SEARCH

SEARCH BY CITATION

Keywords:

  • Cold ischemia time;
  • delayed graft function;
  • kidney transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Increased cold ischemia time (CIT) predisposes to delayed graft function (DGF). DGF is considered a risk factor for graft failure after kidney transplantation, but DGF has multiple etiologies. To analyze the risk of CIT-induced DGF on graft survival, we evaluated paired deceased-donor kidneys (derived from the same donor transplanted to different recipients) in which one donor resulted in DGF and the other did not, using national Scientific Registry of Transplant Recipients data between 2000 and 2009. Of 54 565 kidney donors, 15 833 were excluded for mate kidney nontransplantation, 27 340 because both or neither kidney developed DGF and 2310 for same/unknown CIT. The remaining 9082 donors (18 164 recipients) were analyzed. The adjusted odds (aOR) of DGF were significantly higher when CIT was longer by ≥1 h (aOR 1.81, 95% CI 1.7–2.0), ≥5 h (aOR 2.5, 95% CI 2.3–2.9), ≥10 h (aOR 3.3, 95% CI 2.7–2.9) and ≥15 h (aOR 4.4, 95% CI 3.4–5.8) compared to shorter CIT transplants. In the multivariable models adjusted for recipient characteristics, graft survival between paired donor transplants, with and without DGF, were similar. These results suggest that DGF, specifically induced by prolonged CIT, has limited bearing on long-term outcomes, which may have important implications for kidney utilization.


Abbreviations: 
BMI

body mass index

CIT

cold ischemia time

DCD

donation after cardiac death

DGF

delayed graft function

ECD

expanded criteria donor

ESRD

end-stage renal disease

HLA

human leukocyte antigen

HRSA

Health Resources and Services Administration

OPO

organ procurement organization

OPTN

Organ Procurement and Transplantation Network

PRA

panel reactive antibodies

SCD

standard criteria donor

SRTR

Scientific Registry of Transplant Recipients

UNOS

United Network for Organ Sharing

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

As the disparity between kidney need and availability continues to widen, efforts to reduce kidney discard are critically important. In 2009, 44% of expanded criteria donor (ECD) kidneys recovered in the United States were not transplanted compared to 10% of standard criteria donor (SCD) and 23% of donation after cardiac death (DCD) recoveries (1). Placement of deceased-donor kidneys to centers outside of the local donor service area offers the potential to reduce discard; however, placement of locally rejected kidneys is often delayed because of the time required to find an accepting center (2). This may lead to prolonged cold ischemia time (CIT), which may contribute to the ultimate discard of the kidney. Based on the response-to-injury hypothesis (3–5), early injury from cold ischemia may set the stage for indolent, yet chronically progressive, damage leading to higher rates of chronic graft loss. In addition, many kidneys not accepted by local centers are considered marginal and clinicians may be reluctant to accept kidneys with a long anticipated CIT for fear of an additive deleterious effect (6).

CIT has clearly been shown to be an independent risk factor for delayed graft function (DGF; Refs. 7–9), and DGF is generally associated with inferior graft survival (7–9); however, the direct impact of CIT-induced DGF on graft survival is unclear (7–17). The etiology of DGF is multifactorial, with some causes of DGF, which are potentially more directly associated with outcomes (e.g. donor quality and technical failures) compared to other causes of DGF, which may or may not have a direct causal relationship with long-term graft failures (e.g. center variation in practice or CIT).

To determine the risks associated with transplantation of deceased-donor kidneys with long CIT, we analyzed national registry data for patient and graft survival of adult transplant recipients of deceased-donor kidney pairs with discordant incidence of DGF. An analysis of mate kidneys from the same donor is optimal to control for the predominant effects of donor quality while illustrating the effects of CIT. In addition, we evaluated associations of CIT with the incidence of DGF and acute rejection using the same-paired donor approach.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

We utilized data from the Scientific Registry of Transplant Recipients (SRTR). 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 (OPTN). The Health Resources and Services Administration (HRSA), US Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors.

Data submitted to the SRTR were accessed to identify all kidney-alone transplant recipient pairs with a common deceased donor in the United States between January 2000 and October 2009. Of 54 565 total kidney donors, 15 833 were excluded for nontransplantation of the mate kidney, 27 340 because both or neither kidney developed DGF and 2310 due to same (n = 1982) or unknown (n = 328) CIT. The remaining 9082 donors or 18 164 recipients were analyzed, of which exactly half had DGF.

A Cox regression model was fitted to compute covariate-adjusted patient survival, graft survival and death-censored graft survival hazard ratios (aHR). CIT and donor variables were not included in these models based on the paired-kidney study design. The following recipient variables were included in these models: age (continuous), gender, race (African American, Hispanic, Caucasian, other), cause of end-stage renal disease (ESRD; glomerulonephritis, diabetes, polycystic kidney disease, hypertension, other), re-transplantation (yes/no), time on dialysis pre- and postplacement on the waiting list and before transplantation (categorized; Ref. 18), number of HLA-A, -B and -DR mismatches (0–6), panel reactive antibody (PRA) level (0, 1–10, 11–30, >30), body mass index, year of transplant (continuous), insurance status (private, medicare, medicaid, other), educational attainment (missing, high school, some college, college) and machine perfusion (yes, no, missing). The appropriate functional form of model covariates was determined by exploratory data analysis in unadjusted models and perceived impact on clinical meaningfulness.

Paired donors were categorized using a donor identifier available in the registry. Recipient outcomes were compared between paired donors stratified by CIT group, in which the kidney with the shorter CIT was placed in the short-CIT group, and its mate with the longer CIT in the long-CIT group. ECD was defined as deceased donations deriving from donors with ages >60 years or >50 years with any two of the following donor criteria: (1) Donor serum terminal creatinine >1.5 mg/dL, (2) hypertension or (3) death from cerebrovascular accident. All other donations were considered SCDs. DGF was defined as reported need for dialysis within 1 week posttransplantation. Transplants were classified as nonlocal, if the donor and recipient transplant center were not in the same organ procurement organization (OPO). Acute rejection is defined as treatment given for acute rejection.

The odds of DGF and acute rejection were assessed using a multivariable-generalized estimating equation adjusted for recipient factors, with paired donors considered a repeated measure in the models. The dependence of observations derived from the kidneys from the same donor was accounted for in Cox models, with adjustment of the standard error of the hazard ratio (sandwich estimator). Overall kidney graft survival (defined as time-to-graft loss or death) plots were generated from Kaplan–Meier models. Relevant characteristics of the donor, the recipient and the graft between patient groups were compared using McNemer's test for categorical variables and paired t-tests for continuous variables based on paired observations.

All analyses were performed using SAS software, version 9.2 (SAS Institute, Inc., Cary, NC, USA). Statistical significance was identified by a p value of >0.05 and all confidence intervals (CI) also used a 95% threshold. This study was approved by the Cleveland Clinic Institutional Review Board.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The study population consisted of 18 164 kidney transplant recipient pairs reported to the SRTR between January 2000 and October 2009. Donor characteristics of the study population included 70.8% standard criteria, 19.8% expanded criteria and 9.4% DCD donors.

The average duration of increased CIT in the pair with longer time was 7.5 h (short CIT group, 15.1 ± 7.0 vs. long CIT group, 22.6 ± 8.6 h). Demographic characteristics of recipients are presented in Table 1. The longer CIT group was comprised of significantly lower proportions of preemptively transplanted recipients and recipients with private insurance; there were higher proportions of recipients with diabetes, BMI >30 kg/m2 higher average age, machine-pumped kidneys, kidneys from zero-HLA mismatched donors and kidneys from nonlocal donors, compared to the longer CIT group. The two groups were similar in terms of the other characteristics evaluated.

Table 1.  Recipient characteristics by cold ischemia time (CIT) groups
CharacteristicShorter CIT group (n = 9081)Longer CIT group (n = 9081)p-Value1
  1. BMI = body mass index; CIT = cold ischemia time; PRA = panel reactive antibodies; HLA = human leukocyte antigens; OPO = organ procurement organization.

  2. 1Testing the difference between the long and short CIT groups (McNemer's test for paired observations).

Age (mean ± SD)50 ± 1551 ± 140.04
African American32%33%0.10
Male62%63%0.43
Primary diagnosis of diabetes25%27%0.001
Retransplant13%13%0.54
Preemptive transplant10%9%0.01
BMI >30 kg/m231%33%0.0002
PRA >30%24%24%0.31
Private insurance28%27%0.04
CIT (in h; mean ± SD)15 ± 723 ± 9<0.0001
HLA mismatches >366%67%0.23
Zero-antigen HLA mismatch11%14%<0.0001
Kidney machine perfusion18%19%<0.0001
Nonlocal donor24%35%<0.0001

Delayed graft function

DGF occurred in exactly 50% of cases based on the study design and was incrementally more likely in the mate kidney with longer CIT. Among paired donors with longer CIT, the DGF rate was 57%. On multivariate analysis adjusted for recipient characteristics, the odds of DGF was 81% greater for a CIT of ≥1 h over the shorter CIT group (aOR 1.8, 95% CI 1.7–2.0), 2.5-fold greater when the CIT was ≥5 h longer (aOR 2.5, 95% CI 2.3–2.9), 3.3-fold greater with a ≥10 h longer (aOR 3.3, 95% CI2.7–2.9) and 4.4-fold greater with a 15+ h longer CIT (aOR 4.4, 95% CI 3.4–5.8) relative to the shorter CIT group (Table 2). Corresponding DGF rates for the longer CIT group were 61%, 64% and 68%, respectively (Figure 1).

Table 2.  Adjusted likelihood of delayed graft function by the difference in cold ischemia time between paired donors
Parameter (reference = short CIT group)Adjusted odds ratio95% Confidence limitsPr >|Z|
  1. Generalized estimating equation was adjusted for age (continuous), gender, race (African American, Hispanic, Caucasian, other), cause of end-stage renal disease (ESRD; glomerulonephritis, diabetes, polycystic kidney disease, hypertension, other), retransplantation (yes/no), time on dialysis pre- and postplacement on the waiting list and before transplantation (categorized), number of HLA-A, -B and -DR mismatches (0–6), panel reactive antibody (PRA) level (0, 1–10,11–30, >30), body mass index, year of transplant (continuous), insurance status (private, medicare, medicaid, other), educational attainment (missing, high school, some college, college) and machine perfusion (yes, no, missing) with donors considered a random effect.

CIT ≥1 h longer (n = 18 164)1.811.661.97<0.001
CIT ≥5 h longer (n = 10 350)2.542.272.85<0.001
CIT ≥10 h longer (n = 4792)3.252.733.86<0.001
CIT 15+ h longer (n = 2258)4.443.425.75<0.001
image

Figure 1. Proportion of patients with delayed graft function by CIT groups.“*” represents the delayed graft function defined as need for dialysis within first week posttransplantation based on McNemar's test for paired observations (donors); all comparisons p < 0.001.

Download figure to PowerPoint

Graft and patient survival

Unadjusted graft survival rates between patients with delta CITs of ≥1, ≥5 and ≥10 h were not significantly different between recipients with higher CIT relative to the paired donor recipients with lower CIT (Figures 2A–C); however, there was a significant decrement in overall graft survival in the longer CIT group with a CIT difference ≥15 h compared to the shorter CIT group (Figure 2D). The significant findings of the unadjusted analysis did not persist after adjustment for recipient factors. On multivariate analysis, there were no significant differences in the risk of overall graft loss or death-censored graft loss between short and long CIT groups, regardless of the extent of CIT difference (Table 3).

imageimage

Figure 2. (A) Kaplan–Meier plots of overall graft survival donor pairs with shorter and longer cold ischemia time. (B) Kaplan–Meier plots of overall graft survival of kidney donor pairs with shorter and longer cold ischemia time with ≥5 h difference. (C). Kaplan–Meier plots of overall graft survival of donor pairs shorter and longer cold ischemia time with ≥10 h difference. (D) Kaplan–Meier plots of overall graft survival of donor pairs shorter and longer cold ischemia time with ≥15 h difference, p = 0.01.

Table 3.  Cox proportional hazard models for overall graft loss, death censored graft loss and patient loss by CIT groups
Study group (reference level)Outcome
Overall graft lossPatient deathDeath censored graft loss
AHR95% Confidence intervalAHR95% Confidence intervalAHR95% Confidence interval
  1. All models adjusted for age (continuous), gender, race (African American, Hispanic, Caucasian, other), cause of end-stage renal disease (ESRD; glomerulonephritis, diabetes, polycystic kidney disease, hypertension, other), retransplantation (yes/no), time on dialysis pre- and postplacement on the waiting list and before transplantation (categorized), number of HLA-A, -B and -DR mismatches (0–6), panel reactive antibody (PRA) level (0, 1–10,11–30, >30), body mass index, year of transplant (continuous), insurance status (private, Medicare, Medicaid, other), educational attainment (missing, high school, some college, college) and machine perfusion (yes, no, missing). Standard errors adjusted for dependence of donor pairs using sandwich estimator. AHR = adjusted hazard ratio; CIT = cold ischemia time.

Longer CIT group (shorter CIT group)1.030.97–1.091.010.94–1.091.040.96–1.12
≥5 h longer CIT group (shorter CIT group)1.030.96–1.111.040.94–1.141.050.95–1.16
≥10 h longer CIT group (shorter CIT group)1.060.95–1.181.120.97–1.291.050.90–1.21
15+ h longer CIT group (shorter CIT group)1.150.97–1.351.271.03–1.571.070.86–1.33

Overall patient death rates were not significantly different between the shorter CIT groups relative to the CIT groups with delta CITs of ≥1, ≥5 and ≥10 h (Table 3); whereas, a delta-CIT of ≥15 h was associated with a 27% greater risk of death (aHR 1.27, 95% CI 1.03–1.57), compared to the shorter CIT group (Table 3).

Acute rejection

The overall rate of acute rejection within 1 year after transplantation was 11%. The proportion of patients that were treated for acute rejection within 1 year by CIT group is displayed in Figure 3. Between each of the four delta-CIT levels of shorter and longer CIT, there was no statistically significant difference in the proportion of acute rejection. In the multivariable-generalized estimating equations, these results were consistent and demonstrated no significant association of CIT with acute rejection.

image

Figure 3. Proportion of patients with acute rejection at 1 year by CIT group. Note: Among patients with a minimum of 1-year graft survival; no comparisons statistically significantly different based on McNemar's test for overall paired observations or for increasing CIT groups based on the Mantel–Haenszel chi-square test.

Download figure to PowerPoint

Stratified analyses

In the subset of ECD transplants that were from brain dead donors (n = 3446), there was no statistically significant difference in time to overall graft loss associated with the kidney with the longer CIT (aHR 0.95, 95% CI 0.85–1.07). Similarly, there were no statistically significant differences in time to overall graft loss associated with the kidney with longer CIT for the DCD/SCD or the DCD/ECD groups, although the analysis of the latter subgroup is limited by insufficient sample size (Table 4).

Table 4.  Delayed graft function rates and unadjusted and adjusted hazard ratios for overall graft loss for longer CIT-paired donor by deceased donor category (reference is shorter paired donor)
Deceased donor typeNDGF longer CIT pairDGF shorter CIT pairUnadjusted hazard ratio for overall graft loss (reference: shorter CIT pair)AHR for overall graft loss (reference: shorter CIT pair)
  1. DGF = delayed graft function; SCD = standard criteria donor; ECD = expanded criteria donor; DCD = donation after cardiac death; AHR = adjusted hazard ratio.

  2. 1Sample size insufficient to adjust for full covariate set.

SCD/non-DCD1301658%42%1.06 (0.99–1.13)1.04 (0.98–1.12)
ECD/non-DCD 344654%46%0.98 (0.87–1.10)0.95 (0.85–1.07)
SCD/DCD 154659%41%1.12 (0.88–1.43)1.08 (0.83–1.39)
ECD/DCD  15654%46%1.69 (0.98–2.92)1

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

One of the concerns of the current allocation system for deceased-donor kidneys is that increased CITs, incurred while attempting to place kidneys, may have a deleterious impact on transplant outcome and, thereby, inhibit acceptance rates. Using SRTR data of paired kidney transplants with discordant DGF rates between 2000 and 2009, we found that although the odds of DGF was significantly higher with increasing durations of CIT, graft survival was similar regardless of the difference in CIT between the paired kidneys. This may be important evidence that donors with prolonged CIT offer an important benefit to recipients and are a potential source to expand national transplant rates.

Previous large multivariable analyses have generally reported worse graft survival associated with increasing CIT. The Collaborative Transplant Study found greater risks of graft failure with CITs >18 h (11), and an analysis of US Renal Data System found a continuous worsening of outcome associated with each 6-h increase in ischemia (7). A major limitation of these studies is the likely inability of multivariate models to accurately adjust for important donor quality confounders, which may not always be codified in standard registries, a problem that is ameliorated with the use of a paired kidney analysis. In addition, baseline renal functionality is a strong predictor of long-term renal function (19), yet currently measured variables, such as, serum creatinine and estimated glomerular filtration rate, may not fully account for baseline renal functionality.

The absence of an effect of CIT on graft survival in our study is similar to the negative findings by other paired kidney analyses (15–17). Lim et al. (15) noted that recipients of either shipped or locally transplanted well-matched renal allografts have similar graft and patient survivals. We previously reported overall similar overall graft survival for 441 regional and 311 national nonmandatory share kidneys relative to locally transplanted mates (16). Stegall et al. (17) found no significant difference in the survival of payback kidneys compared with locally transplanted mismatched kidneys. Interestingly, our analysis demonstrated a significant association of CIT with patient survival for the group with delta CITs of ≥15 h. This finding may be related to recipient selection as recipients of the longer CIT donors had higher proportions of known risk factors for patient death (fewer preemptively transplanted recipients and fewer recipients with private insurance; higher proportions of recipients with diabetes, BMI >30 kg/m2 and a higher average age). Although, we adjusted the analysis for known recipient confounders, there may be other risk factors not ascertained in the national dataset that are not included in the analysis. In addition, there may be combinations of donor and/or recipient characteristics or interactions between factors that influence outcomes but are not captured in our multivariate models.

This paired analysis of kidney recipients demonstrates that despite a strong association of CIT with DGF, graft survival was similar regardless of CIT differences of 15 h or more over the CIT of the first transplanted mate kidney. We hypothesize that the DGF caused by prolonged CIT is due to acute tubular necrosis, which is largely sublethal damage and recoverable (20); and therefore, does not impact long-term function. These findings are similar to those seen in graft outcomes in kidney transplantation of DCD kidneys from standard-criteria donors. In spite of the terminal warm ischemia inherent in the DCD-donor organ recovery process, resulting in high DGF rates, it has been shown that short- and medium-term graft survival rates are similar between donation after brain death standard-criteria donors and DCD donor kidney grafts, suggesting that ischemic injury is likely to be a reversible lesion (21).

The national sharing system in the United States is an important method for kidney placement. Most discarded kidneys are not rejected by one, but by many transplant centers. Our finding that CIT induced DGF is not associated with graft survival among kidney pairs, has important implications for transplant centers considering utilization of kidneys with anticipated prolonged CITs. In particular, kidneys currently discarded due to CIT are likely to provide a significant benefit to patients. The perception that these kidneys are too high risk, which may not be fully supported by empirical evidence, may have led to discard, whereas, results of this study could potentially highlight the utility of these organs.

Our analysis demonstrated a significant increase in DGF for kidneys with longer CITs than their mates. Incremental increases in DGF were also seen with increasing duration of CIT from the reference kidney. Although the findings of our study suggest that CIT induced DGF is not an independent risk factor for graft failure in deceased-donor kidney transplants, other consequences of DGF noted in previous studies are substantial including prolonged hospitalization, higher cost of transplantation, increased complexity of management of immunosuppressive drugs and an adverse effect on the rehabilitation potential of transplant recipients (22–25).

Acute rejection was not associated with CIT in our study. These findings are in accordance with the findings of some studies (9,12), but not in others (11,14). Giblin et al. (14) found acute rejection rates to be significantly lower for first kidneys compared to second kidneys transplanted (22.3% vs. 28.1%, p < 0.01) in an unadjusted paired analysis at a single center. Opelz et al. (11) demonstrated a 20% increase in rejection risk on nonpaired multivariate analysis only when kidneys were preserved for more than 36 h and suggested that prolonged cold storage results in increased allograft immunogenicity. Others suggest a correlation of CIT with graft fibrosis (26,27). Kim et al. (26) studied the effects of transient ischemia in mice and demonstrated increased production of reactive oxygen species resulting in fibrosis. Kuypers et al. (27) reported that DGF solely due to ischemia (in the absence of rejection) correlates strongly with the presence of fibrosis in the renal allograft at 3 months posttransplant.

Our results are subject to the limitations inherent in observational data. Because recipients are often not randomly selected to receive kidneys, it is possible that they are in some unmeasured way systemically less (or more) healthy than recipients of kidneys with long CIT kidneys. A recipient selection bias may exist, in which transplant centers that are utilizing a kidney with long CIT may select a “less-healthy” recipient than what would be selected for a kidney with shorter CIT. For example, the differences in recipient characteristics suggest a recipient selection bias that may explain the poorer overall patient survivals in the delta CIT ≥15 h group compared to the shorter CIT group. There is the possibility for residual confounding as a result of recipient- or center-related factors not included in the OPTN data. Our analyses included many, but not all, of the factors that may confer risks at or after transplantation, such as, implantation technique, anastomosis time, recipient anatomy, immunosuppression type and dosing, recipient anatomic abnormalities, preservation solution type utilized during machine perfusion and length of machine perfusion. The paired kidney analysis allows for the adjustment for most donor factors, but it is not possible to capture anatomical abnormalities in one of the kidneys (multiple vessels, extent of atherosclerosis, injured vasculature) that could lead to technical difficulties, independent of recipient factors. In addition, there may be combinations of donor and/or recipient characteristics or interactions between factors that influence outcomes but are not captured in our multivariate models. Lastly, there may be a CIT threshold at which graft outcomes begins to deteriorate that would not be detected in any analysis due to the paucity of cases with extremely long CITs. Potential issues relating to the determination of acute rejection include missing or incomplete data, reporting bias, sampling and technique errors, measures of quantification and subjective interpretation.

There has been extensive focus in the field of transplantation on recovery and placement of all possible donor organs. Although increasing CIT is a risk factor for DGF in our analysis, there is limited effect of CIT on graft survival suggesting that CIT induced DGF may not be associated with diminished long-term outcomes of deceased-donor kidneys. These data may suggest important opportunities to increase transplant rates of previously discarded organs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The data, reported here, have been supplied by the Minneapolis Medical Research Foundation as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References