Idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis

Abstract

Membranous nephropathy has been associated with demyelinating polyneuropathies and antiglomerular membrane disease; however, an association with vasculitic neuropathy has not been described. This case describes a patient with biopsy-proven idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis, who presented with lower limb microvascular ischaemia, peripheral neuropathy and active urinary sediment. Her extensive non-invasive screening for immunological disease and radiological investigations for occult malignancy were unremarkable. The patient received intravenous methylprednisolone and intravenous rituximab induction therapy resulting in complete remission of both the idiopathic membranous nephropathy and small vessel vasculitis at 7 months post treatment.

Background

The clinical presentation of microvascular ischaemia, peripheral neuropathy and glomerulonephritis is uncommon and requires rapid but careful workup.^1–4 This paper reports a woman who presented with ischaemic left toes, lower limb mononeuritis multiplex, and active urinary sediment with subnephrotic range proteinuria. The patient’s extended non-invasive immunological screen was non-diagnostic. A renal biopsy revealed idiopathic membranous nephropathy and a sural nerve biopsy revealed lymphocytic small vessel vasculitis. Rituximab induction therapy was commenced after the exclusion of malignancy with resultant complete remission 7 months post treatment.

Case presentation

A woman in her early 70s presented to hospital with a left calf ulcer, right foot erythema and bilateral lower limb oedema of 1 week’s duration. Her medical history was remarkable for chronic atrial fibrillation, dyslipidaemia, gastro-oesophageal reflux disease and cholecystectomy for cholelithiasis. She was a lifelong non-smoker, non-diabetic and had excellent functional status prior to admission. Her medications at the time of admission were diltiazem (modified release), dabigatran, atorvastatin and pantoprazole. There was no history of non-steroidal anti-inflammatory drugs, over-the-counter or herbal medication use.

On examination, she was afebrile, observations stable and in rate-controlled atrial fibrillation without clinical signs of heart failure or infective endocarditis. Peripheral pulses were normal. Livedo reticularis was present in the lower limbs, petechiae were present on the right second and third toes and a superficial ulcer was present on the left calf (figure 1). The patient’s right foot erythema and left calf ulcer did not improve with broad-spectrum antibiotics. She was noted to have preserved renal function plus active urinary sediment with haematoproteinuria.

Figure 1.

Posterior bilateral lower limb photograph at presentation.

The patient’s extensive investigations for infection, cardiac thromboembolism and immunological diseases were non-diagnostic. A renal biopsy was performed, which revealed idiopathic membranous nephropathy. The patient’s condition subsequently deteriorated with the development of dry gangrene affecting the left second-through-fourth toes and enlargement of the left calf ulcer (figure 2). Macrovascular and microvascular atheroembolic diseases were excluded by CT and MRI, respectively.

Figure 2.

Left lower limb photograph 3 months post presentation.

The patient was subsequently noted to have worsening sensory dysaesthesia in the hands and feet. Examination revealed decreased sensation to light touch, pain and vibration in the thumb, index and middle fingers bilaterally, patchy numbness in the trunk and a right peroneal neuropathy. The patient’s cranial nerve examination, visual acuity, tone, reflexes and coordination were unremarkable.

Nerve conduction studies (NCS) and electromyography (EMG) supported the clinical diagnosis of mononeuritis multiplex. The patient’s lumbar puncture opening pressure was unremarkable and the cerebrospinal fluid (CSF) revealed an elevated protein level. An inpatient quadriceps muscle biopsy and sural nerve biopsy were performed, which revealed denervation without reinnervation and lymphocytic small vessel vasculitis, respectively. Occult malignancy was excluded following the completion of extensive clinical, laboratory and radiological assessments.

Investigations

The patient’s full blood count revealed neutrophilia (13.0×10⁹/L, reference range (RR) 1.9–7.5 × 10⁹/L) and monocytosis (2.0×10⁹/L, RR 0.2–1.0 × 10⁹/L) with mildly elevated C-reactive protein (11 mg/L, RR <5 mg/L) on admission. The patient’s electrolytes, serum creatine kinase, renal function tests, liver function tests, thyroid function tests, HbA1c and coagulation screen were unremarkable. The patient’s midstream urine revealed non-visible haematuria (red blood cells 60×10⁶/L per high-power field (HPF), RR <10 × 10⁶/L per HPF) and subnephrotic range proteinuria (urinary protein-to-creatinine ratio 124 mg/mmol, RR <23 mg/mmol).

There was no growth in multiple sets of blood cultures. Viral serology revealed that the patient was hepatitis B non-immune and negative for hepatitis C and human immunodeficiency viruses. There was no serological evidence of current or past cytomegalovirus infection, and the patient’s tuberculosis interferon-gamma release assay and treponemal screens were negative. Her total immunoglobulin G (IgG) (9.0 g/L, RR 6.0–15.0 g/L), IgA (3.7 g/L, RR 0.8–4.0 g/L) and IgM (1.1 g/L, RR 0.4–2.4 g/L) were unremarkable. The patient’s antinuclear antibody (ANA) revealed speckled staining (negative centromere) with an antibody titre of 1:320. Her extractable nuclear antigen screen was negative. The immunofluoresence for antineutrophil cystoplasmic antibodies (ANCA) was not interpretable due to the high background ANA positivity. The patient’s double-stranded DNA (Farr assay), myeloperoxidase antibodies and proteinase 3 antibodies were negative.

Rheumatoid factor (<10 kIU/L, RR <15 kIUL), anticyclic citrullinated peptide (<10 U, RR <20 U), anticardiolipin IgG (<4 GPL, RR <20 GPL) and anticardiolipin IgM (<4 MPL, RR <20 MPL) were negative. The patient’s IgG subclasses and cryoglobulin screens were unremarkable. Her lactate dehydrogenase, serum protein electrophoresis and serum-free light chains were unremarkable. Lymphocyte subset analysis revealed normal immunophenotype with absolute counts of CD4+ 832 × 10⁶/L (RR 500–1650 × 10⁶/L), CD8+ 331 × 10⁶/L (210–1200 × 10⁶/L), CD3+ 1166 × 10⁶/L (RR 780–2600 × 10⁶/L), CD19+ 141 × 10⁶/L (RR 80–600 × 10⁶/L) and CD16+/CD56+ 359 × 10⁶/L (40–500 × 10 10⁶/L). Antiphospholipase A2 receptor (PLA2R) and antithrombospondin type 1 domain-containing 7A (TSH7DA) antibodies were negative. Extended myositis autoantibody and antineuronal panels were unremarkable.

The patient’s echocardiogram revealed atrial fibrillation, patent foramen ovale and mild-to-moderate tricuspid regurgitation. There was no echocardiographic evidence of infective endocarditis, thrombosis or ventricular dysfunction. A subsequent cardiac MRI excluded myocardial oedema, infiltration and coronary artery disease. The patient’s CT thoracic and abdominal aortogram excluded significant large vessel atherosclerotic plaque and arterial thrombosis. Vascular imaging did not show changes of large or medium vessel inflammation, such as microaneurysms, stenosis or vessel wall thickening.

MRI scan of the abdominal and lower limb arteries excluded venous and arterial stenoses, thromboses and microvascular disease. Multiple investigations were requested to evaluate for occult malignancy. The patient’s mammography and cervical screen were unremarkable. A contrast-enhanced CT chest, abdomen and pelvis excluded masses, lymphadenopathy and bony lesions, and her whole-body scintiscan did not reveal any scintigraphic evidence of localised or metastatic malignancy. A gastroscopy revealed candidiasis of the upper two-thirds of the oesophagus without mucocutaneous ulceration or masses and her colonoscopy was unremarkable. There was no clinical, biochemical or radiological evidence of lymphoproliferative disease.

The patient’s CSF revealed elevated protein (1.29 g/L, RR 0.15–0.45 g/L) with normal glucose and without white blood cells or dysplastic cells. CSF culture did not yield any growth. Her NCS were significant for absent peroneal motor response, slowed motor conduction and prolonged distal motor latencies in the lower limb nerves, and absent digital sensory potentials. Her needle EMG revealed neurogenic changes in the distal upper limb muscles and the muscles innervated by the right L5 myotome.

The patient’s renal biopsy revealed 18 glomeruli (2 sclerosed) with thickened membrane containing craters and normal tubulointerstitium, arteries and arterioles. The Sirius red stain for amyloid was negative. Direct immunofluorescence revealed fine granular membranous IgG (2+) staining (figure 3) and negative staining for IgM, IgA, C3, C1q and anti-PLA2R antibodies. The electron microscopy confirmed subepithelial deposits with resorptive changes and moderate podocyte foot effacement (figure 4).

Figure 3.

Renal histology: direct immunofluorescence showing IgG positivity (2+) in fine granular membranous distribution.

Figure 4.

Renal histology: electron microscopy showing subepithelial deposits (arrows) with resorptive changes (stars) and moderate podocyte foot effacement.

The patient’s left quadriceps muscle biopsy revealed denervation without reinnervation. The left sural nerve biopsy revealed concentric fibrous intimal thickening of the small arteries and arterioles, proliferation of capillaries within the epineurium, perineurium and endoneurium with lymphocytic infiltration in some fascicles, and thickened perineural sheath of individual fascicles with myxoid areas (figure 5). The Congo stain for amyloid was negative and immunohistochemistry confirmed CD3-positive T-cell infiltration with perivascular attenuation (figure 6).

Figure 5.

Sural nerve histology: transverse section of nerve showing patchy, mainly perivascular lymphocytic inflammation and a single blood vessel with marked swelling of endothelial cells and lymphocytic infiltration.

Figure 6.

Sural nerve histology: CD3 immunohistochemistry showing epineural T-cell infiltrate with perivascular cuffing.

Differential diagnosis

The initial differential diagnoses were infective endocarditis with cardiac embolism or large vessel artery–artery thromboembolism. These were excluded by microbiological testing, echocardiogram, and CT and MRI arteriograms. ANCA-associated vasculitis and IgA nephropathy (or IgA vasculitis) subsequently became the chief differential diagnoses, given the patient’s lower limb rash, bilateral lower oedema and active urinary sediment.

Cryoglobulinaemia, amyloidosis and systemic lupus erythematosus were deemed less likely. A diagnostic renal biopsy was requested due to the non-diagnostic non-invasive immunological screen. The histological exclusion of renal vasculitis and diagnosis of membranous nephropathy was unexpected. The anti-PLA2R and anti-TSH7DA titres were negative, which raised the possibility of secondary disease.

The treating team were concerned about occult malignancy and paraneoplastic syndrome; however, these were deemed less likely after extensive investigations. A diagnostic peripheral nerve biopsy was requested to clarify the neurological diagnosis, revealing small vessel vasculitic neuropathy. Following multidisciplinary team discussion, administration of high-dose intravenous methylprednisolone followed by induction therapy with rituximab was deemed the most appropriate course of treatment.

Treatment

Optimised supportive care was considered following the diagnosis of idiopathic membranous nephropathy; however, neither angiotensin-converting enzyme inhibitor nor angiotensin receptor blockade therapy could be initiated due to symptomatic hypotension (systolic blood pressure range 90–100 mm Hg). Given the patient’s normal immunophenotype and unremarkable immunology screen, the patient’s oesophageal candidiasis was deemed secondary to broad-spectrum antibiotic exposure. This was successfully treated with a short course of oral nystatin.

Systemic immunosuppression was not empirically commenced until the completion of multiple investigations to exclude occult malignancy. Following the exclusion of occult malignancy and histological confirmation of mononeuritis multiplex secondary to small vessel vasculitis, the patient received intravenous methylprednisolone 1 g daily for five doses.

The patient subsequently received two doses of intravenous rituximab 1 g 2 weeks apart. High-dose oral glucocorticoid therapy was not coprescribed, given the risk of secondary infection of her left-sided calf ulcer or right-sided necrotic toes. She received 6 months of low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis.

Outcome and follow-up

The patient’s left-sided ischaemic toes, left-sided calf ulcer and peripheral neurological signs resolved 6 months post rituximab induction therapy. She subsequently commenced maintenance therapy 6 months post rituximab with oral methotrexate 20 mg one time per week. The patient’s idiopathic membranous nephropathy entered complete remission 7 months post rituximab. Her immunoglobulins were monitored 3 monthly and there was no evidence of immunoparesis.

The patient’s lymphocyte subsets revealed CD19+ cell suppression (2×10⁶/L, RR 80–600 × 10⁶/L) 4 weeks post rituximab with repopulation (40×10⁶/L, RR 80–600 × 10⁶/L) 12 months later. Both the patient’s mononeuritis multiplex secondary to small vessel vasculitis and idiopathic membranous nephropathy remain in complete remission 30 months post initiation of immunosuppressive therapy. No clinical or radiological evidence of malignancy has been detected at the time of writing this article.

Discussion

An estimated 70% of membranous nephropathy is immune mediated (primary); a significant portion (60%–70%) of which are anti-PLA2R antibody positive followed by a smaller portion (5%–10%) that are anti-TSH7DA positive.⁴ A number of antipodocyte antibodies have also been associated with secondary membranous nephropathy, including anti-NEP, anti-NELL-1, anti-exotosin-1, anti-exotosin-2 and anti-semaphorin 3B.^{4 5}

An estimated 30% of membranous nephropathy is secondary to systemic conditions; of which systemic lupus erythematosus, chronic hepatitis B virus infection, medications and malignancy are the most commonly described associations.⁴ Malignancy is associated with 10% of secondary membranous nephropathy, which is typically diagnosed at a median age of 67 years, with one-fifth of these cases preceding, and one-fifth following, the confirmation of malignancy.⁴

De novo membranous nephropathy has been reported in patients with acute inflammatory polyradiculopathy and chronic inflammatory polyradiculopathy.^6–12 Mononeuritis multiplex is a presenting feature in 25%–30% of classic polyarteritis nodosa and 30%–50% of ANCA-associated vasculitis with histology typically revealing fibrinoid necrosis.¹ Idiopathic small vessel vasculitis accounts for less than 10% of all vasculitic neuropathies and it is a rare cause of mononeuritis multiplex.^1–3

De novo vasculitis following the diagnosis of membranous nephropathy has been reported; however, cases are renal limited, typically present as crescentic glomerulonephritis, and are associated with de novo ANCA or anti-GBM antibody positivity.^{4 13–16} This is the first case report to document the synchronous occurrence of mononeuritis multiplex secondary to small vessel vasculitis and idiopathic membranous nephropathy, and the subsequent achievement of complete remission with rituximab.

A postulated mechanism for systemic immunological disorders following membranous nephropathy is the exposure of glomerular podocyte, endothelial and basement membrane proteins to immune system detection and subsequent attack.^{15 16} It is unclear whether the association documented in this case report ought to be interpreted through Occam’s razor; a new immunological syndrome or by Hickam’s dictum; two unrelated idiopathic immunological disorders occurring simultaneously.

Patient’s perspective.

One day I felt something dripping down the side of my left leg and I looked down to see some fluid coming out of my skin. It was just bubbling out of my skin and I could not see where it was coming from as there was no sore or anything and there was no pain. Also, at the same time my toes were changing colour and going purple. I was a bit anxious so I decided to see my GP and she sent me to hospital to see what was happening. I was admitted as they were not sure why the fluid was leaking, but they had also found my kidneys were leaking protein. The next morning, we were all horrified to see my toes had turned black overnight. I was not a diabetic so they could not understand why that had happened. The toes went black and stayed black and caused the most excruciating pain I have ever experienced. I became worried as my symptoms seem to get worse and I just wanted to know what was going on. It was an incredibly difficult time for me due to the loss of my independence and particularly not being able to work as a Swimming Instructor. Finally, a diagnosis and treatment with rituximab came as relief to heal my kidneys and my toes also started to heal. During the last couple of years; I have been concerned and frustrated regarding what was happening to my body, and am grateful for the doctors who have been monitoring me. I want to get fit again and get back to teaching swimming again on a regular basis.

Learning points.

• Infective endocarditis, arterial thromboembolism and autoimmune disease should be considered in patients presenting with multiorgan illness.

• There is an increasing number of novel antipodocyte antibodies associated with immune-mediated membranous nephropathy.

• Twenty per cent of malignancy-associated secondary membranous nephropathy presents prior to, and 20% present after, the diagnosis of malignancy.

• Excisional biopsies are crucial to investigate vasculitic neuropathy with inconclusive non-invasive screening.

• Infection and malignancy must be excluded prior to the commencement of immunosuppressive therapy for multisystem inflammatory disorders.

Ethics statements

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