Inge B. Brekke

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.

Unrelated living donors in 141 kidney transplantations: a one-center study.

BACKGROUND Kidney transplantation is the optimal treatment for the majority of patients with end-stage renal disease. However, the shortage of kidneys for transplantation is a global problem, and any attempt to improve the donor situation would be of benefit to the growing number of patients on transplant waiting lists. PATIENTS AND METHODS Since 1984, we have transplanted 141 kidneys from genetically unrelated living donors. Donors were most often spouses and were accepted regardless of HLA match grade. Preemptive transplantation was performed in 39% of the patients. Standard triple-drug immunosuppression with prednisolone, cyclosporine, and azathioprine was used. The patients were followed from 6 months to 13 years. RESULTS The incidence of acute rejection during the first 3 months after transplantation was higher in recipients of grafts from unrelated donors than in recipients of grafts from related living donors or cadaveric donors. However, unrelated living donor grafts survived significantly better than did cadaveric grafts (P < 0.02) and had a survival rate similar to that of living-related donor grafts mismatched for one or both HLA haplotypes. The perioperative complication rate for the donor was low. CONCLUSION We consider unrelated living donors an excellent source for alleviating the shortage of donor kidneys.

Fifteen years' experience with renal transplantation in systemic amyloidosis

Abstract. At our center 62 renal transplantations (31 living donor and 31 cadaveric donor grafts) have been performed in 58 patients with amyloid renal disease since 1974. The amyloidosis was secondary to rheumatic disease in 74 % of the patients. Predialytic transplantation was performed in 28% of the patients. Mean follow‐up time was 5.1 years (0.3–14.5 years). One‐year actuarial patient survival was 79%, decreasing to 65% after 5 years. First graft survival was 74 % at 1 year and 62 % at 5 years. Patient death with a functioning graft caused 16 out of 25 graft losses. Infections caused 11 out of 18 deaths (61 %), more than half of them within 3 months. Renal transplant amyloid was diagnosed in about 10% of the cases (6/ 62); however, only about 3% of the grafts (2/62) were lost. These long‐term results encourage transplantation in amyloid renal end‐stage disease.

Individualized T cell monitored administration of ATG versus OKT3 in steroid‐resistant kidney graft rejection

Abstract: Acute steroid‐resistant rejection episodes are recommended to be treated with set doses of anti‐thymocyte globulin (ATG) or anti‐CD3 monoclonal antibody (OKT3). Individualized T cell monitoring has been proposed as a tool for dose finding. A randomized study comparing the efficacy and safety of ATG (n = 27) with OKT3 (n = 28) in the treatment of biopsy verified acute steroid‐resistant rejection (ASRR) when both drugs were administered on the basis of daily individualized T cell measurements. A drop to below 50 cells/mm3 CD2+ T cells was considered adequate and used to guide the dose of ATG/OKT3. Demographic, clinical and histopathological severities of rejections were equal in the two groups. During the 10 days of T cell monitoring and antibody treatment, 13 patients were in need of dialysis (ATG = 7/OKT3 = 6). Two grafts did not respond to antibody treatment and were lost due to rejection (ATG = 1/OKT3 = 1). There were 26 biopsy verified re‐rejections (ATG = 12/OKT3 = 14) within the first 3 months following antibody treatment. Mean serum creatinine (μmol/L) was similar in the two groups (ATG/OKT3: before rejection 157 ± 72/151 ± 88, at start of antibody treatment 308 ± 125/330 ± 94, end of antibody treatment 254 ± 122/246 ± 144 and at follow‐up after a mean of 32 months 166 ± 55 (n = 24)/164 ± 57(n = 23)). To keep the T cell count below 50 cells/mm3, average dose ATG given was 354 ± 151 mg (2.3 administrations, range 1–4) and average OKT3 was 32.5 ± 6.8 mg in 10 doses. In conclusion, individualized T cell monitored administration of ATG and OKT3 is safe and seems as effective as a standard set dose in treatment of ASRR. Tailoring the dose for each individual patient lowers the cost.

Aortoiliac reconstruction in preparation for renal transplantation.

Aortoliac angiography has always been an integral part of the pretransplantation work-up of renal transplant candidates in Norway. The present study was undertaken to investigate the value of this routine. Based on the angiograms of approximately 1400 patients evaluated for renal transplantation during the 7-year period 1984–1991, 26 were found to have aortic and/or iliac atherosclerosis requiring pretransplant vascular reconstruction. Fifteen of the 26 patients had aneurysm of the abdominal aorta and 11 had extensive aortoiliac occlusive disease. A prosthetic graft was inserted in 25 patients and endarterectomy of the aortic bifurcation was performed in one. The cause of death was coronary heart disease in four of six patients who died before, and in one patient who died after, transplantation. Sixteen patients received a renal transplant while four patients are still on the waiting list. Fifteen of the recipients are alive, 14 with functioning renal transplants. The low yield of patients below 40 years of age requiring vascular reconstruction calls into question the routine use of angiographic investigation of renal transplant candidates below this age. However, we recommend this routine for the higher age groups because it often provides the surgeon performing the transplantation with valuable information. Aortoiliac reconstruction as preparation for renal transplantation is advocated when atherosclerosis of a degree that may preclude transplantation is found. Because of the high risk of myocardial infarction in these patients, one must be especially aware of coronary atherosclerosis when evaluating patients for this procedure.

Long-Term Endocrine Function of Duct-Ligated Pancreas Isotransplants in Rats

Duct-ligated pancreas transplants were used to study the long-term B cell function after total acinar atrophy. Vascularized whole-organ pancreas transplantation was performed in 47 streptozotocin-diabetic inbred Wistar rats. Of 31 recipients which survived the first week, 30 were permanently cured of the diabetic state with restoration of normal blood glucose levels within 24 h. Metabolic and morphologic studies were performed for up to 16 months after transplantation, i.e. for most of the normal life span of the rats. The recipients of duct-ligated, heterotopic transplants demonstrated plasma insulin (IRI) values slightly above normal. Median blood glucose values were significantly lower than in the normal controls. Basal and stimulated IRI as well as glucose tolerance tests failed to reveal any reduction in the endocrine capacity of the transplants as compared to nondiabetic control. Light-microscopic examinations of grafts showed total acinar atrophy after the first weeks of duct occlusion. No apparent reduction of islet tissue was noted. The results demonstrate that total occlusion of the exocrine ductal system does not impair B cell function of the rat pancreas. The duct-ligated pancreatic transplant permanently reverses induced diabetes when pancreatitis and immunologic reactions are avoided.

Long-term metabolic control in recipients of combined pancreas and kidney transplants

SummaryMetabolic glucose control was followed in 36 patients at 12-month intervals for up to 5 years after a successful combined kidney and segmental duct-occluded pancreas transplantation. All recipients had normal blood glucose levels at each examination. HbA1 values, intravenous glucose tolerance test, C-peptide levels and C-peptide responses to glucagon stimulation were also, on average, within the normal range. Several individual patients had, however, abnormal values for these parameters. At most 46% had abnormal values for HbA1 and intravenous glucose tolerance test, up to 13% showed low C-peptide values and up to 46% of the stimulated C-peptide responses were inadequate at the different intervals. These parameters did not deteriorate with time. This was true both for the whole group of patients as well as for the 6 patients with a 5-year observation time evaluated separately. Despite these abnormalities in glucose metabolism, all patients remained normoglycaemic without need for exogenous insulin up to 5 years after transplantation. The long-term ability of duct-occluded segmental pancreatic grafts to preserve euglycaemia therefore seems to remain intact at least for 5 years.

Long-Term Metabolic Control in Recipients of Segmental-Pancreas Grafts With Pancreaticoenterostomy or Duct Obstruction

Metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy (performed in Stockholm) or duct obstruction by polymer injection (performed in Oslo) were compared. The recipients were uremic diabetic patients and also received a kidney from the same donor. Because the patient population in the two Scandinavian countries is very similar and the immunosuppressive protocols used are almost identical, such a comparison seemed reasonable. The number of patients available for study at 1, 2, and 3 yr was 22, 10, and 4, respectively, with duct injection and 28, 10, and 3 with pancreaticoenterostomy. The mean age of the patients was somewhat higher in the Oslo series. There were no significant differences regarding immunosuppression or kidney-graft function as estimated by serum creatinine at 1, 2, and 3 yr. No significant differences were found in fasting blood glucose, glycosylated hemoglobin, and intravenous glucose tolerance between the two groups at 1, 2, and 3 yr.

Long-term effect of pancreas transplantation on diabetic hyperglucagonemia.

Pancreas isotransplantation was performed on streptozotocin-diabetic Wistar rats. To study the influence of the graft on diabetic hyperglucagonemia, immunoreactive glucagon (IRG) and its response to alanine (peak IRG) were determined in peripheral blood at intervals for up to 8 months after the transplantation. Concentrations of IRG and immunoreactive insulin (IRI) in effluent blood from host pancreas (portal vein) and graft (caval vein) were measured 4 months after the transplantation to estimate the hormone release from both organs. Following transplantation, caval IRI increased sixfold. Portal IRI increased 180% and reached 65% of the concentration observed in control rats. Peripheral basal and peak IRG were initially restored to normal, but were later increased to levels equal to those of diabetic rats. Also portal and caval IRG concentrations were similar in recipients and diabetic rats. The results show that relatively small amounts of glucagon are released from the graft, and that the exaggerated glucagon release from the host pancreas is only transiently normalized following pancreas transplantation.

Extracorporeal Renal Surgery and Autotransplantation

Effects of Renovascular Disease and Autotransplantation on Blood Pressure and Renal Function.- Radiological Investigation and Interventional Procedures in Patients with Renal Artery Disease.- Renal Radionuclide Studies.- Nephrectomy and Extracorporeal Renal Preservation: Technical Details.- Renal Autotransplantation: Indications, Basic Surgical Techniques, and Complications.- Renal Artery Atherosclerosis.- The Role of Bench Surgery in the Treatment of Renal Artery Stenoses and Aneurysms Caused by Fibromuscular Dysplasia.- Complicated Renal Calculous Disease Treated by Extracorporeal Surgery and Autotransplantation.- Ex Vivo Renal Resection and Autotransplantation for Renal and Urothelial Carcinoma.- Simultaneous Aortic Reconstruction and Renal Autotransplantation.- Management of Ureteral Defects by Renal Autotransplantation.