One of the biggest problems in kidney transplantation is the extreme shortage of donor organs. In the United States, the number of living-donor kidney transplants has recently increased and exceeded that of deceased donor kidney transplants in 2001 (1).
In Japan, even after the establishment of the organ transplantation law in 1997, organ donations from brain-dead donors numbered less than 10 annually. Since then, the number of deceased donor kidney transplants, mostly from donors after cardiac death, has been as low as 200 per year, whereas more than 11,000 kidney patients are on the transplantation waiting list (2).
Since the first clinical kidney transplantation in Japan in 1956, more than 10,000 such operations have been performed. During this period, a lack of deceased donors had led to dependence on living kidney donors in as many as 80% of cases. Furthermore, indications for living-donor kidney donation have been expanding in donor medical status as well as human leukocyte antigen matching and ABO blood type (ABO) incompatibility, thus emphasizing the donor shortage. Because hypertension and diabetes might impair the function of the remaining single kidney after donation, living kidney donors need to be selected carefully. From this viewpoint, the recent publication of the Amsterdam Forum Guidelines outlining international standards for selection of living kidney donors has been useful (3).
Although a recipient registry has been established and the results of graft and recipient survival have been announced periodically by the Japan Society for Transplantation, there are few data on the long-term outcome of living kidney donors (4). Because the safety of living organ donors is paramount, we performed an institutional retrospective investigation of the short- and long-term outcome for previous kidney donors, representing the first study of its kind in Japan.
MATERIALS AND METHODS
Between April 9, 1970 and August 15, 2006, 601 living-donor kidney transplantations were performed at Kyoto Prefectural University of Medicine. Among the donors, 215 were men (35.8%) and 386 were women (64.2%), with a mean age of 52±10 years (range, 21–80 years) at the time of donation. Preoperative complications were found in 144 donors (24.0%), comprising hypertension in 45 (7.5%), peptic ulcer in 27 (4.5%), diabetes in 13 (2.2%), cholelithiasis in 11 (1.8%), malignancy in 7 (1.2%), dyslipidemia in 6 (1.0%), and hyperuricemia in 4 (0.7%). The medical records of these donors were complete and available for analysis of perioperative (surgical) complications, operation time, bleeding amount, and changes in laboratory data during the perioperative period.
To ascertain long-term outcomes, we attempted to contact all 601 donors (or their families) to ask about current physical status. First, we asked the graft recipients to ask the donors to fill out a questionnaire regarding current health, especially regarding the presence of end-stage renal disease. This questionnaire included (1) whether they were dead or alive, (2) presence or history of renal problems (i.e., elevation of serum creatinine level or proteinuria), (3) presence or history of other physical problems including detection by periodical check-up, and (4) presence of hypertension, diabetes, and hyperlipidemia at the time of inspection.
If the donor had died, we asked the recipients or their family to provide details about the time and cause of death. If we were unable to meet the recipients directly, we used the last known donor or recipient address in our records to which the questionnaires were sent. Donor survival rate was compared with the expected survival rate. Expected survival for the donors was calculated from mortality data in Japan provided by the National Cancer Center. Age, gender, and calendar year-specific mortality rates for the general population were used to calculate the expected mortality in the donor cohort. Review and analysis of patient clinical records was undertaken with the approval of the Kyoto Prefectural University of Medicine Institutional Review Board.
The statistical significance of differences in nonparametric data were analyzed using Student’s t test.
Among a total of 601 donor nephrectomies, the mean operation time was 4 hr 25±41 min (range, 2 hr 50 min to 7 hr 25 min), and the bleeding amount was 396±243 (range, 41–2390) g. Blood transfusion was necessary only in four procedures (0.66%) performed before 1990. There was a slight correlation between operation time and bleeding amount (r2=0.461). Three (0.5%) major perioperative complications occurred: femoral nerve compression, pulmonary thrombosis requiring transient mechanical ventilation support, and acute renal failure requiring transient blood purification therapy. Other minor complications in 28 (4.7%) donors included 22 cases of wound infection, 5 cases of liver dysfunction, and 1 case of reexploration for bleeding. All the donors subsequently recovered and left the hospital without complications. In 13 cases (2.2%), hospitalization after donation extended more than 30 days because of perioperative surgical complications. Changes in laboratory data during the perioperative period are shown in Figure 1. In both men and women, serum creatinine was elevated by approximately 50% on day 3, and gradually decreased within the first month, but was still 20% higher than the preoperative level (P<0.05). Hematocrit was decreased by approximately 20% on day 3, and gradually recovered by 1 month, but was also still 10% lower when compared with preoperative level (P<0.05). After the first hospital visit at 1 month, we left follow-up of physical status to the donors themselves, recommending them to visit their family doctor periodically. Therefore, longitudinal long-term follow-up data were not available before this survey.
We conducted a cross-sectional survey and were able (as of April 19, 2007) to obtain information on 481 (80.0%) of the 601 previous donors. Retrieval rates gradually increased with the period after transplantation (Fig. 2). The mean follow-up period was 165±111 (7–406) months, and 426 donors (88.5%) were still surviving. Actual donor survival rates at 5, 10, 20, and 30 years were 98.3%, 94.7%, 86.4%, and 66.2%, whereas expected survival rates, calculated using data for the age- and gender-matched normal population were 97.0%, 92.7%, 81.8%, and 63.7%, respectively (Fig. 3). The mean interval between donation and death was 183±102 (7–375) months, and the mean age at death was 70±11 years (range, 47–88 years). Of the 481 donors, we obtained information on 55 who had died. The cause of death was available for 52: 51 had no kidney disease, but 1 died of chronic renal failure at the age of 84 years (8 years postdonation), probably caused by nephrosclerosis. The leading cause of death was malignancy, and the remaining causes are listed in Table 1. The three earliest deaths occurred within 3 years after kidney donation (7, 27, and 35 months) and were caused by adult T-cell leukemia, pancreatic cancer, and subarachnoid hemorrhage. Causes of death after live kidney donation were compared with the nondonor normal population, with reference to data provided by the Japan Ministry of Health, Labor and Welfare for 1984, 1989, and 2004 (Table 2). Although deaths resulting from malignancy were slightly higher in the previous donors (43.3%) than in the normal population (18.8% in 1974, 27.0% in 1989, and 31.1% in 2004), deaths caused by heart disease and cerebrovascular disorders were not higher in the previous donors (5.7% and 11.3%) than in the normal population (13.8% and 25.1% in 1974, 19.9% and 15.3% in 1989, 15.5% and 12.5% in 2004, respectively) (Table 2). Deaths due to renal failure were also not higher in the previous donors (1.8%) than in the normal population (not assessed in 1974, 1.9% in 1989, and 1.9% in 2004).
In the questionnaire designed to clarify renal problems, 40 (9.4%) of the 426 surviving kidney donors answered that they had a renal problem, including proteinuria in 13 (3.1%) and elevation of the serum creatinine level (>2 mg/dL without hemodialysis) in 3 (0.7%). Three (0.7%) of the previous kidney donors were on hemodialysis at the time of inspection (Table 3). The intervals between donation and hemodialysis were 79, 99, and 276 months, respectively. The possible cause of renal insufficiency in these cases was chronic glomerulonephritis, although this was proven by biopsy only in one case. As for the questionnaire items designed to investigate nonrenal problems, the proportions of previous donors who reported having hypertension, diabetes, and hyperlipidemia at the time of inspection were 30.1% (n=132), 6.8% (n=29), and 10.8% (n=46), respectively.
Because of the extreme shortage of donated organs in Japan, kidney transplantation is dependent on live donors in as many as 80% of cases. Also at our institution, the ratio of living-donor kidney transplants was 87%, 93%, and 88% in 2004, 2005, and 2006, respectively; the rates being high even for Japan. Because of progress in strategies for immunosuppression, including blood purification therapy and the induction of specific antibodies, the selection of candidate live donors has been extended to living-unrelated donor (LURD) or even ABO-incompatible donors. In fact, over the last 5 years (2002–2006) at Kyoto Prefectural University of Medicine, 17% (20/120) of living kidney transplants have been ABO-incompatible and 28% (34/120) have been LURD transplants. Furthermore, the indications for live kidney donation have been expanding in medical status and now include patients with mild hypertension and diabetes. Recently, international standards for candidate live kidney donors, including conditions such as hypertension, obesity, dyslipidemia, diabetes, and renal function, were published in the form of the Amsterdam Forum Guidelines (3).
The major risks of live kidney donation are perioperative morbidity and mortality (5–10). Analyses of large case series have yielded perioperative donor mortality rates of 0.02% (5) and 0.03% (6). Although the leading cause of death was pulmonary embolism (6), a frequent complication was wound infection, pneumothorax, and wound seroma (7). Although fortunately there were no perioperative deaths in our series, two cases of severe complication, involving pulmonary thrombosis (11) and acute renal failure accompanied by respiratory failure, might have proved fatal if therapy had been delayed.
Because in our series we observed a decline in the hematocrit and an increase in the serum creatinine level perioperatively, which had not recovered completely within 1 month after surgery, the possibility that live kidney donation may be associated with the development of kidney disease and premature death is a major long-term concern. A number of previous studies have evaluated the residual renal function (6, 12–19) of surviving live kidney donors and their long-term quality of life (20, 21). Most of the data suggested that the donors had normal renal function, with an incidence of hypertension comparable with that expected in the age-matched general population. However, in those studies, the subjects were limited to surviving donors, and only a few studies have addressed the overall survival rate and causes of death after kidney donation. Fehrman-Ekholm et al. (22) reported that kidney donors lived longer than the age-matched general population, and that the main cause of death was cardiovascular disease in 18 and malignancy in 10 in their series. This mortality pattern was similar to that expected in the normal Swedish population. Another report of nine donor deaths cited malignancy as the leading cause of death in four, although the total number was less because of short the follow-up period (17). Also in our Japanese population, the survival rate of kidney donors was slightly better than the age- and gender-matched general population, and the pattern of causes of death was mostly similar to that of the general population. The number of deaths we analyzed was higher than in previous reports because of the long follow-up period and high data recovery rate (80%). Although these better survival rates for kidney donors may have been due partly to selection bias, they at least suggest that donor longevity may not be compromised.
There have been a few individual case reports of hemodialysis after live kidney donation (23, 24). Among our 426 donors, 3 (0.70%) are currently surviving on hemodialysis. Japan has the highest proportion of dialysis patients among the general population in the world, at 0.20%, and if limited to men between 65 and 69 years of age, 0.62% are receiving hemodialysis, according to the annual report published by the Japanese Society for Dialysis Therapy (25). Therefore, the ratio of 0.70% among our kidney donors seems acceptable.
Through an analysis of the Organ Procurement and Transplantation Network database, Ellison et al. (26) reported that a total of 56 living donors were subsequently listed for cadaveric kidney transplantation. Another report described four kidney donors who developed end-stage renal disease thereafter, three becoming kidney recipients (27). However, a survey of transplant centers in the United States concluded that there is no increase in end-stage renal disease after kidney donation (28).
Quality of life after live kidney donation is also a important issue. Johnson et al. (21) reported that kidney donors scored higher on the Short-Form-36 than the normal population of United States, although some were dissatisfied and regretted the decision to donate. Furthermore, some donors have reported of long-lasting major pain (15, 20). From an economic viewpoint, the insurability of living organ donors is also a critical issue. Although almost all insurance companies claim to provide life and health insurance to living organ donors, some donors do, in fact, encounter difficulties with their insurance (29). Our preliminary data suggest that, at least in Japan, live kidney donors need not pay higher life insurance premiums.
To our knowledge, this report is the first to address the long-term outcome of live kidney donors in Japan, where the kidney transplantation program depends to a large extent on live donors. The relatively favorable donor outcome we observed suggests that living-donor kidney transplantation is an acceptable approach, in view of the superior results it yields in recipients (9). However, efforts to increase the number of cadaveric donors in Japan should be made, and it is also important to develop a registry of long-term kidney function after live donation.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
Living donor; Kidney transplantation; Donor follow-up; Donor outcome; Donor registry