What Kidney Side Effects Can Cancer Immunotherapies Cause, and How Are They Treated?

Immunotherapies are a group of treatments that have brought revolutionary advances in cancer care in recent years. The most widely used type is immune checkpoint inhibitors. Throughout this article, we will refer to these drugs simply as "immunotherapy."

First approved by the FDA (United States Food and Drug Administration) in 2011, these drugs enable the immune system to fight cancer cells by targeting immune checkpoints. These checkpoints are molecular mechanisms that prevent an excessive immune response. However, when immunotherapies inhibit them, the immune system may become overactive and attack the body's own tissues. This can cause various autoimmune reactions, leading to side effects specific to immunotherapy .

Compared with chemotherapy and other targeted drugs, immunotherapies are known to cause fewer side effects , but they may sometimes cause serious adverse effects. Kidney side effects are one example.

The Importance of Kidney Side Effects

Although uncommon, kidney adverse effects associated with immunotherapy can have serious clinical consequences. Kidney damage may reduce quality of life and complicate treatment. Close monitoring of kidney function and early recognition of adverse effects are therefore essential in patients receiving immunotherapy. This review examines their mechanisms, clinical findings, diagnosis, and management strategies.

How Common Are Kidney Side Effects with Immunotherapy?

Kidney adverse effects associated with immune checkpoint inhibitors are generally uncommon, although serious cases can occur. In a meta-analysis involving 10 thousand patients :

• The incidence of any-grade kidney toxicity was 1.2%.
• Low-grade (Grade 1-2) kidney toxicity was reported in approximately 0.7%, and
• High-grade (Grade 3-4) kidney toxicity in approximately 0.6%.

However, some studies report kidney adverse effects in up to 7% with combination immunotherapy or in patients with underlying kidney disease or other comorbidities.

These data emphasize that kidney side effects of immunotherapy are uncommon but require careful monitoring.

Immune Checkpoint Inhibitors and Kidney Side Effects

1. How Immune Checkpoint Inhibitors Work

• The PD-1/PD-L1 Pathway
  • Programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) are important checkpoints regulating the immune response. The PD-1/PD-L1 interaction suppresses T-cell activity, preventing autoimmune responses. Cancer cells, however, can exploit this pathway to evade immunity. PD-1 inhibitors such as pembrolizumab and nivolumab, and PD-L1 inhibitors such as atezolizumab and durvalumab, block this interaction, allowing T cells to attack cancer cells.
• The CTLA-4 Pathway
  • Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is another checkpoint that inhibits T-cell activation. CTLA-4 inhibitors such as ipilimumab block this pathway, increasing T-cell activation and strengthening the antitumor response.

2. Mechanisms of Kidney Side Effects

• Autoimmune Responses
  • Immune checkpoint inhibitors can cause autoimmune reactions in which the immune system targets kidney tissue and causes inflammation.
• Inflammatory Mechanisms
  • Inflammatory responses in the kidneys may cause conditions such as interstitial nephritis and glomerulonephritis. These mechanisms arise when immune cells attack kidney tissue.
• Immune Complex Deposition
  • Deposition of immune complexes in the kidney glomeruli may cause glomerulonephritis. These complexes consist of combined antibodies and antigens and trigger inflammation.

3. Clinical Findings and Diagnosis

Elevated serum creatinine and BUN may indicate kidney injury. Proteinuria and hematuria on urine testing are also important findings.

What Pathologies Can Occur?

• Acute Interstitial Nephritis (AIN)
  • Acute interstitial nephritis is characterized by inflammation of the kidney interstitium. It is often diagnosed through white blood cells in urine tests. It is the most common kidney pathology seen as an immunotherapy side effect. It may present with impaired kidney function, protein and white blood cells in the urine, increased blood eosinophils, and fever.
• Acute Tubular Necrosis (ATN)
  • Acute tubular necrosis results from damage to the kidney tubules and clinically presents as acute kidney failure.
• Glomerulonephritis
  • Glomerulonephritis is characterized by inflammation and damage in the glomeruli. It presents clinically with proteinuria, hematuria, and impaired kidney function.

Imaging and Biopsy

Kidney biopsy is an important method for establishing a definitive diagnosis. It may show interstitial inflammation, tubular injury, or glomerular disease.

How Should Kidney Side Effects Be Treated?

The approach to treating kidney side effects is described step by step below in the Kidney Toxicity Management Algorithm:

Identifying Risk Factors and Monitoring

• Predisposing Factors
  • Factors such as preexisting kidney disease, older age, and concomitant nephrotoxic medications may increase the risk of kidney side effects during immunotherapy.
• Patient Monitoring
  • Kidney function should be monitored regularly in patients receiving immunotherapy. Serum creatinine measurements and urine tests should be performed periodically throughout treatment.

Conclusion

Although immunotherapy's success in cancer treatment is indisputable, its potential kidney side effects must be considered. Kidney adverse effects caused by immune checkpoint inhibitors are generally uncommon, but serious cases must not be overlooked. Regular monitoring of kidney function and early intervention to manage adverse effects are essential for successfully continuing treatment. Effective collaboration between oncologists and nephrologists therefore plays a crucial role in diagnosing and treating these kidney side effects.