OPTA – Education Initiative

1. OPTA – Education Initiative OPTA – Optimal Treatment of Renal Anaemia Improving the Efficacy and Efficiencyof Renal Anaemia Therapy

2. 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.

3. 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

4. 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

5. Epidemiology of Anaemia associated with Chronic Renal Insufficiency 15.5 14.5 men 13.5 Haemoglobin[mg/dl] 12.5 women 11.5 10.5 >80 70–80 60–70 50–60 40–50 30–40 20–30 <20 Creatinine Clearance [ml/min] Hsu et al., J Am Soc Nephrol 2000;13:504–510.

6. Prevalence of Anaemia by Serum Creatinine and Glomerular Filtration Rate <1.6 ≥2 – <2.5 ≥60 ≥15 – <30 100 Hb ≤ 10 g/dL Hb >10 – ≤ 12 g/dL Hb ≤ 12 g/dL 80 13 60 Patients [%] 40 20 0 ≥1.6 – <2 ≥2.5 ≥30 – <60 <15 Serum creatinine [mg/dL] GFR [mL/min/1,73 m2] McClellan W et al., Curr Med Res Opin 2004;20(9):1501–1510.

7. 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

8. Impact of Anaemia in CKD-Patients – Regression of Left Ventricular Hypertrophy Canadian/Australian multicentre trial – development of LVH 120 115 110 105 100 Hb 12–13 g/dL (n=75) Hb 9–10 g/dL (n=80) P=0.019 LVMi [g/m2] initial 1-year 2-year Roger SD et al. J Am Soc Nephrol 2004;15:148–156.

9. 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. 2.0 100 *p<0.05 1.6 1.2 Survival [%] Relative risk of mortality 75 0.8 0.4 RR=0.82* RR=0.82 RR=1.17 0 50 0 19.3 31.4 Time on dialysis since initiation [month] Fink JC et al., Am J Kidney Dis 2001;37:348–355.

10. Impact of Anaemia in CKD-Patients – Progression of Chronic Kidney Disease Mechanism of progression of kidney disease Intermediate Factors HypertensionAnaemia Environmental FactorsToxic exposuresMedicationsSmokingDiet Host FactorsAgeSexEthnicity Genetic susceptibility Hypertension Diabetes mellitus Renal DiseaseGlomerulosclerosisInterstitial fibrosis Renal Failure Rossert et al. J Am Soc Nephrol. 2003;14 (Suppl 2):173-177.

11. Potential Beneficial Effects of Epoetin Treatment Epoetin Anti-apoptotic effectson renal cells (?) Increased number ofred blood cells Increased oxygen delivery Increased protection against oxidative stress Decreased tubular damage Decreased interstitial fibrosis Rossert et al. J Am Soc Nephrol. 2003;14 ( Suppl 2):173-177.

12. 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 rate in predialysis patients of three groups 100 80 60 Cumulative renal survival rate [%] 40 Group I (untreated anaemic, overall) 20 Group II (treated anaemic, overall) Group III (untreated nonanaemic, overall) 0 0 5 10 15 20 25 30 35 40 Time (months) Kuriyama S et al., Nephron 1997;77:176–185.

13. Treatment of Anaemia in Patients with Chronic Kidney Disease – Effect of Anaemia Treatment on Progression of Renal Disease Kaplan-Meier plots for doubling of creatinine, renal replacement, or death (A), and replacement or death (B) in the early (–) versus deferred (–) treatment arms A B 1.0 1.0 0.8 0.8 0.6 0.6 Proportion alive without renal replacement Proportion alive without progression 0.4 0.4 0.2 0.2 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Follow-up [months] Follow-up [months] Gouva C et al, Kidney Int 2004;66:753–760.

14. 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

15. 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).

16. 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

17. Patient Categorisation within Stages ofChronic Kidney Disease • 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

18. 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

19. 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

20. Treatment of Anaemia in Patients with Chronic Kidney Disease – Parameters and Conditions that Need to be Monitored • 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

21. 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 infection2i.e.vasculitis, chronic inflammatory conditions, congestive heart failure or fluid overload

22. 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 blockers2Coombs test

23. 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).

24. 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

25. Effects of Epoetin Therapy on Cellular Level Retina Spinal cord Skin Peripheral nerves Kidney Intestine Erythropoietin: an all-purpose tissue-protective agent? Brain EPO Heart Savino, Ciliberto, Editorial Cell Death and Differentiation 2004;11:S2–S4.