In the current issue of Nefrología, Dr Gonzalez Roncero et al,1 all of whom are members of a study group of thirteen transplant hospitals, present their results regarding the long-term evolution of 133 kidney grafts from expanded criteria donors.
In this study, immunosuppression was used with two doses of daclizumab, mycophenolate mofetil, normal steroid doses, and late introduction of tacrolimus. They present the 5-year evolution of patients that reached one year of graft survival in a study that initially used a prospective design, whose results were published in 2008 in this same journal. The continuation of follow-up with these patients is of great interest, since it is a multi-centre study with an originally prospective study design and shows 5-year results, information that is not commonly presented in the medical literature for these types of donors.
In addition, this article is of special application in Spain, where the age and comorbidity of donors has increased substantially in the past two decades, donor age increasing from 34 years in 1992 to 57 years in 2010. Currently, more than 50% of donors are older than 60 years, and many of them have associated comorbidity, such as diabetes or arterial hypertension.2
As a consequence of these changes in donor characteristics, the scenario surrounding kidney transplants has shifted notably in recent decades.
At the end of the 1990’s and the start of the new millennium, published studies focused primarily on two different aspects: the indications for transplants in elderly recipients, and the evolution of grafts in elderly recipients regardless of the age of the donor.
The indications for kidney transplants in elderly renal failure patients on dialysis was established in a study (among others) by Wolfe et al,3 which compared the mortality of recipients of standard organs, those receiving marginal organs, and those who remained on the kidney waiting list. In their statistical analysis, the authors concluded that the mean expected survival rate was 5 years higher in transplant recipients as compared to those who remained on the wait list.3-5
In the analysis of the evolution of kidney transplants in elderly recipients, regardless of the type of donor, the article published by Waiser et al is especially interesting. They evaluated the 8-year survival of 1269 patients, 176 of which received kidneys from donors older than 55 years (132 were placed in elderly recipients and 44 in young recipients). The relative risk of graft loss after 8 years was 1.97 times higher in young recipients than in recipients >55 years.6 The cause of graft loss in young patients was primarily acute rejection (33.7%) and chronic rejection (24%).
Once the safety and efficacy of transplants in elderly recipients was established, and it was shown that the primary cause of graft loss in these patients was death with a functioning transplant, the majority of transplant teams expanded their criteria for organ donors under the “old for old” policy, in which elderly recipients received organs from expanded criteria donors. This policy is reasonable, since organ survival is not so important in elderly recipients as in young recipients.7-12
Graft survival rates are worse in expanded criteria kidneys due to structural changes in kidneys that come with age. These alterations include glomerulosclerosis, interstitial fibrosis, tubular atrophy, and vascular damage, which make them more sensitive to ischaemia and reperfusion damage. In addition, they have a higher rate of acute tubular necrosis (ATN) than those of young donors, and higher sensitivity to calcineurin inhibitor-related nephrotoxicity. Furthermore, these kidneys have worse renal function one month following transplantation, donor age being the main risk factor for decreased glomerular filtration rate.10-12
Experimental studies performed in rats have suggested that acute failure is more probable in older kidney transplants; however, these experimental data have produced contradictory results in human studies.13-15
Other characteristics of elderly recipients include metabolic changes that can induce differences in the pharmacokinetics of immunosuppressants and other drugs, more cardiovascular risk factors and immune system alterations, making patients more susceptible to infections and tumours.16,17 In fact, in the study by Gonzalez-Roncero et al1 previously mentioned, 7 of the 10 deaths were due to tumours.
All of these physiological changes in elderly donors and recipients have generated substantial interest in achieving optimal immunosuppression when organs are derived from elderly donors in all transplant recipient groups.
In the majority of these studies, induction therapy is used with early introduction of calcineurin inhibitors at lower doses than in standard donors, or, as in the case we are focusing on, with calcineurin inhibitors starting a few days after transplantation.1,15,18-26
Other groups have opted to avoid calcineurin inhibitors altogether, using instead high induction doses with proliferation signal inhibitors or mycophenolate mofetil directly following transplantation.27,28
Unfortunately, we lack prospective randomised studies that might definitively establish an optimal immunosuppression regimen in this group of donors/recipients, who require such a delicate equilibrium between immunosuppression and immunocompetence. This is due to the fact that the majority of clinical trials have excluded elderly recipients in order to avoid the side effects associated with the characteristics of these recipients.
Treatment protocols that do not include calcineurin inhibitors, such as that described by Abrogast and Guba,27,28 may cause an excessive rate of acute rejection, higher than 50%. This study’s protocol was based on high initial induction doses of thymoglobulin at 4mg/kg/day on day zero and two doses of basiliximab followed by high steroid and mycophenolate doses, which did not reduce the rate of ATN or provide benefits in terms of mid-term patient or graft survival.28
In protocols involving late introduction of calcineurin inhibitors (which range between 3 and 7 days), the rate of acute rejection is acceptable, and graft and patient survival rates are adequate.19,20,22,25 In the study published in this issue,1 the acute rejection rate was 13%, and patient and graft survival rates adjusted for patient death after one year of follow-up were 97.7% and 96.1%, respectively, some of the highest rates published in the medical literature.20
One particularly interesting result of this study was the low rate of acute rejection when using two doses of daclizumab, a drug that was initially designed for use in five doses, which without a doubt has considerably decreased the initial costs of treatment for this condition, without increasing the rate of acute rejection.
In this study, the results after 5 years were also good, with patient survival at 93.3% and graft survival at 93.8% (adjusted for patient death). This could be due to close follow-up of patients in this study, with a very strict control of cardiovascular risk factors, since at the end of the follow-up period, 92% of patients received antihypertensive drugs, 63% statins, 18.4% erythropoietin, and 15% oral anti-diabetics or insulin. This very close clinical surveillance, along with low doses and low blood levels of tacrolimus over the 5-year follow-up period, undoubtedly contributed to the good results obtained.
In our hospital, we use a regimen based on induction with basiliximab in two doses, early introduction of calcineurin inhibitors (day +1 post-transplant) at one-half the normal dose, and low target levels. We analysed graft and patient survival in especially elderly donors (older than 70 years). These data were published by Galeano et al26 and showed an acute rejection rate (8.5%) and ATN of 38.5%. Compared with donors aged 50-70 years, very elderly donors do not show a higher rate of acute rejection or ATN. Graft survival rates without adjusting for death are similar between recipients from donors aged 50-70 years and recipients from donors older than 70 years, with evidently higher mortality rates in the group of older recipients.26
The Table summarises the initial immunosuppression treatment, donor and recipient age, incidence of ATN, incidence of acute rejection, and patient and graft survival after 1 and 5 years in elderly recipients in selected articles. It is evident in articles published in recent years that donor and recipient age is very advanced, and is notably higher than in the article published in this issue.1
In the studies by Foss, Collini, Favi, and Galeano,23-26 taking into account the advanced age of both donors and recipients, patient and graft survival rates were adequate and, in comparison to articles published at the start of the new millennium, the mean age of donors and recipients has increased without having established an age limit for donors or recipients.
The results from the three-year BENEFIT EXT study31 were published recently, in which belatacept administered with cyclosporine and mycophenolate mofetil resulted especially beneficial for improving glomerular filtration rates in recipients of organs from elderly donors. There were no significant differences in the rate of acute rejection as compared to the control group, which received cyclosporine, mycophenolate, and steroids.
Without a doubt, organ transplants from elderly donors require special treatment in the immediate postoperative period, including minimal cold ischaemia time, immunosuppression adjusted for donor/recipient characteristics, the highest possible number of HLA compatibilities, and minimal use of calcineurin inhibitors. This study shows the vital importance of continuing optimal treatment over time, minimising the use of calcineurin inhibitors, and proper control of cardiovascular risk factors. The long-term benefits of belatacept in these patients remain to be established.
Table 1. Immunosuppression and evolution of organs from elderly donors
