Introduction

Fibrillary Glomerulonephritis (GN) is a disease affecting the filtering components, called glomerulus, in the kidney causing thin thread-like structures to build up and prevent the removal of waste from the blood. Over time fibrillary GN leads to swelling mediated by the immune system (inflammation) and scarring, impeding the functionality of the kidneys. 

Early and effective treatment is essential in preventing kidney failure.¹ This article aims to explore the effectiveness of immunosuppressive therapy, a treatment which lowers the activity of the immune system to prevent inflammation, in treating fibrillary GN and preventing long-term complications.

Understanding fibrillary glomerulonephritis

Pathophysiology

The unusual accumulation of thread-like fibril formations in the kidney's glomeruli, which are responsible for filtration, is a defining feature of fibrillary glomerulonephritis. As these fibrils build up within the glomerular basement membrane, mesangium, and tubulointerstitial spaces of the kidney, they increasingly disturb the normal filtration barrier.

This barrier allows water and small soluble molecules such as electrolytes and urea to be filtered out of the blood without large proteins from the plasma entering the urine. Plasma proteins in the urine are detrimental to the kidneys due to their size and result in glomerular injury.²

The exact mechanism of fibril buildup is unknown, however, there are three associated conditions which increase susceptibility:

1. Autoimmune diseases, such as systemic lupus erythematosus
2. Infections, such as hepatitis C
3. Malignancies, such as lymphomas

When fibrils are present, they attract the attention of the immune system. This elicits inflammation, the process by which immune cells are sent to a site of damage or infection by chemical signals released by the site to promote healing. However, constant inflammation caused by the persistence of fibrils in the glomeruli can cause damage to the glomeruli, rather than the intended healing. Chemical signals continue to be produced in the glomeruli where fibrils are present, further causing inflammation and worsening damage.

Clinical presentation and symptoms

Patients with fibrillary GN often present with the following symptoms:¹

• Haematuria: blood in the urine
• Proteinuria: urine with a “foamy” appearance caused by protein buildup
• Renal insufficiency: decreased kidney function 
• Hypertension: increased blood pressure

Diagnosis

The first evidence suggesting kidney damage is abnormal blood and urine samples. This prompts your physician to undertake a kidney biopsy, examine it under a microscope and allow an accurate diagnosis. This also eliminates other causes of unexpected biological sample test results, such as autoimmune conditions and cancer. 

Imaging direct samples of the kidneys allows the visualisation of the cause of the symptoms. Fibrillary GN patients show randomly arranged thin thread-like structures in their glomerulus, often coinciding with larger appearing glomerulus due to the inflammation.³

Overview of immunosuppressive therapy

Immunosuppressive therapy works by using medications to dampen or prevent the activation of the immune system, stopping unsolicited and unnecessary reactions. As a result of its suppressive nature, immunosuppressive therapy is often used to treat autoimmune diseases and prevent rejections after organ transplants. However, immunosuppressive therapy is also useful in other conditions, such as fibrillary GN, where the immune system plays a role in disease occurrence and progression.

There are several types of immunosuppressive drugs, targeting different cells at different stages of the immune system response:⁴

1. Corticosteroids: Directly inhibit inflammation and prevent the release of chemical signals called cytokines responsible for recruiting immune cells to the site of the target.
2. Calcineurin inhibitors: Block the activation of the white blood cells which directly target sites of infection called T cells through calcineurin, a molecule which speeds up and facilitates inflammation.
3. Antimetabolites: Stop the DNA in immune cells from dividing to slow down the process of inflammation.
4. mTOR inhibitors: Prevent T cells from replicating therefore slowing down inflammation.
5. Biologics: Specific molecules called monoclonal antibodies to bind to immune B cells to reduce their activity and therefore slow inflammation.

Immunosuppressive therapy in fibrillary GN 

Since fibrillary GN involves immune-mediated damage to the glomeruli of the kidneys, immunosuppressive therapy is a feasible option to reduce this immune response, slow the disease progression and prevent complications. However, the type of immunosuppressive therapy administered depends on several factors such as the patient, the severity of their disease, and their responsiveness to other treatments. 

Corticosteroids, such as prednisone, are often used as the first-line immunosuppressive therapy in fibrillary GN patients due to their fast-acting and quick-onset effects, reducing symptoms as soon as 6 hours after administration. Calcineurin inhibitors and antimetabolites are often administered alongside corticosteroids, where the reaction to the medication is insufficient, to further suppress inflammation and stabilise kidney function.⁵

Recent studies have shown the increased effectiveness of rituximab, a biological immunosuppressive therapy, in the treatment of fibrillary GN. Specifically, rituximab has shown an increased effectiveness in relieving proteinuria (proteins in urine), furthering the preservation of kidney function with limited side effects, therefore preventing kidney failure.⁶

Safety and side effects

Despite the effectiveness of immunosuppressive therapy, these medications often have side effects:⁴

• Corticosteroids: Weight gain, increased blood pressure, diabetes
• Calcineurin inhibitors: Medication-mediated kidney damage called nephrotoxicity, increased blood pressure
• Antimetabolites: Gastrointestinal symptoms
• mTOR inhibitors: Bone marrow suppression prevents the generation of immune cells and therefore leads to increased susceptibility to infections
• Biologics: Infusion reactions, infections

Despite this, these side effects are easily managed by monitoring, switching to a different immunosuppressive treatment or using an alternative therapy.

Alternative and adjunctive therapies

There is currently no standard care of treatment for fibrillary GN patients. However, if immunosuppressive therapies are ineffective patients are often prescribed angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), which lower blood pressure and relieve some fibrillary GN symptoms. 

Summary

• Fibrillary GN is a kidney disease where abnormal fibrils accumulate in the glomeruli, leading to inflammation and scarring, which impedes kidney function and can result in kidney failure if untreated
• The exact cause of fibril buildup is unknown but is associated with autoimmune diseases, infections, and malignancies. These fibrils attract immune cells, causing chronic inflammation and damage to the glomeruli
• Symptoms include haematuria, proteinuria, renal insufficiency, and hypertension. Diagnosis is confirmed through blood and urine tests, followed by a kidney biopsy showing the characteristic fibrils
• Immunosuppressive therapy involves drugs that suppress the immune system, reducing inflammation and immune-mediated damage. Types of immunosuppressive drugs include corticosteroids, calcineurin inhibitors, antimetabolites, mTOR inhibitors, and biologics
• Corticosteroids are often the first line of treatment, sometimes combined with calcineurin inhibitors and antimetabolites. Rituximab, a biologic, has shown promise in reducing proteinuria and preserving kidney function with minimal side effects
• Immunosuppressive drugs can have side effects, such as weight gain, high blood pressure, diabetes, nephrotoxicity, gastrointestinal symptoms, bone marrow suppression, and infections. These side effects are managed through monitoring and adjusting treatments. Alternative therapies, like ACE inhibitors or ARB, may also be used if immunosuppressive therapies are ineffective