EURECA-m e-Newsletter
Year 3 Issue 2 December 2012
In this issue:
 
 
 
 
EURECA-m activities
 
 
 
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)
Bengt Lindholm, Sweden
Alberto Martinez Castelao, Spain
Adrian Covic, Romania
Gultekin Suleymanlar, 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
 
 
Lyon
EURECA-m CME course
April 5-6, 2013
Lyon, France
 
 

It is my pleasure to wish all EURECA-m members all the best for the upcoming Holiday Season as well as a fruitful and serene 2013. As you will see by reading these interesting articles our working group has nice research projects and educational activities planned for 2013 and I look forward our membership becoming even larger than it is now. In addition, as per David Goldsmith’s proposaI, in the future we hope to build up an even stronger interaction with the EURECA-m members through the launch of an EURECA-m Blog; we will keep you updated on all our future initiatives. Enjoy the reading!

Gérard Michel London - EURECA-m Chairman

London
The LUST study: un update
It is a litany that intervention studies in patients with End Stage Kidney Disease (ESKD)  are  invariably  negative. EVOLVE is the most recent trial which adds to a long list of  disappointingly  negative randomized  intervention  studies in this high risk population.  Optimization of volume  control   appears  to be  a research area   where   significant benefits   may be achieved  in dialysis patients. Indeed, the Frequent Hemodialysis Trial  (N Engl J Med. 2010;363:2287-300)  shines as the  sole trial  in these  patients  demonstrating that a   substantial decline (-39%) in a solid co-primary end-point [death  or increase in left ventricular (LV) mass] can be  achieved by  dialysis intensification. Patients with myocardial ischemia and heart failure represent a substantial fraction (about 40%) of the  dialysis  population.
zoccali
Early identification of volume overload may prevent cardiovascular sequel in these patients. However, clinical signs of volume expansion are unsatisfactory to reliably identify patients at risk and to monitor them over time. Extravascular lung water (LW) is a proxy of both, blood volume and LV filling pressure and may therefore be a  much useful criterion to identify patients at a higher risk of volume-dependent adverse clinical outcomes and to monitor the effect of therapy aimed at preventing these outcomes. Recently a quick ( about  5 min.) simple and non-expensive technique which measures extra-vascular lung water by quantifying  the number of B-Lines using standard ultrasound (US) machines has been validated in dialysis patients. Furthermore a very recent  cohort study  (Zoccali et al., JASN  2012, accepted  for publication) shows that  the number of these  US-B lines  is a powerful predictor of death and cardiovascular complications in these patients.
LUST is  a clinical trial funded by the ERA-EDTA  testing a treatment policy guided by US-B lines to 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. This  trial  has been repeatedly presented in previous EURECA-m newsletters.   EURECA-m made an open call for interested Renal Units  in Europe to join the trial. This call arose much  interest  among the membership and  we received 33 submissions by 14 countries. Now  LUST is  near  to the start. In March  the  first  LUST organizational meeting  will be held in Barcelona and actual patients enrolment  will commence  within 3 weeks  after this meeting. We hope that LUST may provide novel, useful information to guide ultrafiltration and drug treatment of high risk dialysis patients and may help  to improve  the  dim health prospects of these patients.  We will keep you all informed about the progress of this trial in future newsletters.

Carmine  Zoccali - EURECA-m Advisor and LUST Study Coordinator
ASN Highlights
On November 3rd 2012 the Evolve study results were published in the NEJM with a simultaneous presentation at the ASN by Glenn Chertow on behalf of the Evolve Investigators at the ASN in San Diego.
We remember that the study was set up many years ago to see if Cinacalcet therapy could influence overall and CV mortality for dialysis patients, by modulating plasma PTH, phosphate and calcium concentrations.
In the event, 3883 patients were recruited and randomised to receive cinacalcet on top of best medical therapy. Selection for inclusion was based on PTH values, as were the titration goals within the study protocol.
David Goldsmith
It was an event driven study, and, as often is seen in clinical trials, theactual recruited population was healthier, so the projected 4 years time horizon became 6 years in fact before over 1800 clinical end-point events could be accumulated.
A difference between the active and placebo arms in the primary composite end-point of mortality and a slew of mainly cardiovascular clinical events was not reached, so, this study was negative. Plain and simple. Cinacalcet did not extend life or promote longer survival. Rather desperate statistical arguments have since been advanced to try to say that negative is really positive, but we should not be deflected by siren voices - the trial was negative. The hugely wide age range of the selected patients did raise the risk of imbalance, but statistically speaking, and biologically speaking, it is hard to believe that age 54 versus age 55 really makes such an impact ? If true, perhaps someone can work out the best age to start (and indeed stop) Cinacalcet-based therapy ?
There were some interesting features though which we should debate and discuss. Many patients dropped-in - that is to say, received commercial cinacalcet in the course of the trial and yet were NOT excluded from the analyses. This is quite extra-ordinary frankly. It is morally and ethically wrong to be able to maintain someone in a trial by adding in a drug which might be one the patient is already taking in the study. This patient (and their doctor) should have played no further part in the study. Of course, there is no true blinding in a study like this, as we all know that patients on a sizeable dose of cinacalcet have low calcium values, and can easily be differentiated from those on placebo. Can you possibly imagine a situation in a trial of an ESA for anaemia (lets use TREAT as an example), or, say, cholesterol, or BP treatment, where the doctor can decide to over-ride the trial and add in active therapy ? Quite incredible. This is one of the reasons why the plasma phosphate, and calcium-phosphate product, values in the control and active arms were so similar. Even the difference in plasma calcium concentration, usually such an integral feature of the use of cinacalcet, was very modest after the first 12 months of the study.
The patients included were prevalent haemodialysis patients (an error of judgement, as these patients are by definition survivors). The main biochemical selection criterion, of PTH 300-800 pg/ml, would have yielded many patients with no evidence of hyperparathyroidism (which can never simply be defined biochemically anyway); many had normal bone-specific alkaline phosphatase levels. The target PTH range (150-300 pg/ml) was another mistake, based on discredited KDOQI advice from 2003. There is no decent evidence to suggest that plasma PTH concentrations have any meaningful impact on patient survival, except perhaps with values < 100 pg/ml where this is probably a surrogate for a sick, frail patient. EVOLVE finally banishes the notion that in targetting plasma PTH values we can advance patient care - for sure, values of < 100 and > 1000 pg/ml are of some value, but in between there is little relevance. The lack of a skeletal impact (fracture rates were the same between the two groups, and bone specific alkaline phosphatase almost the same)also clearly suggests that many patients in this study had no important bone disease at the outset.
Overall then, a tremendously useful trial, if disappointing from the perspective of having a new treatment to use for survival. Cinacalcet undoubtedly in my personal opinion has a place for combatting severe unremitting hyperparathyroidism (higher calciums, higher PTHs, and raised bone specific alkaline phosphatases, and bone symptoms) in patients not eligible for, or willing to undergo, a surgical parathyroidectomy.

For the future, I hope that EURECA-m can build up an even stronger interaction with all its members (encouraging some feedback, etc.) through the launch of a Blog.

David Goldsmith - EURECA-m Newsletter Editor in Chief
EURECA-m activities
EURECA-m CME courses
EURECA-m celebrated a successful CME course in Ankara in September 7th-8th 2012, organized by Gultekin Suleymanlar (http://www.ndt-educational.org/Ankara2012.htm). Five sessions explored CKD and methods for cardiovascular assessment; inflammation, FGF23, sympathetic and NO systems alterations; cardiovascular toxicity; sodium, volume and blood pressure, and cardiovascular  involvement and cardiac ischemia in CKD.
The next EURECA-m CME course will be held in Lyon, France from 5/4/2013 to 6/4/2013, organized by Denis Fouque, University Claude Bernard (http://www.era-edta.org/images/EURECA-m_CME2013_Lyon.pdf).
Ortiz

The CME course will feature 15 talks by exerts in the field grouped into four ssessions, focused on 1) CKD-MBD: novelties and new challenges, 2) Inflammation in CKD: new players; 3) Clinical hypertension and sympathetic system updates and 4) protein and energy balance and uremia. Discussion will include the impact of recent clinical trials such as Advance, Evolve and Impact-SHPT; novel mediators of uremic inflammation; the relevance of post-ischemic conditioning for cardiovascular and kidney diseases; an update on oxidative stress in CKD; the new NICE Guidelines recommendations for 24h ambulatory monitoring; assessment of BP variability; the sympathetic system and its therapeutic targeting in CKD progression and hypertension; assessment of renal function, energy balance, thyroid function and clinical outcomes in CKD, the role of Advanced Glycosilation End Products in renal and cardiovascular toxicity; and the modulation of uremic toxicity by protein restricted diets. The ERA-EDTA offers Travel Grants for young nephrologists. Young nephrologists who are interested in applying to receive this Grant will have to download the application form available at the EDUCATION section of www.era-edta.org (clicking on the specific CME link they wish to attend), fill it in and submit it together with their curriculum vitae and a copy of their ID to the ERA-EDTA Operative Headquarters. The travel grant Winners will receive an official notification from the ERA-EDTA Operative Headquarters and, after the Course, a bank transfer for the due amount. Travel grants also include one-year free ERA-EDTA membership (Junior membership). Both the Grant, as well as the ERA-EDTA Junior memberships, will be granted after the verification of the young nephrologists’ actual participation in the CME Course.
Call for Board members
We would like to draw your attention to the Call for candidates to become an ERA-EDTA EURECA-m Working Group Member. In 2013, the Board composition must be partially renewed and three new members will be elected. Before applying, please read the Working Groups regulations carefully and consider that to be eligible for election in the Board a member must have been an ordinary member of the WG for at least 3 years as well as an active ERA-EDTA member: exceptions to this rule can only be made for non-nephrologists. To download the Working Groups regulations, please click here. In order to apply, each candidate has to send to send a short CV together with two supporting letters from two EURECA-m members (Board members or Ordinary members) to: eureca-m@era-edta.org .
The three new Board Members election will take place in March 2013 during the following EURECA-m Board meeting. The deadline to apply is January 9th 2013.
Spanish Kidney Research Network REDINREN
The Spanish Government has renewed funding for the Spanish Kidney Research Network REDINREN. REDINREN will be coordinated by Alberto Ortiz for the 2013-2016 period. The network efforts will be focused on individualization of kidney transplant immunosuppressants, prevention of CKD progression and prevention of cardiovascular disease in CKD. REDINREN encompasses several collaborative research efforts such as GLOSEN (glomerular disease workgroup of the Spanish Society of Nephrology-SEN) led by Manuel Praga; the NEFRONA cohort of biobanked non-dialysis and dialysis CKD patients with detailed cardiovascular phenotyping (http://www.nefrona.es/) lead by Elvira Fernandez and the Progresser study of diabetic CKD of GEENDIAB (Diabetic nephropathy workgroup of the Spanish Society of Nephrology) led by Alberto Martinez Castelao and Juan Navarro.
REDNREN aims to link with and contribute to ERA-EDTA clinical and basic research efforts by generating biobanked cohorts and providing a coordinated network of nephrology research centres of excellence.

Alberto Ortiz Arduan - EURECA-m Secretary

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