Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

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).

Increased Fatty Acid Oxidation in Differentiated Proximal Tubular Cells Surviving a Reversible Episode of Acute Kidney Injury.

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.

ICU Patients Requiring Renal Replacement Therapy Initiation: Fewer Survivors and More Dialysis Dependents From 80 Years Old.

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 Q1 (≤ 52 yr) to 76% in Q5 (≥ 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. At 3 months, only 6% were living at home, dialysis independent.

Hyperchloremia is not associated with AKI or death in septic shock patients: results of a post hoc analysis of the "HYPER2S" trial.

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.

[Nephrotoxicity of plasma volume expanders]. / Néphrotoxicité des produits de remplissage.

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.

Intravenous immunoglobulin therapy in kidney transplant recipients with de novo DSA: Results of an observational study.

BACKGROUND: 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. METHODS: 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-). RESULTS: 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. CONCLUSIONS: 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.

Recurrent Hemolytic and Uremic Syndrome Induced by Escherichia Coli.

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 kidney injury in elderly patient: Diagnostic and therapeutic aspects]. / Insuffisance rénale aiguë chez la personne âgée : aspects diagnostiques et thérapeutiques.

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.