Background Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. Methods A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). Results Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7–16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2–6] in the L-citrulline group vs. 4 [IQR, 2–7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. Conclusion Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. Trial registration : ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).

Background Recent data suggest that hyperchloremia induced by fluid resuscitation is associated with acute kidney injury (AKI) and mortality, particularly in sepsis. Experimental studies showed that hyperchloremia could affect organ functions. In patients with septic shock, we examined the relationship between serum chloride concentration and both renal function and survival. Methods Post hoc analysis of the “HYPER2S” trial database (NCT01722422) including 434 patients with septic shock randomly assigned for resuscitation with 0.9% or 3% saline. Metabolic parameters were recorded up to 72 h. Metabolic effects of hyperchloremia (> 110 mmol/L) were studied stratified for hyperlactatemia (> 2 mmol/L). Cox models were constructed to assess the association between chloride parameters, day-28 mortality and AKI. Results 413 patients were analysed. The presence of hyperlactatemia was significantly more frequent than hyperchloremia (62% versus 71% of patients, respectively, p = 0.006). Metabolic acidosis was significantly more frequent in patients with hyperchloremia, no matter the presence of hyperlactatemia, p < 0.001. Adjusted risk of AKI and mortality were not significantly associated with serum chloride, hyperchloremia, maximal chloremia and delta chloremia (maximal-H0 [Cl]). Conclusions Despite more frequent metabolic acidosis, hyperchloremia was not associated with an increased risk for AKI or mortality. Trial registration ClinicalTrials.gov, identifier: NCT01722422, registered 2 November 2012

BACKGROUND/AIMS:Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown.METHODS:To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys.RESULTS:In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity.CONCLUSIONS:These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis.

Objectives: To assess the role of advanced age on survival and dialysis dependency after initiation of renal replacement therapy for acute kidney injury. Design: Retrospective pooled analysis of prospectively collected data. Setting: ICUs of two teaching hospitals in Paris area, France. Subjects: One thousand five hundred thirty adult patients who required renal replacement therapy initiation in the ICU. Interventions: None. Measurements and Main Results: Survival and post acute kidney injury chronic dialysis dependency were assessed at hospital discharge according to the quintile (Q) of age. The oldest quintile included 289 patients 80 years old and over. Seventy-three percent of included patients had respiratory and hemodynamic supports at renal replacement therapy initiation, similarly distributed across quintiles. Mortality increased with age strata from 63% in Q 1 (≤ 52 yr) to 76% in Q 5 (≥ 80 yr) ( p < 0.001). After adjustment, age did not increase the risk of death up to 80 years. The oldest patients (≥ 80 yr) had a significant higher risk of dying (adjusted odds ratio, 2.59; 95% CI, 1.66–4.03). Dialysis dependency was more frequent among survivors 80 years old or older (30% vs 14%; p = 0.001). Age 80 years old or older was an independent risk for dialysis dependency only for patients with prior advanced chronic kidney disease ( p = 0.04). Baseline estimated glomerular filtration rate was the only one predictor of dialysis dependency identified. Conclusions: Patients with advanced age represent a substantial subgroup of patients requiring renal replacement therapy in the ICU. From 80 years, age should be considered as an additional risk of dying over the severity of organ failures. Patients 80 years old or older are likely to recover sufficient renal function allowing renal replacement therapy discontinuation when baseline estimated glomerular filtration rate is above 44 mL/min/1.73 m 2 . At 3 months, only 6% were living at home, dialysis independent.

Approximately 25% of kidney transplant recipients develop de novo anti-HLA donor-specific antibodies (dnDSA) leading to acute antibody-mediated rejection (ABMR) in 30% of patients. Preemptive therapeutic strategies are not available.We conducted a prospective observational study including 11 kidney transplant recipients. Inclusion criteria were dnDSA occurring within the first year after transplant and normal allograft biopsy. All patients were treated with high-dose IVIG (2 g/kg 0, 1 and 2 months post-dnDSA). The primary efficacy outcome was incidence of clinical and subclinical acute ABMR within 12 months after dnDSA detection as compared to a historical control group (IVIG-).Acute ABMR occurred in 2 or 11 patients in the IVIG+ group and in 1 of 9 patients in the IVIG- group. IVIG treatment did not affect either class I or class II DSA, as observed at the end of the follow-up. IVIG treatment significantly decreased FcγRIIA mRNA expression in circulating leukocytes, but did not affect the expression of any other markers of B cell activation.In this first pilot study including kidney allograft recipients with early dnDSA, preemptive treatment with high-dose IVIG alone did not prevent acute ABMR and had minimal effects on DSA outcome and B cell phenotype.

A widespread belief is that typical hemolytic and uremic syndrome (HUS) does not recur. We report the case of a patient infected twice with raw milk taken from his own cow and containing a Shiga toxin-producing Escherichia coli O174:H21 that induced recurrent HUS causing severe renal and cerebral disorders. A genomic comparison of the human and bovine Shiga toxin-producing Escherichia coli O174:H21 isolates revealed that they were identical.Typical HUS may recur. Since milk from this animal was occasionally distributed locally, thereby posing a serious threat for the whole village, this particular cow was destroyed.

Acute renal failure in elderly patient is a public health problem. It is worsen by physiological status and anatomical changes associated with age, polymedication and chronic diseases. The etiologies of acute renal failure in the elderly are the same as in adults. Their distribution is specific with a large proportion of obstructive acute renal failure. The diagnostic and therapeutic strategies are the same as for young adults; the injection of iodinated-contrast should be avoided. Therapeutic strategies are discussed in terms of quality of life pre-morbid. Age is not considered a determinant of intensive treatment decisions. Renal replacement therapy in the elderly is not associated with excess mortality. Prevention of acute renal failure should be a permanent concern.

Expansion of extracellular volume is a treatment traditionally proposed to correct abnormalities of renal perfusion and prevent ischemic injury. However, vascular filling is not at risk for tissue oxygenation and renal function. The use of synthetic colloids exposes the patient to the risk of developing lesions such as osmotic nephrosis. Hyperoncotic colloids reduce glomerular filtration pressure. The nephrotoxicity of hydroxyethyl starches is now clearly established regardless of their characteristics. Colloids have never demonstrated their superiority as plasma volume expanders, they should be abandoned in favour of crystalloid solutions. (C) 2018 Published by Elsevier Masson SAS on behalf of Societe francophone de nephrologie, dialyse et transplantation.

Shoulder injury (including isolated gleno-humeral dislocation, fracture dislocation or fracture without evidence of dislocation) is a rare complication of seizures occurring with or without direct trauma.1Finelli P.F. Cardi J.K. Seizure as a cause of fracture.Neurology. 1989; 39: 858-860Crossref PubMed Google Scholar Bilateral posterior fracture dislocation may occur as a direct consequence of the motor manifestations of generalized tonic–clonic seizures (GTCS) in the absence of trauma.2Brackstone Patterson M. Kertesz S.D. Triple A. E syndrome: bilateral locked posterior fracture dislocation of the shoulders.Neurology. 2001; 56: 1403-1404Crossref PubMed Scopus (54) Google Scholar Although described as early as 1902, and considered as pathognomonic of seizures, this type of shoulder injury is the rarest form and few cases are reported in the literature.3Mynter H.X.I.V. Subacromial dislocation from muscular spasm.Annals of Surgery. 1902; 36: 117-119Crossref PubMed Google Scholar The observation of a misdiagnosed bilateral posterior fracture-dislocation following GTCS, prompted us to evaluate the incidence of shoulder injuries in patients admitted with seizures to our intensive care unit (ICU). A 46 year-old woman without significant past medical history was admitted to the emergency room following a first seizure episode. After a series of seven consecutive GTCS with return of consciousness between seizures, she was transferred to our ICU. Upon admission the patient was confused (Glasgow coma scale of 14/15), her temperature 37 °C, and arterial pressure 140/80 mm Hg. Clinical examination did not reveal any focal neurologic deficit or meningism. The rest of the physical exam was normal with the exception of bilateral shoulder pain. Cerebro-spinal fluid and brain CT scan were unremarkable. Chest X-ray performed in bed was normal. There were no pulmonary or bony abnormalities (although the gleno-humeral joints were not captured). The seizures were successfully controlled with a loading dose of phenytoin. There was no acute seizure recurrence and the patient was discharged home two days later with an appointment for a follow-up visit with a neurologist. As shoulder pains and functional disability persisted, however, shoulder X-rays were performed and revealed bilateral posterior fracture-dislocations of the shoulder. A retrospective review of all discharge reports of patients admitted to our ICU for GTCS during the preceding 18-month period revealed three additional cases of shoulder injuries among 56 patients, giving an overall incidence rate of 7% (4/56) (Fig. 1). Different injuries were identified in the 3 additional patients: one anterior dislocation with fracture of the lesser tuberosity (Fig. 2), and one unilateral and one bilateral surgical neck fracture. The diagnosis was suspected because of pain or visible deformation in a patient still comatose, and confirmed by shoulder radiography, whereas the chest X-ray missed one of them.Fig. 2Chest X-ray performed in intensive care unit showing anterior dislocation with fracture of the lesser tuberosity (arrow).View Large Image Figure ViewerDownload Hi-res image Download (PPT) To the best of our knowledge, there is only one report on the incidence of shoulder injuries associated with seizures among 2800 patients admitted to a neurology department.1Finelli P.F. Cardi J.K. Seizure as a cause of fracture.Neurology. 1989; 39: 858-860Crossref PubMed Google Scholar Of 30 patients (1%) having a fracture, only 7 (0.25%) had a shoulder injury (1 bilateral posterior fracture dislocation, 3 surgical neck and 3 anatomical neck fractures).1Finelli P.F. Cardi J.K. Seizure as a cause of fracture.Neurology. 1989; 39: 858-860Crossref PubMed Google Scholar The higher incidence of shoulder injuries recorded in our ICU patients is likely to be explained by the greater severity of the seizure disorders (series of GTCS or GTC status epilepticus) with which our patients presented. Notably, our 7% incidence rate may underestimate the real incidence of ictal shoulder injuries as it reflects only those identified during the course of ICU stay. Some of seizure-related shoulder injuries may have remained undetected during patients' hospital stay and then presented subsequently as shoulder instability. Posterior instability is less common than anterior.4Goudie E.B. Murray I.R. Robinson C.M. Instability of the shoulder following seizures.Journal of Bone and Joint Surgery. British Volume. 2012; 94: 721-728Crossref PubMed Scopus (7) Google Scholar However, in the absence of trauma, posterior dislocation is virtually pathognomonic of seizure, especially if it is bilateral. Moreover, glenohumeral dislocations are frequently associated with injury to the rotator cuff tendons or coracoid fracture. Therefore, even in the absence of confirmed dislocation or fracture, patients with functional impairment of the shoulder joint following seizures should be referred for orthopaedic assessment. Although there are uncertainties about the true incidence of this rare complication, we believe our report should prompt neurologists and intensivists to be more aware of seizure-related shoulder injuries, although they are not well described in textbooks focusing on "seizure" or "status epilepticus". We recommend a comparative clinical bilateral examination of both shoulders with active mobility tests in all patients admitted to the ICU for seizure and a systematic bilateral X-Ray of shoulder in case of shoulder pain. The authors have no conflict of interest to declare in relation to this manuscript and confirm that this manuscript has not been published elsewhere and is not under consideration by another journal.

Thrombotic microangiopathy (TMA) can be frequently observed after lung transplantation with various causes, for example, calcineurin inhibitor (CNI) toxicity or infectious disease (1). Atypical hemolytic-uremic syndrome (aHUS) is a disease related to unregulated complement progression also associated with TMA lesions (2). Plasma exchange or infusion was used to control the progression of the disease, but this therapy is invasive and not effective in all patients. The treatment and the prognosis of aHUS and its recurrence on the renal graft have been modified by the use of eculizumab, a monoclonal antibody that targets complement factor C5 and blocks the activation of the terminal complement cascade. This humanized monoclonal antibody used for the treatment of paroxysmal nocturnal hemoglobinuria has been recently approved for the treatment of aHUS or its recurrence (3, 4). We report here on the efficacy of eculizumab in a combined lung and kidney transplant recipient who presented TMA in the initial period after transplantation. The patient was a 45-year-female who developed end-stage lung disease because of pulmonary fibrosis related to sarcoidosis. She presented an end-stage renal disease (ESRD) with TMA lesion on the renal biopsies of her native kidney performed in 1998 and 2006. The initial nephropathy was considered to be aHUS. However, screening for regulatory factors of the complement system mutations or antibodies against complement factor H was negative. Hemodialysis therapy was initiated in 2008 and she was enlisted for a combined lung and kidney transplantation in 2010. She received a lung and kidney transplant from a deceased donor aged 22. She was not sensitized. Initial immunosuppressive regimen associated polyclonal antithymocyte antibodies, cyclosporine, mycophenolate mofetil, and steroids. The evolution of the lung transplant was uneventful. The initial evolution of kidney transplant was excellent with a serum creatinine at 72 μmol/L on day 5. From day 3, the platelet count falls to reach 22,000/mm3, the hemoglobin was 11.4 g/dL, the lactate dehydrogenase level was 857 UI/mL, haptoglobin was decreased to 0.07 g/L, and the creatinine was 91 μmol/L. The suspected etiologies of this TMA were either a recurrence of aHUS or acute CNI toxicity, although the cyclosporine through levels were within target (145 ng/mL). The renal evolution was unfavorable leading to the initiation of dialysis at performed with no improvement of renal function or platelet count. Eculizumab therapy was started consisting in 900 mg on day 15 and weekly thereafter until day 36. She had received prior meningococcal vaccine and antibioprophylaxis by oracillin maintained during the whole period of treatment. Hemolysis resolved, haptoglobin, and platelet count increased to normal limits and progressively renal graft recovered function leading to dialysis interruption. A renal biopsy was performed on day 20. It revealed no TMA lesion but acute tubular necrosis compatible with CNI toxicity. Histologically, we cannot definitely discriminate between aHUS recurrence and CNI toxicity. The ESRD occurred frequently after transplantation because of CNI nephrotoxicity. On native kidney biopsies in lung transplant recipients, CNI nephrotoxicity is present in 93.3% associated with TMA in 46.7% (1). We know that genetic polymorphisms of complement increased susceptibility to CNI toxicity (5). In our case, we postulate that CNI toxicity could induce an inappropriate regulation of the alternative complement pathway and so an aHUS recurrence. Our observation suggests the positive effect of eculizumab when ESRD occurs after transplantation secondary to CNI toxicity. In this context, eculizumab may be an interesting therapeutic option.FIGURE 1: Treatment effects on posttransplantation TMA: platelet count and haptoglobin evolution with treatment. Morgane Commereuc 1 Alexandre Karras1 Catherine Amrein2 Veronique Boussaud2 Rebecca Sberro-Soussan3 Romain Guillemain2 Veronique Fremeaux Bacchi4,5,6 Eric Thervet1,5,7 1 Renal Unit Hopital Europeen Georges Pompidou Assistance Publique-Hôpitaux de Paris Paris, France 2Thoracic Transplantation Unit Hopital Europeen Georges Pompidou Assistance Publique-Hôpitaux de Paris Paris, France 3 Transplant Unit, Hopital Necker Assistance Publique-Hôpitaux de Paris Paris, France 4 Service d’Immunologie Biologique Hopital Europeen Georges Pompidou Assistance Publique-Hôpitaux de Paris Paris, France 5 INSERM U845 Paris, France 6 University Paris Descartes Paris, France 7 INSERM UMR S775 Paris, France