Younger Donor Age Research Articles

Accuracy of an age-adjusted formula in assessing the graft volume in living donor liver transplantation

In living donor liver transplantation, the estimated graft volume (GV) from young donors tends to be overestimated. One reason for this error may be a decrease in GV due to dehydration by University of Wisconsin (UW) solution. The aim of this study was to clarify (1) the usefulness of an age-adjusted formula and (2) the correlation between the decrease in GV and donor age. First, we created the age-adjusted formula using regression analysis retrospectively in 167 donors, and we evaluated the difference in the error ratio of GV from the age-adjusted formula and 3-dimensional computed tomography (3D-CT) prospectively in 49 donors. Second, we measured intraoperative GV both before and after flushing with UW solution and calculated the decrease ratio, and we then evaluated the difference in the decrease ratio between young donors and older donors prospectively in 41 donors. The age-adjusted formula was created as follows: age-adjusted GV = 70.767 + (0.703 x GV estimated with 3D-CT volumetry) + (1.298 x donor age). The mean error ratio for the age-adjusted formula (9.6%) was significantly lower than that from 3D-CT (14.0%). The mean decrease ratio in all 41 donors was 5.4%, and that in young donors (6.9%) was significantly higher than that in older donors (4.4%). In conclusion, although younger donor age is a major factor for estimation errors in hepatic volumetry, our age-adjusted formula is very useful in reducing the error in estimating GV.

FOXP3 Expression in Human Kidney Transplant Biopsies Is Associated with Rejection and Time Post Transplant but Not with Favorable Outcomes

Expression of the transcription factor forkhead box P3 (FOXP3) in transplant biopsies is of interest due to its role in a population of regulatory T cells. We analyzed FOXP3 mRNA expression using RT-PCR in 83 renal transplant biopsies for cause in relationship to histopathology, clinical findings and expression of pathogenesis-based transcript sets assessed by microarrays. FOXP3 mRNA was higher in rejection (T-cell and antibody-mediated) than nonrejection. Surprisingly, some native kidney controls also expressed FOXP3 mRNA. Immunostaining for FOXP3 was consistent with RT-PCR, showing interstitial FOXP3+ lymphocytes, even in some native kidney controls. FOXP3 expression correlated with interstitial inflammation, tubulitis, interstitial fibrosis, tubular atrophy, C4d positivity, longer time posttransplant, younger donors, class II panel reactive antibody >20% and transcript sets reflecting inflammation and injury, but unlike these features was time dependent. In multivariate analysis, higher FOXP3 mRNA was independently associated with rejection, T-cell-associated transcripts, younger donor age and longer time posttransplant. FOXP3 expression did not correlate with favorable graft outcomes, even when the analysis was restricted to biopsies with rejection. Thus FOXP3 mRNA expression is a time-dependent feature of inflammatory infiltrates in renal tissue. We hypothesize that time-dependent entry of FOXP3-positive cells represents a mechanism for stabilizing inflammatory sites.

Strategies of the donor search for children with second CR ALL lacking a matched sibling donor

During the last 10 years, the number of alternative Haematopoietic stem cell transplantations (HSCTs) performed on children in Europe has increased significantly and has reached 61% of the allografts. In this paper, we provide practical guidelines to help define an algorithm for the treatment of children relapsing during or after first-line chemotherapy for ALL and lacking a matched sibling donor. A simultaneous search for an unrelated donor and for a cord blood unit should be started. This study focuses mainly on the effects of some factors on survival in an effort to highlight the influence that these factors have on our choices. Matching the patient for HLA-A, -B, -C and -DRB1 alleles remains the top priority: a single HLA class I or II allele mismatch has no influence on survival, while multiple mismatching for more than one class I allele and simultaneous disparities in class I and II alleles increase mortality. The impact of additional mismatches for HLA-DQ and -DP loci on survival is still controversial. Young donor age is the most important factor that has a significant effect on better survival from among several other factors, including CMV sero-status, gender and ABO. An 18- to 30-year-old, 8/8 allele-matched donor (excluding allele matching at DQB1) or for many teams 10/10 allele-matched donor; or a 4 out of 6 (considering Ag HLA-A, -B and allelic typing of DRB1) CB unit containing more than 3.0 x 10(7) nuclear cells is considered by most institutions. The choice should be made on the basis of urgency. If a donor or a CB unit is not found within an appropriate time frame, generally less than 3 months after obtention of remission, haploidentical HSCT should be offered. Some institutions consider haploidentical HSCT the second therapeutic option when a matched donor is not available.

Whole Liver Versus Split Liver Versus Living Donor in the Adult Recipient—An Analysis of Outcomes by Graft Type

We studied patient and graft survival rates in adult liver transplant recipients, analyzing outcomes based on donor source (deceased donor [DD] vs. living donor [LD]) and graft type (whole liver vs. partial liver). A retrospective database analysis of all adult liver transpants performed at our center over a 7-year period of time. Between 1999 and 2005, 384 liver transplants were performed in adult recipients, either as a whole liver from a deceased donor (DD-WL, n=284), split liver from a DD (DD-SL, n=31), or a partial transplant from a living donor (LD, n=69). DD-SL transplants were performed with a full right or left lobe graft, while LD transplants used the right lobe. Demographic differences in the three groups were most noticeable for lower model for end-stage liver disease scores in LD recipients (P<0.001) and younger donor age in DD-SL recipients (P<0.001). Superior graft survival results were seen in LD recipients versus either DD-WL recipients or DD-SL recipients (P=0.02 and P=0.05, respectively). Multivariate analysis showed hepatitis C (HR=1.53, P=0.05) and hepatocellular carcinoma (HR=1.74, P=0.03) to be significant risk factors for patient survival. Hepatitis C (HR=1.61, P=0.03) and donor age more than 50 (HR=1.64, P=0.04) were significant risk factors for graft survival. However, neither graft type nor donor source were significant independent risk factors for patient or graft survival. Our data suggests that the status of the recipient is probably a more important determinant of outcome than graft type or donor source.

Working Together Toward a National Kidney Paired Donation Program

To the Editor: Many researchers have addressed compatible pair participation in kidney paired donation (KPD) programs. The concept was first introduced by Woodle and Ross (1Woodle ES Ross LF Paired exchanges should be part of the solution to ABO incompatibility in living donor kidney transplantation.Transplantation. 1998; 66: 406-407Crossref PubMed Scopus (19) Google Scholar) and first implemented clinically by Montgomery et al. (2Montgomery RA Zachary AA Ratner LE et al.Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation.JAMA. 2005; 294: 1655-1663Crossref PubMed Scopus (164) Google Scholar). Comprehensive inclusion of compatible pairs in clinical KPD programs would nonetheless be a new paradigm, as evidenced by ongoing contention in the transplant community about whether to pursue compatible paired donation. In their 2006 discourses, Veatch (3Veatch RM Why organ exchanges serve the interests of Odonors.Am J Transplant. 2006; 6: 856Crossref Scopus (3) Google Scholar) and Spital (4Spital A Veatch’s proposal may not work.Am J Transplant. 2006; 6 (author reply 856): 855Crossref Scopus (5) Google Scholar) each referred to the unknown probability that a compatible pair could benefit from KPD. The goal of our recent manuscript (5Gentry SE Segev DL Simmerling M Montgomery RA Expanding kidney paired donation through participation by compatible pairs.Am J Transplant. 2007; 7: 2361-2370Crossref PubMed Scopus (122) Google Scholar) was to estimate this controversial probability and how it might vary depending on the size and makeup of KPD programs and on the precise definition of benefit. These questions had never been answered. Roth et al. previously suggested that compatible pairs would increase matching opportunities in KPD (6Roth AE Sönmez T ünver MU A kidney exchange clearinghouse in New England.Am Econ Rev. 2005; 95: 376-380Crossref PubMed Scopus (164) Google Scholar). However, because of methodologic limitations, Roth et al. could not address the critical issue later identified by Veatch and Spital. The maximum cardinality-matching algorithm used by Roth et al. assumes that all matches are equally valuable, and as such cannot capture distinctions such as matching to a beneficial donor versus matching to a medically inferior one. The top-trading-cycles algorithm used by Roth et al. requires logistically impossible 26-way matches. In their letter to which we respond, Roth et al. (7Roth AE, Söonmez T, ünver MU. Kidney paired donation with com-patible pairs. Am J Transplant (in press).Google Scholar) describe one difference between our analysis and theirs (that their model considers only unrelated donors) but do not mention the more fundamental contrast and its implications. Rather than maximum cardinality matching, which seeks to maximize the number of transplants, we use maximum edge-weight matching that considers the quality of the matches. Although both algorithms were suggested by Edmonds, only maximum edge-weight matching can respect factors such as varying levels of medical benefit to a recipient who enters KPD with his compatible donor. Furthermore, only maximum edge-weight matching can prioritize local and regional matches. Minimizing travel was a central feature of the UNOS proposal for KPD, and the UNOS consensus statement acknowledged that such prioritization would require edge weighting. Moreover, we have recently shown that it is possible to design maximum edge-weight models so that they will also include the maximum number of transplants, if that is desired. The purpose of our study was to demonstrate the high probability that a compatible pair entering a KPD pool would derive a benefit in terms of younger donor age and better matching, because that fact might encourage a widening of compatible pair participation. This is very different from previous simulation work by Roth et al. concerning compatible pairs in KPD pools, but we did not intend to overlook their contributions. We applaud the interest of economists in the field of transplantation. Our interest has been in developing mathematical models that closely reflect actual medical practice. A national KPD program would yield the greatest benefit to the largest number of patients awaiting transplantation. It is our hope that the transplant community will unite behind the cause of making KPD available to all patients by supporting a national program administered through UNOS.

The Medical Evaluation of Living Kidney Donors: A Survey of US Transplant Centers

The use of living donors for kidney transplantation in the United States is common, and long-term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long-term outcomes in various types of donors with potential morbidities related to donation.

Improved survival of young donor age dopamine grafts in a rat model of Parkinson’s disease

In an attempt to improve the survival of implanted dopamine cells, we have readdressed the optimal embryonic donor age for dopamine grafts. In a rat model of Parkinson’s disease, animals with unilateral 6-hydroxydopamine lesions of the median forebrain bundle received dopamine-rich ventral mesencephalic grafts derived from embryos of crown to rump length 4, 6, 9, or 10.5 mm (estimated embryonic age (E) 11, E12, E13 and E14 days post-coitus, respectively). Grafts derived from 4 mm embryos survived poorly, with less than 1% of the implanted dopamine cells surviving. Grafts derived from 9 mm and 10.5 mm embryos were similar to those seen in previous experiments with survival rates of 8% and 7% respectively. The best survival was seen in the group that received 6 mm grafts, which were significantly larger than all other graft groups. Mean dopamine cell survival in the 6 mm group (E12) was 36%, an extremely high survival rate for primary, untreated ventral mesencephalic grafts applied as a single placement, and more than fivefold larger than the survival rate observed in the 10.5 mm (E14) group. As E12 ventral mesencephalic tissues contain few, if any, differentiated dopamine cells we conclude that the large numbers of dopamine cells seen in the 6 mm grafts must have differentiated post-implantation. We consider the in vivo conditions which allow this differentiation to occur, and the implications for the future of clinical trials based on dopamine cell replacement therapy.

Correction: Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Correction: Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Sixty three patients aged 27-66 years (median 52) were allografted from HLA-matched sibling (n=47), 10 of 10 allele-matched unrelated (n=19), or one-antigen/allele-mismatched (n=7) donors aged 24-69 years (median 46) after a conditioning regimen comprising 100 mg/m(2) melphalan. Cyclophosphamide (50 mg/kg) was also administered to patients who had not been autografted previously. Cyclosporine or tacrolimus, and mycophenolate mofetil were administered to prevent graft-versus-host disease (GVHD). The 2-year cumulative incidences of relapse and TRM were 55 and 24% respectively, and 2-year probabilities of overall survival (OS) and disease-free survival (DFS) were 36 and 21%, respectively. Poor performance status, donor age >45 years and elevated lactate dehydrogenase (LDH) increased the risk of treatment-related mortality (TRM), refractory disease and donor age >45 years increased the risk of relapse, and OS and DFS were adversely influenced by refractory disease, poor performance status, increased LDH, and donor age >45 years. Our data suggest that younger donor age is associated with better outcome after sub-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies due to lower TRM and relapse. This finding raises the question of whether a young 10-allele-matched unrelated donor is superior to an older matched sibling donor in patients where the clinical situation permits a choice between such donors.

Survival Outcome After Hepatic Retransplantation for Hepatitis C Virus–Positive and –Negative Recipients

Introduction Hepatitis C virus (HCV)–related liver disease is the most common indication for liver transplantation in the United States. Recurrence of HCV infection in these recipients is almost uniform. The currently available antiviral treatment is known to cause significant side effects, and the rate of sustained viral response is low. There is still controversy about whether such patients should undergo subsequent transplantations for HCV disease. This study compared outcomes for hepatic retransplantation performed in HCV(+) and HCV(−) recipients at a single center. Patients and methods From December 1994 through November 2003, 68 patients at our institution received a second liver allograft. Nineteen of the recipients were HCV(+) (group A) and 49 were HCV(−) (group B). All patients were followed until January 2004. The mean follow-up time after initial retransplantation was 37 ± 29 months. Patient and graft survival for the two groups were compared. Results Seven recipients in group A (36.8%) and 22 recipients in group B (44.9%) died during follow-up. The actuarial 3-year patient survival after initial retransplantation for groups A and B were 61.7% and 51.6%, respectively. Nine patients required a second retransplantation, 3 (15.8%) in group A and 6 (12.2%) in group B. The actuarial 3-year graft survival from initial retransplantation for groups A and B were 56.3% and 45.7%, respectively. Conclusion We observed slightly better patient and graft survivals at 3 years from initial retransplantation in HCV(+) recipients compared to HCV(−) recipients. This may be due to younger donor age and better selection of HCV(+) recipients in this series.

Pediatric Renal Transplantation: Comparative Study With Renal Transplantation in the Adult Population

Purpose To retrospectively review our experience with pediatric renal transplantation and to compare the results with the adult population. Patients and methods Between January 1981 and August 2003, 74 renal transplants were performed in patients ≤18 years at the time of the transplant—the pediatric group versus 1153 patients in the adult group. We analyzed various risk factors for actuarial kidney graft and patient survivals using the Kaplan-Meier method. Results Median ages were 13.8 ± 3.5 and 42.6 ± 2.4 years, respectively. There was no statistically significant difference in the human leukocyte antigen matching or immunosuppression. There was, however, a younger donor age and shorter ischemia time in the pediatric group. Overall, kidney transplant survival rates for patients ≤18 years at 1, 2, 5, and 10 years were 94.4%, 91.3%, 70.6%, and 58.2%, respectively, with no significant difference for patients older than 18 (91.2%, 89.3%, 78.8%, 60.5%, P = .4325). There was a significantly decreased graft survival in the adult group at 10 years when the donor age was over 60 years and when the ischemia time was ≥20 hours. The incidence of delayed graft function and the creatinine levels of functioning grafts did not differ between the two groups. During the follow-up, acute rejections were more frequent in the younger group. Patient survival in the pediatric group at 1, 2, 5, and 10 years was 98.6%, 98.8%, 98.6%, and 90.3%, respectively, significantly lower in the adult group (95.3%, 94.0%, 87.9%, 76.8%, P < .02). Conclusions Renal transplantation may be successfully performed in the pediatric patients with end-stage renal disease. Overall graft survival at 10 years did not differ significantly between the two groups. There is a higher incidence of acute rejections but longer patient survival in the pediatric population.

The effect of heparin on graft thrombosis in pediatric renal allografts.

Graft thrombosis is an important cause of early (<4 weeks) renal graft loss. Reports show that heparin reduces the incidence of early renal allograft thrombosis. Routine peri-operative administration of unfractionated heparin was introduced in our unit in 1994. We conducted a retrospective study of 254 transplants, undertaken in children, between 1987 and 2000. There were 126 children who did not receive heparin (group 1) and 128 who did (group 2). Recipient characteristics and immunosuppression were similar in both groups. The incidence of graft loss secondary to thrombosis was compared between the groups. Variables previously identified with increased risk of graft loss, including donor age, recipient age, cold ischaemia time (CIT), multiple donor vessels, surgical complications, and side of graft donation, were examined using logistic regression. Thrombosis occurred in 14 grafts in group 1 and 11 grafts in group 2 (odds ratio 0.7, 95% confidence interval 0.3-1.6, P=not significant). The mean time to graft loss was similar in groups 1 and 2 (6.6, SD 3.9, range 2-12 days and 7.9, SD 4.4, range 1-14 days, respectively) ( P=0.445). Young recipient age ( P=0.006), young donor age ( P=0.009), increasing CIT ( P=0.007), and surgical complications ( P=0.002) increased the risk of graft thrombosis. A reduction in the incidence of early renal allograft thrombosis upon introduction of heparin was not demonstrated.

Impact of surgical and immunological parameters in pediatric liver transplantation: a multivariate analysis in 500 consecutive recipients of primary grafts.

To assess the respective impact of surgical and immunologic factors on patient/graft outcome and rejection after pediatric liver transplantation. Orthotopic liver transplantation (OLT) constitutes a validated therapeutic modality for acute liver failure and end-stage liver disease in children. Only a few large studies of factors influencing outcome of pediatric OLT are available in the literature. Studies considering the impact of rejection on graft outcome are scarce in adult OLT and are not even available for pediatric recipients. Five hundred consecutive pediatric recipients (<15 years) of a primary OLT performed between March 1984 and July 2000 were retrospectively reviewed. The main indication was biliary atresia (n = 328). A living related donor graft was used from July 1993 onwards in 82 children (16%). Survival was calculated and multivariate analysis was performed. Actuarial survival rates at 1, 5, and 10 years were 85%, 81%, and 79% for patients, and 76%, 71%, and 70% for grafts, respectively. At the multivariate analysis, only 3 factors were found to be independently correlated with better patient survival: year of transplantation (P = 0.001), pretransplant diagnosis (P < 0.001, worst results for liver tumors), and ABO matching (P < 0.001, worst results for ABO incompatibility). Similarly, 3 factors were independently correlated with better rejection-free graft survival: tacrolimus as primary immunosuppressant (P < 0.001), a negative T-cell crossmatch (P = 0.016), and younger age of the donor (P < 0.001). Pediatric OLT constitutes a complex undertaking with multifactorial impact on results: (1). a strong learning curve effect was shown to impact on overall results; (2). pediatric liver tumors still represent a challenging indication for OLT; (3). primary immunoprophylaxis with tacrolimus provided a lower rejection incidence; (4). the younger donor age effect deserves further immunologic investigations.

Factors that impact on immediate graft function in patients after renal transplantation

Kidney transplantation has become therapy of choice for patients with end-stage renal failure. However, many factors may cause graft rejection or delayed graft function, both of which decrease the prognosis for graft survival. For transplantologists the most important endeavor is to eliminate factors responsible for shortening graft function and to find those predictive of immediate graft function. The aim of the study was to investigate which factors influence early graft function. We retrospectively reviewed 442 renal transplant patients performed between 1990 and 1995 in two Szezecin units. All patients received an identical immunosuppressive drug schedule. Three hundred twelve patients who displayed immediate graft function were included in the study group to analyze donor and recipient age and sex, etiology of ESRD, HLA compatibility AB0 and Rh compatibility cold ischemia time, warm ischemia time, antileukocytes antibodies (PRA), and period of dialysis therapy before transplantation. We observed statistical significance for HLA and AB0 compatibility, younger donor age, and shorter cold ischemia time as the most important factors predictive of early graft function and an improved prognosis for graft survival.

Risk factors for corneal graft failure and rejection in penetrating keratoplasty.

To evaluate risk factors for graft failure and allograft rejection after penetrating keratoplasty (PK). We retrospectively studied clinical results of PKs in terms of graft survival and rejection-free graft survival rates. PKs were done on 271 eyes between 1987 and 1997. Clinical results were analyzed by Kaplan-Meier's life table method and the log-rank test. Relative risks and adjusted survival probabilities for each value of the factor were compared with the risk for a specified reference value. The overall rates of graft survival and rejection-free graft survival in 10 years after PK were 79.3% and 77.9%, respectively. Higher relative risk of graft failure was associated with corneal vascularization (relative risk for within one quadrant = 1.67, two quadrants = 2.37, three or more quadrants = 3.39), regraft (relative risk for one failed previously graft = 2.08, two or more failed previously graft = 2.65), aphakia (relative risk = 2.17) or pseudophakia (relative risk = 3.02), presence of anterior synechia (relative risk = 2.91), presence of posterior synechia (relative risk = 2.56), long (more than 85 minutes) operation time (relative risk = 2.20), and older (more than 50 years) recipient age (relative risk = 2.38). Higher relative risk of rejection was associated with corneal vascularization (relative risk for within one quadrant = 2.35, two quadrants = 2.03, three or more quadrants = 2.63), long (more than 85 minutes) operation time (relative risk = 1.47), and younger (less than 60 years) donor age (relative risk = 2.10). There was no association between graft failure or allograft rejection and graft size or suture technique, respectively. The risk factors for graft failure after PK were corneal vascularization, regraft, aphakia or pseudophakia, presence of anterior synechia, presence of posterior synechia, long operation time, and older recipient age. The risk factors after PK for allograft rejection were corneal vascularization, long operation time, and younger donor age.

Risk factors for late pulmonary homograft stenosis after the Ross procedure

Background. We reviewed our experience with the Ross procedure to identify the prevalence and predictors of late pulmonary homograft stenosis. Methods. Between June 1992 and December 1997, 109 consecutive patients (age 34.5 ± 8.6 years) underwent the Ross procedure, with reconstruction of the right ventricular outflow tract with a cryopreserved pulmonary homograft (22 to 30 mm diameter). There was one early and one late death. Echocardiographic follow-up was available in 105 of 108 patients (97%), with a follow-up of 39 ± 20 months. Homograft donor and preservation measurements and patient variables were subjected to multivariable analyses to identify independent predictors of late homograft performance. Results. The major physiopathologic finding was homograft stenosis. Peak systolic gradients across the homograft were 20 mm Hg or more in 30 of 105 patients (28.5%) and 40 mm Hg or more in 4 of 105 patients (3.8%). One patient required two re-replacements of her homograft for severe stenosis. Moderate or severe homograft insufficiency was noted in 10 of 105 patients (9.5%). The independent predictors of late pulmonary homograft stenosis were younger donor age ( p = 0.03), shorter duration of cryopreservation ( p = 0.01), and smaller homograft size ( p = 0.06). Beating heart donor status, short homograft ischemic time, and other factors that have been shown to be associated with increased graft viability were associated with graft stenosis but did not reach statistical significance. However, mean gradients across the homograft were significantly related ( p = 0.002) to the number of these risk factors in each patient. Conclusions. Stenosis of the pulmonary homograft can be a significant problem following the Ross procedure, and was predicted by younger donor age and shorter duration of cryopreservation. These factors may be related to increased cellular viability, which might actually predispose to late homograft stenosis in a subgroup of patients.

Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors.

It remains uncertain whether autoimmune hepatitis (AIH), as an original indication for orthotopic liver transplantation (OLTX), predisposes to the development of chronic rejection (CR) after surgery and published reports on heterogeneous groups of patients provided conflicting data. In this work we analyzed the incidence and risk factors for CR in a large cohort of adult patients transplanted for AIH in our unit. A total of 1190 adult patients received OLTX in our center between 1982 and 1998. A total of 77 patients (6.5%) were transplanted for AIH and 12 (15.6%) patients from this group developed clinical and histological features of CR within a median time of 3.5 months after OLTX. Patients with AIH who developed CR were younger than other AIH patients at OLTX (32 vs. 44.2 ys; P=0.015) and more often had histological features of moderate or severe acute rejection (83 vs. 34%; P=0.002) on early post-OLTX biopsies. The incidence of CR in AIH patients was significantly higher than in subjects transplanted for other indications such as primary biliary cirrhosis (8.2%; P<0.05), primary sclerosing cholangitis (5.2%; P<0.05) or alcoholic cirrhosis (2.0%; P<0.001). Also, we observed a tendency to decreased incidence of CR with time in all transplanted subjects. Apart from younger age at OLTX and higher incidence of severe acute rejection, patients with AIH who developed CR did not differ from other subjects transplanted for this indication. Unlike other studies, not stratified by diagnosis, recipient CMV negative status, young donor age, and HLA DR matching were not identified as risk factors for CR in AIH.

An algorithm for cadaver kidney allocation based on a multivariate analysis of factors impacting on cadaver kidney graft survival and function

Abstract The large imbalance between cadaver kidney supply and demand makes the implementation of equitable and effective organ allocation systems an urgent need. This has triggered a revision of the criteria used so far for cadaver kidney allocation within the North Italy Transplant program, not least in the light of the many changes that have occurred recently with respect to broader criteria for admission of patients to the waiting list, donor selection, tissue-typing methods, organ preservation and immunosuppressive protocols. We based the critical revision of our cadaver kidney allocation algorithm on univariate and multivariate analysis of a number of immunological, clinical, social and administrative factors that impacted on the transplant outcome in 2,917 patients transplanted in the 12 transplant centers operating within our organization from 1 January 1990 to 30 September 1997. This analysis indicated that younger donor age, absence of pretransplant transfusions, patient dialysis center and level of HLA match showed statistically significant positive associations with graft survival. Younger donor age and male donor gender showed a statistically significant association with excellent graft function at 4 years. The results of this analysis were used to develop a new computer-assisted version of our adult kidney allocation algorithm. It works in two steps (local pool first, then the entire waiting list) and four levels (0-1 HLA MM, PRA +; 2 HLA MM, PRA +; 0-1 MM, PRA-; 2-4 HLA MM, PRA-); within each level, selection takes into account waiting time and age difference from donor age. The evaluation of 731 transplants allocated in 19 months with the new algorithm, as against 698 transplants allocated in the preceding 19 months according to the previous algorithm, showed a significantly higher proportion of recipients who had been on the waiting list for more than 3 years (33.2% versus 22.6%). The use of the new algorithm was also associated with a significantly increased number of transplanted alloimmunized patients (18.8% versus 9.2% with the previous algorithm) and recipients with 0-1 HLA mismatches (22% versus 14.3%). Furthermore, the number of kidneys used locally has steadily increased. Differences in 6-month graft survival and percentage of patients with excellent function at 6 months were not statistically significant in recipients transplanted with the new versus the previous algorithm. Survivals were 93.7% versus 91.8%. Percentages of patients with excellent renal function were 69.9% and 71.8%, respectively. These preliminary data suggest that the new algorithm improves HLA match and reduces the number of patients on the waiting list for 3 or more years without determining significant modifications of 6-month graft survival and function. Moreover, it facilitates the achievement of a fair local balance between organs retrieved and transplanted, the compliance of operators with objective allocation rules and the documentation of the whole allocation process.

Neoral use in the cardiac transplant recipient

CyA is the core immunosuppressant of choice for the majority of transplant patients. The introduction of Neoral, a new microemulsion formulation of CyA. and more recently a range of adjunctive immunosuppressants have further enhanced the efficacy and tolerability of CyA-based immunosuppression. In the first year following transplantation the major causes of morbidity and death are graft failure, acute rejection, and systemic infection. Patients with deteriorated pulmonary circulation before transplantation are at increased risk of early postoperative death. Risk factors for early acute rejection include female donor sex, young donor age, and multiple HLA-DR mismatches. The principal cause of death in the long term is graft vasculopathy which accounted for 40% of all deaths. Risk factors that have been hypothesized to play a role in the pathogenesis of graft vasculopathy include hyperlipidemia, recipient age and gender, donor age, the number of HLA AB and DR mismatches, and CMV infection. Strategies proposed to reduce the risk of graft vasculopathy include aggressive use of lipid-lowering agents, avoidance of low CyA doses, and the use of adjunctive rapamycin or RAD therapy. Rejection surveillance therefore relies on routine serial endomyocardial biopsy. Recent research suggests that a more accurate assessment of the state of the graft can be obtained by considering the results across a number of biopsy samples obtained from different parts of the heart, rather than basing clinical judgment on the worst single result obtained. New molecular markers such as granzyme A mRNA are likely to improve the power of histology to diagnose and predict rejection. Neoral pharmacokinetics give greater bioavailability and less intrapatient variability than Sandimmune. In the keynote OLN 351 study comparing Neoral with Sandimmune in de novo heart transplant recipients, fewer Neoral patients needed antilymphocyte therapy to treat rejection, fewer female patients had rejection episodes in the Neoral group, the tolerability of the two formulations was equivalent, and there was a lower incidence of infections in the Neoral group. The clinical impact of Neoral in comparison with Sandimmune in de novo heart transplant patients has been investigated in a number of additional trials, including long-term studies, which have confirmed that Neoral is associated with: Lower CyA doses than Sandimmune. Equal or greater antirejection efficacy than Sandimmune. Comparable tolerability to Sandimmune. During the administration of intravenous CyA as an induction therapy in the days immediately following transplantation, there is evidence to suggest that a 6-hour infusion given twice daily, which mimics the pharmacokinetic profile of oral dosing, may be clinically more effective than a continuous 24-hour infusion. Milligram-for-milligram dose conversion from Sandimmune to Neoral is feasible. Following conversion, a reduction in the CyA dose may be required in the majority of patients to maintain target levels. In pediatric patients, the rate of elimination of CyA is greater and bioavailability increases with increasing age. Younger patients (less than 8 years of age) may be managed more effectively with a 3-times-daily, rather than a twice-daily dosing schedule. A number of studies have compared the clinical effects of Sandimmune and Neoral in maintenance therapy for cardiac transplant patients. As with de novo patients, these studies have found the new formulation of CyA to be associated with lower rates of acute rejection, lower therapeutic doses, and comparable tolerability. Milligram-to-milligram conversion from the old to the new CyA formulation is generally well tolerated, although in a minority of patients there is a significant increase in CyA levels. These may be associated with a transient increase in side effects which resolve on dose reduction. There is a dose-sparing effect with Neoral. Routine monitoring of both CyA and serum creatinine levels are adv

An algorithm for cadaver kidney allocation based on a multivariate analysis of factors impacting on cadaver kidney graft survival and function.

The large imbalance between cadaver kidney supply and demand makes the implementation of equitable and effective organ allocation systems an urgent need. This has triggered a revision of the criteria used so far for cadaver kidney allocation within the North Italy Transplant program, not least in the light of the many changes that have occurred recently with respect to broader criteria for admission of patients to the waiting list, donor selection, tissue-typing methods, organ preservation and immunosuppressive protocols. We based the critical revision of our cadaver kidney allocation algorithm on univariate and multivariate analysis of a number of immunological, clinical, social and administrative factors that impacted on the transplant outcome in 2,917 patients transplanted in the 12 transplant centers operating within our organization from 1 January 1990 to 30 September 1997. This analysis indicated that younger donor age, absence of pretransplant transfusions, patient dialysis center and level of HLA match showed statistically significant positive associations with graft survival. Younger donor age and male donor gender showed a statistically significant association with excellent graft function at 4 years. The results of this analysis were used to develop a new computer-assisted version of our adult kidney allocation algorithm. It works in two steps (local pool first, then the entire waiting list) and four levels (0-1 HLA MM, PRA+; 2 HLA MM, PRA+; 0-1 MM, PRA-; 2-4 HLA MM, PRA-); within each level, selection takes into account waiting time and age difference from donor age. The evaluation of 731 transplants allocated in 19 months with the new algorithm, as against 698 transplants allocated in the preceding 19 months according to the previous algorithm, showed a significantly higher proportion of recipients who had been on the waiting list for more than 3 years (33.2% versus 22.6%). The use of the new algorithm was also associated with a significantly increased number of transplanted alloimmunized patients (18.8% versus 9.2% with the previous algorithm) and recipients with 0-1 HLA mismatches (22% versus 14.3%). Furthermore, the number of kidneys used locally has steadily increased. Differences in 6-month graft survival and percentage of patients with excellent function at 6 months were not statistically significant in recipients transplanted with the new versus the previous algorithm. Survivals were 93.7% versus 91.8%. Percentages of patients with excellent renal function were 69.9% and 71.8%, respectively. These preliminary data suggest that the new algorithm improves HLA match and reduces the number of patients on the waiting list for 3 or more years without determining significant modifications of 6-month graft survival and function. Moreover, it facilitates the achievement of a fair local balance between organs retrieved and transplanted, the compliance of operators with objective allocation rules and the documentation of the whole allocation process.