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Keywords: IL-6, Tocilizumab, Hemophagocytic lymphohistiocytosis, HLH

Background: Immune checkpoint inhibitors (anti-PD1 or anti-CTLA-4) are increasingly used in various cancers. Immune checkpoint inhibitors (ICI)-related renal disorders are poorly described (9 cases) and were only related to Ipilimumab. Methods: Retrospective collection of clinical charts of all the patients admitted for renal disorders following ICI in the University Hospital of Toulouse (France). Results: We report on adverse renal events that occurred in three patients treated with anti-PD1 (nivolumab or pembrolizumab) or anti-CTLA-4 (ipilimumab). Acute kidney injury occurred at 4–12 weeks after initiation of treatment, and harbored features of tubulo-interstitial nephritis (interstitial polymorphic inflammatory infiltrate with predominant CD3+ CD4+ T cells, associated with granuloma in one). Following withdrawal of ICI and steroid intake, estimated glomerular-filtration rate had improved in all patients. Conclusions: These data suggest that all ICI can lead to acute interstitial nephritis, possibly related to the presence of autoreactive clonal T cells. We recommend that patients receiving ICI should undergo renal monitoring every 2 weeks for 3–6 months.

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6–7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10–62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94–29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.

Viral infections can promote cytokine storm and multiorgan failure in individuals with an underlying immunosuppression or specific genetic background. Hyperinflammatory states, including critical forms of COVID-19, are characterized by a remodeling of the lipid profile including a dramatic decrease of the serum levels of apolipoprotein-A-I (ApoA-I), a protein known for its capacity to reduce systemic and lung inflammation, modulate innate and adaptive immunity, and prevent endothelial dysfunction and blood coagulation. In this study, four immunocompromised patients with severe COVID-19 cytokine storm that progressed despite standard-of-care therapy [Omicron ( n = 3) and Delta ( n = 1) variants] received 2– 4 infusions (10 mg/kg) of CER-001, an ApoA-I-containing HDL mimetic. Injections were well-tolerated with no serious adverse events. Three patients treated while not on mechanical ventilation had early clinical and biological improvement (oxygen withdrawal and correction of hematological and inflammatory parameters, including serum levels of interleukin-8) and were discharged from the hospital 3–4 days after CER-001 infusions. In the fourth patient who received CER-001 after orotracheal intubation for acute respiratory distress syndrome, infusions were followed by transient respiratory improvement before secondary worsening related to ventilation-associated pneumonia. This pilot uncontrolled exploratory compassionate study provides initial safety and proof-of-concept data from patients with a COVID-19 cytokine storm receiving ApoA-I. Further randomized controlled trial evaluation is now required to ascertain whether ApoA-I has any beneficial effects on patients with a COVID-19 cytokine storm.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients’ association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Recent studies suggested that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, developed for the treatment of chronic lymphocytic leukemia, may prevent NLRP3 inflammasome activation in macrophages, IL-1β secretion and subsequent development of inflammation and organ fibrosis. The role of NLRP3 has been underlined in the various causes of acute kidney injury (AKI), a pathology characterized by high morbimortality and risk of transition toward chronic kidney disease (CKD). We therefore hypothesized that the BTK-inhibitor ibrutinib could be a candidate drug for AKI treatment. Here, we observed in both an AKI model (glycerol-induced rhabdomyolysis) and a model of rapidly progressive kidney fibrosis (unilateral ureteral obstruction), that ibrutinib did not prevent inflammatory cell recruitment in the kidney and fibrosis. Moreover, ibrutinib pre-exposure led to high mortality rate owing to severer rhabdomyolysis and AKI. In vitro, ibrutinib potentiated or had no effect on the secretion of IL-1β by monocytes exposed to uromodulin or myoglobin, two danger-associated molecule patterns proteins involved in the AKI to CKD transition. According to these results, ibrutinib should not be considered a candidate drug for patients developing AKI.

Rhabdomyolysis is a risk factor for acute kidney injury, transition towards chronic kidney disease, and death. The role of calcium phosphate deposits in the mechanisms of rhabdomyolysis-induced acute kidney injury (RAKI) is still unclear. Better insight of the role calcium in RAKI could lead to new therapeutic avenues. Here, we show in a mice model of RAKI that calcium phosphate deposits were frequent in the kidney (hydroxyapatite) and partly correlated with the severity of the kidney injury. However, the intensity of deposits was highly heterogeneous between mice. Treatment with sodium chloride, sodium bicarbonate or inorganic pyrophosphate (PPi; an inhibitor of the calcium phosphate crystallization), or combinations thereof, did not improve kidney outcomes and hydroxyapatite deposition during RAKI. Unexpectedly, Abcc6 knockout mice ( ko ), characterized by PPi deficiency, developed less severe RAKI despite similar rhabdomyolysis severity, and had similar hydroxyapatite deposition suggesting alternative mechanisms. This improved kidney outcome at day 2 translated to a trend in improved glomerular filtration rate at month 2 in Abcc6 -/- mice and to significantly less interstitial fibrosis. In addition, whereas the pattern of infiltrating cells at day 2 was similar between wt and ko mice, kidneys of Abcc6 -/- mice were characterized by more CD19 + B-cells, less CD3 + T-cells and a lower R1/R2 macrophage ratio at month 2. In summary, kidney calcium phosphate deposits are frequent in RAKI but hydration with sodium bicarbonate or sodium chloride does not modify the kidney outcome. Blocking ABCC6 emerges as a new option to prevent RAKI and subsequent transition toward kidney fibrosis.

Background The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. Methods In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. Results A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 [3.96–9.59], p  < 0.001) outperforming reference biomarkers (urinary NGAL and [IGFBP7].[TIMP2] product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 [4.73–7.45], p  < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 [2.05–3.38], p  < 0.001). Conclusions An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.

Introduction AL amyloidosis is caused by the proliferation of an immunoglobulin‐secreting B cell clone. AA amyloidosis is a rare complication of chronic inflammation. However, some patients present with diseases combining monoclonal immunoglobulin production and chronic inflammation. The aim of this work was to describe cases of AA amyloidosis associated with monoclonal gammopathies. Patients and methods We reviewed all patients reported in French national amyloid centres presenting with AA amyloidosis and monoclonal gammopathy and performed a literature review. The quality of AA amyloidosis diagnosis and the causal relationship with monoclonal gammopathy were assessed. Results In total, four patients from our centres and eight from the literature fulfilled the inclusion criteria. The haematological disorders presenting with monoclonal gammopathy were as follows: Waldenström macroglobulinaemia (n = 8), Schnitzler syndrome (n = 2), multiple myeloma (n = 1) and monoclonal gammopathy of undetermined significance (n = 1). Treatment strategies varied among the cases, with the treatment of the haematological disorder in 4 and anti‐inflammatory treatment in 2. Conclusion Monoclonal gammopathies might be a rare and poorly known cause of AA amyloidosis. Such monoclonal gammopathies could be named “monoclonal gammopathies of inflammatory significance.”