Styrbjörn Friman

Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring Versus Tacrolimus) was a 6‐month, open‐label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA‐ME, using C2 monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent‐to‐treat population comprised 682 patients (336 CsA‐ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new‐onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA‐ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy‐proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA‐ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2 in the CsA‐ME cohort and 65.9 ± 23.1 mL/min/1.73 m2 with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL‐cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post‐transplant is significantly lower with CsA‐ME than with tacrolimus without a significant difference in short‐term outcome.

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.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)‐associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA‐MPA with lower rates of viremia than Tac‐MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10 copies/mL; p = 0.028). In multivariate models, CsA‐MPA remained associated with less viremia than Tac‐MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac‐MPA compared to CsA‐MPA at month 6 and Tac‐MPA, older age, male gender at month 12 posttransplant.

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well‐differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease‐free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5‐year survival was 90%. The recurrence‐free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long‐term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited. Liver Transpl 13:327–333, 2007.

Successful Combined Partial Auxiliary Liver and Kidney Transplantation in Highly Sensitized Cross-Match Positive Recipients

Combined liver and renal transplantations can be performed against a positive cross‐match, indicating that the liver protects the kidney from the harmful HLA antibodies. This led us to the hypothesis that a partial auxiliary liver graft may have a similar protective effect when performed together with the kidney in highly sensitized patients. Seven patients, with broadly reacting HLA antibodies and positive crossmatches, were transplanted with a partial liver and a kidney from the same donor. In one of the cases a living donor was used. We performed lymphocytotoxic and flow cross‐matches before and after the transplantation. Cross‐matches turned negative after grafting in five of seven cases. The kidney function was excellent, without rejections, during the follow‐up (24–60 months) in these patients. In two cases the cross‐match remained positive after transplantation, one with a never‐functioning renal graft and the other with an early graft failure, probably due to humoral rejection. A simultaneous transplantation of a partial auxiliary liver graft from the same donor, with the sole purpose of protecting the kidney from harmful lymphocytotoxic antibodies, can be performed successfully despite a positive cross‐match and may thus be a new option of treatment for highly sensitized patients waiting for a kidney transplant.

A new microemulsion formulation of cyclosporin: pharmacokinetic and clinical features.

SummaryCyclosporin (cyclosporin A) has been used as an immunosuppressive agent after organ transplantation for more than 15 years. The bioavailability of cyclosporin in its conventional oral formulation ‘Sandimmun’ displays considerable inter- and intra-patient variability. Absorption is also bile dependent. Recently, a new galenic formulation of cyclosporin was introduced, ‘Neoral’, which is a water-free microemulsion of cyclosporin. The microemulsion creates micelles which are absorbed in the small bowel without the presence of bile.Pharmacokinetic studies in healthy volunteers clearly demonstrate an increased bioavailability of the microemulsion formulation of cyclosporin, measured as an increase in maximum drug concentration (Cmax) and area under the drug concentration-time curve, and a reduced time to Cmax. These findings have been confirmed in kidney, liver and heart transplant recipients. With the microemulsion formulation, an improved prediction of cyclosporin concentrations has probably attributed to the decrease found in the variability of cyclosporin absorption. This could probably enable easier and more reliable monitoring of cyclosporin concentrations after transplantation.So far, data on the effects of conversion from the conventional to the microemulsion formulation of cyclosporin are only available in a limited number of patients and with a limited follow-up period. The main questions are related to what the long term consequences of the improved bioavailability of the microemulsion formulation will be. Further long term studies are needed in order to answer these questions.In the present review, we report on the pharmacokinetic properties of, and on clinical experience after solid organ and bone marrow transplantation with, the microemulsion formulation.

Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers

BACKGROUND/AIMS The pathogenesis of the inflammatory lesion in primary sclerosing cholangitis is unknown. The clinical picture is characterized by i.a. episodes of fever, the cause of which also remains speculative. Previous studies of bacterial isolates in the liver or bile ducts in primary sclerosing cholangitis have had the shortcoming of possible contamination associated with the sampling. The aim of this study was to investigate whether bile and bile duct tissue, obtained under sterile conditions in connection with liver transplantation, contain bacteria. METHODS We studied bile from bile duct walls and bile collected from the explanted livers of 36 patients with primary sclerosing cholangitis and 14 patients with primary biliary cirrhosis. RESULTS Positive cultures were obtained from 21 of 36 primary sclerosing cholangitis patients, but from none of the primary biliary cirrhosis patients. The number of bacterial strains was inversely related to the time after the last endoscopic retrograde cholangiography. Treatment with antibiotics or intraductal stent, or the occurrence of fever before liver transplantation did not seem to influence the culture results, whereas antibiotic treatment in connection with endoscopic retrograde cholangiography may possibly have reduced the number of isolates in the cultures. Alpha-haemolytic Streptococci were retrieved as late as 4 years after the last endoscopic retrograde cholangiography. Retrospective analysis of liver laboratory tests after endoscopic retrograde cholangiography did not indicate a deleterious effect of the investigation. CONCLUSIONS The data suggest that antibiotics should be given routinely in connection with endoscopic retrograde cholangiography. They also raise the question of a possible role of alpha-haemolytic Streptococci in the progression of primary sclerosing cholangitis.

Liver transplantation for familial amyloidotic polyneuropathy: Impact on Swedish patients' survival

Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long‐term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long‐term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty‐one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early‐onset controls (P < 0.001). In contrast, no significant difference for late‐onset cases (≥50 years) was found. Transplanted late‐onset females had significantly improved survival in comparison with transplanted late‐onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (≥7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late‐onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early‐onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late‐onset male patients. Liver Transpl 15:1229–1235, 2009.

12‐month follow‐up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

The LIS2T study was an open‐label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA‐ME) (Neoral) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level [predose]) C0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA‐ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased‐ and living‐donor recipients. Significantly fewer hepatitis C–positive patients died or lost their graft by 12 months with CsA‐ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P < 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA‐ME (100 ± 50 days) than with tacrolimus (70 ± 40 days) (P < 0.05). Median serum creatinine at 12 months was 106 μmol/L with CsA‐ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P < 0.01). Of patients who were diabetic at baseline, more tacrolimus‐treated individuals required anti‐diabetic treatment at 12 months (70% vs. 49%, P = 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA‐ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. Liver Transpl 12:1464–1472, 2006.

Indications and Results of Liver Transplantation in Patients with Neuroendocrine Tumors

Metastases from neuroendocrine (NE) tumors of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPTs) can be confined to the liver for long periods and may exhibit slow growth. When considering liver transplantation (LTx) for patients with NE tumors, the expected results with conventional treatment must be weighed against the risk of LTx and immunosuppression. The following indications for LTx may be considered for patients with metastatic NE tumors limited to the liver: (1) tumors not accessible to curative surgery or major tumor reduction; (2) tumors not responding to medical or interventional treatment; and (3) tumors causing life-threatening hormonal symptoms. We excluded patients with poorly differentiated NE carcinoma or well differentiated NE carcinoma with a high proliferation index (Ki 67 > 10%). Over 4 years (1997–2001) we have performed transplants in nine patients (five with EPTs, four with carcinoids) with a mean ± SEM follow-up of 22 ± 5 months (range 4–45 months). Seven patients underwent orthotopic LTx and two multivisceral LTx. Eight patients are alive, six without clinical evidence of disease. Four patients developed recurrent tumors 9 to 36 months after LTx; two were detected at an early stage and underwent resection with curative intent. One patient with multivisceral Tx died after 4 months of posttransplant lymphoproliferative disease without tumor recurrence. In selected series LTx can offer good control of hormonal symptoms, a relatively long disease-free interval, and in individual cases potential cure.