Fitness to Transplant

The patient has, in principle, only one simple question to consider: will the quality and quantity of life be better after a transplant than on dialysis? For many people the answer is clear and unequivocal—either because the alternative of long-term dialysis treatment is not available or unaffordable, or because transplantation is the obvious solution because they are young and otherwise fit. For some people, however, the answer is clouded in uncertainty because of the relative unavailability of organs for transplantation, or because they have comorbid conditions that will be exacerbated by the operation or the ensuing immunosuppression.

Quality of life is perhaps the single most important issue for most people and yet the field has found the social sciences difficult to grasp, and there are few studies comparing quality of life on dialysis and after transplantation. Most clinicians find it hard to identify living individuals with a lower quality of life after a successful transplant than they had or would have had on dialysis, and thus find it easy to advocate for transplantation. This approach ignores the patient deaths and graft failures, and the diminished quality of life for those who struggle with the consequences of immune deficiency, infections, and malignancies. Both governments and transplant programs tend to substitute graft survival data for true quality of life data and use it as a surrogate, but objective, measure of the success that each individual might expect instead of a measured comparison of quantity of life.

In countries without sufficient access to dialysis, the decision to receive a renal transplant is obvious for almost all patients, because transplantation is the only alternative to a slow death from uremia. This does assume access both to lifelong immunosuppressant drugs and specialist medical follow-up, either of which may not be available or affordable and without which transplantation becomes a futile delusion. Understanding by a patient and their family of the lifelong commitment needed for a successful transplant is critical because patient and graft survival rates are substantially affected by compliance with follow-up and adherence to medication protocols. Transplantation has been promoted as a cure, when it is actually a complicated treatment requiring regular follow-up by specialists working in sophisticated medical centers using expensive drugs. If the patient and his of her family fail to understand the costs, level of follow-up, and the adherence that will be required of them, then it is likely that the published statistics of average survival will not apply to them.

Predicting the success rate after transplantation relies on characteristics of both the recipient and the donor. Probably the most comprehensive studies comparing transplant recipients with those remaining on dialysis come from the US where it has been possible to track the outcomes of all individuals entered onto the transplant waiting list and compare those who were transplanted with those who remained on dialysis. These studies show that transplantation carries the greater risk of death for the first 3 months or so, and reverses after that point in time so that the risk of death is equal by 6 to 9 months, thereafter favoring the transplant recipient dependent on donor and patient risk factors. Similar analyses show that the patient who is transplanted preemptively carries an advantage compared with one who has needed a period of time on dialysis; furthermore, the longer the period of dialysis the worse the outcome.

The patients’ expectations from a successful transplant may be that they will die in old age with a perfectly functioning kidney. The reality is that they will die much earlier than an age- and sex-matched individual without renal disease, and more than half will have lost their graft before they die.

Analysis of patient perspectives of the most feared risks after a transplant are a little at odds with physician views because graft loss is feared more than death.

Appropriateness to Transplant

The patient with access to both dialysis and transplantation can compare their prognosis using simple outcome statistics of dialysis and transplant patients, as seen in Fig. 4.2 . Even elderly people who have been accepted for transplantation and received a transplant survive better than those remaining on dialysis. The presumption, from the recipient’s perspective, should thus be to be assessed for fitness to be transplanted.

(A) Prevalent dialysis patient mortality compared with the general age matched population. (B) Prevalent transplant patient mortality compared with the general age matched population.

CI, confidence interval. (ANZDATA Registry 2016 Annual Report, reproduced with permission.

The next issue, for those fit enough for the procedures, is the source of a donated kidney. In many countries this will be restricted to a living donor kidney from a relative or an altruistic friend ( Fig. 4.3 ). Where the luxury of deceased donation exists, organ allocation policies become critical to the options. Careful counseling and education is needed to arrive at a decision. Consider an elderly father or mother in their late 60s without any comorbid conditions, deciding whether or not to accept a donation from a 30-year-old son or daughter. The son or daughter may consider it appropriate to offer a kidney to their parent, acknowledging the small but real immediate and possible long-term risks to themselves. The parent may consider it highly inappropriate to place their offspring at even the slightest risk to provide a few years of better quality of life for them. In the reverse situation it may be considered obvious for a 20-year-old recipient to be transplanted, but not to accept a donor offer from an elderly parent, both because of the increased risk of donation by an older person and because of the worse outcome predicted from an older kidney. It is the responsibility of the transplant unit to provide independent medical advice to ensure that both the donor and the recipient can arrive at a considered and individual decision.

Numbers of living and deceased donor kidney transplants by World Health Organization region as reported by the Global Observatory on Donation and Transplantation, 2015.

From http://www.transplant-observatory.org/data-charts-and-tables/chart/

Waitlisting and Allocation of Deceased Donor Organs

In those countries with deceased organ donor programs the community must decide how to manage the allocation of deceased donor kidney offers. In most countries national, regional, or local waiting lists provide access to the offer, although in some places where deceased donors are rare, selection may be ad hoc. The percentage of dialysis patients actively listed for transplantation varies quite surprisingly. There are not only barriers because of age and comorbidities but also from demographic, geographic, and socioeconomic factors. The community—when asked—almost always regards “equity of access” as the most dominant factor, but the reality is a complex balance of medical utility and sometimes conflicting notions of equity. Healthcare professionals are far from agreed on what should constitute the criteria for medical eligibility and whether or not it is appropriate to include consideration of social and lifestyle factors, ability to understand and adhere to treatment, and medical estimates of prognosis.

There are many published guidelines on assessment for transplant waiting lists. The stated aim of almost all of these guidelines is to provide objective and explicit advice to the clinician assessing an individual patient. Most achieve a comprehensive perspective, but there are substantial differences over the methodology behind each recommendation. There is a largely consistent approach to the required level of renal impairment and medical comorbidities, with most also providing broad statements on age criteria, life expectancy, and both psychological and social factors. The effect of high body mass index (BMI) is interpreted as both a criterion for surgical acceptability and a medical criterion predicting cardiovascular and other morbidity and mortality; however, advice is based on expert opinion rather than hard evidence. There is as yet little effect of formal assessment of frailty for which the data are developing. Shortage of donor organs in most environments leaves a tension between maximizing utility on the one hand and equity on the other. In resolving this tension, most guidelines attempt to promote a transparent decision-making process in the absence of a robust formula that is universally applicable to each individual.

Considerable statistical effort has been expended on predicting patient outcomes based on pretransplant factors in both the donor and the recipient. The donor element is assessed using the kidney donor profile index (KDPI), which uses only data derived from the donor before donation. The recipient element is derived by the Scientific Registry of Transplant Recipients (SRTR) from age, dialysis duration, prior transplant, and diabetes to create an expected posttransplant survival (EPTS). Using these elements it was possible to derive a new kidney allocation system in the US—the early results of which are becoming evident.

In association with new evidence-based reviews, there is now detailed advice on specific issues in recipient assessment. The EPTS and KDPI can be calculated for an individual using a published calculator. Different countries have assessed local adaptations of these formulae with varying reproducibility, demonstrating the principles are widely applicable but the detail has to be adjusted to the demographics of each environment.

What the Patient Needs to Know

The transplant unit has the responsibility to provide each patient with advice based on his or her own medical conditions and education about the options for long-term treatment ( Box 4.1 ). The starting point for such education is thus a comprehensive evaluation of the suitability, availability, and financial cost of dialysis options. The quality of physical and emotional well-being provided by dialysis therapy usually becomes abundantly clear to most patients, either through meeting other patients already on dialysis, or through dialysis education programs and finally, definitively, through direct personal experience, except in that small minority able to undergo preemptive transplantation.

A comprehensive evaluation needs to be provided by the transplant unit of each individual’s medical risks if he or she were to undergo a renal transplant. Much of the rest of this chapter details the medical assessment, but a checklist is provided in Table 4.1 . This list includes those issues that affect the individual patient’s technical transplantability in addition to the short- and long-term factors that influence such outcomes as graft and patient survival. In assessing the patient’s suitability for a transplant operation the physician will be focused on the heart and lungs, the surgeon on the blood vessels and bladder. The surgeon will need to discuss the various complications and risks of the surgical procedure, whereas the physician discussion should revolve around the drugs, long-term risks, and follow-up protocols. Providing the patient with sufficient knowledge on organ allocation processes, the pros and cons of particular donor kidney offers, and on the financial costs that he or she will be expected to bear, are easily left out of a traditional medical consultation. Most established transplant programs thus have additional formal education sessions provided by a range of specialized coordinators, social workers, and pharmacists. The Internet and social media increasingly provide a wide range of both good and bad information, which patients will certainly access extensively. A guide to the better material and warnings against the bad sources of information should also play a part in the advice provided by the transplant program.

Consent

It is, of course, normal practice to seek written informed consent just before undergoing any surgical procedure and all transplant operations are preceded by such a ritual signing of a legalistically phrased document. Somewhere among this scant and hastily signed documentation will be the expectation that the individual has accepted all the risks of transplantation, from transmission of serious disease from the donor, through to the side effects of every drug that they will be given. Many patients will also be presented with a dazzling array of research protocols to sign up for, with patient information sheets of many pages of closely typed and densely constructed language more designed to protect the researcher, hospital, and pharmaceutical company than inform the patient. This documentation of “consent” often takes place under pressure of time and in the middle of the night, sometimes even via the telephone. It is hard to see how anything provided by the patient in the haste of the anesthetic workup, no matter what it is written on, can be argued to be informed consent. Legal opinions have been given that suggest that no reliance can be placed on a patient’s decision taken under the duress of an immediate pretransplant consent, unless backed by extensive prior education and information. In constructing education programs, it would be wise for the transplant unit to consider the traditional “operation consent form” a legally valueless protection.

Cardiac

The first consideration of any CKD patient undergoing a major operation is the state of their heart. Dialysis patients and especially diabetic dialysis patients have high incidences of both symptomatic and asymptomatic ischemic heart disease and thus a careful evaluation of the heart is essential as summarized in the recent American Heart Association guidelines. The diversity of evidence and opinion leaves open the alternative approaches as identified in the European Best Practice Guidelines.

There is agreement that all patients need a careful clinical history and examination, including an electrocardiogram and chest x-ray. In addition, most units will perform an echocardiogram to assess left ventricular function and a stressed ECG, echocardiogram, or myocardial perfusion study to exclude significant ischemic heart disease in asymptomatic high-risk patients. Whereas CKD itself is the strongest risk factor for coronary artery disease, it is also important to assess obesity, family history, lipid profile, blood pressure, smoking history, and diabetes to define risk. Attitudes to smoking history vary among transplant units from outright refusal to transplant those patients that continue to smoke, through to more liberal approaches.

Some transplant programs require routine coronary angiography before acceptance onto a waiting list. There is certainly a rationale for such an approach given the high levels of coronary disease uncovered by such a strategy. The only randomized trial of surgical or medical intervention in this situation (diabetics with CKD) was so unequivocal about the value of intervention that the trial was halted and the nonintervention arm offered surgery or angioplasty. The weaknesses of this study (it only assessed diabetics and the optimum medical therapy would not be considered optimum today) and the lack of alternative randomized studies leave the field with uncertainties, but also a very clear view that diabetic patients need comprehensive cardiac evaluation.

A lesser strategy is to use a noninvasive test such as a stressed dopamine echocardiogram, or stressed nuclear study, or more recently, CT coronary angiography as a screening method for asymptomatic and low-risk patients, thus reserving coronary angiography for those with symptoms, significant risk factors, or a positive screening test. A systematic review of the predictive value of the screening tests suggested a dobutamine stress echocardiogram had the best accuracy. Despite careful screening close to the time of the transplant, patients with disease in minor coronary branches will be operated on, sometimes leading to postoperative chest pain, troponin leakage into the blood, and cardiovascular instability.

Proceeding to transplantation in patients with normal left ventricular function and normal coronary vasculature is the easy decision. The more complex issue is deciding who to transplant despite known cardiac disease, which needs to be considered not only on its own merits, but also because of the implications that it carries for widespread vascular disease. There is no evidence-based answer to this question as yet, and clinicians must thus rely on local opinion based decisions, guided by some general principles:

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  Treatable coronary and valvular disease is almost always worth treating before transplantation rather than afterward, both because of the risks posed by the cardiac disease during the transplant procedure and because of the risks that cardiac interventional procedures carry in the presence of immunosuppression and a functioning transplant.

  
  
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  It is usually wiser to avoid transplantation if, despite treatment of coronary artery and/or valvular disease, there remains a substantial risk of infarction of a large area of myocardium, or there is substantial left ventricular dysfunction. Cardiac disease is the single largest cause of mortality in both the dialysis and transplant populations and there is little evidence that transplantation will beneficially alter the outcome of ischemic heart disease. There is less certainty with respect to congestive cardiac failure, where poorly dialyzed patients may recover significant function when uremia and chronic fluid overload are corrected by transplantation.

  
  
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  In patients with severe and irreversible cardiac dysfunction, the remaining consideration is the option of combined heart and kidney transplantation, available to a limited number of young and otherwise healthy individuals transplanted in highly specialized centers.

Vascular

There is an absolute requirement for an available recipient artery for anastomosis of the transplant renal artery. Atheromatous iliac arteries that have been ossified through years of CKD management must thus be carefully assessed by the surgeon planning to perform the transplant. Absence of intermittent claudication and presence of palpable femoral and pedal pulses may be sufficient to confirm that renal transplantation is technically feasible. There are, however, many potential recipients with a high risk of severe vascular disease, where duplex ultrasound scanning of the femoral and carotid vessels will identify those at significant risk of peripheral or cerebrovascular events either during or after transplantation.

Selection of patients with known preexisting peripheral vascular disease must include a general assessment of their prognosis and specific assessment of the vascular supply needed for the transplant operation. The largest numbers of patients commencing dialysis in most developed countries are elderly obese type 2 diabetics, and many have severe peripheral vascular disease. Only a very small proportion of such patients prove to be suitable for transplantation because of the combined effects of obesity, cardiac, and vascular disease on their operative mortality and 3- to 5-year survival rates. Two-thirds of dialysis patients requiring lower limb amputations are dead within 2 years, implying that this group of patients have such a poor prognosis that only few, very highly selected patients should be accepted for transplantation.

Symptomatic cerebrovascular disease presents a separate problem in selection for transplantation. A history of transient ischemic attacks obviously promotes a search for a cardiac or carotid vascular cause, which if diagnosed and resolved or treated, need not contraindicate subsequent transplantation.

One group of patients that need particular attention are those with adult polycystic kidney disease, especially if they have a personal or family history of cerebral aneurysm. Evaluation of such high-risk patients requires cerebral vascular imaging such as cerebral computed tomography (CT) angiography or a magnetic resonance image angiogram to exclude berry aneurysms before proceeding to transplantation.

Respiratory

Assessment of respiratory disease in the potential transplant candidate has two purposes: to identify patients at risk from the anesthetic and to identify patients who will be at risk of life-threatening infection in the long term as the result of immunosuppression. The former is based around assessment of smoking and both acute reversible and chronic obstructive airway disease. It is no different from the assessment that must be made before any elective operation. The latter is a more complex decision and remains largely subjective. The diseases of importance are bronchiectasis, tuberculosis, and prior fungal infections, all of which may quickly become uncontrollable under the influence of immunosuppression. Formal evaluation of the degree of respiratory compromise and the frequency and severity of infective exacerbations will determine the advisability of transplantation of the patient with bronchiectasis.

Active pulmonary tuberculosis must be identified from routine chest x-ray and effectively treated before consideration of transplantation. Patients at high risk of reactivation of tuberculosis after transplantation include those from areas with high endemic rates, a history of exposure, calcified lesions on chest x-ray or elsewhere, and a positive QuantiFERON Gold test. Transplant units in endemic areas tend to advise high-risk patients to have a full treatment course for tuberculosis after transplantation. In developed countries, based on slender evidence, management usually involves adding a prophylactic course of isoniazid for 6 months.

Hepatic Disease

Infectious Disease (See also Chapter 31 )

Malignancy (See also Chapter 35 )

There is a clear and defined additional risk of malignancy in patients with CKD, especially after transplantation. This increased risk is assumed to be a result of an effect of immunosuppression either on normal mechanisms for control of neoplastic cells or more likely the effect on viral carcinogenesis. This knowledge has been translated to a reluctance to transplant patients who have had a prior cancer for fear that immunosuppression will allow recurrence that might otherwise not happen.

Recent data question this set of assumptions. First, a number of cancers are increased in CKD patients, in patients on dialysis, and in patients after transplantation. Second, the cancers with substantially increased risk are restricted to skin and lip cancers, renal tract cancers, and those for which a viral etiology is either established or suspected. The implication for the potential transplant recipient is that cancers that are now understood to occur at the same rate as in the normal population should probably be considered differently to those where the risk is increased.

It has been standard advice not to transplant a patient within 2 to 5 years of diagnosis and definitive treatment of cancer, depending on which cancer is under consideration. Most guidelines suggest careful screening for cancers in patients on the transplant waiting list. Unfortunately such blanket rules, though easy to apply, do not take into consideration the variability of the biology of the different cancers and especially do not consider the individual risks of recurrence. Table 4.1 gives a list of cancer types that are known to be increased in dialysis and transplant patients and should thus be viewed with considerable caution in patients being assessed for transplantation. Melanoma, for example, is known to respond to T cell immunotherapy and has a substantially increased risk after transplantation. It is known to recur in normal individuals and to metastasize aggressively. Melanoma has also been observed to recur after transplantation with long disease-free intervals pretransplantation and must thus be approached very conservatively despite the advent of checkpoint inhibitors. Breast and prostate cancer, on the other hand, are not increased in most studies of dialysis and transplant populations but have substantial metastatic potential. To avoid transplanting a patient who will succumb to metastatic cancer soon after transplantation, it is thus prudent to advise a waiting period of at least 2 years, depending to a certain extent on the predicted risk of spread in any given individual.

Common cancers occur frequently in dialysis and transplant patients. It is important not to shift the clinical emphasis from common cancers to rare cancers, such as Kaposi’s sarcoma, just because these rare cancers occur with a greatly increased risk compared with the general population. The common cancers in the Australian CKD population include kidney, bladder, colon, lung, melanoma, breast, and prostate ( Table 4.2 ). There is no specific guideline for cancer screening before listing a dialysis patient for transplantation. It would, however, be reasonable to at least ensure that patients are aware of cancer risks and advise that screening guidelines recommended in the general population for cervical, breast, and bowel screening have been undertaken.

Table 4.2

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