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Preferential Allocation of Marginal Kidney Allografts to Elderly Recipients Combined with Modified Immunosuppression Gives Good Results

Segoloni, Giuseppe P.1,4; Messina, Maria1; Squiccimarro, Giuseppe1; Mazzucco, Gianna2; Torta, Elisa1; Leonardi, Gianluca1; Fop, Fabrizio1; Roggero, Stefano3; Vigotti, Federica1; Piccoli, Giorgina B.1

doi: 10.1097/01.TP.0000174134.80947.0A
Original Articles: Clinical Transplantation
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Background. There is an increasing tendency to allocate kidneys from marginal donors in older recipients. This combination optimizes the uses of an expanded donor pool but demands attention for the higher nephrotoxic sensitivity of the kidney and the increased immunosuppression vulnerability of the elderly recipients. We aimed to reduce these hazards by means of a calcineurin-free induction therapy followed by a maintenance regimen targeted to minimize/withdraw steroid.

Methods. Eighty-eight single (43%) or double (57%) transplant recipients (58.4±5.7 years) from 88 marginal donors (67±8.3 years) received monoclonal anti-IL-2 receptor antibodies, mycophenolate mofetil (MMF), and steroid. When serum creatinine was less than 2.6 mg/dL, tacrolimus was started and MMF was withdrawn when the tacrolimus trough level was above 15 ng/ml. Steroid was tapered to 5 mg at day 45 and then progressively reduced

Results. Overall patient and graft survival at the first and fourth year were respectively 100 and 96%, and 98 and 79%. Acute rejection rate was 13.6% (12/88), creatinine clearance remained stable (48.2 ml/min at the sixth month, 50.9 ml/min at 48th month). At the first, second, third, and fourth years, 23, 69, 80, and 100% of recipients were off steroids. For those on steroids, mean dose was respectively 2.6 mg/day from month 12. No recipient reassumed steroids

Conclusions. In the “old-for-old” allocation, the calcineurin-inhibitor avoidance at induction and the steroid withdrawal/minimization during the tacrolimus-based maintenance regimen allow a low acute rejection rate, a stable renal function, and favorable recipient and graft outcomes.

1 Renal Transplant Unit, Nephrology, Dialysis and Transplantation Department, S.Giovanni Battista Hospital, Turin, Italy.

2 University of Turin, Biomedical Science and Human Oncology Department, Turin, Italy.

3 Genetics Institute, Department of Genetics, Turin, Italy.

4 Address correspondence to: Giuseppe Paolo Segoloni, M.D., Renal Transplant Unit, Nephrology, Dialysis and Transplantation, S. Giovanni Battista Hospital, Corso Bramante, 88-10126, Turin, Italy.

E-mail: giuseppe.segoloni@unito.it.

Received 12 August 2004. Revision requested 9 September 2004.

Accepted 5 May 2005.

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.

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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.

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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.

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Immunosuppressive Protocol and Acute Rejection

Three phases were scheduled in sequence for the immunosuppressive regimen.

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Induction Phase

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.

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Switch Phase

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.

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Maintenance Phase

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.

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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.

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RESULTS

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).

FIGURE 1.

FIGURE 1.

The number of overall recipients at risk at the 12th, 24th, 36th, and 48th months were respectively 88, 74, 39, 8.

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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.

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Maintenance Phase

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.

FIGURE 2.

FIGURE 2.

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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.

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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.

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Renal Function

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.

FIGURE 3.

FIGURE 3.

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Clinical Complications

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.

TABLE 1

TABLE 1

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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.

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DISCUSSION

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.

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CONCLUSIONS

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.

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Keywords:

Renal transplantation; Immunosuppression; Marginal donors; Kidney allocation; Elderly

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