EURECA-m e-Newsletter
Year 4 Issue 3 December 2013
In this issue:
 
 
 
CROSSTALK BETWEEN LEUKOCYTES AND ENDOTHELIUM INDUCED BY PROTEIN-BOUND UREMIC TOXINS: DIRECT VISUAL IN VIVO PROOF.
 
EURECA-m EVENTS
 
 
 
EURECA-m Board Members
Gérard Michel London (EURECA-m Chairman)
Alberto Ortiz Arduan (EURECA-m Secretary)
David Goldsmith, UK (Editor in Chief of EURECA-m Newsletter)
Raymond Vanholder, Belgium
Patrick Rossignol, France
Adrian Covic, Romania
Mehmet Kanbay, Turkey
Danilo Fliser, Germany
Andrzej Wiecek, Poland (liaison with National Societies of Nephrology)
Ziad A. Massy, France
 
EURECA-m Advisor and LUST Study Coordinator
Carmine Zoccali, Italy
       

EURECA-m Registry Clinical Coordinator
Francesca Mallamaci, Italy

    
Epidemiology and Biostatistics Consultants
Kitty J Jager, The Netherlands
Friedo W Dekker, The Netherlands
Giovanni Tripepi, Italy
Cecile Couchoud, France
 
 
 
 
 
 
 
 
EURECA-m EVENTS
 
Warsaw
EURECA-m CME Course
July 4-5, 2014
Warsaw, Poland

 
 
 
Iasi
EURECA-m CME Course
September 5-6, 2014
Iasi, Romania
 
 
 
 
OPEN CALL for EURECA-m Ordinary Members
Deadline to apply: February 24th, 2014
 
 
Prof. London

It is my pleasure to wish you all the best for the upcoming Holiday Season as well as a fruitful and serene 2014.
Through our newsletter and blasts, we will continue to keep you updated on all our future initiatives.
Enjoy the reading!

Prof. Gérard Michel London
  
     LUST ON THE ROAD

LUST, the trial endorsed by the EURECA-m ERA-EDTA Working Group and funded by the ERA-EDTA in the frame of its periodical Research Programme Call is now started. The study is a shared effort of 23  Renal units located in the ERA-EDTA geographical area (see below). The units were initially 24 but one centre recently revoked its participation. The  EURECA-m Board, chaired by Prof. Gérard Michel London, created  the needed  basis for  starting this common journey  and  I  have no doubt that  the EURECA-m Board   will maintain full  scientific  support to this   ambitious study.
The goal of the trial is to test whether a treatment policy guided by US-B lines  may prevent death, decompensated heart failure and myocardial infarction as well as progression of LVH and LV dysfunction and hospitalization in high risk dialysis patients with myocardial ischemia  or overt heart failure. The study will also register pulmonary auscultation data along a well standardized auscultation plan.

lust
Group of Reggio Calabria

The coordinator centre, located in Reggio Calabria (Italy, photo), enrolled 27 patients simultaneously in May and these patients will complete the first six months of observation in November. As you will see in another section of this Newsletter, the study at the coordinating centre proceeded very satisfactorily. The local coordinator, Dr. Francesca Mallamaci, is smoothly running the study with no problem with the  part-time help of two young trainees.   To monitor the progress of the  study  we  have organized internal meetings  where  we  systematically  review  the evolution of pre and post-dialysis  US –B lines , body weight and  BP in patients  in the  active arm of the study. These 1-hour meetings were hold every two weeks for the first 2 months and  every month thereafter. With 33 patients,   the top recruiter is, by now, the “Dr. C.I. Parhon” Hospital in Iasi (Romania).  The group of Iasi, leaded by Prof. Adrian Covic,   has  recently published  in NDT a nice  study which   tries  to ponder the relative prognostic value of US-B lines  and  hydration  status  as  measured  by tetrapolar BIA  (Nephrol Dial Transplant. 2013 Jul 4.,  electronic publication).  The same group   will re-examine the issue into greater  detail   within the LUST  study.  In this regard, Prof. Covic in Barcelona presented   a   specific LUST subproject and several LUST centre expressed interest for this proposal.  While maintaining   strong focus on the main scope of the study, the subprojects are undoubtedly a great enrichment and a great opportunity for LUST investigators. communication manager.  By  two  weeks   a new  simple  subproject  aimed  at  studying  pulmonary fibrosis by  exploiting lung scans  clips collected   during the LUST  study  will be posted.
We  will keep you  fully informed  on  LUST in  future newsletters!

I send my best regards to everyone,
Carmine Zoccali

Zoccali
Prof. Carmine Zoccali

   CROSSTALK BETWEEN LEUKOCYTES AND ENDOTHELIUM INDUCED BY PROTEIN-BOUND UREMIC    TOXINS: DIRECT VISUAL IN VIVO PROOF.

Vanholder
Prof. Raymond Vanholder
Pletinck
Dr. Anneleen Pletinck

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD.
Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses leading to cardiovascular damage, corroborating observational in vivo associations between their concentration and outcomes. Indoxylsulfate, p-cresylsulfate and p-cresylglucuronide are prototype representatives of this group.
Up till now studies have essentially evaluated the effect of these compounds on the leukocytes and the endothelium separately and in vitro. An experimental study by our group investigated for the first time the impact of these uremic toxins on the crosstalk between endothelium and leukocytes in an in vivo rat model, and was published ahead-of-print last September the 5th in the Journal of American Society of Nephrology. 
This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate, p-cresylsulfate and p-cresylglucuronide on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. This technique permits in vivo visualization of translucent tissues in living animals in real time.
Acute superfusion with indoxylsulfate induced immediate and firm leukocyte adhesion and enhanced extravasation of the circulating leukocytes. In addition, indoxylsulfate had a dramatic effect on blood flow, resulting in an interruption or even a complete flow stop. Intravenous infusion with indoxylsulfate to mimic more closely the in vivo situation in uremic patients confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating indoxylsulfate -induced flow stagnation. Superfusion with p-cresylsulfate caused a moderate activation only resulting in a rapid increase in leukocyte rolling. Addition of p-cresylglucuronide to p-cresylsulfate caused an impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over p-cresylsulfate alone.
Pathologic loss of the glycocalyx is associated with impaired vascular wall protection throughout the circulatory system. Furthermore, it was already shown that dialysis patients have an impaired glycocalyx barrier, while its constituents are shed into the blood. (Vlahu et al, JASN 2012) Our study showed that infusion of indoxylsulfate quickly elicits increased circulating serum levels of glycocalyx constituents like heparan sulfate, which coincides with a profound reduction in glycocalyx volume.

image

This paper may have an important impact on our understanding of vascular damage in uremia. The results offer direct proof that protein-bound uremic toxins are not only involved in the progression of CKD but also the promotion of cardiovascular disease. It provides in vivo evidence that indoxylsulfate, p-cresylsulfate, and p-cresylglucuronide exert proinflammatory effects that could contribute to vascular damage by stimulating crosstalk between leukocytes and vessels. In addition, indoxylsulfate and the combination of p-cresylsulfate and p-cresylglucuronide induced unusual blood flow patterns, which may adversely affect overall organ perfusion. Endothelial glycocalyx damage seems to play a role in the indoxylsulfate -induced impaired blood flow, and the molecular mechanisms involved are an interesting challenge to be examined further in order to develop future therapeutic strategies.

A Pletinck, G Glorieux, E Schepers, G Cohen, B Gondouin, M Van Landschoot, S Eloot, A Rops, J Van de Voorde, A De Vriese, J van der Vlag, P Brunet, W Van Biesen, R Vanholder. Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall. J Am Soc Nephrol. 2013 Sep 5.

  EURECA-m EVENTS

EURECA-m CME Course
July 4-5, 2014
Warsaw, Poland
Warsaw Warsaw
 
by courtesy of www.warsawtour.pl
 
 
EURECA-m CME Course
September 5-6, 2014
Iasi, Romania
Iasi Iasi
 

OPEN CALL for EURECA-m Ordinary Members
Deadline to apply: February 24th, 2014

EURECA-m Website: http://www.era-edta.org/eureca-m/eureca-m.htm