Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear. We conducted a multicentre case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) with those of patients diagnosed with other IRAEs. Methods: We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, four reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a P < 0.05 were included as covariates in a multivariate analysis. Results: Therefore, 167 ICI-AKI reports were compared with 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 versus 64.6 years; P = 0.0135), and chronic kidney disease was significantly more prevalent (12.0% versus 3.3%; P = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione [adjusted odds ratio (OR) 6.53, 95% confidence interval (95% CI) 2.21-19.31; P = 0.0007], a non-steroidal anti-inflammatory drug (NSAID, OR 3.18, 95% CI 1.07-9.4; P = 0.0368) or a proton-pump inhibitor (PPI, OR 2.18, 95% CI 1.42-3.34; P = 0.0004). Conclusion: This study is limited by a lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a 'second-hit' that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).

Immune checkpoint inhibitors-induced nephropathy: a French national survey.

Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.

Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database.

Remdesivir is approved for emergency use by the US Food and Drug Administration (FDA) and authorized conditionally by the European Medicines Agency (EMA) for patients with coronavirus disease 2019 (COVID-19). Its benefit-risk ratio is still being explored because data in the field are rather scant. A decrease of the creatinine clearance associated with remdesivir has been inconstantly reported in clinical trials with unclear relevance. Despite these uncertainties, we searched for a potential signal of acute renal failure (ARF) in pharmacovigilance postmarketing data. An analysis of the international pharmacovigilance postmarketing databases (VigiBase) of the World Health Organization (WHO) was performed, using two disproportionality methods. Reporting odds ratio (ROR) compared the number of ARF cases reported with remdesivir, with those reported with other drugs prescribed in comparable situations of COVID-19 (hydroxychloroquine, tocilizumab, and lopinavir/ritonavir). The combination of the terms "acute renal failure" and "remdesivir" yielded a statistically significant disproportionality signal with 138 observed cases instead of the 9 expected. ROR of ARF with remdesivir was 20-fold (20.3; confidence interval 0.95 [15.7-26.3], P < 0.0001]) that of comparative drugs. Based on ARF cases reported in VigiBase, and despite the caveats inherent to COVID-19 circumstances, we detected a statistically significant pharmacovigilance signal of nephrotoxicity associated with remdesivir, deserving a thorough qualitative assessment of all available data. Meanwhile, as recommended in its Summary of Product Characteristics, assessment of patients with COVID-19 renal function should prevail before and during treatment with remdesivir in COVID-19.

Case Report: Successful Treatment of Steroid-Refractory Immune Checkpoint Inhibitor-Related Pure Red Cell Aplasia With Cyclosporin.

Anemia associated with Immune checkpoint inhibitor (ICI) is usually hemolytic and regenerative. Cases of non-regenerative pure red cell aplasia are rare, and typically improve upon drug discontinuation and after corticotherapy. We herein report a case of nivolumab-related erythroblastopenia refractory to steroids in a melanoma patient that improved only after treatment with cyclosporin. Nivolumab had been well tolerated for 2 months after being introduced as an adjuvant treatment. Hemoglobin level then progressively decreased from 12.7 g/dl as baseline value to a nadir of 4.3 g/dL despite transfusion with a total of 29 packed red blood cells in 3 months. Extensive workup including repeated bone marrow examinations led to the diagnosis of pure red cell aplasia. Anemia persisted despite nivolumab discontinuation and over a month of corticotherapy, but improved dramatically 3 days after cyclosporin initiation and did not recur upon cyclosporin tapering. The patient remains cancer-free 9 months after nivolumab withdrawal. This case highlights the under-recognized risk of erythroblastopenia in patients treated with ICI and proves cyclosporin is a valid alternative for the treatment of steroid-refractory cases.

Signalling crosstalk at the leading edge controls tissue closure dynamics in the Drosophila embryo.

Tissue morphogenesis relies on proper differentiation of morphogenetic domains, adopting specific cell behaviours. Yet, how signalling pathways interact to determine and coordinate these domains remains poorly understood. Dorsal closure (DC) of the Drosophila embryo represents a powerful model to study epithelial cell sheet sealing. In this process, JNK (JUN N-terminal Kinase) signalling controls leading edge (LE) differentiation generating local forces and cell shape changes essential for DC. The LE represents a key morphogenetic domain in which, in addition to JNK, a number of signalling pathways converges and interacts (anterior/posterior -AP- determination; segmentation genes, such as Wnt/Wingless; TGFß/Decapentaplegic). To better characterize properties of the LE morphogenetic domain, we sought out new JNK target genes through a genomic approach: 25 were identified of which 8 are specifically expressed in the LE, similarly to decapentaplegic or puckered. Quantitative in situ gene profiling of this new set of LE genes reveals complex patterning of the LE along the AP axis, involving a three-way interplay between the JNK pathway, segmentation and HOX genes. Patterning of the LE into discrete domains appears essential for coordination of tissue sealing dynamics. Loss of anterior or posterior HOX gene function leads to strongly delayed and asymmetric DC, due to incorrect zipping in their respective functional domain. Therefore, in addition to significantly increasing the number of JNK target genes identified so far, our results reveal that the LE is a highly heterogeneous morphogenetic organizer, sculpted through crosstalk between JNK, segmental and AP signalling. This fine-tuning regulatory mechanism is essential to coordinate morphogenesis and dynamics of tissue sealing.

In vivo characterization of dynein-driven nanovectors using Drosophila oocytes.

Molecular motors transport various cargoes including vesicles, proteins and mRNAs, to distinct intracellular compartments. A significant challenge in the field of nanotechnology is to improve drug nuclear delivery by engineering nanocarriers transported by cytoskeletal motors. However, suitable in vivo models to assay transport and delivery efficiency remain very limited. Here, we develop a fast and genetically tractable assay to test the efficiency and dynamics of fluospheres (FS) using microinjection into Drosophila oocytes coupled with time-lapse microscopy. We designed dynein motor driven FS using a collection of dynein light chain 8 (LC8) peptide binding motifs as molecular linkers and characterized in real time the efficiency of the FS movement according to its linker's sequence. Results show that the conserved LC8 binding motif allows fast perinuclear nanoparticle's accumulation in a microtubule and dynein dependent mechanism. These data reveal the Drosophila oocyte as a new valuable tool for the design of motor driven nanovectors.