Early, abrupt conversion of de novo renal transplant patients from cyclosporine to everolimus: results of a pilot study.

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.

Should kidneys from older cadaveric donors be age-matched to the recipient?

Persistent shortage of kidneys for transplantation has forced most transplant centers to include procurement and use of kidneys from older donors. It is not clear whether the optimal use of these kidneys involve age-matching to the recipient. The aim of this study was to evaluate the clinical outcome of older cadaveric kidneys (>60 years), transplanted to young recipients (<50 years) and older recipients (>60 years). From 1989 through 2002, 252 first kidney grafts were procured from donors above the age of 60; 149 of the recipients to these grafts were above 60 years and 45 recipients were below 50. Minimum follow-up time was 12 months. Variables for waiting time to transplantation, DR mismatches, PRA, dialysis prior to transplantation, episodes of acute rejection, number of steroid-resistant rejections, creatinine levels, cold ischemia time, and causes of graft loss did not differ between the two groups. There was no significant difference in graft survival for young and older recipients receiving kidney from donors above 60 years of age. Graft survival at 1 year for young recipients was 90% and for older recipients 93% (NS). Five-year graft survival was 72% and 79%, respectively (NS). However, there was a significant positive effect on long-term graft survival if the donor kidney was less than 50 years. From our data, there is no evidence that age-matching of older donors has any beneficial effect on graft survival in kidney transplantation.

Selected activities in Scandiatransplant.

Scandiatransplant is the Nordic organ exchange organization. It has existed for 35 years and it is owned by all organ transplantation hospital departments in the five Nordic countries--Denmark, Finland, Iceland, Norway, and Sweden. The use of living organ donors for kidney transplantation has become a more common procedure not only in Norway but also in Sweden and Denmark. For the first time, in 2003, one transplant center performed relatively more living donor kidney transplantations than with deceased donors. The overall organ transplant activity reveals a remarkably stable situation in the area covered by Scandiatransplant. Scandiatransplant as an organ exchange organization has changed from a solely kidney exchange organization to an organization in which the more immediate vital organs as liver and heart are exchanged more commonly than kidneys.

Monitoring of azathioprine treatment by determination of 6-thioguanine nucleotide concentrations in erythrocytes.

Thioguanine nucleotides (6-TGN) are intracellular metabolites that may contribute to the antiproliferative effects of AZA. The objectives of our study were to describe the variability of 6-TGN concentrations during AZA therapy and to investigate possible correlations between 6-TGN levels and subsequent myelosuppression. We measured 6-TGN concentrations in RBC of 65 renal transplant recipients from day 0 until 11-64 days after transplantation. High 6-TGN concentrations were observed in relation to elevated S-creatinine. In 15 patients, 6-TGN concentrations above 200 pmol/8 x 10(8) RBCs were measured (high 6-TGN group: mean maximal 6-TGN = 552 pmol/8 x 10(8) RBCs, SE = 91). In the remaining 50 patients, mean maximal 6-TGN was 82 pmol/8 x 10(8) RBCs, SE = 6.1 (low t-TGN group). In the former group, mean S-creatinine measured on the day of maximal 6-TGN was 466 mumol/L (SE = 62.3), while in the latter it was 190 (SE = 14.7). In the high 6-TGN group, we observed a lower mean nadir neutrophil count than in the low 6-TGN group (3.4 vs. 5.1 x 10(9) neutrophils/L). The nadir neutrophil count occurred, on the average, 12.7 days after maximal 6-TGN in the high 6-TGN group, with no such delay in the low 6-TGN group. This study demonstrates for the first time that 6-TGN in RBCs may rise to very high levels during impaired renal function. Furthermore, the results support the hypothesis that myelosuppressive side effects of AZA therapy correlate with 6-TGN concentrations. Renal transplant recipients may benefit from the monitoring of AZA through RBC 6-TGN measurements.

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.

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.

Alterations in lymphocyte subsets in blood may predict resectability in carcinoma of cardia or oesophagus.

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.

Morphological studies of baseline needle biopsies from living donor kidneys: light microscopic, immunohistochemical and ultrastructural findings.

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.

Cell-mediated immunity in anorexia nervosa augmented lymphocyte transformation response to concanavalin A and lack of increased risk of infection.

Cell-mediated immunity (CMI) was studied in 33 consecutively admitted patients with anorexia nervosa (AN) who had a mean weight loss of 30%. Clinical infections were not diagnosed in the patients. The acute phase reactant, C-reactive protein, was slightly elevated in only one patient, but was within the normal range in the remainder. The absolute number of T-lymphocytes in peripheral blood was significantly increased (p < 0.01) in the AN-patients compared to the control group while the number of granulocytes was reduced (p < 0.01). However, a significant negative correlation between the relative weight loss and the numbers of both total and T-lymphocytes in the AN-patients was established (p < 0.05). Mitogen stimulation of lymphocytes with phytohemagglutinin (PHA), poke-weed-mitogen (PWM) and concanavalin A (Con A) showed no reduction in the proliferative response in AN-patients compared to the control group. On the contrary, Con A transformation was significantly higher (p < 0.03) in the AN-patients. The lymphocyte response to PWM (p < 0.02) was, however, diminished in the patients with the most advanced weight loss compared to those with the least weight loss.

Alterations in serum cortisol, CD4+ CD8+ lymphocyte sub-population ration and T cell mediated suppression of immune responses in the malnutrition of anorexia nervosa.

Serum cortisol and T lymphocyte sub-populations (CD3+, 4+ and 8+) were studied in 22 consecutively admitted patients with anorexia nervosa (AN) who had a mean weight loss of 30%. In addition Concanavalin A (Con A) mitogen induced T cell suppression of lymphocyte response to PPD (purified protein derivative of tuberculin antigen) was analysed. Increased serum cortisol concentrations were found in the AN-patients compared to the control group, with mean levels 654 and 418 nmol/l respectively. The relative numbers of CD4+ lymphocytes (mean 36.2%) and the CD4+ CD8+ ratio (mean 1.54) were significantly reduced (p < 0.05) in the AN-patients compared to the control group (mean 41.6% and 2.14 respectively). T cell mediated, Con A induced suppression of lymphocyte response to PPD was increased in AN-patients compared to the control group with low (1mug/ml) Con A concentration, but unchanged with high (5 mug/ml) Con A concentration. There was no correlation between serum cortisol concentrations and the numbers of T lymphocyte subpopulations or T cell suppressor activity. In contrast, a highly significant correlation existed between serum cortisol and the duration of AN (p < 0.002), but not with relative weight loss or anthropometric variables: triceps skin-fold (TSF) and arm muscle circumference (AMC). Immunological variables were not correlated with duration of disease. Thus, immunological alterations of the T cell system are detectable in AN, but are subtle and their clinical importance is not well known.