Acute Interstitial Nephritis and Checkpoint Inhibitor Therapy : Single Center Experience of Management and Drug Rechallenge

Background Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported. Objectives To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity. Data Sources We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015. Study Selection Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included. Data Extraction We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes. Data Synthesis 191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab. Limitations Our study is limited by information available in the original reports. Conclusions Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported.

After a grade 2 or higher immune-related adverse event, is an anti–PD-1 or anti–PD-L1 inhibitor rechallenge safe? In this cohort study of 93 French adults who experienced a grade 2 or higher immune-related adverse event and had an anti–PD-1 or anti–PD-L1 rechallenge, 55% experienced a second adverse event. Earlier initial toxic effect was associated with more frequent recurrence, and the second event was not as severe as the first. The risk-reward ratio for anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; rechallenge conditions warrant further investigation in a prospective clinical trial. Although immune checkpoint inhibitors (ICIs), such as anti–PD-1 (programmed cell death 1) or anti–PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE. To investigate the safety of a rechallenge with anti–PD-1 or anti–PD-L1 immunotherapies after an irAE. This cohort study of the safety of an ICI rechallenge involved consecutive adult patients (n = 93) who were referred to the ImmunoTOX assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018. Incidence of a second irAE in patients who had a readministration of an anti–PD-1 or anti–PD-L1 inhibitor after an initial grade 2 or higher irAE. Characteristics of the patients and the irAEs were reviewed, and the primary end point was the rate of occurrence of second irAEs. A total of 93 patients were included, among whom 48 (52%) were female, and the median (range) age was 62.5 (33-85) years. The main cancer types or tumor sites were melanoma (31 [33%]), lung (15 [16%]), colorectal (8 [9%]), and lymphoma (8 [9%]). For the initial irAE, 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%) were found, presenting primarily as hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), or arthralgia (7 [7.5%]). Forty patients (43%) were rechallenged with the same anti–PD-1 or anti–PD-L1 agent. The rechallenged and non-rechallenged groups did not differ in terms of median (range) age (61 [34-84] years vs 63 [33-85] years; P  = .37), time to initial irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles; P  = .32), irAE severity (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4: 22 [52.5%] vs 26 [49%]; P  = .70), or steroid use (17 [42.5%] vs 32 [60%]; P  = .09). With a median follow-up period of 14 months, the same irAE or a different irAE occurred in 22 patients (55%). Shorter time to the initial irAE was linked to the occurrence of a second irAE (9 vs 15 weeks; P  = .04). The second irAEs were not found to be more severe than the first. The risk-reward ratio for an anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; further investigation into rechallenge conditions through a prospective clinical trial is needed. This cohort study evaluates the feasibility, risks, and advantages of resuming immune checkpoint inhibitor therapy in patients with cancer who experienced severe immune-related adverse events.

This study aimed to determine if recovery of kidney function after AKI modifies the association between AKI during hospitalization and adverse outcomes after discharge. The effect of renal recovery after AKI was evaluated in a population-based cohort study (n=190,714) with participants identified from a provincial claims registry in Alberta, Canada, between November 1, 2002 and December 31, 2007. AKI was identified by a two-fold increase between prehospital and peak in-hospital serum creatinine (SCr). Recovery was assessed using SCr drawn closest to 90 days after the AKI event. All-cause mortality and a combined renal outcome of sustained doubling of SCr or progression to kidney failure were evaluated. Overall, 3.7% of the participants (n=7014) had AKI, 62.7% of whom (n=4400) survived 90 days. In the 3231 patients in whom recovery could be assessed over a median follow-up of 34 months, 30.8% (n=1268) of AKI survivors died and 2.1% (n=85) progressed to kidney failure. Participants who did not recover kidney function had a higher risk for mortality and adverse renal outcomes when AKI participants who recovered to within 25% of baseline SCr were used as the reference group (adjusted mortality hazard ratio (HR), 1.26; 95% confidence interval, 1.10, 1.43) (adjusted renal outcomes HR, 4.13; 95% confidence interval, 3.38, 5.04). Mortality HR was notably higher when participants failed to recover within 55% of baseline. Renal recovery after AKI is associated with a lower risk of death or adverse renal outcomes after hospital discharge.