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*
Department of Medicine, University of Michigan, Ann Arbor,
Michigan.
Department of Biostatistics, University of Michigan, Ann Arbor,
Michigan.
Department of Epidemiology, University of Michigan, Ann Arbor,
Michigan.
§
The United States Renal Data System, Division of Kidney, Urologic, and
Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland.
Correspondence to Dr. Akinlolu O. Ojo, Division of Nephrology, TC 3914, Box 0364, Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, MI 48109-0364. Phone: 734-763-9041; Fax: 734-936-9621; E-mail: aojo{at}umich.edu
| Abstract |
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| Introduction |
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In most series, allograft outcomes with marginal kidneys are inferior to that of organs considered to be ideal (15, 20,21,22,23,24,25). Notwithstanding the diminished graft survival of marginal kidneys, renal transplantation improves quality of life (26,27,28,29,30) and economic analysis suggests that transplantation with a marginal donor kidney is more cost-effective than dialysis treatment (31).
Improved patient survival is a well-established benefit of renal transplantation, but the magnitude of increased longevity is not uniform across patient subgroups (32,33,34,35,36). For example, following the excess initial mortality associated with the transplant procedure, the cumulative time to equal mortality between transplant recipients and their wait-listed counterparts (those who remain on dialysis) range from 57 d in recipients aged 20 to 39 yr to 369 d in recipients aged 60 to 74 yr (33, 34). The estimated additional life-years gained from renal transplantation vary from 8 yr in a diabetic recipient who is 60 yr or older to 31 yr in a nondiabetic recipient who is 20 to 44 yr old (33, 35). Thus, any survival advantage to be gained from receiving a marginal donor kidney is also likely to vary between subgroups of recipients. If there is substantial variability in patient survival with marginal donor kidney transplantation, then it stands to reason that some patients may benefit (in the strict sense of average patient survival) from receiving a marginal kidney, whereas others may not.
We previously showed that allograft loss terminates the patient survival benefit accruable from kidney transplantation such that patients who lose graft function are at increased mortality risk unless repeat transplantation is performed (37). Because marginal organs have comparatively diminished allograft survival, we ask whether it is actuarially beneficial for a patient who is on the cadaveric renal transplant waiting list to accept or decline an offer for transplantation with an organ that has one or more characteristics associated with diminished graft survival, i.e., marginal donor kidney. To address this question, we conducted a historical prospective cohort analysis of U.S. national data in which the survival of recipients of marginal kidneys was compared with two groups of patients: wait-listed dialysis patients and recipients of ideal cadaveric donor kidneys (IDK).
| Materials and Methods |
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A total of 122,175 patients were registered on the UNOS renal transplant waiting list during the study period. Waiting list registrants who received multiorgan (n = 2000) or living donor renal transplant (n = 6988) were censored from further analysis. For repeat transplant recipients as well as repeat transplant candidates, the study start date was taken to be the date of waiting list registration for the index (most recent) kidney transplantation. Those who received a cadaveric renal transplant were divided into two groups (marginal kidney recipients and ideal kidney recipients) on the basis of the characteristics of the organ received. This classification was based on the following definition. A recipient was defined as receiving a marginal donor kidney (MDK) if one or more of the following pretransplant factors was present: donor age >55 yr, donor history of hypertension longer than 10 yr duration, donor history of diabetes mellitus longer than 10 yr duration, NHBD, and cold preservation time >36 h. A cadaveric kidney transplant in which none of the listed factors was evident was defined as an IDK. All patients were on the waiting list and most (97%) were on dialysis treatment (WLD) for some time until transplantation or end of follow-up. The number of IDK and MDK recipients studied were 34,438 and 7,454, respectively. The two groups of cadaveric transplant recipients and the WLD patients were followed until the earliest of death or June 30, 1998. As would be expected, exit from the waiting list for medical reasons often preceded death; therefore, patients who were removed from the waiting list were not censored to avoid bias due to informative censoring. Because failure to show up for nonmedical reasons is a rare cause of turning down an allocated kidney, patients who did not receive an assigned organ for nonmedical reasons were also left in the waiting list cohort.
Patient survival was analyzed in an intention-to-treat manner with the
time-dependent, nonproportional Cox regression technique while adjusting for
baseline characteristics including age, race, cause of end-stage renal disease
(ESRD) and time spent on the waiting list. Cox-adjusted relative mortality
risk of transplant recipients was calculated for separate groups after
transplantation using WLD as the reference group. Time to equal mortality
risk, time to cumulative equal survival (i.e., when equal proportions
are dead in both groups), and expected remaining life-years were calculated
for different patient subgroups according to the methods previously described
by Mauger et al. (38)
and Wolfe et al. (35,
39). Graft survival was
estimated with the Cox nonproportional regression in which recipients were
stratified by donor type (MDK versus IDK) such that the logarithmic
hazard ratio between the two groups was allowed to be nonparallel. Delayed
graft function was defined as one or more dialysis treatments in the first
week after transplantation. Acute rejection was noted to have occurred when
reported by the individual transplant center to the Renal Transplant
Scientific Registry. Graft survival estimates were compared by the log
likelihood ratio test. The t and Mantel-Haenszel
2
tests were used for univariate analysis. A P value of 0.05 was
considered significant. Statistical analysis was performed with SAS software
(SAS, version 6.12, Cary, NC).
| Results |
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The most common factor for being classified as a marginal donor was donor age >55 yr, which was present in 63.8% of MDK. Donor hypertension >10 yr, donor diabetes mellitus >10 yr, cold ischemia time >36 h, and NHBD were present in 10.5%, 1.3%, 31.1%, and 4.7% of cases, respectively.
Graft Survival
Graft failure, defined as return to maintenance dialysis or graft
nephrectomy, was more frequent in MDK recipients (35.9%; n = 2678)
compared with 24.9% (n = 8581) of graft failures in IDK recipients
(P < 0.001). Correspondingly, the adjusted 5-yr graft survival
(Figure 1) was significantly
lower in the MDK compared with the IDK recipients (59% versus 72%;
P < 0.001). Among MDK recipients, the 5-yr graft survival was
highest in the other race group (65%) compared with 62% in white (P
< 0.001) and 49% in black recipients (P < 0.001). The risk
factors for graft survival as obtained from multivariate analysis are shown in
Table 2.
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Patient Survival
The primary objective of the study was to determine whether patients who
received a marginal donor kidney transplant have a different survival
experience compared with their wait-listed counterparts. In this study cohort,
the average death rate adjusted for age, race, gender, and cause of death for
wait-listed patients was 6.3% per year, which was significantly higher than
the average adjusted death rate in MDK recipients (4.7%/ yr; P <
0.001) and IDK recipients (3.3%/yr; P < 0.001). The adjusted 5-yr
patient survival was higher in IDK recipients compared with MDK recipients
(85% versus 77%; P < 0.001).
Figure 2 depicts the mortality
experience of MDK and IDK kidney transplant recipients up to 700 d
posttransplantation. At all times during follow-up, IDK recipients had lower
mortality risks compared with MDK recipients. The time to equal mortality
risk, i.e., how long it took the excess risk due to the transplant
procedure to dissipate, was 185 d and 122 d for MDK and IDK recipients,
respectively (P < 0.001). In these adjusted analyses, the same
proportion of transplant recipients and wait-listed patients on dialysis were
dead by 531 d post-transplantation for MDK and 256 d posttransplantation for
IDK recipients. According to the time-dependent Cox regression analysis, the
expected life-years for wait-listed, never transplanted dialysis patients was
15.3 yr compared with 20.4 yr for MDK recipients (P < 0.001) and
28.7 yr for IDK recipients (P < 0.001). Thus, transplantation with
a marginal kidney increased life expectancy by 5.1 yr over maintenance
dialysis treatment, whereas the increase in life expectancy was 13.4 yr for
ideal kidney transplant recipients. Compared with WLD, long-term relative
mortality risk was lower by 25% (relative risk [RR] = 0.75, P =
0.001) and 48% (RR = 0.52, P = 0.001) for MDK and IDK recipients,
respectively.
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Adjusted estimates of mortality risks in subgroups of marginal kidney
transplant recipients are shown in Table
3. Annual death rates among WLD ranged from 2.2% for the age group
18 to 29 yr to 10.0% for patients for the age group
65 yr. Annual death
rates on the waiting list also vary by race and cause of ESRD, with black
patients having a lower death rate compared with white patients (4.8%
versus 7.5%; P < 0.001) and patients with end-stage
diabetic nephropathy having a death rate that was much higher than other
causes of ESRD (10.8% versus 4.3%; P < 0.001). The
underlying variability in mortality on the waiting list was reflected in the
relative magnitude of the additional life-years gained with marginal kidney
transplantation. Recipients in the youngest age group studied had the longest
improvement in survival (6.4 yr) compared with 3.8 yr in the oldest recipient
age group (
65 yr). However, the proportional benefit was not significant
for the younger age groups (RR = 0.85, P = 0.55 for age group 18 to
29 yr and RR = 0.78, P = 0.09 for age group 30 to 44 yr) when
compared with their WLD counterparts. In contrast, older recipients (
65
yr) had a significant proportional increase in longevity (RR = 0.71,
P = 0.03). Similarly, better survival in black patients on the
waiting list was reflected in nonsignificant proportional improvement
following MDK (RR = 0.86, P = 0.13), whereas white patients who had
lower survival on dialysis (7.5% versus 4.3% in black patients) had
proportional significant improvement in post-MDK transplant survival (RR =
0.68, P < 0.001). Compared with white recipients, the gain in life
expectancy for black MDK recipients was marginally lower (3.1 versus
5.9 yr; P = 0.09).
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Table 4 shows the prognostic indicators for patient survival according to the multivariate nonproportional Cox regression analysis. Among the four characteristics used to define an MKD, only the donor age was predictive of patient survival (5-yr mortality increased by 5% for each decade increase in donor age; P < 0.001). Other variables independently associated with patient survival were recipient age and race, primary cause of ESRD, and panel reactive antibody greater than 30% at the time of transplantation. There was no interactive effect of donor and recipient age on patient survival.
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| Discussion |
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The life expectancy for wait-listed black patients was 20 versus 13 yr in white patients. However, posttransplantation increase in life expectancy was greater for white than for black recipients (6 versus 3 yr). Our finding of significantly lower mortality in wait-listed black patients (compared with white patients) is consistent with previous studies that showed lower mortality rates in black patients in the general dialysis population (40,41,42). One possible explanation for this finding is that the previously observed lower overall renal transplantation rates and longer waiting times for black patients (43,44,45,46) leads to a disproportionate enrichment of a black wait-listed dialysis cohort with the patients who have lower burden of comorbid conditions and are thus likely to live longer. That the greatest increase in life expectancy was observed for recipients of other race (10 yr) who had an intermediate death rate (6.3%/yr) on dialysis suggests that other factors independent of the determinants of dialysis survival were responsible for posttransplantation patient survival. Indeed, we found that the 5-yr graft survival for marginal kidney transplants (an indicator of the probability of return to dialysis and therefore greater mortality hazard) was poorest in black recipients (46%), intermediate in white recipients (60%), and highest in the other recipient race group (65%).
Notwithstanding the subgroup differences in the patient outcomes with marginal kidney transplantation, it is important to reinforce the perspective that successful kidney transplantation with ideal or marginal organs is associated with dramatic and substantial improvement in quality of life (26,27,28,29,30). Moreover, receipt of a marginal kidney transplant was not detrimental to patient survival in any subgroup that we examined.
Whereas several investigators have reported on allograft outcomes with marginal kidney transplantation, this study, to our knowledge is the first attempt to examine the patient survival in recipients of marginal kidney transplant. The results should help to clarify whether to accept a marginal kidney. Often, in practice, the transplant physician weighs this question in addition to several other factors before offering a marginal organ to a particular recipient. Should the transplant physician, potential recipient, or both make this determination at the time of organ availability or should this prospect be discussed at the time of transplant evaluation? This needs to be clarified with studies taking into account all of the factors that often come into play when this type of decision is confronted. The perspective informed by the present study does not entail the choice between an ideal or a marginal kidney because this is muted by the well-established fact that, in general, cadaveric kidney transplantation is life saving (35).
Of note is that in the subset of kidney transplants for which preterminal donor renal function data were available, serum creatinine was higher for MDK versus IDK (1.3 ± 2.2 mg/dl versus 1.2 ± 2.0 mg/dl). This implies that other clinical data such as histologic appearance and level of proteinuria may be more pertinent to outcomes (13, 47, 48). Our study suggests that such data are often used to discriminate which marginal kidneys are suitable for implantation. Thus, our results support critical assessment of the suitability of compromised cadaveric donor kidneys as opposed to liberal expansion of donor criteria.
The analysis presented here has a number of limitations. First, we cannot be certain that recipients of marginal donor organs were not specifically selected because the baseline characteristics were dissimilar to that of recipients of ideal cadaveric kidneys with respect to certain important prognostic factors. For example, compared with ideal kidney transplant recipients, the recipients of marginal kidneys were older (47 versus 43 yr; P < 0.001) and less likely to have had end-stage diabetic nephropathy (22 versus 26%; P < 0.001). Thus, the beneficial outcomes observed in marginal kidney transplant recipients may have resulted from implicit donor-recipient matching within the confines of organ allocation policy. Therefore, the result may not be applicable to the average renal transplant candidate. Second, as noted above, we relied on donor age, cold storage time, duration of hypertension and diabetes, and NHBD status to define organ suitability. These factors are not as comprehensive and are not as proximate and precise as detailed histologic and functional analysis of donor kidneys as determinants of organ suitability. Last, this study examined the survival benefit of kidney transplantation with a marginal donor organ but did not address the survival effect of receiving an MDK versus remaining on the waiting list after turning down such a kidney.
In summary, transplantation with organs that fulfill expanded donor criteria account for almost one fifth of cadaveric renal transplantation in recent years. The expanded donor now represents the largest growth in transplantable cadaver kidneys in the United States. The present study demonstrates that the use of such marginal kidneys prolongs the life of the recipient. The gains in life expectancy vary markedly from 3 to 9 yr depending on the characteristics of recipients. To determine whether any subgroup of patients benefits more than others requires a more comprehensive assessment of adjusted quality life-years and assignment of utilitarian values balanced with equity considerations. A prospective evaluation of these issues is warranted to determine whether careful donor-recipient matching of marginal cadaveric kidneys can maximize the efficiency of the organ allocation system.
| Acknowledgments |
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| References |
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