BACKGROUND
Immune checkpoint inhibitors (ICI) use can lead to an array of immune-related adverse events (irAE). Nephritis is considered to be uncommon, with an incidence of 2–7%.1 The factors predisposing to developing ICI-induced nephritis remain unclear, so does the reversibility and management of steroid-refractory toxicity. Additionally, the role of nephrotoxic drugs is unclear. It has been reported that some patients experience incomplete reversibility of toxicity,1 and the utility of additional immunosuppression is currently limited to case reports.2
MATERIALS AND METHODS
This was a retrospective review of a large, single centre with a population of 2.3 million people, consisting of all patients who had received ICIs in the management of multiple malignancies between January 2020–February 2023. There was a centralised referral service for all patients experiencing irAEs from ICIs. Grade 1 nephritis was considered as low-grade nephritis, and Grade 2 or above was defined as high-grade nephritis.
RESULTS
A total of 190 patients developed ICI-induced nephritis. In that same period, 2,645 patients commenced on ICIs with an incidence of 7.2%. Of these, 58% (111/190) developed low-grade nephritis and 42% (79/190) developed high-grade nephritis. Pre-nephritis features such as primary disease, immunotherapy regime, use of combined therapy or monotherapy, ethnicity, gender, or smoking status were not associated with nephritis outcome. The only pre-nephritis feature that was statistically significant was the use of nephrotoxic drugs. Of the patients, 23.4% (26/111) with low-grade nephritis and 32.9% (26/79) of those with high-grade nephritis were on a proton pump inhibitor (PPI) and appeared to predispose patients (odds ratio [OR]: 2.250; 95% CI: 1.134–4.496; p<0.001), as well as the combination of a PPI and ACEi (OR: 7.677; 95% CI: 2.599–22.678; p<0.001). ACEi alone (OR: 1.29; 95% CI: 0.352–4.731) and NSAIDs or the addition of NSAIDs to other therapies (OR: 1.129; 95% CI: 0.0987–12.921) were not associated.
Those who had low-grade nephritis were less likely to require higher grades of treatment such as the use of steroids (P<0.001). However, if toxicity progressed and steroids were necessary, the patients would normally be associated with having a shorter course (P<0.001). There was also an association between the grade of nephritis outcomes and the return to baseline renal function (P<0.001), with patients that had a high-grade being less likely to return to their baseline renal function than those with low-grade nephritis. Across all grades, only 51% of patients had a complete return to baseline.
Use of second-line immunosuppression with mycophenolate mofetil (MMF) was used in 13% (24/190) of patients to treat refractory nephritis not responding to steroids alone. Additional immunosuppression was well tolerated. All patients who were treated with second-line immunosuppression either improved to Grade 1 or their baseline renal function, with 35% (8/23 monotherapy patients) returning to baseline/normal renal function despite being treatment refractory prior to the introduction of MMF.
CONCLUSION
This large series illustrated that there is a concomitant medication predisposition to ICI-induced nephritis, and the clinical need for PPIs should be considered prior to commencing ICI treatment. Additionally, clinical categorisation into low, high, and refectory nephritis is likely to be helpful in treatment. In line with previous studies, return to baseline function was seen in 51% and appears relative to the degree of nephritis; however, the majority of patients resolved to Grade 1 toxicity. Finally, MMF illustrated a benefit in managing refractory nephritis, with the majority resolving to clinically acceptable levels.
