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:

https://www.ncbi.nlm.nih.gov/pubmed/31048326

https://www.ncbi.nlm.nih.gov/pubmed/28076863

https://www.ncbi.nlm.nih.gov/pubmed/27282937

https://www.ncbi.nlm.nih.gov/pubmed/29320654