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NDT Advance Access first published online on December 5, 2006
This version published online on December 18, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl637
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

‘Old-for-old’—new strategies for renal transplantation

Wolfgang Arns1, Franco Citterio2 and Josep M. Campistol3

1Cologne General Hospital, Merheim Medical Center, Cologne, Germany, 2Department of Surgery, Catholic University, Rome, Italy and 3Department of Nephrology, Hospital Clínic, University of Barcelona, Spain

Correspondence and offprint requests to: J M Campistol, Servei de Nefrologia i Transplantament Renal, Renal Transplant Unit, Hospital Clínic, Universitat de Barcelona, 170, Villarroel, 08036 Barcelona, Spain. Email: jmcampis{at}clinic.ub.es

Keywords: calcineurin inhibitor; everolimus; ‘old-for-old’; proliferation signal inhibitors/mTOR inhibitors; renal transplantation



   Introduction
Top
 Introduction
Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
 References
 
Over the past decade, there has been a dramatic increase in the number of patients awaiting kidney transplantation, resulting in a progressive increase in the time spent on waiting list and in the length of time patients are receiving dialysis [1]. Patient survival is lower in patients receiving dialysis than in those who receive a transplant. Furthermore, the duration of pre-transplant dialysis is an important risk factor for both graft and patient survival post-transplantation. Indeed, 10-year graft survival of cadaveric kidney transplantation for patients undergoing pre-emptive transplantation is significantly higher than for patients transplanted when receiving dialysis (69% vs 39% for 24 months on dialysis, respectively) [2]. Reducing the waiting list time improves all aspects of chronic kidney failure, therefore, it is of utmost importance that the transplant community assesses measures to increase donor availability. Age-matching of donors and recipients is one way of expanding the donor pool, and maximizing the use of donated renal allografts through such ‘old-for-old’ transplantation has shown promising results with good graft survival. Over the last decade, there has been a substantial improvement in graft survival rates following renal transplantation. However, maintaining long-term graft and patient survival remains a challenge, with post-transplant malignancies, cardiovascular disease and infections commonly resulting in death with a functioning graft. In fact, patients with pre-existing morbidities such as malignancies, cardiovascular disease, infections and coagulopathies may not benefit as greatly from transplantation [3]. Older recipients receiving a kidney from an older donor have an increased risk of calcineurin inhibitor (CNI) induced nephrotoxicity as well as being at an increased risk of post-transplant infections, malignancy and cardiovascular disease, all of which impact on the patients’ quality of life and long-term patient survival. The newly developed proliferation signal inhibitors, PSIs (also known as mTOR inhibitors) are a class of drugs including the two agents everolimus (Certican®, Novartis Pharma AG, Basel, Switzerland) and sirolimus (Rapamune®, Wyeth Pharmaceuticals, Collegeville, PA, USA). They have both immunosuppressive and anti-proliferative actions and may be beneficial in this population. This editorial reviews the expanding use of ‘old-for-old’ renal transplantation and discusses the potential of PSIs in prolonging graft and patient survival.



   Expanding the donor pool
Top
 Introduction
 Expanding the donor pool
'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
 References
 
Strategies used to expand the donor pool include increasing donor numbers and optimizing the use of all donated kidneys by case selection and reducing graft loss. One approach to increase donor availability is through the use of expanded criteria donors. Expanded criteria donors are described as those having an increased risk of renal allograft failure, this includes donors aged >60 years or donors aged 50–59 years with at least two additional compounding factors—terminal serum creatinine >1.5 mg/dl, cerebrovascular accident as cause of death, or a history of hypertension [4]. Studies have shown that renal transplant recipients receiving a kidney from an expanded criteria donor have improved survival compared with wait-listed dialysis patients [5].



   ‘Old-for-old’ renal transplantation
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
 References
 
Age-matching kidneys between donor and recipient is regarded by many as an efficient use of donated organs [6, 7]. The rationale for age-matching lies within establishing a physiological match between the nephron mass supply and demand, and a match between immunogenicity of the donor organ and the recipient immune response, all of which are affected by age-related characteristics of both the donor and the recipient. Following this, ‘old-for-old’ renal transplantation (age-matching a kidney from an older donor to an older recipient) formed the basis of the Eurotransplant Senior Program (ESP) [7]. Although the ESP uses a cut-off age of 65 years as ‘old’, other studies suggest that 55 or 60 years could be used [6, 8]. The efficacy of ‘old-for-old’ renal transplantation was shown by Waiser et al. [6] with the ‘old-for-old’ group having comparable 8-year actual graft survival to older patients receiving a kidney from a young donor (Figure 1). Conversely, however, placing a kidney from an old donor into a young recipient resulted in significantly worse actual graft survival in a multivariate analysis [P = 0.001; relative risk (RR), 1.97%; 95% CI 1.32–2.94] [6]. Furthermore, recently reported experience from the ESP showed comparable 4-year mortality and graft loss in ESP patients compared with older patients receiving kidneys from younger donors [9]. Given that both the number of older donors and recipients are increasing (34.1 and 30.7% of renal transplant recipients and donors, respectively, in the Eurotransplant region in 2003) [1, 10], and the observation that kidneys from older donors can be successfully transplanted into older recipients, in the absence of an organ from a younger donor, ‘old-for-old’ renal transplantation is an important strategy for expanding the donor pool. From the demographic data [1, 10], this may account for ~30% of renal transplantations. However, the advancing age of both the donor and recipient may affect the way in which immunosuppression is tolerated in this population.


Figure 1
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  		Fig. 1. Kaplan–Meier plot of the influence of age-matching on actual graft survival (using a cut-off age of 55 years). In a study of over 1000 cadaveric renal transplantations, the efficacy of age-matching was shown with the ‘old-for-old’ group (aged over 55 years) having good 8-year actual graft survival. (Permission from Waiser et al.[6]).

 


   Impact of donor age
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
 References
 
Kidneys from older donors exhibit a series of physiological changes which are characterized by increased glomerular, vascular and tubular senescence [11, 12]. Such morphological changes can result in significant functional changes including a decrease in renal blood flow and glomerular filtration rate, leading to an overall deterioration in renal function [13]. Furthermore, these changes may be aggravated by atherosclerosis, hypertension and diabetes, which are highly prevalent in older individuals [13]. The deterioration in renal function can be observed by significantly higher serum creatinine levels in patients receiving older donor kidneys. In one study, performed on 3365 transplant recipients in Spain, patients who received a kidney from a donor over 60 years of age had higher serum creatinine levels at 12 months post-transplant compared with those receiving a kidney from donors aged under 60 years (2.06 mg/dl vs 1.60 mg/dl, respectively; P < 0.0001) [8].

Donors over 60 years of age are classified as expanded criteria donors due to an association with reduced graft survival. This is exemplified in the Collaborative Transplant Study which examined graft survival in all first cadaver kidney transplants from 1985–2003. When stratified for donor age, there was a striking correlation between increasing donor age and decreasing graft survival [14]. Furthermore, in a study by Basar et al., [13] the 1-year graft survival in renal transplant recipients receiving a kidney from a donor over 60 years was 73%, compared with 87% in those receiving a kidney from a donor aged under 60 years (P < 0.05).

Kidneys from older donors have an increased risk for the development of chronic allograft nephropathy (CAN) (Figure 2A) [8]. Risk factors for CAN in these patients include decreased nephrotic mass, an increased risk of acute rejection [15], increased susceptibility to CNI-induced nephrotoxicity [16], higher incidence of delayed renal function and arterial hypertension [8]. Moreover, poor renal function is a risk factor for cardiovascular mortality in recipients of older donor kidneys [17]. The increased risk of acute rejection associated with older donor kidneys was demonstrated in a study by de Fijter et al.[15], in which kidneys from donors aged >50 years were associated with an increase in acute rejection compared with those from donors aged <50 years (RR 1.53, P < 0.005). This trend was consistent in both recipients aged over and under 50 years (Figure 3).


Figure 2
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  		Fig. 2. (A) The impact of donor age on development of CAN (Oppenheimer et al.[8]). (B) The impact of recipient age on outcomes of renal transplantation.

 

Figure 3
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  		Fig. 3. Increased donor age is associated with the incidence of acute rejection (Permission from de Fijter et al.[15]).

 


   Impact of recipient age
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
Immunosuppressive regimens in...
 Conclusions
 References
 
Recipient age impacts on many outcomes of renal transplantation (Figure 2B). In an analysis of ~60 000 renal transplant recipients in the United States Renal Data System database, Meier-Kriesche and colleagues [18] showed that recipient age was a strong and independent risk factor for the development of CAN. Furthermore, modifications to the aging immune system lead to an exponential increase in post-transplant infections in elderly renal transplant recipients (annual adjusted death rate per 1000 patients: over 65 years = 16.7, 40–49 years = 6.1 and 18–29 years = 3.0) [19]. These issues, along with the observation that older recipients are also more susceptible to adverse events [20], are important factors in determining the immunosuppressive regimen in these patients.

Analysis of the Collaborative Transplant Study shows a negative correlation between recipient age and graft survival. However, when these data are further stratified to account for patients dying with a functioning graft, recipient age is no longer a significant risk factor [14]. Pre-transplant malignancy and cardiovascular disease, both increased in older recipients, have been shown to be predictive of reduced graft survival [21]. Older recipients are also at an increased risk of developing de novo post-transplant malignancies than their younger counterparts [19].



   Immunosuppressive regimens in ‘old-for-old’ transplantation
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
Conclusions
 References
 
Preliminary results from the ESP suggest that ‘old-for-old’ transplantation results in good graft survival at 3 years post-transplant (64 vs 67% for ESP and control groups, respectively; P = 0.4), with 86% of recipients surviving at 1-year post-transplant [1, 7]. Further analysis of data stratified for graft function showed that the outcome was significantly worse in patients with delayed graft function (3-year graft survival 81 vs 62%, ESP initial graft function and ESP delayed graft function, respectively; P < 0.0001) [1]. Therefore, there is a need to maximize early graft function through the maintenance of good renal function. A questionnaire of 37 renal transplant centres in Germany revealed that, although 21 centres have established separate protocols for treating ‘old-for-old’ transplant recipients, most centres use high levels of CNIs in both de novo and maintenance therapy. Approximately half the centres (18/37) use induction therapy with antibodies in ‘old-for-old’ patients, with an additional five centres using this approach in all patients and 14 centres never using induction therapy (Figure 4). Of the 37 centres in the evaluation, 32 currently use CNIs in initial therapy [24 with ciclosporine (CsA) and eight with tacrolimus], with only five centres avoiding the use of CNIs. Of these 32 centres, only seven use low-dose CNI (three centres with CsA and four centres with tacrolimus) and three delay the onset of CNIs (all CsA). Given the high risk for CNI-nephrotoxicity and CAN in ‘old-for-old’ renal transplant recipients, minimizing the use of CNIs should be a major consideration of immunosuppressive therapy, as it can potentially improve both graft and patient survival [22].


Figure 4
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  		Fig. 4. Immunosuppressive therapies in ‘old-for-old’ transplantation, results of a questionnaire of German Transplant Centres in May 2005. Induction—regimen includes induction therapy with anti-thymocyte globulin or IL-2 receptor antibodies; initial CNI—CsA or tacrolimus included in the initial regimen immediately post-transplant; low-dose CNI—regimens using low-dose CNI in the initial therapy immediately post-transplant; delayed CNI—regimens which delay the use of CNI to avoid early nephrotoxicity; maintenance CNI—use of CNIs in maintenance therapy.

 
PSIs are becoming increasingly used following renal transplantation, due to their immunosuppressive and anti-proliferative effects. Pre-clinical studies have demonstrated a synergistic immunosuppressive effect of PSIs and CsA following transplantation [23] which may allow for a reduction of CNI exposure. This synergism has specifically been clinically investigated in CNI-free protocols with sirolimus and in CNI-minimization protocols with everolimus. The immunosuppressive efficacy of PSIs in renal transplantation has also been demonstrated in a number of clinical studies [24–26], however, when used in combination with full-dose CNIs, PSIs potentiate CNI-induced nephrotoxicity [25]. Furthermore, there has been concern that PSIs delay the recovery of renal function after acute tubular necrosis; specifically, sirolimus has been shown to inhibit renal cell regeneration and increase renal tubular cell loss by apoptosis [27]. Subsequently, two phase III clinical trials have shown that everolimus with low-dose CsA provides effective protection against efficacy failure in renal transplant recipients, whilst preserving renal function [28]. The use of concentration-controlled everolimus, maintaining everolimus trough blood levels within a 3–8 ng/ml target range, allowed CsA exposure to be reduced by 57% in the first year post-transplant, thus minimizing the risk of CNI-induced nephrotoxicity [29]. Moreover, CsA exposure can be further reduced if induction therapy with basiliximab is included in the regimen [28, 29].

Whilst everolimus is currently being used in CNI minimization protocols, emerging evidence suggests that complete CNI withdrawal may be possible in PSI-based immunosuppressive regimens, with sirolimus being used in CNI-free protocols. In a meta-analysis of six sirolimus studies, CNI withdrawal was associated with an improvement in renal function and hypertension at 1-year follow-up, compared with patients receiving continued CNI therapy. There was no difference in graft loss or death; however, there was an increased incidence of acute rejection in the CNI-withdrawal group (risk difference, 6%; 95% CI 2–10%; P = 0.002) [30]. Conversely, early CsA withdrawal is accompanied by a reduction in the incidence and severity of CAN during the first 3 years post-transplant (chronic allograft damage index score 4.70 vs 3.20, respectively; P < 0.03) [26]. In a multicentre clinical study in de novo renal transplant recipients, patients treated with sirolimus, mycophenolate mofetil (MMF) and steroids had significantly higher rates of acute rejection compared with those treated with CsA, MMF and steroids (17.5% vs. 2.5%, respectively; P = 0.002). Furthermore, the CNI-free treatment group had numerically higher death rates compared with patients treated with CNI [31]. Parallel findings were also observed in a similar treatment group of another clinical trial [31]. The increased incidence of acute rejection in these studies suggests that CNI should not be withdrawn before 3 months post-transplant. Conversion from CNI to a sirolimus-based regimen has also been linked with increased proteinuria, a key marker for predicting chronic renal failure [32–35]. Interestingly, the mechanisms and reasons for this observed proteinuria are controversial and not completely understood [32, 34, 35]. The withdrawal of CNI in everolimus-based regimens is currently being investigated, and preliminary data suggest that a stepwise conversion results in better renal function without an increase in the incidence of acute rejection [36, 37].

CNI-free regimens in ‘old-for-old’ renal transplantation have previously been examined, with MMF being used in combination with steroids and induction therapy [38]. This regimen resulted in good graft and patient survival at 5 years post-transplantation, with satisfactory renal function. However, a recent meta-analysis of PSI reports a lower incidence of acute rejection with PSIs compared with MMF [39]. Since patients in an ‘old-for-old’ transplantation programme have an increased risk of acute rejection, PSIs may confer more benefit with regard to immunosuppressive efficacy in this population. Whilst maximizing graft function is a key aim of transplantation, improving patient survival and quality of life are also highly important. PSIs in combination with low-dose or CNI-free regimens may provide similar benefits with regard to graft survival, whilst also targeting the long-term issues of malignancy and cardiovascular risk which are often increased in the ‘old-for-old’ population [30, 40–43].



   Conclusions
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
References
 
‘Old-for-old’ renal transplantation is an effective approach to expanding the donor pool while maximizing graft survival in older recipients. Due to the increased risk of poor graft function, CNI-induced nephrotoxicity, increased incidence of infections, cardiovascular risk and malignancies in this population, ‘old-for-old’ renal transplant recipients should be considered a special population who require a tailored immunosuppressive regimen. This should be individualized to ensure an effective balance between maintaining graft survival, reducing the impact of immunosuppressive toxicity and maximizing patient quality of life through the reduced incidence of cardiovascular disease and malignancies. Minimization or elimination of CNIs may be particularly beneficial in ‘old-for-old’ renal transplantation in order to reduce the risk of CNI-induced nephrotoxicity. PSIs allow a reduction in CNI exposure following renal transplantation, maintaining renal function and immunosuppressive efficacy. Thus, a PSI immunosuppressive regimen which facilitates CNI minimization or withdrawal may prove particularly beneficial for ‘old-for-old’ renal transplant recipients.

Conflict of interest statement. The authors have received honoraria from Novartis Pharma AG.



   References
Top
 Introduction
 Expanding the donor pool
 'Old-for-old' renal...
 Impact of donor age
 Impact of recipient age
 Immunosuppressive regimens in...
 Conclusions
 References
 

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Received for publication: 7. 3.06
Accepted in revised form: 5. 9.06


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