Kidney Transplantation from Living Unrelated Donors Ricardo Sesso, MD, MSc; Michael J. Klag, MD, MPH; Meide S. Ancao, MD; Paul K. Whelton, MD, MSc; Alexander Seidler, PhD; Daniel Sigulem, MD; and Oswaldo L. Ramos, MD
• Objective: To compare patient and graft survival of recipients of kidneys from living, unrelated donors (LUDs); cadaveric donors; and living, related donors (LRDs) matched for zero (mismatched), one, or two (identical) haplotypes. • Design: Cohort study. • Setting: Sixty-three renal transplantation centers affiliated with the Brazilian Transplantation Registry (accounting for more than 95% of the transplantation activity in Brazil). • Patients: Patients having renal transplantation between January 1987 and March 1991. Of 2892 patients, 165 (6%) received transplants from LUDs; 964 (33%), from cadaveric donors; 183 (6%), from zero haplotype, HLA-matched LRDs; 1259 (44%), from one haplotypematched LRDs; and 321 (11%), from two haplotypematched LRDs. • Measurements: Patient and graft survival. Patients were followed for an average of 15.8 months. • Results: After adjustment for age, race, diagnosis of primary disease, history of previous transplantation, cyclosporine use, and number of transplants from LUDs per center, patient survival did not differ statistically for recipients of kidneys from LUDs and recipients of cadaveric kidneys (risk ratio [RR], 1.16; 95% CI, 0.68 to 1.98). Little difference was seen between the adjusted death rate for recipients of zero haplotypematched LRDs and recipients of cadaveric kidneys (RR, 1.13; CI, 0.69 to 1.87). Similarly, in a multivariate analysis, recipients of kidneys taken from LUDs and zero haplotype-matched LRDs had a risk for graft failure that did not differ statistically from that of cadaveric kidney recipients (RR, 0.74; CI, 0.45 to 1.22 and RR, 0.82; CI, 0.53 to 1.25, respectively). • Conclusions: Graft survival for recipients of kidneys from LUDs is similar to that from zero haplotypematched LRDs and is at least as good as that achieved with cadaveric transplants.
1 ransplantation is the optimal and most cost-effective treatment for end-stage renal disease in both developed and developing countries (1-3). A shortage of kidney donors worldwide, however, has resulted in a progressively increasing gap between the supply of and demand for cadaveric grafts (4-6). As a result, waiting lists for cadaveric transplants in most countries have grown consistently (7-9). Efforts to increase the number of organs available for transplantation in Europe and in the United States have achieved only limited success. To overcome the shortage of cadaveric kidneys, some providers have resorted to transplantation of kidneys from living, unrelated donors (LUDs). This practice is controversial (10-14), reflecting both concern regarding the donor's safety and the associated ethical dilemma. Some authors have reported that patients receiving kidneys from LUDs experience better patient and graft survival compared with those receiving kidneys from cadaveric donors (15-20). These results, however, have been based on relatively small numbers of patients and the use of nonconcurrent cadaveric donor comparison groups and have lacked adjustment for other variables that could affect outcome. A previous univariate analysis of the Brazilian Transplantation Registry suggested that patient and graft success rates were similar among LUD, mismatched (zero haplotype HLA-matched) living related donor (LRDs), and cadaveric donor kidney recipients (21). The main purpose of this report is to contrast patient and graft survival between recipients of kidneys from LUDs and cadaveric donors, in a larger number of patients with longer follow-up and with adjustment for potential confounding variables. For comparative purposes, survival experience of zero-, one-, or two-haplotype-matched recipients of kidneys from LRDs were also analyzed.
Methods The Brazilian Renal Transplantation Registry has collected data from 63 renal transplantation centers in Brazil since January 1987. A list of persons and institutions participating in the Brazilian Transplantation Registry is given in the Appendix. These centers account for more than 95% of the transplantation activity in Brazil. Using standardized forms, we obtained data from each center regarding demographic characteristics, diagnosis of primary disease, immunosuppressive regimen, type of donor, graft function, loss to follow-up, and death. All data were collected prospectively and were reported every Annals of Internal Medicine. 1992;117:983-989. From Escola Paulista de Medicina, Sao Paulo, Brazil; Brazilian Renal Transplantation Registry; and The Johns Hopkins University, Baltimore, Maryland. For current author addresses, see end of text.
Abbreviations LUD living unrelated donor LRD living related donor
© 1992 American College of Physicians
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Figure 1. Patient survival by donor type. Patient survival for recipients of a kidney from a living unrelated donor (LUD), cadaveric donor (CAD), 0-haplotype matched (HLAmismatched) living, related donor (MLRD), 1-haplotype matched living, related donor (HLRD), and 2haplotype matched (identical) living, related donor (ILRD). On the bottom of the graph are the numbers of patients at risk at the beginning of each time interval.
3 months to the study center at Escola Paulista de Medicina in Sao Paulo. All transplants done between 1 January 1987 and 30 March 1991 were considered eligible for analysis. The follow-up period ended on 30 June 1991. Patients were classified into the following five groups according to their donor type: LUD; cadaveric donor; zero-haplotype HLA-matched (mismatched) LRD; one-haplotype-matched (haploidentical) LRD; and two-haplotype-matched (identical) LRD. Transplantation with a LUD kidney was based on altruistic motives and was primarily a result of donation from spouses (65%). In Brazil, serologic HLA typing is not usually done before cadaveric donor and LUD transplantation; therefore, most cadaveric donor and LUD kidney recipients were probably HLA mismatched. Data regarding immunosuppressive therapy represent the initial regimen after transplantation. The most common type of immunosuppressive regimen used was triple therapy with prednisone, azathioprine, and cyclosporine. Antilymphocyte globulin and OKT3 monoclonal antibody were rarely used by the centers during the study period. The main outcome variables studied were patient and graft survival. Patient survival was calculated from the date of transplantation to the corresponding date of death. Death from any cause occurring while a transplant patient's graft was still functional was considered a transplant death. Death occurring within 90 days after graft failure and return to dialysis was also considered a transplant death (22). This classification system assumes that complications related to transplantation and immunosuppressive therapy often occur after graft failure (22). Patients surviving for more than 90 days after return to dialysis were censored at that time. If death did not occur during the study period, patients were censored at their last date of contact. Graft failure was defined as decreased renal function requiring dialysis. All causes of graft loss, both immunologic and nonimmunologic, were considered transplant failures. Persons who died with a functioning graft were censored at the time of death in the survival analysis of graft failure. We used one-way analysis of variance to compare means of continuous variables. Chi-square tests with a Yates correction were used to compare proportions. Patient and graft survival were estimated by the Kaplan-Meier method; statistical significance between survival curves was assessed by the log-rank 984
test. The Cox proportional hazards regression model (BMDP Statistical Software, Los Angeles, California) was used to determine independent associations of several variables with patient and graft survival. The variables tested included age, sex, race (black, white, or other), primary renal disease (diabetes, hypertension, glomerulonephritis, or others), previous transplantation, use of cyclosporine, type of center according to the number of LUD transplants done (none, one, two to five, and more than five), and type of donor (LUD, cadaveric donor, mismatched LRD, haploidentical LRD, or identical LRD). White race, glomerulonephritis, centers that did not do LUD transplants, and cadaveric donors were chosen as the comparison groups for their respective variables. Initially, univariate models were constructed. Later, models including donor type and one or more variables were constructed, and the influence of other variables on the effect of donor type was assessed. All the previously mentioned variables were subsequently included in multivariate models for both patient and graft survival. Adjusted hazard ratios (risk ratios [RR]) and 95% confidence intervals (CIs) for patient death and graft failure were calculated. Likelihood ratio chi-square statistics were used to test for the significance of predictor variables.
Results A total of 2943 transplants was reported to the Registry during the study period. Donor type was unspecified in 51 of the recipients, leaving 2892 cases available for analysis. The mean duration of follow-up was 15.8 months. Demographic profiles and immunosuppressive regimens of patients in each donor category are shown in Table 1. Of the 2892 transplant procedures, 165 (6%) were from LUDs (107 from a spouse donor), 964 (33%) were from cadaveric donors, 183 (6%) were from mismatched LRDs, 1259 (44%) were from haploidentical LRDs, and 321 (11%) were from identical LRDs. Recipients of kidneys from LUDs were older than those receiving cadaveric donor, mismatched LRD,
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haploidentical LRD, and identical LRD kidneys (mean age [±SD], 40.0[±10.7] years compared with 37.4[±12.6], 35.9[±11.1], 31.5[±12.7], and 33.5[±9.6] years, respectively) (P < 0.001 for the comparison of LUD with all the other groups combined). Most recipients in each of the five groups were male and white. Among the recipients of LUD kidneys, the proportion of men was significantly greater than in the other groups. Of the 107 patients who received a donor kidney from a spouse, 83 (78%) were men; 39 (67%) of the 58 nonspousal LUD recipients were men. Only 3% of the recipients were diabetics. Recipients of LUD kidneys were more likely to have an unknown cause of renal disease and were less likely to have chronic glomerulonephritis as a primary cause of their end-stage renal disease than were their counterparts in the other four groups. Cyclosporine use was similar in LUD and mismatched LRD kidney recipients (63% and 61%, respectively) but was more common in LUD (63%) compared with haploidentical LRD or identical LRD kidney recipients (51% and 21%, respectively) and less common in LUD (63%) compared with cadaveric donor kidney recipients (77%). Transplantation of LUD kidneys was done at 30 (48%) of the 63 study centers. Among these 30 centers, the median number of LUD transplants was 3 (range, 1 to 31). Nine centers did one LUD transplant; 11 centers did between two and five LUD transplants; and 10 centers did more than five LUD transplants. Patient Survival Overall, 336 deaths occurred during the study period. Of these, 29 occurred in LUD, 147 in cadaveric donor, 28 in mismatched LRD, 119 in haploidentical LRD, and 13 in identical LRD recipients. Infectious complications
were the main cause of death, occurring in 163 (49%) patients. Patient survival curves, after transplantation and according to donor type, are shown in Figure 1. Patient survival in LUD kidney recipients was similar to that in mismatched LRD and cadaveric donor recipients (78% compared with 79% and 78%, respectively, at 2 years). Patient survival was greater, however, for haploidentical LRD and identical LRD kidney recipients (89% and 96%, respectively, at 2 years) (P < 0.001 compared with LUD group for the overall curves).
Graft Survival Five hundred forty-three graft failures occurred during the study period. The distribution of graft failures among the LUD, cadaveric donor, mismatched LRD, haploidentical LRD and identical LRD groups was 36, 238, 36, 213, and 20, respectively. Acute and chronic rejection were the most commonly reported causes of graft failure (30% and 24%, respectively). For those with a functioning graft, the mean serum creatinine level at their last visit was higher for cadaveric donor than for LUD, mismatched LRD, haploidentical LRD, and identical LRD kidney recipients (193 /imol/L compared with 168, 153, 159 and 127 /imol/L, respectively) (P < 0.001 for the comparison of cadaveric donor with all the other groups combined). Recipients of LUD and mismatched LRD kidneys had better graft survival rates than did cadaveric donor kidney recipients (74% and 76% compared with 68%, at 2 years), but these data were not significant (LUD compared with cadaveric donor, P > 0.2 and MLRD compared with cadaveric donor, P = 0.07 for comparisons of the overall curves) (Figure 2). Recipients of LUD kidneys had a lower graft
Table 1. Characteristics of Kidney Transplant Recipients According to Type of Donor, 1987 to 1991* Characteristic
LUD (n = 165)
CAD (n = 964)
ILRD (n = 321)
Total (n = 2892)
_M/0£,l
55 Male sex Race White Black Other Primary disease Glomerulonephritis Hypertension Interstitial nephritis Diabetes mellitus Other or unknown Previous transplantation Cyclosporine use
HLRD (n = 1259)
MLRD (n = 183)
>
-n{ /o)
t
t
1(1) 99(68) 31 (21) 15 (10) 122 (74)
64(7) 596 (65) 179 (19) 83(9) 615 (64)
8(5) 124 (73) 29 (17) 8(5) 118 (65)
§ 162 (13) 829 (70) 157 (13) 43(4) 804 (64)t
§ 11(4) 263 (85) 29(9) 6(2) 205 (64)t
115 (70) 41 (25) 8(5)
706 (73) 235 (25) 22(2)
118 (65) 54 (29) 11(6)
918 (73) 309 (25) 30(2)
58 (36) 22 (14) 6(4) 4(3) 71 (43) 6(4) 92 (63)
391 (41) 137 (14) 50(5) 44(5) 336 (35) 69(7) 669 (77)§
70 (39) 37 (20) 6(3) 4(2) 64(35) 4(2) 103 (61)
587 (46) 148 (12) 97(8) 33(3) 394 (31) 30(4) 615 (51)
234 (73) 77 (24) 10(3) § 167 (52) 34 (11) 23(7) 8(3) 89 (27) 10(3) 66 (21)
t
246 1911 425 155 1864
(9) (70) (16) (5) (64)
2091 (72) 716 (25) 81(3) 1273 (45) 378 (13) 182 (6) 93(3) 949 (33) 119 (4) 1545 (57)
* CAD = cadaveric donor; HLRD = one-haplotype matched Irving related donor; ILRD = identical living related donor (two-haplotype HLA matched); LUD = living unrelated donor; MLRD = HLA-mismatched living related donor (0-haplotype matched). Missing data were below 1% in all variables except for age and immunosuppressive regimen (4.4% to 11.5%). For age, primary disease, and cyclosporine use, P values represent an overall test of significance. t P < 0.05 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups. X P < 0.01 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups. § P < 0.001 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups.
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Figure 2. Graft survival by donor/ type. Graft survival for recipients of a kidney from a living, unrelated donor (LUD), cadaveric donor (CAD), 0-haplotype matched (HLAmismatched) living, related donor (MLRD), 1-haplotype matched living, related donor (HLRD), and 2haplotype matched (identical) Irving, related donor (ILRD). On the bottom of the graph are the numbers of patients at risk at the beginning of each time interval.
survival than did haploidentical LRD or identical LRD kidney recipients (P = 0.01 and P < 0.01, respectively). Univariate Analyses In univariate Cox proportional hazards analyses, patient survival was associated with several variables. Older age at transplantation was associated with a 5% higher risk for death per year of age. A diagnosis of kidney disease due to diabetes, hypertension, or another cause was also associated with an increased risk for death compared with a diagnosis of glomerulonephritis. A history of previous transplantation was associated with a 71% higher risk for death. Use of cyclosporine was associated with a more than two-fold increase in the risk for patient death. Patient survival varied significantly by type of donor. The risk for death for haploidentical LRD and identical LRD recipients was 48% and 19% of that for cadaveric donor recipients, respectively, whereas it was similar for LUD and mismatched LRD recipients. The risk for death was similar in centers that did LUD transplants compared with those that did not, except for centers doing five or more LUD transplants, where it was statistically lower. The variables associated with a statistically greater risk for graft failure were previous transplantation, cyclosporine use, and donor source (cadaveric donor compared with haploidentical LRD and identical LRD). RisK for graft failure was progressively lower in cadaveric donor, LUD, mismatched LRD, haploidentical LRD and identical LRD recipients. Risk for graft failure did not differ statistically, however, between LUD or mismatched LRD and cadaveric donor kidney recipients. 986
Multivariate Analyses Multivariate survival analysis confirmed the presence of a statistically significant and independent relation between older age, primary disease, previous transplantation, cyclosporine use, type of center according to performance of LUD transplants, and donor type with increasing risk for mortality (Table 2). The adjusted hazard ratio of mortality for LUD and mismatched LRD recipients did not differ statistically from that for cadaveric recipients. The risk for death was greater in LUD and mismatched LRD kidney recipients than in haploidentical LRD and identical LRD recipients, but these differences were not statistically significant. Multivariate analysis identified a history of previous transplantation, race (black compared with white), and type of donor (identical LRD or haploidentical LRD compared with cadaveric donors) as statistically significant and independent predictors of graft failure (see Table 2). Although a tendency toward a reduced frequency of graft failure was noted for LUD compared with cadaveric donor kidney recipients, this estimate did not achieve a conventional level of statistical significance (RR, 0.74; CI, 0.45 to 1.22). The risk for graft failure was similar in LUD and mismatched LRD kidney recipients. For both these groups, graft failure was more common than in the haploidentical LRD and identical LRD groups, but these differences were statistically significant only for the comparison with identical LRD. Risk estimates for graft failure associated with LUD kidney transplantation were consistent in all the models tested. For both patient death and graft failure models, no evidence of an interaction was seen between donor type and either cyclosporine use or race.
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Discussion To our knowledge, this is the largest prospective study of LUD kidney recipients and the only one in which their survival experience was compared with that of other groups with simultaneous adjustment for important covariates. We observed that recipients of LUD, mismatched LRD, and cadaveric donor kidneys had similar patient and graft survival rates for up to 3 years after renal transplantation. In fact, LUD and mismatched LRD recipients had slightly better graft survival rates than did cadaveric donor kidney recipients, but this finding was not significant. These similarities persisted after adjustment for age, sex, race, primary disease, previous transplantation, cyclosporine use, and LUD transplantation activity by centers. Patient and graft survival rates for LUD, mismatched LRD, and cadaveric donor, however, tended to be inferior to those for haploidentical LRD and identical LRD transplant recipients. The power to detect whether graft survival was significantly better in LUD than in cadaveric donor kidney recipients was limited, because many patients were enrolled during the last 2 years of the study and thus had fewer than 2 years of follow-up. Previous reports have suggested that patient and graft survival rates using LUD kidneys were either as good as (16, 18) or better (15, 17, 19, 23) than those achieved using cadaveric donor kidneys. It has also been reported that the graft survival of mismatched LRD recipients is superior to that of cadaveric donor and similar to that of haploidentical LRD recipients (24). Thus, factors other than HLA matching, perhaps related to the minimization of the duration of ischemia, appear to be important for graft outcome. It has been difficult, however, to reach a valid conclusion from these studies
due to limitations such as small sample size, lack of a concurrent comparison group, differing types of immunosuppressive regimens, or lack of adjustment for HLA mismatches and other baseline characteristics. Our report is the first to account for all of these factors. Unfortunately, we could not do a better adjustment for the effect of HLA matching in LUD and cadaveric donor transplant recipients, because these data were not available. It is unlikely, however, that this lack of information biased our conclusions, because HLA typing is not routinely done for these types of transplants in Brazil, and it is highly probable that recipients of these kidneys were mismatched. In our study, recipients of cadaveric donor kidneys had a lower patient survival than that reported by other large registries (8, 25). This finding may be due to a longer waiting period before transplantation for patients in our registry, resulting in a less favorable baseline status (26). Interestingly, cyclosporine use was identified as an independent predictor of patient death, even after adjustment for other variables, including type of donor. This unusual finding may reflect more common use of cyclosporine in patients with higher degrees of HLA mismatching and the possibility that higher-risk patients, such as those hypersensitized to a panel of HLA antigens, may have been selected more often to receive cyclosporine. This preferential selection of higher-risk patients to receive cyclosporine would tend to lead to the observed association of this drug with adverse patient outcomes. In addition, the use of cyclosporine with prednisone and azathioprine may have produced excessive immunosuppression in some patients. After adjustment for several potentially important variables, the risk for graft failure did not differ statis-
Table 2. Multivariate Proportional Hazards Regression Models for Patient Death and Graft Failure in 2892 Renal Transplant Recipients Variable Age,y Male sex Race Black compared with white Other compared with white Primary disease Diabetes mellitus compared with glomerulonephritis Hypertension compared with glomerulonephritis Other compared with glomerulonephritis Previous transplantation Cyclosporine use Type of donor ILRD compared with CAD HLRD compared with CAD MLRD compared with CAD LUD compared with CAD LUD transplants per center, n 1 compared with 0 2 to 5 compared with 0 > 5 compared with 0
Patient Death Hazard Ratio (95% CI)
Graft Failure Hazard Ratio (95% CI)
1.04 (1.03 to 1.05)* 0.85 (0.65 to 1.10)
1.00 (0.99 to 1.01) 0.90 (0.73 to 1.11)
1.22 (0.91 to 1.64) 0.86 (0.38 to 1.96) * 1.81 (0.98 to 3.35) 1.23 (0.84 to 1.82) 1.38 (1.03 to 1.84) 1.79 (1.01 to 3.16) 1.92 (1.43 to 2.56) * 0.44 (0.24 to 0.83) 0.77 (0.57 to 1.04) 1.13 (0.69 to 1.87) 1.16 (0.68 to 1.98)
1.35 (1.07 to 1.70) 1.15 (0.63 to 2.10)
t
1.19 (0.67 to 2.11) 0.97 (0.69 to 1.35) 1.13 (0.90 to 1.41) 1.89 (1.24 to 2.89)$ 1.07 (0.86 to 1.34) 0.24 (0.14 to 0.40) 0.63 (0.49 to 0.80) 0.82 (0.53 to 1.25) 0.74 (0.45 to 1.22)
t 1.14 (0.76 to 1.73) 0.94 (0.67 to 1.31) 0.66 (0.47 to 0.94)
1.15 (0.81 to 1.63) 1.06 (0.81 to 1.39) 0.87 (0.67 to 1.14)
* All variables in the table were included in each model. For each pair, the one listed second is the comparison variable. CAD = cadaveric donor; HLRD = one-haplotype matched living related donor; ILRD = identical living related donor (two-haplotype HLA matched); LUD = living unrelated donor; MLRD = HLA mismatched living related donor (0-haplotype matched). For dichotomous variables, P values represent a Wald test. For race, primary disease, type of donor, and number of LUD transplants per center, P values represent an overall test of significance. t P < 0.05. $P < 0.001.
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tically among LUD, mismatched LRD, and cadaveric donor kidney recipients. Despite the relatively large sample sizes of these patient subgroups, we cannot exclude the possibility of improved graft survival associated with LUD or mismatched LRD compared with cadaveric donor kidney transplantation. Higher graft survival rates might have been attained if antilymphocyte globulin and OKT3 monoclonal antibody therapy had been used more frequently by Brazilian transplantation centers. Several authors have proposed that LUD renal transplantation is justifiable and should be actively considered to reduce the waiting list for kidney transplantation and the burden on dialysis facilities (10, 11, 14-16, 1820). Our results suggest that patient and graft survival rates for LUD are at least as good as those for cadaveric donor kidney transplantation. We were unable, however, to document a significantly superior outcome among those with LUD kidney transplantation despite a shorter cold ischemic time, the avoidance of donor hypotension, and the advantages of planned transplantation. For some patients, LUD may be their only chance to receive a kidney transplant. For others, it reduces the waiting time for transplantation. We agree with the guidelines of the Council of the Transplantation Society (27), which state that the motives for donation should be altruistic and not selfserving or for profit. Payment for the donor or "rewarded gifting" (a compensation for the inconvenience and for the loss of earnings) is unacceptable. We also believe that such monetary transactions corrupt and demean the relationship between the donor and the recipient and impair the public's will to donate organs (28, 29). The practice of LUD transplantation should not, however, impair the development of cadaver-donor transplantation programs. It is a matter of concern that kidneys from only a small percentage of potential cadaveric donors are being harvested for transplantation (9, 10, 14, 30, 31). Of the 165 recipients of LUD kidneys in this study, 107 received their kidney from a spouse. Information regarding the remaining 58 LUDs was not available from our Registry. Previous reports from Brazilian transplant centers suggest that most of these donors were friends who had altruistic motives (32, 33). Finally, it was noteworthy that most LUD recipients were male, particularly among spousal transplants. The reasons for this unequal distribution were not apparent. This issue should be evaluated in future reports. Longer follow-up of the present sample as well as further studies containing additional baseline information and investigating alternate immunosuppressive regimens and donor-specific transfusions will serve to better characterize patient and graft survival after LUD kidney transplantation.
Preto; Maria G. Lima, MD; Luiz Villas Boas, MD: UTR-HSEPITO; Sergio M. Carvalho, MD; Hermogenes P. Filho, MD: HGB/PITO; Frederico Ruzany, MD; Sergio Aguinaga, MD: Hospital Pedro Ernesto; Abrahao S. Filho, MD; Apparicio S. Assis, MD: Hospital das Clinicas-Belo Horizonte; Emil Sabbaga, MD; Sami Arap, MD: Hospital das Clinicas-Sao Paulo; Valter D. Garcia, MD; Guido Cantisani, MD: Santa Casa-Porto Alegre; Lauro Brandina, MD; Altair J. Mocelin, MD: Hospital Evangelico-Londrina; Joao Loewen, MD; Sandro Ziesemer, MD: Hospital Evangelico-Curitiba; Eduardo M. Martinelli, MD; Walter S. Bestane, MD: Hospital Ana Costa; Estevan Viotti, MD; Eduardo R. Tavora, MD: Hospital Felicio Rocho; Jose N. Torres, MD; Carlos A. Gomes, MD: Hospital Evangelico-Vila Velha; Sebastiao Ferreira, MD; Luis C. Araujo, MD: Santa Casa-Juiz de Fora; Manuel P. Almeida, MD; Haward Kano, MD: Hospital Antonio Pedro; Tereza E. Faifer, MD; Antonio P. Galesso, MD: Associacao Hospitalar-Bauru; Joao C. Biernat, MD; Guido Cantisani, MD: Hospital das Clinicas-Dr. Lazzaroto; Luiz M. Santos, MD; Yashicazo Tamura, MD: Hospital Sao Lucas-PR; Lerminio Pimenta, MD: Santa Casa-Belo Horizonte; Eduardo R. Silveira, MD; Gilberto L. Vieira, MD: Hospital Vera Cruz; Lauro M. Vasconcelos, MD; Fabio Pereira, MD: Hospital Sao Jose; Roberto B. Marques, MD; Joao M. Torres, MD: Hospital das ClinicasWalter Cantidio; Fernando S. Tome, MD: Hospital Petropolis; Joao B. Barberato, MD; Eliseu R. Denadai, MD: Hospital Beneficencia Portuguesa-IUNRP; Kleber A. Nogueira, MD; David Abelha, MD: Associacao Evangelica Beneficencia-MG; Domingos D'Avila, MD; Henrique S. Barata, MD: Hospital Sao Lucas/PUC-PA; Roberto C. Manfro, MD; Gilberto Souza, MD: Hospital Maia Filho-PA; Vitor A. Soares, MD; Luiz A. Correa, MD; Hospital das Clinicas-UNESP; Gentil A. Filho, MD; Nelson Rodrigues Neto, MD: UNICAMP-Campinas; Carlos Stabile, MD; Fausto Miranda, MD: Hospital Santa Rita-SP; Elias David, MD; Nelson Montelato, MD: Hospital Umberto I; Sergio G. Marks, MD; Joao A. Rocha, MD: Santa Casa-Curitiba; Jorge L. Ramos, MD; Antonio M. Freire, MD: Policlinica-Pato Branco; Francisco Oliveira, MD; Jose R. Vaz, MD: Santa Casa-Maceio; Nelson Q. Froes, MD; Waldemar C. Abe, MD: Santa Casa-Campo Grande; Alipio D. Coelho, MD; Jorge A. Isaacsonn, MD: Santa Casa-Pelotas; Edson N. Rodrigues, MD; Elias Kallas, MD: Hospital das Clinicas-Samuel Libanio; Paulo C. Oliveira, MD; Neilton Prado, MD: Hospital das Clinicas-Uberlandia; Jose C. Guilhen, MD; Ludvig Hafner, MD: Santa Casa-Marilia; Maria T. Vannucchi, MD; Joao P. Pessoa, MD: Hospital Sao Francisco; Jaelson G. Gomes, MD: Hospital Evangelico-Sorocaba; Helcio A. Tavares, MD; Mario O. Urandecic, MD: BIOCOR-Belo Horizonte; Augusto Laffitte, MD: Hospital de Clinicas-Curitiba; Alaour C. Duarte, MD; Rui C. Donaduti, MD: Hospital Sao Vicente de Paula-RS; Carlos A. Prompt, MD; Walter J. Koff, MD: Hospital de Clinicas-Porto Alegre; Joao S. Yokoyama, MD; Jansen R. Ferreira, MD: Hospital-Maternidade S. Paulo-PR; Luiz A. Fochesato, MD; Norberto Tonietto, MD: Hospital NS Fatima-RS; Francisco W. Carvalho, MD; Marcio A. Correa, MD: Hospital NavalMarcilio Dias; Jorge B. Westphalen, MD; Paulo R. Moreira, MD: Hospital Sta Lucia-RS; Roland Saldanha, MD; Marcos H. Sayao, MD: Beneficencia Portuguesa-SP; Hi K. Ann, MD; Milton T. Tanaka, MD: Hospital NS Salete-PR; Rejane P. Meneses, MD; Antonio Silveira, MD: Hospital Pequeno Principe-PR; Adaelson A. Silva, MD: Hospital Santa Rita-Maringa; Luiz Emed, MD: Hospital Cajuru-PR; William Stanford, MD: Hospital Portugues de Beneficencia-PE; Mario F. Chaves, MD: Hospital Samaritano-PB; Antonio C. Castro, MD: PUCCampinas; Fernando A. Almeida, MD: PUC-Sorocaba; Natalino C. Peixoto, MD; Julio C. Ximenes, MD: Hospital Santa Helena-GO; Pedro Jabur, MD: Santa Casa-Sao Paulo; Rogerio Caffarro, MD: Hospital Brigadeiro-SP; Jose A. Vieira, MD; Osmar S. Hausen, MD: Hospital Hans D. Schmidt; Anuar M. Macni, MD; Antonio M. Fraga, MD: Hospital Regional-PR.
Appendix. Physicians and Institutions Participating in the Brazilian Transplantation Registry
Acknowledgments: The authors thank Mrs. Marlene Sakumoto for technical assistance and Ms. Barbara Pawlovsky for secretarial support.
Jose O. Medina, MD; Alvaro Pacheco-Silva, MD; Claudio J. Almeida, MD: Escola Paulista de Medicina; Agenor S. Ferraz, MD; Antonio C. Martins, MD: Hospital das Clinicas-Ribeirao
Grant Support: By a grant from the Rockefeller Foundation (International Clinical Epidemiology Network), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil), and from the Instituto Paulista de Estudos e Pesquisas em Nefrologia e Hipertensao,
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Brazil. Dr. Sesso is a recipient of a postdoctoral fellowship grant from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil). Dr. Klag is an established investigator of the American Heart Association. Requests for Reprints: Ricardo Sesso, MD, Escola Paulista de Medicma, Division of Nephrology, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. Current Author Addresses: Drs. Sesso and Ramos: Division of Nephrology, Escola Paulista de Medicina, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. Drs. Klag, Whelton, and Seidler: The Johns Hopkins Health Institutions, 600 North Wolfe St., Carnegie 292, Baltimore, Maryland, 21287. Drs. Ancao and Sigulem: Health Informatics Center, Escola Paulista de Medicina, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. References 1. Brunner FP, Selwood NH. Results of renal replacement therapy in Europe, 1980 to 1987. Registration Committee of the EDTA-ERA. Am J Kidney Dis. 1990; 15:384-%. 2. Eggers PW. Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med. 1988;318:223-9. 3. Sesso R, Eisenberg JM, Stabile C, Draibe S, Ajzen H, Ramos O. Cost-effectiveness analysis of the treatment of end-stage renal disease in Brazil. Int J Technol Assess Health Care. 1990;6:107-14. 4. Bart KJ, Macon EJ, Whittier FC, Baldwin RJ, Blount JH. Cadaveric kidneys for transplantation. A paradox of shortage in the face of plenty. Transplantation. 1981;31:379-82. 5. Held PJ, Pauly MV, Bovbjerg RR, Newmann J, Salvatierra O Jr. Access to kidney transplantation. Has the United States eliminated income and racial differences? Arch Intern Med. 1988; 148:2594-600. 6. Smith T. Shortage of donors continues [Editorial]. Br Med J. 1989; 298:776. 7. Cohen B, Persijn G. Eurotransplant Newsletter. 1989; no. 61 (February). 8. U.S. Renal Data System. USRDS 1990 Annual Data Report, Betheseda, Maryland: National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases; 1990. 9. Evans RW, Orians CE, Ascher NL. The potential supply of organ donors. An assessment of the efficacy of organ procurement efforts in the United States. JAMA. 1992;267:239-46. 10. Levey AS, Hou S, Bush HL Jr. Kidney transplantation from unrelated living donors. Time to reclaim a discarded opportunity. N Engl J Med. 1986;314:914-6. 11. Starzl TE. Living donors: con. Transplant Proc. 1987;19:174-5. 12. Blake PG, Cardella CJ. Kidney donation by living unrelated donors [Editorial]. Can Med Assoc J. 1989;141:773-5. 13. Salahudeen AK, Woods HF, Pingle A, Nur-El-Hude, Suleyman M, Shakuntala K, Nandakumar M, et al. High mortality among recipients of bought Irving-unrelated donor kidneys. Lancet. 1990;336: 725-8. 14. Flatmark A, Brynger H, Groth CG. Kidney transplants from living donors: the neglected opportunity. Transplant Int. 1990;3:50-1. 15. Sollinger HW, Kalayoglu M, Belzer FO. Use of the donor-specific transfusion protocol in Irving-unrelated donor-recipient combinations. Ann Surg. 1986;204:315-21.
16. Albrechtsen D, Sodal G, Jakobsen A, Brekke I, Bentdal O, Berg KJ, et al. Kidney transplantation from a spouse: an alternative to years of dialysis waiting for a graft that may never turn up? Transplant Proc. 1990;22:1435. 17. Elick BA, Sutherland DE, GUlingham K, Najarian JS. Use of distant relatives and living unrelated donors: a strategy to increase the application of kidney transplantation to treat chronic renal failure. Transplant Proc. 1990;22:343-4. 18. Squifflet JP, Pirson Y, Poncelet A, Gianello P, Alexandre GP. Unrelated living donor kidney transplantation. Transplant Int. 1990;3: 32-5. 19. Haberal M, Bulut O, Sert S, Gulay H, Hamaloglu E, Altunkan S. Transplantation between husband and wife. Transplant Proc. 1990; 22:342. 20. Berloco P, Alfani D, Bruzzone P, Renna Molajoni E, Rossi M, Pretagostini R, et al. Is unrelated living donor a valid organ source in renal transplantation under CYA therapy? Transplant Proc. 1991; 23:912-3. 21. Sesso R, Ancao MS, Draibe SA, Sigulem D, Ramos OL. Survival analysis of 1563 renal transplants in Brazil: report of the Brazilian Registry of Renal Transplantation. Nephrol Dial Transplant. 1990; 5:956-61. 22. Pollak VE, Fox WR. Definitions and standards for treatment outcomes in patients with end-stage renal disease: Report of a Committee of the National Forum of ESRD Networks. Am J Kidney Dis. 1984;3:391-6. 23. Abouna GM, Panjwani D, Kumar MS, White AG, Al-Abdulla IH, Silva OS, et al. The living unrelated donor—a viable alternative for renal transplantation. Transplant Proc. 1988;20:802-4. 24. Kaufman DB, Sutherland DE, Fryd DS, Noreen H, Najarian JS. Zero-HLA haplotype matched siblings as living related renal donors. Transplant Proc. 1989;21:671-4. 25. Geeriings W, TufVeson G, Brunner FP, Enrich JH, Fassbinder W, Landais P, et al. Combined report on regular dialysis and transplantation in Europe, XIX, 1988. Nephrol Dial Transplant. 1989;4 (Suppl 4):5-29. 26. Sesso R. Sobrevida em dialise. J Bras Nefrol. 1990;12:1-2. 27. Commercialization in transplantation. The problems and some guidelines for practice. The Council of the Transplantation Society [Editorial]. Transplantation. 1986;41:1-3. 28. Morris PJ, Sells RA. Paying for organs from living donors [Letter]. Lancet. 1985;1:1510. 29. Dossetor JB, Manickavel V. Ethics in organ donation: contrasts in two cultures. Transplant Proc. 1991;23:2508-11. 30. Chisholm GD. Time to end softly softly approach on harvesting organs for transplantation [Editorial]. Br Med J. 1988;296:1419-20. 31. Caplan AL, Welvang P. Are required request laws working? Altruism and the procurement of organs and tissues. Clin Transplant. 1989;3:170-6. 32. Sabbaga E, Ianhez LE, Chocair PR, Azevedo LS, Sarturi PS, de Goes GM. Kidney transplants from living nonrelated donors: an analysis of 87 cases, including 20 cases with specific blood transfusions from the donor. Transplant Proc. 1985;17:1741-5. 33. Hoette M, Ruzany F, Tavora E, Mocelin A, Sabbaga E, Monies R, et al. Living-nonrelated kidney donors for transplantation [Abstract]. Kidney Int. 1986;29:430.
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of Internal
Medicine
• V o l u m e 117 • Number 12
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• Objective: To compare patient and graft survival of recipients of kidneys from living, unrelated donors (LUDs); cadaveric donors; and living, related donors (LRDs) matched for zero (mismatched), one, or two (identical) haplotypes. • Design: Cohort study. • Setting: Sixty-three renal transplantation centers affiliated with the Brazilian Transplantation Registry (accounting for more than 95% of the transplantation activity in Brazil). • Patients: Patients having renal transplantation between January 1987 and March 1991. Of 2892 patients, 165 (6%) received transplants from LUDs; 964 (33%), from cadaveric donors; 183 (6%), from zero haplotype, HLA-matched LRDs; 1259 (44%), from one haplotypematched LRDs; and 321 (11%), from two haplotypematched LRDs. • Measurements: Patient and graft survival. Patients were followed for an average of 15.8 months. • Results: After adjustment for age, race, diagnosis of primary disease, history of previous transplantation, cyclosporine use, and number of transplants from LUDs per center, patient survival did not differ statistically for recipients of kidneys from LUDs and recipients of cadaveric kidneys (risk ratio [RR], 1.16; 95% CI, 0.68 to 1.98). Little difference was seen between the adjusted death rate for recipients of zero haplotypematched LRDs and recipients of cadaveric kidneys (RR, 1.13; CI, 0.69 to 1.87). Similarly, in a multivariate analysis, recipients of kidneys taken from LUDs and zero haplotype-matched LRDs had a risk for graft failure that did not differ statistically from that of cadaveric kidney recipients (RR, 0.74; CI, 0.45 to 1.22 and RR, 0.82; CI, 0.53 to 1.25, respectively). • Conclusions: Graft survival for recipients of kidneys from LUDs is similar to that from zero haplotypematched LRDs and is at least as good as that achieved with cadaveric transplants.
1 ransplantation is the optimal and most cost-effective treatment for end-stage renal disease in both developed and developing countries (1-3). A shortage of kidney donors worldwide, however, has resulted in a progressively increasing gap between the supply of and demand for cadaveric grafts (4-6). As a result, waiting lists for cadaveric transplants in most countries have grown consistently (7-9). Efforts to increase the number of organs available for transplantation in Europe and in the United States have achieved only limited success. To overcome the shortage of cadaveric kidneys, some providers have resorted to transplantation of kidneys from living, unrelated donors (LUDs). This practice is controversial (10-14), reflecting both concern regarding the donor's safety and the associated ethical dilemma. Some authors have reported that patients receiving kidneys from LUDs experience better patient and graft survival compared with those receiving kidneys from cadaveric donors (15-20). These results, however, have been based on relatively small numbers of patients and the use of nonconcurrent cadaveric donor comparison groups and have lacked adjustment for other variables that could affect outcome. A previous univariate analysis of the Brazilian Transplantation Registry suggested that patient and graft success rates were similar among LUD, mismatched (zero haplotype HLA-matched) living related donor (LRDs), and cadaveric donor kidney recipients (21). The main purpose of this report is to contrast patient and graft survival between recipients of kidneys from LUDs and cadaveric donors, in a larger number of patients with longer follow-up and with adjustment for potential confounding variables. For comparative purposes, survival experience of zero-, one-, or two-haplotype-matched recipients of kidneys from LRDs were also analyzed.
Methods The Brazilian Renal Transplantation Registry has collected data from 63 renal transplantation centers in Brazil since January 1987. A list of persons and institutions participating in the Brazilian Transplantation Registry is given in the Appendix. These centers account for more than 95% of the transplantation activity in Brazil. Using standardized forms, we obtained data from each center regarding demographic characteristics, diagnosis of primary disease, immunosuppressive regimen, type of donor, graft function, loss to follow-up, and death. All data were collected prospectively and were reported every Annals of Internal Medicine. 1992;117:983-989. From Escola Paulista de Medicina, Sao Paulo, Brazil; Brazilian Renal Transplantation Registry; and The Johns Hopkins University, Baltimore, Maryland. For current author addresses, see end of text.
Abbreviations LUD living unrelated donor LRD living related donor
© 1992 American College of Physicians
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Figure 1. Patient survival by donor type. Patient survival for recipients of a kidney from a living unrelated donor (LUD), cadaveric donor (CAD), 0-haplotype matched (HLAmismatched) living, related donor (MLRD), 1-haplotype matched living, related donor (HLRD), and 2haplotype matched (identical) living, related donor (ILRD). On the bottom of the graph are the numbers of patients at risk at the beginning of each time interval.
3 months to the study center at Escola Paulista de Medicina in Sao Paulo. All transplants done between 1 January 1987 and 30 March 1991 were considered eligible for analysis. The follow-up period ended on 30 June 1991. Patients were classified into the following five groups according to their donor type: LUD; cadaveric donor; zero-haplotype HLA-matched (mismatched) LRD; one-haplotype-matched (haploidentical) LRD; and two-haplotype-matched (identical) LRD. Transplantation with a LUD kidney was based on altruistic motives and was primarily a result of donation from spouses (65%). In Brazil, serologic HLA typing is not usually done before cadaveric donor and LUD transplantation; therefore, most cadaveric donor and LUD kidney recipients were probably HLA mismatched. Data regarding immunosuppressive therapy represent the initial regimen after transplantation. The most common type of immunosuppressive regimen used was triple therapy with prednisone, azathioprine, and cyclosporine. Antilymphocyte globulin and OKT3 monoclonal antibody were rarely used by the centers during the study period. The main outcome variables studied were patient and graft survival. Patient survival was calculated from the date of transplantation to the corresponding date of death. Death from any cause occurring while a transplant patient's graft was still functional was considered a transplant death. Death occurring within 90 days after graft failure and return to dialysis was also considered a transplant death (22). This classification system assumes that complications related to transplantation and immunosuppressive therapy often occur after graft failure (22). Patients surviving for more than 90 days after return to dialysis were censored at that time. If death did not occur during the study period, patients were censored at their last date of contact. Graft failure was defined as decreased renal function requiring dialysis. All causes of graft loss, both immunologic and nonimmunologic, were considered transplant failures. Persons who died with a functioning graft were censored at the time of death in the survival analysis of graft failure. We used one-way analysis of variance to compare means of continuous variables. Chi-square tests with a Yates correction were used to compare proportions. Patient and graft survival were estimated by the Kaplan-Meier method; statistical significance between survival curves was assessed by the log-rank 984
test. The Cox proportional hazards regression model (BMDP Statistical Software, Los Angeles, California) was used to determine independent associations of several variables with patient and graft survival. The variables tested included age, sex, race (black, white, or other), primary renal disease (diabetes, hypertension, glomerulonephritis, or others), previous transplantation, use of cyclosporine, type of center according to the number of LUD transplants done (none, one, two to five, and more than five), and type of donor (LUD, cadaveric donor, mismatched LRD, haploidentical LRD, or identical LRD). White race, glomerulonephritis, centers that did not do LUD transplants, and cadaveric donors were chosen as the comparison groups for their respective variables. Initially, univariate models were constructed. Later, models including donor type and one or more variables were constructed, and the influence of other variables on the effect of donor type was assessed. All the previously mentioned variables were subsequently included in multivariate models for both patient and graft survival. Adjusted hazard ratios (risk ratios [RR]) and 95% confidence intervals (CIs) for patient death and graft failure were calculated. Likelihood ratio chi-square statistics were used to test for the significance of predictor variables.
Results A total of 2943 transplants was reported to the Registry during the study period. Donor type was unspecified in 51 of the recipients, leaving 2892 cases available for analysis. The mean duration of follow-up was 15.8 months. Demographic profiles and immunosuppressive regimens of patients in each donor category are shown in Table 1. Of the 2892 transplant procedures, 165 (6%) were from LUDs (107 from a spouse donor), 964 (33%) were from cadaveric donors, 183 (6%) were from mismatched LRDs, 1259 (44%) were from haploidentical LRDs, and 321 (11%) were from identical LRDs. Recipients of kidneys from LUDs were older than those receiving cadaveric donor, mismatched LRD,
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haploidentical LRD, and identical LRD kidneys (mean age [±SD], 40.0[±10.7] years compared with 37.4[±12.6], 35.9[±11.1], 31.5[±12.7], and 33.5[±9.6] years, respectively) (P < 0.001 for the comparison of LUD with all the other groups combined). Most recipients in each of the five groups were male and white. Among the recipients of LUD kidneys, the proportion of men was significantly greater than in the other groups. Of the 107 patients who received a donor kidney from a spouse, 83 (78%) were men; 39 (67%) of the 58 nonspousal LUD recipients were men. Only 3% of the recipients were diabetics. Recipients of LUD kidneys were more likely to have an unknown cause of renal disease and were less likely to have chronic glomerulonephritis as a primary cause of their end-stage renal disease than were their counterparts in the other four groups. Cyclosporine use was similar in LUD and mismatched LRD kidney recipients (63% and 61%, respectively) but was more common in LUD (63%) compared with haploidentical LRD or identical LRD kidney recipients (51% and 21%, respectively) and less common in LUD (63%) compared with cadaveric donor kidney recipients (77%). Transplantation of LUD kidneys was done at 30 (48%) of the 63 study centers. Among these 30 centers, the median number of LUD transplants was 3 (range, 1 to 31). Nine centers did one LUD transplant; 11 centers did between two and five LUD transplants; and 10 centers did more than five LUD transplants. Patient Survival Overall, 336 deaths occurred during the study period. Of these, 29 occurred in LUD, 147 in cadaveric donor, 28 in mismatched LRD, 119 in haploidentical LRD, and 13 in identical LRD recipients. Infectious complications
were the main cause of death, occurring in 163 (49%) patients. Patient survival curves, after transplantation and according to donor type, are shown in Figure 1. Patient survival in LUD kidney recipients was similar to that in mismatched LRD and cadaveric donor recipients (78% compared with 79% and 78%, respectively, at 2 years). Patient survival was greater, however, for haploidentical LRD and identical LRD kidney recipients (89% and 96%, respectively, at 2 years) (P < 0.001 compared with LUD group for the overall curves).
Graft Survival Five hundred forty-three graft failures occurred during the study period. The distribution of graft failures among the LUD, cadaveric donor, mismatched LRD, haploidentical LRD and identical LRD groups was 36, 238, 36, 213, and 20, respectively. Acute and chronic rejection were the most commonly reported causes of graft failure (30% and 24%, respectively). For those with a functioning graft, the mean serum creatinine level at their last visit was higher for cadaveric donor than for LUD, mismatched LRD, haploidentical LRD, and identical LRD kidney recipients (193 /imol/L compared with 168, 153, 159 and 127 /imol/L, respectively) (P < 0.001 for the comparison of cadaveric donor with all the other groups combined). Recipients of LUD and mismatched LRD kidneys had better graft survival rates than did cadaveric donor kidney recipients (74% and 76% compared with 68%, at 2 years), but these data were not significant (LUD compared with cadaveric donor, P > 0.2 and MLRD compared with cadaveric donor, P = 0.07 for comparisons of the overall curves) (Figure 2). Recipients of LUD kidneys had a lower graft
Table 1. Characteristics of Kidney Transplant Recipients According to Type of Donor, 1987 to 1991* Characteristic
LUD (n = 165)
CAD (n = 964)
ILRD (n = 321)
Total (n = 2892)
_M/0£,l
55 Male sex Race White Black Other Primary disease Glomerulonephritis Hypertension Interstitial nephritis Diabetes mellitus Other or unknown Previous transplantation Cyclosporine use
HLRD (n = 1259)
MLRD (n = 183)
>
-n{ /o)
t
t
1(1) 99(68) 31 (21) 15 (10) 122 (74)
64(7) 596 (65) 179 (19) 83(9) 615 (64)
8(5) 124 (73) 29 (17) 8(5) 118 (65)
§ 162 (13) 829 (70) 157 (13) 43(4) 804 (64)t
§ 11(4) 263 (85) 29(9) 6(2) 205 (64)t
115 (70) 41 (25) 8(5)
706 (73) 235 (25) 22(2)
118 (65) 54 (29) 11(6)
918 (73) 309 (25) 30(2)
58 (36) 22 (14) 6(4) 4(3) 71 (43) 6(4) 92 (63)
391 (41) 137 (14) 50(5) 44(5) 336 (35) 69(7) 669 (77)§
70 (39) 37 (20) 6(3) 4(2) 64(35) 4(2) 103 (61)
587 (46) 148 (12) 97(8) 33(3) 394 (31) 30(4) 615 (51)
234 (73) 77 (24) 10(3) § 167 (52) 34 (11) 23(7) 8(3) 89 (27) 10(3) 66 (21)
t
246 1911 425 155 1864
(9) (70) (16) (5) (64)
2091 (72) 716 (25) 81(3) 1273 (45) 378 (13) 182 (6) 93(3) 949 (33) 119 (4) 1545 (57)
* CAD = cadaveric donor; HLRD = one-haplotype matched Irving related donor; ILRD = identical living related donor (two-haplotype HLA matched); LUD = living unrelated donor; MLRD = HLA-mismatched living related donor (0-haplotype matched). Missing data were below 1% in all variables except for age and immunosuppressive regimen (4.4% to 11.5%). For age, primary disease, and cyclosporine use, P values represent an overall test of significance. t P < 0.05 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups. X P < 0.01 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups. § P < 0.001 for comparisons of LUD with CAD, MLRD, HLRD, and ILRD groups.
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Figure 2. Graft survival by donor/ type. Graft survival for recipients of a kidney from a living, unrelated donor (LUD), cadaveric donor (CAD), 0-haplotype matched (HLAmismatched) living, related donor (MLRD), 1-haplotype matched living, related donor (HLRD), and 2haplotype matched (identical) Irving, related donor (ILRD). On the bottom of the graph are the numbers of patients at risk at the beginning of each time interval.
survival than did haploidentical LRD or identical LRD kidney recipients (P = 0.01 and P < 0.01, respectively). Univariate Analyses In univariate Cox proportional hazards analyses, patient survival was associated with several variables. Older age at transplantation was associated with a 5% higher risk for death per year of age. A diagnosis of kidney disease due to diabetes, hypertension, or another cause was also associated with an increased risk for death compared with a diagnosis of glomerulonephritis. A history of previous transplantation was associated with a 71% higher risk for death. Use of cyclosporine was associated with a more than two-fold increase in the risk for patient death. Patient survival varied significantly by type of donor. The risk for death for haploidentical LRD and identical LRD recipients was 48% and 19% of that for cadaveric donor recipients, respectively, whereas it was similar for LUD and mismatched LRD recipients. The risk for death was similar in centers that did LUD transplants compared with those that did not, except for centers doing five or more LUD transplants, where it was statistically lower. The variables associated with a statistically greater risk for graft failure were previous transplantation, cyclosporine use, and donor source (cadaveric donor compared with haploidentical LRD and identical LRD). RisK for graft failure was progressively lower in cadaveric donor, LUD, mismatched LRD, haploidentical LRD and identical LRD recipients. Risk for graft failure did not differ statistically, however, between LUD or mismatched LRD and cadaveric donor kidney recipients. 986
Multivariate Analyses Multivariate survival analysis confirmed the presence of a statistically significant and independent relation between older age, primary disease, previous transplantation, cyclosporine use, type of center according to performance of LUD transplants, and donor type with increasing risk for mortality (Table 2). The adjusted hazard ratio of mortality for LUD and mismatched LRD recipients did not differ statistically from that for cadaveric recipients. The risk for death was greater in LUD and mismatched LRD kidney recipients than in haploidentical LRD and identical LRD recipients, but these differences were not statistically significant. Multivariate analysis identified a history of previous transplantation, race (black compared with white), and type of donor (identical LRD or haploidentical LRD compared with cadaveric donors) as statistically significant and independent predictors of graft failure (see Table 2). Although a tendency toward a reduced frequency of graft failure was noted for LUD compared with cadaveric donor kidney recipients, this estimate did not achieve a conventional level of statistical significance (RR, 0.74; CI, 0.45 to 1.22). The risk for graft failure was similar in LUD and mismatched LRD kidney recipients. For both these groups, graft failure was more common than in the haploidentical LRD and identical LRD groups, but these differences were statistically significant only for the comparison with identical LRD. Risk estimates for graft failure associated with LUD kidney transplantation were consistent in all the models tested. For both patient death and graft failure models, no evidence of an interaction was seen between donor type and either cyclosporine use or race.
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Discussion To our knowledge, this is the largest prospective study of LUD kidney recipients and the only one in which their survival experience was compared with that of other groups with simultaneous adjustment for important covariates. We observed that recipients of LUD, mismatched LRD, and cadaveric donor kidneys had similar patient and graft survival rates for up to 3 years after renal transplantation. In fact, LUD and mismatched LRD recipients had slightly better graft survival rates than did cadaveric donor kidney recipients, but this finding was not significant. These similarities persisted after adjustment for age, sex, race, primary disease, previous transplantation, cyclosporine use, and LUD transplantation activity by centers. Patient and graft survival rates for LUD, mismatched LRD, and cadaveric donor, however, tended to be inferior to those for haploidentical LRD and identical LRD transplant recipients. The power to detect whether graft survival was significantly better in LUD than in cadaveric donor kidney recipients was limited, because many patients were enrolled during the last 2 years of the study and thus had fewer than 2 years of follow-up. Previous reports have suggested that patient and graft survival rates using LUD kidneys were either as good as (16, 18) or better (15, 17, 19, 23) than those achieved using cadaveric donor kidneys. It has also been reported that the graft survival of mismatched LRD recipients is superior to that of cadaveric donor and similar to that of haploidentical LRD recipients (24). Thus, factors other than HLA matching, perhaps related to the minimization of the duration of ischemia, appear to be important for graft outcome. It has been difficult, however, to reach a valid conclusion from these studies
due to limitations such as small sample size, lack of a concurrent comparison group, differing types of immunosuppressive regimens, or lack of adjustment for HLA mismatches and other baseline characteristics. Our report is the first to account for all of these factors. Unfortunately, we could not do a better adjustment for the effect of HLA matching in LUD and cadaveric donor transplant recipients, because these data were not available. It is unlikely, however, that this lack of information biased our conclusions, because HLA typing is not routinely done for these types of transplants in Brazil, and it is highly probable that recipients of these kidneys were mismatched. In our study, recipients of cadaveric donor kidneys had a lower patient survival than that reported by other large registries (8, 25). This finding may be due to a longer waiting period before transplantation for patients in our registry, resulting in a less favorable baseline status (26). Interestingly, cyclosporine use was identified as an independent predictor of patient death, even after adjustment for other variables, including type of donor. This unusual finding may reflect more common use of cyclosporine in patients with higher degrees of HLA mismatching and the possibility that higher-risk patients, such as those hypersensitized to a panel of HLA antigens, may have been selected more often to receive cyclosporine. This preferential selection of higher-risk patients to receive cyclosporine would tend to lead to the observed association of this drug with adverse patient outcomes. In addition, the use of cyclosporine with prednisone and azathioprine may have produced excessive immunosuppression in some patients. After adjustment for several potentially important variables, the risk for graft failure did not differ statis-
Table 2. Multivariate Proportional Hazards Regression Models for Patient Death and Graft Failure in 2892 Renal Transplant Recipients Variable Age,y Male sex Race Black compared with white Other compared with white Primary disease Diabetes mellitus compared with glomerulonephritis Hypertension compared with glomerulonephritis Other compared with glomerulonephritis Previous transplantation Cyclosporine use Type of donor ILRD compared with CAD HLRD compared with CAD MLRD compared with CAD LUD compared with CAD LUD transplants per center, n 1 compared with 0 2 to 5 compared with 0 > 5 compared with 0
Patient Death Hazard Ratio (95% CI)
Graft Failure Hazard Ratio (95% CI)
1.04 (1.03 to 1.05)* 0.85 (0.65 to 1.10)
1.00 (0.99 to 1.01) 0.90 (0.73 to 1.11)
1.22 (0.91 to 1.64) 0.86 (0.38 to 1.96) * 1.81 (0.98 to 3.35) 1.23 (0.84 to 1.82) 1.38 (1.03 to 1.84) 1.79 (1.01 to 3.16) 1.92 (1.43 to 2.56) * 0.44 (0.24 to 0.83) 0.77 (0.57 to 1.04) 1.13 (0.69 to 1.87) 1.16 (0.68 to 1.98)
1.35 (1.07 to 1.70) 1.15 (0.63 to 2.10)
t
1.19 (0.67 to 2.11) 0.97 (0.69 to 1.35) 1.13 (0.90 to 1.41) 1.89 (1.24 to 2.89)$ 1.07 (0.86 to 1.34) 0.24 (0.14 to 0.40) 0.63 (0.49 to 0.80) 0.82 (0.53 to 1.25) 0.74 (0.45 to 1.22)
t 1.14 (0.76 to 1.73) 0.94 (0.67 to 1.31) 0.66 (0.47 to 0.94)
1.15 (0.81 to 1.63) 1.06 (0.81 to 1.39) 0.87 (0.67 to 1.14)
* All variables in the table were included in each model. For each pair, the one listed second is the comparison variable. CAD = cadaveric donor; HLRD = one-haplotype matched living related donor; ILRD = identical living related donor (two-haplotype HLA matched); LUD = living unrelated donor; MLRD = HLA mismatched living related donor (0-haplotype matched). For dichotomous variables, P values represent a Wald test. For race, primary disease, type of donor, and number of LUD transplants per center, P values represent an overall test of significance. t P < 0.05. $P < 0.001.
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tically among LUD, mismatched LRD, and cadaveric donor kidney recipients. Despite the relatively large sample sizes of these patient subgroups, we cannot exclude the possibility of improved graft survival associated with LUD or mismatched LRD compared with cadaveric donor kidney transplantation. Higher graft survival rates might have been attained if antilymphocyte globulin and OKT3 monoclonal antibody therapy had been used more frequently by Brazilian transplantation centers. Several authors have proposed that LUD renal transplantation is justifiable and should be actively considered to reduce the waiting list for kidney transplantation and the burden on dialysis facilities (10, 11, 14-16, 1820). Our results suggest that patient and graft survival rates for LUD are at least as good as those for cadaveric donor kidney transplantation. We were unable, however, to document a significantly superior outcome among those with LUD kidney transplantation despite a shorter cold ischemic time, the avoidance of donor hypotension, and the advantages of planned transplantation. For some patients, LUD may be their only chance to receive a kidney transplant. For others, it reduces the waiting time for transplantation. We agree with the guidelines of the Council of the Transplantation Society (27), which state that the motives for donation should be altruistic and not selfserving or for profit. Payment for the donor or "rewarded gifting" (a compensation for the inconvenience and for the loss of earnings) is unacceptable. We also believe that such monetary transactions corrupt and demean the relationship between the donor and the recipient and impair the public's will to donate organs (28, 29). The practice of LUD transplantation should not, however, impair the development of cadaver-donor transplantation programs. It is a matter of concern that kidneys from only a small percentage of potential cadaveric donors are being harvested for transplantation (9, 10, 14, 30, 31). Of the 165 recipients of LUD kidneys in this study, 107 received their kidney from a spouse. Information regarding the remaining 58 LUDs was not available from our Registry. Previous reports from Brazilian transplant centers suggest that most of these donors were friends who had altruistic motives (32, 33). Finally, it was noteworthy that most LUD recipients were male, particularly among spousal transplants. The reasons for this unequal distribution were not apparent. This issue should be evaluated in future reports. Longer follow-up of the present sample as well as further studies containing additional baseline information and investigating alternate immunosuppressive regimens and donor-specific transfusions will serve to better characterize patient and graft survival after LUD kidney transplantation.
Preto; Maria G. Lima, MD; Luiz Villas Boas, MD: UTR-HSEPITO; Sergio M. Carvalho, MD; Hermogenes P. Filho, MD: HGB/PITO; Frederico Ruzany, MD; Sergio Aguinaga, MD: Hospital Pedro Ernesto; Abrahao S. Filho, MD; Apparicio S. Assis, MD: Hospital das Clinicas-Belo Horizonte; Emil Sabbaga, MD; Sami Arap, MD: Hospital das Clinicas-Sao Paulo; Valter D. Garcia, MD; Guido Cantisani, MD: Santa Casa-Porto Alegre; Lauro Brandina, MD; Altair J. Mocelin, MD: Hospital Evangelico-Londrina; Joao Loewen, MD; Sandro Ziesemer, MD: Hospital Evangelico-Curitiba; Eduardo M. Martinelli, MD; Walter S. Bestane, MD: Hospital Ana Costa; Estevan Viotti, MD; Eduardo R. Tavora, MD: Hospital Felicio Rocho; Jose N. Torres, MD; Carlos A. Gomes, MD: Hospital Evangelico-Vila Velha; Sebastiao Ferreira, MD; Luis C. Araujo, MD: Santa Casa-Juiz de Fora; Manuel P. Almeida, MD; Haward Kano, MD: Hospital Antonio Pedro; Tereza E. Faifer, MD; Antonio P. Galesso, MD: Associacao Hospitalar-Bauru; Joao C. Biernat, MD; Guido Cantisani, MD: Hospital das Clinicas-Dr. Lazzaroto; Luiz M. Santos, MD; Yashicazo Tamura, MD: Hospital Sao Lucas-PR; Lerminio Pimenta, MD: Santa Casa-Belo Horizonte; Eduardo R. Silveira, MD; Gilberto L. Vieira, MD: Hospital Vera Cruz; Lauro M. Vasconcelos, MD; Fabio Pereira, MD: Hospital Sao Jose; Roberto B. Marques, MD; Joao M. Torres, MD: Hospital das ClinicasWalter Cantidio; Fernando S. Tome, MD: Hospital Petropolis; Joao B. Barberato, MD; Eliseu R. Denadai, MD: Hospital Beneficencia Portuguesa-IUNRP; Kleber A. Nogueira, MD; David Abelha, MD: Associacao Evangelica Beneficencia-MG; Domingos D'Avila, MD; Henrique S. Barata, MD: Hospital Sao Lucas/PUC-PA; Roberto C. Manfro, MD; Gilberto Souza, MD: Hospital Maia Filho-PA; Vitor A. Soares, MD; Luiz A. Correa, MD; Hospital das Clinicas-UNESP; Gentil A. Filho, MD; Nelson Rodrigues Neto, MD: UNICAMP-Campinas; Carlos Stabile, MD; Fausto Miranda, MD: Hospital Santa Rita-SP; Elias David, MD; Nelson Montelato, MD: Hospital Umberto I; Sergio G. Marks, MD; Joao A. Rocha, MD: Santa Casa-Curitiba; Jorge L. Ramos, MD; Antonio M. Freire, MD: Policlinica-Pato Branco; Francisco Oliveira, MD; Jose R. Vaz, MD: Santa Casa-Maceio; Nelson Q. Froes, MD; Waldemar C. Abe, MD: Santa Casa-Campo Grande; Alipio D. Coelho, MD; Jorge A. Isaacsonn, MD: Santa Casa-Pelotas; Edson N. Rodrigues, MD; Elias Kallas, MD: Hospital das Clinicas-Samuel Libanio; Paulo C. Oliveira, MD; Neilton Prado, MD: Hospital das Clinicas-Uberlandia; Jose C. Guilhen, MD; Ludvig Hafner, MD: Santa Casa-Marilia; Maria T. Vannucchi, MD; Joao P. Pessoa, MD: Hospital Sao Francisco; Jaelson G. Gomes, MD: Hospital Evangelico-Sorocaba; Helcio A. Tavares, MD; Mario O. Urandecic, MD: BIOCOR-Belo Horizonte; Augusto Laffitte, MD: Hospital de Clinicas-Curitiba; Alaour C. Duarte, MD; Rui C. Donaduti, MD: Hospital Sao Vicente de Paula-RS; Carlos A. Prompt, MD; Walter J. Koff, MD: Hospital de Clinicas-Porto Alegre; Joao S. Yokoyama, MD; Jansen R. Ferreira, MD: Hospital-Maternidade S. Paulo-PR; Luiz A. Fochesato, MD; Norberto Tonietto, MD: Hospital NS Fatima-RS; Francisco W. Carvalho, MD; Marcio A. Correa, MD: Hospital NavalMarcilio Dias; Jorge B. Westphalen, MD; Paulo R. Moreira, MD: Hospital Sta Lucia-RS; Roland Saldanha, MD; Marcos H. Sayao, MD: Beneficencia Portuguesa-SP; Hi K. Ann, MD; Milton T. Tanaka, MD: Hospital NS Salete-PR; Rejane P. Meneses, MD; Antonio Silveira, MD: Hospital Pequeno Principe-PR; Adaelson A. Silva, MD: Hospital Santa Rita-Maringa; Luiz Emed, MD: Hospital Cajuru-PR; William Stanford, MD: Hospital Portugues de Beneficencia-PE; Mario F. Chaves, MD: Hospital Samaritano-PB; Antonio C. Castro, MD: PUCCampinas; Fernando A. Almeida, MD: PUC-Sorocaba; Natalino C. Peixoto, MD; Julio C. Ximenes, MD: Hospital Santa Helena-GO; Pedro Jabur, MD: Santa Casa-Sao Paulo; Rogerio Caffarro, MD: Hospital Brigadeiro-SP; Jose A. Vieira, MD; Osmar S. Hausen, MD: Hospital Hans D. Schmidt; Anuar M. Macni, MD; Antonio M. Fraga, MD: Hospital Regional-PR.
Appendix. Physicians and Institutions Participating in the Brazilian Transplantation Registry
Acknowledgments: The authors thank Mrs. Marlene Sakumoto for technical assistance and Ms. Barbara Pawlovsky for secretarial support.
Jose O. Medina, MD; Alvaro Pacheco-Silva, MD; Claudio J. Almeida, MD: Escola Paulista de Medicina; Agenor S. Ferraz, MD; Antonio C. Martins, MD: Hospital das Clinicas-Ribeirao
Grant Support: By a grant from the Rockefeller Foundation (International Clinical Epidemiology Network), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil), and from the Instituto Paulista de Estudos e Pesquisas em Nefrologia e Hipertensao,
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Brazil. Dr. Sesso is a recipient of a postdoctoral fellowship grant from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil). Dr. Klag is an established investigator of the American Heart Association. Requests for Reprints: Ricardo Sesso, MD, Escola Paulista de Medicma, Division of Nephrology, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. Current Author Addresses: Drs. Sesso and Ramos: Division of Nephrology, Escola Paulista de Medicina, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. Drs. Klag, Whelton, and Seidler: The Johns Hopkins Health Institutions, 600 North Wolfe St., Carnegie 292, Baltimore, Maryland, 21287. Drs. Ancao and Sigulem: Health Informatics Center, Escola Paulista de Medicina, Rua Botucatu 740, Sao Paulo, SP, 04023, Brazil. References 1. Brunner FP, Selwood NH. Results of renal replacement therapy in Europe, 1980 to 1987. Registration Committee of the EDTA-ERA. Am J Kidney Dis. 1990; 15:384-%. 2. Eggers PW. Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med. 1988;318:223-9. 3. Sesso R, Eisenberg JM, Stabile C, Draibe S, Ajzen H, Ramos O. Cost-effectiveness analysis of the treatment of end-stage renal disease in Brazil. Int J Technol Assess Health Care. 1990;6:107-14. 4. Bart KJ, Macon EJ, Whittier FC, Baldwin RJ, Blount JH. Cadaveric kidneys for transplantation. A paradox of shortage in the face of plenty. Transplantation. 1981;31:379-82. 5. Held PJ, Pauly MV, Bovbjerg RR, Newmann J, Salvatierra O Jr. Access to kidney transplantation. Has the United States eliminated income and racial differences? Arch Intern Med. 1988; 148:2594-600. 6. Smith T. Shortage of donors continues [Editorial]. Br Med J. 1989; 298:776. 7. Cohen B, Persijn G. Eurotransplant Newsletter. 1989; no. 61 (February). 8. U.S. Renal Data System. USRDS 1990 Annual Data Report, Betheseda, Maryland: National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases; 1990. 9. Evans RW, Orians CE, Ascher NL. The potential supply of organ donors. An assessment of the efficacy of organ procurement efforts in the United States. JAMA. 1992;267:239-46. 10. Levey AS, Hou S, Bush HL Jr. Kidney transplantation from unrelated living donors. Time to reclaim a discarded opportunity. N Engl J Med. 1986;314:914-6. 11. Starzl TE. Living donors: con. Transplant Proc. 1987;19:174-5. 12. Blake PG, Cardella CJ. Kidney donation by living unrelated donors [Editorial]. Can Med Assoc J. 1989;141:773-5. 13. Salahudeen AK, Woods HF, Pingle A, Nur-El-Hude, Suleyman M, Shakuntala K, Nandakumar M, et al. High mortality among recipients of bought Irving-unrelated donor kidneys. Lancet. 1990;336: 725-8. 14. Flatmark A, Brynger H, Groth CG. Kidney transplants from living donors: the neglected opportunity. Transplant Int. 1990;3:50-1. 15. Sollinger HW, Kalayoglu M, Belzer FO. Use of the donor-specific transfusion protocol in Irving-unrelated donor-recipient combinations. Ann Surg. 1986;204:315-21.
16. Albrechtsen D, Sodal G, Jakobsen A, Brekke I, Bentdal O, Berg KJ, et al. Kidney transplantation from a spouse: an alternative to years of dialysis waiting for a graft that may never turn up? Transplant Proc. 1990;22:1435. 17. Elick BA, Sutherland DE, GUlingham K, Najarian JS. Use of distant relatives and living unrelated donors: a strategy to increase the application of kidney transplantation to treat chronic renal failure. Transplant Proc. 1990;22:343-4. 18. Squifflet JP, Pirson Y, Poncelet A, Gianello P, Alexandre GP. Unrelated living donor kidney transplantation. Transplant Int. 1990;3: 32-5. 19. Haberal M, Bulut O, Sert S, Gulay H, Hamaloglu E, Altunkan S. Transplantation between husband and wife. Transplant Proc. 1990; 22:342. 20. Berloco P, Alfani D, Bruzzone P, Renna Molajoni E, Rossi M, Pretagostini R, et al. Is unrelated living donor a valid organ source in renal transplantation under CYA therapy? Transplant Proc. 1991; 23:912-3. 21. Sesso R, Ancao MS, Draibe SA, Sigulem D, Ramos OL. Survival analysis of 1563 renal transplants in Brazil: report of the Brazilian Registry of Renal Transplantation. Nephrol Dial Transplant. 1990; 5:956-61. 22. Pollak VE, Fox WR. Definitions and standards for treatment outcomes in patients with end-stage renal disease: Report of a Committee of the National Forum of ESRD Networks. Am J Kidney Dis. 1984;3:391-6. 23. Abouna GM, Panjwani D, Kumar MS, White AG, Al-Abdulla IH, Silva OS, et al. The living unrelated donor—a viable alternative for renal transplantation. Transplant Proc. 1988;20:802-4. 24. Kaufman DB, Sutherland DE, Fryd DS, Noreen H, Najarian JS. Zero-HLA haplotype matched siblings as living related renal donors. Transplant Proc. 1989;21:671-4. 25. Geeriings W, TufVeson G, Brunner FP, Enrich JH, Fassbinder W, Landais P, et al. Combined report on regular dialysis and transplantation in Europe, XIX, 1988. Nephrol Dial Transplant. 1989;4 (Suppl 4):5-29. 26. Sesso R. Sobrevida em dialise. J Bras Nefrol. 1990;12:1-2. 27. Commercialization in transplantation. The problems and some guidelines for practice. The Council of the Transplantation Society [Editorial]. Transplantation. 1986;41:1-3. 28. Morris PJ, Sells RA. Paying for organs from living donors [Letter]. Lancet. 1985;1:1510. 29. Dossetor JB, Manickavel V. Ethics in organ donation: contrasts in two cultures. Transplant Proc. 1991;23:2508-11. 30. Chisholm GD. Time to end softly softly approach on harvesting organs for transplantation [Editorial]. Br Med J. 1988;296:1419-20. 31. Caplan AL, Welvang P. Are required request laws working? Altruism and the procurement of organs and tissues. Clin Transplant. 1989;3:170-6. 32. Sabbaga E, Ianhez LE, Chocair PR, Azevedo LS, Sarturi PS, de Goes GM. Kidney transplants from living nonrelated donors: an analysis of 87 cases, including 20 cases with specific blood transfusions from the donor. Transplant Proc. 1985;17:1741-5. 33. Hoette M, Ruzany F, Tavora E, Mocelin A, Sabbaga E, Monies R, et al. Living-nonrelated kidney donors for transplantation [Abstract]. Kidney Int. 1986;29:430.
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