Jeno Járay

A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard‐dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 ± 0.32 with TAC/MMF/DAC and 0.03 ± 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04–0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05–0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy‐proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Patient Outcomes in Two Steroid-Free Regimens Using Tacrolimus Monotherapy After Daclizumab Induction and Tacrolimus With Mycophenolate Mofetil in Liver Transplantation

Introduction. Long-term steroid administration may predispose liver transplant recipients to infectious and metabolic complications. Maintaining effective immunoprophylaxis while minimizing the negative consequences of steroid therapy could be a key factor in improving clinical outcomes. Methods. Six hundred two patients were randomized to receive tacrolimus (TAC) immunosuppression with a single-steroid bolus and two doses of daclizumab (DAC) or mycophenolate mofetil (MMF). Results. The incidence of biopsy-proven acute rejection was 19.7% in the TAC/DAC group and 16.2% in the TAC/MMF group (ns). Three-month patient and graft survival were similar. Steroid use at month-3 was low at 5.5% in the TAC/DAC group and 3.9% in the TAC/MMF group. Significantly higher incidences of causally related adverse events (AEs) and significantly more dose modifications, interruptions, or discontinuations due to an AE were reported with TAC/MMF. Study withdrawal due to leucopenia was significantly higher with TAC/MMF (0.0% vs. 1.7%. P≤0.05). AEs were generally reported less frequently in the TAC/DAC group. However, specifically headache and supraventricular arrhythmia were significantly higher with TAC/DAC, whereas leucopenia and bacterial infection were significantly higher with TAC/MMF. Laboratory indices of renal function were similar, and increases in serum lipids were negligible in both groups. Incidences of de novo diabetes mellitus (≥2 fasting plasma glucose values ≥7.0 mmol/L) were low at 9.5% (TAC/DAC) and 11.0% (TAC/MMF). Conclusion. Both TAC-based regimens allowed optimization of immunoprophylaxis while eliminating some of the negative consequences associated with steroids. Efficacy outcomes were comparable; however, TAC monotherapy after DAC induction was associated with significantly less leucopenia and less bacterial infection than a dual regimen incorporating MMF.

Attitudes of donors towards organ transplantation in living related kidney transplantations

Abstract The demand for transplantation exceeds the availability of cadaveric organs, which is why the importance of living, related kidney transplantation is increasing. In our study we wanted to evaluate the experiences of living related donors (LRD). Between 1973 and 1996, 1325 kidney transplantations were performed at our Department. Of these 1247 were from cadaver donors while 78 were from LRD. We contacted each living donor by post. We carried out a physical examination, laboratory tests, ultrasound and isotope investigations and they were interviewed and completed a questionnaire. Thirty previous kidney donors came to our Department who were all blood relatives of the recipients. In the recipient group, 16 still have a functioning kidney, the average time since transplantation being 8.92 years. The longest kidney survival time is 18 years. All the donors willingly donated their kidney, none was worried about their own health and their only concern was whether the kidney would function or not. Regarding general attitudes towards living related organ transplantation, all were in favour of blood relative donor transplantation and also husband/wife transplantation. Opinions regarding non‐related transplantation were more mixed; 63.3% would have given their kidneys to a friend, only 46.6% to a stranger. Almost two‐thirds (63.3%) of donors were not in favour of selling and buying organs but, controversially, they would have bought an organ had one been available. All agreed that the donation did not change their general health. In conclusion, the donors of living, related kidney transplantation all agreed that it was a good thing to donate; All confirmed they would go through the same procedure again in order to help. Apart from one person, who emphasised that he is agnostic, all belonged to a Christian religion.

Analysis of differences in outcome of two European liver transplant centers

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1‐, 3‐ and 5‐year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per‐operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni‐ and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri‐operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.

Primary Hepatic Carcinoid in a Renal Transplant Patient

There seems to be a world-wide increase in the incidence of tumors among immunosuppressed patients. Of 1350 renal allografts transplanted in the past 23 years at the Department of Transplantation and Surgery, 56 cases had malignant tumors. The case of a 58-year-old female patient is reported, with disseminated primary carcinoid in the liver detected 86 days after renal transplantation. According to the literature only 39 patients with primary liver carcinoids have been reported until 1997, but this is the first where the carcinoid developed in an immunosuppressed patient. The rapid progression of the carcinoid could be associated with the immunosuppression.

Evaluation of the state of health of living related kidney transplantation donors

Abstract Renal transplantation is the optimal mode of therapy for patients with enD‐stage renal disease; the results are even better with living related donors. This procedure, therefore, favours the recipients, but what are the consequences for the donor? At our Department, between 1973 and 1996, 1325 kidney transplantations were performed, 78 from living, related donors (5.89 %). We decided to follow up these patients and investigate the function of the remaining kidney and also their current general health status. Thirty donors (38.4 %) were investigated. Of these, 25 of had normal blood pressure and 5 were hypertensive, needing antihypertensive treatment. The average age was higher in the hypertensive group (60.2/53.25 years). The time interval since transplantation was longer in the hypertensive group than in the normal one. We carried out a scintigraphy of the kidney with Tc99mMAG‐3. The mean value of the glomerular filtration rate calculated from the MAG clearance was 98.1 ml/min and this value is higher than half of the normal isotope clearance value, i.e. higher then the expected value for a single kidney. We conclude that no impairment of renal function is observed in the living, related kidney donors. In 16.66% a mild hypertension developed. With isotope investigation we found hypertrophy of the remaining kidney. Thus, after a correct preoperative assessment, unilateral nephrectomy has no long‐term consequences in healthy donors.

Corticosteroid-Free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial.

Background Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828–836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. Methods Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. Results Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (−0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. Conclusion Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.

The use of autologous rectus facia sheath for replacement of inferior caval vein defect in orthotopic liver transplantation

Occasionally, during liver transplantation, vascular reconstructions have to be performed. Donor vessels can be harvested for this purpose. However, when these are lacking, alternatives should be available. A possible alternative can be the use of autologous rectus fascia sheath, folded as a tube with the mesothelium on the inside. Earlier experimental studies from our centre showed the successful use of the rectus fascia sheath graft in vascular defects in animal experiments. This report describes the first use of this autologous tubular graft for replacement of the inferior caval vein interponate during liver transplantation in men.

Conversion to tacrolimus once‐daily from ciclosporin in stable kidney transplant recipients: a multicenter study

This 24‐week, open, single‐arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1 mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at −10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n = 42), hypertrichosis (n = 106), hypertension (n = 77) and gingival hyperplasia (n = 76) groups. Relative change in eCrCl was −0.6% in all PPS patients (95% CI, −2.2; 0.9) and −5.3% in the hyperlipidemia (CI, −9.59; −0.97), 0.9% in the hypertrichosis (CI, −2.59; 4.45), −0.1% in the hypertension (CI, −3.8; 3.68), and −1% in the gingival hyperplasia groups (CI, −4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin‐related cosmetic side effects were evident from investigator and patient self‐report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin‐related cosmetic side effects was observed.

Papillary microcarcinoma of the thyroid gland in renal transplant patients: Case reports and review of the literature

Among organ transplant recipients there is a world wide increase in the number of de novo tumors as well as a decrease in the time of the first appearance after the transplantation. Between 1973 and the 31th of August 1999 1709 cadaver renal allograft transplantations were perfomed in our Department. Four thyroid cancers were detected among the renal transplanted patients. Two of them proved to be papillary microcarcinomas. Although the elevated risk of thyroid cancers is well established in the literature papillary microcarcinomas have never been reported before in an immunosuppressed patient. Authors highlight that the thyroid gland should always be carefully checked in organ transplant recipients, since better survival might be achieve even in the immunosuppressed population. Metastatic tumor is relatively benign which is in correlation with the literature, but there has been little experience in organ transplanted patients so far.