© Borgis - Postępy Nauk Medycznych 2/2013, s. 157-163
*Dorota Miszewska-Szyszkowska, Magdalena Durlik
Przeszczepianie nerek u osób w wieku podeszłym
Kidney transplantation in the elderly
Department of Transplantation Medicine and Nephrology, Medical University of Warsaw
Head of Department: prof. Magdalena Durlik, MD, PhD
W pracy przedstawiono aktualny stan wiedzy na temat przeszczepiania nerek u osób w wieku podeszłym. Wobec starzenia się społeczeństwa, w tym populacji ze schyłkową niewydolnością nerek, coraz powszechniejsze staje się przeszczepianie nerek u osób powyżej 65. roku życia. Omówiono zasady alokacji narządów zgodnie z obowiązującym w Polsce stanem prawnym, w tym zasadę old-for-old stosowaną w celu preferencyjnego przeszczepiania nerek od dawców powyżej 65 lat biorcom ponad 60-letnim. Wykorzystanie nerek pochodzących od starszych dawców rodzi istotne problemy natury medycznej, a zadaniem personelu zaangażowanego w ten proces jest zminimalizowanie negatywnego wpływu wieku dawcy oraz czasu zimnego niedokrwienia na rokowanie u biorcy. Starszy wiek biorcy wpływa na upośledzenie mechanizmów naprawczych, zmiany w układzie immunologicznym oraz zaburzoną farmakokinetykę leków immunosupresyjnych.
In this paper current state of the art in kidney transplantation in the elderly is discussed. Due to ageing of the society, including patients with end-stage renal disease, kidney transplantation in individuals over 65 years of age becomes more and more common. Organ allocation policy in accordance with the applicable Polish regulations, including the “old-for-old” principle concerning preferential transplantation of kidneys from donors over 65 years of age to recipients over 60 years old, is discussed. The use of kidneys obtained from elderly donors entails major medical problems and the personnel involved in the process should minimise the negative effects of the donor’s age and the cold ischaemia time on the recipient’s prognosis. The recipient’s elderly age affects the mechanisms of repair, function of the immune system, and pharmacokinetics of immunosuppressive medications.
Kidney transplantation is a recognised and efficacious method of renal replacement therapy in patients with end-stage renal disease (ESRD), cheaper than dialysis therapy and allowing for longer survival. As Wolfe et al. (1) (1999) demonstrated in their classical study, the survival time of kidney transplant recipients is longer than that of dialysed patients or those dialysed and placed on the list of patients awaiting transplantation. However, at the time of publication only 1% of Americans aged over 70 years received a kidney from a dead donor; in addition, advanced age has always been a factor negatively affecting participation of the patients in clinical trials.
Over the last 20 years the demographic situation in the world, including Poland, has changed. According to Polish statistical data, in 2030 people over 65 years of age will constitute ca. 24% of the society; the number of elderly patients with chronic renal disease is also increasing, due to longer life as well as concomitant diseases such as diabetes mellitus and arterial hypertension which, if poorly controlled, affect kidney function. Aging of the society results in older recipients as well as donors – due to the widespread shortage of organs.
According to the “Poltransplant” bulletin (2), by the end of the year 2011 the National Waiting List included 2623 individuals awaiting kidney transplant, including 453 patients aged over 60 years (for the comparison: in 2008 there were 192 patients in this age group); despite a stable number of newly added patients, the number of awaiting elderly patients grew significantly, which also increased the mean age of patients awaiting kidney transplant – 47 years and 3 months at present. The Polish system of kidney allocation for recipients placed on the waiting list is based on medical criteria and functions in accordance with the regulation of the Minister of Health of December 4th, 2009, concerning the national list of patients awaiting transplantation. One criterion of preferential donor-recipient matching is transplantation of a kidney obtained from a donor more than 65 years old to a recipient over 60 years of age (so-called obligatory transplantation, regardless of the score including HLA compatibility, duration of dialysis therapy, the need of retransplantation, and other factors). Such a system for allocation of “old” kidneys is consistent with the European Senior Program (ESP) introduced by Eurotransplant on 1.01.1999 (3). The aim of this program was to increase the number of kidneys obtained from elderly donors and shorten the time of waiting for transplantation for elderly recipients without a negative effect on the organ’s or patient’s survival. In order to shorten the cold ischaemia time and minimise the related risk of ischaemic damage, “old-for-old” transplantations may be possible within local waiting lists; the compatibility of main blood groups is mandatory and the PRA (panel-reactive antibody) value must be less than 5%, while HLA compatibility is not taken into account in the program. Initially the member states of Eurotransplant entered the program voluntarily; after two years the system became mandatory as a part of the European Kidney Allocation System (ETKAS).
A patient awaiting kidney transplant has a chance to receive an organ from a living donor, a deceased donor below 65 years of age, or a deceased donor over 65 years old. In 2011 in Poland 1002 recipients received kidneys from deceased donors, while only 40 patients were transplanted with a kidney from a living donor; therefore, elderly recipients have virtually no chance of receiving a kidney from a living donor. The possibility of discontinuation of dialysis therapy is mainly associated with the “old-for-old” principle, as kidneys from young donors are seldom transplanted to elderly recipients. It must be remembered that the aim of kidney transplantation in a young person is to allow for long-time survival of the patient (and the transplanted organ) and, should the organ cease to function, for retransplantation. A geriatric recipient’s chance for retransplantation is low and the aim of transplantation is to prolong life and increase its quality in comparison with that of a peer on lifetime dialysis.
Kidney transplantation in the elderly is associated with the term “marginal donor”, introduced as early as in 1991, (4) changed in 2002 to “expanded-criteria donor” (ECD) (5, 6): a deceased donor over 60 years of age without concomitant diseases or a deceased donor 50-59 years old meeting at least 2 out of 3 criteria: creatinine concentration over 1.5 mg/dl at the time of death, cerebrovascular death, or a history of arterial hypertension. As a rule, transplantation of a kidney from an ECD is associated with a 70% higher risk of graft failure in comparison with transplantation from a standard-criteria donor (SCD).
PHYSIOLOGICAL AGEING OF THE KIDNEYS
What is the difference between a kidney of an older donor and a younger kidney? The process of ageing affects all organs, including the kidneys (7-9). The weight of a kidney, increasing from birth to ca. 400 g in the 5th decade of life, then continuously falls by ca. 20-30% up to the age of 80 years. This affects in particular the cortical layer, with thinning and changed echostructure (due to scarring secondary to vascular lesions). Lesions typical for the ageing kidney are similar to those observed in other organs: arteriolosclerosis (accumulation of hyaline deposits), fibroblastic hypertrophy of the intima and media of the arcuate arteries and arterioles, and thickening of the basal membrane. Secondary to vascular lesions focal glomerulosclerosis, atrophy of the tubules (mainly proximal), and interstitial fibrosis (mainly in the cortex) develop. Arteriosclerosis is also observed and high pulse waves inflict additional damage on the walls of small vessels. The number of the glomeruli decreases with age (from a mean of 1 million per kidney) by 30-50%, with an increased proportion of “physiologically” sclerotic glomeruli, resulting in compensative hypertrophy and hyperfiltration of the medullar glomeruli, with their secondary segmental and global sclerosis.
The Poltransplant data indicate that in the years 2006-2011 the most common cause of death of donors in Poland were cerebrovascular conditions, i.e. haemorrhagic or ischaemic stroke (59%), and the mean age of a dead donor in 2011 was over 44 years; therefore, transplantation of organs from dead ECDs, mainly to elderly recipients, is a fact and the personnel involved in the process of donor preparation and the operation should minimise the negative effects of the donor’s age and health on the recipient’s prognosis.
QUALITY OF KIDNEYS OBTAINED FROM ELDERLY DONORS
Provided that the probability of the organ being obtained from an ECD increases with the donor’s age (10, 11) and the possibility of transplantation of a kidney from a living donor whose organ – even if not young – is still of better quality than that of a deceased donor (12) is very small, the quality of an “old” kidney becomes very important. Age-related physiological changes in the kidneys combined with the donor’s past diseases, the risk of ischaemic injury, and potential nephrotoxicity of immunosuppressive medications result in the risk of primary graft insufficiency (13). The mechanism of this injury is unclear, although ageing seems to limit the repairing properties of epithelial cells. The number of glomeruli without tubules also increases, as demonstrated in patients with chronic allograft nephropathy (14). Therefore, the correlation of the donor’s age and the cold ischaemia time becomes critical for the recipient’s prognosis. Is it possible to “predict” lower quality of an elderly kidney before transplantation if, as demonstrated by the Third National Health and Nutrition Survey (NHANES III) performed in the USA, only in 7.6% of individuals 60-69 years old and in 25.9% of those aged over 75 years eGFR is below 60 mlmin/1.73 m2 (15)? Preimplantation kidney biopsy is not a new idea (16) – histological assessment of the organ may facilitate the decision to reject an organ or the choice between single and dual kidney transplantation (SKT vs. DKT) in order to increase the final eGFR value. Remuzzi et al.(17) assessed kidney biopsy specimens obtained from potential donors aged over 60 years using a scale concerning specific features (in which 0 represented no abnormalities and 12 – advanced interstitial lesions): kidneys scoring 0-3 were used for single transplantations, those scoring 4-6 – for dual transplantations, and the remaining organs were rejected. After 3 years of follow-up the results of DKT were better than those of SKT for elderly donors. Another “cut-off” parameter may be the number of sclerotic glomeruli. Andres et al. (18) evaluated kidneys obtained from donors aged 60-75 years and performed SKT if the proportion of sclerotic glomeruli was lower than 15% and DKT if the proportion was 15-50%. After a year the kidney survival rate was 90% in the SKT group and 95% in the DKT group.
In Poland in 2011 the DKT procedure was applied in 4 recipients.
On the margin of this review the study by Kasiske and Snyder (19) should be recalled. The authors demonstrated that the prognosis is determined not by the recipient’s age but the donor’s age – the results of “old-for-old” transplantations were better than “old-for-young”.
SELECTION OF GERIATRIC RECIPIENTS
On the recipient’s side concomitant diseases and the transplant waiting time were more significant predictors of post-transplant complications than the recipient’s chronological age. It is known that the sooner the recipient undergoes transplantation (i.e. the shorter their waiting time), the better the prognosis. An American study (published in 2006) concerning this problem (20) demonstrated that the probability of transplantation for elderly patients was the highest in the first year after placement on the waiting list, while those remaining on the list for 5 years had a 4 times lower chance of transplantation of a kidney from a standard donor than recipients 18-39 years old (this is the opposite relationship to that observed in young people, for whom it “pays off” to wait longer for a better organ). In that study patients with diabetes comprised a specific group benefiting from quick transplantation. Similarly, in a large American study (21) published in 2007 the eldest donors (above 70 years of age) benefited from quick transplantation – even from an ECD – in comparison with their peers still undergoing dialysis therapy. Elderly patients are less often placed on the waiting list (22) and the chronological age criterion may “replace” the patient’s actual biological age and their physical (e.g. heart failure, emaciation, bone complications of renal disease) and mental abilities. However, considering that in the first year after kidney transplantation 35% of deaths of recipients aged over 60 years are due to cardiovascular complications (23), caution in offering kidney transplantation to elderly patients is hardly surprising.
IMMUNE SUPPRESSION IN THE ELDERLY
There is no specific immune suppression regimen dedicated to recipients over 65 years of age. Immunosuppressive treatment in any age group consists in balancing between too strong immune suppression resulting in infectious complications (among recipients over 60 years of age 38% of deaths in the first year after transplantation are due to infection!) (23) and malignancies, and too weak suppression resulting in acute graft rejection. In elderly recipients this is combined with physiological changes due to ageing, the immune potential of kidney transplantation from an elderly donor, and lower histological quality of an organ obtained from an ECD, which may result in a higher risk of delayed graft function and worse long-term graft function. Kidney transplantation in the elderly is also associated with a higher risk of nephrotoxicity of medications (especially calcineurin inhibitors – CNI) and, due to a high number of concomitant diseases, a higher probability of adverse drug-drug interactions.
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1. Wolfe RA, Ashby VB, Milford EL et al.: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. New England Journal of Medicine 1999; 341: 1725-1730.
2. Poltransplant Biuletyn Informacyjny 2012; 1(20).
3. Frei U, Noeldeke J, Machold-Fabrizii V et al.: Prospective age-matching in elderly kidney transplant recipients – a 5-year analysis of the Eurotransplant Senior Program. Am J Transplantation 2008; 8: 50-57.
4. Alexander JW, Vaughn WK: The use of “marginal” donors for organ transplantation: the influence of donor age on outcome. Transplantation 1991; 51: 135-142.
5. Port FK, Bragg-Gresham JL, Metzger RA et al.: Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 2002; 74: 1281-1288.
6. Rosengard BR, Feng S, Alfrey EJ et al.: Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor. Am J Transplantation 2002; 2: 701-708.
7. Zdrojewski Z: Nerki u osób w podeszłym wieku. [W:] M. Myśliwiec (red.): Nefrologia. Wyd. Medical Tribune Polska 2009.
8. Kidney senescence and renal function evaluation in the elderly. Journal of Nephrology 2010; 23: S15.
9. Martin JE, Sheaff MT: Renal ageing. J Pathology 2007; 211: 198-205.
10. Huang E, Poommipanit N, Sampaio MS et al.: Intermediate-term outcomes associated with kidney transplantation in recipients 80 years and older: an analysis of the OPTN/UNOS database. Transplantation 2010; 90: 974-979.
11. Segev DL: Evaluating options for utility-based kidney allocation. Am J Transplantation 2009; 9: 1513-1518.
12. Tan JC, Busque S, Blouch K et al.: Efects of ageing on glomerular function and number in living kidney donors. Kidney International 2010; 78: 686-692.
13. Ishani A, Xue JL, Himmelfarb J et al.: Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrology 2009; 20: 223-228.
14. Pagtalunan ME, Oberhauer R, Haas M et al.: Atubular glomeruli in patients with chronic allograft rejection. Transplantation 1996; 61: 1166-1171.
15. Coresh J, Astor BC Greene T et al.: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. American Journal of Kidney Disease 2003; 41(1): 1-12.
16. Remuzzi G, Grinyo J, Ruggenenti P et al.: Early experience with dual kidney transplantation in adults using expanded donor criteria. Double Kidney Transplant Group. J Am Soc Nephrology 1999; 10: 2591-2598.
17. Remuzzi G, Cravedi P, Perna A et al.: Long-term outcome of renal transplantation from older donors. The New England Journal of Medicine 2006; 354: 343-352.
18. Andres A, Morales JM, Herrero JC et al.: Double versus single renal allografts from aged donors. Transplantation 2000; 69: 2060-2066.
19. Kasiske BL, Snyder J: Matching older kidneys with older patients does not improve allograft survival. J Am Soc Nephrology 2002; 13: 1067-1073.
20. Schold JD, Meier-Kriesche HU: Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on. Clin J Am Soc Nephrology 2006; 1: 532-538.
21. Rao PS, Merion RM, Ashby VB et al.: Renal transplantation in elderly patients older than 70 years of age: results from the Scientific registry of transplant recipients. Transplantation 2007; 83(8): 1069-1074.
22. Grams ME, Kucirka LM, Hanrahan CF et al.: Candidacy for kidney transplantation of older adults. J Am Geriat Society 201; 60: 1-7.
23. Kauffman HM, McBride MA, Cors CS et al.: Early mortality rates in older kidney recipients with comorbid risk factors. Transplantation 2007; 83: 404-410.
24. Stankiewicz W, Stasiak-Barmuta A: Starzenie się układu odpornościowego. Polski Merkuriusz Lekarski 2011; 30(179): 377-380.
25. Huang E, Segev D, Rabb H: Kidney transplantation in the elderly. Seminars in Nephrology 2009; 29(6): 621-635.
26. Meier-Kriesche HU, Srinivas TR, Kaplan B: Interaction between acute rejection and recipient age on long-term renal allograft survival. Transplantation Proceedings 2001; 33: 3425-3426.
27. Heldal K, Hartmann A, Leivestad T et al.: Clinical outcomes in elderly kidney transplant recipients are related to acute rejection episodes rather than pretransplant comorbidity. Transplantation 2009; 87: 1045-1051.
28. Pratschke J, Merk V, Reutzel-Seike A et al.: Potent early immune response after kidney transplantation in patients of the European senior transplant program. Transplantation 2009; 87: 992-1000.
29. De Fijter JW, Mallat MJ, Doxiadis II et al.: Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrology 2011; 12: 1538-1546.
30. Reutzel-Selke A, Jurisch A, Denecke C et al.: Donor age intensifies the early immune response after transplantation. Kidney International 2007; 71: 629-636.
31. 2012 Atlas of CKD & ESRD (www.usrds.org).
32. Danovitch GM, Gill J, Bunnapradist S: Immunosuppression of the elderly kidney transplant recipient. Transplantation 2007; 84(3): 285-291.
33. Meier-Kriesche HU, Ojo AO, Hanson JA et al.: Exponentially increased risk of infectious death in older renal transplant recipients. Kidney International 2001; 59: 1539.
34. Kasiske BL, Snyder JJ, Gilbertson DT et al.: Cancer after kidney transplantation in the United States. American Journal of Transplantation 2004; 4: 905.
35. Abecassis M, Bridges ND, Clancy CJ et al.: Solid-organ transplantation in older adults: current status and future research. American Journal of Transplantation 2012; 12: 2608-2622.
36. Gill J, Sampaio M, Gill JS et al.: Induction immunouppressive therapy in the elderly kidney transplant recipient in the United States. Clinical Journal of the America Society of Nephrology 2011; 6: 1168-1178.
37. Arbogast H, Huckelheim H, Schneeberger H et al.: A calcineurin antagonist-free induction/maintenance strategy for immunosuppression in elderly recipients of renal allografts from elderly cadaver donors: long-term results from a prospective single centre trial. Clinical Transplantation 2005; 19: 309-315.
38. Segolini GP, Messina M, Squiccimarro G et al.: Preferntial allocation of marginal kidney allografts to elderly recipients combined with modified immunosuppression gives good results. Transplantation 2005; 80: 953.
39. Meier-Kriesche HU, Morris JA, Chu AH et al.: Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients. Nephrology Dialysis and Transplantation 2004; 19: 2864.
40. Pascual J, Zamora J, Pirsch JD: A systematic review of kidney transplantation from expanded criteria donors. American Journal of Kidney Diseases 2008; 52(3): 553-586.
41. Hartmann EL: Chapter 24: Renal transplantation in the older adult. Geriatric Nephrology Curriculum, American Society of Nephrology 2009.
42. Oniscu GC, Brown H, Forsythe JL: How old is old for transplantation? American Journal of Transplantation 2004; 4: 2067.
43. Meier-Kriesche HU, Ojo AO, Hanson JA et al.: Exponentially increased risk of infectious death in older renal transplant recipients. Kidney International 2011; 59: 1539-1543.
44. Ojo AO, Hanson JA, Wolfe RA et al.: Long-term survival in renal transplant recipients with graft function. Kidney International 2000; 57: 307-313.