Objectives: We explored the categorizing of expanded criteria donors based on systemic disease processes linked to symmetric bilateral renal injury.

Materials and Methods: We evaluated expanded criteria donor kidneys where the paired kidney was discarded owing to biopsy results, termed the discard group compared with those expanded criteria donors (where both were transplanted), termed the nondiscard group. Analysis of the Organ Procurement and Transplant Network data was completed focusing on the effect of glomerulosclerosis.

Results: Our investigation revealed 754 and 9575 recipients in the discard group and nondiscard groups. Fewer glomerulosclerosis was seen the nondiscard group. An assessment revealed improved 1-, 3-, and 5-year graft (P < .001) and patient (P < .05) survivals in the nondiscard group compared with the discard group. However, multivariate analysis demonstrated glomerulo-sclerosis had little to no effect on graft and patient survival. Expanded criteria donor kidneys with 0% to 5% glomerulosclerosis had no significant differences in graft function as compared with expanded criteria donor kidneys that had > 10% glomerulosclerosis. In fact, expanded criteria donor kidneys with 0% to 5% glomerulosclerosis showed no statistically significantly protective effect over any biopsy with > 5% glomerulosclerosis in patient survival.

Conclusions: Owing to the limited supply of biopsy results in predicting outcomes when controlled for pertinent variables, relying on biopsy findings for kidney allocation may result in many valuable kidneys being discarded.

Key words : Transplantation, Glomerulosclerosis, Acute tubular necrosis

Introduction

The kidney transplant waiting list exceeds the donor pool in the United States, generating a challenge for the transplant community. Based on the Organ Procurement and Transplant Network (OPTN) data as of July 20, 2012, ninety-two thousand seven hundred forty-nine kidney transplant candidates were on the wait list while the OPTN reports 16 815 total kidney transplants were performed in 2011.¹ According to the 2009 Scientific Registry of Transplant Recipients (SRTR) annual report, 17.0% of all deceased donor transplants were from expanded criteria donors.² In 2002, the criteria for expanded criteria donors (ECDs) were defined, and consisted of donors aged > 60 years, or those aged 50 to 59 with at least 2 of the following findings: (1) terminal serum creatinine > 132.60 μmol/L (2) cause of death as cerebrovascular accident, or (3) presence of hypertension. Expanded criteria donor kidneys had a relative risk of graft loss of 1.70 compared with standard criteria donor kidneys (SCD).³ Although data have shown inferior results using ECD kidneys compared with SCD kidneys, patient survival has been demonstrated to benefit ECD kidney recipients compared with their counterparts that remain on the kidney transplant wait list.⁴

Expanded criteria donor kidneys have increased the kidney donor pool, and their use continues to expand. From 1997 to 2006, analysis of organ donation and use demonstrated an 88%-fold in the number of patients on the kidney transplant wait list; however, it also showed be noted that 16% of all recovered kidneys were discarded in 2006, which had risen from 10% in 1997. Despite this increase in the percentages of kidneys discarded, the overall number of kidney transplants increased by 23%. The rise in kidney transplants was multifactorial in nature; however, increased kidney recovery from ECD and donation after cardiac death (DCD) played the most important role.⁵

The percentage of kidneys discarded are higher in ECDs than in SCDs for several reasons, and biopsy results have been reported as a leading cause of ECD discard as they are biopsied at a rate more than 3-fold that of SCD kidneys.⁶ Of note, SCD kidneys are rarely biopsied before transplant. These biopsied ECD kidneys are under greater scrutiny due to their high-risk characteristics and biopsy results. While previously published studies show that biopsies demonstrated glomerulosclerosis as an important predictor of graft function,⁷ there are also conflicting data, showing that biopsy results are not always associated with graft performance.⁶

We hypothesized that the glomerulosclerosis reported would be higher in both kidneys in a pair where 1 was discarded owing to biopsy and 1 was used compared with ECD pairs with both kidneys were allocated. Our objective was to determine if ECD kidney performance where the paired kidney from the same donor was discarded owing to biopsy results compared with ECDs where both kidneys were transplanted. Because criteria for ECDs are related to bilateral systemic disease processes, we hypothesized that these discarded kidneys might have endured similar systemic insult and thus could potentially perform the same way in the setting of discrepant biopsies. Based on the fact that these kidneys were (in all likelihood) discarded based on glomerulosclerosis reported, we hypothesized that this is an inadequate measure to determine outcomes for these ECD kidneys.

Materials and Methods

Data source
Upon approval by the Institutional Review Board of Thomas Jefferson University, we reviewed STAR FILES obtained from the United Network for Organ Sharing (UNOS) on all data submitted to the SRTR and OPTN including information on donors and recipients. Data in this study spans April 2, 1994, to June 12, 2010. Outcomes were assessed looking specifically at single-organ transplant with deceased donor ECD kidneys. Kidney donors from before 2002 were considered ECD if they met the criteria defined in 2002.4 Dual kidney transplants (n = 1314) as well as those with missing graft survival time (n = 104) were excluded from the study. The study end date was June 12, 2010. All of the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all subjects.

Method analysis
After excluding patients for the aforementioned reasons, the first group consisted of 754 patients transplanted with an ECD kidney where the paired donor kidney was discarded owing to biopsy findings with this group termed the DG. The second group received ECD kidneys where both kidneys were transplanted into 2 separate recipients termed the NDG. In the NDG, 1 ECD kidney was randomly chosen to perform the evaluation yielding 9575 kidneys to evaluate the decrease in size between the groups.

Biopsy scoring was graded on a standard score reported in the SRTR database related to percentage of glomerulosclerosis within the donor sample listed as 1 (0%-5%); 2 (6%-10%); 3 (11%-15%); 4 (16%-20%); and 5 (> 20%). Biopsy scoring for each group was expressed in mean values in the Results section to compare each cohort.

Variables for analyses were chosen based on differences seen between the NDG and the DG, and also chosen based on known factors that contribute to overall patient survival and graft survival.

Primary outcomes of this study include overall graft survival and overall patient survival. Secondary outcomes included acute and chronic rejection, length of hospital stay, and delayed graft function (DGF). Delayed graft function was defined as the need for dialysis support within the first week after kidney transplant. Differences in glomerulosclerosis were analyzed to evaluate the effect on the primary outcomes mentioned above.

Statistical analyses
Donor and recipient demographics and characteristics were summarized using means and percentages, as appropriate. Groups were compared using the 2-sample t test for continuous variables and Pearson chi-square test for categorical variables. A paired t test was used to compare biopsy scores between discarded and nondiscarded kidneys of the same donor. The distribution of graft and overall survival was estimated using the Kaplan-Meier method, and groups were compared using the log-rank test. Graft survival was censored at the earliest death, the last follow-up, or the last expected follow-up, and the end date of study. Multivariate Cox proportional hazards regression was used to compare groups after adjustment for potential confounding factors. Statistical analyses were completed using SAS (version 9.2; SAS Institute, Cary, NC, USA).

Results

Donor demographics and characteristics were examined showing a difference in donor age between the 2 cohorts with mean age in the DG of 61.9 years compared with 59.7 in the NDG (P < .001). No statistically significant difference in cold ischemia time was identified between the DG and NDG groups at 20.0 and 20.7 hours (P = .0571). Donor terminal serum creatinine was similar in both groups, with DG having a mean value of 109.616 μmol/L and NDG at 107.848 μmol/L (P = .685). Donor cause of death, specifically regarding the cerebrovascular accident, was not different between the groups. Further donor characteristics including donor risk factors are shown in Table 1.

Recipients in the DG group were older (mean age, 58.2 y vs 55.4 y) in the NDG group (P < .001). Hepatitis C virus antibody positivity was also higher in the DG group at 8% compared with 5.5% in the NDG group (P = .016). Additional recipient demographics are reported in Table 1.

Based on the above database scoring system, analysis of reported donor biopsy scores demonstrated significant differences between the 2 cohorts. A mean biopsy score of 1.7 was revealed in kidneys distributed to NDG patients, which was significantly less than mean score of 2.1 in donor kidneys biopsied and distributed in the DG. The paired kidneys of those transplanted in the DG that were discarded demonstrated a mean score of 3.0 (P < .001). Table 2 demonstrates the distribution of glomerulosclerosis among both cohorts including missing biopsy reports.

Delayed graft function was similar and reported in 33.7% and 34.8% of patients in the NDG and DG groups (P = .551). Length of posttransplant hospital stay also was similar with patients in the NDG group staying a mean of 9.8 days, and those in the DG group staying a mean 10.6 days (P = .362). Furthermore, there were no significant differences in acute or chronic rejection between the cohorts. Acute rejection was seen in 9.2% of patients in the NDG and 12.71% of patients in the DG group (P = .122), while chronic rejection was seen in 7.9% in both groups.

Biopsy results also were the most common reason for discard among all pairs of ECD kidneys where 1 kidney was transplanted and 1 was discarded. Examining all discarded ECD kidneys (where the paired kidney was transplanted) revealed that 33.3% were declined owing to biopsy findings. The next most common reported reason for discarding these ECD kidneys was anatomic abnormality at 12.1% of the time. Table 3 lists the other major causes of discard in this ECD group.

Univariate analysis revealed a statistically significant decrease in graft survival in recipients in the DG group with 1-, 3-, and 5-year survival of 77%, 61%, and 44% compared with the NDG group with 1-, 3-, and 5-year graft survival of 83%, 70%, and 56% (P < .001; Figure 1). Multivariate Cox regression analysis demonstrated an increased risk of graft failure in the transplanted kidney when the paired kidney is discarded owing to biopsy results. Having the least glomerulosclerosis (0%-5%) was only significantly protective regarding graft survival compared with those kidneys that had 6% to 10% glomerulosclerosis read on biopsy. Kidneys with biopsies demonstrating > 10% glomerulosclerosis showed no significant decrease in graft survival when compared with those with 0% to 5% glomerulosclerosis. The complete multivariate analysis examining graft survival is shown in Table 4.

Univariate analysis examining patient survival also showed significant differences. The 1-, 3-, and 5-year patient survival were found to be 89%, 78%, and 66% in the DG group, while the NDG group had 1-, -3, and 5-year survival of 91%, 82%, and 72% (P = .0162; Figure 2). On multivariate analysis, no statistically significant difference was demonstrated in patient survival between the DG and NDG groups. Furthermore, having a donor biopsy with the least percentage of glomerulosclerosis (0%-5%) was not protective regarding overall patient survival with no statistically significant difference demonstrated when compared with the other biopsy results including all kidneys with > 5% glomerulosclerosis. The remainder of the multivariate analysis is demonstrated in Table 5.

Discussion

This analysis sought to determine the performance of kidneys that were procured from ECDs, and transplanted with the paired kidney being discarded owing to biopsy findings. Analyses demonstrated that ECD kidneys that were discarded owing to biopsy reports had a worse mean biopsy score when compared with the kidneys transplanted in the DG and NDG groups. Our hypothesis was that these kidneys would have the most glomerulosclerosis reported; however, they would still endure similar systemic insult and thus might perform equivalently to the paired kidney. On multivariate analyses, we found that glomerulosclerosis had a minimal effect on graft and patient survival when controlled for confounding variables. Finding a way to increase the donor pool without compromising graft or patient survival is an important yet difficult challenge for those involved in kidney transplant.

In evaluating all ECD pairs, where 1 kidney was discarded and 1 was transplanted, the most common reason for organ refusal was the biopsy finding in our analysis. Furthermore, there has been a trend where the percentage of kidneys discarded owing to biopsy findings has increased as the number of donor biopsies being performed, especially in ECDs.⁸ Although significantly worse graft function is associated with increased percentage of glomerulosclerosis in the past,⁷ a 3-year graft survival of 74.7% in kidneys that had a donor implantation biopsy consistent with > 25% glomerulosclerosis also has been reported.⁹ The results of our study’s multivariate analysis show that when comparing allograft biopsies showing 0% to 5% glomerulosclerosis, no significant benefit in graft or overall patient survival compared with kidneys with > 10% glomerulosclerosis was reported on biopsies. This particular finding raises the question of reliability of these biopsy scores; perhaps we should not be discarding kidneys from ECDs based on increased glomerulosclerosis readings in the setting of a discrepant biopsy between a pair of ECD kidneys.

We did find some significant differences between the cohorts including donor age, incidence of donor diabetes, and hypertension. This is not surprising given that these are risk factors for glomerulosclerosis in donor kidneys, which have been demonstrated to be higher in the analysis of the biopsies in the DG.¹⁰ There was a significantly older mean recipient age in the DG, which might be explained by the willingness to transplant older patients with ECD kidneys as seen in previous studies.¹¹ In addition, we saw age as an independent risk factor for graft and overall patient survival. The analysis demonstrates that male recipient gender was an independent variable associated with worse graft survival likely due to the hormonal influences including the dihydro-testosterone-mediating effects of androgens on allograft nephropathy.¹² In addition, donor and recipient ethnicity were found to affect graft survival. An African American donor and recipient appear to be associated with worsen graft survival in this analysis, which again, has been previously reported.¹³

Retransplant also has been shown to be an independent risk factor for graft failure, which has been previously reported14; however, some reports do find similar results in retransplanted patients. We found PRA levels to be associated with worse graft and patient survival, similar to reports that show increased rejection and decreased long-term graft survival in these patient populations.^15,16 Additionally, we demonstrated recipient diabetes mellitus, a disease associated with glomerulosclerosis, to have significant negative effects regarding graft and patient survival, and recipient HCV to decrease graft survival, which has been previously reported.¹⁷

The limitations of many studies evaluating deceased donor allograft biopsies are the different biopsy techniques used, lack of comprehensive histologic assessment, and pathologist variability.¹⁸ Differences in wedge biopsy size may cause inconsistent histologic assessment ultimately leading to variable results. In fact, shallow biopsies have been found to overestimate the percentage of glomerulosclerosis in deceased donor kidneys owing to the vulnerability of those glomeruli that are located more superficially.¹⁹ Reproducibility of baseline and follow-up biopsies is also a function of the number of glomeruli sampled.²⁰ The quality of the donor biopsy results must be questioned as surgeons base many decisions on frozen sections and on histologic evaluation by nontransplant pathologists.

Agreement between paired kidneys from the same donor has been evaluated regarding glomerulosclerosis, which is an important aspect in our analysis because it is impossible to look at performance of a discarded kidney such as those in the DG. A previous report states that with < 5% glomerulosclerosis reported there is a 90.2% to 90.6% intrapair agreement. However, above 5% glomerulosclerosis, there was significantly decreased agreement among kidney pairs demonstrated (6%-10% glomerulosclerosis showed 50.8% agreement, 11%-15% showed 31.1% agreement, 16%-20% showed 24.8% agreement, and > 20% showed 63.4% agreement). Interestingly, this same report showed no difference in performance in kidneys among different cohorts that demonstrated > 5% glomerulosclerosis,21 which was similar to our results. The UNOS/OPTN database does not report biopsy size producing variability in glomeruli sampled and perhaps explaining varying results demonstrated in cohorts that have > 5% glomerulosclerosis.

Based on data reported in 2009 by the United States Renal Data System (USRDS), patient survivals at 1, 3, and 5 years while on HD were found to be 79%, 53%, and 35%.²² Patients who received an ECD kidney in the DG had a better survival seen than those patients on HD as reported above. These are not controlled comparisons as the overall HD population includes patients unsuitable for transplant; however, a recent report of patients aged > 60 years on the kidney transplant wait list have a 48% survival at 5 years.²³ Earlier studies have shown survival benefit to ECD transplant over those patients who remain on the wait list.²⁴ In 1 report, it was shown that at 244 days, patient survival was equivalent, but after that time point, transplant inferred a survival benefit,²⁵ which the DG cohort in our study has a mean survival well over that time.

Another important aspect of ECD kidney transplant is the overall cost. Financial expenses of both kidney transplants and HD results in extremely high expenses in the health care community. Analyses have shown that ECD kidney transplant is a less expensive alternative than chronic HD in ESRD patients.²⁶ It is thought that the increase in hospital admission cost during transplant admission seen in ECD transplants when compared to SCD is due to DGF and length of hospital stay.²⁶ Interestingly, kidneys in the DG compare similarly with the NDG regarding DGF and length of hospital stay.

One main limitation of this study is the fact that the paired discarded kidney cannot be analyzed and compared to its counterpart. We can only speculate that based on the limited effect of glomerulosclerosis seen in this study and the fact that ECD criteria are based on systemic disease, these kidneys may have performed similarly. Other limitations of this study include its retrospective, nonrandomized nature, and the use of the SRTR/OPTN database, which contains missing data points, which is a well-known limitation of this type of study. Another limitation is the lack of kidney size reported for the donated kidneys, which might further control for differences among a pair of kidneys. Other pitfalls include variability in donor selection criteria between transplant centers and variability of pathologists reading frozen section slides of the donor biopsy. Any comparison to HD patients is limited because of the difficulty of truly comparing these 2 populations and long-term outcomes given that many HD patients do not meet criteria for transplant. Future studies might aid in comparing overall patient outcomes of those on the transplant waiting list, those on HD, and those who received kidneys such as in the DG. In addition, some variables chosen in our multivariate analysis did not show statistical significance, which might be related to the large sample size discrepancy between the cohorts.

Conclusions

Our group postulates that kidneys that were discarded and transplanted from donors of the DG endured similar systemic insult owing to the nature of the definition of an ECD. Not surprisingly, kidneys in the DG had worse biopsy results when compared with NDG kidneys, and subsequently, the analysis demonstrated better long-term graft performance in the NDG. Despite the findings using univariate analysis, biopsy results, themselves, had a minimal effect on overall graft survival and no influence on patient survival after multivariate analysis. Owing to the results demonstrated with reported glomerulosclerosis, we believe that grafts with discordant biopsies from an ECD should warrant careful and comprehensive evaluation with biopsy findings having less effect on the decision to discard a potentially transplantable kidney.

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