Milano, 22 Settembre 2017

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1 NUOVI TRATTAMENTI IN NEFROLOGIA Milano, 22 Settembre 2017 LA TERAPIA MARZIALE IN DIALISI: L ETERNO DILEMMA TRA E.V E PER OS La terapia con ferro per via endovenosa Lucia Del Vecchio Divisione di Nefrologia e Dialisi, Ospedale A. Manzoni, ASST Lecco

2 FINO A QUALCHE ANNO FA LE IDEE ERANO CHIARE!!!!!!! ND-CKD: FERRO PER OS HD-CKD: FERRO EV

3 VIA DI SOMMINISRAZIONE DEL FERRO E STADIO CKD

4 NON-DIALYSIS CKD Il regno della terapia marziale per via orale Ora nuovo spazio alla somministrazione EV

5 24 trials were identified: -13 including 2,369 patients with CKD stages 3 to 5-11 including 818 patients with CKD stage 5D. Primary Outcome: Percentage of Patients With Hb Response >1 g/dl Patients With CKD Stages 3 to 5 Five trials including 1,404 patients Patients who received IV iron had a significantly higher risk for hypotension and a lower risk for GI adverse events Shepshelovich D et al. Am J Kidney Dis 2016 Nov;68(5):

6 PAZIENTI IN EMODIALISI Il regno della terapia marziale per via EV Quindi oggi mi va bene..

7 Primary Outcome: Percentage of Patients With Hb Response >1 g/dl Patients With CKD 5D: Three trials including 300 patients IV iron Oral iron IV iron sucrose IV ferric gluconate Total ( ) Shepshelovich D et al. Am J Kidney Dis 2016 Nov;68(5):

8 TREAT Study Grande spinta alla terapia marziale

9 IV iron and ESA in haemodialysis: A systematic review and meta-analysis Weighted average percentage reduction in ESA dose/week Of the 28 RCTs identified, 7 met the criteria for inclusion STUDY OPTIMAL IRON SUBOPTIMAL IRON Intervention arms: N Optimal mg IV iron per week Suboptimal < 100 mg per week % change % change N Weighting Difference Roger SD et al. Nephrology (Carlton) Oct 3

10 IV iron and ESA in haemodialysis: A systematic review and meta-analysis Weighted average percentage reduction in ESA dose/week Of the 28 RCTs identified, 7 met the criteria for inclusion STUDY OPTIMAL IRON SUBOPTIMAL IRON Intervention arms: N Optimal mg IV iron per week Suboptimal < 100 mg per week % change % change N Weighting Difference -23% OVERALL range -7% to -55% Roger SD et al. Nephrology (Carlton) Oct 3

11 TRENDS IN US DIALYSIS PRACTICE 1 year period covering August 2010 to August 2011: the median ferritin level increased from 556 to 650 ng/ml Facility variation in ferritin levels (August 2011) 53% 37% 21% Am J Kidney Dis Jul;60(1):160-5

12 HR of all-cause mortality Iron indices and survival in maintenance HD patients with and without polycystic kidney disease 2969 MHD patients with and without PKD from 580 outpatient HD facilities between July 2001 and June Hazard ratio (95% CI) of mortality across the ferritin categories using timeaveraged cox regression analyses in MHD patients without polycystic kidney disease. Ferritin (ng/ml) categories Hatamizadeh P et al. Nephrol Dial Transplant 2013; 28(11):

13 Hazard ratio (95% CI) Associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the DOPPS Study All-cause mortality HR % CI HR % CI Average montly IV iron dose (mg/month) Kidney Int 2015 Jan;87(1):162-8

14 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008 Intravenous iron dose accumulations over 1-, 3-, and 6-month median follow up of 19 months Reduced risk of all-cause mortality with receipt of > 150 mg/month of intravenous iron Miskulin DC et al. Clin J Am Soc Nephrol 9: , 2014

15 There was a non- statistically significant increase in infection-related mortality with receipt of > 1050 mg intravenous iron in 3 months and > 2100mg in 6 months Miskulin DC et al. Clin J Am Soc Nephrol 9: , 2014

16 Mean serum ferritin from 1993 to 2014 among United States patients on hemodialysis Annual rate of hospitalizations with bacteremia/sepsis per 1000 patient-years (USRDS 2013 Annual Data Report) Fishbane S et al. Clin J Am Soc Nephrol 9: ccc ccc, 2014

17 August 2010 Volume 6 Issue 8 e ferro - ferro

18 Guy Rostoker et al. Prospective measure of liver iron concentration by means of T1 and T2* contrast MRI in a cohort of 119 fit HD patients receiving both parenteral iron and ESA N = 9 N = 22 18% N = 36 30% controls Normal 150 Mild Overload Hepatic iron content Moderate Overload Severe Overload Am J Med 2012 Oct; 125:

19 AIFA: Nota Informativa Importante su medicinali contenenti ferro 29 ottobre 2013 L agenzia europea avverte che i preparati a base di ferro devono essere somministrati esclusivamente in un contesto dotato di strutture di rianimazione, in modo che i pazienti che sviluppano una reazione allergica possano essere immediatamente trattati.

20 RLDT at 1st December 2012: 6406 prevalent HD patients: 4138 treated in 48 HCs 2268 In treated in CALs SEZIONE LOMBARDA J Nephrol 2016 Oct;29(5):673-81

21 Disponibilità servizio di rianimazione Con RIA Senza RIA 1 10 Centri Ospedalieri (n= 36) Centri Satelliti (n= 50)

22 Impact of EMA recommendations on IV iron prescription in HD centres in Lombardy June % of the patients receiving IVFe (HDC range ) 29 ottobre 2013 IVFe prescription showed a % decline at the time of the survey Rivera R et al. J Nephrol (2016) 29:673 81

23 Percentuale di pazienti trattati con ferro 67% 66% 70.1% 50.7% Centri Ospedalieri (n= 36) Centri Satelliti (n= 50) Rodolfo Rivera per il CD della SINL

24 La nostra esperienza.. Lecco Ospedale A. Manzoni 1 Centro Ospedaliero 72/ ~ 100 pazienti in terapia marziale 1 Cal in Ospedale 2 CAL ambulatoriali 37/ ~ 100 pazienti in terapia marziale STOP TERAPIA MARZIALE EV NEI CAL DAL DICEMBRE 2013

25 Dose ESA ev/ settimana ASST LECCO Variazioni dose ESA EV al centro e nei CAL dopo la nota AIFA CAL Centro Pre AIFA Post AIFA Pre AIFA Post AIFA Analisi Ing. Fabio Carfagna

26 Ferritina ng/ml ASST LECCO Variazioni ferritina al Centro e nei CAL dopo la nota AIFA CAL Centro Pre AIFA Post AIFA Pre AIFA Post AIFA Analisi Ing. Fabio Carfagna

27 ASST LECCO Coorte fissa Variazioni ferritina al Centro e nei CAL fino ad oggi Analisi Ing. Fabio Carfagna

28 ASST LECCO Coorte mobile Variazioni ferritina al Centro e nei CAL fino ad oggi Analisi Ing. Fabio Carfagna

29 ASST LECCO Coorte mobile Variazioni ERI al Centro e nei CAL fino ad oggi Analisi Ing. Fabio Carfagna

30 Targets for adapting intravenous iron dose in hemodialysis: a proof of concept study Prospective 8-month study of 45 HD patients Intravenous iron administered if: Serum ferritin TSAT <20% and ferritin < 200 μg/l Peters NO et al. BMC Nephrol Mar 20;18(1):97.

31 Targets for adapting intravenous iron dose in hemodialysis: a proof of concept study Prospective 8-month study of 45 HD patients Hemoglobin (g/dl) ESA (ug/28 days) Peters NO et al. BMC Nephrol Mar 20;18(1):97.

32 Iron suppresses erythropoietin expression via oxidative stress-dependent HIF-2 a inactivation + C57BL/6J mice with unilateral ureteral obstruction (UUO) Saccharated ferric oxide Oshima K et al. Laboratory Investigation (2017)97,

33 Iron suppresses erythropoietin expression via oxidative stress-dependent HIF-2 a inactivation EPO mrna HIF-2a mrna HIF-1a mrna Oshima K et al. Laboratory Investigation (2017)97,

34 Ivano Lucy