Essentials of CKD Comorbidities and outcomes in CKD

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 Creatinine clearance (mL/min) Patients (%) 25% >50 44% 35–49 51% 25–34 87% < 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

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

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

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 – –13.0> Time-averaged Hb (g/dL) <11.0 Hazard ratio – –13.0> Time-averaged Hb (g/dL) 4 6 UnadjustedAdjusted UnadjustedAdjusted

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 (%) Hb ranges (g/dL) Hb Hb < Hb < Hb < Hb <10.0 Hb <9.0 HD=haemodialysis; FMCNA=Fresenius Medical Care North America

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 Hb (g/dL) 9.0– – – – – – – – – – 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 <9 9.0–9.49.5– – – – – – – – – MICS, malnutrition inflammation complex syndrome

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 (%) Normal-haematocrit group Months after randomisation Low-haematocrit group

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 ) >10590–10575–<9060–<7545–<6030–<45<30 Diabetes 1 CV disease 1 Hypertension 1

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

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) –5930–4415–29<15 eGFR (mL/min/1.73 m 2 ) Mortality (N=51,424) Age-standardised rate of CV events (per 100 person years) –5930–4415–29<15 eGFR (mL/min/1.73 m 2 ) CV events (N=138,291) Hospitalisation (N=554,651) Age-standardised rate of hospitalisation (per 100 person years) –5930–4415–29<15 eGFR (mL/min/1.73 m 2 )

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