Andrea Ruhenstroth

Cytomegalovirus Prophylaxis and Graft Outcome in Solid Organ Transplantation: A Collaborative Transplant Study Report

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.

No Association of Kidney Graft Loss With Human Leukocyte Antigen Antibodies Detected Exclusively by Sensitive Luminex Single-Antigen Testing: A Collaborative Transplant Study Report

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.

The collaborative transplant study registry.

The Collaborative Transplant Study (CTS) was initiated in 1982. Over the last 30 years, it has collected information on over half a million kidney, liver, heart, lung, and pancreas transplant procedures. Participation is voluntary and the study has strictly scientific objectives. Analyses of the CTS database serve as an international reference source in the field of solid organ transplantation.

Role of minor histocompatibility antigens in renal transplantation.

In hematopoietic stem cell transplantation (HSCT), disparities between recipients and donors for minor histocompatibility antigens (mHags) have been shown to be related to graft‐versus‐host disease (GVHD) and graft‐versus‐leukemia (GVL) effects. We investigated the effect of mHag mismatches on kidney allograft survival. Out of 33 785 kidney transplants on which DNA and clinical data were available to the Collaborative Transplant Study (CTS), 702 recipient/donor pairs could be identified as HLA‐A, ‐B and ‐DRB1 matched first transplants of Caucasian origin. These pairs were typed for genetic polymorphisms of the mHags HA‐1, HA‐2, HA‐3, HA‐8, HB‐1, ACC‐1 and UGT2B17. Because mHags are presented in an HLA‐restricted manner, only HLA‐A*02 positive pairs were included in the analysis of HA‐1, HA‐2 and HA‐8. Similarly, only HLA‐A*01, HLA‐B*44 and HLA‐A*24 positive pairs were considered for the evaluation of HA‐3, HB‐1 and ACC‐1, respectively, whereas UGT2B17 compatible transplants were assessed in HLA‐A*29 and HLA‐B*44 positive pairs. None of the mHag disparities showed a statistically significant effect on death‐censored 5‐year graft survival. This report represents the first large‐scale study on the relevance of mHags in kidney transplantation.

Impact of HLA compatibility on lung transplant survival and evidence for an HLA restriction phenomenon: a collaborative transplant study report.

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.

Genotypic Diversity of Complement Component C4 Does Not Predict Kidney Transplant Outcome

Gene copy number of complement component C4, which varies among individuals, may determine the intrinsic strength of the classical complement pathway. Presuming a major role of complement as an effector in transplant rejection, we hypothesized that C4 genetic diversity may partially explain the variation in allograft outcomes. This retrospective study included 1969 deceased-donor kidney transplants randomly selected from the Collaborative Transplant Study DNA bank. We determined recipient and donor gene copy number of total C4, C4 isotypes (C4A and C4B), and C4 gene length variants (C4L and C4S) by quantitative real-time PCR analysis. Groups defined according to recipient C4 gene copy number (low, intermediate, and high) had similar 10-year allograft survival. Genotypic groups showed comparable rates of graft dysfunction, treatment for rejection, immunological graft loss, hospitalization for infection, malignant disease, and death. Similarly, separate analyses of C4A, C4B, C4L, and C4S; combined evaluation of donor and recipient C4 genotype; or analysis of recipients with higher risk for rejection did not reveal considerable outcome effects. In conclusion, we did not demonstrate that C4 gene copy number associates with transplant outcome, and we found no evidence that the resulting variation in the strength of classical complement activation influences susceptibility to rejection.

Deleterious impact of mismatching for human leukocyte antigen-C in presensitized recipients of kidney transplants.

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.

No impact of KIR-ligand mismatch on allograft outcome in HLA-compatible kidney transplantation.

Natural killer (NK) cell function can be modulated by the killer cell immunoglobulin‐like receptors (KIR) which interact with human leukocyte antigen (HLA) class I molecules on target cells. KIR‐ligand mismatching has recently been shown by van Bergen et al. (American Journal of Transplantation 2011; 11(9): 1959–1964) to be a significant risk factor for long‐term graft loss in HLA‐A, ‐B and ‐DR compatible kidney transplants. To verify this potentially important finding, we performed genotyping of 608 deceased‐donor kidney graft recipients and their HLA‐A, ‐B and ‐DR compatible donors for KIR and HLA, using samples and clinical data provided by the Collaborative Transplant Study. Graft survival of KIR‐ligand‐matched and ‐mismatched transplants was compared. We found no impact of KIR‐ligand mismatching on 10‐year graft survival in HLA‐A, ‐B, ‐DR compatible kidney transplants. Further analysis did not reveal a significant effect of recipient activating/inhibitory KIR or KIR genotypes on graft survival. Our data do not support the concept that KIR‐HLA matching might serve as a tool to improve long‐term renal allograft survival.

Deleterious impact of HLA-DRB1 allele mismatch in sensitized recipients of kidney retransplants.

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.

Donor-specific antibodies require preactivated immune system to harm renal transplant

Highlights • Pretransplant DSA have a deleterious impact on graft survival only in the presence of high pretransplant serum levels of sCD30.• The majority of patients with pretransplant DSA might be transplanted safely without special pretreatment measures. Kidney transplantation in the presence of donor-specific HLA antibodies (DSA) is associated with a high failure rate due to antibody-mediated rejection. Many centers avoid transplantations if DSA are present. Others perform such transplantations after removal of DSA by apheresis under potent immunosuppression. We provide strong evidence that DSA positive recipients reject their grafts at a high rate only if the immune activation marker sCD30 is also high, suggesting that T-cell help from an activated immune system is necessary for pretransplant DSA to exert a deleterious effect on the graft. High-risk patients with DSA and sCD30 may benefit from special treatment measures. The presence of DSA alone may not be deleterious.