b p. 352. There should be no active infection at the time of transplantation; in particular, check: \200 Diabetic foot ulcers. \200 Recent dialysis catheter infections or PD-related infections, such as peritonitis, have been fully treated. UTI. Any recent signi \201 cant infectious disease contact, e.g. TB. \200 Renal transplantati on in patients with HIV, HBV, and HCV is discussed in b Chapter 8. CHAPTER 5 Transplantation 358 Review of previous malignancy \200 Uncontrolled or recent malignancy is a contraindicatio n to transplantation. The use of immunosuppression is associated with an increased risk of both de novo and recurrent malignancy in transplant recipients. \200 As a general rule of thumb, patients with treated malignant disease should be recurrence-free for \211 2 years ( \211 5 years in some situations). \200 H elpful guidance for speci \201 c tumors can be obtained from the Israel Penn International Transplant Tumor Registry (M < http://ipittr.uc.edu >). For the common cancers, see Table 5.4. Table 5.4 Common tumor types and transplant listing Cancer type 9 location Condition Waiting time Cervical carcinoma in situ If cure at time of transplantation None required Basal cell carcinoma If cure at time of transplantation None required Squamous cell carcinoma (skin) If cure at time of transplantation None required Bladder carcinoma 2yr recurrence-free Uterine carcinoma 2yr recurrence-free Renal cell carcinoma <5cm 2yr recurrence-free Renal cell carcinoma >5cm 5yr recurrence-free Breast carcinoma Depends on staging 2 \200\223 5yr recurrence-free Lymphoma Depends on staging 2 \200\223 5yr recurrence-free Colorectal carcinoma Depends on staging 2 \200\223 5yr recurrence-free Cervical carcinoma Depends on staging 2 \200\223 5yr recurrence-free Pre-transplant cancer screening \200 In \231\200 , ensure cervical smear testing and mam mography are current. \200 Encourage self-examination of breasts and testes. \200 Bowel screening with FOB testing is now national practice in the UK for all those aged >60. Patients with a long history of ESRD often develop acquired cystic disease in their native kidneys, which is associated with malignancy \200\224 screening na tive kidneys is included in work-up protocols. Most centers use PSA to screen 4 patients aged >50 or if strong FH of prostate cancer. Serum and urine protein electrophoresis and immuno \201 xation for patients aged >60 should be considered. PRE-TRANSPLANT WORK-UP 359 Native renal disease \200 Many primary renal diseases may recur ( b p. 418). Patients nee d to be counseled regarding the risk for their particular native disease. \200 Certain di sorders must be in remission prior to transplantation, e.g. systemic vasculitis ( b p. 647), anti-GBM disease ( b p. 657), SLE ( b p. 663). Patients with ESRD, caused or complicated by urinary tract obstruction ( 9 urinary infection), require urological assessment. Assessment of mental health Introduction \200 Due attention should be given to psychosoci al issues as they may impact on quality of life (and compliance) post transplant. When iden ti \201 ed, many are correctable \200\224either with individualized treatment or through s ocial intervention. The uncertainty of transplant listing may in itself cause anxiety. Furthermore, dialysis may have already affected a patient \200\231s ability to work, their social engagement, and their self-esteem. Psychosocial support, including counseling, formal psychiatric input, and social work may be necessary. Evaluation of a patient \200\231s social situation, relationships, and \201 nancial situation can be valuable, as many of these factors may be modi \201 able in anticipation of a transplant. Rarely, the capacity of a patient to consent to treatment may require assessment. Pre-existing psychiatric illness \200 Evidence suggests that transplant outcomes in patie nts with pre-existing mental health issues are suboptimal. However, a psychiatric disorder is not an absolute contraindication to transplantation, although careful evaluation is required. With adequate social support, good insight, reliable interpersonal relationships, and copin g strategies in place, patients with mental health issues can be considered for transplanta tion. \200 Chronic illnesses, such as schizophrenia or bipolar affective disorder, may still have a good outcome in selected stable patients. Severe personality disorders are considered a contraindication by most transplant centers. Substance misuse may interfere with compliance. \200 Long-standing anxiety or affective d isorders do not appear to predict worse outcomes after transplant. Drug issues \200 (cid:2) Corticosteroids have well-recognized neuropsychiatric adverse ef fects, including depression, mania, psychosis, and delirium. A minority of patients may suf fer from neuropsychiatric ciclosporin (CIC) toxicity. Tacrolimus (TAC) has been associated with sleep disturbances and irritability. \200 It is important to identify potential inte ractions between immune suppression and psychiatric medication prior to transplantation. Lithium should ideally be avoided post-transplant (nephrotoxicity), but any change in treat ment will require a period of assessment to ensure mood stability. CHAPTER 5 Transplantation 360 Compatibility: matching donor to recipient Introduction Five fundamental issues must be con sidered: \200 Blood group. \200 Tissue type (HLA). \200 Anti-HLA antibodies (particul arly donor-speci \201 c antibody, DSA). \200 Donor characteristics. \200 Recipient cha racteristics. Blood group ABO antigens are cell surface glycoproteins expressed not just on red blood cel ls, but on many cell types, e.g. vascular endothelial cells \200\224 includ- ing those in a transplanted kidney. Naturally occurring anti-blood group antibodies to non-self ABO anti gens develop in early life (probably in response to exposure to bacterial antigens). \200 Group O individuals develop both anti-A and anti-B antibody. \200 Group A and B individu als develop anti-B or anti-A antibody, respectively. Group AB individuals do not develop antibodies. Circulating anti-A or anti-B antibody at the time of transplantation will recognize and bin d ABO antigens on donor endothelium, activate com- plement, and cause catastrophic vascular injury ( l \200\230 hyperacute \200\231 rejection). For this reason, ABO-incompatible tr ansplants are generally avoided, particularly in deceased donor transplantation. The same r ules apply for transplantation and blood transfusions, i.e. group \200\230 O \200\231 are universal donors and \200\230 AB \200\231 universal recipients. However, ABO-incompatibl e transplants can be contemplated in certain circumstances ( b p. 444). Tissue typing Many hundreds of HLA antigens exist, and HLA nomenclature (based on recogniti on with speci \201 c antisera and, more recently, DNA sequencing) has been gradually re \201 ned over time. HLA antigens are allocated numbers as they are identi \201 ed. Where n ewer antisera have allowed a re \201 nement of previous speci \201 cities, the antigens a re referred to as split and shown in brackets, e.g. the antigen formerly known as HLA-A9 ha s been split into A-23 and -24 and written A-23(9) and A-24(9). DNA technology has revealed multiple different HLA alleles, and these are shown with an *, e.g. HLA-A *0101 is an allele of HLA-A1. However, theses alleles are usually still describe d more broadly, using the wider \200\230 traditional \200\231 serological groupings. If an individual inherits the same HLA antigen from each parent, they are homozygous for th at locus. Some antigens are inherited together more often than might be anticipated by chan ce; this is known as linkage disequilibrium . COMPATIBILITY: MATCHING DONOR TO RECIPIENT 361 Relevance The most relevant HLA antigens to clinical transplantation, particularly organ al location, are the 7 50 encompassed serologically by HLA-A and -B (class I) and HLA-DR (clas s II). These were the antigens observed to most signi \201 cantly in \202 uence outcome i n the early days of HLA typing, although their effect is probably less powerful with contem porary immune suppression. The degree of mismatch (rather than match \200\224 and, yes, this is very confus- ing!) be tween the donor and recipient is usually quoted at these three loci, i.e. HLA identical don ors are a 0-0-0 mismatch, whereas donor:recipient pairs who share one HLA-A, one HLA-B, and one HLA-DR are referred to as a 1-1-1 mismatch. If all are different, it is termed a 2-2-2 mismatch. There are a number of minor HLA antigens, but their clinical impact is minimal. Bene \201 ts of a well HLA-matched graft \200 d incidence of acute rejection (less evide nt with modern immune suppression). d incidence of DGF. \200 i long-term graft survival. HLA-DR matching appears the most powerful in this context, but the number of mismatches is important (see Fig. 5.8). This st ill holds true for live donor pairs, particularly for 0-0-0 mismatches, but it is much less powerful ( b p. 373). \200 d subsequent formation of anti-HLA antibodies ( b pp. 361 \200\2234). 2 Each mismatched HLA antigen is likely to initiate an immune response, which m ight be especially relevant if repeat transplantation is ever nec- essary. Recipients may d evelop anti-HLA antibodies or memory T cells against mismatched antigens, making organs wit h these antigens subse- quently \200\230 unacceptable \200\231 for a given recipient. Anti-HLA antibodies HLA matching alone is not suf \201 cient. Anti-HLA antibodies present in the recipient at the time of transplantation may cause aggressive rejection, particularl y if directed against particular HLA antigens in the transplanted kidney, termed donor-spec i \201 c antibody (DSA). Patients are \200\230 sensitized \200\231 (i.e. develop anti-HLA antibodies) when previ- ously exposed to non-self HLA antigens. HLA antibodies may recognize an epitope that is sha red by multiple HLA molecules and are 6 often cross-reactive. Key sensitization events \200 Previous organ transplant ( 2 the degree of mismatching is very important: a 0-0-0 mismatch is less likely to become sensitized). Previous pregnancy (directed against paternal HLA antigens). \200 Previous blood transfus ion. \200 Unknown (possibly caused by cross-reactivity with microbial antigens). CHAPTER 5 Transplantation 362 Screening for HLA antibodies Historically, HLA antibody screening was undertaken with the c omplement-dependent cytotoxicity (CDC) assay and described in terms of panel reactivity . Panel reactive antibodies (PRA) PRA measures the antibody speci \201 cities in an individu al serum sample against a panel of HLA antigens. CDC assay: the patient \200\231s serum is incubated with lymphocytes from a panel of repres entative donors in the presence of complement. The PRA is expressed as the percentage of we lls with cell lysis, e.g. a PRA of 45% implies recipient antibodies against 45% of the most commonly occurring antigens in that population. A PRA >10% generally de \201 nes a sensit ized recipient and >85% highly sensitized. 2 The higher a patient \200\231s PRA, the more l ikely they will have a positive cross-match ( b p. 363) at the time of transplantation. In more recent years, the CDC assay has been superseded by less cum- bersome, and more sensitive, solid phase assays. HLA antibody screening with solid phase assays \200 These are either ELISA- or \202 ow cytometry-based. \200 Advantages over CDC: rapid, quantitative (strength of the \202 uo rescent signal indicates amount of antibody present), highly sensitive, fewer false +ves, e asier to identify antibody speci \201 cities, does not require lymphocytes, can detect non -complement \201 xing antibodies. ELISA: puri \201 ed HLA antigens are bound to wells of an ELISA plate. \200 Flow cytomet ry: puri \201 ed HLA antigens are bound to \202 uorescently labeled microspheres. Now the gold standard technique. Luminex is the most commonly used commercial system. Results are reported as units of median \202 uorescence intensity (MF I) that re \202 ect the amount of antibody to speci \201 c HLA sensitivities present in t he serum. Solid phase assays report individual antibody speci \201 cities but can generate the equivalent of a PRA, based on known population antigen frequencies \200\224 t ermed calculated PRA or reaction frequency. The sensitivity of solid phase assays means that the calculated PRA is higher than a CDC PRA. Non-HLA antibodies \200 Antibody-mediated rejection and transplant glomerulopathy ( b p. 415) can develop despite an absence of anti-HLA antibodies. \200 Non-HLA antibodies, dire cted against non-HLA donor antigens (including proteins on donor vascular endothelium), appear capable of stimulating graft in \202 ammation and have been associated with worse outcomes. It is possible that reperfusion injury (and graft in \202 ammation from other causes) expo ses previously sequestered kidney antigens. \200 Whether such non-HLA antibodies are alwa ys pathogenic or if they might prove useful biomarkers for the prediction of transplant outcomes remains to be seen. COMPATIBILITY: MATCHING DONOR TO RECIPIENT 363 The role of HLA antibody testing Pre-transplantation \200 HLA antibodies should be measur ed at the time of listing for transplantation and about every 3 months thereafter. \200 If present, the antibody speci \201 cities will identify unacceptable antigens. Recipients will not be offered a kidney possessing these antigens. HLA antibodies may be identi \201 ed that subsequently disappear. These antigens are no longer unacceptable , but close surveillance for recurrence is requir ed post-transplantation. (cid:2) The concern is rejection; this may be immediate and aggressive ( \200\230 hyperacute \200\231 ), if pre-formed antibody is present in large a mounts ( 2 cross-matching should prevent this), or early post-transplant if there are lower amounts of antibody initially, but a B cell (or memory T cell) response is initiated. High sensitivity \202 ow cytometric assays can detect antibody in such low amounts that it may not be suf \201 cient to cause a positive cross-match. Althou gh a concern, these antibodies may not preclude transplantation. However, they mandate very close post-transplant surveillance. Post-transplantation \200 Measure monthly for the \201 rst 3 months (weekly in selected cases), then 3-monthly for the \201 rst year, then annually. Also measure if acute or chronic antibody-mediated rejection is suspected. \200 (cid:2) 20% will develop anti-HLA antibodies post-transplantation, increasing the risk of graft loss 3-fold. These outcomes are worse, whether or not the antibody is donor-speci \201 c (DSA). DSA is associated with both acute antibody-mediated rejection ( b p. 409) and transplant glomerulopathy ( b p. 415). The complement-binding capacity of DSA may help identify patients at higher risk for graft loss and help improve risk strati \201 cation when planning management. Cross-matching \200 2 Cross-matching is used to determine whether recipient serum reacts with donor T and B lymphocytes immediately prior to transplantation. The principle was established before the more re \201 ned identi \201 cation of speci \201 c anti-HLA antibodies discussed on b p. 362. It can be undertaken with complement-dependent cytotoxicity (CDC-XM) or by \202 ow cytometry (FC-XM): \200 CDC-XM is performed separately for T and B cells. \200 Dithiothreitol (DTT) is added to serum to disaggregate IgM, as IgM antibodies are not relevant to transplantation. CHAPTER 5 Transplantation 364 Sensitivity can be increased by adding goat anti-human antibody (binds recipient antibody l improved antibody cross-linkage and fuller complement activation). FC-XM is more sensitive and has reduced the early incidence of antibody-mediated rejection. FC-XM also distinguishes between T and B cells (by using \202 uorescent anti-CD3 and anti-CD19 antibodies, respectively). The \202 ow cytometer mixture consists of prepared donor lymphocytes (lymphocytes are used, as donor lymphocytes are relatively easy to isolate), re cipient serum, and anti-Fc antibodies tagged with a \202 uorescent dye. Fluorescence intensity quanti \201 es positivity. Note: A virtual cross-match involves determining the presence or absence of DSA through the comparison of the patients known HLA antibody speci \201 city p ro \201 le to the HLA type of the potential donor, without carrying out a \200\230hot \200\231 or \200\230acute \200\231 CDC-XM or FC-XM. Interpreting the cross-match result \200 T cells express class I HLA, and B cells express both class I and II HLA. \200 HLA antibodies against class I will 6 be active against bo th T and B cells. 2 Since class I HLA is expressed on all nucleated cells, including donor vascular endotheli um, a positive T cell cross-match is a contraindication to transplantation, as it implies p re-formed antibody will react with donor endothelium. X The signi \201 cance of an isolated positive B cell cross-match is less clear, but it is probably an oversimpli \201 cation to suggest that it indicates the prese nce of class II HLA antibodies that do not pose a threat to the graft. Furthermore, donor endothelium will express class II HLA under certain circumstances, especially in \202 ammation. CDC-XM and FC-XM are often performed (and interpreted) together. This interpretation is mad e easier if a recent recipient anti-HLA antibody screen is available, as antibodies causing a reaction in the cross-match might not always be anti-HLA. \200 Positive T cell CDC-XM: a positive T cell CDC-XM almost always indicates anti-class I HLA antibodies. Transplantation is contraindicated. Positive B cell CDC-XM: may be a false positive, and transplantation may proceed under certain circumstances. However, transplantation is contraindicated if cla ss II HLA DSA is known to be present (esp. if speci \201 c for HLA-DR). Positive FC-XM and negative CDC-XM: this implies antibody is present at low titre. However, a positive T cell FC-XM contraindicates transplantation. X A positiv e B cell FC-XM is a more controversial area, and proto- cols differ from center to center. 2 Live donor transplantation can provide the opportunity to proceed with transplantation de spite a DSA 9 a positive cross-match ( b p. 444). COMPATIBILITY: MATCHING DONOR TO RECIPIENT 365 Donor characteristics There are several types of kidney donor. Live kidney donation is disc ussed on b p. 372. Deceased donors are the commonest source of transplant in many countries , including the USA and UK, although live donor pro- grammes in some centers have recently exceeded deceased donor rates. Deceased donors are classi \201 ed according to mode of death. Donation after brain death (DBD) Previously referred to as \200\230 heart-beating \200 \231 donors. The most important donor type historically. Once brainstem death has been diag nosed, the patient is legally dead and can be managed as a potential donor on ITU. This man agement aims to maintain organ suitability for transplantation. Essentially, the donor has irreversible structural brain damage and is unresponsive, in a c oma, and ventilator-dependent. Systemic perfusion is preserved, and organ retrieval occurs whilst some degree of cardiac out- put remains (meaning ischaemic injury is minimized). See Academy of Medical Royal Colleges. A Code of Practice for the Diagnosis and Con \201 r mation of Death, October 2008. M http://www.aomrc. org.uk/publications/reports-a-guidance.h tml . Donor management on ITU \200 Treatment of infection. \200 Line care. \200 Airway mana gement. \200 Maintain MAP >60mmHg. \200 Meticulous \202 uid balance. \200 Most need vasopressor support (e.g. dopamine 9 then noradrenaline). \200 Maintain core temp >35 * C. \200 Common complications: d BP. \200 Arrhythmias. \200 Hypothermia. \200 Diabetes insipidus ( l diuresis, i Na + ); treat with vasopressin. \200 Electrolyte abnormalities. \200 Acidosis. \200 Pulm onary oedema. \200 Hypothyroidism ( l haemodynamic instability); treat with T3 or T4 infusion). Hyperglycaemia (insulin resistance). Warm and cold ischaemic time \200 Warm ischaemic time: period between circulatory arrest and start of cold storage. WIT is extremely injurious to the kidney. Cold ischaemic time: period of cold storage before transplantation. CHAPTER 5 Transplantation 366 Donation after cardiac death (DCD) Previously referred to as \200\230 non-heart-beating \200\231 donors. The number of DCD donors has increased signi \201 cantly over recent year s. DCD involves donors who are not brain-dead, but in whom treatment is withdrawn, as there is no prospect of recovery. This usually occurs in an ITU setting but may also be undertak en in accident and emergency departments. Organs are harvested at subsequent cardiorespirat ory arrest. The time between treat- ment withdrawal and cardiorespiratory arrest will deter mine if the organs are viable for transplantation. The inevitable delay between cardiac arrest and organ perfusion results in a longer period of warm ischaemia time (WIT). WIT is extremely harm- ful to kidneys, so, in some countries, kidneys are allocated locally to pre- vent an additional lengthy period of cold ischaemia. Prolonged WIT increases DGF, but graft survival rates appear compa- rable to DBD if donors are carefully selected. X However, outcomes for DCD donors using more extended criteria ( b p. 368) are uncertain. DCD kidneys are classi \201 ed, according to the Maastricht classi \201 cation: Category I: dead on arrival in hospital. \200 Category II: unsuccessful resuscitation. \200 Category III: expected cardiac arrest. \200 Category IV: cardiac arrest in brainste m-dead donor. \200 Category V: unexplained cardiac arrest in hospital. Categories II and III are the most common scenarios. DCD can only occur in hospitals that h ave invested in the expertise, resources, and infrastruc- ture necessary to support such a program. Between 2011 and 2012, in the UK, there was an 8% increase in the number of deceased donors to 1,088 (the largest number ever). The number of DBD donors increased by 2% to 652, while the number of DCD donors increased by 17% to 436 (see Fig. 5.12). COMPATIBILITY: MATCHING DONOR TO RECIPIENT 367 2 6 0 1 5 5 0 1 6 4 0 1 1100 DBD donors DCD donors Living donors 1 6 9 1000 8 5 8 900 6 1 7 800 2 0 7 7 9 6 4 5 6 2 5 6 7 3 96 9 5 7 3 6 4 3 6 4 2 6 700 1 1 6 9 0 6 r e b m u 500N 400 600 5 8 4 2 7 4 6 3 4 7 9 3 3 7 3 5 3 3 8 8 2 300 0 0 2 9 5 1 7 2 1 200 7 8 3 7 1 6 100 0 2010 \200\2232010 2002 \200\2232003 2003 \200\2232004 2004 \200\2232005 2005 \200\2232006 2006 \200\2232007 2008 \200\2232009 2009 \200\2232010 2011 \200\2232012 2007 \200\2232008 Year Fig. 5.12 Number of deceased and living donors in the UK, 2002 \200\223 2012. Reproduced f rom UK Blood and Transplant Annual Report 2012, with permission. 100 90 80 70 60 50 l a v v r u s i t f a r g % 40 30 20 10 Year of transplant (number at risk on day 0) 1998 \200\2232000 (2890) 2001 \200\2232003 (27 73) 2004 \200\2232006 (2469) 2007 \200\2232010 (2868) 0 0 1 2 3 5 Years since transplant 4 6 7 8 9 10 Fig. 5.13 Long-term graft survival after \201 rst adult kidney-only transplant from DBD d onors, 1998 \200\223 2010. Reproduced from UK Blood and Transplant Annual Report 2012, wit h permission. CHAPTER 5 Transplantation 368 100 90 80 70 60 50 40 30 20 10 0 l a v v r u s i t f a r g % Year of transplant (number at risk on day 0) 1998 \200\2232000 (116) 2001 \200\2232003 (232 ) 2004 \200\2232006 (528) 2007 \200\2232010 (1642) 0 1 2 3 4 5 6 7 8 9 10 Years since transplant Fig. 5.14 Long-term graft survival after \201 rst adult kidney-only transplant from DCD d onors, 1998 \200\223 2010. Reproduced from UK Blood and Transplant Annual Report 2012, wit h permission. Figs 5.13 and 5.14 show graft survival estimates (and con \201 dence inter- vals) for 1, 2 , 5, and 10 years post-transplant. There has been a signi \201 cant improvement in 1-, 2-, and 5-year survival over the time periods shown ( P <0.01 in each case). Note: 1-year patient survival is comparable for DBD and DCD donor transplants in the most recent time periods. Extended criteria donors (ECD) X The use of ECD is increasing rapidly as a means of expandi ng the available donor pool. Previously not considered for transplantation, they now repres ent 7 25% of donors (see Fig. 5.15). Criteria \200 Age >60. \200 Age 50 \200\223 59 an d \211 2 of the following: i BP. \200 SCr >133 mol/L (1.5mg/dL). \200 Cerebrovascular cause of death. \200\230Super \200\231extended criteria donors \200 Age >70. COMPATIBILITY: MATCHING DONOR TO RECIPIENT 369 70+ 60 \200\22369 50 \200\22359 18 \200\22349 0 \200\22317 N= 777 3 770 2 751 3 764 3 793 3 809 3 899 5 959 1010 1088 100% 8 10 11 14 13 13 90% 14 15 17 15 18 80% 20 23 22 25 27 70% 26 25 24 26 24 60% e g a t n e c r e P 23 25 50% 40% 53 52 49 50 50 50 30% 48 46 42 38 20% 10% 8 8 7 7 7 7 5 4 4 4 0% 2002 \200\2232003 2003 \200\2232004 2004 \200\2232005 2005 \200\2232006 2006 \200\2232007 2007 \200\2232008 2008 \200\2232009 2009 \200\2232010 2010 \200\2232010 2011 \200\2232012 Year Fig. 5.15 Age of deceased donors in the UK, 2002 \200\223 2012. Reproduced from UK Blood a nd Transplant Annual Report 2012, with permission. Contraindications to deceased donation \200 Active or untreated malignancy. A history of past treated cancer is more contentious. \200 Primary brain tumors are an exception. Active infection, e.g. encephalitis, TB, HSV, CMV, syphilis: Donation may be possible if the organism and sensitivities are known and treatment has been established prior to donation. \200 In some cases, HBV, HCV, HIV may be allocated to app ropriate recipients ( b pp. 684, 690, 679 respectively). Medical comorbidity: X This is an increasingly controversial area, as factors, such as age >60, diabetes mellitu s, and i BP, are no longer considered contraindications in many transplant centers (for ECD , see b p. 368). Deceased donation: opting in or opting out Organ donation requires consent of the donor or next of kin. In some countries, e.g. most of the UK, potential donors may have given con- s ent during their lifetime, so-called \200\230 opt in \200\231 . Such systems often utiliz e resources, such as donor cards or donor registries (increasingly online). Although the ne xt of kin may not have the automatic right to overrule the previously expressed wishes of a potential donor, it would be usual practice to take their wishes into account. In other countries, e.g. France, Spain (and Wales from 2015), potential donors are presumed to have given consent, unless they previously \200\230 opt out \200\231 . Advocates of t his system point to increased donation rates in these territories, although critics suggest this is more a function of transplant coordination systems that are more sophisticated ove rall. CHAPTER 5 Transplantation 370 Recipient characteristics The median waiting time for a deceased donor kidney is 7 1,200 da ys or 3.3 years. This waiting time is signi \201 cantly in \202 uenced by blood group, wi th blood groups AB, A, B, and O having median waiting times of 7 600, 7 950, 7 1,300, and 7 1,400 days, respectively. The major factors that in \202 uence allocation of a kidney to a potential recipient \200\231s are: \200 Time on the waiting list, with priority to those that have waited the longest. Age: priority to those younger than 18. \200 HLA mismatch, with priority to a zero antige n mismatch. \200 HLA antibodies, with priority to those with a high PRA or calculated RF. Medical priority, e.g. a patient has limited options for sustainable dialysis access. There is a move toward more sophisticated scoring systems that attempt to improve outcomes by matching donor and recipient more effectively, particularly in terms of patient and graf t survival. Such systems usually focus on criteria, such as: (i) estimated survival that a recipient of a speci \201 c donor kidney may expect vs remaining on dialysis; (ii) time al ready spent on dialysis; and (iii) more objective measures of donor organ quality. Donor and recipient should be as closely \200\230 biologically \200\231 matched as pos- s ible; for instance, kidneys from elderly donors do not, on average, last as long as those f rom younger donors and may sensitize younger recipients to subsequent (better matched) graf ts. Speci \201 c recipient issues \200 Age: The proportion of wait-listed patients aged >50 is increasing. \200 This not only re \202 ects longer waiting times, but also larger numbers of more elderly patients being considered for transplantation. This mandates a regular (re) assessment of both \201 tness for, and the risk:bene \201 t ratio of, transplantation. The commonest cause of graft loss beyond age 65 is death with a functioning transplant. Thi s means that long-term graft outcomes may be less important, and appropriate attention must be given to issues, such as quality of life. There is usually an attempt to match the age of donor with the recipient to ensure a suitable \200\230 nephron dose \200\231 . Race: Ensuring equal access to transplantation is a signi \201 cant challenge internationally, as is encouraging donation from all ethnic backgrounds to support HLA matc hing. The proportion of patients waiting for a kidney from black, Asian, and Hispanic backgrounds is increasing. In the UK, 7 4% of donors are from ethnic minority groups while such groups represent 7 8% of the UK ESRD population. Median UK waiting times are Caucasian patients 7 1,100 days; Asian patients 7 1,400 days; black patients 7 1,450 days. COMPATIBILITY: MATCHING DONOR TO RECIPIENT 371 Comorbidity: Diabetes is the commonest cause of ESRD amongst those wait-listed, followed by i BP. This has implications for associated CV morbidity. Careful work-up is essential ( b p. 352) Size: A large recipient ideally requires adequate \200\230 nephron mass \200\231 to achieve a satisfactory post-transplant GFR. A kidney from a small donor (e.g. pediatric) ma y not achieve this. It may be technically dif \201 cult to implant a kidney from a large donor into a small recipient. Large recipient polycystic kidneys may limit placement of the new organ (uni- or bilateral native nephrectomies may be necessary before activation on the waiting list). CHAPTER 5 Transplantation 372 Live donor transplantation Introduction 2 Living donor transplantation is the treatment of choice for ESRD. Living donors enjoy better graft function and patient survival ( b p. 340). They are the co mmonest donor type in many countries, and num- bers have increased signi \201 cantly globa ly in recent years (now approaching 50% of all renal transplants). Live donors may be related or unrelated, although there is generally an established emotion al relationship between the pair (e.g. spouse or close friend). Exchange schemes and protoc ols to reduce recipient ABO or HLA antibodies are helping to expand the live donor pool ( b p. 444). Non-directed altruistic ( \200\230 Good Samaritan \200\231 ) donation refers to the alloca- tion of a live donor kidney to a patient on the deceased donor list, or in the kidney exchange pool (b p. XXX) (with donor/recipient anonymity). Advantages \200 Better graft and patient survival than deceased donor transplantation \200\224 regardless of genetic relationship and HLA mismatch. Pre-emptive transplants (i.e. pre-dialysis) have the best outcome of all. \200 Time on di alysis is associated with poorer transplant outcomes. \200 7 35% of live donor transplant s in the UK are pre-emptive. Live donor transplantation is elective surgery and easier to organize. \200 Laparoscopic donor techniques have helped acceptability ( b p. 378). \200 Closer HLA matching may be p ossible. \200 Live donor transplantation expands the overall donor pool \200\224 leaving deceased donor kidneys for those with no other options. There is minimal ischaemic damage to graft ( 6 d DGF). \200 Less potent immunosuppression (possibly). \200 Psychological bene \201 ts (better compliance, sense of well-being, et c.). Disadvantages \200 Perioperative donor mortality is 7 1 in 3,000 (causes: occult cardiac disease, venous thromboembolism). Major complications occur in 7 2% (intraoperative bleeding, wound problems, DVT). Minor complications occur in 7 20%. \200 Stress to donor (and family). \200 X Later dev elopment of donor i BP, proteinuria, or CKD (mean donor GFR after 25 years is 7 70% of that prior to donor nephrectomy). Dif \201 cult to guarantee \200\230 freely given \200\231 consent \200\224 has the dono r been coerced? Potential donors should be assessed in isolation from recipients and allowe d to withdraw (without explanation) at any stage. Assessment of a potential live donor This is subject to several comprehensive guidelines, e .g. M http://www. bts.org.uk . LIVE DONOR TRANSPLANTATION 373 A successful live donor program requires a multidisciplinary team approach. \200 Willing to donate? Information and discussion are of paramount importance. This should be delivered through a mixture of culturally appropriate written an d visual material as well as face-to-face consultations. A dedicated live donor team, separ ate from the potential recipient \200\231s nephrologist, would usually undertake this. The risks of the live donor process, how the pathway works, and the nature of the necessary inv estigations should all be clearly explained. ABO compatibility ( b p. 360). \200 HLA typing and donor-speci \201 c HLA antibodies ( b pp. 360 \200\2233). The impact of HLA matching is much less powerful in live donor transpl antation: a 1 haplotype mismatched live related graft 1-1-1 (e.g. parent to child) has simi lar outcomes to a 2-2-2 mismatched live unrelated graft (e.g. from a spouse) \200\224 and, in all cases, the outcomes are as good as for a 0-0-0 mismatched deceased donor kidney. Ho wever, HLA matching can help to select between multiple potential donors: 0-0-0 mismatched grafts still have the best outcomes, and poorly HLA-matched grafts risk the subsequent deve lopment of DSA, with potential implications for subsequent repeat transplantation in younge r patients. Medical evaluation: the goals are to protect the health of the donor and to prevent transmissible disease (malignancy and infection) to the recipient. \200 Hi story, clinical examination. \200 BP. \200 Urinalysis (at least x 2 on separate occasio ns), MSU, and uPCR. \200 U&E, SCr, eGFR. \200 FBC, clotting, LFTs, bone 9 Hb electropho resis (? sickle cell trait). \200 Fasting glucose 9 glucose tolerance test (if fasting va lue 6 \200\223 7mmol/L, i BMI, or family history of T2DM). PSA ( 4 > age 60). \200 Estimation of GFR ( b p. 374). \200 ECG 9 ECHO if i BP 9 stress testing if age >60. \200 CXR. \200 HIV, Hep serology, CMV, EBV, syphilis and HTLV-1 an d 2. \200 Age appropriate cancer screen. Psychosocial evaluation. This is a complex area, and many live donor programs will have considerable expertise within their multidisciplinary team. Many d onors \201 nd donation a positive act, associated with increased self-esteem. However, th is is not universal. Psychosocial assessment and support may be required (including formal psychiatric review in some cases). Support may need to continue post-donation. Formal menta l health assessment is recommended for all non-directed altruistic donors in the UK. Donor anatomy: Renal USS: to check there are two normal-sized kidneys. \200 Isotope renography (e.g. DMS A): for split renal function. If there is a difference, the kidney with less function would generally be selected for transplantation. CHAPTER 5 Transplantation 374 Arterial and venous anatomy: CTA is now generally favored over the more invasive, but less revealing, angiography (CT also yields additional anatomical information; e.g. the IVU phas e will identify a duplex ureter). Some centers may prefer MRA. How many arteries and veins? Multiple arteries usually require bench reconstruction prior to transplantation. Will laparoscopic surgery be possible? The l eft kidney is generally favored as the renal vein is longer. Informed consent. The donor should meet the donor surgeon. \200 In the UK, it is a mandat ory requirement of the Human Tissue Authority (HTA) that all potential live donor transplants undergo evaluation by an \200 \230 independent assessor \200\231 . The assessor must be satis \201 ed that adequate inf ormation has been provided (and understood), that consent has been freely given (no coercio n or rewards), and that the relationship between the pair is as described. The transplant m ust then proceed within a certain time frame (usually 6 months). If a donor is unsuitable, it is important that the reasons why are clearly explained (and that any necessary follow-up is organized). Donor nephrectomy. For techniques, see b p. 378. \200 Donors should be seen 4 \200\223 6 weeks post-surgery and then reviewed annually (check eGFR, BP, and urinalysis 9 uPCR). Thi s could be undertaken in primary care (but it is important that outcome data are collected by the transplant center). Renal outcomes Following the initial decline in GFR (as half the donor \200\231s nephron ma ss is removed at the time of surgery), the rate of loss of renal function is no faster than expected with normal ageing, in fact, residual hyper \201 ltration leads to an increase i n GFR to 770% of pre-donation level. There is a small increased risk of low-grade proteinuria ( s to hyper \201 l- tration in t he remaining kidney) and i BP. However, donation increases the absolute cumulative risk of ESRD by <1%. There are data that suggest improved life expectancy for individu- als who have donated, pr esumably re \202 ecting their evident \201 tness at the time of donation and perhaps mot ivation to stay \201 t post-donation. However, this may not continue to hold true as more patients are accepted to donate and their long-term follow-up improves. LIVE DONOR TRANSPLANTATION 375 Assessment of GFR for live donation In many countries (including the USA), GFR is estimated using creatinine clearance (CrCl) on a 24h urine collection. eGFR, using equations, such a s MDRD, are not acceptable, as they are not suf \201 ciently accurate when renal function is normal or near normal ( b p. 34). GFR may also be measured using radioisotopes, such as 51 Cr-EDTA (recommended in the UK). A suitable GFR for donation should be age-adjusted (see Fig. 5.16 and Table 5.5). 120 100 GFR (mL/min/1.73m2) 80 Mean GFR 60 Safe to donate 40 20 0 10 20 30 40 50 60 70 80 Age (years)