin increased, but serum creatinine was 50% higher than two months earlier.

The following factors were taken into account: First, the patient had significant improvement in massive proteinuria and hypoalbuminemia, but there was a trend towards RPGN presentation. Second, pathology excluded sclerosing glomeruli, and three of the remaining 11 glomeruli had crescent formation. Third, RPGN in syphilitic nephritis with a small number of crescents is relatively rare. Although the effectiveness of penicillin therapy has been reported in the literature [7], the use of methylprednisolone, penicillin in combination with steroids and hemodialysis, and plasma exchange has also been supported in the literature [9, 21, 23]. Considering the presence of a cellular crescent (3/11) and a tendency to RPGN, we administered methylprednisolone (20 mg once daily) and mycophenolate mofetil (750 mg twice daily) after communicating with the patient. During the follow-up period, we observed an overall improvement in the patient’s urine protein quantification, albumin levels, and creatinine levels. In terms of treatment for syphilis, the patient received three injections of penicillin and was followed up regularly with no new rashes during this period. In terms of liver function, the patient was retested every 3 months for HBV-DNA quantification, and the values decreased overall to the normal range (300 copies/ml with a high normal limit of 500 copies/ml) at the retest on 17 March 2023. Liver ultrasound did not suggest signs of cirrhosis.

Limitations

The management of this disease has several limitations. First, diagnostic limitations: Syphilis-associated glomerulonephritis is diagnosed based on positive serology, histological evidence of rapid and sustained regression of nephritis after penicillin treatment, or the presence of antimicrobial spirochete antibodies or syphilis spirochete antigens in glomerular deposits [4]. To make the diagnosis, we considered the following factors: (1) Positive serological tests: the presence of EIA and positive expression of TPPA in the patient; (2) The effectiveness of penicillin therapy: proteinuria shows extreme sensitivity to penicillin-based antibiotic therapy; (3) Kidney immunofluorescence: due to the limitations of the test, we did not perform syphilis antibody or antigen testing of the kidney tissue. Immunofluorescence of the patient’s kidney showed IgG, C3, and C1q deposits. Although positive C1q expression in renal tissue is part of the pathological characteristics of lupus nephritis [24], the presence of positive C1q expression in renal tissue from syphilitic nephritis is also supported in the literature after excluding lupus [25–26]. Therefore, we excluded the patient from having lupus and suggested the possibility of syphilitic nephritis. However, it is important to note that we also observed a weakly positive expression of HBsAg, which means we cannot entirely exclude the association with Hepatitis B-related nephritis. The predominance of lymphocytes and monocytes with focal plasma cells and a few neutrophils seen in the patient’s renal interstitium also supports the interstitial pathology of syphilitic nephritis [27]. (4) The patient’s condition improved overall, and repeat renal biopsies were not performed to observe the renal pathology. There are some limitations in our practice, including not performing syphilis antibody or antigen testing of kidney tissue and not performing repeat kidney punctures to verify the effectiveness of treatment. Second, therapeutic limitations: There are only individual case reports of syphilis-associated nephritis, and there is a lack of clinical management and pathology in large sample studies. After treatment with penicillin based on previous experience, we observed that the patient’s proteinuria improved, but the creatinine level still increased. Considering the presence of crescentic glomeruli in the patient’s renal tissue, there was significant proliferation of endothelial and mesangial cells and stroma, and overall active proliferation of glomerular cells and other pathological features. Previous studies have shown that steroid therapy is effective in some patients with the presentation of acute nephritis. We therefore used moderate doses of glucocorticoids and mycophenolate mofetil, but there are some therapeutic limitations to this approach because of the limited reference material available. Moreover, the presence of Hepatitis B Virus (HBV) adds another layer of complexity to the treatment strategy, as it may influence the response to therapy and the progression of the disease.

Conclusions

With the global increase in syphilis cases, syphilis should be considered a potential cause of nephritis in high-risk groups, such as HIV-positive individuals, sexually active people, or intravenous drug users. Furthermore, the role of Hepatitis B Virus (HBV) as a contributing factor in the development of nephritis should not be overlooked. For patients with latent syphilis, even without systemic symptoms or typical skin and mucosal manifestations, it should be considered a treatable cause of reversible nephritis. A comprehensive assessment of the patient’s clinical and pathological characteristics should be conducted, following the advice of dermatopathologists. After penicillin treatment, close monitoring of the patient’s condition is necessary, and if necessary, glucocorticoids or immunosuppressive drugs may be used, with the patient’s prognosis being tracked. The potential impact of HBV on the course of the disease and response to treatment should be further investigated in future studies.