OPTA – Education Initiative

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OPTA – Education Initiative

OPTA – Optimal Treatment of Renal Anaemia

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Existing Recommendations

OPTA – Haemodialysis Patients

OPTA – Therapy with Iron and Recombinant Human Erythropoietin

OPTA – Influence of Inflammation/Infection on Anaemia Therapy

OPTA – Patients with Chronic Kidney Disease

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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 at transfering standards of care into daily practice and optimising efficacy and efficiency of anaemia therapy by focussing on major and minor factors influencing treatment of renal anaemia.

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Optimal Treatment of Renal Anaemia in Diabetic Patientswith Chronic Kidney Disease

Faculty: W.H. Hörl, Austria G. Ghirlanda, Italy A. Bren, Slovenia

A. M. Castello, Spain C. Hasslacher, GermanyJ. Tapia, Sweden

C. Wanner, Germany


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Content

Introduction Definition of diabetic kidney disease Definitions of metabolic abnormalities Definitions of abnormalities in albumin excretion Anaemia and diabetic kidney disease Anaemia definition and diagnosis Anaemia treatment of DKD patients Changes of laboratory and treatment aspects during progression

of DKD Clinical practice management in DKD Stages

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Diabetes is the leading cause of CKD in developed countries and is rapidly increasing in developing countries

In Europe, Diabetes affects ~ 40 million people

Overall risk to develop DKD varies about 25–40% of type 1 and type 2 diabetic patients after 25 years of diabetes duration

Approximately 75% of people with diabetes die of CVD related causes (ADA* 2002)

Under-diagnosis of Diabetes and CKD leads to lostopportunities for prevention

Diabetes and Diabetic Kidney Disease (DKD)

* American Diabetes Association

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Definitions of abnormalities in albumin excretion

Definitions of Diabetic Kidney Disease

Adapted from KDOQI-Guidelines

Category Spot 24 hour Timedurine collection collection(mg/g creatinine) (mg/24h) (µg/minute)

ACR AER

Normo-albuminuria < 30 < 30 < 20

Micro-albuminuria 30–299 30–299 20–199

Macro-albuminuria ≥ 300 ≥ 300 ≥ 200

AER = Albumin Excretion RateACR= Albumin Creatinine Ratio

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Likelihood of DKD according to eGFR and level of albuminuria

Definitions of Diabetic Kidney Disease

Adapted from KDOQI-Guidelines

eGFR CKD Normo- Micro- Macro-(ml/min) Stage albuminuria albuminuria albuminuria

> 60 1 + 2 At risk Possible DKD DKD

30–60 3 Unlikely Possible DKDDKD DKD

< 30 4 + 5 Unlikely Unlikely DKDDKD DKD

In most patients with Diabetes, CKD is attributable to the diabetes if;

-Macroalbuminuria is present OR

-Microalbuminuria is present in presence of diabetic retinopathy, in type 1 diabetes of at least 10 years duration

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Recommendation

Other cause(s) of CKD should be considered in the presence of any of the following circumstances: absence of diabetic retinopathy slow or rapidly declining GFR rapidly increasing proteinuria or nephrotic syndrome refractory hypertension presence of active urinary sediment (special attention to microhaematuria) signs or symptoms of other systemic disease greater than 30% reduction in GFR within 2–3 months after

initiation of an ACE inhibitor or ARB treatment

Chronic Kidney Disease not attributable to Diabetes

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Recommendation

Screening for diabetic kidney disease should begin after:

- 5 years of type 1 diabetes

- at the diagnosis of type 2 diabetes,(due to inability to establish the onset of type 2 diabetes with certainty)

Definitions of abnormalities in albumin excretion

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Individuals at high risk of type 2 Diabetes

Body Mass Index > 25 kg/m²

Waist Hip Ratio > 1.0 (men) > 0.85 (women)

Waist circumference > 102 cm

Definitions of metabolic abnormalities

-Type 2 Diabetes is frequently not diagnosed until complications appear-~one third of all people with diabetes may be undiagnosed

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Target organ damage in patients with diabetes

Retina (diabetic retinopathy) Kidney (diabetic nephropathy) Peripheral nerves (diabetic polyneuropathy) Heart (ischemic heart disease, cardiomyopathy,

congestive heart failure) Peripheral arteries (peripheral artery disease)

Anaemia and Diabetic Kidney Disease

¹ Ritz, Haxen; Europ J Clin Invest 2005;35 (Suppl. 3):66¹ Ritz, Haxen; Europ J Clin Invest 2005;35 (Suppl. 3):66–74.74.² Thomas MC et al., Diabetologia 2006;49:1151–1157.

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Anaemia is a common complication of CKD affecting is a common complication of CKD affecting over half of all patients.over half of all patients.¹¹

Diabetes is the most common cause of CKD² and thereforemost common cause of CKD² and thereforeof renal anaemia.of renal anaemia.

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

Diabetics display a higher incidence of anaemia in the earlier stagesof CKD.

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


¹ ¹ US Renal Data System 2001US Renal Data System 2001² McClellan 2004² McClellan 2004

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Possible mechanism of Anaemia in diabetic kidney disease

Decreased Epo production due to kidney interstitial fibrosis(a classical feature of diabetic kidney disease)

Decreased Epo release through autonomic neuropathy

Urinary losses of Epo associated with nephrotic range proteinuria

Shortened erythrocyte half life¹¹

HIF-1α polymorphism in type 2 diabetic patients and hyperglycaemia

Iron malabsorption due to diabetic autonomic disease of the gut²

The HIF-factor one is subunit of HIF transcription factor, response to hypoxia


¹ ¹ Ritz, Haxen; Europ J Clin Invest 2005;35 (Suppl. 3):66–74.² Thomas MC, Nat Clin Pract Nephrol 2007;3:20–30.

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Anaemia is more severe in chronic kidney disease patients with diabetes.


Ishimura E et al, J Nephrol 1998;11:83–86.

Diabetic Non-diabetic patients patients(n=19) (n=19)

Age [years] 59 ± 11 56 ± 13

Sex [male/female] 13 / 6 13 / 8

Serum creatinine [mg/dl] 3.5 ± 1.6 3.8 ± 1.5

Haemoglobin [g/dl] 9.5 ± 2.1 11.2 ± 2.0*

Serum erythropoietin [mU/ml] 19.8 ± 6.2 18.6 ± 5.6

HbA1c 7.6 ± 1.8 –

19 Bosman DR et al., Diabetes Care 2001;24:495–499.

Anaemia with erythropoietin deficiency occurs early in diabetic nephropathy 53 patients with chronic kidney disease

– 27 type 1 diabetic patients with diabetic nephropathy

– 26 patients with glomerulonephritis

– serum creatinine < 180 µmol/l

Results

– 13/27 diabetic patients with anaemia Hb 10.6 ± 0.9 g/dl

– 0/26 glomerulonephritis patients Hb 13.7 ± 1.4 g/d


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Mean haemoglobin in different CKD groups in diabetic andnon-diabetic patients with renal disease


Al-Khoury S et al, Diabetologia 2006;49:1183–1189.

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10

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CKD 1 and 2 CKD 3 CKD 4 und 5

Mea

n H

b [g

/dl]

Non-diabetic patients (n=264)

Diabetic patients (n= 204)

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Haemoglobin distribution in type 2 diabetic patients at baseline


Mohanram A et al, Kidney Int 2004;66:1131–113.

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100

0

Num

ber o

f par

ticip

ants

7 8 9 10 11 12 13 14 15 16Haemoglobin g/L

150

Mild anaemia (<13.8g/dL )is a risk factor for progression to ESRD in type II diabetes

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Normoalbu-minuric

Microalbu-minuric

Macroalbu-minuric

M F M F M F

N 46 60 18 28 5 4

HbA1c [%] 7.8 7.7 8.4 8.9 9.3 9.8

Serum creatinine [µmol/l] 81 70 108 83 114 96

Cystatin C [mg/dl] 1.1 1.0 1.1 1.0 1.7 2.6

Haemoglobin [g/dl] 14.8 13.1 14.5 13.6 14.3 11.7

Erythropoietin [mU/ml] 6.4 9.0 5.1 5.0 4.9 3.5

Clinical and biochemical characteristics of the patients groupedaccording to the degree of albuminuria


Mojiminiyi OA et al., Diabet Med 2006;23:839–844.

EPO loss increases as protein loss increases

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Prevalence of anaemia, stratified according to level of creatinine clearance and albuminuria in type 2 DM patients


Thomas MC et al, Diabetologia 2006;49:1151–1157.

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Patients should receive a diagnostic work-up for anaemia

when creatinine clearance falls below

– 70 ml/min in men

– 50 ml/min in women when Hb-level falls below:

– 11.5 g/dl in adult female patients1

– 13.5 g/dl in adult male patients1

– 12 g/dl in adult male patients aged > 701

– 11 g/dl in pre-pubertal subjects and pre-menopausal females2

– 12 g/dl in adult males and post-menopausal females2

1 Revised EBPGs, NDT 2004;19.2 K/DOQI, Am J Kidney Dis 2001;37.

Diagnosis of Anaemia – Recommendation I

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Diabetic patients should receive a diagnostic work-up for anaemia

with macroalbuminuria: eGFR > 60 ml/min without macroalbuminuria: eGFR < 60 ml/min

1 Revised EBPGs, NDT 2004;19:2 K/DOQI, Am J Kidney Dis 2001;37:

Diagnosis of Anaemia – Recommendation II

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Anaemia treatment of DKD patients: Target Hb-levels

Anaemia treatment should be initiated when haemoglobinlevels fall below 11 g/dl and a value of 11 to 12 g/dl appearsto be the best option to aim at

Anaemia should not be completely corrected in patientswith diabetic kidney disease. The target Hb level fordiabetic patients should not exceed 12 g/dl.¹

1 Revised EBPGs, NDT 2004;19:??–-??.

Treatment of Anaemia – Recommendation

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Glycemic control in diabetes and CKD during all stages of CKD

HbA1c: < 7%

Postprandial capillary glucose: 90–130 mg/dl (5.0–7.2 mmol/l)

Peak postprandial capillary glucose: < 180 mg/dl (<10 mmol/l)

Changes of laboratory and treatment aspectsduring progression of DKD

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Glycemic control in diabetes and CKD during CKD stages 3–5

Patients in CKD increased risk for hypoglycemiastages 3–5: due to decreased clearance of insulin and impaired renal gluconeogenesis

close self monitoring of glucose levels

Recommendation: Patients with progressive DKD and on insulin treatment should be monitored closely in stages 3–5 due to higher risk of developing hypoglycaemia

Changes of laboratory and treatment aspectsduring progression of DKD

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Risk factor management is the cornerstone of therapy in diabetickidney disease patients

Intensive management of

– hypertension

– hyperglycaemia

– dyslipidaemia

– protein intake

Risk Factor Management

Revised EBPGs, NDT 2004;19:??–??.

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* Goals should be individualized. Certain populations (children, pregnant women, and elderly) require special considerations. More stringent glycaemic goals (i.e., a normal HbA1c, <6%) may further reduce complications at the cost of increased risk of hypoglycaemia. Less intensive glycaemic goals may be indicated in patients with severe or frequent hypoglycaemia. Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals.

**, if insulin treated*** helpful in patients with gastroparesis† Postprandial glucose measurements should be made 1–2 h after the beginning of the meal. ‡ Current NCEP/ATP III guidelines suggest that in patients with triglycerides >200 mg/dl, the “non-HDL cholesterol” (total cholesterol minus HDL) should be utilized (55).

Clinical Practice Management in DKD Stages (1/2)

Laboratory Parameters Target levels monitoring frequency

Glycaemic control• HbA1c < 6.5 %* 3 monthly • Preprandial capillary 90–130 mg/dl 4 or more times daily** plasma glucose (5.0–7.2 mmol/l)• Peak postprandial <180 mg/dl as needed*** capillary plasma glucose† (<10.0 mmol/l)Systolic/diastolic blood pressure < 130/80 mmHgCholesterol < 175 mg/dlTriglycerides < 150 mg/dl (<1.7 mmol/l)Non-HDL Cholesterol‡ < 130 mg/dlLCL Cholesterol < 100 mg/dl (<2.6 mmol/l)

Option < 70 mg/dlProteinuria < 0.5 g/g creatinineACE-I or ARB irrespective of blood pressureAspirin 100 mg/day

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Patient Care Target levels Monitoring frequency

Retinopathy avoid annually

Foot ulcers avoid daily visual inspection

Smoking cessation

Clinical Practice Management in DKD Stages (2/2)

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Nutritional status/Eating patterns

Weight history/healthy weight

Details of previous treatment programs

Nutrition and diabetic self-management education

Prior or current infections: particularly skin, foot, dental,genitourinary

Risk factors for atherosclerosis: smoking, hypertension, obesity, dyslipidemia, family history

Lifestyle/Lifestyle changes

Additional Relevant Factors

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In patients with diabetic kidney disease, anaemia develops earlierand is more distinct.

Hb development should be monitored closely in patients withdiabetic kidney disease.

Anaemia is an independent risk factor for progression and mortalityin patients with diabetic kidney disease.

Anaemia treatment should be initiated when haemoglobin levels fallbelow 11 g/dl and a value of 11 to 12 g/dl appears to be the best option to aim at. The target Hb level for diabetic patients should not exceed 12 g/dl.

In patients with diabetic kidney disease, hypertension, hyperglycaemia

and dyslipidaemia should be intensively managed. Changes in life style of patients with diabetic kidney disease should

be encouraged even if success rate is limited.

Summary

OPTA – Education Initiative

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