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Diabetes, Anemia and Chronic Kidney Disease Josephine Carlos-Raboca,M.D., F.P.S.E.M., Endocrinology, Diabetes and Metab

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

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Diabetes, Anemia and Chronic Kidney Disease Josephine Carlos-Raboca,M.D., F.P.S.E.M., Endocrinology, Diabetes and Metab

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  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 ofChronic 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/1.73m2 • 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 FunctioneGFR • 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 GFR in mg/dL GFR in umol/l Where Constant is 1.23 for men and 1.04 for women

  7. Stages of CKD by Glomerular Filtration Rate (GFR) †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’ NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266

  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 20 Hb (men)Hb (women) 15 Hb (g/dL) 10 5 60 30 15 Glomerular filtration rate (ml/min) Astor et al, Arch Int Med 2002; 162: 1401-1408

  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 Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15

  13. Defining Anemia

  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. 120 days Circulation Amino acids Erythropoiesis in bone marrow Globin Fe3+ Transferrin Fe Heme Ferritin and haemosiderin Biliverdin Bilirubin Bilirubin Liver Macrophage in spleen, liver or red bone marrow EXCRETION The Lifecycle of the RBC

  16. 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

  17. Regulation of ErythropoiesisFeedback loop Erythroid marrow CirculatingRBCs RBCs Kidney O2 Erythropoietin Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

  18. Stage 1: CD-34 Stage 2: Erythron Mature cells Stem cell pool Progenitor cells BFU-E, CFU-E Precursor cells erythroblasts The Role of Erythropoietin in Erythropoiesis GM-CSF IL-3, IGF-1 SCF Erythropoietin Erslev & Besarab. Kidney Int. 1997;51:622-630

  19. EPO Membrane P P JAK2 JAK2 STAT P P STAT P P Target genes 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

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

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

  22. 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

  23. 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

  24. Reciprocal Relationship :Renal Anemia, Diabetes & CVD

  25. Cardiovascular disease in early chronic kidney disease • HDFP study1 • subjects with serum creatinine >150 µmol/L vs. < 150 µmol/L OR for death after 8 years 2.2 • Framingham study2 • increased incidence of cardiovascular disease in those with renal insufficiency • Canadian multicenter cohort3 • 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 Dis1999; 34: 125

  26. Anaemia in CKD • Anaemia in CKD induces • increased cardiovascular (CV) workload leading toleft ventricular hypertrophy (LVH) • reduced exercise capacity • fatigue • Anaemia in CKD is linked with • increased CV morbidity and mortality

  27. Framingham study, N = 6223 • 8% mild CRF (males serum creatinine 136-265, females 120-265 µmol/L) Percentage (%) No renal insufficiencyChronic renal insufficiency ECG LVH=echocardiogram left ventricular hypertrophy CHD=coronary heart disease CHF=congestive heart failure CVD=cardiovascular disease Culleton et al Kidney Int 1999; 56: 2214-2219

  28. CKD and Anaemia Increase the Risk of CHFStage 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

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

  30. 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

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

  32. Hospitalisation Risk Increases with Hb <11 g/dLDialysis patients RR of hospitalisation n=7998 P<0.0001 P=0.001 P=0.05 P=0.77 Hb level (g/dL) Pisoni et al. Am J Kidney Dis. 2004;44:94-111

  33. 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

  34. Subjective1 well-being life satisfaction happiness psychological affect Objective1 energy level functional ability activity level health status Others cardiac status2  blood transfusions3  hospitalisation4  mortality5 Why do we treat renal anaemia? 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

  35. 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

  36. 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

  37. Building the evidence: Mortality & hospitalisation • Collins et al1 • Relative risk of death and/or hospitalisation lowest at Hct levels of 36-39% • Fink et al2 • 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 20012. Fink et al Am J Kidney Dis 2001;37:348-355

  38. Mortality and haematocrit level: First year follow up, all dialysis patients Diabetes mellitus 400 No diabetes mellitus 350 300 250 Deaths per 1000 patient 200 years 150 100 50 0 <30 30 - <33 33 - <36 36+ Haematocrit USRDS prevalent patients 1994-1997

  39. Duration of Hb <11 g/dL Increases Mortality RiskDialysis patients Relative mortality risk ** n=41 919 ** ** * * Time with Hb <11 g/dL over 2 years (%) *P<0.05; **P<0.001 Ofsthun et al. Nephrol Dial Transplant. 2005;20(Suppl 5):v261 (abstract MP204)

  40. Probability of survival 1.00 0.95 Hb ≥13.0 g/dL 0.90 12−12.9 g/dL 0.85 0.80 11−11.9 g/dL 0.75 <10 g/dL 10−10.9 g/dL Log-rank test: P=0.0001 0.70 0 3 6 9 12 15 18 21 24 27 31 33 37 Months from Hb result Hb Levels Predict Survival Prior to Dialysis InitiationCKD patients not on dialysis Levin et al. Nephrol Dial Transplant. 2006;21:370-377

  41. Anaemia Treatment Greatly Reduces Blood TransfusionsDialysis patients Mean units per patient per 4 weeks 0.6 0.5 0.4 0.3 0.2 0.1 0 Commencement ofanaemia therapy * Pre 4 12 20 28 36 44 52 Weeks *autologous blood donation ahead of elective hip surgery Eschbach et al. Ann Intern Med. 1989:111:992-1000

  42. Building the evidence: delaying progression of chronic renal failure • 63 patients (serum creatinine > 300 μmol/L, creatinine clearance < 15 mL/min/1.73 m2) • 20 with Hb < 10 g/dL = study group (epoetin+) 43 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

  43. 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

  44. The CHOIR and CREATE Studies: OverviewCKD patients not on dialysis • †Original targets before protocol amendment: • Group 1: 13.0–13.5 g/dL • Group 2: 10.5–11.0 g/dL §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 Singh et al. N Engl J Med. 2006;355:2085-2098 Drüeke et al. N Engl J Med. 2006;355:2071-2084

  45. CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dLStage 3–4 CKD patients Time to the primary composite endpoint 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Hb target 13.5 g/dL Hb target 11.3 g/dL Probability of composite event Events: 125 vs 97 HR=1.34 (1.03–1.74) Log rank test P=0.03 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Month Patients at risk Group 1 715 654 587 520 457 355 270 176 101 72 55 23Group 2 717 660 594 539 499 397 293 182 107 67 44 23 Singh et al. N Engl J Med. 2006;355:2085-2098

  46. CREATE: No Significant Difference in Time to First CV EventCKD patients not on dialysis Time to the primary endpoint of a first cardiovascular event† 100 90 80 70 60 Hb target 13–15 g/dL Hb target 10.5–11.5 g/dL Event-free Survival (%) 50 40 Events: 58 vs 47 HR=0.78 (0.53–1.14) Log rank test P=0.20 30 20 10 0 0 6 12 18 24 30 42 48 36 Month Patients at risk Group 1 301 279 268 249 207 158 97 56 2 Group 2 302 286 272 257 223 177 121 61 2 †Before censoring of data on patients at the time of initiation of dialysis Drüeke et al. N Engl J Med. 2006;355:2071-2084

  47. The Anaemia CORrection inDiabetes (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

  48. Standard treatment Target Hb: 10.5–11.5 g/dl ACORD: Study design Hb (g/dl) 16 14 12 10 8 6 16 14 12 10 8 6 m Early intervention • Randomisation f Target Hb: 13–15 g/dl Inclusion: Hb 10.5–13.0 g/dlCreatinine clearance ≥30 ml/min n=160 Time

  49. Maintaining the Right Hb RangeSummary • 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

  50. 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

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