1. Epidemiology of Anaemia in CKD1

2. An Under-Recognised Condition
The Burden of CKD
An Under-Recognised Condition
Key messages
Under-recognition is a major obstacle to CKD treatment and is due to a lack of understanding of effective CKD diagnosis.
The CKD Network must correct the perception that sCr is a good indicator of renal function and encourage the more appropriate use of eGFR to diagnose CKD.

3. Stages of CKD by Glomerular Filtration Rate (GFR)
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
<15 or dialysis
The GFR is widely accepted as the best overall measure of kidney function in health and disease. CKD progression has been defined in stages according to the progressive decline of GFR (NKF-K/DOQI 2002).
All individuals with GFR <60 mL/min/1.73 m2 for ≥3 months are classified as having CKD, irrespective of the presence or absence of kidney damage.
†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
NKF-K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266. 3

4. CKD as a Continuum 1 2 3 4 5 Progression Stage GFR ≥90 60–90 30–60
Diagnosis and treatment of comorbid conditions
Estimate progression
Evaluate and treat complications
Preparation for dialysis e.g. access
Dialysis if uraemia present 1 2 3 4 5
Stage
GFR
≥90
60–90
30–60
15–30
<15
According to clinical practice guidelines, an action plan has been devised for each disease stage to prevent the progression of CKD and to improve outcomes at each stage (NKF-K/DOQI 2002).
Progression
Kidney transplant or dialysis
NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266
NKF-K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266. 4

5. 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
Key message
The perception that sCr is a good measure of kidney function is wrong.

6. 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
Key message
The definition of terms (eGFR and sCr) is important for clarity in the following discussion of CKD diagnosis.
Reviewed by Agarwal. Am J Kidney Dis 2005; 45:
Agarwal. Estimating GFR from serum creatinine concentration: Pitfalls of GFR-estimating equations.
Am J Kidney Dis 2005; 45:

7. Serum Creatinine is Not a Good Measure of eGFR
Age
Gender
Body weight
Muscle mass
Race
Key message
A clear illustration of the inappropriateness of sCr as a sensitive indicator of kidney function.
sCr
120 mmol/L
120 mmol/L
eGFR
30 mL/min
130 mL/min
Reproduction courtesy of PE Stevens

8. 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
Key message
eGFR is also determined easily and conveniently.
Reviewed by Agarwal. Am J Kidney Dis 2005; 455:
Agarwal. Estimating GFR from serum creatinine concentration: Pitfalls of GFR-estimating equations
Am J Kidney Dis 2005; 45:

9. Serum Creatinine Hides Early Renal Damage
600
400
sCr (µmol/L)
200
Key message
The relation between sCr and eGFR is not linear.
Misdiagnoses can occur as the creatinine secretion in the early stages of CKD leads to overestimation of eGFR. Thus, sCr only becomes a sensitive indicator of falling eGFR at late stages of CKD - at which time, the opportunities to improve outcome are much reduced. 5 4 3 2
CKD stage 35 70
105
140
eGFR (mL/min/1.73m2)
Adapted from D Newman

10. Serum Creatinine Misdiagnoses CKD
sCr or eGFR among patients with diabetes
220
200
180
160
140
120
100 80
220
200
180
160
140
120
100 80
Males
Females
sCr (µmol/L)
79.4%
sCr (µmol/L)
98.4%
Key message
Misdiagnoses can occur as sCr only becomes a sensitive indicator of falling eGFR at late stages of CKD. Strikingly, if 150 mmol/L sCr is used to diagnose CKD, up to 79% males and 98% females with diabetes can remain undetected.
27.7%
81%
eGFR (ml/min/1.73m2)
eGFR (ml/min/1.73m2)
Middleton et al. Renal Association 2004

11. Prognosis Declines with CKD Progression CKD patients not on dialysis
Death
Rates per 100 person-years 5 10 15
≥60
30−44
45−59
15−29
<15
GFR (mL/min/1.73m2)
Hospitalisation
GFR (mL/min/1.73m2)
CV events 10 30 40 20
≥60
30−44
45−59
15−29
<15
Rates per 100 person-years 50
100
150
Rates per 100 person-years
Increasing event rate
The multivariate association between estimated GFR and the risk of hospitalisation, cardiovascular (CV) events and death was examined using data from adult (>20 years) patients (n= ) in a US Renal Registry from 1996 to 2000 (Go et al 2004).
Age-adjusted rates of hospitalisation, CV events and death increased substantially with progressively lower estimated GFRs. The adjusted risk of hospitalisation, CV events and death increased by 310%, 340%, and 590%, respectively, in patients with GFR <15 mL/min/1.73 m2 compared with those with GFR ≥60 mL/min/1.73 m2.
≥60
30−44
45−59
15−29
<15
GFR (mL/min/1.73m2)
Decreasing GFR
Go et al. N Engl J Med. 2004;351:
Go AS et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351: 11

12. CKD is Highly Prevalent Worldwide
Increasing prevalence expected
aging population
global epidemic of type 2 diabetes1
Patients with stage 1–4 CKD outnumber patients with stage 5 CKD by ~50:1 in the US2
>1 million patients with CKD on dialysis worldwide
Approximately new patients diagnosed with CKD each year3
The main factors contributing to the continued growth in CKD prevalence are the aging population and the global epidemic of type 2 diabetes (El Nahas & Bello 2005).
The number of patients with stage 1–4 CKD probably exceeds the number of patients with stage 5 CKD by as much as a factor of 50 in the US (Coresh et al 2003).
There are over 1 million patients with CKD on dialysis worldwide, with about a quarter of a million new patients diagnosed each year (Moeller et al 2002).
1. El Nahas & Bello. Lancet. 2005;365:
2. Coresh et al. Am J Kidney Dis. 2003;41:1-12
3. Moeller et al. Nephrol Dial Transplant. 2002;17:
El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365:
Coresh J et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1-12.
Moeller S et al. ESRD patients in 2001: Global overview of patients, treatment modalities and development trends. Nephrol Dial Transplant. 2002;17: 12

13. Prevalence of CKD US and Canada
CKD Stage
Description
GFR (mL/min/1.73 m2)
US1,2
Canada3 1
Kidney damage with normal or  GFR
≥90 2
Kidney damage with mild  GFR
60−89 3
Moderate  GFR
30−59 4
Severe  GFR
15−29
29 000 5
Kidney failure
<15 or dialysis
14 500
The prevalence of CKD by stage has been estimated for US and Canadian populations. A total of 19.3 million and 1.58 million patients are estimated to have CKD in US and Canada, respectively, with the majority having stage 3 disease.
1. Coresh et al. J Am Soc Nephrol. 2005;16: USRDS Annual Data Report Stigant et al. CMAJ. 2003;168:
Coresh J et al. Chronic kidney disease awareness, prevalence, and trends among US adults, 1999 to J Am Soc Nephrol. 2005;16:
U.S. Renal Data System, USRDS 1998 Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, MD, 1998.
Stigant C et al. Nephrology: 4. Strategies for the care of adults with chronic kidney disease. CMAJ. 2003;168: 13

14. Prevalence and Incidence of Patients Receiving RRT (US)
No. of patients
50 000
Prevalent dialysis patients (2003: )
Prevalent transplant patients (2003: )
In the US, < new patients began dialysis treatment in 2003 (2% more than in 2002), while the prevalent dialysis population reached approximately (3.8% higher than in 2002).
Both dialysis- and transplant-prevalent populations have doubled since Although there has been continued growth in the number of treated patients, the growth in incident rates has become slower (USRDS 2005).
Incident dialysis patients (2003: )
Year
RRT=renal replacement therapy
USRDS Annual Data Report. 2005
U.S. Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005. 14

15. Incidence of Patients Receiving RRT (Europe)
Incident rate (patients per million population)
The incidence of renal replacement therapy (RRT) was studied in nine European countries from 1990 to 1999 (Stengel et al 2003). The adjusted incidence rate of RRT increased from 79.4 per million population in to per million population in 1998−1999, which represents an increase of 4.8% each year.
Stengel et al. Nephrol Dial Transplant. 2003;18:
Stengel B et al. Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, Nephrol Dial Transplant. 2003;18: 15

16. The Growing Prevalence of Patients with CKD on Dialysis Worldwide
No. of patients on dialysis (x1000)
Projected growth: 7% per year
Historically, the number of patients with CKD on dialysis worldwide has been expanding at a rate of 7% per year (Lysaght 2002). In 1990, the year-end global maintenance dialysis population was less than 0.5 million. If current trends in prevalence continue, the worldwide dialysis population is expected to exceed 2 million patients by the year 2010. † †
†Projected
Lysaght. J Am Soc Nephrol. 2002;13(Suppl 1):S37-S40
Lysaght MJ. Maintenance dialysis population dynamics: current trends and long-term implications. J Am Soc Nephrol. 2002;13(Suppl 1):S37-S40. 16

17. CKD is Associated with High Treatment Costs
In Europe, dialysis alone takes up ~2% of healthcare budgets with <0.1% of the population needing treatment1
In the US in 2003, Medicare costs for stage 5 CKD were US $18 billion, 6.6% of total Medicare expenditure2
In Europe, dialysis alone takes up approximately 2% of healthcare budgets, with only a small proportion (<0.1%) of the population needing treatment (El Nahas & Bello 2005).
In the US, Medicare costs for stage 5 CKD increased to US $18.1 billion in 2003, which was 6.6% of total Medicare expenditures for the year (USRDS 2005).
1. El Nahas & Bello. Lancet. 2005;365:
2. USRDS Annual Data Report. 2005
El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365:
U.S. Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005. 17

18. Costs of Stage 5 CKD Have Increased Over Time
Medicare expenditure per person per year (US $, thousands)
Annual Medicare costs for treating stage 5 CKD have increased over time; expenditure person per year increased by 54% between 1991 and 2003 (USRDS 2005).
Year
USRDS Annual Data Report. 2005
U.S. Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005. 18

19. 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 3–5 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
Anaemia is highly prevalent in patients with CKD and, as kidney function declines, there is a corresponding decrease in Hb levels (Astor et al 2002).
Anaemia becomes evident in stage 3 CKD (Thorp et al 2006) and up to 50% of patients with stage 3–5 CKD may have anaemia (McClellan et al 2004).†
Anaemia is associated with significant mortality and morbidity in patients with CKD; higher Hb levels were associated with decreased relative risk of mortality and hospitalisation (Locatelli et al 2004).
Anaemia has been shown to be a key component not only of CKD but also of cardiovascular disease (Silverberg 2003).
Anaemia associated with CKD has an adverse impact on health-related QoL; Hb levels were found to be positively associated with higher mental and physical QoL scores (Perlman et al 2005).
†Adult patients >18; serum creatinine mg/dL (females) or 2.0–6.0 mg/dL (males) for 1 year; no dialysis within the past 2 months; no anaemia therapy. Anaemia defined as Hb ≤12 g/dL independent of gender.
Astor et al. Arch Intern Med. 2002;162:
2. Thorp et al. Dis Manag. 2006;9:
3. McClellan et al. Curr Med Res Opin. 2004;20:
3. Locatelli et al. Nephrol Dial Transplant. 2004;19:
4. Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-12
5. Perlman et al. Am J Kidney Dis. 2005; 45:
Astor BC et al. Association of kidney function with anemia: the third national health and nutrition examination survey ( ). Arch Intern Med. 2002;162:
Thorp ML et al. Managing the burden of chronic kidney disease. Dis Manag. 2006;9:
McClellan W et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin. 2004;20:
Locatelli F et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:
Silverberg D. Outcomes of anaemia management in renal insufficiency and cardiac disease. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-ii12.
Perlman RL et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis. 2005;45: 19

20. Increased Presence of Anaemia with Declining Kidney Function Patients enrolled in NHANES III
Patients with anaemia (%)
44.1
In a population-based sample of participants (≥20 years) in the Third National Health and Nutrition Examination Survey (conducted from 1988 to 1994), the prevalence of anaemia (Hb <12 g/dL in men, <11 g/dL in women) was 1.9% overall. Anaemia was commonly found in patients with early stages of CKD. Estimated GFR <60 mL/min per 1.73 m2 was associated with a higher prevalence of anaemia (Astor et al 2002).
5.2
1.8
1.3
GFR (mL/min per 1.73 m2)
Anaemia defined as Hb <12 g/dL in men, <11 g/dL in women; NHANES=National Health and Nutritional Survey
Astor et al. Arch Intern Med. 2002;162:
Astor BC et al. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey ( ). Arch Intern Med. 2002;162: 20

21. Probability of survival
Hb Levels Predict Survival Prior to Dialysis Initiation CKD patients not on dialysis
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
The relationship between Hb levels and patient survival was assessed in a large cohort of patients (n=3028) with GFR <60 mL/min per 1.73 m2, who were not yet on dialysis (Levin et al 2006).
Hb level at time of referral was a statistically independent predictor of survival (RR=0.875 for every 1.0 g/dL, 95% CI: , P=0.0001).
Levin et al. Nephrol Dial Transplant. 2006;21:
Levin A et al. Haemoglobin at time of referral, prior to dialysis, predicts survival: as association of haemoglobin with long-term outcomes. Nephrol Dial Transplant. 2006;21: 21

22. Anaemia is Significantly Associated with Mortality and Morbidity in Patients on Dialysis
Relative risk of death
Relative risk of hospitalisation RR
RR overall=0.95 per 1 g/dL higher Hb (P=0.03)
RR overall=0.96 per 1 g/dL higher Hb (P=0.02)
The relationship between Hb levels and mortality and morbidity (as indicated by hospitalisation rates) was investigated in an analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) (Locatelli et al 2004).
Higher Hb levels were associated with decreased relative risk of mortality (RR=0.95 for every 1 g/dL higher Hb, P=0.03) and hospitalisation (RR=0.96 for every 1 g/dL higher Hb, P=0.02).
Hb (g/dL) at study entry
RR=relative risk
Locatelli et al. Nephrol Dial Transplant. 2004;19:
Locatelli F et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19: 22

23. Hospitalisation Risk Increases with Hb <11 g/dL Dialysis patients
RR of hospitalisation
n=7998
The relationship between Hb levels and hospitalisation was investigated in an analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) (Pisoni et al 2004).
Data were collected from nationally representative samples of patients on haemodialysis (n=11,041) receiving epoetin alpha, epoetin beta or darbepoetin alpha. Of the sample, 7998 patients were evaluated for the relationship between Hb levels and hospitalisation.
Consistent with other data, DOPPS found that higher Hb levels were associated with decreased relative risk of hospitalisation (RR=0.94 for every 1 g/dL higher Hb, P=0.0001) and better patient outcomes. Therefore, there are important benefits for patients when Hb concentrations are increased in line with current and established clinical guidance.
Recently, questions have been raised regarding data arising from studies of CKD patients not on dialysis, where higher Hb levels were associated with negative outcomes (Singh et al 2006). The differences between the patient populations in these studies and that of DOPPS make direct comparison difficult.
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
Pisoni RL et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:
Singh AK et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355: 23

24. The CHOIR and CREATE Studies: Overview CKD patients not on dialysis
CHOIR (n=1432)
CREATE (n=605)
Patient Population
Stage 3–4 patients with renal anaemia and not on renal replacement therapy (RRT)‡
Stage 3–4 CKD patients with renal anaemia not on RRT§
Duration
16 months 700 patients completed trial
48 months 476 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: 13–15 g/dL
Group 2: 10.5–11.5 g/dL
CHOIR and CREATE were both randomised controlled trials which tested the correlation between higher haemoglobin and patient outcomes.
The CHOIR study included 1432 patients with stage 3–4 CKD randomised to either a high Hb group (Hb target of 13.5 g/dL) or low Hb group (11.3 g/dL). Both groups received epoetin alpha subcutaneously (SC) once weekly (QW), with administration once every 2 weeks (Q2W) permitted if Hb was stable. The primary endpoint was the time to the composite of death, myocardial infarction, hospitalisation for congestive heart failure or stroke.
The CREATE study included 605 patients with stage 3–4 CKD randomised to either a complete correction of anaemia (Hb target 13–15 g/dL) or partial correction (10.5–11.5 g/dL). Both groups received epoetin beta SC QW as appropriate to achieve Hb target. The primary endpoint was the time to first cardiovascular event, including sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalisation for 24 h or more, or prolongation of hospitalisation, complication of peripheral vascular disease or cardiac arrhythmia resulting in hospitalisation for 24 h or more.
†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: Drüeke et al. N Engl J Med. 2006;355:
Singh AK et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:
Drüeke TB et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355: 24

25. Duration of Hb <11 g/dL Increases Mortality Risk Dialysis patients
Relative mortality risk **
n=41 919 ** ** * *
The relationship between Hb levels and mortality was investigated in a retrospective cohort study using data for stage 5 CKD patients with and without cardiac comorbidities in the FMC-NA database from July 1, 2000 to June 30, 2002 (Ofsthun et al 2005).
Any time spent with Hb <11 g/dL was associated with a significantly increased risk of mortality.
Minimising the amount of time a patient spends with Hb <11 g/dL may therefore decrease the risk of death in this patient population.
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)
Ofsthun N et al. The association of mortality and hospitalization with hemoglobin (Hb) and missed dialysis treatments in stage 5 chronic kidney disease (CKD) patients with and without cardiac comorbidities. Presented at the XLII European Renal Association and European Dialysis and Transplant Association (ERA-EDTA) Congess, June 4-7, 2005 (Nephrol Dial Transplant. 2005;20(Suppl 5):v261 [abstract MP204]). 25

26. Probability of composite event
CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dL Stage 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
CHOIR evaluated the time taken for stage 3–4 CKD patients to reach a composite endpoint of death, myocardial infarction, hospitalisation for congestive heart failure or stroke. A total of 222 composite events occurred during CHOIR: 125 events in the high Hb group (Hb target of 13.5 g/dL) compared with 97 events in the low Hb group (target 11.3 g/dL) (hazard ratio 1.34;95% CI: [P=0.03]). There were 98 deaths during the study: 57 in the high target Hb group, compared with 36 in the low target Hb group. There was an improvement in QoL in both groups, but no statistically significant incremental benefit in the higher target Hb versus the lower target Hb group.
The investigators concluded that the use of a target Hb level of 13.5 g/dL (compared with 11.3 g/dL) was associated with increased risk and no incremental improvement in QoL.
A number of limitations must be taken into consideration with the CHOIR study:
The study was interrupted after an interim analysis to investigate an inability to demonstrate a benefit in the higher Hb arm.
The protocol was changed after approximately 400 patients had been randomised to target an absolute level of Hb rather than a range.
High EPO doses (initially units) were used. This was chosen to reflect dosing strategies in the United States at the time of the study.
The majority of patients in the high Hb group did not reach Hb >13 g/dL (median was 12.8 g/dL).
The study arms may not have been well balanced as there was a greater prevalence of coronary artery bypass grafts and hypertension in the high Hb group at baseline.
CHOIR suffered a high dropout rate. Of the original cohort of 1400, over half were lost in each group. One of the reasons for this loss was commencement of dialysis, accounting for approximately half of the dropouts. Although this was pre-defined in the protocol, given the objective of the study to examine CVD outcomes in patients with CKD, this was unfortunate, since the intention of optimal pre-dialysis care should be to improve patient outcomes on dialysis (Levin 2007).
CHOIR underwent a protocol change during the study after 400 patients had been randomised to therapy. Specifically, the target Hb definition was changed to an absolute level instead of a range.
Month
Patients at risk
Group Group
Singh et al. N Engl J Med. 2006;355:
Levin A. Understanding recent haemoglobin trials in CKD: methods and lessons learnt from CREATE and CHOIR. Nephrol Dial Transplant 2007;22:
Singh AK et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355: 26

27. 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†
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
In the CREATE study 105 patients had a first cardiovascular event: 58 in the complete correction (Hb target g/dL) group and 47 in the partial correction (Hb target 10.5–11.5 g/dL) group. There was no significant difference in the likelihood of a first cardiovascular event between groups (hazard ratio 0.78; 95% CI: ; P=0.2).
The investigators concluded that early, complete correction of anaemia does not reduce the risk of cardiovascular events. However, closer examination of the data suggests that there may have been an effect on time to commencement of dialysis as there was a trend towards more rapid progression to dialysis in the patients randomised to complete Hb correction.
It should be noted that the annual cardiovascular event rate in CREATE was much lower than expected (6% versus an expectation of 15%). The investigators suggested that this may be brought about through a progressive increase in participating physicians’ awareness of protection against cardiovascular disease throughout the trial, coupled with the better than average prognosis for patients enrolled in trials. 10 6 12 18 24 30 36 42 48
Month
Patients at risk
Group
Group
†Before censoring of data on patients at the time of initiation of dialysis
Drüeke et al. N Engl J Med. 2006;355:
Drüeke TB et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355: 27

28. All-cause mortality hazard ratio
Impact of Stable Hb Maintenance Greater mortality risk with Hb outside 11.0−12.9 g/dL
12000 5
n= incident and prevalent patients
Unadjusted
Case mix
Case mix & MICS
10000 3
8000
Number of patients
All-cause mortality hazard ratio 2
6000
4000
The majority of studies looking at the impact of Hb levels on patient outcomes have examined associations between baseline Hb values and survival without considering variations in clinical and laboratory measures over time.
A study by Regidor et al used time-dependent Cox regression models to investigate the longitudinal associations between survival, Hb levels and erythropoietin-stimulating agent (ESA) dose over a 2-year period for patients receiving haemodialysis. Analyses are shown for three models:
the unadjusted model, which included Hb level as the predicting variable and all-cause or cardiovascular mortality as outcome variable;
case mix-adjusted model, which included additional covariates, including age, gender and diabetic status;
case mix- and MICS (malnutrition-inflammation complex syndrome)-adjusted models, which also included 12 indicators of nutritional status and inflammation.
The study found that, in all groups, Hb levels between 11.0 and 12.9 g/dL were associated with the greatest survival. A steady increase in mortality risk is evident with decreasing Hb levels. Hb levels of >13.5 g/dL were also associated with a trend toward increased mortality risk.
Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, a requirement for higher doses was also an indicator of higher death risk.
The analysis shown here demonstrates that the further away from Hb 11.0–12.9 g/dL a patient is, the greater the risk of mortality. 1
2000
0.8
<9
≥14
9.0−9.4
10.5−10.9
12.0−12.4
9.5−9.9
10.0−10.4
11.0−11.4
11.5−11.9
12.5−12.9
13.0−13.4
13.5−13.9
MICS=malnutrition-inflammation complex syndrome
Hb level (6 months)
Regidor et al. J Am Soc Nephrol. 2006;17:
Regidor DL et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17: 28

29. Cardiovascular mortality hazard ratio
Impact of Anaemia on CV Risk Greater CV risk with Hb outside 11.0–12.9 g/dL
Unadjusted
Case mix
Case mix & MICS
n= incident and prevalent patients 5 3
Cardiovascular mortality hazard ratio 2
The Regidor study also examined cardiovascular mortality risk. Greater cardiovascular mortality was evident in patients with Hb levels <11 g/dL and >12 g/dL. Hb levels in the range 11.0–12.9 g/dL were associated with the lowest risk (Regidor et al 2006). 1
0.8
<9
≥14
9.0−9.4
9.5−9.9
10.0−10.4
10.5−10.9
11.0−11.4
11.5−11.9
12.5−12.9
13.0−13.4
13.5−13.9
12.0−12.4
Hb level (g/dL)
Regidor et al. J Am Soc Nephrol. 2006;17:
Regidor DL et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17: 29

30. Anaemia Increases Risk of Stroke in Patients with CKD Patients from the ARIC study
Stroke rate per
1000 person-years
Anaemia defined as Hb <13 g/dL in men, <12 g/dL in women
Creatinine clearance
≥60 mL/min
<60 mL/min
The association of kidney function and anaemia with incident stroke (hospitalised non-fatal or fatal stroke) was investigated over 9 years in adults in the ARIC Study (Abramson et al 2003).
In the presence of anaemia, CKD was associated with a substantially higher risk of stroke compared with no CKD (RR=5.43, 95% CI: 2.04–14.41) (P<0.01 for the interaction between CKD and anaemia on the risk of stroke). No increased risk of stroke was found in those with CKD in the absence of anaemia.
Abramson et al. Kidney Int. 2003;64:
Abramson JL et al. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: The ARIC study. Kidney Int. 2003;64: 30

31. Anaemia May Increase the Risk of Progression of CKD to Dialysis
Patients on dialysis (%) 60 50 40 30 20 10
Baseline Hb by quartile (Q, g/dL)
Q1: 6.8–11.3
Q2: 11.3–12.5
Q3: 12.5–13.8
Q4: 13.8–18.0
Q1 (n=378)*
Q2 (n=377)*
Q3 (n=363)*
Anaemia has been found to be a contributing factor for the progression of CKD to dialysis (Kuriyama et al 1997).
The relationship between baseline Hb levels and progression of diabetic nephropathy was studied in 1513 patients (Mohanram et al 2004).
Anaemia was found to be an independent predictor for progression of CKD to dialysis. The proportion of patients progressing to dialysis was significantly higher for those in the first, second and third Hb quartiles compared with those in the fourth quartile.
Q4 (n=395)
Time (years)
*P<0.05 versus Q4
Mohanram et al. Kidney Int. 2004;66:
Kuriyama S et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997;77:
Mohanram A et al. Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy. Kidney Int. 2004;66: 31

32. Hb Increases Improve Quality of Life CKD patients not on dialysis65 60 55 50 45 40 35 30 26 25 24 23 22 21 20 19 18
LASA overall QoL score (mm)
Overall KDQ score
Hb level (g/dL)
Overall QoL
Overall KDQ
In patients with anaemia, Hb increases are known to correlate with improvements in QoL, as well as physical activity, social activity and brain function status. In a retrospective study, Lefebvre et al studied the absolute and incremental effect of Hb increase on QoL in 1326 CKD patients not on dialysis.
QoL was evaluated at baseline, week 8, and week 16 following initiation of weekly epoetin in patients with baseline Hb ≤10 g/dL. Evaluations were made using two separate, self-report instruments: a Linear Analogue Scale Assessment (LASA) of energy level, ability to perform daily activities and overall QoL, and the Kidney Disease Questionnaire (KDQ).
The study confirmed a positive and significant relationship between Hb levels and QoL. A direct relationship exists, with all LASA and KDQ QoL parameters improving with increasing Hb levels during treatment. The greatest incremental gains in QoL occurred around a Hb level of 10–12 g/dL.
n=1326 patients not on dialysis
KDQ=kidney disease questionnaire
Lefebvre et al. Curr Med Res Opin. 2006;22:
Lefebvre P et al. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. 2006;22: 32

33. Anaemia Treatment Greatly Reduces Blood Transfusions Dialysis patients
Mean units per patient per 4 weeks
0.6
0.5
0.4
0.3
0.2
0.1
Commencement of anaemia therapy
One of the key clinical benefits of anaemia treatment is avoidance of the necessity for blood transfusions.
A study of 333 CKD patients receiving haemodialysis showed that patients required a total of 1030 transfusions during the 6 months before initiation of epoetin therapy (an average of 0.52 units per patient per four weeks) to maintain Hb at a level that permitted usual daily activities. Following the start of epoetin therapy, transfusion requirements dropped progressively. After the second month of treatment, almost all patients were free of the need for transfusion, and remained so thereafter. *
Pre
Weeks
*autologous blood donation ahead of elective hip surgery
Eschbach et al. Ann Intern Med. 1989:111:
Eschbach JW et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111: 33

34. Epidemiology of Anaemia in CKD Summary
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
The prevalence of CKD is high and is expected to increase (El Nahas & Bello 2005).
The presence of anaemia increases with declining kidney function (Astor et al 2002) and is associated with significant morbidity and mortality in patients with CKD (Locatelli et al 2004).
Anaemia also has a negative impact on QoL among CKD patients (Lefebvre et al 2006).
Overall CKD is associated with high treatment costs (USRDS 2005) and any approaches that can reduce the impact of the deleterious effects of anaemia are welcome.
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:
El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365:
McClellan W et al. The prevalence of anemia in patients with chronic kidney disease. Curr Med Res Opin. 2004;20:
Astor BC et al. Association of kidney function with anemia: the third national health and nutrition examination survey ( ). Arch Intern Med. 2002;162:
Mohanram A et al. Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy. Kidney Int. 2004;66:
Locatelli F et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19:
Lefebvre P et al. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. 2006;22:
Levin A et al. Haemoglobin at time of referral, prior to dialysis, predicts survival: as association of haemoglobin with long-term outcomes. Nephrol Dial Transplant. 2006;21:
Regidor DL et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17: 34