RENAL ANAEMIA

South West Renal Training Scheme Cardiff October 2018

Dr Soma Meran Clinical Senior Lecturer and Honorary Consultant Nephrologist, University Hospital of Wales. 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 MechanismPhysiology of of Erythropoiesis Anaemia Role of Hepcidin in Renal Anaemia Mechanisms of anaemia in CKD

B12 and Folate Decreased EPO deficiency High hepcidin, infection production & inflammation Iron deficiency (malnutrition & poor absorbtion)

Co-morbidities Anaemia in CKD

Blood loss – circuit Medication e.g. or GI bleeds ACE inhibitors Bone Marrow suppression by CKD and mineral uraemia bone disorders Diagnosis of iron deficiency

Absolute Iron Deficiency Functional Iron Deficiency (Fe sequestration) Low Fe stores High Fe stores CRP < 10 mg/L CRP > 20 mg/L Low Hepcidin Levels High hepcidin levels Low serum Ferritin < 100 ng/mL Serum Ferritin > 100ng/mL

TSAT < 20 % TSAT < 20 %

1. Pearson TA, et al. Circulation 2003;107:499–511; 2. Okonko DO, et al. J Am Coll Cardiol. 2011;58:1241–51; 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;29:2075–84; 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 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 IV Iron reduces ESA dosing in dialysis patients Correcting Iron Deficiency Intravenous Irons Oral Irons • CosmoFer (Iron Dextran) – LMW • Ferrous Sulphate, Ferrous Gluconate • Diafer (Iron Isomatoloside 1000 • New Iron preparations: Iron Maltol, • Ferinject (Ferric Caroxymaltose) Heame Polypeptide

• Monofer (Iron Isomaltoside 1000) • Iron based phosphate binders – Ferric Citrate • Venofer (Iron Sucrose)

Others • Intradialytic Iron – Soluble Ferric Pyrophosphate • HIF stabliisers • Hepcidin Targets 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 Limitations of oral iron and better Hb response with IV iron

McDougall et al. KI 1996 Risks of IV Iron • Anaphylactic reactions

• Hypophosphataemia

• Labile reactions (too much too rapidly)

• Increased oxidative stress

• Iron overload

• Increased susceptibility to infections Monitoring Iron

Aim for : • Serum ferritin 100-500 microg/l • TSAT 30-40% 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. 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 1989.

• 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? CHOIR (n = 717)

Singh et al. Correction of anemia with epoetin alfa in chronic kidney disease, N Engl J Med, 2006 CREATE (n=605) st Group 1: hb 13-15 g/dL Time to 1 CV Event Group 2: 10.5-11.5g/dL

Time to CV death

Drueke et al., Normalisation of Hb levels in patients with CKD and Anaemia, NEJM 2006. TREAT (n=4038) • Double-blind RCT • 24 countries. • 623 sites

Group 1: Target Hb 13 g/dL

Group 2: No ESA until Hb < 9g/dL

Pfeffer et al., NEJM 2009. TREAT: Safety Concerns 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 Causes of ESA Resistance

Easily Correctable • Iron Deficiency Potentially Correctable • Underdialysis • Aluminum overload (now rare) • ACEi and ARBs (ESA resistance) • Compliance • Vitamin B12 or Folate deficiency • Bleeding • Hypothyroidism • PRCA • Infection • Hyperparathyroidism

Difficult to Correct • Occult Malignancy • Unsuspected haematological disorders • Chronic inflammation Hepcidin targets Hypoxia Inducible Factor-1 ODD Domain • Produced by most cells in response to hypoxia HIF1-alpha • Dimer of 2 proteins: HIF1-alpha and HIF1-beta HIF1-beta

• 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 Hypoxia Inducible Factor stabilisers Phase 2 clinical trials

“Off Target” Effects 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 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. • 74 year old male Case 3 • 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 Investigations

Bone Marrow Reticulocyte Count Biopsy 9 Absence of erythroid Case 1 : 28 x 10 /mL 9 precursor cells with Case 2: 4.2 x 10 /mL 9 otherwise normal features Case 3: 5 x 10 /mL

Erythropoietin antibodies

Diagnosis ? 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 1998 – 2003 • 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 Pure Red Cell Aplasia: Diagnosis and Management

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