In the changing scenario of renal transplantation, two features are emerging: the increasing prevalence of so-called marginal donors and the growing request from elderly uremics to enjoy the clinical and social advantages a successful renal transplantation may offer. A preferential allocation of kidneys form older/marginal donors to elderly recipients, the so-called old-for-old allocation (1–2), may either favor a better utilization of the extended pool donor and smooth the way for the transplantation of elderly patients without penalty for young uremics in the waiting list. Two different risk factors are putatively associated with this allocation. The first one is represented by the higher nephrotoxic susceptibility of the marginal kidneys. Among the approaches proposed to protect suboptimal kidneys (3, 4), calcineurin inhibitor (CNI)-free regimens have been advocated as an interesting option, especially in the early posttransplant period. Grinyò et al. reported interesting results with the combined use of MMF, antilymphocyte globulin, and steroid. The overall acute rejection (AR) and the viral infectious incidence, however, were not negligible (5, 6). The second problem is the increased clinical vulnerability to the side effects of the immunosuppressive treatment in the elderly recipients (7, 8). The steroid withdrawal/minimization policy is unanimously considered highly clinically rewarding in the elderly recipients, particularly prone to develop steroid jatrogenic complications (9). Tacrolimus (TAC) has been reported to allow a safe steroid withdrawal, from the beginning of its use (10) and recently, as well (11).
With the aim to reduce the nephrotoxic damage in the early posttransplant period without increasing the AR risk and to ensure a steroid free long maintenance treatment to the patients, the Authors have adopted a 3 phases immunosuppressive protocol in 88 kidney transplantations performed, in the period 1998–2002, according to an “old for old” allocation. The protocol was designed to provide freedom from CNI therapy in the early postoperative period, and a safe steroid withdrawal/minimization in the long run.
MATERIALS AND METHODS
From November 1998 to December 2002, 354 cadaver transplants have been performed in the Turin Kidney Transplantation Center: 10 kidney-pancreas transplants, 54 double kidney transplants, and 290 single kidney transplants.
In that period, 126 donors (36%), 50 years of age or older or with a history of severe hypertension, were submitted according to our routine protocol to a bilateral biopsy at harvesting time. The renal biopsy specimens were stained with trichromic periodic Schiff acid and processed by means of the microwave oven to allow a diagnostic evaluation within 3 hr. Biopsy specimens were scored by the Pathologist according the semiquantitative scale adopted by Karpinsky et al. (12). In 38 donors, the histological picture of the biopsy (mean score 1.7±1) and the Cockcroft-Gault calculated clearance (mean 98,7±38 ml/min) did not support the marginality label, a priori suspected on the basis of age or severe hypertension history. Those kidneys, therefore, have been transplanted according to our standard algorithm of allocation (basically driven by the HLA A, B, DR matching) and the recipients have been treated according our standard immunosuppressive protocol (basiliximab, TAC, in some cases associated with MMF, and steroid). In the remaining 88 cases, the donors have been considered arbitrarily as marginal donors on the basis of the following factors, isolated or in combination: age older than 70 years or a Cockcroft-Gaul calculated clearance equal or less than 70 ml/min or a histological total score ≥3 or a vascular score of 2.
In this group, a vascular cause of death occurred in 79,3% of the cases; age, histological total score and Cockcroft-Gault calculated clearance resulted respectively 67.3±8.33 years (min 48 to max 86 years), 2.7±1.3, and 77.7±26.4 ml/min.
The corresponding kidneys have been allocated according to our old-for-old algorythm (based on age match) either as double (57%) or single (43%) transplants. The recipients (mean age 58.4±5.71 years; min 48 to max 74 years, male 63.6%, mean mismatch 3.08±0.86, mean follow-up 34.4±11.4 months) have been treated with the study protocol.
Admission in Waiting List and Allocation Criteria for the Old-for-Old Program
The Turin Kidney Transplantation Center is operating on a waiting list, in the period of the study of average 590 candidates. Of the patients, 60% are living in Piemonte (population of 4.3 million in Northern Italy) and 40% in other Italian regions. Of the patients on the active waiting list in December 2003, 45% were older than 50 years. Patients are accepted to our waiting-list without an age limit: those older than 50 years are first submitted to cardioscan with dipiridamole provocative test or to cardioultrasound dobutamine test. If the cardioscan test is positive for inducible ischemia, angiography is performed and coronary bypasses (or stenting if appropriate) are requested. Patients older than 60 years are checked this way every 2 years.
Donors older than 50 years, if considered suitable for single transplant, were preferentially allocated into recipients of the same age ± 8 years according to HLA matching. When in this range of age, it was not possible to find a recipient with a minimum match (one HLA DR and one HLA A) an age difference greater than 8 years was considered, provided that at least one of the following conditions were present: 1) the donor and the recipient shared at least four HLA matches, 2) the histological score was ≤3 with a zero vascular score, and 3) the calculated creatinine clearance was ≥80 ml/min.
Donors suitable for the double transplant were exclusively allocated, any HLA match, among patients older than 50 years and living in our region, to reduce the cold ischemia time.
Immunosuppressive Protocol and Acute Rejection
Three phases were scheduled in sequence for the immunosuppressive regimen.
From day 0 to the day when serum creatinine (sCr) level was <2.6 mg/dL, the recipients have been treated with antithymocyte globulins (thymoglobulin; Sangstat) or anti IL-2 receptor monoclonal antibody (basiliximab; Simulect, Novartis), an antiprolipherative drug (azathioprine or MMF) and steroid. The first four patients were treated with antilymphocyte globulins, the subsequent 84 with the anti IL-2 receptor monoclonal antibody basiliximab (20 mg during surgery and 20 mg on day 4, IV). Seven patients used azathioprine (2 mg/kg/day) due to the previous history of a gastroduodenal pathology, 81 patients used MMF 2 g/day. All received steroids, according to our routine protocol, methylprednisolone (MP) 500-200-50 mg IV in postoperative day 0, 1, 2 respectively; afterwards, 20 mg/day of prednisone orally.
When sCr was <2.6 mg/dL, TAC at a starting dose of 0.1 mg/kg BW/day bid was added to MMF 2 g/day and steroid. MMF was subsequently withdrawn, when TAC trough level was >15 ng/ml.
TAC was progressively reduced to a target maintenance trough level of 8 ng/ml at the end of the first year and steroid was tapered to 5 mg/day at day 45 with the aim of a subsequent reduction or withdrawal.
The diagnosis of AR was biopsy proven in all treated patients. Treatments for AR were started only after the biopsy-proven evidence of AR was obtained. They consisted of three pulses of 250 mg of MP each other day with intermediate dose of 100 or 50 mg/day and rapid tapering to prerejection dosage.
Organizational Aspects and Therapeutic Handling of Outpatient Surveillance
Outpatients in our center are followed by two dedicated nephrologists of the kidney transplantation team, closely collaborating with the nephrologists of the Nephrology Unit where the recipient was dialyzed while in waiting list. The decision to reduce steroid below 5 mg/day is, generally, taken by the Kidney Transplant Center nephrologist in agreement with the local nephrologist on the basis of the patient’s clinical conditions together with sCr and TAC trough levels. Steroid withdrawal is suggested when sCr has remained unchanged with a steroid dosage of 2.5 mg each other day, and it is was carried out only after the patient’s signed informed consent.
Patient and Graft Survival
The cumulative survival of the patient and the graft at the first, second, third, and fourth months were respectively 100, 96, 96, and 96% and 98, 92, 90, and 79% without difference between single and double transplants (Fig. 1).
The number of overall recipients at risk at the 12th, 24th, 36th, and 48th months were respectively 88, 74, 39, 8.
Immunosuppression Induction and Switch Phase
In all, 84 recipients (95.4%) have been treated with basiliximab (Simulect, Novartis), with thymoglobulin (Sangstat) used in the first four patients. Eighty-one recipients (92%) received MMF (seven cases received azathioprine). MMF was employed for a mean period of 20.8±11.2 days and then stopped. The mean dose of MMF was 1.9±0.22 g/day. TAC was started after 14.8±7.2 days when sCr was <2.6 mg/dL at a starting dose 0.1 mg/kd/day bid. TAC/MMF were used together (for a mean period of 5 days) until the TAC level was above 15 ng/ml.
At the end of the first month, mean TAC daily dose and trough levels were 6.79±3.8 mg/day and 15.4±4.64 ng/ml, respectively. TAC dosages (mg/day) and levels (ng/ml) at 12, 24, 36, and 48 months were respectively 3.9±2.1, 3.3±1.8, 3.6±2.1, and 3.0±0.9 for dosages and 9.1±2.5, 8.2±2.2, 8.5±1.6, and 8.0±0.8 for levels. As far as the steroid is concerned the daily dose was progressively tapered to 5 mg at the 45th day in all patients and progressively reduced. At the 12th, 24th, 36th, and 48th months, the percentage of off-steroid recipients (Fig. 2) and the mean steroid dosage of those still on steroid were respectively 23%, 69%, 80%, 100% and 2.64±1.2, 2.45±1.04, 1.5±0.7 mg. At month 48, all recipients were off steroids.
Cause of Death and Graft Losses
Three recipients died (one sepsis, one cardiovascular, one neoplasia): two in the single and one in the double transplant group. Five grafts were lost: two acute vascular rejections, one chronic rejection, one pyelonephritis, one nephroangiosclerosis and nephrotoxicity.
Acute Rejection Rate
Twelve episodes of biopsy-proven AR were recorded (13.6%): seven in the single-transplant (16.7%) and five in the double-transplant group (16.9%). Two of seven AR in the single group were steroid resistant vascular rejections, occurring in the induction phase and resulting in graft loss. No kidney was lost for rejection in the double transplant group. In all, 92% (11/12) of the overall AR occurred in the first 6 months, 42% of them (5/12) in the induction phase. The rate of AR in the 38 recipients of kidneys from donors older than 50 years who were treated, from the beginning, with our standard protocol (basiliximab, TAC, steroid with or without MMF), was 11% (P=NS with the study group AR). No AR episode was recorded concomitantly or after steroid withdrawal.
Renal function remained quite stable during the observation period in all recipients, independently from the type of graft (single or double) (Fig. 3). Calculated clearance and sCr at the first and fourth years were respectively: 49.4±19.7 ml/min and 1.59±0.54 mg/dL, and 50.9±16.5 ml/min and 1.51±0.64 mg/dL.
The overall rate of major clinical complications (Table 1) was not different from the one observed in our recipient pool younger than 50 years (unpublished data). Some aspects however, deserve separate comments. Five malignancies (4.4%) have been observed during the follow-up: one carcinoma of the bladder, one basalioma of the skin, one prostatic carcinoma, and one jejunal adenocarcinoma. The fifth malignancy was that observed in the recipient who died. In this case the primary lesion was not determined and the biopsy of the hepatic metastasis demonstrated undifferentiated cells of unknown origin. As far as the posttransplant diabetes is concerned, seven (8%) recipients needed a transitory insulin treatment and seven patients (8%) were permanently insulin treated.
Immunosuppressive Regimen Modifications
During the period of follow-up some recipients have modified the regimen for clinical reason. In the induction phase, in seven cases (8%) MMF has been substituted by azathioprine. In the maintenance phase, in 15 (17%) recipients rapamicine has been added to TAC (3/15 cases after the occurrence of a malignancy, 11/15 to reduce the TAC dosages, 1 after an AR episode). In seven cases (8%), MMF was added to reduce TAC dosages. One patient, after developing uremic-haemolytic syndrome when in rapamicine and TAC low doses therapy, was permanently switched to azathioprine and steroid.
The worldwide problem of an increasingly aged population is a scenario the social and the scientific communities are compelled to deal with (13–16). In Italy, the most recent ISTAT (Italian Demographic Institute) survey reports that in 2003 the population older than 65 years reached the 18.9% of the total (one out of five Italians) with a further increase of 0.3 points in comparison with 2002. These demographic changes determined as consequence of the increasing of age of the donors and of the recipients. In this case these changes fit together as there is a shared tendency to allocate older and/or marginal donors into elderly recipients. This so-called old-for-old allocation avoid an age-mismatched transplantation in the young patients, liberalizes the transplantation of old candidates without sponging on the scarce young donors pool, and reduces the rate of nonuse of older donors. In the clinical handling of this sensible combination, several approaches have been proposed. Recently, Shaffer et al. have reported promising results with basiliximab (Simulect, Novartis) or thymoglobulin (Sangstat) associated with rapamicine, MMF and steroids in a small group of patients to protect the kidney (17). In this study, however, the criteria to define the marginality the donor were not clearly established and the recipient’s mean age was 47 years.
Among the strategies recommended to warrant the elderly recipients from the risk of the iatrogenic damage, the steroid rapid tapering and its withdrawal whenever possible remain the most often recommended strategy.
The AR risk, however, must be taken in to account. Some authors have demonstrated a blunted inflammatory and immune response and a lower incidence of rejection (18, 19), but some recent evidences put into question the general belief that older recipients are less likely to reject (20). As it is reported, organs from aged donors are more likely to develop vascular endothelial ischemic damage and consequently they have an increased potential to increase their alloimmunogenic signals (21). Moreover, the DGF, more frequent in kidneys grafted from older donors, may increase the rate and the severity of AR episodes in elderly recipients (22).
To get through the crossfire of these difficulties in our study, where the mean age of the donors was 67 years and the mean age of the recipients 58 years, we started with an anti IL-2 Receptor antibody, MMF and steroid to provide an induction therapy with a limited risk of AR and to avoid the hazard of the CNI nephrotoxicity. The results have been favorable and well in keeping with the results report by Emparan et al., with a similar regimen, in 15 recipients with a 6 month follow-up (23).
Once an acceptable renal function was achieved, the recipient was switched to TAC and steroid with the target of its rapid tapering and a possible withdrawal. This CNI drug was chosen on the basis of the documented evidence that steroid, could be easily and safely withdrawn in patients treated with TAC based-regimens (11). In this pilot study this combined protocol turned out to be appropriate within an allocation program “old for old,” to protect the kidney (marginal donor) from immunologic and nephrotoxic injuries and to warrant the recipient (elderly recipient) an acceptable comorbidity rate putatively immunosuppression related.
Some considerations, in our opinion, can be drawn from this study. The biopsy-proven AR rate was not significantly different from that recorded in the same type of recipients treated with our standard protocol (basiliximab, CNI from the beginning, with or without MMF, and steroid) and the sCr levels have been stable all along the follow-up. It is likely that in the elderly kidney transplantation the protocols routinely employed, despite reduced and tailored doses, might often be disproportionate in excess and this consideration could be also usefully taken into account in the design of the trials including recipients older than 60 years.
The mortality rate encountered in the first 48 months was particularly low, especially if the recipient age is considered, but the rate and the type of clinical complications however, was not significantly diminished when compared with the rate encountered in recipients treated with a standard immunosuppressive protocol (unpublished data). It should be stressed, in our opinion, that 16.6% of cardiac complications (atrial flutter/fibrillation or angina) encountered despite the careful cardiovascular assessment, 21% of viral infections, and 18% of bacterial infections despite a low immunosuppressive burden testify to the clinical vulnerability of these recipients. Therefore, the question whether the current regimens in elderly kidney transplant recipients are too aggressive, raised by Meier–Kriesche et al. (24), still is one of the most important issues in this clinical setting.
It remains a matter of doubt whether time spent in performing steroid reduction, mainly due to our overstated “nephrologic” prudence, has been detrimental or not for diminishing steroid side-effects (e.g., posttransplant diabetes). The low AR rate and the lack of AR during the weaning process with no need to reassume steroids after withdrawal strongly support the feasibility of a more rapid withdrawal, within the first 6 to 12 months. Besides, another field of further investigation is how much the dosages of the primary immunosuppressant adopted could be reduced with time.
In the “old-for-old” allocation, the CNI avoidance at induction and the steroid withdrawal/minimization during the tacrolimus-based maintenance allow an acceptable AR rate, a stable renal function and favorable recipient and graft outcomes.
1. Kruger B, Zulke C, Fischereder M, et al. Early experience with the ET senior Program “Old for Old”, better to be number one? Transpl Int
2002; 15: 541.
2. Beckurts UTE, Stippel D, Pollok M, et al. Single center experience with the “Old for Old” program for renal transplantation
. Transplant Proc
2001; 33: 3779.
3. Suarez JF, Riera LI, Franco E, et al. Preservation of kidneys from marginal donors
with pulsatile perfusion machine. Transplant Proc
1999; 31: 2292.
4. Grinyò JM. for the BN 52021 Study group in renal transplantation
: BN52021: a platetelet activating factor antagonist for preventing post transplant renal failure. A double blind randomised study. Ann Intern Med
1994; 57: 211.
5. Theodorakis J, Schneeberger H, Illner W-D, et al. Nephrotoxicity-free, Mycophenolate Mofetil-base induction/maintenance immunosuppression
recipients of renal allografts from elderly
cadaveric donors. Transplant Proc
2000; 32: 9S.
6. Grinyò JM, Gil-Vernet S, Seroin D, et al. Primary immunosuppression
with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft. Nephrol Dial Transplant
1998; 13: 2601.
7. Meier-Kriesche H-U, Ojo A, Hanson J, et al. Increased immunosuppressive vulnerability in elderly
renal recipients. Transplantation
2000; 69: 885.
8. Meier-Kriesche H-U. Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int
2001; 59: 1539.
9. Ponticelli C. Should renal transplantation
be offered to older patients? Nephrol Dial Transplant
2000; 15: 315.
10. Shapiro R, Jordan M, et al. Scantlebury FK 506 in clinical kidney transplantation. Transplant Proc
1991; 23: 3065.
11. Boots JM, Christiaans MH, van Duijnhoven EM, et al. Early steroid withdrawal in renal transplantation
with tacrolimus dual therapy: a pilot study. Transplantation
2002; 74: 1703.
12. Karpinsky J, Lajoie G, Cattran D, et al. Outcome of kidney transplantation from high risk donor is determined by both structure and function. Transplantation
1999; 67: 1162.
13. Pascual J, Liaño F. and the Madrid Acute Renal Failure Study Group. Causes and prognosis of acute renal failure in the very old. J Am Geriatr Soc
1998; 46: 721.
14. Grinyò JM. Borderline kidney graft donors- what are the problems? Nephrol Dial Transplant
2000; 15: 950.
15. Cecka JM, Terasaki Pi The UNOS Scientific Transplant Registry –1991. Clin Transpl
1991; 1: 1.
16. Report AIRT 2003;2004:29 2004 Editrice Compositori 40128 Bologna (Italy).
17. Shaffer D, Langone A, Nylander WA, et al. A pilot protocol of a calcineurin – inhibitor free-regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function. Clin Transpl
2003; 17: (Suppl 9): 31.
18. Cantarovich D, Baatard R, Barangere T, et al. Cadaveric renal transplantation
after 60 years of age. A single center experience. Transpl Int
1994; 7: 33.
19. Tesi RJ, Elkhammas EA, Davies EA, et al. Renal transplantation
in older people. Lancet
1994; 343: 461.
20. EBPG Expert Group on Renal Transplantation
European best practice guidelines for renal transplantation
: Section IV: long term management of the transplant recipient IV. 12 Elderly
(specific problems). Nephrol Dial Transplant
2002; 17 Suppl 4: 58.
21. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol
2001; 13: 114.
22. de Fijter JW, Mallat Mj, Doxiadis II, et al. Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol
2001; 12: 1538.
23. Emparan C, Laukotter M, Wolters H, et al. Calcineurin –free protocols with Basiliximab induction allow patients included in “old to old” program achieve standard kidney transplant function. Transplant Proc
2003; 35: 1326.
24. Meier-Kriesche HU, Kaplan B. Immunosuppression
renal transplant recipients. Are current regimens to aggressive? Drugs Aging
2001; 18: 751.