The authors have the following interests. This work was partly supported by Roche Laboratory, and K. Trébern-Launay is the recipient of a grant for epidemiology and biostatistics research from Novartis Pharma. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Conceived and designed the experiments: MG JD JPS. Performed the experiments: KTL. Analyzed the data: KTL YF MG JD JPS. Contributed reagents/materials/analysis tools: CL HK MK ML NK LR VG GM EM. Wrote the paper: KTL YF MG JD JPS.
Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate.
To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (N = 3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization.
We showed that STR have a higher risk of graft failure than FTR (HR = 2.18, p = 0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HR = 1.01, p = 0.9675) or steroid-resistant ARE (HR = 1.27, p = 0.4087).
The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally.
Nowadays, repeat transplantation provides the best chance for long-term survival and quality of life in patients facing allograft loss, as compared to maintenance dialysis therapy
Some previous studies have demonstrated that STR have a lower graft survival than first transplant recipients (FTR)
Whereas factors influencing second graft survival have been well studied
Data were prospectively collected from the DIVAT (Données Informatisées et VAlidées en Transplantation) French multicentric database
To guarantee the comparability between FTR and STR, adjustments were made for all of the following possible pre- or per-transplant immunological and non-immunological confounding factors: transplantation period (before or after 2005, which corresponds to the routine utilization of high sensitivity techniques for panel-reactive antibody, PRA), recipient gender and age, primary diagnosis of end stage renal disease (ESRD), comorbidities, highest historical levels of pre-transplant PRA against class I and II antigens, deceased or living donor status, donor age, cold ischemia time (CIT), HLA-A-B-DR mismatches and induction therapy. The high sensitivity techniques correspond to pre-transplant anti-HLA identification obtained by multiplex screening test (LAT-M; One lambda, Canoga Park, CA).
French law does not authorize the storage of race information (specific authorization may be obtained in specific circumstances, such as for genetics population studies). The induction therapy was differentiated according to its effect on lymphocytes: horse or rabbit antithymocyte globulin antibodies or anti-CD3 antibody were considered as lymphocyte-depleting agents whereas anti-interleukin-2 receptor antibodies (basiliximab) were considered as a non lymphocyte-depleting agent. Since not all of the biopsies were analyzed with the recent Banff classification but as therapeutic strategies were nevertheless mostly based on a histological diagnosis regardless of the time period, and as the therapeutic strategies did not differ according to the graft rank regardless of the period, we opted to grade acute rejection episode (ARE) according to their response to steroid bolus therapy: steroid-sensitive ARE were considered as non-severe, whereas steroid-resistant ARE requiring rescue with additional therapy were considered as severe.
Comparisons of baseline characteristics between the FTR and STR were based on the chi-square test. Different times-to-event distributions were described including the time between the transplantation and: (a) the graft failure, i.e. the first event between the return to dialysis and the patient death with a functioning graft (patient-and-graft survival); (b) the return to dialysis, i.e. patient deaths were censored (graft survival); (c) the patient death with a functioning graft, i.e. the returns to dialysis were censored (patient survival); (d) the first ARE and (e) the first severe ARE, i.e. non-severe ARE were censored. Survival curves were estimated using the Kaplan-Meier estimator. Only the main outcomes, i.e. PGS and ARE/severe ARE occurrences, were analyzed in multivariate. A first selection of covariates using the Log-rank test (p<0.20) was performed before the Cox model (Wald test with p<0.05, step-by-step descending procedure). Cox models were stratified per center. Baseline parameters differentially distributed between FTR and STR were also introduced in the models. Because the Cox model was performed by using all the recipients regardless the graft rank, we did not take into account specific covariates for STR, such as the survival time of the first transplant
Hazards proportionality was checked by plotting log-minus-log survival curves and by testing the scaled Schoenfeld residuals
Statistical analyses were performed using version 2.12.0 of the R software
The demographic and baseline characteristics at the time of transplantation are presented in
Characteristics | All grafts (N = 3103) | First graft (N = 2462) | Second graft (N = 641) | |||
N | (%) | N | (%) | N | (%) | |
Transplantation period<2005 | 887 | (28.6%) | 685 | (27.8%) | 202 | (31.5%) |
Male recipient | 1900 | (61.2%) | 1516 | (61.6%) | 384 | (59.9%) |
Recipient≥55 years of age | 1295 | (41.7%) | 1100 | (44.7%) | 195 | (30.4%) |
Potentially recurrent causal nephropathy | 1016 | (32.7%) | 744 | (30.2%) | 272 | (42.4%) |
Presence of dialysis prior transplantation | 2782 | (89.8%) | 2197 | (89.5%) | 585 | (91.3%) |
History of diabetes | 336 | (10.8%) | 295 | (12.0%) | 41 | (6.4%) |
History of hypertension | 2527 | (81.4%) | 2013 | (81.8%) | 514 | (80.2%) |
History of vascular disease | 381 | (12.3%) | 296 | (12.0%) | 85 | (13.3%) |
History of cardiac disease | 1011 | (32.6%) | 766 | (31.1%) | 245 | (38.2%) |
History of dyslipemia | 880 | (28.4%) | 731 | (29.7%) | 149 | (23.2%) |
History of malignancy | 248 | (8.0%) | 161 | (6.5%) | 87 | (13.6%) |
History of B or C hepatitis | 191 | (6.2%) | 110 | (4.5%) | 81 | (12.6%) |
Positive recipient CMV serology | 1844 | (59.8%) | 1413 | (57.8%) | 431 | (67.6%) |
Positive recipient EBV serology | 2886 | (96.1%) | 2289 | (96.0%) | 597 | (96.8%) |
Recipient BMI≥30 kg.m−2 | 291 | (9.5%) | 256 | (10.5%) | 35 | (5.5%) |
Positive anti-class I PRA | 822 | (26.5%) | 420 | (17.1%) | 402 | (62.7%) |
Positive anti-class II PRA | 889 | (28.6%) | 410 | (16.7%) | 479 | (74.7%) |
Male donor | 1817 | (58.9%) | 1421 | (58.0%) | 396 | (62.4%) |
Donor≥55 years of age | 1265 | (40.8%) | 1056 | (42.9%) | 209 | (32.6%) |
Deceased donor | 2785 | (89.8%) | 2181 | (88.6%) | 604 | (94.2%) |
Cerebro-vascular cause of donor death | 1480 | (49.7%) | 1168 | (49.7%) | 312 | (50.0%) |
Donor serum creatinine≥133 µmol/l | 385 | (12.6%) | 311 | (12.9%) | 74 | (11.8%) |
Positive donor CMV serology | 1582 | (51.2%) | 1266 | (51.6%) | 316 | (49.7%) |
Positive donor EBV serology | 2639 | (94.3%) | 2104 | (94.6%) | 535 | (93.0%) |
HLA-A-B-DR incompatibilities>4 | 432 | (13.9%) | 390 | (15.8%) | 42 | (6.6%) |
HLA-A incompatibilities≥1 | 2437 | (78.5%) | 1993 | (81.0%) | 444 | (69.3%) |
HLA-B incompatibilities≥1 | 2774 | (89.4%) | 2248 | (91.3%) | 526 | (82.1%) |
HLA-DR incompatibilities≥1 | 2310 | (74.4%) | 1919 | (77.9%) | 391 | (61.0%) |
Cold ischemia time≥24 h | 905 | (29.2%) | 668 | (27.1%) | 237 | (37.0%) |
Induction with a lymphocyte-depleting agent | 1385 | (44.7%) | 883 | (35.9%) | 502 | (78.3%) |
BMI, body mass index; PRA, panel reactive antibody; HLA, human leukocyte antigen; CMV, cytomegalovirus; EBV, Epstein-Barr virus.
p<0.05.
The patient-and-graft survival at 1, 5 and 10 years respectively were: 92%, 79% and 56% for STR and 94%, 83% and 66% for FTR (
(
Variables | Hazard Ratio | 95% CI | p |
Graft rank before 4 post-transplant years (2/1) | 1.05 | 0.75–1.47 | 0.7830 |
Graft rank after 4 post-transplant years (2/1) | 2.18 | 1.35–3.50 | 0.0013 |
Transplantation period (<2005/≥2005) | 1.32 | 1.01–1.72 | 0.0427 |
Recipient gender (male/female) | 1.01 | 0.82–1.25 | 0.9364 |
Recipient age (≥55 years/<55 years) | 1.49 | 1.17–1.89 | 0.0012 |
Causal nephropathy (recurrent/non recurrent) | 1.13 | 0.91–1.39 | 0.2734 |
History of diabetes (positive/negative) | 1.28 | 0.96–1.71 | 0.0947 |
History of hypertension (positive/negative) | 0.86 | 0.67–1.12 | 0.2665 |
History of vascular disease (positive/negative) | 1.05 | 0.80–1.38 | 0.7449 |
History of cardiac disease (positive/negative) | 1.34 | 1.09–1.65 | 0.0057 |
History of dyslipemia (positive/negative) | 1.16 | 0.93–1.45 | 0.1971 |
History of malignancy (positive/negative) | 1.17 | 0.84–1.62 | 0.3483 |
History of B/C hepatitis (positive/negative) | 1.06 | 0.72–1.57 | 0.7587 |
Number of HLA-A-B-DR mismatches (>4/≤4) | 1.30 | 0.99–1.71 | 0.0639 |
Anti-class I PRA (positive/negative) | 1.43 | 1.11–1.85 | 0.0055 |
Anti-class II PRA (positive/negative) | 0.98 | 0.74–1.30 | 0.8970 |
Induction therapy (depleting/non depleting) | 0.88 | 0.69–1.12 | 0.2852 |
Cold ischemia time (≥24 h/<24 h) | 1.18 | 0.95–1.45 | 0.1370 |
Donor age (≥55 years/<55 years) | 1.19 | 0.94–1.49 | 0.1459 |
Recipient/donor relationship (deceased donor/living donor) | 2.19 | 1.35–3.57 | 0.0015 |
BMI (≥30 kg.m−2/<30 kg.m−2) | 1.54 | 1.14–2.09 | 0.0050 |
Donor EBV serology (positive/negative) | 1.80 | 1.17–2.77 | 0.0076 |
CI, confidence interval; BMI, body mass index; PRA, panel reactive antibody; HLA, human leukocyte antigen; EBV, Epstein-Barr virus.
In order to explain the previous delayed excess risk in the STR group after few years post transplantation, we first made the hypothesis of a higher frequency of ARE or severe ARE in this group, with the associated delayed consequences on the patient-and-graft survival.
The cumulative probability of ARE at 1, 3 and 12 months respectively were 10%, 13% and 19% for STR and 8%, 14% and 20% for FTR (
(
Variables | Hazard Ratio | 95% CI | p |
Graft rank (2/1) | 1.01 | 0.80–1.27 | 0.9675 |
Transplantation period (<2005/≥2005) | 0.80 | 0.64–1.01 | 0.0592 |
Recipient gender (male/female) | 1.13 | 0.97–1.33 | 0.1233 |
Recipient age (≥55 years/<55 years) | 0.79 | 0.65–0.96 | 0.0173 |
Causal nephropathy (recurrent/non recurrent) | 1.03 | 0.88–1.22 | 0.6928 |
History of diabetes (positive/negative) | 1.17 | 0.92–1.48 | 0.2128 |
History of hypertension (positive/negative) | 1.18 | 0.96–1.45 | 0.1127 |
History of vascular disease (positive/negative) | 1.16 | 0.91–1.48 | 0.2267 |
History of cardiac disease (positive/negative) | 0.95 | 0.80–1.12 | 0.5334 |
History of dyslipemia (positive/negative) | 0.95 | 0.80–1.14 | 0.6096 |
History of malignancy (positive/negative) | 1.02 | 0.76–1.37 | 0.8861 |
History of B/C hepatitis (positive/negative) | 0.75 | 0.53–1.08 | 0.1206 |
Number of HLA-A-B-DR mismatches (>4/≤4) | 1.46 | 1.18–1.81 | 0.0004 |
Anti-class I PRA (positive/negative) | 1.07 | 0.87–1.31 | 0.5205 |
Anti-class II PRA (positive/negative) | 1.29 | 1.04–1.59 | 0.0180 |
Induction therapy (depleting/non depleting) | 0.65 | 0.54–0.77 | <0.0001 |
Cold ischemia time (≥24 h/<24 h) | 0.88 | 0.73–1.07 | 0.1984 |
Donor age (≥55 years/<55 years) | 1.06 | 0.89–1.27 | 0.5027 |
Recipient/donor relationship (deceased donor/living donor) | 0.92 | 0.73–1.15 | 0.4490 |
CI, confidence interval; BMI, body mass index; PRA, panel reactive antibody; HLA, human leukocyte antigen.
The cumulative probability of severe ARE at 1 and 12 months respectively were 2% and 5% for STR, and 1% and 2% for FTR (
Variables | Hazard Ratio | 95% CI | p |
Graft rank (2/1) | 1.27 | 0.72–2.21 | 0.4087 |
Transplantation period (<2005/≥2005) | 0.52 | 0.28–0.95 | 0.0329 |
Recipient gender (male/female) | 1.10 | 0.71–1.68 | 0.6762 |
Recipient age (≥55 years/<55 years) | 1.52 | 0.93–2.48 | 0.0930 |
Causal nephropathy (recurrent/non recurrent) | 0.97 | 0.63–1.51 | 0.9086 |
History of diabetes (positive/negative) | 0.85 | 0.40–1.80 | 0.6769 |
History of hypertension (positive/negative) | 1.41 | 0.78–2.54 | 0.2516 |
History of vascular disease (positive/negative) | 0.99 | 0.51–1.91 | 0.9758 |
History of cardiac disease (positive/negative) | 0.92 | 0.59–1.44 | 0.7299 |
History of dyslipemia (positive/negative) | 0.81 | 0.49–1.33 | 0.4045 |
History of malignancy (positive/negative) | 0.76 | 0.34–1.68 | 0.4952 |
History of B/C hepatitis (positive/negative) | 0.51 | 0.19–1.41 | 0.1964 |
Number of HLA-A-B-DR mismatches (>4/≤4) | 1.34 | 0.76–2.36 | 0.3051 |
Anti-class I PRA (positive/negative) | 1.20 | 0.72–2.00 | 0.4911 |
Anti-class II PRA (positive/negative) | 2.26 | 1.33–3.85 | 0.0027 |
Induction therapy (depleting/non depleting) | 0.84 | 0.53–1.33 | 0.4545 |
Cold ischemia time (≥24 h/<24 h) | 1.46 | 0.93–2.29 | 0.0997 |
Donor age (≥55 years/<55 years) | 0.59 | 0.36–0.96 | 0.0347 |
Recipient/donor relationship (deceased donor/living donor) | 0.93 | 0.46–1.87 | 0.8427 |
CI, confidence interval; BMI, body mass index; PRA, panel reactive antibody; HLA, human leukocyte antigen.
Based on an overview of the literature, the prognosis of STR compared to FTR is still unclear. As the demand for kidney transplants largely exceeds the supply, it is important to evaluate the excess risk related to STR and to identify patients with the worst chances of long-term outcome.
In 2003, Coupel et al. compared 233 STR to 1174 FTR and observed no difference in the 10-year survival
In this paper, we used a specific methodology for an accurate comparison between FTR and STR, by taking into account all the possible confounding factors and modeling the time-dependent effect of the graft rank. To our knowledge, such an analysis has never been performed. Our results, based on recipients from a large multicenter cohort under similar recent immunosuppressive maintenance therapy, show that STR have a poorer long-term prognosis than FTR. We show for the first time that this risk is delayed and appears significant beyond four years of follow-up. This cut-off definitely does not correspond to a sudden modification of the graft failure risk. We should rather retain that the excess of risk of STR appears after few years of transplantation. This time-dependent association may be a major point as it was only after its introduction that we showed the significant excess risk of graft failure for STR: it may explain that the majority of the other papers did not demonstrate significant correlation between the survival of FTR and STR.
The difference in PGS could have been due to a higher frequency of ARE or severe ARE for STR than for FTR during the follow-up. However, we did not demonstrate such a difference in ARE, nor in severe ARE occurrences. For this last endpoint, we showed that STR tended to have a higher risk of severe ARE than FTR. The lack of statistical power (only 96 severe ARE were observed in the whole cohort) may explain why this finding did not reach statistical significance.
As always in observational studies, there are several limitations to this study. (i) The use of different techniques for PRA identification may introduce a bias, limited by the fact that STR and FTR were compared over the same period/center and by adjusting on the year of transplantation. (ii) It was not possible to include the causes of graft loss in our analyses (immunologic versus non-immunologic causes) since this the collection of this information has only recently been initiated. (iii) It was unfortunately not possible to adjust for the pretransplant duration of dialysis and the duration of first transplant survival, as only covariates common to FTR and STR can be taken into account in a Cox model. To overcome this difficulty, we adjusted for the comorbidities at transplantation. (iv) Adjustment for long-term immunosuppression regimens was not done, as it is more a reflection of a therapeutic adaptation to a clinical situation and it depends on the center, on the clinician and on the therapeutic advances. (v) A possible effect of the transplantation policy might introduce some bias that is overcome by the adjustment in the multivariate model and by the matched case-control design in the sub-analysis model. (vi) Our study also failed to eliminate the effects of some confounding factors such as medication compliance; as in every large-sized cohort, this information cannot be realistically collected. (vii) Delayed graft function (DGF) was not included as a covariate in the analysis as only pre- and per-transplant covariates were taken into account. However, an additional analysis including DGF did not provide new possible explanations for the different first and second transplant outcomes (data not shown). (vii) Although all ARE were biopsy-proven, a small number were classified using the most recent Banff criteria. It will take a few years before we are able to explore the possible link between biopsy-proven antibody-mediated ARE occurrence and a worse outcome. (viii) Finally, due to the long-term follow-up period, the information about preformed DSA was available for only a very small part of our cohort, although this covariate is suspected to be related to risk of graft failure.
In conclusion, this observational study on a large multicenter cohort confirmed other findings showing that STR have a lower patient-and-graft survival compared to FTR. However, this study eliminates some confounding factors from the current literature. The excess risk of graft failure for STR was delayed after several years post transplantation. This effect did not seem to be related to a higher frequency of ARE or severe ARE for second grafts. Regardless of the limitations of such an observational cohort; the current study supports the hypothesis of a higher propensity for STR to develop donor specific antibodies post-transplantation. These findings justify further expensive systematic and prospective monitoring of antibodies in both populations. Further investigations are still needed to understand the biological/immunological mechanisms underlying graft failure, to identify patients specifically at risk of graft failure and also to provide a strategy for improving outcome in STR. But in practice, physicians should not consider second and first kidney transplant recipients equally.
We wish to thank members of the clinical research assistant team (S. Le Floch, J. Posson, C. Scellier, V. Eschbach, K. Zurbonsen, C. Dagot, F. M'Raiagh, V. Godel, X. Longy).