Adrian D. Hibberd

Behavioral conditioning prolongs heart allograft survival in rats

Conditioned immunosuppression using a taste aversion paradigm has been demonstrated in a number of laboratory models but few reports have demonstrated changes in immunity sufficient to be of clinical relevance. The experiments reported here demonstrate that the survival of heart allografts in rats can be prolonged by behaviorally conditioned immunosuppression using cyclosporin A (CsA) as an unconditioned stimulus in taste aversion conditioning. Conditioned animals received saccharin as the conditioned stimulus paired with an injection of CsA at 10 and 6 days prior to transplantation. They were reexposed to saccharin alone 1 day prior to and 3 days after transplantation. On these occasions the conditioned group displayed taste aversion behavior when offered saccharin and a significant prolongation of heart graft survival was observed compared to the conditioned and nonconditioned control groups. These experiments suggest that behaviorally conditioned immunosuppression may have important clinical implications as an adjunct to drug treatments in transplantation medicine.

Use of the Fistula Assessment Monitor to Detect Stenoses in Access Fistulae

Twenty-three unselected hemodialysis patients with functioning access arteriovenous fistulae were studied prospectively to determine the best technique for detecting stenoses within the fistulae. Combined clinical assessment and fistula assessment monitoring were compared with transbrachial angiography. Fistula assessment monitoring was more accurate (96%) than combined clinical assessment (accuracy, 52%) in stenosis detection. Complications of angiography occurred in 17% of patients; there were no complications of fistula assessment monitoring. Fistula assessment monitoring was better than combined clinical assessment in predicting clinical outcome for arteriovenous fistulae over 6 months and was as good as angiography. Routine fistula assessment monitoring could reduce inappropriate angiography and detect clinically significant silent stenoses. It is an ideal method for monitoring arteriovenous access fistulae.

Castanospermine, an oligosaccharide processing inhibitor, reduces membrane expression of adhesion molecules and prolongs heart allograft survival in rats

Abstract The inhibition of intracellular oligosaccharide processing is a new approach to immunosuppression in allotransplantation. The net effect of such inhibition is reduction in the membrane expression of certain glycoproteins. Hence cellcell interaction in allorejection may be impaired in the presence of glycoprotein processing inhibitors because the expression of key ligand-receptor pairs of N-linked glycoproteins including adhesion molecules is inhibited. The aims of this study were to measure the immunosuppressive ability of castanospermine (CAST) in a rat heart allograft model, to measure its effect on membrane expression of adhesion molecules (LFA-1α, LFA-1β, ICAM-1), class I and class II MHC antigens and on other T cell associated molecules (CD4, CD8, CD39, CD45, W 3 13 ), to test its tolerogenic potential and its toxicity. Membrane expression of these molecules was measured by flow cytometry for single cells and by immunoperoxidase staining for the allograft. In grafted rats CAST significantly reduced the expression of LFA-1α on lymphoid cells in the thymus, lymph node, spleen and heart allografts, ICAM-1 expression on endothelial cells of the allograft vasculature, class I and class II MHC expression on lymphoid cells in the thymus, class II MHC expression on lymphoid cells in the allograft; and CD4, CD8, CD45 and W 3 13 expression on lymphoid cells in some organs. By contrast, in non-grafted rats CAST significantly upregulated expression of class I MHC and CD45 in the thymus, lymph node and spleen, ICAM-1 and CD4 on lymphoid cells in the spleen, but reduced expression of LFA-1α on lymphoid cells in the thymus. It also prolonged rat heart allograft survival in a dose-dependent manner and with limited testing was relatively non-toxic. In conclusion, CAST is an immunosuppressive molecules which may work by downregulation of the ligand-receptor adhesion molecule pair, LFA-1α-ICAM-1 although subtle downregulation of class I and II MHC, CD4 and CD8 molecules could also contribute to its immunosuppressive activity. Hence, both lymphocyte-endothelial cell binding and lymphocyte activation may be inhibited by CAST. This work suggests that CAST may hold significant potential as a transplant immunosuppressant probably as an adjuvant agent to inhibitors of interleukin 2 secretion.

Eosinophils in acute renal allograft rejection.

Tissue eosinophils have been previously implicated in allograft rejection and graft loss. The aim of this study was to evaluate the role of eosinophils in acute renal allograft rejection. Data from 71 patients with 114 renal biopsies with acute allograft rejection were compared with those from 26 controls. The median tissue eosinophil density (0.4-1.1 eosinophils per micron2 x 10(6)) and the median peripheral blood eosinophilia (1.5-3.0%) in all grades of acute interstitial rejection and in acute vascular rejection were higher than in controls (0.0 eosinophils per micron2 x 10(6), p < 0.0023, and 0.9%, p < 0.035). In all grades of rejection, 36-54% of biopsies had tissue eosinophil density > or = 1 eosinophil per micron2 x 10(6), and 20-36% of patients had peripheral blood eosinophilia > or = 4%, compared with 0% and 4%, respectively, in controls (p < 0.000 and p = 0.0245). The sensitivity, specificity and overall accuracy of predicting acute rejection with tissue eosinophil density > or = 1 eosinophil per micron2 x 10(6) is 41%, 100% and 52%, and for peripheral blood eosinophila > or = 4% is 23%, 96% and 40%, respectively. The median tissue eosinophil density in acute rejection with graft loss was 1.9 eosinophils per micron2 x 10(6) compared to 0.2 eosinophils per micron2 x 10(6) in acute rejection without graft loss (p = 0.014), and 67% of acute rejection with graft loss had tissue eosinophil density > or = 1 eosinophil per micron2 x 10(6) compared with 28% of acute rejection without graft loss (p = 0.028).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the Bioequivalence of a Generic Cyclosporine A by a Randomized Controlled Trial in Stable Renal Recipients

Background. The aim of this study was to determine the bioequivalence of Cysporin, a generic cyclosporine A, compared with Neoral in stable renal transplant recipients. Methods. Study design consisted of an open label, two-way crossover, randomized controlled trial of Cysporin versus Neoral in stable renal transplant recipients. In all, 33 patients were enrolled; 31 were randomized and 28 were evaluable. AUCs 0–12 were done on day 14 and 28; C0 and C2 were done on days 0, 7, 21 and 35. Dose conversion was 1:1. Outcome measures for serum cyclosporin A concentrations expressed as the mean±SD were AUC 0–12 (&mgr;g.hr/L), Cmax (&mgr;g/L), C2 (&mgr;g/L), Tmax (hr) and T1/2 (hr). Mean and 90% CI of the ratio Cysporin/Neoral of log-transformed data were calculated using a general linear model. Results. The main pharmacokinetic features were: AUC0–12: Cysporin 3495±1319, Neoral 3853±1378 (P<0.05); Cmax: Cysporin 755±301, Neoral 881±368 (P<0.05); C2: Cysporin 613±235, Neoral 672±255 (P>0.05); Tmax: Cysporin 1.9±0.8, Neoral 1.4±0.6 (P<0.005); and T1/2: Cysporin 8.8±4.3, Neoral 8.7±6.2 (P>0.05). Estimated ratios of Cysporin/Neoral were: AUC 0.93 (90% CI 0.88–0.98; P<0.05); Cmax 0.88 (90% CI 0.80–0.97; P<0.05); and Tmax 1.32 (90% CI 1.14–1.53; P<0.005). Conclusions. Both the extent and rate of absorption of Cysporin are significantly less than those of Neoral. The 90% CI for the ratios of Cysporin/Neoral for AUC and Cmax lie within 0.80–1.25. Hence in this clinical context Cysporin is pharmacologically bioequivalent with Neoral. This study illustrates the importance of testing bioequivalence of generic cyclosporine A products in transplant recipients not healthy volunteers.

Why potential live renal donors prefer laparoscopic nephrectomy: a survey of live donor attitudes

To address donor attitudes and reasons for selecting either laparoscopic or open donor nephrectomy (LDN, ODN), as despite the increased interest in laparoscopic procedures, organ donation continues to lag behind the demand for organs, and many new initiatives have failed to reduce the gap.

Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study.

Background To measure the risk of cancer in renal transplantation for recipients who had previously been treated with immunosuppressive agents for primary renal disease. Methods A retrospective population-based cohort study of 5970 renal transplant recipients in Australia registered on the Australia and New Zealand Dialysis and Transplant Registry between 1982 and 1997 and followed until 2007. Data about the incidence of a range of cancer types from this Registry were compared with cancer incidence data for the general population matched for cancer type, year of incidence, age, and gender derived from national cancer records. Outcome measures for each cancer group with or without pretransplantation immunosuppression were cancer-specific standardized incidence ratios and a multivariate hazard ratio (HR) standardized to 1. Results For those treated with pretransplantation immunosuppression, the risks for four cancer groups during renal transplantation were significantly increased: anogenital cancer (HR, 3.13; confidence interval [CI], 1.92–5.11; P<0.0001), non–Hodgkin’s lymphoma (HR, 2.37; CI, 1.53–3.68; P=0.0001), breast cancer (HR, 2.52; CI, 1.13–5.61; P=0.024), and urinary tract cancer (excluding kidney) (HR, 1.84; CI, 1.13–3.01; P=0.015). However, the risks of cancer in the oral cavity and pharynx, kidney, thyroid, colon, leukemia, lung, melanoma, prostate, and stomach were not significantly increased. Conclusions Pretransplantation immunosuppression for primary renal disease increases the risks of four cancer types in renal transplantation while sparing the others. Patients in whom this treatment is being considered should be informed of these risks.

Salvaging kidneys with renal allograft compartment syndrome.

Renal allograft compartment syndrome is an under recognized cause of early allograft dysfunction which can be reversed by early intervention. It occurs early after renal transplantation where closure of the anterior abdominal wall seems to compress the transplant in the limited retroperitoneal space. The literature about this syndrome in renal transplantation is sparse. Our report describes the diagnostic criteria and the management of two renal transplant recipients with this syndrome. Its diagnosis depends upon duplex vascular scan findings of reversed or absent diastolic flow in the renal vasculature in the absence of any perigraft collection or severe acute tubular necrosis. In our hands emergency laparotomy, decompression of the transplant and closure with interposition mesh salvaged these kidneys.

Measurement of glomerular filtration rate in renal transplant recipients: A comparison of methods

SUMMARY: While single injection radionuclide and radio‐contrast glomerular filtration rate (GFR) clearance methods are widely used, the relative accuracy of single versus multiple sample techniques continues to be debated. In addition, GFR calculated from the serum creatinine concentration is considered by some to produce results comparable to clearance methods. In this study, 109 patients with stable renal transplant fraction were prospectively evaluated by yearly 51Cr EDTA clearance as well as by three published formulae used to predict GFR from serum creatinine. Analysis of 362 measurements demonstrated a highly significant correlation between multiple and single point clearance results, as well as the serum creatinine nomograms using least squares regression analysis (P<0.001). the mean GFR was, however, significantly higher using the Cockcroft and Gault formula; 64 ± 18 compared with 47 ± 14 and 50 ± 14 with other serum creatinine formulae, and 46 ± 21–50 ± 17mL/min per 1.73m2 with the three 51Cr EDTA methods (P<0.01). However, further statistical analysis using more appropriate methods, including an analysis of difference and least product regression analysis did not support any of the methods tested as reliable alternatives to multiple sample 51Cr EDTA clearance, because both fixed and proportional bias was noted. In a subgroup of 29 patients evaluated yearly over the 7‐year study period, serum creatinine derivations all demonstrated a greater year to year mean fluctuation compared with clearance methods. It is oncluded that while each GFR method has similarities, they are not interchangeable. Until clearance methods and serum creatinine formulae are directly compared with inulin clearance with the use of appropriate statistical evaluation, it is recommended that the Chantler 3 sample 51Cr EDTA method be the method of choice in clinical laboratories.

Reversal of acute glomerular renal allograft rejection : a possible effect of OKT3

Abstract. A major cause of renal allograft loss is glomerulovascular rejection. This case report is about an episode of histologically proven acute glomerular rejection that was successfully reversed. Monoclonal antibody OKT3 may have been the effective agent.