RENAL ANAEMIA

South West Renal Training SchemeCardiff October 2018

Dr Soma MeranClinical 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

Physiology of AnaemiaMechanism of Erythropoiesis

Role of Hepcidin in Renal Anaemia

Mechanisms of anaemia in CKD

Anaemia in CKD

Decreased EPO production

Iron deficiency (malnutrition & poor

absorbtion)

B12 and Folate deficiency

CKD and mineral bone disorders

Blood loss – circuit or GI bleeds

Bone Marrow suppression by

uraemia

Medication e.g. ACE inhibitors

Co-morbidities

High hepcidin, infection & inflammation

Diagnosis of iron deficiency

Absolute Iron Deficiency

Low Fe stores

CRP < 10 mg/L

Low Hepcidin Levels

Low serum Ferritin < 100 ng/mL

TSAT < 20 %

Functional Iron Deficiency(Fe sequestration)

High Fe stores

CRP > 20 mg/L

High hepcidin levels

Serum Ferritin > 100ng/mL

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, etal. 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

Oral Irons

• Ferrous Sulphate, Ferrous Gluconate

• New Iron preparations: Iron Maltol, Heame Polypeptide

• Iron based phosphate binders – Ferric Citrate

Intravenous Irons

• CosmoFer (Iron Dextran) – LMW

• Diafer (Iron Isomatoloside 1000

• Ferinject (Ferric Caroxymaltose)

• Monofer (Iron Isomaltoside 1000)

• Venofer (Iron Sucrose)

Others • Intradialytic Iron – Soluble Ferric Pyrophosphate • HIF stabliisers• Hepcidin Targets

Oral Iron has efficacy in Non-Dialysis Dependent CKD patients

Fishbane et al., JASN 2017

• RCT comparing Fe Citrate versus placebo

• N = 232

• Primary EP: increase in Hbby 1 g/dl in 16 weeks

• GI disorders most common adverse event.

Limitations of oral iron and better Hb response with IV iron

McDougall et al. KI 1996

• Anaphylactic reactions

• Hypophosphataemia

• Labile reactions (too much too rapidly)

• Increased oxidative stress

• Iron overload

• Increased susceptibility to infections

Risks of IV Iron

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 oraliron 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 irontherapy) 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 60minutes, 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)

• Intravenous/subcutaneous

- Epoetin alpha (Eprex)- Epoetin beta (NeoRecormin)- Darbopoetin alpha (ARANESP)- Pegylated ESA – Methoxy polyethylene glycol-epoetin beta (MIRCERA)

• Recombinant Human Epo: First introduced in 1989.

• What are the Hb targets with ESAs?

• Erythropoetin: Glycoprotein produced by renal peritubular cells.Stimulates proliferation and differentiation of erythroid progenitor cells in bone marrow

CHOIR (n = 717)

Singh et al. Correction of anemia with epoetin alfa in chronic kidney disease, N Engl J Med, 2006

CREATE (n=605)

Drueke et al., Normalisation of Hb levels in patients with CKD and Anaemia, NEJM 2006.

Group 1: hb 13-15 g/dLGroup 2: 10.5-11.5g/dL

Time to 1st CV Event

Time to CV death

TREAT (n=4038)• Double-blind RCT• 24 countries.• 623 sites

Pfeffer et al., NEJM 2009.

Group 1:Target Hb 13 g/dL

Group 2: No ESAuntil Hb < 9g/dL

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

Potentially Correctable

• Aluminum overload (now rare)• Compliance• Bleeding• PRCA

Easily Correctable

• Iron Deficiency• Underdialysis• ACEi and ARBs (ESA resistance)• Vitamin B12 or Folate deficiency• Hypothyroidism• Infection• Hyperparathyroidism

Difficult to Correct • Occult Malignancy • Unsuspected haematological disorders• Chronic inflammation

Hepcidin targets

Hypoxia Inducible Factor-1

• Dimer of 2 proteins: HIF1-alpha and HIF1-beta

• Produced by most cells in response to hypoxia

• HIF1-beta constitutively expressed• HIF1-alpha has an oxygen dependent degradation (ODD) domain, and is quickly degraded

in “normoxic” conditions

HIF1-alpha

HIF1-beta

ODD Domain

• 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 stabilisersPhase 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.

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

Reticulocyte Count

Case 1 : 28 x 109/mLCase 2: 4.2 x 109/mLCase 3: 5 x 109/mL

Bone Marrow Biopsy

Absence of erythroid precursor cells with

otherwise normal features

Investigations

Diagnosis ?

Erythropoietin antibodies

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

• Increase transfusion requirement

• Normal platelet and WCC

• Reduced reticulocyte count

• EPO antibodies

• BM: Erythroid hypoplasia

• Stop ESA Medication

• Transfusion for symptomatic anaemia

• Immunosuppressive therapy? (IV Ig, Steroids, Rituximab, PEX)

• Peginesatide: EPO Receptor agonist

• Consider re-exposure to ESA

THANK YOU