Oude of nieuwe fosfaatbinders? Papendal, 3 december 2015 Marc Vervloet Internist-nephrologist VU university medical center, Amsterdam

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1 Oude of nieuwe fosfaatbinders? Papendal, 3 december 2015 Marc Vervloet Internist-nephrologist VU university medical center, Amsterdam

2 Disclosure belangen spreker: Marc Vervloet (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Zie hieronder Bedrijfsnamen Sanofi, AbbVie, FMC, Shire, Amgen Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Als boven en Baxter Helaas niet Eva

3 Oude of nieuwe?

4 Hutchison, Nat Rev Nephr 2011 Fosfaat balans

5 Fosfaat verlagen: Waarom ook al weer?

6 Omdat: KDIGO het zegt NIAZ NFN kwaliteitsindicator

7 Wat zegt KDIGO over fosfaat? Consider biomarkers simultaneously (not in isolation) Consider trends Treat towards normal

8 Samenhang: Should you treat PTH? Should you treat phosphate? Block et al. Clin J Am Soc Nephrol 2013;8:

9 Trend over 1 jaar tijd N=132,087 HD patients PTH Calcium Phosphorus Block et al. Clin Neph 2015, in press

10 Individuele patienten data PTH categorieen > < <30 <15 Block et al. Clin Neph 2015, in press

11 Hazard Ratio Hazard Ratio Gevolg daling fosfaat: Baseline Serum Phosphorus mg/dl Baseline Serum Phosphorus >5.2 mg/dl Model 1 Model 2 Model 3 Univariate 95% CI (Model 3) 1,50 1,50 1,25 1,25 1,00 1,00 0,75 Observations distribution 0,75 Observations distribution 0, , Decrease Increase Decrease Increase Serum Phosphorus change (mg/dl) Serum Phosphorus change (mg/dl) Fernandez-Martin, Cannata-Andia, et al, COSMOS. Nephrol Dial Transplant 2015 ;30:

12 Quintiles of P range Blue: Binder Red: No Binder Isakova et al. J Am Soc Nephrol 2009;20:388 96

13 Wat zijn de mogelijkheden? Oude Aluminiumhydroxide Calcium carbonaat Calcium acetaat Combinatie Al-Mg (antagel) Nieuwe Sevelamer carbonaat Lanthanum carbonaat Osvaren (Ca-Mg combi) Velphoro (sucroferric oxyhydroxide) IJzer citraat Nicotinamide (Chitosan is out )

14 Hoe te kiezen???

15 Effectiviteit: Overwegingen Fosfaatverlagend effect Afname calcificatie Afname sterfte, of andere klinische eindpunten Bijwerkingen Compliance Kosten

16 PBC ( mmol/l / standard pill) PBC ( mg/dl / standard pill) PBC: Decrease in sp/pill Al(OH) 3 CaCO3 CaAc SevHCl SevCO 3 La 2 (CO 3 ) 3 CaMg Colest SFOH FeCit CKD 1-5 Dialysis * high P value EOT * * * * * * ,4 Slatopolsky ,3,24,25 Katopodis ,9 Almirall ,11 d'almeida ,65 Yang ,14 Naghibi ,20 Bleyer ,22 Hervás ,23 Quinibi ,27 Evenepoel ,37,48 Block ,42,67 Lewis 2015 Vervloet et al. ERA-EDTA Londen Chertow Slatopolsky Chertow ,52 Itoh ,47 Sprague Clin Neph Fan ,50 de Francisco Ahmadi ,57-60 Wuethrich Tzanno-Martins ,56 Locatelli ,66 Yokoyama NDT Ketteler Moustafa 41,61 Floege Al Baaj ,45 Shigematsu Sprague CJASN Takahara Kurihara Locatelli ,64 Dwyer Yokoyama CJASN 2014

17 PBC ( mmol/l / standard pill) PBC ( mg/dl / standard pill) PBC: Decrease in sp/pill (Dialysis patients, studies with n>50) CaCO3 CaAc SevHCl SevCO 3 La 2 (CO 3 ) 3 CaMg Colest SFOH FeCit * high P value EOT * * * * 1, ,4 D'Almeida ,41 Yang ,10 Bleyer ,12 Hervás ,13 Qunibi ,15 Evenepoel ,24,45 Lewis Slatopolsky Chertow ,32 Itoh ,28 Sprague 2009 (Clin Nephr) 17,31 de Francisco ,44 Yokoyama 2014 (NDT) Moustafa ,40 Floege Al Baaj ,29 Shigematsu Locatelli ,34-37 Wüthrich ,41 Dwyer 2013 Vervloet et al. ERA-EDTA Londen 2015

18 PBC (mg/standard pill) PBC: P absorption/pill (excretion studies, CKD patients) Al(OH) 3 CaCO 3 CaAc SevCO 3 La 2 (CO 3 ) 3 SFOH FeCit Urine Feces ,2 Clarkson ,4 Cam ,8 Mai ,7 Hill ,10,12 Block Sprague 2009 (CJASN) 13 Takahara Hergesell Yokoyama 2014 (CJASN) Vervloet et al. ERA-EDTA Londen 2015

19 Osvaren (FMC) Calciumacetaat/Magnesiumcarbonaat

20 De Roij van Zuijdewijn et al. PLoS One nov 2015

21 Velphoro (FMC/Vifor)

22 Sucro Ferric (III)-oxyhydroxide (PA21) binds phosphate by replacing hydroxide groups HO Fe(III) OH Phosphate O O Fe(III) P O OH PA21 is a mixture of: Iron ~21% m/m (equivalent to approx. 33% m/m of iron(iii)-oxyhydroxide) Sucrose ~30% m/m Starch ~28% m/m Water <10% m/m

23 Head-head SFOH-sevelamer Floege et al. Nephrol Dial Transplant 2015

24 Resultaten

25 IJzercitraat Fe Saturatie Ferritine Hemoglobine Block et al. Am J Kidney Dis 2015

26 Nicotinamide (niacin, vitamine B3) Vlees, vis, groente, fruit Biosynthese (tryptofaan) Verdwijnt met kookvocht

27 Actief en passief transport Isakova, J Am Soc Nephrol 2015

28 Giral, Am J Physiol 2009 Jejenum histologie: NaPi-2b

29 Katai, Nephrol Dial Transpl 1999 Effect Nicotinamide

30 Conclusie: Wat is redelijk?

31 Fosfaat verlaging (CKD 5d) Dieet (fosfaat voedings additieven) Lage dosis Ca-houdend, CaMg houdend Erbij of vervangend: sevelamer (veel pillen), lanthanum, SFOH* Bij hoog PTH: fosfaat uit bot! *Sevelamer en lanthanum: Intermediaire eindpunt studies op calcificaties

32 Het behoeft controle

33

34 Balance study

35 Odds ratio for CV event Odds ratio for CV event Epidemiology: Phosphate and CV events Complete population Normal kidney function CKD stage 1-2 CKD stage 3-4 McGovern, PLoS One 2013 Serum phosphate level Serum phosphate level

36 Kalantar-Zadeh 2007 Stage V CKD

37 Palmer, Strippoli JAMA 2011

38 Calcium, PTH and Phosphate: Palmer, Strippoli JAMA 2011

39 What is proof in medical science? Biological plausibility: Mechanisms Prospective trial: Intermediate endpoints Epidemiological association Prospective trial: Clinical endpoints

40 Razzaque Kidney Int 2011 Key role for phosphate

41 Phosphate: Crystal formation Boonrungsiman S et al. PNAS 2012

42 Flow mediated dilation (FMD)

43 Shuto, J Am Soc Nephrol 2009 Phosphate enriched diet in healthy subjects n=11 normal kidney function 400 mg phosphate Flow Mediated Vasodilatation 1200 mg phosphate

44 High P diet and FMD Low P diet High P diet Before meal 2 hours after meal Shuto J Am Soc Nephrol 2009

45 Summary of P vasculotoxicity Gross et al, Circulation J 2014

46 Principles: Therapeutic approaches Dietary modification Prevent P-absorption by binders Prevent P-liberation from protein Specific blockade GI phosphate transporters Inhibit P-release from bone

47 Moe, Clin J Am Soc Nephrol 2011 Vegetarian diet

48 Mankind lack enzyme phytase.

49 so we compensate by inorganic phosphates

50 Inorganic Organic Animal Meat/ Fish Phosphorus availability Plant Adema, Vervloet J Ren Nutr 2013

51 Hyperphosphatemic CKD stage 4 Caglar Clin J Am Soc Nephrol 2008

52 DOPPS: Observational patients Global dialysis patients On or off P-binders Lopes, Am J Kidney Dis 2012

53 Well described ArMORR cohort Prospective incident HD cohort Comparator: PB use or no use in first 90 days Propensity score correction (mimicking randomisation) Isakova, J Am Soc Nephrol 2009

54 Quintiles of P range Blue: Binder Red: No Binder Isakova, J Am Soc Nephrol 2009

55 Why difficult to proof? Normal phosphate: No indication High phosphate: Assumed indication Placebo Intervention 1: CCPB Intervention 2 N-CCPB Outcome Outcome

56 Conclusion 1/2 Biological plausibility: Mechanisms Prospective trial: Intermediate endpoints Epidemiological association Prospective trial: Clinical endpoints

57 Conclusion 2/2: Be very careful! Absence of level 1A proof that lowering phosphate is beneficial should not lead to indifference Urge for novel methods to limit phosphate uptake

58

59

60 P-release from bone? PTH Ca 2+ and PO 4 2-

61 Cinacalcet phase 3 trials Cinacalcet effects