Alemtuzumab (Campath-1H) and Tacrolimus Monotherapy After Renal Transplantation: Results of a Prospective Randomized Trial

The lymphocyte-depleting antibody alemtuzumab was evaluated in a prospective randomized multicenter trial in deceased donor kidney transplantation.
The 65 patients in the study group received induction with alemtuzumab followed by delayed tacrolimus monotherapy, while the 66 patients in the control group were started on tacrolimus in combination with mycophenolate mofetil and steroids. Tacrolimus levels of 8–12 ng/mL for the first 6 months and 5–8 ng/mL thereafter were aimed for in both groups.
At 12 months the biopsy-proven rejection rate was 20% in the study group and 32% in the control group (p = 0.09). Patient survival at 1 year was 98% for both groups. Graft survival was 96% for the study group versus 90% for the control group (p = 0.18).
Graft function was identical in both groups. Adverse events were similar in both groups apart for more CMV infections in the study group. At the end of the first year 82% of the patients in the study group were steroid-free and 71% continued on tacrolimus monotherapy.
These results suggest that alemtuzumab induction together with tacrolimus monotherapy is at least as efficient in renal transplantation as is a tacrolimus-based triple-drug regimen with a similar safety profile but more CMV infections.     

Living Donor Renal Transplantation Using Alemtuzumab Induction and Tacrolimus Monotherapy

Alemtuzumab was used as an induction agent in 205 renal transplant recipients undergoing 207 living donor renal transplants. All donor kidneys were recovered laparoscopically. Postoperatively, patients were treated with tacrolimus monotherapy, and immunosuppression was weaned when possible. Forty-seven recipients of living donor renal transplants prior to the induction era who received conventional triple drug immunosuppression without antibody induction served as historic controls. The mean follow-up was 493 days in the alemtuzumab group and 2101 days in the historic control group. Actuarial 1-year patient and graft survival were 98.6% and 98.1% in the alemtuzumab group, compared to 93.6% and 91.5% in the control group, respectively. The incidence of acute cellular rejection (ACR) at 1 year was 6.8% in the alemtuzumab group and 17.0% (p < 0.05) in the historic control group. Most (81.3%) episodes of ACR in the alemtuzumab group were Banff 1 (a or b) and were sensitive to steroid pulses for the treatment of rejection. There was no cytomegalovirus disease or infection. The incidence of delayed graft function was 0%, and the incidence of posttransplant insulin-dependent diabetes mellitus was 0.5%. This study represents the largest series to date of live donor renal transplant recipients undergoing alemtuzumab induction, and confirms the short-term safety and efficacy of this approach.     

Laparoscopic Versus Open Renal Procurement for Pediatric Recipients of Living Donor Renal Transplantation

Despite reports demonstrating the safety of laparoscopic donor nephrectomy (LDN) for pediatric recipients of renal transplants, recent evidence has challenged using LDN for recipients 5 years of age or younger. We retrospectively reviewed the records of all pediatric recipients of living donor renal transplants from September 2000 through August 2004. We compared those who received allografts recovered by LDN (n = 34) with those recovered by open donor nephrectomy (ODN, n = 26). Outcomes of interest included operative complications, postoperative renal function, the incidence of delayed graft function or episodes of acute rejection and long-term graft function. Donor and recipient demographic data were similar for the LDN and ODN groups. Serum creatinine and calculated creatinine clearance were not significantly different between groups both in the early postoperative period and at long-term follow-up (p > 0.142). Rates of delayed graft function and acute rejection did not differ between groups. Among recipients aged 5 years old or younger stratified by donor technique (9 LDN, 5 ODN recipients), no difference was noted in graft outcomes both early and long-term (p > 0.079). At our center, pediatric LDN recipients have graft outcomes comparable to those of ODN recipients. At experienced centers, we recommend continued use of LDN for pediatric recipients of all ages.     

Three-Times-Daily Monotherapy with Tacrolimus (FK 506) in Kidney Transplantation

Background: Tacrolimus (FK 506) was introduced into organ transplantation as a powerful immunosuppressive but with several adverse effects. In fact, an appropriate protocol for using this agent has not yet been established. On the basis of pharmacokinetic studies and the reports of its administration as a continuous intravenous infusion, we designed the regimen of every eight hours in order to reduce the daily dosage.
Methods: Tacrolimus was given to nine patients in the Japanese FK506 study. Although it was discontinued in two patients within two months because of adverse effects and acute rejection, seven other patients tolerated the agent for a long period and received the drug three times a day. Concomitant prednisolone was gradually tapered and finally withdrawn in these patients.
Results: The smaller dosage of tacrolimus led to a higher trough concentration of 14.1 ± 1.6ng/mL in the three-times-a-day regimen compared with 12.7 ± 1.9ng/ml in twice-a-day therapy ( P < 0.01). The daily dosage of tacrolimus proved to be reducible even further. Our target trough concentration was decreased finally to < 5ng/mL. Concomitant prednisolone was withdrawn in all of the seven patients. The course of these patients has been uneventful for a year after withdrawal of prednisolone. Conclusion: Our regimen of three-times-a-day oral administration of tacrolimus is a likely protocol for reduction of its daily dosage, which lowers its adverse effects while maintaining its immunosuppressive action at a lower trough concentration without concomitant prednisolone.     

American Society of Transplantation Executive Summary on Pediatric Lung Transplantation

Lung transplantation in children poses distinctly different challenges from those seen in the adult population. This consensus statement reviews the experience in the field of pediatric lung transplantation and highlights areas that deserve further investigation.     

Preliminary Experience With Alemtuzumab Induction Therapy Combined With Maintenance Low-Dose Tacrolimus Monotherapy in Small-Bowel Transplantation in China

Introduction

The goal of combining alemtuzumab induction therapy with low-dose tacrolimus monotherapy in small-bowel transplantation (SBTx) is to enable improved graft acceptance without immunologic unresponsiveness caused by stronger immunosuppression regimens. Herein, we report preliminary experience using this protocol in 5 patients who underwent SBTx in China.

Methods

Patients received methylprednisolone sodium succinate (Solu-Medrol), 1 g, followed by alemtuzumab infusion, 30 mg, during SBTx and another gram of prednisolone before reperfusion. Tacrolimus monotherapy without steroid was used for maintenance immunosuppression. Tacrolimus trough levels were 10 to 15 ng/dL during the first 3 months, and weaned to 5 to 10 ng/mL after 3 months.

Results

Three recipients have survived for longer than 1 year; 1 patient is currently alive at 9 months, and another at 5 months post-SBTx. Grafts in these 5 recipients achieved excellent function, and in all patients, total parenteral nutrition was discontinued at 2 to 3 weeks postoperatively and normal oral intake was resumed. One recipient died at 13 months post-SBTx of severe rejection; the condition of the other 4 recipients who were still alive was good. Pathologic analysis of ileoscopic biopsy specimens revealed 4 episodes of indeterminate to mild acute cellular rejection (ACR) at 1 to 3 months, 3 episodes of indeterminate to mild ACR at 4 to 6 months, 3 episodes of moderate ACR at 7 to 12 months, and 1 episode of severe ACR at 13 months. All episodes of indeterminate to moderate ACR were totally resolved; only treatment of severe ACR failed. One patient experienced an episode of invasive fungal infection and another episode of cytomegaloviral infection, with total recovery after treatment.

Conclusions

Our preliminary experience in these 5 cases showed that the protocol combining alemtuzumab induction therapy with low-dose tacrolimus monotherapy without maintenance steroid therapy past-SBTx can effectively control rejection with excellent graft function. Nevertheless, close surveillance of ACR should be still performed after 6 months.     

A Randomized Double-Blind, Placebo Controlled Trial of Steroid Withdrawal after Pediatric Renal Transplantation

In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n = 73) versus continued low-dose steroids (n = 59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p = 0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p = 0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.     

Comparison of Sirolimus with Low-Dose Tacrolimus Versus Sirolimus-based Calcineurin Inhibitor-Free Regimen in Live Donor Renal Transplantation

Between May 2001 and January 2003, 132 live donor renal allotransplant recipients were included in a prospective, randomized controlled trial where they were divided into two groups. All patients received steroids and basiliximab induction therapy. For maintenance immunosuppression, tacrolimus and sirolimus were used in group A. In group B, mycophenolate mofetil (MMF) and sirolimus were utilized. Patients were followed up for a minimum of 24 months. One-year patient and graft survival rates were not significantly different between group A (96.9%, 92.3%) and group B (100%, 98.4%), respectively. However, the incidence of biopsy-proven acute rejection was less in group B but the difference was not statistically significant (13.5% vs. 18.5% in group A). Statistically significant better renal function was encountered among group B patients at two years post-transplantation as measured by serum creatinine (1.25 vs. 1.43 mg/dl; P = 0.017) and calculated glomerular filtration rate (GFR) (94.9 vs. 79.6 ml/min; P = 0.005). One year protocol biopsies showed insignificant differences relative to chronic allograft damage index (CADI) between either group (Group A: 2.41 vs. Group B: 2.69; P = 0.436). Conclusion: Similar outcome was noted among patients in whom calcineurin inhibitors were not included in their immunosuppressive regimen. The long term impact of this observation on graft survival and function needs longer follow up.     

儿童肾移植的临床特点(附22例报告)

目的:探讨儿童肾脏移植的手术、围手术期处理及免疫移植剂应用的特点.方法:对我院22例儿童尿毒症患者行肾移植术,尸体肾移植21例,活体亲属供肾的肾移植1例.供肾动脉与受者的髂总动脉吻合8例,供肾动脉与受者的髂外动脉吻合3例,供肾动脉与受者的髂内动脉吻合11例.免疫抑制剂方案:7例为CsA加Aza加Pred;9例为CsA加MMF加Pred;6例为FK506加MMF加Pred.结果:1、3、5年人/肾存活率分别为 96.6%/ 94.8%, 88.2%/ 81.8%, 82.5%/ 76.3%;急性排斥反应、急性肾小管坏死发生率各为 18.1%;术后免疫抑制剂每千克体重剂量较成人显著高.结论:良好的组织配型、成功的手术和正确的围手术期处理,对患者相当重要;加强随访,提高患儿的依从性.     

Conversion of Twice‐Daily Tacrolimus to Once‐Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

The pharmacokinetics, efficacy and safety of once‐daily tacrolimus formulation (Tac‐OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice‐daily tacrolimus formulation (Tac‐BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac‐OD on a 1:1 basis and maintained on a once‐daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C₀ concentrations (4.10 ± 1.16–3.53 ± 1.10 ng/mL, p = 0.004), and AUC_0–24 (151.8 ± 41.6–129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac‐OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac‐BID can be safely converted to Tac‐OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

     

Pediatric Transplantation in the United States, 1997–2006

This article represents the sixth annual review of the current state of pediatric transplantation in the United States from the Scientific Registry of Transplant Recipients (SRTR). It presents updated trends, discussion of analyses presented during the year by the SRTR to the committees of the Organ Procurement and Transplantation Network (OPTN) and discussion of important issues currently facing pediatric organ transplantation. Unless otherwise stated, the statistics in this article are drawn from the reference tables of the 2007 OPTN/SRTR Annual Report. In this article, pediatric patients are defined as candidates, recipients or donors aged 17 years or less. Data for both graft and patient survival are reported as unadjusted survival, unless otherwise stated (adjusted patient and graft survival are available in the reference tables). Short-term survival (3 month and 1 year) reflects outcomes for transplants performed in 2004 and 2005; 3-year survival reflects transplants from 2002 to 2005; and 5-year survival reports on transplants performed from 2000 to 2005. Details on the methods of analysis employed may be found in the reference tables themselves or in the technical notes of the 2007 OTPN/SRTR Annual Report, both available online at http://www.ustransplant.org .     

Combined Pancreatic Islet and Kidney Transplantation in a Child With Unstable Type 1 Diabetes and End‐Stage Renal Disease

Islet transplantation after successful kidney transplantation is a recognized treatment for adults with diabetes and end‐stage renal disease (ESRD), but has not been considered an option in the pediatric population. To our knowledge, we report the first combined islet and kidney transplant in a child. The patient was born with bilateral renal hypoplasia and was diagnosed with type 1 diabetes mellitus at age 13 months. He had erratic glycemic control and hypoglycemia unawareness. At 6 years of age, the child safely underwent simultaneous islet and live donor kidney transplantation. Although function of the islet graft was transient, the combined transplant provided significant benefits in terms of glucose control and overall growth and development. Such an approach represents a viable treatment option for pediatric patients with ESRD and unstable diabetes.     

Renal allograft immunosuppression

The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli--Bowman capsular thickening and global glomerular sclerosis--were also less frequent in the triple therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mycoplasma hominis Septic Arthritis in a Pediatric Renal Transplant Recipient: Case Report and Review of the Literature

Septic arthritis (SA) typically occurs in young children, often from Staphylococcus. With chronic immunosuppression, however, pathogens may be atypical. A 15-year-old African-American female developed Mycoplasma hominis SA in her right hip 2 months following cadaveric renal transplant (Tx). Her presentation was subtle and indolent, without fever or leukocytosis. Although reported in adult Tx recipients, M. hominis infections have not been described in pediatric recipients. Early immunosuppression (basiliximab, prednisone, tacrolimus, mycophenolate mofetil and Thymoglobulin) may have increased her susceptibility to M. hominis. Optimal therapy for M. hominis SA is not well established and relapses occur. This patient underwent joint incision and drainage, treatment for 8 weeks with doxycycline and levofloxacin guided by in vitro sensitivities, and a reduction in immunosuppression. She has been free of ongoing infection for 3 years with stable graft function (Cr 1.1 mg/dL) on moderate immunosuppression with prednisone, tacrolimus and MMF.     

A Synergistic Effect Between PG490-88 and Tacrolimus Prolongs Renal Allograft Survival in Monkeys

This study was undertaken to determine if PG490-88 and tacrolimus (Tac) act synergistically to prevent renal allograft rejection in monkeys and to explore possible mechanisms of synergy between these agents. MHC-mismatched renal allografts were transplanted into cynomolgus monkeys after bilateral nephrectomy. Recipients were divided into the following groups: (i) no treatment; (ii) PG490-88 (0.03 mg/kg); (iii) Tac (1 mg/kg); (iv) PG490-88 (0.01 mg/kg) + Tac (1 mg/kg) and (v) PG490-88 (0.03 mg/kg) + Tac (1 mg/kg). Through synergy PG490-88 and Tac inhibited anti-CD3/PMA-induced T-cell proliferation and IFN-gamma expression in vitro. Tac monotherapy only marginally prolonged survival (27 +/- 3.2 days), while the combination of PG490-88 and Tac significantly prolonged graft survival to a median of 99 days (PG490-88 at 0.03 mg) and 38.5 days (PG490-88 at 0.01 mg/kg). Prolonged survival correlated with inhibited IgM production as well as reduced T-cell infiltration, IL-2 protein expression and NF-AT/NF-kappaB activity. We conclude that PG490-88 and a subtherapeutic dose of Tac significantly prolong renal allograft survival in monkeys through the synergistic inhibition of T-cell activation and a decrease in IFN-gamma production and NF-AT/NF-kappaB activity.     

Monozygotic Transplantation: Concerns and Opportunities

We describe the case of a 24‐year‐old female with end‐stage renal disease from focal segmental glomerulosclerosis (FSGS) diagnosed at age 16, who underwent monozygotic triplet transplantation at age 21 from her sister. Monozygosity was established by buccal smear DNA PCR amplification using short tandem repeat ( 1 ) profiling for 16 genetic alleles. All immunosuppression was discontinued by 1 month posttransplant. To evaluate the use of immunosuppression in HLA identical monozygotic transplantation, we interrogated the OPTN (Organ Procurement Transplant Network) database for all transplants conducted from 1987 to 2006. We identified 194 probable identical twin transplantations based on age, gender, race, ethnic category, blood type and HLA match. We evaluated the use of various immunosuppressive agents at discharge, 6 months and 1, 2 and 3 years after transplantation. Seventy‐one percent of these patients at discharge and 34% at the end of 1 year were on immunosuppression. At discharge 61% received steroids and 30% received calcineurin inhibitors and 66% of these remained on calcineurin inhibitors at 1 year. Renal function was superior among those not maintained on immunosuppression. Thus, monozygotic transplantation confers an immunologic advantage that allows immunosuppression elimination despite a risk of recurrent glomerular disease such as FSGS with appropriate evaluation and management.     

Subclinical Inflammation and Chronic Renal Allograft Injury in a Randomized Trial on Steroid Avoidance in Pediatric Kidney Transplantation

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid‐free (SF; n = 60) or steroid‐based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow‐up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody‐mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.     

Changes in Pediatric Renal Transplantation After Implementation of the Revised Deceased Donor Kidney Allocation Policy

In October 2005, the United Network for Organ Sharing (UNOS) implemented a revised allocation policy requiring that renal allografts from young deceased donors (DDs) (<35 years old) be offered preferentially to pediatric patients (<18 years old). In this study, we compare the pre- and postpolicy quarterly pediatric transplant statistics from 2000 to 2008. The mean number of pediatric renal transplants with young DDs increased after policy implementation from 62.8 to 133 per quarter (p < 0.001), reflecting a change in the proportion of all transplants from young DDs during the study period from 0.33 to 0.63 (p < 0.001). The mean number of pediatric renal transplants from old DDs (≥35 years old) decreased from 22.4 to 2.6 per quarter (p < 0.001). The proportion of all pediatric renal transplants from living donors decreased from 0.55 to 0.35 (p < 0.001). The proportion from young DDs with five or six mismatched human leukocyte antigen (HLA) loci increased from 0.16 to 0.36 (p < 0.001) while those with 0 to 4 HLA mismatches increased from 0.18 to 0.27 (p < 0.001). Revision of UNOS policy has increased the number of pediatric renal transplants with allografts from young DDs, while increasing HLA-mismatched allografts and decreasing the number from living donors.