Pre-implant biopsy predicts outcome of single-kidney transplantation independent of clinical donor variables.

CLINICAL

AND

TRANSLATIONAL RESEARCH

Pre-Implant Biopsy Predicts Outcome of Single-Kidney Transplantation Independent of Clinical Donor Variables Johannes Hofer,1,2 Heinz Regele,1 Georg A. Bo¨hmig,3 Georg Gutjahr,4 Zˇeljko Kiki(,3 Ferdinand Mu¨hlbacher,5 and Josef Kletzmayr6,7 Background. Pre-implant biopsy findings account for the discard of many donor kidneys although their clinical value is not fully understood. We retrospectively investigated the predictive value of pre-implant histology, which in our center was obtained for protocol purposes, not for transplant decisions, on long-term allograft and recipient outcome after single-kidney transplantation. Methods. This single-center study included 628 consecutive adult recipients of 174 Expanded Criteria Donor (ECD) and 454 Standard Criteria Donor kidneys. Chronic donor organ injury was assessed applying a chronic lesion score differentiating between mild, moderate, and severe histologic organ injury based on the integration of glomerular, vascular, tubular, and interstitial lesions. Recipients were followed over a median time of 7.8 years. Results. Donor kidneys exhibiting mild or moderate chronic lesions yielded almost identical graft and recipient survival independent of ECD status or other clinical covariables (HR 1.20, 95% CI 0.83Y1.74, P=0.326, and HR 1.27, 95% CI 0.83Y1.95, P=0.274, respectively). However, if allograft injury was severe, occurring in 3% of transplanted kidneys, graft and recipient survival was significantly reduced (HR 3.13, 95% CI 1.61Y6.07, PG0.001 and HR 2.42, 95% CI 1.16Y5.04, P=0.005, respectively). Conclusion. The results suggest that donor kidneys displaying moderate chronic injury can safely be transplanted as single kidneys, while organs displaying severe injury should be discarded. Thus, pre-implant biopsy might offer an effective approach to increase the utilization of renal donor organs, especially from ECD and donors with cerebrovascular accident as cause of death, and to improve overall graft outcome. Keywords: Donor-derived damage, Kidney transplantation, Expanded criteria donor, Allograft survival, Dual-kidney transplantation. (Transplantation 2014;97: 426Y432)

n the Unites States, the number of patients suffering from end-stage renal disease (ESRD) waiting for a renal donor organ is still growing, while in the Eurotransplant region a decline in the number of transplant candidates can be observed (1, 2). One reason for this might be the more liberal use of organs from older donors in Eurotransplant as reflected by a steady increase in the median donor age over the last years. Since 2007, the median age for deceased kidney donors in Eurotransplant has been above 50 years (2), while

the respective data from the United Network of Organ Sharing (UNOS) in the United States show an increase to just 40 years (3). To increase utilization of kidneys from deceased donors, UNOS implemented the definition of the Expanded Criteria Donor (ECD) based on clinical donor data (4, 5). ECD kidneys carry a relative risk of graft loss of greater than 1.7 as compared to organs from Standard Criteria Donors (SCD). An ECD is defined by age greater than 60 years or

Supported in part by Health Resources and Services Administration contract 234-2005-370011C The authors declare no conflict of interest. 1 Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria. 2 Institute of Immunology, Medical University of Vienna, Vienna, Austria. 3 Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria. 4 Competence Centre for Clinical Trials, University of Bremen, Bremen, Germany. 5 Department of Surgery, Medical University of Vienna, Vienna, Austria. 6 Department of Medicine III, SMZ-Ost/Donauspital, Vienna, Austria. 7 Address correspondence to: Josef Kletzmayr, M.D., Department of Medicine III, SMZ-Ost/Donauspital, Langobardenstrasse 122, 1220 Vienna, Austria. E-mail: [email protected]

J.H., H.R., G.A.B., and J.K. participated in making the research design. J.H., H.R., and J.K. performed the research. Zˇ.K. participated in performing the research. J.H., H.R., G.A.B., G.G. F.M., and J.K. analyzed and interpreted the data. G.G. performed the statistical analyses. J.H. and J.K. wrote the article. All authors participated in the correction and finalization of the article. Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Received 22 April 2013. Revision requested 7 May 2013. Accepted 6 September 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9704-426 DOI: 10.1097/01.tp.0000437428.12356.4a

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& Volume 97, Number 4, February 27, 2014

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

* 2014 Lippincott Williams & Wilkins

by age 50 to 59 plus at least two out of the following three criteria: cerebrovascular accident (CVA) as cause of death, serum creatinine greater than 1.5 mg/dL, or history of hypertension. ECD kidneys are allocated to ESRD patients who have given informed consent to accept such an organ. Despite this promising concept, the proportion of ECD whose organs are utilized has leveled off at 16% (3), mostly because of the discard of recovered organs based on preimplant biopsy findings, which accounted for 51% of ECD-kidney discards in the United States in 2009, corresponding to 699 kidneys (3). Pre-implant histology has been widely used for organ selection (6, 7); however, to date there are no generally accepted protocols for the histologic assessment of organ quality with respect to transplant outcome. To increase utilization of available donor kidneys, especially those from ECD, reliable prognostic tools for the estimation of graft survival are needed and will be indispensable for developing innovative concepts of kidney allocation (8 Y10). The present retrospective single-center study on a large unselected cohort aimed to assess whether pre-implant biopsy findings would allow for the identification of organs from both ECD and SCD carrying an increased risk of allograft failure independent of clinical donor data. The verification of this hypothesis would provide a scientific basis for an increased utilization of kidneys from both ECD and SCD carrying chronic tissue injuries, while identifying those organs with an unacceptable risk of allograft failure.

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RESULTS Donor and Recipient Characteristics and Degree of Chronic Lesions in ECD and SCD Kidneys The degree of chronic donor organ injury as expressed by the chronic lesion score (CLS; see Materials and Methods; see also Table S1, SDC, http://links.lww.com/TP/A886) was significantly higher in ECD kidneys than SCD organs (PG0.001), and kidneys displaying severe chronic tissue injury (CLS 7Y12) significantly more often derived from ECD (PG0.001; Fig. 1; see Figure, S1, SDC, http://links.lww.com/TP/A886). The same was true for the four individual histologic lesions: amount of globally sclerotic glomeruli and degrees of arterial/ arteriolar narrowing, tubular atrophy, and interstitial fibrosis (PG0.001; see Figure, S2, SDC, http://links.lww.com/TP/A886). ECD and SCD kidneys exhibited a median CLS of 4 and 2, respectively (PG0.001). While the majority of SCD kidneys displayed mild chronic lesions (CLS 0Y3; 85.9%), a small proportion of organs was moderately injured (CLS 4Y6; 12.8%), and only a few exhibited severe chronic lesions (1.3%). Among ECD kidneys, the proportion of both severe and moderate graft injury was considerably higher (7.5 and 44.8%, respectively). About half of the ECD kidneys displayed mild tissue injury (47.7%; see Table S2, SDC, http://links.lww.com/TP/A886). CVA as cause of death was significantly more frequent in ECD than SCD (PG0.001). However, in all cases of severe chronic lesions in ECD and SCD organs, donors had died of CVA (Table 1; see Table S2, SDC, http://links.lww.com/TP/A886).

FIGURE 1. Kaplan-Meier analysis of death-censored graft and recipient survival. Graft and recipient outcomes were assessed among recipients of ECD and SCD kidneys with respect to pre-implant histologic donor organ injury applying the chronic lesion score (CLS).


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TABLE 1. Characteristics of donors and recipients at the time of transplantation

Donors N (total N=421) Age, median (IQR), yr Sex, % male Creatinine, median (IQR), mg/dL CVA, % Hypertension, % Recipients N (total N=628) Age, median (IQR), yr Sex, % male Sensitization (PRA 95%), % HLA mismatch, % 0 1Y2 3Y4 5Y6 Cold ischemia time, % G12 h 12Y23 h Q24 h

SCD

ECD

P

315 42.5 (16.6) 40.6 0.71 (0.31)

106 63.8 (8.0) 59.4 0.75 (0.34)

0.036 0.001 0.899

49.0 7.9

85.5 50.0

G0.001 G0.001

454 49.3 (12.0) 39.6 23.6

174 56.9 (13.5) 35.6 20.1

12.6 29.5 50.0 7.9

3.4 19.5 63.8 13.2

33.7 53.5 12.8

47.1 41.4 11.5

0.541 0.406 0.405 G0.001

G0.001

SCD, standard criteria donors; ECD, expanded criteria donors; CVA, cerebrovascular accident as cause of death; P, P value, considered significant if PG0.05.

While in ECD hypertension was present significantly more often than in SCD (PG0.001), there was no significant difference in the renal function of ECD and SCD (P=0.899; Table 1; see Table S2, SDC, http://links.lww.com/TP/A886). Initial immunosuppression among ECD-kidney and SCD-kidney recipients was comparable (see Table S3, SDC, http://links.lww.com/TP/A886).

Graft and Recipient Outcomes All 628 recipients were followed for a median time of 6.8 years (interquartile range, 6.3). Median follow-up time for recipients without event was 7.8 years. Twenty-four recipients (3.8%) were lost in the follow-up. Up to 5 years after transplantation, ECD kidneys exhibiting mild or moderate chronic lesions did not differ with respect to allograft and recipient survival rates (Fig. 1). However, after 5 years there was a trend towards inferior graft and recipient outcome for ECD kidneys with moderate as compared to mild organ injury. In contrast, graft and recipient survival for SCD organs with mild or moderate chronic lesions were comparable over the whole observation period. In a multivariate model, the trend towards inferior graft and recipient survival for organs with CLS 4 to 6 as compared to CLS 0 to 3 after 5 years disappeared following adjustment for clinical donor and recipient risk factors (Table 2). If organ injury was severe, graft and recipient survival rates were markedly reduced for both ECD and SCD kidneys. Importantly, reduced graft and recipient


outcomes of severely injured organs were not influenced by fully adjusting the model for clinical covariables. These findings on 628 kidney allograft recipients were verified in the recipients of the 529 kidneys that underwent histologic analysis (see Materials and Methods; see Table S4, SDC, http://links.lww.com/TP/A886). Among the causes for allograft loss in recipients of severely injured organs, allograft rejection was of minor importance (see Table S5, SDC, http://links.lww.com/TP/A886), and the major cause of death among these recipients was sepsis (see Table S6, SDC, http://links.lww.com/TP/A886). None of the four individual histologic lesions constituting the CLS predicted graft survival, although there was a trend for the amount of globally sclerotic glomeruli (P=0.07; see Table S7, SDC, http://links.lww.com/TP/A886). Graft function 1 year and 5 years after transplantation showed a significant deterioration with increasing CLS (Fig. 2A; PG0.001). For functioning donor kidneys exhibiting mild, moderate, or severe lesions, the eGFR (mL/min) was 60.2T27.8, 44.3T25.7, or 36.8T28.7 1 year and 55.1T29.7, 37.8T25.4, or 34.2T20.5 5 years after transplantation, respectively. Delayed graft function (DGF) significantly more often occurred in recipients of ECD organs than in recipients of SCD kidneys (24 vs. 16%; P=0.018), but DGF rates among recipients of ECD or SCD organs with the same CLS were similar (Fig. 2B). An analysis of graft survival in our cohort based on ECD criteria revealed ECD kidneys to carry a relative risk for graft failure of 1.76 as compared to SCD kidneys (95% confidence interval 1.31Y2.35, PG0.001). Adjusting these data for the CLS reduced the elevated relative risk for graft loss of ECD kidneys to 1.54, but the difference remained significant (95% confidence interval, 1.12Y2.12, PG0.007).

DISCUSSION The present study indicates that allograft and recipient survival after transplantation of single kidneys displaying moderate chronic lesions (CLS 4Y6) in pre-implant biopsy are similar to that of organs exhibiting mild tissue injury (CLS 0Y3). Only the presence of severe chronic lesions (CLS 7Y12) was a significant predictor for allograft loss and reduced recipient survival. The latter effect remained statistically significant in the multivariate analysis and is, therefore, assumed to be independent of clinical donor and recipient risk factors. While the absence of a significant difference in survival rates between CLS 0 to 3 and CLS 4 to 6 does not prove that no such difference exists, the small effect estimate suggests that any such possible effect will not be clinically relevant. This thesis is supported by the post hoc power analysis (outlined in Materials and Methods) showing that the study would have had a high probability to detect any effect difference of clinically meaningful magnitude. As expected, allograft function 1 year and 5 years after transplantation was significantly better for organs displaying mild lesions as compared to the other groups. Although graft function of moderately injured organs was significantly better than that of functioning organs exhibiting severe injury, the difference in eGFR was small. However, this does not contradict the superior graft and recipient survival of moderately injured organs, as severely damaged organs may


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TABLE 2.

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Model of graft and recipient survival with adjustment for donor and recipient risk factors (also see Table S4) Death-censored graft survival

Graft survival

Unadjusted CLS 0Y3 CLS 4Y6 CLS 7Y12 Adjusted for donor age CLS 0Y3 CLS 4Y6 CLS 7Y12 Adjusted for donor creatinine 91.5 mg/dL CLS 0Y3 CLS 4Y6 CLS 7Y12 Adjusted for donor hypertension CLS 0Y3 CLS 4Y6 CLS 7Y12 Adjusted for CVA as donor cause of death CLS 0Y3 CLS 4Y6 CLS 7Y12 Adjusted for donor age, donor creatinine 91.5 mg/dL, hypertension, and CVA as donor cause of death CLS 0Y3 CLS 4Y6 CLS 7Y12 Fully adjusted* CLS 0Y3 CLS 4Y6 CLS 7Y12

Recipient survival

HR

95% CI

P

HR

95% CI

P

HR

95% CI

P

1.00 1.45 3.24

Reference 1.05Y2.00 1.74Y6.04

0.023 G0.001

1.00 1.57 3.11

Reference 1.07Y2.29 1.57Y6.18

0.020 0.001

1.00 1.57 3.11

Reference 1.07Y2.29 1.57Y6.18

0.020 0.001

1.00 1.30 2.88

Reference 0.91Y1.84 1.52Y5.44

0.147 0.001

1.00 1.31 2.62

Reference 0.86Y1.99 1.29Y5.30

0.203 0.008

1.00 1.31 2.62

Reference 0.86Y1.99 1.29Y5.30

0.203 0.008

1.00 1.50 3.37

Reference 1.08Y2.07 1.81Y6.29

0.014 G0.001

1.00 1.61 3.22

Reference 1.10Y3.36 1.62Y6.40

0.015 G0.001

1.00 1.61 3.22

Reference 1.10Y2.36 1.62Y6.40

0.015 G0.001

1.00 1.43 3.14

Reference 1.02Y1.99 1.66Y5.94

0.036 G0.001

1.00 1.53 3.00

Reference 1.04Y2.27 1.48Y6.07

0.033 0.002

1.00 1.53 3.00

Reference 1.04Y2.27 1.48Y6.07

0.033 0.002

1.00 1.51 3.39

Reference 1.08Y2.10 1.81Y6.35

0.015 G0.001

1.00 1.55 3.08

Reference 1.05Y2.31 1.52Y6.20

0.029 0.002

1.00 1.55 3.08

Reference 1.05Y2.31 1.52Y6.20

0.029 0.002

1.00 1.36 3.05

Reference 0.95Y1.94 1.60Y5.79

0.091 G0.001

1.00 1.35 2.72

Reference 0.88Y2.07 1.32Y5.60

0.168 0.007

1.00 1.35 2.72

Reference 0.88Y2.07 1.32Y5.60

0.168 0.007

1.00 1.20 3.13

Reference 0.83Y1.74 1.61Y6.07

0.326 G0.001

1.00 1.27 2.42

Reference 0.83Y1.95 1.16Y5.04

0.274 0.018

1.00 1.27 2.42

Reference 0.83Y1.95 1.16Y5.04

0.274 0.018

CLS, chronic lesion score; HR, hazard ratio; CI, confidence interval; CVA, cerebrovascular accident; * for donor age, donor creatinine 91.5 mg/dL, donor hypertension, and CVA as donor cause of death, body mass index, adrenalin-use pre-procurement, recipient age, number of previous transplantations, recipient sensitization, HLA-mismatch, and cold ischemia time; P, P value, considered significant for PG0.05.

exhibit a reduced adaptive capacity towards peritransplant and posttransplant insults (11, 12). Internationally, the assessment of pre-implant histology has been an important tool for the selection of donor kidneys for many years (6, 7), leading to the discard of a considerable number of recovered organs (3). Although there are a number of studies identifying glomerular (13 Y19), vascular (20 Y26), or tubular and interstitial lesions (23, 24, 26 Y29) as well as composite histologic lesion scores (30 Y32) as potential predictors of transplant outcome, various limitations of these investigations have to be considered, such as small study size, short follow-up times, the application of varying tissue sampling procedures (wedge vs. needle core biopsy), preferential tissue sampling from kidneys of older donors, and, finally, a lack in comprehensive consensus-based protocols for the assessment of pre-implant histology. Strikingly, in ECD kidneys the mere performance of pre-implant biopsy was found to be significantly associated with increased odds of organ discard

(33). Thus, non-use of donor organs based on pre-implant biopsy findings can hardly be considered to be evidence based. To avoid these drawbacks, the present study was conducted on a large unselected cohort applying the CLS, a composite histologic scoring system assessing chronic renal lesions in pre-implant biopsies, which was proven to yield both reproducible and representative results (34). At the center, pre-implant wedge biopsy of donor kidneys is routinely performed for protocol purposes only, not for organ selection, thus excluding any pre-analysis selection bias. To allow for a reliable assessment of long-term graft and recipient outcome, the cohort was followed over a median time of 6.8 years (interquartile range, 6.3), recipients without event even for 7.8 years, representing considerably longer follow-up times than most previous studies (13, 16, 20, 21, 24, 32, 35). Another biopsy-based approach to increase utilization of kidneys from older donors is dual-kidney transplantation


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FIGURE 2. Renal allograft function. A, graft function 1 year and 5 years after transplantation was significantly dependent on the CLS (PG0.001, ANOVA). Box plots indicate median, IQR, and range. Outliers are indicated as open dots. B, the delayed graft function (DGF) rate of ECD or SCD organs from the distinct CLS groups.

(36, 37), based on the idea of supplying a transplant candidate with both kidneys of a suboptimal donor to provide an adequate functional nephron mass. In the largest published series, based on the same histologic scoring system we applied, moderately injured organs were successfully transplanted as dual kidneys, while organs exhibiting severe injury were discarded (32). In the series of single-kidney transplantations, outcomes of ECD kidneys displaying mild or moderate lesions were similar, thus, questioning the rationale for dual-kidney transplantation in this specific context. This view is supported by the fact that patients undergoing dual-kidney transplantation who had experienced failure of one kidney were reported not to require dialysis since the second of the two kidneys remained functional (32). The application of the dual-kidney transplantation policy to our cohort would have reduced the number of recipients provided with ECD kidneys by 24%, corresponding to 39 patients. Our data on a significantly increased risk of graft failure for ECD kidneys as compared to SCD organs (HR 1.76) are in line with the UNOS ECD definition (5) confirming its suitability to identify donor organs with an elevated risk

Transplantation


of graft failure. However, pre-implant histology was independently associated with outcome in recipients of both ECD and SCD if organ injury was severe, thus making histology a reliable tool to identify both ECD and SCD organs carrying a markedly elevated risk of graft failure. There are some limitations to the present study, like its retrospective design, or the performance of wedge biopsy, resulting in the presence of arteries in a minority of samples. The issue of adequate tissue sampling was addressed in a recent study providing evidence that the performance of a standardized pre-implant biopsy using a skin punch biopsy tool was safe and more reliable for the assessment of donorderived chronic allograft damage than the performance of wedge biopsy (38). Organs of the collective displaying severe tissue injury had a CLS of 7 or 8, representing the lower range of the CLS for severe injury (CLS 7Y12). Consequently, graft survival for organs with CLS greater than 8 cannot be estimated by the present study. Whether a 5-year graft survival of approximately 50% for these organs is acceptable or not, or whether these organs might be suitable for dual-kidney transplantation, will require discussion on a broad basis. An ‘‘unacceptable risk’’ for graft loss needs to be defined and, thus, a cut-off CLS to exclude unsuitable organs. These questions can only be answered by a prospective study. In conclusion, a moderate degree of chronic lesions even in ECD kidneys can safely be accepted yielding excellent allograft and recipient outcomes after single-kidney transplantation. Only a small proportion of donor kidneys displaying severe tissue injury showed a significantly reduced graft survival. These organs obviously were unsuitable for single-kidney transplantation and should have been discarded. Because all kidneys exhibiting severe chronic lesions were derived from donors who died from CVA, the assessment of a standardized pre-implant punch biopsy in all kidneys originating from these donors according to the CLS is proposed, independent of ECD status. Allografts originating from donors whose cause of death was not CVA can safely be allocated according to ECD criteria. Thus, the assessment of pre-implant histology according to the CLS could act as a safety net on the way to maximize usage of available donor kidneys.

MATERIALS AND METHODS Study Patients and Donor Evaluation Consecutive patients undergoing adult deceased donor single-kidney transplantation at the Vienna General Hospital between January 1, 1999 and December 31, 2003 were included in the present study. Patients experiencing combined organ transplantations were excluded, as well as organs from donors after circulatory death. Pre-implant wedge biopsy was routinely performed for protocol purposes alone, thus excluding any pre-analysis selection bias. A total of 658 organs were available. Biopsies were performed for 555 organs (84.2%), while for the remaining 103 organs (15.8%) only values from their corresponding partner kidneys were available. While these 103 donor organs were excluded from the histologic analysis, they were included in the recipient follow-up analysis, based on the analysis of 105 pairs of corresponding partner kidneys showing fair agreement in the CLS (rank correlation coefficient r=0.620; see Table S8, SDC, http://links.lww.com/TP/A886). From these 658 organs, 30 organs (4.6%) with biopsies containing less than 10 glomeruli were excluded from the analysis. Thus, the follow-up analysis was performed with the recipients of 628 kidneys derived from 421 donors, 174 kidneys (27.7%) originating from 106 (25.2%) ECD, and 454 kidneys (72.3%) deriving from 315 SCD


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(74.8%; Table 1). The follow-up analysis was then repeated using only organs for which a biopsy was performed and which contained at least 10 glomeruli (529 organs; see Table S4, SDC, http://links.lww.com/TP/A886). Clinical donor and recipient data were collected from the databases of the Vienna Transplant Centre and Eurotransplant International Foundation, Leiden, The Netherlands. Clinical endpoints comprised date of graft loss, patient death, and estimated glomerular filtration rate in patients with functioning grafts calculated according to the Mayo Clinic equation (39). Donors were classified according to the ECD definition (5). To assess the influence of distinct clinical covariables on the prognostic reliability of pre-implant histology, we analyzed long-term graft and recipient survival rates adjusting for clinical donor and recipient risk factors (for details see Statistics section). The study was approved by the institutional review board of the Vienna General Hospital (EK Nr. 812/2009).

ACKNOWLEDGMENTS The authors thank Axel Rahmel for help with the retrieval of data from Eurotransplant International Foundation and Mario Pones from the Transplant Coordination Office of the Vienna General Hospital for the retrieval of data from the local transplant data bank. We are indebted to Catherine Monstello from the Organ Procurement and Transplantation Network for providing data on biopsy-driven organ discard of ECD and SCD kidneys.

REFERENCES 1. 2.

Tissue Processing and Histologic Evaluation Pre-implant wedge biopsies were processed for routine light microscopy. Formalin-fixed, paraffin-embedded 2-Hm tissue serial sections were stained with hematoxylin and eosin, Periodic Acid-Schiff, Acid Fuchsin Orange-G, and methenamine silver. The histologic evaluation was performed by a blinded single observer (J.H.), intermittently verified by a second observer (H.R.) applying a protocol for the histologic evaluation of chronic renal organ damage that was proven to yield both reproducible and representative results (34, 37, 40). The number of glomeruli in pre-implant wedge biopsies ranged from 10 to 163 with a mean of 36T21. In 18.2% of the biopsies, at least one artery was present. According to this composite scoring system, the amount of globally sclerotic glomeruli and the degrees of arterial/arteriolar narrowing, tubular atrophy, and interstitial fibrosis were assessed (see Table S1, SDC, http://links.lww.com/TP/A886). The severity of lesions found for each of these histologic criteria were scored from 0 to 3, with 0, 1, 2, and 3 representing no, mild, moderate, and severe tissue injury, respectively. The four single scores were summed up to form a sum score ranging from 0 to 12, to which we refer to as the chronic lesion score (CLS) throughout this manuscript. Depending on the CLS, the kidneys of a respective donor were classified either mildly (CLS 0Y3), moderately (CLS 4Y6), or severely injured (CLS 7Y12).

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Statistics Baseline characteristics of donors and recipients in the SCD and ECD groups were summarized by median and interquartile range for continuous variables and by proportions for categorical variables. Increase in proportions of organs from ECD donors over ordinal lesion categories were tested by chi-square tests for trend (Cochran-Armitage trend test). Survival functions were estimated using the product-limit (Kaplan-Meier) method. Because for some donors both organs were transplanted, survival times are not independent. To account for the correlation between organs from the same donor, frailty models (mixed-effects Cox models) were applied. These survival analyses were performed with respect to three distinct end points (graft survival, death-censored graft survival, and patient survival) and different covariate adjustment (unadjusted or adjusted for clinical donor risk factors like age, creatinine 91.5 mg/dL, hypertension, CVA as cause of death, body mass index or adrenalin-use pre-procurement, and recipient risk factors like age, number of previous transplantations, sensitization, HLA mismatch, and cold ischemia time). Because of their small number, missing values were excluded from the statistical model. Covariables were selected based on UNOS-ECD criteria and medical expertise. P values below 5% were considered significant. To validate the findings on the predictive significance of the CLS on graft survival, a post hoc power calculation was performed for the comparison of CLS 0 to 3 versus 4 to 6; the power for a postulated hazard ratio of 1.5 or 1.7 would have been 81% or 97%, respectively. In addition, a post hoc power calculation was performed for the comparison of 0 to 6 versus 7 to 12; the power for a postulated hazard ratio of 3 or 4 would have been 70 or 84%, respectively.

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