Search

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.

FoxP3 and Vav1 are known to be involved in the development of regulatory T cells. Two polymorphic sites in the FoxP3 promoter (rs3761548 and a (GT) n -dinucleotide repeat) and 2 single nucleotide polymorphisms in intron 1 of the Vav1 gene (rs2546133 and rs2617822) have been shown to correlate with gene expression levels. We investigated a potential impact of FoxP3 and Vav1 genetic variants on kidney allograft failure using samples and data of the Collaborative Transplant Study. A cohort of 384 kidney transplant patients was tested. We found no significant association of FoxP3 promoter rs3761548 or (GT) n repeat length with presumed immunological graft failure. The genotype frequencies of Vav1 intron polymorphisms did not significantly differ between patients with graft failure and matched controls., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Regulatory T cells (Tregs) are a cornerstone of graft acceptance. High numbers of Tregs are associated with better long-term graft survival. Recently, Vitamin D was suggested as an immunomodulator, in addition to its classical role in calcium metabolism. Vitamin D modulates Tregs and might, thereby, promote graft acceptance and long-term graft survival., Methods: One hundred twenty-three renal allograft recipients attending either Heidelberg nephrology or Giessen internal medicine clinic were enrolled in this cross- sectional study. Sixteen healthy controls were studied in addition. Sixty-nine patients were receiving no vitamin D, 38 calcitriol, and 16 cholecalciferol supplementations. We evaluated whether there was a difference in the absolute numbers of Helios(+), Helios(-), CTLA-4(+), IFNg(+), and total Tregs among the patient groups., Results: Cholecalciferol supplementation was associated with higher absolute numbers of Helios(+), CTLA-4(+), and total Tregs than calcitriol (p < 0.001, p = 0.004, p = 0.001 respectively). Helios(+) Tregs were also higher in cholecalciferol than no vitamin D supplementation patients (p = 0.001), whereas CTLA-4(+) and total Tregs were similar in both groups (p = NS). Helios(+), Helios(-), CTLA-4(+), IFNg(+), and total Tregs were similar in the cholecalciferol and healthy control groups (p = NS)., Conclusion: Our findings indicate that cholecalciferol, even when administered at low dosages, has a stabilizing effect on Tregs (particularly the Helios + subset), in contrast to calcitriol which showed neither a stabilizing nor a proliferation-inducing effect on the same cell population.

Background: Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor., Methods: Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival., Results: Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted for recipient and donor characteristics demonstrated a 13% higher risk (hazard ratio, 1.13; 95% confidence interval, 1.06-1.21) with 1 mismatch and a 64% higher risk (hazard ratio, 1.64, 95% confidence interval, 1.56-1.73) with 6 mismatches. Dividing the mismatch categories into 27 ordered permutations, and testing their 57 within mismatch category differences, demonstrated that all but 1 were equal, independent of locus., Conclusions: A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.

Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4⁺CD25⁺FoxP3⁺ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans.

Background: There is an increasing appreciation of the deleterious effects of antibody and B cells on acute and chronic transplant outcomes. Many effector functions of antibody are mediated by a family of receptors (FcγRs) that are expressed on most immune cells, including neutrophils, natural killer cells, and B cells. Most FcγRs are activating and controlled by a single inhibitory receptor, FcγRIIB (CD32B), which also regulates some aspects of B-cell activation and antibody production. FcγRIIB-deficient mice develop severe chronic arteriopathy in a murine cardiac allograft model. A single nucleotide polymorphism in human FcγRIIB (rs1050501) results in profound receptor dysfunction and is associated with systemic lupus erythematosus. The frequency of this FcγRIIB-I/T232 polymorphism also shows significant racial variation., Methods: In the present study, we sought to determine whether the FcγRIIB-I/T232 single nucleotide polymorphism rs1050501 affected susceptibility to renal allograft rejection or loss and transplant recipient survival. FcγRIIB-I/T232 genotype was determined in 2,851 Caucasian and 570 Afro-Caribbean renal transplant recipients, and in 236 transplant recipients with a primary diagnosis of systemic lupus erythematosus, all of whom were enrolled into the Collaborative Transplant Study., Results: We found no significant difference in pretransplant panel reactive antibodies, acute rejection at 1-year nor in 10-year transplant or patient survival in individuals with differing FcγRIIB-I/T232 genotype., Conclusion: This negative result is surprising, given the importance of this receptor in modulating antibody effector function.

Death with a functioning graft remains a major challenge following kidney transplantation. Steroid dosing may be a modifiable risk factor. Collaborative Transplant Study (CTS) data were analyzed to assess the relationship between long-term steroid dose and death with function during years 2-5 posttransplant in 41 953 adult recipients of a deceased-donor kidney transplant during 1995-2010. Steroid dose at year 1 correlated significantly with death with function overall, and with death due to cardiovascular disease or infection (all p < 0.001). In patients with optimal graft function (serum creatinine <130 µmol/L) and no anti-rejection treatment during (a) year 1 (b) years 1 and 2, these significant associations remained (all p < 0.001). The center-specific incidence of steroid withdrawal during year 2 showed a significant inverse association with death due to cardiovascular disease (p < 0.001) or infection (p < 0.001) overall, and within the subpopulation with good graft function and no rejection during year 1 (p = 0.002 and p < 0.001, respectively). Maintenance steroid dose shows a highly significant association with death with a functioning graft caused by cardiovascular disease or infection during years 2-5 after kidney transplantation, even in patients with good graft outcomes in whom steroid treatment would appear to be unnecessary., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Objective: Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor-specific antibodies (DSA)., Methods: Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization. Six patients were negative in CDC as well as ELISA screening but positive in Luminex for DSA., Results: The 23 patients received a median of 8 apheresis treatments before and 5 treatments after transplantation. Induction therapy was performed with either thymoglobulin (N = 11) or basiliximab (N = 12). The 2-year graft survival rate was 100%. At last follow up, a median of 12 months after transplantation, median serum creatinine was 1.42 mg/dL, median MDRD-GFR 59.5 mL/min/1.73 m(2), and median urinary protein-to-creatinine ratio 0.12. Ten out of fourteen patients (71%) who had completed the first year after transplantation by the time of analysis had no DSA by day 360. Acute T-cell mediated rejection was diagnosed in one patient (4%), and antibody-mediated changes were found in 5 patients (22%). Four out of these 5 patients showed evidence of persistent (N = 2) or reemerging plus/minus de novo DSA (N = 2) on day 360, and the 2 patients with persistent DSA lost their allograft subsequently on days 750 and 810, respectively. Infectious complications were infrequent., Conclusions: Our previously described treatment algorithm for desensitization of living donor kidney transplant recipients with DSA results in good graft outcomes with a low rate of side effects., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

In current clinical praxis, monitoring of immunosuppressive agents in organ transplantation is restricted to measurement of drug blood levels and does not consider the drug's variable effect on the individual patient's immune system. Establishment of biological markers that measure the biological effect of immunosuppressive drugs is desirable and would enable the identification of patients who are at risk of developing rejection, or patients who are suitable for minimization or weaning of immunosuppressive therapy. Several studies demonstrated that the technically simple posttransplant measurement in serum of the T cell activation marker soluble CD30 (sCD30) allows prediction of subsequent graft loss in kidney transplant recipients. sCD30 is a relatively large molecule and therefore an attractive biological marker which is resistant to repeated thawing cycles and temperature differences and easily determined using commercial ELISA. Whether sCD30-based prospective adjustment of immunosuppressive therapy can prevent irreversible graft damage and improve long-term graft outcome awaits evaluation in randomized controlled trials., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Objectives: The pretransplant dialysis modality might influence renal allograft and patient survival after transplantation. Studies published to date yielded conflicting results., Methods: Deceased-donor allograft recipients reported to the 'Collaborative Transplant Study' were analysed, using multivariate Cox regression analysis, considering potential confounders which included pretransplant patient cardiovascular risk evaluation as well as immunological and treatment parameters. Primary end points were all-cause graft survival, death-censored graft survival and patient survival., Results: In total, 60,008 recipients were analysed. Patients who were on peritoneal dialysis (PD) (n = 11,664) prior to transplantation demonstrated a 10% lower all-cause mortality (P = 0.014) but similar death-censored graft survival (P = 0.39) as recipients treated with haemodialysis (n = 45,651). This lower all-cause mortality in PD patients was primarily a consequence of a significantly lower rate of cardiovascular death with a functioning graft (P < 0.013) in a subcohort of patients defined as at increased risk., Conclusions: Pretransplant dialysis modality per se has no significant impact on allograft outcome. Superior all-cause survival of PD patients is primarily due to a lower rate of cardiovascular death in a subcohort of high-risk recipients. This might explain the conflicting results published to date.

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)

The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti-human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR(+) vs 63% in AMR(-) patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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: Sensitized patients have a lower chance of receiving a crossmatch-negative kidney and, if transplanted, are at risk of antibody-mediated allograft rejection., Methods: For safe and timely transplantation of sensitized patients at our center, we developed an integrative algorithm that includes identification of high-risk patients, good human leukocyte antigen match, inclusion in the Eurotransplant Acceptable Mismatch Program when applicable, apheresis, anti-CD20 therapy, posttransplant antibody monitoring, and protocol biopsies. Thirty-four high-risk recipients of a deceased donor kidney (DDK: n=28) or living donor kidney (LDK: n=6) were transplanted using this algorithm., Results: One-year graft survival, death-censored graft survival, and patient survival rates in DDK recipients were 92.4%, 96.4%, and 95.8%, respectively. No graft loss or patient death was observed in the six LDK patients. Median serum creatinine at 1 year in DDK and LDK recipients was 1.2 and 1.4 mg/dL, respectively. Eleven DDK and three LDK patients experienced at least one biopsy-proven acute rejection episode, mostly showing borderline changes. Antibody-mediated rejection without graft loss was diagnosed in two DDK and one LDK patients. Delayed graft function was observed in 13 DDK and 1 LDK patients. Infectious complications were infrequent., Conclusions: We describe an algorithm for the categorization and treatment of presensitized high-risk patients. This protocol provides effective prevention of antibody-mediated rejection and is associated with a low rate of side effects and good graft outcome.

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.

HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that are expressed on natural killer (NK) cells. Based on their KIR specificity, HLA-C alleles can be divided into two groups, termed HLA-C1 and HLA-C2. Donor HLA-C group has recently been identified by Hanvesakul et al. (Am J Transplant 2008) as a critical determinant of clinical outcome following liver transplantation: Possession of at least one HLA-C group 2 allele by the donor was associated with significantly improved long-term graft and patient survival, presumably due to an inhibition of host NK cell function. To verify this study, we performed genotyping of 913 deceased liver donors for the relevant KIR epitopes of HLA-C and correlated the presence or absence of donor HLA-C2 genotype with graft and patient survival. In our study, donor HLA-C2 genotype had no impact on 10-year graft or patient survival. We cannot confirm a major role of donor HLA-C2 genotype on long-term allograft survival after liver transplantation.

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.

It is a matter of debate whether pancreas allografts independently contribute to renal allograft and patient survival in individuals who have type 1 diabetes and receive a simultaneous pancreas and kidney transplant (SPK). Using data from the Collaborative Transplant Study, we studied patients who had type 1 diabetes and were recipients of deceased-donor kidneys (DDK), living-donor kidneys (LDK), or SPK. We analyzed graft and patient survival rates with a maximum of 18 yr of follow-up. DDK recipients had inferior graft and patient survival compared with LDK and SPK recipients. LDK recipients had superior graft and patient survival rates initially, but SPK recipients demonstrated equal survival rates toward the end of follow-up. Multivariate analysis, adjusting for pretransplantation cardiovascular risk, showed that patient survival of SPK recipients was superior to that of LDK recipients beyond the 10th year after transplantation (hazard ratio 0.55; P = 0.005). In summary, the early survival advantage of LDK over SPK is lost during long-term follow-up, probably as a result of improved glycemic control in SPK recipients.

Background: In haematopoietic stem-cell transplantation, male recipients of female grafts have an increased risk of graft-versus-host disease and female recipients have both an increased risk of rejection of male grafts and of specific T-cell and antibody reactivity against H-Y encoded gene products. By contrast, in kidney transplantation, the role of H-Y as a minor histocompatibility antigen has been disputed. We aimed to investigate whether an immunological H-Y effect occurs in kidney transplantation., Methods: We did a retrospective cohort study between 1985 and 2004 in 195 516 recipients of allografts from deceased donors. We used multivariate statistical methods to compare graft survival and death-censored graft survival rates for female and male donor kidneys in female and male recipients at 1 and 10 years., Findings: Graft loss was more common with kidneys from female donors than with those from male donors (p<0.001) after both 1 and 10 years. Female recipients had a lower rate of graft failure between the end of the first year and the end of the tenth year (p<0.001). Compared with all other combinations of sex, transplantation of male donor kidneys into female recipients was associated with an increased risk of graft failure during the first year (hazard ratio [HR] 1.08, 95% CI 1.03-1.14, p=0.003; death censored HR 1.11, 1.04-1.19, p=0.003) and between 2 and 10 years (HR 1.06, 1.01-1.10, p=0.008; death censored HR 1.10, 1.05-1.16, p<0.001)., Interpretation: H-Y minor histocompatibility affects human kidney transplantation.

There is evidence that interferon-gamma (IFN-gamma)-dependent interactions of dendritic cell (DC), T regulatory (Treg), and T suppressor (Ts) subpopulations contribute to allograft acceptance. We measured DC subsets, CD3+CD4+CD25+ (Treg phenotype) and CD3+CD8+CD28(-) (Ts phenotype) peripheral blood lymphocytes (PBL) expressing Foxp3, Th1 or Th2 cytokines, peripheral T- and B-cell counts, and plasma cytokines in 33 kidney transplant recipients with a serum creatinine of < or =1.8 mg/dl and 32 recipients with a serum creatinine of > or =2.0 mg/dl more than 100 days post-transplant. Cell subsets were measured in whole blood using four-color flow cytometry. Patients with increased creatinine had less frequently detectable CD3+CD4+CD25+IFN-gamma+ PBL than patients with good graft function (P = 0.017). In patients with good graft function, CD3+CD4+CD25+IFN-gamma+ PBL were associated with high Foxp3+, IL-2+, IL-12+, IL-4+, and IL-10+ CD3+CD4+CD25+ T PBL (P < 0.001), low CD3+CD8+CD28(-)Foxp3+ (P = 0.002), CD3+CD4+DR+ (P = 0.002), CD3+CD8+DR+ T (P = 0.005) and CD19+ B PBL (P = 0.005), and low lineage(-)HLA-DR+CD11c+CD123(-) DC1 (P = 0.006). Patients with impaired graft function did not show these associations. Additional flow cytometric analysis confirmed strong co-expression of IFN-gamma and Foxp3 by CD4+CD25+ PBL particularly in patients with good graft function. Our data support an immunoregulatory role of CD3+CD4+CD25+Foxp3+IFN-gamma+ cells in a subgroup of transplant recipients with good graft acceptance.

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.

We found recently that patients with good graft outcome showed higher IFN-gamma and IL-2, and lower IL-10 plasma levels late post-transplant than early post-transplant. In this retrospective study, we compared cytokine plasma levels in 33 symptom-free outpatients with those of 33 renal transplant recipients with early acute rejection (EAR), 29 with chronic rejection (CR), and 34 healthy controls (HC) to assess whether there is evidence for Th1 activation late post-transplant in patients with good graft outcome. Cytokines were measured pre-transplant, one wk, one month, six months, one yr, and two yr after transplantation. Twelve and 24 months post-transplant, IFN-gamma plasma levels were significantly higher (p = 0.001; p = 0.001, respectively) and IL-4 plasma levels significantly lower (p = 0.028; p = 0.003, respectively) in patients with stable graft function than those in controls. Six, 12, and 24 months post-transplant, patients with stable graft function had similar IFN-gamma and IL-4 plasma levels as patients with successfully treated EAR (p = n.s.), and higher IFN-gamma (p = 0.013; p = 0.001; p = 0.0005, respectively) and lower IL-4 (p = 0.007; p = 0.417; p = 0.0001, respectively) plasma levels than patients with CR. These data suggest that increased plasma IFN-gamma and decreased plasma IL-4 late post-transplant might be involved in the induction of mechanisms that facilitate good long-term graft outcome.

We investigated the possible impact of vascular endothelial growth factor (VEGF) 936 C/T gene polymorphism on kidney graft outcome. DNA samples of 290 first deceased donor kidney graft recipients with well-functioning grafts and no rejection treatment during the first transplant year (WFG), 265 recipients with graft failure within the first transplant year (F), and 187 healthy control subjects were tested using the polymerase chain reaction restriction fragment length polymorphism technique. Although VEGF 936 CT genotype and T allele carrier frequencies in 555 kidney graft recipients did not differ significantly from frequencies observed in healthy control subjects, significantly higher frequencies were found in WFG patients (CT: 19.0%, T: 20.7%) than in F patients (CT: 11.7%, p=0.019; T: 12.8%, p=0.017, respectively). The VEGF 936 CT genotype and T allele appear to be associated with good outcome in renal transplantation and, if confirmed, might be helpful for the pretransplant identification of recipients with low risk of graft rejection.

Background: It has been proposed that inherited risk factors of venous thromboembolism, such as factor V G1691A (FV-Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T, might be associated with poorer survival rates of transplanted kidneys. On the basis of this hypothesis, we performed a multicenter study, involving recipients of primary and repeat kidney transplants, to investigate the potential effect of these three single nucleotide polymorphisms (SNP) on graft survival., Methods: The study consisted of 676 first and 651 retransplant patients. Using the polymerase chain reaction-sequence specific primers method, we typed all patients for the three SNP and analyzed graft survival., Results: We could not find a statistically significant association between graft survival and factor V Leiden or MTHFR C677T genotypes. A better 3-yr graft survival was found for first transplant recipients with the genotype prothrombin 20210 G/G as compared to those with the G/A genotype (P=0.031). However, Bonferroni correction for the three SNPs investigated in this series rendered the P value insignificant (P(corrected)=0.093)., Conclusion: We did not find a statistically significant association of SNP factor V Leiden G1691A and MTHFR C677T with renal graft survival. Prothrombin G20210A resulted in a significant association that was not sustained after Bonferroni correction. This SNP might be an interesting candidate for future studies.

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.

Mitomycin C (MMC) is an alkylating agent which suppresses allogeneic T-cell responses. We analyzed the effect of graft perfusion with MMC on transplant survival. Hearts from Brown-Norway (BN) rats were perfused ex vivo with MMC-containing solution, stored and implanted into Lewis (LEW) rats. In order to analyze the in vivo effect of MMC, recipients received MMC posttransplantation or were pretreated with MMC-incubated donor-derived peripheral blood mononuclear cells (PBMCs). The results show that MMC-perfusion significantly prolongs graft survival. Treatment of recipients with MMC has no effect, whereas MMC-treated donor PBMCs injected into the recipient prolong graft survival. Our findings indicate that the targeted perfusion of donor hearts with MMC-containing solution protects the graft from rejection.

It was reported recently that treatment of kidney transplant recipients with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) is associated with strikingly improved long-term graft and patient survival. This finding has important implications for future posttransplantation therapy recommendations. In an analysis of 17,209 kidney and 1744 heart transplant recipients, an association of treatment with ACEI/ARB with improved transplant outcome could not be confirmed. It is concluded that recommendations for a widespread use of ACEI/ARB treatment in transplant recipients are unwarranted.

Despite the introduction of new immunosuppressive agents, a steady decline of functioning renal allografts after living donation is observed. Thus nonpharmacological strategies to prevent graft loss have to be reconsidered, including donor-specific transfusions (DST). We introduced a cyclosporine-based DST protocol for renal allograft recipients from living-related/unrelated donation. From 1993 to 2003, 200 ml of whole blood, or the respective mononuclear cells from the potential living donor were administered twice to all of our 61 recipient candidates. The transplanted subjects were compared with three groups of patients without DST from the Collaborative Transplant Study (Heidelberg, Germany) during a 6-year period. Six patients were sensitized without delay for a subsequent cadaveric kidney. DST patients had less often treatment for rejection and graft survival was superior compared with subjects from the other Swiss transplant centers (n = 513) or from Western Europe (n = 7024). To diminish the probability that superior results reflect patient selection rather than effects of DST, a 'matched-pair' analysis controlling for relevant factors of transplant outcome was performed. Again, this analysis indicated that recipients with DST had better outcome. Thus, our observation suggests that DST improve the outcome of living kidney transplants even when modern immunosuppressive drugs are prescribed.

Natural killer cells express killer immunoglobulin-like receptors (KIR) that bind to MHC class I antigens. Lack of self-MHC on the target cell can cause NK-cell mediated killing. Here, we analyzed the effect of KIR ligand incompatiblity on renal allograft survival in humans. Kidney recipient/donor pairs were separated according to their HLA-Cw alleles and HLA-Bw4 specificity which are considered epitopes for KIR. A total of 2,757 renal transplants were examined. Graft survival rates were computed according to the Kaplan-Meier method. No effect of KIR ligand matching on graft survival was observed in cadaver kidney transplants. Our results indicate that KIR ligand matching cannot be recommended as a strategy for improving renal allograft survival.

A large prospective study of steroid withdrawal was performed within the framework of the Collaborative Transplant Study to analyze long-term graft and patient outcome in renal and heart transplant recipients. Steroids were withdrawn no earlier than 6 months posttransplantation. A comparison of 7-year outcomes in renal transplant recipients (94% receiving cyclosporine; 97% Caucasian) showed a benefit of steroid withdrawal versus steroid continuation in retrospectively matched controls, for graft survival (81.9% +/- 1.8% vs. 75.3% +/- 1.2%, p = 0.0001), patient survival (88.8% +/- 1.5% vs. 84.3 +/- 1.0%; p = 0.0016) and death-censored graft survival (91.8% +/- 1.3% vs. 87.9%+/- 1.0%: p = 0.0091). Steroid withdrawal was associated with improved graft survival in heart recipients also (76.2% +/- 2.4% vs. 66.9% +/- 1.7%, p = 0.0008). A total of 58.6% of renal recipients and 44.3% of heart recipients never required steroids during follow up. Rates of acute rejection and renal dysfunction did not differ between steroid-free and steroid-continuation groups. Steroid withdrawal was associated with significantly improved cardiovascular risk factors compared with steroid continuation. Rates of the development of osteoporosis and cataracts did not differ in the entire patient cohort, but were strikingly lower in patients taken off steroids during the first posttransplant year.

The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (> or = 9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vss usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR V beta families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.

Single nucleotide polymorphisms (SNPs) of cytokine genes have been shown to influence cytokine plasma levels. Cytokines are important mediators during organ graft rejection. It was reported that certain cytokine genotypes are associated with improved kidney graft survival. In the present study, SNPs within the IL10 promoter gene, the first exon of the TGFbeta1 gene, the TNFalpha promoter gene, and the IL4Ralpha gene were analyzed in 2298 first and 1901 repeat cadaver kidney recipients. We found no significant effect on the survival rate of first grafts. Among retransplants, we observed that recipients who were homozygous for the high TNFalpha producer genotype -308 A had a significantly lower graft survival rate than patients who were carriers of the low producer genotype -308 G (at 3 years: 63.0% vs. 79.5%; pcorrected = 0.0116). The results of this large-scale study suggest that IL10, TGFbeta1, TNFalpha, and IL4Ralpha cytokine genotypes do not affect the survival of primary kidney grafts. The outcome of retransplants appears to be affected by TNFalpha genotypes only.

Background: On the basis of cross-reactive antibodies that react with different human leukocyte antigens (HLA) with shared epitopes, HLA-A and -B antigens can be assigned to cross-reactive groups (CREG). In the context of renal transplantation, it has been reported that matching for CREG results in improved graft outcome and reduces the requirement for rejection treatment. Because CREG matching also improves the equity of kidney distribution to ethnic minorities, a CREG-based cadaver kidney allocation policy was introduced in the United States a few years ago., Methods: The authors reexamined the immunologic relevance of matching according to CREG using the data of the international Collaborative Transplant Study. A total of 91,917 patients who received a first cadaver kidney transplant between 1991 and 2002 formed the basis of this analysis., Results: The authors found that the underlying impact of matching for HLA antigens accounts entirely for the observed positive effect of CREG matching. For patients with a particular HLA antigen match grade, matching for CREG had no advantageous effect on graft outcome or rejection treatment. An immunologic basis for CREG matching could thus not be found in this large analysis of cadaver kidney transplants., Conclusions: The findings indicate that CREG matching for kidney allocation is conceptually flawed from an immunologic viewpoint.

It is a matter of debate whether pretransplant anti-human leukocyte antigen (HLA) class II antibodies contribute to the increased graft rejection rate found in presensitized recipients. We investigated the influence of preformed anti-HLA class II antibodies on graft survival in 5949 cadaver kidney transplants. Pretransplant recipient sera were tested in enzyme-linked immunosorbent assay (ELISA) for immunoglobulin (Ig)G-anti-HLA class I and IgG-anti-HLA class II antibodies. A total of 672 recipients with antibodies against HLA class II but not against HLA class I had a 3-year graft survival rate of 80 +/- 2%, identical to the 80 +/- 1% rate in 4561 recipients who were negative for anti-HLA class I and II (p = NS). Graft survival was significantly lower in 365 recipients who were positive for both anti-HLA class I and II (65 +/- 3%, p < 0.0001). Compatibility for HLA-A+B+DR influenced graft survival significantly in anti-HLA class I- and II-positive recipients (p = 0.0016), whereas no significant HLA effect was found in patients with antibodies directed against only class I or II. Surprisingly, not even incompatibility for HLA class II antigens of the DR locus caused a significant impairment of graft survival in anti-class II-positive recipients. We conclude that the risk associated with sensitization against HLA class II in the absence of sensitization against HLA class I is negligible.

We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.

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.

Differences in actuarial graft survival according to donor gender have been reported for renal allografts and for cardiac and hepatic allografts, but for the latter in small series with limited biostatistical power. Using the large database of the Collaborative Transplant Study (CTS), this study is an evaluation of graft survival according to donor and recipient gender for renal (n = 124,911), cardiac (n = 25,432), and hepatic (n = 16,410) transplants. Confounders, such as calendar year, geographical area, race, donor and recipient age, HLA mismatch, cold ischemia time, and others, as well as interaction terms were taken into consideration. Death-censored actuarial renal allograft survival from female compared with male donors was less in female recipients and even more so in male recipients. The donor gender-associated risk ratio for graft loss was 1.15 in female recipients and 1.22 in male recipients. The age-gender interaction term was statistically significant, the gender effect being more pronounced for younger (16 to 45 yr) compared with older (>45 yr) donors. Serum creatinine concentrations 1 yr after transplantation were also higher for recipients with kidney grafts coming from female donors irrespective of recipient gender. For first cardiac transplants, graft survival was inferior when the donor was female and the recipient male, but no statistical difference according to donor gender was demonstrable in female recipients. For first hepatic transplants overall, no significant differences according to donor gender were noted. The proportion of recipients who had treatment for rejection crisis during the first year was higher for male recipients of kidneys from female donors compared with male donors. No difference according to donor gender was demonstrable in female recipients. For cardiac and hepatic grafts, no significant effect of donor gender on the proportion of patients treated for rejection episodes was noted. The data show that adverse effects of female donor gender for different organs is much less uniform than reported in the past. An important confounder is donor age. A gender effect on graft survival is also observed for cardiac allografts. Therefore, in addition to potential "nephron underdosing," further pathomechanisms must play a role, possibly differences in immunogenicity according to donor gender.

Background: It is well known that kidney transplant recipients with preformed lymphocytotoxic antibodies against HLA antigens have an increased graft rejection rate. However, the individual contribution of anti-HLA class I and class II antibodies to this phenomenon is poorly understood. We investigated the clinical relevance of preformed anti-HLA class I and class II antibodies on graft outcome in more than 4000 kidney recipients., Methods: Pretransplant sera of 4136 cadaver kidney recipients from 28 transplant centers were tested in ELISA for IgG-anti-HLA class I and IgG-anti-HLA class II antibodies. The influence of antibody reactivity on graft survival was analyzed., Results: Four hundred eighty of the anti-HLA class I antibody-positive recipients had a graft survival rate at 2 years of 77+/-2%, compared with an 84+/-1% rate in 3656 anti-HLA class I antibody-negative recipients (P<0.0001), and 770 anti-HLA class II-positive recipients had a graft survival rate of 79+/-2%, compared with an 84+/-1% rate in 3366 anti-HLA class II-negative patients (P<0.0001). Importantly, good 2-year graft survival rates of 85+/-3% and 84+/-2%, respectively, were observed in 206 anti-HLA class I-positive/class II-negative and 496 anti-HLA, class I-negative/class II-positive recipients. In contrast, the 274 recipients positive for both types of antibodies showed a poor graft survival rate of 71+/-3% (P<0.0001). Among 853 patients who received a well-matched kidney (0 or 1 HLA-A+B+DR mismatch), sensitization against either class I or class II, or both, had no deleterious effect. However, in 113 class I and class II antibody-positive patients who received a kidney with > or =3 HLA-A+B+DR mismatches, the 2-year graft survival rate was only 60+/-5%., Conclusion: Presensitization of first kidney transplant recipients against either HLA class I or class II is of no clinical consequence, whereas sensitization against both HLA class I and class II results in increased rejection of HLA mismatched grafts.

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.

Background: Preliminary studies showed an excellent success rate of kidney grafts in patients with high pretransplantation serum levels of IgA autoantibodies directed against the Fab region of the human IgG molecule., Methods: With the collaboration of 30 centers from around the world, we attempted to verify the role of IgA-anti-Fab autoantibodies in kidney transplantation in an entirely new series of 4316 cadaveric kidney transplants, with special consideration of presensitized and poorly HLA-matched recipients., Results: In agreement with previously published preliminary findings, 147 recipients with a high pretransplantation IgA-anti-Fab of >1000 had a 2-year kidney graft survival rate of 88+/-3% (+/- SE), compared with an 80+/-1% rate in 851 recipients with a low IgA-anti-Fab of <60 (P = 0.02). Even in patients at an increased risk of graft rejection, high pretransplantation IgA-anti-Fab autoantibody activity was associated with superior graft survival. Among 815 presensitized patients, 31 had a high pretransplantation IgA-anti-Fab activity of >1000 and their 2-year graft survival rate was 94+/-4%, in contrast to a 71+/-4% rate in 165 presensitized recipients with a low IgA-anti-Fab of <60 (P = 0.02). Of 2294 recipients who received a kidney with > or =3 HLA-A+B+DR mismatches, 79 recipients had a high pretransplantation IgA-anti-Fab of >1000 and a 2-year graft survival rate of 90+/-4%, as compared with a 79+/-2% rate in 459 patients with a low IgA-anti-Fab of <60 (P = 0.04)., Conclusions: The present study confirms that kidney graft recipients with high pretransplantation IgA-anti-Fab activity have excellent graft survival, and it extends this observation to presensitized recipients and poor HLA matches.