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

2. 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

3. What is Chronic Kidney Disease (CKD) ?

4. 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

5. 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; 455:610-613

6. Glomerular Filtration Rate Where Constant is 1.23 for men and 1.04 for women GFR in mg/dL GFR in umol/l

7. 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’

8. Symptoms of CKD

9. 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;162:1401-1408

10. 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: 1401-1408 Hb (g/dL) Glomerular filtration rate (ml/min) 5 10 15 20 603015 Hb (men) Hb (women)

11. Aetiology of anaemia

12. Red Blood Cell (RBC) Production 2 000 000 cells/sec 120 000 000 cells/min 173 000 000 000 cells/day RBC parameter Normal values in adults MenWomen Hb (g/dL)15.7±1.713.8±1.5 Haematocrit (%)46.0±4.040.0±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

13. 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

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

15. 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

16. 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

17. 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 35-40 ml/min but may occur at higher levels in diabetic kidney disease

18. Regulation of Erythropoiesis Feedback loop Erythropoietin RBCs Erythroid marrow Circulating RBCs Kidney Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441 O2O2

19. Erslev & Besarab. Kidney Int. 1997;51:622-630 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

20. 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

21. 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

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

23. 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

24. 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

25. Effects 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

26. 1.Astor et al. Arch Intern Med. 2002;162:1401-1408 2. Thorp et al. Dis Manag. 2006;9:115-121 3. McClellan et al. Curr Med Res Opin. 2004;20:1501-1510 3. Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132 4. Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-12 5. Perlman et al. Am J Kidney Dis. 2005; 45:658-666 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

27. Reciprocal Relationship : Renal Anemia, Diabetes & CVD

28. 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):I80-93 2. Culleton et al Kidney Int 1999; 56: 2214-2219 3. Levin et al, Am J Kidney Dis 1999; 34: 125

29. Anaemia in CKD 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

30. Framingham study, N = 6223 Culleton et al Kidney Int 1999; 56: 2214-2219 8% mild CRF (males serum creatinine 136-265, females 120-265 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

31. 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;47:186-192 2. Foley et al. Am J Kidney Dis. 1996;28:53-61

32. 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

33. 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: 610-615

34. ARIC study – influence of anaemia (WHO) Stroke rate Abramson et al, Kidney Int 2003; 64: 610-615 Cr Cl ≥ 60 ml/min Cr Cl < 60 ml/min 2.06 3.7 1.52 10.53 2.12 2.85

35. 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;44:94-111 RR of hospitalisation Hb level (g/dL)

36. Summary : CKD and CVD 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

37. 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

38. 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; 263:825-830 2. Winearls Nephrol Dial Transplant 1995; 10(suppl10):3-9 3. Fellner et al Kidney Int; 1993; 44:1309-1315 4 Churchill et al Clin Nephrol 1995; 43:184-188 5. US Renal Data System 1998

39. 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

40. 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: 548-554

41. 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 = 0.0004) –decrease in left ventricular end-diastolic volume (p <0.0001) Adapted from Silverberg et al. Can J Cardiol 1990; 6: 1-4

42. 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 2001 2. Fink et al Am J Kidney Dis 2001;37:348-355

43. 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;37:348-355

44. Mortality and haematocrit level: First year follow up, all dialysis patients USRDS prevalent patients 1994-1997 Haematocrit 0 50 100 150 200 250 300 350 400 <3030 - <3333 - <3636+ Deaths per 1000 patient years Diabetes mellitus No diabetes mellitus

45. 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=41 919 *P<0.05; **P<0.001

46. Levin et al. Nephrol Dial Transplant. 2006;21:370-377 0369121518212427313337 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=0.0001 0.75 0.80 0.85 0.90 0.95 1.00 0.70 Hb Levels Predict Survival Prior to Dialysis Initiation CKD patients not on dialysis

47. Mean units per patient per 4 weeks 0.6 0.5 0.4 0.3 0.2 0.1 0 Pre4122028364452 Weeks Eschbach et al. Ann Intern Med. 1989:111:992-1000 * *autologous blood donation ahead of elective hip surgery Commencement of anaemia therapy Anaemia Treatment Greatly Reduces Blood Transfusions Dialysis patients

48. 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: 307-312

49. 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

50. 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;355:2085-2098 Drüeke et al. N Engl J Med. 2006;355:2071-2084 ‡ 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

51. Time or creatinine CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta) Hb (g/dl) 15 12.5 10 Group 1 (Hb 13-15 g/dl) Group 2 (Hb 10.5-11.5 g/dl) 600 subjects glomerular filtration rate 15-35 ml/min randomised to 2 groups, early intervention and standard practise

52. Time or creatinine CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency) Hb (g/dl) 15 12.5 10 Group 1 (Hb 13-13.5 g/dl) Group 2 (Hb 10.5-11.0 g/dl) 2000 subjects GFR 15-50 ml/min randomised to 2 groups

53. CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dL Stage 3–4 CKD patients 036912151821242730333639 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Probability of composite event Month Hb target 13.5 g/dL Hb target 11.3 g/dL Patients at risk Group 1715654587520457355270176101725523 Group 2717660594539499397293182107674423 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;355:2085-2098

54. 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 100 90 80 70 60 50 40 30 20 10 0 Event-free Survival (%) 0612182430 36 4248 Month Patients at risk Group 1 301 279 26824920715897562 Group 2 302286272257223177121612 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;355:2071-2084

55. 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

56. Hb (g/dl) 16 14 12 10 8 6 16 14 12 10 8 6 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

57. Maintaining the Right Hb Range Summary Efficacy of SC epoetin beta confirmed by Hb response according to different Hb targets both in CREATE and ACORD Complete Hb correction improves QoL and was not associated with any consistent hazard Trend towards decrease in LVMI with complete anaemia correction among those with higher baseline LVMI –In CREATE and ACORD annual CV event rate lower than expected from previous studies Prospective international randomised trials (CREATE, ACORD) show no added benefit of complete Hb correction to 13-15 g/dL on CV outcome measures and CKD progression –But it may still be beneficial as CV event rates were low

58. 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 11-12 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

59. Iron stores Target –serum ferritin > 100  g/l (aim for 200-500) –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

60. 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)

61. RECORMON DOSING GUIDE for CKD Patients with Renal Anemia: Correction Phase Subcutaneous AdministrationIntravenous Administration 60 IU/kg Body weight per week120 IU/kg Body Weight per Week Dosage maybe increase every 4 weeks by 60IU/kg BW/wk if the increase in PCV is <0.5 volume % per week or <0.5 g/dL Hb every 2 weeks. Dosage maybe increase every 4 weeks by 120IU/kg BW/wk if the increase in PCV is <0.5 volume % per week or <0.5g/dL Hb every 2 weeks. Maintenance Phase: Dose can be reduced to 50% or adjusted at intervals of one or two weeks individually for the patients to maintain target Hb and Hct.

62. contraindications Uncontrolled HPN, MI or stroke a month before Unstable angina Pregnancy and lactation Risk of deep vein thrombosis Adverse reactions Increased BP, platelet count and anaphylactoid reaction Special precaution Monitor K and phosphate regularly

63. The clear differences Epeotin Beta RecormonEpoetin alpha Half lifeSC 12-28 hours IV 4-12 hours SC 12-18 hours IV 4-6 hours StabilizersGlycine Poylsorbate 20 Urea Calcium Chloride Complex of 5 amino acids Glycine Polysorbate 80 Storage and handling2-8 degrees centigrade can be removed from refrigeration and store at 25 degrees centigrade for a single period of up to 3 days Can tolerate shaking 2-8 degrees at all times Can not tolerate shaking TolerabilityAlmost pain free at the injection siteWith pain at the injection site Dose Recommendation (Correction) 60 IU/kg Body weight/wk100 IU/kg Body Weight /wk Shelf Life (PFS)24 months18 months

64. Iron treatment For iron deficiency: Tsat <20% Ferritin < 100 mg/L Stop if TSAT>50% or Ferritin>800mg/L

65. 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

66. Thank you