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From the Division of Nephrology, The Ottawa Hospital, Ottawa, Ont. (Knoll); Division of Nephrology, University of Alberta Hospital, Edmonton, Alta. (Cockfield); Division of Pediatric Nephrology, University of Manitoba, Winnipeg, Man. (Blydt-Hansen); Division of Nephrology, McGill University Health Centre, Montréal, Que. (Baran); Division of Nephrology, Queen Elizabeth II Health Sciences Centre, Halifax, N.S. (Kiberd); Division of Nephrology, St. Paul's Hospital, Vancouver, B.C. (Landsberg); Division of Nephrology, University of Manitoba, Winnipeg, Man. (Rush); Division of Nephrology, University of Toronto, Toronto, Ont. (Cole)
Correspondence to: Dr. G. Knoll, Division of Nephrology, The Ottawa Hospital, Riverside Campus, 1967 Riverside Dr., Ottawa ON K1H 7W9; fax 613 738-8337; gknoll{at}ottawahospital.on.ca
Since 1980, the incidence and prevalence of end-stage renal disease (ESRD) have increased each year in Canada and throughout the world.1,2 From 1981 to 1999, the number of new patients with ESRD grew at a compound annual rate of 7.3%1 and similar trends were documented worldwide.2 By 31 Dec. 2000, 24 921 Canadians were receiving life-sustaining treatment for ESRD; dialysis was the treatment modality for 14 567 patients and the remaining 10 354 patients (41.5%) had a functioning kidney transplant.3 The development of ESRD is associated with a substantial reduction in health-related quality of life4,5 and premature death.6 Kidney transplantation is the treatment of choice for ESRD as it prolongs survival,7 improves quality of life4,5 and is less costly than dialysis.4
Despite the benefits of kidney transplantation, not all patients with ESRD take this route and there is considerable variation in transplantation rates across Canada; for example, the renal transplantation rate (per million population) is only 27.4 in Saskatchewan compared with 51.8 in the Atlantic provinces.3 It is not known to what extent this variation is due to differences in rates of referral and acceptance for transplantation (i.e., perceived eligibility) or to differences in availability of donors. The purpose of this consensus document was to outline which patients, in the growing Canadian ESRD population, are currently eligible for transplantation. We hope that these guidelines will lead to consistency in determining which patients are eligible and accepted for kidney transplantation.
Canadian patients with ESRD comprise a unique mixture including minority groups8,9 who receive treatment in a universally funded health care system. Health care coverage or insurance should not be an issue in determining transplantation eligibility in Canada as it may be in other regions of the world.10 The methods used to develop these guidelines were designed to ensure that the recommendations reflect a Canadian consensus so that they would be adopted across the country.
These guidelines are based on the best available evidence. However, clinical judgment plays a role in decision-making and, thus, there will still be variability in clinical practice across the country. This consensus document specifically addresses eligibility criteria for kidney transplantation and is not meant to outline the individual tests required for assessment or reassessment of patients awaiting kidney transplantation. Published clinical practice guidelines from the United States and Europe already exist in this area.10,11,12
These guidelines were developed with a wide audience in mind. General recommendations are provided in summary form for review by health care workers and physicians working in primary care, who may want to know whether their patient with ESRD is eligible for transplantation. We also expand on the recommendations for those interested in more detail. The guidelines refer to both children and adults and, as such, will be of interest to health care workers and physicians treating either age group.
Methods
The Kidney Transplant Working Group, a subcommittee of the Canadian Society of Transplantation (CST), was asked to prepare eligibility criteria for renal transplantation by the CST president and the Executive Council. Dr. E. Cole, the chair of the Kidney Transplant Working Group, appointed a guidelines steering committee made up of 7 other physicians from the working group (the authors of this article) based on geographic representation (British Columbia, Alberta, Manitoba, Ontario, Quebec, Atlantic Provinces) as well as specialty (adult and pediatric nephrology).
The chair and the members of the guidelines committee developed a list of 19 items that would be reviewed in these guidelines. Each of the 19 topics was assigned to a committee member. The author for each topic was given the responsibility of performing a comprehensive literature review and creating the first draft of each guideline. The guidelines committee met in person to review the draft guidelines. The recommendations were critiqued by the committee and revised accordingly until consensus was reached. No formal voting took place, but rather the documents were repeatedly revised until all members of the committee were satisfied with the content of the recommendations.
The strength of evidence supporting each recommendation was graded using the system developed by the Canadian Task Force on Preventive Health Care13 as follows:
Once the guidelines committee had reached consensus, the resulting document was circulated to all members of the Kidney Transplant Working Group. This larger group included both transplant physicians and transplant surgeons representing all of the Canadian renal transplant programs (adult and pediatric). Members of the Kidney Transplant Working Group were asked to share the draft guidelines with other transplant professionals at their institutions for further comment. The draft guidelines were then presented at the annual Kidney Transplant Working Group meeting, which is held in conjunction with the CST's Annual Meeting. At this meeting, comments and criticism were reviewed and the guidelines document was finalized. Again, no formal voting took place but rather the guidelines were reworked until the recommendations were acceptable to the members of the working group.
The Kidney Transplant Working Group received unrestricted grants from the following organizations to hold the in-person meetings needed to create these guidelines: Fujisawa Canada (now known as Astellas Pharma Canada), Novartis Pharmaceuticals Canada, Hoffmann-La Roche, Wyeth Canada and SangStat Canada (now known as Genzyme Canada). In addition, the Kidney Transplant Working Group received financial support from the Canadian Council for Donation and Transplantation to publish these guidelines. Representatives of these sponsors were allowed to attend the committee and working group meetings; however, none of the sponsors reviewed the draft documents or provided input into the content. Also, no sponsor had to review the final set of guidelines before publication.
General considerations
Recommendations
Renal transplantation is the treatment of choice for many patients with ESRD. Despite an increased risk of death in the early post-transplant period, transplantation improves long-term survival and quality of life compared with dialysis.7,14,15 A report from the United States Renal Data System (USRDS), in which a time-dependent non-proportional hazards model was adjusted for such covariates as age, race, gender and cause of ESRD in more than 250 000 patients initiating renal replacement therapy (RRT) between 1991 and 1996, revealed that the long-term mortality rate of patients who received a first deceased-donor renal transplant was 48–82% lower than that of patients who remained on the waiting list.7 Although greater benefits were seen among younger patients with or without diabetes, the survival benefit extended to those between 60 and 74 years of age. Thus, the decision regarding eligibility for transplantation must be made in the best interests of the patient and be based on medical and surgical grounds.
There are relatively few absolute contraindications to kidney transplantation. It is contraindicated in the context of active infection, malignancy, substance abuse or non-adherence to therapy; or in cases where comorbidities are expected to limit life expectancy and the ability to benefit from kidney transplantation significantly. Many of these barriers to transplantation may be overcome with appropriate intervention followed by a period of observation to evaluate the success of the intervention. Selected patients with ESRD and other types of organ failure may be considered for combined organ transplantation, performed either simultaneously or sequentially (e.g., liver–kidney transplantation in a patient with cirrhosis who has developed kidney failure). Each of the following sections addresses the absolute and relative contraindications in greater detail. However, it is important to identify early in the assessment process candidates who are unlikely to ever receive a kidney transplant. When patients with obvious contraindications are referred for assessment, not only are scarce resources used inappropriately, but the patients also suffer unnecessary psychological stress.
Timing of referral
Recommendations
Referral to a transplant program should occur sufficiently early so that preemptive transplantation from a living donor remains a realistic goal for those not yet requiring RRT. For those already requiring dialysis, referral should occur as early as possible to minimize the wait time for kidney transplantation, as time on dialysis is an important determinant of long-term outcome.16,17,18 This is particularly important for dialysis-dependent patients who may have a living donor. For patients without a living donor, the timing of referral and completion of assessment may not be as critical, provided these steps do not unnecessarily prolong the waiting time for a deceased-donor transplant. Currently, most Canadian transplant programs use the date of initiation of dialysis as the point at which waiting time starts to accumulate, even if there are significant delays in the referral for or completion of the transplant assessment. Similarly, most progrado not deduct the waiting time during which a patient may be on temporary "hold" or "inactive" status for acute issues. In the absence of a uniform national policy, each program should evaluate its practices regarding the timing of referral and listing to minimize waiting time on dialysis.
The process of evaluation for transplantation may be complex and involve health professionals from multiple disciplines, many of whom may be external to the transplant program. In a patient with significant comorbid conditions, completion of the evaluation may take as long as 6–12 months. Sufficient time must also be allowed for patients to receive adequate information concerning the risks and benefits of transplantation and the options with respect to type of transplantation (living donor vs. deceased donor, usual vs. extended-criteria deceased-donor kidneys, kidney transplantation alone vs. a combined procedure, such as simultaneous kidney–pancreas transplantation, etc.). For patients planning a preemptive transplant from a living donor, the time of referral for evaluation must also take into account the time required to assess the potential living donor(s).
Although timely referral for transplant assessment is desired, premature referral should be discouraged in most cases. Valuable resources may be inappropriately used in these assessments and attempts to slow progression of native renal disease may not be pursued to the maximum extent possible.
Renal function
Recommendations
Preemptive kidney transplantation is the preferred treatment option for patients with ESRD. It requires a careful estimate of when the patient will need RRT, such that the benefits of maximizing the use of native renal function are realized and the risk that dialysis must be initiated is reduced. Preemptive transplantation is associated with multiple benefits for both the patient and health care system. It avoids the morbidity and cost of dialysis and dialysis access procedures and is associated with improved long-term survival of both the patient and graft.16,17,18,19,20,21,22,23 Preliminary data suggest that these benefits occur across all age groups.24 The procedure may also minimize disruption in work and education and promote the return to usual activities. Although concerns have been expressed that permitting preemptive transplants from either living or deceased donors may result in premature transplantation, this has not been supported by clinical experience.25
The ability of a transplant program to deliver preemptive transplantation is heavily dependent on donor sources and current waiting times for deceased-donor kidneys. In many jurisdictions, prolonged waiting times for deceased-donor kidneys mean that preemptive transplantation is only feasible in the context of living kidney donors.
Age and functional capacity
Recommendations
Older patients with ESRD who have no medical or surgical contraindications should be considered for kidney transplantation. Over the last decade, there has been marked increase in the proportion of patients receiving dialysis support who are over 65 year of age. This population has an age-specific rate of ESRD several-fold that of younger people; by 2003, almost 54% of patients initiating RRT were in this age category.26 Improved patient and graft survival with current immunosuppressive protocols has broadened the application of kidney transplantation to selected elderly patients and increasing numbers of patients over the age of 65 are receiving transplants. Although life expectancy is less, such recipients experience death-censored graft survival rates that are at least as good as those of younger patients.27,28 Moreover, survival of the older patient is superior with transplantation compared with remaining on the waiting list.7,29,30 The older recipient is at greater risk of perioperative complications, including death, largely due to infection31 and cardiovascular disease.32
Older patients, as well as younger patients with significant comorbidities, should be encouraged to consider their current quality of life on RRT in the context of what they could reasonably expect following kidney transplantation. Because physiologic age and the burden of comorbid conditions is more likely to influence outcome, a detailed evaluation with emphasis on screening for cardiovascular disease, occult gastrointestinal disease, infection and malignancy is warranted. The decision regarding eligibility for transplantation must be made in the best interests of the patient and be based on medical and surgical grounds. These patients should also be reviewed regularly while they are on the waiting list for transplantation.
Although there are few data on the influence of functional capacity or pretransplant nutritional status on outcomes, extrapolation from other disease states suggests that poor functional capacity or protein malnutrition is associated with greater probability of adverse events including death while waiting for transplantation and perioperative morbidity and mortality. Poorer functional capacity may limit the success of rehabilitation and return to premorbid activities. Careful evaluation of potential for improvement in current functional status and participation in a rehabilitation program may be helpful adjuncts in the assessment process for some patients. Investigation of the etiology of poor nutrition is indicated; patients may benefit from additional medication to control gastrointestinal symptoms, the use of dietary supplements to meet daily requirements and modifications in the dialysis prescription to control uremic symptoms better. In some cases, a period of supplemental feeding with enteral feeds may be warranted.
In the decision to proceed with wait listing and transplantation, consideration must be given to the length of current waiting times and the probability of surviving beyond that period given the current scarcity of donor organs. Full evaluation and maintenance on the waiting list consumes considerable resources; there should be a reasonable expectation that the patient will survive long enough following kidney transplantation to realize the benefits.
Elderly patients or those with poor functional capacity may be more likely to be offered an extended-criteria donor kidney; discussions should occur at the time of listing regarding the risk–benefit ratio of accepting such an offer, particularly in regions where waiting times may otherwise be prolonged. Recent data suggest that this strategy may produce acceptable results.33,34
The timing of transplantation in small children is influenced in part by the technical challenges inherent in performing the transplant operation with an adult-sized donor kidney, especially in infants less than 1 year of age. Small size, however, is not an absolute contraindication to transplantation, and centres with expertise in the transplantation of infant recipients have been successful in achieving graft outcomes that are similar to those in older children.35,36,37 To avoid the deleterious effects on growth and development associated with uremia, children should be considered for preemptive transplantation whenever possible. Initiation of the evaluation for transplantation should, therefore, not be delayed until children are large enough to undergo transplantation; rather it should allow a transplant to be performed at the earliest date that it is technically feasible.
Children with developmental delay and their caregivers may benefit from an improved quality of life associated with freedom from dialysis. The transplant procedure can be performed safely in children with developmental delay, and graft outcomes are similar to those in other children.38,39 Renal transplantation has also been associated with improvements in cognitive and psychomotor function.40 This may allow children with developmental delay to reach their maximum potential. Thus, children, who would otherwise be considered for RRT, should not be excluded from consideration for transplantation solely on the basis of diminished cognitive or physical capacity. The decision to embark on RRT in children with severe developmental delay is made in consultation with the treating physician and family and considering the best interests of the child with regard to the benefits and morbidity of RRTs.
Obesity
Recommendations
30 kg/m2) patients should be denied transplantation based on obesity per se (Grade C).
An estimated 10–18% of patients evaluated for kidney transplantation are obese as defined by body mass index (BMI) 30 kg/m2.10 Obesity has been associated with hypertension, the development of type 2 diabetes mellitus and increased risk of death in the general population. Obese patients undergoing kidney transplantation are similarly at risk of adverse outcomes. They are at higher risk of delayed graft function10,41,42 and suffer from more wound complications,10,43,44 resulting in increased length of hospital stay and greater cost of transplantation. In a recent analysis of USRDS data, obesity was an independent risk factor for the development of new onset diabetes after kidney transplantation, with a relative risk of 1.73 (p < 0.0001).45 Obesity has also been associated with a higher risk of graft loss and death-censored graft loss in some10,42,45 but not all studies.44,46,47 In some analyses, patient survival was also adversely affected by obesity.10,42 In patients with a BMI above 33 kg/m2, the risks of transplantation may be even greater. Based on an analysis of USRDS data, the increased risk of death first becomes significant when BMI is 34–36 kg/m2.42 The relative risk of death is even greater when BMI at transplant is above 36 kg/m2.42 These data suggest that transplantation at this level of BMI may be associated with unacceptably higher risk and will need careful consideration.
It is prudent to strongly recommend weight reduction to a BMI < 30 kg/m2 before kidney transplantation. Obese patients should be referred to a multidisciplinary program targeting obesity to optimize chances of success. The role of surgical intervention for weight loss in this patient population is uncertain but may be considered in extreme cases. Obese patients should be carefully evaluated for pretransplant abnormalities in glucose metabolism, dyslipidemias and cardiovascular disease. Whether a patient should be denied kidney transplantation solely on the basis of obesity is a matter of debate. The risk of perioperative complications and inferior outcomes (graft and patient survival, rehabilitation potential and quality of life) must be balanced against the considerable risk of remaining on dialysis.
Cause of end-stage renal disease
Recommendations
The cause of ESRD may influence several aspects of kidney transplantation, including the appropriate timing, the risk of early or late recurrent disease and both short-term and long-term graft survival. It is well recognized that many forms of both primary and secondary renal disease may recur in the renal allograft. Notable exceptions include polycystic kidney disease, chronic pyelonephritis and Alport's syndrome. Assessment of the risk of recurrence is confounded by the significant proportion of patients experiencing ESRD of unknown etiology, the lack of biopsy information in a significant proportion of renal allograft recipients with deteriorating allograft function and the variable duration of follow-up. Issues related to transplantation in patients with ESRD due to inherited or acquired systemic disorders are addressed in the following section.
Recurrent glomerulonephritis has been reported in 5–20% of patients transplanted for ESRD due to glomerulonephritis and the prevalence of recurrence increases with duration of follow-up.10,11,48Allograft loss due to recurrent disease occurred in 8.4% of Australian patients transplanted for ESRD due to glomerulonephritis over 10 years of follow-up; it was the third leading cause of graft loss after chronic rejection and death with a functioning graft.48 The type of glomerulonephritis was an independent predictor of graft loss, with the greatest risk of graft loss occurring in those with focal segmental glomerulosclerosis (FSGS; hazard ratio 2.03) and membranoproliferative glomerulonephritis (MPGN) type I (hazard ratio 2.91). Graft loss tended to occur earlier in patients with these forms of recurrent disease. The risk of recurrence is particularly high with FSGS (15–50%), MPGN type I (20–50%), MPGN type II (most recur) and IgA nephropathy (20–40% and may approach 100% by 10–20 years follow-up).10,11 Factors such as rate of progression of the primary disease, duration of pretransplant dialysis, the degree of matching of donor and recipient human leukocyte antigen (HLA) and younger age of onset have variably been reported to predict the risk of recurrent glomerulonephritis. However, it is difficult to predict either the risk of recurrence or the aggressiveness with which recurrent disease may progress in an individual transplant recipient. Thus, otherwise eligible patients should be offered transplantation, and patients should be made aware of the risk of recurrent disease during their pretransplant education.
It is reasonable to proceed with living-donor kidney transplantation despite the risk of recurrent glomerulonephritis. Although some analyses have suggested a higher risk of recurrent FSGS resulting in premature graft loss in recipients of HLA-identical live-donor grafts, a recent analysis of the USRDS database suggests that annually adjusted death-censored graft loss was lowest in recipients of such grafts; recipients of mismatched living-donor kidney transplants also experienced better death-censored graft survival than recipients of either HLA-matched or mismatched deceased-donor kidneys.49 Living kidney donors should be made aware of the possibility of recurrent disease and the potential impact this may have on long-term graft survival in the recipient.
Every effort should be made to define the cause of previous allograft failure, as the risk of recurrence in a second transplant approaches 80% in some settings. Of particular concern is the risk of recurrent FSGS leading to premature graft failure in a patient who has already experienced graft loss from recurrent FSGS; some have suggested that this is a relative contraindication to retransplantation with a living-donor kidney.10
Issues related to the transplantation of patients with ESRD due to urologic abnormalities or systemic disease processes are addressed in sections below. Patients with ESRD due to drug nephrotoxicity (i.e., lithium, analgesics) should be considered for kidney transplantation although consideration should also be given to conversion to alternative non-nephrotoxic agents before transplantation. Patients with ESRD due to calcineurin nephrotoxicity or other causes in the setting of a prior non-renal solid organ transplant should be considered for kidney transplantation based on the same eligibility criteria used for kidney transplantation in general.
Systemic diseases
Recommendations
Systemic diseases can recur in the transplanted kidney, but the risk for a specific patient is difficult to predict.10 The studies examining recurrence have been problematic because in most patients cause of ESRD is not confirmed before transplant, the length of follow-up is highly variable and the reasons for biopsy (routine versus clinical indication) are different from study to study.10 In the guidelines that follow, the influence of the systemic disease on outcome is evaluated by comparing allograft survival rate to the overall allograft survival rate published by the United Network for Organ Sharing (UNOS). In the most recent UNOS cohort, the 1- and 3-year deceased-donor renal allograft survival rates were 90.9% and 81.5%, respectively.50
Diabetes mellitus is the single leading cause of ESRD in Canada; over 40% of patients requiring RRT are diabetic. Patients with diabetes derive the same benefits from kidney transplantation as non-diabetic people, including greater survival compared with their dialysis-dependent wait-listed counterparts.7 The assessment of eligibility of a diabetic patient with ESRD should be guided by the same principles applied to non-diabetic patients.10 Due to their high risk for cardiovascular disease, particular attention should be paid to the assessment of vascular health. Periodic reassessment during the wait time is recommended, although controversy exists about the optimal screening method (see sections on cardiac and peripheral vascular disease). Diabetic nephropathy may recur in a renal allograft, although it rarely leads to graft failure. Although there are no outcome data, it is likely that the risk of recurrent diabetic nephropathy would be ameliorated by the same strategies used in the general population, namely tight control of glucose and blood pressure. Patients with diabetes should be warned that glucose metabolism is influenced by some of the immunosuppressive agents employed and by resolution of uremia. This may necessitate significant changes to therapy, particularly for patients previously controlled with lifestyle or oral hypoglycemic agents.
Patients with primary hyperoxaluria (type I) have an enzyme deficiency that leads to increased excretion of calcium oxalate. Recurrent stones and nephrocalcinosis lead to ESRD. The recurrence rate is high following renal transplantation without forced diuresis and pyridoxine.10 It is controversial whether patients should undergo kidney transplantation alone or combined liver–kidney transplantation. An analysis of the USRDS database51 showed that recipients of a combined liver–kidney transplant had improved death-censored renal allograft survival compared with isolated renal transplant recipients with oxalosis. However, there was no difference in patient survival. Another analysis from the United States52 showed similar patient and renal allograft survival rates for patients receiving combined liver–kidney transplant or isolated renal transplants. The authors suggest that isolated renal transplantation is an option for patients with oxalosis, as liver–kidney transplantation can still be performed if the initial renal allograft fails. Good renal outcomes have been reported in pyridoxine-sensitive patients who received isolated renal transplants.53 Recent UNOS data also suggest good outcomes for patients with oxalosis. From 1998 to 2001, in the 20 patients who received an isolated deceased-donor renal transplant for oxalosis, the 1- and 3-year renal allograft survival rates were 89.4% and 89.4%, respectively.54
It is recommended that isolated kidney transplantation be offered to patients with primary hyperoxaluria who are pyridoxine-sensitive with minimal oxalate deposition. Preemptive, living donation should also be encouraged to minimize tissue oxalosis as native renal function declines. Combined liver–kidney transplantation should be offered to patients with severe systemic oxalosis.
Patients with Fabry's disease have an enzyme deficiency that results in the systemic accumulation of glycosphingolipid. Histologic recurrence of disease is very common but rarely leads to allograft failure.10 In an analysis of the USRDS database, 5-year patient and allograft survival rates were found to be no different for the 93 patients with Fabry's disease compared with a matched control group.55From 1998 to 2001, 20 patients received a deceased-donor renal transplant for Fabry's disease; their 1- and 3-year renal allograft survival rates were 94.7% and 94.7%, respectively.54 It is not clear whether the use of recombinant enzyme replacement will improve outcomes. We recommend that patients with Fabry's disease be considered for renal transplantation if the systemic disease is not severe.
Patients with sickle-cell disease can develop recurrent renal disease following transplantation; however, long-term allograft outcome is really dependent on patient survival.10 Patients with sickle-cell disease have a risk of death following transplantation that is 7.9 times that of patients with IgA nephropathy.56 The 3-year renal graft survival rate was 48% for patients with sickle-cell disease compared with 60% for a control group of African-Americans; however, patient survival for those transplanted was much better than for similar patients with sickle-cell disease who remained on the wait list.57 From 1998 to 2001, among the 33 patients who received a deceased-donor renal transplant for sickle-cell disease, the 1- and 3-year renal allograft survival rates were 80.1% and 74.4%, respectively, which was far below the national average.50,54 Patients with sickle-cell disease should be considered for renal transplantation if the systemic disease is not severe.10 Transplantation should probably be delayed if there are frequent sickle-cell crises, but there are no data to support this recommendation.10
Patients with anti-glomerular basement membrane (anti-GBM) disease can have histologic recurrence in up to 50% of cases, but clinical recurrence in less than 10%.10 Recurrent cases reported in the literature usually had circulating anti-GBM antibody present at the time of transplantation.11 In a recent study, none of the 44 patients with anti-GBM disease had graft failure due to recurrent disease.48 From 1998 to 2001, for the 56 patients who received a deceased-donor renal transplant for anti-GBM disease, the 1- and 3-year renal allograft survival rates were 88.1% and 83.5%, respectively.54 Patients with anti-GBM disease should be considered for renal transplantation if the circulating anti-GBM antibody is undetectable and they have quiescent disease (off cytotoxic agents) for at least 6 months post-treatment.
Patients with systemic amyloidosis (primary or secondary) can develop recurrent disease in 10–40% of cases following renal transplantation.10,11 Several studies have shown decreased patient survival following renal transplantation for those with amyloidosis.56,58,59 In 1 study, the risk of death post-transplantation was increased 3.7 times compared with recipients with IgA nephropathy.56 The outcome after kidney transplantation is mainly influenced by the severity of systemic (cardiac) disease.10 From 1998 to 2001, 31 patients received a deceased-donor renal transplant for amyloidosis.54 The 1- and 3-year renal allograft survival rates were 90.1% and 76.1%, respectively.
We recommend that patients with amyloidosis be considered for renal transplantation if there is no evidence of cardiac involvement. Patients with primary amyloidosis should not undergo renal transplantation if there is associated multiple myeloma. Patients with secondary amyloidosis should not undergo renal transplantation until the underlying inflammatory condition is in remission. Patients with familial Mediterranean fever should receive colchicine to prevent recurrent disease in the allograft.10,11 Auto stem cell transplant may be curative and could be considered before renal transplantation in primary amyloidosis.60
Patients with systemic lupus erythematosus (SLE) were thought to have recurrent disease in fewer than 10% of renal transplants.10 However, a recent report found histologic recurrence in 30% of patients with SLE.61 Recurrent SLE rarely leads to allograft failure.11,61,62 From 1998 to 2001, 824 patients received a deceased-donor renal transplant for SLE.54 The 1- and 3-year renal allograft survival rates were 90.4% and 78.1%, respectively. Patients with SLE should be considered for renal transplantation if they have quiescent disease for at least 6 months off cytotoxic agents. Patients may still be on low-dose prednisone (
10 mg/day) at the time of transplantation. Patients with SLE have a higher incidence of coagulation abnormalities and may benefit from screening (see section on hematologic disorders).
Patients with scleroderma develop recurrent disease in approximately 20% of cases post-transplantation.10 An analysis of the UNOS database from 1987 to 1997 showed that the 5-year renal graft survival was 47% for the 86 patients with scleroderma.63 This allograft survival rate was similar to that of a group of patients with SLE transplanted during the same period.63 However, patients with scleroderma have a risk of death following transplantation that is 2.6 times greater than patients with IgA nephropathy.56 From 1998 to 2001, 32 patients received a deceased-donor renal transplant for scleroderma.54 The 1- and 3-year renal allograft survival rates were 68.6% and 54.3%, respectively. Patients with scleroderma should be considered for renal transplantation if they have quiescent disease for at least 6 months off cytotoxic agents. The presence of extra-renal disease (gastrointestinal, cardiac and pulmonary) must be evaluated closely before proceeding with transplantation.
Patients with vasculitis (Wegener's granulomatosis, microscopic polyangiitis, pauci-immune necrotizing glomerulonephritis and Henoch-Schonlein purpura) have a 17% incidence of recurrent disease post-transplantation.64 Graft loss due to recurrent disease occurred in only 2% of 102 patients with vasculitis.48 The type of underlying vasculitis appears to have no influence on disease recurrence.48,64 The presence of circulating anti-neutrophil cytoplasmic antibodies at the time of transplantation was also not predictive of disease recurrence.48,64 From 1998 to 2001, 130 patients received a deceased-donor renal transplant for vasculitis.54 The 1- and 3-year renal allograft survival rates were 93.0% and 78.7%, respectively. Patients with vasculitis should be considered for renal transplantation if they have quiescent disease for at least 12 months off cytotoxic agents.
In a recent meta-analysis,65 28% of patients with hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) experienced recurrent disease; recurrence was associated with significantly poorer graft survival. Factors associated with an increased risk of recurrence included older age of onset, shorter interval between HUS onset and transplantation, a living-donor kidney and the use of calcineurin inhibitors. Of interest, there was no difference in the rate of recurrence between first and second transplants and the duration of dialysis before transplantation had no impact on recurrence. The risk of recurrent disease is greatest with familial HUS; epidemic HUS (associated with toxigenic Escherichia coli) rarely recurs.10,11 It seems reasonable to recommend that kidney transplantation in patients with HUS or TTP be deferred until the disease process is quiescent.
Non-epidemic HUS in children is associated with a 21% recurrence rate post-transplantation, but the rate may be as high as 45% in children with HUS associated with factor H deficiency.66 Currently, there are no specific features that reliably predict recurrence of non-epidemic HUS in children after the first transplantation.66 In autosomal dominant forms of HUS, there is the risk that related donors may later develop HUS themselves, if they carry the same mutation.66 Potential living donors and recipient must be made aware of these risks, so that they may provide fully informed consent.
Congenital nephrotic syndrome due either to Finnish-type nephrotic syndrome or diffuse mesangial sclerosis is associated with growth delay, a high risk of thrombotic complications and death due to sepsis. Experience with early bilateral nephrectomy, especially in patients with Finnish-type nephrotic syndrome, demonstrates that good growth, freedom from infectious and thrombotic complications and, ultimately, renal transplantation can be achieved.66,67,68,69,70 Children with diffuse mesangial sclerosis present the additional challenge of increased risk of Wilms' tumour considering the association of diffuse mesangial sclerosis with the Denys–Drash syndrome. Serial screening by ultrasound every 3 months has been advocated for these patients until bilateral nephrectomy can be performed.70
Patients with cystinosis have a defective lysosomal cysteine carrier that causes intracellular accumulation of cysteine. Compared with other causes of ESRD, patients with cystinosis have among the best renal allograft survival rates, and although cysteine crystals have been demonstrated in graft-infiltrating cells, there is no significant recurrence of renal disease after transplantation.71,72 Although patients approaching ESRD often have significant polyuria and proteinuria, these have not been associated with an increased risk of thrombotic complications with transplantation, and preemptive transplantation should be considered when feasible.73 Extra-renal disease continues to progress after transplantation, and continued treatment with cysteamine is strongly recommended to attenuate this process.74
Although renal transplantation is successful in treating the renal failure associated with autosomal recessive polycystic kidney disease, the extra-renal manifestations can result in significant morbidity, including hepatic fibrosis with the development of portal hypertension and the risk of variceal bleeding, feeding disturbances and pulmonary compromise related to mass effects from the markedly enlarged kidneys.75,76 Portal hypertension typically develops in the second decade of life and is progressive with the appearance of splenomegaly, cytopenia and gastrointestinal bleeding. In 1 large series, it was responsible for 4 deaths post-transplantation (29% mortality risk) and had a long-term prevalence of 63%.77 In children born without pulmonary hypoplasia, growth of the abnormal kidneys postnatally may compress the stomach, resulting in feeding difficulties, or may compress the diaphragm causing respiratory compromise. Optimum management in this case is either unilateral or bilateral nephrectomy.75,78,79 Evaluation for transplantation may also require consideration of nephrectomy to allow sufficient space for a young child recipient to accommodate an adult donor allograft.
Infections
Recommendations
Patients with sepsis, including active tuberculosis, parasitic or viral disease should be excluded from transplantation until the infection is fully resolved and antimicrobial therapy has been discontinued without evidence of recurrence. The number of different infections to be considered is large and beyond the scope of this document. The reader is referred to the recently published and comprehensive guidelines addressing the infectious diseases occurring in the context of solid organ transplantation for a more complete discussion.80 Our recommendations concerning eligibility for kidney transplantation are consistent with these published practice guidelines. Recommendations concerning hepatitis B and C are discussed in the section on liver disease.
A careful clinical history should be obtained to identify factors that may increase the risk of developing serious infections post-transplant, including prior splenectomy, prior chemotherapy or prior exposure to anti-proliferative immunosuppressive therapy, prior bone marrow transplantation or the presence of inherited or acquired immunodeficiencies, such as hypogammaglobulinemia. Although the presence of these conditions should not necessarily preclude transplantation, consultation with experts in hematology or infectious disease or both may be warranted to determine fully the risks of post-transplant immunosuppression and to devise optimum prophylaxis strategies to reduce the risk. In addition to routine vaccination against the usual childhood infections, ESRD patients should receive immunizations against influenza, pneumococcal infection and hepatitis B. Patients at risk of infection with encapsulated organisms, such as asplenic individuals, should also be considered for vaccination against Haemophilus influenzae and Meningococcus. Ideally, vaccinations should be administered as early as possible in the course of renal disease as response rates are superior with better kidney function. Patients who are seronegative for Varicella zoster virus should be immunized before transplantation. Vaccination against Varicella reduces the risk, morbidity and cost of post-transplant infection and should be administered to all children without protective antibody titers.81,82 If transplantation is imminent, vaccination may be withheld pretransplantation as the Varicella vaccine is live attenuated.
Dialysis-related infections (peritonitis, tunnel infections, catheter- or arteriovenous graft-related bacteremia, etc.) should be fully treated and their eradication documented before transplantation. This may be particularly important in the context of recurrent peritonitis or bacteremia with organisms predisposed to seeding of joints or leading to endocarditis. An appropriate interval between an adequately treated infection and transplantation has not been defined. Early removal of a peritoneal dialysis catheter post-transplantation may reduce the risk of subsequent peritonitis.83,84
Occult dental infections have also been reported post-transplant, and an international survey suggests that most transplant centres include a dental examination and treatment as part of their pretransplant assessment.85 It seems reasonable to delay kidney transplantation until dental infections have been eradicated.
There appears to be an increased incidence of mycobacterial disease in both dialysis and transplant patients.86 In uremic patients, these infections may be asymptomatic; the diagnosis is made more difficult by the frequency of anergy in this patient population. Post-transplant exposure to immunosuppressive therapy may result in disseminated aggressive disease, the therapy of which is complicated by interactions between certain anti-tuberculous therapy and the immunosuppressive medications. Therefore, it is critical to determine the risk of reactivation of mycobacterial disease as part of the pretransplant assessment. Obtaining a clinical history regarding risk factors, duration and type of prior tuberculous therapy, PPD skin testing and review of recent chest radiography are appropriate initial steps. It is less clear whether prophylaxis reduces the incidence of reactivation of tuberculosis.87 However most centres currently require pre- or post-transplant prophylaxis in patients with a positive PPD skin test in the absence of prior treatment, provided there are no contraindications to therapy.88,89 Referral to an infectious disease specialist may be warranted in such cases.
The incidence and severity of post-transplant infections with CMV or Epstein-Barr virus depend on multiple factors including the presence of latent infection in the donor, the serostatus of the recipient and the immunosuppressive protocol employed.90,91 Over the last decade, tremendous strides have been made in developing highly sensitive assays that permit prospective monitoring of viral load post-transplant, prophylaxis strategies and preemptive therapy to reduce the severity of infection, and improved treatment protocols for those with active infection. Thus, although serologic status for these infections should be determined as part of the routine transplant assessment, the results should not otherwise influence eligibility for transplantation. Patients at higher risk of such infections, particularly those at risk for primary infection with CMV or Epstein-Barr virus, should be informed of their increased risk and appropriate monitoring and management protocols should be implemented post-transplant based on current practice guidelines.
Those infected with HIV have historically been excluded from consideration for organ transplantation because of the potential impact of immunosuppressive therapy on the risk of opportunistic infections and post-transplant neoplasia.92 Additional concerns include the presence of co-infection with hepatitis B or C, the risk of transmission of HIV to health care workers and drug interactions between certain anti-retroviral agents and the immunosuppressive medications. With the advent of highly active anti-retroviral therapy (HAART) and improved infection prophylaxis, the morbidity and mortality of patients infected with HIV has decreased dramatically. End-stage organ failure from HIV, co-existing infection with the viral hepatitides or unrelated disease processes now influence life expectancy more than HIV disease itself. Recent clinical experience with liver or kidney transplantation in highly selected HIV-infected patients has been favourable, yielding short-term results similar to those in uninfected people.93,94,95,96,97 and leading to reconsideration of HIV infection as an absolute contraindication to solid organ transplantation.98,99,100 Current prospective clinical trials are underway to better define the risks and outcomes of kidney transplantation in HIV-infected people. Until those results are available, it seems prudent to restrict kidney transplantation to HIV-positive ESRD patients who have no AIDS-defining complications, have undetectable viral loads and CD4 counts exceeding 200–300/mL and who are able to tolerate a HAART protocol. Special considerations may apply to HIV-positive patients, who are co-infected with hepatitis C virus, as they require an assessment for the presence of cirrhosis, frequent monitoring of their liver disease and consideration of pretransplant therapy for hepatitis C (see liver disease, below). Eligible patients should be treated in centres whose personnel are experienced in the management of both HIV infection and kidney transplantation. If possible, HIV-positive patients should be enrolled in clinical trials being conducted in this patient population to help define the risks and outcomes of kidney transplantation.
BK virus infection has emerged as a significant clinical problem, with current immunosuppressive protocols leading to premature renal allograft failure in many people with this complication.101,102 Infection is ubiquitous, affecting up to 90% of the population. Thus, the great majority of renal transplant recipients are already infected at the time of transplantation. Polyomavirus persists in the renal epithelium in a latent state, and reactivation and viral shedding in the urine occur frequently in the context of immunosuppression. The relative roles of donor-derived vs. recipient-derived virus are unclear. Emerging data suggest that retransplantation in patients who have experienced prior allograft failure due to polyomavirus-associated nephropathy may be successful,103,104,105,106,107although recurrences of viral nephropathy have been reported. At present, there is no consensus regarding the need for transplant nephrectomy before retransplantation; recurrences have been described despite removal of the previous allograft. Although some have suggested delaying retransplantation until urine and plasma viral loads have become negative, there are few prospective data to support this recommendation. Nor is there sufficient evidence to recommend a particular immunosuppressive protocol in patients undergoing retransplantation.
Malignancy
Recommendations
3), low-risk (T1a, T1c) disease may not require any waiting period (Grade C). Patients with advanced disease (grade 4 or 5, T3c, T4, N+, M+) should not undergo renal transplantation (Grade B). Malignancy accounts for 9–12% of deaths following transplantation; elimination of cancer in transplant candidates is expected to decrease post-transplant mortality.10 Patients with successfully treated cancer are generally considered candidates for renal transplantation.10 The decision regarding suitability for transplantation should be made in consultation with the appropriate cancer specialist (medical oncologist, radiation oncologist, surgical oncologist, urologist, general surgeon, etc.). A past or current history of malignancy does not preclude referral for evaluation for kidney transplantation; earlier referral may define the recommended waiting times in specific types of malignancy or influence the choice of therapy recommended in some forms of low-grade malignancy.
For most cancers, post-transplant recurrence rate increases as the waiting time from treatment to transplantation is reduced.10 For example, the cancer recurrence rate was 54% in those who waited less than 2 years from cancer treatment to renal transplantation, 33% for those who waited 2–5 years and 13% in those who waited more than 5 years before transplantation. Waiting times for specific cancers are addressed below.
Screening for pretransplant malignancy is particularly important in the older patient. Except in specific circumstances, identified below, screening should be performed according to clinical practice guidelines developed for the general population for breast cancer, cervical cancer, colorectal cancer and prostate cancer. As these guidelines are frequently revised, transplant programs should periodically review them and adapt their assessment process accordingly. At present, it seems reasonable to require a screening mammogram in all women 50 years and older and those with a family history of breast cancer as recommended by the Canadian Task Force on Preventive Health Care.108 Female transplant candidates should undergo pretransplant cervical cytology testing and pelvic examination.10 Chest radiography should be part of the routine pretransplant evaluation.10 Screening tests for colorectal cancer should be undertaken according to risk level; patients at higher risk include those with longstanding inflammatory bowel disease, a personal or family history of familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer. Screening for prostate cancer in the general population is controversial, and there are no universally accepted guidelines. However, pretransplant digital rectal examination should be considered for male renal transplant candidates 50 years of age and older.
Patients with preexisting bladder carcinoma have a recurrence rate of 18–26% following transplantation.109,110 Most recurrences have been in patients who waited less than 2 years from treatment to transplantation.110 Patients with a prior history of invasive bladder cancer should wait a minimum of 2 years from cancer treatment to renal transplantation. Patients with superficial lesions (pTa, unifocal, grade 1 disease) have a high risk of local recurrence (up to 60%) but a low risk of invasive or metastatic disease. These patients may not require any waiting period between treatment and transplantation,10 but should undergo periodic surveillance with imaging of the upper urinary tract, urine cytology and cystoscopy as recommended by the urologist both pre- and post-transplant. Carcinoma in situ is considered a high-grade lesion; such patients should undergo treatment and be disease-free for 2 years before renal transplantation.
There are few data to support cystoscopy as a routine screening procedure before transplantation. However, patients at high-risk for cancer (analgesic nephropathy, cyclophosphamide use) should be considered for pretransplant cystoscopy.10
Patients with preexisting breast carcinoma have a recurrence rate of 5.4–63.6% following transplantation.10,110,111 The stage at presentation seems to be the most important factor influencing recurrence; patients with stage I and stage II disease had a recurrence rate of 5.4% and 8%, respectively, whereas those with stage III disease had a recurrence rate of 63.6% following transplantation.111 The mortality rate from breast cancer after transplantation varies from 4% to 76% and again depends on stage of the cancer at presentation.10,111 Most patients studied have waited at least 5 years from treatment to transplantation.110,111 Thus, patients with a past history of breast cancer should wait at least 5 years from treatment to transplantation. Patients with advanced disease at presentation (stages III and IV) should not be offered transplantation because of the high risk of recurrence. Patients with in situ lesions (e.g., ductal carcinoma in situ) at presentation may require only a 2-year wait.
Patients with preexisting cervical carcinoma have a recurrence rate of 5–6% following transplantation.110,112 Most patients studied have waited longer than 5 years from treatment to transplantation.110,112 The mortality rate from recurrent cervical cancer after transplantation was 66% in 1 study.110 The prognosis for those with in situ lesions is more favourable and these patients may require shorter waiting times.110 Patients with successfully treated, localized cervical cancer should wait at least 2 years from treatment to transplantation.10 No firm recommendation can be made for patients with more invasive disease, but they should probably wait at least 5 years before transplantation.10 Patients with in situ cervical lesions may proceed with transplantation after waiting less than 2 years as long as gynecologic surveillance is ongoing.
Patients with preexisting colorectal carcinoma have an overall recurrence rate of 12–21% following renal transplantation.10,110,113 Patients with Duke's stage A or B1 disease (no extension into pericolic fat or nodes) have recurrence rates of 14% and 19%, respectively; patients with more advanced disease have a recurrence rate of 42%.113 Most recurrences have occurred in patients who waited 2–5 years from treatment to transplantation.10 Mortality from recurrent colorectal cancer following transplantation was as high as 63% in 1 report.110 Patients with successfully treated colorectal cancer should wait at least 5 years from treatment to transplantation.10 Patients with Duke's stage A or B1 disease have lower recurrence rates and could be considered for transplantation after waiting 2–5 years.10
Patients with preexisting lymphoma (Hodgkin's disease and non-Hodgkin's lymphoma) have a recurrence rate of 11% following renal transplantation.10,110 Records show that most patients (72%) with lymphoma had waited at least 5 years from treatment to transplantation.110 Patients with successfully treated lymphoma should wait at least 2 years from treatment to transplantation.10 Although there are limited data on recurrence of leukemia following renal transplantation, it seems prudent for patients with successfully treated leukemia to wait at least 2 years from treatment to transplantation.10
Post-transplant lymphoproliferative disorder (PTLD) may result in allograft failure leading to repeat transplantation. The overall recurrence rate of PTLD in repeat transplantation is 3%, with the median interval from diagnosis to repeat transplantation of 37 months.114 The survival rate of renal transplant recipients is greater than that of recipients of other solid organs.114 For patients with successfully treated PTLD, it seems prudent to wait at least 2 years from treatment to repeat transplantation.114
There are limited data on the recurrence of lung cancer following renal transplantation; however, for patients with successfully treated lung cancer it seems prudent to wait at least 2 years from treatment to transplantation.10
Patients with preexisting melanoma have a recurrence rate of 21% following renal transplantation.10 In 1 report, the mortality rate with recurrence was 100%.110 Most patients (83%) with recurrent melanoma waited less than 5 years before transplantation.110 The rate of recurrence of in situ lesions is lower than that of invasive disease.10 Patients with successfully treated melanoma should wait at least 5 years from treatment to transplantation, although patients with in situ melanoma may be considered for transplantation after a waiting period of 2 years.10
Patients with preexisting multiple myeloma have a recurrence rate of 67% following renal transplantation.10 The mortality rate with recurrence following transplantation was 100% in 1 report.110 We recommend that patients with multiple myeloma not undergo renal transplantation.10 Newer regimens (e.g., bone marrow transplantation) may lead to long-term remission. However, there are insufficient data to make a recommendation on waiting time from successful bone marrow transplantation to renal transplantation.
Patients with preexisting non-melanoma skin cancer have a recurrence rate of 48–62% following renal transplantation.10,110 Squamous cell carcinoma of the skin can lead to local invasion, metastases and death in this setting.110 Of the patients with recurrent disease, 61% had been treated less than 2 years before transplantation, 35% between 2 and 5 years and 4% had been treated more than 5 years before transplantation.110 A waiting period of 2 years may eliminate some recurrent skin cancers but the impact of this intervention is unknown given the potent immunosuppressive regimens in use today.10 There are few data on which to base a recommendation for a specific waiting time for verrucous or human papillomavirus-related cancers, although concerns exist regarding the recurrence rate in the setting of immunosuppression. It seems prudent to recommend a minimum 2-year waiting time before transplantation. Patients with basal cell carcinomas do not require any waiting time after successful removal.10
Prostate cancer is common and affects 30% of men over the age of 50. One in 8–10 men will develop clinically significant prostate cancer. Most will be Gleason's grade 3 disease with a doubling time of 2 to 3 years. The medium-risk population has a life expectancy of about 10 years if the cancer is untreated. Patients with preexisting prostate cancer have a recurrence rate of 18% following renal transplantation.10,115 Those with localized disease (T1 and T2) had recurrence rates of 14–16% and those whose disease extended beyond the prostate capsule (T3+) had a recurrence rate of 36% and a mortality rate of 27%.115 Of those with recurrent disease, 40% had been treated less than 2 years before transplantation.110 Most patients with a past history of prostate cancer should wait at least 2 years between treatment and transplantation. Patients with advanced disease (outside the prostate capsule; T3+, T4, N+, M+) at presentation should not be offered transplantation because of the high risk of recurrence. Patients with low-risk prostate cancer may not require any waiting period.
Patients with a history of symptomatic renal cell cancer have a recurrence rate of 30% following renal transplantation.110 Of the patients with recurrent disease, 61% had been treated less than 2 years before transplantation, 33% between 2 and 5 years before transplantation and 6% had been treated more than 5 years before transplantation.110 Death due to recurrent disease may be as high as 80%.10 The recurrence rate of incidentally discovered renal cell carcinoma is less than 1%.10 Most patients with a past history of symptomatic renal cell carcinoma should wait at least 2 years from treatment to transplantation.10 Large ( 5 cm) or invasive renal cell cancers may require a 5-year waiting period because of their higher risk of recurrence.10 Small (< 5 cm), incidentally discovered renal cell cancers may not require any waiting period before transplantation.10
Wilms' tumour is a common childhood malignancy that presents as unilateral or bilateral disease or in association with extra-renal findings, such as aniridia, or as part of the syndrome of male pseudohermaphrodism, gonadal dysgenesis and diffuse mesangial sclerosis known as the Denys–Drash syndrome. These syndromes are commonly associated with mutations in the Wilms' tumour suppressor gene WT1.116,117 Bilateral nephrectomy before transplantation is advocated for children with bilateral Wilms' tumour or with the Denys–Drash syndrome to be certain of removing tissue with potential malignancy.118 In the future, identification of mutations in WT1 may be helpful in determining which patients may benefit from pretransplant nephrectomy. Survival, in general, is poorer for patients with bilateral Wilms' tumour compared with unilateral disease.119,120 The recurrence risk is greatest when transplantation is performed less than 1 year after completion of chemotherapy; thus, renal transplantation should be delayed until at least 1 year after completion of treatment,118,120 although some advocate a delay of 2 years or more.121
Patients with a history of testicular cancer have a recurrence rate of 3–12% following renal transplantation110,122 with most (> 75%) recurrences appearing within 2 years. Mortality due to recurrent disease ranges from 0% to 8%.110,122 Most patients have waited more than 5 years before transplantation.110,122 Patients with a history of testicular cancer should wait at least 2 years from treatment to transplantation.10
Patients with a history of thyroid cancer have a recurrence rate of 7–8% following renal transplantation.110,123 Low-grade papillary tumours and those incidentally discovered at the time of parathyroidectomy portend a favourable prognosis.10 Patients with a history of thyroid cancer should wait at least 2 years from treatment to transplantation.10
Pulmonary disease
Recommendations
