Fibrillary glomerulonephritis in a patient with systemic lupus erythematosus with no evidence of lupus nephritis

Abstract

Fibrillary glomerulonephritis (FGN) is a rare proliferative form of glomerular disease characterised by randomly oriented fibrillary deposits with a mean diameter of 20 nm. It has a rare association with systemic lupus erythematosus (SLE). We report the case of a female in her mid-50's with a 20 year history of SLE, who developed proteinuria due to FGN and had no histological evidence of lupus nephritis. She was maintained on azathioprine and prednisolone. A renal biopsy revealed randomly arranged fibrillary deposits that positively stained for DNAJB9, consistent with a diagnosis of FGN. Azathioprine was switched to mycophenolate mofetil, and the patient showed significant improvement in proteinuria. This case-based review describes the diagnosis, management and clinical outcome of FGN in association with SLE in the absence of lupus nephritis.

Background

Fibrillary glomerulonephritis (FGN) is a rare form of immune-mediated glomerulonephritis. Renal biopsy findings of organised, randomly oriented, non-branching electron-dense fibrils with a mean diameter of 20 nm (range 15–25 nm) are diagnostic of this condition. Immunofluorescence stains positive for IgG, C3, κ and λ, suggesting a mix of antibodies and antigens largely confined to glomeruli. Biopsies also stain negative for Congo red, which distinguishes this condition from amyloidosis. The incidence of FGN in native biopsies has been found to be less than 1%.¹

DNAJB9, a protein involved in the stress response of endoplasmic reticulum, has been found to be highly concentrated in the glomerular capillary and mesangium of patients with FGN. Staining for DNAJB9 was found to have a sensitivity of 98% and a specificity of 99% for the diagnosis of FGN.² The majority of patients diagnosed with FGN are idiopathic, but the association of FGN with pre-existing autoimmune conditions has been reported to be between 5% and 14%.¹

Here we report a patient diagnosed with FGN following presentation of worsening proteinuria and a background of SLE and no evidence of lupus nephritis. The patient showed good response to mycophenolate mofetil (MMF) and a weaning regime of high-dose steroids.

Case presentation

A female patient in her mid-50s with a 20 year history of SLE with skin, joint and neurological involvement presented in late 2020 with new-onset proteinuria. She had no known previous renal involvement. SLE was stable and the disease activity score calculated using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 4 due to proteinuria. She was on azathioprine, hydroxychloroquine and prednisolone 5 mg once daily. She also had a background of diabetes mellitus, hypertension and ischaemic heart disease.

Proteinuria was quantified using a spot urine protein creatinine ratio (PCR) at 246 mg/mmol (approximately 2.5 g of proteinuria per day). She had a serum creatinine of 73 mmol/L and an estimated glomerular filtration rate (eGFR) of 85 mL/min/1.73 m², according to the CKD-EPI method of calculation. Anti-nuclear antibodies quantified using ELISA were positive at low levels of 1.9 (normal ratio <1.0); serum C3 and C4 levels were normal at 1.34 and 0.27 g/L, respectively. Anti-neutrophilic cytoplasmic antibodies, anti-dsDNA antibodies and anti-phospholipase A2 receptor antibodies were negative.

Initial differentials included diabetic nephropathy and lupus nephritis. A renal biopsy under light microscopy showed glomeruli with segmental to near global mesangial matrix increase and mesangial hypercellularity. There was no interstitial fibrosis or tubular atrophy. There were rare spikes on silver stain, but no evidence of capillary wall thickening, endocapillary proliferation or crescents. Immunohistochemistry revealed diffuse granular positivity of capillary walls and mesangium for IgG1, IgG4, C3 and C1q. There was a strong stain for DNAJB9 (figure 1) in the capillary walls and mesangium. Congo red staining was negative. Electron microscopy showed diffuse foot process effacement and deposition of numerous randomly oriented and arranged fibrils that measured between 11.9 and 20 nm (figure 2). There was no evidence of discrete electron-dense immune-type deposits, thereby ruling out the involvement of SLE. A diagnosis of fibrillary glomerulonephritis was made.

Figure 1.

Immunohistochemical staining for DNAJB9 is strongly positive in the mesangial matrix (original magnification x400).

Figure 2.

Electron microscopy shows transmembrane deposits of randomly arranged fibrils measuring a mean diameter of 20 nm (original magnification x25 000).

Treatment

The patient was switched from azathioprine to MMF at a maximum tolerated dose of 1000 mg two times per day. Prednisolone dosage was increased to 40 mg for 4 weeks and then tapered down to a maintenance of 5 mg once daily.

Outcome and follow-up

The patient showed very good response to the treatment, but achieved partial remission at the time of her last follow-up. Her urine PCR improved to 47 mg/mmol (approximately 0.5 g of proteinuria per day). Her serum creatinine was 76 mmol/L and eGFR was 76 mL/min/1.73 m². She is continuing on regular follow-up with no further worsening of proteinuria or renal function.

Discussion

FGN is thought to be a rare immune-mediated glomerulopathy with poor prognosis and can be diagnosed exclusively through renal biopsy, showing Congo red-negative, electron-dense fibrillary deposits in the mesangium and the glomerular basement membrane. The fibrils are approximately 12–24 nm (mean 20 nm) in diameter.^{1 3} The understanding of its pathogenesis is limited. DNAJB9, a 223-amino-acid member of the DNAJ family of proteins, was recently discovered and found to be most abundant in the FGN glomerular proteome. Although it is unclear how DNAJB9 produces fibrils, an autoimmune process with DNAJB9 acting as a putative auto-antigen has been suggested.⁴

FGN has been associated with five different histological patterns of glomerular involvement by light microscopy.⁵ The mesangioproliferative pattern has been the most common pattern reported so far.^{2 6 7} This is characterised by solely mesangial proliferation and expansion in the absence of involvement of the glomerular capillary lumen. Other histological patterns include membranoproliferative, membranous, diffuse proliferative and diffuse sclerosing patterns. Our patient had a mesangioproliferative pattern.

FGN has an association with hepatitis C, malignancies, diabetes mellitus and autoimmune disorders.¹ The association of autoimmune disorders with FGN in three large studies was reported between 5% and 14% (average 11%). Examples of autoimmune diseases in patients with FGN include Crohn’s disease, lupus, Grave’s disease and idiopathic thrombocytopenic purpura.2 5 6 8 The literature on associations of SLE with FGN is limited. The Mayo Clinic reported two SLE patients in their cohort of 66 patients with FGN.⁶ Rosenstock et al reported one patient with SLE from their case series of 67 patients.⁵ None of those patients had evidence of lupus nephritis in the biopsies. In these cohorts, there was no description of disease activity or histological patterns specific to SLE. To our knowledge, apart from these cases, only four other cases of FGN associated with SLE have been reported.^9–11

There is limited data to suggest optimal therapy for FGN; as a result, there is no guideline on how to treat these patients. The prognosis of patients with FGN remains poor with approximately 50% of patients reaching end-stage renal disease (ESRD) within 5 years from diagnosis despite immunosuppressive therapy.^{5 6 12} Various regimes, including high-dose steroids alone or in combination with additional agents such as cyclophosphamide, cyclosporine or rituximab, have been used in reported cases.^{5 6 8} Conclusions regarding immunosuppressive therapy cannot be drawn from these limited data, although rituximab may offer benefit in patients with FGN, particularly those with relatively normal baseline renal function.¹³ With regard to MMF, there is also paucity of data. Six patients from the Mayo Clinic and one from the University of North Carolina were given MMF.^{6 8} It is not clear from the literature whether it was given as monotherapy or in combination with high-dose steroids. An SLE patient from the Mayo Clinic achieved partial remission on prednisolone and MMF.⁶ We adopted a similar approach in switching our patient’s azathioprine to a maximum tolerated dose of MMF at 1000 mg two times per day and increased her prednisolone to 40 mg once daily for 4 weeks. This was tapered down at 5 mg per week from the previous maintenance dose of 5 mg once daily. Within 3 months of commencing treatment, the patient achieved partial remission of proteinuria.

We conclude that FGN as a cause of renal involvement in SLE should be considered as a differential diagnosis. Although this is a rare association, it has implication on treatment and prognosis.

LEARNING POINTS

• The association between systemic lupus erythematosus and fibrillary glomerulonephritis is very rare but significant due to implications on treatment with immunosuppressive therapy.

• Fibrillary glomerulonephritis has a poor prognosis and so early recognition and management is very important.

• There are no guidelines on the management of fibrillary glomerulonephritis, and treatment is purely based on existing limited evidence; therefore, early consultation with a specialist clinician is recommended.

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