Diabetes, Anemia and Chronic Kidney Disease

Josephine Carlos-Raboca,M.D., F.P.S.E.M., Endocrinology, Diabetes and Metabolism

Makati Medical Center

OUTLINE

Defining Chronic Kidney Disease(Diabetic Renal Disease)

Pathophysiology of Anemia in CKD Effects of Anemia of CKD Benefits of Early Treatment of Anemia Clinical Trials with Epoietin beta Conclusion

What is Chronic Kidney Disease(CKD) ?

Definition 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

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

Glomerular Filtration Rate

Where Constant is 1.23 for men and 1.04 for women

GFR in mg/dL

GFR in umol/l

Stages of CKD by Glomerular Filtration Rate (GFR)

Stage DescriptionGFR

(mL/min/1.73m2)

1Kidney 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

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’

Symptoms of CKD

Diabetic kidney disease and anaemia

Anaemia is prevalent in people with diabetic kidney disease and is largely unrecognised and untreated

Anaemia occurs earlier in diabetic kidney disease than is commonly recognised

Anaemia worsens with declining kidney function .

Astor et al. Arch Intern Med. 2002;162:1401-1408

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/d

L)

Glomerular filtration rate (ml/min)

5

10

15

20

60 30 15

Hb (men)Hb (women)

Aetiology of anaemia

Red Blood Cell (RBC) Production

2 000 000 cells/sec

120 000 000 cells/min

173 000 000 000 cells/day

RBC parameterNormal values in adults

Men Women

Hb (g/dL) 15.7±1.7 13.8±1.5

Haematocrit (%) 46.0±4.0 40.0±4.0

RBC count (x1012/L) 5.2±0.7 4.6±0.5

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

Defining Anemia

Guideline Definition of Anemia

European Best Practice Guidelines (EBPG) 2004 Anemia Guideline

<12.0 g/d: in males and postmenopausal females;

<11.0 g/dL in premenopausal females and prepubertal patients

Kidney Disease Outcomes Quality Initiative (KDOQI) 2006 Anemia Guideline

<13.5 g/dL males

<12.0 g/dL females

Potential causes of anaemia in chronic kidney disease

Shortened red blood cell survival Iron deficiency Malnutrition and other deficiencies Chronic inflammation Decreased erythropoietin production Inhibition of erythropoiesis

The Lifecycle of the RBC

EXCRETIONMacrophage in spleen, liver or red bone marrow

Globin

Amino acids

Heme

Biliverdin

Bilirubin

Fe

Bilirubin

Circulation120 days

Fe3+ Transferrin

Ferritin and haemosiderin

Liver

Erythropoiesis in bone marrow

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

Regulation of ErythropoiesisFeedback loop

Erythropoietin

RBCsErythroid marrow

CirculatingRBCs

Kidney

Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441

O2

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

GM-CSFIL-3, IGF-1SCF

Erythropoietin

Stage 1: CD-34 Stage 2: Erythron

Stem cell pool

Progenitor cellsBFU-E, CFU-E

Mature cellsPrecursor cellserythroblasts

The Role of Erythropoietin in Erythropoiesis

Erythropoietin Receptor

508 amino acids, 66–78 kDa glycoprotein

Located on erythroid progenitor cell surface

Approximately 1000 erythropoietin receptors per cell

Expression– primarily on CFU-E– small numbers on BFU-E– no receptors present once

cells become reticulocytes

Membrane

JAK2P JAK2 P

P

P

P

P

EPO

Target genes

STAT

STAT

Hb O2transportcapacity

peripheral hypoxia

kidneyperitubular cells

serum EPO

precursor cells

erythroblasts

reticulocytes erythrocytesHb

O2transportcapacity

Hb and Erythropoietin: the Anaemic Patient with CKD

DAMAGED

INSUFFICIENT

ANAEMIA

Diabetes and Anaemia

Diabetes

Hyperglycaemia ↓Serum EPO response

RBC abnormalities ↓ RBC survival

Anaemia

Nephropathy (35%) CKD

Neuropathy (50%) ↓Serum EPO level

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

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

Reciprocal Relationship :Renal Anemia, Diabetes &

CVD

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):I80-932. Culleton et al Kidney Int 1999; 56: 2214-22193. Levin et al, Am J Kidney Dis 1999; 34: 125

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

Framingham study, N = 6223

0

5

10

15

20

25

ECG LVH CHD CHF CVD

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 insufficiencyChronic renal insufficiency

ECG LVH=echocardiogram left ventricular hypertrophyCHD=coronary heart diseaseCHF=congestive heart failureCVD=cardiovascular disease

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;47:186-1922. Foley et al. Am J Kidney Dis. 1996;28:53-61

The Cardio-Renal Anaemia SyndromeA 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

Cardiacoutput

CHF=congestive heart failure

CHF

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

ARIC study – influence of anaemia (WHO)

Str

oke

rat

e

Abramson et al, Kidney Int 2003; 64: 610-615

0

2

4

6

8

10

12

Total sample Anaemic group Nonanaemic group

Cr Cl ≥ 60 ml/minCr Cl < 60 ml/min

2.06

3.7

1.52

10.53

2.122.85

Hospitalisation Risk Increases with Hb <11 g/dLDialysis patients

1.16 1.091.00 1.01

1.55

0.0

0.5

1.0

1.5

2.0

<8 8−9.99 10−10.99 11−11.99 ≥12

P=0.77P<0.0001 P=0.001 P=0.05

n=7998

Pisoni et al. Am J Kidney Dis. 2004;44:94-111

RR of hospitalisation

Hb level (g/dL)

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

Why do we treat renal anaemia?

Subjective1

– well-being– life satisfaction– happiness– psychological affect

Objective1

– energy level– functional ability– activity level– health status

Others– cardiac status2

– blood transfusions3

– hospitalisation4

– mortality5

1. Evans et al J Am Med Soc. 1990; 263:825-8302. Winearls Nephrol Dial Transplant 1995; 10(suppl10):3-93. Fellner et al Kidney Int; 1993; 44:1309-13154 Churchill et al Clin Nephrol 1995; 43:184-1885. US Renal Data System 1998

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

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

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

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

<30 30 - <33 33 - <36 36+

Deaths per 1000 patient

years

Diabetes mellitus

No diabetes mellitus

Duration of Hb <11 g/dL Increases Mortality RiskDialysis patients

1.001.10 1.12

1.32

1.52

1.82

0

1

2

0 1−20 21−40 41−60 61−80 81−100

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

Levin et al. Nephrol Dial Transplant. 2006;21:370-377

0 3 6 9 12 15 18 21 24 27 31 33 37

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 InitiationCKD patients not on dialysis

Mean units per patient per 4 weeks

0.6

0.5

0.4

0.3

0.2

0.1

0Pre 4 12 20 28 36 44 52

Weeks

Eschbach et al. Ann Intern Med. 1989:111:992-1000

*

*autologous blood donation ahead of elective hip surgery

Commencement ofanaemia therapy

Anaemia Treatment Greatly Reduces Blood TransfusionsDialysis patients

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

Trials in treatment of CKD anaemia

CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta)

CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency)

ACORD (Anaemia CORrection in Diabetes)

Aims of the studies : to establish whether early intervention– prevents development of left ventricular hypertrophy– reduces cardiovascular mortality and morbidity– delays progression of chronic renal failure– reduces stroke and heart failure related hospitalisations

The CHOIR and CREATE Studies: OverviewCKD 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 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: 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

CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dLStage 3–4 CKD patients

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.30

0.25

0.20

0.15

0.10

0.05

0.00

Pro

bab

ilit

y o

f co

mp

osi

te e

ven

t

Month

Hb target 13.5 g/dLHb target 11.3 g/dL

Patients at riskGroup 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

Time to the primary composite endpoint

Events: 125 vs 97HR=1.34 (1.03–1.74)Log rank test P=0.03

Singh et al. N Engl J Med. 2006;355:2085-2098

CREATE: No Significant Difference in Time to First CV EventCKD 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

Eve

nt-

free

Su

rviv

al (

%)

0 6 12 18 24 30 36 42 48

MonthPatients at riskGroup 1 301 279 268 249 207 158 97 56 2Group 2 302 286 272 257 223 177 121 61 2

Events: 58 vs 47HR=0.78 (0.53–1.14)Log rank test P=0.20

Hb target 13–15 g/dLHb target 10.5–11.5 g/dL

Drüeke et al. N Engl J Med. 2006;355:2071-2084

The Anaemia CORrection in Diabetes (ACORD) study

The ACORD study is investigating the effects of anaemia correction with subcutaneous epoetin beta on – cardiac structure

– cardiac function In patients with early diabetic nephropathy Primary endpoint

– effect of early anaemia treatment on left ventricular hypertrophy as a cardiovascular risk marker

Hb (g/dl)

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/dlCreatinine clearance ≥30 ml/min

m

f

Time

n = 160

Randomisation

ACORD: Study design

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

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

Iron stores

Target– serum ferritin > 100 g/l (aim for 200-500)

– hypochromic red blood cell count < 10%, TSAT > 20% (aim for < 2.5% & 30-40%)

Level B Treatment strategies

– predialysis and CAPD oral intravenous

– HD will need intravenous

Level B

How should epoetin be administered to predialysis patients with diabetes and

anaemia?

EBPG & KDOQI recommend epoetin treatment for anaemia due to CKD when Hb < 11 g/dL

Hb correction should be gradual to avoid:– exacerbation of hypertension– increased viscosity with adverse haemodynamics

Guidelines recommend an increase of Hb 0.5 g/dL every 2 weeks

Common practice suggest a target Hb of 11–12 g/dL (or ?12-13 g/dL)

RECORMON DOSING GUIDE for CKD Patients with Renal Anemia:

Correction Phase

Subcutaneous Administration Intravenous Administration

60 IU/kg Body weight per week 120 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.

The clear differencesEpeotin Beta Recormon Epoetin alpha

Half life SC 12-28 hoursIV 4-12 hours

SC 12-18 hoursIV 4-6 hours

Stabilizers GlycinePoylsorbate 20UreaCalcium ChlorideComplex of 5 amino acids

GlycinePolysorbate 80

Storage and handling

2-8 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 timesCan not tolerate shaking

Tolerability Almost pain free at the injection site

With pain at the injection site

Dose Recommendation(Correction)

60 IU/kg Body weight/wk 100 IU/kg Body Weight /wk

Shelf Life (PFS) 24 months 18 months

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

Thank you