1. OPTA – Education Initiative
OPTA – Optimal Treatment of Renal Anaemia

2. Anaemia Therapy – State of the Art
Hb levels – State of the art
DOPPS (Data from 2000)
ESAM 1998/99
ESAM 2003
100 80 60 40 20
Patients [%] 47
47.0
33.8 23
28.2
20.9
18.8
13.0
Hb < 11 g/dl
Hb < 10 g/dl
Hb < 11 g/dl
Hb 10–11 g/dl
Hb < 10 g/dl
Locatelli F et al., NDT 2004;19:121–132.
Hörl W et al., NDT 2000;15(Suppl4):45–45.
Moreno F et al., Am J Kidney Dis 1996;27(4):548–556.

3. Importance of Haemoglobin Level
Recommended target haemoglobin of ≥ 11 g/dl leads to
Decreased risk of mortality (5% lower for every 1 g/dl)
Decreased risk of hospitalisation (4% lower for every 1 g/dl)
Decreased risk of infections
Increased quality of life
Locatelli F et al., NDT 2004;19:121–132.
Hörl W et al., NDT 2000;15(Suppl4):45–45.
Moreno F et al., Am J Kidney Dis 1996;27:548–556.

4. Factors influencing Anaemia Treatment and impacting EPO Dose
Factor Impact on EPO dose
Haemodialysis adequacy up to 54%
Haemodialysis quality / quantity up to 30%
Iron 20–70%
Inflammation / Infection 30–70%
Locatelli F et al., NDT 2004;19:121–132.
Hecking E, NDT 2004;19:100–107.
Richardson D, NDT 2002;17 Suppl 1:53–59.
Sitter T et al., NDT 2000;15:1207–1211.
Kato A et al., Nephron 2001;89(1):110–112.
Stenvinkel P, NDT 2002;17 Suppl 5:32–37.
Nitta K, Acta Haematol 2002;108;168–170.

5. Factors influencing Anaemia Treatment
AT = Adjuvant therapy D i a l y s d e q u c I n f t o , m r p B A T

6. Content Impact of Inflammation/Infection
Diagnosis of Inflammation/Infection Potential Sources of Inflammation/Infection Treatment of Inflammation/Infection
Concomitant Anaemia Treatment

7. Impact of Inflammation/Infection
Inflammation/Infection is an important predictor of subsequent cardiovascular mortality in dialysis patients
15% of the deaths of haemodialysis patients are attributable to infectious causes
45–55% of HD patients have CRP levels of > 5 mg/L
In the HD population, a single episode of sepsis is associated with an increased risk of all cause mortality and also of acute myocardial infarction for up to five years
Inflammation/Infection has major influence on efficacy and effectiveness of anaemia therapy
Kaysen G., J AmSoc Nephrol 12: , 2001 Zimmermann J et al.., Kidney Int 1999;55:648–658. Barany P. Nephrol Dial Transplant 16: , 2001
Foley, J AmSoc Nephrol15: , 2004.

8. Impact of Inflammation/Infection
All cause mortality Cardiovascular mortality
100 90 80 70 60 50 40
Follow-up [month]
Survival [%] 12 24 36 48
Follow-up [month]
Survival [%] 12 24 36 48
100 90 80 70 60 50 40
CRP < 3,3 mg/L CRP 3,3–7,4 mg/L CRP 7,5–14,8 mg/L CRP > 15,8 mg/L
Zimmermann J et al., Kidney Int 1999;55:648–658.

9. Impact of Septicaemia in dialysis patients
Mortality after first septicaemic event
180
160
140
with sepsis
without sepsis
120
100
Adjusted mortality rate / 100 pt yrs 80 60 40 20 6 12 18 24 30 36 42 48 54 60
Months
Foley RN et al., J Am Soc Nephrol 2004;15:1038–1045.

10. Impact of Inflammation/Infection
Impact on Erythropoiesis
Direct Impact Indirect Impact
Proliferation of erythroid progenitor cells
Endogenous erythropoietin production
Destruction of erythrocytes
Reactive increase of erythropoietin in response to decreased Hb-levels
Intestinal iron absorption
Release of stored iron
Synthesis of transferrin
Gastrointestinal blood loss (NSAID)
Synthesis of lactoferrin
Weiss G., Goodnough L.; N Engl J Med 2005; 352; Macdougall IC, Copper A, Nephrol Dial Transplant 2002;17 Suppl1::48–52.

11. Uraemia (± other inflammatory states) Erythroid progenitor cells
Impact of Inflammation/Infection
Impact on erythropoiesis
Uraemia (± other inflammatory states)
Immune activation
Iron metabolism
Fe absorption and availabilty Functional iron deficiency
IL-2 sIL-2R
IL-4 IL10
T-cell Th2
T-cell Th1
T-cell anergy +
Mono- cytes
IL-12
IL-6 Neopterin
Erythroid progenitor cells
IFN gamma –
pro-apoptotic
anti-apoptotic +
Epoetin +
TNF alfa
Kaysen G., J AmSoc Nephrol 12: ,2001 Macdougall IC, Copper A, Nephrol Dial Transplant 2002;17 Suppl1::48–52.

12. Inflammation – Impact on Anaemia Treatment
Influence of CRP concentration on EPO dose
30–50% of CKD patients have serological evidence of an activated inflammatory response (CRP > 8–10 mg/l).
180
160
140
120
100 80 60 40 20
EPO dose [IU/kg/week]
Group I:
CRP ≥ 10 mg/l
Group II:
CRP < 10 mg/l
P<0.01
138.7 92
34% difference in EPO dose
Stenvinkel P, NDT 2002;17 Suppl 5:32–37.
Nitta K, Acta Haematol 2002;108;168–170.

13. Infection – Impact on Anaemia Treatment
Infection has similar impact on anaemia or erythropoiesis as inflammation
175
150
125
100 75 50 25
EPO dose [IU/kg/week] 1 2 3 4 5 6
Month
CRP ≥ 50 mg/l CRP < 50 mg/l
Hörl W et al., NDT 2000;15(Suppl4):43–45.

14. Infection – Impact on Anaemia Treatment
Impact on Hb-level 14 12 10 8 6 4 2
Mean Hbl-level [g/dl] 1 2 3 4 5 6
Month
CRP ≥ 50 mg/l CRP < 50 mg/l
Macdougall IC, Copper A, Nephrol Dial Transplant 2002;17 Suppl1::48–52.

15. Diagnosis of Inflammation/Infection
Classification of CRP ranges
CRP- level
50 mg/L
5 mg/L
0 mg/L
High CRP > 50 mg/L rapidly rising from normal to high > infection is likely
Smoldering CRP 5–50 mg/L (chronically raised but stable)
Check: - falling Hb S-albumin Epoetin dose
Normal (only for HD-population)
Continue to monitor monthly
Healthy general US-population = 1.5 mg/L
Normal: 45–50% of HD patients Smoldering: 35–45% of HD patients
High: ~ 10% of HD patients

16. Diagnosis of Inflammation
Auditing – Clinical and diagnostic procedures on unit level
Monitor CRP monthly –> high sensitivity CRP would be preferable
Create a unit population distribution curve for CRP and benchmark with regional/national data
Check the demographics of your population (% of diabetics)
Check water and haemodialysis fluid quality twice per year*
Audit vascular access status in centre**
Ensure optimisation of dialysis protocols and dialysis doses
Review choice of dialysis modality (PD versus HD)
* According to EBPG Haemodialysis (Part 1)
** Guidelines recommend documentation of type of vascular acces

17. Diagnosis of Inflammation
Auditing – Clinical and diagnostic procedures on individual patient level
Evaluate CRP* monthly – if elevated perform a clinical review of history and examination
Focus clinical attention on patients with higher (> 5 mg/L) and rising CRP-levels
Define: – underlying renal diagnosis – chronic inflammatory co-morbidities – exclude overt infections and malignancy * high sensitivity CRP would be preferable

18. Potential Sources of Inflammation/Infection I
Patients with
CRP 5–50 mg/L smoldering or chronically raised
CRP > 50 mg/L or rapidly raising
Specific causes in PD patients

19. CRP 5–50 mg/L smoldering or chronically raised
Potential Sources of Inflammation/Infection I
CRP 5–50 mg/L smoldering or chronically raised
Ischemic, neuropathic and venous ulcers
Chronic chest disease (obstructive pulmonary disease)
Congestive heart failure
Inflammatory bowel disease
Peridontitis
Arthritis
Hepatitis
Major surgery
Failed kidney transplant in situ
Biofilm (grafts, catheters, HD-machine)
Silent (encapsulated) infection of AV or arterial grafts
Chronic obstructive uropathies
Calciphylaxis
Cholesterol emboli
Peripheral arterial disease and silent ischemia
Silent cardiac ischemia

20. Potential Sources of Inflammation/Infection I
Patients with
CRP 5–50 mg/L smoldering or chronically raised
CRP > 50 mg/L or rapidly raising
Specific causes in PD patients

21. CRP > 50 mg/L or rapidly raising
Potential Sources of Inflammation/Infection II
CRP > 50 mg/L or rapidly raising
Underlying renal diagnosis (infected cysts in ADPKD)
Vasculitis relapse, sinusitis, otitis
Discitis, osteomyelitis, endocarditis
Urinary tract infection, urosepsis, biliary sepsis
Septicemia, any cause (foreign material)
Malignancy, de-novo and recurrent

22. Potential Sources of Inflammation/Infection I
Patients with
CRP 5–50 mg/L smoldering or chronically raised
CRP > 50 mg/L or rapidly raising
Specific causes in PD patients

23. Potential Sources of Inflammation/Infection III
Specific causes in
PD patients
Biocompatibility of PD solutions
Impurity of PD solutions
Exit site infection, tunnel infection
Peritonitis
Sclerosing peritonitis
Fluid overload and leaky gut hypothesis

24. Inflammation/Infection – Recommendations
In the presence of both, a high Ca x PO4 product and high serum CRP level, patients should be screened and treated for calciphylaxis
Patients coming back from transplantation should be monitored carefully since rejected grafts may be a source of inflammation
In patients with failed renal allograft still in place or in patients with intravenous catheters a higher dose of epoetin may be needed to correct anaemia
In patients with continuous rise in CRP and a past history of systemic disease causing renal failure, recurrence of the disease should be excluded

25. Diagnosis of Inflammation/Infection – Recommendations
Despite the absence of overt clinical symptoms dialysis patients with a stable CRP between 5 and 50 mg/L should undergo a thorough clinical review
In patients with CRP levels greater than 50 mg/L or 5–50 mg/L and rising rapidly, an underlying infection is most likely and screening should include all measures to detect overt infection

26. Inflammation/Infection – Recommendations
In patients with elevated CRP (> 5 mg/l) biocompatibility of dialyser membrane and haemodialysis fluid quality should be checked
If chronic inflammation persists, optimisation of the dialysis protocol and dialysis dose should be aimed for
Patients with chronic inflammation should be screened for silent infection of haemodialysis access grafts (visual control), peridontal disease or any low grade infection (diabetic foot ulcers)
Elderly patients should be screened for urinary tract infection when epoetin requirements increase

27. Treatment of Inflammation/Infection
Intermediate Impact
Lower Impact
High Impact
Diagnosis and treatment of any cause of infection, recurrent vasculitis or malignancy
Nephrectomy of failed kidney transplant
Reduction of in centre use of lines for dialysis access
Approach maximal use of native a.v. fistula
Removal of clotted arterial grafts (if appropriate)
Provision of ultra-pure dialysis water
Calciphylaxis: Withdrawal of warfarin and dialysis dose increase
Use of biocompatible membrane

28. Concomitant Anaemia Therapy
Inflammation/infection has a strong inhibiting effect on the effectiveness of EPO therapy and Hb level
All patients with an epoetin dose in the range of –150 IU/kg/week or higher or a haemoglobin level below 11g/dl or falling should be evaluated for epoetin resistance
If necessary EPO dosage should be increased up to IU/kg/week to reach recommended target Hb-level of ≥11g/dl (EBPG)
Inhibited iron mobilisation is found in high states of CRP
Iron supplementation should be stopped during documented infection, since i.v. iron therapy may enhance bacterial growth and increase oxidative stress

29. Summary I
Inflammation/Infection is an important predictor of subsequent cardiovascular mortality, all cause mortality and hospitalisation rate in dialysis patients
Already a moderate level of inflammation > 5 mg/L requires an active workup of the patients and a monthly follow up (despite absence of overt clinical symptoms)
45–55% of the dialysis patients have CRP levels > 5 mg/L (10% > 50 mg/L)
CRP levels of > 10 mg/L lead to a 30–70% dosage increase of epoetin.

30. Summary II
CRP level should be evaluated monthly, at least every three months
Diagnose and treat any cause of infection, recurrent vasculitis or malignancy
Stop iron supplementation during documented infection
Iron supplementation can be continued during inflammation
Increase EPO dosage (up to 300 IU/kg/week) to reach recommended target Hb-level ≥ 11g/dl

31. OPTA
Needs
Regular control of treatment influencing factors in all patients
Close and regular follow up of Hb-development

32. OPTA – Education Initiative
OPTA – Optimal Treatment of Renal Anaemia