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In a single-center study, 20 kidney transplant patients without prior rejection were abruptly converted from cyclosporine to everolimus at seven wk post-transplant. All patients received basiliximab induction with maintenance enteric-coated mycophenolate sodium and corticosteroids. Biopsy-proven acute rejection had occurred in three of 20 patients (15.0%) by the end of week seven post-conversion. All episodes were mild and reversible, with subsequent recovery of renal function. Calculated glomerular filtration rate (GFR) improved significantly (51 +/- 11 mL/min at time of conversion, 58 +/- 12 mL/min at week seven post-conversion, 57 +/- 17 mL/min at month six post-conversion; p = 0.001). No patient developed proteinuria in the nephrotic range. Twenty-two adverse events were reported in 10 patients, three of which had a suspected relationship to everolimus. Mean leukocyte and platelet count decreased significantly, and triglyceride level increased. This study suggests that kidney transplant patients without prior rejection can be converted abruptly from cyclosporine to everolimus at seven wk post-transplant, resulting in significantly improved renal function with no apparent increase, in risk of rejection and good tolerability.

Background. To gain insight into complement activation in kidney grafts, we studied the deposition of components from all complement pathways in protocol biopsies from living-donor recipients that were taken 1 week (median 7 days) after transplantation. Methods. Graft protocol biopsies (n=37) were taken consecutively and stained for two-color immunofluorescence, with antibodies to C4d, C3, C1q, factor B, C6, terminal C5b-9 complement complex, mannose-binding lectin (MBL), and MBL-associated serine protease-1, combined with an endothelial marker. Light and electron microscopy were performed in all cases. Clinical acute rejection (AR), graft loss, and long-term kidney function were recorded. Baseline biopsies from 15 of the patients served as controls. Results. Endothelial C4d deposition was demonstrated in peritubular capillaries in 11 of 37 cases (30%), of which 9 of 11 (82%) experienced clinical AR but only 6 of 11 (55%) experienced AR as defined by histopathologic criteria. Biopsies from three patients, two with early graft loss, showed diffuse global C4d in the glomerular endothelium with codeposition of C3 in all patients and MBL-associated serine protease-1 in one patient. Focal peritubular capillary C3 deposition was found in two additional C4d-positive cases with AR. No posttransplant deposition was demonstrated for the other components. Conclusions. Early diffuse C4d deposition in the kidney graft capillaries is closely related to acute humoral rejection, whereas focal staining may occur with mild AR or, rarely, without rejection. Codeposition of C3 indicates early AR with a higher risk of graft loss. In most cases, activation was limited to C4d, indicating efficient in situ regulation of complement activation.

Background. T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lasting 1 year and performed in 10 transplant centers in Europe. Methods. A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. Results. There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). Conclusion. Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.

BACKGROUND: Azathioprine (AZA) is widely used in organ transplantation. Common practice is to adjust dose according to body weight only, despite documented pharmacokinetic variability. The purpose of this study was to investigate whether high-dose AZA treatment monitored by 6-thioguanine nucleotides (6-TGN) levels reduces the incidence of rejection episodes in renal transplantation without a corresponding increase in myelotoxicity. METHODS: Patients receiving cyclosporine, steroids, and AZA were randomized into either the low-dose AZA group (3 mg/kg on day 0, then 2 mg/kg/day the first week and 1 mg/kg/day thereafter) or the high-dose AZA group. In the latter, AZA was started at 5 mg/kg/day and then adjusted to keep 6-TGN concentrations (measured twice weekly) between 100 and 200 pmol/8 x 10(8) RBCs. RESULTS: A total of 360 transplant recipients were included in the final analysis. The cumulative incidence of first rejection episodes was reduced by 21%, from 62.8% in the low-dose group to 49.4% in the high-dose group (difference: 13.3%; 95% confidence interval: 3.2-23.5). Similar results were found in subgroups according to HLA-DR match. The 6-TGN concentration was significantly higher in the high-dose AZA group during the first month, and the reduction in rejection episodes was achieved in the same period. A larger proportion of patients in the high-dose group had nadir white blood cell count below 2.0 x 10(9) leukocytes/L (13.3% vs. 4.4%; difference: 8.9%; confidence interval: 3.1-14.7). CONCLUSIONS: High-dose AZA therapy in a triple-drug regimen, monitored by 6-TGN, will keep myelotoxicity within acceptable limits with the benefit of a reduction in acute rejection episodes.

Fifty-seven consecutive living donors (31 women and 26 men aged 20.7-72.3 years, mean 50.6 years) were subjected to needle biopsy during nephrectomy, immediately before removal of the kidney. By light microscopy, semiquantitative scoring (0-3) was performed for arteriosclerosis, arteriolar hyalinosis (hyalin arteriolosclerosis), glomerulosclerosis, interstitial mononuclear cell infiltration, and interstitial fibrosis/tubular atrophy. Whereas vascular changes were striking in many biopsies (arteriosclerosis grades 2-3: 28/54 cases, arteriolar hyalinosis grades 2-3: 15/55 cases), glomerular and tubulointerstitial changes were mostly low grade. The morphological changes tended to be more pronounced in middle-aged and older individuals, but, in particular, vascular changes were seen also in the younger age group. Immunofluorescence microscopy revealed glomerular granular staining for IgM in 52.7% of the cases, IgA in 9.1%), IgG in 1.8%, and C3 in 12.7%. The main ultrastructural finding was glomerulosclerosis; one case with diffuse glomerular IgA showed distinct dense deposits, and one case showed similar dense deposits without IgA deposition. Arteriolar wall deposition of C3 was found in 58.2% of the cases, and IgM in 10.9%. Especially C3 occurred both with arteriolar hyalinosis and in arterioles without light microscopic alterations. The observation of significant vascular changes in baseline biopsies is relevant especially in the differential diagnosis of chronic rejection and cyclosporine nephropathy. The immunohistochemical findings strongly indicate the occurrence of immunoglobulins and complement factor C3 in both glomeruli and arterioles without clinical or morphological signs of renal disease. The possible pathophysiological significance of such deposits remains, however, uncertain.

The objectives of this study were to establish monitoring of azathioprine (AZA) treatment in renal allograft recipients by red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) measurements and to characterize the variability of RBC thiopurine methyltransferase (TPMT) activity and the effects on 6-TGN levels and the incidence of rejection episodes. In 82 renal allograft recipients, the effect of standard AZA dosage (3 mg/kg tapered to 1 mg/kg) was compared with higher dosages (3 mg/kg for several days) under 6-TGN monitoring. The authors measured TPMT in these patients and in a group not receiving AZA. The authors did not find an inverse correlation between RBC TPMT activity and 6-TGN concentrations, and baseline TPMT activity did not predict the incidence of rejection episodes The slight increase in RBC TPMT activity after transplant was associated with the use of furosemide rather than AZA; in the five patients receiving furosemide for less than 10 days, TPMT activity declined. The higher AZA dosage in the 6-TGN monitored group was not sufficient to increase RBC 6-TGN to target levels (100 to 200 pmol/8 x 10(8) RBC); median 6-TGN levels were similar in the two groups, as was the incidence of rejection episodes. Based on these findings, the authors suggest that higher dosages be studied in conjunction with 6-TGN monitoring, to explore the possibilities for therapeutic improvements.

The purpose of this study was to examine the pharmacokinetics of mercaptopurine (6-MP) and thioguanine nucleotides (6-TGN) during azathioprine treatment. Plasma profiles and urinary excretion of 6-MP and 6-TGN concentrations in red blood cells (RBCs) were measured repeatedly during the first 3 weeks following transplantation in 10 adults, who had received kidney grafts from living related donors. Mean maximal 6-MP plasma concentration (Cmax) was 340 nmol/L (SD = 290), mean time to Cmax (Tmax) was 2 h (SD = 1.8), and mean area under the plasma concentration-time curve (AUC) was 930 nmol/L/h (SD = 770). The mean fraction of azathioprine dose excreted as 6-MP in urine was 1.32% (SD = 1.11). Up to eightfold variability of Cmax and AUC was observed from day to day within each patient. The correlation between 6-MP AUC and amount excreted in the urine was weak (r = 0.37, 95% CI from 0.02 to 0.64). In this group of patients the observed 6-TGN levels in RBCs were low; maxima during the observation period ranged from undetectable to 250 pmol/8 x 10(8) RBCs. In individual patients, 6-TGN levels were relatively stable throughout the dosing interval ("within-dose-interval-CV" < 19%), even when sharp and high 6-MP peaks in plasma were observed.

In the present study a new method for selectively determining parent cyclosporine (CsA) in whole blood, a fluorescence polarization immunoassay (FPIA; TDx Abbott), was compared with a RIA method (Sandimmun, Sandoz Ltd, Basle, Switzerland). A total of 974 samples were collected during the first 3 post-operative months from 63 renal, cardiac, and liver transplant recipients. The CsA concentrations measured with FPIA ranged from 14% to 19% above RIA (specific) in the middle ranges. Regression equations in renal transplants: FPIA = 1.001 x RIA + 28; in heart transplants: FPIA = 1.08 x RIA + 27 and in liver transplants: FPIA = 1.13 x RIA + 13. Considering the improved precision of the new method (inter-assay CV with FPIA: 3.8-9.5%; with RIA: 18.6%), the slightly lower specificity will usually be of minor importance in the therapeutic range for whole blood CsA concentrations following organ transplantations. The FPIA measurements which deviated most from the regression line compared with RIA-specific CsA values, tended to coincide with high CsA concentrations or rather extreme RIA specific to RIA non-specific ratios. In addition to analytical imprecision with the RIA-specific method, lower specificity of the FPIA vs. some of the metabolites may explain these deviations. The majority of these observations occurred as isolated episodes with normal relationship between RIA specific and FPIA on preceding and following days. Accordingly large dosage adjustments should await verification in repeated samples. Following these precautions the FPIA method may prove useful and safe in the monitoring of cyclosporine treatment.

To gain insight into complement activation in kidney grafts, we studied the deposition of components from all complement pathways in protocol biopsies from living-donor recipients that were taken 1 week (median 7 days) after transplantation.Graft protocol biopsies (n=37) were taken consecutively and stained for two-color immunofluorescence, with antibodies to C4d, C3, C1q, factor B, C6, terminal C5b-9 complement complex, mannose-binding lectin (MBL), and MBL-associated serine protease-1, combined with an endothelial marker. Light and electron microscopy were performed in all cases. Clinical acute rejection (AR), graft loss, and long-term kidney function were recorded. Baseline biopsies from 15 of the patients served as controls.Endothelial C4d deposition was demonstrated in peritubular capillaries in 11 of 37 cases (30%), of which 9 of 11 (82%) experienced clinical AR but only 6 of 11 (55%) experienced AR as defined by histopathologic criteria. Biopsies from three patients, two with early graft loss, showed diffuse global C4d in the glomerular endothelium with codeposition of C3 in all patients and MBL-associated serine protease-1 in one patient. Focal peritubular capillary C3 deposition was found in two additional C4d-positive cases with AR. No posttransplant deposition was demonstrated for the other components.Early diffuse C4d deposition in the kidney graft capillaries is closely related to acute humoral rejection, whereas focal staining may occur with mild AR or, rarely, without rejection. Codeposition of C3 indicates early AR with a higher risk of graft loss. In most cases, activation was limited to C4d, indicating efficient in situ regulation of complement activation.

Metabolic 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.

Introduction. Chronic changes in biopsies from long-term stable kidney allografts have been reported to correlate with graft prognosis. Morphological changes in baseline (zero-hour') biopsies have been described as well, but their importance for long-term prognosis have been less clear. The aim of the present study was to evaluate biopsy changes from baseline to 1 year after transplantation in patients receiving kidneys from living donors, and to assess the possible prognostic implications of these findings. Methods. Light microscopical changes in 18 gauge full-core biopsies were scored semi-quantitatively in 33 patients 1 year after transplantation, and compared to baseline changes previously reported [1]. All cases were also examined with transmission electron microscopy. The semi-quantitative data from baseline and at 1 year were correlated with kidney function 1 and 3 years after transplantation. The reproducibility of baseline findings regarding arteriosclerosis and arteriolar hyalinosis was tested by comparison with biopsies 1 week after transplantation (n=43). Results. We found a significant increase in mesangial glomerular sclerosis (P

Monitoring of azathioprine (AZA) therapy by the measurement of 6-thioguanine nucleotides (6-TGN) concentrations in red blood cells (RBC) may improve safety and ensure optimal immunosuppressive effects of AZA in organ transplantation. The authors explored the rationale for such monitoring by measuring thiopurine metabolites in peripheral blood cell types that are more relevant to the effects and kinetics of AZA and its active metabolites. Neutrophil granulocytes were isolated by density gradient centrifugation, and CD4+ lymphocytes and reticulocytes by using specific immunomagnetic beads. In neutrophils, 6-TGN concentrations had median measurements 31 times higher than in RBCs. In contrast to the high methylated mercaptopurine (me-MP) concentrations in RBCs, these metabolites were not detected in the neutrophils. Thiopurine metabolite levels were lower than the analytic limit of detection in all the CD4+ samples. The concentrations of 6-TGN and me-MPs were lower in reticulocytes than in RBCs in general, indicating that thiopurine metabolites are taken up by RBCs in the circulation. This study's findings, that 6-TGN concentrations are very high in neutrophils, whereas me-MPs are undetectable, many explain the specific neutropenic adverse effect of AZA. The results also add support to monitoring AZA through measurements of 6-TGN and me-MPs in RBCs.

In 1966 Scott reported on an attempt to remove a renal tumor at a sidetable, but the renal remnant proved to be insufficient for reimplantation (Scott 1966). From the early 1970s there are case reports about successful bench surgery treatment of renal (Calne 1971; Gelin et al. 1971; Flatmark et al. 1977) and urothelial carcinomas (Rhame 1973; Pettersson et al. 1979). Bench surgery and subsequent renal autotransplantation was shown to be a valid alternative to radical nephrectomy in selected patients with bilateral renal neoplasms or when malignancy occurs in a solitary kidney. However, only a few centers have reported more than ten cases (Rohl et al. 1979; Jacobs et al. 1980; Flatmark et al. 1989; Novick et al. 1990; Stormont et al. 1992), and large series are still lacking.

The management of ureteral defects by renal autotransplantation was first reported by Hardy in 1963, when he described the application of this technique in a patient with severe ureteral injury (Hardy 1963). Renal autotransplantation has since become an established procedure in the treatment of various urological disorders. Some authors have suggested ureteral injury, defect, or disorder to be a main indication for renal autotransplantation (Stewart et al. 1977; Novick et al. 1981; Rembrink et al. 1993). Rembrink et al. (1993) reported excellent results with this technique in the treatment of retroperitoneal fibrosis affecting the ureters, and renal autotransplantation has been shown to represent a valid therapeutic option in patients requiring replacement of all or a major portion of the ureter (Novick et al. 1990).

Impaired immune responses in patients with carcinoma of cardia or oesophagus have previously been reported. However, we do not know whether resectability correlates with specific immunological variables. Immunological assessment was performed in 35 such cancer patients including measurement of total T cells (CD3+) and T cell subsets (CD4+ and CD8+), NK cells (CD16+) and B cells (CD19+) in blood. In vitro lymphocyte responses to phytohemagglutinin (PHA) separated from peripheral blood were quantitated. The numbers in peripheral blood of both total T cells (CD3+) and B lymphocytes (CD19+) were significantly lower in the inoperable patients compared to resected patients (P < 0.01). The number of NK cells (CD16+) was, however, not significantly lower in the inoperable patients compared to the patients operated for cure. Lymphocyte responses to PHA in vitro were similar in resectable and non-resectable patients, but significantly lower in inoperable patients compared to the controls (P < 0.01). In conclusion, resectability in carcinoma of cardia or oesophagus is associated with changes in both T (CD3+) and B (CD19+) cell subsets.

LIVING RELATED liver transplantation (LRLT) in children is well established with excellent results in elective recipients, but this procedure should not be performed in an emergency situation according to the Council of Europe recommendation no. R (97) 16. We have performed LRLT in a child following hepatectomy of the primary liver graft due to thrombosis of both the hepatic artery and the portal vein.

Over a 16-year period (1973–1989), 63 renal autotransplants were performed in 59 patients for fibro-muscular dysplasia (FMD) with renal artery stenoses (42 kidneys) or aneurysms (21 kidneys). About two-thirds of the autotransplants were performed before percutaneous transluminal angioplasty (PTA) was established for clinical use. However, vascular disease at a site or type not suitable for PTA was present in 57 (90%) of the kidneys. Hypertension was the leading symptom in 56 patients, including four in whom renal autotransplantation was performed as an emergency for acute renal artery occlusion or malignant hypertension. Blood pressure returned to normal or improved in 51 (91%) and remained unchanged in five patients (9%) following autotransplantation. Three patients with renal artery aneurysm in whom haematuria and loin pain were the indications for treatment, became asymptomatic following surgical intervention. Bilateral renal autotransplantation was performed synchronously in one and sequentially in three patients. There were no operative deaths, but two kidneys were lost postoperatively in two 2-year-old children owing to renal vascular thrombosis. In the follow-up period (mean 4.3 years), one additional kidney was lost at 3 months owing to progressive FMD. Blood pressure and renal function remained stable in all other patients. Based on the excellent results achieved in this series, it is concluded that extracorporeal vascular repair and renal autotransplantation is a safe procedure for the patient as well as the kidney affected by FMD. The procedure is advocated as an alternative to in situ reconstruction in patients with renal artery disease not accessible to PTA, such as aneurysms and complex branch renal artery stenoses.

Twenty-seven Type I diabetic patients in end-stage renal failure were followed after combined pancreas-kidney transplantation. All patients received duct-occluded segmental pancreas grafts. Clinical progression of extrarenal diabetic complications was studied in 11 patients with long-term functioning pancreatic and renal transplants (Group 1), and in 16 patients who had lost pancreatic graft function, but retained renal graft function (Group 2). Pretransplant, extrarenal diabetic complications were equally distributed in the two groups. In the follow-up period, however, the progress of these complications was less severe in patients with functioning pancreatic transplants. No differences were found between the groups concerning rehabilitation, working capacity, need of help or hospital admittance. It is suggested that pancreas transplantation performed in an earlier stage of diabetes before serious complications have developed, would probably improve rehabilitation and quality of life in these patients.