1. Essentials of CKD Comorbidities and outcomes in CKD

2. Anaemia is Prevalent in CKD and its Severity Increases with Worsening Kidney Function Anaemia is prevalent in the CKD population (e.g. 47.7% of a population of 5,222 CKD patients) 1 Prevalence of anaemia increases with declining renal function 1,2 p<0.05 between all categories LVM=left ventricular mass Hb <12–11 g/dL Hb <11–10 g/dL <10 g/dL Hb 13–12 g/dL 0 5 10 15 20 25 Creatinine clearance (mL/min) Patients (%) 25% >50 44% 35–49 51% 25–34 87% <25 30 1. McClellan W et al. Curr Med Res Opin 2004;20:1501–1510; 2. USRDS 2008 Annual Data Report, Atlas of CKD. Am J Kidney Dis 2009;53(suppl 1):S23–S36 3. Levin A et al. Am J Kidney Dis 1999;34:125–134 Canadian multicentre prospective cohort study 3 N= 446 renal insufficiency patients

3. Anaemia is Defined by a Reduction in Haemoglobin Levels There are numerous groups that have defined anaemia in patients with CKD 1 EBPG 2004KDOQI TM 2006/2007ERBP 2008 Hb <11.5 g/dL (F) Hb <13.5 g/dL (M 70 years) Hb 70 years) Hb <12 g/dL (F) Hb <13.5 g/dL (M) Hb <12 g/dL (F) Hb <13.5 g/dL (M) 1. Locatelli F et al. Nephrol Dial Transplant 2009;24:348–354 EBPG=European Best Practice Guidelines; KDOQI=Kidney Disease Outcomes Quality Initiative; ERBP=European Renal Best Practice; Hb=haemoglobin; F=female; M=male

4. Anaemia can be Caused by Numerous Factors Related to CKD EPO deficiency/resistance 1 Shortened red cell life span (uraemic milieu) 1 Iron deficiency 1 Blood loss – dialysis and GI bleeding 1 Hyperparathyroidism 1 Nutritional deficiencies 1 Inflammation 1 Drugs (e.g., ACE inhibitors, aspirin, ARBs) 1 1. Kazory A & Ross EA. J Am Coll Cardiol 2009;53:639–647 EPO, erythropoietin; GI, gastrointestinal; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker

5. Falling Hb Levels are Related to Increased Hazard Ratio for ESRD and All-cause Mortality 853 pre-dialysis patients, CKD Stage 3–5 Male US veterans referred to a single nephrology clinic between January 1990 and December 2004 Kovesdy CP et al. Kidney Int 2006;69:560–564 ESRD, end-stage renal disease ESRD All-cause mortality <11.0 Hazard ratio 1 11.1–12.012.1–13.0>13.0 0 5 10 15 17 Time-averaged Hb (g/dL) <11.0 Hazard ratio 1 11.1–12.012.1–13.0>13.0 0 2 3 5 7 Time-averaged Hb (g/dL) 4 6 UnadjustedAdjusted UnadjustedAdjusted

6. Low Hb Levels are Associated with Reduced Rate of Survival Retrospective, longitudinal study of 44,550 HD patients from FMCNA database Ofsthun N et al. Kidney Int 2003;63:1908–1914 Days follow-up 80 Survival (%) 1800306090120150 100 90 Hb ranges (g/dL) Hb 13.0 12.0 Hb <13.0 11.0 Hb <12.0 10.0 Hb <11.0 9.0 Hb <10.0 Hb <9.0 HD=haemodialysis; FMCNA=Fresenius Medical Care North America

7. Unadjusted Case-mix Case-mix & MICS Hb 12–13 g/dL is Associated with a Greater Chance of Survival in HD Patients Regidor DL et al. J Am Soc Nephrol 2006;17:1181–1191 Prospectively collected data of a 2-year historical cohort of all HD patients in the national database of DaVita Inc <9 All cause mortality hazard ratio 0.8 3 1 5 2 Hb (g/dL) 9.0–9.4 9.5–9.9 2000 4000 6000 8000 10000 12000 0 10.0–10.4 10.5–10.9 11.0–11.411.5–11.9 12.0–12.412.5–12.9 13.0–13.4 13.5–13.9 14 Unadjusted Case-mix Case-mix & MICS Frequency All-cause death in all patients (Incident and prevalent) n=58,058 All-cause death in all patients (Incident and prevalent) n=58,058 Hb (g/dL) Cardiovascular mortality hazard ratio 1 0.8 2 3 5 <9 9.0–9.49.5–9.9 10.0–10.410.5–10.911.0–11.4 11.5–11.912.0–12.4 12.5–12.913.0–13.413.5–13.9 14 MICS, malnutrition inflammation complex syndrome

8. No. at risk Normal haematocrit Low haematocrit 1,233 patients on HD for 3 years – 65±12 years (normal group), 64±12 years (low group) – CHF, ischemic heart disease 39–45 % 27–33 % Besarab A et al. N Engl J Med 1998;339:584–590 Lower Haematocrit has been Shown to be Associated with Reduced Mortality 0 Probability of death or myocardial infarction (%) 0 10 20 30 40 Normal-haematocrit group Months after randomisation 36912151821242730 50 60 Low-haematocrit group 6185404764153532591861246926 6155374854343912922161318020

9. Numerous Comorbidities are Associated with CKD CV disease, diabetes and hypertension are also common comorbidities observed in patients with CKD 1 1. USRDS 2008 Annual Data Report, Atlas of CKD. Am J Kidney Dis 2009;53 (suppl 1):S23–S36 Prevalence (%) eGFR (mL/min/1.73 m 2 ) 0 25 50 75 100 >10590–10575–<9060–<7545–<6030–<45<30 Diabetes 1 CV disease 1 Hypertension 1

10. CV Morbidity and Mortality Increase with Worsening Kidney Function CKD progression leads to a requirement for dialysis and/or kidney transplantation 1 However, most patients with CKD die prematurely of CVD 2 – CV morbidity and mortality increases with decreasing kidney function 3–5 1. Zhang Q-L & Rothenbacher D. BMC Public Health 2008;8:117; 2. Besarab A et al. N Engl J Med 1998;339:584–590; 3. Go AS et al. N Engl J Med 2004;351:1296–1305; 4. Shlipak MG et al. JAMA 2005;293:1737–1745; 5. Keith DS et al. Arch Intern Med 2004;164:659–663

11. KPRR=Kaiser Permanente Renal Registry;HR=hazard ratio Risk of CV Events and Hospitalization Increases with Declining Kidney Function Cohort of 1,120,295 pre-dialysis patients from the KPRR studied for 2.84 years 1 1. Go AS et al. N Engl J Med 2004;351:1296–1305 Age-standardised rate of death from any cause (per 100 person years) 0.76 60 1.08 45–5930–4415–29<15 eGFR (mL/min/1.73 m 2 ) 15 10 5 0 Mortality (N=51,424) Age-standardised rate of CV events (per 100 person years) 2.11 60 3.65 45–5930–4415–29<15 eGFR (mL/min/1.73 m 2 ) 40 20 0 CV events (N=138,291) Hospitalisation (N=554,651) Age-standardised rate of hospitalisation (per 100 person years) 13.54 60 17.22 45–5930–4415–29<15 eGFR (mL/min/1.73 m 2 ) 150 100 50 0 30 10 11.29 21.80 36.60 4.76 11.36 14.14 42.26 86.75 144.61

12. Anaemia Contributes to the Incidence of CVD in Patients with CKD CV events 1–5 and disease progression? 2,4 – Anaemia is a risk factor for CVD in patients with CKD 1–4 In the NKFs KEEP cohort of 37,000 patients, anaemia and GFR were independently associated with CVD and decreased survival 3 – Anaemia is a risk factor for worse outcomes in patients with CKD 4,5 – Anaemia is a risk factor for progression of CKD? 2,4 1. Mix TC et al. Am Heart J 2005;149:408–413; 2. Walker AM et al. J Am Soc Nephrol 2006;17:2293–2298; 3. McCullough PA et al. Arch Intern Med 2007;167:1122–1129; 4. Thorp ML et al. Nephrology 2009;14:240–246; 5. Schmidt RJ & Dalton CL. Osteopath Med Prim Care 2007;1:14 CVD=cardiovascular disease; NKF=National Kidney Foundation; KEEP,=Kidney Early Evaluation Program