Significant Improvement In Graft Survival Research Articles

Improving outcomes of in situ split liver transplantation in Italy over the last 25 years

Split liver transplant(ation) (SLT) is still considered a challenging procedure that is by no means widely accepted. We aimed to present data on 25-year trends in SLT in Italy, and to investigate if, and to what extent, outcomes have improved nationwide during this time. The study included all consecutive SLTs performed from May 1993 to December 2019, divided into three consecutive periods: 1993-2005, 2006-2014, and 2015-2019, which match changes in national allocation policies. Primary outcomes were patient and graft survival, and the relative impact of each study period. SLT accounted for 8.9% of all liver transplants performed in Italy. A total of 1,715 in situ split liver grafts were included inthe analysis: 868 left lateral segments (LLSs) and 847 extended right grafts (ERGs). A significant improvement in patient and graft survival (p <0.001) was observed with ERGs over the three periods. Predictors of graft survival were cold ischaemia time (CIT) <6h (p= 0.009), UNOS status 2b (p <0.001), UNOS status 3 (p= 0.009), and transplant centre volumes: 25-50 cases vs. <25 cases (p= 0.003). Patient survival was significantly higher with LLS grafts in period 2 vs. period 1 (p= 0.008). No significant improvement in graft survival was seen over the three periods, where predictors of graft survival were CIT <6h (p= 0.007), CIT <6h vs. ≥10h (p= 0.019), UNOS status 2b (p= 0.038), and UNOS status 3 (p= 0.009). Retransplantation was a risk factor in split liver graft recipients, with significantly worse graft and patient survival for both types of graft (p <0.001). Our analysis showed Italian SLT outcomes to have improved over the last 25 years. These results could help to dispel reservations regarding the use of this procedure. Split liver transplant(ation) (SLT) is still considered a challenging procedure and is by no means widely accepted. This study included all consecutive in situ SLTs performed in Italy from May 1993 to December 2019. With more than 1,700 cases, it is one of the largest series, examining long-term national trends in in situ SLT since its introduction. The data presented indicate that the outcomes of SLT improved during this 25-year period. Improvements are probably due to better recipient selection, refinements in surgical technique, conservative graft-to-recipient matching, and the continuous, yet carefully managed, expansion of donor selection criteria under a strict mandatory split liver allocation policy. These results could help to dispel reservations regarding the use of this procedure.

Primary Liver Transplantation vs. Transplant after Kasai Portoenterostomy for Infants with Biliary Atresia.

Introduction: Primary liver transplants (pLT) in patients with biliary atresia (BA) are infrequent, since most babies with BA undergo a prior Kasai portoenterostomy (KPE). This study compared transplant outcomes in children with BA with or without a prior KPE. We hypothesized that pLT have less morbidity and better outcomes compared to those done after a failed KPE. Methods: A retrospective review of patients with BA transplanted at our institution was performed. Patients were included if they received a pLT or if they were transplanted less than 2 years from KPE. Outcomes were compared between those groups. Comparisons were also made based on era (early: 1997–2008 vs. modern: 2009–2020). p < 0.05 was considered significant. Results: Patients who received a pLT were older at diagnosis (141.5 ± 46.0 vs. KPE 67.1 ± 25.5 days, p < 0.001). The time between diagnosis and listing for transplant was shorter in the pLT group (44.5 ± 44.7 vs. KPE 140.8 ± 102.8 days, p < 0.001). In the modern era, the calculated PELD score for the pLT was significantly higher (23 ± 8 vs. KPE 16 ± 8, p = 0.022). Two waitlist deaths occurred in the KPE group (none in pLT, p = 0.14). Both the duration of transplant surgery and transfusion requirements were similar in both groups. There was a significant improvement in graft survival in transplants after KPE between eras (early era 84.3% vs. modern era 97.8%, p = 0.025). The 1-year patient and graft survival after pLT was 100%. Conclusions: Patient and graft survival after pLT are comparable to transplants after a failed KPE but pLT avoids a prior intervention. There was no significant difference in pre- or peri-transplant morbidity between groups other than wait list mortality. A multicenter collaboration with more patients may help demonstrate the potential benefits of pLT in patients predicted to have early failure of KPE.

Racial disparities and trends in kidney transplant outcomes in patients with Alportsyndrome.

Registry data from Europe has shown an increase in age at end-stage kidney disease for patients with Alport syndrome in recent years. Whether a similar delay in transplant age has occurred in the United States for Alport patients across all racial/ethnic groups is unknown. We used data from the Scientific Registry of Transplant Recipients (SRTR) to identify 3,794 Alport patients transplanted between 12/1987 and 12/2017. We divided the study period into five equal eras to assess temporal trends in age at transplant, graft survival, and patient survival across racial groups using linear regression and Cox regression models. The mean age at transplant for Blacks (28.3 years; difference (Black vs. White): 8.9 years; p < 0.0001) and Hispanics (28.7 years; difference (Hispanics vs. White): 8.7 years; p <0.0001) was significantly younger compared with that of Whites. We observed a temporal increase in age at transplant for Whites but not for Blacks and Hispanics (p-value for interaction: 0.001). Black recipients were at a higher risk of graft loss (aHR: 1.78; 95% CI: 1.47, 2.15; p<0.0001) and death (aHR: 1.73; 95% CI: 1.11, 2.69; p=0.02) compared with White recipients. We observed significant improvements in graft survival with each successive era (p<0.01). Temporal trends in graft survival (interaction p=0.46) were not modified by race. We found racial disparities in age at transplant and long-term graft survival for patients with Alport syndrome in the United States. The age at transplant increased over time for Whites but not Black and Hispanic patients.

Replacement of mycophenolate mofetil with a JAK inhibitor, AS2553627, in combination with low-dose tacrolimus, for renal allograft rejection in non-human primates

In renal transplant patients, using mycophenolate mofetil (MMF) with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus [TAC]) has led to a significant improvement in graft survival. However, reducing or withholding MMF due to its gastrointestinal adverse events increases rejection risk. CNI-sparing strategies are important to avoid CNI-related nephrotoxicity in clinical settings. Here, we investigated AS2553627, a JAK inhibitor replacing MMF in combination with a sub-therapeutic dose of TAC to treat allograft rejection in a monkey model. AS2553627 inhibited proliferation of IL-2 stimulated T cells with little species difference between monkeys and humans. In MMF monotherapy, oral administration of 20 or 40 mg/kg/day prolonged graft survival with median survival times (MSTs) of 16.5 days and 33 days, respectively, whereas untreated animals showed MST of 6 days. In MMF/TAC (1 mg/kg/day, p.o.) combination therapy, pharmacokinetic analysis indicated that MMF 20 mg/kg/day achieved the clinical target AUC0-24h and prolonged renal allograft survival, with MST of 24 days. Oral administration of AS2553627 0.24 mg/kg/day in combination with TAC significantly prolonged renal allograft survival to MST of >90 days with low plasma creatinine levels. Histopathological analysis revealed that acute T cell-mediated rejection events such as vasculitis and interstitial mononuclear cell infiltration were significantly inhibited in AS2553627/TAC-treated allografts compared with MMF/TAC-treated allografts. All AS2553627/TAC-treated monkeys surviving >90 days exhibited less interstitial fibrosis/tubular atrophy than monkeys in the MMF/TAC group. These results suggest that AS2553627 replacing MMF is an attractive CNI-sparing strategy to prevent renal allograft rejection.

Superior Two-Year Graft Survival After Robotic Kidney Transplantation in Obese Recipients: Does Wound Infection Really Matter?

Introduction We hypothesize that robotic kidney transplant (R-KT) in obese individual could decrease the rate of surgical site infections (SSI) and improve outcomes Materials and Methods From June 2009 to October 2013, a prospective cohort of 90 morbidly obese patients underwent R-KT at our Institution. Twenty-eight of these patients in robotic group (RG), with a follow-up period of 24 months after transplant, were frequency matched with a control group (CG) of 28 morbidly obese patients who underwent standard open KT. Results The mean BMI was 42.6±7.8 kg/m2 in RG and 38.1±5.4 kg/m2 in CG (p=0.02). Two of 28 patients in each group underwent deceased donor KT, while the remaining patients had a living donor KT.Seven patients in the RG and five patients in the CG experienced biopsy proven acute rejection (p=NS). The mean follow-up was 28±8.8 months in RG and 54±24.6 months in CG. At 24 months after transplant, the GFR was 54.5±18.1 ml/min/1.73m2 in RG and 60.6±21.8 ml/min/1.73m2 in CG (p=NS). The rate of SSI was significantly higher in the CG in comparison with the RG (28.6% vs. 0%, p=0.004). At two year post transplant, 8 patients in the CG (28.5%) in comparison to only one in the RG (3.5%) experienced graft loss; the difference was statistically significant (p=0.02). Only two patients out of the eight who lost the graft in the CG had concomitant SSI. The patients survival at 24 months was 96.5% in robotic group and 92.8% in control group (p=NS). Conclusions At two year follow-up, we have documented a statistically significant improvement in graft survival in the robotic group. The decreases rate of SSI can explain only partially the improved graft survival. Further study is currently on going to identify other pertinent factors.

Highlights from the latest articles in pharmacogenomics of solid organ transplantation.

2014 Understanding the pharmacogenetics of tacrolimus may help in adequate immunosuppression Evaluation of: Li CJ, Li L, Lin L et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS ONE 9(1), e86206 (2014). Solid organ transplantation is the treatment of choice for patients with end-stage organ failure. Recent studies have shown a significant improvement in graft survival. This improvement results from the introduction of new immunosuppressive drugs that prevent rejection episodes. The susceptibility to developing adverse events or therapeutic failure varies between patients. An important part of this variability in drug response is thought to be the consequence of interindividual differences in drug metabolism. Some individuals have relatively fast drug clearance, while others exhibit a slower drug elimination rate. Because there is no reliable monitoring of the immunological status of patients receiving immunosuppressive drugs, many attempts have been made to optimize therapeutic drug monitoring by determining the blood concentrations of these drugs. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters has led to the hypothesis that genetic factors may be implicated in the interindividual variability of pharmaco kinetics and pharmacodynamics of immunosuppressive drugs [1]. The role of pharmacogenetics and specific genetic polymorphisms in the choice of treatment is of growing interest. Tacrolimus is a macrolide antibiotic that is widely used to prevent acute rejection after solid organ transplantation. This drug is indicated for the prevention of organ rejection in patients receiving a liver, kidney or heart transplant [2]. Because tacrolimus is metabolized extensively by CYP3A4 and CYP3A5 isoenzymes, polymorphisms in CYP3A4 and CYP3A5 genes have been reported that affect tacrolimus dosing and serum concentrations, and may be helpful in dosing of tacrolimus in kidney transplant recipients [3,4]. Li and colleagues designed a study in the search for genetic determinants of tacrolimus metabolism in Chinese renal transplant recipients [5]. In the retrospective study, the authors evaluated the influence of CYP3A4, CYP3A5, COMT, IL-10 and POR SNPs on concentration/dose ratio (C0/D) and the time required to reach the target blood concentration range during the early phase after transplantation. They found that CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C polymorphisms presented a significant association with tacrolimus C0/D at different time points after transplantation. Moreover, the CYP3A5*3 allele and CYP3A4 rs4646437 T>C were strongly associated with tacrolimus pharmacokinetics. IL-10 rs1800871 polymorphism was associated with tacrolimus blood concentration at week 3 after transplantation. None of the COMT and POR variants had a significant association with C0/D. This study confirmed the results of previous investigators indicating an association between CYP3A4 and CYP3A5 polymorphisms and tacrolimus pharmacokinetics. Understanding the pharmacogenetics of tacrolimus may enable individualized therapy, resulting in adequate Highlights from the latest articles in pharmacogenomics of solid organ transplantation

Improving graft survival for patients undergoing liver transplantation

Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998-2002) and Era 2 (2003-2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3-65.9) vs. 75.4 (68.9-81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non-HCV patients up to three yr. The change in management of donor organs into HCV and non-HCV patients likely contributed to this outcome.

Mycophenolic acid agents: is enteric coating the answer?

Correspondence: Matthew Cooper Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA Tel +1 410 328 7336 Fax +1 410 328 6343 email mcooper@smail.umaryland.edu Abstract: Addition of mycophenolate mofetil (MMF) to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological and gastrointestinal (GI) side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.

Deletion of the Chemokine Receptor CCR1 Prolongs Corneal Allograft Survival

Many corneal grafts undergo immune rejection, and current therapies are associated with many side effects. The purpose of this study was to identify critical chemokine pathways involved in generating the alloimmune response to corneal transplants. Orthotopic corneal transplantation was performed in fully mismatched strains. Cytokine and chemokine receptor gene expression was determined by the RNase protection assay. Knockout (KO) strains for chemokine-chemokine receptors that are upregulated after transplantation underwent corneal transplantation. Results derived from KO murine hosts were compared with cyclosporine (Cy) therapy. In addition to graft survival, graft infiltration, allospecific delayed-type hypersensitivity (DTH), and cytokine expression were compared among the recipient groups. Initial experiments revealed gene upregulation of the chemokine receptors CCR1, -2, and -5 after corneal allorejection. Although CCR1 KO hosts showed a significant increase in graft survival compared with wild-type (WT) hosts, allografts in CCR5, CCR2/CCL3(MIP-1alpha), CXCR3, CXCL10/IP-10, and CCL3/MIP-1alpha KO mice did not show a significant improvement in graft survival. Further, CCR1 KO hosts showed a significantly higher survival rate than with systemic Cy therapy in WT hosts. Moreover, graft infiltration by leukocytes and gene expression of proinflammatory cytokines were reduced in CCR1 KO mice compared with both Cy treated and untreated WT mice, as was the induction of allospecific DTH. These studies provide, for the first time, evidence that targeting of specific chemokine pathways can significantly promote survival of corneal transplants, and suggest that select deletion or suppression of CCR1 can be a useful therapeutic target in corneal transplant immunity.

Prevalence of CCR5Δ32 polymorphism in long-term survivors of heart transplantation

Background CC chemokine receptor 5 (CCR5) contributes to the alloimmune response following solid organ transplantation. In individuals homozygous for the CCR5Δ32 mutation, the receptor is inactive and lymphocyte recruitment and leukocyte trafficking during rejection are inhibited. A significant improvement in graft survival following renal transplantation has been observed in homozygous CCR5Δ32 patients, although conflicting data exist. To determine whether CCR5Δ32 homozygous heart transplant recipients may also benefit compared to those with a normally functioning CCR receptor, the proportion of patients with CCR5Δ32 mutation was examined in a large cohort of patients surviving for a long period after heart transplantation. Methods The prevalence of CCR5 genotype was identified in patients who had survived ≥ 7 years after heart transplantation. Genotyping was performed centrally by polymerase chain reaction (PCR). Results A total of 555 patients were recruited at three heart transplant centers in Germany. Of these, 442 patients (79.6%) were homozygous for the wild-type allele, 106 (19.1%) were heterozygous for CCR5Δ32 and 7 (1.3%) were homozygous for CCR5Δ32. No statistically significantly differences were observed between the incidence of CCR5Δ32 homozygosity in the study population and the estimated incidence in the normal population. Conclusions In the absence of a control arm, it cannot be established if homozygous carriers of the CCR5Δ32 allele experience a long-term survival benefit following heart transplantation that may be masked by underrepresentation of the CCR5Δ32 allele in recipients of a heart transplant. To answer this question, the prevalence of CCR5Δ32 homozygosity needs to be established in patients awaiting heart transplantation.

RABBIT ANTITHYMOCYTE GLOBULIN AS INDUCTION IMMUNOTHERAPY FOR PEDIATRIC DECEASED DONOR KIDNEY TRANSPLANTATION

There is scant literature describing the long-term outcome of the use of antithymocyte globulin induction immunotherapy in pediatric deceased donor kidney transplants. We retrospectively studied the long-term results and safety of antithymocyte globulin as induction immunotherapy in all children undergoing transplantation at our institution since 1991. A total of 120 kidney transplants were performed in 95 patients 18 years or younger between January 1986 and December 1998. Patients were divided into 2 groups. The control group (63 patients) received cyclosporine, azathioprine and prednisolone, while the treatment group (59 patients) received rabbit antithymocyte globulin (RATG) induction immunotherapy for 6 to 10 days, combined with cyclosporine, azathioprine and prednisolone. Actuarial patient survival rates at 1, 3, 5 and 10 years were 96%, 95%, 95% and 90%, respectively. Actuarial graft survival rates at 1, 3, 5 and 10 years were 76%, 69%, 64% and 49%, respectively. The 1, 3, 5 and 10-year graft survival rates in the control group were 62%, 57%, 51% and 36%, respectively, compared to 90%, 82%, 79% and 69%, respectively, in the RATG group (p = 0.001). There was a significant difference in the incidence of graft loss secondary to acute cellular rejection between the control and RATG groups (19.7% vs 3.3%, p = 0.008). There was no difference in infectious complications between the control and RATG groups (13% vs 20%, p = 0.33), and there was no case of post-transplant lymphoproliferative disorder encountered in either group. The use of rabbit antithymocyte globulin in pediatric deceased donor kidney transplant recipients resulted in significant improvement in graft survival and was relatively safe.

Pediatric Renal Transplantation: 13 Years of Experience—Report From The Chilean Cooperative Multicenter Group

Between 1989 and 2002, 178 renal transplants were performed in 168 pediatric patients in Chile. The mean age was 10.9 ± 3.7 years (range 1 to 17.9). End-state renal disease etiologies were: congenital renal hypoplasia/dysplasia, chronic glomerulonephritis, and reflux nephropathy. Seventy received a graft from a living donor (LD), and 108 from a cadaveric donor (CD). Only 9% received antibody induction. Acute rejection episodes were reported in 76 patients: 38% in LD recipients and 48% in CD recipients ( P = NS). One-, 3-, and 5-year graft survivals were 88%, 84%, and 76%, respectively, for LD and 86%, 79%, and 68% for CD recipients. Actuarial graft survival was significantly better among those patients with serum creatinine < 1 mg/dL at 1 year posttransplant compared with those with creatinine > 1 mg/dL ( P < .05). The graft survival rate has improved from the first period (1989 to 1996) to the second period (1997 to 2002); ( P = .05). Patient survival rates at 1, 3, and 5 years were 98%, 98%, and 98%, respectively, for LD, and 95%, 94%, and 94% for CD. Global height/age Z-score decreased from −0.7 at birth to −1.5 when dialysis started, and to −2.4 at the time of transplantation. The Z-score height/age at 1, 3, and 5 years posttransplantation was −2.25, −2.24, and −2.5. No significant differences were observed in transplant outcomes comparing patients younger than 7 years with those older ones. In conclusion, pediatric renal transplant has been performed in Chile with acceptable morbidity. The patient and graft survivals are similar to the reported international experience. In the last period there was a significant improvement in graft survival.

Improvement in long-term graft survival in cadaveric renal transplant recipients treated with mycophenolate mofetil

Abstract Though mycophenolate mofetil has markedly reduced the incidence of acute rejection in renal transplantation, a significant improvement in graft survival has been more difficult to demonstrate. This retrospective study compares an historical control group of 210 consecutive renal transplant patients, who had received ATG induction associated with cyclosporin, prednisolone and azathioprine, with 187 patients receiving mycophenolate instead of azathioprine. The incidence of acute rejection was decreased with mycophenolate. In rejection-free patients, the 3-year graft survival rates were equivalent. In contrast, graft survival at 3 years improved significantly for patients who experienced a rejection crisis and remained under the initial triple drug regimen with mycophenolate compared to the patients of the historical group who were kept on azathioprine after a rejection episode. In conclusion, mycophenolate mofetil is not only able to reduce the incidence of acute rejection but could also improve the prognostic significance of acute rejection crises.

AN EVALUATION OF HLA CROSS-REACTIVE GROUP (CREG) MATCHING ON GRAFT SURVIVAL IN DECEASED DONOR KIDNEY RECIPIENTS

P2 Aims: Since Sept. 20, 1999 our organ procurement organization (OPO) that serves an ethnically diverse local distribution area has allocated kidneys from deceased donors using a UNOS approved kidney allocation variance that awards 7 points for a 0-CREG,0-DR mismatch (MM) and 6 points for a 0-A,B MM. Points were also given for waiting time (3) and panel-reactive antibodies (PRA) >80% (3). Previously we showed that awarding points for 0-CREG,0-DR MM in kidney allocation improves the access to HLA matched transplants for all racial groups, especially the black race. In this study we evaluated if there are graft outcome benefits as well. Methods: One and 3 year uncensored graft survival (GS) data were provided by Scientific Registry of Transplant Recipients (SRTR) and analysed for the influence of HLA mismatching on graft outcome in black and non-black recipients. Results: Overall, 1 year GS was 87.4% (N=1,197) and not significantly different for blacks (86.1%, N=467) and non-blacks (88.2%, N=730); 3 year GS was 74.6% (N=1,245) and significantly lower for blacks (68.5%, N=480) vs. non-blacks (78.4%, N=765), p=0.0001.Figure* = less than 30 cases No significant improvement in GS (p=NS) was seen with HLA matching, including 0-CREG, 0-DR MM, for either the black or non-black recipients (Table) and also not seen when data was stratified for patients non-sensitized (PRA≤10%) and sensitised (PRA >10%) at the time of transplant. Of those relisted after a failed graft, the 0-A,B,DR MM group was the least sensitized (6%, N=16) as expected, and there was a trend for less sensitization in the 0-CREG,0-DR MM group (33%, N=9), compared to those with other HLA mismatches (67%, N=126). Conclusions: In conclusion, based on 1-year and 3-year follow-up data, there are no apparent graft oucome benefits for either CREG matching or conventional HLA matching in our service area. Such benefits may become apparent with longer follow-up.

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.

Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review.

Nonadherence to immunosuppressants is recognized to occur after renal transplantation, but the size of its impact on transplant survival is not known. A systematic literature search identified 325 studies (in 324 articles) published from 1980 to 2001 reporting the frequency and impact of nonadherence in adult renal transplant recipients. Thirty-six studies meeting the inclusion criteria for further review were grouped into cross-sectional and cohort studies and case series. Meta-analysis was used to estimate the size of the impact of nonadherence on graft failure. Only two studies measured adherence using electronic monitoring, which is currently thought to be the most accurate measure. Cross-sectional studies (n=15) tended to rely on self-report questionnaires, but these were poorly described; a median (interquartile range) of 22% (18%-26%) of recipients were nonadherent. Cohort studies (n=10) indicated that nonadherence contributes substantially to graft loss; a median (interquartile range) of 36% (14%-65%) of graft losses were associated with prior nonadherence. Meta-analysis of these studies showed that the odds of graft failure increased sevenfold (95% confidence interval, 4%-12%) in nonadherent subjects compared with adherent subjects. Standardized methods of assessing adherence in clinical populations need to be developed, and future studies should attempt to identify the level of adherence that increases the risk of graft failure. However, this review shows nonadherence to be common and to have a large impact on transplant survival. Therefore, significant improvements in graft survival could be expected from effective interventions to improve adherence.

The effect of cross-reactive epitope group matching on allocation and sensitization.

Some polymorphisms on HLA molecules are shared by different HLA types, which allows us to group HLA molecules into 'families' or groups based on the shared epitope. These cross-reactive epitope groups (CREGs) can be used as a basis for matching donors to recipients for renal transplantation. The current allocation system uses HLA-B,DR mismatching for assigning HLA points. Graft survival using newer immunosuppressive drugs still shows a significant improvement in graft survival for 0-mismatched donors (3-year survival approximately 90%) and a significantly worse graft survival for 5 and 6 HLA-mismatched donors (3-year graft survival approximately 75%). However, the difference in graft survival between 1-, 2-, 3- and 4-mismatched donors are nor significantly different from each other (80-85% survival at 3 year). This has led to a reassessment of the UNOS allocation system and the need to re-evaluate the role of HLA in graft survival, minority allocation, and HLA sensitization. One of the problems with the current algorithm is that very few recipients are actually getting well-matched kidneys (approximately 3% get 1 mismatch and 10% get 2 mismatch). Transplant centres using the UNOS CREG variance (10 points awarded for 0 CREG, 0 DR mismatches) were able to find matches at a sixfold higher rate over 0 BDR mismatches. The size of the list affects the likelihood of finding a good match and the CREG variance was more successful in larger transplant programs. The effect of HLA on equity in renal allocation is also being addressed. There is some concern that HLA points may be at least partially responsible for the decreased transplant rate in African Americans. The 1999 UNOS data showed that 46.9% of the list were Caucasian, while 55.2% of the transplants were in Caucasian recipients. Conversely, African Americans made up 35.8% of the list and only 27% of the transplants went to African Americans. Since most of the donors were Caucasian (75.9% vs. 11.2%), it has been speculated that the Black population may be disadvantaged because they have less chance of getting HLA points. The impact of HLA on transplant rate is still being disputed and may not be a major factor since so few recipients actually benefit from the points given for BDR mismatches. However, CREG matching has the advantage of equalizing the HLA effect since rare HLA antigens are grouped with common HLA antigens sharing the same public epitopes. Another advantage for CREG matching is the protection from sensitization to HLA. The effect of HLA matching on sensitization is increased with each HLA match. Black recipients are more likely to be sensitized than Caucasians with the same level of mismatch. Also, once sensitized, Black recipients are less likely to get transplanted than Caucasians because of greater difficulty in finding a well-matched donor. Of patients transplanted with 0 CREG-mismatched donors, 82% remained unsensitized to Class I, compared with less than 60% in recipients who received greater than 2 BDR mismatches. The use of CREG matching in renal allocation offers better matching to a larger group of recipients and significantly reduces sensitization to HLA.

Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats.

The introduction of cyclosporine into the immunosuppressive armamentarium has revolutionized transplant surgery with significant improvements in graft survival. The apparent lack of effect of cyclosporine on humoral rejection mechanisms makes the search for other immunosuppressive agents desirable. Two anti-metabolites affecting nucleotide synthesis via different pathways have recently been evaluated for their immunosuppressive potential. DUP-785 (DUP), also known as brequinar sodium, reversibly inhibits de novo pyrimidine synthesis by blocking dihydro-orotate dehydrogenase, thus resulting in the deletion of critical precursors for RNA and DNA synthesis. RS-61443, a morpholinoethyl ester of mycophenolic acid, reversibly and non-competitively blocks inosin monophosphate dehydrogenase, the key enzyme in purine de novo synthesis. A possible additive effect of both drugs was investigated in the rat heart allograft model.

Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats

The introduction of cyclosporine into the immunosuppressive armamentarium has revolutionized transplant surgery with significant improvements in graft survival. The apparent lack of effect of cyclosporine on humoral rejection mechanisms makes the search for other immuno-suppressive agents desirable. Two anti-metabolites affecting nucleotide synthesis via different pathways have recently been evaluated for their immunosuppressive potential. DUP-785 (DUP), also known as brequinar sodium, reversibly inhibits de novo pyrimidine synthesis by blocking dihydro-orotate dehydrogenase, thus resulting in the delretion of critical precursors for RNA and DNA synthesis [2]. RS-61443, a morpholinoethyl ester of mycophenolic acid, reversibly and non-competitively blocks inosin monophosphate dehydrogenase, the key enzyme in purine de novo synthesis [10]. A possible additive effect of both drugs was investigated in the rat heart allograft model.

生体腎移植における donor specific blood transfusion の効果

Donor specific blood transfusion (DST), given prior to living related kidney transplantation has resulted in significant improvement in graft survival. This improvement, however, has been accomplished with a high rate of adverse sensitization against the donor. In an attempt to reduce the incidence of sensitization, we have employed DST with intermittent coverage of cyclophosphamide. A comparative study was done between 2 methods of DST with or without the coverage of immunosuppressant for prospective kidney transplant recipients from living related donors. In addition, the beneficial effect of DST on graft survival was evaluated in our recent series of living related transplantation using cyclosporine A (CsA) as postoperative immunosuppression. Twenty-nine prospective kidney transplant patients received 200 ml of fresh whole blood 3 times at 2 week intervals from HLA one-haploidentical living related donors. The first 13 patients received DST alone, while the remaining 16 were given cyclophosphamide (CPM 1.5 mg/kg/day) for 3 days prior to each DST. In patients with CPM coverage, 6.3% (1 of 16) developed positive T-warm antibody against donor and 15% of patients (2 of 13) with DST alone developed it. Like-wise 19% (3 of 16) of the former and 38% (5 of 13) of the latter became positive B-warm crossmatch. The difference in sensitization rates between these 2 groups was not statistically significant. Nineteen patients receiving DST were compared to 21 non-DST patients in incidence of acute rejection, graft function and graft survival with the same immunosuppressive regimen, such as CsA, prednisolone, and mizoribine.(ABSTRACT TRUNCATED AT 250 WORDS)