Successful living donor renal transplantation despite ABO incompatibility and a positive crossmatch

Potential live kidney donors have been rejected when the prospective recipients are blood type or crossmatch incompatible. By utilizing plasmapheresis combined with intravenous immune globulin (PP/IVIg) prior to surgery, donor-specific antibodies against blood group or human leukocyte antigens (HLA) have been removed, thereby allowing successful renal transplantation. A 26-yr-old male with a panel reactive antibody level of 100% and repeated positive crossmatches against deceased donor kidney offers, including zero HLA mismatched donors, successfully underwent ABO-incompatible kidney transplantation from his HLA-identical but nevertheless crossmatch-incompatible sister. The initial anti-A blood group isoagglutinin titers were 128, 256, and 1024 at room temperature, 37 degrees C, and 37 degrees C anti-IgG enhanced, respectively. With an individualized PP/IVIg regimen based on donor-specific antibody titer, however, the relevant antibodies were adequately reduced and hyperacute rejection avoided. Subsequent antibody-mediated rejection, likely directed against a minor histocompatibility antigen, was diagnosed on postoperative day 7 and successfully treated. Neither ABO, or crossmatch incompatibility, or both in combination prohibit kidney transplantation.     

Relevance of a positive crossmatch in liver transplantation

We studied 27 liver transplants in 24 patients performed between November 1984 and January 1988. We investigated retrospectively the importance of donor reactive HLA class I and class II and of non-HLA antibodies for graft survival in these patients. In order to determine the specificity and class of the antibodies, we used monoclonal antibodies to HLA-A,-B,-C and DR and DQ antigens to block cytotoxicity of sera and the reagent dithiothreitol to characterize the immunoglobulin class. We found that humoral immunity to HLA antigens in liver-grafted patients, demonstrable as the presence of cytotoxic antibodies reactive with donor splenic T and/or B cells in the pretransplantation period, is associated with significantly lower graft survival as compared with patients without demonstrable preformed HLA antibodies (P=0.01). In addition we found that a substantial proportion of patients had donor-reactive cytotoxic antibodies which were not HLA specific. Thus, our study shows that HLA immunity can influence liver allograft survival, and that it is useful to have patient cytotoxic antibodies characterized with regard to HLA reactivity prior to transplantation.     

T-cell flow-cytometry crossmatch and long-term renal graft survival

Flow cytometry crossmatch (FCXM) is a more sensitive technique than classical complement-dependent cytotoxicity (CDC) for the detection of donor-directed antibody before renal transplantation. Nevertheless, the role of FCXM in predicting long-term survival of kidney grafts is still unclear. The purpose of our study was to evaluate the impact of a positive T-cell FCXM (T-FCXM) on long-term kidney allografts outcome. Of the 184 consecutive kidney transplantations performed in our center between 1 January1991 and 15 November 1996 a FCXM, performed concurrently to the pre-transplant CDCXM, was available for 170 patients. The CDCXM was negative in all recipients. Among these recipients, 12 (7.1%) had a positive T-FCXM. These patients were not different from patients with a negative T-FCXM for donor and recipient age, sex, frequency of second transplantation, number of human leukocyte antigen matches or mismatches. Frequency of immunized patients was higher in kidney recipients with a positive FCXM (58.3% vs. 24.7%; p=0.02, chi-square test). Survival analysis revealed that kidney graft outcome was better in negative T-FCXM recipients (p=0.03), while patient survival was not statistically different. Our results suggest that a positive pre-transplant T-FCXM despite a negative CDCXM is associated with an impaired long-term graft survival in renal allotransplantation.     

Kidney transplantation with positive complement-dependent lymphocytotoxicity crossmatch with negative flow crossmatching and Luminexx donor-specific antibodies

Abstract

The presence of positive anti-human, globulin-enhanced, complement-dependent cytotoxicity crossmatches (AHG-CDC-XM) generally has been considered as a contraindication to kidney transplantation (KTx). Flow cytometry crossmatch (FCXM) and solid phase antibody screening are most sensitive and specific methods for immunological assessment. The outcome effect of donor-specific antibody (DSA) positive by Luminexx platform and CDCXM negative has been evaluated,?but not the outcome of CDCXM positive and DSA negative. This is a case report describing KTx in a patient with pre-transplant positive AHG-CDC-XM but negative FCXM and without detectable DSA by Luminexx single antigen beads. CDCXM, FCXM, DSA were negative after transplantation, and kidney allograft biopsy did not show immune injury with negative C4d. Our report suggests that KTx with positive AHG-CDC-XM can be considered if FCXM and DSA were negative with careful immunological monitoring after transplantation. In our case, the IgM-antibodies were responsible for the positive AHG-CDC-XM result. The patient with positive CDC XM has a good outcome in the absence of DSA. Further work is needed to determine under what circumstances CDCXM positive transplants can be performed with FCXM and DSA negative.     

Kidney and pancreas transplantation

Data from the Scientific Registry of Transplant Recipients offer a unique and comprehensive view of US trends in kidney and pancreas waiting list characteristics and outcomes, transplant recipient and donor characteristics, and patient and allograft survival. Important findings from our review of developments during 2002 and the decade's transplantation trends appear below.
The kidney waiting list has continued to grow, increasing from 47 830 in 2001 to 50 855 in 2002. This growth has occurred despite the increasing importance of living donor transplantation, which rose from 28% of total kidney transplants in 1993 to 43% in 2002.
Policies and procedures to expedite the allocation of expanded criteria donor (ECD) kidneys were developed and implemented during 2002, when 15% of deceased donor transplants were performed with ECD kidneys. Unadjusted 1- and 5-year deceased donor kidney allograft survivals were 81% and 51% for ECD kidney recipients, and 90% and 68% for non-ECD kidney recipients, respectively.
Although more patients have been placed on the simultaneous kidney-pancreas waiting list, the number of these transplants dropped from a peak of 970 in 1998 to 905 in 2002. This decline may be due to competition for organs from increasing numbers of isolated pancreas and islet transplants.     

Adverse impact of high panel-reactive antibody (PRA) and positive cytotoxic crossmatch in liver transplantation

Abstract Of 91 liver transplants (LTX) performed from October 1988 to December 1992, 13 (14.2%) of the patients received a liver from a lymphocytotoxicpositive crossmatch (CM) donor. Severe early rejection resulting in graft floss occurred in seven positive CM patients. Three of the remaining positive CM patients suffered several rejection episodes leading to chronic rejection and FK 506 was required as rescue treatment. A significant difference in mean panel-reactive antibody (PRA) of 8.6% and 56.9% was found in negative and positive CM patients, respectively ( P = 0.012). A higher mean PRA (67.7%) was found in positive CM patients with rejection compared with positive CM patients without rejection (PRA 38%). Overall graft and patient survival were 31.9% and 35% in positive CM patients compared with 57.0% and 61.9% in negative CM patients. These differences were statistically significant ( P = 0.023). In our experience the risk of developing severe acute rejection with graft failure and chronic rejection is related to PRA > 60% and positive CM. We recommend that in patients with PRA > 60%, the result of CM should be awaited before proceeding to LTX.     

Research in a non-academic setting: it can be done

The need for quality research to promote evidence-based practice and optimize patient care is well recognized. This is particularly relevant in orthopedic trauma care, as trauma is a leading cause of morbidity and mortality worldwide. Across the spectrum of academic, clinical, and health care administration physician roles, research remains fundamental to bridging theory, practice, and education. A gap exists, however, between research and practice, especially for those physicians practicing outside traditional academic centers. Orthopedic trauma surgeons are well situated to contribute to important research; however the majority of those in practice at non-academic centers do not have a significant research component structured into their physician role. In this article, the authors outline the importance of orthopedic trauma surgeons outside of academic centers being engaged in research and present some advice on how to effectively participate in these endeavors. In this setting, orthopedic trauma research involvement includes asking researchable questions, being a savvy manager of research collaborators, staff, and funding, and finding one's own level of research involvement.     

Overcoming a Positive Crossmatch in Living-Donor Kidney Transplantation

Many patients who have an otherwise acceptable living-kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer 相似文献   

Current status of kidney and pancreas transplantation in the United States, 1994–2003

This article reviews the OPTN/SRTR data collected on kidney and pancreas transplantation during 2003 in the context of trends over the past decade. Overall, the transplant community continued to struggle to meet the increasing demand for kidney and pancreas transplantation. The number of new wait-listed kidney registrants under the age of 50 has remained relatively stable since 1994, but the number of new registrants aged 50 to 64 has doubled. However, there was only a 2.3% increase in the total number of kidney transplants performed in 2003. Expanded criteria donor kidneys made up 20% of all recovered kidneys and 16% of all transplants performed, compared with 15% in the prior year. In May 2003, new rules were implemented to promote equity in kidney organ allocation. These changes seem to have improved access for historically disadvantaged groups, though they have reduced the quality of HLA matching. The effects on long-term outcomes have yet to be measured. Although the majority of SPK recipients are white (82%), the percentage of simultaneous kidney-pancreas recipients who are African-American has increased from 9% in 2000 to 16% in 2003. The percentage of Hispanic/Latino recipients increased from 5% to 9% over the same period.     

Diabetic retinopathy after combined kidney–pancreas transplantation

Diabetic retinopathy (DR) is amenable to good diabetic control; however, only successful pancreas transplantation can achieve sustained normoglycaemia. The aim of this long-term study was to examine the course of DR in insulin-dependent diabetic recipients of a simultaneous kidney and pancreas transplant (SPK). Successful SPK recipients (n = 46) and failed pancreas transplant with a functioning kidney transplant (n = 8) were assessed by baseline and regular post-transplant ophthalmic examinations (n = 432) for up to 10 yr after SPK. At the time of SPK (n = 108 eyes), the mean duration of diabetes was 25 +/- 7 yr, ten eyes were blind, and 79% of eyes had advanced DR that had panretinal laser (panretinal photocoagulation, PRP. Successful SPK recipients had normal glucose control with a mean HBA1C of 5.2 +/- 0.6%. DR remained stable in 75% of both the study and control groups, with no difference between groups. The DR mostly evolved towards inactive proliferative DR. After SPK, 14% of non-blind eyes showed improvement of DR, 76% remained stable and 10% progressed. Early vitreous haemorrhage occurred in 6.1% of eyes, and was related to established DR. Cataract of all types increased after transplantation (p < 0.01), which reduced visual acuity (VA) in affected eyes. The mean overall VA remained unchanged for the study duration. In summary, uremic patients from diabetic nephropathy had a high prevalence of severe proliferative DR and blindness at the time of presentation for SPK. This was subsequently stabilised to inactive proliferative DR by appropriate laser therapy followed by metabolic control achieved by SPK.     

Specificity of preformed alloantibodies causing B cell positive flow crossmatch in renal transplantation

The specificity of alloantibodies (alloAb) and their clinical significance in association with T-/B+ flow cytometry crossmatch (FCXM) in kidney transplantation are not clearly defined. This study was undertaken to examine the HLA specificity and clinical relevance of Ab causing B+ FCXM in pre-transplant (final XM) recipients' serum samples. Final FCXM serum samples were analyzed from 457 renal transplant patients followed for 10 months post-transplantation. Two hundred and sixty patients had T-/B+ final FCXM. The control group included 197 recipients with T-/B- FCXM at time of transplantation. Class I/class II PRA and specificity of anti-HLA class I and class II Ab in final FCXM serum samples were analyzed by FlowPRA Class I Screening Test and FlowPRA Class II Screening Test. We found no correlation between graft outcome and pre-transplant T-/B- and T-/B+ FCXM status. Additionally, we observed no clinical relevance of B+ FCXM in retransplant patients. However, MCS > or =200 in B+ FCXM retransplant recipients was associated with anti-class II Ab to previous mismatches in regrafted patients (n = 46). This finding was confirmed by specificity analysis of anti-DR/DQ Ab in patients with high ( > or =15%) class II PRA. In 63% (12 of 19) of retransplants having T-/B+ FCXM, we defined the specificity of alloAb to first graft mismatched class II antigens. In contrast, anti-class II Ab was detected in only 5.7% (2 of 35) of single-graft recipients with different PRA values. Significantly greater MCS (240 +/- 61 vs. 163 +/- 48; p = 0.022) was observed in retransplant patients having short ( < or =5 m) previous graft survival time (PGST) than in those with long PGST ( > or =5 m). Only 2% of retransplant recipients with B + FCXM had non-HLA Ab. In contrast, the overwhelming majority of primary recipients had no detectable alloAbs. No significant difference in class I PRA was found between B- and B+ FCXM recipients. However, class II PRA was significantly higher in patients having B + FCXM (p = 0.028). Collectively, these data show that MCS intensity is not always a reliable criterion for anti-HLA Ab detection because of the presence of non-HLA Ab. These results can be explained by low titers of anti-class II Ab, at which concentration these Ab cannot produce a deleterious effect. FlowPRA and Flow screen beads appeared to be reliable and sensitive methods for detection and specificity analysis of anti-class II alloAb.     

Renal transplantation in sensitized recipients with positive luminex and negative CDC (complement‐dependent cytotoxicity) crossmatches

Recently, Luminex‐crossmatch (LumXm) was introduced. The aim of this study was to evaluate clinical outcomes in sensitized recipients with a positive Luminex‐crossmatch (LumXm (+)) and a negative complement‐dependent cytotoxicity crossmatch (CDCXm (?)) after renal transplantation. Fifty‐five renal transplant recipients with a CDCXm (?) and PRA class I or II ≥20% were enrolled in this study between February 2008 and December 2010 at Severance Hospital. Eighteen patients displayed LumXm (+) defined as LumXm positive class I or II and 37 patients displayed LumXm (?). Mean duration of follow‐up was 18.9 ± 8.3 months. During this period, no patient death or graft loss occurred. The incidence of biopsy‐proven or clinically presumed rejection was higher in the LumXm (+) group (n = 12, 66.7%) than in the LumXm (?) group (n = 6, 18.2%) (P = 0.001). All biopsy‐proven acute rejections (n = 12) were diagnosed as acute cellular rejection. No significant difference in mean serum creatinine level or eGFR was observed between the groups at 18 months post‐transplantation. The short‐term outcome of renal transplantation in sensitized patients with a LumXm (+) and a CDCXm (?) may be considered to be acceptable. However, patients with a LumXm (+) have a substantially higher immunological risk for the development of acute cellular rejection.     

Clinical implications of flow cytometry crossmatch with T or B cells in living donor liver transplantation

BACKGROUND: Acute allograft rejection (AR) in solid organ transplantation is generally regarded to develop through cell-mediated immune response following activation of helper T cells. Since production of antibodies is also mediated by helper T cells, humoral immunity may play some roles in AR. Although flow cytometry crossmatch (FCXM) is reported as a useful method for the detection of antibodies against donor antigen, specific role of T- or B-cell FCXM and its sensitivity for AR is controversial. METHODS: T- and B-cell FCXM using fresh donor peripheral lymphocytes were performed before and after blood-type compatible living donor liver transplantation in 47 patients. IgM and IgG anti-donor antibodies were analyzed in relation to clinical AR. RESULTS: Positive pre-transplant T-cell FCXM was associated with a high incidence of positive post-transplant T-cell FCXM (p=0.017). Four of five cases (80%) with positive pre-transplant T-cell FCXM experienced earlier AR (day 8.0+/-4.4, mean+/-SD) than 16 of 42 cases (31%) with negative pre-transplant T-cell FCXM (17.3+/-6.8; p=0.016). In addition, higher dose of steroids was given to treat AR episodes in cases with positive pre-transplant T-cell FCXM (79.9+/-10.3 mg/kg/month) than in those with negative pre-transplant T-cell FCXM (47.1+/-26.6; p=0.039). In the first month after transplantation, 13 episodes of positive post-transplant T-cell FCXM were all concomitant with or preceded clinical AR compared with seven ARs in T-cell FCXM-negative cases (p<0.0001). T-cell FCXM between positive sera and third parties revealed some crossreactions. In contrast, detection of antibodies by B-cell FCXM in pre- and post-transplant phases was scarcely associated with AR, and no correlation was found between T- and B-cell FCXM before and after transplantation. CONCLUSIONS: Positive T-cell FCXM is closely related with AR and that before transplantation is a predictor of early and refractory AR as well as post-transplant FCXM. In contrast, not a few detections of antibodies irrelevant to AR are observed in B-cell FCXM, suggesting its low specificity.     

Kidney and Pancreas Transplantation in the United States, 1996–2005

Kidney and pancreas transplantation in 2005 improved in quantity and outcome quality, despite the increasing average age of kidney graft recipients, with 56% aged 50 or older. Geography and ABO blood type contribute to the discrepancy in waiting time among the deceased donor (DD) candidates. Allocation policy changes are decreasing the median times to transplant for pediatric recipients. Overall, 6% more DD kidney transplants were performed in 2005 with slight increases in standard criteria donors (SCD) and expanded criteria donors (ECD). The largest increase (39%) was in donation after cardiac death (DCD) from non-ECD donors. These DCD, non-ECD kidneys had equivalent outcomes to SCD kidneys. 1-, 3- and 5-year unadjusted graft survival was 91%, 80% and 70% for non-ECD-DD transplants, 82%, 68% and 53% for ECD-DD grafts, and 95%, 88% and 80% for living donor kidney transplants. In 2005, 27% of patients were discharged without steroids compared to 3% in 1999. Acute rejection decreased to 11% in 2004. There was a slight increase in the number of simultaneous pancreas-kidney transplants (895), with fewer pancreas after kidney transplants (343 from 419 in 2004), and a stable number of pancreas alone transplants (129). Pancreas underutilization appears to be an ongoing issue.     

Living-donor pancreas and small-bowel transplantation

Background: In contrast to renal and liver transplantation, only a limited number of pancreas and intestinal live-donor transplants have so far been reported. Patients: The vast majority of live segmental pancreas transplants have been performed at the University of Minnesota. From 1979 to 1993, a total of 78 solitary pancreas transplants – 28 after kidney and 49 pancreas transplants alone – were performed and, from 1994 to August 1999, 27 simultaneous pancreas/kidney transplants. For the first intestinal transplant, a segment of ileum from the mother was used in Boston in 1964. In 1970, 170 cm of jejuno-ileum from a human leukocyte antigen (HLA)- identical sister was removed and transplanted in New York. In 1988, an intestinal transplant from a haplotype-identical sister was performed at Kiel University, Germany. In the 1990s, a few more intestinal transplants from live donors were reported to the registry. Results: No death occurred among pancreas or intestinal donors. Altogether, seven pancreas donors required splenectomy and several donors required drainage of abscesses or fluid collections. Three of the 78 pancreas donors and at least two of the 27 pancreas/kidney donors required insulin post-donation. Twenty-seven of the solitary segmental pancreas transplants failed for technical reasons. Graft survival of technically successful pancreas transplants was 68% after 1 year and 38% after 10 years. Patient and renal allograft survival of combined kidney/pancreas transplants after 1 year was 100%, while 1-year pancreas survival was 84%. The first recipient of a live-donor intestinal transplant died only 12 h after surgery. The second case lived for 79 days and was able to eat for 6 weeks. A patient transplanted in 1988 lived for 4 years mainly on oral nutrition. Many of the live-donor intestinal transplants carried out in the 1990s became long-term survivors. Conclusion: Pancreas and small-bowel transplantation using organs from live donors is possible in experienced centers, with no donor mortality and excellent survival rates for recipients and grafts. Since abnormal glucose tolerance post-donation cannot be excluded with certainty and since, for the time being, there is no pancreas or small-bowel shortage in Europe, live donation of these organs should be restricted mainly to highly sensitized patients with a cross-match-negative relative or HLA-identical donor-intestinal recipient combinations. Received: 20 October 1999 Accepted: 27 October 1999     

Everolimus with low‐dose tacrolimus in simultaneous pancreas and kidney transplantation

The efficacy and safety of everolimus (EVR) in simultaneous pancreas and kidney transplantation (SPKT) is unclear. We retrospectively evaluated 25 consecutive SPKT recipients at our center from November 2011 to March 2013. All patients received dual induction (Thymoglobulin/basiliximab) and low‐dose tacrolimus plus corticosteroids. Nine patients who received EVR were compared with 14 patients who received enteric‐coated mycophenolate sodium (EC‐MPS); two patients who received sirolimus were excluded from the analysis. With a median follow‐up of 14 months, the pancreas graft survival rate was 100% in both groups, and the kidney graft survival rate was 100% and 93% in EVR and EC‐MPS patients, respectively. One EC‐MPS patient lost her kidney graft from proteinuric kidney disease. Another EC‐MPS patient received treatment for clinically diagnosed pancreas and kidney graft rejection. No rejection was observed in EVR patients. Serum creatinine and HbA1c levels were similar between the groups. There was no significant difference of surgical or medical complications. In conclusion, EVR seems to provide comparable short‐term outcome to EC‐MPS when combined with low‐dose tacrolimus/steroids and dual induction therapy. A larger study with a longer follow‐up is required to further assess this combination.     

Baseline Donor‐Specific Antibody Levels and Outcomes in Positive Crossmatch Kidney Transplantation

Renal transplant candidates with donor‐specific alloantibody (DSA) have increased risk of antibody‐mediated allograft injury. The goal of this study was to correlate the risk of antibody‐mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (?XM) transplants performed between April 2000 and July 2007. Using a combination of cell‐based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and ?XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of ?XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody‐mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long‐term allograft survival highlighting the need for improved therapy for these candidates.