The clinical “syndrome” of CKD-MBD has been recognized as an important contributor to morbidity and mortality throughout all stages of CKD. In the past, research centers have traditionally and individually focused on some isolated aspects of this newly recognized entity. Nevertheless, CKD-MBD is a complex interaction of multiple disturbances finally resulting in heterogeneous sequelae. Thus, a common platform for educational, intellectual and personal-fellow exchange needed facilitate research in a field where many efforts are still needed.
It was felt that large scale cooperation between centers with special interest in these matters needed improvement in order to achieve a global and translational approach to pathophysiology, prevention and treatment of CKD-MBD. Research targets have not always met clinical needs and some urgent research targets have not still been adequately addressed, specially referring to important hard end-points.
Part of this kind of cooperation, such as exchange of expertise including fellow scholar and exchange programs started in 2010 as an international cooperative structure for centers with both scientific as well as clinical interests in CKD-MBD.
As a first step, four scientific symposia (Amsterdam 2010, Prague EDTA 2011, Barcelona 2011, Paris EDTA 2012), two Fellow Days – where young fellows had the opportunity to meet and interact with experts in CKD-MBD) and an additional Fellow Training Day2011 at UDETMA (Atherothrombotic Disease Detection and Treatment Unit), Lleida (Spain), have already been organized.
Marc Vervloet (Netherlands) – Chair
Sandro Mazzaferro (Italy) – Vice Chair
Etienne Cavalier (Belgium)
Mario Cozzolino (Italy)
Juan F. Navarro-González (Spain)
Markus Ketteler (Germany)
Mathias Loberg Haarhaus (Sweden)
Mariano Rodriguez Portillo (Spain)
Smeeta Sinha (United Kingdom)
Peter Stenvinkel (Sweden)
Ziad Massy (France) – External Consultant
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Being a ordinary member of the CKD-MBD Working Group means being part of a network which facilitates exchanges of in the field of interest of CKD-MBD and Bone Mineral disorders in CKD.
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The role of phosphate in kidney disease
on behalf of the ERA–EDTA Working Group on Chronic Kidney Disease–Mineral and Bone Disorders and the European Renal Nutrition Working Group,
Nature Reviews Nephrology, November 2016
CKD-MBD related publications in the ERA-EDTA journals
The ERA-EDTA acknowledges the high clinical and scientific relevance of the CKD-MBD syndrome, reflected by several key publications in the journals of our society. We hereby summarize the content of several recent important papers, providing a link to their abstracts.
From July to December 2019, 23 CKD-MBD related articles, including several editorial comments and experimental studies, have been published; 18 in Nephrology Dialysis and Transplantation and 5 in Clinical Kidney Journal.
Phosphate (P) control (i.e. through diet and/or P-binders) remains as an iterative issue in many publications. Salomo et al(Nephrol Dial Transplant 34 (10):1691) found short-term favorable effects on the P axis (dramatic reduction of 24-h urinary P) using the New Nordic Renal Diet (realistic, feasible, unsupplemented whole-foods dietary pattern). An editorial devoted to this article and other “renal diets” (mainly on P physiology) is reviewed by J.J. Scialla and P.-H. Lin(Nephrol Dial Transplant 34 (10):1619). Two post-hoc analyses of phase 3 trials, G.A. Block et al(Nephrol Dial Transplant 34 (7):1115), on ferric citrate, and M. Ketteler et al(Nephrol Dial Transplant 34 (7):1163), on sucroferric oxyhydroxide and sevelamer, analyze their effects on CKD-MBD parameters. Ferric citrate reduced intact fibroblast growth factor-23 (FGF23) and C-terminal FGF23, partially via changes in iron balance (for C-terminal FGF23) and serum P (for intact FGF23) and partially via unknown/unmeasured mechanisms. Sucroferric oxyhydroxide and sevelamer also reduced serum FGF23 and increased bone formation marker levels. Short-term effects of sevelamer (carbonate) on FGF23 and pulse wave velocity (PWV) in patients with normophosphatemic stage 3 CKD were evaluated by A.B. de Krijger et al(Clin Kidney J 12 (5):678) and found that sevelamer did not improve PMV. However, in subgroup analysis it did improve in patients with no or limited abdominal aorta calcifications. A related editorial by J. Bover and M. Cozzolino(Clin Kidney J 12 (5):673) refers to this small steps towards the potential of “preventive” treatment of early P loading in CKD.
Wakasugi et al(Nephrol Dial Transplant 34 (7):1207) described that functional impairment was significantly associated with 1-year mortality and attenuated the effect of hyperphosphatemia on mortality among prevalent dialysis patients. Calcemia and PTH were associated with mortality irrespective of the functional status. A related editorial (P.A. Ureña-Torres and M. Cohen-Solal; Nephrol Dial Transplant 34 (7):1077) analyzed this and other factors able to modify this association. On the other hand, in an experimental study, Y. Sakaguchi et al(Nephrol Dial Transplant 34 (8):1310) demonstrated that a low magnesium diet aggravates P-induced kidney injury and P metabolism (by impairing PTH secretion and down-regulating renal α-Klotho). T. Oka et al(Nephrol Dial Transplant 34 (7):1154) described that hypomagnesemia was a common electrolyte abnormality in patients with CKD and that renal magnesium tubular wasting was associated with proteinuria.
Regarding vascular calcification, in two experimental studies, Bouabdallah et al(Nephrol Dial Transplant 34 (7):1125) showed that P and indoxyl sulphate induced human aortic smooth muscle cell calcification, which was significantly exacerbated by endothelial cell-conditioned medium and highlighted the novel role of IL-8. K. Belmokhtar et al(Nephrol Dial Transplant 34 (12):2018) demonstrated that receptor for advanced glycation end-products (RAGEs), through the modulation of Pit-1 expression, is a key molecule in the genesis of vascular calcification in CKD. Clinically, M.C. Lamarche et al(Nephrol Dial Transplant 34 (10):1715) reported that in stages 3–5 CKD patients, coronary artery calcification (CAC) is an independent predictor of both end-stage renal disease (ESRD) and mortality at 10 years. Those who developed ESRD at the fastest rate either had the highest CAC score or the worst CKD-MBD derangements (lowest calcidiol, and highest serum P). Finally, A. Galassi et al(Clin Kidney J 12 (4):546) showed the improvement of wounds in a hemodialysis patient affected by calciphylaxis, treated by multipronged intervention including both intravenous and intralesional sodium thiosulphate.
Several pleiotropic effects of FGF23 were analyzed in different studies. Experimentally, A. Navarro-García et al(Nephrol Dial Transplant 34 (11):1864) demonstrated that FGF23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes. Interestingly, both contraction dysfunction and pro-arrhythmic Ca2+ events induced by FGF23 were blocked by soluble Klotho. M.R. Hanudel et al(Nephrol Dial Transplant 34 (12):2057) analyzed the effects of erythropoietin on the production and metabolism of FGF23 in a translational study (mice and humans). H. Xu et al(Nephrol Dial Transplant 34 (12):2051) found, in contrast to the common notion that FGF23 causes clinically significant sodium retention, that FGF23 is independently associated with an increased FENa in non-dialysis CKD patients. Therefore, C.A. Wagner et al(Nephrol Dial Transplant 34 (12):1986) analyzed in an editorial what the role of FGF23 is in cardiovascular disease, and that it may be more complicated than initially anticipated. Finally, J.M. Valdivieso et al(Nephrol Dial Transplant 34 (12):2079) described that the presence of the allele T of the single nucleotide polymorphism rs495392 of the Klotho gene is associated with a decrease in the odds of progression of atheromatosis in CKD patients.
Miscellany: Rottembourg et al(Clin Kidney J 12 (6):871) underlined the importance of early treatment of secondary hyperparathyroidism (SHPT) by retrospectively analyzing parathyroid hormone (PTH) control in French hemodialysis patients treated with cinacalcet. T. Sato et al (Clin Kidney J 12 (5):686) examined the relationship between renal tubular damage after parathyroidectomy and potential signaling pathways. K. Hamada-Ode et al(Nephrol Dial Transplant 34 (8):1426) described different kinetics of serum Dkk1 and sclerostin in their Japanese patients with CKD, and that in stage 1-3 CKD, Dkk1 is a prognostic indicator for the progression of CKD. Finally, M. Bonani et al(Nephrol Dial Transplant 34 (10):1773) described the beneficial effect of denosumab not only on bone mineral density but also on the trabecular bone score (TBS) in the novo kidney transplant patients.
Dr Jordi Bover and Sandro Mazzaferro
on behalf of the EDTA CKD-MBD Working Group
Acknowledgement: Dr Carolt Arana for her valuable assistance
EUropean Renal OsteoDystrophy (EUROD): This bone-biopsy network aims at joining nephrologists, endocrinologists and pathologists (Coordinator: Pieter Evenepoel). It is expected to collect the largest possible bone samples to be examined homogeneously, in order to improve knowledge on the role of bone in systemic disease CKD-MBD risk prediction score development. A web based registry, educational activities, training fellowships are part of the activities carried out by the group. Steering Committee: P. Evenepoel, M. Vervloet, S. Mazzaferro, P. D’Haese, J. Bacchetta, J. Cannata-Andia, A. Ferreira, M. Haarhaus, MH Lafage Proust, S. Salam S, G. Spasovski.
Concerted Action in Renal Osteosdystrophy (CAiRO): This project consists of a population-based cohort study and a pilot biomarker study. It builds on unique epidemiological resources and cutting-edge analytical expertise, already available within the European-ROD (EUROD) initiative.
European Calciphylaxis registry (Eucalnet)Netherlands, Belgium, Portugal and lately Spain announced their involvement in the project. The critical points, mostly on the local Ethical Committee rules. The project is supported by AMGEN. ERA-EDTA/CKD-MBD is scientifically but not financially involved. This may have to be changed in the nearby future, with ERA-EDTA being the legal partner for fund givers. The registry has been online for 3 years. 39-40 patients have been enrolled in 3 years.
CKD-MBD risk prediction score development: project aims at evaluating data from large registries to develop a score to identify independent risk of several CKD-MBD phenotypes. CKD-MBD was invited by ESPN (chaired by Dr Justine Bacchetta) to join the committee to develop the guideline for the use of calcimimetics in children.
CKD-MBD phenotypes and all cause mortality. Collaboration with EuroDOPPS. Steering committee: M. Vervloet, Z. Massy, M. Cozzolino, A. Bellasi, T. Hoekstra. The analysis has been run by Dr D. Siriopol (Romania).