Diabetes, Anemia and Chronic Kidney Disease

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 lt60 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
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
45610-613
6
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
455610-613
7
Serum CreatinineMisleads 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

8
Serum CreatinineHides Early Renal Damage
600
400
sCr (µmol/L)
200
2
3
4
5
CKD stage
0
eGFR (mL/min/1.73m2)
Adapted from D Newman
9
Stages of CKD by Glomerular Filtration Rate (GFR)
Stage Description GFR (mL/min/1.73m2)
1 Kidney damage with normal or ? GFR 90
2 Mild ? GFR 60-89
3 Moderate ? GFR 30-59
4 Severe ? GFR 15-29
5 Kidney failure lt15 or dialysis
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. 200239(Suppl
1)S1-S266
10
CKD as a Continuum
Diagnosis and treatment of comorbid conditions
Estimate progression
Evaluate and treat complications
Preparation for dialysis e.g. access
Dialysis if uraemia present
1
2
5
4
3
Stage
GFR
90
6090
3060
1530
lt15
Progression
Kidney transplant or dialysis
NKF-K/DOQI. Am J Kidney Dis. 200239(Suppl
1)S1-S266
11
Symptoms of CKD

12

• Epidemiology of Anaemia in CKD

13
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.
  20021621401-1408

14
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
15
Aetiology of anaemia
16
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 Normal values in adults
RBC parameter Men Women
Hb (g/dL) 15.71.7 13.81.5
Haematocrit () 46.04.0 40.04.0
RBC count (x1012/L) 5.20.7 4.60.5
Adapted from Williams et al. In Williams
Hematology. 5th ed. 19958-15
17
Defining Anemia
Guideline Definition of Anemia
European Best Practice Guidelines (EBPG) 2004 Anemia Guideline lt12.0 g/d in males and postmenopausal females lt11.0 g/dL in premenopausal females and prepubertal patients
Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline lt13.5 g/dL males lt12.0 g/dL females
18
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

19
Iron deficiency and anaemia in chronic kidney
disease
Women Women Men Men
? (g/dL) P ? (g/dL) P
Fer 100 ng/mL TSAT 20 reference reference
Fer lt 100 ng/mL TSAT 20 - 0.2 0.002 - 0.1 0.30
Fer 100 ng/mL TSATlt 20 - 0.3 0.001 - 0.4 0.004
Fer lt 100 ng/mL TSAT lt 20 - 0.6 lt0.0001 - 0.8 lt0.0001
Ferferritin TSATtransferrin saturation
Hsu et al, J Am Soc Nephrol 2002132783-86
20
The Lifecycle of the RBC
21
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
22

• Erythropoietin in Anemia of Chronic Kidney Disease

23
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

24
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

25
Regulation of ErythropoiesisFeedback loop
Erythroid marrow
CirculatingRBCs
RBCs
Kidney
Erythropoietin
O2
Adapted from Erslev Beutler. In Williams
Hematology. 5th ed. 1995425-441
26
The Role of Erythropoietin in Erythropoiesis
GM-CSF IL-3, IGF-1 SCF
Erythropoietin
Erslev Besarab. Kidney Int. 199751622-630
27
Erythropoietin Receptor

• 508 amino acids, 6678 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

28
Hb and Erythropoietin the Non-Anaemic Patient
O
kidney
2
peripheral
Hb
peritubular
transport
hypoxia
cells
capacity
serum EPO
precursor cells
O
2
transport
capacity
erythroblasts
reticulocytes
erythrocytes
Hb
EPOerythropoietin
29
Diabetes and Anaemia
Nephropathy (35)
CKD
?Serum EPO level
Neuropathy (50)

• Diabetes

Anaemia
?Serum EPO response
Hyperglycaemia
RBC abnormalities
? RBC survival
30
CKD Regulation of ErythropoiesisDisrupted
feedback loop
Erythroid marrow
CirculatingRBCs
RBCs
Kidney
Erythropoietin
O2
Adapted from Erslev Beutler. In Williams
Hematology. 5th ed. 1995425-441
31
Defining Renal Anaemia Erythropoietin levels in
patients with non-renal and renal anaemia
Adapted from Caro et al. J Lab Clin Med.
197993449-458
32
Hb and Erythropoietin the Anaemic Patient with
CKD
O
kidney
2
peripheral
Hb
peritubular
transport
hypoxia
cells
capacity
DAMAGED
serum EPO
precursor cells
O
2
transport
capacity
erythroblasts
ANAEMIA
reticulocytes
erythrocytes
Hb
INSUFFICIENT
33
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
34
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

35
Epidemiology of Anaemia in CKDSummary

• CKD prevalence is high and is expected to
  increase1
• Anaemia is highly prevalent and worsens with
  declining kidney function2
• Anaemia has a negative impact on QoL
• Anaemia increases the risk of CV mortality and
  morbidity3 according to
• number of episodes of Hb outside of target range
• length of time Hb outside target range5
• magnitude of Hb levels out of range6
• Discussion continues on defining the upper and
  lower limits of target Hb range

1. El Nahas Bello. Lancet. 2005365331-340. 2.
Astor et al. Arch Intern Med. 20021621401-1408.
3. Locatelli et al 2004 Nephrol Dial Transplant.
200419121-132. 4. Lefebvre et al. Curr Med Res
Opin. 2006221929-1937. 5. Levin et al. Nephrol
Dial Transplant. 200621370-377 6. Regidor et
al. J Am Soc Nephrol. 2006171181-1191.
36
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

37
Anaemia and CKD

• Anaemia is highly prevalent in patients with CKD,
  and Hb levels decrease with declining GFR1
• anaemia becomes evident in stage 3 CKD2
• up to 50 of patients with stage 35 CKD may have
  anaemia3
• Anaemia is associated with significant mortality
  and morbidity in patients with CKD4
• Anaemia in patients with CKD increases the burden
  of CVD5
• Quality of life (QoL) is negatively affected by
  anaemia in patients with CKD6

• Astor et al. Arch Intern Med. 20021621401-1408
• 2. Thorp et al. Dis Manag. 20069115-121
• 3. McClellan et al. Curr Med Res Opin.
  2004201501-1510
• 3. Locatelli et al. Nephrol Dial Transplant.
  200419121-132
• 4. Silverberg. Nephrol Dial Transplant.
  200318(Suppl 2)ii7-12
• 5. Perlman et al. Am J Kidney Dis. 2005
  45658-666

38
Reciprocal Relationship Renal Anemia, Diabetes
CVD
39
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

40
Cardiovascular disease in early chronic kidney
disease

• HDFP study1
• subjects with serum creatinine gt150 µmol/L vs. lt
  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 gt50
  ml/min and rose to 45.3 in those with glomerular
  filtration rate lt25 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
41
Anaemia in CKDManifestations

• 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

42
Framingham study, N 6223
8 mild CRF (males serum creatinine 136-265,
females 120-265 µmol/L)
Percentage ()
No renal insufficiencyChronic renal insufficiency
ECG LVHechocardiogram left ventricular
hypertrophy CHDcoronary heart disease CHFcongest
ive heart failure CVDcardiovascular disease
Culleton et al Kidney Int 1999 56 2214-2219
43
Cardiovascular disease in early chronic kidney
disease

• SOLVD study1
• increase relative risk of mortality of 1.44 and
  relative risk of pump failure of 1.68 in subjects
  with glomerular filtration rate lt60 ml/min
  compared with gt 60 ml/min
• HOPE study2
• cardiovascular disease mortality, myocardial
  infarction or stroke 22.2 in subjects with serum
  creatinine 124-200 µmol/L vs. 15.1 in those with
  serum creatinine lt 124 µmol/L
• Cardiovascular Health Study3
• OR 2.34 for cardiovascular disease in subjects
  with serum creatinine gt 132 µmol/L in males and gt
  114 µmol/L in females

1. Dries et al, J Am Coll Cardiol, 2000 35
681-689 2. Mann et al, Ann Int Med,
2001134629-36 3. Manjunath et al, Kidney Int,
2003 63 1121-1129
44
Prevalence of cardiovascular abnormalities is
higher among diabetic patients with
CKDNewfoundland/Montreal study
p0.0003 pns plt0.0001
plt0.0001
Relative risk
CV cardiovascularIHD ischaemic heart disease
CCF chronic cardiac failure
Foley et al Diabetologia 1997 40 1307-1312
45
CKD and Anaemia Increase the Risk of CHFStage 5
CKD patients on dialysis (n433)

• 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. 199547186-192 2.
Foley et al. Am J Kidney Dis. 19962853-61
46
The Cardio-Renal Anaemia SyndromeA vicious circle
Hypoxia
CKD
Anaemia
Serum EPO production Apoptosis
Cardiacoutput
Fluid retention
Sympathetic activity TNF-a
Renal vasoconstriction Uraemia
Hypoxia
CHF
Adapted from Silverberg et al. Kidney Int Suppl.
2003(87)S40-S47
CHFcongestive heart failure
47
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

48
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 lt 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 lt 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
49
ARIC study influence of anaemia (WHO)
10.53
Cr Cl 60 ml/min Cr Cl lt 60 ml/min
Stroke rate
3.7
2.85
2.12
2.06
1.52
Abramson et al, Kidney Int 2003 64 610-615
50
Effect of 1g/dL fall in Hb
1.55
1.6
1.49
1.4
1.24
1.25
1.2
1
1
1.0
Relative risk
0.8
0.6
0.4
0.2
0
CLVH
LV Dil
SDF
CCF
IHD
Death
CLVH concentric left ventricular hypertrophyLV
Dil left ventricular dilatation SDF systolic
dysfunctionCCF chronic cardiac failureIHD
ischaemic heart disease
Foley et al Am J Kidney Dis 1996 28 53-61 .
51
Hospitalisation Risk Increases with Hb lt11
g/dLDialysis patients
RR of hospitalisation
n7998
P0.77
Plt0.0001
P0.001
P0.05
Hb level (g/dL)
Pisoni et al. Am J Kidney Dis. 20044494-111
52
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

53
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

54
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/PO4 abnormalities
• anaemia
• MIA syndrome
• oxidative stress
• ? Homocysteine
• thrombogenic factors
• ? GFR

55
Why do we treat renal anaemia?

• Others
• ?cardiac status2
• ? blood transfusions3
• ? hospitalisation4
• ? mortality5

• Subjective1
• well-being
• life satisfaction
• happiness
• psychological affect
• Objective1
• energy level
• functional ability
• activity level
• health status

1. Evans et al J Am Med Soc. 1990 263825-830 2.
Winearls Nephrol Dial Transplant 1995
10(suppl10)3-9 3. Fellner et al Kidney Int
1993 441309-1315 4 Churchill et al Clin
Nephrol 1995 43184-188 5. US Renal Data System
1998
56
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

57
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

58
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
59
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

60
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 lt0.0001)

Adapted from Silverberg et al. Can J Cardiol
1990 6 1-4
61
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

62
Building the evidence Mortality
hospitalisation

• Lombardy registry1
• all cause mortality and hospitalisation risks
  reduced with Hct levels gt32 compared with lt27
  (n5302)
• Ma et al2
• RR mortality reduces as Hct rises, 1.51 at Hct lt
  27 to 0.9 at Hct 33-36 (n96,369)
• Xia et al3
• hospitalisation risks lowest in patients with Hct
  33-36 (n71,717)

1. Lombardy registry Nephrol Dial Transplant
1998131642-442. Ma et al J Am Soc Nephrol
199910610-6193. Xia et al J Am Soc Nephrol
1999101309-1316
63
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 (n4866, 1107
  epoetin)

• 1. Collins et al J Am Soc Nephrol November
  20012. Fink et al Am J Kidney Dis
  200137348-355

64
Epoetin therapy correlates with reduced mortality
and less hospitalisation
Hospitalisation days per patient-year
1
0.8
p lt0.001
p lt0.05
0.6
Odds ratio
0.4
0.2
0
Adjusted general mortality (n5302)
Adjusted CVmortality (n5302)
Hct 2732
Hct lt27
Hct gt32
Patients with diabetes 7.6
Adapted from Locatelli et al Nephrol Dial
Transplant 1998
65
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 200137348-355
66
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
lt30
30 - lt33
33 - lt36
36
Haematocrit
USRDS prevalent patients 1994-1997
67
Duration of Hb lt11 g/dL Increases Mortality
RiskDialysis patients
Relative mortality risk

n41 919




Time with Hb lt11 g/dL over 2 years ()
Ofsthun et al. Nephrol Dial Transplant.
200520(Suppl 5)v261 (abstract MP204)
Plt0.05 Plt0.001
68
Hb Levels Predict Survival Prior to Dialysis
InitiationCKD patients not on dialysis
Levin et al. Nephrol Dial Transplant.
200621370-377
69
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. 1989111992-1000
70
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

71
Reversal of anaemia by epoetin can retard
progression of chronic renal failure
Cumulative renal survival rate ()
Adapted from Kuriyama et al Nephron 1997 77
176-185
72
Building the evidence delaying progression of
chronic renal failure

• 63 patients (serum creatinine gt 300 µmol/L,
  creatinine clearance lt 15 mL/min/1.73 m2)
• 20 with Hb lt 10 g/dL study group (epoetin) 43
  with Hb gt 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

73
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

74
The CHOIR and CREATE Studies OverviewCKD
patients not on dialysis
CHOIR(n1432) CREATE(n605)
Patient Population Stage 34 patients with renal anaemia and not on renal replacement therapy (RRT) Stage 34 CKD patients with renal anaemia not on RRT
Duration 16 months700 patients completed trial 48 months476 patients completed trial
Primary Endpoints Composite(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 1315 g/dL Group 2 10.511.5 g/dL

• Original targets before protocol amendment
• Group 1 13.013.5 g/dL
• Group 2 10.511.0 g/dL

127 and 111 patients in groups 1 and 2,
respectively, progressed to RRT during study
Singh et al. N Engl J Med. 20063552085-2098
Drüeke et al. N Engl J Med. 20063552071-2084
127 and 111 patients in groups 1 and 2,
respectively, progressed to RRT during study
75
CREATE trial (Cardiovascular risk Reduction by
Early Anaemia Treatment with Epoetin beta)

• 600 subjects glomerular filtration rate 15-35
  ml/min randomised to 2 groups, early
  intervention and standard practise

Time or creatinine
76
CHOIR trial (Correction of Haemoglobin and
Outcomes In Renal Insufficiency)

• 2000 subjects GFR 15-50 ml/min randomised to 2
  groups

Time or creatinine
77
CHOIR Increased Risk of Composite Event with
Target Hb 13.5 g/dLStage 34 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 HR1.34 (1.031.74) Log rank
test P0.03
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 2
70 176 101 72 55 23Group 2 717 660 594 539 499 39
7 293 182 107 67 44 23
Singh et al. N Engl J Med. 20063552085-2098
78
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 1315 g/dL Hb target 10.511.5 g/dL
Event-free Survival ()
50
40
Events 58 vs 47 HR0.78 (0.531.14) Log rank
test P0.20
30
20
10
0
0
6
12
18
24
30
36
42
48
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. 20063552071-2084
79
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

80
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 1315 g/dl
Inclusion Hb 10.513.0 g/dlCreatinine clearance
30 ml/min
n 160
Time
81
European recommendations for optimising treatment
of renal anaemia

• Indication for start of epoetin therapy
• repeated Hb measurements lt11g/dL
• after exclusion of non-renal causes of anaemia
  (bleeding, nutritional deficiencies,
  hypothyroidism, iron deficiency, haemolysis)
• Target haemoglobin
• general Hb gt11 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 12 g/dL per
  month

van Ypersele de Strihou Nephrol Dial Transplant
1999 14 (suppl 2) 37-45
82
Iron stores

• Target
• serum ferritin gt 100 ?g/l (aim for 200-500)
• hypochromic red blood cell count lt 10, TSAT gt
  20 (aim for lt 2.5 30-40)
• Level B
• Treatment strategies
• predialysis and CAPD oral ? intravenous
• HD will need intravenous
• Level B

83
How should epoetin be administered to predialysis
patients with diabetes and anaemia?

• EBPG KDOQI recommend epoetin treatment for
  anaemia due to CKD when Hb lt 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 1112 g/dL
  (or ?12-13 g/dL)

84
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