Checkpoint Inhibitor Associated Renal Disease

In this GlomCon Conference, Drs. Manohar, Cornell, and Hermann shared their expertise and reviewed renal effects of immune checkpoint inhibitors. Our Moderator’s Notes are derived from their live presentation, which you can watch here:

Moderator’s Notes
Author: Dr. Jessica Lapasia
Editors: Dr. Ali Poyan Mehr

Key points:

Background
• Immune-checkpoint proteins, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) or the programmed cell death protein 1 (PD1) help T-cells maintain immune tolerance and differentiate between “self” versus “foreign” antigens. Certain cancer cells use these immune-checkpoint pathways to hide from the immune system and further proliferate. Immune-checkpoint inhibitors are a new class of immunoglobulin based anti-tumor therapeutics, which block the “receptor-ligand” interaction of immune-checkpoint proteins and remove this protection from the cancer cells, allowing T-cell activation and destruction of cancer cells.

• Drugs currently approved by the FDA and their respective targets:
o Pembrolizumab, nivolumab: Targeting PD-1 (programmed cell death protein 1)
o Atezolizumab, avelumab, durvalumab: Targeting PD-L1 (PD-1 ligand)
o Ipilimumab: Targeting CTLA-4 (cytotoxic T-lymphocyte 1)

• Incidence of AKI with immune-checkpoint inhibitor use: 2.2% in one study but the presenters mentioned that this is likely to increase. Further, there is a higher incidence of AKI in patients receiving a combination of immune-checkpoint inhibitors

• Average time from immune-checkpoint inhibitor exposure to development of AKI is 14 weeks.

Immune-related adverse events (IRAEs) affecting the kidney

  1. Tubulointerstitial disease
    • Acute interstitial nephritis (AIN) is most common pathologic finding on biopsy.
    • Kidney biopsy: interstitial infiltrate composed of mostly mononuclear cells, tubulitis, evidence of tubular injury; may also see interstitial edema and fibrosis.
    • Acute tubular injury also seen in several cases.

  2. Autoimmune disease
    • Blocking immune-checkpoint pathways may exacerbate underlying autoimmune disease.
    • Animal models of CTLA-4 depletion show spontaneous autoimmunity.

  3. Glomerulopathy
    • Wide variety of conditions have been described with immune-checkpoint inhibitor use: Minimal change disease, membranous nephropathy, lupus nephritis, pauci-immune GN, IgA nephropathy, C3 glomerulopathy, FSGS.

  4. Electrolyte abnormalities
    • Hypokalemia and hypocalcemia have been seen amongst others.
    • Can be associated with RTA (distal or proximal), similar to what is seen in certain autoimmune diseases.

Management
• Removal of all potential culprits for AKI, particularly any possible other causes of AIN.
• Glucocorticoids.
• Significant risk of recurrent AKI with repeat exposure – switching classes may help.
• Immune-checkpoint inhibitor use in the post-transplant population is associated with a high risk of graft loss. Both acute cellular and antibody-mediated rejection have been described.
• There are studies ongoing to help identify risk factors for development of AKI with immune-checkpoint inhibitor use.

Selected References: