Syphilis: a reversible cause of nephrotic syndrome

Abstract

A patient in his late 30s presented with symptoms consistent with a nephrotic syndrome. Renal biopsy revealed membranous nephropathy. He also mentioned a spontaneous resolving ‘rash’ at his glans penis after unprotected intercourse. Therefore, he was tested for sexually transmitted diseases as a possible underlying cause of his nephrotic syndrome. Serology for syphilis was positive with high titres. After a single penicillin injection, there was fast and complete clinical recovery.

Background

Nephrotic syndrome is a relatively uncommon problem characterised by overt proteinuria, low serum albumin, peripheral oedema and hyperlipidaemia. Supportive treatment (protein, salt and water restriction, loop diuretics, ACE-inhibition and statins) and often steroids or immunosuppressants are the mainstay therapy. However, when an underlying cause can be identified, this could simplify therapeutic management. Syphilis is a re-emerging infectious disease in the western world that should be considered as a cause of nephrotic syndrome in patients at risk.

Case presentation

A Caucasian man in his late 30s, without any remarkable medical history, presented with symptoms of malaise/myalgia, headache, sore throat, lymphadenopathy and night sweating. He also gained weight (10 pounds since 1 week) and he had noticed pedal oedema and swollen eyelids. He denied haematuria, although his urine was darker than usual. About 3 weeks before presentation, he had a non-itching and painless ‘rash’ on his glans penis, which had resolved spontaneously after unprotected intercourse. Just 3 months ago, he was tested negative for any sexually transmitted disease. He smoked one packet of cigarette a day, his alcohol intake was modest (1–2 consumptions a day) and he denied recreational use of drugs, although 6 months ago he had used anabolic steroids as part of a fitness regime.

At the time of physical examination, we observed a muscular man, not acutely ill, with a swollen face and bilateral peripheral oedema. The blood pressure was elevated (145/90 mm Hg). Jugular venous pressure was normal. Cervical lymph nodes were tender but not enlarged, and there were multiple enlarged inguinal lymph nodes. No abnormalities were found on inspection of the glans penis. There were no clinical signs of thrombotic complications or infections, and the remaining physical examination was unremarkable.

Investigations

Initial investigations confirmed the clinical diagnosis of nephrotic syndrome. Blood testing revealed very low albumin levels (22 g/l), normal total cholesterol (6 mmol/l), high-normal creatinine levels (111 μmol/l, previously 92 μmol/l); complete blood count, C reactive protein, glucose, liver function tests and creatine kinase were unremarkable. The urine dipstick revealed 3+ proteinuria in the absence of haematuria or leukocyturia. 24 h urine analysis confirmed the presence of severe proteinuria (16.8 g/24 h), but his endogenous creatine clearance was normal (108 ml/min).

Since a primary nephropathy was suspected, additional laboratory tests were performed and early renal biopsy was scheduled. Results from additional investigations were negative for paraproteins, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibody (ANCA) and antidouble-stranded DNA antibody (dsDNA). Complement (C3/C4) and immunoglobulin levels (IgA/IgG/IgM) were normal. Serology for Streptococcus (antistreptolysin O), HIV, hepatitis B and C were negative. However, Treponema pallidum chemiluminescence immunoassay (CLIA) was positive with a high Venereal Disease Research Laboratory test (VDRL) titre (1:64), suggestive of active syphilis, later confirmed by a positive T pallidum IgG blot. Renal ultrasound revealed non-specific diffuse increased echogenicity of the renal parenchyma. Light microscopy revealed only subtle irregularities in the glomeruli (figure 1A). Immunofluorescence showed granular deposits along the glomerular basement membrane for IgG and C3c with negativity for IgA and IgM, suggesting membranous nephropathy (MN; also membranous glomerulonephritis). This was later confirmed by electron microscopy (figure1B).

Figure 1.

(A) In light microscopy, barely discernible irregularities in the glomerular basement membrane were observed with, again, barely discernible subepithelial eosinophilic deposits along the outer subepithelial rim (blue arrows); no spikes are visible at this stage (methenamine silver stain, ×40 original magnification); (B) electromicroscopy confirmed the presence of electron dense deposits (representing immune complex deposits; white arrows) on the outer subepithelial side of the glomerular basement membrane (black arrows). Podocytes show the effacement of foot processes (End,  endothelium; Pod, podocyte; L, capillary lumen; ×10 000 original magnification).

Differential diagnosis

Because of the profound proteinuria, a primary glomerular disease was suspected. After additional investigations, only MN and minimal change nephropathy were considered. Analysis of the renal biopsy established the diagnosis of MN (figure 1), since this pathological diagnosis has been associated especially with syphilis. Our final clinical diagnosis was: early stage MN, related to secondary syphilis.

Treatment

After the clinical suspicion of nephrotic syndrome was confirmed, the patient was advised to restrict protein (0.8 g/kg), salt (3 g/24 h) and water intake (1.5 l/24 h) and immediate smoking cessation. In addition, the patient was started on loop diuretics (furosemide 80 mg twice daily), ACE inhibitors (lisinopril 5 mg once daily) and statins (simvastatin 20 mg once daily), pending the results from additional investigations (blood, urine and renal biopsy). Tromboprophylaxis was not indicated (serum albumin >20 g/l). Directly after establishment of the diagnosis, the patient was treated with a single injection of benzathine penicillin (2.4 million units intramuscularly).

Outcome and follow-up

Initial therapy had a modest effect; however, there was a dramatic clinical response after penicillin injection. Three weeks later, the patient had fully recovered and did not require medication anymore: all symptoms resolved, and the body weight, serum albumin and kidney function were completely normalised; the proteinuria was undetectable and VDRL titres were significantly reduced.

Discussion

Nephrotic syndrome is a relative uncommon problem characterised by overt proteinuria (>3 g/24 h), low serum albumin (<30 g/l) and often peripheral oedema; the most important related complications are thromboembolism, infection, hyperlipidaemia and acute renal failure.¹ Supportive treatment (protein, salt and water restriction, loop diuretics, ACE inhibition and statins) and dependence on the cause steroids and/or immunosuppressants are the mainstay therapy. In white patients younger than 60 years, MN is the most common cause of nephrotic syndrome (40% of the cases). The defining feature of MN is immune complex formation beneath podocytes on the subepithelial (outside) surface of the glomerular basement membrane, resulting in podocyte detachment and increased glomerular permeability to large molecules, like albumin. MN can be idiopathic or due to autoimmune disease, infection, malignancy, medication or other causes. Only in a minority of patients can a secondary cause of MN be identified, as in our patient. The exact mechanism for syphilis to trigger immune complex formation and MN is unknown. MN is probably a rare complication of syphilis, as we could only find five case reports in PubMed in the past 20 years.^2–6 Interestingly, all the reported cases involved a young man with risky sexual behaviour, and often co-infections with HIV or hepatitis were found. It is very important to identify a possible underlying disease, as it could simplify treatment, as demonstrated in our patient. Furthermore, no unnecessary immunosuppressive treatment was initiated, and relapse of the disease after inappropriate treatment was prevented.⁷

Syphilis, caused by T pallidum, is a common sexually transmitted disease worldwide and a re-emerging infection in the western world.⁸ The lesion of primary syphilis occurs at the site of initial inoculation and spontaneously heals 4 or 5 weeks later. In the secondary stage, it becomes a systemic infection, often accompanied by generalised macular popular rash (not in our patient), lymphadenopathy, fever and malaise. In less than 10%, secondary syphilis may lead to a broad range of syndromes, such as hepatitis, iritis, nephritis and neurological problems (early meningovascular syphilis). The main manifestations of late syphilis, with an incubation period of 5–10 years, are neurosyphilis, cardiovascular syphilis and gummatous syphilis. Serology tests for syphilis are the mainstay of diagnosis, owing to the complexity of direct visualisation techniques. Non-treponemal tests like VDRL are used for screening and are also valuable to monitor disease activity. In populations of low disease prevalence, rapid treponemal enzyme immunoassay tests like T pallidum CLIA could also be used for screening, although additional confirmatory testing is still advised, for example, by T pallidum IgG blot. Primary and secondary syphilis is easily treated with a single dose of benzathine penicillin.

Learning points.

• The diagnostic criteria for nephrotic syndrome are clinical evidence of peripheral oedema, proteinuria (>3 g/24 h), low serum albumin (<30 g/l) and hyperlipidaemia.

• Protein, salt and water restriction, ACE inhibition, statins and (cause-dependent) steroids and/or immunosuppressants are part of the therapy.

• Always consider an underlying cause of glomerular nephropathy (preferably guided by a pathological diagnosis), as it could highly simplify and optimise treatment, for example, syphilis (depending on the patient characteristics).

• Syphilis is a re-emerging infection in the western world; diagnosis is made by serological testing, and primary and secondary syphilis is easily treated with a single injection of penicillin.