Diversification of human plasmacytoid predendritic cells in response to a single stimulus.

Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.

Human inflammatory dendritic cells induce Th17 cell differentiation.

Dendritic cells (DCs) are critical regulators of immune responses. Under noninflammatory conditions, several human DC subsets have been identified. Little is known, however, about the human DC compartment under inflammatory conditions. Here, we characterize a DC population found in human inflammatory fluids that displayed a phenotype distinct from macrophages from the same fluids and from steady-state lymphoid organ and blood DCs. Transcriptome analysis showed that they correspond to a distinct DC subset and share gene signatures with in vitro monocyte-derived DCs. Moreover, human inflammatory DCs, but not inflammatory macrophages, stimulated autologous memory CD4(+) T cells to produce interleukin-17 and induce T helper 17 (Th17) cell differentiation from naive CD4(+) T cells through the selective secretion of Th17 cell-polarizing cytokines. We conclude that inflammatory DCs represent a distinct human DC subset and propose that they are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses.

Rheopheresis for severe peripheral arterial disease in hemodialysis patients: A clinical series.

BACKGROUND: Rheopheresis is a double-filtration plasmapheresis that removes high-molecular-weight molecules from the plasma and thereby lowers blood viscosity. This treatment has been proposed in hemodialysis (HD) patients for chronic limb-threatening ischemia (CLTI), but very few studies have evaluated the usefulness of this technique. PRINCIPAL OBJECTIVE: To assess 1-year amputation-free survival (AFS) of HD patients suffering from CLTI treated by rheopheresis. MATERIAL AND METHOD: We conducted a retrospective study of 28 consecutive HD patients treated by rheopheresis in three French dialysis centers between 1 February 2017 and 30 April 2019 in two indications resulting from CLTI, namely chronic ulceration or recent minor amputation with delayed healing. RESULTS: One-year AFS rate reached 53.6 (-19.8; +16.3)%. One-year overall survival rate reached 67.9 (-20.5; +13.1)%. Main causes of death were infections and related to palliative care implying reduction or withdrawal of regular dialysis treatment. Hypotension episodes were the main rheopheresis adverse events with a prevalence rate of 13.5%. Rheopheresis sessions significantly reduced fibrinogen, C-reactive protein, α2-macroglobulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, IgM, and estimated plasma viscosity (P < .0001). CONCLUSION: Rheopheresis may improve clinical outcomes of CLTI in HD patients. The assessment of rheopheresis effectiveness needs to be confirmed by a multicenter randomized controlled trial, such as the ongoing project in France (RHEO-PAD, NCT: 03975946).

Electrochemical skin conductance by Sudoscan®: a new tool to predict intradialytic hypotension.

BACKGROUND: Intradialytic hypotension (IDH), a common complication in haemodialysis (HD) patients, is associated with multiple risk factors including cardiac dysfunction and alterations of the peripheral autonomic nervous system. To what extent dysautonomia may contribute to the occurrence of IDH remains elusive. We sought to investigate the clinical utility of Sudocan®, a device that quantifies dysautonomia, in the prediction of IDH. METHODS: We conducted a prospective monocentric study in adult HD patients from July 2019 to February 2020. Dysautonomia was assessed by the measurements of hand and foot electrochemical skin conductance (ESC) using Sudocan®, before HD. The primary endpoint was the incidence of IDH (The National Kidney Foundation/Kidney-Dialysis Outcome Quality Initiative definition), according to the presence of a pathological hand and/or foot ESC value, during the 3-month study period. RESULTS: A total of 176 HD patients (64 ± 14 years old) were enrolled. Mean pre-dialysis HD hand and foot ESC was 45 ± 20 and 54 ± 22 µS, respectively. About 35% and 40% of patients had a pathological ESC at the hand and foot, respectively. IDH occurred in 46 patients. Logistic regression showed that pathologic pre-dialysis HD hand ESC was associated with an increased risk of IDH [odds ratio = 2.56, 95% CI (1.04-6.67), P = 0.04]. The cumulative risk incidence of IHD during the study was 5.65 [95% CI (2.04-15.71), P = 0.001] and 3.71 [95% CI (1.41-9.76), P = 0.008], with a pathological hand and foot ESC, respectively. CONCLUSIONS: A pathological hand ESC, as assessed by a non-invasive Sudoscan® test, is associated with an increased risk of IDH.

From combined heart-kidney to kidney transplantation program: what nephrologists should know about dilated cardiomyopathy.

A 42-year-old hemodialysis (HD) patient was investigated in our department for symptomatic heart failure (HF) despite daily home dialysis. He had a history of living donor kidney transplantation at the age of 18 that lasted 7 years. Home dialysis was then started. At the age of 40, he developed acute heart failure symptoms. Echocardiography revealed severe dilated cardiomyopathy (DCM). Coronarography and myocardial perfusion scintigraphy showed no abnormal findings. Betablockers were administrated, and RAAS inhibitor dosing was optimized. Dyspnea persisted, and patient was referred to our department. At admission, blood pressure was 116/82 mmHg, and pulse 68 beats/min. No peripheral edema was observed. Dry weight was 62.5 kg. Patient was anuric. Hemoglobin level was 9.8 g/dl, highly sensitive troponin level was 62 ng/ml, and BNP level was 1527 ng/ml. The liver enzyme levels were normal. C-reactive protein was 4.2 mg/ml. Vitamin level, zinc levels, and thyroid function were normal.

From combined heart-kidney to kidney transplantation program: What nephrologists should know about dilated cardiomyopathy.

A 42-year-old hemodialysis (HD) patient was investigated in our department for symptomatic heart failure (HF) despite daily home dialysis. He had a history of living donor kidney transplantation at the age of 18 that lasted 7 years. Home dialysis was then started. At the age of 40, he developed acute heart failure symptoms. Echocardiography revealed severe dilated cardiomyopathy (DCM). Coronarography and myocardial perfusion scintigraphy showed no abnormal findings. Betablockers were administrated and RAAS inhibitor dosing was optimized. Dyspnea persisted and patient was referred to our department. At admission, blood pressure was 116/82 mmHg, and pulse 68 beats/min. No peripheral edema was observed. Dry weight was 62.5 kg. Patient was anuric. Hemoglobin level was 9.8 g/dl, highly sensitive troponin level was 62 ng/ml and BNP level 1527 ng/ml. The liver enzymes levels as were normal. C-reactive protein was 4.2 mg/ml. Vitamin level, zinc levels and thyroid function were normal.

Feasibility and outcomes of native arteriovenous fistula in octogenarians.

INTRODUCTION: While the native arteriovenous fistula (AVF) is the preferred dialysis access, it is a matter of debate for individuals older than 80 years due to reduced primary patency rates. MATERIALS AND METHODS: We initiated a single-center, observational retrospective analysis of adult dialysis patients from January 2015 to December 2018. We included all patients older than 70 years with a minimum of 12 months of follow-up, beginning from the AVF creation. Patients were separated into two groups, octogenarians (> 80 years old) and controls (70 - 79 years old). The primary end point was the primary patency (the interval from arteriovenous access creation to the first intervention). The secondary end point were the complications at 3 months (failures of puncture, canceled dialysis sessions, local hematoma, AVF bleeding). RESULTS: 29 patients (octogenarian = 17, control = 12) were included in the analysis. The AVF radio-cephalic was the most common vascular access in each group. Primary patency was comparable between groups, but octogenarians required 40% more procedures to obtain or maintain patency. Overall, a functional AVF was obtained for all patients except in cases of complications such as hematomas, which were more frequent in octogenarians compared to controls (25 vs. 82%, p < 0.01). All catheters were removed at 6 months follow-up, with a median time to removal of 27 days (range 5 - 157 days). DISCUSSION: Despite a higher rate of interventions and local complications during the first 3 months, AVF and particularly radio-cephalic AVF, is a valid procedure for octogenarians, without lengthening the exposure time to the catheter.

Mathematical model to predict B-type natriuretic peptide levels in haemodialysis patients.

AIM: Clinical interpretation of B-type natriuretic peptide (BNP) levels in haemodialysis (HD) patients for fluid management remains elusive. METHODS: We conducted a retrospective observational monocentric study. We built a mathematical model to predict BNP levels, using multiple linear regressions. Fifteen clinical/biological characteristics associated with BNP variation were selected. A first cohort of 150 prevalent HD (from September 2015 to March 2016) was used to build several models. The best model proposed was internally validated in an independent cohort of 75 incidents HD (from March 2016 to December 2017). RESULTS: In cohort 1, mean BNP level was 630 ± 717 ng/mL. Cardiac disease (CD - stable coronary artery disease and/or atrial fibrillation) was present in 45% of patients. The final model includes age, systolic blood pressure, albumin, CD, normo-hydrated weight (NHW) and the fluid overload (FO) assessed by bio-impedancemetry. The correlation between the measured and the predicted log-BNP was 0.567 and 0.543 in cohorts 1 and 2, respectively. Age (ß = 3.175e-2 , P < 0.001), CD (ß = 5.243e-1 , P < 0.001) and FO (ß = 1.227e-1 , P < 0.001) contribute most significantly to the BNP level, respectively, but within a certain range. We observed a logistic relationship between BNP and age between 30 and 60 years, after which this relationship was lost. BNP level was inversely correlated with NHW independently of CD. Finally, our model allows us to predict the BNP level according to the FO. CONCLUSION: We developed a mathematical model capable of predicting the BNP level in HD. Our results show the complex contribution of age, CD and FO on BNP level.

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/- atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity. METHODS: The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronicallyHCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. RESULTS: The Tbet+CD11c+CD27+CD21- AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127-/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region. CONCLUSION: Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses. LAY SUMMARY: B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells.

Functional erythropoietin-hepcidin axis in recombinant human erythropoietin independent haemodialysis patients.

AIM: Relatively few haemodialysis (HD) patients remain independent of recombinant human erythropoietin ('rHU-EPO free patients'). We investigated the role of EPO and hepcidin, two key hormones involved in anaemia. METHODS: We report a monocentric case-control series. Iron status, EPO and hepcidin levels were analysed in 15 Adult HD (Age > 18 years) with a stable haemoglobin (Hb) level that have not received rHU-EPO for at least 6 months (=rHU-EPO free patients); and in 60 controls with a stable rHU-EPO dose and Hb level. RESULTS: The rHU-EPO free patients had a higher Hb level compared to controls (12.1 ± 0.99 g/dL vs 11.1 ± 0.73, P = 0.0014), and a lower ferritin level (183 ± 102 vs 312 ± 166 ng/mL, P = 0.001). Hepcidin levels were lower in the rHU-EPO free patients (12.53 ± 10.46 ng/mL) compared to the controls (37.95 ± 34.33 ng/mL), P = 0.0033. Hepcidin levels correlated significantly with ferritin levels; but neither with transferrin saturation, C-reactive protein nor EPO levels. Unsupervised analysis revealed that rHU-EPO free patients had a specific clinical/biological profile (presence of renal cyst, longer dialysis vintage, lower ferritin, and EPO and hepcidin levels compared to the control group). Finally, we showed that a lower ferritin level might be a surrogate marker of a lower hepcidin status in this population. CONCLUSION: Recombinant human erythropoietin free patients seem to restore the EPO-hepcidin axis that is critical for erythropoiesis. A specific combination of clinical and biological parameters may help to detect future rHU-EPO free patients.

Rituximab in anti-GBM disease: A retrospective study of 8 patients.

OBJECTIVES: Anti-glomerular basement membrane (GBM) disease is a rare autoantibody-mediated disorder presenting as rapidly progressive glomerulonephritis, and often with pulmonary hemorrhage. Antibody removal with plasmapheresis and immunosuppressive drugs are the cornerstones of the treatment. Data regarding the use of specific B-cell depleting therapy such as rituximab are lacking. METHODS: We conducted a retrospective observational study of 8 patients with severe and/or refractory GBM disease that received rituximab therapy. RESULTS: Eight patients (2 men, 6 women) with a mean age of 26 ± 13.1 years old were included. Seven had severe renal involvement [median creatinin level was 282 µmol/l, range (65-423)] requiring high immunosuppressive or plasmapheresis dependent, and two had relapse of pulmonary hemorrhage including one with renal failure. Patients received an initial immunosuppressive treatment including steroid and cyclosphosphamide (n = 8) and plasmapheresis (n = 5). Except one late relapse, rituximab therapy was started within two months after diagnosis. All patients except one received 4 weekly dose of rituximab (375 mg(2)). Anti-GBM antibodies were still present in 6/8 patients, at rituximab initiation. Complete remission was observed in 7 out of 8 patients, mostly 3 months after rituximab therapy. After a mean follow-up of 25.6 months (range 4-93), patient and renal survival were 100% and 75% respectively, but rituximab use did not improve GFR. Anti-GBM antibodies remained negative for all patients during follow-up. Only one patient developed a severe bacterial infection but no opportunistic or viral infections were reported. CONCLUSION: Rituximab may represent an additional and/or alternative therapy in the induction treatment of anti-GBM disease.

Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a major proallergic cytokine that promotes TH2 responses through dendritic cell (DC) activation. Whether it also plays a role in human autoimmune inflammation and associated pathways is not known. OBJECTIVE: In this study we investigated the potential role of several epithelium-derived factors, including TSLP, in inducing IL-23 production by human DCs. We further dissected the role of TSLP in patients with psoriasis, an IL-23-associated skin autoimmune disease. METHODS: The study was performed in human subjects using primary cells and tissue samples from patients with psoriasis and healthy donors. We analyzed the production of IL-23 in vitro by blood and skin DCs. We studied the function for TSLP and its interaction with other components of the inflammatory microenvironment in situ and ex vivo. RESULTS: We found that TSLP synergized with CD40 ligand to promote DC activation and pathogenic IL-23 production by primary blood and skin DCs. In situ TSLP was strongly expressed by keratinocytes of untreated psoriatic lesions but not in normal skin. Moreover, we could demonstrate that IL-4, an important component of the TH2 inflammation seen in patients with atopic dermatitis, inhibited IL-23 production induced by TSLP and CD40 ligand in a signal transducer and activator of transcription 6-independent manner. CONCLUSION: Our results identify TSLP as a novel player within the complex psoriasis cytokine network. Blocking TSLP in patients with psoriasis might contribute to decreasing DC activation and shutting down the production of pathogenic IL-23.

Diagnosis and management of pruritus associated with chronic kidney disease in hemodialyzed patients / Diagnostic et prise en charge du prurit associé à la maladie rénale chronique chez les patients hémodialysés

Chronic kidney disease-associated pruritus (CKD-aP) is a disabling symptom which is frequent and often underestimated. Pa-MRC has a negative impact on quality of life, and is frequently accompanied by sleep disorders and depression. The approval of difelikefalin ­ a kappa opioid receptor agonist ­ in this indication requires updated recommendations. As a first step, secondary causes of pruritus without skin lesions must be ruled out, and general measures taken (emollients, psychological support, optimization of dialysis, normalization of serum calcium, phosphate and PTH in the range proposed by the KGIDO guidelines, treatment of iron deficiency). A therapeutic test with a non-sedating oral antihistamine may be proposed. If this test is negative, Pa-MRC must be strongly suspected, and its intensity (WI-NRS scale) and impact on quality of life assessed. In the case of mild Pa-MRC (WI-NRS ≤ 3), only general measures are implemented. If Pa-MRC is moderate to severe (WI-NRS ≥ 4), specific treatment with difelikefaline can be initiated for 6 months in addition to general measures. At 3 months, if the response is complete (WI-NRS score ≤ 1) or partial (decline ≥ 3 points), treatment is continued. At 6 months, if the response is complete, treatment may be discontinued with the patient's agreement; treatment is maintained if the response is partial. At 3 or 6 months, if response is insufficient (decline < 3 points) and/or in the event of intolerance, treatment is discontinued and an alternative treatment (e.g., gabapentinoids, UVB) may be considered after dermatological consultation.

Le prurit associé à la maladie rénale chronique (Pa-MRC) est un symptôme invalidant qui est fréquent et souvent sous-estimé. Le Pa-MRC a des conséquences négatives sur la qualité de vie et s'accompagne fréquemment de troubles du sommeil et de dépression. L'approbation de la difélikéfaline ­ agoniste des récepteurs opioïdes kappa ­ dans cette indication nécessite l'actualisation des recommandations. Les causes secondaires de prurit sans lésions cutanées doivent être exclues et des mesures générales doivent être prises (émollients, aide psychologique, optimisation de la dialyse, équilibre phosphocalcique avec parathormone [PTH] dans la cible KDIGO [Kidney Disease: Improving Global Outcomes], traitement de la carence martiale). Une épreuve thérapeutique avec un antihistaminique oral non sédatif peut être proposée. En cas de test négatif, il faut fortement suspecter un Pa-MRC et évaluer son intensité (échelle WI-NRS [Worst Itch Numeric Rating Scale]) et son impact sur la qualité de vie. En cas de Pa-MRC léger (WI-NRS ≤ 3), seules les mesures générales sont mises en œuvre. Si le Pa-MRC est modéré à sévère (WI-NRS ≥ 4), un traitement spécifique par difélikéfaline peut être instauré pour 6 mois en plus des mesures générales. À 3 mois, si la réponse est complète (score WI-NRS ≤ 1) ou partielle (baisse ≥ 3 points), le traitement est poursuivi. À 6 mois, si la réponse est complète, l'arrêt du traitement peut être envisagé avec l'accord du patient ; il est maintenu en cas de réponse partielle. À 3 ou 6 mois, en cas de réponse insuffisante (baisse < 3 points) et/ou d'intolérance, le traitement est interrompu et un autre traitement (par exemple, gabapentinoïdes, ultraviolet de type B [UVB]) peut être envisagé après avis dermatologique.

Pruritus associated with chronic kidney disease in hemodialysis patients: a survey in French nephrologists / Prurit associé à la maladie rénale chronique chez les patients hémodialysés : une enquête auprès des néphrologues français

Background: Chronic kidney disease-associated pruritus (CKD-aP) is common in hemodialysis patients and severely impairs their quality of life, but the practices of nephrologists remain poorly known. Methods: The objective of this on-line survey was to describe the management of CKD-aP in French nephrologists affiliated with the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) and involved in hemodialysis. Results: In total, 122 questionnaires were completed and 100 were usable. Nephrologists reported they personally managed a median of 52 patients; they estimated that the CKD-aP prevalence in their hemodialysis patients was a median of 10% (IQR, 6.3-17.2); 6% of nephrologists reported not following any patient with CKD-aP. In case of CKD-aP, the first-intention intervention was the evaluation of phosphocalcic metabolism (53.5%) and verification of dialysis adequacy (52%). For moderate-to-severe CKD-aP, the first-line prescription was topical therapy (71.3%), antihistamine (23.2%) and membrane change (15.9%). Patients were referred to a dermatologist mainly in case of treatment failure (86.9%) or scratching lesions (40.4%). Available treatments were considered ineffective for 50.5% of nephrologists, partially effective for 45.5% and effective for only 4%. Conclusion: These results show that according to the opinion of nephrologists, the pruritus prevalence is low in dialysis patients. This is inconsistent with studies based on systematic patient interviews, thus suggesting that pruritus is a symptom overlooked by nephrologists. In the context of the arrival of a new drug for pruritus, patients should be more questioned about this symptom in order to propose this treatment.

Introduction: Le prurit associé à l'insuffisance rénale chronique (Pa-IRC) est fréquent chez les patients hémodialysés et altère gravement leur qualité de vie, mais les pratiques des néphrologues restent mal connues. Méthodes: L'objectif de cette enquête en ligne était de décrire la prise en charge du Pa-IRC par les néphrologues français hémodialyseurs affiliés à la Société francophone de néphrologie, dialyse et transplantation (SFNDT). Résultats: Au total, 122 questionnaires ont été remplis et 100 étaient utilisables. Les néphrologues suivaient personnellement 52 patients (médiane). Ils estimaient que la prévalence du Pa-IRC chez ces patients était de 10 % (médiane ; écart interquartile : 6,3-17,2) ; 6 % des néphrologues ont déclaré ne suivre aucun patient atteint de Pa-IRC. En cas de Pa-IRC, l'intervention de première intention était l'évaluation du métabolisme phosphocalcique (53,5 %) et la vérification de la qualité de dialyse (52 %). Pour le Pa-IRC modéré à sévère, la prescription de première intention était un traitement topique (71,3 %), un antihistaminique (23,2 %) et un changement de membrane (15,9 %). Les traitements disponibles étaient considérés comme inefficaces pour 50,5 % des néphrologues, partiellement efficaces pour 45,5 % et efficaces pour seulement 4 %. Conclusion: Ces résultats montrent que selon l'opinion des néphrologues, la prévalence du prurit est faible chez les patients dialysés. Ceci est en contradiction avec les études basées sur des entretiens systématiques avec les patients, suggérant ainsi que le prurit est un symptôme sous-estimé par les néphrologues. Dans le contexte de l'arrivée d'un nouveau médicament pour le prurit, les patients devraient être davantage interrogés sur ce symptôme afin de proposer ce traitement.

Moderate-to-severe pruritus in untreated or non-responsive hemodialysis patients: results of the French prospective multicenter observational study Pruripreva.

Background: Chronic kidney disease-associated pruritus (CKD-aP) is a common condition in patients treated with hemodialysis, and has a negative impact on quality of life (QoL). Due to the lack of standardized diagnostic tools and frequent underreporting, pruritus prevalence remains poorly documented. Methods: Pruripreva was a prospective multicenter observational study that aimed to evaluate the prevalence of moderate to severe pruritus in a cohort of French hemodialysis patients. The primary endpoint was the rate of patients with mean Worst Itch Numerical Rating Scale (WI-NRS) score ≥4 calculated over 7 days (moderate pruritus, 4-6; severe, 7-8; very severe, 9-10). Impact of CKD-aP on QoL was analyzed according to its severity (WI-NRS), using 5-D Itch scale, EQ-5D and Short Form (SF)-12. Results: Mean WI-NRS was ≥4 in 306 patients (mean age, 66.6 years; male, 57.6%) out of 1304 and prevalence of moderate to very severe pruritus was 23.5% (95% confidence interval 21.2-25.9). Pruritus was unknown prior to the systematic screening in 37.6% of patients, and 56.4% of those affected were treated for this condition. The more severe the pruritus, the poorer the QoL according to the 5-D Itch scale, EQ-5D and SF-12. Conclusion: Moderate to very severe pruritus was reported in 23.5% of hemodialysis patients. CKD-aP was underrated although it is associated with a negative impact on QoL. These data confirm that pruritus in this setting is an underdiagnosed and underreported condition. There is an urgent demand for new therapies to treat chronic pruritus associated with CKD in hemodialysis patients.

Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease.

BACKGROUND: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology. OBJECTIVE: To determine the nature of T cells driving inflammatory lesions in BD. METHODS: T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = 20]) and 20 healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis. RESULTS: We found a marked increase in T(H)17 cells and a decrease in the frequency of CD4(+) forkhead box P3(+) regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4(+) T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21- and IL-17A-producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4(+) T cells with IL-21 increased T(H)17 and T(H)1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the T(H)17 and Treg homeostasis in patients with BD. CONCLUSION: We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting T(H)17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD.

Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use.

PURPOSE OF REVIEW: Here, we review recent advances and new insights in mechanistic target of rapamycin (mTOR) biology (signalling pathway, kidney biology and immune system), and recent clinical data on mTOR inhibitors related to solid organ transplantation. RECENT FINDINGS: The mTOR pathway is a major integrator of signals governing protein and lipid biosynthesis and growth factor-driven cell cycle progression. Recent findings have emphasized a critical role of mTOR in cellular homeostasis with a crucial role in podocyte function. Beyond CD8(+) and regulatory T-cell control, mTOR protein is involved in critical biological functions of T helper cells or dendritic cells. New specific inhibitors of mTORC1/C2 are available and shed new light on mTOR functions. Finally, clinical trials have better defined the use of mTOR inhibitors and emphasized their role in cancer prevention. SUMMARY: The mTOR pathway is considered as a key integrator of multiple inputs that drives numerous biological processes in cell biology. mTOR inhibitors are potent immunosuppressive drugs for solid organ transplantation. Newly designed specific inhibitors of mTOR complex 1 and 2 offer promising therapeutic effects and a better understanding of the pathway. Many conditions may benefit from mTOR inhibition for a short period, but tolerance of treatment in a chronic setting remains a major concern.

Nouvelles thérapies dans la prise en charge du patient avec maladie rénale chronique souffrant de prurit : une revue de la littérature New therapies in the management of chronic kidney disease associated pruritus.

Chronic Kidney Disease associated Pruritus (CKD-aP) is a well-established and frequent complication observed in patient with CKD, especially in dialysis patients. However, the management of CKD-aP remains a challenge as the pathophysiology and research studies are too small. Finally, there are a few proposed treatment options with significant clinical benefits. This general review will summarize all the available treatments for the CKD-aP and will highlight the clinical efficacy and limits of the current drugs. Notably, we will focus on the implication of the opioid receptor in the pathophysiology of the CKD-aP and the recently Kappa opioid receptor agonist. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.

Semaglutide for treatment of obesity in hemodialysis patients waiting for a kidney transplant: new hope?

Obesity limits the access to kidney transplantation and increases the risk of complications and mortality posttransplantation. Usual noninvasive measures, including lifestyle changes and dietary education, do not provide long-term and consistent body weight reduction. In many cases, only bariatric surgery allows patients to significantly reduce body weight. We here report two cases of obese hemodialysis (HD) patients who were successfully treated with off-labeled semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA). The first patient had a body mass index (BMI) of 45.7 kg/m2 despite a history of partial gastrectomy. The second patient had a history of type 2 diabetes mellitus and a BMI of 36.5 kg/m2. Both patients started semaglutide at the maximal subcutaneous dose of 1 mg/week, which was clinically well tolerated. During the 9-month follow-up, body weight loss ranged from 6.5 to 9.0 kg, ∼1 kg/month. GLP-1RAs, such as semaglutide or liraglutide, could be a novel pharmacological alternative to bariatric surgeries for these HD patients.

Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production.

T helper 17 (Th17) cells produce IL-17 but can also make tumor necrosis factor, interleukin (IL)-6, IL-10, IL-21, and IL-22. These cytokines collectively contribute to the functional outcome of the Th response. IL-22 plays a critical role in some Th17-associated diseases, such as psoriasis, but its relationship to IL-17 remains controversial. Here, we used a systematic multiparametric analysis of Th-17-associated cytokines, which revealed the unexpected finding that the regulation pattern of IL-22 was most closely related to interferon-gamma, the prototypical Th1 cytokine, and not to IL-17. To explain this observation, we systematically tested the role of Th1- and Th17-inducing cytokines. We could show that IL-12 and IL-23 induced high levels of IL-22 but no IL-17. Conversely, transforming growth factor-beta inhibited IL-22 production but promoted IL-17. Thus, IL-17 and IL-22 are differentially regulated during cytokine-induced Th cell differentiation. This has important implications for the understanding and pharmacologic manipulation of Th17-associated pathologies.