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OPTA – Education Initiative

OPTA – Optimal Treatment of Renal Anaemia

Improving the Efficacy and Efficiencyof Renal Anaemia Therapy

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OPTA – Rationale

European Best Practice Guidelines and KDOQI Guidelines provide scientific evidence on optimal treatment of renal anaemia.

European Surveys of Anaemia Management (ESAM I &II,PRESAM, TRESAM) and Dialysis Outcomes and Practice Patterns Study (DOPPS) demonstrate relevant gaps between standards of care of anaemia treatment and daily practice.

OPTA aims to transfer standards of care into daily practice and to optimise efficacy and efficiency of anaemia therapy by focusing on major and minor factors influencing treatment of renal anaemia.

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Content

Diagnosis and start of anaemia treatment

Impact of anaemia in patients with chronic kidney disease

Patient categorisation within stages of chronic kidney disease

Treatment of anaemia in patients with chronic kidney disease

Effects of epoetin therapy at a cellular level

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Diagnosis and Start of Anaemia Treatment

Reasons for delayed start of anaemia treatment

In early stage of CKD anaemia is non-symptomatic, patients adapt to declining Hb-levels

Under estimation that modest decreases in renal function lead to a decrease in Hb levels

Late referral of patients with chronic kidney disease

Late initiation of treatment

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Epidemiology of Anaemia associated withChronic Renal Insufficiency

Hsu et al., J Am Soc Nephrol 2000;13:504–510.

15.5

14.5

13.5

12.5

11.5

10.5

>80 70–80 60–70 50–60 40–50 30–40 20–30 <20

Creatinine Clearance [ml/min]

men

women

Hae

mo

glo

bin

[m

g/d

l]

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Prevalence of Anaemia by Serum Creatinine and Glomerular Filtration Rate

McClellan W et al., Curr Med Res Opin 2004;20(9):1501–1510.

20

40

1380

100

0

Pat

ien

ts [

%]

Serum creatinine [mg/dL]

60

<1.6≥1.6 – <2

≥2 – <2.5≥2.5

≥15 – <30≥60≥30 – <60 <1

5GFR [mL/min/1,73 m2]

Hb ≤ 10 g/dLHb >10 – ≤ 12 g/dLHb ≤ 12 g/dL

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Impact of Anaemia in CKD-Patients on:

Cardiovascular events/LVH

Quality of life (ability to work, exercise capacity)

Hospitalisations

Impact on mortality

Progression of chronic kidney disease

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Impact of Anaemia in CKD-Patients –

Regression of Left Ventricular Hypertrophy

Roger SD et al. J Am Soc Nephrol 2004;15:148–156.

Canadian/Australian multicentre trial – development of LVH

120

115

110

105

100

LV

Mi

[g/m

2]

1-yearinitial 2-year

Hb 12–13 g/dL (n=75)Hb 9–10 g/dL (n=80) P=0.019

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Impact of Anaemia in CKD-Patients –

Impact on Mortality

Kaplan-Meier plots show survival of new end-stage renal disease patients in Network 5 treated with EPO before the initiation of dialysis versus patients who were not treated. Histograms represent risk of mortality associated with EPO use within 3 tertiles of follow-up after starting dialysis: 0–19.3 month, 19.4–31.4 month and ≥ 31.5 month.

Fink JC et al., Am J Kidney Dis 2001;37:348–355.

50

100

75

2.0

1.6

1.2

0.8

0.4

0

Su

rviv

al [

%]

Rela

tive risk o

f mo

rtality

RR=0.82RR=0.82* RR=1.17

Time on dialysis since initiation [month]

*p<0.05

19.3 31.40

15 Rossert et al. J Am Soc Nephrol. 2003;14 (Suppl 2):173-177.

Impact of Anaemia in CKD-Patients –

Progression of Chronic Kidney Disease

Mechanism of progression of kidney disease

Host FactorsAgeSex

EthnicityGenetic susceptibility

HypertensionDiabetes mellitus

Intermediate FactorsHypertension

Anaemia

Renal Failure

Renal DiseaseGlomerulosclerosisInterstitial fibrosis

Environmental FactorsToxic exposures

MedicationsSmoking

Diet

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Epoetin

Increased number ofred blood cells

Increased oxygen delivery

Increased protection against oxidative stress

Decreased tubular damage

Decreased interstitial fibrosis

Anti-apoptotic effectson renal cells (?)

Potential Beneficial Effects of Epoetin Treatment

Rossert et al. J Am Soc Nephrol. 2003;14 ( Suppl 2):173-177.

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Treatment of Anaemia in Patients with Chronic Kidney Disease –

Effect of Anaemia Treatment on Progression of Renal Disease

Effect of EPO on the cumulative renal survival ratein predialysis patients of three groups

Kuriyama S et al., Nephron 1997;77:176–185.

Group I (untreated anaemic, overall)Group II (treated anaemic, overall)Group III (untreated nonanaemic, overall)

80

100

60

40

0

20

Time (months)0 5 10 15 20 25 3530 40

Cu

mu

lati

ve r

en

al s

urv

ival

rat

e [%

]

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Kaplan-Meier plots for doubling of creatinine, renal replacement, or death (A), and replacement or death (B) in the early (–) versus deferred (–) treatment arms

Gouva C et al, Kidney Int 2004;66:753–760.

Pro

po

rtio

n a

live

wit

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ut

pro

gre

ssi

on

Pro

po

rtio

n a

live

wit

ho

ut

ren

al

rep

lac

emen

t

A B

Treatment of Anaemia in Patients with Chronic Kidney Disease –

Effect of Anaemia Treatment on Progression of Renal Disease

0.8

0.6

0.4

0

0.2

1.0

Follow-up [months]

0 6 12 18 24 30

0.8

0.6

0.4

0

0.2

1.0

Follow-up [months]

0 6 12 18 24 30

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Patient Categorisation within Stages ofChronic Kidney Disease

CKD patient categories with high risk of anaemia development

Diabetes mellitus

Congestive heart failure

Diseases e.g. vasculitis, lupus erythematosus

Advanced age

Kidney transplantation

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Patient Categorisation within Stages ofChronic Kidney Disease

Patients with diabetes mellitus

Display a higher incidence of anaemia in the earlier stagesof CKD.

Risk of developing anaemia is two to three times higher than CKD patients with comparable kidney function.

Lower Hb-levels are linked with development/worsening of diabetic complications (retinopathy, diabetic nephropathy).

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Patient Categorisation within Stages ofChronic Kidney Disease

Patients with congestive heart failure

Anaemia is correlated with symptoms of congestive heart failure, even in patients with

– preserved renal function

– normal ejection fraction

Patients with systemic diseases

Inflammation/ elevated serum concentrations of C-reactive protein lead to

– decrease in Hb level

– decrease response to erythropoietin

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Patients with advanced age

Elderly patients are more likely to develop anaemia

Patients with kidney transplantation

Post transplant anaemia has a prevalence of 20-40%.

Risk factors in this patient group are:

– decrease in kidney function (GFR)

– immunosuppressive drugs

Patient Categorisation within Stages ofChronic Kidney Disease

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Patient Segments within Stages ofChronic Kidney Disease

Recommendation

Chronic kidney disease patient categories with

– Diabetes mellitus

– Congestive heart failure

– Diseases e.g. vasculitis, lupus erythematosus

– Advanced age

– Kidney transplantation

are at very high risk for anaemia development and should receivea higher level of attention and care

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Treatment of Anaemia in Patients with Chronic Kidney Disease –

Parameters and Conditions that Need to be Monitored

Major Parameters

Kidney function by estimation of glomerular filtration rate

Proteinuria1

Iron status2

Haemoglobin3

C-reactive protein (CRP)4

1 24 h or spot urine protein/creatinine2 Ferritin and transferrin saturation; distinguish absolute or functional iron deficiency in 3 month intervals or according to stages of CKD3 Monitor at every visit, including white cell and platelet count4 Monitor at every visit, preferably high sensitivity CRP

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Minor Parameters

Parathyroid hormone1

BMI and nutrition status (SGA)2

Screen for blood loss or haemolysis3

Serum B12 and folate levels4

Haemoglobinopathies

1 Monitor PTH twice a year (under specific conditions and stages of CKD every three months2 Determine BMI, body mass index and SGA, subjective global assessment in 3 month intervals or according to stages of CKD3 Order a Coombs test for diagnosis of autoimmunolysis if appropriate

Treatment of Anaemia in Patients with Chronic Kidney Disease –

Parameters and Conditions that Need to be Monitored

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Treatment of Anaemia in Patients with Chronic Kidney Disease –

Major Treatment influencing Factors

Intravenous treatment with iron

Inflammation and overt infection1

Underlying disease and co-morbidity2

Chronic allograft nephropathy (CAN) and type of immunosuppression

Age and sex

1 i.e. diabetic ulcers or ADPKD cyst infection2 i.e.vasculitis, chronic inflammatory conditions, congestive heart failure or fluid overload

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Treatment of Anaemia in Patients with Chronic Kidney Disease –

Minor Treatment influencing Factors

BMI and nutrition

Concomitant medication1

Malignancies (recurrent and de novo)

Occult blood loss and haemolytic anaemia2

Parathyroid hormone

Vitamin B12 and folate deficiency

Proteinuria (interstitial nephritis)

Hypothyroidism

Haemoglobinopathy

1 NSAIDS, ACE-inhibitors and angiotensin-II blockers2 Coombs test

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Management of Major Treatment Influencing Factors – Recommendations

Recommendation

If the Hb of the patient is not > 11g/dl, exclude any other factor before treatment that can be related to anaemia.

Iron status should be measured and corrected before anaemia is treated. In practice, the EBPG for haemodialysis patients should be applied for CKD patients.

Patients with absolute iron deficiency should be treated with intravenous iron administration, at least at the start of anaemia treatment.

Epoetin treatment should be started when haemoglobin is below 11 to increase haemoglobin to above 11 g/dl (EBPG) with an option to further increase haemoglobin to 12.5 g/dl (K/DOQI).

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Summary

Anaemia has a significant impact on patients with CKD, and there is substantial room for improvement in its treatment

Anaemia should be diagnosed and treated early to avoid a negative impact on the kidneys and the cardiovascular system

Patients with CKD and diabetes mellitus, chronic heart failure,or kidney transplantation are at very high risk of developing anaemia and should receive a higher level of attention

Efficiency of anaemia treatment can be improved by better management of the major treatment-influencing factors

Erythropoietin stimulates erythroid progenitor cells, has anti-apoptotic effects, and stimulates angiogenesis

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Erythropoietin: an all-purpose tissue-protective agent?

Savino, Ciliberto, Editorial Cell Death and Differentiation 2004;11:S2–S4.

Effects of Epoetin Therapy on Cellular Level

Brain

Heart

IntestineKidney

Peripheral nervesSkin

Spinal cordRetina

EPO