issue # 1 june moving forward!...european renal best practice page 8 working group diabesity page 9...

ERA-EDTA NEWS / ISSUE 1 / JUNE 3rd, 2017 / page 1

“We were the first discipline that could replace an organ function over a period of many years – something that is still not possible with the lungs or the heart – and I am optimistic that we will be the first to regenerate organ function”

ISSUE 1 / JUNE 3, 2017

Cristina Ortiz, “Moving forward”, 2014, mixed technique, 120 cm x 70 cm, from the exhibition “Aspirations”

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54rd Congress Madrid Spain June 3rd – 6th 2017

DAILY CONGRESS NEWS ISSUE # 1 JUNE 3rd

54TH ERA-EDTA

CONGRESS

Working Group EURECA-m � page 4

Immunonephrology Working Group � page 4

Working Group DESCARTES � page 5

Working Group EUDIAL � page 6

ERA-EDTA Registry � page 7

European Renal Best Practice � page 8

Working Group DIABESITY � page 9

Working Group ERN � page 10

Working Group WGIKD � page 11

European Uremic Toxin Working Group � page 11

Working Group CKD-MBD � page 14

ERA-EDTA Membership Info � page 17

Moving forward!JORGE B. CANNATA

Madrid, SpainPresident of the 54th ERA-EDTA Congress

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Professor Cannata-Andía, the main overarching theme or banner of the Congress is “Moving for-wards” – and the Congress CI is a picture of a Spanish contemporary artist showing a woman moving forwards. Why do you think nephrology has to move forwards?Well, the first motto we had chosen for this Con-gress was “Nephrology is much more than kid-ney disease”. Chronic kidney disease (CKD) is strongly related to aging somehow, and is even synonymous with premature aging. Moreover, it often affects older people, so it is also associat-ed with cardiovascular disease, bone disease, hy-pertension, diabetes or rheumatic disease. That explains why there are so many overlaps be-tween nephrology and other specialties of inner medicine. In my opinion, nephrology has to move forward in terms of its self-conception: Nephrol-ogy is still mainly perceived of as an organ-cen-tered specialty focusing on the kidneys only. But we European nephrologists need to understand our discipline as a more general one, dealing with a kind of systemic disease, because kidney diseases affect many other organ systems and

cause many comorbidities. We need to acquire the full picture, not just concentrate on the small core of renal replacement therapy, as it is often the case. Nephrology has to move forward and also has to occupy and strengthen its more pe-ripheral areas. By doing so, we can develop and intensify our productive collaboration with other disciplines. We are already involved in many in-terdisciplinary projects, and there are many joint sessions at our Congress. But there is still room for improvement. Nephrology is not only about substituting for renal function – we have to move forward and revive every facet of our fascinat-ing, overarching specialty. This is what we had in mind when we combined the initial banner theme with “Moving forwards”.

Which general challenges does European ne-phrology face? What are the solutions to these challenges?One of the most important challenges is to re-verse the trend of diminishing interest in ne-phrology among young doctors. Between the 1960s and the 1980s, when nephrology was a young discipline, there was enormous enthusi-asm – and many doctors wanted to be trained as nephrologists. It was perceived to be a very attractive and innovative specialty characterized by a pioneering spirit and entrepreneurial inge-nuity. Dialysis was progressing rapidly and tech-nological progress attracted many young talents. In recent decades, however, no groundbreak-ing changes in dialysis techniques have been achieved – from the outside it might even appear that progress is stultified. That is not the case, of

course, because many advancements have been made, but they are certainly not as awe-inspir-ing as new inventions and new technologies. It is therefore time to widen our focus, as I point-ed out before. There is so much thrilling basic research going on – and I am sure that in 30 to 40 years’ time we will no longer be talking about renal replacement therapy, but might even be able to regenerate kidney function or “grow” kid-neys. We were the first discipline that could re-place organ function for a period of many years – which is still not possible with the lungs or the heart – and I am optimistic that we will be the first to regenerate organ function so that our pa-tients will not have to rely on the support of ma-chines. So nephrology is still the same innova-tive, exciting and pioneering specialty as it was 40 years ago – the problem is that we neglected to communicate this, and that both the public and students of medicine perceive nephrologists as merely being the providers of dialysis care. This is what we have to aim at. We have to move for-ward and present the merits of present-day ne-phrology to the world.

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“We were the first discipline that could replace an organ function over a period of many years – something that is still not possible with the lungs or the heart – and I am optimistic that we will be the first to regenerate organ function”

ISSUE 1 / JUNE 3, 2017





54rd Congress Madrid Spain June 3rd – 6th 2017

DAILY CONGRESS NEWS ISSUE # 1 JUNE 3rd

54TH ERA-EDTA

CONGRESS

Working Group EURECA-m � page 4

Immunonephrology Working Group � page 4

Working Group DESCARTES � page 5

Working Group EUDIAL � page 6

ERA-EDTA Registry � page 7

European Renal Best Practice � page 8

Working Group DIABESITY � page 9

Working Group ERN � page 10

Working Group WGIKD � page 11

European Uremic Toxin Working Group � page 11

Working Group CKD-MBD � page 14

ERA-EDTA Membership Info � page 17

Moving forward!JORGE B. CANNATA

Madrid, SpainPresident of the 54th ERA-EDTA Congress

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Professor Cannata-Andía, the main overarching theme or banner of the Congress is “Moving for-wards” – and the Congress CI is a picture of a Spanish contemporary artist showing a woman moving forwards. Why do you think nephrology has to move forwards?Well, the first motto we had chosen for this Con-gress was “Nephrology is much more than kid-ney disease”. Chronic kidney disease (CKD) is strongly related to aging somehow, and is even synonymous with premature aging. Moreover, it often affects older people, so it is also associat-ed with cardiovascular disease, bone disease, hy-pertension, diabetes or rheumatic disease. That explains why there are so many overlaps be-tween nephrology and other specialties of inner medicine. In my opinion, nephrology has to move forward in terms of its self-conception: Nephrol-ogy is still mainly perceived of as an organ-cen-tered specialty focusing on the kidneys only. But we European nephrologists need to understand our discipline as a more general one, dealing with a kind of systemic disease, because kidney diseases affect many other organ systems and

cause many comorbidities. We need to acquire the full picture, not just concentrate on the small core of renal replacement therapy, as it is often the case. Nephrology has to move forward and also has to occupy and strengthen its more pe-ripheral areas. By doing so, we can develop and intensify our productive collaboration with other disciplines. We are already involved in many in-terdisciplinary projects, and there are many joint sessions at our Congress. But there is still room for improvement. Nephrology is not only about substituting for renal function – we have to move forward and revive every facet of our fascinat-ing, overarching specialty. This is what we had in mind when we combined the initial banner theme with “Moving forwards”.

Which general challenges does European ne-phrology face? What are the solutions to these challenges?One of the most important challenges is to re-verse the trend of diminishing interest in ne-phrology among young doctors. Between the 1960s and the 1980s, when nephrology was a young discipline, there was enormous enthusi-asm – and many doctors wanted to be trained as nephrologists. It was perceived to be a very attractive and innovative specialty characterized by a pioneering spirit and entrepreneurial inge-nuity. Dialysis was progressing rapidly and tech-nological progress attracted many young talents. In recent decades, however, no groundbreak-ing changes in dialysis techniques have been achieved – from the outside it might even appear that progress is stultified. That is not the case, of

course, because many advancements have been made, but they are certainly not as awe-inspir-ing as new inventions and new technologies. It is therefore time to widen our focus, as I point-ed out before. There is so much thrilling basic research going on – and I am sure that in 30 to 40 years’ time we will no longer be talking about renal replacement therapy, but might even be able to regenerate kidney function or “grow” kid-neys. We were the first discipline that could re-place organ function for a period of many years – which is still not possible with the lungs or the heart – and I am optimistic that we will be the first to regenerate organ function so that our pa-tients will not have to rely on the support of ma-chines. So nephrology is still the same innova-tive, exciting and pioneering specialty as it was 40 years ago – the problem is that we neglected to communicate this, and that both the public and students of medicine perceive nephrologists as merely being the providers of dialysis care. This is what we have to aim at. We have to move for-ward and present the merits of present-day ne-phrology to the world.


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ERA-EDTA Scientific Working Groups

DESCARTES and ERBP publication was top-read paper in the “Transplant Library” 2016!

In May 2016, the paper “Does pre-emptive transplantation versus post start of dialysis transplantation with a kidney from a living do-nor improve outcomes after transplantation? A systematic literature review and position state-ment by the Descartes Working Group and ERBP” was published in Nephrology, Dialysis and Trans-plantation. The publication was the most popular article in the “Transplant Library” in 2016 and was read more than 700 times. “This is flattering, of course. But in my view, this success mainly reflects the efficient and praxis-oriented collab-oration of the DESCARTES (Developing Educa-tion Science and Care for Renal Transplantation in European States) working group and ERBP (European Renal Best Practice)”, explains Prof. Wim Van Biesen, ERBP chairman. “The fact that

we – two organizations of high reputation un-der the roof of the ERA-EDTA – worked together has obviously enhanced the impact of the pa-per. Besides, we addressed a topic of high rel-evance.” The review showed that pre-emptive transplantation in patients with a living donor can improve patient and graft survival and re-duces the risk of acute rejection. The authors therefore recommended pre-emptive transplan-tation when a living donor is available, but they also discussed the other side of the coin: too early transplantation. Patients should be pre-pared timely, so actual transplantation can take place at the moment kidney function reaches a level where otherwise dialysis would be started. Besides, the paper suggests to set up a quality registry with the aim to measure the outcomes

Hypertension in Dialysis Patients – Joint Consensus Document by EURECA-m and ESH

In patients with end-stage renal disease (ESRD) treated with haemodialysis or peritoneal dialysis, hypertension is common and often poorly con-trolled. This is the reason why the European Re-nal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Associa-tion–European Dialysis and Transplant Associ-ation (ERA-EDTA) and the Hypertension in the Kidney working group of the European Society of Hypertension (ESH) prepared a joint position paper (leading author: Professor Pantelis Sara-fidis, Greece) on the diagnosis and treatment of hypertension in dialysis patients, that was pub-lished in NDT – one of the two official journals of the ERA-EDTA. The following recommendations are given in the paper: For the diagnosis of hy-pertension in hemodialysis patients a 24h (even better 44 h) ambulatory blood pressure monitor-ing (ABPM) should be made during a mid-week day free of dialysis. The diagnosis should not be based on pre- or post-dialysis blood pressure. Al-ternatively, home blood pressure (BP) measure-ments can be used to diagnose hypertension. One of the main pathogenic mechanisms of hyperten-sion in dialysis patients is volume (and sodium) overload. This is why targeting this is fundamen-tal for BP reduction in this population. The main non-pharmacological measures to reduce vol-ume (and sodium) overload in hemodialysis pa-tients are reaching the individual patient`s dry-

weight, the minimization of inter- and intradia-lytic sodium gain (e.g. by restriction of sodium intake to 1.5 g of sodium or 4 g of sodium chlo-ride per day), and avoidance of short (i.e. <4 h) dialysis sessions. “These non-pharmacological interventions should be carefully implemented before considering pharmacological treatment”, explains Professor Carmine Zoccali, NDT edi-tor-in-chief. “This is a task for the patient – he has to comply with a salt-reduced diet –, but for the nephrologist, too: he has to optimize the di-alysis treatment”. If medication is necessary, the use of β-blockers followed by dihydropyridine calcium channel blockers should be considered, while the first-line use of ACEIs and ARBs in this dialysis population is not supported by random-ized trials. “Nevertheless, we have to keep in mind that the use of any antihypertensive agents is associated with improvement in cardiovascu-lar outcomes – and might therefore be benefi-cial for the patients”, comments Professor Zoc-cali. As the authors of this position paper empha-size, properly designed epidemiology studies and clinical trials to define BP targets for treatment and evaluate treatment effects in this population are still needed. ◘

of the transplanted patients and their donors. “This is important, because we have to evalu-ate and outweigh possible benefits for the re-cipient and possible donors´ risks”, concluded

Van Biesen. “We are very happy that our article helped to spread the word!” ◘

ERA-EDTA Working Groups encourage research, communication of knowledge, teaching and contribute to

education. Working groups refer to areas of large interest for nephrology. They are created for the follow-

ing reasons:

• To improve the outcomes of renal patients

and/or to promoting and facilitate research in

specific fields

• To foster communication among specialists

with similar interests, with various other ERA-

EDTA WG’s and/or Committees

• To collaborate in the organization of

educational activities of the ERA-EDTA

• To foster communication with other Scientific

Societies, and with other bodies that may

support research in the field

In the moment, ERA-EDTA supports 8 scientific groups, all of which are very active. Find out about the working groups´ CME courses on the following pages!

Is that the reason why this year’s plenary speak-ers will be delivering mainly lectures on basic research topics? Yes, they will all be speaking about promising ideas and concepts on the horizon that will influ-ence, if not totally change, nephrology. Juan Car-los Izpisua Belmonte, from La Jolla in California, will talk about “New approaches towards kid-ney regeneration” – a topic I have already men-tioned. Hiroki Ueda from Tokyo will talk about

“Whole-body and whole-organ clearing and im-aging”, Steven Benner from Alachua in Florida on “Re-creating life”. The title of the lecture by Miguel Hernan from Boston is “Comparative ef-fectiveness research in nephology: using elec-tronic health records to emulate randomized tri-als”. This is of special importance to nephrology, a relatively small specialty with limited resourc-es. One problem we face is that we cannot af-ford studies with a very long follow-up, but we have seen that many studies missed their pri-mary endpoints because the period of interven-tion was too short for a study population char-acterized by multifactorial diseases. You need staying power if you are going to prove whether a singular intervention is beneficial or not. This

“staying power” costs a lot, and the industry is not willing to invest these amounts of money in nephrology, because they fear they might not get a proper return on their investment, due to the relatively small number of patients (com-pared to cancer patients, for example). So what can be done? Miguel Hernan will give an out-line of how “big data” can be used, and how we might simulate clinical trials with databas-es containing the electronic health records of our patients. I am sure that “big data” will pro-vide an enormous impetus to innovate our dis-cipline in the near future.

Apart from the plenary lectures, what are the main highlights of the scientific program, in your personal opinion?That’s impossible to say! We have a great pro-gram with more than 60 sessions – it would be unfair to name one or two only. The lectures will all be of high quality and everybody should chose his/her “personal Congress program” ac-cording to his or her particular interests. I, per-sonally, am very interested in the topics of ag-ing and CKD, the bone-cardiovascular axis and all the mechanisms related to it, in new bio-markers that can help us to detect CKD pro-gression early, and in glomerular diseases. All the sessions on diabetes will also be very excit-ing, I am sure, due to the new drugs that have been introduced. On top of that, I am very inter-ested in the topic of “physical exercise in renal patients”. According to recent studies, patients’ morbidity and quality of life can be improved if patients do exercises during dialysis. This is an opportunity we have failed to exploit so far. I am also looking forward to the sessions on DOPPS and COSMOS. These observational studies de-liver new data every year that help in the man-agement of everyday practice.

What do you think makes this Congress especial-ly attractive for young nephrologists?I believe one reason to attend the congress is its sheer wealth of content. The whole field of nephrology is covered – and the program offers news and reviews! On Saturday we have the edu-cational symposia, and I think these CME courses should be of special interest to young colleagues. Let me highlight and invite to one special session which will be held on Saturday from 12 to 2 pm, namely the symposium on the future of nephrol-ogy. There we want to discuss with young doc-tors why they decided to become nephrologists – or why they decided not to do so. We started an online survey and received responses from more than 1,000 participants. The results will be pre-sented and discussed.

In addition, I am very proud that we will be hand-ing over the certificates for the “European Ne-phrology Exam” to all those who passed. The Exam was held for the first time this year and will facilitate the physicians to work in other EU countries. We initiated this project and therefore I am greatly committed to it – we nephrologists still believe in Europe!

To what extent does the scientific program re-flect Spanish topics and speakers?You know, in 1999, when I was Congress Secre-tary of the ERA-EDTA Congress in Madrid, only about 2 % of the faculties were from Spain. Now, more than 12 % of the faculties are Spanish col-leagues, and that, I think, shows that Spanish nephrology is “healthy” and highly productive. I am happy to be part of this scientific communi-ty – muchas gracias a todos!

Speaking of Spain – what should participants from abroad who are in Madrid for the first time make sure they see or do (apart from attend-ing the Congress)? What’s your insider’s advice?First of all, I would like to mention the muse-ums – the Prado, the Reina Sophia and many other museums of classical and contemporary art. Another highlight are the palaces. You should come and see the Royal Palace, at least, and stroll around the parks surrounding it. They have a very special atmosphere, especially in ear-ly summer evenings. And, of course, you must visit the old town, the Plaza Mayor, and the in-numerable tapas bars. You’ll love it! Bienveni-dos a Madrid! ◘


“We doctors always focus on medical aspects, but there are many other aspects that have a clear impact on how patients feel and also on their outcome.”

Patient-Doctor-Communication acted out: An innovative way to further improve your communication skills!

Managing CKD, Diabetes& CVD: Is epigenetics a

new way forward?

EBAC ACCREDITED SYMPOSIUM TO BE HELD DURINGERA-EDTA 2017, MADRID, SPAIN

CO-CHAIRMENCarmine Zoccali, MD – CNR-IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy

Vincent M Brandenburg, MDUniversity Hospital RWTH Aachen, Germany

AGENDA13:45 – 13:50 Introduction Vincent M Brandenburg, MD – Aachen, Germany

13:50 – 14:05 The high risk diabetes patient: What is the need for novel approaches to reduce cardiovascular and renal risk?

Luis M Ruilope, MD – Hospital 12 de Octubre, Madrid, Spain

14:05 – 14:20 Molecular mechanisms involved in the beneficial effect of BET inhibition in experimental renal disease

Marta Ruiz-Ortega – Fundación Jiménez Díaz, Madrid, Spain

14:20– 14:40 BET inhibition in renal and cardiovascular disease: What is the clinical roadmap? Kamyar Kalantar-Zadeh, MD – UC Irvine School of Medicine, Irvine, Ca, USA

14:40 – 14:45 Discussion & summary Carmine Zoccali, MD – Reggio Calabria, Italy

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Physicians’ Academyfor Cardiovascular Education

MONDAY, JUNE 5 2017, 13:45 – 14:45 HRS • SALA RETIROSupported by an unrestricted educational grant from Resverlogix.

“In compliance with EBAC guidelines, all speakers/Chairpersons participating in this programme have disclosed or indicated potential conflicts of interest which might cause a bias in the presentations.

The Organising Committee/ Course Director is responsible for ensuring that all potential conflicts of interest relevant to the event

are declared to the audience prior to the CME activities.”

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WIM VAN BIESEN

Ghent, Belgium

Special Interactive SessionJune, 3, 10.45 – 11.45 Difficult patient or wrong communication? June, 3, 14.15 – 16.15 Shared Decision Making with patients: opportunities and pitfalls”Sala Retiro

A new event format will be introduced at this year´s ERA-EDTA Congress, which takes place on June 3 – 6, 2017, in Madrid, Spain. In this interactive workshop, various techniques to improve the communication with the patients can be learnt. The innovative thing about this session: The knowledge is not transported in a “dry” lecture-style, but acted out right be-fore your eyes, to enhance learning experi-ence and content retention.

Two professional actors will play various sce-narios, typical scenes of a nephrologist´s every-day-life, in which the patient-doctor-communica-tion can be sub-optimal. After the negative exam-ple has been acted out, Professor Van Biesen will

give a short analysis, in which the audience will be involved, why the communication was poor and what could be done to improve it. Then, the actors will give a positive example of the same situation, in which the communication is done in a more effective style. “The motto of our sympo-sium is `experience & learn´ instead of `lecture & learn´, because learning through experience is the most effective way”, explains Van Biesen.

Being asked why it is important for nephrolo-gists to further improve their communication skills the expert answers: “We doctors always fo-cus on medical aspects, but there are many oth-er aspects that have a clear impact on how pa-tients feel and also on their outcome. This is of-ten underestimated. Take adherence, for exam-ple. If you do not bring the patients perspective in when you make a certain therapeutic decision, the chances are high that the patient will not ad-here to the therapy. This is why patient-doctor-in-teraction is extremely important”.

The interactive workshop is divided into two parts. The first session will focus on communication in general. “There are different archetypes of pa-tients, e. g. the non-responder or the one who knows everything better, and the audience learns how to best deal with each type”, explains Van Biesen. The second session in the afternoon will focus on shared decision making, especially on how you can enable a patient to make a (thera-peutic) decision. “Active patient participation is really important nowadays. We moved from the

concept of compliance – which somehow means that the patient just has to obey – to that of ad-herence, which means that the patient under-stands, agrees to a certain therapy and is there-fore willing to follow and stick to it.” But how can this aim be reached? The key to it is “empathic listening”. It is central to acknowledge the emo-tional state of a patient first (“I see that you are a bit upset, can you explain why?”), then to lis-ten to him and to work out a solution for her/his problems together with her/him – instead of as-sess a problem from the medical side only and presenting a solution without having involved the patient. But this is all the presenters like to re-veal at this point. The rest, they say, can be ex-perienced and learned onsite. “I hope that many

of my colleagues are interested in this interactive workshop and I would like to invite everyone to it – I am sure, it will be enlightening and fun!” ◘


Atherosclerosis is very prevalent, accelerated and closely associated with cardiovascular events

Therapy must be tailored to the needs and preferences of each patient

MÅRTEN SEGELMARK

Linköping, SwedenVice Chair of the IWG

JOSE M VALDIVIELSO

Lleida, Spain

Personalized treatment in ANCA-associated vasculitis

ERA-EDTA Immunonephrology Working Group

European Renal and Cardiovascular Medicine

Patient size and age

Renal and liver function

Comorbidities

Disease severity and phenotype

Response to treatment and previous responses to treatment

Biomarkers

Genetics including pharmacogenetics

Patient preferences

Table 1: Patient factors influencing treatment decisions in ANCA associated vasculitis.

Cardiovascular risk in CKD: novel insights from the NEFRONA study

CME 1 – IWGNews in the pathogenesis and treat-ment of glomerular diseaseSaturday, 08.30 – 11.45, Hall 10A

When reading recently published guidelines on the treatment of ANCA-associated vasculitis (AAV), one can get the impression that the same regimen should be offered to all patients. That one size fits all. However, when looking at the text more carefully it becomes evident that the therapy should be tailored according to a whole series of factors. Beyond the guidelines, there are data from observational studies, not supported by hard evidence, that can be taken into account when finalizing the prescription for the individu-al patient (Table 1).

Most drugs, like azathioprine (AZA), are adjust-ed by patient weight, while others like rituximab (RTX) is adjusted by body surface area. Many drugs should be reduced in renal insufficien-cy, but the reduction is not always proportional to the decline in glomerular filtration rate (GFR).

This is, for instance, the case with cyclophospha-mide (CYC). The dose of CYC is also lowered in elderly patients without renal failure due to pre-sumed bone marrow sensitivity.

These crude dose adaptations could be refined with better knowledge of the individual pharma-cokinetic profile of the patient. Measurement of trough levels is not easily available for most drugs used in AAV. For AZA, it is possible to mea-sure gene variants leading to reduced activity of the main metabolizing enzyme (thiopurine meth-yltransferase) or directly measure the enzyme ac-tivity in vitro. For CYC, polymorphisms in metabo-lizing enzymes also affect drug efficacy and toxi-cology, but have not yet reached clinical practice.

The EUVAS study group, which has launched many of the pivotal studies in the field of AAV, has based their trial design on two assumptions. One is that disease severity should be taken into ac-count and the other is that the disease phenotype should not be considered. The first assumption is supported by the Five Factor Score developed by the French Vasculitis Study Group. According to the FVSG, at least eosinophilic granulomato-sis with polyangiitis (EGPA) but maybe also mi-croscopic polyangiitis (MPA) with a score of zero can be treated with steroids alone. On the other

hand, EUVAS studies with methotrexate and my-cophenolate in non-severe AAV show that such induction therapy is associated with a very high relapse rate. At the other end of the spectrum, guidelines call for the addition of methylpred-nisolone and/or plasma exchange in life-threat-ening disease.

The lumping together of MPA and granuloma-tosis with polyangiitis (GPA) in treatment rec-ommendations has been questioned. GPA has a much higher relapse rate than MPA, which has a bearing on the length and intensity of the main-tenance therapy. Data from observational stud-ies indicate that certain features, such as lung involvement or serology (PR3-ANCA, MPO-ANCA or ANCA-negative), may be even more important than the MPA/GPA dichotomy.

Persistence and recurrence of antineutrophil cy-toplasmic antibody (ANCA) seem also to influence the risk of relapse, but the value of ANCA to guide therapy is debated. Views ranging from ‘useless’

to ‘very helpful’ can heard. Recent data suggest that changes in ANCA levels are more informative in AAV with renal disease as compared to non-re-nal vasculitis. B-cell count has, along with ANCA, been suggested as a biomarker for predicting relapses after RTX. There are ongoing studies comparing preemptive re-treatment based on biomarkers with re-treatment at fixed intervals.

Exactly how previous treatment and previous re-sponse to therapy should be taken into account when deciding upon treatment is open for de-bate. The RAVE trial shows that RTX is superior to CYC in patients previously treated with CYC, and similarly the MAINRITZAM trial shows that in patients induced by CYC, RTX maintenance ther-

apy is superior to AZA. This does not necessari-ly mean that RTX is also superior as first-line in-duction therapy. Actually, data from the RAVE tri-al show (numerically but not statistically) better results in treatment-naïve MPO-ANCA patients with CYC compared to RTX.

Patient preference is naturally an important as-pect of individualized therapy. A wish to pre-served fertility is a common reason for choosing RTX instead of CYC, and intermittent intravenous CYC instead of daily oral dosing. Side effects and fear of relapse should influence length of main-tenance therapy. ◘

Cardiovascular disease is the main cause of death in patients with chronic kidney disease (CKD), in whom cardiovascular death is a more likely outcome than progression to end-stage re-nal disease (ESRD). Although numerous studies show an association between decreased kidney

function and cardiovascular disease and mortal-ity, mechanisms underlying this association are incompletely understood. Thus, the contribution of atherosclerosis to the increased cardiovascu-lar morbimortality in CKD has been usually ne-glected, probably because the main cardiovas-cular event types in ESRD seem to be related to electrolyte imbalance.

However, some of the events labeled as sud-den death could be undiagnosed silent myocar-dial infarctions, as are often found in this pop-ulation. In addition, atherotrombotic events are very prevalent in earlier stages of CKD. Further-more, the JUPITER and SHARP trials demonstrat-ed that treatments aimed to reduce lipid burden

are effective in reducing cardiovascular events, mainly in early stages of CKD. Thus, the NEFRO-NA study was designed to determine the role of subclinical atheromatosis on cardiovascular events of CKD patients.

The study recruited 3004 subjects (559 controls, 950 CKD stage3, 807 CKD stage 4 – 5, 688 dial-ysis) in 81 hospitals of Spain with a median fol-low-up of 48 months. The cross-sectional anal-ysis of the population showed that the preva-lence of atherosclerosis increased progressive-ly with more advanced CKD stages, suggesting that there is a close association between ath-erosclerosis and CKD. The multivariate logis-tic regression model identified CKD as an in-dependent factor associated with the presence of plaque, with a higher odds ratio in more ad-vanced stages.

The analysis also identified several CKD-relat-ed factors as independent factors associated with plaque presence. For instance, higher phos-phate levels and lower 25(OH) vitamin D levels emerged as new variables that can explain at least part of the higher incidence and severity

of atherosclerosis in CKD. In the case of phos-phate, further analysis revealed that the blood levels associated with the presence of plaque are different in men and women. Although phos-phate levels within the normal range are associ-ated with the presence of atheromatous plaque in men, this association is not found in women until phosphate reaches pathological levels. Due to this differential effect regarding sex, recom-mended serum phosphate levels could be differ-ent for male and for female CKD patients.

The study has also confirmed that low sTWEAK levels, which are associated with atherosclerosis in the general population, also show a strong as-sociation with subclinical atherosclerosis in CKD patients. In addition, angiotensin-converting en-zyme 2 (ACE 2), an enzyme that converts angio-tensin 2 to angiotensin 1 – 7 and angiotensin I

to the nonapeptide angiotensin 1 – 9, has been identified as a new marker of silent atheroscle-rosis in CKD.

The rate of atherosclerosis progression has been also analyzed in the cohort. Data indicate that


Uncertainties exist, but provide opportunities for patients and nephrologists

Programme13:30 Lunchboxes will be provided 13:45 Chair’s welcome and introduction

Danilo Fliser (Saarland University Medical Centre, Homburg, Germany)

13:55 Interactive panel discussion Open panel discussion based on expert experience and recommendations for treating iron deficiency Danilo Fliser Iain Macdougall (King’s College Hospital, London, UK) Carlo Gaillard (University of Utrecht Medical Centre, Utrecht, The Netherlands) Austin Stack (Health Research Institute, Limerick, Ireland) Josep Comin-Colet (Bellvitge University Hospital, Barcelona, Spain) Darlington (Obi) Okonko (King’s College Hospital, London, UK)

Meeting close

54th ERA-EDTA Congress 2017, Madrid, Spain

Is there a role for iron beyond erythropoiesis in patients with chronic kidney disease?

Chair: Professor Danilo Fliser

Sunday 4 June 201713:30–15:00Hall 10.B, IFEMA Feria de Madrid (North Congress Centre)

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www.era-edta2017.org

Objectives Î Discuss benefits of treating non-haematological effects of iron in nephrology Î Review clinical evidence from cardiology studies and interpret them from a

nephrologist’s perspective

Developing Education Science and Care for Renal Transplantation in European States

CME 2 – EURECA-mNovel therapeutic opportunuties to decrease cardiovascular risk in CKDSaturday, 08.30 – 11.45, Hall N103 – 104

Before wait-listing: pre-transplant cardiac work-up

PADDY MARK

Glasgow, United Kingdom

progression of atherosclerosis is strongly in-fluenced by the presence of plaque at base-line. Thus, patients free from the disease remain mostly atherosclerosis-free during the next two years. These ‘protected’ patients are a very spe-cial subpopulation within the NEFRONA cohort, and are of high interest in order to identify pos-sible protective factors.

Another interesting result showed that patients who exhibited progression of CKD were more likely to have progression of atheromatosis, un-derscoring the close association between both pathologies. Furthermore, several CKD-related variables like phosphate, uric acid and 25(OH) vi-tamin D are predictors of subclinical atheroscle-rosis progression over two years. Finally, anal-ysis of the cardiovascular events identified the presence of plaque as a very strong predictor of an event, confirming atherosclerosis as a fac-tor influencing cardiovascular mortality in CKD.

In summary, atherosclerosis in CKD is very prev-alent, accelerated and closely associated with cardiovascular events. Its determination by a simple method like ultrasound could be very useful in calculating cardiovascular risk in CKD patients. ◘

Optimal cardiovascular work-up for potential renal transplant recipients remains controver-sial. Cardiovascular disease (CVD) is the lead-ing cause of death of patients with end-stage renal disease (ESRD), whether treated with di-alysis or following successful renal transplanta-tion. Moreover, CVD is a leading cause of death with a functioning kidney transplant, and there-fore should be considered a major cause of pre-mature kidney transplant failure. Furthermore, as well as improving life expectancy and quality of life, successful renal transplantation is associ-ated with a dramatic reduction in cardiovascular risk compared to dialysis. Therefore, transplan-

tation represents an intervention that reduces long-term risk of cardiovascular events in ESRD, albeit this is untested in a prospective random-ized controlled trial.

So, what are the goals of cardiovascular work-up in patients going on the list for kidney trans-plantation? Importantly are there any benefits for an individual patient? Critically, patients whose perioperative risk of a cardiovascular event is unacceptably high, in whom safe anesthesia is contraindicated, should be identified. Revers-ible cardiovascular risk factors should be ad-dressed or cardiovascular status should be op-timized; e. g. patients with symptomatic critical coronary artery disease should undergo revas-cularization. Timing of cardiovascular work-up and intervention should be scheduled such that potential perioperative cardiovascular or bleed-ing risk is minimized, whilst avoiding undue de-lay to transplant listing.

Where availability of organs for transplantation is outweighed by the number of patients on the

transplant list, some consideration of the utility of the transplanted organ compared to expect-ed long-term survival of the recipient should be given, although using cardiovascular screening to ration organs should not be acceptable. If the patient’s cardiovascular status permits safe un-dertaking of the transplant operation, then those patients at higher cardiovascular risk also most likely experience relative benefit compared to staying on dialysis. Sadly however, some patients may always remain at such extreme high cardio-vascular risk that transplantation cannot be un-dertaken. In these cases, objective cardiovascular testing may permit informed discussion with the patient about why the decision not to list them for a transplant has been taken.

For many patients with kidney failure, cardiovas-cular assessment is fraught with potential dilem-mas. The prevalence of cardiovascular risk fac-tors such as hypertension, diabetes, dyslipidemia and left-ventricular hypertrophy is high. Stan-dard investigations for cardiovascular assess-

ment such as ECG, echocardiography (often with dobutamine stress), myocardial perfusion scan-ning, or coronary CT scanning often reveal ab-normalities that have prognostic significance, but may not lead to inventions such as coronary re-vascularization. These abnormalities may lead to some delay in transplant listing whilst consid-eration is given to whether they require specif-ic therapy. Expert assessment by the multidisci-plinary team (surgeons, nephrologists, cardiolo-


Yes it is, and its potentially important implications warrant clinical trials

E-ISSUE

Find more articles in the electronic issuewww.era-edta2017.org

Desensitization for ABO-incompatible and for HLA-incompatible kidney transplantation

LIONEL ROSTAINGGrenoble, France

E-ISSUE


High-volume hemo-diafiltration: the new standard treatment

PETER J. BLANKESTIJNUtrecht, The Netherlands

CME 3 – DESCARTESHot topics in the management of pre- and postkidney transplantationSaturday, 08.30 – 11.45, Hall N101 – 102

European Dialysis Working Group

Incremental hemodialysis: ready to return to prime time?

CARLO BASILE

Acquaviva delle Fonti, Italy

References

1. Basile C, Casino FG, Kalantar-Zadeh K. J Nephrol

2017 Mar 23rd.

2. Casino FG, Basile C. Nephrol Dial Transplant

2017;32:182 – 190

Figure 1: Relationship between residual renal urea clearance (Kru) and 24-h urine output as measured after about 3 months from the start of HD in 130 consecutive patients. They started HD on different treatment schedules: 40 patients on 3HD/wk, 60 on 2HD/wk, and 30 on 1HD/wk regimens, respectively. © Basile

View the ERA-EDTA 2017 Broadcast on the YouTube playlist here.

Imprint

ERA-EDTA Operative HeadquartersVia XXIV Maggio 3843123 Parma, Italy

Editor-in-chiefBettina Albers, PhDERA-EDTA Press Office

gists and anesthetists) should lead to rapid res-olution of these dilemmas to allow timely wait listing or further testing where required.

Whilst these uncertainties exist, cardiovascu-lar assessment for kidney transplantation pres-ents opportunities for both patients with kid-ney failure and their nephrologists. Cardiovas-cular assessment for transplantation should be personalized to be appropriate for that patient’s background risk. Discussing cardiovascular as-sessment permits dialogue between patient and clinician around the nature of cardiovascular dis-ease in kidney failure and may lead to optimiza-tion of treatment to minimize future cardiovascu-lar risk, not only for renal transplantation.

Consideration can be given to management post-transplantation to minimize cardiovascular risk, such avoidance of post-transplant diabetes, steroid avoidance or maintenance of a healthy lifestyle to address obesity and hypertension. Fi-nally, although of less direct benefit for individual patients, over the years cardiovascular screen-ing for transplantation has provided several in-sights into the nature of CVD in kidney failure and continues to provoke clinicians to optimize nov-el techniques for assessment of cardiovascular disease in this patient group. ◘

During the upcoming decade about 1 million peo-ple in the US are expected to make the transi-tion to maintenance dialysis therapy. The major-ity of dialysis patients are currently treated with a fixed-dose, thrice-weekly hemodialysis (HD) (3HD/wk) regimen, irrespective of whether they are starting dialysis therapy (incident) or have been receiving dialysis for some time (prevalent), and without consideration for their residual re-nal function (RKF).

The RKF provides effective and naturally contin-uous clearance of both small and middle mole-cules; it is associated with better patient surviv-al and greater health-related quality of life; and plays a major role in effective phosphorus excre-tion, and endogenous vitamin D and erythropoi-etin production. [1] While the RKF and urine out-put do not measure the same physiologic quan-tities – the former is clearance while the latter is just a fluid volume – they are closely related, as documented by some of our own data (Figure 1). Preservation of the RKF requires a careful ap-proach, including regular monitoring, avoidance

of nephrotoxins, gentle control of blood pressure to avoid intradialytic hypotension, and an individ-ualized dialysis prescription including consider-ation of incremental HD.

Although the regulatory agencies might consid-er the 3HD/wk regimen as ‘standard of care’ and ‘adequate requirement’, it is by no means per-fect. The 3HD/wk regimen has been assumed, until recently, almost as a dogma in the dialysis community. Historically, however, HD started with two treatment sessions per week in the 1960s and 1970s, but by the early 80s HD frequency had increased to 3HD/wk. Incredibly, the 3HD/wk schedule has been widely accepted world-wide without ever undergoing any randomized controlled trial (RCT) to examine whether less frequent HD treatment would be inadequate or harmful.

Owing to this background, it is easy to under-stand why an HD frequency of less than 3HD/wk is rarely prescribed in Europe (currently in only 5.2 % of all patients in Europe), and even much less so in the US and Canada (probably less than 1 %). In contrast to Europe and the US, a recent study reported that 26 % of the Chinese dialysis population are treated using a 2HD/wk schedule, which may be the result of socioeconomic con-ditions, including less access to dialysis therapy and inadequate resource availability. [1]

There is currently no standardized method of applying incremental HD in practice. Infrequent (once- to twice-weekly) HD regimens are often used arbitrarily, without identifying the patients who would benefit most from them or how to escalate the dialysis dose required as RKF de-clines over time. The recently heightened inter-est in incremental HD has been hindered by the current limitations of urea kinetic models (UKM), which tend to overestimate the dialysis dose in the presence of substantial RKF. This is due to an erroneous extrapolation of the equivalence between renal urea clearance (Kru) and dialyz-er urea clearance (Kd), correctly assumed by the UKM, to the clinical domain. In this context, each ml/min of Kd clears the urea from the blood just as 1 ml/min of Kru does.

By no means should such kinetic equivalence im-ply that 1 ml/min of Kd is clinically equivalent to 1 ml/min of urea clearance provided by the na-tive kidneys. [1] A recent paper by Casino and Basile suggested a variable target model (VTM), which gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF, as opposed to the fixed target model, based on the wrong concept of the clinical equivalence between Kru and Kd. [2] An RCT comparing in-cremental HD with the standard 3HD/wk in inci-dent HD patients is urgently needed and should be planned to test the VTM hypothesis formulat-ed by Casino and Basile. [2]

In conclusion, the potentially important clinical and financial implications of incremental HD ren-der it highly promising and warrant RCTs. The UKM is the keystone for conducting such studies. ◘

ERA-EDTA NEWS / ISSUE 1 / JUNE 3rd, 2017 / page 6-A

Due to the scarcity of deceased kidney donors, live-kidney donation is now widely implement-ed; however, ABO-incompatibility (ABOi) and/or HLA incompatibility (HLAi) are often problematic. HLAi refers to the presence, at pretransplant, of preformed donor-specific alloantibodies (DSAs). In the setting of ABOi, we have to deal with isoag-glutinins (both IgG and IgM). If we want ABOi and/or HLAi kidney transplantation to succeed, isoagglu-tinins titers need to be lowered to < 1/16 and DSA levels to < 3,000 MFI (mean fluorescence inten-sity) at pretransplant. This can be achieved by de-sensitization, which relies on immunosuppressive drugs, e. g., rituximab, tacrolimus, mycophenoloc acid (MPA), which can prevent antibody synthe-sis, and on apheresis (plasmapheresis, double-fil-tration plasmapheresis, immunoadsorption, both specific and semi-specific), which can remove the culprit antibodies (isoagglutinins or DSAs).

Desensitization has proven to be very effective at treating patients that are ABOi. The ABOi Japa-nese registry showed that the long-term patient and graft survival rates of > 2,300 ABOi kidney transplant recipients were very similar to the data from ABO-compatible kidney transplant patients. This is particularly striking as rituximab has now replaced splenectomy. In this registry, it was ob-served that isoagglutinin-mediated acute rejec-tion mainly occurred within the first 3 weeks post-transplant, irrespective of the isoagglutinin titer at the time of transplantation. Beyond three weeks posttransplant, there were almost no graft rejec-tions, because at this point accommodation has taken place. However, one of the concerns with re-gard to ABOi kidney transplantation is the high oc-currence of posttransplant BKV replication, which could be minimized by replacing at posttransplant MPA by everolimus.

HLAi kidney transplantation is much more chal-lenging, because depending on the pretransplant DSA level, it can be very difficult to decrease the threshold level to below 3,000 MFI. It has been recognized that when the DSA level at transplant is below 3,000, the risk of acute antibody-mediat-ed rejection is quite low. There are two scenarios: living-kidney or deceased-kidney transplantation. In case of living-kidney transplantation, desensiti-

zation takes place pretransplant. In some instanc-es, this can be achieved with IVIg + rituximab, rit-uximab + IVIg + plasmapheresis, or with ritux-imab + semi-specific immunoadsorption (SSIA). In our experience, rituximab + SSIA (Globaffin® col-umns) + membrane filtration, i. e., Monet®, is very efficient. However, at present, it is almost impos-sible to desensitize patients that have a DSA lev-el of > 15,000 MFI. In this situation, tocilizumab may be of value. A series of HLAi kidney patients at Cedars Sinai Hospital (LA, USA) that had failed de-sensitization with IVIg + rituximab were success-fully desensitized with tocilizumab, and had good outcomes after transplantation, without increas-ing the risk of opportunistic infections. In the USA, a retrospective study that included > 1,000 HLAi living-kidney transplant recipients that had un-dergone pretransplant desensitization has shown that those who were HLA-desensitized had signifi-cantly better long-term patient survival rates com-pared to matched kidney patients that were on a waiting list, and who subsequently had a trans-plant from a deceased donor, or than those who remained on dialysis.

In case of HLAi deceased-kidney transplant desen-sitization takes place both at pre- and post-trans-plant. The first step is to have a negative cross-match by microlymphocytotoxicity, e. g. immedi-

ately before transplantation, the patient is submit-ted to an apheresis session plus one injection of rituximab; posttransplant desensitization is pro-longed by apheresis sessions, IVIg, and rituximab. Immediately before transplantation, the patient is submitted to an apheresis session plus one injec-tion of rituximab; posttransplant desensitization is prolonged by apheresis sessions, IVIg, and ritux-imab. However, despite HLA desensitization re-gardless of the type of donors, these desensitized patients experience significantly higher rates of antibody-mediated rejection; nonetheless, this does not impair long-term allograft survival rates.

The use of Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) could soon change dramatically the way we envision pre- and post-transplant HLA desensitization. ◘

LIONEL ROSTAING

Grenoble, France

Desensitization for ABO-incompatible and for HLA-incompatible kidney transplantation

CME 3 – DESCARTESHot topics in the management of pre- and postkidney transplantationSaturday, 08.30 – 11.45, Hall N101 – 102

Convective renal replacement therapies, espe-cially online hemodiafiltration, raise an increas-ing scientific and clinical interest. The number of patients treated with online hemodiafiltration is growing, and the highest prevalence of end-stage kidney disease (ESRD) patients treated with this modality is found in Europe. The Euro-pean nephrology community has been leading in this field of renal replacement therapy for more than two decades.

Randomized controlled trials comparing the out-comes of ESRD patients treated either with on-line hemodiafiltration or with conventional he-modialysis have been concluded over the past few years. A recent meta-analysis of all individ-ual data from these available trials, which was performed with the financial help of EuDial, sug-gests improved clinical outcome in patients who are on online hemodiafiltration. This is especial-ly the case when convection volume is 23 L/ses-sion or more (which equals to approximately 70 L/week). [1, 2] The existence of this ‘minimum dos-age’ to fully obtain the benefits of online hemo-diafiltration has been confirmed by large obser-vational studies.

The actual achieved convection volume per treat-ment session may differ from the set target vol-ume. Main determinants of achieved volume are treatment time (4 h/session or more), blood flow rate through the extracorporeal circuit (minimum of 350 – 400 ml/min) and set filtration fraction (ratio of ultrafiltration volume/blood flow rate through extracorporeal circuit: aim at 30 – 33 %). Studies suggest that when these factors are tak-en into account, the minimum convection volume of 23 L/session can be achieved in the great ma-jority of patients.

Further analysis indicates that in particular the risk for mortality due to cardiac causes is re-duced. [3] To date, the mechanism(s) of this ben-eficial effect is(are) not completely understood. These may include: improved hemodynamic sta-bility, enhanced clearance of uremic toxins, re-duced chronic inflammatory state, and others. Importantly, none of the trials has raised any safety concern about the large-scale use of on-line hemodiafiltration.

In this presentation, the question will be ad-dressed whether online hemodiafiltration is ready to be accepted as the new standard of treatment.

Still questions remain open. So, for the near fu-ture EuDial working group will remain focused not only on increasing the knowledge of this field, but also on organizing CMEs and other ac-tivities to review and share the information with others. Future studies should focus on the mech-anism(s) of a beneficial effect of online hemodi-afiltration. Further, little is known on the effects

on aspects of quality of life. Any clear improve-ment may be very relevant, especially in the ab-sence of an effect on so-called hard clinical end-points. Most studies so far have been done in the currently more or less accepted standard sched-ule of three treatment sessions per week. Virtual-ly no data exist on the role of online hemodiafil-tration in more intensive schedules such as dai-ly and nocturnal dialysis. Finally, only few studies have evaluated the role of online hemodiafiltra-tion in pediatric nephrology, where the treatment may have advantages when compared to stan-dard hemodialysis. ◘

PETER J. BLANKESTIJN

Utrecht, The Netherlands

High-volume hemodiafiltration: the new standard treatment

CME 4 – EUDIALImpoving the outcome of dialysisSaturday, 08.30 – 11.45, Hall N105 – 106

References

1. Peters SA, Bots ML, Canaud B et a., for HDF Pool-

ing Project Investigators. Nephrol Dial Transplant

2016; 31: 978 – 984

2. Davenport A, Peters SA, Bots ML et al., for HDF

Pooling Project Investigators. Kidney Int 2016; 89:

193 – 199

3. Nubé MJ, Peters SAE, Blankestijn PJ et al; for

HDF Pooling Project investigators. Nephrol Dial

Transplant 2017; 32: 548 – 555


Yes, but we need to overcome the challenges of using big data

“The hardest thing of all is to find a black cat in a dark room, especially if there is no cat” (Confucius)

CME 4 – EUDIALImpoving the outcome of dialysisSaturday, 08.30 – 11.45, Hall N105 – 106

Hemodiafiltration has no (significant) advantage over high-flux HD

Can we use routine primary care data to estimate the number of people with CKD?

STEVEN VAN LAECKE

Gent, Belgium

DOROTHEA NITSCH

London, United Kingdom

Figure 1: The effect of convective therapy versus high/low flux hemodialysis on mortality: summary of published meta-analyses. © van Laecke

0,0 1,0 2,0

RR

Overall mortality

Cardiovascular mortality

Susantitaphong et al (2013) (N=12,182; 65 studies) Hemodiafiltration, hemofiltration, ace-tate-free biofiltration, high-flux (super high-flux) vs. low-flux hemodialysis

Overall mortality


Nistor et al (2014) (N=4,039; 35 studies) Hemodiafiltration, hemofiltration, acetate-free biofiltration vs. high-flux or low-flux hemodialysis

Overall mortality


Wang et al (2014) (N=3,220; 16 studies) Hemodiafiltration, acetate-free biofiltration, hemofiltration vs. high-flux or low-flux hemodialysis

Overall mortality


Mostovaya et al (2014) lN=1,318; 6 studies) Hemodiafiltration, hemofiltration vs. high-flux or low-flux hemodialysis

ERA-EDTA Registry

Men

Prevalence (%)

40

25–34 35–44 45–54

Age (years)

55–64 65–74 75+

35

30

25

20

15

10

5

0

Women

(%)

40

25–34 35–44 45–54

Age (years)

55–64 65–74 75+

35

30

25

20

15

10

5

0

CPRD

HSE

Figure 1: Prevalence of eGFR < 60 ml/min/1.73 m2 modified according to [1] © Nitsch

Approximately two million people worldwide receive renal replacement therapy. The pan-demic of obesity and diabetes will boost the prevalence of end-stage kidney disease (ESKD)

in the future. This will obviously translate into incremental costs and imminent pressure on global health budgets. Luckily, the search for optimization of hemodialysis (HD) is still ongoing.

Online hemodiafiltration (HDF) is a safe tech-nique that is increasingly being used in many, especially European, dialysis centers, because of its optimized clearance of larger uremic re-tention solutes, the so-called middle molecules. The increased clearance of these solutes, in-cluding cytokines and beta-2 microglobulin, is expected to improve overall survival and car-diovascular outcome. How can we now ex-plain the seemingly exponential rise in utiliza-tion of this expensive technique with doubtable cost-efficiency when compared to low-flux HD?

As often, this behavior mainly originates from the uncountable retrospective studies that al-most consistently demonstrate a better surviv-al and lower morbidity in prevalent HD patients allocated to HDF instead of low- or high flux-HD. But sometimes, and sadly too often, we hear a story that is too good to be true. These studies repeatedly suffer from incurring bias (especial-ly selection bias, informative bias, lead time bias and others). That is why randomized controlled trials (RCT) should do the trick.

Unfortunately, the majority of RCTs, of which three larger ones are dominating the current ev-

idence, were characterized by a moderate- to high-risk of bias. Moreover, they principally failed to demonstrate a significant beneficial effect of HDF on overall mortality according to published meta-analyses that were not overly restrictive in their inclusion of trials (Figure 1). Also, effects on secondary or surrogate endpoints were often variable, negligible or even absent. In post hoc analyses, patients receiving the highest convec-tive volume consistently and dose dependent-ly had a better outcome. Unfortunately, as those studies were not a priori designed to clarify this issue, we cannot exclude that the ability to reach a maximally attainable convective volume teach-es us more about the health state of the patient (with vascular access as a proxy) or the dialysis center than of the utilized technique. Without ad-justment for body surface and with variable and

seemingly random thresholds, the external valid-ity and the translation from this technical issue to the floor (of the dialysis unit) remain undefined.

So we have to ask ourselves what advantages online HDF can offer, apart from fewer hypoten-sive episodes during dialysis? According to a re-cent RCT, HDF was not associated with a short-er recovery time from dialysis, nor better quality of life according to standardized measurement tools. The field now gets more slippery and the question of whether we should prescribe this still more expensive and laborious technique to all HD patients cannot be answered entirely by the current evidence. Also, a bothering fact re-mains in the staggering melting pot of practic-es in the intervention (pre-, post- or mixed dilu-tion), but especially the comparator groups (low-flux HD, high-flux HD or a mix of both), in both observational, interventional and pharmacoeco-

nomic studies (Figure 1). We should choose our cards and design our studies accordingly. Ironi-cally, high-flux HD should be considered a hybrid technique, as well incorporating low-volume con-vection of less than 10 L per session.

Finally, the actual evidence for the potential add-ed value of convection should be accessible to all stakeholders, including patients and healthcare providers. Shared decision-making and a more patient-centered approach should definitely be-come a therapeutic target. ◘

Using routine data from primary care to esti-mate the number of patients with chronic kid-ney disease (CKD) would enable big-data re-search on the burden of CKD, its risk factors, and outcomes. It would also enable better plan-

ning of local health services. There are a few is-sues that need to be considered when using big data, which are best understood if we contrast the best case scenario with what happens in re-ality – here I use the example of the UK system.

If we did a survey, we would want to measure a representative sample of the population at one point in time using blood and urine tests, using the same assays for everybody. This happened in the UK in 2009/10 as part of the Health Sur-vey for England. If we want to use routine care data instead of doing a survey, we first need to understand the denominator data – i. e. who are the people seen in primary care? Is it everybody,

or would we only see sections of the population depending on their income or other factors? What exactly is recorded in primary care data?

The UK has a gatekeeper system in which access to health care requires registration with a gener-al practitioner (GP). GP practices have been com-puterized since the early 1990s, capturing clin-ical diagnoses using Read-codes, prescriptions, and laboratory test results. If appropriate ethical approvals are in place, anonymous data can be used for research for a fee. The Clinical Practice Research Datalink (CPRD) covers 7 – 8 % of the UK population and is representative in terms of distribution of sex, age and ethnicity [1]. Hence, in theory, if we use CPRD we could assume that we have a snapshot of a percentage of the UK population.

A survey would test everybody with the same as-say to find the people with biochemical evidence of CKD (numerator). In reality, not every patient undergoes testing for renal function in primary care – currently this is only advised in the UK for people who are considered at risk of CKD. There-fore, a large proportion of the registered practice population will not have a creatinine test on file.


References

1. The Clinical Practice Research Datalink (https://

www.cprd.com/home/)

2. The National Chronic Kidney Disease Audit: Na-

tional Report (Part 1). http://www.hqip.org.uk/re-

sources/national-chronic-kidney-disease-au-

dit-national-report-part-1/

3. Iwagami M, Tomlinson LA, Mansfield KE, et al. Va-

lidity of estimated prevalence of decreased kid-

ney function and renal replacement therapy from

primary care electronic health records compared

with national survey and registry data in the Unit-

ed Kingdom. Nephrol Dial Transplant 2017 in

press (doi: 10.1093/ndt/gfw318.)

CME 5 – ERA-EDTA-REGISTRYCross-talk in Renal EpidemiologySaturday, 08.30 – 11.45, Hall 10.B

CME 6 – ERBPGood guidance can save your patientSaturday, 08.30 – 10.00, Sala Retiro

E-ISSUE


Using marginal structural models in clinical research in nephrology

PIETRO RAVANICalgary, Canada

Sample size calculations

MARLIES NOORDZIJAmsterdam, The Netherlands

European Renal Best Practice

Reading a systematic review: a hands-on experience

ERBP Vascular Access Guideline – Work in progress and the next steps

MARIA HALLER

Vienna, Austria

MARKUS HOLLENBECK

Bottrop, Germany

References

1. Tordoir J, et al. Nephrol Dial Transplant 20107;22

Suppl 2:ii33 – 117

PLENARY LECTURESNew Approaches Towards Kidney Regeneration Juan Carlos Izpisua Belmonte Today, 17.00 – 18.30 (Opening Ceremony), Hall 10 Plenary

Whole-body and whole-organ clearing and imaging Hiroki Ueda Sunday, 10.45 – 11.30, Hall 10 Plenary

Re-Creating Life Steve Benner Monday, 10.45 – 11.30, Hall 10 Plenary

Comparative effectiveness research in nephology: using electronic health records to emulate randomized trials Miguel Hernan Tuesday, 09.45 – 10.30, Hall 10 Plenary

When interpreting data over time it is also import-ant to consider whether there are incentives for testing or diagnosing CKD. Not every patient with an abnormal creatinine test will necessarily be re-tested or recorded as having CKD. Indeed, this was one of the reasons why the National Health Service (NHS) commissioned the National CKD Audit [2]. The Audit shows that testing patterns vary by general practice and by type of risk fac-tor, and testing for albuminuria is poor for any-one without diabetes.

The contrast between the perfect scenario and routine primary care data shows the challenges when using big data. However, we can learn from the Audit to make some assumptions. If we can assume that the majority of people with an esti-mated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 end up being tested by their GP within a defined time period, the prevalence of eGFR < 60 ml/min/1.73 m2 in the CPRD should mirror the prevalence in the Health Survey for England. This is indeed the case (Figures) [3]. The CME talk discusses in more detail various sensitivity analyses in terms of using different eGFR formulae, the role of creatinine calibra-tion, and varying time-periods for capturing cas-es of CKD. ◘

In 2014, the European Renal Best Practice (ERBP) team decided to update parts of the current vascular access guideline, which was published in 2007. [1] It was the objective of

the ERBP team to identify clinical topics re-garding vascular access care in hemodialysis patients that are considered a high priority by clinicians and patients. By focusing on high-pri-ority topics, ERBP aims to increase the rele-vance of the guideline for daily clinical practice.

The topics were selected after a survey includ-ing nephrologists, nurses and patients from Austria, Belgium, Spain, The Netherlands and the United Kingdom. We analyzed which top-ics were covered by other organizations and

whether topics could be appropriately ad-dressed by systematic review. A list of suitable topics was than analyzed in Delphi rounds be-tween clinicians and patients.

The final guideline scope covers four sub-groups: catheter-related topics; pre-opera-tive-related topics; peri-and postoperative top-ics; and topics related to surveillance/mainte-nance/follow-up. In each subgroup there were 7 to 11 questions to answer. All national nephro-logic societies within the EDTA-ERA were asked to recommend experts to support the core group and the ERBP methodological team to do the data extraction and to draft statements.

Every question was analyzed in duplicate by two experts. Thousands of papers were re-viewed, data extracted, the grading of evi-dence checked and flowcharts drawn if appro-priate. The progress within the different ques-tions is displayed in the table. Next steps will be the draft of all statements, the draft of the guideline and an internal and external review. We think that we can finalize this by the end of 2017. ◘

What is a systematic review and what are they good for?Systematic reviews are key to evidence-based medicine and are the cornerstone of trustworthy guideline development. Relevant research for daily practice is scattered throughout the medi-cal literature, and with ever-increasing numbers of studies published, it has become impossible

to stay up to date. Systematic reviews provide a summary of the available empirical evidence for a specific clinical question, and are thus a practi-cal way to stay informed without having to search for and read through all primary research stud-ies ourselves.

What’s so special about read-ing a systematic review?Despite a clear argument for having systematic re-views, some are more trustworthy than others and,

like any other study results, need to be applied to the individual patient. This lecture will cover how users can read a systematic review critically to in-form our clinical practice. Important steps in con-ducting systematic reviews will be outlined and a tool to appraise the quality of systematic reviews will be introduced with practical examples.

Who should attend this CME session?Anyone who is interested in evidence-based med-icine and who wants to learn how to critically as-sess the quality of a systematic review with some hands-on experience. ◘


In some study designs, information on a treat-ment (or exposure) and an outcome are updated over time. Analyses including this ‘time-varying’ information are useful in obtaining estimates of the effects of a treatment on the outcome that address time-related changes of the treatment. For example, studying the effects of the change in use or dose of beta-blockers over time on mor-tality from myocardial infarction can provide dif-ferent insights as compared to a study of mor-tality by baseline assignment to beta-blockers.

Confounding is a major problem with non-ran-domized studies, i. e. studies that do not ensure group comparability. A confounder is a variable that is unequally distributed between groups, and affects both the likelihood of treatment and the outcome. Controlling for confounding factors measured at baseline (age, smoking or history of hypertension or diabetes) is easily addressed both in studies that compare the effects of base-line assignment to an intervention and in studies of the effects of its changes over time.

Some longitudinal studies, however, collect infor-mation on time-varying changes in potential con-founders, which are often affected by previous treatment. For example, changes in blood pres-sure values over time impact both the treatment and the outcome (blood pressure level is a con-founder), but are also affected by previous treat-ment. When a time-varying confounder is af-fected by prior treatment, standard methods for

confounding control are inappropriate, because over time the covariate plays both the role of confounder and mediator of the effect of treat-ment on outcome.

Marginal structural models have been designed and used to control for the effect of confounding variables that change over time, and are affect-ed by previous treatment. A marginal structur-al model is a statistical procedure that involves several analytical steps. To address confound-ing, marginal structural models first calculate a weight to assign to each observation in the study. These weights reflect the extent to which obser-vations with certain characteristics are under- or

over-represented in the sample with respect to a target population in which these characteris-tics are balanced across treatment groups. Then, marginal structural models estimate the outcome of interest when accounting for these weights, therefore enhancing group comparability. Mar-ginal structural models are a powerful method of confounding control in longitudinal study de-signs that collect time-varying information on treatment (or exposure), outcome and other co-variates. ◘

PIETRO RAVANI

Calgary, Canada

Using marginal structural models in clinical research in nephrology


A powerful method of controlling confounding in longitudinal study designs

The sample size is the number of patients or other experimental units included in a study and calculation of the sample size required to answer the research question is one of the first steps in setting up a study. Although most statistical textbooks describe techniques for sample size calculation – also known as pow-er calculation – it is often difficult for investi-gators to decide which method to use. There are many formulas available which can be ap-plied for different types of data and study de-signs. However, all of these formulas should be used with caution since they are sensitive to errors and small differences in selected param-eters can lead to large differences in the sam-ple size. For those reasons, the ERA-EDTA Reg-istry published in 2010 a paper on sample size calculations in “Nephrology Dialysis Transplan-

tation” [1]. According to the journal’s statistics, this paper is already for a long time listed in the top 5 of most read NDT papers, indicating that there is great interest in this topic. There-fore, it was decided to present the basic prin-ciples of sample size calculations, in this years’ session “Crosstalk in Renal Epidemiology”. In this talk, it will be explained why, when, how and by whom sample size calculations should be performed. In addition, examples of sample size calculations in different situations will be given. Below the most important messages of the talk are summarized.

Why – The primary aim of a sample size calcu-lation is to determine the number of participants needed to detect a clinically relevant treatment effect. Usually, the number of patients in a study is restricted because of ethical, cost and time considerations. However, if the sample size is too small, one may not be able to detect an important existing effect, whereas samples that are too large may waste time, resources and money. It is therefore important to optimize the sample size. Moreover, calculating the sample size in the designing phase of the study is of-ten a requirement when seeking ethical com-mittee approval for a research project.

When – A sample size calculation should be the first step after formulating the research question and choosing the study design. Pre-study cal-culation of the required sample size is warrant-ed in the majority of quantitative studies. They are particularly of interest in the design of ran-domized controlled trials (RCTs). In RCTs, a lot of money is invested, and it is therefore import-ant to be sufficiently sure that enough patients are included in the study arms to find a differ-ence that we assume there is in the population, as statistically significant.

How – To calculate the sample size, it is required to have some idea of the results expected in a study. In general, the greater the variability in the outcome variable, the larger the sample size re-quired to assess whether an observed effect is a true effect. On the other hand, the more effec-tive (or harmful!) a tested treatment is, the small-er the sample size needed to detect this positive or negative effect.

The calculation of the sample size for a trial typ-ically requires four basic components: the type I error (alpha), the power, the smallest effect of interest and the variability of the (primary) out-come. These components can be inserted in one

of the formulas to calculate the sample size. For-mulas for sample size calculation differ depend-ing on the type of study design and the studies outcome(s).

Who – Many of the formulas available to calcu-late sample size are not straightforward, and we recommend to ask for the help of a statistician in all but the most basic studies. ◘

MARLIES NOORDZIJ

Amsterdam, The Netherlands

Sample size calculations


References

1. Noordzij M, Tripepi G, Dekker FW et al. Nephrol

Dial Transplant 2010; 25: 1388 – 1393


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54th ERA-EDTA Congress 2017

Management of CKD-MBD: time for new concepts?

Chair: Professor Markus Ketteler, Germany

Sunday 4 June 201718.45–19.45Hall 10.B, IFEMA Feria de Madrid

Programme

18.45 Chair’s introduction: how new evidence is guiding the guidelines Markus Ketteler, Germany

18.55 Management of MBD on dialysis: how can we improve the control of hyperphosphatemia? Jürgen Floege, Germany

19.15 Treatment of MBD before reaching ESRD: what is the role of 25(OH)D3? John Cunningham, UK

19.35 Q&A and meeting close Markus Ketteler, Germany

Light refreshments will be provided prior to the symposium

VIF1002 ERA EDTA (210x297mm) Ad.indd 1 27/04/2017 11:04

Diabesity – Working Group researching on the nephrological impact in relation to diabetes and obesity

HD or PD for obese diabetic patients?

ROBERT EKART

Ljubljanska, Slovenia

Figure 1: Patient Survival based on Kaplan-Meier curves. Non-DM. Modified according to [2],

by courtesy of J. Heaf

Figure 2: Patient Survival based on Kaplan-Meier curves. DM. Modified according to [2],

by courtesy of J. Heaf

Obesity is closely linked to the development of hypertension, dyslipidemia and type 2 diabe-tes, which together constitute the metabolic syn-drome. Together, they are well-established inde-pendent risk factors for cardiovascular (CV) dis-ease and chronic kidney disease. Two leading causes of end-stage renal disease (ESRD) are type 2 diabetes and hypertension, which together account for more than 70 % of patients with ESRD. Since the growing prevalence of obesity is a key driver for the continued increase in the prevalence of type 2 diabetes, it is hard to study the individual contribution of obesity, type 2 diabetes or hyper-tension to the development of ESRD. The question

of the optimal choice of dialysis modality – perito-neal dialysis (PD) or hemodialysis (HD) – remains a matter of debate, especially in diabetic patients with ESRD. In contrast to the general population, a higher body mass index (BMI) in HD patients is not associated with an increase in mortality risk. Studies have shown the presence of ‘reverse’ ep-idemiology, a seemingly paradoxical observation that the presence of hypercholesterolemia, hyper-tension and high BMI is associated with improved survival in patients on maintenance HD.

In PD patients, reverse epidemiology is less ev-ident or even inverted; i. e. the so-called ‘para-dox-in-paradox’ PD. The additional glucose load in PD could be a contributing factor to obesity in ESRD patients leading to adverse outcomes, which is not seen in HD patients. PD offers sever-al advantages including better preservation of re-


Intestinal phosphate absorption depends on the nutrient

E-ISSUE


Reducing weight to slow GFR decline in patients with obesity and diabetes: The CRESO study

PIERO RUGGENENTIBergamo, Italy

CME 7 – DiabesityDiabesity and Obesity in Renal DiseaseSaturday, 08.30 – 11.45, Hall N107 – 108

PABLO ANTONIO URENA TORRES

Paris, France

European Renal Nutrition Working Group

EUROPEANRENALNUTRITION

Not all phosphate-containing foods are the same

Figure 1: Schematic diagram of intestinal phosphate absorption from nutrients © Urena Torres

E-ISSUE


Education and information: make a choice, nutritional education program

STANISLAS TROLONGEBordeaux, France

CME 8 – ERNPhosphate and Nutrition in CKDSaturday, 08.30 – 11.45, Sala Colon

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View the ERA-EDTA 2017 Broadcast

References

1. Ekart R, Hojs R. Eur J Intern Med 2016; 32:1-6

2. Heaf JG, Wehberg S. PLoS ONE 2014; 9(3):

e90119

sidual renal function, as well as better or similar patient satisfaction when compared to in-center and nocturnal HD. In the literature, conflicting data on the association of increased BMI with survival in PD are found. The apparently conflicting results regarding the effect of BMI on PD outcome may re-late in part to the inability of BMI to differentiate between muscle mass and fat tissue. In principle, two types of patients with high BMI must be dis-tinguished: obese patients and muscular patients. The latter usually have increased body water and are more difficult adequately to dialyze than the obese patients.

The association between BMI and outcomes in the HD population has been studied more fre-quently and more intensively than in the PD pop-ulation. BMI does not characterize excess of cen-trally distributed obesity, which is more consis-tently associated with adverse effects on metab-olism. Central adiposity confers more CV risk than peripheral subcutaneous adiposity. The waist-to-hip ratio has a better discrimination power for atherosclerosis than BMI, and in future waist circumference may become a much more reli-able tool than BMI for assessing metabolic risk and CV events.

No randomized controlled clinical trial compar-ing outcomes in PD or HD obese diabetic pa-tients with ESRD has been published. Which dialysis modality should be advised in clinical practice to the obese diabetic patient? Taking all factors into consideration, the decision in an obese diabetic patient is not simple and should be individualized.

Based on the current data, obesity is not con-sidered to be an absolute contraindication for PD treatment, and there is a priori no reason to advise obese patients to choose HD, especial-ly if the desire for PD is present. Ultimately, we have to assess each patient individually, and if the Kt/V values are reduced or there are other clinical problems, such as hypervolemia, then we have the possibility of earlier switching to HD treatment. According to the latest European Clinical Practice Guidelines, all the different renal replacement therapy modalities should be equal-ly available for all patients, and we should allow free modality choice to patients. ◘

Phosphorus (P) is essential for life and is one of the major mineral elements in the body. It binds with oxygen to make phosphate forms, and with molecules such as calcium, sodium, and potas-sium. Four forms of phosphate can be present in solutions: H3PO4, H2PO4

-, HPO42-, and PO4

3-, but at physiological pH (6.8 – 7.4) only H2PO4

-, and HPO4

2- are quantitatively represented.

The body contains approximately 700 – 800 g of P, distributed in bones (85 %), intracellularly in muscle, soft tissues and blood cells (14 %), and in extracellular fluids (1 %). Only 0.02 % of P is found in the serum – approximately 130 mg for a phosphatemia of 0.85 – 1.45 mmol/l. This is tightly regulated by the hormones produced by three organs, the parathyroid glands (PTH), the kidney (calcitriol) and bone (fibroblast growth factor [FGF] 23), through three feedback loops controlling intestinal P absorption.

In humans, two thirds of intestinal P absorption occurs in the duodenum and jejunum, and the other third in the ileum. Net intestinal P absorp-

tion (50 – 80 %) is a linear function of P intake, and is ensured by a passive paracellular trans-port and by an active sodium-dependent trans-cellular transport, which depends mainly on the NPT2b cotransporter and to a lesser extent to PiT1, PiT2, and NHE3 (sodium hydrogen exchang-er 3) (Figure). This P transport decreases with age, following an age-related reduction of intestinal NPT2b expression. Low P intake, vitamin D, es-trogens, and metabolic acidosis increase NPT2b expression and P absorption, whereas high P in-take, glucocorticosteroids, MEPE (matrix extra-cellular phosphoglycoprotein), and nicotinamide downregulate NPT2b and reduce P absorption.

Although there is a positive correlation between P intake and phosphatemia, intestinal P absorp-tion only accounts for 10 – 12 % of the total. This

is because of the variability in the estimation of P intake, the time of blood sampling, which often does not take into consideration physiologic cir-cadian P cycling, and differences in P bioavail-ability from protein sources, food additives and dietary patters. Likewise, foods that significant-ly lower the calcium-phosphate ratio (Ca:P) can also increase net intestinal P absorption.

The recommended nutritional intakes of P are 750 – 850 mg/day for adults. European and North American surveys have shown that mean dai-ly P intake actually ranges from 1100 to 1700 mg. Phosphate deficiency rarely exists. Howev-er, some drugs can neutralize intestinal P absorp-

tion, and include gastric antacids containing albu-min and magnesium salts, and P binders. Dietary P overdose is rare. Although usual foods provide more P than is physiologically needed, the risks of acute or chronic toxicity are virtually exclud-ed. However, an excess of P may disrupt calci-um metabolism and bone mineralization. For this reason, a safety limit of 2.5 g/day of P is high-ly recommended.

Three types of P can be found in foods:

(1) Plant-derived P, mostly from seeds (beans, peas, cereals, nuts) that contain a form of P called phytic acid (phytate). Humans are gener-ally unable to hydrolyze and use phytate. This P form is poorly bioavailable and has the lowest rate of intestinal absorption (20 – 40 %).

(2) Animal or protein-derived P, which is found in meat (beef, pork, lamb), milk, eggs, poultry, fish and seafood. Its absorption is slightly great-er than plant P (40 – 60 %).

(3) The third type of P is found in food additives as phosphate salts used in processing for re-taining moisture and smoothness. This P is rap-idly dissociated in gut acidity and is highly ab-sorbed (70 – 100 %).

Finally, another important issue to take into con-sideration regarding intestinal P absorption is the P/protein ratio of nutrients (normally 13 – 14 mg/g). However, some foods such as cream

cheese have the greatest ratio (58 mg/g), where-as egg white has the lowest (1.4/g). ◘


Obesity, especially if centrally located, and di-abetes are both associated with renal dysfunc-tion sustained by glomerular hyperfiltration, a risk factor for accelerated renal function loss, and on-set and progression of nephropathy. Thus, glo-merular hyperfiltration might be one of the possi-ble pathogenic links between obesity and chronic kidney disease (CKD). Calorie restriction (CR) re-mains the principal method for inducing weight loss. We evaluated whether and to what extent measured glomerular filtration rate (GFR) (by the iohexol plasma clearance technique) could be af-fected by 25 % CR in the context of a controlled, randomized clinical trial: Caloric REstriction in Subjects with abdominal Obesity and Type-2 di-abetes at increased risk (C.RE.S.O.).

Data showed that in 70 type 2 diabetic patients with abdominal obesity, 25 % CR for six months significantly decreased GFR compared to stan-dard diet (SD). This effect was largely driven by GFR reduction in patients with a higher base-line GFR, and was associated with a reduction in waist circumference, body weight, body mass

index (BMI), systolic and diastolic blood pres-sure (BP), blood glucose, serum LDL/HDL cho-lesterol levels, and amelioration of insulin sensi-tivity as assessed by euglycemic hyperinsuline-mic clamps in all patients. Of interest, every 1 kg weight loss was associated with approximately 1 ml/min GFR reduction. Both CR and SD were well tolerated and no side effects possibly relat-ed to inadequate or unbalanced nutrient supply were observed throughout the study.

These findings could have clinical implications, since persistent hyperfiltration predicts a faster GFR decline and an excess risk of progression to micro- or macroalbuminuria in patients with type-1 [1] or type-2 diabetes. In contrast, amelio-ration of hyperfiltration is associated with a slow-er long-term GFR decline and nephroprotection. We previously found that in a large cohort of pa-tients quite similar to the C.RE.S.O. cohort, a larg-er GFR reduction at six months strongly and in-dependently predicted a slower long-term GFR decline. In particular, a 7.6 % short-term GFR reduction similar to that achieved by CR pre-dicted a mean (SEM) long-term GFR decline of 0.08 (0.13) ml/min/1.73 m2 per month, where-as a 2.7 % reduction similar to that observed in patients on SD predicted a long-term decline of 0.36 (0.07) ml/min/1.73 m2 per month.

If the above findings are generalized to our C.RE.S.O. cohort, we can speculate that CR might reduce the rate of long-term GFR decline by ap-proximately four- to fivefold as compared to SD. This renoprotective effect might translate into a rate of renal function loss similar to that ob-served in healthy adults with aging. Interestingly, the benefit of CR on glomerular dysfunction was more consistent and clinically relevant in those

patients with the highest GFR at baseline. Thus, the renoprotective effect of CR is expected to be greater in those patients who, because of hyper-filtration, are at increased risk of accelerated re-nal function loss.

In conclusion, CR-induced negative energy bal-ance results in substantial improvements of sev-eral major risk factors for the initiation and pro-gression of CKD in diabetic patients with abdomi-nal obesity and without evidence of renal involve-ment. In particular, CR and weight loss, along with amelioration of insulin resistance and other functional and metabolic abnormalities, achieved a significant short-term reduction in the GFR that conceivably reflected amelioration of glomerular hyperfiltration and that resembled the reduction observed following an invasive procedure such as bariatric surgery [2]. Long-term randomized clinical trials (C.RE.S.O.-2) are needed to assess whether calorie restriction may achieve clinical-

ly relevant protection against progressive renal function loss and development of nephropathy in the long-term, as well as reduce patients’ over-all cardiovascular risk. ◘

PIERO RUGGENENTI

Bergamo, Italy

Reducing weight to slow GFR decline

CME 7 – DiabesityDiabesity and Obesity in Renal DiseaseSaturday, 08.30 – 11.45, Hall N107 – 108

Figure 1: Renal and Systemic Effects of Calorie Restriction in Patients with Type 2 Diabetes with Abdominal Obesity: A Randomized Controlled Trial © Ruggenenti

References

1. Ruggenenti P, Porrini EL, Gaspari F et al. Diabetes

Care 2012, 35: 2061 – 2068

2. Ruggenenti P, Abbate M, Ruggiero B et al. Diabe-

tes 2017; 66: 75 – 86

Can we achieve nephroprotection in patients with obesity and diabetes?

ERA-EDTA NEWS / ISSUE 1 / JUNE 3rd, 2017 / page 10-B

As renal insufficiency progresses, accumulation of phosphates increases. From an advanced stage of chronic kidney disease (CKD) to end-stage renal disease (ESRD) treated by hemo-dialysis or peritoneal dialysis, reducing dietary phosphate intake is recommended, even in the absence of hyperphosphatemia.

Nonadherence in the ESRD population ranges from 22 % to 74 % and affects all areas of phos-phorus management self-care. Hyperphospha-temia is a frequently asymptomatic complica-tion. It requires regular treatment several times a day, adaptation of eating habits without signs of physical improvement apart from a better re-sult on its blood tests in the long term.

Health behavior model [1,2]The health behavior model may explain this fre-quent non-adherence. The model suggests that people's beliefs about health problems, per-ceived benefits of action and barriers to action, and self-efficacy explain engagement (or lack of engagement) in health-promoting behavior

Perceived susceptibility is a person’s belief about the likelihood of acquiring a disease or reaching a harmful state through a behavior. Phosphorus is not a well-known mineral, or is seen as positive because of its supposed ben-efits for memory or its connection with calcium.

To move on to the next step, we need to use open questions to allow the patient to express his or her knowledge, opinions, and beliefs.

Perceived severity is the main problem posed by the absence of symptoms of hyperphospha-temia. One educational strategy to promote per-ception of the gravity of a condition is to ’create a symptom’. This consists of educating the pa-tient to improve understanding of the results of blood tests. [3]

Absence of perceived benefits for the patient apart from the satisfaction of a good blood result represents another major difficulty. The educa-tional strategy here is to promote awareness of the potential impact on future access to health interventions such as transplantation.

Perceived barriers to taking phosphate bind-ers are common, and adherence is largely in-adequate. It is well known that adherence im-proves when the patient has a choice of treat-ment. Collaboration between the patient and the health professional is another factor for success. For example, accept that the patient forgets to take the binders, and agree the action to take when this happens. Linking intake of phosphate binders to food consumption promotes self-ad-justment and improves self-efficacy.

Phosphate additivesA new dietary strategy that targets phosphate ad-ditives is needed before reducing consumption of naturally phosphate-rich foods, in order to avoid malnutrition due to protein deficiency.

The first step is to target, evaluate and educate about the presence of additives in the patient’s food choices. Digital tools exist for both patients and caregivers to better identify these additives. Open Food Facts (https://world.openfoodfacts.org) is a collaborative website that is a data-base of food products from around the world. It allows the user to search for the brands of food consumed by the patient and to identify the pres-ence of additives in the list of ingredients. It is also possible to list food brands according to search criteria, such as the presence of phos-phate additives.

As a second step, it may be necessary to adjust the qualitative and quantitative consumption of food sources of organic phosphorus. Nutridial® is a digital application that allows patients to self-evaluate in real time their food consumption and the achievement of their objectives.

Targeting phosphate addi-tives: does this work?Bump [4] in 2016 strongly supported targeting phosphate additives because of their high ab-sorption rate and their presence in lists of in-gredients. However, in 2009 Sullivan [5] alerted us to the very important contribution of a single portion of an industrial food to intake of phos-phate additives and the absence of information on restaurant menus. She also sensitized us to the difficulty for patients in combining dietary advice about several nutrients (phosphorus, po-tassium...). However, we can support this strat-egy, thanks to de Fornasari [6], who showed in March 2017 that a significant decrease in phos-phorus levels was associated with targeted ed-ucation on phosphate additives. ◘

STANISLAS TROLONGE

Bordeaux, France

How can we modify nutrient habits toward a lower phosphate intake?

CME 8 – ERNPhosphate and Nutrition in CKDSaturday, 08.30 – 11.45, Sala Colon

Figure 1: XXX © Trolonge

Perceived Susceptibility

Perceived Severity

Perceived Benefits

Perceived Barriers

Self- efficacity

Cues to action

References

1. Janz NK, Becker MH. Health Education 1984; 11:

1–47

2. Rosenstock IM. Health Education Behavior 1974;

2: 328–335

3. Crozet C, d’Ivernois J-F. Recherches & educations

2010; 3: 197-219

4. Bump M. J Ren Nutr 2016; 26 :e31–e33

5. Sullivan C, Sayre SS, Leon JB. JAMA 2009; 301:

629-35

6. de Forsinari ML, Dos Santos Sens YA. J Ren Nutr

2017; 27: 97-1056


Primary genes, modifier genes and environmental factors are all implicated

Hydrogen sulfide (H2S) is the third gaseous vaso-dilator after nitric oxide and carbon monoxide [1]. Its beneficial effects on the cardiovascular and

nervous systems have recently been re-eval-uated [2]. In particular, it has been shown that lanthionine, a side product of H2S biosynthesis, which was initially used to monitor H2S produc-tion in vivo, was increased in the circulation by over two orders of magnitude in uremic patients, while H2S release was impaired [3]. These find-ings as a whole allowed us to conclude that lan-thionine is not a marker of H2S production and to characterize lanthionine as a novel uremic toxin.

The aim of our research is to define the mech-anism(s) of lanthionine toxicity and to explore

possible therapeutic approaches to reduce its negative effect(s). Acetyl-glutathione (AcGSH) is a promising molecule, itself devoid of toxicity, which could counteract lanthionine biochemical-ly and developmentally, thus preventing its tox-icity. We hypothesized that AcGSH may activate Cystathionine-β-Synthase (CBS), a main in vivo H2S-producing enzyme, through its glutathionyla-tion. Moreover, AcGSH may influence H2S biosyn-thesis, showing long-lasting effect on its produc-tion, probably because of its increased intrinsic stability with respect to its natural analog.

We demonstrated that lanthionine hampers H2S increase in endothelial cells, and it is associat-ed with a significant reduction in CBS levels. As an in vivo experimental model, we used zebraf-ish (D. rerio).

Our data from zebrafish were highly consistent with results we obtained from cell cultures. We used a high-throughput monitoring of zebrafish embryogenesis (Danio Vision tracking system) in order to identify all possible toxic effects of lan-thionine. In particular, prolonged treatment of ze-brafish with lanthionine tended to induce an in-crease of heart rate, provoked arrhythmia, and it induced behavioral alterations, which could be a consequence of nervous system impairment.

AcGSH showed the ability to partially hamper lan-thionine toxic effects on zebrafish heart rate and its behavior. We could conclude that zebrafish is a very suitable animal model to monitor the ef-fects of uremic toxins in vivo. ◘

ALESSANDRA PERNA

Naples, Italy

European Uremic Toxin

Lanthionine: a prospective novel uremic toxin

References

1. Pena AF, Ingrosso D. Nephrol Dial Transplant

2012; 27: 486 – 493

2. Perna AF, Zacchia M, Trepiccione F et al. Toxins

2017; 9: 26

3. Perna AF, Di Nunzio A, Amoresano A et al. Bio-

chimie 2016; 126: 97 – 107

CME 9 – EUToxThe new uraemic toxins and innovative endeavors to treat uraemic toxicitySaturday, 08.30 – 11.45, Sala Neptuno

CONSTANTINOS DELTAS

Nicosia, Cyprus

Working Group on Inherited Kidney Disorders

Collagen IV glomerulopathies: an underdiagnosed phenotypic chameleon?

1 – 30 years

Hematuria ESRDHematuria,

Proteinuria, FSGS

Hematuria, Proteinuria, FSGS, CRF

No symptoms

Protective genes ??? Predisposing modifier genes / Environment ???

Cut off for progression to CRF

Predisposing modifier genes / Environment ???

30 – 50 years 40 – 70 years

Figure 1: Illustration of the spectrum of phenotypes caused by mutations in the collagen IV genes. According to the chameleon hypothesis, same or similar mutations can manifest with very mild or very severe phenotypes, under the operation of primary genes, modifying genes and environment. During aging, any patient may progress from one to another place of the spectrum. © Deltas

(continued on page 12)

Collagen IV nephropathies comprise a geneti-cally and phenotypically heterogeneous group of disorders, invariably presenting with famil-ial microscopic hematuria since childhood that may or may not progress to severe kidney func-tion decline. Depending on genetic background and environmental factors, allelic mutations in the COL4A3/A4/A5 genes behave as a pheno-typic chameleon, with phenotypes that are dis-parate enough to justify a different diagnosis by the clinicians, a phenomenon we termed: Unilo-cus mutational and phenotypic diversity.

One could also argue that all patients are on a phenotypic spectrum ranging from isolated mi-croscopic hematuria all the way to severe chron-ic kidney disease (CKD) and even end-stage re-nal disease (ESRD). Specifically, patients with heterozygous COL4A3/A4 mutations have been diagnosed as having inherited one or more of the following:

(a) Thin basement membrane nephropathy (TBMN), a purely histological description in the presence of microscopic hematuria, caused by heterozygous COL4A3 or COL4A4 mutations. This was formerly synonymous with familial benign hematuria, but most experts agree to abandon this term, as it is not always true and is a misno-mer leading to the wrong impression. Perhaps a better term for a subset of patients is (b).

(b) Later-onset Alport-related nephropathy, for those patients who present with familial mi-croscopic hematuria in childhood due to TBMN

(and heterozygous COL4A mutations), but for yet largely unknown reasons, they develop serious CKD and even ESRD, usually after the fifth de-cade of life.

(c) Autosomal dominant Alport syndrome (AS), for those rare occasions where heterozygous COL4A mutations are associated with ultrastructural and extrarenal features pathognomonic of AS. The age at onset is usually at much later ages, com-pared to classical X-linked AS in males or auto-somal recessive AS in patients of either gender.

(d) Focal and segmental glomerulosclerosis, an-other purely histological description.

Notwithstanding that most patients with hetero-zygous COL4A mutations will have a rather mild disease course, the truth of the matter is that clinical presentation can be complex. A key un-answered question is: why some patients fol-low a mild course, while others with the same or similar primary mutations develop progressive renal dysfunction? According to the chameleon hypothesis, the full phenotypic spectrum of this monogenic single disorder behaves as a mul-tifactorial condition, implicating primary genes,

modifier genes and environmental factors (Fig-ure 1). In previous work, we and others have re-ported on two candidate variants in the NPHS2 gene (podocin) and one in the NEPH3 gene (fil-trin), both expressed in the slit diaphragm of the glomerular filtration barrier. However, these variants explain only a small part of the herita-ble heterogeneity.

To address this chameleon hypothesis, we per-formed unbiased whole-exome-sequencing of 260 Hellenic people from Cyprus and Greece, harboring a limited number of pathogenic het-erozygous COL4A3/A4 mutations. About half of the patients are classified as ‘mild’ or ‘severe’ based on set criteria. Initial examination of the data does not support the existence of common variants with substantial effects, although one such variant is under further evaluation. The ho-listic analysis of data suggests the presence of a large number of variants that, when co-inher-ited in different combinations, might confer a high risk of, or protect from, manifesting a ‘se-vere’ disease. The development of an algorithm to enable prediction is in progress. We anticipate that such an algorithm could also allow the pre-diction of a similar risk


CME 10 – WGIKDDiagnosis and management of inherited kidney diseases: What’s New?Saturday, 08.30 – 11.45, Hall N117 – 118

OLIVER GROSS

Goettingen, Germany

Alport syndrome: a treatable – but the diagnosis is often made too late

Diagnosis

clinic: 1. hematuria 2. family history positive 3. hearing loss 4. ocular changesKidney biopsy always including EM or Moleculargenetic testing

Alport-Syndrome heterozygous Alport-patient

Hematuria or Micro-Albuminuria

Proteinuria > 0.3 g/day

Hematuria

yearly follow-up for risk-factors and proteinuria

If progress use add-on therapy: • AT1-Antagonist• RR-target below 125/75 mmHg• Statins• Paricalcitol

ACE-inhibitorACE-inhibitor

Hematuria or Micro-Albuminuria

Proteinuria > 0.3 g / day

YES RISKNO RISK

screen for additional risk factors such as high blood pressure, smoking, additional renal diseases, diabetes, nephro-toxic medications

considertherapy

thin basement membrane

! Please report every patient to national or international Alport-registry !

EARLY PRO-TECT Alport-Study

Studies with new medications:• HERA• CARDINAL

Figure 1: Synopsis of the (diagnostic and) therapeutic approach © Gross

Diagnosis of Alport syndrome includes standard nephrological workup including complete family history (check

all relatives for micro-hematuria), inner ear hearing impairment and ocular changes.

(continued from page 11)

Patients with the hereditary disease Alport syn-drome (AS) develop progressive renal fibrosis due to mutations in type IV collagen genes. If diagnosed early, AS has become treatable, re-nal failure can be delayed by years, and life expectancy can be improved. Unfortunately, the diagnosis is often made too late. Every nephrol-ogist should check his/her Alport patients (in-cluding heterozygous patients) for proteinuria and other risk factors every year.

Timing and methods for diagnosis Screening for microhematuria should start be-fore elementary school. Any renal microhema-turia should lead to early transfer to a Pediat-ric nephrologist. Every suspected case of AS, including heterozygous girls, should receive a complete workup including genetic testing. Ear-ly diagnosis is mandatory because it enables early therapy. Kidney biopsies must include electron microscopy, because light-microscop-ic changes can be misdiagnosed as focal seg-mental glomerulosclerosis (FSGS).

Mode and frequency of control investigationsHeterozygous patients with X-chromosomal or autosomal-recessive disease must be in-formed about their risk: up to 40 % develop renal failure, up to 20 % require dialysis. Time-ly RAAS-blockade can avoid dialysis in most heterozygous patients. Therefore, care for het-erozygous patients must include – for life – an-nual follow-up. Adults with microalbuminuria must be treated by RAAS-blockade; therapy in heterozygous children should start with on-set of proteinuria.

In ALL other patients with hemizygous, com-pound-heterozygous or homozygous mutations, the timespan until renal failure depends on start of RAAS-blockade and type of mutation. There-fore, care for all patients must include – for life – at least half-yearly follow-up by the nephrologist.

In daily practice for adult nephrologists, every patient with renal microhematuria should be in-formed about her/his potential risk of AS. If mi-cro-albuminuria develops, immediate work-up by a nephrologist should exclude or confirm the diagnosis of AS. In children with microhematu-ria, especially those with a positive family history, early transfer to a Pediatric nephrologist should lead to clinical and genetic work-up.

Optimal start of therapy Expert recommendations guide the nephrologist through off-label therapy, until prospective clin-ical trials further improve evidence. Every pa-tient should be reported to a national or inter-national registry. All children must be treated at the onset of proteinuria; an earlier start of ther-apy may be considered in ‘severe’ mutations. In 2019, the EARLY PRO-TECT Alport trial will hope-fully answer the question about the optimal start of early therapy.

Suggested guidelinePatients with classical Alport syndrome: Start ACE inhibition in children if proteinuria rises > 0.3 g/day; AT1-antagonists are second-line. Use rami-pril at its highest tolerable dose of 10 mg/day (6 mg/m2 in children). At present, children in ear-lier stages should only be treated in clinical trials.

Heterozygous patients, including thin base-ment membrane: Start ACE inhibition in adults with microalbuminuria and in all children with proteinuria.

Supportive careThe effectiveness of supportive care is greatly undervalued in AS. Recurrent bacterial infections, poor dental health, high salt intake, extreme mus-cle-building, smoking, high blood pressure and

overweight harm the weak glomerular basement membrane (GBM) in AS. It is likely that chang-es in lifestyle can further delay renal failure by many years.

Escalation of therapyDespite ACE inhibition, AS progresses in all pa-tients. If proteinuria (or blood pressure) increas-es, add-on therapy often includes AT1-antag-onists. All other antihypertensive drugs can be used, preferably long-lasting calcium antagonists, diuretics and spironolactone. Target blood pres-sure should be below 125/75 mmHg. Therapeu-tic goals are the reduction of proteinuria and pro-tection of the GBM from hyperfiltration.

Therapeutic options and goals in secondary complicationsBecause of antifibrotic properties shown in Al-port mice, statins are recommended in adults with dyslipoproteinemia and paricalcitol in pa-tients with hyperparathyroidism. Both medica-tions have the potential to further delay renal fail-ure by months or even years and decrease car-diovascular risk.

Future therapeutic optionsIn 2017, new phase 2 and 3 interventional inter-national studies with new medications can be of-fered to many patients worldwide (please refer to websites of HERA and CARDINAL Alport stud-ies for further information).

Conflict of interestThe author’s employer, University of Goettingen, receives financial compensation for his consul-tancy activities for Reata Pharmaceuticals and Regulus Therapeutics. Please contact the author for all literature cited. ◘

to people of the gen-eral population by aging. This, in turn may pave the way for new personalized treatments.

AcknowledgementsMany thanks to all collaborators of the Molecular Medicine Research Center (MMRC) of University of Cyprus, clinicians and researchers. This work is funded partly by a grant from the European Renal Association-European Dialysis and Trans-plant Association.

Relevant selected literatureVoskarides K, Damianou L, Neocleous V et al. J Am Soc Nephrol 2007; 18: 3004 – 3016Gast C, Pengelly RJ, Lyon M et al. Nephrol Dial Transplant 2016; 31: 961 – 970Voskarides K, Stefanou S, Pieri M et al. PLoS One 2017; 12: e0174274 Deltas C, Savva I, Voskarides K et al. Nephron 2015; 130: 271 – 280 ◘


Clinical implications of the good, bad, and ugly

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ANDREAS KRONBICHLER

Innsbruck, Austria

Rheumatology for nephrologists

Bacterial microbiota in ANCA vasculitis

CME 11Rheumatology for nephrologistsSaturday, 12.00 – 15.15, Hall 10.A

E-ISSUE


Autoinflammatory diseases – an update for nephrologists

BIRGIT KORTUS-GÖTZEMarburg, Germany

Antiphospholipid antibody syndrome: a catastrophic disease?

RICARD CERVERABarcelona, Spain

Environmental factors have been implicated in the etiopathogenesis of ANCA-associated vascu-litis, including air pollution (i. e. silica exposure), drug exposure (cocaine, propylthiouracil, etc.) as well as infections (Staphylococcus aureus and granulomatosis with polyangiitis (GPA), as well as proposed molecular mimicry with Gram-neg-ative bacteria and onset of ANCA-associated re-nal disease).

In 1994, the first study systematically investigat-ed the impact of chronic S. aureus carriage and risk of relapse in GPA. A randomized, controlled trial, which assigned participants to either tri-methoprim-sulfamethoxazole (2 tablets daily for 2 years), found a significant reduction in relaps-es during the follow-up period compared to the control group. Further studies published to date have found a S. aureus carriage rate of around 65 – 70 %. This is three times higher than in the general population, and the question remains whether presence of S. aureus in GPA is dis-ease-related or follows chronic damage due to active vasculitis. More recently, analysis of two early EUVAS (European Vasculitis Society) trials revealed that chronic carriage during initial di-agnosis was comparable to that in the gener-al population. Analysis of cases with GPA high-lighted an association between higher relapse risk and chronic carriage in patients with ‘gen-eralised’ GPA and a borderline significance for patients with ‘early systemic’ GPA. Prophylactic treatment with trimethoprim-sulfamethoxazole (three times a week 1 tablet) did not lower the re-lapse risk, but did reduce the number of patients with chronic nasal S. aureus carriage.

To further investigate microbial diversity in pa-tients with GPA, we performed a cross-section-al study and recruited patients with either active

disease or during remission. Patients with eosin-ophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA), and healthy volunteers served as controls. Our findings illus-trate the diversity and the inter-individual differ-ences in the nasal microbiome. Although num-bers were low for the microbiome analysis study,

16S PCR analysis did not show a clear associa-tion between active vasculitis and S. aureus car-riage. Nevertheless, we could provide evidence that patients with active disease and those in re-mission may be sub-divided according to their di-versity of bacterial colonisation. Clearly, more re-search and a prospective follow-up of these pa-tients is necessary to propose a ‘bacterial panel’ that may be implicated in either onset or recur-rence of active disease.

Autoantibodies of patients with pauci-immune glomerulonephritis recognize an epitope within human lysosomal membrane protein-2 (LAMP-2), which has 100 % homology to the bacterial adhesin FimH (present on Escherichia coli, Kleb-siella pneumoniae and Proteus mirabilis). Kain and co-workers demonstrated that antibodies to LAMP-2 are present during active disease, disappear in the majority of patients during the remission phase, and may re-appear when pa-tients have a relapse. Moreover, the presence of LAMP-2 antibodies in patients with ANCA-nega-tive disease was demonstrated. However, a lim-itation of testing LAMP-2 antibodies is the cur-

rently complex approach that involves combin-ing different laboratory strategies, which clearly limits such testing in clinical practice.

Taken together, bacteria play a pivotal role in the onset of ANCA-associated vasculitis in general and GPA in particular. Further research is need-ed to further characterize the bacterial microbi-ome in these patients. ◘


Autoinflammatory diseases are disorders charac-terized by recurrent episodes of fever and acute multisystemic inflammation in the absence of an infectious or autoimmune stimulus. The autoin-flammatory diseases are rare and belong to the class of orphan diseases.

The main autoinflammatory diseases are famil-ial Mediterranean fever (FMF), the tumor-ne-crosis factor receptor-associated periodic syn-drome (TRAPS), the cryopyrin-associated peri-odic syndrome (CAPS) and the hyper-IgD syn-drome. In addition to general symptoms, there is a wide range of systemic and organ involve-ment. AA-amyloidosis, especially renal amyloi-dosis, is the life-threatening long-term compli-cation and so prognosis is mainly determined by the rate of progression of amyloidosis. In over 90 % of patients the first sign of AA-amyloido-sis onset is glomerular proteinuria. In the course

of time the kidney damage progresses in an un-predictable manner and results in nephrotic syn-drome, renal failure or even end-stage renal dis-ease (ESRD). Therefore, a close monitoring of re-nal function is necessary.

In our clinic we have long-term experience in the diagnostic evaluation, care and treatment of pa-tients with Muckle-Wells syndrome, one of three entities of CAPS. The general symptoms include recurrent episodes of fever, urticaria, myalgia and arthralgia, conjunctivitis, headache and fatigue syndrome. The long-term effects are progressive sensorineural hearing loss, social isolation due to fatigue syndrome and AA-amyloidosis, most-ly resulting in renal amyloidosis. In our patients we observed various developments of renal func-tion in biopsy proven AA-amyloidosis. In 2010 we successfully performed kidney transplantation in one of our female patients with ESRD due to AA amyloidosis in Muckle-Wells syndrome. Today, she has a stable kidney transplant function and no sign of recurring amyloidosis. The underlying Muckle-Wells syndrome is in very good remis-sion under a specific anti IL-1 inhibition. In future, we need more clinical studies to assess patients with these rare diseases. ◘

BIRGIT KORTUS-GÖTZE

Marburg, Germany

Autoinflammatory diseases – an update for nephrologists


Prognosis is mainly determined by the rate of progression of amyloidosis

The descriptive adjective ‘catastrophic’ was add-ed in 1992 to define an accelerated form of the antiphospholipid syndrome (APS) in order to highlight a new subset of this syndrome that re-sults in multiorgan failure that is often fatal. Pa-tients with catastrophic APS have in common:

(a) Clinical evidence of multiple organ involve-ment that develops over a very short period of time,(b) Histopathological evidence of multiple small vessel occlusions, and (c) Laboratory confirmation of the presence of an-tiphospholipid antibodies (aPL), usually in high ti-ter. Fortunately, less than 1 % of patients with the APS develop this complication, but its potential-ly lethal outcome emphasizes its importance in clinical medicine today.

Although it is still unclear why some patients de-velop recurrent thromboses, mainly of large ves-sels (simple or classic APS), while others devel-op rapidly recurrent vascular occlusions, pre-dominantly affecting small vessels (catastroph-ic APS), our knowledge on this severe variant has increased a great deal during the last 25 years of intensive research.

Due to the rarity of catastrophic APS, an interna-tional registry (the CAPS Registry) was created in 2000. This registry documents the entire clinical, laboratory and therapeutic data of all published cases with catastrophic APS, as well as of many additional patients whose data have been fully registered. The periodical analysis of this regis-try has allowed us to increase our knowledge of this condition.

In the most recent analysis of the CAPS Registry including 500 patients, precipitating factors were identified in 65 % of the episodes. The most fre-quent factors were infections (49 % of episodes), mainly in the respiratory tract (33 %), followed by the urinary tract (19 %), and the skin (13 %). The clinical picture was characterized by renal in-volvement (73 %), with variable degree of renal failure, and lung involvement (60 %) in the form of acute respiratory distress syndrome or pul-monary embolism (26 %). Up to 56 % of patients showed central nervous system manifestations because of stroke or encephalopathy. The heart

was affected in half of the episodes, mainly due to myocardial infarction or valvulopathy. Lupus anticoagulant, IgG anticardiolipin and IgG an-ti-β2-glycprotein antibodies were the most of-ten implicated antiphospholipid antibodies (83 %, 81 % and 78 %, respectively). Death occurred in 37 % of episodes.

Management of the catastrophic APS is challeng-ing. Early diagnosis and aggressive therapies are essential. In any APS patient, particular atten-tion should be given to the following guidelines:

(1) Any infection should be energetically treated with the appropriate antibiotics;(2) APS patients undergoing surgical proce-dures should all receive parenteral anticoagu-lation during the procedure instead of remain-ing on warfarin; (3) The puerperium should be adequately cov-ered for a minimum of 6 weeks with parenteral anticoagulants; and (4) Severe systemic lupus erythematosus (SLE) flares should also be treated with parenteral anticoagulation.

Unfortunately, there is an absence of prospec-tive and randomized therapeutic studies in cat-astrophic APS. In fact, the evidence-based infor-mation about current treatment also comes from the CAPS Registry:

(a) The higher recovery rate was achieved by the combination of anticoagulation (AC) plus glu-cocorticoids (GC) plus plasma exchange (PE) (77.8 % versus 55.4 %, p = 0.083), followed by AC plus GC plus PE and/or intravenous immuno-globulins (IVIG) (69 % versus 54.4 %, p = 0.089); (b) Treatment with cyclophosphamide (CYC) did not demonstrate an additional benefit; (c) Isolated use of GC was related to a lower rate of recovery (18.2 % versus 58.1 % of episodes not treated with GC; p = 0.01);(d) More interestingly, the mortality rate de-creased from 53 % in the patients diagnosed before 2000 to 33.3 % in those diagnosed from 2001 to February 2005 (p = 0.005; odds ratio [OR], 2.25; 95 % confidence interval [CI], 1.27 to 3.99). The main explanation for this significant reduction in mortality was the more frequent use of combined treatment with AC plus GC plus PE and/or IVIG. Additionally, there are few data on new therapeutic approaches, including rituximab and eculizumab. ◘

RICARD CERVERA

Barcelona, Spain

Antiphospholipid antibody syndrome: a catastrophic disease?




SANDRO MAZZAFERRO

Rome, Italy

BEN SPRANGERS

Leuven, Belgium

Working Group on Chronic Kidney Disease – Mineral and Bone Disorders

Position in CKD of novel compounds to treat bone disease

Cytotoxic drugs and their renal side effects

Figure 1 © Mazzaferro

CME 12 – WGIKDImplementation of the KDIGO update on CKD-MBD – Part 2Saturday, 12.00 – 15.15, Hall N103 – 104

Oncology for Nephrologists

References

1. Hotta K et al. J Clin Oncol 2004: 22: 3852 – 3859

2. Ardizzoni A et al. J Natl Cancer Inst 2007; 99:

847 – 857

3. Cohen EP et al. Am J Kidney Dis 2015; 66:

869 – 883

4. Prasaja Y et al. Asian Pac J Cancer Prev 2015;

16: 1117 – 1122

5. Ozkok A et al. Biomed Res Int 2014: 967826

6. Dugbartey GJ et al. Toxicology 2016: 371:

58 – 66

7. de Jongh FE et al. Br J Cancer 2003; 88:

1199 – 1206

8. Tan XL, et al Clin Cancer Res 2011; 17:

5801 – 5811

9. Khrunin A et al. Pharmacogenomics 2012; 13:

171 – 178

10. Fridley BL et al. OMICS 2014; 18: 34 – 41

11. Lavole A et al. Bull Cancer 2012; 99: E43-E48

12. Tiseo M et al. Tumori 2007: 93: 138 – 144

13. Moon HH et al. World J Gastroenterol 2011; 17:

3510 – 3517

14. Launay-Vacher V et al. Cancer Chemother Phar-

macol 2008: 61: 903 – 909

15. Santoso JT et al. Cancer Chemother Pharmacol

2003: 52: 13 – 18

16. Mulder RL et al. Cancer Epidemiol Biomarkers

Prev 2013: 22: 1736 – 1746

17. Skinner R et al. Eur J Cancer 2009; 45:

3213 – 3219

18. Skinner R et al. Pediatr Blood Cancer 2010; 54:

983 – 989

View the ERA-EDTA 2017 Broadcast

The clinical spectrum of Chronic Kidney Dis-ease-Mineral Bone Disorders (CKD-MBD) goes beyond bone lesions to include an increased bur-den of morbidity and mortality for any cause or for cardiovascular disease. Part of this increased morbidity and mortality has been recently re-ferred to the high incidence and prevalence of bone fractures in Chronic Renal Failure (CRF). Not surprisingly, we are witnessing a renewed interest for bone histology in renal patients, aim-ing at recognizing not only the classical different types of renal osteodystrophy (ROD), but also the three bone parameters on which the new classi-fication is focused: Turnover, Mineralization and Volume (so called TMV classification of ROD). The aim of this new classification is to highlight the mechanical and metabolic competences of bone rather than its morphologic aspects.

A further awareness of recent years is that an increased rate of fractures, similarly responsi-ble for morbidity and mortality, is evident in CRF patients not on dialysis. This widens the popula-tion potentially affected by ROD, deserving eval-uation and, possibly, preventive therapies. Inevi-tably, searching for bone fractures in early stag-es of CKD means dealing with aged people at risk of osteoporosis (OP), the other metabolic condi-tion responsible for increased fracture and mor-bidity/mortality in the general non-renal popula-tion. A practical consequence is that distinguish-ing between OP and ROD in early stages of CKD, is becoming a frequent issue in the daily prac-tice. Another consequence is that nephrologists are ever more required to decide on the use of drugs developed for OP but in patients with CRF.

Available trials, exclusively designed for OP (ei-ther postmenopausal or of aged males) and unin-tentionally including cases with reduced glomer-ular filtration rate (GFR), indicate that biological drugs could be safely employed in patients with GFR reduction, down to CKD stage 3.

This presentation examines available data, po-tential indications and possible side effects in re-nal patients of three drugs: parathyroid hormone (PTH), denosumab and romosozumab. At vari-ance with classical drugs for OP that cure bone through indirect actions (e. g. on Calcium balance or PTH secretion), these drugs are specifically de-signed to act on bone cells activity so that a di-rect modification of the balance between appo-sition and resorption is made possible. As illus-trated in the figure, PTH interacts with its recep-tor on osteoblasts and increases bone formation; denosumab knocks down the osteoblast activator RANKL and thus reduces bone resorption; romo-sozumab blocks sclerostin and thus at the same time increases osteoblasts activity and reduces osteoclast recruitment. Evidently, each of these actions could theoretically be useful to improve specific types of ROD. However, the complexi-ty of bone pathophysiology in renal patients and the systemic implications of CKD-MBD, warrants

randomized clinical trials specifically designed for renal patients in order to identify the patients that will benefit mostly. ◘

Cytotoxic drugs are widely used chemothera-peutics, and their use has resulted in increased survival rates in patients with different types of solid tumors. Cisplatin is the best-known plati-num-based chemotherapy drug and is a corner-stone in the treatment of solid tumors such as ovarian and cervical cancer, testicular cancer, head and neck cancer including nasopharyngeal, and lung cancer. Although carboplatin and oxal-iplatin, which are platinum derivates, have few-er side effects, cisplatin is still used more exten-sively as it is more potent and results in better survival rates [1, 2].

The most notable and important cytotoxic side ef-fect is nephrotoxicity. Cisplatin, ifosfamide, car-boplatin, oxaliplatin and pemetrexed have all been associated with acute kidney injury (AKI) [3]. Besides acute kidney injury, cytotoxic drugs have also been associated with chronic kidney disease (CKD) and other renal symptoms such as Fanconi’s syndrome. Cytotoxic drug-induced renal side effects are associated with important morbidity, mortality and economic costs.

Platinum-based chemotherapy is associated with the occurrence of AKI in around 30 % of patients. For example, a recent study from Indonesia re-ported that cisplatin-induced nephrotoxicity oc-curred in more than one-third of patients after the fourth cycle of chemotherapy and that pro-phylactic strategies could not prevent its occur-rence [4]. Carboplatin is less nephrotoxic than cisplatin and only a few reports have been pub-lished regarding oxaliplatin-induced AKI.

The pathophysiology of cisplatin-induced nephro-toxicity is complex and multifactorial [5,6]. Neph-rotoxicity associated with cisplatin is dose de-pendent and transient in nature. However, the cumulative dose of cisplatin has convincingly been associated with reduced glomerular filtra-tion rate (GFR). In addition, several non-modifi-able factors have been shown to increase the risk of cisplatin-induced nephrotoxicity, such as ge-netic factors, race, gender, age, cardiac disease and diabetes [7 – 11]. Various strategies have been proposed to reduce cisplatin nephrotoxici-ty; e. g. fractionated dosing, reduced infusion rate

and intensive hydration with or without concom-itant diuretics [12,13]. However, it is not possible to completely prevent cisplatin-induced nephro-toxicity. Based on the limited available evidence, clinical practice guidelines have been developed to prevent cisplatin-induced kidney injury [14].

These recommendations focus on optimization of volume status, administration of parenter-al crystalloids during drug administration, and prevention and treatment of chemotherapy-in-duced vomiting and nausea. At this time, sever-al aspects regarding optimal hydration such as the duration of hydration and the use of diuret-ics are still controversial [12, 15]. However, re-cent studies have shown that diuretics should probably be avoided in patients receiving plati-num-based chemotherapy, as diuretics are not protective and probably even harmful.

With improved survival, it has become evident that cytotoxic chemotherapeutics are also as-sociated with the development of CKD. In child-hood cancer it has been established that loss of GFR occurs early and especially in children treat-ed with ifosfamide and higher doses of cispla-tin [16]. Carboplatin-induced nephrotoxicity did not change significantly over time, and was more pronounced in children older at time of treatment and in patients treated with a higher carboplatin dose [17]. In contrast, ifosafmide-induced neph-rotoxicity could not be predicted based on cumu-lative dose or age at the time of treatment [18].

Besides tubular injury, cisplatin has been asso-ciated with hemolytic uremic syndrome and if-osfamide has been associated with Fanconi syn-drome. These side effects are rare, but clinical practitioners should be aware of them in order to be able to diagnose and treat them effectively. ◘


Duplex ultrasound can be used by all team members to optimize their patient’s lifeline

CME 13Oncology for nephrologistsSaturday, 12.00 – 15.15, Hall N101 – 102

E-ISSUE


Targeted therapies in oncology and nephro-toxicity

PETRA TESAROVAPrague, Czech Republic

From “primary” amy-loidosis to monoclonal gammopathy of renal significance

ELENA ZAKHAROVAMoscow, Russia

Dialysis and malignancy– a gro-wing problem

MARIA PIPPIASAmsterdam, The Netherlands

SIMON VAN HOOLAND

Gent, Belgium

From theory to clinical practice: vascular access ultrasonography

Practical issues in vascular access care

Multidisciplinary vascular access (VA) care is gaining in importance due to an increase in dif-ficult VAs as the epidemiology of the dialysis population is changing (age, obesity, diabetes etc.). Duplex ultrasound (DU) can be used by all the members of the VA team (dialysis nurse, ne-phrologist, vascular surgeon and interventional radiologist) as an additional way to further opti-mize the care of their patient’s lifeline.

To perform VA ultrasonography, one needs a (por-table) ultrasound machine combining B Mode with Doppler Mode (Color Flow, Pulsed Wave and Power Doppler), a linear transducer, gel as a coupling agent, a tourniquet and sufficient train-ing (theory and practice). Duplex ultrasound of VA is useful before, during and after VA creation. Preoperative mapping of the vascular structures of the upper limbs should be performed in all patients in need for a VA, especially difficult ac-cess. Mapping leads to the creation of more native arteriovenous (AV) fistulas and fewer AV grafts, a lower rate of negative exploration, an increased proportion of patients dialyzed with an AV fistula, and improved fistula adequacy. During the procedure, there is a selection of the most appropriate dialysis access modality, anatomi-cal site and vessels. According to the European Best Practice Guidelines on VA (2007), dialysis catheter placement should be performed under ultrasound guidance, as this method is superi-or to and safer than the blind, landmark tech-nique. One can choose between the transversal (out of plane) or longitudinal (in plane) approach. In our experience, the transversal approach is the most convenient, at least in the setting of dialysis VA. In established VA, ultrasound can be used to visualize fluid around a dialysis cathe-ter (hematoma, tunnelitis). In dialysis AV fistu-las and AV grafts, ultrasound has its role in the following indications:

• Absent/diminished thrill • As per protocol (surveillance)• Dialysis VA-related problems: cannulation

difficulties and other problems, including el-evated venous pressures, low Kt/V and high recirulation, low access flow, aspiration of blood clots, local pain on cannulation, pro-longed bleeding after cannulation.

• Arm swelling (local versus generalized) • Arm pain (ischemia).

Although no pathologic lesion is found in up to 36 % of angiography procedures performed be-cause of cannulation difficulties, stenosis is the most frequent underlying problem. Borderline and significant stenoses are both characterized by a > 50 % lumen diameter reduction and a peak systolic velocity (PSV) ratio > 2, whereas a VA with a significant stenosis has at least one of the following additional criteria: a residual diam-

eter < 2 mm, flow reduction > 25 % and/or an ac-tual flow volume < 600 ml/min. Other problems besides stenosis include incorrect needle posi-tion, venous side branches, a too deep or too tor-


PETRA TESAROVA

Prague, Czech Republic

Most targeted cancer therapies have a degree of nephrotoxicity


Appropriate dose reduction and careful monitoring of renal function are essential

Renal function may be compromised by differ-ent drugs used in the diagnosis and treatment of patients with malignancies, including che-motherapy, bisphosphonates, or contrast agents. Targeted treatment aims to inhibit the specific molecules participating in tumor growth, pro-gression and dissemination. Targeted signaling pathways are often involved in the regulation of cell division or inhibition of apoptosis, which both play an important role in many process-es in the healthy organism, so their inhibition may be associated with many adverse events.

The clinical trials IRMA-1 and IRMA-2 demon-strated that more than 50 % of patients with cancer may have at least slightly decreased renal function (glomerular filtration rate [GFR] < 90 ml/min/1.73 m2), and the prevalence of chronic kidney disease (CKD) stage 3 – 5 (ex-cluding patients on dialysis) was about 12 %. On the other hand, CKD is often associated with a higher incidence of cancer (not only in patients with end-stage renal disease). Tar-geted treatment is more often used in these types of cancer, as breast, colorectal, kid-ney and cervical cancer occur more frequent-ly in patients with CKD. Antiangiogenic target-ed treatment with monoclonal antibodies (bev-acizumab, or ramucirumab), or tyrosine kinase

inhibitors (TKI) (e.g. sunitinib, sorafenib, axitinib, regorafenib or nitedanib and aflibercept) inhibit either vascular endothelial growth factor (VEGF), or its receptor (VEGFR)-mediated signaling. Lo-cal production of VEGF in the kidney (namely by podocytes) plays an important role in the pres-ervation of normal glomerular function, normal morphology of the glomerular endothelium, me-sangial cells and podocytes and overall integri-ty of the glomerular filtration barrier. Toxicity of antiangiogenic treatment usually presents clin-ically with hypertension, proteinuria, reduced glomerular filtration rate, or even thrombotic microangiopathy.

Drugs aimed at epidermal growth factor (EGF), the monoclonal antibodies cetuximab and pani-tumumab, and TKIs blocking downstream activa-tion mediated through the EGF receptor (e.g. erlo-tinib, gefitinib and afatinib) interfere with tubular reabsorption of magnesium in the distal nephron, resulting in hypomagnesemia that may require magnesium supplementation.

Anti-HER2 therapy with trastuzumab or lapati-nib (usually, but not exclusively used in breast cancer) is not directly associated with impair-ment of kidney function, but the putative cardio-toxicity of this treatment is more pronounced in patients with CKD. Pertuzumab (which inhibits

the dimerization of HER2 and HER3) is, however, without renal toxicity.

Drugs used in patients with metastatic melano-ma with BRAF mutation, such as vemurafenib and dabrafenib, are not highly nephrotoxic. How-ever, case reports of renal failure have been re-ported in patients with diabetes and hyperten-sion treated with vemurafenib.

Crizotinib, which is used in patients with non-small cell lung cancer with ALK mutation, may cause hypophosphatemia and, rarely, induce the formation of renal cysts. Severe nephrotoxicity

may be associated with the use of the multiki-nase inhibitor vandetanib, which interferes with renal transporters MATE1 and MATE2K. The re-sults are disorders of mineral metabolism (in-cluding hypocalcemia, hypercalcemia and hy-ponatremia), renal toxicity (hypertension, pro-teinuria, nephrolithiasis, hematuria, renal failure), and also micturition problems, including dysuria with pollakisuria).

On the other hand, PDL-1 (programmed cell death protein 1) inhibitors are not believed to be nephrotoxic, but there have been rare reports of hypophosphatemia and proteinuria. Safety of im-munotherapy is now the subject of many studies.

Treatment targeted on RANKL, used in patients with bone metastases, is supposed to be rel-atively safe. This contrasts with bisphospho-nates, which are associated with significant re-nal toxicity.

Oncologists also use mTOR inhibitors with well-established, but different nephrotoxicity. Temsirolimus seems to be the least nephrotox-ic, with occasional reports of hypophosphate-mia. Everolimus is more toxic, with reported hy-pertension, proteinuria, elevation of serum cre-atinine and renal failure, and also hypophospha-temia and hyponatremia.

Most drugs used in the targeted treatment of ma-lignancies have a certain degree of nephrotox-icity. Fortunately, it is usually less severe. Neph-rotoxicity of targeted treatment may be further enhanced if it is combined with chemotherapy. Appropriate dose reduction and careful monitor-ing of renal function in patients treated for can-cer are the best prevention of progressive dam-age to the kidney. ◘


End-stage renal disease (ESRD) has long been linked to malignancy and patients with ESRD are more likely than the general population to die from cancer. In recent years the number of dialysis patients receiving a diagnosis of cancer has been shown to increase, but how ‘big is the problem’? Is it really the case that patients re-ceiving dialysis are ‘developing’ more cancer? Or have the methods in which we screen, diag-nose and manage patients with cancer on dial-ysis changed? What is the mortality rate of pa-tients with cancer on dialysis and how different is this from that of the general population?

During the talk titled “Dialysis and malignancy- a growing problem” I will start with a brief de-scription of the potential mechanisms between patients receiving dialysis and malignancy. I will then, using data from renal registry studies and individual studies attempt to quantify ‘how big the problem is’ by describing the current in-cidence and prevalence of cancer in patients

receiving dialysis and recent trends. However quantifying ‘how big the problem is’, is not very straightforward and during this talk I will also ex-plain why this is difficult to quantify and any bi-ases that may be influencing the findings. Finally I will show the survival outcomes of patients re-ceiving dialysis with cancer and how these com-pare to the general population. ◘

MARIA PIPPIAS


Dialysis and malignancy – a growing problem


ELENA ZAKHAROVA

Moscow, Russia

170 years from departure to arrival


1845, departure: Bence Jones explained the un-usual properties of urine in a patient with mol-lites ossium (in fact multiple myeloma, which was already described but not yet named) and edema by the presence of ‘hidrated deutoxide of albumin’.1846: Dalrymple found replacement of bones by a ‘gelatin-form substance of a blood-red col-or and unctuous feel’, and round nucleated cells in the bones, when examining a patient’s autop-sy material.1854: Virchow proposed the term ‘amyloid’ in-stead of ‘lardaceous’ or ‘waxy’. 1856: Wilks described kidney and other organ amyloidosis unrelated to known associated con-ditions, later referred to as ‘primary amyloidosis’.1867: Weber reported a case of mollites ossium with renal amyloidosis.1875: von Waldeyer-Hartz coined the term ‘plas-ma cell’, currently named after him. 1876: von Rustizky introduced the term ‘multi-ple myeloma’ (MM) to describe tumors of bone marrow.1880: Fleischer first used the term ‘Bence Jones protein’ (BJP) for unusual pathologic urine substance.

1889: Kahler described a patient with plasma cells in the ribs and vertebrae, and BJP in the urine; Weber claimed that bone marrow was the site of production of the BJP.1899: Ellinger supposed that the blood of pa-tients with MM contains abnormal protein, sim-ilar to urinary BJP.1909: von Decastello showed an association be-tween MM and tubular plugging by an amor-phous substance, later named ‘myeloma kidney’ or ‘cast nephropathy’.

1922: Bayne-Jones and Wilson reported two types of BJP.1929: Short and Crawford confirmed the pres-ence of BJP in the serum of patients with MM; Lubarsh identified ‘primary amyloidosis’ as a distinct group. 1933: Wintrobe and Buell recognized cryoprecip-itation and discriminated pathologic serum pro-teins in MM from all normal proteins.1939: Longsworth detected serum ‘M-spike’, representing abnormal immunoglobulins or frag-ments thereof.1947: Lerner and Watson introduced the term ‘cryoglobulinemia’.1956: Korngold and Lipari identified two class-es of BJP, designated in their honor as immuno-globulins LC kappa and lambda.

1961: Waldenström developed the concept of clonality, which led to today's definition of BJP as a monoclonal globulin protein in the blood or urine1962: Edelman and Gally confirmed identical properties of serum LC and urinary BJP from the same patient. 1957: Kobernik and Whiteside reported non-am-yloid nodular glomerulosclerosis in MM.1963: Constanza and Smoller presented an as-sociation between MM and acquired Fanconi

syndrome, later named ‘proximal light chain tubulopathy’.1969: Porush and Churg reported paraprotein-emia and cryoglobulinemia associated with atyp-ical glomerulonephritis (GN).1970: Morel-Maroger described IgM subendo-thelial deposits in patients with Waldenström’s macroglobulinemia.1976: The Nomenclature Committee proposed to replace the terms primary amyloidosis and my-eloma-related amyloidosis by the term ‘AL amy-loidosis’. Randall reported systemic non-amyloid LC deposition with the name ‘light chain depo-sition disease’. Since then non-amyloidogenic monoclonal LC are called ‘Randall-type’.1981: Schwarz and Lewis coined the term ‘im-munotactiod glomerulonephritis’ for GN with or-

ganized microtubular monoclonal immunoglob-ulin deposits.1984: Meyrier presented crescentic GN in mono-clonal gammopathies.1993: Aucoututier described heavy chain depo-sition disease.2004: Nasr published a description of prolif-erative GN with monoclonal immunoglobulin deposition.2005: Dingly and Kyle reported monoclonal gammopathy-associated focal and segmental glomerulosclerosis.2006: Merlini and Stone introduced the concept of ‘dangerous small B-cell clones’, producing a very toxic paraprotien that aggregates and de-posits systemically.2012: The International Kidney and Monoclonal Gammopathy Research Group (IKMGRG) synthe-sized the data concerning renal consequences of low-grade paraproteinemias, and proposed the term ‘monoclonal gammopathy of renal signifi-cance’ (MGRS) to stress the pathologic nature of these diseases.2015, arrival: The IKMGRG postulated that MGRS encompasses all renal disorders caused by monoclonal immunoglobulins, secreted by nonmalignant B-cell clones. ◘

From ’primary’ amyloidosis to the ‘monoclonal gammopathy of renal significance’



References

1. van Hooland S, Malik J. J Vasc Access

2010;11:255 – 262

RAMON ROCA TEY

Barcelona, Spain

Vascular access stenosis: what do the guidelines say?

References

1. Ibeas J, Roca-Tey R et al. Spanish Clinical Guide-

lines on vascular access for hemodialysis. Nefro-

logia 2017, in press

2. Roca-Tey R. Nefrologia 2010; 30(3): 280-7

3. Roca-Tey R et al. J Vasc Access 2012; 13(3): 321-8

CME 15Practical issues in vascular access careSaturday, 12.00 – 14.00, Sala Retiro

E-ISSUE


How to prevent and treat vascular access complications

JOSÉ IBEASBarcelona, Spain

Central vein catheters in haemodialysis: how to improve performance

MAURIZIO GALLIENIMilano, Italy

How to correct and avoid vascular access malposition

MARIA GUEDES MARQUESCoimbra, Portugal

WELCOME CEREMONY17.00 – 18.30HALL 10

Presentation of the ERA-EDTA Award for Outstanding Basic Science Contributions to Nephrology to Dontscho Kerjaschki

Presentation of the ERA-EDTA Award for Outstanding Clinical Contributions to Nephrology to Giuseppe Remuzzi

Presentation of the ERA-EDTA Award for Outstanding Educational Contributions to Nephrology to Peter Stenvinkel

Presentation of the Award for Outstanding Contributions to ERA-EDTA to Jonathan G. Fox

Presentation of the Stanley Shaldon Award for Young Investigators to Albertien van Eerde

Presentation of the ERA-EDTA Honorary Membership to François Berthoux

Welcome address Jorge B. Cannata-Andía, Congress President

Presidential address Andrzej Więcek, ERA-EDTA President

Plenary LectureNew approaches towards kidney regeneration

Juan Carlos Izpisua Belmonte, La Jolla, U.S.A.

Welcome Cocktail in the Exhibition

tuous outflow vein, a stent or a mural thrombus in an outflow vein, and collections (pseudoaneurism, hematoma, seroma) surrounding the AV fistula/AV graft. In these cases, ultrasound can guide the dialysis nurse before/during cannulation.

The downside of ultrasound is its operator depen-dency and substantial learning curve, while train-ing is often neglected in the curriculum of ne-phrologists, surgeons and dialysis nurses. Hand-

sonecho.com is a useful online resource for the beginner ultrasonographer in the field of dialy-sis VA. ◘

There are four essential steps in diagnosis and management of this common complication

The current clinical guidelines on vascular access underline that hemodialysis units must have pro-tocolized programs for follow-up of arteriovenous access, whether native fistula or graft, with mul-

tidisciplinary participation. [1] These programs should include screening methods for the ear-ly detection of stenosis, and location of its ori-

gin, as well as the performance of elective treat-ment before thrombosis. [2] According to these recommendations, we can highlight four steps in the diagnosis and management of arteriovenous access stenosis.

STEP 1: early diagnosis of stenosis by applying monitoring and/or surveillance screening techniques We can classify these methods in two groups: first- and second-generation techniques. The first-gen-eration methods are: clinical monitoring (physical examination, problems during hemodialysis ses-sion, QB stress test); pressure of vascular access (dynamic venous pressure, static intra-access pressure); recirculation; and inexplicable drop in dose of dialysis (Kt and kt/v index, urea reduc-tion ratio). The second-generation techniques al-low the direct (by Doppler ultrasound) or indirect (by dilutional screening methods like ultrasound dilution or Delta-H or thermodilution) estimation of blood flow rate (QA). The surveillance tech-niques (determination of static intra-access pres-sure, Doppler ultrasound and dilutional screen-ing methods) involve special instrumentation [3]; the remaining techniques are monitoring meth-ods. All these techniques are not exclusive but complementary.

STEP 2: diagnosis of stenosis by applying an imaging exploration (Doppler ultrasound/fistulography) to confirm suspected stenosis. Any repeated alteration of monitoring and/or sur-veillance parameter should be a criterion to per-form an imaging exploration of the arteriovenous

access under suspicion of pathology. Although it cannot replace fistulography as gold standard, Doppler ultrasound is a method of imaging di-agnosis that is noninvasive, harmless to the pa-tient, and has greater availability (it can be used ’in situ’ in the hemodialysis room). It also provides high sensitivity and specificity for the diagnosis of stenosis, and valuable additional functional infor-mation, with a favorable cost-effectiveness pro-file. The new Spanish Clinical Guidelines on vas-cular access for hemodialysis recommend per-forming a Doppler ultrasound as the initial imag-ing exploration if there is any suspicion of stenosis reserving fistulography for cases where there is a negative ultrasound result and a persistent suspi-cion of stenosis. [1] The diagnosis of stenosis can be established by the simultaneous presence of two main ultrasound criteria: vascular lumen re-duction > 50 % associated with peak systolic ve-locity ratio > 2.

STEP 3: diagnosis of significant stenosis or stenosis at high risk of thrombosis. It has been shown that some arteriovenous ac-cess stenoses remain stable without changing QA or degree of stenosis over time. Preventive in-tervention on these stenoses at low risk of throm-bosis represents an unnecessary procedure with notable cost and it can lead accelerated reste-nosis. Therefore, according the Spanish Clinical Guidelines, the indication for elective interven-tion should be established only for stenosis at high risk of thrombosis – that is, significant arteriove-nous access stenosis – if it meets the two main criteria mentioned above and, at least, one addi-tional morphological (residual diameter < 2 mm) or functional [QA (ml/min) < 500 (AVF)-600 (AVG) or QA reduction > 25 % if QA < 1000 ml/min] cri-terion on Doppler ultrasound. [1]

STEP 4: elective intervention before thrombosis. The Spanish Clinical Guidelines recommend that, because of the high risk of thrombosis, elective in-tervention with angioplasty and/or surgery should be performed only when the diagnosis of signifi-cant arteriovenous access stenosis has been es-tablished. [1] ◘


Vascular access is a fundamental part of renal replacement therapy with hemodialysis. Sup-port for its role is based on two main character-istics: it is needed, firstly, to make optimum use of the technology required in hemodialysis, and secondly, to reduce the morbidity related to ac-cess complications.

For this reason, it is essential to establish strate-gies aimed at increasing the incidence and prev-alence of native vascular access, and to avoid the use of grafts, and especially catheters, as much as possible. When they are necessary, catheters require optimum management to minimize com-plications, as most vascular access-related pa-thology is associated with their use

In arteriovenous fistulas, preventive measures must be designed to prevent early failure and improve long-term patency with the lowest pos-sible number of complications. There are sever-al phases that have to be systematically moni-tored. These are preparation for the creation of the arteriovenous fistula, its care and follow-up, treatment of complications, and at the same time, associated measures to manage catheter care.

For this reason, it is important to bear in mind procedures needed prior to vascular access cre-ation, from the moment the decision is taken to

create the access to the surgery itself, through the search for the best vascular bed using map-ping, and including the prevention of complica-tions such as ischemia. Care management plays an increasingly fundamental role in the preven-tion of complications, and nursing staff are a vi-tal part of this care, which involves maturation, aseptic methods and needling.

Follow-up or surveillance is probably one of the aspects that has sparked most controver-sy relating to its necessity and, particularly, to its function. Available evidence, albeit scarce, is beginning to indicate the probable need to per-form systematic surveillance and, more impor-tantly, to implement diagnostic criteria for ste-nosis based on both hemodynamic and clini-cal features.

There are different types of treatment for com-plications in native arteriovenous fistulas and grafts. These depend on different special-ists who, in addition, use different techniques. Complications essentially include stenosis and thrombosis, but those related to infections, isch-

emia, aneurysms and pseudoaneurysms, and those derived from high flow are also relevant. As there are no standardized treatment indica-tions for many of these complications, treatment is not efficacious. However, evidence review is now beginning to allow us to recommend in-dications for some of these pathologies, espe-cially stenosis.

Central venous catheters are undoubtedly the main source of complications, especially mortal-ity. It is important not only to avoid use of cathe-ters as far as possible, but also to prevent both infectious and functional complications. And when these complications occur, they should be treated appropriately. There are similarly import-ant limitations here to the evidence. But there is no doubt that intervention protocols can be es-tablished to reduce associated morbidity.

Finally, a factor that usually does not appear in vascular access management protocols, but which will become the cornerstone of optimiza-tion, is management of quality indicators. This is the only way in which the different special-ties involved in care management, and espe-cially administrators and managers, will be-come aware of the issue as results begin to improve. ◘

JOSÉ IBEAS

Barcelona, Spain

Care management is key


How to prevent and treat vascular access complications

If correctly managed, they can last for years with few complications

Although nephrologists aim to obtain arteriove-nous access for hemodialysis whenever possi-ble, the use of central venous catheters (CVCs) is increasing in most countries. CVCs are there-fore essential in the management of hemodialy-sis patients, but they also carry unintended neg-ative consequences, in particular thrombosis and infection, adversely affecting patient morbidi-ty and mortality. In other words, although CVCs may increase the risk of death (and therefore they should be avoided whenever possible), they may on the other hand also be lifesaving.

CVC management is a crucial issue in hemodial-ysis. If CVC dysfunction occurs, the clinical per-formance of dialysis may be also impaired, af-fecting the efficiency of depuration. Dr Maurizio Gallieni, nephrologist from the University of Milan, Italy, who is also a past-president of the Vascu-lar Access Society (www.vascularaccesssociety.com), is addressing the issue of how to improve performance of CVCs in hemodialysis patients during the CME course ‘Practical issues in vas-cular access care’ on Saturday, June 3rd.

The design of the catheter is important in deter-mining its performance. Better materials, larger diameters and innovative tip design have allowed blood flow rates up to 500 ml/min, although CVC flow rates of less than 300 ml/min may provide adequate hemodialysis, if duration of the dialysis session is adapted to the patient’s needs. Sym-

metric-tip CVC have been recently introduced, enabling low access recirculation and ease of catheter tip positioning in the right atrium. A step-tip CVC in conjuction with reversed lines induces blood recirculation and reduces the adequacy of hemodialysis treatment, especially when the re-circulation rate exceeds 10 %.

A better CVC performance can be achieved by avoiding dysfunction, which may be divided into early or late, based on the time of occurrence af-ter catheter placement. The causes of early dys-function are generally technical, and the CVC shows blood flow impairment immediately (in the procedure room) or at its first use due to in-correct tip positioning, catheter damage or kink-ing. Using ultrasound guidance and fluoroscopy during the tunneled CVC insertion is of great help in avoiding early dysfunction.

Late CVC dysfunction and poor performance are mainly related to thrombosis, which can be classified as either intrinsic or extrinsic. Throm-bus formation, as well as the development of fi-brous connective tissue sheath (commonly fibrin sheath), play a central role in establishing CVC dysfunction. Right atrial or mural thrombus may also determine blood-flow impairment.

Prevention and treatment of thrombosis-relat-ed CVC dysfunction can improve catheter per-formance and increase its duration in time. Pre-vention of intrinsic CVC thrombosis with antico-agulant locks is commonly used. When preven-tion fails, thrombolysis with urokinase or rTPA

can be undertaken in the dialysis unit, restoring adequate blood flow in most patients, preserving the existing catheter, and avoiding vein abandon-ment or costly interventional procedures.

However, if thrombolytic agents fail, a timely in-terventional procedure is indicated. To resolve dysfunction due to the presence of the fibrous connective tissue sheath, catheter exchange with fibrin sheath disruption may be success-ful and preserve the venous access site. In case of central vein thrombosis, relocating the cathe-ter to a new vein may be successful in the short term, but vein abandonment increases the risk of future vein exhaustion and poor dialysis per-formance. Recently, techniques for catheteriza-tion of thrombosed veins have become available, such as the inside-out puncturing of the right in-ternal jugular vein from a right femoral vein ap-proach. If correctly managed, CVCs can last for years with low complication rates. ◘

MAURIZIO GALLIENI

Milano, Italy

Improving performance of central venous catheters in HD



A suitable and well-functioning vascular access is an ongoing challenge in hemodialysis. De-spite international recommendations advocat-ing an arteriovenous fistula as the hemodialysis access of choice, for several reasons the use of central venous catheters (CVCs) remains wide-spread among both incident and prevalent he-modialysis patients. [1]

Vascular access dysfunction is a major cause of morbidity. Early dysfunction usually happens as a result of mechanical issues. Malposition is one of the most common causes of dysfunction and is mainly associated with dialysis catheters.

The optimal site for placement of tunneled ve-nous catheters is the right internal jugular vein (RIJV). [1] The correct location of a catheter de-pends on two main steps: the correct vessel in-sertion and the final tip position. According to published data, 29 % of catheters placed with-out imaging guidance have a malpositioned cath-eter tip. [2]

Regarding the insertion procedure, ultra-sound-guided puncture avoids the incorrect ves-sel because it reduces complications like arte-rial or small vein puncture. Even after an ultra-sound-guided correct vein puncture, if the guide wire is inserted without imaging control, it can go through the wrong vein due to tip-wire an-gle and anatomical variations or pathology (Fig-

ure 1). Malposition in a small-caliber vessel can result in low blood flow and high recirculation rate. Reinsertion of a misplaced catheter is not without potential complications and there is also the possibility of repeating the malposition if im-aging is not used.

After insertion of the catheter, the ideal position is yet to be determined. Clinical studies have demonstrated that there is significant movement of the catheter tip when the patient changes po-sition. Additionally, the direction and degree of catheter tip movement is dependent on several variables, including the type of catheter, inser-

tion site, and body habitus of the patient. For ex-ample, when the patient has a CVC in the RIJV and changes from a supine to an upright or sit-ting position, the catheter tip moves upward on average 2 – 3 cm. [2]

A tunneled catheter tip that is initially positioned in the right atrium will often retract upward into the lower superior vena cava (SVC), which can limit its ability to achieve a high level of perfor-mance because the tip may ‘suck’ against the adjacent vascular wall when aspiration is ap-plied. On the other hand, positioning the tip too deeply into the upper right atrium can cause ar-rhythmias and may also ‘suck’ against the atri-al wall. So, the ideal position advocated by most authors is the SVC/right atrial junction, which will rarely evoke a clinically significant arrhythmia or blood flow problems.

The assessment of tip location should be ideal-ly made by fluoroscopy, because it allows the visualization of all endovascular manipulations during the catheter insertion procedure and the exact confirmation of the tip position. However, due to resource limitations, external anatomical landmarks and chest X-rays, which are often imprecise, are still used to confirm catheter lo-cation in many centers. Many authors state that the most reliable radiographic landmark to de-fine the borders of the SVC is the right tracheo-bronchial angle, which is located at a median dis-tance of 5 cm to the SVC/atrial junction.[3] This means that a catheter tip positioned 3 cm be-low the right tracheobronchial angle would al-ways be within the SVC.

Although malposition is mostly a catheter prob-lem, the outflow tract of fistulas or grafts can be located in less accessible areas, mainly too deep, which may compromise cannulation and be associated with several complications such

as hematomas (Figure 2). Ultrasound mapping is a powerful tool to precisely locate outflow tract and to guide cannulation.

In conclusion, there are several factors to take into account to avoid catheter malposition. The best position for its tip requires an understanding of numerous clinical variables, including catheter type, insertion site, and the patient’s body habi-tus or movements, among others. Insertion pro-cedure should always be guided by ultrasound and final tip position should be assessed by flu-oroscopy. If fluoroscopy is not available, knowl-edge of radiographic landmarks is essential to estimate tip location, while bearing in mind its lack of precision. Repositioning of CVCs should always be done with fluoroscopy to avoid addi-tional complications. ◘

MARIA GUEDES MARQUES

Coimbra, Portugal

Correcting and avoiding vascular access malposition


References

1. Clinical practice guidelines for vascular access.

Am J Kidney Dis 2006;48:S248 – S257

2. Vesely TM. J Vasc Interv Radiol

2003;14:527 – 534

3. Rutherford JS, Merry AF, Occleshaw CJ. Anaesth

Intensive Care 1994; 22(3):267 – 271

Figure 1: Central vein catheter inserted in the left internal jugular vein with tip position in the right brachiocephalic vein. © Marques

Figure 2: Brachiocephalic fistula with a deep cephalic vein. © Marques


PETER J. BLANKESTIJN

Utrecht, The Netherlands

“In the coming period I would like to work with the Council on several challenges. We need to further increase the contribution and visibility of young nephrologists. Since the care for kid-ney disease patients is so multidisciplinary, we should strengthen the collaboration with our part-ners in this care. The rapidly increasing inter-net technology offers us opportunities of which many of us are insufficiently aware. The Coun-cil should initiate/support initiatives that evalu-ate and define how these developments could benefit our field. Finally, a hardly unexplored is-sue is the fact that medicine in general and ne-phrology care in particular are not very environ-mental friendly activities. Together with sister medical organizations, we should start to real-ize that and explore ways to decrease the bur-den to the environment. I hope that you will sup-port my candidacy.”

HANS-PETER MARTI

Bergen, Norway

“Most importantly, to strengthen the relatively weak links between Norway (plus some parts of Scandinavia) and ERA-EDTA. Intention to partic-ipate in the organisation of an annual ERA-EDTA congress in 2021, 2022 or 2023, as congress president (see below). Support of young nephrol-ogists by increasing exchange programs with personalized career plans. Increase funding for kidney research through already established in-dustry contacts. Defend the idea of European uni-ty based on insights from my professional activi-ties in Norway (Bergen), France (Paris), USA (San Francisco), New Zealand (Dunedin, Christchurch, Auckland) and Switzerland (Bern, Zurich), which is further facilitated by my dual Swiss-Italian background. Strengthen the role of ERA-EDTA as a prime forum for kidney diseases also beyond Europe with help of my leadership experience.”

ANNETTE BRUCHFELD

Stockholm, Sweden

“What I would hope to achieve as an Ordinary Council Member? By standing for the election I hope to contribute with my clinical, educational and scientific experience to promote the aims of the Society. I am interested in supporting activi-ties to make the Society relevant to all its mem-bers in particular our younger colleagues strug-gling to balance their careers with family life. Im-portant initiatives such as YNP could be strength-ened by role models within the ERA-EDTA to support the new generation of nephrologists. Fur-thermore I believe that the Society should en-courage gender equality in all its activities. The Swedish Society of Nephrology has, as a re-flection of its membership mix, an endorsement policy of a minimum of 40/60 % of either gen-der lecturing at educational activities and scien-tific meetings. Finally I wish to promote aware-ness of CKD and emerging health issues on a European level.”

DIMITRIOS GOUMENOS

Patras, Greece

ALEXANDER ROSENKRANZ

Graz, Austria

“I would focus on three aspects: 1. Patients: Since we have successfully imple-mented a screening program for CKD in Austria, I would focus on a European-wide concerted ef-fort for implementing a screening program.2. Young Academics: We are starting to face a tre-mendous shortage of nephrologists in Europe. I would like to organize a European-wide effort to attract young doctors to the field of nephrology.3. Compliance rules of the industry: In recent years companies have installed new compliance rules which regulate the interactions between physicians and industries. This leads to uncer-tainties how to handle invitations for congress-es, and undersigning complicated legal contracts. I would establish a plan with clear rules in close cooperation with the industry for all ERA-EDTA members, which should lead to a more transpar-ent way of providing education to our members.”

“My contribution will be focused in the following: Collaboration between National Societies espe-cially in south eastern Europe in development and planning clinical trials and basic research proj-ects. Further development of educational strate-gies by organizing more CME Courses focusing in all fields of nephrology. Collaboration between National Societies and Patients’ Associations in European countries and incorporation of this im-plementation by ERA-EDTA. Initiatives for promo-tion of nephrology as a very competitive special-ty in clinical and research setting to increase in-terest of junior doctors choosing nephrology. This could be approached by contact with the Medi-cal Schools and students’ associations to intro-duce nephrology to junior doctors.”

TALIA WEINSTEIN

Tel Aviv, Israel

“1. I would aim to promote nephrology training throughout Europe, and work together to plan strategies that would help recruit the best ne-phrology fellows.2. Engage European medical societies in initia-tives to establish national programs for the de-tection and treatment of chronic kidney disease, with emphasize on measures to address risk fac-tors, and to cope with inequality in populations with less access to medical care.3. Multi-national collaboration in clinical research.4. Encourage communication and collaboration with other Scientific Societies that treat CKD pa-tients, particularly in the field of diabetes.”

Are you a nephrologist? Do you want to be part of the most authoritative European Association in this field? Become a member of ERA-EDTA today! All the information can be found at the ERA-EDTA booth in the exhibition area or ERA-EDTA membership desk in the registration area of the IFEMA North Congress Center.

The Candidates – and what they hope to achieve as Council Members

The voting station, located next to the ERA-EDTA membership desk, in the registration area, will be open on 3 – 4 June 2017 during the opening hours of the registration desks. On 5 June 2017 the voting station will close at 09.00. Voting will also be possible immediately before the start of the General Assembly, which will take place from 09.30 – 10.45, 5 June 2017, Room N117 – 118, Level 1, IFEMA North Congress Center.

If a full member has lost his/her voting credentials, a valid identification document (i.e a passport or national identity card) will be required in order to receive them again. Voting by proxy is NOT possible. A short curriculum for each candi-date will be on display at the voting station as well as on the ERA-EDTA website.

Don’t forget to vote

ERA-EDTA MEMBERSHIP INFO

ERA-EDTA MEMBERSHIP DESK INFO

for your candidates for the ERA-EDTA Council !


Progression of loss of renal and cardiovascular (CV) function has been ‘attacked’ by controlling well-known risk factors like lifestyle (smoking, sodium and protein intake, exercise), high blood glucose (diabetes), high blood pressure, high cholesterol, and high albuminuria. Although we have been able to attenuate disease progression, we still have a huge unmet need, in particular in type 2 diabetes patients.

Mainstay therapies such as interventions in the renin-angiotensin-system (ACE-inhibitors and ARBs) have proven value, but only scratch the surface of the problem when one looks at the population at risk. Many new approaches and new drug-interventions have been tested, but these have proved of no additional benefit. We are currently left with three promising avenues: SGLT-2 inhibition, aldosterone-inhibition, and en-dothelin receptor antagonism, which still all have to prove themselves.

A more important development for halting pro-gression of renal/CV function loss is the recog-nition that our interventions are effective only in a select group of patients at risk. Although trials and guidelines suggest that we should adhere to the concept ‘one drug fits all’, recent analysis of trials and cohorts show clearly that only a rela-tively small proportion of patients respond well to the therapies. This variation in response will have to guide us in the very near future if we re-ally want to combat renal/CV disease progression with success. New study designs that enrich for responders, and the investigation of alternatives for the non-responders/bad-responders are cur-rently being tested in many disease areas. Ne-phrology is following, albeit slowly.

Finally, the most promising avenue for improv-ing our personalized individual care is provided

by the opportunities to measure and detect oth-er and better biomarkers and/or surrogates for disease progression, as well as response to in-tervention. System biology that integrates ge-netics, proteomics and metabolomics will give us a better view on the individual patient’s risk, and more importantly also a better view of the effectiveness of an intervention in an individual patient. Large European Consortia such as Sys-Kid and BEAt-DKD are progressing this field in nephrology/diabetes.

The question “Can we really slow progression of renal/CV disease” is to be answered with a

“yes… but”. The “yes” is related to the fact that we have shown that we can slow progression of the disease to some degree. The “but” is re-lated to the fact that we have still a huge un-met need that can only be addressed if we are able to align our efforts to unravel the reasons for variation in response to current successful therapies. ◘

VIANDA STEL


The changing pattern of kidney diseases at dialysis onset

Variation in Pre-Dialysis nephrology care

The answer at present must be: “Yes…but…”

References

1. Pippias M, Jager KJ, Kramer A et al. Nephrol Dial

Transplant. 2016; 31: 831 – 41

E-ISSUE


How to avoid over- and underdiagnosis of Chronic Kidney Disease

MARC E. DE BROEAntwerp, Belgium

CME 17Variation in Pre-Dialysis nephrology careSaturday, 12.00 – 14.00, Sala Colon

DICK DE ZEEUW

Groningen, The Netherlands

Can we really slow progression of renal/cardiovascular function loss in CKD?

Cappuccino with Claudio RoncoTake a break and enjoy a cappuccino while watching a video of Professor Claudio Ronco on www.youtube.com

The attendees of the 54th ERA-EDTA Congress are invited to join his "Cappuccino with Claudio Ronco" series on Youtube (enter "Cappuccino with Claudio Ronco" into the search mask on Youtube). In his short films Professor Ronco discusses new topics with other experts.

Fresh videos will be available tomorrow!

Worldwide renal registries report on the trends of the primary renal disease (PRD) of end-stage renal disease (ESRD) patients starting renal re-placement therapy (RRT) in annual reports and/or scientific papers. The United States Renal Data System (USRDS) provides an international com-parison of trends in the treatment of RRT, current-ly including data from 60 countries or regions. IN addition, USRDS specifically reports the trends of incident patients on RRT with diabetes melli-tus (DM) as the primary cause of ESRD. Also, the ERA-EDTA Registry reports on the trends of DM as PRD, as well as on other PRDs such as glo-merulonephritis, hypertension and renal vascu-lar disease in patients starting RRT. [1]

This presentation on ’The changing pattern of kidney disease at dialysis onset’ will provide an overview of the trends of PRDs of patients start-ing renal replacement therapy (RRT) worldwide.

We will first provide an overview of renal regis-tries worldwide (of which European countries are covered by the ERA-EDTA Registry) reporting on one or more PRDs in patients starting RRT in the period from 2005 – 2014. For the worldwide com-parison, the following PRDs were considered to be comparable across renal registries: diabetes mellitus (type 1 and 2 as one group), glomeru-lonephritis, autosomal dominant polycystic kid-ney disease (ADPKD), renal vascular disease and hypertension (as one group), miscellaneous, and unknown and missing PRD (as one group).

Additionally, we will show the results of a sys-tematic review focusing on papers published in scientific journals reporting on at least five-year trends on one or more of PRDs of patients start-ing RRT for ESRD. The vast majority of the pub-lished papers (24 out of 25 papers) reported on the trend of DM as PRD. Several papers published on other PRDs like glomerulonephritis (15 out of 25 papers) and ADPKD (13 out of 25 papers).

Finally, we will pay special attention to Europe, as we were able to analyze the European data in more detail using the ERA-EDTA Registry data-base. The ERA-EDTA Registry database contains data on dialysis and transplant patients from 35 European countries. We will, among other results, illustrate differences in the trends of PRD in pa-tients starting RRT across European countries.

Moreover, in addition to calculating the unadjust-ed trends, we standardized the numbers per mil-lion population by the European Union 2005 pop-ulation. Following standardization, the age distri-bution at the start of RRT was similar across all years (2005 – 2014). This means that, although the mean age at the start of RRT may change over time, due to standardization the effect of age at start of RRT on the trends in PRDs was eliminated.

The results may provide valuable information to determine which patients could benefit from a new or existing treatment, assess the effec-tiveness of treatment modalities – for example identify effective preventive measures – and ul-timately stimulate improvements in healthcare quality. ◘


There is no doubt that the introduction of KDIGO guidelines 14 years ago and their subsequent adaptations have substantially contributed to the early detection of different stages of chronic kid-ney disease (CKD). Several recent studies from Europe and other parts of the world describe a CKD prevalence of 3.3 % – 17.3 %. In a recent randomized, high-response rate (85 %) study (MAREMAR) that was representative of the adult population of Morocco and rigorously respect-ed the KDIGO guidelines, we found a low preva-lence of 3.9 % and 2.9 % when adjusted for the total adult population.

Reasons for this low prevalence were identified: the tagine-like population pyramid of the Mare-mar subjects, but even more important, the proof of chronicity (three months after first screening result) by the reduced estimated glomerular fil-tration rate (eGFR) and the confirmation of the proteinuria found at first screening, so eliminat-ing the false positives (45 %) .The impact of the

yes or no confirmation of the decreased eGFR is far from negligible, in contrast to what some au-thors have suggested.

In Maremar we found 32 % of false positives, mainly in the CKD3A group. In the NHANES III study, GFR was estimated by the MDRD study equations. In a random sample of 98 patients with eGFR < 60 ml/min/1.73 m², a second exam-ination (in a median period of only two weeks) classified the same patients in the same catego-ry (stage 3A CKD) in only 77 %. Thus, 23 % who would have been considered as ‘diseased’ have moved to ‘healthy’ only after a second creatinine measurement.

In 2006, Eriksen et al published the results of patient and renal survival in the population of Tromsø, Norway. Over a 10-year period, 17.9 % had an eGFR < 60 ml/min/1.73 m². Considering only patients for whom a second measurement was available, 40.7 % of subjects with a first eGFR < 60 mL/min/1.73 m² were not confirmed as being CKD on the second estimation. These authors also illustrated that the prevalence of

CKD is further lowered by prolonging the period of time used for the chronicity criterion.

In 2015, Inker et al published a study with longi-tudinal creatinine measurements (and eGFR by the CKD-EPI equation) of 3888 residents aged between 31 – 59 years in Reykjavik, Iceland, with a mean follow-up of 25 ± 10 years and base-line eGFR > 60 mL/min/1.73 m². He used sever-al modalities for proof of chronicity. In all analy-ses (men/woman, different ages and different fol-low-up), the CKD lifetime risk was systematically the highest when defined by a single eGFR result.

Confirmation of albuminuria (or proteinuria) found at first screening is another essential condition of the KDIGO guidelines before classifying an indi-vidual as having CKD, or not. Many factors may influence albumin excretion, including obesity, age, sex, distant inflammation, high blood pres-sure, infection, and drug use resulting in wide fluctuations – hence the false positivity of albu-minuria. Several authors found a high percent-age (> 50 %) of false-positive albuminuria at low values (urinary UACR: 30– 50 mg/gram; dipstick proteinuria (+) ), less at higher values or dipstick ++ and +++.

Together with the absence of proof of low eGFR chronicity, this non-confirmation of albuminuria (or proteinuria) in almost all epidemiological stud-ies of the last 15 years, results in an import-

ant false positivity of CKD prevalence of at least 50 % or more.

It was found that when an arbitrary single thresh-old of eGFR rate (< 60 ml/min/1.73 m²) is used to classify CKD3,4,5, it leads to a substantial ‘overdiagnosis’ (false positives) in the elderly (> 55 years of age), particularly in those without proteinuria, hematuria or hypertension. It also results in a significant ‘underdiagnosis’ (false negatives) in younger individuals with an eGFR > 60 ml/min/1.73 m² (no proteinuria) and below the 3rd percentile of their age/sex category. The use of 3rd percentile eGFR rate level as cut-off based on age/sex-specific reference values of eGFR allows the detection of these false posi-tives and negatives.

There is an urgent need for additional quality studies of the prevalence of CKD, using the re-cent KDIGO guidelines in the correct way, in or-der to avoid a 50 % or more overestimation of the true disease state of CKD, with potential dramat-ic consequences. ◘

MARC E. DE BROE

Antwerp, Belgium

Identifying subjects with CKD using KDIGO guidelines

CME 17Variation in Pre-Dialysis nephrology careSaturday, 12.00 – 14.00, Sala Colon

There is an urgent need for more quality studies to determine true prevalence

ciency and some morphological findings were correlated with poor outcome. [2]

Epidemics of chronic kidney disease of unknown origin (CKDu) have also been reported in rural ar-eas of other countries with a hot climate; e.g. Sri Lanka and India. Different causes of the CKDu in Sri Lanka have been suggested, mainly focusing on environmental toxins like heavy metals and agrochemicals in drinking water, but no definite causes have been found. A few biopsy studies have been performed but they are not directly comparable as the inclusion and exclusion cri-teria have been different. Our group is therefore, in collaboration with local researchers, currently finalizing a third biopsy study in Sri Lanka where similar criteria will be used.

In summary, MeN is a common cause of end-stage renal disease among agricultural work-ers in Central America. The endemics in Sri Lan-ka and India show many similarities with MeN in their clinical and epidemiological presentations, but it is not yet clear if they represent similar di-agnostic entities. More biopsy studies are need-ed where morphological and biochemical studies are combined with protein- and gene expression

analysis to confirm the suggested pathogenesis of MeN and to clarify if it represents a disease of different continents. ◘

What is the pathology of mesoamerican nephropathy?

ANNIKA WERNERSON

Stockholm, Sweden

Phot

o by

Gus

tav

Mår

tens

son,

KI.

BR

CME 20Emerging global causes of chronic kidney diseaseSaturday, 14.15 – 16.15, Hall N107 – 108

References

1. Wegman D et al. Mesoamerican nephropathy.

Report from the Second International Research

Workshop on MeN. in Mesoamerican Nephropa-

thy. 2015. San Jose, Costa Rica: Central Ameri-

can Program for Work, Environment and Health-

SALTRA Central American Institute for Studies

on Toxic Substances (IRET) Universidad Nacional

(UNA), Costa Rica.

2. Wijkström J, González-Quiroz M, Hernandez M et

al. Am J Kidney Dis 2017 [Epub ahead of print]

We need more biopsy studies to confirm the suggested pathogenesis

In 2002 it was reported that a high proportion of patients who started dialysis in El Salvador had kidney failure of unknown etiology. Since then, a number of reports have been published show-ing high prevalence of endemic renal failure due to unclear cause in several countries in Central America. The disease, called mesoamerican ne-phropathy (MeN), mainly affects male agricul-tural and, in particular, sugar-cane workers. The affected patients often lack traditional risk fac-tors for chronic renal failure such as hyperten-sion or diabetes mellitus. [1] In some areas, 20 % of men of working age are affected, and in many cases, the disease progresses to terminal renal failure – a devastating diagnosis for people liv-ing in Central America, where dialysis resources are limited and no functioning kidney transplant programs are available.

The clinical picture in MeN patients is character-ized by reduced glomerular filtration rate (eGFR), but no hematuria and no or low proteinuria. Pa-tients often exhibit low Na, K and Mg levels, and sometimes hyperuricemia. The cause of the dis-ease has not yet been fully understood, but stren-uous physical work in a hot climate with the risk of repeated dehydration and salt deficien-cy is one of the leading hypotheses. [1] Intake of NSAIDs and rhabdomyolysis may also contribute

to the renal damage, while no support has been found for several other suggested factors, includ-ing inorganic arsenic, aristolochic acid, mycotox-ins, pesticides or alcoholic beverages.

Only a few biopsy studies have been conduct-ed in this region. In 2012 our research team in collaboration with nephrologists in El Salva-dor, performed the first study of kidney biop-sies in patients suffering from MeN. Eight sug-ar-cane workers were included in the study and

we showed a unique renal morphology, with damage in both the glomerular and tubulointer-stitial compartments. Widespread glomeruloscle-rosis, glomerular hypertrophy, signs of glomerular ischemia and mild to moderate tubulointerstitial damage were observed. Electrolyte disturbanc-es, with low levels of potassium and sodium in plasma were seen in many patients. By immuno-fluorescence and electron microscopy, immune complex disease could be excluded and signs of podocytic injury could be identified.

Our research team has subsequently conducted a second study of 19 sugar-cane workers with MeN in Nicaragua. The results show a similar morphological picture in the kidney biopsies and similar electrolyte imbalances. We have also fol-lowed up the biopsy patients in El Salvador and Nicaragua and then seen that the progression rate in MeN patients varies and that salt defi-



References

1. Ballew SH et al. Am J Kidney Dis 2017; 69:

228 – 236

CME 18Geriatrics and rehabilitation of CKD patients – what should the nephrologist know?Saturday, 12.00 – 14.00, Sala Neptuno

CME 20Emerging global causes of chronic kidney diseaseSaturday, 14.15 – 16.15, Hall N107 – 108

AUD HØIEGGEN

Oslo, Norway

RICHARD J. JOHNSON

Denver, USA

How to reduce the pill burden in elderly people with CKD?

Heat stress nephropathy provides insight into classical CKD

Geriatrics and rehabilitation of CKD patients – what should the nephrologist know?

HELGA GUDMUNDSDOTTIR

Oslo, Norway

Drug abuse and renal disease

Emerging global causes of chronic kidney disease

E-ISSUE


Pathology of mesoamerican nephropathy

ANNIKA WERNERSONStockholm, SwedenPh

oto

by G

usta

v M

årte

nsso

n, K

I. BR

The prevalence of chronic kidney disease (CKD) is increased in the elderly (usually defined as > 65 years) and is reported to be as high as 20 – 47 %, varying according to age and the definition of CKD. Frailty, comorbidity and poly-pharmacy (defined as more than five drugs or more drugs than needed) are frequently asso-ciated with old age and CKD. The number of drugs increases with declining glomerular fitra-tion rate (GFR) due to the complex nature of re-nal disease and frequent comorbidity. Polyphar-macy increases the risk of side effects, interac-tions, non-adherence, drug accumulation and health-care costs. Pharmacokinetic changes de-velop with increasing age and with the severi-ty of CKD. Accurate estimation of kidney func-tion is challenging in the frail elderly population due to low muscle mass and altered nutrition-al state, and estimated GFR (eGFR) using serum creatinine (CKD-EPI or MDRD) may often over-estimate their kidney function. Including albu-minuria in the definition of CKD identifies more patients than eGFR alone. Estimated GFR using cystatin C or creatinine clearance may be supe-rior to eGFR using creatinine in the elderly [1]. An accurate measure of GFR is especially import-ant when dosing drugs with a narrow therapeu-tic window and for drugs with mainly renal ex-cretion. Deprescribing tools may reduce the high pill burden of CKD patients. ◘

Epidemics of chronic kidney disease (CKD) have recently been recognized in rural regions of Cen-tral America, Mexico, India, and Sri Lanka. Unlike the CKD commonly observed in urban areas, this type of CKD is typically not associated with dia-betes, hypertension, glomerulonephritis, or poly-cystic kidney disease. The primary groups affect-ed are individuals performing manual work out-side in typically hot environments. Onset of CKD typically begins the 20s, and many subjects of-ten die from kidney failure, as dialysis is not al-ways available. To date, there have been more than 50,000 deaths attributable to kidney dis-ease from these areas. There are some striking similarities in the clinical presentation and histo-logical findings among the various places where the epidemics have been reported. Most sub-jects are men, and they present with low-grade proteinuria with asymptomatic elevations in se-rum creatinine. Some have hyponatremia, hypo-kalemia and hyperuricemia. Some have dysuria in the absence of urinary tract infection, likely from crystalluria. Biopsies tend to show chronic tubulointerstitial nephritis with variable presence of glomerulosclerosis. While this is the chronic presentation, there is some evidence that sub-jects may be suffering bouts of acute kidney in-jury, as noted by elevated biomarkers, some-times with fever or leukocyturia.

A wide variety of etiologies have been consid-ered, including exposure to heavy metals, insec-ticides, agrochemicals, and infectious diseases (hanta and leptospirosis). However, the common denominator appears to be heat stress. Recently recurrent heat stress has been shown to cause CKD in laboratory animals. A variety of mech-

anisms have been implicated, including inju-ry induced by hyperosmolarity (such as from chronic activation of the vasopressin and poly-ol-fructose pathways), from subclinical rhabdo-myolysis, from urate crystalluria, and from vol-ume depletion/low blood pressure, and from in-creased body temperature. Indeed, it is known that heat stroke can lead to an acute kidney in-jury as well as chronic kidney disease.

The concept that the disease may be mediated by recurrent heat stress is consistent with cli-mate maps that typically show that the regions affected are associated with high solar radia-tion and areas commonly associated with heat waves. Indeed, our group has suggested that the reported increase in CKD in these regions may be due in part to climate change with an increase in extreme temperatures (heat waves).

Insights into the role of inadequate hydration and heat stress as risk factors for CKD also may be relevant to classical forms of CKD. There is increasing evidence that CKD due to diabetes and other causes may also be influenced by hydration status, circulating vasopressin (co-peptin) levels, and heat. Clinical trials to deter-mine if increasing hydration can slow the pro-gression of CKD are being conducted. Such simple and inexpensive new therapies for CKD would be welcome. ◘

Abuse of illicit drugs is common, it is often com-plicated with a variety of medical problems with high morbidity and mortality and is an import-ant contributor to the global burden of disease. Opioid and amphetamine dependence are the two most common forms of illicit drug depen-dence worldwide. A multitude of renal diseases are associated with drug abuse including rhab-domyolysis, interstitial nephritis and glomerulo-nephritis. Additionally, viral infections like hep-atitis-B and -C and HIV are highly prevalent in drug abusers and renal disease associated with those infections has increased. Hepatitis-C relat-ed membranoproliferative glomerulonephritis has emerged as the most prevalent kidney disease in drug abusers worldwide. The last decade, the in-cidence of AA-amyloidosis as a cause of chron-ic renal disease in intravenous drug abusers has increased and is now the most common cause of renal failure in that patient population in Nor-way. This is thought to reflect the increased lon-gevity of drug users and the concomitant long-standing bacterial and viral infections. The prog-nosis is poor.

Longstanding treatment of chronic kidney dis-ease, including dialysis in chronic users of illicit drugs with variable adherence to recommended treatment is costly and can be challenging and raise many ethical questions. The prevalence of illicit drug dependence is increasing in developed countries. The global burden of renal disease re-lated to abuse of illicit drugs might therefore be expected to increase in the years to come. Ef-ficient strategies to reduce the burden of drug abuse are needed. ◘


“When I finish my treatment, I try to have a fulfilling life, as healthy people do.”

MARTIN WILKIE

Sheffield, United Kingdom

EuroPD

Infection in PD: from bench to bedside

References

1. Li PK, Szeto CC, Piraino B et al. Perit Dial Int

2016; 36: 481 – 508

2. Toleman MA. Perit Dial Int 2017; 37: 134 – 40

3. Sethna CB, Bryant K, Munshi R et al. Clin J Am

Soc Nephrol 2016; 11: 1590 – 6

E-ISSUE


Starting a patient on PD: troubleshooting the first 3 months

MIGUEL PEREZ FONTANLa Coruña, Spain

CME 21State of the art in Peritoneal Dialysis in 2017Saturday, 14.15 – 16.15, Sala Colon

CME 22Quality of life in people with kidney diseaseSaturday, 14.15 – 16.15, Sala Neptuno

DANIEL GALLEGO-AZURRO Torrent (Valencia), Spain

Being a ‘renal person’ – The patient’s perspective on quality of life

Infection is a key potential complication of peri-toneal dialysis (PD) – although it is important to observe that it is also a major risk for peo-ple treated with hemodialysis. The consequenc-es of PD-related peritonitis include technique failure, hospitalization, morbidity, mortality, and loss of residual renal function. In the early days of PD, patients experienced peritonitis every few months, however improvements in technical as-pects of treatment, combined with approaches in prevention, diagnosis and treatment, have result-ed in rates of one infection every 3 to 4 years of patient treatment at many centers. This raises a couple of key issues. Firstly, that the improve-ment in infection rates has leveled off since the millennium and, secondly, that there remains considerable variation between centers. Cen-tral to the management of PD-related perito-nitis is diagnosis, which should be prompt and accurate, leading to appropriate and responsive antibiotic use. There are quality-control issues with the current approach to the diagnosis that impact on the likelihood of characterizing an infection. These include the robustness of the recognized definition of peritonitis, approaches to sample collection and culture techniques, as well as the impact of prior exposure to antibi-otics. Immediate and accurate diagnosis would be a potential game-changer for the practice of PD. Several companies are developing products that enhance near patient testing, with the goal of rapid characterization of the infecting organ-ism that would facilitate the immediate use of appropriate antibiotics.

Prevention is underpinned by several strategies including: appropriate placement of PD catheters using approaches and in environments that are demonstrated to reduce risk; the use of prophy-lactic antibiotics at catheter insertion and as top-ical agents as part of routine exit site care; and high quality training of patients and staff. Guid-ance that summarizes the best evidence and makes recommendations for healthcare teams is available from the International Society of Peri-toneal Dialysis (at ISPD.org). [1] Evidence of the value of targeted refresher training for patients comes from the Prevention of Peritonitis in Peri-toneal Dialysis (PEPS). The Australasian Kidney Trials Network is in the process of setting up an open, cluster-randomized controlled trial of a standardized education program (TEACH-PD).

Antimicrobrial resistance (AMR) is a major emerging concern that presents challenges for the whole medical community, with specific is-sues for PD. [2] Gram-positive resistance has been a fact of life for 20 years – steps to re-duce impact have had some success in at least controlling the impact of methicillin-resistant Staphylococcus aureus (MRSA). There is much greater concern in relation to the more virulent Gram-negative enteric bacteria that produce ex-tended spectrum β-lactamases and carbepene-mases, a situation that is compounded by a very limited pipeline of new antibiotics. There are sev-eral international examples of quality improve-ment initiatives that have resulted in reduced in-fection rates. The ANZDATA registry has demon-strated progress on peritonitis rates over the last few years, which would not have been achieved if that registry had not been collecting the ap-propriate information. It is essential, therefore, that registries around the world include infec-tion among their data fields. The SCOPE collabo-rative from North America recently reported that compliance with catheter care bundles is asso-ciated with a reduction in the individual risk of PD-related infection. [3]

Ultimately, peritoneal infection is a key issue where resolution depends on high quality train-ing of staff and patients couched in robust quality improvement mechanisms. Accessible near-pa-tient testing has the potential to reduce variabil-ity in diagnosis and allow targeted therapy to be used promptly and to improve outcomes. AMR is a particular threat and requires specific and urgent attention, which is the focus of initiatives from the World Health Organization. ◘

I often think about myself in terms of my disease, and of course, I am a patient. However, I only feel I am a kidney patient during my hemodial-ysis (HD) sessions at the hospital, which I have been attending since 1995. When I finish my

treatment, I am a person with dreams and hob-bies, and try to have a fulfilling life, as healthy people do. I love traveling worldwide, and even when undergoing HD treatment, I have traveled to countries such as India, Philippines, Indonesia, Japan, Thailand….and many more. So the dis-ease cannot be the stigma that defines me as a person. We depend on a machine to survive, but this machine is available worldwide (if you can afford it…). During 21 years of renal replacement therapy, I have seen remarkable changes, espe-cially those approaches that tackle the problems that matter to patients. The technical changes in dialysis machines have improved the quality of the treatment, which has led to better adaptation to the burden of dialysis every two days. In addi-tion, medicines such as calcimimetics and phos-phate binders have been a revolution in improv-ing mineral bone disorders.

However, psychological and emotional disorders must be addressed in chronic kidney disease

(CKD). Sleeplessness, thirst, sexuality, dietary re-strictions…we must tackle CKD as a global is-sue. Our society celebrates everything by eating and drinking, so we need resources and tools to manage everyday situations.

In addition, we need to work on accepting CKD, promoting healthy habits, physical activity, and adherence to the treatment, with positive think-ing and love, compassion and empathy, and ongoing assessment, not only when patient is diagnosed.

The human touch, kind words, are sometimes more therapeutic than the treatment…and could make the difference. We need to involve patients in their disease, with self-care and empowerment.

A kidney patient should have, must have, a ful-filling life. ◘


The last decades have seen a marked improve-ment in the survival rates of patients treated with peritoneal dialysis (PD). Despite this ad-vance, mortality remains high among these pa-tients. On the other hand, progress in terms of PD technique failure has been less satisfactory, and this outcome represents a major concern in the day-to-day practice of PD nephrologists.

The first months on PD constitute a critical phase in the clinical course of the PD patient. Mortality is particularly high during this peri-od. Preexisting comorbidity is a main determi-nant of this adverse outcome, demanding in-terventions oriented to improve modifiable risk factors. In addition, adequate selection of pa-tients, timely initiation of PD with a function-ing peritoneal catheter, and prompt and effi-cient attention to early complications (includ-ing volume overload and infections) may help to reduce mortality during this period. The first months on PD also represent the right time to implement measures oriented to sustain resid-ual kidney function, prevent PD-related meta-bolic complications and preserve the peritone-al membrane, which will all likely improve lat-er survival of these patients.

A high proportion of PD drop-outs to hemodi-alysis occur during the first months of therapy, and have a great impact on overall PD tech-nique survival rates. The causes of this com-plication are quite specific to this phase, with an overrepresentation of technical complica-tions and psychosocial reasons (often a surro-gate of inadequate technique selection). Peri-toneal infection represents a permanent threat,

while other causes of technique failure, in-cluding inadequacy and ultrafiltration failure, are less frequently observed than in the later phases of therapy. This is relevant, because the main factors leading to early technique failure may be largely preventable, provided well de-signed interventions are applied. Timely initia-tion of PD, correct catheter insertion and care, systematic training and close clinical surveil-lance (with an emphasis on preventing infec-tions), and prompt attention to abdominal and technical complications are advisable measures that will likely improve early technique survival. In addition, the prescription must fit the life-style of the patient, and automated PD provides a useful tool for this purpose. Again, preserv-ing residual kidney function and protecting the peritoneal membrane should be kept in mind from the start of PD, to ensure long-term PD technique survival.

Early technique failure is frequently a conse-quence of an inadequate selection for PD. Unfor-tunately, preventing this kind of error is not easy in clinical practice. Many studies have attempted to define predictive patterns for success or fail-ure of PD, and an array of demographic and clin-ical factors have been claimed to portend these outcomes. Overall, and aside from some unques-tionable medical and social contraindications for PD, it may be hard to predict how an individu-al patient will get along with this therapy. Timely, complete and understandable information, and implementation of shared decision-making ap-proaches may help to minimize wrong decisions. Once PD is initiated, early detection of new (or previously occult) barriers is essential. Assisted PD has proven to be of great value in this setting, particularly for the management of older patients and in non-optimal social environments.

To summarize, the first months on PD represent a risky period, demanding organized strategies ori-ented to reduce mortality and ensure technique survival. Should these measures be insufficient to sustain successful PD, do not neglect a well-planned transfer to hemodialysis, including time-ly creation of a permanent vascular access. ◘

MIGUEL PÉREZ FONTÁN

La Coruña, Spain

Start right from the beginning

CME 21State of the art in Peritoneal Dialysis in 2017Saturday, 14.15 – 16.15, Sala Colon

Improving outcome of patients on peritoneal dialysis

KITTY JAGER


ERA-EDTA was definitely the key to my career success

Survival of Children receiving dialysis varies widely

References

1. Chesnaye NC, Schaefer F, Bonthuis M et al.

Lancet 2017 Mar 20 [epub ahead of print]

BAXTER ERA-EDTA SYMPOSIA 2017

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Long-term Dialysis Dependence after Acute Kidney Injury (AKI):the Health-Economic Impact

4 JUNE18:45 - 19:45

Hall N107-108

SYMPOSIUM

Remote Patient Management(RPM) in Home Dialysis:Changing the Paradigm of Care

5 JUNE13:30 - 15:00

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Making possible personal.

Join us for 3 symposia that will highlight current unmet needs in dialysis and help uncover the potential in what comes next.

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Kitty Jager is professor of medical informatics and kidney epidemiology at the University of Amsterdam’s Faculty of Medicine (AMC-UvA). In 2000 as an epidemiologist she became the managing director of the ERA-EDTA Registry – and with this, a success story started for both, the Registry and Kitty. Thanks to her firm com-mitment and hard work as well as that of her team the ERA-EDTA Registry became a scien-tific registry of highest international reputa-tion, often consulted by developing renal reg-istries and set as an example for modern kid-ney epidemiological research. The Registry is now staffed by 7 persons, among them med-ical doctors, epidemiologists and IT-staff. The list of publications by the Registry is impres-sive. In 2016, for examples, 28 articles were published in highly cited papers, among them The Lancet, JASN, and NDT. In addition to this, the Registry publishes a comprehensive annual report. “But this can only be done because all the renal registries in Europe that kindly send us their invaluable data for free each and ev-ery year, provide a solid basis for our collabo-rative kidney epidemiology research network”, Kitty remarks. It is undeniable that Kitty Jager has been a gain for the ERA-EDTA Registry. And vice versa, as she emphasizes. “I have been given the fantastic opportunity to work with

some great European nephrology research-ers of my time, like Professor Carmine Zocca-li (Reggio Calabria/Italy), Prof. Christoph Wan-ner (Würzburg/Germany) or Prof. Ziad Massy (Paris/France). Besides, all the collaboration with the ERA-EDTA under the umbrella of the Registry has provided me with lots of oppor-tunities”. As instances she quotes the idea by Professor Zoccali, former ERA-EDTA Registry Chairman, of organizing epidemiology cours-es, writing educational articles, which have also added immensely to Kitty´s scientific rep-utation – and might have helped her to be ap-pointed as full professor at the AMC-UvA. Other examples are the invitations to present data of the Registry at various international congress-es or to build an international network with the aid of the ERA-EDTA Fellowship programs for young nephrologists or nephrology research-ers or the countless workshops and courses run by the ERA-EDTA and/or the Registry. For example, the Registry office has established the fruitful ‘ERA-EDTA Registry Clinical Epide-miology Learning and Research Centre’ host-ing visiting researchers from all across Europe and even Latin America cross-fertilizing (in-ter)national clinical knowledge and research skills. ”ERA-EDTA was definitely the key to my career success, but it also opened up promis-ing opportunities for many other people. I think, ERA-EDTA has set a great example of how pro-fessional associations can serve their mem-bers by providing education and research op-portunities. I am extremely proud to be part of this association and I would advise my young-er colleagues to make use of all opportunities that ERA-EDTA has to offer.” ◘

All European Union Member States have made commitments towards reducing inequalities in access to health care and in health outcomes. But substantial differences in mortality rates persist in the paediatric renal replacement ther-apy population across Europe. This is the sad result of a study published in The Lancet [1]. The authors extracted and carefully analyzed patients´ data from the European Society for Paediatric Nephrology/European Renal Asso-ciation-European Dialysis and Transplant As-sociation (ESPN/ERA-EDTA) Registry from 32 European countries. In summary, the analysis showed that public health expenditure was in-versely associated with mortality risk and ex-plained 67 % of the variation in renal replace-ment therapy mortality rates between coun-tries. Moreover, differences between countries in their ability to treat the youngest patients, who are typically the most complex and cost-ly to treat, were an important driver for poor outcomes. “We hope that this study is a huge wake-up call for policy makers in Europe”, ex-plains Professor Kitty J. Jager, Managing Direc-tor of the ERA-EDTA Registry. Throughout Eu-rope there are vast inequalities in access to re-nal care. Especially Eastern European countries

remain burdened by stringent austerity mea-sures and limited health-care budgets, which results in higher mortality rates. “In some coun-tries children are still dying, because renal care does not meet the European standards. This is something we are not willing to accept any lon-ger. Measures for improvement have to be tak-en!” But what measures would be promising? The study observed a positive trend between the number of paediatric nephrologists in a coun-try and the time patients spent in nephrological care before starting renal replacement therapy.

“This makes an early referral a key factor for a better survival of pediatric dialysis patients und underlines the value of specialist care as it has already been shown for adult patients”, com-ments Professor Dr Andrzej Więcek, president of the ERA-EDTA. ”Nephrology is a key subspecial-ty of internal medicine which has to be strength-ened within the healthcare systems.” ◘


“A direct result of the continuously ongoing lobbying activity of EKHA”

Session 0.2ERA-EDTA RegistrySunday, 08.00 – 09:30, Hall N101 – 102

The EDITH project

ROMALDAS MACIULAITIS

Kaunas, Lithuania

Addressing scientific issues related to clinical development

R&D Patient Care

EfficacyFocused on responder analysis ans mean values measuring by clinically meaningful endpoints Focused on individual patient need, such

as off-label use, including downgrading contraindications

SafetyRisk should be clearly specified and manageable

B/R (+)

Guided by targeted product profile during R&DShould be (+) at the time of Marketing Authorization

Usually more than just binary decision

Table: CT for drug approval vs patient care

Symposium of the ERA-EDTA & Japanese Society of Nephrology (JSN)Chairs: Motoko Yanagita & Andrzej Wiecek

Endothelial Dysfunction: a common mechanism underlying diabetic kidney disease Naoki Kashihara, Kurashiki, Japan (President of JSN)

AGEs-RAGE system as a promising therapeutic target for diabetic kidney disease Kei Fukami, Kurume City, Japan (Member of the Global Liaison Committee)

What do cohort studies tell us about CKD and diabetes? Christian Combe, Bordeaux, France

Genetic and epigenetic factors associated with diabetic kidney disease A. Peter Maxwell, Belfast, UK


Good news: The European Union has taken a vi-tal interest in evaluating the treatment modalities for patients with end stage renal disease (ESRD) in respect of effectiveness and costs – and ini-tiated a new program: On 1 January of this year the EDITH project started, which is funded by the 3rd Health Programme of the European Union. The acronym stands for “The Effect of Differing

Kidney Disease Treatment Modalities and Or-gan Donation and Transplantation Practices on Health Expenditure and Patient Outcomes” – and

the project aims to examine the effect of differ-ing kidney disease treatment modalities, organ donation and transplant practices on health ex-penditure and patient outcomes.

“The EDITH program is long-overdue”, explains EDITH project manager at the ERA-EDTA regis-try, Amsterdam/The Netherlands, epidemiologist

Doctor Vianda Stel. “In the moment, the over-all management of ESRD as well as access to dialysis and kidney transplantation varies a lot

across Europe, and nobody really knows which treatment strategy is best for patients and most efficient for the health systems.” The results of the EDITH project might therefore impact future treatment choices by patients and will also be a valuable source of information for health care policy and reimbursement authorities.

The EDITH consortium is led by the Deutsche Stiftung Organtransplantation (DSO) from Ger-many, and consists of 10 partners from all over Europe together with collaborating stakeholders including renal registries, the ERA-EDTA, the Eu-ropean Kidney Patients Federation (EKPF), the Eu-ropean Kidney Health Alliance (EKHA), the French Agence de la Biomédicine and national kidney foundations. The project consists of various work packages.

The ERA-EDTA Registry participates in the one that will address the epidemiology and costs of

different treatment modalities for ESKD. This in-cludes the assessment of 1) the frequency of the various treatment modalities for ESKD, 2) factors that influence the choice of those treatment mo-dalities by patients and doctors, and 3) the im-pact of treatment modality choice on health out-comes as patient survival and quality of life as well as on health care budgets. The analyses on health care budgets will be performed by the Ital-ian National Transplant Center (CNT – ISS). The other work packages will set up a European Liv-ing Donor Registry and a European Kidney Trans-plant Registry for the follow-up of living donors and transplant recipients.

The project duration will be three years. “For sure, we will gain important insights in 2020 and I am optimistic that the project is a big step towards better treatment choices in ESRD. Besides, the initiation of the program shows that renal care has been brought into the focus of European pol-icy makers. I believe this is a direct result of the continuously ongoing lobbying activity of EKHA, which is supported in its work by the ERA-EDTA.” More information about the EDITH project can be found on www.edith-project.eu ◘

European medicines regulators have had several recent experiences in precompetitive and prod-uct-specific interactions with the academic ne-phrology community. These interactions can be productive in coping with uncertainties during scientific and regulatory assessment of medi-cines in the European Union (EU). This is valid for both authorization/development plans (such as scientific advice, protocol assistance, inno-vation task force debates, and classification and certification procedures), and for more gener-al discussions on study designs (such as pre-paring guidance documents for product devel-

opment in a particular disease area or biomark-er qualification).

Very interesting lessons were learned during dis-cussions with academia and R&D representatives from both sites of Atlantic. These included the AD-PKD foundation, the Critical Path Institute (C-Path), the Innovative Medicines Initiative (IMI), the FNIH Biomarkers Consortium Kidney Safety Biomarker Project Team and the C-Path’s Predictive Safety Testing Consortium Nephrotoxicity Working Group (FNIH BC/PSTC NWG), SAFE-T, the International Society of Nephrology (ISN), and KDIGO.

Fortunately, we can learn from the examples of diverse interpretations of study results by scien-tific regulatory and academic experts. These ex-amples highlight the different values put on ac-ademic studies and studies for regulatory deci-sion-making purposes (see Table). We should be more active in learning from these different ap-proaches to interpreting the same study results. Now we see that several scientific issues that are

being discussed under the umbrella of ‘How to speed up R&D in nephrology?’ There is a living list of unresolved issues that deserves more in-tensive dialog among regulatory, academic/con-sortia and industry experts, such as: can 30 % decrease in glomerular filtration rate serve as an early surrogate for hard clinical endpoints?; can 25 % or 30 % decrease in albuminuria serve

as a surrogate for functional clinical endpoints?; what is the definition of a valid ‘early’ endpoint/biomarker? These types of question highlight the need for more comprehensive and constant plat-forms to address these and other emerging is-sues in a timely manner. Regulators also see the need to draw upon more EU academic expertise in this respect. ◘


As a member you will become part of one ofthe most infl uential European Medical Associations!Check out all benefi ts:

• NDT (Nephrology Dialysis Transplantation) subscription, including exclusive access to the archives.

• Exclusive live streaming sessions during ERA-EDTA Annual Congress.

• Unlimited access to ERA-EDTA Congress E-materials, to all ERA-EDTA members who participate at the Congress.

• Exclusive access to special content on ENP (i.e. CME courses slides, ERA-EDTA Dialogue).

• Possibility to organize ERA-EDTA sponsored CME courses.

• Active participation in the decision making policies of the Association.

• Special discounted congress membership fees at the annual congress.

• Special discounts (35%!) on the purchase fees of Oxford University Press (OUP) books.

• Participation in the Young Nephrologists’ Platform (YNP), if you are less than 40 years old.

• Take advantage of special membership fees for low income countries.

• Exclusive free access to EuroPD videos.

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Lorem ipsum dolor sit amet, consectetur adipiscing elit. Etiam vel lacus suscipit ipsum scelerisque pharetra. Donec cursus libero elit, vel iaculis ex ultrices sed. Sed faucibus orci nulla.

View the presentations of the JSN/ERA-EDTA Joint Symposium at the 59th Annual Meeting of Japanese Society of Nephrology!

Get ready for the European Nephrology Examination!

Discover Madrid, the venue of the 54th ERA-EDTA Congress!

ERA-EDTA and ESPN has signed a Collaboration Agreement

Clinical Practice Guideline on manage-ment of older patients with chronic kidney disease stage 3b or higher (eGFR <45 mL/min/1.73 m2)

The 53rd ERA-EDTA Congress will be held in Vienna, Austria from May 21st to May 24th, 2016; jointly with the Austrian Society of Nephrology.

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Benefits versus costs and the role of health technology assessment

ANDREA TAFT


The EMA and medicines evaluation in the European Union

JONATHAN FOX


New medicine evaluation after licensing

IVANA SILVA


Introducing a new framework for collaboration

Special SessionEMA/ERA-EDTASaturday, 13.00 – 15:30, Hall 10B

TOMORROW´S HIGHLIGHTSERA-EDTA Registry 08.00 – 09.30, Hall N 101 – 102

Late Breaking Clinical Trials 11.45 – 13.15, Hall 10 Plenary

American Society of Nephrology Highlights (ASN) 15.15 – 16.45, Hall 10 Plenary

The Lancet/ERA-EDTA 15.15 – 16.45, Hall 10 A

NDT Polar Views 17.00 – 18.30, Hall N 101 – 102

ERA-EDTA & Japanese Society of Nephrology (JSN) 17.00 – 18.30, Hall 10.B

Professor Jonathan Fox will give a lecture enti-tled ‘New medicines evaluation after licensing – benefits versus costs’ in a special session on the topic ‘Development of therapies for kidney dis-eases – a framework of regulatory agency, aca-demia and industry’ organized by ERA-EDTA and the European Medicines Agency (EMA).

Professor Fox said: ”It is a pleasure to be able to give this talk, which covers a topic that has re-ceived insufficient attention in nephrology, namely the post-licensing evaluation of clinical and cost effectiveness of medicines, in order to decide whether or not they should be introduced into clinical practice. This is becoming increasing-ly important given the rising costs of new medi-cines, some of which offer only marginal benefit over existing therapies.” He continued: “Licens-ing bodies such as the EMA and the Food and Drug Administration (FDA) of the USA do vital work to ensure that all new medicines satisfy standards of quality, safety and efficacy, but they do not as-sess comparative clinical effectiveness or cost effectiveness. This is the job of the increasing number of health technology assessment (HTA) agencies around the world, such as the National Instititute for Health and Care Excellence (NICE) in England, the Scottish Medicines Consortium (SMC) in Scotland, the Gemeinsamer Bundesau-sschuss (GBA) in Germany and the Haute Autorité de Santé (HAS) in France.

”As well as working as a National Health Service (NHS) Consultant Nephrologist in the Glasgow Re-nal & Transplant Unit, I have been involved with the assessment of medicines for many years,” he added. Most recently this has been as the Chair-man of the SMC, which evaluates the clinical and cost effectiveness of all new medicines and sig-nificant new indications for existing medicines. Acceptance by the SMC is necessary before any new medicine can be routinely prescribed in the NHS in Scotland. In common with other HTA bod-ies, SMC is a multidisciplinary organization that includes clinicians (doctors, pharmacists, nurses), health economists and NHS managers, but also has public partners and representatives of the pharmaceutical industry as full voting members.

”My talk in this very interesting and innovative symposium organized by Professor Markus Ket-teler will cover key concepts in HTA, including opportunity cost (in this context, what could be gained if the funds needed for a new medicine were spent on other healthcare strategies or, to put it another way, the benefit that would be lost elsewhere by funding a new therapy), and the quality adjusted life year (QALY) and its use in assessing comparative cost effectiveness. It is the cost effectiveness, or value for money, of a treatment that is important, not simply the price – there are many expensive medicines that are cost effective, and cheap medicines that are not.”

Professor Fox concluded: “HTA may be seen to be particularly relevant to publicly funded heathcare systems, such as the NHS in the United Kingdom, but it is also important for any system where there is a limit to funding – at some level, this surely in-cludes all healthcare systems in the modern era, if arbitrary and inequitable decisions about funding new therapies are to be avoided. There is a mor-al dimension to HTA: if therapies that do not offer value for money are funded, then patients requir-ing other therapies may lose out.” ◘

As a science-driven organization, the European Medicines Agency (EMA) has developed a frame-work to formalize, structure and further devel-op interactions with the academic community in the context of the European medicines regulato-ry network. The framework and an action plan for the next three years were adopted by EMA’s Management Board at its March 2017 meeting. The framework’s overall objectives are:

• Raising awareness of the mandate and work of the European medicines regulatory net-work to increase academia’s trust in and en-gagement with the regulatory system

• Fostering the translation of academic re-search into novel methodologies and medi-cines that meet regulatory standards and ad-dress the needs of public and animal health

• Ensuring that the best scientific expertise and academic research are available on time to support effective evidence generation, regulatory advice and guidance, as well as decision-making in regulatory processes

• Working with academia to develop regula-tory science that embraces scientific prog-ress in medicines development without com-promising patient safety, such as, for ex-ample, the use of novel endpoints or novel methodologies.

The framework builds on EMA’s experience in interacting with stakeholder associations rep-resenting patients and consumers, healthcare professionals and the pharmaceutical industry, which is based on the fundamental principles of transparency, independence and integrity, ac-countability, and broad representation.

Along with the framework, EMA has developed an action plan that includes, among, other activities, initiatives for mutual education and training, staff exchange programs to promote mutual learning, a strategic research agenda for regulatory sci-ence and the creation of an EMA entry point for academia to receive information on available support within the EU Regulatory Network.

The session ‘ERA-EDTA & EMA’ is an excellent opportunity to deliver on the first objective of the framework. My presentation will elaborate further on the way EMA interacts with academia, build-ing upon two other EMA presentations focusing on how medicines are developed and authorized in the EU and on specific scientific issues related to clinical development in nephrology.

For further details please refer to the EMA dedicated webpages on academia www.ema.europa.eu/ema. ◘

The European Medicines Agency (EMA) is a de-centralized agency of the European Union, lo-cated in London, UK. The Agency is responsible in the centralized procedure for the coordina-tion and conduct of the scientific evaluation of applications for European Union (EU) marketing authorizations for human and veterinary medi-cines that are being developed by pharmaceuti-cal companies for use in the European Union. It began operating in 1995.

The mission of the EMA is to foster scientific ex-cellence in the evaluation and supervision of medicines, for the benefit of public and animal health in the EU. The EMA also plays a role in stimulating innovation and research in the phar-maceutical sector, for example:

• It gives scientific advice and protocol assis-tance to companies on the development of new medicines

• It develops and publishes guidelines on the requirements for the quality, safety and effi-cacy testing of medicines

• It provides special assistance to micro, small and medium-sized enterprises (SMEs) through its SME office

• It issues opinions on orphan designation for medicines for rare diseases

• It manages the Innovation Task Force, a group that provides a forum for early dia-logue with applicants, and others.

Involvement of EMA in the kidney and renal dis-ease management will be highlighted, such as authorization of medicinal products for treat-ment of related conditions, development of sci-entific guidelines, role of the scientific advice, etc. Transparent interaction with all stakehold-ers, including health care professionals, patient organizations, learned societies and academia in general, are among the priorities in order to use state-of-art knowledge and expertise in the clin-ical field. The opportunities for further expansion of EMA/ERA-EDTA collaboration are welcome. ◘


Benefits versus costs and the role of health technology assessment

ANDREA TAFT


The EMA and medicines evaluation in the European Union

JONATHAN FOX


New medicine evaluation after licensing

IVANA SILVA


Introducing a new framework for collaboration

Special SessionEMA/ERA-EDTASaturday, 13.00 – 15:30, Hall 10B

TOMORROW´S HIGHLIGHTSERA-EDTA Registry 08.00 – 09.30, Hall N 101 – 102

Late Breaking Clinical Trials 11.45 – 13.15, Hall 10 Plenary

American Society of Nephrology Highlights (ASN) 15.15 – 16.45, Hall 10 Plenary

The Lancet/ERA-EDTA 15.15 – 16.45, Hall 10 A

NDT Polar Views 17.00 – 18.30, Hall N 101 – 102

ERA-EDTA & Japanese Society of Nephrology (JSN) 17.00 – 18.30, Hall 10.B

Professor Jonathan Fox will give a lecture enti-tled ‘New medicines evaluation after licensing – benefits versus costs’ in a special session on the topic ‘Development of therapies for kidney dis-eases – a framework of regulatory agency, aca-demia and industry’ organized by ERA-EDTA and the European Medicines Agency (EMA).

Professor Fox said: ”It is a pleasure to be able to give this talk, which covers a topic that has re-ceived insufficient attention in nephrology, namely the post-licensing evaluation of clinical and cost effectiveness of medicines, in order to decide whether or not they should be introduced into clinical practice. This is becoming increasing-ly important given the rising costs of new medi-cines, some of which offer only marginal benefit over existing therapies.” He continued: “Licens-ing bodies such as the EMA and the Food and Drug Administration (FDA) of the USA do vital work to ensure that all new medicines satisfy standards of quality, safety and efficacy, but they do not as-sess comparative clinical effectiveness or cost effectiveness. This is the job of the increasing number of health technology assessment (HTA) agencies around the world, such as the National Instititute for Health and Care Excellence (NICE) in England, the Scottish Medicines Consortium (SMC) in Scotland, the Gemeinsamer Bundesau-sschuss (GBA) in Germany and the Haute Autorité de Santé (HAS) in France.

”As well as working as a National Health Service (NHS) Consultant Nephrologist in the Glasgow Re-nal & Transplant Unit, I have been involved with the assessment of medicines for many years,” he added. Most recently this has been as the Chair-man of the SMC, which evaluates the clinical and cost effectiveness of all new medicines and sig-nificant new indications for existing medicines. Acceptance by the SMC is necessary before any new medicine can be routinely prescribed in the NHS in Scotland. In common with other HTA bod-ies, SMC is a multidisciplinary organization that includes clinicians (doctors, pharmacists, nurses), health economists and NHS managers, but also has public partners and representatives of the pharmaceutical industry as full voting members.

”My talk in this very interesting and innovative symposium organized by Professor Markus Ket-teler will cover key concepts in HTA, including opportunity cost (in this context, what could be gained if the funds needed for a new medicine were spent on other healthcare strategies or, to put it another way, the benefit that would be lost elsewhere by funding a new therapy), and the quality adjusted life year (QALY) and its use in assessing comparative cost effectiveness. It is the cost effectiveness, or value for money, of a treatment that is important, not simply the price – there are many expensive medicines that are cost effective, and cheap medicines that are not.”

Professor Fox concluded: “HTA may be seen to be particularly relevant to publicly funded heathcare systems, such as the NHS in the United Kingdom, but it is also important for any system where there is a limit to funding – at some level, this surely in-cludes all healthcare systems in the modern era, if arbitrary and inequitable decisions about funding new therapies are to be avoided. There is a mor-al dimension to HTA: if therapies that do not offer value for money are funded, then patients requir-ing other therapies may lose out.” ◘

As a science-driven organization, the European Medicines Agency (EMA) has developed a frame-work to formalize, structure and further devel-op interactions with the academic community in the context of the European medicines regulato-ry network. The framework and an action plan for the next three years were adopted by EMA’s Management Board at its March 2017 meeting. The framework’s overall objectives are:

• Raising awareness of the mandate and work of the European medicines regulatory net-work to increase academia’s trust in and en-gagement with the regulatory system

• Fostering the translation of academic re-search into novel methodologies and medi-cines that meet regulatory standards and ad-dress the needs of public and animal health

• Ensuring that the best scientific expertise and academic research are available on time to support effective evidence generation, regulatory advice and guidance, as well as decision-making in regulatory processes

• Working with academia to develop regula-tory science that embraces scientific prog-ress in medicines development without com-promising patient safety, such as, for ex-ample, the use of novel endpoints or novel methodologies.

The framework builds on EMA’s experience in interacting with stakeholder associations rep-resenting patients and consumers, healthcare professionals and the pharmaceutical industry, which is based on the fundamental principles of transparency, independence and integrity, ac-countability, and broad representation.

Along with the framework, EMA has developed an action plan that includes, among, other activities, initiatives for mutual education and training, staff exchange programs to promote mutual learning, a strategic research agenda for regulatory sci-ence and the creation of an EMA entry point for academia to receive information on available support within the EU Regulatory Network.

The session ‘ERA-EDTA & EMA’ is an excellent opportunity to deliver on the first objective of the framework. My presentation will elaborate further on the way EMA interacts with academia, build-ing upon two other EMA presentations focusing on how medicines are developed and authorized in the EU and on specific scientific issues related to clinical development in nephrology.

For further details please refer to the EMA dedicated webpages on academia www.ema.europa.eu/ema. ◘

The European Medicines Agency (EMA) is a de-centralized agency of the European Union, lo-cated in London, UK. The Agency is responsible in the centralized procedure for the coordina-tion and conduct of the scientific evaluation of applications for European Union (EU) marketing authorizations for human and veterinary medi-cines that are being developed by pharmaceuti-cal companies for use in the European Union. It began operating in 1995.

The mission of the EMA is to foster scientific ex-cellence in the evaluation and supervision of medicines, for the benefit of public and animal health in the EU. The EMA also plays a role in stimulating innovation and research in the phar-maceutical sector, for example:

• It gives scientific advice and protocol assis-tance to companies on the development of new medicines

• It develops and publishes guidelines on the requirements for the quality, safety and effi-cacy testing of medicines

• It provides special assistance to micro, small and medium-sized enterprises (SMEs) through its SME office

• It issues opinions on orphan designation for medicines for rare diseases

• It manages the Innovation Task Force, a group that provides a forum for early dia-logue with applicants, and others.

Involvement of EMA in the kidney and renal dis-ease management will be highlighted, such as authorization of medicinal products for treat-ment of related conditions, development of sci-entific guidelines, role of the scientific advice, etc. Transparent interaction with all stakehold-ers, including health care professionals, patient organizations, learned societies and academia in general, are among the priorities in order to use state-of-art knowledge and expertise in the clin-ical field. The opportunities for further expansion of EMA/ERA-EDTA collaboration are welcome. ◘

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