Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). UK National Transplant Database (maintained by NHS Blood and Transplant). Box 5.1 Key facts \200 The 1-year survival for deceased donor renal transplants is 7 91%. Patient survival is >95%. The 1-year survival for live donor renal transplants is 7 97%. Patient survival is >98%. This has steadily improved over the last two decades. \200 The 5-year survival for deceas ed donor renal transplants is 7 70%. Patient survival is 7 80%. The 5-year survival for live donor renal transplants is 7 82%. Patient survival is 7 90%. The 10-year survival for deceased donor renal transplants is 7 45%. Patient survival is 7 60%. The 10-year survival for live donor renal transplants is >55%. Patient survival is 7 75%. TRANSPLANTATION OUTCOMES 341 t f a r g 10 g n n o i t c n u f / All-cause graft failure 8 i Return to dialysis or retransplant 6 w s r a e y 4 Death with function t p 0 0 1 / e t a R 2 0 92 94 96 98 00 02 04 06 08 10 Transplant year Fig. 5.6 The overall graft failure rate among adult (age >18) transplant recipients per 100 patient years is falling year on year, although the percentage that die with a functioning graft remains unchanged. Reproduced from USRDS 2012 annual report, with permission. Patient survival The principal causes of death post-transplantation are CV disease, infec- tion, and malignancy (see Fig. 5.7). 35 30 s t n e i t a p 25 20 f o e g a t n e c r e P 15 10 5 0 Infection CVD Unknown Malignancy Other Fig. 5.7 Causes of death in patients with a functioning graft. Reproduced from USRDS 2012 a nnual report, with permission. Factors in \202 uencing graft survival \200 Delayed graft function (DGF): Variably de \201 ned ( b p. 404). \200 7 3% in live donor and 7 20% in deceased donor ki dneys (the rate will vary signi \201 cantly, e.g. 7 30% for ECD kidneys and 7 40% for DCD kidneys). CHAPTER 5 Transplantation 342 DGF is itself a function of i donor age, i cold ischaemic time, and the presence of signi \201 cant anti-HLA antibodies ( b p. 405). DGF is associated with d graft survival, i mortality, i rejection ( l probably enhanced graft immunogenicity post-reperfusion). HLA matching: For deceased donor kidneys, better HLA matching is associated with improved graft survival. This falls progressively with increasing mismatch (see Fig. 5.8). \200 The effect is much less pronounced for live donor kidneys, whether related or unrelated. Timing of transplantation: Pre-emptive transplantation provides a survival bene \201 t for both graft and recipient. Graft survival deteriorates, with longer times on dialysis pre-transplantation. Reasons: more recipient CV disease, higher incidence of DGF, socio-eco nomic factors. In the UK, 7 35% of adult live donor and just 7 10% of deceased donor transplants are pre-emptive. 100 80 60 0 MM 1 MM 2 MM 3 MM 4 MM 6 MM 5 MM ) g o l ( 40 l a v v r u s i 20-year estimate 43 % 37 % 36 % 35 % 33 % 28 % 28 % Half-life (years) 17.4 15.4 14.6 14.2 13.8 12.0 12.3 t f a r g % 0 MM 1 MM 2 MM 3 MM 4 MM 5 MM 6 MM 20 10 0 2 4 6 8 10 Years 12 14 16 18 20 Fig. 5.8 Percentage survival HLA A + B + DR mismatches: \201 rst cadaver kidney transplan ts, 1985 \200\223 2011. Reproduced from the Collaborative Transplant Study ( M http://www. ctstransplant.org ), with permission. TRANSPLANTATION OUTCOMES 343 Donor factors: Age: 5-year survival of a deceased donor kidney from a donor age 18 \200\223 34 is 7 80%, compared to 7 55% for donor age >65. (cid:2) This is a very important issue, as the average donor age is progressively increasing. Living donor grafts last longer than deceased donor grafts (less cold ischaemia, better health of donor, often less time on dialysis accruing CV disease and other complications, higher nephron mass, better recipient compliance). See Box 5.1 on b p . 340. Donation after brain death (DBD) kidneys have better outcomes than those donated after card iac death (DCD) ( b pp. 365 \200\2238). \200 ECD kidneys have poorer, if acceptable, outc omes overall (although this can be dif \201 cult to predict at the time of transplantation). i cold ischaemic time (CIT) l i DGF l d graft survival. This risk is particularly high when CIT >18h. The time it will take to transportation a kidney is usually taken into account i n organ allocation schemes ( b p. 365). \200 Recipient factors: Age. The commonest cause of graft loss beyond age 65 is death with a functioning transplant. Race. In the USA, black recipients of deceased donor transplants have poorer outcomes than Caucasian recipients. This is partly due to i DGF in black recipi ents as well as inferior HLA matching (the donor pool is predominantly Caucasian). Obesity and other comorbidities ( i BP, CV disease) ( b pp. 370 \200\2231). \200 The natu re of the recipient \200\231s original native kidney disease and the risk of this disease recurring in the transplant. Rejection episodes ( b p. 408): 2 A single episode of rejection reduces 5-year graft survival by 7 10%. The greater the number of episodes, the worse the outcome. HLA antibodies ( b p. 361 \200\2234): About 7 20% recipients develop anti-HLA antibodies post-transplantation. The development of such antibodies trebles the risk of graft failure (whether or not they are donor-speci \201 c). Donor-speci \201 c anti-HLA antibodies (DSA) are associated with chronic antibody-mediated rejection ( b p. 414 \200\2236). Proteinuria: As in native kidneys, a marker of renal injury, the risk of progressive renal dysfunction, and overall CV morbidity and mortality. May also herald recurrent native disease. Number of previous transplants (see Fig. 5.9). CHAPTER 5 Transplantation 344 100 90 80 70 ) g o l ( 60 l a v v r u s 1. TX 2. TX 3. TX > 3. TX i 50 t f a r g % 40 30 20 10 0 0 2 4 6 8 10 Years Fig. 5.9 Graft survival over time, according to number of previous transplants in an indivi dual. Reproduced from the Collaborative Transplant Study ( M http://www. ctstransplant.org ), with permission. TRANSPLANTATION OUTCOMES 345 CHAPTER 5 Transplantation 346 Basic transplant immunology Introduction A transplanted kidney will be antigenically distin ct from its new host and recognized as foreign and initiate an immune response, unless it i s from a genetically identical individual (essentially, an identical twin). In the context of transplantation, these antigens are known as alloantigens (and the donor kidney is often referred to as an allograft). The most relevant alloantigens to transplantation are a grou p of histocompatibility genes known as the major histocompatibility complex (MHC). Minor hi stocompatibility anti- gens are also relevant although less important. Alloantigen recognit ion triggers immune cell activity and the activation of multiple potent effectors of the im mune response. Histocompatibility and allorecognition The MHC presents fragments of \200\230 non-self \200\231 proteins to T cells in order to initiate an immune response. In humans, the MHC ge nes on chromosome 6 encode a polymorphic group of proteins called human leucocyte anti- gen s (HLA). Their main function is to present antigens to T cells. There are two classes: \200 Class I HLA includes HLA-A, HLA-B, and HLA-C and is present on all nucleated cells, i ncluding vascular endothelium. They exist as a heterodimer with B 2 microglobulin. Class I molecules present non-self peptides to cytotoxic CD8+ T cells, leading to their activation. Self-antigens are not recognized, as immunological tolerance, to them, has developed durin g T cell maturation. Class II HLA includes HLA-DR, HLA-DQ and HLA-DP and is present mainly on antigen-presenting cells (APCs), including macrophages, mesangial cells, and dendritic cells. Other cells can be induced to express class II HLA during conditions of in \202 ammation. They are also h eterodimers but consist of two polymorphic chains (i.e. no B 2 microglobulin). Class II ant igens present peptides to CD4+ T cells, leading to their clonal expansion. In addition, act ivated CD4+ cells release cytokines that activate CD8+ cells. Each individual inherits an HLA allele from each parent (a haplotype). The recognition of transplanted HLA by recipient T cells is by direct and indirect pathways (see Fig. 5.10). \200 Direct pathway. Donor (passenger) APCs present fo reign peptides to recipient cytotoxic CD8+ T cells, leading to their activation. This pathway is largely r esponsible for early acute cell-mediated rejection. \200 Indirect pathway. Donor cells or donor proteins shed from cell surfaces are engulfed by recipient APCs and presented to recipient CD4+ helper T cells. This is thou ght to mediate more chronic graft damage. The binding of a T cell to an APC leads to the initiation of the immune reaction. This proc ess requires three distinct steps or \200\230 signals \200\231 : \200 Signal 1 (TCR act ivation). Binding of APC MHC-peptide complex to the T cell receptor (TCR) activates multipl e intracellular pathways. One of these pathways involves the phosphatase calcineurin ( i in tracellular BASIC TRANSPLANT IMMUNOLOGY 347 Ca 2+ l activation of calcineurin l activation of nuclear factor of activated T cells (NFAT ) l IL-2 release (but only in the presence of signal 2). Signal 2 (co-stimulation). Binding of complementary co-stimulatory pathway molecules presen t on APC and T cells (e.g. CD40:CD40 ligand and ICAM:LFA1) l activation of tyrosine kinase, which, together with signal 1, leads to induction of IL-2 and other T cell activation gene s. Other interactions, such as B7:CTLA4, are inhibitory. Signal 3. Signals 1 + 2 l induction of cytokine, cytokine receptors, and cell activation ge nes (including IL-2 and IL-2R) l clonal proliferation. If signal 1 occurs without the subsequent signal 2, then T cell activation is not initiated , and instead apoptosis results. T cell activation T cell activation involves their proliferation and clonal expansion (mean - ing all cells express the same TCR), prior to differentiation into effector cells (which no longer require co-stimulation for activation) (see Fig. 5.11). CD4+ effector cells inclu de TH1, TH2, regulatory and memory cells: \200 TH1 cells activate macrophages, provide he lp to B cells, and synthesize several important cytokines. TH2 cells mainly provide B cell help (including immunoglobulin class switching). TH17 cells are involved in in \202 ammatory responses (e.g. to bacteria). \200 Regulator y T cells (Tregs) suppress T cell responses. \200 Memory T cells are a component of immun ological memory (the ability to respond promptly and intensely, following antigen representation). CD8+ cells develop into a single cytotoxic effector cell population, involved in the killin g of both infected cells and tumor cells. B cells B cells are responsible for antibody production. B cell activation follows antigen recognition via the B cell receptor (BCR \200\224 itself a type of anti- body) and require s additional T cell help (provided by CD4+ TH1 and TH2 cells \200\224 see above). B cells represent the antigen that has triggered them (with MHC class II), so T cells reactive to t he same antigen pro- vide the help. Activation leads to proliferation prior to differentiat ion into antibody-producing plasma cells (usually found in bone marrow). A small proportion of activated B cells will become memory B cells. CHAPTER 5 Transplantation 348 Direct pathway Indirect pathway Recipient APC Donor APC Donor APC MHC molecule CD4 T cell receptor CD8 Alloantigen Alloantigen CD4 Recipient helper T cell Recipient cytotoxic T cell Recipient helper T cell Cytokines Delayed type hypersensitivity Activated cytotoxic T cell Recipient macroph- ages Recipient B cell Alloantibodies Fig. 5.10 Direct and indirect recognition. Signal 3 APC Other cytokines IL2 Signal 1 Signal 2 T Tyrosine Tyrosine IL2 and other cytokine receptors Rise in intracellular Ca2+ De novo nucleotide TOR Cyclin Calcineurin Induction of cytokine and T cell activation genes NFAT Cell cycle Fig. 5.11 T cell activation. TOR, target of rapamycin (sirolimus). BASIC TRANSPLANT IMMUNOLOGY 349 Tolerance \200 The holy grail of organ transplantation: permanent survival of a transplant without the need for maintenance immunosuppression. \200 Tolerance implies tha t alloreactive cells have either been deleted or do not respond to transplanted alloantigens. An important and exciting focus of international research efforts in transplantation (see M http://www.immunetolerance.org ). \200 Rare cases of tolerance are recognized in renal transplantation (usually in the context of non-compliance!). The induction of tolerance has proved possible in rodent models but remains elusive in huma ns, probably because we have a much more extensive immunological memory. Many reports claim partial tolerance, based on the minimal use of immunosuppressive drugs (e.g. lower levels of maintenance immune suppression, following ind uction with alemtuzumab). Complete tolerance has been described in the context of renal after bone marrow transplanta tion (BMT) from the same donor. This is because BMT may result in the total replacement of the recipient \200\231s bone marrow (and 6 haematopoietic cells) with the donor \200\231s \200\224 a state known as full chimerism. Similar principles have been applied with some success to patients with multiple myeloma an d ESRD undergoing combined BM and renal transplantation. It is also known that infusion of donor-derived bone marrow cells can improve graft survival, and there is interest in translating this into immunosuppressiv e strategies. Successful protocols have been reported, utilizing donor cell infusions (CD34 +ve progenitor cells and CD3 +ve T cells), but they require formidable cond itioning regimens (total lymphoid irradiation and T cell depletion) so are unlikely to be u niversally accepted. \200 In addition, these protocols involve well HLA-matched transplan ts. It is not clear how such approaches will translate to the much more challenging setting of HLA-mismatched transplantation (BMT across HLA barriers is problematic l i rejection an d graft vs host disease). A likely future approach will be to speci \201 cally bioengineer cell therapy with haematopoietic stem cells (e.g. see M http://www. onestudy.org ). CHAPTER 5 Transplantation 350 Pre-transplant work-up Patient selection All patients approaching ESRD should be considered for transplantation, unless there is an absolute contraindication. The \201 rst step is appropriate education so that they understand the need to proceed through a series of struc tured investigations. Contraindications UK BTS guidelines suggest the following absolute contraindications: \200 Uncontrolled malignancy. \200 Uncontrolled infection. \200 X Life expectancy of <5 ye ars. Additional potential contraindications \200 Cirrhosis (unless combined liver and kid ney transplant). \200 Primary oxalosis (unless combined liver and kidney transplant). \200 Substance abuse. \200 Morbid obesity ( X cut-off BMI unclear). \200 Recent MI or coronary intervention (see Assessment for cardiovascular disease, b p. 352). Ejection fraction <30%. \200 Habitual, irremediable, non-compliance. Note: age alone is not a contraindication to transplantation. Patient education Before formal pre-transplant investigations, potential transplant recipi- ents should ideally attend a local education session. The purpose of this forum is to prov ide patients (and relatives) with a greater insight into the following: \200 Risk and ben e \201 ts of renal transplantation. \200 Live donor transplantation vs deceased donor tr ansplantation. \200 The nature and rationale for work-up investigations. How long these may take. Waiting time for deceased donor kidneys. \200 Different types of deceased donor; DBD, DCD , ECD. \200 What to expect in the post-operative period. \200 The nature and frequency of outpatient follow-up. \200 Immunosuppression and its side effects. \200 The crucial importance of compliance with medication. The sessions should be hosted by members of the entire transplant team, including nurse spe cialists, pharmacists, physicians, and surgeons. It is also an opportunity to introduce the patient to others who have previously undergone transplantation. Pre-transplant assessment Potential recipients must be \201 t to undergo surgery and long -term immune suppression. Routine assessment starts with a detailed history and a PRE-TRANSPLANT WORK-UP 351 thorough physical examination. Most transplant centers have a checklist of work-up investig ations (for example, see b p. 352). This assessment is a multidisciplinary process, during which both a neph- rologist and a tr ansplant surgeon should review the patient and the results of their investigations. Transpl ant coordinators, specialist nurses, psychol- ogists, urologists, cardiologists, and tissue typists will also play important roles in the work-up of patients to a greater or lesser e xtent, depending on individual need. 2 In the UK, patients may be listed for deceased donation when dialysis is predicted within the subsequent 6 months. It is important to avoid unnecessary delays (and investigations) \200\224 annual mortality whilst await- ing a transplant is 7 6%. Goals of transplant work-up \200 To determine physical \201 tness for transplantation ( esp. CV \201 tness). \200 To con \201 rm that a transplant is surgically (+ urological ly) feasible. \200 To identify any potential impediments to transplantation and any corrective interventions that might remove them. \200 To provide adequate and ongoing pat ient education. Goals of medical assessment \200 Assessment for CV disease. \200 Assessment of other me dical comorbidities. \200 Review of thrombosis/bleeding history. \200 Assessment of inf ection risk/history. \200 Review of any previous malignant disease. \200 Review of unde rlying native renal disease. \200 Review of immunological history (anti-HLA antibody stat us). Goals of surgical assessment \200 Assessment of vasculature, particularly iliac and perip heral vessels. \200 Previous abdominal surgery and hernias. \200 Previous renal transpl ant history. \200 Assessment of BMI and surgical risks. \200 Assessment of previous uro logical history or current symptoms. \200 Is the recipient \200\231s bladder function lik ely to be adequate post-transplant? Is bladder out \202 ow adequate? Assessment of native kidneys, e.g. do large polycystic kidneys require removal? Which side will the graft be placed? General \200 Assessment of compliance. \200 Assessment of mental health (see Assessment of mental health, b p. 359). Plans for pregnancy in \231\200 of childbearing age. \200 Social factors: employment, fa mily support, etc. CHAPTER 5 Transplantation 352 Box 5.2 Typical recipient work-up Immunological \200 Blood group. \200 HLA type. \200 HLA antibody screen. Virology \200 HIV. \200 Hepatitis B. \200 Hepatitis C. \200 Epstein \200\223 Barr virus (EBV). \200 Cytomegalovirus (CMV). \200 Varicella zoster virus (VZV). \200 Toxo plasma. \200 Syphilis. \200 HTLV 1 and 2 (only for Caribbean/Japanese or HIV +ve). Hematology \200 FBC, platelet count, PT/INR/APTT. \200 Thrombophilia screen (if previou s thrombotic event, relevant FH, SLE, or recurrent miscarriages). Serum and urine protein electrophoresis and immuno \201 xation (age >60 years). Other \200 CXR. \200 ECG. \200 X echo. \200 Additional cardiac assessment (see foll owing \200\230Assessment for cardiovascular disease \200\231). Iliac (arterial and venous) Doppler studies. Further imaging, such as CT or formal angiography, may be required if abnormal. Carotid artery Doppler (if previous TIA/CVA). \200 Ultrasound of native kidneys. \200 U rological (e.g. satisfactory bladder function). \200 PSA (if age >50 or FH of prostate ca ncer). \200 Smear test/mammogram (as per national cervical/breast screening). \200 FOB (if age >60 as per national bowel cancer screening). \200 Lung function testing (based on previous history). Assessment for cardiovascular disease Cardiovascular disease burden in CKD Advanced CKD is associated with a high risk of CV disease, ranging from coronary artery disease (CAD) and h eart failure to PVD and stroke. Potential renal transplant candidates need to be scrutinize d for CV disease and CV risk factors and to have them proactively treated to maximize graft and patient survival post-transplantation. PRE-TRANSPLANT WORK-UP 353 CV disease is the leading cause of death after transplantation. \200 7 50% of deaths with a functioning graft occurring within 30 days of transplantation are due to CAD. The relationship between CKD and CV disease is described on b p. 198. Certain risk factors are discussed in the following section, as they are relevant for risk strati \201 cation a nd guiding choice of pre-transplant cardiac investigations. CV assessment prior to transplantation is considered an essential exercise by most transplant centers \200\224however, optimal investigations and interventio ns remain controversial. Most centers take into consideration: (i) current cardiac symptoms; (ii) prior history of established cardiac disease; (iii) risk factors. (cid:2) All potential recipients have a degree of CV risk, as relative risk of CV disease is disproportionally high in young ESRD patients. Risk factors Many centers use a single risk factor from the list below as a trigger for non -invasive cardiac stress testing. i BP ( 9 LVH) and i lipids are not included, as they are so highly prevalent in ESRD patients. \200 Diabetes. \200 Age >50. \200 Previous coro nary revascularization. \200 Established non-cardiac vascular disease (i.e. PVD or CVA). (See Table 5.3.) Abnormal resting ECG (other than LVH). \200 Smoking. \200 Dialysis duration >12 months. \200 Previous renal transplant. Approach to CV assessment \200 History . Angina, d exercise tolerance, breathlessness, cl audication, and symptoms suggestive of cerebrovascular disease. Traditional cardiac risk fa ctors. Examination. Evidence of cardiac failure, murmurs, and review of peripheral vasculature (pa lpable aortic aneurysm, vascular bruits, missing pulses, distal limb ischaemic changes). All patients will need a CXR and an ECG. \200 Echo if clinical suspicion of a valve lesio n, cardiac failure, pericardial effusion, signi \201 cant LVH on ECG, or cardiomegaly on CXR. An ejection fraction <30% is considered a contraindication to deceased donor transplantatio n ( l i perioperative mortality, poor early graft perfusion, and increased risk of transpla nt vein thrombosis). Cardiopulmonary exercise testing (CPET) can identify patients at high risk of post-operative complications. Risk strati \201 cation Based on the CV assessment, patients can be strati \201 ed as fol lows: Symptomatic patients \200 Symptomatic patients should be referred to a cardiologist for c oronary angiography. CHAPTER 5 Transplantation 354 Additional functional tests, such as dobutamine stress echocardiography (DSE), may be considered, but the key symptomatic and prognostic question is whether the patient will bene \201 t from coronary revascularization. (cid:2) The risks of contrast nephropathy 9 cholesterol emboli need careful consideration i n this group of patients. Patients may be rendered temporarily, or permanently, dialysis-de pendent. Asymptomatic patients with risk factors \200 Whilst there is no convincing evidence that anatomical or functional testing is of either diagnostic or prognostic value in asymptomati c patients without renal failure, it is generally accepted that patients with renal failure are a unique group and that such assessment is highly desirable. (cid:2) The absence of symptoms is not always reliable \200\224 many patients with ESRD ha ve limited exercise capacity, and volume overload may obscure myocardial ischaemia. In diabetic patients, symptom burden is a poor indicator of ischaemia (autonomic neuropathy l defective \200\230 anginal warning \200\231 ). Asymptomatic patients with any of the risk factors listed should 6 undergo stress testing, with either a DSE or a myocardial perfusion scan (MPS). The interpretation of non-invasive cardiac investigations must be guarded in the context of ESRD (see Table 5.1). The sensitivity, speci \201 city, and positive and negative predict ive values of these investigations are shown in Table 5.2. Head-to-head comparison of DSE vs MPS reveals that neither is better nor perfect, but both are superior to alternatives. The FAME study highlighted the importance of combining anatomical \201 ndings with functional tests: \200 Fractional \202 ow reserve (FFR) may help to guide management of a coronary stenosis in an asymptomatic dialysis patient. If the stenosis is associated with downstream ischaemia (identi \201 ed either by an abnor mal FFR or a reversible perfusion defect), the patient should be offered revascularization. Asymptomatic patients without risk factors \200 Resting ECG and CXR to determine the need for either an echo or MPS/DSE. Otherwise, no further investigation is usually necessary. PRE-TRANSPLANT WORK-UP 355 Table 5.1 The utility of non-invasive cardiac investigation in advanced CKD Non-invasive tests Potential problems Resting ECG Normal ECG does not exclude CAD. Abnormal ECG predicts CAD but non-speci \201 c (up to 40% of dialysis patients have an abnormal ECG). Exercise stress testing (EST) Poor exercise performance \200\224 several studies have documented that only 7 \200\223 5 3% of dialysis patients achieve the target heart rate. A high proportion of patients have baseline ECG abnormalities. Not recommended for transplant cardiac assessment. Balanced ischaemia does not show on an MPS, as the technique measures relative, as opposed to absolute, perfusion. However, an abnormal test suggests a high risk of signi \201 cant CAD. Myocardial perfusion scan (MPS) Dobutamine stress echo (DSE) Operator-dependent, and adequate acoustic window is not possible in 7 20% of patients. Many dialysis patients do not achieve target heart rate ( l d sensitivity of the test \200\224 although failure to attain maximal stress may itself be a risk factor for subsequent cardi ac events). CT coronary angiogram Low speci \201 city due to high coronary artery calcium burden. Cardiac MRI Avoidance of gadolinium due to risk of nephrogenic \201 brosing dermopathy ( b p. 51) mak es this of limited use. CPET A non-invasive measurement of haemodynamic variables and gas exchange but not used to predi ct presence of CAD. Adapted from Nicholas Torpey et al. (Oxford Specialist Handbook) Renal Transplantation (201 0), with permission from Oxford University Press. Table 5.2 Sensitivity, speci \201 city, and positive and negative predictive values of non -invasive cardiac investigations in advanced CKD Cardiac test Sens (%) Spec (%) PPV (%) NPV (%) Resting ECG 67 \200\223 77 52 \200\223 58 43 47 EST 35 64 63 36 DSE 47 \200\223 88 85 \200\223 95 63 \200\223 90 66 \200\223 89 MPS 37 \200\223 80 37 \200\223 73 53 \200\223 58 60 \200\223 67 Sens, sensitivity; Spec, speci \201 city; PPV, positive predictive value; NPV, negative pr edictive value. CHAPTER 5 Transplantation 356 Rescreening \200 Patients may wait for several years for a transplant, so regular assessment is essential. Data concerning the annual incidence of cardiac events in CKD patients after normal stress imaging test suggest rates increase from 4 \200\223 12% within 2 years to 10 \200\223 30% beyond 2 years. This implies cardiac rescreening should be undertaken every 2 years (soone r if symptomatic). It is interesting to note that cardiac event rates, following a normal MPS in the general p opulation, are <1% per year, underlining the increased CV risk for patients with advanced C KD. Revascularization \200 The purpose of CAD intervention (either by surgical means or percutaneously through the use of stenting) is to restore blood \202 ow to an ischaemic a rea of myocardium. Revascularization procedures do not alter the pathophysiological process es involved in CAD but simply serve to improve blood \202 ow and prevent infarction. The best method of revascularization for patients with ESRD has not been established. Studi es can only be extrapolated from the general population, but support both surgical and perc utaneous options as effective in symptomatic disease. CABG complication rates are 7 10% higher in ERSD patients. However, it is the treatment of choice for patients with multivessel disease and LV dysfunction ( l symptomatic and prognos tic bene \201 t). \200 Any patient who has had a STEMI/NSTEMI, but not required revascularization, should not be considered for transplantation until cleared by a cardiolo gist 6 months after the event (this will usually involve further investigation). Stented patients need to wait until dual antiplatelet therapy has ceased ( l intraoperative bleeding risk). Generally, 12 months for a drug-eluting stent and 3 months for a bare metal stent. Table 5.3 Important non-cardiac issues Respiratory Pulmonary function tests (PFT) if asthma, COPD, or parenchymal lung disease 9 anesthetic as sessment. (cid:2) Stop smoking! GI symptoms may require further evaluation to exclude malig nancy. GI Persistent vomiting or malabsorption (e.g. pancreatic insuf \201 ciency) may cause problem s with immunosuppression. Cholecystitis post-transplant can be severe. Screen patients with a relevant history for ga llstones. Hyperparathyroidism Parathyroidectomy post-transplantation is associated with graft dysfunction through uncerta in mechanisms ( 6 control hyperparathyroidism pre-transplant). PRE-TRANSPLANT WORK-UP 357 Thrombotic or bleeding tendency Pro-thrombotic tendency \200 Any evidence of a pro-thromb otic tendency should be investigated with a thorough thrombophilia screen. Examples: \200 Previous transplant loss due to arte rial or venous thrombosis. \200 Recurrent AVF thrombosis. \200 History of DVT/PE. \200 SLE (associated APS, b p. 664). \200 Recurrent miscarriages. A pro-thrombotic history or condition does not preclude transplantation, but patients should have an agreed treatment plan established in advance, with the aim of minimizing thrombotic complications and early graft loss. Bleeding tendency \200 Thrombocytopenia or prolonged INR or APTT warrant hematological investigation. Anticoagulant and antiplatelet drugs \200 Anticoagulation should be reversed prior to tra nsplantation: IV unfractionated heparin should be started as soon as is deemed surgically acceptable post -transplant in high-risk patients (e.g. prosthetic valve or thrombotic tendency). Aim APTT 1.5 \200\223 2.0. \200 Avoid LMWH until GFR has normalized post-transplant. \200 Re-anticoagulate prior to discharge Antiplatelet drugs: Aspirin may be continued peri-transplantation. \200 Dual antiplatelet therapy is consider ed a relative contraindication to transplantation in many centers. Infection risk and infection history \200 Ensure serological screening has been undertake n. See Box 5.2 , 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