Anaemia Secondary to Chronic Kidney Disease ( CKD ) in Childhood and Adolescence - Guidelines for the Management of

Publication: 01/01/2010  --
Last review: 22/01/2018  
Next review: 22/01/2021  
Clinical Guideline
CURRENT 
ID: 1931 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the Management of Anaemia Secondary to Chronic Kidney Disease (CKD) in Childhood and Adolescence

Background

The normal distribution of Haemoglobin concentration (Hb) varies according to age, sex, ethnicity and altitude. There is however considerable variation within the population having normal renal function. A diagnosis of anaemia secondary to chronic kidney disease (CKD) can be made if there is significant renal impairment and no other cause of anaemia can be identified.

There is a large volume of data supporting improved quality of life/well being and decrease in co-morbidity with correction of anaemia in CKD. Erythropoietin deficiency is the primary cause of renal anaemia. Erythropoietin is produced by peritubular cells and maintains normal proliferation and differentiation of erythroid progenitor cells in the bone marrow.

Treatment of anaemia in CKD requires the use of erythropoiesis-stimulating agents (ESAs) and iron supplementation. Patients with CKD have increased iron requirements especially on haemodialysis (HD). This is due to decreased iron absorption and increased losses. Supplementary iron is also required to obtain maximum benefits from ESAs. A small number of pre-dialysis patients may see an improvement in Hb with iron supplementation alone before ESAs are indicated. Intravenous administration is the optimum route for delivery of iron.

Serum ferritin is the standard test used to assess iron stores. Ferritin may also increase during inflammation, malignancy and liver disease. However functional iron deficiency may exist even when ferritin levels are elevated. The availability of iron can be determined by either % hypochromic rbc (% cells with <28g/dL of Hb) or saturation of transferrin receptors (TSAT).

% hypochromic rbc <2.5% = normal
% hypochromic rbc > 6% = definite functional iron deficiency

TSAT is usually expressed as the percentage of total iron binding capacity (TIBC) [serum iron/TIBC x 100%]. TSAT < 20% is indicative of functional iron deficiency. However TSAT is very variable being affected by serum albumin level and cytokine release.

Hb content of reticulocytes, zinc protoporphyrin and circulating transferrin receptors are other possible indicators of iron availability

These Departmental Guidelines are based upon NICE clinical guideline 39, “Anaemia Management in Chronic Kidney Disease: National clinical guideline for management in adults and children.” www.nice.org.uk/CG039

Modifications in target Hb have been made in accordance with latest Summary of Product Characteristics (SPC) for NeoRecormon® (epoetin beta) and Aranesp® (darbepoetin alfa) updated on the electronic Medicines Compendium (eMC). Further information on product information is available from the European Medicines Agency (EMEA). www.emea.europa.eu

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Definitions

Anaemia secondary to CKD
Hb < 11g/dL (or <10g/dL in child < 2 years of age)
In children with eGFR < 60mL/min/1.73m2 where non-renal causes and haematinic deficiency have been excluded.

Iron deficiency anaemia in CKD
Serum ferritin < 100micrograms/L
In children with eGFR < 15mL/min/1.73m2
(Plus considered with eGFR < 60mL/min/1.73m2).

Functional iron deficiency anaemia in CKD
Anaemia associated with serum ferritin > 100micrograms/L
in association with either
% hypochromic rbc (HRC) > 6%
or TSAT < 20%  

Children with functional iron deficiency are most likely to benefit from intravenous (IV) iron supplementation.

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Differential Diagnosis & Investigation

Other causes of anaemia in CKD

Chronic blood loss

Vitamin B12 or folate deficiency

Hypothyroidism

Chronic infection or inflammation

Hyperparathyroidism

Haemolysis

Bone marrow infiltration

Malignancy

Pure red cell aplasia

Aluminium toxicity

Drugs e.g. ACEI/ Mycophenolate mofetil (MMF) / Azathioprine/ co-trimoxazole

Assessment of Anaemia requires:
Hb concentration
Rbc indices (MCV, MCH)
Serum ferritin – to assess iron stores
Percentage hypochromic red blood cells / transferrin saturation – measurement of functional iron availability
CRP – to assess inflammation
B12, folate

Additional tests that maybe indicated:
Hb electrophoresis
Haemolysis(Coomb’s test, haptoglobin, LDH, bilirubin)
Blood film/ bone marrow aspirate
PTH
Thyroid function tests
Absolute reticulocyte count – to assess erythropoietic activity
Serum aluminium 
Erythropoietin antibody titre 

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When to consider treating anaemia secondary to CKD

Treatment should be considered in CKD when Hb ≤ 11g/dL (or ≤ 10g/dL in children < 2 years) in symptomatic patients.

In pre-dialysis patients, absolute or functional iron deficiency should be corrected before deciding whether ESA therapy is necessary.

Dialysis patients will require iron therapy in combination with ESAs.

Peritoneal dialysis and pre-dialysis patients who do not respond to oral iron or have evidence of functional iron deficiency should be given intravenous iron.

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Targets

Haemoglobin:
Hb 10.0 – 12.0 g/dL for adults and children ≥ 6months
Hb 9.5 – 11.5g/dL for children < 6months

Iron stores:
Serum ferritin between 200micrograms/L and 500micrograms/L in both haemodialysis and non-haemodialysis patients

And either
% hypochromic red cells (HRC) < 6% (unless ferritin > 500 microgram/L)
or transferrin saturation (TSAT) > 20% (unless ferritin > 500 microgram/L)

Note:
Ferritin is an acute phase protein which will rise during infection and inflammation and this should be taken into account when interpreting results.

Therefore:
Ferritin levels above 800micrograms/L should be avoided as there is a risk of haemosiderosis.
Ferritin levels between 500 - 800micrograms/L should be repeated after a week interval if there is a possibility of infection before alteration of iron dose.

Refer to Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age

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Monitoring

Aim is to keep rate of Hb increase ≥ 1g/dL and ≤ 2g/dL in 4 weeks.

Haemoglobin: 
Every 2-4 weeks in induction phase of ESA therapy
Every 1-3 months in maintenance phase of ESA therapy
More frequently (every 1-2 weeks) after any ESA dose adjustment or change in route of administration or when switching from recombinant human erythropoietin (r-HuEpo) e.g. NeoRecormon® to Aranesp®.

Serum ferritin and %RCH should be assessed:
Monthly on Haemodialysis (HD)
Up to 3 monthly on Peritoneal dialysis (PD)/ pre-dialysis

 

Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age

Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age

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Prescription of erythropoiesis-stimulating agents (ESAs) & Dose adjustment of ESAs:

Starting Dose **:

Table 1: NeoRecormon® (Epoetin beta): for all ages

Administration Route

Correction Phase (Hb < 10g/dL)

Maintenance Phase (Hb ≥ 10g/dL ≤ 12g/dL)

Sub-cutaneous (SC)

Initially 20 units/kg 3 times weekly for 4 weeks

Increased according to response at intervals of 4 weeks in steps of 20 units/kg 3 times weekly if the rate of rise in Hb <1g/dL over 4 weeks. 

Once Hb ≥10g/dL prescribe 50% of the correction phase dose.

Reduce dose by approximately 25% if rise in haemoglobin concentration exceeds 2 g/dL over 4 weeks or if Hb concentration approaches or exceeds 12 g/dL. 

Intravenous (IV)

Initially 40 units/kg 3 times weekly for 4 weeks

Increased if rise in Hb< 1g/dL over 4 weeks up to 80 units/kg 3 times weekly after 4 weeks.

 Thereafter, if required further increase dose at intervals of 4 weeks in steps of 20 units/kg 3 times weekly. 

Once Hb ≥ 10g/dL prescribe 50% of the correction phase dose.

Reduce dose by approximately 25% if rise in haemoglobin concentration exceeds 2 g/dL over 4 weeks or if Hb concentration approaches or exceeds 12 g/dL.

Maximum dose

720 international units/kg/week

 

 
Table 2: Aranesp® (Darbepoetin alfa)

Age

Administration Route

Correction Phase (Hb < 10g/dL)

Maintenance Phase (Hb ≥ 10g/dL ≤ 12g/dL)

≥ 11 years

SC

0.45 micrograms/kg/week
Or
0.75micrograms/kg/fortnight

If Hb increase <1g/dL over four weeks increase dose by 25%*

Continue weekly at same dose as final correction dose or double dose fortnightly.
May be given up to monthly in pre-dialysis patients.

≥ 11 years

IV

0.45 micrograms/kg/week

If increase <1g/dL over four weeks increase dose by 25%

Continue weekly at same dose as final correction dose or double dose fortnightly.

< 11 years

IV or SC

No data on correction dose in this age group

Switch from r-HuEpo – see conversion

** All children < 11years of age should be commenced initially on NeoRecormon® (Epoetin beta). Children <11years on haemodialysis may then be switched to IV Aranesp® (Darbepoetin alfa) once target Hb level has been achieved.
Children ≥ 11 years may be commenced on either NeoRecormon® (Epoetin beta) or Aranesp® (Darbepoetin alfa) according to patient preference.

ESA dose adjustments

Dose adjustments should only occur every 4 weeks unless Hb > 12g/dL

If increase in Hb is inadequate i.e. <1g/dL in four weeks see Table 1 or 2.

If increase in Hb excessive i.e. > 2g/dL in four weeks or Hb >12g/dL then reduce ESA dose by approximately 25%*. Recheck Hb after 2 weeks, if Hb continues to rise reduce ESA dose by a further 25%* and if Hb >13.5g/dL omit ESA until Hb falls and is <12.5g/dL and restart at a dose 25%* less than last administered ESA dose.

* When making ESA dose alterations round dose to the nearest measurable unit dose for NeoRecormon® (see table 4) or 5-10 micrograms Aranesp®

ESA administration:

ESAs are routinely given IV for HD patients and SC for PD and pre-dialysis patients.

NeoRecormon® can be administered up to three times per week in correction phase followed by weekly and up to fortnightly in maintenance phase.

Aranesp® is generally given weekly in correction phase and weekly or every fortnight in maintenance phase. It can be given monthly in pre-dialysis patients once they have attained target Hb.

Conversion from NeoRecormon® to Aranesp®:

Paediatric dose of Aranesp® (microgram/week) can be determined by dividing the total weekly dose of NeoRecormon® (International units/week) by 240. Due to the individual variability, titration to the optimal therapeutic dose is expected for individual patients. When substituting Aranesp® for NeoRecormon® the Hb should be monitored every one or two weeks and the same route of administration should be used. Dosing should be titrated as necessary to maintain the Hb in target range.

NOTE: Intravenous and subcutaneous Aranesp® are dose equivalent, however some studies have shown that NeoRecormon® given intravenously is less potent than when given subcutaneously.  Local practice is not to amend the NeoRecormon® dose when switching the route of administration but to monitor Hb carefully and adjust doses accordingly after 4 weeks.

ESA storage:
Store at 2 to 8 °C, do not freeze, keep the container in the outer carton, in order to protect from light.

 

Table 3: ESA storage information

ESA and preparation

Maximum storage out of the refrigerator

NeoRecormon® pre-filled syringes

For the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 3 days.

Dispose of any used/ expired syringes in provided sharps bin

Aranesp® pre-filled syringes
 
and

Aranesp® SureClick device.

For the purpose of ambulatory use, Aranesp may be removed from storage once for a maximum single period of seven days at room temperature (up to 25°C). Once a syringe has been removed from the refrigerator and has reached room temperature (up to 25°C) it must either be used within 7 days or disposed of.

Dispose of any used/ expired syringes and SureClick devices in provided sharps bin

 

 

Table 4: Available ESA products and suggested uses

Age, modality & administration route

Drug

Preparation(s)

Dose options

Comments

Age: Any

Hb correction or maintenance

PD or pre-dialysis

Route: SC

OR

Age: Any

Hb correction or maintenance

HD

Route: IV

Epoetin beta

NeoRecormon® pre-filled syringe, preservative free, single use, variable dose.

NeoRecormon® pre-filled syringes are licensed from the age of 1 year and do not contain benzyl alcohol. 

The needle included with each 500 unit pre-filled syringe is 30G, half inch.
The needle included with each 2000 or 3000 unit pre-filled syringe is 27G, half inch.
 
Shorter BD Microlance® needles are available from supplies dept (0.45 x 10mm) if needed. 

NeoRecormon®
500 unit pre-filled syringe
(turquoise)

200 units
300 units
400 units
500 units

 

NeoRecormon® 2000 unit pre-filled syringe (orange)

1000 units
1500 units
2000 units

 

NeoRecormon® 3000 unit pre-filled syringe
(blue)

1500 units
2000 units
2500 units
3000 units

 

Age: >11 years

PD or pre-dialysis

Route: SC

OR

Age: > 11 year

HD

Route: IV

NOTE: Aransep® is only licensed and should only be prescribed for initial Hb correction in patients ≥ 11 years.

Darbepoetin alfa

Aranesp® pre-filled syringes preservative free, single use, variable dose.
OR
Aranesp® SureClick® preservative-free single use pre-filled pen.
SureClick® subcutaneous pen devices may produce large bruises in small children and therefore is reserved for children over 25kg.
Aranesp® currently holds the LTHT ESA contract.  Children registered with this service will have Aranesp® delivered to a designated address (e.g. home) as per homecare prescription.

Aranesp® preservative-free single use, variable dose pre-filled syringes

OR

Aranesp® SureClick® preservative-free standard dose single use pre-filled pen.

10 micrograms
15 micrograms
20 micrograms
30 micrograms
40 micrograms
50 micrograms
60 micrograms
80 micrograms
100 micrograms
130 micrograms
150 micrograms
300 micrograms
500 micrograms

NOTE: All strengths of pre-filled syringes and SureClick® pens are available through homecare; however, LTHT do NOT stock all strengths of the SureClick® device.

Note: NeoRecormon® 10,000 and 20,000 cartridges for Recopen and the 1000 unit pre-filled syringes were discontinued by Roche Ltd in January 2010 for financial reasons.

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Prescription of maintenance intravenous iron & correction of iron deficiency

Preparation concentration & storage
Intravenous iron(III)-hydroxide sucrose complex (Venofer®) 100mg in 5 mL (20mg/mL)

Do not store above 25°C

Maintenance dose

Weight < 50kg: 1mg/kg weekly as single IV dose on HD
3mg/kg monthly as single IV dose on PD/ pre-dialysis
Weight > 50kg: 50mg weekly as single IV dose on HD
150mg monthly as single IV dose on PD/ pre-dialysis

 

Correction dose

Total iron deficit = [wt (kg) x (target Hb [g/L] – actual Hb [g/L]) x 0.24] + depot iron

Note: Calculation to determine iron deficit must use Hb in g/L i.e. Hb of 10g/dL = 100g/L

Target Hb varies with age

Depot iron

Weight < 35 kg: 15mg/kg to a maximum of 500mg
Weight > 35kg: 500mg total 

Iron correction should be given in divided doses over 4 to 6 weeks. Each dose administered should not exceed 3mg/kg (up to a maximum of 200mg/dose). No more than 3 doses should be administered each week. If the total necessary dose exceeds the maximum allowed single dose, then administration has to be split.

Worked example:
Patient 15kg
Hb 7g/dL i.e. 70g/L
Target Hb 110g/L
Iron deficit = [15 x (110 – 70) x 0.24] + (15 x 15)
= 369mg (rounded to 360mg)
Maximum dose per session = 3mg/kg ie 45mg
Therefore give Venofer® 45mg twice per week for four weeks and then review

Administration of intravenous iron sucrose (Venofer®):

Venofer® should be prescribed by a doctor on an infusion chart.

Anaphylactic reactions are rare however the first dose of Venofer® should be administered in a clinical setting with full resuscitation facilities available.

Dilute Venofer® to at least 1mg/mL with normal 0.9% sodium chloride.

A test dose is required at the start of treatment with a doctor present. Test dose is a 25% of total dose (not to exceed 20mg) to be given at HD session/ clinic visit. This should be infused over 15 minutes. If there are no adverse events over a further 15 minutes then the remainder of the dose should be given over 30 - 60minutes. (Infusion rate not to exceed 3mg/kg/hr)

Further doses of Venofer® may be administered over 30 to 60 minutes (infusion rate not to exceed 3mg/kg/hr) in clinic via a peripheral cannula or in the latter half of haemodialysis via the dialysis circuit. Hypotensive episodes may occur if the injection is administered too rapidly.

Pre and post infusion blood pressure (BP) should be checked and the patient observed for 15 minutes following the end of the infusion.

Para-venous leakage (extravasation***) must be avoided because leakage of Venofer® at the injection site may lead to pain, inflammation, tissue necrosis and brown discoloration of the skin.

Note: Intravenous iron may in theory impede neutrophil function and therefore should be omitted when patient shows signs of sepsis ie fever, raised CRP.

***Action to be taken in event of extravasation of Venofer®

  1. Remove cannula
  2. Apply cold compress
  3. Elevate limb
  4. Encourage mobilisation
  5. Give analgesia appropriate for patient
  6. DO NOT massage area as this will distribute the iron
  7. Contact duty pharmacist for further advice if required

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Management of resistant anaemia

Loss of Effect (LOE) is defined as a sudden decrease in Hb
(≥ 2g/dL within one month) without any other contributing factor in a patient who has received a therapeutically effective dose of an ESA for at least 3 weeks with a previously stable Hb.

A differential diagnosis and additional investigations should be carried out as per guidelines.

In the absence of an identifiable cause Pure Red Cell Aplasia (PRCA) should be considered.

PRCA is a severe anaemia characterised by the absence of RBC precursors in the bone marrow and reticulocytes < 10,000/mm3.

Causes of PRCA include:
Tumours
Autoimmune disorders
T – cell disorders
Viral infections
Medications

EPO antibody mediated PRCA
EPO antibody testing can be arranged through Ortho-Biotech (A Biopharmaceutical Division of Janssen-Cilag).  ESAs should not be given four days prior to test.

When EPO antibody mediated PRCA is suspected the ESA should be stopped.

Do not switch to another ESA.

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Provenance

Record: 1931
Objective:

Scope of Guidelines
These guidelines are aimed for use by clinicians and nurse practitioners working in the Regional Paediatric Nephrology Unit, Leeds Teaching Hospitals NHS Trust for the management of Anaemia secondary to CKD in childhood and adolescence.

The aim of these guidelines in conjunction with NICE is to achieve a more consistent approach to the management of Anaemia secondary to CKD in childhood and adolescence and thereby improve attainment of target Hb and serum ferritin levels. Maintaining target Hb levels in children and adolescents with CKD should improve general well-being and reduce lifetime risk of co-morbid factors such as coronary heart disease.

Clinical condition:

Chronic Kidney Disease

Target patient group: Children and Adolescents with Chronic Kidney Disease
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

  • “Anaemia Management in Chronic Kidney Disease: National clinical guideline for management in adults and children.” NICE clinical guideline 39. www.nice.org.uk
  • “Revised European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure.” Nephrology Dialysis Transplantation, Vol. 19 (May 2004), Suppl. 2.
  • “Strategies for iron supplementation: Oral versus intravenous.” MacDougall IC. Kidney International, Vol. 55, Suppl. 69(1999); p S-61 – S-66.
  • “Pure red-cell aplasia and epoetin therapy.” Bennett CL, Luminari S, Nissenson AR et al. N Engl J Med 2004; 351: 1403-1408.
  • electronic Medicines Compendium (eMC). SPC for Aranesp® (darbepoetin alfa) solution for injection in a pre-filled syringe, Amigen Ltd. [Online] Dec 10, 2008. [Cited: Nov 04, 2009.] http://emc.medicines.org.uk.
  • electronic Medicines Compendium (eMC). SPC for Aranesp® SureClick (darbepoetin alfa) solution for injection in a pre-filled pen, Amgen Ltd. [Online] Dec 10, 2008. [Cited: Nov 04, 2009.] http://emc.medicines.org.uk.
  • electronic Medicines Compendium (eMC). SPC for Venofer® (100 mg iron(III)-hydroxide sucrose complex per 5mL), solution for injection or concentrate for solution for infusion, Syner-Med (Pharmaceutical Products) Ltd. [Online] Oct 05, 2006. [Cited: Nov 04, 2009.] http://emc.medicines.org.uk.
  • electronic Medicines Compendium (eMC).  SPC for NeoRecormon® (epoetin beta) and solvent for solution for injection in cartridge, Roche Products Limited. [Online] Nov 05, 2008. [Cited: Nov 04, 2009.] http://emc.medicines.org.uk.
  • electronic Medicines Compendium (eMC). SPC for NeoRecormon® (epoetin beta) solution for injection in pre-filled syringe, Roche Products Limited. [Online] Nov 05, 2008. [Cited: Nov 04, 2009.] http://emc.medicines.org.uk.
  • British Medical Association, The Royal Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health, and the Neonatal and Paediatric Pharmacists Group. British National Formulary for Children (BNFC). London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 2009.
  • Tomlin, S and Arenas-Lopez, S, [ed.]. Guy's and St. Thomas', KingsCollege and UniversityLewishamHospital’s Paediatric Formulary. 7th Ed. London: Guy's and St Thomas' NHS Foundation Trust, 2005.

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Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

Suggested Audit Points:

  • Percentage of patients achieving Hb ≥10g/dL within 6 months of commencing ESA
  • Percentage of patients achieving Hb within target range within 6 months of commencing ESA
  • Percentage of patient months achieving Hb within target range within 6 months of commencing ESA
  • Percentage of patients achieving serum ferritin > 100 within 6 months of commencing ESA
  • Percentage of patients achieving serum ferritin within target range within 6 months of commencing ESA
  • Percentage of patient months achieving serum ferritin within target range within 6 months of commencing ESA
  • Average ESA usage /kg/ patient 6 months post commencement dialysis
  • Average IV iron sucrose usage/kg/ patient 6 months post commencement dialysis

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Glossary of terms and abbreviations

ACE inhibitor: Angiotensin converting enzyme inhibitor
AVF: Arterio-venous fistula
BP: Blood pressure
CKD: Chronic Kidney Disease
CRP: C-reactive protein
CVL: Central venous line
dL: Decilitre (100mL)
eGFR: estimated Glomerular Filtration Rate
EPO: Erythropoietin
ESA: Erythropoiesis stimulating agent
Hb: Haemoglobin
HD: Haemodialysis
IV: Intra-venous
LOE: Loss of effect
MCH: Mean corpuscular haemoglobin
MCV: Mean corpuscular volume
MMF: Mycophenolate mofetil
PD: Peritoneal dialysis
PRCA: Pure red cell aplasia
PTH: Parathyroid hormone
RBC: Red blood cell
r-HuEpo  
SC: Sub-cutaneous
SG: Synthetic Graft
TIBC: Total iron binding capacity
TSAT: Saturation of transferring receptors
% HRC: Percentage hypochromic red blood cells
<: Less than
≤: Less than or equal to
>: Greater than
≥: Greater than or equal to

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Equity and Diversity

The Leeds Teaching Hospitals NHS Trust is committed to ensuring that the way that we provide services and the way we recruit and treat staff reflects individual needs, promotes equality and does not discriminate unfairly against any particular individual or group.