Royal Liverpool and Broadgreen University NHS Hospital Trusts
Trust Clinical Protocol
Directorates of Renal Transplant, Nephrology and
Pharmacy
Protocol for immunosuppression following renal
transplantation (including prophylaxis of
opportunistic infection)
Document Control
Author/Contact
J.A.Sexton, (for A. Hammad/I. Hart)
Document File Path
EQMS No 107
Document impact
assessed
Yes/No
Version
2
Status
Ratified
Publication Date
7th September 2012
Review Date
7th September 2014
Approved by
Mr Walker
07/09/2012
Ratified by
Clinical and Cost
Effectiveness SubCommittee
07/09/2012
Date:
Distribution:
Royal Liverpool and Broadgreen University Hospitals NHS Trust Policy
Website
Please note that the Policy Website version of this document is the only
version that is maintained.
Any printed copies must therefore be viewed as “uncontrolled” and as such,
may not necessarily contain the latest updates and amendments.
1
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Table of Contents
Heading
Page Number
Control Sheet
1.0
Introduction
3
2.0
Objective
3
3.0
Scope of Policy
3
4.0
Policy
3
4.1 The “standard” transplant
4.2 The transplant where there are graft factors
4.3 The “non-standard” patient
4.4 Non-ABO compatible and highly sensitised donations
4.5 The management of acute rejection
4.6 Use of prophylactic anti-infective agents
4.7 Prevention of hepatitis B virus (HBV)
and varicella zoster virus (VZV) by vaccination
4
4
5
5
7
7
5.0
Roles and Responsibilities
12
6.0
Associated documentation and references
12
7.0
Training & Resources
12
8.0
Monitoring and Audit
12
8.0
Equality and Diversity
12
8.1
12
Recording and Monitoring of Equality & Diversity
Appendices
1.
Glossary of Terms used within Policy
2.
Document History/Version Control
2
8
Royal Liverpool and Broadgreen University NHS Hospital Trusts
1.0
Introduction
This protocol provides a framework to assist staff in the prescribing and
monitoring of immunosuppression following renal transplantation to adults on
the Sir Peter Medawar Renal Transplant Unit at the Royal Liverpool University
Hospital (RLUH). It represents the consensus view of the Consultant
Transplant Surgeons, Nephrologists and Virologists and represents the best
evidence-based practice. It is not intended to replace individual clinicians’
judgement in specific cases.
The protocol also covers the regime for transplanting of a non-ABO
compatible kidney and also steps that should be taken to minimise infection
with varicella zoster virus (VZV), cytomegalovirus (CVM) and Pneumocystis
jirovecii pneumonia in newly transplanted patients.
2.0
Objective
The objective of this protocol is to ensure that all relevant staff understand the
agreed initial choices of immunosuppression, when an adult patient is
transplanted at the RLUH, and that opportunistic infections are prevented as
much as possible.
3.0
Scope of Policy
This policy applies to all adult patients receiving a cadaveric or live-donor
kidney at the RLUH.
4.0
Policy
The policy is divided into seven areas:
4.1 The “standard” transplant
4.2 The transplant where there are graft factors
4.3 The “non-standard” patient
4.4 Non-ABO compatible and highly sensitised donations
4.5 The management of acute rejection
4.6 Use of prophylactic anti-infective agents
4.7 Prevention of hepatitis B virus (HBV) and varicella zoster virus (VZV) by
vaccination
Immunosuppression should always be prescribed by brand name, except for
prednisolone, azathioprine and mycophenolate mofetil. The use of generic
names for other immunouppressants presents the risk of the wrong
formulation being prescribed or dispensed in primary care.
LD = live donation
DBD = donation after brain death (formerly “heart-beating- HBD” donors)
DCD = donation after cardiac death (formerly “non-heart-beating- NHBD”
donors)
PRA = panel-reactive antibodies
Myfortic is allowed only if mycophenolate mofetil is not tolerated
Advagraf is allowed only if twice daily Prograf is not tolerated/stabilised
3
Royal Liverpool and Broadgreen University NHS Hospital Trusts
4.1



The “standard” transplant at the RLUH
All LRD with negative cross-match and not-sensitised (PRA <20%)
DBD (HBD) cadaveric transplants without graft factors
No “2 DR” mismatch
Induction:
0.5-1g IV methylprednisolone in theatre, with
Basiliximab (Simulect) 20mg IV on day 0 and day 4
Maintenance:
Prograf to 8-12 mcg/L for 3 months, then 5-8mcg/L thereafter, with
mycophenolate mofetil 1500-2000mg daily
All patients should receive dalteparin 2,500-5000units daily for VTE
prophylaxis until mobile and may be started on aspirin 75mg daily with PPI
cover.
4.2 Transplants with graft factors



Extended criteria DBD (HBD) cadaveric transplants (>60yrs, or >50yrs
with two or more of hypertension, creatinine >135micromol/L, or
cerebrovascular accident as cause of death)
All DCD (NHBD) cadaveric transplants
Anticipation of delayed graft function (less than 10% fall in serum
creatinine or haemodialysis required within first 24 hours post-operatively
except for hyperkalaemia)
These kidneys require a lower exposure to calcineurin inhibitor to minimise
delayed graft function.
Induction:
0.5-1g IV methylprednisolone in theatre, with
Alemtuzumab (MabCampath) 30mg SC injection perioperatively on day 0
(and again 30mg by SC injection on day 1 (day after surgery) if not over 60
years of age)
(Unlicensed use; approved by Trust Medicines Management Group but
requires patient consent documenting in the case notes)
Each dose of alemtuzumab should be preceded by 100mg hydrocortisone IV
and 10mg chlorphenamine 10mg IV. The second dose should also be
preceded by 1g paracetamol (any route).
Maintenance:
Prograf to 5-8mcg/L, with mycophenolate mofetil 1000mg daily
All patients should receive dalteparin 2,500-5000units daily for VTE
prophylaxis until mobile and should be started on aspirin 75mg daily with PPI
cover if appropriate.
4
Royal Liverpool and Broadgreen University NHS Hospital Trusts
4.3 The “non-standard” risk patient



All patients with 2 DR mismatch
All patients with PRA >20%
Second transplant where first transplant had early graft loss due to acute
rejection
These kidneys require a higher degree of immunosuppression to minimise the
risk of graft loss due to acute rejection.
Induction:
0.5-1g IV methylprednisolone in theatre, with
Alemtuzumab (MabCampath) 30mg SC injection perioperatively on day 0
(and again 30mg by SC injection on day 1 (day after surgery) if not over 60
years of age)
(Unlicensed use; approved by Trust Medicines Management Group but
requires patient consent documenting in the case notes)
Each dose of alemtuzumab should be preceded by 100mg hydrocortisone IV
and 10mg chlorphenamine 10mg IV. The second dose should also be
preceded by 1g paracetamol (any route).
Maintenance:
Prograf to 8-12 mcg/L for 6 months, then 5-8mcg/L thereafter, with
mycophenolate 1000mg daily with prednisolone if required.**
**(Where the patient was >60 years and had only one dose of
alemtuzumab, give all patients prednisolone 20mg for one week and
taper to zero over three months).
All patients should receive dalteparin 2,500-5000units daily for VTE
prophylaxis until mobile and should be started on aspirin 75mg daily with PPI
cover if appropriate.
4.4
Transplanting from a live donor where there is ABO
incompatibility or highly sensitised recipient status.
Emerging evidence shows that if managed well, ABO and HLA incompatible
transplants can have similar results to standard transplantation. The RLBUHT
Transplant Unit has received permission to follow the Tyden protocol (see
references). If no suitable ABO compatible LD kidney is available, but an
ABO-incompatible kidney is offered, informed consent should be obtained
providing relevant blood group antibody titres of less than or equal to 1/256
are measured.
5
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Treatment schedule
Antibody titres of less than 1:8 prior to transplant are associated with a good
outcome; if not then an extra week (4 more sessions of immunoabsorption)
should be performed prior to transplantation. Antigen-specific
immunoabsorption is performed using AC-D citrate anticoagulant solution.
The schedule below is for ABO-incompatible transplantation although highlysensitised patients may require a less intensive regime, possibly involving
anti-thymocyte globulin but not plasmapheresis. The precise regime used will
be decided by the multi-disciplinary team meeting prior to transplantation.
Day
(in relation to
Transplant)
-30
Action
Notes
Rituximab 375mg/m2 (according
to Pharmacy administration
protocol)
-13
Stop any ACE-Is and ARBs
-10
-6
Start regular
immunosuppression
maintenance regime
Plasmapheresis 1
NOT if allergy to
mouse proteins,
infections, or severe
heart failure.
These increase the
risk of reactions during
immunoabsoption
Normal posttransplantation
practice
-4
Plasmapheresis 2
-2
Plasmapheresis 3
-1
Plasmapheresis 4
Give 0.5g/kg IV
immunoglobulin (preferably
Privigen)
0
Transplant performed
Basiliximab and steroid
induction regimen
+3
Plasmapheresis 5
+6
Plasmapheresis 6
+9
Plasmapheresis 7
6
Administration as per
Trust policy. Prior
approval not needed
but pharmacists to
complete Trust
documentation.
NOT if antibody titres
>1:8 (see above)
Royal Liverpool and Broadgreen University NHS Hospital Trusts
4.5
Management of acute rejection
4.5.1 Acute cellular rejection
Methylprednisolone 0.5-1g IV for 3 days
Partial response (creatinine falls but still more than 20% over baseline on day
5): oral prednisolone 100mg reducing to 20mg over 8 days. If steroid resistant
rejection; no response or worsening of renal function; then consider antithymocyte globulin (ATG).
4.5.2 Acute vascular rejection
Antithymocyte globulin (ATG) (Thymoglobuline) 1.5-3mg/kg through a central
line (unlicensed dose and frequency), (following IV chlorphenamine 10mg and
oral paracetamol 1g, and IV steroid if not already on a steroid). The patient is
redosed when CD3 count rises to 50/microlitre (0.050x109/L) to cover a 14
day period. (This is an unlicensed dose regime).
Tacrolimus and mycophenolate preparations are stopped on initiation of ATG
and restarted on day 10; oral prednisolone 20mg daily is started on initiation.
4.4.3 Antibody-mediated rejection (diagnosed on C4D/DSA)
Plasma exchange plus IV immunoglobulin 0.5g/kg daily for 5 days, and then
according to response.
Dalteparin at therapeutic dose can be used if evidence of high resistive index
(>95 on Doppler scan) or biopsy proven thrombotic arteritis.
Rituximab is an option if C4D staining/DSA confirm the diagnosis.
4.6 Prophylaxis of infection
4.6.1 Pneumocystis carinii pneumonia
Co-trimoxazole 480mg daily to all patients for 6 months. A three month
course should be initiated after this period if a transplant patient has
their immunosuppression changed or increased. (European Best
Practice Guidelines, Nephrol Dial Transplant (2002) 17: 36-39). If
patients are allergic to co-trimoxazole, or this causes dyscrasias,
dapsone 50mg BD may be used.
4.6.3 Cytomegalovirus prophylaxis
CMV status of potential recipients is to be tested for every six months.
CMV negative patients are asked if they would accept a kidney from a
CMV-positive donor. After transplant, valganciclovir is prescribed for
100days as below.
Donor(D)/Recipient(R) combinations:
D-ve/R-ve Not required
D-ve/R+ve REQUIRED IF HAD ALEMTUZUMAB/ATG
D+ve/R+ve REQUIRED IF HAD ALEMTUZUMAB/ATG
D+ve/R-ve REQUIRED FOR ALL TRANSPLANT PATIENTS
7
Royal Liverpool and Broadgreen University NHS Hospital Trusts
4.7
Prevention of hepatitis B virus (HBV) and varicella zoster virus
(VZV) by vaccination
There is a Trust protocol for screening and vaccinating dialysis and
pre-dialysis patients against hepatitis B virus (HBV). The earlier in the
chronic kidney disease process a patient is vaccinated the more likely
vaccination is to achieve adequate immune response. Vaccination can
be carried out during immune suppression but is much less effective.
Patients listed for transplant must have their HBV immune status
documented at the time of listing.
VZV can carry the risk of producing life-threatening illness in the
immunocompromised. It is thus important to ensure that all patients
awaiting transplantation are screened to ensure immunity (usually
conferred by childhood chicken pox) and offered vaccination BEFORE
TRANSPLANT if appropriate, although contraindications may preclude
this.
If a patient is unsuitable for or declines vaccination, full documentation
should be made in the case notes. These patients should be warned to
avoid contact with patients with chickenpox or shingles if they are
transplanted and immunosuppressed. Any contact requires hospital
referral; suspicion of varicella or shingles contact should be treated as
an emergency and discussed with a Consultant Medical Virologist.
4.7.1 Contraindications to VZV vaccination
Varicella zoster virus (VZV) vaccine is a live vaccine and unsuitable for
use in patients who are already immunocompromised, including all
those receiving immunosuppression of any sort, including high-dose
oral steroid therapy.
Other contraindications include:
 Pregnancy- avoid between doses and for three months after the
second vaccination
 Breast feeding
 Sensitivity to neomycin or other excipients
 Reactions to the first dose
 Acute febrile illnesses
 Blood dyscrasias
8
Royal Liverpool and Broadgreen University NHS Hospital Trusts
4.7.2 Following vaccination
Patients requiring VZV vaccination will need to be suspended from or
deferred entry to the Transplant list for the 8 weeks between doses and
for three months afterwards- a total of 5 months. During this time,
pregnancy MUST be avoided and newly vaccinated patients should
avoid close contact for at least six weeks with immune-negative
pregnant patients and the immunocompromised. This becomes
essential if the vaccinated patient develops skin lesions after
vaccination.
Six weeks after vaccination the patient’s VZV immune status should be
checked. Following this, three months after the second vaccination the
patient can be activated on the Transplant waiting list again.
9
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Sir Peter Medawar Unit/Renal Transplant Unit
Dr M Howse
Date
Tel: 0151 706 3517
Fax: 0151 706 5439
MH/LBS
Dear Patient
Re: Vaccination Against Chickenpox Before Transplantation
The Royal Liverpool University Hospital Transplant Unit has recently been
reviewing its policies for patients waiting for kidney transplants. We have
decided to offer patients who do not have immunity to chickenpox a
vaccination against chickenpox. This is because chickenpox infection after a
kidney transplant can sometimes be a serious disease.
Your blood tests show that you are not immune against chickenpox and we
would, therefore, like to offer you this vaccination.
What Does Vaccination Entail?
Vaccination involves two injections given eight weeks apart. These contain a
live-virus that has been altered so it cannot cause disease. The injections will
be given by Jane Smith, our Nurse Clinician on Ward 9A.
Who Should Not Have The Vaccination?
People undergoing treatment for cancers with chemotherapy and those on
high doses of steroids should not have the vaccine. If you live with someone
with someone with these conditions you should not be vaccinated. Similarly
people suffering from AIDS and women who are, or could be, pregnant or
breastfeeding should not be vaccinated.
How Effective Is The Vaccine?
The vaccine will make between 60 and 70% of people immune to chickenpox.
They will have a greatly reduced risk of developing the disease following
transplantation.
10
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Are there any side effects from the vaccination?
Serious side effects are very uncommon but include allergic reactions.
However, patients often experience symptoms of a “cold” for a few days after
the injection. You must not become pregnant for 3 months after the vaccine.
Can I Remain On The Transplant List At The Time Of Examination?
You will have to be suspended from the transplant list for a period of 18
weeks following the 1st injection. During this time you will continue to be
accredited waiting time points by the UK Transplant System.
Can I Have The Vaccine After Transplantation?
Because the vaccine is live you cannot receive after the transplant
I Think I Have Had Chickenpox – Should I Have The Vaccine?
In this case you should have the blood test for immunity repeated. If the
repeat test shows you are not immune we recommend you have the vaccine.
Do I have to have the Vaccination?
The decision for vaccination is yours alone although we would recommend it.
You may wish to discuss your decision with family and friends, your General
Practitioner, Nephrologist or Transplant Surgeon.
If you wish to have the vaccine, or would like further information please
contact Jane Smith on 0151 706 ****
Yours sincerely
Dr M Howse
Consultant Nephrologist
11
Royal Liverpool and Broadgreen University NHS Hospital Trusts
5.0
Roles and Responsibilities
Responsibility for the approval and implementation of this protocol lies
with the Clinical Director of Renal Transplant. All clinical staff, and
especially medical staff and pharmacists are required to work within it,
or document deviation from it.
6.0



Associated documentation and references
Guidance is drawn from established RLBUHT practice and:
British Transplantion Society (2011) Guidelines for antibodyincompatible transplantation.
British Transplantation Society (2011) Guidelines for the Prevention
and Management of CMV Disease after Solid Organ Transplantation
Tyden G, Kumlien G, Genberg H et al. ABO-incompatible kidney
transplantation without splenectomy using antigen specific
immunoadsorption and rituximab. American Journal of Transplantation
2004;5(1):145-8.
7.0
Training & Resources
No change in practice is required to implement this protocol.
New medical staff are inducted within the Renal Transplant Directorate.
8.0
Monitoring and Audit
It is not expected that audit of compliance with this protocol will be
required. Deviations from it must be confirmed by pharmacists before
authorising medication prescriptions.
9.0
Equality and Diversity
Trust is committed to an environment that promotes equality and
embraces diversity in its performance as an employer and service
provider. It will adhere to legal and performance requirements and will
mainstream equality and diversity principles through its policies,
procedures and processes. This policy should be implemented with
due regard to this commitment.
To ensure that the implementation of this policy does not have an
adverse impact in response to the requirements of the Equality Act
2010 this policy has been screened for relevance during the policy
development process and a full equality impact analysis conducted
where necessary prior to consultation. The Trust will take remedial
action when necessary to address any unexpected or unwarranted
disparities and monitor practice to ensure that this policy is fairly
implemented.
This policy and procedure can be made available in alternative formats
on request including large print, Braille, moon, audio, and different
languages. To arrange this please refer to the Trust translation and
interpretation policy in the first instance.
12
Royal Liverpool and Broadgreen University NHS Hospital Trusts
The Trust will endeavour to make reasonable adjustments to
accommodate any employee/patient with particular equality and
diversity requirements in implementing this policy and procedure. This
may include accessibility of meeting/appointment venues, providing
translation, arranging an interpreter to attend appointments/meetings,
extending policy timeframes to enable translation to be undertaken, or
assistance with formulating any written statements.
9.1
Recording and Monitoring of Equality & Diversity
The Trust understands the business case for equality and diversity and
will make sure that this is translated into practice. Accordingly, all
policies and procedures will be monitored to ensure their effectiveness.
Monitoring information will be collated, analysed and published on an
annual basis as part Equality Delivery System. The monitoring will
cover the nine protected characteristics and will meet statutory duties
under the Equality Act 2010. Where adverse impact is identified
through the monitoring process the Trust will investigate and take
corrective action to mitigate and prevent any negative impact.
The information collected for monitoring and reporting purposes will be
treated as confidential and it will not be used for any other purpose.
13
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Appendix 1
Glossary of Terms used within Policy
ABO-incompatibility
Calcineurin inhibitor
Extended-criteria grafts
Immunosuppressant
Induction
immunosuppressant
Graft
Highly sensitised
Maintenance
immunosuppressant
Renal transplant
Where the donor and recipient have different blood
groups
An immunosuppressant of the class that
tacrolimus and ciclosporin belong to.
Kidneys from donors who are older or sicker than
average leading to an anticipation of delayed graft
function
A therapy that reduces the likelihood of an organ
being rejected
One given at the time of transplantation
The transplanted organ
Recipients who are at high risk of rejecting new
kidney
One given in the longer term after transplantation
The transplantation of a kidney from a living or
cadaveric (deceased) donor into a recipient with
chronic kidney disease
Maintain a record of the documents history or reviews and key changes
made, including versions and dates)
14
Royal Liverpool and Broadgreen University NHS Hospital Trusts
Appendix 2
Version
Date
1
25/5/12
2
July 2012
Comments
Author
Preparation of first draft
J Sexton
based on three existing but
expired protocols and
policies
(Previous
immunosuppression protocol,
non-ABO protocol, and VZV
protocol, all now expired)
Comments from Consultant
Transplant Surgeons
incorporated
J Sexton
Review Process Prior to Ratification:
Name of Group/Department/Committee
Medicines Management Group
Clinical & Cost Effectiveness Group
15
Date
August 2012
September 2012