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Clinical and Translational Research

Long-Term Impact of Donor-Recipient Size Mismatching in Deceased Donor Kidney Transplantation and in Expanded Criteria Donor Recipients

Goldberg, Ryan J.1; Smits, Gerard2; Wiseman, Alexander C.1,3

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doi: 10.1097/TP.0b013e3181f24e75
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Abstract

With an ever-growing waiting list for kidney transplantation and a plateau in the number of deceased donor kidneys over recent years (1), a primary goal of kidney transplantation remains the optimization of long-term graft survival. Improvements in pretransplant immunologic risk assessment and immunosuppresion protocols have decreased the rate of acute rejection; however, the long-term survival of kidney allografts has not changed significantly over the past decade (2–4). Chronic allograft nephropathy or interstitial fibrosis and tubular atrophy affects a majority of transplants by 5 years and is believed to be mediated by both immune-dependent and immune-independent factors (5, 6). Among the immune-independent factors is a possible role for inadequate nephron dosing leading to glomerular hyperfiltration and progressive graft damage.

Physiologists have postulated that a significant size discrepancy would negatively impact grafts based on animal models incorporating transplants or partial nephrectomies, which demonstrate progressive renal decline after hypertrophy of remaining nephrons (7–9). Some degree of hyperfiltration likely occurs in all renal transplants. However, the degree to which recipient/donor (R/D) size discrepancy may impact graft or patient survival because of hyperfiltration remains unclear. This question has become increasingly important as the use of expanded criteria donors (ECDs), with inherent differences in functional nephron mass compared with standard criteria donors, has increased.

The available data that have investigated size discrepancies in kidney transplantation is mixed, with some studies demonstrating that large recipients fare worse with small donors because of “inadequate nephron dosing,” whereas other studies have shown no difference (10–12). Currently, there is no validated technique that allows in vivo determination of nephron number; however, there are a number of clinical surrogates that have been used to determine a rough estimate of adequate nephron number in normal adults, including low birth weight, preterm birth, low renal volume, and kidney mass (13). Data from autopsy studies have also provided correlation between glomeruli number and kidney mass (14, 15). Body surface area (BSA) correlates with renal mass and has been used by several studies to estimate nephron dose (14). Kasiske et al. (16) used United States Renal Data System data from 1994 to 1999 to review 32,083 transplants and studied donor and recipient BSA characteristics, categorizing patients by small (<1.6 m2), medium (1.6–2.2 m2), and large (>2.2 m2) BSA. In patients surviving greater than 4 months, the risk for graft failure was increased 43% for large recipients of kidneys from small donors (1.5% of entire cohort). For medium size recipients of kidneys from small donors, the risk of late failure was increased 16% (12% of entire cohort). More recently, the effect of donor/recipient BSA differences were analyzed from a single-center pediatric kidney transplant program that found that a donor/recipient ratio of less than 0.8 was associated with a worse 5-year graft survival than similarly size-matched donor or recipient pairs (82% vs. 94.9%, P=0.01) (17).

In an attempt to put these findings into clinical context and consider the impact of R/D size mismatching in ECD recipients, we used recipient-to-donor BSA ratios to clarify the impact of R/D size mismatching across a continuum of size discrepancies. We also have extended the analysis to 10-year follow-up that includes a more modern era, report Kaplan-Meier estimated graft survival for size-mismatched pairs, and include a subset analysis for ECD donors.

RESULTS

Of the 77,289 deceased donor transplants performed between 1992 and 2005, 69,737 had available recipient and donor information for the calculation of BSA. Figure 1 shows the distribution of all transplants segregated by R/D BSA ratio. Data were then analyzed by examining the differences in outcome by candidate and donor size when segregated by ratio of R/D BSA (Fig. 1). Five categories of BSA ratios were developed based on the frequency distribution of transplants performed during this time period. Fifty percent (34,743) of transplants were performed with an R/D BSA of 0.87 to 1.13. This middle 50% of transplants were used as the control group and were considered to be “size-matched” (R=D). For R/D pairs in which the recipient was larger than the donor, 20% (n=14,339) with a R/D BSA more than 1.13 to 1.37 were considered moderate disparity (R>D), and 5% (n=3495) with a R/D BSA more than 1.38 were considered to have severe disparity (R≫D). Similarly, for R/D pairs in which the donor was larger than the recipient, 20% (n=13,400) with a R/D BSA 0.72 to 0.87 were considered to have moderate disparity (R<D), and 5% (n=3760) with a R/D BSA less than 0.72 were considered to have severe disparity (R≪D). The rationale for segregating patients based on R/D ratios rather than specific BSA values is that if indeed, size discrepancies do contribute to graft survival, and these discrepancies should be noted regardless of recipient size (i.e., a 6-ft tall, 70-kg recipient may have an “average” BSA of 1.89 but may have differences in graft survival when receiving a kidney from a 5-ft 45-kg donor [BSA of 1.39, R/D ratio 1.36] compared with a 5-ft 6-in, 65-kg donor [BSA 1.74, R/D ratio 1.09]). Figure 2 (a and b) represents Kaplan-Meier survival curves for 10-year patient and graft survival between BSA ratio groups. Ten-year patient survival was highest in the less than 0.72 BSA ratio group (R≪D) perhaps demonstrating a moderate survival advantage in recipients who receive kidneys from significantly larger donors compared with the control group (70% vs. 60%, P<0.0001). In cohorts where the donor was significantly smaller than the recipient, there was little difference in survival in moderate (R>D) and severe (R≫D) BSA ratio disparity transplants compared with the control group (58% and 59% vs. 60%, P=0.01 and P=0.35, respectively). Ten-year unadjusted graft survival followed a similar trajectory again showing a slight graft survival disadvantage in higher BSA ratio transplants (39% for control vs. 36% and 35% for moderate [R>D] BSA disparity and severe [R≫D] BSA disparity, respectively, P<0.0001, P=0.008).

FIGURE 1.
FIGURE 1.:
Sixty-nine thousand seven hundred thirty-seven deceased donor kidney transplants performed from 1992 to 2005 with available recipient and donor size information. Recipient/donor pairs were segregated into five groups by recipient/donor body surface area (BSA) ratio based on their frequency distribution.
FIGURE 2.
FIGURE 2.:
(a) Kaplan-Meier curve for months to patient survival by recipient/donor (R/D) body surface area (BSA) ratio. (b) Kaplan-Meier curve for months to kidney graft survival by R/D BSA ratio.

Given a greater focus on ECD utilization in recent years and the potential for an enhanced impact of factors detrimental to graft survival in the setting of ECD kidney transplantation, we performed a subset analysis of ECD donors within the BSA ratios defined in Figure 1. Figure 3 (a and b) represents Kaplan-Meier survival curves for 10-year patient and graft survival between BSA ratio groups in ECD recipients. Within the ECD cohort, patients with moderate (R>D) and severe (R≫D) BSA disparity had a survival disadvantage (46% and 30%, respectively, 10-year estimated survival vs. the control ECD group, 49%, P=0.43 and P=0.06, respectively) that did not reach statistical significance. Kaplan-Meier analysis of 10-year kidney allograft survival also demonstrated worse outcomes again in the moderate (R>D) and severe (R≫D) BSA groups (18% and 10%, respectively, 10-year estimated graft survival vs. the control ECD group 22%, P<0.09, P<0.0006, respectively).

FIGURE 3.
FIGURE 3.:
(a) Kaplan-Meier curve for months to patient survival by recipient/donor (R/D) body surface area (BSA) ratio in ECD recipients. (b) Kaplan-Meier curve for months to kidney graft survival by R/D BSA ratio in ECD recipients.

Table 1 provides comparisons of delayed graft function (DGF), 1-year acute rejection, serum creatinine, and death-censored graft survival rates for the entire cohort and the ECD cohort. For the entire cohort, donor/recipient size disparity had minimal to no effect on these parameters; but in the ECD cohort, severe size disparity was associated with higher rates of DGF, numerically higher rates of acute rejection, higher mean serum creatinine, and worse death-censored graft survival.

TABLE 1
TABLE 1:
Selected clinical events for entire deceased donor kidney transplant cohort and for recipients of extended donor criteria kidneys 1992–2005, segregated by BSA ratio

To determine whether discrepancies in recipient and donor BSA were independently associated with kidney graft loss and patient death, Cox multivariate analysis was performed (Table 2) using variables shown to influence graft and patient survival. After adjusting for donor, recipient, and transplant risk factors, BSA ratio did not have a significant effect on patient survival. R/D BSA disparity did become a risk factor for graft loss, however, with moderate BSA disparity R>D associated with a 6% increased risk of graft loss (hazard ratio [HR] 1.06, P=0.0002) and severe BSA disparity R≫D associated with a 15% increased risk of graft loss (HR 1.15, P<0.0001). This association was not explained by poorer outcomes because of recipient obesity per se, for when examining the effect of obesity by body mass index (>30 kg/m2) in patients with moderate to large BSA (>1.8 m2), donor/recipient size disparity was not associated with graft loss (Table 2). When comparing the impact of severe R≫D BSA disparity on graft survival with other known risk factors for graft loss, the HR for graft loss is similar to the impact noted with (a) dialysis time 12 to 24 months versus no dialysis, (b) donor age 35 to 49 years versus less than 35 years, (c) recipient diagnosis HTN, and (d) recipient age more than 50 versus less than 35 years. In ECD transplants, BSA ratio was not independently associated with patient survival, but severe R/D BSA disparity was independently associated with worse allograft survival to a similar degree as the entire cohort, demonstrating an 18% increased risk of graft loss (HR 1.18, P=0.04).

TABLE 2
TABLE 2:
Multivariate analysis of risk factors for patient and graft survival, including BSA ratios for entire deceased donor transplant cohort and ECD cohort 1992–2005
TABLE 2
TABLE 2:
Continued

DISCUSSION

In this study, we show that BSA differences between donor and recipient do contribute to long-term graft survival; but even in the setting of severe size discrepancies, the magnitude of the effect is relatively small. For those recipients who receive kidneys from donors with smaller BSAs, there is a statistically significant, but perhaps less clinically significant, increase in graft loss in unadjusted analysis, which on multivariate analysis is similar to the impact on long-term graft function conferred from donors aged 35 to 49 years and recipients with dialysis waiting time 12 to 24 months. Patient survival is only minimally impacted. Thus, in the overall cohort, BSA disparity may be considered a minor risk factor for graft loss and may be of minimal consideration when assessing if a given deceased donor is appropriate for a recipient.

This is the first report of the impact of donor/recipient size differences in recipients of ECD kidneys. Patients who receive extended criteria donor kidneys are receiving a graft that is known to provide diminished graft and patient survival (18). The early graft loss noted in the R≫D ECD cohort compared with other ECD cohorts on unadjusted analysis (Fig. 3) provides indirect evidence that BSA disparity may contribute to worse early function and graft loss in settings of an already-compromised kidney graft. Our additional findings that severe size disparity was associated with higher rates of DGF, numerically higher rates of acute rejection, higher mean serum creatinine, and worse death-censored graft survival in the ECD cohort (Table 1) support the hypothesis that these posttransplant complications may be more common because of the additional challenges in clinical management (e.g., immunosuppression) of the recipient of both an ECD and size-disparate kidney transplant. However, when considering the historically poor outcomes of potential ECD candidates who remain on dialysis, even these differences in complications and graft survival may not be of sufficient magnitude to support its consideration when determining whether a particular ECD donor kidney is acceptable for a given candidate. Given that patient survival in the R≫D cohort is better than survival of candidates on dialysis historically, and on multivariate analysis, severe donor/recipient size mismatching was not independently associated with mortality (Table 2), the utility of using R/D BSA discrepancy as a significant criterion in donor selection in ECD candidates cannot be supported.

This study is the largest known study to examine size discrepancy over a 14-year period, including time in the modern era of immunosuppression. By using BSA ratios and defining our “severe disparity” cohort to include 5% of all transplants performed, compared with the severe disparity group by Kasiske et al., which included 1.5% of all transplants performed, we hoped to better capture the impact of BSA discrepancies that were of greater frequency and relevance to current transplant practices. Our findings may be less robust in demonstrating an impact of recipient-donor BSA discrepancy on graft survival potentially due to our broader “inclusion criteria.” However, at larger recipient BSA, our cohorts would not be expected to be different. As a hypothetical comparison, inclusion criteria for a given 5-ft 3-in, 120-lb donor with a BSA of 1.56 m2 would permit inclusion of a 6-ft 0-in, 200-lb recipient with a BSA of 2.15 m2 (R/D BSA ratio of 1.39) in our study, whereas the analysis by Kasiske et al. would permit inclusion of a nearly indistinguishable 6 ft 0 in, 210 lb recipient (BSA >2.2 m2).

The proposed mechanism of inadequate nephron dosing contributing to worse graft outcome is that to meet the metabolic demands of the transplant recipient, the donor kidney undergoes glomerular hyperfiltration (13). This hyperfiltration then leads, in part, to progressive interstitial fibrosis contributing to the interstitial fibrosis and tubular atrophy pathologic condition of late allograft failure. The mechanism leading to fibrosis, however, is less clear. It is postulated that the required hyperfiltration from a decreased total number of glomeruli would cause sodium retention, increased risk of hypertension, and reduced renal reserve limiting the functioning glomeruli from being able to compensate in response to injury (13). The degree to which kidneys have already been hyperfiltrating in standard criteria large donors before transplantation is unclear. Luyckx and Brenner hypothesized that a decreased nephron number would predispose individuals to hypertension, proteinuria, and chronic kidney disease, factors likely to be detected on pretransplant donor studies. Some degree of hyperfiltration may already be occurring in ECD kidneys regardless of the donor size. Tan et al. (19) studied the quality of organs by biopsy in a more than 59-year-old cohort and found more sclerotic glomeruli, decreased filtration capacity, and hypertrophy of the remaining patent glomeruli. This study provides a histopathologic basis for our finding that ECD kidneys are less able to tolerate transplantation into size discrepant recipients perhaps because they are already functioning at a maximum level without the ability to hyperfiltrate further. Interestingly, in our study, a relationship between donor/recipient size disparity and graft outcomes was not identified in obese recipients, a finding that is corroborated by the findings of Kasiske et al. It is likely that obesity itself may confer a risk of graft loss and patient survival that minimizes the impact of donor/recipient size mismatching (20). Our study places the risks of donor/recipient size mismatching into context by using a surrogate marker for nephron dosing (R/D BSA ratio) and comparing this risk factor with other commonly accepted risk factors for graft loss. It seems that BSA discrepancies do contribute in a biologic sense to graft survival but perhaps not to a degree that may influence kidney allocation practices.

There have been recent reports of excellent 5-year kidney graft outcomes using pediatric donors to adult recipients, with one study showing a small effect on graft survival when comparing kidneys transplanted to adults from donors weighing 20 to 60 kg versus 10 to 19 kg and a greater effect from donors weighing 5 to 9 kg (21, 22). The potential for enhanced glomerular functional reserve in pediatric kidneys clouds comparisons between pediatric donors and adult donors, and for this reason, our study specifically excluded pediatric donors and en bloc dual kidney transplant recipients. However, these findings are consistent with our findings of a small impact of donor/recipient size mismatching in the adult donor population.

As with any retrospective database analysis, there are weaknesses of this study. The use of BSA is accepted as the most accessible surrogate marker of kidney weight or nephron mass available for large-scale analyses (15), but BSA may not always accurately reflect kidney volume or nephron number (13, 15). A recent publication demonstrated that kidney weight/recipient weight incompatibility is associated with diminished graft survival (23), but this calculation cannot be used in clinical decision making for organ acceptance before surgery, unlike the donor/recipient BSA ratio. There may be additional variables that are predictive of outcomes that were not included in this study and may influence the findings on multivariate analysis. Data regarding immunosuppression were not collected; therefore, we cannot exclude the possibility that differences in outcomes among the various cohorts could have been explained by differences in the type or degree of immunosuppression. We attempted to mitigate this possibility on multivariate analysis by including era as an independent variable and to control for differences in immunosuppression regimens over time.

In conclusion, the issue of nephron “underdosing” determined by donor and recipient BSA disparity and its impact on kidney transplant graft survival can be summarized best as a significant factor of modest consequence. When combined with other risk factors for chronic graft loss, such as in the setting of ECD kidney transplantation, its relevance may be enhanced. Circumstances in which kidney allocation or utilization should be influenced by the goal of minimizing donor/recipient size disparity are unusual and are potentially warranted only in the setting of multiple combined risk factors for graft loss and balanced with the risk of continued waiting time for transplant.

MATERIALS AND METHODS

We used Standard Analysis Files supplied by the Scientific Registry of Transplant Recipients (SRTRs) to perform a retrospective database analysis of 77,289 deceased donor transplants performed from January 1992 through December 2005. The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network, and has been described elsewhere. The Health Resources and Services Administration, US Department of Health and Human Services provides oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors. Transplant pairs without BSA data available for both recipient and donor were excluded from the analysis. Additional exclusion criteria included recipients and donors younger than 18 years and those recipients of dual en-bloc kidneys, leaving 69,737 donor/recipient pairs available for analysis. Donor and recipient BSA was calculated using the Mosteller formula: BSA (m2)=([height {cm}×weight {kg}]/3600)½.

Primary endpoints were 10-year patient and graft survival. For patient survival, patients were followed up until death or kidney graft loss. For graft survival, patient death was included as graft loss regardless of the functional status of the kidney graft at the time of death.

Statistical analysis of baseline characteristics included the Wilcoxon rank sum test for comparison of continuous variables and the chi-square test for association for comparison of categorical variables. Survival analysis was performed using the Kaplan-Meier (product-limit) estimator of survival and the log-rank test to compare survival curves. Univariate analysis and subsequent multivariate analysis using Cox regression was performed to control variables believed to influence the primary endpoints. This study was reviewed and approved by the Colorado Multiple Institutional Review Board.

ACKNOWLEDGMENTS

The authors thank the Scientific Registry for Transplant Recipients for providing Standard Analysis Files of donors and recipients for this study.

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Keywords:

Body surface area; Nephron mass; Kidney transplantation

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