Incidence Of Chronic Rejection Research Articles

PSUN228 Incidence and Predictors of New Onset Diabetes After Transplant (NODAT) in Liver Transplant recipients.

Abstract Background NODAT (New onset Diabetes after Transplant) is associated with multiple complications in liver transplant recipients which has to be diagnosed and treated early to prevent graft failure, cardiovascular morbidity and mortality. With improvement in the care of liver transplant recipients, post-transplant survival has significantly increased. With improved survival, incidence of chronic rejection, Diabetes, Hypertension, Dyslipidemia, etc. complications incidence also increasing. Aims and Objectives To know the incidence and predictors of NODAT. Methodology This was a prospective study of non-Diabetic recipients who underwent Liver Transplantation at Yashoda Hospital, Secunderabad from January 2020 to May 2021. The follow-up duration was 6 months. Total 65 patients were enrolled after excluding recipients who were <18 years of age, were already having diabetes, whose survival was less than 6 months of transplantation and who were not of an Indian origin. All the relevant clinical and biochemical data were collected. Appropriate statistical tests were applied to compare NODAT and Non-diabetes groups (recipients who did not develop diabetes after liver transplantation) to know the predictors of NODAT. Diagnosis of NODAT was be established by the standard ADA guidelines using Fasting blood sugar (FBS), Post prandial blood sugar(PPBS) or HbA1C. Diagnosis of NODAT required the presence of one of the four parameters: (i) fasting blood glucose levels ≥ 126 mg/dL on two occasions OR (ii) Insulin therapy requirement for >= 30 days OR (iii) oral hypoglycemic agent use for ≥ 30 consecutive days OR (iv) HbA1c ≥ 6.5. Transient NODAT was defined as the resolution of hyperglycemia within 6 months of transplantation. Results Total incidence of NODAT in our study was 29.2%. Among them 47.36% were transient NODAT and 52.67% were persistent NODAT. Factors significantly associated with occurrence of NODAT were: Type of Transplant (Living donor liver transplant v/s Deceased donor liver transplant), Presence of Impaired fasting glucose (IFG), presence of post-operative hyperglycemia, lower pre-transplant Magnesium & Immediate post-operative Magnesium level, lower post-operative Albumin, higher trough Tacrolimus level at 3 Months, higher Tacrolimus and steroid dose at 3 months. Factors for which association with NODAT could not be found were: Age, Hepatitis C cirrhosis, alcoholic cirrhosis, pre-transplant BMI, baseline MELD score, pre-transplant FBS, donor age, donor gender, donor BMI, donor FBS & Hba1c, donor CT LAI (Liver Attenuation Index, L-S) value, Steroid dose at discharge, immediate post-op trough Tacrolimus level and use of Everolimus. CONCLUSION: NODAT is the significant entity to be addressed. A robust strategy should be in place for the screening of NODAT. Lower Magnesium levels, presence of pre-transplant IFG and post-operative hyperglycemia give an early opportunity for detection of NODAT. Minimizing Tacrolimus level and steroid dose could be an effective strategy for the prevention of NODAT. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Incidence of de novo autoimmune hepatitis in children and adolescents with increased autoantibodies after liver transplantation: a meta-analysis.

The objective of this meta-analysis was to assess the incidence of de novo autoimmune hepatitis (AIH) in children and adolescents with increased autoantibodies after liver transplantation. We systematically retrieved studies from PubMed, Embase, Central, CNKI, VIP and Wanfang published before February 1, 2020. All analyses were conducted using R-4.0.1 statistical package (Meta). Seven studies with high quality were pooled in our final analysis (N=251 participants). The incidence of de novo AIH was 9% [95% confidence interval (CI) 1-23%, I2 =86%]. Subgroup analysis suggested that publications not using the International Autoimmune Hepatitis Group (IAIHG) criteria have marginally significantly higher incidence of de novo AIH than those using IAIHG criteria (P for interaction=0.08). The incidence of chronic rejection was 8% (95% CI 2-17%, I2 =72%). Meta-regression indicated significant correlation (P=0.04; estimate: 1.51) between the incidence of de novo AIH and the rate of increase of antibodies to liver/kidney microsome (anti-LKM). It is still challenging to distinguish de novo AIH and chronic rejection in children and adolescents with increased autoantibodies after liver transplantation. The diagnostic criteria for de novo AIH in children and adolescents and the role of anti-LKM in the development of de novo AIH deserve future investigation.

Effect of Hepatitis C Virus Treatment on Rejection Incidence and Severity in Post-Liver Transplant Recipients

Abstract Background and Aims HCV is a worldwide cause of chronic liver disease, particularly in Egypt where the most prevalent is genotype 4. HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation (OLT) among adults. HCV infection remains a problem after transplantation, and recurrent hepatic infection is the leading cause of graft failure. Little is known about the long-term effects of direct acting antiviral therapy in patients after liver transplantation. We examined the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with DAAs relative to the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with Interferon based therapy and patients who didn’t receive any treatment for HCV after transplantation. Patients and Methods The study was conducted on 90 patients who had underwent liver transplantation between 2010 and 2017 at Ain Shams Center for Organ Transplantation (ASCOT) with a minimum follow up period of 6 months. Patients were divided into three groups: group I included 16 patients that didn’t receive antiviral treatment after liver transplantation, group II included 20 patients that had received interferon based therapy after liver transplantation and group III included 54 patients that had received direct acting antivirals after liver transplantation. Results Amongst group I, 2 patients (12.5%) developed acute graft rejection while in group II 2 patients (10%) developed chronic graft rejection and in group III 6 patients (11.11%) developed chronic rejection. In group I, all the patients (100%) had developed rejection that was diagnosed within one year of liver transplantation. In group II, 2 patients (100%) developed chronic graft rejection which occurred after one year of liver transplantation, one of them was on treatment with peg interferon and the other had already completed treatment. In group III, 2 patients (40%) had developed chronic rejection within one year of transplantation, while 4 patients (60%) had developed chronic rejection after one year of transplantation. One patient (16.67%) had developed rejection on treatment while 5 patients (83.33%) had developed rejection after the end of treatment. Conclusion It was found that the incidence of chronic rejection was more in patients that had received antiviral treatment after liver transplantation, however no difference was noted between DAAs and peg-interferon. Chronic rejection was found to be more common when treatment was given over one year after liver transplantation (6 cases) as compared to within the 1st year (2 cases). This may be related to the withdrawal of immunosuppression treatment after one year of transplantation and maintenance on monotherapy.

Liver-inclusive intestinal transplantation results in decreased alloimmune-mediated rejection but increased infection

Background and aimsA co-transplanted liver allograft has been thought to protect other organs from rejection-mediated injury; however, detailed analyses of co-transplanted liver on intestinal allograft outcomes have not been conducted to date. The aim of the study was to compare immune-mediated injury, causes of graft failure and clinical outcomes between recipients who underwent either a liver-inclusive intestinal transplant (LITx) or liver-exclusive intestinal transplant (LETx).MethodsBetween May 2000 and May 2010, 212 adult patients undergoing LITx (n =76) and LETx (n =136) were included. LITx underwent either liver combined intestinal or full multivisceral transplantation. LETx underwent either isolated intestinal or modified multivisceral transplantation.ResultsDuring 44.9 ± 31.4 months of follow-up, death-censored intestinal graft survival was significantly higher for LITx than LETx (96.9%, 93.2% and 89.9% vs 91.4%, 69.3% and 60.0% at 1, 3 and 5 years; p =0.0001). Incidence of graft loss due to rejection was higher in LETx than in LITx (30.9% vs 6.6%; p <0.0001), while infection was the leading cause of graft loss due to patient death in LITx (25.0% vs 5.1%; p <0.0001). Despite similar immunosuppression, the average number (0.87 vs 1.42, p =0.02) and severity of acute cellular rejection episode (severe grade: 7.9% vs 21.3%; p =0.01) were lower in LITx than in LETx. Incidence of acute antibody-mediated rejection was also significantly lower in LITx than in LETx (3.6% vs 15.2%; p =0.03). Incidence of chronic rejection was reduced in LITx (3.9% vs 24.3%; p =0.0002).ConclusionsIntestinal allografts with a liver component appear to decrease risk of rejection but increase risk of infection. Our findings emphasize that LITx has characteristic immunologic and clinical features. Lower immunosuppression may need to be considered for patients who undergo LITx to attenuate increased risk of infection.

Translational implications of endothelial cell dysfunction in association with chronic allograft rejection.

Advances in therapeutics have dramatically improved short-term graft survival, but the incidence of chronic rejection has not changed in the past 20 years. New insights into mechanism are sorely needed at this time and it is hoped that the development of predictive biomarkers will pave the way for the emergence of preventative therapeutics. In this review, we discuss a paradigm suggesting that sequential changes within graft endothelial cells (EC) lead to an intragraft microenvironment that favors the development of chronic rejection. Key initial events include EC injury, activation and uncontrolled leukocyte-induced angiogenesis. We propose that all of these early changes in the microvasculature lead to abnormal blood flow patterns, local tissue hypoxia, and an associated overexpression of HIF-1α-inducible genes, including vascular endothelial growth factor. We also discuss how cell intrinsic regulators of mTOR-mediated signaling within EC are of critical importance in microvascular stability and may thus have a role in the inhibition of chronic rejection. Finally, we discuss recent findings indicating that miRNAs may regulate EC stability, and we review their potential as novel non-invasive biomarkers of allograft rejection. Overall, this review provides insights into molecular events, genes, and signals that promote chronic rejection and their potential as biomarkers that serve to support the future development of interruption therapeutics.

Evaluation of growth in low-body-weight kidney transplant Egyptian children: 25-year experience

Identification of problems associated with kidney transplantation in low-body-weight children is an essential step toward improving graft function and patient survival as well as quality of life. This study comprised 63 renal transplant children weighing 25 kg or less at time of renal transplantation. All children received a living donor renal allotransplant between December 1984 and March 2009. These children were retrospectively evaluated regarding their survival, graft survival as well as physical growth. Our patient and graft survival rates at 1, 5 and 10 years were 98.4%, 96.8% and 96.8%, and 94.9%, 82.6% and 58.4%, respectively. Significant risk factors for growth retardation post renal transplant were identified and included older age at time of transplant (p=0.019), female sex (p=0.010), retarded growth at time of transplant (p=0.011, by univariate analysis, and p=0.028, by multivariate analysis), incidence of chronic rejection (p=0.012), higher steroid cumulative dose (p=0.013) and graft dysfunction (p=0.009, by multivariate analysis). The current final height of low-body-weight transplant Egyptian children has remained suboptimal. The management of growth retardation posttransplant is multifactorial and should start early before transplantation, with optimal care of growth in children with chronic kidney disease. Moreover, expedited transplantation, whenever indicated, and optimization of posttransplant graft function with minimal steroid exposure are essential factors which were shown to be possible using immunosuppression based on tacrolimus plus mycophenolate mofetil, after basiliximab induction.

Comparison of Sirolimus with Azathioprine in a Tacrolimus-based Immunosuppressive Regimen in Lung Transplantation

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. To determine the potential benefit versus risk of sirolimus in lung transplantation. We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Comparison of Renal Allograft Outcomes in Combined Liver-Kidney Transplantation Versus Subsequent Kidney Transplantation in Liver Transplant Recipients: Analysis of UNOS Database

There may be an allograft-enhancing effect by the liver on the renal allograft in the setting of simultaneous combined liver-kidney transplantation (CLKT) from the same donor. This study was performed to investigate whether an existing liver allograft could protect a kidney allograft from immunologic injury due to histoincompatibility in liver transplant recipients who received sequential kidney transplantation (KALT). Using the United Network for Organ Sharing database covering January 1996 to December 2003, outcomes of 352 KALT were compared to 1,136 CLKT. Incidence of acute and chronic rejection and rejection-free renal graft survival was compared between two groups. Renal half-life of KALT allografts was shorter than CLKT group (6.6+/-0.9 vs. 11.7+/-1.3 years, P < 0.001). Incidence of chronic rejection in KALT group was higher than CLKT group (4.6 vs. 1.2%, P < 0.001). One and three-year rejection-free renal graft survival of KALT and CLKT groups were different (77% and 67% KALT vs. 85% and 78% CLKT, respectively; P < 0.001). Among human leukocyte antigen mismatched and sensitized patients, rejection-free renal graft survival of KALT group was inferior to the CLKT group (75% at 1 year and 61% 3 years vs. 86% at 1 year and 79% 3 years, P < 0.001). Liver allograft provided renal graft immunoprotection if both organs are transplanted simultaneously (immunogenetic identity), but not for kidneys transplanted subsequently.

Evaluation of CD86 gene polymorphism at + 1057 position in liver transplant recipients

Background Efficient T cell–APC interaction requires the participation of primary and co-stimulatory signals. The main co-stimulatory pathway involves the interaction of CD80 and CD86, expressed on the APCs, with their T cell counter-receptor, CD28 and CTLA-4. Recently, a G to A transition has been described at position + 1057 of the CD86 gene, located in their cytoplasmic tail. Methods CD86 polymorphism was analyzed by sequence based typing in DNA samples obtained from 205 liver transplant recipients. Acute rejection and chronic rejection were diagnosed based upon conventional clinical, biochemical and histological criteria. Results The study of CD86 + 1057 (G/A) polymorphism revealed that recipients bearing the A allele or the AA genotype have a reduced risk of acute rejection. In fact, the AA genotype was absent in the group of patients showing acute rejection episodes, whereas its frequency in those patients without acute rejection episodes was 8.8% ( P = 0.009, OR = 0.07). This polymorphism did not reveal any association with the incidence of chronic rejection, but patients bearing the AA genotype showed a higher graft survival rate (83.3%) than those bearing the GA genotype (49.3%) or GG genotype (56.5%). Conclusions The results of the present report suggest that the CD86 AA genotype at + 1057 position could be involved in liver transplant acceptance, given that its presence is related to a decrease of acute rejection frequency and to a graft survival increase.

The Influence of Late Acute Rejection Episodes on Long-Term Graft Outcome After Liver Transplantation

Acute cellular rejection represents the most important single risk factor for the occurrence of chronic rejection after organ transplantation. We correlated late acute rejections with the occurrence of chronic graft failure after liver transplantation. We followed 1426 liver transplants for late acute rejection episodes defined as occurring >3 months after OLT. The overall incidence of chronic rejection in our patient population was 3.7%. In summary, we observed a predictive increase of transaminase levels prior to routine biopsies among patients with histologic evidence of late acute rejections. In contrast to other organ systems, late acute rejection episodes were not associated with the occurrence of chronic graft deterioration in liver grafts.

Thymoglobulin Versus ATGAM Induction Therapy in Pediatric Kidney Transplant Recipients: A Single-Center Report

Induction immunosuppressive therapy with the anti-T-cell antibody Thymoglobulin decreases the incidence of acute rejection in adult kidney transplant (KTx) recipients, but limited data are available for pediatric KTx recipients. We conducted a historical cohort study to compare rates of survival, rejection, and infection in pediatric (age <19 years) KTx recipients who received induction therapy with polyclonal antibody, ATGAM (n=127) or Thymoglobulin (n=71), from December 1, 1992, to January 31, 2003. Maintenance immunosuppression included cyclosporine, azathioprine or mycophenolate mofetil, and prednisone. Mean follow-up was 90+/-25 months for ATGAM recipients and 32+/-15 months for Thymoglobulin recipients. Overall, the incidence of acute rejection was lower in Thymoglobulin recipients versus ATGAM recipients (33% vs. 50%, P=0.02). Epstein-Barr virus (EBV) infection was higher in Thymoglobulin recipients versus ATGAM recipients (8% vs. 3%, P=0.002). But the two groups did not significantly differ in patient and graft survival rates, incidence of chronic rejection, EBV lymphoma, or other infection. Thus, Thymoglobulin induction was associated with a decreased incidence of acute rejection and an increased incidence of EBV infection in pediatric KTx recipients. EBV monitoring should be performed in EBV-naive recipients receiving Thymoglobulin.

B7‐H3 promotes acute and chronic allograft rejection

The B7 homolog B7-H3 is important for the regulation of immune responses though its functions in vivo are controversial. We report the first clinical and experimental data concerning expression and function of B7-H3 in alloresponses. Immunohistological and molecular analyses showed B7-H3 expression by cells mediating rejection of human and mouse allografts. To analyze the significance of B7-H3 in rejecting allografts, we generated B7-H3-/- mice and showed that targeting of B7-H3 was synergistic with other forms of immune modulation; e.g. a regimen of rapamycin gave 12-14 days of survival in wild-type controls but led to permanent cardiac and islet allograft survival in B7-H3-/- mice. Cardiac allografts in treated B7-H3-/- mice showed markedly decreased production of key cytokine, chemokine and chemokine receptor mRNA transcripts as compared to wild-type controls. The incidence of chronic rejection in two different cardiac allograft models was also inhibited in B7-H3-/- as compared to wild-type recipients. Lastly, in addition to the expected antigen-presenting cell expression of B7-H3, CD4 and CD8 T cells showed B7-H3 induction upon cell activation, and both dendritic cell- and T cell-expressed B7-H3 each enhanced T cell proliferation in vitro and in vivo. We conclude that B7-H3 promotes T cell-mediated immune responses and the development of acute and chronic allograft rejection.

Urolithiasis after Kidney Transplantation in Pediatric Recipients: A Single Center Report

Urolithiasis occurs in approximately 6% of adult kidney transplant (KTx) recipients. Limited data are available on urolithiasis after pediatric KTx. We report the incidence, management of, and risk factors for stone development in children after KTx. We reviewed the medical records of 399 children who received KTx at our center between September 1986 and January 2003. Transplant outcomes were compared in stone formers and controls. Twenty (5%) patients, age 9+/-5 (X +/- SD) years, developed stones over the follow-up period (74+/-53 months). Time to stone presentation was 19+/-22 months post-KTx. Presenting features were urinary tract infection (UTI), 8; gross hematuria, 5; microscopic hematuria, 2; dysuria without infection, 6; difficulty voiding, 3; and silent stones, 2. Stones were removed by cystoscopy in 11 (55%) patients. Stone composition was determined in 11 patients: calcium phosphate (55%), calcium oxalate (18%), mixed calcium phosphate and oxalate (9%), and struvite (18%). Factors predisposing to stones in study patients included suture retention (n = 4), elevated urinary calcium excretion (n = 2), recurrent UTI (n = 2), and urinary stasis (n = 2). The incidence of UTI was higher (P = 0.003) and of acute rejection was lower (P = 0.02) in stone patients compared with controls. Patient and graft survival rates and the incidence of chronic rejection did not significantly differ between study patients and controls (P = NS). Urolithiasis is not uncommon in pediatric KTx patients. Factors associated with post-KTx urolithiasis include retention of suture material, recurrent UTI, hypercalciuria, and urinary stasis. Treatment is associated with excellent outcome and low recurrence rate.

ENDOTHELIAL NITRIC OXIDE SYNTHASE AND ANGIOTENSIN II TYPE 1 RECEPTOR GENE POLYMORPHISMS CAN INFLUENCE CHRONIC INFLAMMATORY STATE IN RENAL TRANSPLANT PATIENTS

Abstract Serum C-reactive protein (CRP) is a sensitive indicator of inflammation. Because increasing evidence shows the effect of endothelial nitric oxide synthase (eNOS) and the renin–angiotensin system on inflammation, we studied the association among chronic inflammation, chronic rejection, and gene polymorphisms of angiotensin II type 1 receptor (ATR1) and eNOS in renal transplant patients. Methods Data from 80 male and 35 female renal transplant patients (mean follow-up, 60.6 ± 22.2 months) were analyzed. Patients were grouped according to posttransplant CRP levels: group 1 patients ( n = 46) had normal CRP levels (CRP n = 26), and group 3 had persistently elevated ( n = 43) CRP levels. eNOS and ATR1 gene polymorphisms of the groups and the impact of posttransplant CRP response on development of chronic rejection and graft failure were analyzed. The bb allele of the eNOS gene was found in 74% of the patients, whereas 62% had AA allele of ATR1. Results Patients in group 1 had a significantly lower incidence of chronic rejection and graft failure when compared with patients in groups 2 and 3 ( P = .05 and P = .02 respectively). The bb allele of the eNOS gene predominated in group 1 ( P = .02); presence of non-AA allele of ATR1 1166 gene was found less frequently in group 3 ( P = .01). Conclusions The presence of the bb allele of the eNOS and non-AA allele of ATR1 1166 gene is associated with an anti-inflammatory state and may predict renal outcome in transplant patients.

Basiliximab-Chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study

Basiliximab is a monoclonal antibody that binds to the α subunit (CD 25) of the interleukin-2 receptor of activated T lymphocytes. The advantage of basiliximab in organ transplantation is the reduce possibility to calcineurin inhibitor dosages to avoid nephrotoxicity. Basiliximab has significantly reduced the incidence of acute rejection (AR) in renal transplant recipients; however, the results are uncertain in liver transplantation (LT). The objective of this investigation was to assess the effect of basiliximab to prevent AR in the first 6 months after pediatric LT. From March 2000 to October 2001, 32 recipients of a primary orthotopic cadaveric or living donor LT were given basiliximab by intravenous bolus injection on the day of transplantation (day 0) and on day 4. Four children who received one dose were excluded from the study. The rate and the intensity of AR episodes, the incidence of chronic rejection, serum creatinine level, incidence of infections, adverse side effects, and daily oral dosage of cyclosporine (Neoral) to maintain the target blood level of 850 to 1000 mg/dL at C2, 2 hours after the administration, were analyzed in the remaining 28 recipients. Results were compared to those obtained from a matched historical group ( n = 28) of similar age, weight, and hepatic diseases distribution. None of the analyzed parameters was statistically significant ( P > .05) except for the daily oral dose of cyclosporine (7 to 13 mg/kg/dose, P < .05). In our series, the addition of basiliximab to the immunosuppressive therapy did not reduce the incidence of AR in pediatric LT.

Mycophenolate mofetil: what is the evidence that it decreases chronic rejection?

Purpose of review The question addressed in the title of this paper iscontroversial because of the lack of clear data and conflicts due to the paucity of existing data. Therefore, the purpose of this review is to summarize some of the relevant clinical and experimental findings. Recent findings It has recently been suggested by a retrospective analysis of the United States Renal Data System data that mycophenolate mofetil (MMF) therapy is associated with a significant decrease in the relative risk of chronic allograft failure. Chronic allograft failure, however, may differ from a biopsy-proven chronic allograft nephropathy (CAN). MMF has been shown to inhibit antibody formation in animal models, and alloantibody does correlate with development of chronic allograft injury. Hence, there is compelling rationale to expect MMF therapy to decrease the incidence of chronic rejection of allografts in humans. Nevertheless, current data are only provocative and suggest a need for further direct study of this important question. Summary In summary, it is unclear at this time whether MMF has a direct salutary or deleterious effect on CAN in human renal transplantation.

Effect of Donor/Recipient Body Weight Mismatch on Patient and Graft Outcome in Living-Donor Kidney Transplantation

Background/Aims: There have been conflicting reports showing that kidneys from small donors may be at risk for graft loss if they are transplanted into large recipients. The aim of this work was to examine the donor/recipient body weight ratio (D/RBWR) on patient and graft outcome. Methods: During the period from January 1990 to January 2002, 856 kidney transplants were performed. Of these, 776 kidney transplant recipients were selected after exclusion of pediatric, second transplant patients and those with a body mass index of ≧35. All patients achieved a minimum follow-up of 1-year. According to D/RBWR, patients were divided into 3 groups: low (≤0.9), medium (0.91–1.2) and high (≧1.2). Data were collected on graft function, acute and chronic rejection, post-transplant complications, and 1- and 5-year graft and patient survival. Results: There was a statistically significant increase in the incidence of chronic rejection, post-transplant hypertension and diabetes mellitus in the low group. The incidence and frequency of acute rejection episodes were nearly the same in the 3 groups. Graft function, estimated by serum creatinine at 1 year, was significantly lower in the low group. The 5-year graft and patient survival was 71, 80, 88 and 81, 85 and 92%, in the low, medium and high groups, respectively. Conclusions: We conclude that a low D/RBWR may contribute to inferior long-term renal allograft survival. The hyperfiltration hypothesis due to low nephron mass in the low D/RBWR group may explain these findings.

Prevention of Chronic Rejection with Immunoregulatory Cells Induced by Intrathymic Immune Modulation with Class I Allopeptides

Intrathymic immune modulation with RT1.Aa allopeptides in the PVG.R8-to-PVG.1 U rat strain combination leads to long-term survival of cardiac allografts. This regimen, however, does not induce transplantation tolerance, since most long-surviving allografts undergo chronic rejection. We investigated recipients with chronic rejection for donor-specific immune nonresponsiveness and immunoregulatory cells as possible mechanisms responsible for long-term graft survival. There was a significant reduction in the proliferative response of T cells from long-term allograft recipients to donor alloantigens as compared with that of naïve T cells. Adoptive transfer of splenocytes from intrathymically manipulated primary long-term graft survivors into minimally irradiated secondary hosts resulted in indefinite survival of > 80% of allografts, providing evidence for immunoregulatory cells. Secondary recipients had total absence of donor-reactive cellular and humoral responses. Immunoregulation was also transferable from secondary to tertiary graft recipients. More importantly, there was a significant reduction in the incidence of chronic rejection in secondary hosts (> 85%) and complete prevention of acute and chronic rejection in tertiary hosts. This study demonstrates that intrathymic immunomodulation with class I allopeptides results in the generation of immunoregulatory cells that do not block chronic rejection in primary hosts where they develop, but prevent both acute and chronic allograft rejection when adoptively transferred into secondary and tertiary recipients.

The current state of, and future prospects for, cardiac transplantation in children.

During the last two decades, several advances have resulted in marked improvement in medium-term survival, with excellent quality of life, in children undergoing cardiac transplantation. Improved outcomes reflect better selection of donors and recipients, increased surgical experience in transplantation for complex congenital heart disease, development of effective surveillance for rejection, and wider choice of immunosuppressive medications. Despite all of these advances, recipients continue to suffer from the adverse effects of non-specific immunosupression, including infections, induction of lymphoproliferative disorders and other malignancies, renal dysfunction, and other important end-organ toxicities. Furthermore, newer immunosuppressive regimes, thus far, appear to have had relatively little impact on the incidence of chronic rejection. Progress in our understanding of the immunologic mechanisms of rejection and graft acceptance should lead to more targeted immunosuppressive therapy and avoidance of non-specific immunosupression. The ultimate goal is to induce a state of tolerance, wherein the recipient will accept the allograft indefinitely, without the need for long-term immunusupression, and yet remain immuno-competent to all non-donor antigens. This quest is currently being realized in many animal models of solid organ transplantation, and offers great hope for the future.

Concerns about human hand transplantation in the 21st century.

The decision to perform a human hand transplant was justified perhaps on less than an ideal scientific basis-only approximately 60 rat limb transplants and 2 primate limb transplants have survived for longer than 200 days and only 8 of 19 pig limb osteomyocutaneous transplants showed no signs of rejection at 90 days. It seems unlikely that the survival of a human hand transplant will be any better than the survival of a kidney transplant, which has a half-life of approximately 7.5 to 9.5 years. Fourteen hand transplants, however, have now been performed in 11 humans with the skin component of 1 remaining viable up to 3 years after surgery. Intermittent episodes of acute rejection seem to have been relatively simple to reverse by temporarily increasing the dose of immunosuppressive agents and steroids. Chronic rejection has occurred in 1 patient, necessitating re-amputation of the transplanted hand. Active range of motion of the digits has been surprisingly better than would have been expected based on previous results of replantation, but return of sensibility has been less than optimal. The immunosuppression has been well tolerated without any major medical problems or life-threatening episodes, but some patients have developed chronic viral and fungal infections and several have developed posttransplant diabetes. Extrapolating from the previous experience of solid-organ transplants, chronic immunosuppression may predispose a hand transplant patient to an 80% chance of developing an infection, a 20% potential risk of developing posttransplant diabetes, and a 4% to 18% potential risk of developing a malignancy. Even though there is universal agreement that composite tissue allograft transplantation will become the ultimate reconstructive option, no one can predict the eventual role of hand transplantation in the future, but perhaps an international database of these hand transplant patients should be established so that independent reviewers can more objectively evaluate their functional outcome, the incidence of chronic rejection, and the risks of long-term immunosuppression.