Because of advances in the management of end-stage renal disease (ESRD), the number of patients undergoing maintenance hemodialysis is increasing, and it has now exceeded 280,000 in Japan. However, the proportion of such patients who can undergo kidney transplantation is limited because of a shortage of deceased donors. Therefore, most kidney transplantations involve living donors, and as a result there has been a need to expand the eligibility criteria for live kidney donation. Against this background, the prevalence of diabetes, including mild glucose intolerance (GI), is estimated to be as high as 20% among Japanese adults, and thus there is a correspondingly high incidence of GI among prospective kidney donors. In this study, to clarify the indications for live kidney donation in GI in terms of their safety, we reviewed donor nephrectomies performed at our institution from 1985 to 2008, when the 75-g oral glucose tolerance test (OGTT) was routinely included in live kidney donor evaluation.
SUBJECTS AND METHODS
Between January 1985 and November 2008, 444 living-donor kidney transplantations were performed at Kyoto Prefectural University of Medicine, Kyoto, Japan. During this period, the 75-g OGTT was routinely included in live kidney donor evaluation, and all these donors were enrolled in this study. Among the donors, 164 (37%) were men and 280 (63%) were women, with a mean age of 54±10 (range, 22–80) years at the time of donation. Mean body mass index (BMI) was 23.1±3.1 (range, 16.0–35.2), and 44 (9.9%) of them suffered from hypertension (HTN), defined as more than 140/90, or having medication for HTN.
Evaluation of GI by the 75-g OGTT
All the donors were evaluated by the 75-g OGTT before donation to determine whether they had GI. For the 75-g OGTT, the person fasts overnight (for at least 8 hr but not >16 hr). Then first, the fasting blood glucose level is tested. After this test, the person receives Trelan-G75 (Ajinomoto Pharma Co., Ltd., Tokyo, Japan), which contains 75 g of glucose in 225 mL of sweet-tasting liquid. Blood samples are taken up to four times (30, 60, 90, and 120 min) to measure the blood glucose. The results of the 75-g OGTT were divided into three categories: a normal pattern with a fasting blood sugar level of less than 110 mg/dL and a 120-min blood sugar level of less than 140, a diabetes mellitus (DM) pattern with a fasting blood sugar of more than or equal to 126 mg/dL, and a 120-min blood sugar of more than or equal to 200 mg/dL, and an impaired glucose tolerance (IGT) pattern that was not included in the other two categories. The patients were divided into two groups, including two subgroups, based on the results of the 75-g OGTT: a GI group (n=71) who showed a DM pattern (n=27) or IGT pattern (n=44), and a non-GI group (n=373) who showed normal pattern. Five donors in the DM group had already been diagnosed as having diabetes and had been treated with oral medication. If the donor candidates were diagnosed as having OGTT abnormality, with careful informed consent we accepted them as kidney donors only if they had no diabetic complications or urinary protein (even microalbuminuria), and if blood glucose was well controlled with a hemoglobin A1c (HbA1c) of less than 6.5%. Otherwise, they were excluded as donor candidates. Since 2004, at least four prospective donors have actually been excluded because of uncontrollable HbA1c, whereas other two were excluded based on pretransplant biopsy findings.
Backgrounds and Perioperative Issues
Background factors including age, gender, BMI and coexistence of HTN, and perioperative issues, including estimated blood loss, hospital length of stay after surgery, perioperative and postoperative glucose values, need for perioperative insulin, and occurrence of postoperative complications, were compared between the three groups.
To ascertain the long-term effect of GI on a single kidney, we attempted to contact all 444 donors (or their families) to ask about their 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 ESRD. 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 periodic check-up, (4) presence of diagnosed HTN, DM, and hyperlipidemia at the time of assessment. If the donor had died, we asked the recipients or their families 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 we sent the questionnaire.
Long-term survival rate of live donors and cause of death were compared in each group. Frequencies of HTN, DM, hyperlipidemia, and renal dysfunction including ESRD were also compared in each group.
Five donors, who had already been diagnosed as having DM before evaluation as live kidney donors and been treated with oral medication, were followed up closely to examine the development of diabetic complications as well as measurement of HbA1c, urinary microalbumin excretion, and serum creatinine level.
Review and analysis of patient's clinical records were undertaken with the approval of the Kyoto Prefectural University of Medicine Institutional Review Board. The statistical significance of differences in nonparametric data was analyzed using Student's t test. Kaplan–Meier survival curves were compared with the log-rank test. Significance for all tests was set at 0.05.
Prevalence and Backgrounds
Among the 444 live kidney donors, 71 showed an abnormal OGTT pattern (DM pattern in 27 donors and IGT pattern in 44), and the remaining 373 showed normal pattern. The annual proportion of GI (DM+IGT) ranged from none (1986 and 1989) to 41% (2008), showing a gradual increase with time.
There was no difference in gender (men/women=32/39 vs. 132/241, NS), BMI (23.6±3.2 vs. 23.1±3.1, NS), or frequency of HTN (14% vs. 9%, NS) between the GI and non-GI groups, although mean age was significantly higher in the GI group (57.9±7.7 vs. 53.2±10.4, P<0.05; Table 1a).
All donor nephrectomy before 2000 was performed by open procedure, whereas hand-assisted laparoscopic nephrectomy has been introduced in selected cases since 2001. The proportion of hand-assisted laparoscopic nephrectomy procedure in DM, IGT, and non-GI group was 37% (10/27), 30% (13/44), and 21% (78/373), respectively. Estimated blood loss (436±399 g vs. 291±206 g vs. 347±264 g, NS) and length of stay after surgery (14.0±4.3 day vs. 13.0±2.4 day vs. 13.3±5.0 day, NS) in DM, IGT, and non-GI groups were equivalent, and the incidence of perioperative complications (i.e., wound infection, incisional hernia, pulmonary complication) was not higher in GI group than that in the non-GI group (4.2% vs. 5.4%, NS). However, in the GI group, the incidence of perioperative complication was higher in DM group than that in IGT group without statistical significance. There was no increase in the rate of infectious complications in the GI group (Table 1b).
Perioperative and postoperative glucose values were higher in the DM and IGT groups as compared with non-GI group as shown in Figure 1, although only one case in DM group needed insulin coverage (Table 1b).
We conducted a cross-sectional survey and were able to obtain information on 409 (92.1%) of the 444 donors: 91.5% (65/71) in the GI group and 92.2% (344/373) in the non-GI group. The mean follow-up period was 123±81 (range, 14–299) months, at which time 391 donors (95.6%) were still alive. The mean follow-up period of DM, IGT, and non-GI group were 88±71 (range, 14–225), 101±82 (range, 19–275), and 128±81 (range, 14–299) months, respectively. Postdonation survival rates in the GI group at 5, 10, and 20 years were 98.3%, 95.1%, and 89.2%, respectively, whereas those in the non-GI group were 98.1%, 96.1%, and 91.5%, respectively, thus showing equivalent mortality. Survival rates in the DM and IGT subgroup also showed equivalent mortality (Fig. 2). The causes of death in the two groups are listed in Table 2. The GI group showed no increase in the rates of cardiovascular and renal death. One donor in non-GI group died with renal cancer in remaining kidney which was inoperable when detected, and another one in non-GI group died at the age of 84 years with renal failure presumably caused by hypertensive glomerular sclerosis 8 years after donation. In the long-term follow-up, 7 of 24 survivors (29.2%) in the DM group received oral medication for DM, compared with none in the IGT or non-GI group. None of the them in the DM group had developed severe diabetic complications or ESRD after a mean follow-up period of 88±71 (range, 14–225) months.
The present statuses of the surviving live kidney donors ascertained by self-report in the two groups are listed in Table 3. There were no significant differences between the two groups in the incidences of HTN, hyperlipidemia, and renal dysfunction, although there was a significant intergroup difference in the incidence of DM.
Consequences for Diabetic Donors
Five of the 444 donors had already been diagnosed as having DM and treated with oral medication before evaluation for live kidney donation. We accepted them as kidney donors because they had no diabetic complications or urinary protein, and their blood glucose had been well controlled with HbA1c basically less than 6.5%. They were followed up closely for possible development of diabetic complications, and underwent periodic measurement of HbA1c, urinary microalbumin excretion, and serum creatinine level. Among these five donors, the one who donated first was lost to follow-up because of emigration from the local area. However, none of the remaining four developed severe proteinuria and maintained the same level of HbA1c similar to that at the time of donation, although one had mild proteinuria (Table 4).
The prevalence of ESRD is increasing and is currently more than 2000 per million population in Japan. More than 40% of incident ESRD is due to DM (1). Moreover, because of the extreme shortage of organ donors in Japan, kidney transplantation is dependent on live donors in as many as 80% of cases. Therefore, the indications for live kidney donation have been expanding in medical status, and now include patients with mild HTN, older age, and mild decline of the glomerular filtration rate. However, GI needs to be considered carefully. Recently, international standards for candidate live kidney donors were published in the form of the Amsterdam Forum Guidelines, which excluded individuals showing a diabetic OGTT pattern as living-kidney donor candidates (2).
A recent survey demonstrated that the estimated prevalence of DM, including mild GI, among Japanese adults was as high as 20%. In this situation, we frequently encounter living-kidney donor candidates who show GI during evaluation, and sometimes even diabetic patients who are eager to donate. Although most guidelines have excluded diabetic patients as donors, even those with a borderline OGTT pattern (2–4), these guidelines were based on a situation in which cadaveric donors were relatively plentiful, with donor waiting times of less than 5 years. We have been carefully evaluating living donor candidates and harvesting their kidney on condition that they do not have diabetic complications including microalbuminuria, and that good control of their diabetes is anticipated in the future. If a decision about donor suitability has not been initially possible, we have been carrying out preoperative kidney biopsy before donation in three cases. Among them, two cases were considered inappropriate for donation because of histologically obvious diabetic change such as hyalinization of efferent arteriole, whereas one donated the kidney because specific diabetic change was absent (5). From the analysis of 76 consecutive baseline (1 hr) biopsies, we have never seen obvious diabetic pathology, and the result of the OGTT did not correlate with pathologic findings in these baseline biopsies. On the other hand, donor age and presence of HTN was well correlated with the pathologic changes (unpublished data).
The first major concern regarding living-kidney donation is the incidence of perioperative surgical complications. In a previous study of 601 donors between 1970 and 2006, we found that perioperative complications occurred in approximately 5% of cases of which wound infection was the leading one (6), which usually occurs more frequently in diabetic patients. However, our analysis demonstrated that the GI group showed no increase in surgical complications, and the three complications that occurred in this group were pneumothorax, atelectasis, and chylocele, which are not believed to be directly associated with GI but with surgical procedure itself.
The second, and more serious, concern is the possibility that live kidney donation by diabetic patients may be associated with the development of kidney disease and premature death. A number of previous studies have evaluated the residual renal function (7–16) of surviving live kidney donors and their long-term quality of life (17, 18). Most of the data suggested that such donors had normal renal function, with an incidence of HTN comparable with that expected in the age-matched general population. However, in those studies, the subjects were usually limited to healthy donors.
However, our major concern is that heminephrectomy in diabetic patients might lead to the accelerated development of diabetic glomerulopathy. In fact, several studies have indicated that loss of renal mass in animals with experimentally induced DM leads to exaggerated hypertrophy of the remaining nephrons and accelerated diabetic glomerulopathy (19, 20). Clinical data have also suggested that nephrectomy in a patient with type 2 DM might increase microalbuminuria and accelerate progression of the disease (21). In contrast, another clinical study has shown that a reduction in nephron number is not associated with accelerated development of diabetic glomerulopathy in patients with type 1 DM (22).
In our study, frequency of renal dysfunction was much higher in DM group than that in the IGT group (16.7% vs. 2.4%), although no significant difference was observed between GI and non-GI groups. These results demonstrated the possibility that DM pattern in predonation OGTT is one of the risk factors for renal dysfunction postdonation, which support the Amsterdam Forum Guidelines. However, further precise assessment including measurement of microalbuminuria and glomerular filtration rate is essential because our results were only based on the self-report.
To our knowledge, the present report is the first to address the issue of preexisting GI in kidney donors. The relatively favorable donor outcome we observed suggests that living-donor kidney transplantation from a donor with GI is an acceptable approach in the condition that they had no diabetic complications or urinary protein, and their blood glucose would be well controlled. Needless to say, it is essential that the candidate donor fully understands the long-term risk and provides spontaneous consent to become a donor.
However, efforts should be made to increase the number of deceased donors in Japan, and it is also important to develop a registry of long-term kidney function after live donation and follow-up diabetic donors for a longer period after kidney donation.
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