Kidney disease affects millions worldwide, and its causes are varied, ranging from diabetes and hypertension to genetic conditions and infections. One critical player in the development and progression of many kidney diseases is the immune system. As a nephrologist with over 23 years of experience, I aim to explain how the immune system contributes to kidney disease and how treatments like immunosuppressant therapy and immunotherapy can help manage these conditions. This article is written for patients to provide clear, actionable insights into these complex processes.

The Immune System and Kidney Disease: How It All Begins

The immune system is your body’s defense mechanism, designed to protect against infections and harmful substances. However, when it malfunctions, it can mistakenly attack healthy tissues, including the kidneys, leading to inflammation and damage. This process is central to many kidney diseases, particularly those classified as immune-mediated.

Direct Immune-Mediated Kidney Diseases

In some kidney diseases, the immune system directly targets kidney tissues. For example:

• Anti-Glomerular Basement Membrane (GBM) Disease: The immune system produces antibodies that attack the glomerular basement membrane, a key structure in the kidney’s filtering units (glomeruli). This leads to rapid kidney damage and conditions like Goodpasture’s syndrome.
• Membranous Nephropathy: Autoantibodies target proteins in the glomeruli, causing protein leakage into the urine (proteinuria), which can progress to nephrotic syndrome.
• Focal Segmental Glomerulosclerosis (FSGS): Immune-related factors, including circulating proteins, may damage the glomeruli, leading to scarring and reduced kidney function.

Indirect Immune-Mediated Kidney Diseases

In other cases, the immune system contributes indirectly by triggering inflammation that harms the kidneys. Examples include:

• IgA Nephropathy: Abnormal immunoglobulin A (IgA) molecules deposit in the glomeruli, triggering inflammation and kidney damage. This is often linked to mucosal infections and immune overactivation.
• Lupus Nephritis: In systemic lupus erythematosus (SLE), the immune system produces antibodies that form complexes, depositing in the kidneys and causing inflammation.
• ANCA-Associated Vasculitis: Autoantibodies (antineutrophil cytoplasmic antibodies, or ANCA) attack small blood vessels in the kidneys, leading to severe inflammation and damage.

The kidneys also interact with the immune system in other ways. They produce immune-regulating substances, and kidney damage can lead to systemic inflammation, further worsening disease progression. For instance, chronic kidney disease (CKD) is often associated with elevated inflammatory markers like C-reactive protein and interleukin-6, which accelerate kidney damage.

Treatment Options: Immunosuppressant Therapy and Immunotherapy

Managing immune-mediated kidney diseases requires calming the overactive immune response or boosting the immune system’s ability to fight disease without harming the kidneys. Two key approaches are immunosuppressant therapy and immunotherapy. Below, I explain how these treatments work and when they are used.

Immunosuppressant Therapy

Immunosuppressant drugs reduce the immune system’s activity to prevent it from attacking the kidneys. These are commonly used in autoimmune kidney diseases and after kidney transplantation to prevent rejection. Key immunosuppressants include:

• Corticosteroids (e.g., Prednisone): These reduce inflammation and are often the first line of treatment for conditions like lupus nephritis and minimal change disease. They are highly effective but can cause side effects like weight gain, diabetes, and osteoporosis with long-term use.
• Cyclophosphamide: This drug suppresses immune cell activity and is used in severe cases of lupus nephritis or ANCA vasculitis. It is often given in cycles to minimize side effects like infection risk.
• Rituximab: A monoclonal antibody that targets B cells (which produce harmful antibodies), rituximab is effective in membranous nephropathy, lupus nephritis, and ANCA vasculitis. Trials like MAINRITSAN 3 have shown that extended rituximab use reduces relapse risk in vasculitis.
• Calcineurin Inhibitors (e.g., Tacrolimus, Cyclosporine): These drugs block T-cell activation and are used in conditions like FSGS and to prevent transplant rejection. However, they can be toxic to the kidneys with prolonged use.
• Azathioprine and MycophenolateMofetil: These are used for maintenance therapy in lupus nephritis and other conditions to keep the immune system in check with fewer side effects than cyclophosphamide.

When is it used?

Immunosuppressants are typically prescribed for active immune-mediated diseases with significant inflammation or proteinuria (e.g., >1 g/day). However, mild cases, such as early IgA nephropathy, may only require supportive care like blood pressure control with renin-angiotensin-aldosterone system (RAAS) blockers.

Challenges: Immunosuppressants increase infection risk and may cause other side effects. Balancing immune suppression with the need to maintain immune function is critical, especially in transplant patients where over-suppression can lead to malignancies like post-transplant lymphoproliferative disorders.

Immunotherapy

Immunotherapy enhances or modulates the immune system to treat kidney diseases, particularly in the context of kidney cancer or immune-related complications. It is less common in primary kidney diseases but has growing applications.

• Immune Checkpoint Inhibitors (ICIs): Drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) block proteins (PD-1/PD-L1 or CTLA-4) that cancer cells use to evade the immune system. These are used for advanced kidney cancer (renal cell carcinoma). For example, pembrolizumab, combined with axitinib, is a first-line treatment for metastatic kidney cancer, reducing tumor size and improving survival. However, ICIs can cause immune-related kidney injury, such as acute interstitial nephritis (AIN), which requires prompt corticosteroid treatment.
• Cytokines (e.g., Interleukin-2): These proteins boost the immune system and are used in specific cases of kidney cancer. They can shrink tumors but are less common today due to side effects.
• Emerging Therapies: New drugs like sibeprenlimab, which neutralizes APRIL (a protein involved in IgA nephropathy), are showing promise in clinical trials like the VISIONARY Phase II trial. These therapies target specific immune pathways to reduce harmful IgA production without broad immunosuppression.

When is it used?

Immunotherapy is primarily used for kidney cancer but is being explored for autoimmune kidney diseases like IgA nephropathy. In transplant patients, ICIs are challenging because they increase rejection risk by activating T cells, requiring careful immunosuppressive adjustments.

Challenges: ICIs can overactivate the immune system, leading to kidney injury (e.g., AIN, glomerulonephritis) in up to 5% of patients. Early recognition and treatment with corticosteroids are crucial to prevent permanent damage.

What Patients Should Know

1. Diagnosis is Key: If you have symptoms like blood in the urine, swelling, or high blood pressure, consult a nephrologist. Tests like kidney biopsies, blood tests (e.g., for ANCA or anti-GBM antibodies), and urine analysis help identify immune-mediated kidney diseases.
2. Personalized Treatment: Not all kidney diseases require immunosuppression or immunotherapy. Your doctor will tailor treatment based on the disease type, severity, and your overall health. For example, mild IgA nephropathy may only need lifestyle changes and RAAS blockers, while severe lupus nephritis may require aggressive immunosuppression.
3. Monitor Side Effects: Immunosuppressants and immunotherapies can cause side effects like infections, diabetes, or kidney injury. Report symptoms like fever, fatigue, or reduced urine output to your doctor immediately.
4. Lifestyle Matters: A low-salt diet, regular exercise, and avoiding smoking can reduce kidney inflammation and improve treatment outcomes. Always discuss dietary changes with your doctor, especially if you have proteinuria.
5. Stay Informed: Ask your nephrologist about clinical trials for new therapies like sibeprenlimab or atrasentan, which may offer targeted treatment with fewer side effects.

Conclusion

The immune system plays a dual role in kidney disease: it can protect but also harm the kidneys when dysregulated. Advances in our understanding of immune-mediated kidney diseases have led to effective treatments like immunosuppressants (e.g., rituximab, corticosteroids) and immunotherapies (e.g., pembrolizumab, sibeprenlimab). As a nephrologist, I encourage patients to work closely with their healthcare team to understand their condition, explore treatment options, and adopt a kidney-friendly lifestyle. With the right approach, many immune-mediated kidney diseases can be managed effectively, improving quality of life and kidney health.

#Keywords: Kidney Disease, Immune System, Immunosuppressant Therapy, Immunotherapy, Glomerulonephritis, IgA Nephropathy, Lupus Nephritis, ANCA Vasculitis, Membranous Nephropathy, Kidney Cancer, Rituximab, Pembrolizumab, Sibeprenlimab, Corticosteroids, Kidney Transplant

References:

1. Tecklenborg J, Clayton D, Siebert S, Coley SM. The role of the immune system in kidney disease. Clin Exp Immunol. 2018;192(2):142-150.
2. Beck LH, Salant DJ. Advances in understanding of pathogenesis and treatment of immune-mediated kidney disease: a review. Am J Kidney Dis. 2022;79(2):213-227.
3. American Cancer Society. Immunotherapy for kidney cancer. Updated April 30, 2024. Available at: www.cancer.org
4. Gupta S, Short SAP, Sise ME, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9(10):e003467.
5. Latus J. Advances in therapy to address proteinuria in patients with immunoglobulin A nephropathy. EMJ Nephrol. 2024;12(1):12-20.
6. Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: a narrative review. Am J Nephrol. 2017;45(2):160-169.

Dr. Anil Prasad Bhatt is the Director of Nephrology and Kidney Transplant at Max Super Speciality Hospital, Noida. With over 1,000 successful kidney transplants under his leadership, he is dedicated to advancing kidney care through research and patient education. For appointments, visit www.maxhealthcare.in or call +91 9205133938.

Note: This article is for informational purposes only and should not replace professional medical advice. Always consult your doctor for diagnosis and treatment plans tailored to your condition.