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NDT Advance Access originally published online on October 30, 2007
Nephrology Dialysis Transplantation 2008 23(3):1054-1060; doi:10.1093/ndt/gfm709
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Effect of the shipment of cadaveric renal allografts on allograft survival

Michèle Kessler1, Jean-Marc Virion2,3, Mourad Hachicha1, Bruno Moulin4, Olivier Toupance5, Jean-Michel Rebibou6 and Francis Guillemin2,3

1 Department of Nephrology, Nancy, France 2 Department of Clinical Epidemiology and Evaluation Nancy, France 3 CIC-EC INSERM, Strasbourg, France 4 Department of Nephrology, Strasbourg, France 5 Department of Nephrology, Reims, France 6 Department of Nephrology, Besançon, France

Pr Michèle Kessler, Service de Néphrologie, Hôpitaux de Brabois, Hôpital d’Adultes, rue du Morvan, 54511 Vandoeuvre cedex, France. Tel: +33-383153163; Fax: +33-383153169; E-mail: m.kessler{at}chu-nancy.fr



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
Background. Since 1996, the allocation of grafts in France has been based on a hierarchical three-level system: national, regional and local. The objective of this study was to determine whether the shipment of cadaveric kidneys according to these new exchange rules affects allograft outcome in the Eastern region of France.

Methods. This retrospective study analysed all renal transplants performed in the four centres of the French Eastern region during 3 years (1996 to 1998). All patients were followed up until death, return to dialysis, last information date or the end of June 2003. Information regarding the donors, recipients and treatments, as well as patient and graft outcome, was recorded. Factors associated with graft loss were analysed using Cox proportional hazard methods.

Results. 542 transplants were analysed, 287 (53%) kidneys were transplanted locally, 229 (42.2%) kidneys coming from exchanges within the region and 26 (4.8%) from another region. There were statistically significant differences between the four centres for donors’ and recipient’ characteristics and for immunosuppressive treatment, but there was no difference between centres regarding patient survival (94.4% at 5 years), graft survival (83.7% at 5 years) or death-censored graft survival (87.8% at 5 years). Compared to locally transplanted grafts, shipped grafts had significantly better human leukocyte antigen (HLA) matching (2.5 ± 1.3 versus 2.1 ± 1.0 matches, P = 0.0005 but a longer cold ischaemia time (23.2 ± 7.9 versus 19.2 ± 7.8 h, P < 0.0001). Three independent factors were associated with a reduced graft survival: at least one acute rejection, delayed graft function and a shipped graft.

Conclusion. The results of this study suggest that the shipment of cadaveric renal allografts in a regional distribution system is associated with better HLA matching but is a significant predictor of graft loss at 5 years. It would be advisable to restrict graft sharing to patients whose access to transplantation is limited, taking special care to avoid any additional factors having a detrimental effect on the outcome.

Keywords: exchange rules; HLA matching; ischaemia time; renal transplant; shipped kidney; survival



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 
Kidney transplantation is the therapy of choice for end-stage renal diseases. Its success has contributed to larger numbers of patients on waiting lists, while the number of available cadaveric kidneys is declining. Organ allocation algorithms have been designed and implemented to balance equity and efficiency, but the persistent shortage of organs has led to a quest for improved allocation schemes. Several kidney-sharing programmes have been based on results of human leukocyte antigen (HLA) matching leading to national or regional sharing systems [1,2,3]. Some have argued that this kind of program is associated with an increased duration of cold ischaemia time which is a strong risk factor for delayed graft function and graft loss in patients receiving mismatched pay-back kidneys [4,5]. On the other hand, the allocation of cadaveric kidneys on the basis of HLA compatibility might be considered as disadvantageous in small centres because the chance of receiving a matching organ is reduced [6]. It is also disadvantageous for minority populations [7].

New rules regarding organ allocation were written in France when the Etablissement Français des Greffes, the national agency in charge of organ transplantation, was established in 1994. The country was divided into seven geographical ‘regions’ grouping together local centres, enabling the creation of a three-level (national, regional, local) hierarchical system for cadaveric kidney allocation. Priority categories were set up within each level with possible appeal to expert committees concerning exceptional cases of priority or derogation [3].

The Eastern region included four renal transplant centres located in Besançon (Franche-Comté), Nancy (Lorraine), Reims (Champagne-Ardennes) and Strasbourg (Alsace) University Hospitals, which provide care for a total population of 6 413 530 inhabitants. In January 1996, after approval from the Etablissement Français des Greffes, the four centres implemented new regional exchange rules designed to give regional priority to patients with two HLA-DR compatibilities. At this time, HLA class II compatibility was shown to be associated with a positive effect on graft survival [8]. Because of the number of specificities, the two DR matche rule was expected to result in a substantial number exchange grafts.

The objective of this retrospective study was to determine whether the shipment of cadaveric kidneys according to the new French exchange rules affects allograft outcome in the Eastern region.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Statistical analysis
 Results
 Discussion
 References
 
At the time of this study, grafts were allocated according to the following rules in decreasing order of priority: national priority for hyper-sensitized patients (PRA >80% anti-HLA antibodies) with five or six HLA matches, full-matched kidneys, paediatric recipients and patients awaiting a combined kidney-heart or kidney-liver transplant; regional priority for patients with two DR matches on the basis of a team-to-team reciprocity, an iso-group kidney being returned within the next 6 months and local priority, the kidney being transplanted locally. In addition to the exchange rules described above, the shipment of a kidney within the region was always possible.

All the renal transplants performed in the four centres of the French Eastern region during 3 years (1996 to 1998) were retrospectively examined using the databases of the Etablissement Français des Greffes and the transplant centres. Among the 610 identified renal transplantations, transplantations with a living donor (n = 12), paediatric transplantations (<16 years old, n = 13), combined kidney–heart, kidney–liver or kidney–pancreas transplantations (n = 27) and pre-emptive transplantations (n = 16) were excluded from the analysis. All patients were followed up until death, return to dialysis, last information date or the end of June 2003.

The following parameters were analysed: age, gender, cause of death, body mass index (BMI) and the Cytomegalovirus (CMV) status of the donor; duration of cold ischaemia; age, sex, BMI, number of previous grafts, delay between the current graft and the time of listing, delay between the current graft and the start of dialysis, CMV status, number of HLA matches, presence of historical anti-HLA antibodies, for the recipient; after the transplantation, use of anti-lymphocyte antibodies as induction treatment, need for dialysis and number of sessions, acute rejection during the first year following the transplantation, last available information about graft function and immunosuppressive treatment were recorded.



   Statistical analysis
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 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
Results
 Discussion
 References
 
Quantitative data were compared between local and shipped grafts using the Kruskall–Wallis test, qualitative data using a {chi}2 test. Patients’ survival analyses were performed by the centre using the Kaplan–Meier method and compared using a log-rank test. Graft survival was analysed using the Kaplan–Meier method for data from the donor, the recipient and the on exchange procedure. As 84% of the patients who died had a functional graft, a death-censored graft survival analysis was also performed. These analyses were followed by a Cox proportional hazards regression analysis. All statistical analyses were performed using SAS software, version 8.2 (SAS Institute, Inc., Cary, NC, USA).



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
Discussion
 References
 
Out of the 610 renal transplants performed in the Eastern region from January 1996 to December 1998, 542 were included in the analysis. Taking into account the rules defined above, 9 kidneys (1.7%) were allocated according to the national priority, 107 (19.7%) according to the regional priority and 248 (45.8%) according to the local priority. The remaining 178 kidneys (32.8%) were pay-back kidneys according to the regional exchange rules or corresponding to out-of-priority exchanges.

By consequence, 286 (52.8%) kidneys were transplanted locally: 229 (42.2%) kidneys coming from exchanges within the region and 27 (5%) from another region (Figure 1).


Figure 1
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  		Fig. 1 Geographical origin of renal graft for each centre.

 
There were significant differences between the centres regarding donors’ age (P = 0.017), duration of cold ischaemia (P < 0.0001), maximal historical level of anti-HLA antibodies (P = 0.021) and use of peritoneal dialysis before the transplantation (P = 0.029) There were also significant differences between centres regarding induction treatment with anti-lymphocyte globulins (P < 0.0001), rate of patients with at least one acute rejection (P = 0.001) and the last immunosuppressive treatment (P < 0.0001).

Characteristics of local and shipped grafts were compared (Table 1). Significant differences were found regarding cold ischaemia time: 19.2 ± 7.9 h for graft locally transplanted versus 23.2 ± 7.9 h (P < 0.0001) for shipped graft, with a larger rate of shipped grafts having a cold ischaemia time longer than 20 h (56.1% of shipped grafts versus 30.4% of local grafts, <0.001). Significant differences were also found regarding immunologic parameters confirming that the exchanges rules were respected. Finally, renal function was better for local grafts compared with shipped grafts: plasma creatinine level at the end of follow-up was 133.4 ± 51.9 versus 150.3 ± 93.4 µmol/L.


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  		Table 1 Comparison of local and shipped grafts

 
The mean follow-up was for 53 months [0–85]. During the study period, 32 deaths were reported. The survival rates were therefore 98.1, 95.7 and 94.4% at 1, 3 and 5 years respectively with no difference between centres. Dialysis was resumed for 63 patients. The graft survival estimate was 92.2, 87.2 and 83.7% at 1, 3 and 5 years respectively, with no difference between centres. The death-censored graft survival rate was estimated to be 93.3% at 1 year, 90.4% at 3 years and 87.8% at 5 years, with no difference between centres.

Comparing locally transplanted versus shipped grafts using Kaplan–Meier analysis, survival was significantly better for local than for shipped grafts (93.3, 90.1 and 87.5% versus 91, 83.9 and 79.4% at 1, 3 and 5 years respectively (P = 0.026) (Figure 2).


Figure 2
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  		Fig. 2 Kaplan–Meier survival of locally transplanted versus shipped renal allografts.

 
Univariate analysis demonstrated that two factors were significantly associated with decreased graft survival (Table 2): acute rejection (RR = 2.08 [95% CI 1.35–3.20]) and delayed graft function requiring dialysis (RR = 2.01 [1.27–3.19]). A local graft (RR = 0.59 [0.39–0.90]) was associated with a better graft survival. Donor age, as a continuous variable was not significant (P = 0.382) and we confirmed that it was not kept significant in the multivariate model (P = 0.504). Shipped grafts were more frequently allocated to pre-sensitized recipients but an interaction of pre-sensitization could not be demonstrated (P = 0.882 with PRA >5% and P = 0.254 with PRA >50%). Multivariate analysis demonstrated that acute rejection, delayed graft function and a local graft were independent predictors of graft survival (Table 3).


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  		Table 2 Risk factors for graft loss—univariate analysis

 

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  		Table 3 Risk factors for graft loss—multivariate analysis

 
Among the 256 shipped kidneys, 78 were exchanged according to priorities and 178 were pay-back or out-of-priority kidneys. Table 4 shows comparison of these grafts with priority-based kidneys. As expected, they had a lower HLA compatibility but there was no other significant difference. Kaplan–Meier analysis of priority-based shipped grafts (89.7, 83.2 and 79.7% at 1, 3 and 5 years) showed that survival was similar for pay-back and out-of-priority grafts: 91.6, 84.2 and 79.3% (P = 0.97).


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  		Table 4 Comparison of priority and pay-back and out-of-priority shipped grafts

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
References
 
In the French Eastern region, from January 1996 to December 1998, 53% of the transplantations were performed with kidneys harvested locally, while 42% of grafts were the results of exchanges within the region, half of them following the regional priority. These data should be compared with the rates of 44 and 46% for local and regional graft origin respectively, for the whole France in 1998 [9]. Under these conditions, 21% of renal transplants were HLA-DR identical. Following the established priority rules improved the regulation of the activity of the four centres. Simultaneous transplants, known to be a difficult burden for the medico-surgical teams, were avoided as was any prolonged period of interrupted activity due to slow retrieval activity.

The patient survival rate was 98.1, 95.7 and 94.4% at 1, 3 and 5 years respectively, similar to the national rates of 96.2% at 1 year and 93.8% at 3 years for patients transplanted between 1992 and 1997 [9].

Graft survival in the Eastern region was 83.7% at 5 years, to be compared with a national 5-year graft survival of 79.7% for patients transplanted between 1995 and 2002 [10].

The significant variables associated with graft survival in our study were ‘acute rejection’, ‘delayed graft function’ and ‘graft shipping’.

The data on the influence of shipment on graft survival should be compared with the results of a study assessing the survival of shipped and locally transplanted cadaveric renal allografts from 5446 pairs of cadaveric kidneys in which one kidney was shipped and the other was transplanted locally [4]. After adjustment for the degree of HLA mismatching, shipped organs had a significantly higher rate of allograft failure than locally transplanted organs in the first year after transplantation. The authors conclude that the degree of HLA mismatching and the duration of cold ischaemia are important determinants of the survival of shipped allografts, but the effect of one offsets the effect of the other. In our study, the negative impact of shipment remains despite better matching, with 30.5% HLA-DR identical kidneys within the exchanged kidneys versus 11.3% within the local ones (P < 0.001). The multivariate analysis of graft survival at 5 years showed the absence of an HLA effect, including the absence of any DR-matching effect. While the usefulness of zero-HLA mismatch has been amply demonstrated regarding renal graft survival [8,11–13], the number of renal transplantations performed in France is insufficient to have a large number of fully matched grafts. In the Mange population [4], there was only one fully matched graft in each group, while 17.2% of exchanged kidneys and 1.1% of local kidneys were fully matched. This result is consistent with the recent results from Su et al. who demonstrated, in the United States, a time trend suggesting that HLA matching was of diminishing significance, while no immunologic factors remained equivalently important [14]. A recent Spanish study assessed the evolution of graft failure after the first year in 3865 adult patients who underwent transplantation in 1990, 1994 and 1998. Although a worsening in the degree of HLA matching was reported, there was a significant improvement in graft survival in this centre where harvesting and transplantation are performed in the same hospital, facilitating the reduction of cold ischaemia time, as organized by the Spanish system [15].

Delayed graft function needing dialysis and occurrence of at least one acute rejection were considered as two independent factors associated with a negative outcome in our study, as also reported by Salahudeen et al. [5]. These factors are usually considered as associated with a longer cold ischaemia time [5], a parameter usually reported as associated with a poorer graft survival [11,16]. It is noteworthy that, in our study, despite a significant difference between centres regarding the rate of rejection, there was no difference regarding graft survival. Possible explanations could be found in different biopsy decision-making processes in the case of renal function impairment, and in different immunosuppressive treatments [6].

Although cold ischaemia time did not appear in our study to be a significant factor directly associated with a negative outcome, the location of transplant in comparison with the place of retrieval was identified as a significant factor, with a significantly better survival for grafts locally transplanted (difference of 6% for the graft survival at 5 years) in comparison with exchanged grafts. The comparison of locally transplanted grafts and shipped grafts demonstrated that cold ischaemia time above 20 h, a threshold which has been previously considered as associated with an appreciable increase in the failure rate [5], was more common among shipped grafts. Plasma creatinine at last visit was higher for shipped grafts. Better results regarding graft survival with grafts locally transplanted have already been demonstrated [4–6]. Moreover, it has been demonstrated [17] that a significant increase in cold ischaemia time when sharing zero-mismatched kidneys is not associated with an increased risk for graft loss, neither, as expected, for zero-HLA mismatched kidneys, nor, more surprisingly, for pay-back kidneys. These results associated with the lesser impact of HLA matching have led some authors to advocate regional [5,14] or local [6] distribution of organs and less stringent tissue matching. In our study, which was limited to the regional level in France, sharings were associated with shorter survival and cold ischaemia times were similar to those reported in the United States where the geographical distances are much greater. CIT was significantly longer for shipped grafts but other potential donor-, recipient- or transplantation- dependent factors were not analysed. Among shipped grafts, 69.5% were pay-back or out-of-priority kidneys. It could be hypothesized that these kidneys were of lower quality and as such more readily proposed than a ‘good’ transplant. We searched for significant factors but found that except for the expected better HLA-DR compatibility for priority-based shipped grafts, no other difference could be identified. The methodological issues associated with a retrospective study and its usual bias in terms of data collection cannot be ignored.

Because of the geographic disparities in organ allocation operating in France at the time of the study, it is difficult to extrapolate these results to the whole country [18]. A similar study, performed on a national basis, with controlled data and rigorous statistical methodology would be useful. Our results suggest that the shipment of renal allografts is associated with an increased rate of graft failure at 5 years. It would thus be advisable to restrict sharing to patients whose access to transplantation is limited, taking special care to avoid additional factors having a detrimental effect on the outcome.



   Acknowledgments
 
This study has been supported by a grant from the Etablissement Français des Greffes. We acknowledge the contribution of Laurence Saya, MD, Altius Pharma CS, Paris, France, in writing this manuscript.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Statistical analysis
 Results
 Discussion
 References
 

  1. United Network for Organ Sharing (UNOS) Policies 2004. http://www.unos.org/PoliciesandBylaws/policies/pdfs/policy_70.pdf (1 September 2005, date last accessed).
  2. De Meester J, Persijn GG, Wujciak T, et al. The new eurotransplant kidney allocation system: report one year after implementation. Eurotransplant International Foundation. Transplantation (1998) 66:1154–1159.[CrossRef][Web of Science][Medline]
  3. Ministère du travail et des Affaires Sociales. Arrêté du 6 novembre 1996 portant homologation des règles de répartition et d’attribution des greffons prélevés sur une personne décédée en vue de transplantation d’organes. J.O n° 263 du 10 novembre 1996, p. 16475.
  4. Mange K, Chrerikh WS, Maghirang J, et al. A comparison of the survival and locally transplanted cadaveric renal allografts. N Engl J Med (2001) 345:1237–1242.[Abstract/Free Full Text]
  5. Salahudeen AK, Haider N, May W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int (2004) 65:713–718.[CrossRef][Web of Science][Medline]
  6. Gillish MS, Heimbach D, Schoeneich G, et al. Comparison of blood group versus HLA-dependent transplantation and its influence on donor kidney survival. Nephrol Dial Transplant (2002) 17:884–886.[Abstract/Free Full Text]
  7. Gaston RS, Ayres I, Dooley LG, et al. Racial equity in renal transplantation. The disparate impact of HLA-based allocation. JAMA (1993) 270:1352–1356.[Abstract/Free Full Text]
  8. Held PhJ, Kahan BD, Hunsicker LG, et al. The impact of HLA mismatches on the survival of first cadaveric kidney transplants. N Engl J Med (1994) 331:765–770.[Abstract/Free Full Text]
  9. Etablissement français des Greffes. Rapport du Conseil médical et Scientifique de l’Etablissement français des Greffes. Le prélèvement et la greffe en France en 1998.
  10. Etablissement français des Greffes. Rapport d’activité et bilan d’activité des activités de greffe en France Année 2003. http://www.efg.sante.fr/fr/pro/actu-point.asp (29 September 2004, date last accessed).
  11. Morris PJ, Johnson RJ, Fuggle SV, et al. (on behalf of the HLA Task Force of the Kidney Advisory Group of the United Kingdom Transplant Support Service Authority). Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK. Lancet (1999) 354:1147–1152.[CrossRef][Web of Science][Medline]
  12. Takemoto SK, Terasaki PI, Gjertson DW, et al. Twelve years’experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med (2000) 343:1078–1084.[Abstract/Free Full Text]
  13. Bresnahan BA, Johnson CP, McIntosh MJ, et al. A comparison between recipients receiving matched kidneys and those receiving mismatched kidney from the same cadaver donor. Am J Transplant (2002) 2:366–372.[CrossRef][Web of Science][Medline]
  14. Su X, Zenious SA, Chakkera H, et al. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant (2004) 4:1501–1508.[CrossRef][Web of Science][Medline]
  15. Seron D, Arias M, Campistol JM, et al. (for the Spanish Chronic Allograft Nephropathy Study Group). Late renal allografts failure between 1990 and 1998 in Spain: a changing scenario. Transplantation (2003) 76:1588–1594.[CrossRef][Web of Science][Medline]
  16. Connolly JK, Dyer PA, Martin S, et al. Importance of minimizing HLA-DR mismatch and cold preservation time in cadaveric renal transplantation. Transplantation (1996) 61:709–714.[CrossRef][Web of Science][Medline]
  17. Stegall MD, Dean PG, McBride MA, et al. and the Organ Procurement and Transplantation Network for Organ sharing Kidney/Pancreas Transplantation Committee. Survival of mandatorily shared cadaveric kidneys and their paybacks in the zero mismatch era. Transplantation (2002) 74:670–675.[CrossRef][Web of Science][Medline]
  18. Roudot-Thoraval F, Romano Ph, Spaak F, et al. Geographic disparities in access to organ transplant in France. Transplantation (2003) 76:1385–1388.[CrossRef][Web of Science][Medline]
Received for publication: 31.10.06
Accepted in revised form: 11. 9.07


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