Occurrence Of Acute Rejection Research Articles

The relationship between adenosine triphosphate within CD4+ T lymphocytes and acute rejection after liver transplantation

There have been increasing interests in the relationship between CD4(+) T lymphocytes and acute rejection (AR) in transplantation. In this study, we explore the role of CD4(+) T lymphocytes after liver transplantation. From February to October 2009, 87 patients underwent liver transplantation. They were divided into the AR group and non-acute rejection (NAR) group, with 56 healthy individuals in the control group. Blood specimens were collected preoperatively and at one, two, and four wk postoperatively for all groups and also on the day when AR occurred and one wk after intravenous glucocorticoid therapy for the AR group. Adenosine triphosphate (ATP) levels were measured using the ImmuKnow™ test kits for immune cell functions. After transplantation, the ATP levels within CD4(+) T lymphocytes were significantly elevated in the two groups when compared with the preoperative levels. It peaked in the AR group and was significantly higher than that of the NAR group (p < 0.05). By ROC curve analysis, the obvious elevation of the ATP value one wk after transplantation had better sensitivity and specificity in diagnosing the AR. The ATP sensitivity rate for early AR was 85.7% and specificity rate 80.9% when the cutoff value was 407 μg/L. The ATP value collected on the day of AR occurrence has apparently positive correlation with the rejection acting index (RAI) (p < 0.01). After the intravenous glucocorticoid therapy, all the ARs were reversed and the ATP value declined significantly compared with the control group and that on the day when AR occurred (p < 0.01). During the early postoperative period (especially at first week after liver transplantation), the elevation of ATP levels within CD4(+) T lymphocytes has good sensitivity and specificity in diagnosing the AR at early stage. And the degree of AR has positive relationship with ATP value. After the intravenous glucocorticoid therapy, the obvious declination of AR might be used in evaluating the effectiveness of anti-rejection treatment.

Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes

The main cause of late morbidity and mortality after lung transplantation is bronchiolitis obliterans syndrome (BOS). This study assesses the prevalence of gastroparesis among lung-transplant recipients and its association with BOS. The files of 139 patients who underwent nuclear gastric emptying studies before and/or three and 12 months after lung transplantation were reviewed, and the correlation of gastric emptying time (GET) at each time point with the occurrence of acute rejection or BOS (stage 0p or higher) was evaluated. Delayed gastric emptying (DGE; t(1/2) > 90 min) was documented in 50% of patients before transplantation - 74% at three months and 63% at 12 months. Median pre-transplant t(1/2) was 108 min in patients who acquired BOS and 77 min in BOS-free patients (p = 0.022). Among patients with pre-transplant DGE, 58% were BOS-free at 24 months post-operatively and 37% at 36 months; corresponding rates in patients with normal motility were 78% and 63% (p = 0.084). On multiple regression analysis adjusting for other measures of upper gastrointestinal dysfunction, GET before or three months after transplantation was significantly associated with BOS (OR 1.05 [95% CI 1.01-1.09] and OR 1.001 [1.001-1.005] per minute t(1/2)). Gastroparesis is common in lung-transplant recipients and associated with the development of BOS.

Association Between Interleukin-3 Gene Polymorphism and Acute Rejection After Kidney Transplantation

Acute rejection (AR) after kidney transplantation resulting from alloimmune responses has a negative effect on graft survival. AR is mainly caused by T-cell immune responses activated by cytokines, including interleukin (IL)-2, -4, and -7. Many reports have shown that single nucleotide polymorphisms (SNPs) of these cytokines can affect the occurrence of AR. IL-3, which is secreted by activated T cells, can mediate AR. Our study sought to investigate the association between SNPs of the IL3 gene and the occurrence of an AR episode (ARE). We analyzed 3 SNPs of IL3 (rs181781, rs2073506, and rs40401) among 330 renal recipients, 60 of whom had developed an ARE. SNPs of the IL3 gene, including 1 exonic SNP (rs40401) and 2 regulatory thought to be promoter SNPs (rs181781 and rs2073506). The genotypes of 60 ARE subjects and the 270 patients without AR demonstrated a significant relationship between genotype frequencies and the SNPs. The occurrence of an ARE was associated with rs181781 (P = .041, dominant model), rs2073506 (P = .009, codominant 1 model; P = .003, dominant model), and rs40401 (P = .014, recessive model). Among haplotypes, AAT showed a significant association with ARE. (P = .0033). Our results suggest that IL3 gene polymorphisms were associated with this event.

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications.

Association of high anti-donor alloreactivity and low frequency of FoxP3-expressing cells prior to kidney transplantation with acute graft rejection

Acute rejection (AR) is an important factor for the development of chronic allograft dysfunction following kidney Tx. Identification of patients who would benefit from closer clinical surveillance to allow individual tailoring of immunosuppression and hence reducing the rate of AR is highly desired. Aim of this study was to investigate the association of pre-transplant alloreactivity and frequency of regulatory T cells (T(regs) ) with AR following living-donor kidney Tx. Peripheral blood mononuclear cells were isolated from 40 patients prior to Tx. T-cell alloreactivity against donor and third-party antigen was assessed by proliferative responses in mixed lymphocyte culture and enzyme linked immunospot technique. Pre-transplant frequency of CD4(+) CD25(+) CD127(low) FoxP3(+) T(regs) was determined by flow cytometry. Experimental data were correlated with occurrence of AR. We found that patients with rejection-free (RF) post-Tx courses showed significantly lower pre-transplant alloreactivity to donor antigen compared to individuals with borderline findings (BL) or AR. For RF patients, the proliferative T-cell responses to third-party antigen were significantly higher than for stimulation with donor cells whereas lymphocytes of the AR group showed the inverse pattern. A significantly higher expression of FoxP3 within the CD4(+) CD25(+) CD127(low) subset for RF and BL compared to the AR group was observed. In conclusion, pre-transplant anti-donor alloreactivity and FoxP3 expression within the CD4(+) CD25(+) CD127(low) subpopulation might prove useful to further define the patient's risk for AR.

Relation of ATP content in CD4+ T cells to acute rejection after liver transplantation

Objective To explore the relationship between ATP content in CD4+ T lymphocytes and acute rejection after liver transplantation(LT). Methods This study contained 77 patients who received LT from February to October 2009, They were divided into AR (acute rejection) and NAR (non-acute rejection) groups while 56 healthy people were enrolled to serve as the control group.Blood specimens were collected preoperatively and at 1, 2 and 4 weeks postoperatively. For the AR group, specimens were also collected on the day when AR occurred and 1 week after steroid bump together with that of the healthy people. ImmuKnowTM test kits for immune cell function were used to assay the ATP value. Results ATP values within CD4+T lymphocytes were elevated significantly in each group compared with those preoperatively. Peak level was reached in the AR group and was significantly higher than that of the contemporary NAR group (P＜0.05). ROC curve analysis showed that the obvious elevation of the ATP value within CD4+ T lymphocytes 1 week postoperatively had better sensitivity and specificity in diagnosing AR. The ATP sensitivity rate for early AR was 84.6 %and specificity rate 81 %. The ATP value within CD4+ T lymphocytes on the day of AR occurrence had a positive relationship with the rejection acting index(RAI), while relative index (r) was 0. 876(P＜0.05). After the steroid dump treatment, AR in all the patients was reversed and the ATP value declined significantly as compared with the control group and the day when AR occurred(P＜0. 05).Conclusion During the postoperative period, the dynamic change of ATP value within CD4 + T lymphocyte had a close relationship with acute rejection after liver transplantation. Thus, it might be used as a feasible and noninvasive monitoring index for diagnosing AR and the effectiveness of the anti-rejection treatment. Key words: Liver transplantation; Rejection; T lymphocyte; Adenosine triphosphate

Analysis of Transcriptional Factors and Regulation Networks in Patients with Acute Renal Allograft Rejection

Acute rejection (AR) remains a major clinical challenge, leading to the development of chronic renal allograft failure. The aim of the present study was to explore potential transcriptional factors and regulation networks in the disease to predict the occurrence and process of AR and understand potential strategies to prevent from the disease. Three-hundred fifty-two patients with renal failure had kidney transplantation during March 2006 and March 2010, of which 85 suffered from AR. Plasma from 13 patients with kidney transplantation was collected, of which 5 were from patients with AR and 8 from those without AR. Among the 179 proteins identified by using iTRAQ labeling and quantitative proteomic technology, 66 proteins were at least 2-fold different between patients with or without AR. The results demonstrated that the dominant processes and responses were associated with inflammation and complement activation in AR. A number of transcription factors were identified in AR patients, including nuclear factor-κB, signal transducer and activator of transcription 1, signal transducer and activator of transcription 3. The analysis of transcription regulation networks suggested that the cross-talks among these key transcription factors might contribute to the acute response and coagulation pathway. Thus, our study provides a new description and insight into the molecular events in AR and potential strategies for identifying diagnostic biomarkers.

Expanding the criteria of renal kidneys for transplantation: use of donors with acute renal failure

Increased numbers of patients waiting for renal transplantation have led to widening selection criteria for grafts. Thus, we have evaluated the outcome of transplanted kidneys procured in the presence of acute renal failure (ARF). Transplant patients (n = 52) with a kidney procured with ARF were studied. Clinical data from donors and recipients, serum creatinine (SCr), creatinine clearance [estimated glomerular filtration rate (eGFR)], cold ischaemia duration, time to urine flow recovery or renal function recovery, and the number of haemodialysis sessions, were collected retrospectively. Mean donor age was 45.7 +/- 12.7 years, and the mean SCr at the time of harvesting was 276.3 +/- 104.2 micromol/l. Recipients' mean age was 51.1 +/- 12.1 years. After transplantation, recovery of renal function was observed after 7.6 +/- 7.1 days, and required 1.9 +/- 3.0 haemodialysis sessions. SCr was 124.6 +/- 49.5 micromol/l, and eGFR was 56.2 +/- 19.8 ml/min at last follow-up. eGFR was significantly lower if the donor's death was due to stroke or cerebral haemorrhage (CH), or if the donors had previous cardiovascular disease (CVD) (P < 0.02). Patients with eGFR of <50 ml/min (n = 23) had donors who were older, and whose cause of death was more frequently related to CVD factors or to CH/stroke (P < 0.03). There were no significant differences between the two groups regarding age of recipient, gender of the donor or recipient, cold ischaemia time, occurrence of cardiac arrest, collapse or acute rejection. Linear regression analysis indicated that donor age and occurrence of acute rejection were independent factors associated with eGFR. ARF before organ procurement does not have a negative effect on subsequent renal function. However, old age, CVD risk factors or CH, and late renal function recovery after transplantation are correlated with subsequent lower renal function. Thus, renal grafts with ARF can be used for renal transplantations.

Acute Rejection Features in Dual Kidney Transplant Recipients from Elderly Donors: Comparison of Calcineurin Inhibitor-Based and Calcineurin Inhibitor-Free Immunosuppressive Protocols

Features of acute rejection in dual kidney transplant have not been studied. The aim of this study is to compare acute rejections in dual kidney transplant recipients from elderly donors on different immunosuppressive protocols. Sixty-nine patients were evaluated: 28 received calcineurin inhibitor-based (group 1) and 41 received calcineurin inhibitor-free immunosuppression (group 2). Histology of all donor kidneys was evaluated before implantation. All rejections showed tubulitis in both groups, and were classified as T-cell mediated acute rejections. Incidence and Banff grade of rejections in the two groups were not significantly different. Late rejections however, were observed in group 1 (P < 0.01) whereas steroid-resistant rejections occurred in group 2 (P < 0.03). C4d deposition was only observed in group 2. Occurrence of acute rejection was significantly associated with graft loss due to interstitial fibrosis/tubular atrophy in both groups. In group 1 mean serum creatinine levels of patients with rejections at six months and one year were higher than those of patients without rejections (P < 0.03 and P < 0.009, respectively). In group 2 they were higher at six months (P < 0.01) but not at one year. In addition, graft loss due to interstitial fibrosis/tubular atrophy occurred in 3/28 patients in group 1 (10.7%, OR= 1.95, 95%CI 1.02-3.71), and in 1/41 patients in group 2 (2.4%, OR= 0.41, 95%CI 0.07-2.24). Taken together these results suggest better renal function in patients on calcineurin inhibitor-free immunosuppression. In conclusion, acute rejections were detrimental irrespective of the type of immunosuppression, but different features were observed with each therapy. A tailored approach should be advantageous for prevention and treatment of acute rejections.

Long-Term Results of Percutaneous Bilioenteric Anastomotic Stricture Treatment in Liver-Transplanted Children

The purpose of this study was to evaluate the mid- and long-term results of percutaneous transhepatic cholangiography (PTC) and biliary drainage in children with isolated bilioenteric anastomotic stenosis (BAS) after pediatric liver transplantation. Sixty-four children underwent PTC from March 1993 to May 2008. Nineteen cholangiograms were normal; 10 showed intrahepatic biliary stenosis and BAS, and 35 showed isolated BAS. Cadaveric grafts were used in 19 and living donor grafts in 16 patients. Four patients received a whole liver, and 31 patients received a left lobe or left lateral segment. Roux-en-Y hepaticojejunostomy was performed in all patients. Indication for PTC was based on clinical, laboratory, and histopathologic findings. In patients with isolated BAS, dilation and biliary catheter placement, with changes every 2 months, were performed. Patients were separated into 4 groups according to number of treatment sessions required. The drainage catheter was removed if cholangiogram showed no significant residual stenosis and normal biliary emptying time after a minimum of 6 months. The relationship between risk factors (recipient's weight <10 kg, previous exposure to Cytomegalovirus, donor-recipient sex and weight relations, autoimmune disease as indication for transplantion, previous Kasai's surgery, use of reduced liver grafts, chronic or acute rejection occurrence) and treatment was evaluated. Before PTC, fever was observed in 46%, biliary dilation in 23%, increased bilirubin in 57%, and increased gamma-glutamyltransferase (GGT) in 100% of patients. In the group with BAS, 24 of 35 (69%) patients had histopathologic findings of cholestasis as did 9 of 19 (47%) patients in the group with normal PTC. Of the 35 patients, 23 (65.7%) needed 1 (group I), 7 needed 2 (group II), 4 needed 3 (group III), and 1 needed 4 treatment sessions (group IV). The best results were observed after 1 treatment session, and the mean duration of catheter placement and replacement was 10 months. The primary patency rate was 61.2%, and the recurrence rate was 34.3% (group I). Seven patients (7 of 35; 20%) had their stricture treated with a second treatment session (group II). The average drainage time in group II was 24 months. During a period >20 months, 4 patients (4 of 35; 11.4%) required 1 additional treatment session (group III), and 1 patient (1 of 35; 2.9%) had a catheter placed at the end of the study period (group IV). Drainage time in group I was significantly shorter than those in groups II, III, and IV (p < 0.05). There was no statistically significant relation between therapeutic response and the selected risk factors (p > 0.05). The majority of complications, such as catheter displacement and leakage, were classified as minor; however, 2 patients (5.7%) with hemobilia were noted. Complications increased according to the need for reintervention. In conclusion, balloon dilation and percutaneous drainage placement is safe and effective, and it has long-term patency for children with BAS after liver transplantation. Because of prolonged treatment time, reintervention may be necessary, thereby increasing the complication rate. Balloon dilation and percutaneous drainage placement should be considered as the first treatment option because of its minimally invasive nature.

Basiliximab as an Alternative to Antithymocyte Globulin for Early Immunosuppression in Lung Transplantation

Objective Basiliximab (BAS), an interleukin-2 monoclonal antibody, has shown promising results as induction therapy in liver and kidney transplantation. We compared the efficacy and patient tolerability of BAS and antithymocyte globulin (ATG) in lung transplantation (LTx). Patients and Methods The study included 37 patients in two groups (ATG and BAS, respectively). The indication for LTx was emphysema in 62.6% of patients in group 1 and 57.1% of patients in group 2. Mean (SD) patient characteristics compared in the two groups included age (52.0 [9.8] vs 54 [10.6] years), height (172.0 [10.1] vs 169 [7.55] cm), and weight (73.9 [15.3] vs 64.4 [14.2] kg) ( P = .049). Induction therapy after LTx in the two groups was as follows: in 16 transplantation procedures (eight single and eight bilateral) performed between April 1998 and December 2002, ATG, 3 mg/kg/d for 3 days, was administered, and in 21 transplantation procedures (15 single and 6 bilateral) performed between January 2003 and July 2005, BAS, 20 mg on days 0 and 4, was given. Dosages of cyclosporine, azathioprine, and steroids for maintenance therapy were equivalent in the two groups. We retrospectively compared patient tolerability, occurrence of acute rejection or infection (from bacteria, cytomegalovirus [CMV], or Aspergillus), and outcomes between the two groups during 2 years of follow-up. Results No cytokine-mediated reaction was observed in either group; however, there was a difference in hematologic effects. On day 2, mean (SD) platelet count was significantly lower in the ATG group at 113,500 (56,400)/mm 3 vs 151,900 (57,300)/mm 3 ( P = .046). Because of severe thrombocytopenia, three patients could not be given ATG on day 3. The overall incidence of aspergillosis (18.8% vs 19.0%) and CMV infection (31% vs 57%) was similar in the two groups. However, when the recipient was CMV-positive and the donor was CMV-negative, the there was a clear trend (33.3% vs 88.9%). The number of acute rejection episodes was similar (43.8% vs 52.4%). Survival increased by 20% in the BAS group ( P = .03). Conclusion In LTx, safety of BAS use is as good as or better than that of ATG, with no difference in acute rejection episodes or infections, with the possible exception of increased reactivation of CMV infection. Thus, BAS could be an alternative to ATG as induction therapy in LTx; however, further studies are necessary.

Predictive factors for cytomegalovirus reactivation in cytomegalovirus‐seropositive kidney‐transplant patients

The aims of the present study were to assess the incidence of cytomegalovirus (CMV) reactivation, and to determine the predictive factors for CMV reactivation in CMV seropositive kidney-transplant patients. One hundred ninety CMV seropositive kidney-transplant patients were included in this study; of these, 39 patients had received CMV prophylaxis. CMV DNAemia was assessed by real-timepolymerase chain reaction assay every 2 weeks until day 120, then every 3-4 weeks until day 180, and then every month until day 365. One hundred seven patients (56.3%) had at least one positive CMV DNAemia within the first year. The time between renal transplantation and the first positive CMV DNAemia was 59 +/- 5 days. The number of positive CMV DNAemia/patient was 3.28 +/- 0.22. CMV viral load at first positive CMV DNAemia was 704 (10-742,000) copies/ml. The donor CMV seropositivity, the absence of CMV prophylaxis, and the occurrence of acute rejection before CMV reactivation were independent factors associated with CMV reactivation within the first year after kidney transplantation. Hence, CMV reactivation is frequent after kidney transplantation. CMV prophylaxis in CMV seropositive kidney-transplant patients should be offered to avoid CMV-related side-effects.

Cold Ischemia is a Major Determinant of Acute Rejection and Renal Graft Survival in the Modern Era of Immunosuppression

The aim of our study was to examine, in a recent cohort of kidney transplant recipients who have received modern immunosuppressive therapy, the respective role of cold ischemia time (CIT) and delayed graft function (DGF) on acute rejection (AR) rates and long-term graft survival. We retrospectively reviewed the charts of 611 renal transplantations between 1996 and 2005. Most patients received a calcineurin inhibitor as maintenance therapy, either cyclosporine (43%) or tacrolimus (52%) and 76% of the patients received an antilymphocyte induction therapy. Study endpoints were DGF, first-year AR, and long-term graft survival. Uni- and multivariate analyses were performed to determine factors that may have influenced the study outcomes. DGF was observed in 16.2% of patients. Both older donor age and longer CIT were significant risk factors for DGF. DGF rates were similar whether patients received a calcineurin inhibitor before transplantation or not. AR occurred in 16.5% of grafts during the first year. Independent predictors of AR by multivariate analysis were duration of dialysis, CIT, current panel-reactive lymphocytotoxic antibody more than 5%, and the number of human leukocyte antigen-A, B, and DR mismatches. Each hour of cold ischemia increases the risk of rejection by 4%. With respect to death-censored graft survival, three pretransplant parameters emerged as independent predictors of graft loss: younger recipient age, peak panel-reactive lymphocytotoxic antibody more than 5% and longer CIT. The detrimental effect of CIT on graft survival was entirely because of its propensity to trigger AR. When AR was added to the multivariate Cox model, CIT was no longer significant whereas first-year AR became the most important predictor of graft loss (Hazards ratio, 4.6). Shortening CIT will help to decrease not only DGF rates but also AR incidence and hence graft loss. Patients with prolonged CIT should receive adequate immunosuppression, possibly with antilymphocyte preparations, to prevent AR occurrence.

KIR Gene and KIR Ligand Analysis to Predict Graft Rejection After Renal Transplantation

The identification of transplant patients at high risk for rejection after reduction of immunosuppression would allow minimization of immunosuppression and avoidance of side effects in low-risk patients. Next to T cells, innate natural killer (NK) cells may contribute to graft rejection. NK cell activation depends on the balance between activating and inhibitory signals, delivered by self-human leukocyte antigens (HLA) through binding of killer-cell immunoglobulin receptors (KIR). In transplantation, KIR and/or HLA mismatching may lead to NK cell activation. In this study, we have evaluated whether acute rejection after reduction of immunosuppression after renal transplantation was associated with peripheral blood NK cell frequencies or with predicted NK cell alloreactivity based on KIR gene and ligand analysis. HLA and KIR genotyping was used to analyze the presence of single KIR genes and haplotypes, and to predict NK cell alloreactivity based on the "missing self" and "missing ligand" hypothesis. NK cell frequencies were analyzed using flow cytometry. No association was found between NK cell alloreactivity based on KIR gene analysis or peripheral blood NK cell subset frequencies and the occurrence of acute rejection after reduction of immunosuppression. Our data suggest that in a setting where immunosuppression is reduced, prior analysis of NK cell reactivity cannot identify patients at risk for subsequent graft rejection.

Randomized Trial of Steroid-Free Induction Versus Corticosteroid Maintenance Among Orthotopic Liver Transplant Recipients With Hepatitis C Virus: Impact on Hepatic Fibrosis Progression at One Year

Due to the known high recurrence rate of hepatitis C virus (HCV) among orthotopic liver transplant (OLT) recipients who receive tacrolimus+corticosteroid maintenance, use of steroid-free induction was considered. OLT recipients with HCV were randomized to receive tacrolimus+daclizumab (steroid-free) vs. tacrolimus+corticosteroids during 1999-2001 and then tacrolimus+mycophenolate mofetil (MMF)+daclizumab (steroid-free) vs. tacrolimus+MMF+corticosteroids during 2002-2005. Patients in the steroid-free arm of both periods received no steroids except for treating biopsy-proven rejection. Primary objective was to compare mean fibrosis stage at the 1-year protocol biopsy, between the steroid-free and corticosteroid arms, stratifying by period. No noticeable differences in mean fibrosis stage between the two treatment arms, either averaging across periods (P=0.99) or during either period (P>0.35) were found. Occurrence of acute rejection during the first year was the only factor associated with a significantly increased fibrosis stage at 1 year (P=0.0003); stage > or =2 was seen in 63% (17 of 27) vs. 19% (8 of 43) of those with vs. without rejection. In addition, MMF use was associated with significantly fewer patients experiencing acute rejection during the first 6 and 12 months posttransplant (P=0.006 and 0.046). Regarding steroid-related side effects, posttransplant diabetes mellitus occurred in 10% vs. 45%, and wound infection in 6% vs. 31% of steroid-free vs. corticosteroid patients (P=0.003 and 0.01). OLT recipients with HCV tolerated the steroid-free protocol with fewer side effects; however, its use had no apparent impact on hepatic fibrosis progression. Occurrence of acute rejection was strongly associated with increased hepatic fibrosis at 1 year, and MMF use appears to have significantly reduced the rejection rate.

Kidney Transplant Rejection in Australia and New Zealand: Relationships Between Rejection and Graft Outcome

Although acute rejection rates have fallen over time, how this relates to graft outcomes is not known. Using data from the ANZDATA Registry, we examined associations of rejection within six months of transplantation with graft and patient outcomes among kidney-only transplants performed between April 1997 and December 2004 in Australia and New Zealand. Associations of biopsy histology with outcomes of the rejection episode were also examined. Outcomes were examined among 4325 grafts with 1961 rejection episodes in total. Crude rejection rates have fallen by one-third over that time, but rates of graft survival are constant. The occurrence of acute rejection was associated with an increased risk of graft loss after 6 months (HR, adjusted for donor and recipient characteristics, 1.69 [1.36-2.11], p<0.001). Late rejection (first rejection >or=90 days) was associated with higher risk of graft loss (adjusted HR 2.46 [1.70-3.56], p<0.001). Vascular rejection was also associated with a higher risk of graft loss 2.07 [95% CI 1.60-2.68], p<0.001. The occurrence of acute rejection is associated with an ongoing increased risk of graft loss, particularly if that episode occurred late or included vascular rejection. The reduced rates of rejection have not been associated with improved graft survival.

The Predictive Value of HLA-DR Matching and Cytokine Gene Polymorphisms in Renal Allograft Acute Rejection: a Living-unrelated Donor (LURD) Study.

In addition to Human Leukocyte Antigens (HLA) compatibility, gene polymorphism in cytokines might be important in the quality of allogeneic immune response. In this study HLA-DR matching and a number of cytokine gene polymorphisms have been evaluated in occurrence of acute rejection after living-unrelated donor (LURD) kidney transplantation. A total of 42 renal transplants that were performed at Hashemi Nejad Kidney Hospital (Tehran/Iran) and then followed up for 3 months post-transplantation were included in our study. Using PCR-SSP, HLA-DR alleles (DR1-18) of recipient and donor pairs and gene polymorphisms in TNF-, TGF-1, IL-10, IL-6, and IFN- of recipients were determined. Acute rejection was observed in 11(26.2%) of 42 renal recipients. The frequency of one and two HLA-DR mismatches in rejector and nonrejector groups were 2(18.2%), 9(81.8%) and 13(41.9%), 17(54.8%) respectively. HLA-DR incompatibility was not significantly higher in rejector (1.820.40) than nonrejector (1.520.57) recipients (P=0.069) and more than half of nonrejectors had completely mismatched HLA-DR antigens with their donors. Polymorphisms associated with all the cytokines mentioned above were found to have no correlation with acute rejection. Regarding to high frequency of HLA-DR mismatching in nonrejector group, we can postulate that the immunogenecity of LURD renal transplant is not similar to the cadaveric one, and predictive value of HLA-DR mismatching for acute rejection is not as reliable as in cadaveric transplant. Although, there is no doubt about influence of HLA compatibility on allograft survival. In addition, we failed to demonstrate further association between combined recipient cytokine genotypes and HLA-DR matching with acute rejection in this study. Thus, we conclude that a more detailed immunogenetic profile is necessary to predict transplant outcome or immunosuppression tailoring.

Retrospective analysis of renal transplantation outcomes in children admitted to a paediatric intensive care unit in Brazil

Renal transplantation has been described as the main treatment for children with end-stage renal disease. Traditionally, infants and small children represented a high-risk group with poor allograft survival. However, studies conducted mainly in developed countries have been demonstrated improvements in allograft survival rates. The aim of this study was to identify demographic characteristics of recipients and kidney donors and to analyse the outcomes of children who received postoperative care following renal transplantation in one Paediatric Intensive Care Unit (PICU). This retrospective study was carried out in a university hospital in Brazil. The data were collected through reviewing the follow up of medical records of recipients and kidney donors between 1988 and 2002. Chi-square or Fisher exact tests were used to analyse differences in outcome between living and donor transplants, whereas Mann-Whitney and Kruskal-Wallis tests were used to compare differences in outcome by age groups and by the number of complications affecting recipients. A total of 44 children were admitted for renal transplantation. Within this group, the median age was 10.1(+/-3.2) years, 63.6% were men and 38% were non-Caucasians. In contrast, the donor group had a median age of 17.5(+/-12.5) years, of which 51.3% were male, 56.8% were Caucasian and 70.5% were cadaver donors. The average length of PICU stay was 31.4 h, with complications being identified in the majority of the transplanted children. The occurrence of four or more complications was significantly associated with acute rejection (p= 0.009). In conclusion, the main outcomes of this study were similar to those observed in developed countries, in terms of acute rejections (52.3%), dialysis resumption (31.8%), graft loss (29.5%), chronic rejections (9.1%) and death (4.5%). Complications during PICU stay were significantly linked to the occurrence of acute rejection.

Circadian Pharmacokinetics of Mycophenolic Acid and Implication of Genetic Polymorphisms for Early Clinical Events in Renal Transplant Recipients

We investigated the mycophenolic acid (MPA) chronopharmacokinetics and the relation between MPA circadian exposure and the incidence of acute rejection (AR). The association between selected genetic polymorphisms and clinical events or MPA circadian exposure was also studied. Thirty recipients were studied one month after renal transplantation. Mycophenolate mofetil (MMF) was administered twice a day at a single dose of 0.5 g in four patients, 0.75 g in eight patients, and 1 g in 18 patients. The daytime area under the concentration-time curve (AUC0-12) was larger than the nighttime AUC0-12 (55.09 vs. 50.54 microg.hr/ml, P=0.049). The Cmax and tmax of MPA after the morning dose were respectively higher and shorter than those after the night dose. Seven patients (23.3%) had AR episodes. The MMF single dose per body weight (12.46 mg/kg in patients with AR vs. 16.99 in patients without AR), daytime and nighttime AUC0-12 (32.41 vs. 62.00 and 24.44 vs. 57.88 microg.hr/ml) and morning trough level of MPA (1.03 vs. 3.83 microg/ml) were significantly lower in patients with AR than in those without AR. The percentage of patients requiring diminished dose of MMF due to diarrhea was higher among patients with the multidrug resistance 1 (MDR1) C3435T T allele than among those with the CC genotype (P=0.049). MPA pharmacokinetics showed circadian variations, and a lower MPA AUC in both daytime and nighttime was associated with the occurrence of AR in the early stage after renal transplantation. The MDR1 C3435T polymorphism might be associated with diarrhea due to MPA.

The Efficacy and Safety of an Immunosuppressive Regimen Including the Use of Mycophenolate Mofetil and an Interleukin-2 Monoclonal Antibody in Heart Transplant Patients

Background and Objectives:An immunosuppressive regimen including the use of mycophenolate mofetil (MMF) and an interleukin-2 monoclonal antibody (IL2mAb) has shown promise to prevent acute rejection after heart transplantation. There has been a lack of report on the evaluation of the efficacy and safety of this regimen in patients receiving heart transplants in Korea. Subjects and Methods:From November 1992 to December 2003, 111 consecutive patients who had received heart transplants in our institute were classified into two groups: patients who received the immunosuppressive regimen with MMF and an IL2mAb (group A, n=51) and patients who did not receive the regimen (group B, n=60). We compared the clinical outcomes of patients in each group including the survival rate and the occurrence of acute rejection and infection at 24 months post transplantation. Results:Both drugs were tolearated in all patients except in 5 patients who complained of gastrointestinal side effects due to MMF. Despite a longer ischemic time (137.4±54.6 vs. 92.3±25.8 hours, p<0.05) and a lower serum level of cyclosporine (212.3±66.8 vs. 259.1±62.1 ng/mL, p<0.05), the rate of treatment for acute rejection was lower in group A than in group B (16% vs. 53%, p<0.05). In addition, the median time to the first treatment for acute rejection was almost twice as long for group A as for group B (91 vs. 43 days, p<0.05). The 2-year survival rate and the incidence of major infection requiring hospitalization in both groups were 94% vs. 88% and 26% vs. 21%, respectively, which were not statistically different. Conclusion:An immunosuppressive regimen including the use of MMF and an IL2mAb is efficacious and safe as a prophylaxis against acute rejection without the increased risk of major infection in patients who have received heart transplants in Korea. (Korean Circulation J 2006;36:794-801)