RENAL ANAEMIA. South West Renal Training Scheme Cardiff October 2018

Transcription

1 RENAL ANAEMIA South West Renal Training Scheme Cardiff October 2018 Dr Soma Meran Clinical Senior Lecturer and Honorary Consultant Nephrologist, University Hospital of Wales.

2 Aims Biology of renal anaemia Iron therapy in CKD ESA therapy in CKD Future targets for therapy in renal anaemia Clinical cases of refractory anaemia in CKD

3 Physiology of Anaemia Mechanism of Erythropoiesis

4 Role of Hepcidin in Renal Anaemia

5 Mechanisms of anaemia in CKD High hepcidin, infection & inflammation Decreased EPO production B12 and Folate deficiency Iron deficiency (malnutrition & poor absorbtion) Co-morbidities Anaemia in CKD Medication e.g. ACE inhibitors Bone Marrow suppression by uraemia CKD and mineral bone disorders Blood loss circuit or GI bleeds

6 Diagnosis of iron deficiency Absolute Iron Deficiency Low Fe stores CRP < 10 mg/l Low Hepcidin Levels Low serum Ferritin < 100 ng/ml Functional Iron Deficiency (Fe sequestration) High Fe stores CRP > 20 mg/l High hepcidin levels Serum Ferritin > 100ng/mL TSAT < 20 % TSAT < 20 % 1. Pearson TA, et al. Circulation 2003;107: ; 2. Okonko DO, et al. J Am Coll Cardiol. 2011;58: ; 3. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kid Int Suppl 2012;2:283 87; 4. Macdougall IC, et al. Nephrol Dial Transplant 2014;29: ; 5. Bhandari S. Anaemia management in people with chronic kidney disease. NICE guidelines. BMC Nephrology 2017; 6. Fishbane S, et al. Kid Int 1997;52:217 22

7 Iron in Biology Iron is an essential trace element used by most living organisms Essential component of haemogloblin Transports oxygen in haemoglobin and myoglobin Cell respiration Important in function of catalytic enzymes and proteins for DNA synthesis Role in oxidative phosphorylation Role in ATP formation

8 IV Iron reduces ESA dosing in dialysis patients

9 Intravenous Irons CosmoFer (Iron Dextran) LMW Diafer (Iron Isomatoloside 1000 Ferinject (Ferric Caroxymaltose) Correcting Iron Deficiency Oral Irons Ferrous Sulphate, Ferrous Gluconate New Iron preparations: Iron Maltol, Heame Polypeptide Monofer (Iron Isomaltoside 1000) Venofer (Iron Sucrose) Iron based phosphate binders Ferric Citrate Others Intradialytic Iron Soluble Ferric Pyrophosphate HIF stabliisers Hepcidin Targets

10 Oral Iron has efficacy in Non-Dialysis Dependent CKD patients RCT comparing Fe Citrate versus placebo N = 232 Primary EP: increase in Hb by 1 g/dl in 16 weeks GI disorders most common adverse event. Fishbane et al., JASN 2017

11 Limitations of oral iron and better Hb response with IV iron McDougall et al. KI 1996

12 Risks of IV Iron Anaphylactic reactions Hypophosphataemia Labile reactions (too much too rapidly) Increased oxidative stress Iron overload Increased susceptibility to infections

13 Monitoring Iron Aim for : Serum ferritin microg/l TSAT 30-40%

14 KDIGO Guidelines: Use of Iron to treat anaemia in CKD CKD patients with anaemia NOT on ESA: Trial of IV iron (or in CKD NDD patients trial 1-3 months oral iron therapy) if TSAT <30% and Ferritin < 500ng/ml. CKD patients ON ESA therapy: Trial of IV iron (or in CKD NDD patients trial 1-3 months oral iron therapy) if TSAT <30% and Ferritin < 500ng/ml CKD NDD patients: Select the route of iron administration based on the severity of iron deficiency, availability of venous access, side effects based with prior oral/iv use, patient compliance and cost. When initial dose of IV non-dextran iron is administered: patients need to be monitored for 60 minutes, and resuscitation facilities and personnel be available. Iron during infection: Avoid administering IV iron to patients with active systemic infections.

15 Erythropoetin Stimulating Agents (ESA s) Erythropoetin: Glycoprotein produced by renal peritubular cells. Stimulates proliferation and differentiation of erythroid progenitor cells in bone marrow Recombinant Human Epo: First introduced in Intravenous/subcutaneous - Epoetin alpha (Eprex) - Epoetin beta (NeoRecormin) - Darbopoetin alpha (ARANESP) - Pegylated ESA Methoxy polyethylene glycol-epoetin beta (MIRCERA) What are the Hb targets with ESAs?

16 CHOIR (n = 717) Singh et al. Correction of anemia with epoetin alfa in chronic kidney disease, N Engl J Med, 2006

17 Group 1: hb g/dl Group 2: g/dL CREATE (n=605) Time to 1 st CV Event Time to CV death Drueke et al., Normalisation of Hb levels in patients with CKD and Anaemia, NEJM 2006.

18 Double-blind RCT 24 countries. 623 sites TREAT (n=4038) Group 1: Target Hb 13 g/dl Group 2: No ESA until Hb < 9g/dL Pfeffer et al., NEJM 2009.

19 TREAT: Safety Concerns

20 KDIGO Guidelines: Use of ESAs to treat anaemia in CKD Address all correctable causes of anaemia prior to initiation of ESA therapy Recommends caution in patients with: - Active malignancy - Previous malignancy - Previous CVA - Recurrent vascular access thrombosis Hb > 100g/l ESA not initiated (individualised if symptoms). Patients with CKD on ESA should achieve Hb between 100 and 120 g/l

21 Causes of ESA Resistance Easily Correctable Iron Deficiency Underdialysis ACEi and ARBs (ESA resistance) Vitamin B12 or Folate deficiency Hypothyroidism Infection Hyperparathyroidism Potentially Correctable Aluminum overload (now rare) Compliance Bleeding PRCA Difficult to Correct Occult Malignancy Unsuspected haematological disorders Chronic inflammation

22 Hepcidin targets

23 Hypoxia Inducible Factor-1 Produced by most cells in response to hypoxia HIF1-alpha Dimer of 2 proteins: HIF1-alpha and HIF1-beta HIF1-beta ODD Domain HIF1-beta constitutively expressed HIF1-alpha has an oxygen dependent degradation (ODD) domain, and is quickly degraded in normoxic conditions Stimulates EPO production pill that stabilises HIF-1 and increases endogenous EPO production The first oral therapy in the treatment of renal anaemia Anti-inflammatory Regulates iron absorbtion: reduces Hepcidin levels

24 Hypoxia Inducible Factor stabilisers Phase 2 clinical trials Off Target Effects

25 Case 1 83 year old male CKD secondary to FSGS Other Background: MGUS, prostate Ca, IHD Commenced ESA in August 2008 NeoRecormin Changed to EPREX in January 2009 (in line with contractual change for EPO procurement in the dept) ESA resistant anaemia in May 2010 CT Abdoment and pelvis Normal Endoscopy (upper and lower GI) Normal No evidence of coeliac disease

26 Case 2 75 year old male CKD stage 4 secondary to Diabetic Nephropathy Other Background: T2DM with retinopathy, previous CVA, Hypertension. Commenced ESA in 2009 subcutaneous EPREX February 2011 drop in Hb, which persisted despite increase in dose of ESA No symptoms suggestive of blood loss.

27 Case 3 74 year old male CKD5 predialysis. CKD unknown cause: small scarred kidneys Other Background: Hypertension Commenced ESA in 2008 NeoRecormin Changed to EPREX in January 2010 (in line with contractual change for EPO procurement in the dept) ESA resistant anaemia in July 2011 associated with symptoms of lethargy, dyspnoea and generally unwell WCC and platelets normal No symptoms of blood loss

28 Investigations Bone Marrow Biopsy Absence of erythroid precursor cells with otherwise normal features Reticulocyte Count Case 1 : 28 x 10 9 /ml Case 2: 4.2 x 10 9 /ml Case 3: 5 x 10 9 /ml Erythropoietin antibodies Diagnosis?

29 Pure Red Cell Aplasia Profound, sudden onset progressive anaemia characterised by absence of erythroblasts in the bone marrow. Idiopathic (associated with Lymphoproliferative disorders, thymoma) Rare & serious AE of ESA use: Autoantibody production against erythropoietin in patients treated with rhuepo Immunogenecity recognised with ESA use Largest number of cases reported between Largely associated with sc injection of Epoetin alpha (rather than IV administration) Modification of cold-stain storage, manufacturing, handling and transport implemented Tungsten in EPO syringes: promotes aggregation of immunogenicity of EPO molecules Slight resurgence in 2009 in UK: Reasons unclear

30 Pure Red Cell Aplasia: Diagnosis and Management Sudden decrease in Hb Increase transfusion requirement Normal platelet and WCC Reduced reticulocyte count Stop ESA Medication Transfusion for symptomatic anaemia Immunosuppressive therapy? (IV Ig, Steroids, Rituximab, PEX) EPO antibodies BM: Erythroid hypoplasia Peginesatide: EPO Receptor agonist Consider re-exposure to ESA

31 THANK YOU