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Guideline Summary
Guideline Title
Immunosuppression after kidney transplantation. In: Guidelines on renal transplantation.
Bibliographic Source(s)
Immunosuppression after kidney transplantation. In: Kälble T, Alcaraz A, Budde K, Humke U, Karam G, Lucan M, Nicita G, Süsal C. Guidelines on renal transplantation. Arnhem, The Netherlands: European Association of Urology (EAU); 2009 Mar. p. 55-65. [78 references]
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Transplant rejection following kidney transplantation

Guideline Category
Assessment of Therapeutic Effectiveness
Management
Prevention
Risk Assessment
Treatment
Clinical Specialty
Allergy and Immunology
Nephrology
Pharmacology
Surgery
Urology
Intended Users
Advanced Practice Nurses
Hospitals
Nurses
Pharmacists
Physician Assistants
Physicians
Guideline Objective(s)
  • To present current knowledge about renal transplantation
  • To provide recommendations for immunosuppression after kidney transplantation
Target Population

Kidney transplant recipients

Interventions and Practices Considered

Primary Immunosuppressive Prophylaxis

  1. Calcineurin inhibitors (CNIs) (cyclosporine A micro-emulsion [CsA-ME] and tacrolimus)
    • Drug level monitoring
  2. Mycophenolates (mycophenolate mofetil [MMF] and enteric-coated mycophenolate sodium [EC-MPS]) with or without tacrolimus
  3. Azathioprine
  4. Corticosteroids
  5. Mammalian target of rapamycin (m-TOR) inhibitors
    • Sirolimus, everolimus
    • Drug level monitoring
  6. T-cell depleting induction therapy such as anti-thymocyte globulin (not recommended routinely)
  7. Interleukin-2 (IL-2) receptor antibodies
    • Daclizumab, basiliximab
Major Outcomes Considered
  • Patient survival
  • Allograft survival
  • Renal function
  • Rejection rate
  • Trough levels
  • Side effects of drugs

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

A structured literature search is performed for all guidelines but this search is limited to randomised controlled trials and meta-analyses, covering at least the past three years, or up until the date of the latest text update if this exceeds the three-year period. Other excellent sources to include are other high-level evidence, Cochrane review and available high-quality guidelines produced by other expert groups or organizations. If there are no high-level data available, the only option is to include lower-level data. The choice of literature is guided by the expertise and knowledge of the Guidelines Working Group.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Level of Evidence

1a Evidence obtained from meta-analysis of randomised trials

1b Evidence obtained from at least one randomised trial

2a Evidence obtained from at least one well-designed controlled study without randomisation

2b Evidence obtained from at least one other type of well-designed quasi-experimental study

3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports

4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

General Methods Used to Formulate the Recommendations

  • The first step in the European Association of Urology (EAU) guidelines procedure is to define the main topic.
  • The second step is to establish a working group. The working groups comprise about 4 to 8 members, from several countries. Most of the working group members are academic urologists with a special interest in the topic. Specialists from other medical fields (radiotherapy, oncology, gynaecology, anaesthesiology, etc.) are included as full members of the working groups as needed. In general, general practitioners or patient representatives are not part of the working groups. Each member is appointed for a four-year period, renewable once. A chairman leads each group.
  • The third step is to collect and evaluate the underlying evidence from the published literature.
  • The fourth step is to structure and present the information. All main recommendations are summarised in boxes and the strength of the recommendation is clearly marked in three grades (A–C), depending on the evidence source upon which the recommendation is based. Every possible effort is made to make the linkage between the level of evidence and grade of recommendation as transparent as possible.

Specific Methods Used for This Guideline

As renal transplantation is very much an interdisciplinary field, the Guidelines Group contains not only urologists but also an immunologist and a nephrologist. Besides medical and technical aspects, the Guidelines Group has also considered ethical, social and political aspects. This was necessary because of the still-increasing gap between 'supply' and 'demand' for kidney transplants, and the large differences in organ donation rates between several European countries, suggesting European countries can learn from each other on how to increase organ donation rates.

There are few prospective randomised studies for most sections of the Guidelines, and sometimes none. Thus, the grades of recommendation, which are evidence-based, seldom exceed grade C. Instead, the Guidelines are well supported by a wealth of clinical experience based on several decades of work in renal transplantation, as in, for example, technical aspects of transplantation and explantation.

A level of evidence and/or grade of recommendation have been assigned where possible. The aim of grading recommendations is to provide transparency between the underlying evidence and the recommendation given.

Rating Scheme for the Strength of the Recommendations

Grade of Recommendation

  1. Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomied trial
  2. Based on well-conducted clinical studies, but without randomised clinical trials
  3. Made despite the absence of directly applicable clinical studies of good quality
Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Internal Peer Review
Description of Method of Guideline Validation

There is no formal external review prior to publication.

The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was used to analyse and assess a range of specific attributes contributing to the validity of a specific clinical guideline.

The AGREE instrument, to be used by two to four appraisers, was developed by the AGREE collaboration (www.agreecollaboration.org External Web Site Policy) using referenced sources for the evaluation of specific guidelines. (See the "Availability of Companion Documents" field for further methodology information.)

Recommendations

Major Recommendations

Note from the European Association of Urology (EAU) and the National Guideline Clearinghouse (NGC): The following recommendations were current as of the publication date. However, because EAU updates their guidelines frequently, users may wish to consult the EAU Web site External Web Site Policy for the most current version available.

Grades of recommendation (A–C) are defined at the end of the "Major Recommendations" field.

Primary Immunosuppressive Prophylaxis

Calcineurin Inhibitors (CNIs)

  • Rejection prophylaxis with CNIs represents current best practice pending publication of long-term results using newer agents. (Grade of recommendation: A)
  • The choice of CNI depends on the immunological risk, recipient characteristics, concomitant immunosuppression and socio-economic factors. (Grade of recommendation: A)
  • Blood-level monitoring of both cyclosporine and tacrolimus is mandatory to prevent under-immunosuppression (enhanced risk of rejection) and excessively high blood levels (resulting in a high risk of chronic side-effects, particularly nephrotoxicity). (Grade of recommendation: A)

Mycophenolates

  • Mycophenolates are the current standard of care. The standard dose of mycophenolate mofetil (MMF) combined with cyclosporine is 1 g twice daily (bid) or enteric-coated mycophenolate sodium (EC-MPS) 720 mg bid. (Grade of recommendation: A)
  • Combination therapy of mycophenolates with tacrolimus is not formally approved. Optimal mycophenolate dosing is not yet clear, as tacrolimus-treated patients develop higher mycophenolic acid (MPA) exposure compared to cyclosporine-treated patients. The standard starting dose of MMF combined with tacrolimus is MMF 1 g bid or EC-MPS 720 mg bid. This dosage, which is applied in most centres, is often reduced resulting in 30% to 50% lower doses at 1 year. (Grade of recommendation: A)
  • Mycophenolate drug monitoring cannot be recommended for all patients due to limited evidence supporting its benefit. (Grade of recommendation: A)

Azathioprine

  • Azathioprine may be used in a low-risk population as initial immunosuppression, especially for those intolerant to MPA formulations. (Grade of recommendation: A)
  • There is no firm evidence for the efficacy of azathioprine in combination therapy with CNIs and steroids. (Grade of recommendation: A)

Steroids

  • Initial steroid therapy remains the standard in perioperative and early post-transplant period. (Grade of recommendation: A)
  • There is increasing evidence that steroids may be safely stopped in most patients after 3 to 12 months on combination therapy with CNI and MPA. (Grade of recommendation: A)
  • Steroid-free long-term therapy is inherently associated with a reduction of steroid-induced side-effects. (Grade of recommendation: A)

Inhibitors of the Mammalian Target of Rapamycin (m-TOR)

  • Acute rejection can be effectively prevented by m-TOR inhibitors, such as sirolimus and everolimus, in combination with CNIs. This combination regimen is associated with enhanced nephrotoxicity and inferior outcomes. CNI dosage must be significantly reduced to prevent aggravated nephrotoxicity. (Grade of recommendation: A)
  • Initial CNI-free combination therapy of m-TOR inhibitors with MPA and steroids is not sufficient to effectively prevent acute rejection compared to a standard regimen. (Grade of recommendation: A)
  • Use of m-TOR inhibitors is associated with impaired wound healing. Prophylactic surgical measures must be implemented if patients receive m-TOR inhibitors during the peri-operative period. (Grade of recommendation: A)
  • m-TOR inhibitors can safely replace CNIs beyond the early post-transplant period. They are a valid alternative to CNIs when there are severe CNI related side-effects (e.g., nephrotoxicity). (Grade of recommendation: A)
  • Blood levels of both sirolimus and everolimus must be measured at regular intervals. (Grade of recommendation: A)

T-cell Depleting Induction Therapy

  • Potential life-threatening side-effects of T-cell depleting biological induction therapy include a higher incidence of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative disease. (Grade of recommendation: B)
  • Use of T-cell depleting antibodies has not been associated with improved outcomes in the overall population. (Grade of recommendation: B)
  • T-cell depleting antibodies should not be routinely used in a low-risk first-transplant recipient. (Grade of recommendation: B)
  • If such induction therapy is used, the increased risks of infection and cancer must be explained to the patient before starting therapy. (Grade of recommendation: B)

Interleukin-2 Receptor (IL-2R) Antibodies

  • Use of IL-2R antibodies for preventing rejection is efficacious and safe, and effectively reduces the rate of acute rejection, enabling CNI- and steroid-sparing regimens. (Grade of recommendation: A)
  • Formal evidence for improved patient and graft outcome is lacking, although recent large clinical trials suggest such a benefit. (Grade of recommendation: A)

Definitions:

Grades of Recommendation

  1. Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial
  2. Based on well-conducted clinical studies, but without randomised clinical trials
  3. Made despite the absence of directly applicable clinical studies of good quality
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate use of immunosuppressives after kidney transplantation to suppress rejection without endangering the recipient's health

Potential Harms

Adverse Effects of Drugs

Non-specific side-effects of immunosuppression include a higher risk of malignancy and infection, particularly opportunistic infections. All immunosuppressants also have dose-dependent specific side-effects.

Calcineurin Inhibitors (CNIs)

Both cyclosporine and tacrolimus have significant side-effects that are hazardous to the graft and patient. Most importantly, both are nephrotoxic, and long-term use is a major cause of chronic allograft dysfunction, eventually leading to graft loss or severe chronic kidney disease in recipients of non-renal organs.

Although cyclosporine-A microemulsion (CsA-ME) has proven efficacy and safety, it is a 'critical-dose' drug, so that any deviations from exposure can lead to severe toxicity or failure of efficacy. The demonstration of bioequivalence in healthy volunteers according to standard criteria is not sufficient evidence to support treatment of all renal allograft recipients with generic formulations of cyclosporine. Until more data are available, the patient and physician prescribing generic cyclosporine formulations must be aware of potential differences in exposure, maximal drug concentration, variability and food effects. Precautions (e.g., close surveillance and determination of drug levels) should be instituted after conversion from one cyclosporine formulation to another.

Cyclosporine causes hypercholesterolaemia, hypertension, gum hypertrophy, constipation, hirsutism and acne. Therapeutic drug monitoring is mandatory because of its narrow therapeutic window and the potential for drug-to-drug interaction.

Use of tacrolimus is associated with diabetes, neurological side-effects (tremor, headache), hair loss, gastrointestinal side-effects (e.g., diarrhoea, nausea, vomiting) and hypomagnesaemia. In combination with a mycophenolate, it may also more often cause over-immunosuppression, namely polyoma nephritis. Because of its narrow therapeutic window and the potential for drug-to-drug interaction, tacrolimus should be monitored using trough levels, which provide a reasonable estimate for exposure.

Mycophenolates

Mycophenolic acid (MPA) inhibits bone marrow function and may cause gastrointestinal side-effects particularly diarrhoea. Other side-effects include the potential for over-immunosuppression, especially a higher incidence of cytomegalovirus (CMV) infections and severe CMV disease, and a higher incidence of polyoma nephropathy, especially when mycophenolate is combined with tacrolimus. Regular monitoring for polyoma is recommended in patients given MPA combined with tacrolimus.

Steroids

Corticosteroids have a large number of side-effects, especially with long-term use.

Inhibitors of the Mammalian Target of Rapamycin (m-TOR)

m-TOR inhibitors exhibit dose-dependent bone marrow toxicity. Other potential side-effects include hyperlipidaemia, oedema, development of lymphocoeles, wound-healing problems, pneumonitis, proteinuria, and impaired fertility. When combined with CNIs, pneumocystis prophylaxis is mandated, e.g., low-dose cotrimoxazole. Most importantly, combination therapy with CNIs aggravates CNI-induced nephrotoxicity, although m-TOR inhibitors themselves are non-nephrotoxic. Therapeutic monitoring of trough levels is recommended because of the narrow therapeutic window and the risk of drug-to-drug interactions. Emerging side-effects including proteinuria and infertility warrant an individual and cautious approach.

T-cell Depleting Agents

Induction therapies with T-cell depleting agents carry an increased risk of postoperative opportunistic infections and cancer, especially post-transplant lymphoproliferative disease.

Qualifying Statements

Qualifying Statements

As attitudes and practice to renal transplantation vary significantly, these guidelines provide general guidance only.

Implementation of the Guideline

Description of Implementation Strategy

The European Association of Urology (EAU) Guidelines long version (containing all 19 guidelines) is reprinted annually in one book. Each text is dated. This means that if the latest edition of the book is read, one will know that this is the most updated version available. The same text is also made available on a CD (with hyperlinks to PubMed for most references) and posted on the EAU websites Uroweb and Urosource (http://www.uroweb.org/guidelines/online-guidelines/ External Web Site Policy and http://www.urosource.com/diseases/ External Web Site Policy).

Condensed pocket versions, containing mainly flow-charts and summaries, are also printed annually. All these publications are distributed free of charge to all (more than 10,000) members of the association. Abridged versions of the guidelines are published in European Urology as original papers. Furthermore, many important websites list links to the relevant EAU guidelines sections on the association websites and all, or individual, guidelines have been translated to some 15 languages.

Implementation Tools
Foreign Language Translations
Pocket Guide/Reference Cards
Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
IOM Domain
Effectiveness
Safety

Identifying Information and Availability

Bibliographic Source(s)
Immunosuppression after kidney transplantation. In: Kälble T, Alcaraz A, Budde K, Humke U, Karam G, Lucan M, Nicita G, Süsal C. Guidelines on renal transplantation. Arnhem, The Netherlands: European Association of Urology (EAU); 2009 Mar. p. 55-65. [78 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Mar
Guideline Developer(s)
European Association of Urology - Medical Specialty Society
Source(s) of Funding

European Association of Urology

Guideline Committee

Renal Transplantation Guidelines Writing Panel

Composition of Group That Authored the Guideline

Primary Authors: T. Kälble; A. Alcaraz; K. Budde; U. Humke; G. Karam; M. Lucan; G. Nicita; C. Süsal

Financial Disclosures/Conflicts of Interest

All members of the Renal Transplantation Guidelines writing panel have provided disclosure statements on all relationships that they have and that might be perceived to be a potential source of conflict of interest. This information is kept on file in the European Association of Urology (EAU) Central Office database. This guidelines document was developed with the financial support of the EAU. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the European Association of Urology Web site External Web Site Policy.

Print copies: Available from the European Association of Urology, PO Box 30016, NL-6803, AA ARNHEM, The Netherlands.

Availability of Companion Documents

The following are available:

  • EAU guidelines office template. Arnhem, The Netherlands: European Association of Urology; 2007. 4 p.
  • The European Association of Urology (EAU) guidelines methodology: a critical evaluation. Arnhem, The Netherlands: European Association of Urology; 18 p.

The following is also available:

  • Guidelines on renal transplantation. 2009, Pocket guidelines. Arnhem, The Netherlands: European Association of Urology; 2009 Mar. 12 p. Electronic copies: Available in Portable Document Format (PDF) in English External Web Site Policy and Russian External Web Site Policy from the European Association of Urology Web site. Also available as an e-book from the EAU Web site External Web Site Policy.

Print copies: Available from the European Association of Urology, PO Box 30016, NL-6803, AA ARNHEM, The Netherlands.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on April 19, 2010. The information was verified by the guideline developer on May 21, 2010.

Copyright Statement

This summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Downloads are restricted to one download and print per user, no commercial usage or dissemination by third parties is allowed.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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