1Med. Klinik m.S. Nephrologie und Intern. Intensivmedizin and 2Klinik für Allgemein-Viszeral- und Transplantationschirurgie, CharitéUniversitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Correspondence and offprint requests to: Professor Ulrich Frei, Med. Klinik m.S. Nephrologie und Intern. Intensivmedizin, CharitéUniversitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Email: ulrich.frei{at}charite.de
Keywords: donor; elderly; kidney transplantation; recipient
The population of patients with end-stage renal disease is growing worldwide. In most of the western countries, the median age of patients on dialysis is now 65 years. Although transplantation is considered the treatment of choice in the elderly as compared with dialysis treatment, so far it has not been offered to elderly patients in an adequate way. To address the topic of Renal transplantation in the elderly in depth, a 2 day satellite symposium was organized in Weimar by the Nephrology Department of the University Hospital Charité, Campus Virchow-Klinikum, Berlin, Germany. Twenty internationally renowned experts in the field of aging and kidney transplantation discussed and shared their experience with 80 transplant clinicians from all over the world. The main topics of discussion were the following: anatomy, physiology and immune responses of the aging kidneys, experimental models of rejection, single-centre experiences and views from databases on outcome of transplantation in the elderly. The aim of the symposium was to advance treatment and improve care in elderly end-stage renal failure patients by promoting old-for-old kidney allocation (harvesting of kidneys from
65-year-old donors into
65-year-old recipients).
Old-for-old kidney allocation: rationale
In the opening session, U. Frei (Berlin, Germany) outlined the background of this meeting. Studies in the last decade have suggested that age matching (old kidney into old recipients) might be beneficial for elderly kidneys, as it provides both a physiological match (nephron mass demand and supply) and an immunogenicityimmune response match. The parallel widening of the gap between the demand and supply of kidneys for elderly patients prompted the initiation of a specialized allocation programme, the old-for-old programme in Europe [Eurotransplant Senior Program (ESP) by the Eurotransplant Kidney Advisory Committee; chair: U. Frei] in January 1999. The prime aim was to achieve more efficient use of kidneys from donors 65 years of age and to reduce the waiting time for elderly patients (
65 years of age) by allocating kidneys mainly driven by age matching and short cold ischaemia time, disregarding the effects of HLA compatibility. By preferentially transplanting older donor kidneys into older recipients, overall allograft survival may be optimized, as in this population long-term allograft survival is not as important as in younger recipients. Moreover, this strategy would also help to expand the donor and the recipient pool.
P. Halloran (Edmonton, Canada) provided an update on the impact of increasing donor and recipient age on allograft function and survival [1]. The older kidney displays an increased probability of delayed allograft function, acute rejection, chronic allograft nephropathy, increased baseline creatinine and consequently, an increased rate of early and late allograft failure. Older recipient age is associated with increased incidence of death with a functioning allograft, decreased initial function and increased delayed graft function. Nonetheless, transplantation still remains the best treatment option for elderly patients with end-stage renal disease, irrespective of the underlying comorbidities, as was demonstrated by R. Wolfe (Ann Arbor, USA). He pointed out the magnitude of organ shortage for the increasing elderly uraemic population worldwide, and showed that transplantation substantially prolonged life not only in young recipients but also in elderly patients over age 65 as compared with dialysis [2]. V. Jassal (Toronto, Canada), utilizing a theoretical decision analysis model, also showed that both cadaver and living-donor transplantation increased life expectancy and quality-adjusted life expectancy for patients of all ages and comorbidity groups at a reasonable financial cost. However, survival advantages and economic attractiveness decreased with prolonged waiting time on dialysis. In line with the above results, A. Matas (Minneapolis, USA) presented data suggesting that early/pre-emptive living-donor transplantation was ideal for elderly patients as it reduced the waiting time and increased patient and allograft survival as compared with cadaver transplantation.
Anatomy and physiology of the aging kidney
S. Bachman (Berlin, Germany) reviewed in detail the anatomic changes of the kidney with senescence, highlighting the role of telomere shortening as a mechanism for renal aging. Discussing the functional changes, D. Fliser (Hannover, Germany) showed that in the healthy elderly, glomerular filtration rate is only modestly decreased at the expense of an increased filtration fraction and post-glomerular vasoconstriction. These age-related changes are accentuated in patients with comorbidities such as hypertension, atherosclerosis and heart failure. In addition, the ability of post-glomerular vessels to dilate in response to stimuli such as acetylcholine, amino acids or nitric oxide (NO) is also reduced in the elderly. He also provided data suggesting that asymmetric dimethyl arginine (ADMA) blood levels are increased in the elderly which may reduce NO availability by NO synthase inhibition and thus contribute to endothelial dysfunction and arteriosclerosis, and finally lead to increased renovascular resistance and hypertension.
Immune response in the elderly
G. Pawelec (Tübingen, Germany) reviewed data showing that immunosenescence leads to an increased incidence and severity of infectious diseases in the elderly. His results suggest that the basic mechanism of immunosenescence is accumulation of dysfunctional memoryphenotype cells with age. An immunologic risk phenotype (IRP) can be determined in the very old which seems to be independent of current clinical health status, and which may help identify patients with impaired immunity. IRP is characterized by a CD4:8 ratio of <1, poor T-cell proliferative responses, increased CD8-positive CD28-negative cells, low B cells and CMV seropositivity. Improving the definition of IRP will help to understand and thus prevent or reverse age-associated immune dysfunction. J. Morales (Barcelona, Spain) discussed the poor tolerability of immunosuppressive drugs in the elderly (more infections, malignancies and side effects), increased sensitivity to nephrotoxicity induced by cyclosporine/tacrolimus and an increase of cardiovascular risk. Therefore, he recommended careful assessment of cardiovascular status and tailored immunosuppression in older recipients. The evaluation of new potential immunosuppressive protocols is in progress using a combination of anti-IL2 receptor monoclonal antibody, steroids, mycophenolic acid and sirolimus/RAD, while trying to eliminate or minimize the use of calcineurin inhibitors and withdrawing steroids as early as possible.
The above observations suggest that the immune system, and thus the immune response, become impaired with age. Consequently, the incidence and severity of acute rejections in the elderly should be lower than in younger recipients, providing an argument to support the concept of age matching in renal transplantation. However, this impression was not substantiated by P. Reinke (Berlin, Germany) who reported results of acute rejection in the ESP. An increased incidence of acute rejection was found in the first year of the ESP when a calcineurin inhibitor-free protocol (reduced immunosuppression) was used. The rate of acute rejection decreased after addition of calcineurin inhibitor and IL2 receptor antibody, without an enhanced risk of infectious complications. When evaluating immune function, it was found that elderly ESP recipients did not show signs of relative immunodeficiency as compared with younger recipients pre-transplant. Instead, a significantly higher monocyte APC activity, higher CD4 counts and comparable memory T-cell responses were found in these patients.
Experimental models and rejection
S. Tullius (Berlin, Germany) evaluated experimental kidney transplantation in rats in different age combinations and showed that allografts from older donors are more sensitive to inflammatory change than younger donors, and that donor pretreatment with induction of haeme oxygenase gene is protective and may be of relevance when utilizing older kidneys. Older recipients showed an altered immune response, suggesting that age-adapted immunosuppression may be important in the clinical situation.
J. Grinyo (Barcelona, Spain) provided experimental evidence that cold ischaemia is mostly responsible for tubulointerstitial damage while allogenicity induces vascular and glomerular damage, and the association of both factors accelerates and aggravates the progression of experimental chronic allograft nephropathy. After prolonged cold ischaemia in rats, concomitant rapamycin and cyclosporine therapy offered the best protection against chronic allograft nephropathy. He stated that it was time to use prophylactic therapies (e.g. donor preconditioning) for prevention of ischaemiareperfusion injury.
Supporting the view that less intensive immunosuppressive therapy is desirable in the elderly, B. Bradley (Bristol, UK) demonstrated that the risk of acute rejection decreased with increasing recipient age. His experiments looking at underlying cellular mechanisms suggest that this decline may be due both to immunosenescence and decreased resistance to immunosuppressive drugs. However, J. deFijter (Leiden, The Netherlands) indicated based on his results that older donor kidneys are more immunogenic than young donor kidneys and that the prognostic impact of an acute interstitial rejection episode is worse in older kidneys because of age-related impaired ability to restore tissue integrity. These findings, together with those of P. Reinke, suggest that old-for-old transplantation in the ESP would require more intense initial immunosuppression. It remains to be seen whether elderly recipients are able to tolerate this approach of powerful immunosuppression over a longer period of time.
Outcome of kidney transplantation in the elderly: single centre experiences
Single centre reports from Geneva, Switzerland (I. Binet), Vienna, Austria (V. Fabrizii) and Edinburgh, UK (G. Oniscu) implicated that kidney transplantation is safe, enhances the life expectancy and therefore, is the best treatment option for the elderly patients. Long-term patient and allograft survival was shown to be similar in the elderly compared with younger patients, after excluding death with a functioning allograft. The consensus was that a thorough and standardized work-up and treatment of pre-existing comorbidities need to be performed in elderly recipients before transplantation.
Outcome of kidney transplantation in the elderly: experience from large databases
According to the data from the USRDS analysed by H. U. Meier-Kriesche (Gainsville, USA), waiting time on dialysis was the strongest modifiable risk factor for renal transplant outcomes [3]. Donor and recipient age had an independent, equivalently detrimental effect on renal allograft survival. In addition, an overall additive and in the long term, synergistic deleterious effect on renal allograft survival was observed for the interaction of donor and recipient age.
B. Kasiske (Minneapolis, USA) provided evidence contrary to the popular belief that overall allograft survival is improved by giving older kidneys to older recipients and vice versa [4]. He presented results from the USRDS for cadaver renal transplants which showed that the adverse effects of increasing donor age on allograft and patient survival were similar for recipients of all ages. After taking into account the independent effects of donor and recipient age per se, matching older kidneys to older recipients did not improve overall allograft survival. However, there may be moral and ethical reasons for age matching in the allocation of deceased donor kidneys for transplantation.
G. Opelz (Heidelberg, Germany) voiced a different opinion regarding the current kidney allocation criteria in the ESP which focuses on short cold ischaemia time, ignoring HLA matching. He presented data from the Collaborative Transplant Study which showed that HLA matching had a significant impact on allograft survival even with cold ischaemic preservation of only 012 h [5]. These data raise a highly relevant question: would it make sense to consider limited HLA matching in addition to the cold ischaemia time in the current kidney allocation criteria for the ESP?
U. Frei concluded the session by emphasizing the growing need of kidneys for elderly patients on dialysis as they have a long waiting time for transplantation with an increased mortality rate while wait listed. He presented 3 year results of the ESP (unpublished observations). The ESP recipients, as compared with the control group of recipients (any age) who received older kidneys (65 years of age) but allocated by a normal allocation scheme, showed a comparable renal function and allograft outcome in the two groups, and a slightly lower but acceptable patient survival in the ESP group. The data from the University Hospital Charité comparing ESP patients with recipients
60 years old who received kidneys from donors of any age allocated by a normal allocation scheme (EKTAS) showed a successful expansion of the donor and recipient pool without any adverse effects on 1 year patient and allograft survival [6]. Death with a functioning allograft was the main cause of allograft loss in both groups, which further stresses the need for thorough pre-transplant screening and treatment of comorbid conditions in elderly recipients. There was an increased risk of acute rejection in the ESP patients which significantly correlated with the degree of HLA matching. Therefore, efforts are warranted to improve HLA matching within the allocation algorithm in the ESP balancing against the detrimental effects of prolonged preservation.
Plenary discussion
The plenary discussion concluded that several important issues remain to be addressed before recommending specialized senior programmes in general. Further research is necessary to develop guidelines on how to select, pretreat, preserve and transplant kidneys from elderly donors. These include the question whether it is worthwhile to increase the yield of organs from elderly (non-traditional) donors. There are also some issues with respect to the recipient population; in particular, whether there is an age limit for listing or considering elderly recipients, a limit where risk/benefit ratio is balanced or even turned worse. Based on the serious concern that arose in the meeting, we should reconsider whether we should allocate elderly organs according to cold ischaemia time only as is done at present or also include limited HLA matching in the allocation criteria. To improve the post-transplant course and outcome, protocol biopsies in the ESP should be considered, which might help to identify elderly recipients who are at increased risk of rejection. Although there is evidence of impaired immune response in elderly recipients, particularly with respect to infectious complications, the available data from the ESP contradict this observation. The immunosuppressive regimen in such a programme needs to be adapted to the increased risk of rejection early on, while taking into account the increased risk of infectious complications later on.
The symposium provided insight into many of these issues which will enable us to improve the outcome of renal transplantation in the elderly. Some aspects still remain unanswered and need to be explored further.
Acknowledgments
The meeting was supported by educational grants from Hoffmann-LaRoche, Grenzach, Germany and Fuijsawa, Germany.
Conflict of interest statement. None declared.
References