Outcome of Renal Transplantation in Children Given Rabbit Anti-Thymocyte Globulin (rATG) as Induction Therapy

BackgroundInduction immunosuppressive therapy is used to prevent rejection and maintain allograft function in transplantation. Rabbit antithymocyte globulin (rATG), a T-cell depleting antibody, is the most commonly used induction agent for kidney transplantation. To date there is still limited data on outcomes of pediatric kidney transplants with rATG as induction therapy.MethodsRetrospective single-center study of first-time kidney transplant recipients ≤18 years old who received rATG induction between 2005 and 2019 at the National Kidney and Transplant Institute. Data were collected up to 1 year post transplant.ResultsEleven patients were included in the study. They received rATG at 1.5 mg/kg/dose (±0.3 mg/kg/dose) once a day for 3 days. Patient survival was 100% at 6 months, and 90.9% at 1 year. Graft survival was 90.9% at 6 months, and 81.8% at 1 year. Four patients (36.4%) had a glomerular filtration rate of <60 at 1 year. One died of sepsis at 7 months. One patient (9.1%) had acute allograft rejection with recurrence of disease, C3 glomerulopathy, on day 13. A total of 3 patients (27.3%) developed leukopenia and 4 patients (36.4%) developed thrombocytopenia. The majority were anemic at baseline (9.7 mg/dL), and a significant increase in the mean hemoglobin was seen at 4 weeks (11.6 mg/dL) to 1 year (13 mg/dL). Incidence of recurrent infections was 9.1% (with culture growth) and 36.4% (no culture growth). Hypertension remained unchanged before and after transplant.ConclusionsInduction with single dose rATG at 1.5 mg/kg/dose (±0.3 mg/kg/dose) for 3 days provided effective and safe outcomes in pediatric kidney transplant patients in this study.     

Critical threshold of azathioprine dosage for maintenance immunosuppression in kidney graft recipients. Collaborative Transplant Study

BACKGROUND: There are conflicting reports in the literature concerning the efficacy of maintenance immunosuppression in renal transplantation with a regimen of azathioprine and steroids. METHODS: The daily dosage (mg/kg) of azathioprine administered 1 year after transplantation was analyzed in relation to subsequent long-term graft outcome. Transplants performed from 1985 to 1996 and reported to the Collaborative Transplant Study were analyzed. RESULTS: In patients on maintenance immunosuppression without cyclosporine, the daily dosage of azathioprine had a highly significant influence on long-term graft outcome. Patients who received > 1.5 mg/kg/ day of azathioprine had a 69% graft survival rate at 7 years, compared with a 55% rate in patients receiving 1.01-1.5 mg/kg/day (P<0.0001) and a 45% rate in patients receiving < or = 1.00 mg/kg/day (P<0.0001). This observation was valid for patients who were taken off cyclosporine during the first year as well as for patients who were treated with azathioprine and steroids (without cyclosporine) from the beginning. CONCLUSION: Maintenance immunosuppression with azathioprine and steroids results in good long-term kidney graft survival, provided azathioprine is administered at a daily dose of >1.5 mg/kg.     

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (Sangstat).

BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.     

Calcineurin inhibitor-free immunosuppression based on antithymocyte globulin and mycophenolate mofetil in cadaveric kidney transplantation: results after 5 years

Kidney grafts from suboptimal donors are more likely to suffer the nephrotoxic side-effects of cyclosporine than kidneys from standard donors. In an attempt to avoid the use of cyclosporine, we carried out a prospective study in low-immunological risk recipients of suboptimal kidneys, using an immunosuppressive protocol combining Thymoglobuline in induction with a bi-therapy of mycophenolate mofetil (MMF) and steroids. Patients with panel reactive antibodies (PRA) <50% receiving a first renal transplant from a suboptimal donor (age 50, non heart beating, arterial hypertension, or acute renal failure) or a kidney at risk of delayed graft function (DGF) because of a prolonged cold ischaemia time (CIT) of 24 h or more, were eligible for this trial. Between September 1996 and December 1999, 30 patients were enrolled for the trial and treated with MMF 2 g orally, pre-operatively, and 3 g daily, post-operatively; Thymoglobuline 2 mg/kg IV pre-operatively, 1.5 mg/kg IV the next day, and for doses of 1 mg/kg IV given on alternate days; and prednisolone 0.25 mg/kg per day, reduced progressively from the end of the first month to 0.1 mg/kg per day by 3 months post-transplant. Cyclosporine was added only if rejection grade II or higher, or a reduction in MMF below 1 g daily, occurred. Ten patients (30%) suffered from DGF, and one kidney suffered primary non function. Seven patients (24%) suffered acute rejection (six were biopsy proven, 3 grade I and 3 grade II). MMF dosage was reduced in 28 patients because of adverse events, and calcineurin inhibitors were introduced in 16 patients. There were 14 episodes of opportunistic infection (cytomegalovirus (CMV 10), Herpes zoster 2, Listeria monocytogenes 1, Pseudomonas aeuruginosa 1), and 7 malignancies (skin 2, thyroid 1, lung 1, Kaposi's sarcoma 2, post-transplantation lymphoproliferative disorder 1). Mean serum creatinine was 178, 199, 213, and 218 mol/l at 1, 2, 3 and 5 years after transplantation, respectively. Actuarial patient and graft (after censoring for death) survival was 94% and 83% after 1 year and 79% and 65% after 5 years, respectively. These results show that with the combination of MMF, Thymoglobuline and steroids the use of cyclosporine can be delayed, and in a few cases completely avoided, with good efficacy in terms of prevention of rejection and recovery of renal function. Regardless of acceptable patient and graft survival, side-effects of MMF at the doses used in this protocol were common and led to overimmunosuppression in the long-term. Starting MMF at low dose, MPA monitoring and probably CMV prophylaxis may improve the results of this regimen.     

Low dose antithymocyte globulins in renal transplantation: daily versus intermittent administration based on T-cell monitoring

BACKGROUND: Despite the long history of use of antithymocyte globulins (ATG) in renal transplantation, ideal doses and duration of ATG administration based on the monitoring of T lymphocytes have yet to be defined. METHODS: Two immunosuppressive regimens based on low-dose rabbit ATG (Thymoglobuline; Imtix-Sang-stat, Lyon, France) were assessed during the first year after transplantation: daily ATG (DATG; n=23) where 50 mg of ATG was given every day and intermittent ATG (IATG; n=16) where similar doses of ATG were given for the first 3 days and then intermittently only if CD3+ T lymphocytes (measured by flow cytometry) were > 10/mm3. Both groups received steroids, azathioprine, and cyclosporine. RESULTS: ATG-induced depletion was similar for peripheral blood lymphocytes and T cells in both groups: it began at day 1 after transplantation, was submaximal at day 3, and reached maximum intensity between days 6 and 8, from which time cell counts progressively increased. However, T-cell depletion was still present at day 20. The total ATG dose per patient (381.5+/-121 vs. 564+/-135 mg/patient) and the mean cumulative daily dose of ATG (0.60+/-0.17 vs. 0.80+/-0.14 mg/kg/day) were significantly lower in the IATG group (P=0.0001 and 0.0006, respectively). The overlap of ATG and cyclosporine treatment was 6.7+/-3 vs. 7.4+/-4.3 days (P=NS), and the mean duration of ATG therapy was 11.3+/-3.2 vs. 11.6+/-2.7 days in the IATG and DATG groups, respectively (P=NS). ATG was given in an average of one dose every 1.6 days in the IATG group compared with one dose daily in the DATG group (P=7 x 10(-7)). There was no significant difference in renal graft function, the number of acute graft rejections, or ATG-related side effects and complications. Despite the daily immunological follow-up, there was a net saving of $760/patient in the cost of treatment in the IATG group. CONCLUSION: IATG had the advantage of a reduction in the dose of ATG and in the cost of treatment, while offering similar T-cell depletion and effective immunosuppression. This approach could be proposed as an induction protocol, particularly for patients with poor graft function in whom cyclosporine introduction has to be delayed or those with increased risk of cytomegalovirus infections or secondary malignancies.     

Tonsillectomy in the treatment of pediatric Henoch-Schönlein nephritis

The exact pathophysiology of HSN remains to be elucidated. Hence, a therapeutic strategy that enables curative treatments for all the various grades of HSN patients has yet to be established. We report our experience performing tonsillectomy combined with steroid therapy for 16 pediatric proteinuric Henoch-Sch?nlein nephritis (HSN) patients. All patients exhibited hematuria and proteinuria in their first HSN attack with the mean age of onset 7.7 years (range 4.75 - 13.9 years). Nine patients were diagnosed with clinically severe HSN presenting with massive proteinuria (> 1 g/m(2)/day). Renal biopsy findings performed in 6 patients were Grade II (3), Grade III (2) and Grade IV (1) according to the International Study of Kidney Diseases in childhood classification. Tonsillectomy was performed after 1-4 cycles of methylprednisolone pulses during oral prednisolone (0.5 - 1.5 mg/kg/day) therapy. In 2 patients, oral cyclophosphamide therapy was added before the tonsillectomy. The interval between the onset of HSN and tonsillectomy was 97.4 +/- 24.5 days (range 27 424 days). In all patients, proteinuria had disappeared by 6 months after the tonsillectomy and the urine findings had normalized. The interval between therapy initiation and complete remission was 9.6 +/- 2.0 months (range 2 - 26 months). Over follow-up periods of 4.9 +/- 0.6 years (range 2.2 - 9.3 years), no recurrences of Henoch-Schonlein purpura or HSN were observed. There was a significant correlation between early tonsillectomy performance and decreased time until normalization of the urine findings, indicating that the tonsils may have pivotal roles in the initiation and progression of HSN. Their elimination might promote the reversal of nephritis. Although this study is retrospective, we suggested that tonsillectomy at an early stage of HSN may be beneficial by shortening the period of illness and contributing to clinical recovery. Randomized controlled trials will be needed to confirm this supposition.     

Pediatric renal transplantation under FK-506 immunosuppression.

Renal transplantation (11 cadaveric and 1 living-related donor) was performed in 12 pediatric recipients (mean age 10.8 years) under FK-506 immunosuppression in combination with prednisone therapy. At a mean followup of 6.1 months, patient and graft survival rates were 100% and 92%, respectively. The only graft loss was due to the recurrent hemolytic uremic syndrome 4 days after transplantation. In the functioning grafts the mean serum creatinine is 1.59 +/- 1.27 mg./dl. and the mean blood urea nitrogen is 36.3 +/- 24.6 mg./dl. Three patients take no prednisone, 5 are receiving 0.15 to 0.25 mg./kg. per day and 3 are taking 0.35 to 0.5 mg./kg. per day. There was a total of 8 rejection episodes in 5 patients. All rejection episodes were successfully reversed. Complications of transplantation included an episode of seizures in 1 patient, cytomegalovirus infection in 1 and steroid-induced diabetes mellitus in 1. Since pediatric transplant recipients are a group in whom the reduction or elimination of steroids is highly desirable, FK-506 immunosuppression may be particularly suited for use in this population.     

Noninvasive assessment of treatment of cardiac allograft rejection with indium-111-labeled lymphocytes

We have shown previously that cardiac allograft rejection can be detected noninvasively with gamma scintigraphy after administration of indium-111 (111In)-labeled lymphocytes. To determine whether this technique could be used to monitor salvage immunosuppressive therapy in reversing rejection, 5 dogs were studied after thoracic heterotopic cardiac transplantation. Initial postoperative immunosuppression was maintained with cyclosporine (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 7 days after transplantation and then discontinued. Scintigraphy after administration of labeled lymphocytes was performed during initial immunosuppression and every 3 days after its termination. Endomyocardial biopsies were obtained on each day scintigraphy was performed. Once scintigraphic criteria for rejection were met (111In-lymphocyte uptake greater than mean +/- 2SD of normal myocardium), animals were treated with high dose methylprednisolone and cyclosporine. Myocardial 111In-lymphocyte activity compared with that in blood was 0.7 +/- 0.8 during initial immunosuppression, increased to 5.7 +/- 3.5 after termination of therapy (P less than 0.01), and diminished with salvage immunosuppressive therapy to 0.5 +/- 0.8 (P = NS compared with native hearts or allografts during initial immunosuppression). Scintigraphy accurately predicted all but one episode of biopsy-documented rejection and accurately detected reversal of rejection during salvage. Thus, scintigraphy with 111In-labeled lymphocytes should facilitate noninvasive monitoring of antirejection therapy in patients.     

Adding Sirolimus to Tacrolimus-Based Immunosuppression in Pediatric Renal Transplant Recipients Reduces Tacrolimus Exposure

In adult renal recipients, coadministration of tacrolimus (TAC) and sirolimus (SIR) results in reduced exposure to TAC at SIR doses of 2 mg/day. Eight pediatric renal recipients (median age at transplant 2.0 years, range: 1.2-12.9 years) were converted to TAC- and SIR-based immunosuppression as a rescue therapy. All patients had biopsy-proven chronic allograft nephropathy. TAC levels were measured using a commercially available EMIT assay and SIR levels with a newly developed assay based on the LC-MS MS technology. SIR was started at 0.13+/-0.05 mg/kg/day (3.51+/-1.26 mg/m2/day) in two divided doses. TAC was given at 0.14+/-0.09 mg/kg/day, resulting in a trough level of 6.3+/-2.5 ng/mL. After the addition of SIR, the median dose required to keep TAC blood trough concentrations within the target range increased by 71.2% (range: 21.9-245.4%), dose-normalized TAC exposure (AUC) decreased to 67.1% and the dose-normalized C(max), a surrogate for absorption rate, to 53.8% (both geometric means) while terminal half-life (t1/2), a pharmacokinetic parameter characterizing systemic elimination, remained unchanged (p<0.93). Adding SIR to TAC-based immunosuppression in young pediatric renal transplant recipients results in a significant decrease of TAC exposure. TAC trough levels should be monitored frequently.     

Comparison of two dosages of thymoglobulin used as a short-course for induction in kidney transplantation

Thymoglobulin is used effectively as an induction agent in kidney transplantation, but the optimal dose is not well established. We evaluated the degree and durability of T-cell clearances with two different thymoglobulin regimens in adult kidney transplant recipients (KTR). Seven KTR received a 3-day thymoglobulin-based induction of 1.0 mg/kg/day while nine received 1.5 mg/kg/day, in addition to maintenance immunosuppression. Lymphocyte subsets were monitored for 6 months. Renal function, infections and malignancies were monitored for 24 months. T-cell subsets were significantly lower by day 30 with the thymoglobulin 1.5 mg/kg/day regimen when compared with the 1.0 mg/kg/day regimen; this trend was sustained at 6-month (CD3(+): 438 +/- 254 vs. 1001 +/- 532 cells/mm(3), P = 0.016). Renal function between the two groups was not significantly different at 6- and 24-months post-transplant. One case of BK Virus viremia in the 1.5 mg/kg/day thymoglobulin group was detected. No acute rejection episodes, cytomegalovirus infections, or malignancies were noted in either group. Thymoglobulin induction was efficacious in both groups, but with a significantly sustained T-cell clearance in the 1.5 mg/kg/day regimen. A more profound T-cell clearance within the first 6 months postinduction therapy may translate into a decreased risk of immunological injury and improved long-term outcome after kidney transplantation.     

Cancer pain therapy in children and adolescents using morphine

Systematic treatment in children suffering from cancer pain is a field of pediatric oncology that was neglected for a long time. Investigations have shown that pain therapy oriented to the special situation of the child's body is urgently necessary. In Germany, an unpublished study by Fengler (Berlin), who reviewed all pediatric cancer centers, revealed serious deficiencies in the therapy of pain in children. In our study, we attempted to develop a new concept of cancer pain management, with the emphasis on cooperation between pediatric oncologist and anesthesiological pain therapists. PATIENTS AND METHODS. A total of 36 children and adolescents suffering from malignant tumors and in whom pain therapy according to WHO stage III was necessary were treated. After being seen by a pediatric oncologist and an anesthetist (pain therapist) each patient received either slow release oral morphine (MST, 0.5-1 mg/kg per dose) two to three times a day or a continuous infusion of morphine (0.05 mg/kg per h). The amount of morphine administered was quickly raised until the young patients were free of pain. Drug actions (pain score) and side effects were registered continuously with a documentation form. The morphine was combined with dipyrone 5-15 mg/kg per dose five times a day. The intravenous dosage of oral dipyrone was 2-5 mg/kg per h. RESULTS. The average age of the patients treated was 12 years (1.5-19 years); 10 were inpatients, and 26 were outpatients. All patients were treated successfully. The doses of morphine required for pain relief varied substantially (1-25 mg/kg per day p.o. and 0.05 mg-1 mg/kg per h i.v.). We did not observe extreme sedation or respiratory depression. In our patients we did not observe opioid-induced nausea such as is frequently seen in adults. All children needed laxatives. In 2 children, intolerable itching was experienced after oral administration of slow-release morphine. In 20 patients cortisone was given as adjuvant therapy, in 5 patients with neuropathic pain, anticonvulsants e.g., carbamazepine. In 6 patients we administered benzodiazepines successfully for sedation and anxiolysis. CONCLUSIONS. Therapy of pain in children with advanced cancer requires interdisciplinary cooperation. In most children therapy of pain can be successfully administered with slow-release morphine in combination with dipyrone, so that the children can remain in their usual social environment.     

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections

Purpose

Treatment of Gram-positive osteoarticular infections requires an adequate surgical approach combined with intensive antimicrobial therapy. The aim of this study was to evaluate the safety and efficacy of a combined regimen of high-dose daptomycin and rifampicin, in patients with various types of Gram-positive osteoarticular infections.

Methods

This single centre, non-comparative, prospective study evaluated the safety and efficacy of a combined regimen of intravenous daptomycin (8 mg/kg/day) and oral rifampicin (600 mg/day) in patients with Gram-positive osteoarticular infections, with a minimal follow-up of one year. Creatine phosphokinase, transaminases, bilirubinaemia, and serum creatinine, were measured at baseline and regular intervals.

Results

The median daily doses of daptomycin and rifampicin, administered for a median duration of 21 (range, 10–122) days to 16 patients (median age, 63.5 years; 11 males, five females) presenting with staphylococcal (n = 15) or streptococcal (n = 1) osteoarticular infections, were 8.15 (range, 6.6–8.9) mg/kg/day and 600 (range, 600–900) mg/day, respectively. The combined regimen of daptomycin and rifampicin was well tolerated by all except one patient, without requiring treatment adjustment or discontinuation. One patient developed allergic responses probably due to rifampicin after 42 days. Fifteen (94 %) patients showed favourable clinical and microbiological outcomes.

Conclusions

The combined regimen of high-dose daptomycin and rifampicin was well tolerated and may provide a useful alternative to standard glycopeptide therapy for Gram-positive osteoarticular infections.     

Induction therapy after cardiac transplantation: a comparison of anti-thymocyte globulin and daclizumab in the prevention of acute rejection.

BACKGROUND: Induction therapy with antibodies decreases and delays early allograft rejection. We compared the safety and efficacy of daclizumab and anti-thymocyte globulin (ATG) with respect to the frequency and severity of acute cardiac allograft rejection in heart transplant recipients. METHODS: Forty sequential adult patients were retrospectively studied. In the first 20 patients ATG (2.5 mg/kg daily for 3 to 5 days peri-/and post-operatively) was used as induction therapy and, in the remaining 20 patients, daclizumab (1 mg/kg peri-operatively and every 2 weeks thereafter for a total of 5 doses) was used. A standard triple-drug immunosuppression regimen was administered to all patients. RESULTS: Baseline characteristics and trough levels of cyclosporine in the 2 groups were similar. During the induction period, defined as the first 3 months, 12 acute rejection episodes requiring treatment (ISHLT Grade > or =2) occurred in the ATG group and 9 in the daclizumab group (p > 0.05). However, the number of biopsies with Grade 1 rejection was increased >2-fold in the daclizumab group (n = 35) compared with the ATG group (n = 17; p = 0.04). The total number of biopsies performed within the first 3 months increased by 26% in the daclizumab group. The number and severity of rejection episodes after 3 months was similar in the 2 groups. The overall occurrence of bacterial infections was significantly higher in the ATG group than in the daclizumab group (p = 0.05). CONCLUSIONS: ATG and daclizumab are equally effective in preventing acute rejections requiring treatment (ISHLT Grade > or =2). Due to the significantly greater frequency of Grade 1 rejections, daclizumab was found to be associated with an increased number of additional biopsies for monitoring rejection status. This implies additional costs to the transplant program, and the long-term implications of the increased number of low-grade rejection episodes remains to be determined.     

Immunosuppressive Treatment of Primary Cadaveric Renal Transplant Patients Receiving Kidneys from Non-Heart Beating Donors

Abstract: Since November 1982, 276 primary cadaveric kidney transplants have been performed using kidneys from non-heart beating donors. Between November 1982 and December 1986, 49 transplant patients were treated with cyclosporine and steroid immunosuppressive therapy (CSA regimen). Twenty-seven patients were treated with low dose cyclosporine (initial dosage, 4 mg/kg/day), steroid therapy, and a 21-day course of 500 mg/day anti-lymphocyte globulin (ALG 1 regimen) between January 1987 and December 1987. Seventy-nine patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin (ALG 2 regimen) between January 1988 and June 1990, and 85 patients were treated with low dose cyclosporine (initial dosage, 6 mg/ kg/day), steroid therapy, and a 14-day course of 1,000 mg/day antilymphocyte globulin followed by 2 mg/kg/day mizoribine (ALG 3 regimen) between July 1990 and May 1995. Ten patients, who showed hypersensitivity to antilymphocyte globulin therapy, were treated with low dose cyclosporine, steroid therapy, and mizoribine. Finally, 26 patients were treated with FK506 and steroid therapy (FK.506 regimen) between June 1990 and February 1992. Graft survival was 78% at 1 year, 69% at 3 years, 63% at 5 years, and 51% at 10 years in the CSA regimen group and 67% at 1 year, 52% at 3 years, and 48% at 5 years in the ALG 1 regimen group. It was 85% at 1 year, 70% at 3 years, and 62% at 5 years in the ALG 2 regimen group and 87% at 1 year and 67% at 3 years in the ALG 3 regimen group. In the FK506 regimen group, graft survival was 92% at 1 year and 80% at 3–5 years. Never-functioning grafts were observed in 3 CSA patients (6%), I ALG 1 patient (4%), 3 ALG 2 patients (4%), 3 ALG 3 patients (4%), and I FK506 patient (4%). These results indicate that low dose cyclosporine (initial dosage, 6 mg/kg/day), steroid therapy, and a 14 day course of antilymphocyte globulin therapy is beneficial for cadaveric renal transplant patients receiving kidneys from non-heart beating donors; FK506 and steroid therapy might be more effective than cyclosporine based immunosuppressive therapies even in such patients.     

One-year results of basiliximab induction and tacrolimus associated with sequential steroid and MMF treatment in pediatric kidney transplant recipient

We report the 1-year results with a triple immunosuppressive regimen in pediatric recipients of a first kidney transplant, in order to evaluate its safety and efficacy in the prevention of acute rejection and in the reduction of steroid side effects. The immunosuppression is as follows: (i) basiliximab (20 mg if body weight >30 kg; 10 mg if < 30 kg) is given pretransplant and at day 4; (ii) tacrolimus (Tac) is administered in order to obtain blood trough levels of 10-20 and 5-10 ng/ml during and after the first 2 months post-transplant, respectively; (iii) steroids are tapered during the first 6 months and then replaced by mycophenolate mofetil (depending on previous rejection episodes, infection status and the result of a routine biopsy) at a dosage of 4-600 mg/m(2) body surface area. Fifty-three children (median age 13 years, range 2-20) have entered this protocol. One-year patient and kidney survival are 100% and 94% respectively. During the first year a total of nine rejections in seven patients (13% of the cohort study) occurred, all but one responsive to steroids. Renal function was satisfactory throughout the first year (mean CrCl was 63.8 +/- 18 and 60.9 +/- 15.5 ml/min/1.73 m(2) at 6 and 12 months respectively). Subclinical signs of rejection were absent in more than 80% of biopsies (grade I Banff) at 6 months (n = 47); at the 12th month biopsy (n = 42) score I was stable in 20 patients (16 after stopping steroids) and had worsened in eight biopsies (six after stopping steroids). Major complications were insulin-dependent diabetes in three (5.6%) children with the need of insulin for a mean of 3 months; transient hyperglycemia (11 patients), treated with a dietary regimen, symptomatic viral infections (in 11 patients: two parvovirus B19, three cytomegalovirus and two Epstein-Barr virus systemic infections, three interstitial pneumonia, two BK nephritis). Tac doses more than 0.3-0.4 mg/kg/day are at significantly higher risk of viral infection. In conclusion, this immunosuppressive regimen is associated with a low percentage of clinical (13%) and subclinical rejections, but with a relatively high number of infections, prevented by a reduction in Tac doses (<0.3 mg/kg/day) during the first 2 months after transplantation. The assessment of steroid withdrawal needs a longer follow-up.     

Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy.

BACKGROUND: Steroid-free immunosuppression is feasible in selected patients after heart transplantation. Survival and incidence of acute rejection are important parameters to evaluate when weighing risks and benefits of steroid withdrawal. METHODS: One hundred thirty-seven patients were retrospectively reviewed who underwent heart transplant at Emory University between January 1988 and April 1994 and survived >1 year. Standard immunosuppression (cyclosporine, azathioprine and prednisone) without induction therapy was used. Weaning from steroids was attempted in all patients. Scheduled endomyocardial biopsy was used for long-term surveillance screening. RESULTS: Seventy-two patients (52.5%) underwent successful prednisone withdrawal (Group P0) at an average of 13 months after heart transplant, whereas 65 patients (47.5%) did not achieve steroid-free immunosuppression (Group P1). Group P0 had a mean of 1.3 treated rejection episodes (ISHLT Grade > or = 1b) during the first post-transplant year and Group P1 a mean of 2.3 (p <0.0001). In Group P0, 40 patients (55.6%) suffered a subsequent acute rejection with an ISHLT Grade > or = 1b, resulting in treatment. Of these, 15% were ISHLT Grade 1b, 47.5% Grade 2, 35% Grade 3a and 2.5% Grade 3b. The estimated risk of suffering from acute rejection of at least Grade 1b after achieving steroid-free immunosuppression was 50% at 21 months. Estimated survival at 5 years after heart transplant was 92.9% in Group P0 and 72.3% in Group P1 (p <0.01). Cox proportional hazard modeling revealed black recipient race as effect modifier of group status with decreased survival time in both groups. CONCLUSION: Steroid-free immunosuppression in white heart transplant recipients is associated with improved survival. A low acute rejection score during the first year predicts successful steroid withdrawal. Black recipient race appears to be negatively associated with survival and deserves further detailed study. Long-term surveillance screening using endomyocardial biopsy is recommended.     

Rabbit antithymocyte globulin as induction immunotherapy in pediatric heart transplantation

BACKGROUND: There is little published data on the use of antithymocyte globulins in children. This retrospective study describes the use of Thymoglobulin (Imtix, SangStat, Lyon, France) in pediatric cardiac transplantation over a 13-year period in a single center that adjusted the dose of Thymoglobulin according to platelet count monitoring and examines the short-term hematological effects as well as longer-term outcomes. METHODS: Data for all children who received a heart transplant at the H?pital Cardiologique at Lyon from 1984 to 2001 and who were given Thymoglobulin as part of their immunosuppressive protocol were extracted. The dose of Thymoglobulin given depended on baseline platelet count and was 2, 1.5, or 1 mg/kg per day over 5 days for the following platelet count groups: greater than 150,000/mm (normal group), 100 to 150,000/mm (mild thrombocytopenia group), and 50 to 100,000/mm (moderate thrombocytopenia group). RESULTS: Thirty children of median age 14.2 years were given a median cumulative dose of Thymoglobulin of 8 mg/kg per patient; the moderate thrombocytopenia subgroup was given significantly less (6.4 mg/kg) ( P=0.032). Immediate tolerability of Thymoglobulin was good, with no cases of first-dose syndrome, anaphylaxis, or serum sickness. The platelet count decreased at the start of therapy, but recovered after discontinuation, and did not give rise to clinical concern. Patients were followed up for a median of 6.3 years (7 days-15.5 years); actuarial survival was 90%, 86%, and 74.5%, respectively, at 1, 5, and 10 years. In the first year, 50% of patients suffered an episode of rejection. The overall incidence of infection in the month following transplantation was 40%. One lymphoma occurred at 5 months. CONCLUSIONS: The use of Thymoglobulin in pediatric heart-transplant patients as part of an immunosuppressive protocol, with dose adjustment according to platelet levels, has been shown to be effective in terms of rejection rate and patient survival and safe in terms of the incidence of infections and malignancy.     

Low dose ciclosporin from the early postoperative period yields potent immunosuppression after renal transplantation

This study sought to determine if low doses of ciclosporin (CS) designed to give fasting serum levels of 50-100 ng/ml achieve effective immunosuppression when used from the early postoperative period after renal transplantation. Ninety-four primary renal transplant recipients were studied. Group 1 patients were treated with CS 100 ng/ml and prednisone (0.15 mg/kg/day). Group 2 patients received CS 50 ng/ml, prednisone (0.15 mg/kg/day) and azathioprine (1 mg/kg/day). These patients were compared to a control group of 26 patients (group 3) maintained on only prednisone and azathioprine. CS-treated patients suffered significantly fewer rejection episodes than control subjects (rejection episodes per patient in first year: group 1: 0.3 +/- SD 0.6; group 2: 0.7 +/- SD 0.7; group 3: 1.3 +/- SD 1.1, p less than 0.005). In addition, a greater number of CS-treated patients were completely free of rejection episodes during the first year posttransplant (group 1: 63%; group 2: 64%; group 3: 19%, p less than 0.005). Patient and graft survival were similar in all groups after 1 year (group 1: 92 and 92% respectively; group 2: 95 and 87% respectively; group 3: 96 and 85% respectively). These data suggest that the dose of CS required for effective immunosuppression in vivo is lower than has been previously thought.     

Polyomavirus-associated nephropathy in simultaneous kidney-pancreas transplant recipients: a single-center experience

BACKGROUND: With the introduction of more potent immunosuppressive agents, rejection rates have decreased markedly in simultaneous pancreas-kidney transplant (SPK) recipients. However, with more intense immunosuppression, opportunistic infections such as polyoma virus have been more frequent. The purpose of this article is to outline the clinical course of SPK patients who developed documented polyoma infection in the transplanted kidney. METHODS: A retrospective review of 146 consecutive SPK recipients from 1996 to 2002 was performed. Induction and maintenance immunosuppression, surgical complications, rejection episodes, and opportunistic infections were reviewed. Patients who developed biopsy-proven polyoma virus infection in the renal allograft were identified. RESULTS: Nine patients (6%) were identified who developed polyoma. All had received induction therapy with either OKT3 (5 mg/d for 10.5 days) or thymoglobulin (5.7 mg/kg). Patients without polyoma had received similar induction. Maintenance immunosuppression included Prograf/MMF in six patients, CsA/MMF in two, and CsA/azathioprine in one. Time to diagnosis was an average of 359.3 days (range 136 to 836) after transplantation. Two patients had undergone treatment for kidney rejection prior to the diagnosis of polyoma. Immunosuppression was decreased in all patients when polyoma was identified, and more recently Cidofovir has been administered. Despite these interventions, five of the nine lost kidney function (creatinine > 5.0 or resumption of dialysis). However, none of the nine developed pancreatic abnormalities as demonstrated by normal blood glucose and amylase and no requirement for exogenous insulin. Two patients underwent LRRT more than 1 year after polyoma diagnosis; both have normal kidney function (Cr < 1.5 mg/dL) at 4 years of follow-up. Polyoma virus was the leading cause of renal loss in this cohort of patients. CONCLUSIONS: Polyoma is a serious concern for SPK transplant recipients. The pancreas, however, is spared from clinical evidence of infection, and no rejection was noted when immunosuppression was decreased. These graft losses appear to be a penalty of more potent immunosuppression, and a better treatment strategy is needed to prevent renal graft loss when polyoma is diagnosed. Retransplantation can be considered based on our limited experience.     

Effectiveness of interferon-beta, ACNU, and radiation therapy in pediatric patients with brainstem glioma.

Sixteen pediatric patients with brainstem glioma were treated with a combination of interferon-beta, 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride (ACNU), and radiation therapy (IAR therapy). All patients received 1-1.5 million IU/day of interferon-beta intravenously for 1 week of each 6-week cycle. In addition, ACNU (2-3 mg/kg) was given on the 2nd day of each cycle. Conventional focal irradiation (1.5-2 Gy/day for 5 days to a total dosage of 40-60 Gy) was administered beginning on day 3. Patients underwent at least two 6-week cycles. Adverse effects included nausea, vomiting, and myelosuppression, but were mild and transient. Response to treatment was evaluated by the reduction in tumor size measured on postcontrast computed tomographic scans and magnetic resonance images. Responses occurred in 10 of 11 patients with the intrinsic type of brainstem glioma, including three complete and seven partial responses. Two of five patients with exophytic type gliomas partially responded. The median survival was 15.7 months, a remarkable improvement over the natural course of this disease. These results indicate that IAR therapy is a useful primary treatment for pediatric patients with brainstem gliomas.