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Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers., Methods: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30)., Results: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group., Conclusions: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy., Impact and Implications: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy., Clinical Trial Number: NCT03065699., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In this report we present pharmacokinetic (Pk) data of daptomycin given intravenously in a peritoneal dialysis patient. Daptomycin plasma levels were within therapeutic range; however, half-life of the drug was prolonged compared to haemodialysis. Both plasma and dialysate levels were found to be consistently above the minimal inhibitory concentration for daptomycin sensitive strains.

Aims: To define the role of asymmetric dimethylarginine (ADMA) in the control of blood pressure (BP) during hemodialysis (HD)., Methods: L-Arginine, ADMA and symmetric dimethylarginine (SDMA) levels of patients with (n = 18) or without (n = 13) hypotensive episodes during HD sessions were measured before and after HD treatment by liquid chromatography-mass spectrometry. Clinical variables, laboratory parameters and underlying pathologies of end-stage renal disease (ESRD) were comparable in the groups. BP was serially recorded., Results: In patients with ESRD, plasma dimethylarginines were markedly elevated and decreased significantly by the end of the HD sessions. ADMA levels in patients having hypotensive episodes during HD were significantly higher than in those maintaining their BP (before HD: 0.62 +/- 0.11 micromol/l vs. 0.71 +/- 0.13 micromol/l, p = 0.04; after HD: 0.31 +/- 0.11 micromol/l vs. 0.43 +/- 0.11 micromol/l, p = 0.01). There was a significant inverse relationship of the minimum systolic and diastolic BP during HD to the predialysis ADMA levels (for systolic BP r = -0.50, p < 0.01; for diastolic BP r = -0.59, p < 0.01) and to the postdialysis ADMA levels (for systolic BP r = -0.49, p < 0.01; for diastolic BP r = -0.51, p < 0.005), respectively., Conclusions: It is suggested that excessive NO generation is involved in the HD-associated hypotension and induces an increase in plasma ADMA levels to prevent further fall in BP., ((c) 2008 S. Karger AG, Basel)

Experimental and clinical evidence has been accumulated to indicate that elevated plasma asymmetric dimethylarginine (ADMA) levels can be regarded as a marker of endothelial dysfunction that mediates cardiovascular morbidity by impairing NO-dependent vascular reactions; therefore, it may have a role in the cardiopulmonary adaptation of the neonate. The present study was undertaken to investigate the perinatal NO metabolism by measuring L-arginine, the NO synthase substrate, ADMA, the endogenous inhibitor of NO synthase, and symmetrical dimethylarginine (SDMA), the biologically inactive L-arginine metabolite in umbilical venous and arterial plasma and in peripheral plasma of the neonate. Measurements were done in ten healthy pregnant women at term delivery and in their newborn infants on the second day of life by using liquid chromatography-mass spectrometry method. It was demonstrated that cord blood L-arginine, ADMA, and SDMA levels were markedly elevated with a moderate, but consistent veno-arterial difference suggesting that they are mainly generated by the placental endothelium. L-Arginine and ADMA levels were found to fall significantly (p < 0.001) by the second postnatal day, whereas SDMA remained unaltered. This finding indicates accelerated enzymatic ADMA elimination and reduction in the inhibition of NO-synthase activity. It is concluded that ADMA may play a role in the control of feto-placental circulation and the circulatory adaptation of the neonate.

Background: It has been suggested that hemodiafiltration (HDF) is more efficient than hemodialysis (HD) in lowering plasma levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), which is a strong and independent predictor of overall mortality in ESRD patients., Methods/patients: Twenty ESRD patients (11 women) were studied during both a single online HDF session and a single HD session. In each patient, ADMA, L-arginine, SDMA, beta(2)-microglobulin and urea were measured at several time points., Results: Although HDF was clearly superior to HD in decreasing plasma beta(2)-microglobulin, there was no difference in the elimination characteristics of ADMA. However, HDF but not HD eliminated the nitric oxide synthase substrate L-arginine, making HD superior in increasing the L-arginine/ADMA ratio., Conclusion: Neither HD nor HDF sufficiently removes the putative uremic toxin ADMA. The clinical significance of HD better improving the L-arginine/ADMA ratio (parameter of NO production) as compared to HDF needs to be determined.

1. Endothelium-derived nitric oxide (NO), a major modulator of vascular tone, is synthesized from the terminal guanidino nitrogen of L-arginine. This reaction is inhibited by analogues of L-arginine, such as N-nitro-L-arginine methyl ester (L-NAME). Many of the biological effects of NO are mediated by the second messenger cGMP. NO is rapidly oxidized to NO3-, which, like cGMP, is eliminated via excretion into the urine. In a placebo controlled study, we investigated whether oral bolus administration of L-arginine and L-NAME affects the urinary excretion rates of NO3- and cGMP in Munich Wistar Frommter (MWF) rats. 2. Twenty MWF rats were kept in metabolic cages and received L-arginine (3 g/kg bodyweight), L-NAME (50 mg/kg), or placebo (0.9% saline) in randomized order. Urine samples were sequentially collected for 10 h and analysed for creatinine, NO3- and cGMP. 3. L-Arginine inducted a slight, but prolonged increase in urine flow, whereas L-NAME induced an early, transient increase in urine flow which was followed by a decrease. Creatinine clearance decreased by 65% after L-NAME, but was not affected by L-arginine or placebo. 4. Urinary NO3- and cGMP excretion rates transiently increased after L-arginine (NO3-: + 29%; cGMP: +16%) for 4-5 h, whereas L-NAME induced an immediate, pronounced and lasting inhibition of urinary NO3- and cGMP excretion (NO3-: -76%; cGMP: -46%). Urinary NO3- and cGMP excretions were significantly correlated (r = 0.755; P < 0.001). 5. Urinary excretion rates of NO3- and cGMP, expressed as mu mol/h, were correlated to urine flow (mL/h; r = 0.617 and 0.649, respectively; both P < 0.05), whereas after correction by urinary creatinine (mu mol/mmol creatinine) no correlation with urine flow was observed, indicating that these excretion rates were independent of renal excretory function. Thus we conclude that changes in the urinary excretion rates of NO3- and cGMP represent changes in NO production rates in vivo when expressed in relation to urinary creatinine. Urinary NO3- and cGMP excretion is modulated by acute NO synthase inhibition or substrate provision.