Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Numerical analysis of blood flow in reconstructed glomerular capillary segments.

Poiseuille's formula is conventionally used to calculate hydraulic resistance of blood capillaries. This law, however, applies to tubes with constant diameter and straight axis. Since blood capillaries, especially in the glomerular microcirculation, are far from having these features, we wanted to estimate the effect of the shape of glomerular capillary segments on the calculation of their hydraulic resistance in comparison to the values obtained with Poiseuille's formula. We studied blood flow through capillary segments of a reconstructed glomerular network from a normal Munich-Wistar rat. Geometrical parameters of capillary segments derived from serial section reconstruction of the glomerulus were used to perform numerical analysis of blood flow. Non-Newtonian properties of blood were simulated by calculating apparent blood viscosity as a function of local rheological parameters for each capillary segment. The numerically calculated hydraulic resistances were always higher than those given by the Poiseuille equation (from 22 to 99%), and this was attributed to the geometrical complexity of the reconstructed vessels. We also performed simulations of the blood flow and filtration along the glomerular network using a previously developed theoretical model that considers the topographical organization of the network structure and dimensions of individual capillary segments. Considering higher hydraulic resistances (as estimated with the numerical analysis) we found that the calculated ultrafiltration coefficient did not change appreciably, but the total network pressure drop and the fraction of filtering surface area at filtration equilibrium were higher than previously estimated.

Effects of angiotensin-converting enzyme inhibition on glomerular capillary wall ultrastructure in MWF/Ztm rats.

Previous studies have documented that treatment with angiotensin-converting enzyme (ACE) inhibitors prevents spontaneous proteinuria and enhances the glomerular ultrafiltration coefficient in male MWF/Ztm rats. The aim of this study was to study whether these beneficial effects of ACE inhibitors on glomerular capillary wall function are derived from the preservation of its ultrastructure. Conventional morphometrical analysis of kidney tissue, by light and electron microscopy, was used to quantify glomerular structural changes in the male MWF/Ztm rats treated with the ACE inhibitor cilazapril for 2 and 6 months and in age-matched untreated controls. At the end of the observation periods, both systolic blood pressure and urinary protein excretion were significantly reduced in treated animals as compared with controls. Glomerular volume increased significantly with time but was comparable in control and in treated rats. Surface area available for filtration (measured as peripheral capillary wall) was comparable in control and in treated animals at the same time and increased significantly with time only in treated rats. Mesangial volume was significantly higher in cilazapril-treated animals than in controls after 2 months of treatment and was comparable after 6 months. ACE inhibitor treatment did not induce significant ultrastructural changes such as basement membrane thickness, configuration of epithelial podocytes, and the width and the frequency of the epithelial slit diaphragms. These results indicate that the previously observed increase in the glomerular ultrafiltration coefficient by an ACE inhibitor in these animals is not the consequence of changes in filtering surface area but likely reflects an increase in membrane hydraulic permeability.(ABSTRACT TRUNCATED AT 250 WORDS)