Overview 

What is fibrillary glomerulonephritis (FGN)?

Fibrillary glomerulonephritis (FGN), first depicted in 1977 by Eliakim and Rosenmannis a rare but severe glomerular disease characterised by the deposition of fibril proteins (ranging from 10-30 nm in diameter) at the site of the glomerulus.¹ These fibrils are Congo-red negative, non-amyloid proteins.² The protein deposition activates the immune system and causes inflammation and damages the structure of the glomerulus, ultimately slowing down the filtration rate of the kidney. As the disease progresses, large amounts of protein are excreted into the urine, and the kidneys lose their ability to filter the blood.²

The real cause of disease is still unknown, but most of the time it is due to a primary disease such as autoimmune disorder, cancer, hepatitis C, hypertension, or diabetes. It mostly affects people aged between 40-60 years.³ It is usually diagnosed by kidney biopsies, and its clinical symptoms are haematuria, proteinuria, hypertension, swelling in legs and feet, insufficient kidney function, and about 50% of patients progress to end-stage kidney disease.¹

What is rituximab?

Rituximab is a CD20 monoclonal antibody that was first approved in 1977 by the FDA for the treatment of cancer. Since then, it has been used to treat various types of B-cell lymphomas.

It targets CD20, a protein that is found specifically on B-lymphocyte cells.⁴ The binding of rituximab to CD20 results in lysis of lymphocytes. Lysis of cells can be done by 3 mechanisms:⁴

• Antibody dependent cytotoxicity
• Complement dependent cytotoxicity 
• Apoptosis 

It is used to treat non-hodgkin’s lymphomas, leukemias, rheumatoid arthritis, granulomatosis, polyangiitis, and pemphigus vulgaris.⁵ It is also used in myasthenia gravis as an off-label drug.⁶ 

Key Points

• Pathological findings of fibrillary glomerulonephritis
• Etiology of disease
• What are the diagnostic tests of FGN?
• Treatment options for fibrillary glomerulonephritis
• Role of rituximab in fibrillary glomerulonephritis 
• Case studies and clinical trials of rituximab therapy

Pathological finding of fibrillary glomerulonephritis 

The pathological finding of FGN includes non-amyloid fibril deposition (abnormal protein fibers that do not have the structure of amyloid deposits), ranging from 12-24 nm in diameter. A heat shock protein named DNAJB9 (a type of protective protein that helps cells deal with stress)  is also found in patients with FGN. Most cases are congo-red negative, deposition of IgG antibodies (immune system proteins that help fight infections) and extraglomerular immune systems can also be seen in patients.⁷ Light microscopy shows proliferative mesangial and membranous GN (an abnormal increase in certain kidney cells and thickening of structures involved in filtering blood). 25% of renal biopsies show proliferative and inflamed cells in Bowman’s capsule. IgG, C3 and IgG4 (specific immune proteins) are present in immunofluorescence microscopy. A Small amount of IgA, IgM and C1q are also present.⁹ 

Etiology 

The etiology of FGN is still idiopathic. However, some studies show it is caused by the accumulation of fibril protein in glomerulus resulting in inflammation. Some underlying diseases like autoimmune disorders (grave’s disease, crohn’s disease, thrombocytopenia), cancer (leukemias, lymphomas), hepatitis C can also become the reason for the disease.³

Diagnostic test

Assessment of kidney function is done by routine lab tests, for example, a urine test and a blood test to analyse proteinuria or loss of blood. Other than lab tests, renal biopsy is performed to examine kidney tissue and identify the presence of disease. In case of fibrillary glomerulonephritis, deposition of fibrils is shown in the test. Electron microscopy is also used as a diagnostic tool to help in the assessment of the fibril’s type. Several other blood tests can also be done for the confirmation of diagnosis or comorbid condition.²

Treatment options for fibrillary glomerulonephritis 

There are no successful treatments available for fibrillary glomerulonephritis. Most of the time, treatment depends on the symptoms or underlying condition. Agents that are used previously to treat illness include steroids, immunosuppressants, cyclophosphamide, cyclosporine, and plasmapheresis.³ Plasmapheresis is a procedure to remove protein from the blood. Steroids are used most commonly for treatment with or without a second drug.² However, immunosuppressants do not show any benefit in the improvement of disease. If disease progresses to end stage kidney failure, the patient needs a dialysis or kidney transplant. In some cases, disease will relapse even after transplantation.⁸

Treatment of fibrillary glomerulonephritis with rituximab

Since other therapeutic options have failed to treat FGN successfully and their use is limited, rituximab proves to be an emerging approach and a better alternative therapy.  It reduces the progress of disease and decreases the chances of end-stage renal disease. Although its safety and efficacy are still unknown.¹⁰

How does rituximab work in fibrillary glomerulonephritis? 

Rituximab has beneficial effects for treating autoimmune disorders like FGN and transplant disorders. It is a genetically modified CD20 antibody that works by removing B-cells from blood. CD20 is a protein present on the surface of B-cells (mature and immature cells), which helps in the production and differentiation of B-cells. Binding of rituximab to CD20 on the cell surface results in depletion of B-cells in blood.¹¹ 

Dosing of rituximab

Two doses of rituximab (1g IV dose each ) are given to patients at the beginning of therapy, with the same dosing is repeated at the interval of 6 months.¹⁰

Adverse effects 

Nasal congestion, fatigue, and muscle cramps; no potent adverse effects are reported with use of rituximab.¹⁰

Contraindications of rituximab

Rituximab is contraindicated in the following conditions, including:

• Patient who have active or severe infection
• Immunocompromised patient
• Hypersensitivity to drug or murine protein
• Cardiac problem or heart failure⁶

Comparison of rituximab with other therapies

A study shows that rituximab is a promising approach to treat FGN. Treatment with rituximab shows a rapid reduction in proteinuria level, and it increases the duration of relapse. It is used as an alternative in patients who fail to tolerate other therapies like immunosuppressants and steroids.¹²

A clinical trial of 12 patients in which rituximab is given as a therapy, out of which 4 patients get beneficial effects of the drug. Patients with glomerular crescent should be treated with cyclophosphamide rather than rituximab. Rituximab is also used with steroids to produce more effective results.¹³

Case study and clinical trial of rituximab therapy

In 2021, a study was conducted; it was a 12-month pilot study to assess the safety and efficacy of rituximab in fibrillary glomerulonephritis also to evaluate the effect of rituximab on DNAJB9 levels. In this trial, 1g dosing of rituximab was given to patients at the beginning and a repeat at the interval of 6 months. After the completion of the time period, the result came out to be, which shows a reduction in proteinuria level;  the clearance level did not show any significant change. There is no effect of rituximab on DNAJB9 level. However, rituximab therapy stabilises kidney function.¹⁰

Another clinical trial was conducted in 2008; 3 patients having FGN were treated with rituximab and antiproteinuric therapy. The result shows a decrease in proteinuria level, and kidney function was also maintained. Moreover, no side effects are shown in those patients throughout the treatment. Thus, this clinical trial proves that rituximab is considered as a good choice of drug.¹⁴

Summary 

Fibrillary glomerulonephritis (FGN), first described by Eliakim and Rosenmann in 1977. It is a rare but severe kidney disorder in which fibril protein deposits at the site of the glomerulus and makes it inflamed. Fibrils are non-amyloid and congo-red negative, causing damage to the kidney. The etiology of fibrillary glomerulonephritis is still unknown. However, some studies suggest that it is caused due to the underlying disorders like autoimmune diseases, cancers, hepatitis C, and more. White people are more prone to disease; it can be diagnosed by kidney biopsies. The main signs and symptoms of FGN are proteinuria, haematuria, and hypertension; if the disease progresses, it may lead to end-stage kidney disease. Steroids and immunosuppressants are used as treatment options, but their success rate is limited. Currently, rituximab is considered as the new approach to treat FGN; it works by depletion of B–cells, and studies also show positive results. When patients are treated with rituximab, there is a rapid reduction in proteinuria, and kidney function becomes stable. It slows down the progression of disease, but further research is going on to evaluate its safety and efficacy.

FAQs

How does B-cell depletion reduce disease?

B-cells depletion reduces the symptoms of autoimmune disorder.

What is the marker of the disease fibrillary glomerulonephritis?

DNAJB9 is the marker of FGN disease.

What is DNAJB9 and its function?

DNAJB9 is an amino acid protein belonging to the DNAJ family of chaperones. Its function is to regulate the cell processes with the help of heat shock protein.

What to check before starting rituximab therapy?

Check the antibody level in the blood before starting the rituximab therapy.