#2944 BIOPSY-PROVEN ACUTE TUBULOINTERSTITIAL NEPHRITIS IN PATIENTS ON IMMUNE CHECKPOINT INHIBITORS: A POOLED ANALYSIS OF CASE REPORTS
Authors: Bottini Annarita , Lecini Elvina , Cappadona Francesca , Piaggio Michela , Macciò Lucia , Genova Carlo , Viazzi Francesca , Esposito Pasquale 
Published: June 2023

Abstract

Background and Aims
Acute kidney injury (AKI) is a major complication in cancer patients receiving immune checkpoint inhibitors (ICIs). Previous studies have not accurately distinguished the various potential underlying causes of AKI due to the limited use of renal biopsy. Here, we reviewed cases of biopsy-proven acute tubulointerstitial nephritis (ATIN) in patients treated with ICIs to describe the clinical and laboratory characteristics and outcomes of this condition.

Method
We conducted a pooled analysis of clinical cases published up to 1 May 2022. The search terms on PubMed were [(Pembrolizumab OR Nivolumab OR Ipilimumab OR Atezolizumab OR Avelumab OR Durvalumab) AND (Nephritis)]. Only cases with biopsy-proven ATIN were included. Among a total of 111 patients identified, 83 were eligible for this analysis. We added two patients from our Institution. We collected data on clinical characteristics, renal biopsy findings, and laboratory examinations. AKI was graded according to the KDIGO criteria. As outcomes, we considered: complete renal recovery if serum creatinine returned to baseline +0.3 mg/dL, no recovery if patients needed dialysis and partial recovery in other cases.

Results
Overall, 85 patients (56 male) with an age of 61.4±19 years were evaluated. 43 patients (51%) had melanoma, 25 (30%) non-small cell lung cancer, 8 renal carcinoma, and 9 other cancers. ICI treatment consisted of PD-1, PDL-1 (nivolumab, pembrolizumab, atezolizumab) and CTLA4 inhibitors (i) (ipilimumab) or combination PD-1i-CTLA4i (Table 1). Renal toxicity developed after a median of four cycles of therapy, but in most cases (n = 59) after at least three treatment cycles. Eleven patients (14%) presented with AKI stage 1, 16 patients (20.5%) with stage 2, and 51 patients (65.5%) with AKI stage 3, including five patients requiring dialysis. Among AKI3 patients there was a significantly higher prevalence of patients at the first therapy line (p = 0.04), while all the 19 patients treated with the dual ICI blockade developed AKI3, compared with 29 patients out of the 52 taking a single agent (Figure 1A). Seventy-seven patients received steroids, while 7 patients did not receive any therapy. ICI treatment was withdrawn in 65 out of 69 patients with available data. Following AKI resolution, in 15 patients ICI was restarted, but in six (40%) AKI recurred. Overall, 32 patients (40%) presented a complete renal recovery, 45 patients (56.2%) had a partial recovery, and 3 patients (3.8%) did not recover. Among patients who did not fully recover, there was a higher prevalence of those treated with dual ICI blockade and presenting with AKI stage 3 (Figure 1B). At logistic regression, complete renal recovery was inversely associated with dual ICI blockade (OR 0.1, 95CI 0.02-0.5, p = 0.006) and AKI 3 (OR 0.31, 95CI 0.1-0.9, p = 0.04), but only the association with dual ICI therapy remained significant at multivariate analysis.

Conclusion
ICI-related ATIN may develop late after the initiation of therapy. It may present as a severe form of AKI, particularly in patients with dual ICI blockade. Although this complication may be partially reversible, concerns remain about the renal function sequelae and the possibility of restarting treatment after AKI resolution due to the risk of recurrence.