Lorette Noiret

Interorgan ammonia metabolism in liver failure: the basis of current and future therapies.

Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia‐regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches.

Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury.

In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury.

Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats.

BACKGROUND & AIMS In liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this study were to determine the protein expression and activity of GS and GA in individual organs in a rat model of chronic liver disease and to test whether the treatment with the ammonia-lowering agent ornithine phenylacetate (OP) modulates their activities. METHODS 49 SD rats were studied 35 days after sham-operation or bile duct ligation (BDL). The BDL group received: L-ornithine (0.6 mg/kg/day), Phenylacetate (0.6 mg/kg/day), OP (0.6 mg/kg/day) or placebo (saline) for 5 days prior to sacrifice. Arterial ammonia, amino acids and liver biochemistry were measured. Expressions of GS and GA were determined by Western-blotting and activities by end-point methods in liver, muscle, gut, kidney, lung, and frontal cortex. RESULTS In BDL rats, hepatic GS enzyme activity was reduced by more than 80% compared to sham rats. Further, in BDL rats GA activity was reduced in liver but increased in the gut, muscle and frontal cortex compared to sham rats. OP treatment resulted in a reduction in hyperammonemia in BDL rats, associated with increased GS activity in the muscle and reduced gut GA activity. CONCLUSIONS In a rat model of chronic liver failure, hyperammonemia is associated with inadequate compensation by liver and muscle GS activity and increased gut GA activity. OP reduces plasma ammonia by increasing GS in the muscle and reducing GA activity in the gut providing additional insights into its mechanism of its action. GS and GA may serve as important future therapeutic targets for hyperammonemia in liver failure.

Arterial ammonia levels in cirrhosis are determined by systemic and hepatic hemodynamics, and by organ function: a quantitative modelling study

Hyperammonaemia is a common complication of chronic liver failure. Two main factors are thought to underlie this complication: a loss of hepatic detoxification function and the development of portosystemic shunting. However, few studies have tried to quantify the importance of portosystemic shunting. Here, we used a theoretical approach to test the hypothesis that the development of portosystemic shunting is sufficient to cause hyperammonaemia in cirrhosis.

Mathematical Model of Ammonia Handling in the Rat Renal Medulla

The kidney is one of the main organs that produces ammonia and release it into the circulation. Under normal conditions, between 30 and 50% of the ammonia produced in the kidney is excreted in the urine, the rest being absorbed into the systemic circulation via the renal vein. In acidosis and in some pathological conditions, the proportion of urinary excretion can increase to 70% of the ammonia produced in the kidney. Mechanisms regulating the balance between urinary excretion and renal vein release are not fully understood. We developed a mathematical model that reflects current thinking about renal ammonia handling in order to investigate the role of each tubular segment and identify some of the components which might control this balance. The model treats the movements of water, sodium chloride, urea, NH3 and NH4+, and non-reabsorbable solute in an idealized renal medulla of the rat at steady state. A parameter study was performed to identify the transport parameters and microenvironmental conditions that most affect the rate of urinary ammonia excretion. Our results suggest that urinary ammonia excretion is mainly determined by those parameters that affect ammonia recycling in the loops of Henle. In particular, our results suggest a critical role for interstitial pH in the outer medulla and for luminal pH along the inner medullary collecting ducts.

Determinants of red blood cell alloantibody detection duration: analysis of multiply alloimmunized patients supports peritransfusion factors

Alloimmunization to red blood cells (RBCs) can cause serious transfusion reactions and complicate the search for compatible blood products. Alloantibodies can be detected for periods ranging from a few days to several years, yet the mechanisms controlling the duration of detectability remain unknown. We studied the detection durations in patients forming multiple antibodies to investigate whether the duration is more strongly determined by conditions present at the time of each transfusion (peritransfusion factors) or by more stable patient‐specific factors likely to persist across transfusions.

White blood cell population dynamics for risk stratification of acute coronary syndrome

Significance Medical doctors use blood counts to help diagnose and monitor almost all diseases. In the process of counting blood cells, most hematology analyzers actually measure features of thousands of individual blood cells, but this single-cell information is rarely utilized, and only the derived total cell counts are used to guide clinical care. This single-cell information helps further characterize each patient’s inflammatory or immunologic state. Using a mathematical model, we show how this routinely available single-cell information can help distinguish healthy and sick patients in general and those with acute coronary syndrome in particular. More broadly, our study shows how mathematical modeling of existing routine clinical laboratory data can help realize the vision of precision medicine today. The complete blood count (CBC) provides a high-level assessment of a patient’s immunologic state and guides the diagnosis and treatment of almost all diseases. Hematology analyzers evaluate CBCs by making high-dimensional single-cell measurements of size and cytoplasmic and nuclear morphology in high throughput, but only the final cell counts are commonly used for clinical decisions. Here, we utilize the underlying single-cell measurements from conventional clinical instruments to develop a mathematical model guided by cellular mechanisms that quantifies the population dynamics of neutrophil, lymphocyte, and monocyte characteristics. The dynamic model tracks the evolution of the morphology of WBC subpopulations as a patient transitions from a healthy to a diseased state. We show how healthy individuals and hospitalized patients with similar WBC counts can be robustly classified based on their WBC population dynamics. We combine the model with supervised learning techniques to risk-stratify patients under evaluation for acute coronary syndrome. In particular, the model can identify more than 70% of patients in our study population with initially negative screening tests who will be diagnosed with acute coronary syndrome in the subsequent 48 hours. More generally, our study shows how mechanistic modeling of existing clinical data can help realize the vision of precision medicine.

588 ALBUMIN RESTORES RENAL BLOOD FLOW (RBF) AUTOREGULATION IN PATIENTS WITH REFRACTORY ASCITES AND ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) THROUGH STABILIZATION OF ENDOTHELIAL FUNCTION

Introduction Haemodynamic alterations in liver failure are associated with endothelial dysfunction, a pro-inflammatory state and sympathetic activation which lead to disturbed RBF autoregulation and renal failure. Albumin is a multifunctional protein that has been shown in several studies to prevent and treat renal dysfunction in patients with advanced cirrhosis and liver failure. We hypothesised that the beneficial effects of albumin in cirrhosis is likely to be through mechanisms in addition to volume expansion. The aims of the study were to investigate the effects of albumin on systemic and renal haemodynamics, inflammation and endothelial dysfunction in refractory ascites and patients with acute kidney injury (AKI) in the setting of ACLF. Methods Twenty-two patients were recruited [Group 1, n=12, refractory ascites; Group 2, n=10 patients with AKI admitted with an acute deterioration of their liver function due to either alcoholic hepatitis or infection]. Both groups were treated with Albumin 60 g/d over 3–4 days. Cardiac output (CO) and renal blood flow (RBF) haemodynamics were measured. Endothelial dysfunction was assessed through measurement of von Willebrand factor (vWF) and serum nitrite (NO) levels. F2α Isoprostanes (F2α), resting neutrophil burst and Interleukin (IL)-6 were quantified as markers of oxidative stress, endotoxemia and inflammation respectively. Results Albumin therapy was associated with significant improvements in haemodynamic parameters (increased RBF, MAP, decreased CO, HR; p 2 =0.55, p Conclusion This study suggests that albumin infusion improves albumin function which has pleiotropic effects and results in a reduction in inflammation and improvement in endothelial function leading to improved systemic haemodynamics and renal blood flow autoregulation. Competing interests None declared.