Diabetes, Anemia and Chronic Kidney Disease Josephine Carlos-Raboca,M.D., F.P.S.E.M., Endocrinology, Diabetes and Metabolism Makati Medical Center

OUTLINE Defining Chronic Kidney Disease(Diabetic Renal Disease) Pathophysiology of Anemia in CKD Effects of Anemia of CKD Benefits of Early Treatment of Anemia Clinical Trials with Epoietin beta Conclusion

What is Chronic Kidney Disease (CKD) ?

Definition of Chronic Kidney Disease (CKD) CKD in early stages is characterised by kidney damage and level of kidney function CKD in later stages is defined as an estimated glomerular filtration rate (eGFR) for at least 3 months of –eGFR <60 mL/min/1.73m 2 Stages of CKD are ranked by classifying severity of disease with declining eGFR and kidney damage CKD is a serious complication of diabetes mellitus NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31

Measures of Kidney Function eGFR is used to assess kidney function GFR can be measured using filtration markers such as inulin, iohexol or iothalamate but such methods are costly and cumbersome sCr is an alternative that is easily measured but affected by factors such as age, gender, race & body size Reviewed by Agarwal. Am J Kidney Dis 2005; 45:

Diagnosis of Kidney Function eGFR eGFR can be more accurately predicted from variables such as age, gender, race and body sizes with sCr –Commonly used prediction equations Cockcroft-Gault uses sCr, age, weight and sex MDRD (Modification of Diet in Renal Disease) in its simplest form uses sCr, age, sex and race eGFR is a better indicator of renal function than sCr alone eGFR easily determined from routine analyses Reviewed by Agarwal. Am J Kidney Dis 2005; 455:

Serum Creatinine Misleads CKD Diagnosis CKD is silent and under-diagnosed in earlier stages Late diagnosis is often due to the incorrect perception that serum creatinine (sCr) is a good measure of kidney function sCr hides early kidney disease

Serum Creatinine Hides Early Renal Damage sCr (µmol/L) eGFR (mL/min/1.73m 2 ) CKD stage Adapted from D Newman

Stages of CKD by Glomerular Filtration Rate (GFR) StageDescription GFR (mL/min/1.73m 2 ) 1 Kidney damage † with normal or  GFR ≥90 2 Mild  GFR 60 − 89 3 Moderate  GFR 30 − 59 4 Severe  GFR 15 − 29 5Kidney failure<15 or dialysis NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266 † Kidney damage is defined by the National Kidney Foundation as ‘pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies’

Stage GFR Diagnosis and treatment of comorbid conditions Estimate progression Evaluate and treat complications Preparation for dialysis e.g. access Dialysis if uraemia present Kidney transplant or dialysis Progression ≥ 90 60–9030–6015–30<15 CKD as a Continuum NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266

Symptoms of CKD

Epidemiology of Anaemia in CKD

Diabetic kidney disease and anaemia Anaemia is prevalent in people with diabetic kidney disease and is largely unrecognised and untreated Anaemia occurs earlier in diabetic kidney disease than is commonly recognised Anaemia worsens with declining kidney function. Astor et al. Arch Intern Med. 2002;162:

Anaemia develops early in CKD NHANES III –15,419 non-institutionalised adults over the age of 20 –Prevalence of anaemia (KDOQI) increased from 1% at glomerular filtration rate of 60 ml/min to 9% at 30 ml/min and 33% at 15 ml/min Astor et al, Arch Int Med 2002; 162: Hb (g/dL) Glomerular filtration rate (ml/min) Hb (men) Hb (women)

Aetiology of anaemia

Red Blood Cell (RBC) Production cells/sec cells/min cells/day RBC parameter Normal values in adults MenWomen Hb (g/dL)15.7± ±1.5 Haematocrit (%)46.0± ±4.0 RBC count (x10 12 /L)5.2±0.74.6±0.5 Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15

Defining Anemia GuidelineDefinition of Anemia European Best Practice Guidelines (EBPG) 2004 Anemia Guideline <12.0 g/d: in males and postmenopausal females; <11.0 g/dL in premenopausal females and prepubertal patients Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline <13.5 g/dL males <12.0 g/dL females

Potential causes of anaemia in chronic kidney disease Decreased erythropoietin production Shortened red blood cell survival Iron deficiency Inhibition of erythropoiesis Malnutrition and other deficiencies Chronic inflammation

Iron deficiency and anaemia in chronic kidney disease WomenMen  (g/dL) P P Fer ≥ 100 ng/mL & TSAT ≥ 20% reference Fer < 100 ng/mL & TSAT ≥ 20% Fer ≥ 100 ng/mL & TSAT< 20% Fer < 100 ng/mL & TSAT < 20% - 0.6< < Hsu et al, J Am Soc Nephrol 2002;13: Fer=ferritin TSAT=transferrin saturation

The Lifecycle of the RBC EXCRETION Macrophage in spleen, liver or red bone marrow Globin Amino acids Heme Biliverdin Bilirubin Fe Bilirubin Circulation120 days Fe 3+ Transferrin Ferritin and haemosiderin Liver Erythropoiesis in bone marrow

Anaemia in diabetic nephropathy Aetiology Decreased erythropoietin levels resulting from: Tubulointerstitial damage Autonomic dysfunction Use of ACE inhibitors? Reviewed in Bilous Acta Diabetol 2002; 39: S15-19

Erythropoietin in Anemia of Chronic Kidney Disease

The Role of Erythropoietin in Erythropoiesis Erythropoietin ensures the maturation of progenitor cells into RBCs Erythropoietin rescues neocytes from apoptosis Erythropoietin helps to sustain RBC proliferation and differentiation

Erythropoietin (EPO) Produced predominantly by peritubular fibroblasts in the kidneys and released in response to anaemia and hypoxia Release is modulated through the sympathetic nervous system (ß-adrenergic receptors) Anaemia associated with EPO deficiency usually occurs at a glomerular filtration rates below ml/min but may occur at higher levels in diabetic kidney disease

Regulation of Erythropoiesis Feedback loop Erythropoietin RBCs Erythroid marrow Circulating RBCs Kidney Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995; O2O2

Erslev & Besarab. Kidney Int. 1997;51: GM-CSF IL-3, IGF-1 SCF Erythropoietin Stage 1: CD-34Stage 2: Erythron Stem cell pool Progenitor cells BFU-E, CFU-E Mature cells Precursor cells erythroblasts The Role of Erythropoietin in Erythropoiesis

Erythropoietin Receptor 508 amino acids, 66–78 kDa glycoprotein Located on erythroid progenitor cell surface Approximately 1000 erythropoietin receptors per cell Expression –primarily on CFU-E –small numbers on BFU-E –no receptors present once cells become reticulocytes Membrane JAK2 P P P P P P EPO Target genes STAT

Hb O 2 transport capacity peripheral hypoxia kidney peritubular cells serum EPO precursor cells erythroblasts reticulocytes erythrocytesHb O 2 transport capacity Hb and Erythropoietin: the Non-Anaemic Patient EPO=erythropoietin

Diabetes and Anaemia Diabetes Hyperglycaemia ↓Serum EPO response RBC abnormalities ↓ RBC survival Anaemia Nephropathy (35%)CKD Neuropathy (50%) ↓Serum EPO level

Erythropoietin RBCs Erythroid marrow Circulating RBCs Kidney O2O2 CKD: Regulation of Erythropoiesis Disrupted feedback loop Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;

Adapted from Caro et al. J Lab Clin Med. 1979;93: Defining Renal Anaemia Erythropoietin levels in patients with non-renal and renal anaemia Bilateral nephrectomy Non-renal anaemia CKD Serum EPO (mU/mL) Haematocrit, %

Hb O 2 transport capacity peripheral hypoxia kidney peritubular cells serum EPO precursor cells erythroblasts reticulocytes erythrocytesHb O 2 transport capacity Hb and Erythropoietin: the Anaemic Patient with CKD DAMAGED INSUFFICIENT ANAEMIA

Erythropoietin and the Pathophysiology of Renal anaemia Renal disease in progressive renal failure is almost always accompanied by a normochromic, normocytic anaemia † Severity of anaemia correlates with severity of kidney disease Anaemia associated with kidney disease results from multiple factors –failure of the erythropoietin response as a result of kidney damage –significant reduction in circulating RBC lifespan secondary to uraemia –reduced bone marrow response to circulating erythropoietin † anaemia characterised by RBCs which are normal in morphology and Hb content, but are too few to sustain adequate oxygen transport

Anaemia in CKD: Summary The hormone erythropoietin is the physiological regulator of RBC production and lifespan In individuals with CKD, damage to the kidney compromises erythropoietin production Anaemia correlates with the severity of CKD Strong inter-relationships exist between CKD, anaemia, and CVD

1. El Nahas & Bello. Lancet. 2005;365: Astor et al. Arch Intern Med. 2002;162: Locatelli et al 2004; Nephrol Dial Transplant. 2004;19: Lefebvre et al. Curr Med Res Opin. 2006;22: Levin et al. Nephrol Dial Transplant. 2006;21: Regidor et al. J Am Soc Nephrol. 2006;17: Epidemiology of Anaemia in CKD Summary CKD prevalence is high and is expected to increase 1 Anaemia is highly prevalent and worsens with declining kidney function 2 Anaemia has a negative impact on QoL Anaemia increases the risk of CV mortality and morbidity 3 according to 1.number of episodes of Hb outside of target range 2.length of time Hb outside target range 5 3.magnitude of Hb levels out of range 6 Discussion continues on defining the upper and lower limits of target Hb range

Why should we be aware of anaemia in diabetic renal disease? The risk of coronary heart disease in people with diabetes is 2-4x higher than the general population and the risk of cerebrovascular disease up to 5x higher Anaemia develops early in chronic kidney disease The risks of cardiovascular disease develop early in the course of chronic kidney disease and are increased by diabetes Combination of anaemia and chronic kidney disease substantially increases stroke risks Anaemia predicts  left ventricular mass, left ventricular dilation, heart failure and death

1.Astor et al. Arch Intern Med. 2002;162: Thorp et al. Dis Manag. 2006;9: McClellan et al. Curr Med Res Opin. 2004;20: Locatelli et al. Nephrol Dial Transplant. 2004;19: Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii Perlman et al. Am J Kidney Dis. 2005; 45: Anaemia and CKD Anaemia is highly prevalent in patients with CKD, and Hb levels decrease with declining GFR 1 –anaemia becomes evident in stage 3 CKD 2 –up to 50% of patients with stage 3–5 CKD may have anaemia 3 Anaemia is associated with significant mortality and morbidity in patients with CKD 4 Anaemia in patients with CKD increases the burden of CVD 5 Quality of life (QoL) is negatively affected by anaemia in patients with CKD 6

Reciprocal Relationship : Renal Anemia, Diabetes & CVD

Why should we be aware of anaemia in diabetic renal disease? The risk of coronary heart disease in people with diabetes is 2-4x higher than the general population and the risk of cerebrovascular disease up to 5x higher The risks of cardiovascular disease develop early in the course of chronic kidney disease and are increased by diabetes Combination of anaemia and chronic kidney disease substantially increases stroke risks Anaemia predicts  left ventricular mass, left ventricular dilation, heart failure and death

Cardiovascular disease in early chronic kidney disease HDFP study 1 –subjects with serum creatinine >150 µmol/L vs. < 150 µmol/L OR for death after 8 years 2.2 Framingham study 2 –increased incidence of cardiovascular disease in those with renal insufficiency Canadian multicenter cohort 3 –incidence of cardiovascular disease already 35.2% in those with glomerular filtration rate >50 ml/min and rose to 45.3% in those with glomerular filtration rate <25 ml/min 1. Shulman et al Hypertension 1989; 13(5):I Culleton et al Kidney Int 1999; 56: Levin et al, Am J Kidney Dis 1999; 34: 125

Anaemia in CKD Manifestations Anaemia in CKD induces –increased cardiovascular (CV) workload leading to left ventricular hypertrophy (LVH) –reduced exercise capacity –fatigue Anaemia in CKD is linked with –increased CV morbidity and mortality

Framingham study, N = 6223 Culleton et al Kidney Int 1999; 56: % mild CRF (males serum creatinine , females µmol/L) Percentage (%) No renal insufficiency Chronic renal insufficiency ECG LVH=echocardiogram left ventricular hypertrophy CHD=coronary heart disease CHF=congestive heart failure CVD=cardiovascular disease

SOLVD study 1 –increase relative risk of mortality of 1.44 and relative risk of pump failure of 1.68 in subjects with glomerular filtration rate 60 ml/min HOPE study 2 –cardiovascular disease mortality, myocardial infarction or stroke 22.2% in subjects with serum creatinine µmol/L vs. 15.1% in those with serum creatinine < 124 µmol/L Cardiovascular Health Study 3 –OR 2.34 for cardiovascular disease in subjects with serum creatinine > 132 µmol/L in males and > 114 µmol/L in females Cardiovascular disease in early chronic kidney disease 1. Dries et al, J Am Coll Cardiol, 2000; 35 : Mann et al, Ann Int Med, 2001;134: Manjunath et al, Kidney Int, 2003; 63:

Relative risk p= p=ns p< p< CV = cardiovascular IHD = ischaemic heart disease CCF = chronic cardiac failure Foley et al Diabetologia 1997; 40: Prevalence of cardiovascular abnormalities is higher among diabetic patients with CKD Newfoundland/Montreal study

CKD and Anaemia Increase the Risk of CHF Stage 5 CKD patients on dialysis (n=433) At start of dialysis –31% had CHF –19% had angina –14% had coronary artery disease On dialysis, for each 1 g/dL fall in Hb –42% increased risk of LVH –18% increased risk of CHF –14% increased risk of death 1. Foley et al. Kidney Int. 1995;47: Foley et al. Am J Kidney Dis. 1996;28:53-61

The Cardio-Renal Anaemia Syndrome A vicious circle Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47 CKD Anaemia Hypoxia Sympathetic activity TNF-α Renal vasoconstriction Uraemia Fluid retention Serum EPO production Apoptosis Hypoxia Cardiac output CHF=congestive heart failure CHF

Why should we be aware of anaemia in diabetic renal disease? The risk of coronary heart disease in people with diabetes is 2-4x higher than the general population and the risk of cerebrovascular disease up to 5x higher Anaemia develops early in chronic kidney disease The risks of cardiovascular disease develop early in the course of chronic kidney disease and are increased by diabetes Combination of anaemia and chronic kidney disease substantially increases stroke risks Anaemia predicts  left ventricular mass, left ventricular dilation, heart failure and death

Anaemia, chronic kidney disease and risk of stroke – the ARIC study, n = 13,716 Community based cohort, 9 yr follow up –mean age 54.1 ± 5.7, mean Hb 13.9, 10.6% diabetic –15 percent Cr Cl < 60 ml/min, mean blood pressure 120/71 –85 percent Cr Cl ≥ 60 ml/min, mean blood pressure 121/74 –Use of anti-hypertensives 24.6% & 23.5% Lower Cr Cl associated with higher crude stroke rate –Cr Cl < 60 ml/min, stroke rate 3.7 –Cr Cl ≥ 60 ml/min, stroke rate 2.06 Abramson et al, Kidney Int 2003; 64:

ARIC study – influence of anaemia (WHO) Stroke rate Abramson et al, Kidney Int 2003; 64: Cr Cl ≥ 60 ml/min Cr Cl < 60 ml/min

Effect of 1g/dL fall in Hb CLVHLV DilSDFCCFIHDDeath Foley et al Am J Kidney Dis 1996; 28: Relative risk CLVH = concentric left ventricular hypertrophy LV Dil = left ventricular dilatation SDF = systolic dysfunction CCF = chronic cardiac failure IHD = ischaemic heart disease

Hospitalisation Risk Increases with Hb <11 g/dL Dialysis patients P=0.77P<0.0001P=0.001P=0.05 n=7998 Pisoni et al. Am J Kidney Dis. 2004;44: RR of hospitalisation Hb level (g/dL)

Why should we be aware of anaemia in diabetic renal disease? The risk of coronary heart disease in people with diabetes is 2-4x higher than the general population and the risk of cerebrovascular disease up to 5x higher Anaemia develops early in chronic kidney disease The risks of cardiovascular disease develop early in the course of chronic kidney disease and are increased by diabetes Combination of anaemia and chronic kidney disease substantially increases stroke risks Anaemia predicts  left ventricular mass, left ventricular dilation, heart failure and death

Conclusions Anaemia is prevalent in people with diabetic kidney disease and is largely unrecognised and untreated Anaemia occurs earlier in diabetic kidney disease than is commonly recognised The association between chronic kidney disease and all forms of cardiovascular disease begins early in the evolution of chronic kidney disease, anaemia significantly amplifies this association Cardiovascular events and mortality in chronic kidney disease are increased in patients with diabetic kidney disease and are closely related to anaemia

Cardiovascular risk factors in chronic kidney disease Traditional –older age –male gender –  BP & LVH –  LDL-C  HDL-C –diabetes –smoking –inactivity –menopause CKD related –RAS activity –ECFV overload –Ca/PO 4 abnormalities –anaemia –MIA syndrome –oxidative stress –  Homocysteine –thrombogenic factors –  GFR

Why do we treat renal anaemia? Subjective 1 –well-being –life satisfaction –happiness –psychological affect Objective 1 –energy level –functional ability –activity level –health status Others –  cardiac status 2 –  blood transfusions 3 –  hospitalisation 4 –  mortality 5 1. Evans et al J Am Med Soc. 1990; 263: Winearls Nephrol Dial Transplant 1995; 10(suppl10): Fellner et al Kidney Int; 1993; 44: Churchill et al Clin Nephrol 1995; 43: US Renal Data System 1998

What do we hope to achieve by the early treatment of renal anaemia? Increased exercise capacity, improved quality of life, cognitive function and sexual function Regression of left ventricular hypertrophy Reduced mortality and hospitalisation Reduced transfusion requirements ?Regression of chronic renal failure progression

What do we hope to achieve by the early treatment of renal anaemia? Increased exercise capacity, improved quality of life, cognitive function and sexual function Regression of left ventricular hypertrophy Reduced mortality and hospitalisation Reduced transfusion requirements ?Regression of chronic renal failure progression

Epoetin improves quality of life in predialysis patients 83 predialysis patients entered into a parallel-group, open-label clinical trial and randomised to –epoetin –no treatment Epoetin treatment significantly improved anaemia and –energy –physical function –home management –social activity –cognitive function Revicki et al Am J Kidney Dis 1995; 25:

What do we hope to achieve by the early treatment of renal anaemia? Increased exercise capacity, improved quality of life, cognitive function and sexual function Regression of left ventricular hypertrophy Reduced mortality and hospitalisation Reduced transfusion requirements ?Regression of chronic renal failure progression

Correction of anaemia improves left ventricular hypertrophy in dialysis patients 22 dialysis patients studied by echocardiogram before and after correction of their anaemia with epoetin Hb increased at least 3.0 g/dL over baseline Correction of anaemia produced: –decrease in left ventricular mass (p = ) –decrease in left ventricular end-diastolic volume (p <0.0001) Adapted from Silverberg et al. Can J Cardiol 1990; 6: 1-4

What do we hope to achieve by the early treatment of renal anaemia? Increased exercise capacity, improved quality of life, cognitive function and sexual function Regression of left ventricular hypertrophy Reduced mortality and hospitalisation Reduced transfusion requirements ?Regression of chronic renal failure progression

Building the evidence: Mortality & hospitalisation Lombardy registry 1 –all cause mortality and hospitalisation risks reduced with Hct levels >32% compared with <27% (n=5302) Ma et al 2 –RR mortality reduces as Hct rises, 1.51 at Hct < 27% to 0.9 at Hct 33-36% (n=96,369) Xia et al 3 –hospitalisation risks lowest in patients with Hct 33-36% (n=71,717) 1. Lombardy registry Nephrol Dial Transplant 1998;13: Ma et al J Am Soc Nephrol 1999;10: Xia et al J Am Soc Nephrol 1999;10:

Building the evidence: Mortality & hospitalisation Collins et al 1 –Relative risk of death and/or hospitalisation lowest at Hct levels of 36-39% Fink et al 2 –Pre-dialysis epoetin treatment leads to a relative risk of mortality of 0.8 (n=4866, 1107 epoetin) 1. Collins et al J Am Soc Nephrol November Fink et al Am J Kidney Dis 2001;37:

Epoetin therapy correlates with reduced mortality and less hospitalisation Adapted from Locatelli et al Nephrol Dial Transplant 1998 Hct < 27% Patients with diabetes = 7.6% Hospitalisation days per patient-year Adjusted general mortality (n=5302) Odds ratio Adjusted CV mortality (n=5302) rh EPO-treated haemodialysis patients Untreated haemodialysis patients p <0.001 p <0.05 Hct 27–32% Hct >32%

Reduced mortality with anaemia treatment pre-dialysis 4,866 patients, median follow up 26.2 months 1,107 treated with epoetin pre-dialysis Relative risk of death for epoetin-treated pre-dialysis = 0.8 Most significant survival benefit was in those with the highest haematocrit Concluded that epoetin use pre-dialysis confers survival benefit Fink et al, Am J Kid Dis 2001;37:

Mortality and haematocrit level: First year follow up, all dialysis patients USRDS prevalent patients Haematocrit < < <3636+ Deaths per 1000 patient years Diabetes mellitus No diabetes mellitus

Duration of Hb <11 g/dL Increases Mortality Risk Dialysis patients Time with Hb <11 g/dL over 2 years (%) Ofsthun et al. Nephrol Dial Transplant. 2005;20(Suppl 5):v261 (abstract MP204) Relative mortality risk * * ** n= *P<0.05; **P<0.001

Levin et al. Nephrol Dial Transplant. 2006;21: Months from Hb result Probability of survival Hb ≥13.0 g/dL 12 − 12.9 g/dL 11 − 11.9 g/dL 10 − 10.9 g/dL <10 g/dL Log-rank test: P= Hb Levels Predict Survival Prior to Dialysis Initiation CKD patients not on dialysis

Mean units per patient per 4 weeks Pre Weeks Eschbach et al. Ann Intern Med. 1989:111: * *autologous blood donation ahead of elective hip surgery Commencement of anaemia therapy Anaemia Treatment Greatly Reduces Blood Transfusions Dialysis patients

What do we hope to achieve by the early treatment of renal anaemia? Increased exercise capacity, improved quality of life, cognitive function and sexual function Regression of left ventricular hypertrophy Reduced mortality and hospitalisation Reduced transfusion requirements ?Regression of chronic renal failure progression

Reversal of anaemia by epoetin can retard progression of chronic renal failure Adapted from Kuriyama et al Nephron 1997; 77: Cumulative renal survival rate (%) p= p= p= Months of follow-up Hct <30%, treated with epoetin Hct >30%, untreated Hct <30%, untreated n=108

Building the evidence: delaying progression of chronic renal failure 63 patients (serum creatinine > 300 μmol/L, creatinine clearance < 15 mL/min/1.73 m 2 ) 20 with Hb 10 g/dL= control group Significant reduction in rate of progression of chronic renal failure in study group, no change in control group Jungers et al Nephron Dial Transplant 2001; 16:

Trials in treatment of CKD anaemia CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta) CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency) ACORD (Anaemia CORrection in Diabetes) Aims of the studies : to establish whether early intervention –prevents development of left ventricular hypertrophy –reduces cardiovascular mortality and morbidity –delays progression of chronic renal failure –reduces stroke and heart failure related hospitalisations

The CHOIR and CREATE Studies: Overview CKD patients not on dialysis CHOIR (n=1432) CREATE (n=605) Patient PopulationStage 3–4 patients with renal anaemia and not on renal replacement therapy (RRT) ‡ Stage 3–4 CKD patients with renal anaemia not on RRT § Duration16 months 700 patients completed trial 48 months 476 patients completed trial Primary EndpointsComposite (death, MI, HF, stroke) Composite (sudden death, MI, acute HF, CVA, TIA, hosp for angina or arrhythmia, PVD complications) Hb Targets Group 1: 13.5 g/dL † Group 2: 11.3 g/dL † Group 1: 13–15 g/dL Group 2: 10.5–11.5 g/dL † Original targets before protocol amendment: Group 1: 13.0–13.5 g/dL Group 2: 10.5–11.0 g/dL Singh et al. N Engl J Med. 2006;355: Drüeke et al. N Engl J Med. 2006;355: ‡ 127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study § 127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study

Time or creatinine CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta) Hb (g/dl) Group 1 (Hb g/dl) Group 2 (Hb g/dl) 600 subjects glomerular filtration rate ml/min randomised to 2 groups, early intervention and standard practise

Time or creatinine CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency) Hb (g/dl) Group 1 (Hb g/dl) Group 2 (Hb g/dl) 2000 subjects GFR ml/min randomised to 2 groups

CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dL Stage 3–4 CKD patients Probability of composite event Month Hb target 13.5 g/dL Hb target 11.3 g/dL Patients at risk Group Group Time to the primary composite endpoint Events: 125 vs 97 HR=1.34 (1.03–1.74) Log rank test P=0.03 Singh et al. N Engl J Med. 2006;355:

CREATE: No Significant Difference in Time to First CV Event CKD patients not on dialysis Time to the primary endpoint of a first cardiovascular event † † Before censoring of data on patients at the time of initiation of dialysis Event-free Survival (%) Month Patients at risk Group Group Events: 58 vs 47 HR=0.78 (0.53–1.14) Log rank test P=0.20 Hb target 13–15 g/dL Hb target 10.5–11.5 g/dL Drüeke et al. N Engl J Med. 2006;355:

The Anaemia CORrection in Diabetes (ACORD) study The ACORD study is investigating the effects of anaemia correction with subcutaneous epoetin beta on –cardiac structure –cardiac function In patients with early diabetic nephropathy Primary endpoint –effect of early anaemia treatment on left ventricular hypertrophy as a cardiovascular risk marker

Hb (g/dl) Early intervention Target Hb: 13–15 g/dl Standard treatment Target Hb: 10.5–11.5 g/dl Inclusion: Hb 10.5–13.0 g/dl Creatinine clearance ≥30 ml/min m f Time n = 160 Randomisation ACORD: Study design

European recommendations for optimising treatment of renal anaemia Indication for start of epoetin therapy: –repeated Hb measurements <11g/dL –after exclusion of non-renal causes of anaemia (bleeding, nutritional deficiencies, hypothyroidism, iron deficiency, haemolysis) Target haemoglobin: –general: Hb >11 g/dL (no upper limit) –in CHD: Hb g/dL Administration of epoetin: –SC dosing preferred; IV dosing also an option in HD patients –the goal is to increase Hb levels by 1–2 g/dL per month van Ypersele de Strihou Nephrol Dial Transplant 1999; 14 (suppl 2): 37-45

Iron stores Target –serum ferritin > 100  g/l (aim for ) –hypochromic red blood cell count 20% (aim for < 2.5% & 30-40%) Level B Treatment strategies –predialysis and CAPD oral  intravenous –HD will need intravenous Level B

How should epoetin be administered to predialysis patients with diabetes and anaemia? EBPG & KDOQI recommend epoetin treatment for anaemia due to CKD when Hb < 11 g/dL Hb correction should be gradual to avoid: –exacerbation of hypertension –increased viscosity with adverse haemodynamics Guidelines recommend an increase of Hb 0.5 g/dL every 2 weeks Common practice suggest a target Hb of 11–12 g/dL (or ?12-13 g/dL)

Conclusions Anaemia is prevalent in diabetic kidney disease and occurs earlier than is commonly recognised Proven benefits of treatment of anaemia with epoetin (± intravenous iron) include –improved quality of life and performance status –regression of left ventricular hypertrophy –reduced transfusion requirements Potential benefits of early anaemia treatment include –reduced cardiovascular mortality and morbidity –delayed progression of chronic renal failure –reduced stroke and heart failure related hospitalisations