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Background: Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown., Methods: In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age., Results: Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity., Conclusions: Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss., Competing Interests: A.J.V. has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. A.M. is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. C.S. is supported by the European Union’s Horizon 2020 Research and Innovation Programme (grant 952512). G.W. is supported by National Health and Medical Research Council Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). R.S.-P. is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant 254386) and Canadian Institutes of Health Research (grant FRN-156730). The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown., Methods: We estimated the association between recipient sex and death-censored graft loss in patients of all ages recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study registries who received a first deceased donor kidney transplant (1988-2019). We used multivariable Cox regression models, accounting for the modifying effects of donor sex and recipient age, in each registry separately; results were combined using individual patient data meta-analysis., Results: We analyzed 438 585 patients. Young female patients 13-24 y old had the highest crude graft loss rates (female donor: 5.66; male donor: 5.50 per 100 person-years). Among young recipients of male donors, females showed higher graft loss risks than males (0-12 y: adjusted hazard ratio [aHR] 1.42, (95% confidence interval [CI], 1.17-1.73); 13-24 y: 1.24 (1.17-1.32); 25-44 y: 1.09 (1.06-1.13)). When the donor was female, there were no significant differences by recipient sex among those of age <45 y; however, the aHR for females was 0.93 (0.89-0.98) in 45-59 y-old and 0.89 (0.86-0.93) in ≥ 60 y-old recipients. Findings were similar for all 3 registries in most age intervals; statistically significant heterogeneity was seen only among 13-24-y-old recipients of a female donor (I2 = 71.5%, P = 0.03)., Conclusions: There is an association between recipient sex and kidney transplantation survival that is modified by recipient age and donor sex., Competing Interests: A.J.V. has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. A.M. is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. G.W. is supported by NHMRC Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). R.S.-P. is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant no. 254386) and CIHR (grant FRN-156730). This study was supported by funding from the Canadian Institutes of Health Research PJT-165832. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients aged ≥60 y represent the fastest growing population among kidney transplant recipients and waitlist patients. They show an elevated infection risk and are frequently transplanted with multiple human leukocyte antigen mismatches. Whether the choice of calcineurin inhibitor influences graft survival, mortality, or key secondary outcomes such as infections in this vulnerable recipient population is unknown., Methods: A total of 31 177 kidney transplants from deceased donors performed between 2000 and 2019 at European centers and reported to the Collaborative Transplant Study were analyzed using multivariable Cox and logistic regression analyses. All recipients were ≥60 y old and received tacrolimus (Tac) or cyclosporine A on an intention-to-treat basis, combined with mycophenolic acid or azathioprine plus/minus steroids., Results: The risk of 3-y death-censored graft loss and patient mortality did not differ significantly between Tac- and cyclosporine A-treated patients (hazard ratio 0.98 and 0.95, P = 0.74 and 0.20, respectively). No difference was found in the overall risk of hospitalization for infection (hazard ratio = 0.95, P = 0.19); however, a lower incidence of rejection treatment (hazard ratio = 0.81, P < 0.001) was observed in Tac-treated patients. Assessment of pathogen-specific hospitalizations revealed no difference in the risk of hospitalization due to bacterial infection (odds ratio = 1.00, P = 0.96), but a significantly higher risk of hospitalization due to human polyomavirus infection was found among Tac-treated patients (odds ratio = 2.45, P = 0.002). The incidence of de novo diabetes was higher for Tac-based immunosuppression (odds ratio = 1.79, P < 0.001)., Conclusions: Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in ≥60-y-old kidney transplant recipients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The use of kidney allografts from ≥70-y-old donors has increased persistently over the last 20 y. Prolonged cold ischemia time (CIT) is well known to increase graft failure risk. However, despite their growing importance, no data are available on the impact of CIT, specifically on survival of allografts from ≥70-y-old donors., Methods: In total, 47 585 kidney transplantations from expanded criteria donors (ECDs) performed during 2000-2017 and reported to the Collaborative Transplant Study were analyzed. The impact of CIT on 5-y death-censored graft and patient survival was studied for transplantations from <70-y (n = 33 305) and ≥70-y-old ECDs (n = 14 280)., Results: Compared with the reference of ≤12 h CIT, a CIT of 13-18 h did not increase the risk of graft failure significantly, either for recipients of kidneys from <70-y or from ≥70-y-old ECDs. In contrast, graft failure risk increased significantly when CIT exceeded 18 h, both in recipients of kidneys from <70-y and, more pronounced, from ≥70-y-old ECDs (CIT 19-24 h: hazard ratio [HR] = 1.19 and 1.24; P < 0.001; CIT ≥24 h: HR = 1.28 and 1.32, P < 0.001 and P =0.003, respectively). Within the 18-h CIT interval, additional HLA matching further improved survival of ECD transplants significantly, whereas the negative impact of a prolonged CIT >18 h was stronger in ≥65-y-old recipients and for transplants with multiple HLA mismatches. The influence of CIT on patient survival was less pronounced., Conclusions: CIT, as long it is kept ≤18 h, has no significant impact on survival of kidney transplants, even from ≥70-y-old ECDs., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite steadily increasing donor age, there are no general guidelines for the use of organs from elderly donors in liver transplantation. This study focuses on identifying the recipients who are less affected from an old-donor organ graft and conversely in whom a rather unfavorable outcome is expected because of high donor age., Methods: Forty-eight thousand two hundred sixty-one adult liver transplantations, performed between 2000 and 2017 and reported to the Collaborative Transplant Study, were analyzed., Results: The proportion of ≥65-year-old donors has risen to >33% in recent years. The donor age has an approximately linear influence on graft survival. On average, each year's rise in the donor age was associated with a 0.9% increase in the risk of graft loss (hazard ratio [HR], 1.009; P < 0.001). The impact of donor age was strong in patients with hepatitis C-related cirrhosis (HR, 1.013; P < 0.001), substantial in patients with alcoholic cirrhosis (HR, 1.007; P < 0.001) and rather weak in patients with hepatocellular carcinoma (HR, 1.003; P = 0.038). The increase in the risk of graft loss per year rise in donor age was 1.4% for 18 to 49 year olds, 1.0% for middle-aged, and only 0.4% for ≥60-year-old recipients (all P < 0.001)., Conclusions: Consequently, older recipients and especially patients with hepatocellular carcinoma seem to be less affected by an increased donor age, whereas the donor age is an important factor in all other patient groups.

Background: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are important predictors of graft and patient survival in renal transplantation. Pulse pressure (PP), the difference between systolic and diastolic pressure, has been associated with cardiovascular and renal morbidity in nontransplant epidemiological studies and clinical trials., Methods: In this large retrospective analysis of prospectively collected data, transplant recipients from 1995 to 2015 were examined for patient and death-censored graft survival., Results: In 43 006 recipients, a higher 1-year PP was significantly associated with inferior 10-year patient and death-censored graft survival. In patients 60 years or older, SBP but not DBP was associated with 10-year survival, an effect that was pronounced in patients with a normal SBP of <140 mm Hg and an increased PP of 60 mm Hg or greater, highlighting the superior impact of PP on survival in elderly recipients. In recipients 60 years or older, higher PP was associated with increased mortality due to circulatory system diseases but not to infection or cancer. The combination of PP 60 mm Hg or greater and high SBP of 140 mm Hg or greater showed the strongest association with death-censored graft survival across all age groups., Conclusions: We found convincing evidence that PP 1-year posttransplant is predictive of patient survival, especially in elderly recipients with normal SBP. Combined analysis of SBP and PP showed that high PP confers additional predictive information for patient survival beyond that derived from analysis of SBP alone. With regard to prediction of death-censored graft survival, the combination of high SBP and high PP showed the best correlation across all age groups.

Background: Whether kidney transplant recipients who were treated for a malignant tumor before transplantation are at an increased risk of developing a tumor posttransplantation has not been adequately quantified and characterized., Methods: We studied more than 270 000 patients on whom pretransplant and posttransplant malignancy data were reported to the Collaborative Transplant Study. More than 4000 of these patients were treated for pretransplant malignancy. The posttransplant tumor incidence in these patients was compared to that in recipients without a pretransplant tumor. Cox regression, considering multiple confounders, was applied., Results: Significant increases in posttransplant tumor incidence with hazard ratio ranging from 2.10 to 5.47 (all P < 0.001) were observed for tumors in the site-specific pretransplant locations, suggesting tumor recurrences. There were also significantly increased de novo tumors in new locations with hazard ratio ranging from 1.28 to 1.89. Pretransplant basal cell carcinoma of the skin and male genital cancer were associated with significantly increased death-censored graft survival, suggesting impaired immune responsiveness against transplanted kidneys. Time interval from pretransplant tumor occurrence to transplantation and posttransplant mammalian target of rapamycin inhibitor treatment was not found to be of significant relevance in this study., Conclusions: Patients who experienced a pretransplant tumor are at significant risk of tumor recurrence, regardless of the length of interval between tumor treatment and transplantation. There is also some increased risk for de novo tumors, suggesting impaired immune surveillance. Impaired tumor immunity appears to extend to a lower rate of transplant rejection because patients with pretransplant tumors tended to show improved death-censored graft survival.

Background: Chronic kidney disease is common after heart or liver transplantation, with calcineurin inhibitors (CNI) considered the key contributor. A possible influence of posttransplant blood pressure has not been extensively examined., Methods: Data from adult recipients of a first heart or liver transplant were analyzed regarding the relationship between blood pressure at year 1, renal function at year 5, and CNI therapy., Results: Although we confirmed the well-known detrimental effect of increased 1-year systolic blood pressure on 5-year kidney graft survival, heart or liver graft survival was not affected. However, among 2534 heart transplant recipients with good renal function at year 1, increasing systolic blood pressure at year 1 was associated with higher rates of poor renal function at year 5 posttransplant. This association was confirmed on multivariate analysis overall (odds ratio, 1.25 per 20 mm Hg increment; P < 0.001) and within subgroups. Similar results were observed in 1822 liver transplant recipients (odds ratio, 1.35; P < 0.001). Neither the type of CNI nor CNI dose or trough level at year 1 showed a significant association with kidney function at year 5., Conclusions: One-year blood pressure was identified as the major modifiable risk factor associated with deteriorating kidney function between years 1 and 5 after heart or liver transplantation.

Background: Based on an analysis of 542 pediatric kidney transplants recorded by the UK Transplant Registry from 2000 to 2012, it was concluded that the survival rate of HLA poorly matched living donor transplants is not inferior to that of HLA well-matched deceased donor transplants., Methods: We analyzed the impact of HLA matching on kidney graft survival in 3627 pediatric living donor transplants performed during 2000 to 2015 using the data of the Collaborative Transplant Study. The impact of HLA mismatches on graft survival was analyzed and survival rates of transplants from poorly matched living donors were compared with those from well-matched deceased donors. Multivariate Cox regression analysis was used to account for the influence of confounders., Results: HLA matching had a statistically significant impact on graft survival of pediatric kidney transplants (P < 0.001). Ten-year graft survival of pediatric transplants from living donors with 4 to 6 HLA-A+B+DR mismatches was significantly worse than that of transplants from well-matched deceased donors with 0 to 1 HLA mismatch (log rank, P = 0.006)., Conclusions: In pediatric kidney transplantation, graft survival of kidneys from deceased donors with 0 to 1 HLA mismatches compares favorably with that of grafts from living donors with 4 to 6 HLA mismatches. If possible, living donor pediatric kidney transplants should be performed from donors with fewer than 4 HLA-A+B+DR mismatches.

Background: Patients with previous cancer have increasingly been accepted for renal transplantation. Posttransplant cancer risk and survival rates of these patients are unknown. Our objective was to assess the risk of posttransplant cancer in this patient group., Methods: In this retrospective, nested case-control study, we assessed the outcome of all (n = 95) renal transplanted patients with pretransplant cancer diagnoses in the Uppsala-Örebro region, Sweden. The control group was obtained from the Collaborative Transplant Study registry and included European patients without pretransplant cancer. The other control group comprised the entire renal transplanted population in Uppsala. Development of recurrent cancer, de novo cancer, and patient survival were determined., Results: Patients with pretransplant cancer showed higher incidence of posttransplant cancers and shorter survival compared with the control groups (P < 0.001). No obvious pattern in malignant diagnoses was observed. Death-censored graft survival was unaffected., Conclusions: Despite previously adequate cancer treatments and favorable prognoses, almost half of the patients experienced a posttransplant cancer. These observations do not justify abstaining from transplanting all patients with previous malignancies, because more than 50% of the patients survive 10 years posttransplantation. A careful oncological surveillance pretransplant as well as posttransplant is recommended.

Background: Evidence is limited regarding the effect of stopping smoking before kidney transplantation., Methods: Collaborative Transplant Study data from 46 548 recipients of first kidney transplants (1995-2012) were analyzed to 10 years after transplantation., Results: Compared with patients who had never smoked (n = 31,462), patients who stopped smoking before transplantation (n = 10,291) only had a modestly increased risk of all-cause graft failure (hazard ratio [HR], 1.1; 95% confidence interval [95% CI], 1.0-1.1; P < 0.001) or death (HR,1.1; 95% CI, 1.0-1.2; P < 0.001) and a similar risk of death-censored graft failure (HR,1.0, 95% CI, 1.0-1.1; P = 0.19), but a 40% increase in death from malignancy (HR, 1.4; 95% CI, 1.2-1.7; P < 0.001). The risk of events was generally markedly higher in patients who continued to smoke (n = 4795) versus those who had stopped. For tumors of the lip, oral cavity and pharynx, digestive organs, respiratory tract, female genitalia and urinary tract, HR values increased significantly from never-smoked to former smokers to current smokers. The risk of respiratory tumors or cervical cancer was approximately halved when smoking was stopped versus continued., Conclusions: This large series provides clear evidence that patients who stop smoking before transplantation experience substantial benefits, including a substantial reduction in certain types of malignancy.

Background: The association of donor-specific HLA antibodies (DSA) with kidney graft failure has been addressed previously; however, the majority of studies were based on small numbers of patients with graft failure., Methods: We investigated 83 patients with failed kidney transplants for a possible association of de novo development and persistence or loss of pre-existing DSA with graft failure. Single Antigen Bead assay-detected DSA and non-DSA antibodies were compared between patients with graft loss and matched controls with functioning grafts., Results: The incidence of weak de novo DSA or non-DSA at a mean fluorescence intensity of 500 or higher was higher in the graft loss than in the nonrejector group (76% vs 40%, P < 0.001). Because of the low number of patients developing de novo DSA, the DSA results did not reach statistical significance (only 22% of patients with graft loss developed de novo DSA). However, at all cutoffs, there was a significantly higher rate of graft loss in patients with de novo non-DSA. The incidence of strong pretransplant DSA that persist after transplantation was higher in the graft loss group (10% vs 1%, P = 0.034). When C1q-binding ability in sera of rejectors and nonrejectors with posttransplant de novo or persistent DSA was compared, none of the nonrejectors demonstrated C1q positivity, whereas 43% of patients with graft loss showed C1q-positive antibodies, although not necessarily donor-specific (P < 0.001)., Conclusions: Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.

Background: It is unknown how death with a functioning graft (DWFG) is affected in renal transplant recipients who receive prophylaxis for cytomegalovirus (CMV) infection., Methods: Data from 61,927 adult recipients of a deceased donor kidney transplant in 1990 to 2012 registered with the Collaborative Transplant Study were analyzed., Results: Cytomegalovirus prophylaxis was administered in 18%, 75%, 27% and 34% of R-/D- (recipient-negative, donor-negative), R-/D+, R+/D- and R+/D+ transplants, respectively. Only in R-/D+ transplants was CMV prophylaxis associated with significantly improved patient survival versus no prophylaxis (P<0.001). Unexpectedly, in the R-/D+ subgroup, DWFG because of infection was not significantly affected by use of CMV prophylaxis (P=0.16) but death from cardiovascular disease was significantly lower (P<0.001). Cox regression analysis confirmed that the primary impact of CMV prophylaxis on DWFG in R-/D+ transplants was because of reduced cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.51-0.85; P=0.002), an effect restricted to patients aged 40 years or older (hazard ratio, 0.61; 95% confidence interval, 0.46-0.81; P<0.001)., Conclusion: We conclude that CMV prophylaxis is associated with a significant benefit for risk of cardiovascular DWFG among R-/D+ kidney transplant patients aged ≥ 40 years. Cytomegalovirus prophylaxis appears particularly critical in this patient subpopulation.

Background: Reports from experienced centers suggest that recipients of an ABO-incompatible living-donor kidney transplant after reduction of ABO antibodies experience no penalty in graft and patient survival versus ABO-compatible transplants, but confirmation that these results can be widely replicated is lacking., Methods: Living-donor kidney transplants from ABO-incompatible donors after ABO antibody reduction registered with the Collaborative Transplant Study during 2005 to 2012 were analyzed and compared with (i) a matched group of ABO-compatible transplant recipients and (ii) all ABO-compatible transplants from centers that performed at least five ABO-incompatible grafts during the study period., Results: One thousand four hundred twenty living-donor ABO-incompatible kidney transplants were analyzed. Three-year death-censored graft survival was virtually identical for ABO-incompatible transplants versus matched and center controls (P=0.92 and P=0.60, respectively). Patient survival rates were also similar (P=0.15 and P=0.11, respectively). Early patient survival was lower in ABO-incompatible grafts (P=0.006 vs. matched controls; P=0.001 vs. center controls) because of a higher rate of early infectious death (P=0.037 and P<0.001, respectively). Death-censored graft and patient survival were not significantly affected by induction therapy and anti-CD20 treatment. ABO antibody reduction by column adsorption was associated with similar death-censored graft survival to plasmapheresis., Conclusion: In this analysis of prospectively collected data from a large series of ABO-incompatible living-donor kidney transplants performed at 101 centers, death-censored graft and patient survival rates were similar to those achieved in ABO-compatible control groups over the same period.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are widely prescribed after kidney transplantation, but evidence for an improvement in outcomes is mixed. A recent trial demonstrated a significantly lower incidence of major cardiovascular events in ACEI-treated recipients., Methods: Collaborative Transplant Study data on cardiovascular death during years 2 to 10 after kidney transplantation in patients with a functioning graft were analyzed according to whether ACEI/ARB or other antihypertensive therapy (excluding diuretics) was administered at year 1., Results: Of 39,251 transplants analyzed, 15,250 (38.9%) received ACEI/ARB and 24,001 (61.1%) received other antihypertensive therapy at year 1 after transplantation. The mean duration of follow-up was 5.8 years. During years 2 to 10 after transplantation, cardiovascular death occurred in 918 patients (cumulative incidence=4.7%) with a functioning graft. The rate of cardiovascular death was similar in patients who received ACEI/ARB therapy or other antihypertensive treatment overall and in subpopulations of patients who were considered by the transplant center to be at an increased cardiovascular risk, had no pretransplant risk factors, were aged 60 years and older, were treated for diabetes at year 1, or had serum creatinine of 130 μmol/L or higher at year 1. Multivariable Cox regression analysis confirmed that treatment with ACEI/ARB did not confer a beneficial effect beyond that conferred by other antihypertensive treatments on the cumulative incidence of cardiovascular death during years 2 to 10 (hazard ratio=1.1, P=0.24)., Conclusions: This large-scale retrospective analysis of prospectively collected data shows that the rate of cardiovascular death in kidney transplant recipients receiving ACEI/ARB or other antihypertensive medications is virtually identical.

Background: Recipient death is a leading cause for renal allograft loss. Cardiovascular mortality is the most important cause of death among this patient group. Single nucleotide polymorphisms (SNPs) in a noncoding region close to the CDKN2a/b senescence genes have been associated with higher cardiovascular morbidity and mortality in nontransplant populations., Methods: We selected 2064 renal transplant recipients: 688 with a known cardiovascular cause of death and 1376 matched controls. DNA specimens were genotyped for the three SNPs with known risk allele (rs10757274, rs2383206, and rs10757278) and one SNP without risk allele (rs518394). Genotyping results were analyzed according to the frequency of risk alleles in the two groups., Results: The risk allele for three SNPs was detected significantly more often in patients with a known cardiovascular cause of death than in matched controls (all P<0.05). Diabetes and time on dialysis were modifiers of this effect with the presence of high-risk alleles having a stronger impact in diabetic patients and those with longer dialysis time. There was no difference between groups for the investigated SNP without risk allele., Conclusions: Our results support data from large cohort studies in normal nontransplant populations, which suggested a higher risk for cardiovascular events in individuals carrying certain SNPs in senescence-associated genes. Notably, this finding was obtained in a population known to be at increased risk of cardiovascular death.

Background: Kidney graft survival has never been systematically compared between Europe and the United States., Methods: Applying period analysis to first deceased-donor (DD) and living-donor kidney grafts from the United Network for Organ Sharing/Organ Procurement and Transplantation Network for the United States and the Collaborative Transplant Study for Europe, we compared overall and age-specific 1-, 5-, and 10-year graft survival for Europeans and white, African, and Hispanic Americans for the 2005 to 2008 period. A Cox regression model was used to adjust for differences in patient characteristics., Results: For the 2005 to 2008 period, 1-year survival for DD grafts was equal (91%) between Europeans and white and Hispanic Americans, whereas it was slightly lower for African Americans (89%). In contrast, overall 5- and 10-year graft survival rates were considerably higher for Europe (77 and 56%, respectively) than for any of the three U.S. populations (whites, 71 and 46%, Hispanic, 73 and 48%, and African American, 62 and 34%). Differences were largest for recipient ages 0 to 17 and 18 to 29 and generally increased beyond 3 to 4 years after transplantation. Survival patterns for living-donor grafts were similar as those seen for DD grafts. Adjusted hazard ratios for graft failure in United Network for Organ Sharing white Americans ranged between 1.5 and 2.3 (all P<0.001) for 2 to 5 years after transplantation, indicating that lower graft survival is not explained by differences in baseline patient characteristics., Conclusions: Long-term kidney graft survival rates are markedly lower in the United States compared with Europe. Identifying actionable factors explaining long-term graft survival differences between Europe and the United States is a high priority for improving long-term graft survival.

Background: Whether mismatches between donor and recipient of a kidney transplant at the HLA allele level can elicit an immune response strong enough to impact graft survival is not known., Methods: We examined the influence of HLA-DRB1 allele level mismatch on graft survival based on high-resolution typing, utilizing blood samples and clinical data provided by the Collaborative Transplant Study. HLA-DRB1*04 was selected as a model for this investigation because it is the most common HLA-DRB1 allele group and consists of several alleles with relatively high frequencies, allowing for analysis of transplants matched at the antigen level but mismatched at the allele level. Nine hundred and ninety-six recipient/donor pairs were typed for HLA-DRB1 at high resolution., Results: No effect of HLA-DRB1*04 allele mismatch was observed in first transplants. However, in retransplants, HLA-DRB1*04 allele mismatch was associated with significantly decreased graft survival, albeit only in sensitized (PRA>5%) patients (hazard ratio 3.98, P=0.014)., Conclusion: Our finding reinforces the concept that HLA compatibility significantly influences the outcome of kidney transplants, in sensitized retransplant recipients even at the allele level.

Background: Interindividual variation in inosine monophosphate dehydrogenase (IMPDH) enzyme activity and adverse effects caused by mycophenolate mofetil (MMF) inhibition may be genetically determined, and if so, transplant recipients should receive personalized dosing regimens of MMF, which would maximize efficacy and minimize toxicity. Some studies have demonstrated a relationship between the single nucleotide polymorphism and the risk of acute rejection with IMPDH I variants rs2278293 and rs2278294 and IMPDH II variant rs11706052, whereas others have failed to exhibit an effect. The aim of this work was to investigate the influence of these polymorphisms on acute rejection rates, graft survival and function, and MMF doses in a large cohort of patients., Methods: A random sample of 1040 recipients from the Collaborative Transplant Study DNA bank was genotyped for the variants IMPDH I rs2278293 and rs2278294 and IMPDH II rs11706052., Results: The presence of the T (rs2278293) and G alleles (rs2278294) in the IMPDH I variants and carriage of the G allele (rs11706052) in the IMPDH II variant did not increase the risk of rejection or affect graft function by 1 year after transplantation. There was no association with MMF dose tolerated at 1 year. Furthermore, these polymorphisms did not impact graft or patient survival at 5 years., Conclusion: This study represents the largest cohort of patients with the longest follow-up to date and does not support previous evidence for an association between these IMPDH variants and renal allograft rejection and graft survival.

Background: Allocation of deceased donor kidneys is commonly based on matching for human leukocyte antigen (HLA)-A, -B, and -DR, whereas HLA-C is currently disregarded. We investigated the influence of HLA-C compatibility on renal allograft survival. In addition, we tested an approach of matching for HLA-C epitopes., Methods: A cohort of 2260 deceased donor kidney transplants were typed for HLA-C using polymerase chain reaction-sequence specific primer method. Samples for DNA typing, serum results on presensitization (lymphocytotoxicity), and clinical data were provided by transplant centers participating in the Collaborative Transplant Study., Results: HLA-C mismatch was found to be associated with significantly decreased graft survival in presensitized (P<0.001) but not in non-presensitized (P=0.75) recipients. Mismatch of certain HLA-C epitopes seemed to be more influential than others, with mismatches showing a negative impact on graft survival in presensitized patients., Conclusions: HLA-C mismatch has a substantial deleterious effect on graft survival in presensitized kidney recipients. Our study points out the need for investigations directed at identifying donor-specific HLA-C antibodies and evaluating their relevance in transplantation. In view of the fact that current assays for determining HLA-C specific antibodies are hampered by additional detection of clinically irrelevant antibodies, matching for HLA-C may provide a reasonable approach to improve transplant outcomes in presensitized kidney transplant recipients.

Background: Reliable markers for assessing the biological effect of immunosuppressive drugs and identification of transplant recipients at risk of developing rejection are not available., Methods: In a prospective multicenter study, we investigated whether posttransplant measurement of the T-cell activation marker soluble CD30 (sCD30) can be used for estimating the risk of graft loss in kidney transplant recipients. Pre- and posttransplant sera of 2322 adult deceased-donor kidney recipients were tested for serum sCD30 content using a commercial enzyme-linked immunosorbent assay., Results: sCD30 decreased posttransplant and reached a nadir on day 30. Patients with a high sCD30 of more than or equal to 40 U/mL on day 30 showed a subsequent graft survival rate after 3 years of 78.3±4.1%, significantly lower than the 90.3±1.0% rate in recipients with a low sCD30 on day 30 of less than 40 U/mL (log-rank P<0.001; Cox hazard ratio 2.02, P<0.001). Although an association was found between pre- and posttransplant sCD30 levels, patients with high sCD30 on posttransplant day 30 demonstrated significantly lower 3-year graft survival irrespective of the pretransplant level., Conclusions: Our data suggest that posttransplant measurement of sCD30 on day 30 is a predictor of subsequent graft loss in kidney transplant recipients and that sCD30 may potentially serve as an indicator for adjustment of immunosuppressive medication.

Background: It is unclear whether kidney transplant recipients with preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) detectable only in the highly sensitive Luminex single-antigen (LSA) assay are at an increased risk of graft failure., Methods: We studied 3148 patients who received a deceased donor kidney graft between 1996 and 2008 and were enrolled in the prospective serum project of the Collaborative Transplant Study. There were 118 patients with graft loss during the first 3 years after transplantation on whom recipient and donor DNA was available for complete HLA typing. We compared the incidence of LSA-detected DSA in these patients with graft failure and matched controls with functioning grafts. All patients were found negative in the less-sensitive complement-dependent lymphocytotoxicity and enzyme-linked immunosorbent assays., Results: When mean fluorescence intensity (MFI) of greater than or equal to 1000 was used as a cutoff for Luminex positivity, 118 patients with graft loss did not show a higher incidence of DSA against HLA-A, -B, -C, -DRB1/3/4/5, -DQA1, -DQB1, -DPA1, or -DPB1 antigens than 118 matched controls without graft loss (for all loci P not significant). The incidence of strong DSA (MFI ≥2000 or MFI ≥3000) detected only by LSA was low (for all loci between 0% and 5%) and did not identify unacceptable antigens that were relevant for graft loss within the first 3 years after transplantation., Conclusion: We conclude that, given currently practiced crossmatch procedures and immunosuppressive regimens, exclusion of donor organs carrying "unacceptable" HLA based exclusively on sensitive LSA antibody testing is not justified., (© 2011 by Lippincott Williams & Wilkins)

Background: Bone fractures are a frequent complication after kidney transplantation, for which various predisposing factors have been identified. It has been suggested that human leukocyte antigen (HLA) mismatch increases the risk., Methods: Data on hip fractures occurring in the first 5 years posttransplant were analyzed among kidney transplants from deceased donors performed between 1995 and 2008 and reported to the Collaborative Transplant Study., Results: In the 20,509 patients analyzed, the cumulative rate of hip fracture by year 5 posttransplant was 0.85%. Cox regression analysis identified the following risk factors: female recipients aged 40 to 59 years (hazard ratio [HR] 2.26, P=0.029), female recipients 60 years or older (HR 5.14, P<0.001), male recipients 60 years or older (HR 2.39, P=0.028), and donor age more than or equal to 60 years (HR 1.75, P=0.009). Using the rate of fractures in recipients with zero HLA-DR mismatch as the reference, the risk of hip fracture increased for grafts with one HLA-DR mismatch to HR 1.85 (95% confidence interval [CI] 1.18-2.89, P=0.007) and with two HLA-DR mismatches to HR 2.24 (CI 1.25-4.02, P=0.007). There was a significant association between the number of HLA-DR mismatches and the diagnosis of osteoporosis 5 years after transplantation: one HLA-DR mismatch risk ratio 1.26 (CI 1.12-1.43, P<0.001) and two HLA-DR mismatches risk ratio 1.45 (CI 1.20-1.74, P<0.001)., Conclusion: The risk of hip fracture after kidney transplantation seems to be markedly exacerbated by HLA-DR mismatching. These findings add to the growing base of evidence that HLA-DR matching influences morbidity after kidney transplantation.

Background: Data concerning the impact of human leukocyte antigen (HLA) compatibility on lung transplant survival rates are limited., Methods: Using the Collaborative Transplant Study database, 5-year graft outcome according to HLA mismatch was examined in 8020 deceased donor lung transplants performed during 1989 to 2009., Results: Graft survival rates showed a stepwise decrease as the combined number of HLA-A+B+DR mismatches increased from one to six (P<0.001). Surprisingly, the 28 grafts with 0 mismatches at all 3 loci had a 1-year survival rate of only 49.7%, significantly lower than for 1, 2, 3, 4, 5, or 6 mismatches (P=0.002, <0.001, <0.001, <0.001, 0.002, and 0.003, respectively). Multivariate regression analysis confirmed that, paradoxically, transplantation of grafts with zero HLA-A+B+DR mismatches was associated with a 19% increase in relative risk of failure. Donor lung preservation for up to 12 hr was not associated with inferior graft survival versus shorter preservation times (P=0.60)., Conclusions: Our data show that a high number of HLA mismatches or zero mismatches impacts unfavorably on lung transplant survival.

Background: Borderline rejection (Bord-R) is a frequent diagnosis in renal transplantation, and there is increasing evidence that regulatory T lymphocytes are involved in its pathogenesis. Current histopathologic practice does not differentiate between graft-protecting and -damaging T lymphocytes, and patients with Bord-R routinely receive rejection treatment. We analyzed Treg-associated forkhead box P3 (Foxp3) gene expression in Bord-R and more severe forms of acute rejection episodes (ARE)., Methods: Foxp3 transcripts were measured in 520 serial peripheral blood samples from 177 kidney graft recipients obtained during the first 20 days posttransplantation., Results: The highest Foxp3 transcripts were observed in patients with Bord-R or without rejection and the lowest in patients with ARE. Patients with Bord-R on posttransplant days 5 to 7 showed an increased Foxp3 transcript level of 156%, which increased to 302% by posttransplant days 14 to 16. In contrast, patients with ARE demonstrated significantly lower Foxp3 gene expression than that observed in Bord-R, nonrejectors, or acute tubular necrosis patients (P=0.001, P<0.001, and P=0.005, respectively, on days 11-13). Acute tubular necrosis patients demonstrated intermediately high Foxp3 gene expression., Conclusions: Our data indicate that increased Treg activity in peripheral blood is a frequent feature of Bord-R. This finding questions the appropriateness of rejection treatment in all patients with the histopathologic diagnosis "Bord-R".

Background: The impact and relationship of donor age, human leukocyte antigen (HLA) matching, and posttransplant non-Hodgkin lymphoma in pediatric kidney recipients are not completely understood., Methods: We analyzed Collaborative Transplant Study data from 9209 pediatric kidney transplant recipients to examine the effects of donor age and HLA match on graft survival and the relationship between HLA match and occurrence of non-Hodgkin lymphoma., Results: Survival rates using donors aged 11 to 17, 18 to 34, or 35 to 49 years were similar. Cox regression analysis showed that two HLA-DR mismatches were associated with lower graft survival in transplants performed during 1988 to 1997 (P<0.001) but not during the 1998 to 2007 period (P=0.95). A hierarchical relationship was observed for the effect of increasing numbers of combined HLA-A+B+DR mismatches on graft survival during the 1988 to 1997 (P<0.001) and the 1998 to 2007 period (P<0.001). An association between two HLA-DR mismatches and non-Hodgkin lymphoma was demonstrated by multivariate analysis (hazard ratio for 2 vs. 0-1 DR mismatches 2.04, P=0.021), and the result was consistent during both 10-year periods., Conclusion: We recommend that (1) kidneys from deceased donors up to 49 years be allocated to children, (2) an acceptable HLA-A+B+DR match be attempted in patients with relatively common HLA phenotypes, and (3) transplants with two HLA-DR mismatches be avoided to reduce the risk of posttransplant non-Hodgkin lymphoma.

Background: Posttransplant non-Hodgkin lymphoma is a rare complication but associated with high mortality. The extent to which human leukocyte antigen (HLA) mismatching influences the rate of posttransplant lymphoma has not been clarified., Methods: Data on lymphomas occurring in the first 3 years posttransplant were analyzed among first kidney transplants from deceased donors performed between 1985 and 2007 and reported to the Collaborative Transplant Study., Results: Of 152,728 patients included, 593 non-Hodgkin lymphomas were diagnosed. Cox multivariate regression analysis showed that HLA-A mismatches had no influence on the rate of lymphoma. One and two HLA-DR mismatches were associated with a hazard ratio (HR) of 1.21 (95% confidence interval 1.00-1.45, P=0.047) and 1.56 (95% confidence interval 1.21-1.99, P<0.001), respectively. For lymphoma of the kidney and central nervous system, HRs for two HLA-DR mismatches were 2.29 (P=0.007) and 2.17 (P=0.029), respectively. Two HLA-B mismatches were also significantly associated with lymphoma in the kidney (HR 2.82, P=0.009)., Conclusion: Mismatches at the HLA-DR locus are a significant risk factor for posttransplant non-Hodgkin lymphoma, particularly in the kidney and central nervous system, whereas two HLA-B mismatches increase the risk for the development of lymphoma of the kidney.

BACKGROUND.: Despite the importance of non-Hodgkin lymphoma (NHL) as a posttransplant complication, the relationship between NHL and recipient seropositivity for Epstein-Barr virus (EBV) or cytomegalovirus (CMV) is incompletely understood. METHODS.: Kidney, heart, and liver transplant recipients reported to the Collaborative Transplant Study with known pretransplant EBV and CMV serostatus were analyzed in terms of clinically manifest NHL. Cox multivariate regression analysis was performed to account for a wide range of possible confounders. RESULTS.: In total, 18,682 kidney, 2042 heart, and 2616 liver transplant recipients were analyzed. Regardless of age, pretransplant EBV serostatus was significantly associated with risk of NHL in kidney transplant recipients (P<0.001). There was no significant difference in lymphoma rates according to CMV and CMV serostatus among EBV and EBV recipients (log-rank P=0.55 and P=0.57, respectively), but hospitalization for CMV disease during year 1 posttransplant was associated with subsequent NHL (hazard ratio [HR] 6.1; 95% confidence interval [CI] 2.0-18.4; P=0.001). EBV serostatus was also associated with increased risk of NHL in heart transplant patients (HR 3.6; 95% CI 1.1-11.3; P=0.031) but, contrary to expectation, not in liver recipients (HR 0.6; 95% CI 0.1-1.7; P=0.32). CONCLUSIONS.: In view of the striking increase in risk of NHL in EBV kidney transplant recipients of all ages, EBV serostatus should be determined pretransplant in all age groups. CMV serostatus was not independently associated with risk of NHL after kidney transplantation. Surprisingly, in liver transplantation, the risk of NHL was virtually unaffected by EBV serostatus.

Objective: Previously, we reported that high pretransplant sIL-6R plasma levels are associated with posttransplant acute tubular necrosis (ATN). In this study, we examined associations of pretransplant plasma levels of sgp130 with ATN., Patients and Methods: Pretransplant serum creatinine (Cr), plasma neopterin, and sgp130 levels were studied in 105 first renal transplant recipients who received grafts from deceased donors. Although 57 patients had immediate and sustained graft function, ATN was diagnosed in 30 patients within the first 11.3+/-7.8 posttransplant days and acute rejection in 18 patients during the first 27.1+/-27.6 days., Results: Pretransplant serum Cr and plasma neopterin were similar in the three patient groups. Pretransplant sgp130 plasma levels, however, were significantly lower in patients with ATN than in patients with immediate graft function (P=0.004) or acute rejection (P=0.009). Multivariable logistic regression analysis for ATN showed an odds ratio of 4.3 of patients with pretransplant sgp130 less than or equal to 250 pg/mL with posttransplant ATN (P=0.006)., Conclusion: Patients at risk of ATN showed immediately before transplantation low anti-inflammatory sgp130, suggesting a contribution of the IL-6 cytokine family to the development of ATN. It might be useful to measure IL-6 family plasma levels pretransplant to identify patients who are at an increased risk of developing ATN.

Background: Adverse events occurring early after kidney transplantation were reported to influence graft outcome., Methods: In a prospective multicenter study initiated in 2001, we investigated the relationship between human leukocyte antigen (HLA) alloantibodies, early adverse events, and graft outcome., Results: Pretransplant presence of HLA class I antibodies was associated with a higher rate of no immediate function (NIF) of the graft (odds ratio [OR] 1.78, P=0.023) and acute rejection episodes (ARE) during the first 3 months after transplantation (OR 2.53, P<0.001). NIF and ARE during posttransplant days 15 to 90 were associated with increased risk of graft loss to year 3 (OR 2.06 and 3.75, P=0.006 and P<0.001, respectively). ARE within the first 2 posttransplant weeks did not increase the risk significantly, especially if they occurred in nonsensitized patients without antibodies. Graft survival at 3 years in patients with both NIF and ARE during the first 3 months was significantly lower (81.3%+/-6.2%) than in patients who did not experience NIF or ARE (95.1%+/-1.0%, P<0.001). Importantly, neither NIF nor ARE had an impact on subsequent graft survival if good graft function (serum creatinine <130 mumol/L) was observed at the end of the third month., Conclusion: Our results show that NIF and ARE associated with pretransplant antibodies against HLA class I, and they suggest that early diagnosis and treatment of adverse events with the aim of obtaining normal 3-month graft function should be pursued rigorously. Good 3-month graft function is associated with excellent long-term survival, even in patients with pretransplant HLA antibodies and posttransplant adverse events.

Background: There have been striking changes during the last 10 years concerning the choice of calcineurin inhibitor and antimetabolite agent prescribed after kidney transplantation., Methods: A retrospective analysis of 51,303 patients undergoing deceased-donor kidney transplantation during 1998 to 2007 was performed using multivariate regression analysis. All patients received cyclosporine A (CsA) or tacrolimus (Tac) with azathioprine (AZA) or mycophenolic acid (MPA) on an intention-to-treat basis with corticosteroids plus/minus antibody induction. Graft survival rates and secondary outcomes were analyzed. A subanalysis was performed for transplants undertaken during 2002 to 2007, in which all patients were treated with MPA plus corticosteroids and CsA or Tac., Results: All-cause graft failure and death-censored graft failure to 5 years posttransplant did not differ significantly between Tac and CsA. We found no evidence in support of previous claims that MPA results in superior long-term graft survival compared with AZA treatment. At the end of year 1, Tac was associated with a lower risk for serum creatinine more than or equal to 130 mumol/L (P<0.001) and hypercholesterolemia (P<0.001) versus CsA, but a higher risk for de novo posttransplant diabetes (P<0.001). MPA treatment was associated with a lower risk of acute rejection (P<0.001) but a higher risk of hospitalization because of infection (P<0.001) versus AZA., Conclusions: Five-year graft survival in deceased-donor kidney transplant recipients is equivalent in patients receiving CsA- or Tac-based immunosuppression, and in those receiving MPA or AZA. The absence of a survival benefit with modern agents is relevant in the current cost-conscious era of prescribing.

Background: Data are scarce concerning the impact of maintenance immunosuppression dose reductions posttransplant., Methods: Graft survival according to dose reduction or discontinuation of calcineurin inhibitors or mycophenolate mofetil (MMF) after the first year posttransplant was evaluated in 25,045 patients undergoing kidney transplantation during 1996 to 2005. No patient in this analysis had experienced a rejection and all had good graft function before dose reduction., Results: Reduction of cyclosporine (CsA) dose to less than or equal to 150 mg/day, tacrolimus to less than or equal to 2 mg/day, or MMF to less than or equal to 1.0 g/day in patients on CsA or less than or equal to 0.5 g/day in patients on tacrolimus during the second year posttransplant was associated with a statistically significant reduction in graft survival (hazard ratios between 1.37 and 1.65). Withdrawal of CsA, tacrolimus, or MMF during year 2 was also associated with an increase in the risk of graft loss compared with continuing treatment (hazard ratio 1.52-1.73)., Conclusions: This observational analysis indicates that in kidney transplant patients with good graft function, withdrawing maintenance CsA, tacrolimus or MMF, or reducing the dose of these agents below certain thresholds after the first year posttransplant is associated with a significant risk of graft loss.

Background: The aim of this analysis was to investigate the relationship of acute rejection episodes (ARE) at different times posttransplantation with reversibility of graft dysfunction and long-term graft failure using data from the Collaborative Transplant Study database., Methods: A total of 28,867 patients receiving their graft between 1995 and 2005 from deceased donors were included in the analysis. The time from renal transplantation to first treated ARE was divided into intervals up to 3 years. Long-term graft survival and half-life rates were calculated and hazard ratios (HR) for failure were computed using multivariate Cox regression analysis., Results: Compared with patients who did not receive rejection treatment during the first posttransplant year, HR for graft survival increased to 1.35 for patients with rejection 0 to 90 days (P<0.001), 2.05 with rejection 91 to 180 days (P<0.001), and 2.74 with rejection 181 to 365 days of posttransplantion (P<0.001). First rejections occurring during the second year were associated with HR 3.35 (P<0.001) and rejections during the third year with HR 3.17 (P<0.001). In addition to the time of rejection, the degree of functional recovery after rejection treatment was found to be important for subsequent graft survival., Conclusion: The time point of occurrence and the degree of functional recovery after rejection treatment were found to significantly influence the impact of ARE on long-term graft survival, and we were able to quantify the associated risks.

Background: Based on an analysis of United Network for Organ Sharing data, it was reported that the influence of human leukocyte antigen (HLA) matching in renal transplantation has diminished in recent years, prompting the suggestion that donor kidney allocation algorithms should be revised., Methods: We compared the impact of HLA matching on kidney graft survival during the decades 1985-1994 and 1995-2004 using the data of the Collaborative Transplant Study. Results for the last 5 years (2000-2004) were analyzed separately in addition. Multivariate Cox regression analysis was used to account for the influence of confounders., Results: Our results show that, while graft survival rates have improved overall over time, the relative impact of HLA matching on the graft survival rate has remained strong and highly significant. Both the need for posttransplant rejection treatment and the graft survival rates showed statistically highly significant associations with HLA matching regardless of the interval analyzed (P<0.001)., Conclusions: We conclude that HLA mismatches significantly influence the outcome of kidney transplants and that kidney exchange programs for the purpose of achieving better HLA matches continue to be meaningful.

Background: Kidney preservation is an integral part of clinical kidney transplantation. Changes in the use of preservation methods and storage solutions, ischemic preservation times, and the relationship between ischemia time and human leukocyte antigen (HLA) match have not been extensively studied in recent years., Methods: The Collaborative Transplant Study database was used to analyze effects of kidney preservation methods and times. Graft survival and death-censored functional survival were used as endpoints. In all, 91,674 transplants from deceased donors were analyzed using univariate and multivariate methods., Results: Cold storage accounted for more than 95% of kidney preservations from 1990-2005. Increasing ischemia up to 18 hr was not detrimental for graft outcome, whereas the risk of graft failure rose with ischemia 19-24 hr to relative risk (RR) 1.09, 25-36 hr to RR 1.16, and >36 hr to RR 1.30 (P<0.001). As compared to other preservation solutions, University of Wisconsin (UW) solution was associated with significantly better outcome when ischemia exceeded 24 hr. Short ischemia did not eliminate the effect of HLA matching. Kidneys from young or old donors were affected by prolonged ischemia to similar degrees. Pulsatile machine perfusion was not superior to cold storage., Conclusion: Kidneys from deceased donors should ideally be transplanted within 18 hr. Within the 18-hr window, the time of ischemia has no significant influence on graft survival. UW solution should be used if preservation for longer periods is envisioned. HLA matching improves graft survival regardless of length of ischemia.

Background: It is widely assumed that the graft-enhancing properties of antilymphocyte induction agents and their lymphoma-inducing potential are intimately related., Methods: The Collaborative Transplant Study (CTS) database was used to evaluate graft survival and non-Hodgkin lymphoma at 3 years according to type of induction in 112,122 patients receiving a deceased-donor renal transplant during 1985 to 2004., Results: The relative risk of 3-year graft loss versus no induction was 1.07 (95% confidence interval [CI], 1.01-1.13; P=0.016) with murine anti-CD3 monoclonal antibody (OKT3), 1.03 (95% CI, 0.95-1.11; NS) with antithymocyte globulin (ATG)-Fresenius, 1.18 (95% CI, 1.02-1.35; P=0.021) with ATGAM, 0.74 (95% CI, 0.68-0.81; P<0.001) with Thymoglobulin, and 0.78 (95% CI, 0.72-0.84; P<0.001) with interleukin (IL)-2RA induction. The standardized incidence ratio of lymphoma compared with a similar nontransplant population was 21.5 (95% CI, 15.7-28.8; P<0.001) with OKT3, 4.9 (95% CI, 1.6-11.5; P=0.008) with ATG-Fresenius, 29.0 (95% CI, 12.5-57.1; P<0.001) with ATGAM, 21.6 (95% CI, 14.3-31.2; P<0.001) with Thymoglobulin, 7.8 (95% CI, 4.4-12.9; P<0.001) with IL-2RAs, and 9.4 (95% CI, 8.3-10.6 P<0.001) with no induction., Conclusions: Those agents that offered the highest rates of graft survival were not necessarily associated with the highest risk of lymphoma. Graft survival was significantly improved with Thymoglobulin and IL-2RA induction, whereas lymphoma rates were highest with ATGAM, OKT3, and Thymoglobulin. IL-2RA agents seem to offer the best risk-to-benefit ratio for this patient population overall in terms of graft survival and lymphoma.

Background: Whereas some authors reported that kidney transplants were protected from rejection by simultaneous liver grafts, other authors failed to obtain evidence for a kidney graft-protective role for the liver., Methods: The survival rate of 383 kidney grafts in recipients of combined kidney-liver transplants performed between 1985 and 2000 and reported to the international Collaborative Transplant Study (CTS) was analyzed and compared retrospectively with that of a matched group of control patients who were transplanted with kidneys only. In addition, 105 combined kidney-heart transplants performed during the same time period were analyzed., Results: At 1 year, the survival rate of kidney grafts in recipients of kidney-liver transplants was significantly lower than that in kidney only recipients (P<0.0001). Subsequently, however, kidneys in kidney-liver recipients fared much better so that the success rates were virtually identical after 8 years of follow-up (62.1+/-3.5% vs. 61.9+/-2.3%, P=ns). Half-life times after the first posttransplant year were 27.6 and 14.5 years for combined or single kidney grafts, respectively, and the projected 20-year graft survival rates were 46% and 35%, respectively. The 8-year survival rate of kidney grafts in recipients of combined kidney-heart recipients was 63.5+/-6.2%, the associated half-life time 31.6 years, and the projected 20-year graft survival rate 49%., Conclusions: The long-term kidney graft survival rate is higher in recipients of combined kidney-liver transplants than in recipients of kidney grafts only. Because the success rate is equally high in recipients of combined kidney-heart transplants, it is necessary to reexamine the hypothesis that the liver possesses a unique capacity of protecting a simultaneous kidney graft from rejection.

Background: In the present study, we investigated whether the soluble form of CD30 (sCD30), a marker for T helper 2-type cytokine-producing T cells, is increased in sera of potential kidney graft recipients. We also investigated whether the pretransplantation serum sCD30 content is related to kidney graft survival., Methods: Pretransplantation sera of 844 cadaver kidney recipients from three transplant centers in Germany were tested for serum sCD30 content using a commercially available ELISA kit., Results: Kidney graft recipients showed a significantly higher serum sCD30 content than healthy controls (P<0.0001). High sCD30 serum content was associated with graft rejection. The 2-year graft survival rate in recipients with a high pretransplantation serum sCD30 was 68+/-6%, significantly lower than the 86+/-1% rate in recipients with a low sCD30 (P<0.0001). Importantly, high sCD30 was indicative of an increased risk of graft loss even in recipients without lymphocytotoxic alloantibodies., Conclusion: These data show that an elevated pretransplantation serum sCD30 reflects an immune state that is detrimental for kidney graft survival.

Background: Previous analysis of kidney transplant data from the Collaborative Transplant Study database showed that patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 7 years posttransplantation. Longer-term and additional analyses have now been performed., Methods: Data from cadaver kidney transplants performed between 1985 and 1998 were analyzed retrospectively. Patients were included if they had a functioning graft 1 year posttransplantation, and the daily cyclosporine dose administered 1 year posttransplantation was reported. Data on cyclosporine dose, serum creatinine concentration, and systolic blood pressure were recorded 1 and 5 years after transplantation; information on graft survival was documented at yearly intervals., Results: Patients receiving cyclosporine 3-6 mg/kg/day 1 year posttransplantation had the best graft survival rate 10 years posttransplantation. Cyclosporine <2 mg/kg/day was least beneficial overall and in subanalyses based on age, risk level, and 1-year serum creatinine concentration. The microemulsion cyclosporine formulation (Neoral) was associated with a significantly higher 4-year graft survival rate than the conventional formulation (Sandimmune; P=0.0001). Median systolic blood pressure 5 years posttransplantation was similar in each 1-year cyclosporine dose category (range of medians 139.0-140.0 mmHg). The percentages of patients with serum creatinine concentrations of <130, 130-260, 260-400, or >400 micromol/L 1 and 5 years posttransplantation were similar across 1-year cyclosporine dose categories, with the exception of >6 mg/kg/day, where there was a shift toward a less favorable serum creatinine concentration over time., Conclusions: The 1-year cyclosporine dose was significantly associated with long-term graft survival, with evidence of underimmunosuppression at doses <3 mg/kg/day and overimmunosuppression at doses >6 mg/kg/day, but had little influence on systolic blood pressure or serum creatinine concentration at doses up to 6 mg/kg/day.