Ferenc Perner

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

Abstract This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac (n=103) or CyA microemulsion (n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baselinecharacteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute re-jection (36.9%) compared with CyA therapy (59.1%) (P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group (P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62±20 ml/min per 1.73 m2, n=84) than in the CyA group (56±21 ml/min per 1.73 m2, n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences (P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.

Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation

Recent data suggest that optimal cyclosporine (CsA) exposure early post‐transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration‐controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral.

Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation : results of the Atlas study.

Background. The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. Methods. This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). Results. The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 &mgr;mol/L (triple therapy), 134.7 &mgr;mol/L (Tac/MMF) and 135.8 &mgr;mol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. Conclusion. Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (NeoralTM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection.

Influence of Obesity on Lymph Node Recovery from Rectal Resection Specimens

Careful lymph node dissection from colorectal resection specimens is important procedure for cancer staging. Present study intended to assess the impact of surgical technique and patient’s obesity on this process. Number of lymph nodes harvested by manual dissection from resection specimens of 141 patients with rectal cancer and the rate of nodal metastases were analyzed and compared in different groups of patients selected by length of resection specimen and body mass index. The median and mean number of lymph nodes found per patient were 6 and 6,7. The shorter resection specimens (≤16 cm after formalin fixation) yielded significantly lower number of nodes than those with length > 16 cm (5.7 versus 7.9). Most significant reduction in mean number of lymph nodes was observed in obese patients with short specimens (4.8). This subset of patients presented the lowest rate of nodal metastases (38%). The surgical technique seems to be an important factor for lymph node recovery from rectal resections specimens. The patient’s obesity had an unfavourable impact on this procedure. Standardized surgery and histopathological examination are needed even in non-specialized centers to harvest adequate number of lymph nodes.

Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study.

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus‐MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC‐SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC‐SRL0.5 mg) and 327 patients 1 g MMF (TAC‐MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy‐proven acute rejection was lower in the TAC‐SRL2 mg group (15.7%) compared with the TAC‐SRL0.5 mg (25.2%, p = 0.003) and the TAC‐MMF groups (22.3%, p = 0.036). Six‐month graft survival was 91.0% (TAC‐SRL2 mg), 92.6% (TAC‐SRL0.5 mg) and 92.4% (TAC‐MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty‐four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC‐SRL2 mg, TAC‐SRL0.5 mg and TAC‐MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC‐SRL2 mg group (24.0%) compared with 19.4% (TAC‐SRL0.5 mg) and 11.0% (TAC‐MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.

Malignancies after renal transplantation during 33 years at a single center.

This study provides an analysis of incidence and characteristics of malignant tumors of 2535 patients who underwent renal transplantation between 1973 and 2007 at the Transplantation Center in Budapest. One hundred ninety-three malignant diseases were found in 188 patients (7.6%). The incidence of thyroid-, renal-hepatic-, skin- and gastric cancers as well as of Kaposi sarcoma and lymphomas increased in our transplant patient cohort compared to the figures of the general population based on the data of our Cancer Registry. On the other hand, colorectal-, oralprostate and lung cancers were underrepresented in our patient cohort. The mean time of diagnosis of malignancies following kidney transplantation was 58.5± 44.8 months. One fifth of the tumors were detected within the first year. Patients with malignancies were distributed into four groups based on the immunosuppressive regimen: group I (8.5%), azathioprine + prednisone; group II (59.0%), cyclosporine + prednisone; group III (26.6%), cyclosporine + mycophenolate mofetil + prednisone; group IV (5.9%), tacrolimus + mycophenolate mofetil + prednisone. The mean age of patients was 47.3, 53.5, 55.5 and 58.1 years in group I, II, III and IV, respectively. Oncologic and immunosuppressive therapy was decided individually. Immunosuppression was switched to rapamycin-containing regimens in 63 cases. We lost 92 patients (48.9%) with a mean survival time of 25.8± 39.4 months. Cumulative 1- and 5-year survivals were 69.5% and 52%, respectively. The increasing number of cancers seen early after transplantation and the increased risk of developing a cancer due to the older age of recipients draw attention to the importance of regular oncologic screening in patients on the waiting list and after transplantation.

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.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

Background Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) belongs in the group of neuroendocrine tumors with early lymphatic and hepatic dissemination. A high rate of undetectable metastases is hypothesized to be responsible for the frequent mismatch between the apparent relatively small tumor burden and the elevated plasma tumor marker level.