The Transplant Unit

A favourable match is defined as having a maximum of one mismatched antigen at either the HLA-A and HLA-B locus or at both (denoted 100, 010, 110). Recent analysis of UK data has shown significantly increased transplant survival in recipients of a 000 mismatched transplant. Also favourably matched transplants had a significantly increased transplant survival when compared to transplants of other match grades (Morris et al, 1999). 000 mismatched kidneys are allocated through tier 1 other favourably matched kidneys are allocated through tier 2. A points score is used as a discriminator should be there equally matched patients, currently based on recipient age, donor-recipient age difference, accumulated waiting time, sensitisation to HLA antigens, HLA antigen matchability and transplant unit balance of exchange. Wherever possible, tier 3, i.e. non-favourably matched organs are used locally.

7.31 Mismatches for common HLA antigens should be avoided wherever possible, particularly in young recipients, to decrease the possible generation of HLA-specific antibodies reactive with a high proportion of potential donors. Such antibodies would make re-transplantation more difficult should the transplant fail.

7.32 A pre-transplant donor/recipient cross-match is a crucial procedure to prevent hyperacute or accelerated transplant rejection. Each centre must therefore have an agreed and documented policy describing the cross-match tests to be performed prior to transplantation, the selection of samples to be tested and the interpretation of results. The policy must clearly define those circumstances when pre-transplant cross-matching is not considered mandatory and this policy must be evidence based. Relevant sera from all patients on the current waiting lists must be stored and readily available for use in cross-match tests.

7.33 The value of cross-matching by flow cytometry has been documented, particularly in recipients at high risk of rejection such as those with high levels of circulating antibody or a previous failed transplant [Martin et al, 1993; Bryan et al, 1998]. Careful standardisation and quantification of the results are necessary [Harmer et al 1996; Shenton et al 1997]

7.34 The laboratory must have a comprehensive screening programme for the detection and definition of HLA specific antibodies. Sensitised patients are those who have been exposed to HLA allo-antigen through pregnancy, blood transfusion or a previous transplant and who have demonstrated an antibody response.

The definition of sensitisation depends crucially upon the techniques used. The assay most widely used is the complement dependent cytotoxic assay using a panel of lymphocytes as target cells. ELISA and flow cytometric techniques are also commonly used [Martin & Taylor 1999]. The panel must be carefully selected to contain HLA specificities (HLA-A, -B, -Cw, -DR, -DQ) occurring in combinations that allow efficient interpretation of results. Non-HLA antibodies should be distinguished from those with specificity for HLA antigens. Although the degree of reactivity to the panel (PRA) is often expressed as a percentage, this can be misleading since the panel is chosen to represent a wide range of antigens and not the population as a whole.

Complete definition of antibody specificity should be the goal of a screening programme since the failure to fully account for a patient's PRA in the specificities recognised by the antibody will adversely affect the points awarded by the national allocation programme. Assays used to detect allo-sensitisation must have a sensitivity equivalent to the cross-matching techniques used by the laboratory.

7.35 Evidence of sensitisation in the form of circulating antibodies varies with time, so serum samples must be taken within 2 weeks of any blood transfusion, in the immediate post-transplant period and in all patients on the transplant waiting list at least quarterly. Ideally for female patients the HLA types of the father(s) of all pregnancies should be available. All HLA specificities against which the recipient reacts must be recorded as unacceptable antigens. Other known HLA antigens to which the recipient has previously been exposed may be considered unacceptable.

7.36 Conventionally, highly sensitised patients (HSPs) are defined as those who react with more than 85% of panel cells, despite the caveat in section 7.34. To qualify as an HSP, the potential recipient must be shown to have antibodies specific for HLA alloantigens. Non-specific or autoreactive IgM antibodies may give the impression of high panel reactivity, but since these antibodies do not prevent successful transplantation their presence must be carefully defined. However IgM HLA-specific antibodies do occur, and may be deleterious, so simple in vitro destruction of IgM antibodies before testing is not recommended [Taylor et al 1989].

If antibody screening is carried out regularly after transplantation, accurate screening and cross-matching for re-transplantation can help achieve success rates after re-transplantation as good as those for first transplant [Martin & Taylor 1999].

Immunosuppressive Regimens and Early Complications

Transplant Units should provide written documentation on an agreed policy regarding immunosuppressive protocols, cytomegalovirus, pneumocystis and renal vein thrombosis prophylaxis and management of delayed graft function. These protocols should be reviewed annually in the light of published research and in house experience (good practice).

7.37 At the moment there are insufficient data to permit specific recommendations on the various immunosuppressive regimens involving monotherapy, double or triple therapy using Prednisolone, Azathioprine, Cyclosporin microemulsion (Neoral TM), Tacrolimus, Mycophenolate mofetil or Rapamycin. Nor is the role of protein immunosuppressants (Basiliximab, dacluzimab, antilymphocyte globulin, OKT3 etc) clear. It is likely that the Mycophenolate mofetil and/or Tacrolimus will become increasingly used during the next few years because the number of early rejections using regimens which include these drugs appear to be lower, and lower rates of early rejection in turn are correlated with better long term function and graft survival.

7.38 Graft survival rates appear to be similar with most of the regimens in current use, but graft survival is lower and rejection more common with regimens containing only Prednisolone and Azathioprine compared with those containing Cyclosporin (Opelz et al 1995), and the other newer agents. Also early rejection rates appear to be lower with the newer drugs (Mycophenolate mofetil and Tacrolimus). However longer term experience may show that this beneficial effect is offset by more infections and other side effects. It is likely that a greater diversity of regimens will be used in future to "tailor" therapy more specifically to individual patients' needs.

7.39 New agents such as Mycophenolate and Tacrolimus are still being assessed, and only further prospective studies will allow more precise recommendations to be made. Until these studies are completed, outcomes need careful auditing to allow accumulation of informative data. The choice of immunosuppressive regimen has substantial cost implications, which will need discussion with purchasers, but the high costs of a failed graft must be borne in mind also; cost effectiveness data are needed urgently in this area.

7.40 Renal transplant recipients are susceptible to opportunistic infections such as cytomegalovirus, pneumocystis and tuberculosis. The early detection of and/or prophylaxis against these infections in high risk patients (eg CMV -ve recipient of a CMV +ve kidney) is possible and their use must be judged taking into account potential hazards and expense.

7.41 Delayed graft function prolongs inpatient stay, increases the risk of renal vein thrombosis and may have an adverse effect on long term outcome following recovery of renal function. Although evidence from prospective studies is lacking strategies should be considered to minimise delayed function and to prevent renal venous thrombosis in susceptible patients.

Clinical Outcome and Audit

Organs should be retrieved from at least 15 donors per million population per year. Each unit should transplant at least 25 patients per million population per year using cadaver kidneys. Efforts should be made to limit the cold ischaemic time to less than 30 hours in all cases. Each transplant unit which has appropriate resources to perform live donor transplantation should transplant a minimum of 5 living donor grafts per million population per year, but it is hoped that a higher number than this can be achieved in the future. At least 60% of recipients should receive a 000 mismatch or favourable match kidney.

At least 70% of heart beating cadaver kidney transplants should function immediately, and at least 95% should function eventually. Graft survival of second grafts should be the same as for first grafts, provided that adequate analysis of alloantibodies and FACS cross-matching are used (see Appendix 4.6 in second edition). There should be at least 95% patient survival at 1 year after transplantation for recipients of live donor and cadaveric kidneys. More than 84% of cadaver grafts and 90% of live grafts should still be working at 1 year and at least 68% of cadaver grafts and 73% of live donor grafts should still be working at 5 years (good practice).

7.42 Clinical and medical audit should be an integral part of the work of the transplant unit. A list of items that should be regularly audited before and after transplantation is included in Appendix 3 (A3.3). Patient survival, morbidity and transplant outcomes depend critically upon a number of case-mix factors such as the age and comorbidity of the population transplanted (see Appendix 4.7). This in turn depends upon the criteria for the selection process used among patients who are regarded as potential transplant recipients.

7.43 Data for outcomes of transplantation in the United Kingdom for 1996-98 are available in the renal transplant audit document published by the UKTSSA (2000). At the moment recommended standards can be set for only some of the audit points for transplantation that are listed in Appendix 3.3, for patients without major comorbidity and whose ages lie between 15 and 50 years of age. The figures suggested below are minimum acceptable results for cadaveric transplantation; clearly, if every unit in the United Kingdom were to achieve something near the present mean or better, the average standard would rise considerably. In 1996-8 the mean cadaver organ donor rate in the UK was 14 donors per million population per year while the mean figure for cadaver kidneys retrieved was 27 per million population. Lengthy cold ischaemic times (>30h) are associated with inferior graft survival in some studies (Cecka et al 1992), and this is supported by data from the UK Transplant (Morris et al 1999)

*graft failures include deaths with functioning grafts.

(It is recommended that, unlike the outcome data given for all patients entering ESRF programmes in the UK given in Appendix 3 (A3.8), these data include patients of all ages, and diabetics. However, the age profile of transplanted patients resembles closely that of the data analysed in Appendix 3.)

7.44 For live donor transplants the UK mean was 4 per million population in 1998, whilst in several European countries it was more than 5 per million population per annum and in Norway exceeded 17 per million population per annum. The median waiting time on the cadaver transplant list in the UK is just under 500 days, but differs markedly for sensitised and non-sensitised patients, and is affected also by age, previous grafting and blood group. Policies vary from unit to unit as to which patients, and what proportion, are placed on transplant waiting lists but the UK mean is 30% of the dialysis population. There will be variation according to the case-mix of patients on dialysis, and especially their comorbidity and age. In this area, equity and optimum use of the scarce resources of transplantable kidneys are in conflict. Currently only 13% of recipients in the UK receive a 000 mismatch and 48% a favourable match (see 7.30 for definition).

The following are mean figures for the UK for first cadaver transplants performed form 1990 to 1997 and the recommended standards. It should be noted that these standards are based on outcome data which do not take account of case mix differences between different units.

7.45 The mean rate of achieving immediate renal function following renal transplantation in the UK is around 70%, and is dependent upon the types of kidney accepted for use, and their handling within the transplant unit. It is known that the kidneys which function immediately provide better long term graft survival. In the UK 5% of kidneys never function.

7.46 It is much more difficult to set targets for transplant recipients with diabetes mellitus and/or other significant comorbidity until some standard way of describing this and assessing the risk has been achieved. A suggested standard which can be used in collecting data is given in Appendix 4 (A4.7); in the future it should be possible to set standards for these patients. It should be noted that at the time of writing a draft Department of Health document is being prepared which may have more ambitious targets for cadaveric and live donor numbers.

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We would very much like your comments on this document

Please send them to Alison MacLeod, Chairman, Standards & Audit Subcommittee of the Renal Association, at: mmd175@abdn.ac.uk