Table 2 shows the characteristics of the recipients from the three groups. Group III recipient age was significantly lower than that of groups I and II, in accordance with our recipient selection policy that established that the donor and recipient ages should be similar. However, the high mean age in the group I recipients was slightly but significantly lower than the mean recipient age in group II. The mean mismatches in the six HLA, A, B, and DR loci were lower in the group III recipients. The only 10 patients with panel reactive antibodies of more than 50% who received a graft during our trial are included in group III. The most frequently used initial immunosuppressant therapy was a triple therapy consisting of CS+CSA+MMF. Twenty-one patients from group III, four patients from group II and five patients from group I were also treated with ATG. Twenty recipients from group III and five recipients from group II received triple therapy with FK506, although several recipients were changed from CSA to FK506 during the evolution of the trial so that 48 patients were taking this drug at the end of the follow-up. Three recipients were administered initial immunosuppressant treatment with rapamycine, but only one continued on such therapy at the end of the follow-up. As could be expected from our immunosuppressant protocol, the CSA doses and levels were significantly higher in group III than in the groups II and I and the FK506 levels and doses were also higher in group III (Table 2).
Table 3 shows the most outstanding data on the posttransplantation evolution of the recipients in the three groups. The mean follow-up time was similar in the three groups. The mean cold ischemia time was long in all three of our groups but it was significantly longer in groups I and II. Notably, double renal graft recipients had a significantly higher rate of immediate renal function than the other two groups and those patients in group I who suffered graft renal function delay required a significantly lower number of posttransplantation hemodialysis sessions. The highest incidence of delayed graft function was observed in group II. PNF incidence was low in the three groups. Graft thrombosis and exitus were the main causes of PNF. Only one patient from group III had a PNF due to acute rejection.
The incidence of acute rejection using a triple immunosuppressant regime with MMF was very low in the three groups (Table 3). The low percentage of rejections in group I and II patients stands out, this being lower than 10%. Group II showed the lowest rejection rate, the difference being statistically significant in regards to group III. Acute rejection was diagnosed by renal biopsy in one case (50%) in group I, in two cases (66%) in group II and in 23 cases (88%) in group III. All groups I and II rejections were corticosteroid-sensitive. The six patients who suffered a corticosteroid nonresponsive rejection and required treatment with antilymphocytic globulins belonged to group III. Three of them totally lost renal function before the third posttransplantation month.
Table 3 shows actuarial graft and patient survival rates at 3, 6, and 12 months of evolution. These values are excellent for the three groups, there being no significant differences among them. To calculate graft survival, a group I recipient was considered to have a functional graft if at least one of the grafts maintained its functionality so that the patient did not require dialysis. At 6 months, which was the minimum follow-up period, renal function was conserved in 93% of group III recipients and 95% of those in groups I and II. Mortality rate at 6 months was 0, 3, and 2% in groups I, II, and III, respectively.
Surgical complications are shown in Table 4. The early renal graft thrombosis incidence was higher in group I. Five (12%) renal graft thrombosis occurred in four patients among the 42 implants in group I. In one patient, this thrombosis was bilateral and occurred in the early postoperative due to arterial causes. In the other three patients it was only unilateral, two of which occurred in the early postoperative, also due to arterial causes, and the other on the fourth day of evolution simultaneously with an acute rejection episode. However, renal function was preserved in these three patients as the contralateral renal graft remained functional. The other most commonly appearing surgical complication was the development of lymphoceles that compressed the urinary tract. Most of these cases were produced in group III, although no significant differences for the groups were found. There was scarce incidence of urinary tract fistulae and no surgical wound infections were observed in any of the groups.
The incidence of cytomegalovirus (CMV) infection was significantly higher in the double renal graft group (6 cases or 28.5%) (Table 4). Three of these six recipients had received immunosuppressant therapy with ATG and specific prophylactic treatment against CMV with ganciclovir in the immediate posttransplant period. Donor/recipient CMV serological status of renal transplantations from all groups was positive/positive in 159 cases, negative/negative in 2 cases, and negative/positive in 17 cases. There were only three cases with CMV positive/negative status which were found, one in group II and two in group III. These patients were treated prophylactically with ganciclovir and anti-CMV hyperimmune globulin and CMV infection did not develop. The clinical picture of CMV infection was mild in 18 of the 19 cases found in all the groups. In these 18 cases, only fever and viremia were observed with no visceral involvement. The only patient who had visceral involvement (pneumonitis) belonged to group III, and had not received ATG at any time. Response to intravenous ganciclovir was excellent in all nineteen patients. No other opportunistic infections were observed.
Most of the complications which led to renal graft lost were produced in the immediate posttransplantation period and resulted in PNF (see Table 3). Late complications that led to the remaining renal graft losses were two cases of acute rejection and one exitus with functioning renal graft in group III and one case of late thrombosis (seventh month) of the renal graft after a renal artery transluminal angioplasty due to stenosis and one exitus with functioning renal graft in group II.
Table 5 shows the serum creatinine levels in recipients with functioning grafts at 1, 3, 6, and 12 months posttransplantation. In general, the mean serum creatinine levels were excellent although those found in groups I and III were significantly better than those of group II. However, the serum creatinine levels in 25 group II recipients (63%) were under 2 mg/dl at the end of the follow-up period. No statistically significant differences were observed in the serum creatinine levels between groups I and III in the four time periods analyzed, except at the 6-month evaluation.
None of the four patients who died had received a double renal graft. Causes of death were cardiogenic shock and aspergillosis, respectively, in the two group III recipients and gastric hemorrhage and lung carcinoma in the two group II recipients.
The results of our series of simultaneous double renal transplantation from extremely aged donors (mean age 75±7 years) and a mean glomerulosclerosis percentage of 19±10% are excellent. In addition, the low incidence of delayed graft function and acute rejection episodes and the good middle term serum creatinine levels obtained by the recipients should be emphasized.
However, the results of single renal grafts from donors older than 60 years of age, when the guidelines of our protocol are considered (i.e., donors <75 years and glomerulosclerosis percentage <15%), are excellent. With a mean donor age of 67±4 years and graft glomerulosclerosis of 5±4%, these patients presented excellent graft and patient survival in single renal transplantation, there being no statistically significant differences with the double renal graft recipient group or control group, and maintained excellent serum creatinine levels at 1 year (1.9±0.8 mg/dl).
The mean donor age in our series of double renal grafts is much greater than that of all the series using this technique that have been published up to now in the literature. In addition, the mean age of our single renal graft advanced age donor group also exceeds that of the donors of these same series of double grafts (15, 20–23). After they reviewed their results on double and single renal grafts retrospectively, Alfrey et al. (22) recommended double kidney transplantations when the donor creatinine clearance was lower than 90 ml/min by the Crockcoft-Gault formula and the donor age was equal to or more than 59 years, and recommended that the cold ischemia time of the kidneys be limited to no more than 24 hr. The single renal graft outcome in the Alfrey’s series in which these circumstances occurred was worse. Nevertheless, these authors suggest that these criteria should be reviewed and improved with new data (24).
We have used a morphological criterion of the percentage of glomerulosclerosis in the pregraft biopsy to establish the indication of double renal grafts with kidneys from donors older than 60 years. This criterion is easy to quantify and highly efficient when predicting renal graft outcome (19). In view of our results, our protocol has been very useful to establish the double or single renal graft indication when the donor is aged 60 years or more. In addition, it has made it possible to perform single or double kidney implants with kidneys from extremely aged donors (12 of them older than 75 years and 3 older than 80 years). Such kidneys had not been routinely used in renal transplantation up to now.
Due to the excellent results of the double transplantation found in our series, it can be suggested that the 70- to 79- and 80- to 89-year-old population groups should be considered as potential organ donors, groups that had not been considered adequate for kidney donations until now (25). The nontraumatic stroke incidence for these age groups is hundreds of times higher than in a younger population (26), and brain death appears in many of the cerebral vascular events. Up to now, due to their age, these extremely elderly patients with brain death were not considered as potential donors and thus no steps were taken to initiate the donation process (27). This study opens up the possibility of using the kidneys from these extremely old donors, which will undoubtedly increase the number of cadaver kidney donors and reduce the number of recipients on the waiting list.
The existence of worse serum creatinine levels in single kidney graft recipients from donors older than 60 years confirms our policy of using these kidneys in elderly recipients. In such recipients, by using a triple immunosuppressive therapy with micophenolate mofetil and low doses of CSA or FK506, it has been possible to avoid nephrotoxicity and also to obtain a low incidence of acute rejection episodes. The extremely low incidence of acute rejection in this group of patients will be a positive factor to maintain the long-term graft function (28, 29). Moreover, the lower life expectancy in those elder patients, above all when in dialysis (30), justifies single kidney transplantation from aged donors. Most of the renal grafts will still be functioning when the recipient dies (11).
On the contrary, the excellent creatinine levels reached in the double implant patients with a low incidence of acute tubular necrosis and acute rejection in spite of the advanced age of the donors makes us reconsider the age of the recipients that we should select. Given that immediate renal function and acute rejection episodes are the main parameters affecting the long-term evolution of the graft (28, 29, 31–33), these double renal grafts are in the best situation for long-term survival. Although the advanced age of the donors is a negative factor for the long-term survival (34, 35), this is compensated for by the double renal graft as the number of nephrons is increased. Thus, due to the increase in nephrons, the mechanisms of glomerulosclerosis by hyperfiltration that provoke long-term loss of the renal graft will also decrease (36). If the double renal graft recipients age is lowered, from the surgical point of view, we must keep in mind that there may be successive transplants and that surgically usable fields should be available in both iliac fossae to be used in successive renal graft placements.
The incidence of surgical complications was not very high in each group. It should be highlighted that no surgical wound infection was observed. The only important point that merits comment is the higher incidence of graft thrombosis in the double graft group, however, this difference was only statistically significant when compared with the control group. Given the donor and recipient ages, the atherosclerotic changes in the renal and iliac arteries increase the risk of arterial graft thrombosis. The double implantation procedure made it possible for three of the four recipients with graft thrombosis to maintain their renal function with the contralateral functioning kidney. However, this complication warns us about the need to be very meticulous in the selection of the double implant recipients and to discard those recipients with severe atherosclerosis and calcifications in the aortoiliac tract.
A high incidence of mild CMV infection in the double renal graft group was observed. However, the clinical picture only consisted in viremia and fever and the patient response to treatment with ganciclovir was excellent. Three of the five patients in this double transplantation group who presented this infectious complication had been treated with ATG and prophylactic ganciclovir. We have no clear explanation to this fact, which hypothetically could be related to the greater volume of transplanted kidney tissue.
In conclusion, double renal graft with kidneys from extremely aged donors is a technique that provides highly satisfactory short-term results and opens new perspectives to increase the number of donors, thus increasing the number of renal transplants and reducing the waiting lists. However, the rational use of kidneys from donors aged 60 to 74 years old in single transplant, keeping the percentage of glomerulosclerosis (<15%) in mind, also provides excellent results. In all, by using our protocol, we extend the age limit of cadaver renal donors with good results and rationalize the use of kidneys from donors older than 60 years for single or double transplantation, thus optimizing the number of transplant recipients. Recipient and donor ages must be matched when older cadaver kidney donors are used.
We thank to the National Organization of Transplants in Spain and especially all the Spanish Hospital Transplant Coordinators, without whose efforts to detect and obtain the elderly donors it would not have been possible to perform the renal transplants in this series.
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