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mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome.

BackgroundRenal transplantation is increasingly associated with the presence of comorbidity factors such as dyslipidemia which could influence the graft outcome. We hypothesized that hypercholesterolemia could affect vascular repair processes and promote post-transplant renal vascular remodeling through the over-expression of the anti-angiogenic thrombospondin-1 interacting with vascular endothelial growth factor-A levels.MethodsWe tested this hypothesis in vitro, in vivo and in a human cohort using (1) endothelial cells; (2) kidney auto-transplanted pig subjected (n = 5) or not (n = 6) to a diet enriched in cholesterol and (3) a renal transplanted patient cohort (16 patients).ResultsCells exposed to oxidized LDL showed reduced proliferation and an increased expression of thrombospondin-1. In pigs, 3 months after transplantation of kidney grafts, we observed a deregulation of the hypoxia inducible factor 1a—vascular endothelial growth factor-A axis induced in cholesterol-enriched diet animals concomitant with an overexpression of thrombospondin-1 and a decrease in cortical microvessel density promoting vascular remodeling. In patients, hypercholesterolemia was associated with decreased vascular endothelial growth factor-A plasma levels during early follow up after renal transplantation and increased chronic graft dysfunction.ConclusionsThese results support a potential mechanism through which a high fat-diet impedes vascular repair in kidney graft and suggest the value of controlling cholesterolemia in recipient even at the early stage of renal transplantation.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1764-4) contains supplementary material, which is available to authorized users.

Background: Delayed hemolytic transfusion reaction (DHTR) is an unpredictable and severe complication of transfusion, especially in Sickle Cell Disease (SCD) patients (Habibi Am J Hematol 2016). The clinical presentation is a vaso occlusive crisis (VOC), often associated with one or more organ failures, after packed red blood cell transfusion (pRBC). The hypothesis of complement activation through the classical pathway by alloantibodies and/or the alternative pathway by free heme (released by hemolysis) suggests that an inhibitor of complement activation may be a treatment option for DHTR. Methods: This retrospective study focuses on the SCD patients who received anti-C5 monoclonal antibody during DHTR treatment after consulting with our French SCD referral center between 2013 and 2018. DHTR diagnosis associated VOC signs occurring 5 to 20 days after pRBC transfusion, with no other cause for intravascular hemolysis, and one or more of the following: - rapid decrease in, or unexpectedly low, hemoglobin A (HbA) concentration - hemoglobinuria defined by dark urines - direct antiglobulin test (DAT) positivity or new antibody formation. The treatment efficacy was evaluated through patients' clinical and biological data. Findings: Sixteen patients received anti-C5 for a DHTR defined by a VOC 5 to 20 days after a transfusion and the following criteria: 12 had low HbA or rapid decrease of HbA, 10 had hemoglobinuria, and 10 had positive DAT or antibody formation. One patient received anti-C5 for hyperhemolysis without being able to discriminate DHTR from hemolysis under Extracorporeal Membrane Oxygenation and was excluded from the analysis. The 16 patients included in the analysis had severe DHTR at diagnosis, with one or more organ failures (N=7), median hemoglobin concentration 57 g/L [30-97], LDH 2807 UI/L [510-12500], total bilirubin 92 mmol/L [15-730]. Two additional patients had organ failures during the follow-up. Lowest hemoglobin concentration was 32 g/L [19-58] and highest LDH 4238 UI/L [510-24000]. One to 3 anti-C5 doses were given at 1 week intervals, associated with symptomatic treatment (hydration, oxygen, analgesia; N=16), erythropoietin (N=15), pRBC transfusions (N=12), immunoglobulins (N=8), plasma exchange (N=4), steroids (N=1). The outcome was favorable for 13 patients. The number of pRBC transfused were limited as much as possible. Three patients died. All three had acute liver failure that required emergency liver transplant. Two patients improved after anti-C5 and could be grafted, but died of infectious complications unrelated to anti-C5: Klebsiella pneumoniae pulmonary infection 11 days after transplant for one, and digestive and urinary infection 47 days after transplant for the other. For the third patient, no compatible organ could be found. Conclusion: In association with other therapies (EPO, plasma exchange, limiting pRBC transfusions), anti-C5 can be a treatment option for severe DHTR despite its high cost, in the absence of effective alternatives. Disclosures Michel: Amgen: Consultancy; Rigel: Consultancy; Novartis: Consultancy. Bartolucci:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Anti-C5 is currently used to treat paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

CASE REPORTS Anti-C5 antibody treatment for delayed hemolytic transfusion reactions in sickle cell disease Delayed hemolytic transfusion reaction (DHTR) is an unpredictable severe complication of transfusion in patients with sickle cell disease (SCD). It presents clinically as a vaso-occlusive crisis (VOC), often associated with the failure of one or more organs, after the transfusion of packed red blood cells (pRBC). 1,2 Hyperhemolysis is encountered in the most severe forms. Both transfused and autologous red blood cells (RBC) are lysed. The mechanisms underlying DHTR remain unclear. Continuous variables are expressed as means ± one standard deviation (SD) or medians (MD, [interquartile range]), depending on whether they are normally or asymmetrically distributed. Categorical variables are expressed as numbers (%). For comparison with the largest published delayed hemolytic transfusion reaction (DHTR) series, the data in column 2 are reprinted from Habibi et al.1 with permission. The patients of our series, who received anti-C5 antibody, had very severe DHTR with hyperhemolysis (P-values in column 3 compare our patients with those of the historical series). *Six patients had not even been discharged, due to the severity of their DHTR, **All patients in both series also received supportive vaso-occlusive crisis (VOC) treatment, hydration, oxygenation, and analgesia. † Values were converted to g/L (from g/dL in Habibi et al.). ‡ Delta hemoglobin (Hb) is the difference between the highest and lowest values available post-transfusion. F: female; M: male; pRBC: packed red blood cells, LDH: lactate dehydrogenase, EPO: erythropoietin.

In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemiareperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.

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