Introduction
Immune checkpoint inhibitors (ICPIs), Ipilimumab and Nivolumab are used as either monotherapy or combination therapy for metastatic melanoma. They improve survival by blocking inhibitory receptors, PD1 and CTLA4 respectively, enhancing T-cell-mediated anti-tumour responses. ICPIs can cause a spectrum of autoimmune phenomena known as Immune-related adverse events (IRAEs) which occur in up to 55% of patients, with acute kidney injury (AKI), typically due to acute interstitial nephritis (AIN), less common than colitis, rash and endocrine complications. Observational data suggest that treatment with glucocorticoids is beneficial in ICPIs related AIN.
Case report
CB, a 62-year-old-woman, was diagnosed with metastatic melanoma in lungs (BRAF wild type) in May 2022, and commenced induction combination ICPIs therapy with Ipilimumab and Nivolumab in July 2022. Baseline renal function was normal. After Cycle-3, she developed severe lethargy, nausea, and generalised unwellness. Investigations revealed ICPIs related hypophysitis leading to secondary hypocortisolism, thyroiditis followed by primary hypothyroidism, moderate transaminitis, and acute kidney injury (AKI). All IRAEs resolved with Prednisolone 1mg/kg (oral), tapering over 8 weeks. AKI improved but was maintained at a new baseline serum creatinine (SCr) 110umol/L and eGFR 45ml/min. She required cortisol 37.5mg/day and levothyroxine 50mcg/day as ongoing daily replacement therapy. Cycle-1 maintenance Nivolumab (4weekly) was started in January 2023.Three weeks later, she developed AKI with nadir SCr 190umol/L, urea 8.8, eGFR 24ml/min. Renal imaging was unremarkable, and urinalysis ruled out infection, proteinuria, haematuria, and sediments. Renal biopsy confirmed tubulo-interstitial nephritis with no other pathology. AKI resolved and renal function improved and maintained at nadir SCr 110umol/L and eGFR around 45ml/min. High dose prednisolone was weaned off successfully to cortisol 37.5mg/day (daily requirement dose for her secondary hypocortisolism) without recurrence of AKI. The treatment resulted in a complete metabolic response in PET/CT scan.
Conclusion
Monitoring of renal function and prompt diagnosis is important to allow early use of steroids in cases of AIN due to ICPI. Deciding which patients should be rechallenged with ICPIs after experiencing serious IRAEs such as AKI is extremely challenging. In this case, rechallenge with Nivolumab whilst on weaning steroids resulted in renal function decline secondary to ICPI related interstitial nephritis, which was resolved with high dose steroid. However, to avoid depriving patients of a potentially life-saving therapy, the balance between risk of IRAE and improved survival needs to be considered as there are limited alternative treatments.