Acute and chronic vascular rejection in nonhuman primate kidney transplantation.

A nonhuman primate (NHP) study was designed to evaluate in nonlife-supporting kidney allografts the progression from acute rejection with transplant endarteritis (TXA) to chronic rejection (CR) with sclerosing vasculopathy. Group G1 (n = 6) received high cyclosporine A (CsA) immunosuppression and showed neither TXA nor CR during 90 days post-transplantation. Group G2 (n = 6) received suboptimal CsA immunosuppression and showed severe TXA with graft loss within 46 days (median). Arterial intimal changes included infiltration of macrophages and T lymphocytes (CD3, CD4, CD8) with few myofibroblasts, abundant fibronectin/collagen IV, scant collagens I/III, high rate of cellular proliferation and no C4d accumulation along peritubular capillaries. Group G3 (n = 12) received suboptimal CsA and anti-rejection therapy (rabbit ATG + methylprednisolone + CsA) of TXA. Animals developed CR and lost grafts within 65 days (median). As compared to G2, the arterial intimal changes showed less macrophages and T lymphocytes, an increased number of myofibroblasts, abundant fibronectin/collagen IV and scar collagens I/III, C4d deposition along capillaries in 60% of animals and transplant glomerulopathy in 80% of animals. In conclusion, CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts, and progressive deposition of collagens in the intima. Our experimental design appears well suited to study events leading to CR.

Safety of percutaneous ultrasound-guided biopsy of renal allografts in the cynomolgus monkey: results of 348 consecutive biopsies.

The safety of a technique for ultrasound-guided biopsy of renal allografts was evaluated based on 348 consecutive procedures in cynomolgus monkeys. A spring-loaded biopsy device with an 18G tru-cut biopsy needle was used to biopsy renal allografts in 139 cynomolgus monkeys performed either on clinical indication (n = 95 animals) or as serial protocol biopsies (n = 44 animals) for a total of 348 biopsies. Monkeys having serial biopsies received between 3-9 biopsies per animal. All others received non-protocol biopsies that were performed on clinical indication, and the range was 1-15 biopsies per animal. No life-threatening complications or deaths occurred and there were no clinically detectable minor complications such as macrohematuria. Self-limiting complications such as small arteriovenous fistulas (n = 4, 3-5 mm large) were detected with Doppler ultrasound and resolved hemodynamically after 2-4 weeks. Three animals developed hematomas ranging 4 mm-2 cm in diameter and were no longer sonographically evident 2-4 weeks later. Ultrasound-guided biopsy of renal allografts can be performed with a high degree of safety in small (3-5 kg) laboratory animals such as the cynomolgus monkey and provides a valuable tool for renal transplantation research. Even when cores were taken at two week intervals no major complications occurred and only rarely were clinically irrelevant complications detected. Experience with diagnostic ultrasound, both gray scale and Doppler, is important for both safety and the recognition of complications that may arise.

Ultrasonographic findings of functioning renal allografts in the cynomolgus monkey (Macaca fascicularis).

PURPOSE: The purpose of this study was to describe the findings of serial ultrasound investigations of functioning and histologically normal renal allografts in the cynomolgus monkey. METHODS: Ten cyclosporine (Neoral) treated cynomolgus monkeys underwent renal allograft transplantation with bilateral nephrectomy, seven of which were examined serially with ultrasound. Ultrasound findings were compared to serum creatinine, and the results of histology from allograft biopsy on day 150 post-transplantation. RESULTS: Allografts increased in volume up to one and a half to twice that of their original volume and appeared morphologically similar to native kidneys. Allograft ureters were dilated postoperatively but decreased in size with time. Other than in two cases of ureter complications, the resistive index (RI) was normal in functioning grafts. CONCLUSIONS: Elevations in RI, as well as graft enlargement and increased cortical thickness, were related to graft pathology, but not necessarily to rejection histologically. The ultrasound findings of functioning grafts and of surgical complications after renal allograft transplantation in the cynomolgus monkey were similar to those in humans.

Ultrasonography of the normal kidney in the cynomolgus monkey (Macaca fascicularis): morphologic and Doppler findings.

The purpose of this study was to obtain sonographic measures of normal kidneys in cynomolgus monkeys (Macaca fascicularis). The kidneys of 27 healthy female cynomolgus monkeys were examined with two-dimensional, duplex and power Doppler under sedation or general anesthesia. Except for shape and sinus echogenicity, the kidneys of the cynomolgus monkey are morphologically similar to those of humans. Left kidney volume estimations (mean, 5.1 cm3) were significantly smaller (P<0.001) than those of the right (mean, 5.9 cm3), and both increased significantly with increasing body weight (P<0.05, r = 0.408). The mean resistive index (RI) of ketamine-sedated monkeys was 0.54, with an upper limit of 0.74 for the renal artery. The mean RI under general anesthesia was 0.65, with an upper limit of 0.77. Morphologic and Doppler ultrasound assessments of the kidneys can be consistently performed in the conscious cynomolgus monkey, and anesthesia can have hemodynamic effects that alter the Doppler arterial waveform.

The novel immunosuppressant FTY720 induces peripheral lymphodepletion of both T- and B-cells in cynomolgus monkeys when given alone, with Cyclosporine Neoral or with RAD.

OBJECTIVE: FTY720 is a new immunosuppressant active in transplantation models, which modulates lymphocyte recirculation, leading to transient peripheral lymphopenia and increased lymphocytes in lymph nodes and Peyer's patches. Here, we investigated the susceptibility of cynomolgus monkeys to FTY720 given orally either alone or in combination with two other immunosuppressants, Cyclosporin Neoral or RAD, as an introductory study to transplantation protocols. METHODS: Each of the three phases of the study comprised a 3-week treatment period with FTY720 administered daily orally at 0.3, 0.1 or 0.03 mg/kg/day, respectively, followed by a 3-week recovery. FTY720 was given as single compound during the first week and in combination with Neoral at 20 mg/kg/day p.o. or RAD at 0.5 mg/kg/day p.o. during the subsequent 2 weeks. MAIN FINDINGS: These treatment regimen were well tolerated, except for some body weight loss at high FTY720 dose (0.3 mg/kg/day). FTY720 treatment resulted in a rapid decrease of white blood cell counts which reached a plateau after 3 days. A decrease in both T- and B-lymphocyte counts by up to 80-90% was seen with FTY720 doses of 0.1 and 0.3 mg/kg/day. FTY720 blood levels, both trough levels and AUC(0-24 h), showed a linear relationship with FTY720 dose. The reduction in lymphocyte counts was not directly proportional to FTY720 blood levels. The exposure to FTY720 significantly increased upon coadministration of Neoral. This pharmacokinetic interaction was not observed for coadministration of RAD. However, the peripheral lymphodepletion was slightly increased after coadministration of RAD but not of Neoral. This may be related to the intrinsic effects of RAD on hematopoietic cells. CONCLUSIONS: FTY720 given orally was effective in terms of peripheral T- and B-lymphodepletion and was well tolerated in cynomolgus monkeys even in combination with Cyclosporine Neoral or RAD, indicating that such combination protocols could be used in allo- and xenotransplantation in this species. However, the data indicate a potentiation of FTY720 exposure by CsA coadministration and additional lymphodepletion by coadministration of FTY720 and RAD which should be carefully monitored.

[Is insufflation with carbon dioxide as an ambulatory procedure for evaluating tubal patency obsolete today?]. / Ist die Pertubation mit Kohlendioxid als ambulantes Verfahren zur Prüfung der Tubendurchgängigkeit heute obsolet?

UNLABELLED: Tubal insufflation with carbon dioxide is one of the ambulatory and non-invasive procedures in use for the evaluation of tubal patency. The aim of the present study was to investigate whether the findings obtained at tubal insufflation are reliable enough to avoid laparoscopy with instillation of dye for its inherent risk of severe operative complications. Diagnostic accuracy, positive and negative predictive value of tubal insufflation were compared with that of the reference method (laparoscopy) in 107 infertile patients of childbearing age without previous pelvic inflammatory disease, tubal or ovarian surgery. No result was obtained from tubal insufflation in 13 patients for intolerance or technical problems. The positive predictive value (percentage of correct positive findings, i.e., tubes patent) was 0.79 (130/165 tubes), the negative predictive value (percentage of correct negative findings) 0.43 (10/23) with an overall diagnostic accuracy (percentage of correct findings) of 0.74. If both tubes were reported patent on insufflation (68 patients), this finding was confirmed in 82% (56/68) on laparoscopy. The remaining 18% also include the rate of false negative findings (tubes falsely reported as occluded) on laparoscopy which may account for up to 10% according to the literature. False negative findings on insufflation were reported at a frequency of 21% (35/165 tubes). COMMENT: The diagnostic accuracy of tubal insufflation with carbon dioxide is definitely inferior to that of laparoscopy. In view of the frequency of false negative findings, its use as a screening procedure should be restricted to young patients with a low probability of tubal occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the new calcium antagonist PN 200-110 on the myocardium and the regional peripheral circulation in anesthetized cats and dogs.

The effects of PN 200-110 (PN), isopropyl 4-(2,1,3- benzoxadiazol -4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dim ethyl-3- pyridinecarboxylate , on the cardiovascular system were investigated. In chloralose-urethane-anesthetized cats PN decreased blood pressure (BP) and heart rate (HR) and increased cardiac output (CO) and total peripheral resistance dose dependently after intravenous doses of 1-10 micrograms/kg. Regional blood flow changes effected by an intravenous dose of 10 micrograms/kg were measured with microspheres. Flow to the heart, brain, and skeletal muscle increased selectively, and intramyocardial flow was redistributed in favor of the left ventricular subepicardial layer. The duration of action differed for various effects. The bradycardia was short lasting, and the cerebral vasodilatation persisted longest. It was not possible to predict the duration of action of PN on different target tissues by observing only one variable such as BP. Chloralose-urethane-anesthetized open-chest dogs appeared to be more sensitive to PN than cats. A dose of 3 micrograms/kg i.v. markedly increased coronary flow, lowered BP, increased CO, and tended to lower HR and to increase myocardial contractility. Myocardial oxygen consumption was lowered. PN did not alter diastolic excitation threshold or any electrocardiographic intervals in closed-chest anesthetized dogs. Absence of myocardial depression, potent vasodilator activity, and long duration of action might render PN useful for the treatment of hypertension and angina pectoris.

Pindolol--the pharmacology of a partial agonist.

1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs.