|Year : 2005 | Volume
| Issue : 4 | Page : 431-442
|Renal Transplantation in Seniors - A Review
Ali Alobaidli1, Sarbjit V Jassal2
1 Renal Transplant Fellow, Canada
2 Assistant Professor, University of Toronto, Canada
Click here for correspondence address and email
|How to cite this article:|
Alobaidli A, Jassal SV. Renal Transplantation in Seniors - A Review. Saudi J Kidney Dis Transpl 2005;16:431-42
| Introduction|| |
In the early 1980's, nephrologists began to see a gradual rise in the number of seniors (defined as those over 65 years of age) starting renal replacement therapy (RRT). This growth was initially attributed to the increased availability of dialysis, and the lifting of age-related restrictions. Over the next one or two decades the numbers of patients starting dialysis did not plateau as was expected, but rather, growth continued at fairly high rates. The most striking feature noted by epidemiologists was the difference in the rate of growth across different age bands for the initiation of dialysis. While the rate per million population (PMP) of younger patients starting dialysis stabilized, the rate of growth in the older population starting dialysis (i.e. either those in the age band 65-74yrs old or those >_75 yrs) continued to rise. Although small differences were noted across the world, for example Canadian and American data showed the most dramatic increases for those >75 yrs while data from Europe, Australia and Japan showed most growth in those >60yrs of age, the trend was global. ,,,,,
The statistics for kidney transplantation differ. Overall, the rate of kidney transplantation, regardless of age, is declining across the world (shown as a thick line in [Figure - 1]. However the absolute number of transplants done is growing albeit slowly, with the largest increase in absolute numbers being seen for older patients [Figure - 1]. Limited organ availability has led to political and medical debates to rage over the appropriateness of transplantation in seniors. The objective of this manuscript is to review the data supporting, and the data against, transplantation surgery for seniors, and to describe some of the unique considerations required.
| ESRD / Transplant Demographics|| |
Both dialysis and transplant demographics are dependent on a variety of factors. Amongst them are the baseline rate of renal disease, the availability of dialysis and the rate of organ procurement. As a result there is a wide variation across the world in both the numbers and the reporting methods used [Table - 1]. In the US, for example (where there is a high prevalence of diabetes) there is a high incidence of patients starting renal replacement therapy. Most patients are maintained on hemodialysis (in 2001, 485,950 patients were on either peritoneal or hemodialysis in the US) and only a relatively small proportion are transplanted (in 2001, 2.9% of prevalent dialysis patients got a kidney transplant). However, when reported as the overall rate of kidney transplantation PMP, the rate of transplantation was 50. In contrast, the total number of patients on dialysis in Saudi Arabia is small (7687 in the year 2002, personal communication), with a higher percentage (4%) undergoing transplantation in any one year. However when transplantation statistics are reported as per million population, the rates appear lower than in the US (13 transplants p.m.p). Unlike US data, (most transplants in the US, Canada and Australia are with cadaveric organs) ,,, most transplants in Saudi Arabia are from living related or unrelated donors. To further contrast how demographics vary across the world because of health care policies, the recent introduction of government funded and controlled living unrelated donor programs in Iran have resulted in very high rates of successful transplantation, with 95% of all transplants being done using organs from living donors (related and unrelated), and 79% from living unrelated donors. At the present time there is no waiting list in Iran. As a result of the new policy however, Ghods reported that at least 84% of donors and > 50% of recipients came from a low socio-economic class. ,
Transplantation Offers a Survival Advantage over Dialysis Therapy Regardless of Age Group
Patient survival rates with transplantation remain impressive across all age groups [Table - 2]. In patients aged 65+ yrs, recent USRDS data show 1, 3, 5 and 10 yrs patient survival rates of 87.9%, 76.1%, 61.7% and 24.5% respectively. The data show a gradual improvement in both patient and graft survival over time, particularly since the advent of cyclosporine and newer immunosuppressive therapies.
The observational data reported in [Table - 1] are useful, but do not answer the question "how much better is transplantation for older individuals?" Direct comparisons are difficult - for example, the comparison of the survival of an over 65 year old person to the survival of younger patients is fraught with difficulties - younger patients, regardless of comorbidity, can be expected to have a longer life expectancy by virtue of their age. Comparisons to older patients who remain on dialysis are equally unsatisfactory as clinicians screen out patients and usually only offer transplantation to those with no or few comorbidities. As a result, researchers have struggled to compare dialysis and transplantation outcomes using innovative mathematical models. Two such methods are described here.
Probably the best-known method is that published first by Port et al,  and subsequently by Wolfe et al  and Rabbat et al.  By selecting only patients who were currently being treated with dialysis but who had been screened and placed on a waiting list for a cadaveric transplant, they assumed that any selection bias that may have occurred was minimized and the dialysis and transplant cohorts were comparable at baseline. This selected dialysis population was then compared to those who actually received a transplant. The data were reported both as estimated life expectancy and as the relative risk of death for patients on the waiting list for transplantation compared to those receiving a transplant. The disadvantage of this method is that patients who actually get a transplant have survived their time on the waiting list on dialysis (patients who would have died would not have been transplanted!) and therefore the methodology results in a 'survivorship bias'. The results showed dialysis patients had a stable risk of death equal to 6.3 per 100 pt.yrs. (Patient years (pt.yrs.) are best interpreted using an example, e.g. a total of 100 patient years can be collected either by following two patients for 50 years each, by following 10 patients for 10 years each, or, as more commonly done, by following 100 patients for an average of 1 year each). Transplant patients had a higher immediate post-operative risk of death (17.9 per 100 pt.yrs) falling with time to a baseline mortality rate of 3.8 per 100 pt.yrs. The higher perioperative mortality risk fell rapidly such that by 159 days the risk of death was equal in dialysis and transplant patients. In diabetic patients, this time to equal risk was lower (89 days) because of a higher baseline risk of death with diabetes. Specific death rates for patients aged >_60 years (per 100 pt.yrs) were estimated at 23.2 for those on dialysis, 10.0 for those on the waiting list, and 7.4 for those with a transplant. Life expectancy estimates differed greatly between the two modeled treatment strategies, however the calculated life expectancies are higher than those currently observed [Table - 1].
An alternative method that has been used also showed transplantation to be superior to dialysis. Using decision analysis, a mathematic model of probability, patients on the waiting list for transplantation were compared with those who would receive a transplant. Survivorship bias was removed by making the assumption that the time of transplantation could be controlled, and the models built to reflect scenarios where patients underwent transplantation immediately (as with living donor transplants) or after a waiting period of 2 or 4 years. The models were validated against registry data, to ensure that predicted life expectancies matched those actually observed [Figures 2]a and b, and the population characteristics varied to reflect patients of different ages, and comorbidity profiles. The results showed that transplantation offered significant life expectancy benefits in patients of all ages, but that the overall advantages decreased with increased age and longer waiting times [Table - 3].
Subsequent publications continue to show benefits for those seniors undergoing transplantation ,,,,,,,, (summarized in [Table - 2]). Recently Fabrizii et al  described a single centre retrospective cohort of 627 patients >50 yr who underwent kidney transplantation between 1993 and 2000. Although a younger cohort (patients recruited included mostly those <65 yrs) the study results are notable for 4 points.
- Older individuals (defined as those over 65 yrs of age) seemed to have a different comorbidity profile compared to younger patients, with lower rates of hypertension and an increased prevalence of coronary artery disease (a not unexpected finding!);
- In their centre there was a preference for using older organs in older patients - a clinical practice which is increasingly common but which may adversely affect overall patient and graft survival rates (see section Practical Issues);
- Patients in the age groups 60-64 and those aged ≥65 yrs have similar patient and graft outcomes;
- Perioperative mortality and hospital stay lengths were similar across all ages. One major strength of the study was the detailed information collected on patient demographics, comorbidities, the standardized and explicit workup process required in recipient evaluation and complete data on immunological and donor characteristics. In contrast however, only 151 patients over 65 yrs were included, making it possible that they had insufficient power to detect small but clinically significant differences in survival and hospitalization outcomes across the age groups.
Graft Outcomes in Older Individuals
Graft survival rates are traditionally defined as the number of patients with a functioning graft at a particular time (e.g. 1 year after transplantation) divided by the number of patients who underwent kidney transplantation. Consequently, populations with a high mortality rate, who die with a functioning renal allograft, appear to have unexpectedly low graft survival rates. Data from the early 1970's, tended to demonstrate disappointing graft survival rates in older individuals with average 1-year graft survival rates of 50-60% for those aged ≥50 years while those <50 yrs had rates of 70% or more [Table - 2]. Although newer immunosuppressive regimes have had a great impact on graft survival rates, the data still remain disappointing if one considers absolute graft survival rates alone.
More recently, an increasing number of centres are reporting censored graft survival rates where patients who died with a functioning renal allograft are censored at the time of death. Using this methodology graft survival rates appear to be equal to, or possibly better in older individuals. ,,,,
| Specific Problems Seen in the Elderly Post-Transplantation|| |
Previous studies in healthy individuals have shown a decrease in immunocompetence with age. In the dialysis and transplant population patients are at risk of further immunocompromise because of uraemia and, in transplant patients, anti-rejection protocols. In an elegant study, using data from USRDS transplant and waitlisted patients, Meier-Kreische showed an exponential increase in the risk of infectious death in those over 55yrs of age, with a corresponding decrease in the risk of acute rejection with age (28% in patients of 18-29 years, 19.7% in patients older than 65 years).  As survival studies show a benefit from transplantation despite the higher rate of infectious death, further research in the field of immunomodulation may be most beneficial for seniors with a transplant.
Modification of Immunosuppression in the Elderly
Specifically tailored immunotherapy may help modify the risk of infectious complications in seniors. Furthermore, it seems reasonable to assume the elderly would be at higher risk of falls, fractures and proximal myopathy than younger individuals. Thus it seems wise, though unproven, to reduce the exposure to prednisone. In the pre-cyclosporine era, most physicians prescribed a combination of azathioprine and low dose prednisone. The subsequent introduction of cyclosporine led to decreases in the doses of prednisone used, with a corresponding improvement in patient and graft survival rates and the number of sepsis-related complications. Studies advocating cyclosporine monotherapy have been successful in highly selected patient populations but little data is available specifically for seniors. 40-42 Xenos et al  showed, in an observational study of 21 patients aged over 60 yrs, that the use of tacrolimus, steroid and either mycophenolate mofetil or azathioprine was associated with reduced rates of acute rejection and superb patient and graft survival at one year. Sufficient data from randomized controlled trials of older patients are not available, however, to make specific recommendations for one regime compared with the other.
Drug pharmacology and metabolism is altered with age. One commonly seen example is the gradual age related decline in cytochrome P450 activity. Cytochrome P450 is responsible for the removal of both steroid and cyclosporine, and a decreased volume of distribution for lipid-soluble drugs. 44 Consequently older patients are more prone to the side effects of calcineurin inhibitors and dose modification may be required. Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug that inhibits the proliferation of T and B cells by blocking the enzyme inosine monophosphate dehydrogenase. Retrospective, observational studies suggest older patients may be at increased risk of hospitalization secondary to infections, especially those caused by cytomegalovirus and fungus, with MMF therapy. 45,46 Although the results of these studies are of concern, the observed higher infection rates need to be balanced against the proven benefits of less rejection and better graft survival. Data in regard to the use of IL-2 or antilymphocyte induction therapy are conflicting, and further work is required. ,, Suggested new immune suppression protocols specifically tailored to the older individual include either the use of anti-IL2R Mo antibody, steroid, sirolimus and MMF or Anti-IL2R Mo antibody, steroid, sirolimus and low dose calcineurin inhibitor. Neither of these regimes, however, has been evaluated in randomized controlled trials. 
Seniors are at higher risk of increased dependency for simple activities associated with healthy living. For example a substantial proportion of older individuals require help with housework, shopping, or may have difficulties with managing their own financial affairs. In the geriatric literature, functional independence measured using performance indicators predict the need for institutional care and survival. In the transplant literature, Nyberg et al studied a small subset of patients of all ages before and after kidney transplantation.  Patients were tested for handgrip strength, the ability to step up onto a chair, and their quadriceps strength. Younger patients showed an improvement in handgrip and quadriceps strength. In contrast older individuals had a decrease in all functional measures, even 1 year after transplantation.
Effects of Waiting Times
Within Canada, and particularly within our own transplant service, the number of donor kidneys (both cadaveric and living) has remained stable over the past 10 years.  In contrast, the number of individuals waitlisted for transplant continues to increase. The result - as in many transplant centres across the world - is an increase in the time from initial wait-listing to organ transplantation. More recent studies have shown the outcome of kidney transplantation to be poorer in those with a longer period pre-transplantation on dialysis.  Recent studies have suggested the cost-effectiveness for older individuals, and the overall quality of life benefits from transplantation, are highest if older patients can be encouraged to find a willing live organ donor [Figure - 3]. 
| Quality of Life Post Renal Transplantation|| |
There is little doubt that successful renal transplantation improves overall quality of life (QoL) of patients with ESRD. Older individuals report improved QoL scores post transplantation with higher functional autonomy, less comorbidity and improved rehabilitation as compared to patients on continued hemodialysis. ,, In a recent meta-analysis Cameron et al  compiled the results of 49 studies which looked at differences in QoL across different renal replacement therapy modalities. Using rigorous meta-analytical tools they found successful renal transplantation was associated with lower distress and greater well-being than in center hemodialysis or continuous ambulatory peritoneal dialysis patients. Sadly, study validity was compromised by significant case-mix variation across the three treatment groups, a factor commonly seen in cross sectional studies comparing transplantation to dialysis.
| Practical Issues|| |
Patient Selection and Pre-Transplant Assessment
In general, older patients have more comorbid conditions than younger patients. The Dialysis Outcomes and Practice Patterns Study (DOPPS) study showed that patients aged 18-44 yrs old had on average 2.2 comorbid conditions, while those aged >70 yrs had 4.1 comorbid conditions.  Based on these observations we believe the utility of a thorough pretransplant workup is even higher in seniors. In our own unit older patients undergo through routine pretransplant assessment adapted from numerous guidelines and reports. ,, We place special emphasis on the cardiovascular assessment, as well as including a thorough screening process for malignancy and infections. Below we have summarized some pretransplant screening tests that may be particularly relevant to older patients.
- Full history and physical examination
- Baseline electrocardiogram, echocardiogram and cardiac stress testing (for example using thallium or dipyridamolethallium scans)
- Cardiac catheterization is recommended if one or more of these noninvasive tests are abnormal or if the patient is symptomatic.
- It is recommended that the asymptomatic patients with diabetes also undergo cardiac catheterization given the high prevalence of silent cardiac disease.
Peripheral Vascular Disease
- Doppler studies and arteriography to detect peripheral ischemia.
Gastrointestinal Evaluation and Screening for Malignancy
- Colonoscopy to exclude active diverticulitis or occult colonic malignancy for those >50 years old.
- Routine digital rectal examination and a prostatic specific antigen in elderly men
- Routine mammography
- Ultrasound evaluation for the exclusion of gallstones (Although there is no data to support treatment of the asymptomatic patient with cholelithiasis, there is increased concern that infection related to gallstones may be significant - this remains highly debated!). 
- Screening for gastric ulceration or H. pylori - likewise this is controversial, particularly in an asymptomatic patient.  In support of the argument is data published by Fabrizii et al showing that the presence of gastrointestinal comorbidity was highly associated with both patient death and graft loss. 
Screening for Occult Infections
- Tuberculosis screening e.g. using Purified Protein Derivative (PPD) and/or chest X ray evaluation.
Frequency of Screening Re-Evaluation
- Although no clear recommendations can be made older patients on the waiting list for transplantation should probably be reevaluated more frequently. An abbreviated screening system at more frequent intervals than typical for younger patients may be considered though the cost-utility of this policy remains unknown.
| Factors Limiting Kidney Transplantation for Seniors: Issues and Possible Solutions|| |
Organ shortage is the most limiting factor in the number of transplants done worldwide. Ethical debates rage about the ethical implications of allocating a scarce resource, such as a cadaveric or living donor kidney, to an individual with a limited life span. Both sides have valid arguments - those in favor who cite the fact that many of these individuals are survivors, who have contributed to society over the years, and now are deserving of societal resources, while those against cite the limited life span of the individual and naturally of the transplanted organ. It is neither the premise nor the objective of this review to enter into this debate. Suffice to say, all measures should be taken to increase the number of cadaveric organs available, and to improve living donation rates, particularly in Europe and North America.
In the ideal setting all older recipients should identify a living donor. This would not only reduce the burden on an already restricted organ pool but also offer a clear survival benefit.  However failing that the use of other methods to maximize organ retrieval is imperative. Recent interest has focused on the use of less than perfect organs, 61-63 which are called 'Extended Criteria Donor (ECD)' or 'Marginal Donor' kidneys. (Marginal donor kidneys are defined as those kidneys taken from a donor aged over 55 yr; with a 10yr history of diabetes or hypertension; from a donor who died from a cerebral vascular accident (stroke); or organs procured from a non-heart beating donor.) More recently the use of double cadaveric kidney transplants was described to limit the discard rate of ECD kidneys coming from marginal donors. 'Double or two-kidney transplants' describe transplant surgeries where 2 kidneys, both with higher levels of scarring are transplanted into one individual. These are increasingly commonly used, in an attempt to close the gap between supply and demand for organs. Optimal kidneys undoubtedly show superior graft and patient survival than ECD kidneys. However when compared to remaining on dialysis, the use of marginal kidneys was still preferential (in terms of survival benefit) for older patients [Table - 4]. 
Adjusted mortality estimates, the days to equal risk and time to equal survival were reported for recipients aged 18-29yrs, 30-44yrs, 4455yrs, 55-64yrs and for those aged >65 yrs [Table - 3]. Although the projected extra lifetime decreased with increasing recipient age, marginal organs still offered a survival benefit above that from dialysis alone. Consequently, in our own centre we encourage those without a living donor to accept marginal donor organs.
| Summary|| |
The above review summarizes the data available, to date, on the role of transplantation in seniors. Increasing amounts of data continue to emerge supporting the role of transplantation across all age groups. Acknowledging the importance of the ongoing debate about organ allocation strategies, and assuming societal acceptance, we recommend that seniors be encouraged to consider kidney transplantation if surgically suitable. In our opinion, living donor transplantation is significantly preferable to cadaveric-organ transplantation or dialysis.
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Sarbjit V Jassal
11EN-225, 200 Elizabeth St. Toronto, M5G 2C4, Ontario
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]
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