Øystein Bentdal

A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.

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 lastingl 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.

Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation

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.

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.

Complement activation in early protocol kidney graft biopsies after living-donor transplantation1

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.

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.

Patterns of Azathioprine Metabolites in Neutrophils, Lymphocytes, Reticulocytes, and Erythrocytes: Relevance to Toxicity and Monitoring in Recipients of Renal Allografts

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 studys 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.

Possibilities for Therapeutic Drug Monitoring of Azathioprine: 6-thioguanine Nucleotide Concentrations and Thiopurine Methyltransferase Activity in Red Blood Cells

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.

Kinetics of mercaptopurine and thioguanine nucleotides in renal transplant recipients during azathioprine treatment.

Summary 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 (7max) 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 108 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.

Bilateral nephrectomy simultaneously with renal allografting does not alleviate hypertension 3 months following living-donor transplantation

Severe hypertension prior to renal transplantation has traditionally been an indication for bilateral nephrectomy. The reasons for hypertension after successful renal transplantation are however many, and the impact of simultaneous bilateral nephrectomy (BN) in this setting has not been well documented. We retrospectively evaluated 158 living-donor renal graft recipients. BN had been performed in 76 patients at the time of the transplantation and 82 were not nephrectomized (controls). All received a triple immunosuppressive drug regimen. Before transplantation, patients in the BN group used 1.8 +/- 0.9 (mean +/- SD) antihypertensive drugs/day, significantly more than in the control group (1.3 +/- 0.8; P < 0.05). Three months after renal transplantation no difference was found (0.9 +/- 1.0 drugs/day in the BN group vs 1.0 +/- 0.8 drugs/day in the control group). No difference was found with respect to serum creatinine, whole blood cyclosporin A (CsA) concentration or blood pressure between the groups. The number of blood transfusions during the first week after transplantation was significantly increased in the BN group (66 SAG units vs 4 SAG units). The median hospitalization length was also longer in the BN group (21 days vs 16 days). In order to circumscribe the pre-transplant difference in use of antihypertensive medication we studied a subgroup of 62 hypertensive recipients (BN/control = 31/31) matched for number of antihypertensive drugs at the time of transplantation (2.3 +/- 0.5 drugs/day in the BN group, 2.1 +/- 0.3 drugs/day in the control group). Three months after transplantation the use of antihypertensive drugs remained the same in the two groups (1.3 +/- 1.0 drugs/day in the BN group vs 1.3 +/- 0.9 drugs/day in the control group). At 3 months no difference was found between the two hypertensive subgroups regarding serum creatinine, whole blood CsA and haemoglobin concentration or systolic blood pressure. However, the BN patients were younger than the control group (38 +/- 10 years vs 49 +/- 11 years, P < 0.05) and this may explain the marginally lower diastolic blood pressure observed in the BN group (82 +/- 10 mmHg vs 87 +/- 7 mmHg, P < 0.05). It is concluded that, in recipients of living-donor grafts, bilateral nephrectomy performed at the time of transplantation did not influence the number of antihypertensive drugs used 3 months after a successful transplantation. Bilateral nephrectomy did however increase the need of blood transfusions during the first week after transplantation and also the hospitalization length.

Nutritional assessment of anorexia nervosa patients—Analysis of anthropometric and biochemical variables to evaluate patients at risk

The nutritional status of 33 consecutively admitted patients with anorexia nervosa (AN), was evaluated by anthropometric and biochemical methods. Mean weight loss was 30%, i.e., 17 kg body mass. Both mean triceps skin fold (TSF) and arm muscle circumference (AMC) were below the 5th percentile which is an indication of severe malnutrition. Mean creatinine height index (CHI) was 55% of the reference value which is also below the lower limit of the normal range. Serum transferrin was significantly reduced (p<0.01) compared to the control group, while serum albumin and retinol-binding-protein (RBP) were significantly increased (p<0.01) in the AN-group. Serum prealbumin concentration was within the 95% confidence interval of the control group. The levels of serum immunoglobulins IgA and IgM were also well preserved while IgG was significantly decreased (p<0.04). Serum complement C3 component was also significantly reduced (p<0.01), but not the C4 component. Serum zinc and vitamin B12 were found to be within the normal range in most patients, while serum potassium, iron and folic acid were significantly lower (p<0.01) than the control group. There were significant correlations between relative weight loss and both the anthropometric variables TSF (p<0.05) and AMC (p<0.01) on the other hand and the biochemical serum variables: prealbumin (p<0.05), transferrin (p<0.02) and magnesium (p<0.02). The sensitivity and specificity of the best biochemical variable, serum transferrin, was only 87% and 32%. In comparison the sensitivity and specificity of the best anthropometric variable, TSF, to confirm the diagnosis of AN was 100 and 95%, respectively. Extremely low relative weight loss, TSF and AMC values in addition to low serum levels of albumin, zinc and electrolytes were observed in the two patients with fatal outcome who both had bulimic symptoms. In conclusion, a nutritional assessment including both anthropometric and certain biochemical measurements may give valuable information concerning the evaluation of patients at risk.