Novel aspects of anemia and iron management in renal patients with or without cardiorenal syndrome Renal Unit, King’s College Hospital, London, UK 2002 2012 Killini 2012 2008 2018 2000 2010 2004 Erythropoiesis Hepcidin system Activation of HIF under hypoxic P300conditions HIF-β HIF-2α HIF-PH HRE EPO gene Plasma HIF system Fe-Tf Erythropoietin Iron SCF, IL-1, IL-3, SCF, GM-CSF, IL-6, IL-11 IL-3 About 8 Days Pluripotent Burst-Forming Colony-Forming Proerythro- Erythro- Reticulocytes RBCs Stem Cell Unit-Erythroid Unit-Erythroid blasts blasts Cells (BFU-E) Cells (CFU-E) Outline of lecture • What‘s new in anemia management? • What‘s new in iron management? • What‘s new in patients with cardiorenal syndrome? Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA Is there anything new in relation to target haemoglobin? Hb correction with ESA therapy 15 14 13 12 11 10 Hb (g/dl) Hb 9 • Reduced transfusions • Improved QoL, esp. physical domain 8 • Improved physical capacity • Positive cardiac effects 7 6 Hb correction with ESA therapy 15 14 13 12 11 10 Hb (g/dl) Hb 9 • Reduced transfusions • ? Improved QoL / ↑exercise capacity 8 • Increased CVS events, stroke, VTE • Increased cancer-related deaths 7 6 Hb correction with ESA therapy 15 14 13 12 11 10 Hb (g/dl) Hb 9 8 7 6 Safety Concerns in the TREAT Study 10 Darbepoetin alfa 8.9§ 8 Placebo 7.5‡ 7.1 6 5.0† 4 Patients (%) Patients 2 2.6 2.0‡ 0.6 1.1 0 Stroke Venous Arterial Cancer-related thromboembolic thromboembolic mortality* event event †, p<0.001 versus placebo ‡, p=0.02 versus placebo §, p=0.04 versus placebo *Amongst patients with a history of malignancy at baseline Pfeffer MA et al. N Engl J Med 2009;361:2019–2032. EPO has non-erythropoietic actions High EPO levels • 2+ VSMC [Ca ]i VSMC proliferation • • RAS activation EC proliferation Platelet production • • ET-1 Angiogenesis Platelet activity • Thromboxane • E selectin ¯ Prostacyclin • P selectin • ADMA • vWF ¯ • PAI-1 ¯ NO Blood access stenosis Proliferative retinopathy Vascular remodeling Hypertension Thrombosis Tumor growth Vaziri ND & Zhou X. Nephrol Dial Transplant 2009; 24: 1082–1088. Erythropoietin concentration-time profiles EPO conc. (mU/mL) Three 40 U/kg SC doses/wk 1000 Two 60 U/kg SC doses/wk One 120 U/kg SC dose/wk 100 Erythropoiesis ]range 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (days) Besarab et al, J Am Soc Nephrol 1992. Hb predicts survival in observational studies HD patients If a patient is NOT on ESA therapy and has a high Hb, is there a need to venesect / lose circuits? Ofsthun et al, Kidney Int 2003; 63: 1908-1914. Hb predicts survival in observational studies ND-CKD patients Survival of CKD Patients by Hemoglobin Level 1.00 0.95 Hemoglobin >= 130 g/L 0.90 120-129 g/L 0.85 0.80 110-119 g/L Probability of Survival of Probability 0.75 Log-Rank Test: p =0.0001 < 100 g/L 100-109 g/L If a patient0.70 is NOT on ESA therapy and has 0a 3high6 9 12Hb,15 18 is21 there24 27 30 33a 36need to Months from Hg Result venesect? ABSOLUTELY NOT! Levin A. et al, Nephrol Dial Transplant 2006; 21: 370-377. What about the trigger haemoglobin to initiate ESA therapy? When to initiate Hb therapy? 15 10 Hb (g/dL) 5 Caveats? Stage Stage Stage CKD stages 1–2 • Hb < 11 g/dL plus3 symptoms4 5 • Individualisation120–60 59–30 29–15 < 15 Declining GFR (mL/min) NHANES 3 data. What about the future of anaemia management in CKD? Erythropoietin concentration-time profiles EPO conc. (mU/mL) Three 40 U/kg SC doses/wk 1000 Two 60 U/kg SC doses/wk One 120 U/kg SC dose/wk New strategy 100 Erythropoiesis ]range patient’s own EPO level 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (days) Besarab et al, J Am Soc Nephrol 1992. Evolution of CKD Anaemia Treatment Transfusions ESAs HIF�stabilisers� HIF stabilisers – prolyl hydroxylase inhibitors Regulation of erythropoietin Hypoxia-Inducible Factor? (HIF) Regulation of HIF activity Inhibition of HIF under Activation of HIF under normoxic conditions hypoxic conditions HIF-PH HIF-PH HIF-α HIF-α HIF-α Proteasome O2 O2 P300 OH OH OH OH HIF-β VHL HIF-α HIF-α HIF-α Proteasomal degradation HRE Gene eg EPO HIF stabilisers l HIF is degraded by a prolyl hydroxylase enzyme l Orally-active inhibitors of PH have been synthesised l These drugs cause HIF levels to increase l More HIF leads to more EPO HIF PHIs in development Company Molecule Drug name Phase of development FibroGen FG-4592 Roxadustat Phase 3 Astellas Astra Zeneca GSK GSK 1278863 Daprodustat Phase 3 Akebia AKB-6548 Vadadustat Phase 3 Mitsubishi Otsuka Vifor Fresenius Bayer BAY 85-3934 Molidustat Phase 2/3 Japan Tobacco Inc JTZ-951 Phase 1 J Am Soc Nephrol 2016 Apr;27(4):1225-33. Roxadustat increases haemoglobin levels Besarab et al. J Am Soc Nephrol 2016 Apr;27(4):1225-33. The Erythropoietic Response mediated by HIF Roxadustat lowers hepcidin levels EPO Roxadustat Provenzano et al. ASN 2012 Abstract Besarab et al. J Am Soc Nephrol 2016 Apr;27(4):1225-33. Outline of lecture • What‘s new in anemia management? • What‘s new in iron management? • What‘s new in patients with cardiorenal syndrome? Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA Iron supplementation Dietary iron Oral iron IV iron Better Hb response with IV iron compared to oral or no iron 14 *p<0.05, **p<0.005 vs IV iron 12 ESA + IV iron ** ESA + oral iron 10 * ESA + no iron Hb (g/dL) Hb * **** ** * **** * 8 6 0 4 8 12 16 Time (weeks) Macdougall et al, Kidney Int 1996. Meta-analysis showed intravenous iron to be more favourable vs oral iron therapy in patients with ND-CKD Haemoglobin (Hb) level or change from baseline Study WMD (random) Weight WMD (random) or sub-category 95% CI % 95% CI Stoves 2001 6.27 -0.52 (-1.33, 0.29) Aggarwal 2003 8.04 0.49 (-0.21, 1.19) Charytan 2005 16.12 0.25 (-0.19, 0.69) van Wyck 2005 25.45 0.30 (0.02, 0.58) Agarwal 2006 18.75 0.20 (-0.18, 0.58) Spinovitz 2006 25.37 0.60 (0.32, 0.88) Total (95% CI) 100.00 0.31 (0.09, 0.53) Test for heterogeneity: Chi2 = 8.42, df = 5 (P=0.13), 2 = 40.6% Test for overall effect: Z=2.79 (P=0.005) -1 -0.5 0 0.5 1 Favours oral Favours IV • Most studies had short duration of follow-up • More randomized trials are required Rozen-Zvi et al. Am J Kidney Dis 2008;52:897–906. Oral iron – anything new? Newer oral iron preparations • Ferric citrate • Ferric maltol • Liposomal (sucrosomial) iron • Heme iron polypeptide Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA Intestinal absorption of iron Ferrous sulphate Ferrous fumarate Ferric citrate Ferrous succinate Heme iron Ferric maltol Ferrous gluconate polypeptide Adapted from G. Barragán-Ibañez et al. Rev Med Hosp Gen Mex 2016;79:88-97. Ferric citrate as a phosphate-binder 8 6 4 Active Control Ferric Citrate 2 Mean Phosphorus, mg/dL 0 Baseline Week 12 Week 24 Week 36 Week 48 Week 52 Treatment Difference at Week 52 ANCOVA, p=0.8 Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA Effect of phosphate-binders on ferritin Mean Ferritin Active Control Ferric Citrate (ng/mL) (n=135) (n=252) Baseline (Day 0) 609 593 Week 12 649 751 Week 24 652 846 Week 36 631 862 Week 48 619 881 Week 52 624 898 Change from Baseline at Week 52 15 305 % Change from Baseline 2.5% 51.4% Least Squares Mean Difference at Week 52 285 P-value <0.0001 41 Effect of phosphate-binders on TSAT Mean TSAT Active Control Ferric Citrate (%) (n=135) (n=252) Baseline (Day 0) 31 31 Week 12 31 40 Week 24 31 40 Week 36 31 40 Week 48 29 41 Week 52 30 39 Change from Baseline at Week 52 -1 8 % Change from Baseline -3.2% 25.8% Least Squares Mean Difference at Week 52 9 P-value <0.0001 42 Effect of phosphate-binders on IV iron use Last 6 and 9 months with no IV iron in the study Active Control Ferric Citrate % Subjects % 43 Effect of phosphate-binders on ESA dose 12,000 10,000 8,000 6,000 4,000 2,000 0 1st Quarter 2nd Quarter 3rd Quarter 4th Quarter Ferric Citrate Mean ESA Units/Week Active Control Mean ESA Units/Week Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA What’s new with IV iron? Included 7 RCTs comparing higher-dose IV iron with lower-dose intravenous iron, oral iron, or no iron in patients treated with dialysis that had all-cause mortality, infection, cardiovascular events, or hospitalizations as outcomes Besarab et al, 2002 Single-center (US), open-label, randomized, prospective 6-month study in HD patients N = 42 IV iron dextran (25-150 mg/wk to maintain TSAT 20-30%) (n=19 -- 15 completed) R IV iron dextran 4-6 x 100 mg doses to increase TSAT >30% and thereafter to maintain TSAT at 30-50% (n=23 -- 17 completed) Primary outcome: EPO dose (40% lower) No differences in hospitalizations or infection rate were noted Each group had 1 admission for an infectious etiology (pneumonia in the control group, line-related sepsis in the study group) Coyne et al, 2007 (“DRIVE”) Open-label, randomized, controlled, multicenter trial (37 US centers) N = 134 1 g of ferric gluconate (Ferrlecit) administered in 8 consecutive 125-mg doses R No iron 6-weeks follow-up Better Hb response (p<0.03) 13 infection episodes in 10 patients occurred in the control arm, and 12 infection episodes occurred in 8 patients in the IV iron arm Lewis et al, 2015 Phase 3, sequential, randomized, open-label trial (60 sites in the US and Israel) N = 441 Ferric citrate 1 g (210 mg ferric iron) R Calcium acetate (667 mg) or sevelamer (800 mg) 52-weeks follow-up Primary outcome – phosphate level 12.5% of patients