Lower Incidence Of Acute Rejection Research Articles

Study 2: steroid withdrawal in African American kidney transplant recipients receiving sirolimus and tacrolimus: analysis of renal function beyond 1 year

S teroid withdrawal in African American kidney transplant recipients has traditionally resulted in high rates of acute rejection. Conversely, we have previously reported excellent short-term outcomes among 30 African Americans withdrawn from prednisone between 3 and 5 months after primary kidney transplantation and maintained on a regimen of concentration-controlled doses of sirolimus (SRL) (target trough concentrations, 10-15 ng/mL) and tacrolimus (TAC) (target trough concentrations, 5-8 ng/ mL). After a mean follow-up of 14 months, only 2 of 30 patients (6.7%) experienced biopsy-proven acute rejection and 90% of patients remained steroid-free. This cohort of patients has now been followed up for 12 to 35 months (mean, 24 7 months). Acute rejection, prompting renewal of steroid therapy, has occurred in 4 patients (13%), including episodes in 2 patients occurring at 15 and 16 months, respectively, after steroid withdrawal. Two of the 4 episodes of acute rejection occurred in the setting of prolonged delayed graft function and were discovered on “protocol” biopsies. The other 2 episodes were related to gross noncompliance. There has been a single graft loss and no deaths (97% graft survival, 100% patient survival). Prednisone was renewed for medical reasons unrelated to rejection in 2 other patients, including 1 with a late case of hemolytic uremic syndrome and another with intractable bone pain prompting discontinuation of TAC. At last follow-up, 24 of 30 patients (80%) remained steroid-free. For the cohort of 29 patients with functioning grafts, serum creatinine concentration increased from 1.4 0.44 mg/dL before steroid withdrawal to 2.2 1.8 mg/dL at last follow-up (P .028). For the 24 patients who remain off prednisone and free of clinically overt acute rejection, serum creatinine concentration has increased from 1.44 0.4 to 1.65 0.4 mg/dL (P .006). Multiple linear regression was performed to determine the influence of age, gender, body weight, delayed graft function (occurring in 24% of patients), acute rejection, pretransplant panel reactive antibody (ranging from 0% to 84%), and the number of human leukocyte antigen mismatches (A, B, and DR loci) on serum creatinine level at last follow-up. For the entire cohort, independent correlates of serum creatinine level at last follow-up were acute rejection (P .0001), pretransplant panel reactive antibody levels (P .05), and body weight (P .004). For the steroid-free group, the independent correlates of serum creatinine at last follow-up were delayed graft function (P .05), panel reactive antibody (P .05), and male gender (P .003). Conclusion: Results of this uncontrolled study suggest that use of SRL and TAC allows the withdrawal of steroid therapy in African American kidney transplant recipients with a low incidence of acute rejection up to 3 years after transplantation. However, steroid withdrawal may be associated with longterm deterioration of renal function, even in the absence of clinically overt acute rejection. In addition to acute rejection, delayed graft function and pretransplant sensitization contribute to declining renal function over time and might be considered relative contraindications to withdrawing steroid therapy from African American kidney transplant recipients in future studies. From the Departments of Medicine and Surgery, University Hospitals of Cleveland, Cleveland, OH. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.029

Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption.

There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0-4) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C2) provides the optimal single-time point marker for AUC0-4. Clinically, dose management based on C2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes. This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant. Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2 correlated more closely with AUC0-4 and with AUC0-12 than did the pre-dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 microg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 microg/mL (P < 0.05). Binary logistic regression analysis showed that C2 level >1.7 microg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0-4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR. C2 level provides a more reliable marker for CsA exposure than C0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2 target of 1.7 microg/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit.

Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation.

The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients. The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii. A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections. We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Increased expression of cytotoxic effector molecules: different interpretations for steroid-based and steroid-free immunosuppression.

Cytotoxic T lymphocyte (CTL) effector molecules have been studied as markers of acute rejection in renal allograft recipients on steroid-based immunosuppression. We hypothesized that basal CTL gene expression may vary with time post-transplantation as well as with different immunosuppression protocols (steroid-based or steroid-free). Variations in CTL gene expression may thus impact on the ability to predict acute allograft rejection. We used the non-invasive method of quantitative competitive-reverse transcription-polymerase chain reaction (QC-RT-PCR) to quantify the amounts of CTL effector molecules (granulysin, GL; perforin, P; granzyme B, GB) in serial peripheral blood lymphocyte (PBL) samples from steroid-free and steroid-based adult and pediatric renal allograft recipients. Patients on both protocols were clinically monitored by protocol biopsies at 1, 3, 6, and 12 months post-transplantation and for graft function at 1 yr post-transplantation in a separate clinical study. Steroid-free patients with stable graft function showed an increase in GL, P, and GB gene expression over time post-transplantation with the increase being seen largely by the first post-transplant month. A further increase in GL expression was noted at the end of the first post-transplant year in the absence of acute rejection, whereas GB and P levels were unchanged. At comparative time-points post-transplantation, CTL genes were found to be higher in steroid-free patients with stable graft function, compared to steroid-based recipients with either clinically stable graft function or acute rejection. This study suggests that levels of CTL gene expression, although important in a steroid-based regimen to monitor the risk of acute rejection, may not be similarly applied in patients on steroid-free immunosuppression. The early increase in levels seen in steroid-free patients appears to correlate with the total absence of steroids. As steroid-free patients seem to have a lower incidence of acute rejection and better long-term graft function at 1 yr, the early increase in CTL genes in the absence of acute rejection may suggest an early adaptive immune activation response, promoting early graft acceptance in this protocol.

Factors contributing to long graft survival in non-heart-beating cadaveric renal transplantation in Japan: a single-center study at Kitasato University.

A total of 107 cadaveric kidneys from non-heart-beating donors (NHBDs) have been transplanted between 1974 and 2000 at Kitasato University Hospital, Sagamihara, Japan. The patient survival of the 107 recipients of cadaveric renal transplants at 1, 5 and 10 yr was 0.857, 0.770 and 0.746, respectively. The 50% graft survival was 3.8 yr. The 5 and 10-yr graft survival was 0.457 and 0.337, respectively. Twenty of the 107 recipients of non-heart-beating cadaveric renal transplantation had graft survival longer than 10 yr. Of these 20 patients, 14 survivors still maintain functioning renal grafts and two died with functioning graft, although the remaining four reverted to dialysis because of chronic rejection and nephropathy. The average graft survival of these 20 patients at the time of study was 13.3 yr and the longest was 21.4 yr. The average serum creatinine level at 10 yr after transplantation was 1.63 mg/dL, almost identical to that at 5 yr post-transplant. The donors aged on average 40.2 yr; 13 were male and seven were female. The youngest donor was 9-yr-old and the oldest was 66. The graft survival was significantly better in the group with donor age younger than 55 yr (Log-rank: p=0.007). The average weight of the renal graft was not different between the long and shorter graft survival groups. The average warm ischemic time and total ischemic time were 9.7 and 539.7 min, respectively. The duration of post-transplant acute tubular necrosis averaged 9.2 days. These parameters tended to be shorter than those in recipients with graft survival >10 yr, but with no statistical significance. The mean numbers of acute rejection (AR) episode within 3 months after transplantation were 0.25 +/- 0.66 and 0.92 +/- 0.90 (p=0.020) in long survival and shorter survival groups, respectively. Long survivors had a significantly lower incidence of AR. Two of 20 cases received conventional immunosuppression with prednisolone, azathioprine and mizoribin, and 18 had prednisolone and calcineurin inhibitor (CNI). Kaplan-Meier analysis showed a significant contribution of CNI to graft survival (p=0.036). However, the graft survival reduction rate after 1 yr post-transplant did not differ between conventional and CNI immunosuppression. These data suggest that renal grafts retrieved with proper organ procurement procedures from NHBDs may survive long-term and help to overcome donor shortage.

Single centre experience with basiliximab in paediatric renal transplantation.

Introduction of IL-2-receptor antagonists has led to significantly decreasing numbers of acute rejection episodes in renal transplantation in adults. No data are available in paediatric recipients. Between 1997 and 2000, 78 renal transplantations were performed in 77 children aged 0.5-16 years. Basiliximab, cyclosporin A (CsA) and prednisolone were administered in 48 children (age 7.8 +/- 5.3 years) and compared with 29 children (age 7.3 +/- 5.2 years) receiving CsA and prednisolone only. The number of acute rejections, survival, glomerular filtration rate (GFR) and side effects were determined for 3 years after transplantation. All 77 patients survived the observation period. One year graft survival in the basiliximab group was 95%, which is similar to the comparison group (93%). Children receiving basiliximab showed a lower incidence of acute rejection than the comparison group (14% vs 34%). The calculated GFR was lower in the basiliximab group when discharging from hospital, with 51 compared with 66 ml/min/1.73 m(2) in the non-basiliximab group. This was associated with higher CsA trough levels (214 vs 174 ng/ml) in the basiliximab patients. After 1 year the GFR was comparable in both groups (58 vs 52 ml/min/1.73 m(2)). Basiliximab offers excellent allograft survival, a lower incidence of acute rejections and almost no side effects. Therefore it can be recommended for routine immunosuppressive therapy in paediatric renal transplantation.

Simple tacrolimus-based immunosuppressive regimens following renal transplantation: a large multicenter comparison between double and triple therapy

LOW incidences of acute rejection can be achieved with tacrolimus-based regimens without the need of aggressive regimens adding mycophenolate mofetil, sirolimus, or antibody preparations. In large multicenter clinical trials comparing tacrolimus-based therapies with either standard or microemulsified cyclosporine-based therapies, statistically significant lower rates of acute rejection were observed with tacrolimus treatment. In these studies, a triple-drug regimen consisting of tacrolimus, corticosteroids, and azathioprine was used. Contrary to current emphasis, we investigated whether an easy and simple dual-regimen consisting of tacrolimus and corticosteroids is as efficacious and safe as a triple-drug regimen.

Defining the Risk of Elective Cyclosporine Withdrawal in Stable Kidney Transplant Recipients

Although it is known that elective cyclosporine (CsA) withdrawal increases the risk for acute rejection, few studies have been large enough to identify risk factors for acute rejection after CsA withdrawal. We examined risk factors for acute rejection in 464 kidney transplant recipients who underwent elective CsA withdrawal. The incidence of acute rejection within 6 months of CsA withdrawal was 20/141 (14.2%) in the period January 1986 to May 1989, but only 14/323 (4.5%) since May 1989 (p = 0.0002). Among those transplanted since May 1989, the incidence was 5/20 (25%) for those with both 2 HLA-B and 2 HLA-DR mismatches, compared with only 9/298 (3.0%) for those with fewer mismatches (p < 0.0001). In Cox proportional hazards analysis, risk factors for acute rejection within 6 months, or at any time after elective CsA withdrawal, were date of transplant January 1986 to May 1989 (compared with more recently May 1989 to March 1999), younger age, obesity, as well as B and DR mismatches. Recipient race (83% were white), acute rejection during the first year before withdrawal (31%), mycophenolate mofetil (17%), and other variables failed to predict postwithdrawal acute rejection. We concluded that avoiding CsA withdrawal in the relatively small number of recipients with both 2 HLA-B and 2 HLA-DR mismatches could further reduce our already low incidence of acute rejection following elective CsA withdrawal.

Thymoglobulin induction decreases rejection in solitary pancreas transplantation.

Solitary pancreas transplants, both pancreas transplant alone (PTA) and pancreas after kidney (PAK), have higher rejection rates and lower graft survivals than simultaneous pancreas-kidney transplants (SPK). The aim of this study is to compare three different antibody induction regimens in solitary pancreas transplant recipients and to assess the role of surveillance pancreas biopsies in the management of these patients. Solitary pancreas transplant recipients between 01/98 to 02/00 (n=29) received induction with either daclizumab (1 mg/kg on day 0, 7, 14), OKT 3 (5 mg/day x0-7), or thymoglobulin (1.5 mg/kg/day x0-10). Maintenance immunosuppression was similar for the three groups. All rejections were biopsy-proven either by surveillance/protocol or when clinically indicated. The 1-year graft survival was 89.3% overall and 91.7% in the thymoglobulin group. Thymoglobulin significantly decreased rejection in the first 6 months when compared with OKT3 or daclizumab (7.7 vs. 60 vs. 50%). Acute rejections were seen on surveillance biopsies in the absence of biochemical abnormalities in 40% of patients. Thymoglobulin induction regimen led to a low incidence of acute rejection and a high rate of graft survival in solitary pancreas transplants. In addition, surveillance biopsies were useful in the detection of early acute rejection in the absence of biochemical abnormalities.

Th2 cytokine profile in infants predisposes to improved graft acceptance after liver transplantation.

The T helper cell type 1 (Th1) cytokines interleukin (IL)-2 and interferon (IFN)-gamma are mediators of acute graft rejection after liver transplantation and Th2 cytokines, such as IL-4 and IL-10, may have a protective role and correlate with graft acceptance. To test the hypothesis that infants aged <1 year have an immunological advantage with regard to graft acceptance because of a partially immature immune system with a physiological balance toward a Th2 cytokine profile, we conducted the present study. We compared the T helper serum cytokine profiles in 105 infants and children after liver transplantation with or without acute graft rejection and analyzed the normal age-distributed concentrations of T helper cytokines in 51 healthy controls. The incidence of acute graft rejection was as follows: 0 to 12 months, 26.8%; 1 to 3 years, 40.0%; and >3 years, 71.8%. There was a significantly lower incidence of acute rejection in infants 0 to 12 months of age compared with children >1 year (11/41 vs. 38/64; P=0.001). In healthy infants, significant increasing Th1 cytokine concentrations and decreasing Th2 cytokine concentrations were found with increasing age. Patients with acute rejection had significantly higher values of Th1 cytokines compared with nonrejecting subjects, who had significantly higher concentrations of Th2 cytokines. A longitudinal analysis of serum cytokines from patients showed that changes of the cytokine patterns in the follow-up did not differ significantly from preoperative values, except in the 4 weeks posttransplant. We conclude from the data that the physiological balance toward a Th2 cytokine profile of infants in the first months of life predisposes to improved graft acceptance. Transplantation of children with biliary atresia as early as possible, avoiding Th1 stimulation by recurrent infections and vaccinations, may have a positive impact on overall tolerance.

Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients

Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.

Immunosuppression in liver transplantation.

Prevention of graft rejection while minimizing morbidity remains the single most important objective in liver transplantation. Advances in immunosuppression have provided excellent patient and graft survival with relatively low incidences of acute rejection. However, it is apparent that the toxicity of the present immunosuppressive drugs accounts for much of the morbidity after transplantation. Attention is now being focused on combination drug therapies to reduce morbidity while maintaining the excellent results achieved with present immunosuppressive agents.

DACLIZUMAB INDUCTION FOR PRIMARY KIDNEY TRANSPLANT RECIPIENTS USING TACROLIMUS, MYCOPHENOLATE MOFETIL AND STEROIDS AS MAINTENANCE IMMUNOSUPPRESSION.

239 Recent reports have demonstrated the efficacy of IL2-receptor blockers in lowering the incidence of early acute rejection in cyclosporine-treated kidney recipients when compared to patients not induced with an antibody product. The current report analyzes a group of primary kidney transplant recipients who received tacrolimus (FK), mycophenolate mofetil (MMF), methylprednisolone (MP) and daclizumab induction (Group 1; n=55). This cohort was compared to a historical control group of primary kidney recipients who received FK, MMF, steroids and either OKT3 (n=62) or ATGAM (n=5) induction (group 2; n=67). Daclizumab (1 mg/kg) was given on the day of surgery, followed by every other week for a total of 5 doses. OKT3 (5mg/day) or ATGAM (10 mg/kg/day) were given for the initial 7-10 days post transplant. MMF was started on day 1 (1 gm BID) and adjusted for side effects and WBC count. FK was withheld until the serum creatinine was <4 mg/dl. Results: The groups did not differ in age, race, gender, source of organ, original disease or ABDR mismatch. Cold ischemia time was longer (p=0.03) while the PRA was lower (p=.006) in group 1 vs group 2 patients. The median initial hospital length of stay (LOS) for group 1 was 9 days (range 5-20) vs 15 days (range 9-70) in group 2 (p<0.05). The mean doses of FK (mg/kg), MMF (mg/day) and steroids (mg/kg) as well as FK blood levels and serum creatinine did not differ between groups during the first 6 months post transplant (Table). Among patients with a minimum follow-up of 6 months, there has been 1 biopsy-proven early acute rejection (AR) episode (<6 mo) in the daclizumab group (3.3%) vs 3 rejections in group 2 (4.5%) (p=NS).TableFew serious complications have occurred. Specifically, there were no lymphoproliferative disorders in either group whereas there was 1 tissue-invasive CMV infection and 4 asymptomatic CMV viremias, all confined to group 2 patients. In summary, the combination of FK, MMF, steroids and daclizumab is a safe and effective immunosuppressive regimen for primary kidney recipients, resulting in a low incidence of acute rejection and a shortening of the initial hospitalization when compared to our previous protocol. Moreover, initial hospital pharmacy charges will be reduced by replacing the cost of a 10 day course of OKT3 ($5600) with one dose of daclizumab ($1038/70 kg).

EFFICACY OF A MODIFIED DACLIZUMAB REGIMEN IN PREVENTING ACUTE REJECTION IN KIDNEY AND KIDNEY-PANCREAS TRANSPLANT RECIPIENTS.

307 Acute rejection (AR) occurs in 30 - 50% of first cadaver kidney transplant recipients receiving cyclosporine (CsA) based immunosuppressive regimens. Use of CsA in the immediate post-transplant period, in the setting of a prolonged cold ischemic time (CIT), has been reported to be associated with an increased incidence of delayed graft function (DGF). In a recent multi-center study, use of daclizumab (Zenapax®, Dczb), a monoclonal antibody directed against the Interleukin-2 receptor, together with prednisone, azathioprine and CsA, reduced the incidence of AR to 22%. Patients received five doses of Dczb (1mg/Kg) at 2-week intervals and CsA was started either before or within 24 hours of transplantation. The efficacy of shorter courses of Dczb, its use without the immediate initiation of CsA, and its use with Tacrolimus (Tac) has not been reported. We report our preliminary experience with use of Dczb in patients receiving kidney or kidney-pancreas transplants, thought to be at risk for DGF, in whom CsA or Tac was not started until improving renal allograft function was evident. Eleven patients (age 20 - 62 yrs, 5 males & 6 females, 10 whites & 1 black), receiving first cadaver kidney (N=10) or kidney-pancreas transplants, thought to at risk for DGF (CIT > 24 hrs in 7 patients (64%), non-heart beating donor in 1 patient and advanced donor age together with a long CIT in 3 patients), received 2 mg/Kg body weight of Dczb immediately prior to transplantation. All patients received prednisone and mycophenolate mofetil. Introduction of CsA or Tac was deferred until serum creatinine had declined to <50% of its pretransplant level. All patients received a second dose of Dczb (1mg/Kg) between post-operative day (POD) 5 & 9. Nine patients (82%) had 5 or more HLA mismatches. Five patients (45%) had DGF and CsA or Tac was not commenced until after the 5th POD (range 6 - 15 days). Four patients received CsA or Tac on the 2nd POD and 1 patient on the 1st POD. One patient did not receive CsA or Tac. This patient had early, severe, vascular rejection refractory to treatment with OKT3, and underwent allograft nephrectomy. Seven patients have been followed for > 120 days (range 127 - 249 days), and 3 patients have been followed for > 3 weeks (range 22 to 56 days). All have excellent allograft function (mean creatinine 1.3 mg/dl, range 0.9 - 1.6), with no episodes of rejection to date. The only complications noted in the patients with functioning allografts were CMV disease (1 patient), Candida glabrata infection in a perinephric fluid collection (1 patient) and a diabetic foot ulcer (1 patient). We conclude that Dczb used in a 2-dose perioperative regimen results in a very low incidence of AR even when CsA or Tac is not commenced in the immediate post-transplant period. This abbreviated dose regimen may simplify the use of this effective induction immunosuppressive agent.

Pediatric liver transplantation with cadaveric or living related donors: Comparative results in 90 elective recipients of primary grafts

Study design: Between July 1993 and March 1997, 110 children were listed for primary elective liver transplantation with cadaveric (Cad: n = 68) or living-related (LR: n = 42) donors. Pregraft mortality, post-transplant survival, and surgical and immunologic complications were retrospectively compared in both groups. Results: The pregraft mortality rate was 10 (15%) of 68 versus 1 (2%) of 42 in the Cad and LR groups, respectively ( P = .049). Postliver transplantation 1-year patient and graft survival rates were 87% and 75% in the Cad group (n = 49) versus 92% and 90% in the LR group (n = 41), respectively (NS). The incidence of post-transplant complications was as follows: hepatic artery thrombosis (Cad: 16%; LR: 0%, P = .020), portal vein thrombosis (Cad: 8%; LR: 2%, NS), and biliary complications (Cad: 14%; LR: 34%, P = .044). The overall incidence of acute rejection was similar in both groups; however, a lower incidence of acute rejection occurred in LR graft recipients treated with tacrolimus. Conclusions: The introduction of an LR donor liver transplantation program allowed a significant decrease in the pretransplant mortality rate, with a consequent overall improvement in patient survival compared with the Cad series. The incidence of biliary complications was higher in the LR series, whereas better human leukocyte antigen matching in this subgroup did not result in a lower rejection incidence. (J Pediatr 1999;134:280-6)

Role of HLA compatibility in pediatric liver transplantation.

The influence of HLA mismatching in liver transplantation remains controversial. To date, few studies have focused solely on the pediatric population, and none have investigated DR and DQ mismatches using molecular genotyping. We sought to investigate HLA-A, -B, -DR, and -DQ mismatches in a large series of primary pediatric liver transplant recipients. Living-related liver transplants were excluded. A total of 138 consecutive first liver transplants performed between January 1991 and July 1996 were studied. Minimum follow-up was 1 year, and both patient and graft survival rates were assessed. The incidence of the most common complications was analyzed. HLA-A and -B phenotyping was performed by complement-dependent microcytotoxicity or polymerase chain reaction (PCR)-sequence-specific primer protocols in 133 of 138 patients. HLA-DR and -DQ genotyping was performed by standard PCR-sequence-specific oligonucleotide and/or PCR-sequence-specific primer protocols in 135 patients. Overall, there was no influence of HLA mismatching on either graft or patient survival rates. However, patients with two mismatches at the A locus showed a significantly lower incidence of acute rejection than those with one A mismatch (52% vs. 72%; P < 0.03) and patients with two B locus mismatches had a better graft survival rate at 5 years than those with one mismatch (76% vs. 62%), although this was of only borderline significance (P < 0.09). No differences were found in the severity of the episodes of rejection, incidence of chronic rejection, cytomegalovirus hepatitis, and other causes of graft loss. This study indicates that HLA-A, -B, -DR, and -DQ mismatches are not detrimental in primary pediatric liver transplantation.

Low Incidence of Acute Rejection in Kidney Grafts Treated With Initial Quadruple Therapy: A Retrospective Analysis Comparing Two ATGs

Low Incidence of Acute Rejection in Kidney Grafts Treated With Initial Quadruple Therapy: A Retrospective Analysis Comparing Two ATGs

FK 506 and Mycophenolate Mofetil in Renal Transplant Recipients: Six-Month Results of a Multicenter, Randomized Dose Ranging Trial

The effective dose of MMF with FK 506 has not been previously studied in a prospective, randomized, controlled setting. In the present study, we evaluated two different daily doses of MMF (1 and 2 g) and compared it to the historically conventional therapy of AZA. At 6 months post-transplant, we found no significant difference in the incidence of acute rejection between the AZA group and the MMF 1 g group. However, patients who started on MMF 2 g/d had significantly delayed and lower incidence of acute rejection as compared to the other two groups. We found that patients who were initiated on MMF 2 g frequently had their dose lowered, primarily for gastrointestinal or hematologic symptoms; by 6 months after-transplant, patients in the MMF 2 g group had a mean dose of 1.5 g. It is unclear from this study if initiating patients on MMF 1.5 g in combination with FK 506 would be as effective as initiating a patient on MMF 2 g. Further studies of the combination of FK 506 and MMF in kidney transplant recipients to further define the optimal dosing regimen are warranted. In summary, the combination of FK 506 and MMF is well-tolerated, safe, and effective in cadaveric kidney transplant recipients.

Liver transplantation and bile analysis: a parallel evolution.

Liver transplantation and bile analysis: a parallel evolution.

Pediatric lung transplantation at St. Louis Children's Hospital, 1990-1995.

Although accepted therapy in adults, lung transplantation in children is less well established. Reports from the few existing pediatric centers have involved relatively small patient number. Seventy-nine patients underwent 88 lung transplant procedures at St. Louis Children's Hospital between June 1990 and August 1995. Twenty-one transplants (24%) were done in 19 infants and children under the age of 3 yr. Twelve-, 24-, and 48-mo actuarial survival for the primary transplants was 69%, 67%, and 60%, respectively. Survival improved over the course of the program: 12-mo survival for patients transplanted during the first 18 mo was 42% compared with 78% for those transplanted after December 1991. Survival of children transplanted at younger than 3 yr of age was comparable to older children and adults. However, younger children had a lower incidence of acute rejection; none developed bronchiolitis obliterans. Both graft growth and linear growth occurred. Risk factors for early mortality included presence of aortopulmonary collateral vessels and prior thoracic surgery. Risk factors for survival duration included requiring assisted ventilation at the time of transplant, continuous supplemental oxygen requirement, and presence of aortopulmonary collateral vessels. The major late complication was bronchiolitis obliterans, which occurred in 27% of patients and played a role in 64% of late deaths. Investigation of the lower incidence of acute rejection and bronchiolitis obliterans in younger versus older children may reveal important information about the etiology of this disease. The ultimate long-term success of lung transplantation will depend on identification and treatment of the mechanisms responsible. A multicenter data registry would facilitate further clinical studies of pediatric lung transplantation.