Is Rituximab Used for RPGN? An Evolving Role in Rapidly Progressive Glomerulonephritis

October 12, 2025 •

5 min read

Historically, the management of rapidly progressive glomerulonephritis (RPGN) relied on broad-spectrum immunosuppressants, like cyclophosphamide and corticosteroids. The emergence of targeted therapies, including the anti-CD20 monoclonal antibody rituximab, has introduced a new treatment paradigm for certain forms of the disease, prompting the question: Is rituximab used for RPGN?.

Quick Summary

Rituximab is used for specific types of rapidly progressive glomerulonephritis, notably ANCA-associated vasculitis, where it is a standard of care for inducing and maintaining remission. Its role varies by underlying disease and is often reserved for refractory cases or when standard therapies are contraindicated.

Key Points

Standard Therapy for ANCA-Associated Vasculitis: Rituximab is a primary and effective treatment for RPGN caused by ANCA-associated vasculitis, used for both inducing and maintaining remission.
Superior for Relapse Prevention: In AAV, rituximab has demonstrated superiority over traditional agents like azathioprine for preventing relapses during maintenance therapy.
Targeted Action on B-Cells: Rituximab works by specifically depleting B-cells, thereby reducing the production of autoantibodies and mitigating the autoimmune response.
Evidence Varies by RPGN Cause: The effectiveness of rituximab is highly dependent on the underlying cause of RPGN, with robust data for AAV but weaker, less consistent evidence for conditions like anti-GBM disease or as initial therapy for lupus nephritis.
Important for Refractory Cases: For RPGN secondary to lupus nephritis, where initial trials were negative, rituximab is a valuable option for patients who do not respond to standard treatment.
Potential for Non-Immune Effects: Beyond B-cell depletion, rituximab may have direct, protective effects on the kidney's podocytes, which can help reduce proteinuria.
Careful Side Effect Monitoring: Potential side effects include infusion reactions and an increased risk of serious infections, necessitating careful patient monitoring and consideration of prophylaxis.

The Evolving Role of Rituximab in RPGN

Rapidly progressive glomerulonephritis (RPGN) is a severe kidney condition characterized by a rapid decline in renal function over days to weeks. It is a complex syndrome with various underlying causes, most of which are autoimmune in nature. The treatment approach for RPGN is highly dependent on the specific type and severity of the disease. While traditional immunosuppressants have been the mainstay of therapy, rituximab, a monoclonal antibody, has emerged as a key treatment for certain RPGN subtypes due to its targeted action on B-cells.

Is Rituximab Used for RPGN? The Role in Different Subtypes

The applicability of rituximab in treating RPGN is not universal; its use is guided by the specific cause of the kidney injury. The following are some of the key RPGN subtypes and rituximab's role within them.

RPGN Due to ANCA-Associated Vasculitis (AAV)

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a leading cause of RPGN. The B-cells in AAV produce pathogenic ANCA autoantibodies that play a crucial role in disease development. For this reason, rituximab, a B-cell depleting agent, has been extensively studied and is a cornerstone of therapy.

Remission Induction: Landmark trials like the RAVE study demonstrated that rituximab is non-inferior to cyclophosphamide for inducing remission in AAV. It is now a first-line treatment option, used in combination with glucocorticoids.
Remission Maintenance: Rituximab has shown superior efficacy over azathioprine for maintaining remission in AAV, especially in patients with relapsing disease. This has made it a preferred choice for long-term management.
Kidney-Specific Outcomes: Studies focusing on severe renal involvement in AAV have found rituximab to be as effective as cyclophosphamide for remission induction in maintaining kidney function.

RPGN Due to Anti-Glomerular Basement Membrane (Anti-GBM) Disease

Anti-GBM disease, which includes Goodpasture syndrome, is a rare but severe cause of RPGN. It is characterized by antibodies directed against the glomerular basement membrane. Standard treatment involves plasmapheresis, corticosteroids, and cyclophosphamide.

Limited Evidence: The evidence for rituximab in anti-GBM disease is limited to case reports and small studies. While it has been shown to reduce anti-GBM antibody titers and can improve pulmonary outcomes, its effect on renal function is less consistent, especially in cases with severe kidney injury at presentation.
Not a First-Line Agent: Due to the scarcity of data, rituximab is not recommended as a first-line therapy for anti-GBM disease and should not be used as a stand-alone treatment. It may be considered as an add-on or rescue therapy for refractory cases, but this remains an off-label use.

RPGN Secondary to Lupus Nephritis

Systemic lupus erythematosus (SLE) can cause severe kidney inflammation known as lupus nephritis (LN), which can sometimes present as RPGN. B-cell activation and autoantibody production are central to the pathogenesis of LN.

Contradictory Trial Results: The pivotal LUNAR trial failed to show a significant difference in renal response rates between rituximab and placebo for induction therapy in proliferative LN. However, the trial design was criticized for using a highly effective background immunosuppression regimen, which may have obscured rituximab's effect.
Use in Refractory Cases: Despite the LUNAR trial's findings, observational studies and meta-analyses support the use of rituximab for refractory LN that has not responded to standard therapies. The 2024 KDIGO guidelines reflect this, not recommending it for initial therapy but mentioning its use in refractory cases.

Understanding Rituximab's Mechanism of Action

As an anti-CD20 monoclonal antibody, rituximab works by targeting B-cells, which are critical in autoimmune disease development. The mechanisms of action include:

Antibody-Dependent Cellular Cytotoxicity (ADCC): Rituximab binds to CD20 on B-cells, and the Fc portion of the antibody attracts immune effector cells, such as Natural Killer (NK) cells, leading to the destruction of the B-cell.
Complement-Dependent Cytotoxicity (CDC): The binding of rituximab to B-cells triggers the complement cascade, causing cell lysis.
Induction of Apoptosis: Rituximab can also directly induce programmed cell death in B-cells.
Non-Immunological Effects: Beyond B-cell depletion, rituximab may have direct, non-immunologic effects on podocytes, the specialized cells in the kidney's filtration barrier. It is thought to stabilize the podocyte cytoskeleton, which may help in reducing proteinuria in some conditions.

Current Evidence and Guidelines for Rituximab in RPGN

The therapeutic landscape for RPGN has evolved significantly with the introduction of biologics. Rituximab is now a standard-of-care agent for ANCA-associated vasculitis, particularly for maintenance therapy and relapsing disease. Its use in other forms of RPGN is less defined, though it serves as an important option for refractory cases. The following table compares rituximab to cyclophosphamide, a traditional immunosuppressant, in the context of ANCA-associated RPGN.


Feature	Rituximab in ANCA-Associated RPGN	Cyclophosphamide in ANCA-Associated RPGN
Effectiveness (Induction)	As effective (non-inferior) as cyclophosphamide for inducing remission, with a potentially better relapse profile.	Long-established efficacy for inducing remission, but associated with higher relapse rates.
Effectiveness (Maintenance)	Superior to azathioprine for maintaining remission, especially in relapsing disease.	Standard maintenance therapy has a lower relapse prevention rate compared to rituximab.
Mechanism of Action	Targets CD20 on B-cells, leading to specific B-cell depletion and reducing autoantibody production.	Non-specific cytotoxic agent that suppresses both B-cells and T-cells, with broader immunosuppression.
Side Effect Profile	Lower risk of long-term malignancy compared to cyclophosphamide. Risks include infusion reactions, infections, and rare serious conditions like PML.	Significant risk of infections, bone marrow suppression, and a higher long-term risk of malignancy due to cumulative dose.
Role in Therapy	First-line option for remission induction and preferred for maintenance, especially in relapsing disease.	First-line option for remission induction, particularly in severe cases, but less favored for long-term maintenance due to toxicity.

Conclusion

Rituximab has secured a definitive role in treating RPGN, particularly in cases stemming from ANCA-associated vasculitis. For these patients, it offers a targeted, effective, and often preferred treatment over traditional cytotoxic agents like cyclophosphamide, especially in preventing disease relapse. However, its application in other RPGN subtypes, such as anti-GBM disease and lupus nephritis, is more nuanced. In these conditions, it is typically reserved for refractory or relapsing cases or used in combination with other therapies due to less consistent evidence of efficacy as a primary agent. Continued research will further refine the optimal use, dosing, and long-term safety of rituximab for the various causes of RPGN.

For more detailed clinical practice guidelines on the use of rituximab and other treatments for vasculitis, consult authoritative sources such as the Johns Hopkins Vasculitis Center.

Frequently Asked Questions

Rituximab treats specific types of RPGN by depleting B-cells, which are immune cells that produce pathogenic autoantibodies. By binding to the CD20 antigen on the surface of B-cells, it triggers their destruction through several immune mechanisms, effectively halting the autoimmune attack on the kidneys.

No, rituximab is not always a first-line treatment for all types of RPGN. It is a standard first-line therapy for ANCA-associated vasculitis but is typically reserved for refractory or relapsing cases of other RPGN subtypes, like lupus nephritis.

For ANCA-associated RPGN, rituximab is considered as effective as cyclophosphamide for inducing remission, but it has shown to be superior for maintaining remission and has a more favorable long-term toxicity profile. Cyclophosphamide carries a higher cumulative risk of malignancy and other toxicities.

Common side effects include infusion-related reactions (fever, chills, rash), infections (respiratory or urinary tract), headache, and nausea. Serious but rare side effects include progressive multifocal leukoencephalopathy (PML), Hepatitis B reactivation, and severe allergic reactions.

Evidence for rituximab use in anti-GBM disease is limited and inconsistent. While it can reduce anti-GBM antibody levels, it does not reliably improve kidney function in severe cases and is not a recommended first-line treatment.

For lupus nephritis, rituximab is not typically used as an initial therapy due to inconsistent results in major trials. However, observational studies support its use and efficacy in cases that are refractory to standard immunosuppressive treatments.

For induction in AAV, rituximab is typically given as a series of infusions over a few weeks. For maintenance therapy, it is usually administered every 6 months, though dosing schedules can be adjusted based on the patient's response and specific center protocols.