OPTA – Education Initiative OPTA – Optimal Treatment of Renal Anaemia

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.

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.

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.

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

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

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: 1549-1557, 2001 Zimmermann J et al.., Kidney Int 1999;55:648–658. Barany P. Nephrol Dial Transplant 16:224-227, 2001 Foley, J AmSoc Nephrol15:1038-1045, 2004.

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.

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.

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;1011-23 Macdougall IC, Copper A, Nephrol Dial Transplant 2002;17 Suppl1::48–52.

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: 1549-1557,2001 Macdougall IC, Copper A, Nephrol Dial Transplant 2002;17 Suppl1::48–52.

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.

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.

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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 130–150 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 300 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

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.

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

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

OPTA – Education Initiative OPTA – Optimal Treatment of Renal Anaemia