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To assess the effect of food intake on the pharmacokinetics of grapiprant administered orally at 2 mg/kg, and to estimate its oral bioavailability in dogs.Eight healthy female Labrador Retriever dogs, aged 4-10 years were used. In the initial trial two dogs were administered a 0.5 mg/kg I/V bolus of grapiprant dissolved in ethanol. In the second trial, six dogs were assigned to two treatment groups, using a randomised cross-over design, and received 2 mg/kg of grapiprant orally, as pure powder, after fasting for 12 hours or after being fed. Blood samples were collected at preassigned times up to 36 hours after administration, and concentrations of grapiprant in plasma determined using validated high performance liquid chromatography.After I/V administration in the two dogs the terminal half life was 5.30 and 6.06 hours, clearance was 444 and 476 mL/hours/kg, and volume of distribution was 3,642 and 3,883 mL/kg. Compared with fasted dogs, oral administration in fed dogs resulted in reduced median peak concentrations in plasma (1,598 vs. 614 ng/mL) and delayed median time of peak concentration (1.0 vs. 3.0 hours). The estimated bioavailability in fasted and fed dogs was 111.9 and 59.1%, respectively. Concentrations of grapiprant in plasma following oral administration, in either fed or fasted dogs, remained higher than 164 ng/mL for up to 6 hours. This concentration has been estimated to be the minimal effective concentration required to control pain in dogs.Oral administration of 2 mg/kg grapiprant in fed and fasted dogs resulted in different pharmacokinetics of the drug, but did not influence the length of time when concentrations in plasma exceeded theoretical effective concentrations. Further studies are necessary to verify these findings using pharmacokinetic-pharmacodynamic studies and in clinical subjects.

The overall fibrinolytic activity is depressed in patients with chronic renal failure where a prothrombotic state is described, thereby enhancing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics were studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant concentration of t-PA and PAI-1 was found among the groups studied. After stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, the HUVEC supernatant levels of PAI-1 in the uremics were higher than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. This impaired endothelial fibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia.

ince promulgation of the Surface Water Treatment Rule (SWTR)1 and confirmed outbreaks of cryptosporidiosis2 and giardiasis,3,4 interest in particle counters as a process monitoring device for water treatment facilities has increased. Under the SWTR, credit is given for log removal and inactivation of Giardia cysts based on the unit process operations in a treatment facility. No regulatory requirement currently exists for removal of Cryptosporidium oocysts. Prudent utility management practice, however, suggests a need to demonstrate the actual removal efficiency of a facility, especially in the particle size ranges of 8–12 μm and 4–5 μm associated with Giardia cysts5 and Cryptosporidium6 oocysts, respectively. Consequently, particle counters that can distinguish between counts within defined size classes Particle counting methods for use in a water treatment facility were analyzed to compare counts made by a particle counter with a forward-angle light scatter (FALS) sensor with counts made with a scanning electron microscope and by microscopic particulate analysis. A separate study compared an FALS sensor with a light obscuration sensor when challenged with latex spheres and cultured microorganisms and when performing continuous in-line counts of the facility’s filter effluent. Log removal values were comparable among the particle counting methods and did not vary significantly across various size ranges of an FALS sensor. Microorganisms were undersized by both sensor types compared with sizes determined with an optical microscope. These results suggest counters accurately indicate facility particle removal efficiency. However, counts made by a particle counter within a specific size range should be interpreted after characterizing the nature of the particles in the source

Background. Since it has been demonstrated that soy diet can improve endothelial function, in the present study we evaluated the effect of dietary substitution of 25 g of animal proteins with soy proteins on endothelial dysfunction in renal transplant patients. Methods. In 20 renal transplant patients (55 � 11 years, serum creatinine 1.7 � 0.6 mg/dl), brachial artery flow mediated dilation (FMD) and endotheliumindependent vasodilation (sublingual nitroglycerine, 25mg) were measured at baseline, after 5 weeks of a soy diet and finally after 5 weeks of soy wash-out. Changes in plasma lipids, markers of oxidative stress (lipid peroxides, LOOH) and inflammation (C-reactive protein), isoflavones (genistein and daidzein), asymmetric dimethyl arginine (ADMA) and L-arginine were also evaluated. Results. At baseline, patients showed a significantly lower FMD as compared with age-matched healthy subjects (3.2 � 1.8 vs 6.3 � 1.9, respectively; P < 0.001), while response to nitroglycerine was similar. After soy diet, actual protein intake was not changed, cholesterol and lipid peroxides were significantly reduced, and isoflavones were detectable in plasma. Soy diet was associated with a significant improvement in FMD (4.4 � 2.0; P ¼ 0.003 vs baseline), while response to nitroglycerine was unchanged. Improvement in FMD was related to L-arginine/ADMA ratio changes, but no significant relation was found to changes in cholesterol, lipid peroxides or genistein and daidzein plasma concentrations. After 5 weeks of soy diet discontinuation, FMD (3.3 � 1.7%) returned to baseline values and isoflavones were no longer detectable in plasma. Conclusions. A soy protein diet for 5 weeks improves endothelial function in renal transplant patients. This effect seems to be strictly dependent on soy intake as it disappears after soy withdrawal and is mediated by an increase in the L-arginine/ADMA ratio, independently of change in lipid profile, oxidative stress or isoflavones.

due to congenital vesico-ureteral reflux. In 1990 haemoAIDS or organ transplant immunodepressed patients dialysis treatment was started and in 1993 he received are susceptible to infectious diseases from weakly a cadaveric renal transplant. Six months later he prepathogenic bacteria. This is the case of infection from sented with a rejection episode treated by prednisone Rhodococcus equi, a Gram-positive aerobic bacterium pulse therapy. Subsequently, renal function was stable with intracellular tropism that is usually present in and serum creatinine ranged from 2.2 to 2.5 mg/dl. stools of horses and in soil [1 ]. In veterinary medicine Chronic immunosuppression was achieved with predit is well known as a pathogen for several mammalians, nisone (10 mg/day), cyclosporine A (175 mg/day) and including horses, cows, and others. Humans are rarely azathioprine (75 mg/day). a ected with the infection limited to immunodepressed One month before admission he presented with fever patients [1]. reaching 39.5°C in the late afternoon and decreasing Rhodococcus equi was first described in 1923 as during the night, with weakness, pain on the left side Corynebacterium equi by Magnusson, who isolated it of the chest with submammary irradiation, and fascicfrom the lungs of 10 foals with pneumonia. The first ulations. Broad spectrum antibiotic and analgesic drug case of human disease from R. equi was reported in therapy were unsuccessful, as well as paravertebral 1967 by Golub et al. who described cavitary pneumonia (D8–D9) injections of steroids and anaesthetic drugs. in a steroid-treated patient a ected by plasma cell A thoracic radiograph revealed an opacity in the mid hepatitis [1 ]. portion of the left lung. Until 1983, only 12 cases of R. equi infection had At admission, we observed a seriously sick patient, been described in humans, eight of them receiving complaining of dyspnea, weakness, chest pain on the immunosuppressive therapy for haematological disleft side, and unproductive cough. Physical examinaeases and four for renal transplantation [2]. In 1986, tion revealed a 3 cm diameter subcutaneous nodule Samies et al. described a case of R. equi infection in a with warm, erythematous skin in the left interscapulopatient with AIDS [3]. During the following years, rachidean region. Breath sound reduction and rales these cases have been reported more frequently due to were detected in the lower area of the left lung. Axillary the increasing number of cases of AIDS and transtemperature was 39°C. planted patients. In the last review of the literature, Biochemistry showed serum creatinine 2.7 mg/dl, Verville et al. reports 72 cases of infectious diseases creatinine clearance 17.3 ml/min, cyclosporinemia from R. equi in humans [4]. More recently, Tang et al. 168 ng/ml, WBC count 4900 (neutrophils 90%), RBC described a R. equi peritonitis in two patients on 3.49×106, haemoglobin 10.9 g/dl, HCT 33%, and continuous ambulatory peritoneal dialysis [5]. platelets 246.000; sGOT 47 U/l, sGPT 29/Ul, and c-GT We report a successfully treated sepsis from 75 U/l. Serum glucose, bilirubin, total cholesterol, triRhodococcus equi in an adult male patient on maintenglycerides, electrolytes, total protein, electrophoresis, ance immunosuppression for renal transplantation. and urine analysis were normal. HIV-Ab, HBV-Ag

Background. The close relationship between protein–energy malnutrition and quality of life, morbidity and mortality, makes mandatory a careful evaluation of the nutritional status and muscle mass in chronic renal failure (CRF) patients. Methods. Nutritional and skeletal muscle data were obtained from 28 nondiabetic patients with severe CRF (glomerular filtration rate, GFR < 15 mL min−1) on conservative treatment. Of them, 14 (8 males, 4 females) were on a conventional low-protein (0.6 g kg−1 body weight) diet (LPD) and 14 (8 males, 4 females) were on a very low-protein (0.3 g kg−1 body weight) diet supplemented with essential amino acids and ketoacids (Ketodiet); 28 healthy sex- and age-matched subjects served as controls. We evaluated biochemistry, anthropometry, bioelectrical impedance vector analysis, and three noninvasive tests investigating some skeletal muscle features: (a) myoelectrical fatigue phenomenon was studied using a surface electromyography technique that provides data on conduction velocity (CV), median frequency of power spectrum (MDF) and average rectified value (ARV) of myofibre action potential, at 15 and 35 Hz stimulation frequency; (b) muscle oxidative metabolism was studied by serum lactate following aerobic exercise; and (c) muscle strength of the legs was studied using an isokinetic exercise test at two different angular velocities (60° and 180° s−1). Results. No difference between patients and controls was detected regarding CV, MDF and ARV, at 35 and 15 Hz testing. Serum lactate was higher in patients than in controls at 1, 5, 10 and 30 min recovery. A decreased knee extension and flexion strength was detected in CRF patients both at low (60° s−1) and at high (180° s−1) angular velocity; muscle strength deficit negatively correlated to serum albumin (r = −0.52, P

Primary hyperparathyroidism (PHP) is a rare disease that must be suspected in all the cases of recurrent calcium nephrolithiasis, and that may be totally corrected by surgery. The imaging techniques permit to locate the hyperplastic gland or adenoma before intervention, but their usefulness in patients without a history of previous neck surgery is still debated. Several imaging techniques have been proposed with the aim of locating parathyroid hyperfunctioning glands, including high resolution sonography (US) with color-Doppler (CD), scintigraphy, computed tomography (CT) and magnetic resonance imaging (MRI). We report here a case of recurrent calcium oxalate nephrolithiasis sustained by PHP, which demonstrates how US coupled with CD and echocontrast enhancement is useful in the preoperative location of parathyroid glands. US is the first choice technique in the evaluation of PHP because it is less expensive and useful in detailing lesions of the neck when carried out by a skilled operator. CD should be regarded as a useful complement of US enhancing its sensitivity (80 vs 90%) especially in the cases of associated thyroid gland diseases. Tc-99m SESTAMIBI scintigraphy coupled with MRI is mandatory in high risk surgical patients, namely in those undergoing repeated neck surgery. In conclusion, considering that surgeon must explore all the four parathyroid glands (because of the possibility of multiple adenomas or hyperplasia) a well definite location of the adenomatous lesion may reduce the risks and the time of intervention, and allow the use of alternative procedures, such as videoscopic surgery. On this view and in terms of economy, only US and CD coupled with Tc-99 SESTAMIBI scintigraphy should be considered before surgery.

The aim of this work is to describe an approach allowing extracorporeal hemodialysis (HD) with administration of low molecular weight heparin (LMWH) and to compare the dialyzer efficiency of this approach versus infractionated heparin (UFH) used alone.Low molecular weight heparin (Nadroparin, molecular weight 4500 d) administered in a single injection (dose 3075 IU AXa) plus prostacyclin (Epoprostenol sodium salt, molecular weight 375 d) by continuous infusion (3 ng/kg/min) have been used as anticoagulants during hemodialysis in 8 patients. In comparison, standard continuous heparinization by unfractionated heparin was used. Hemodialysis efficiency (dialyzer clearance for urea, creatinine, uric acid and phosphate), coagulation (activated partial thromboplastin time, antithrombin III, fibrinogen platelet count, prothrombin time) and hemodynamic parameters (blood arterial pressure and heart rate) were also evaluated during dialysis.Simultaneous infusion of low molecular weight heparin plus prostacyclin allowed safe and effective anticoagulation without affecting hemodialysis efficiency.

Vascular disease is frequent in uremics and may contribute to tissue malnutrition and damage. The aim of this study was to detect whether uremic patients show also changes of microcirculation and to evaluate the effects induced by hemodialysis (HD) session. Eleven uremics on HD (7 males, 4 females, aged 25-65 years) were studied; 11 healthy subjects, age- and sex-matched, served as controls. Skin microcirculatory basal flow (BF), maximal postischemic flow (PIF-max) and flow motion index (FMI) were determined at the upper limb contralateral to arteriovenous fistula, by means of a laser Doppler flowmeter. The measurements were taken before, at 1 and 2 h after starting HD and 30 min after the end of HD. In uremics, FMI was lower than in controls (mean +/- SD: 15.2 +/- 13.6 vs. 29.1 +/- 7.4%; p0.005); just 1 h after the start of HD, a significant improvement (28.4 +/- 17.7%; p0.01) versus basal values was observed and it persisted throughout the HD session. No statistical correlation was observed between the changes of FMI and those of plasma levels of Na+, K+, HCO-3, urea, iPTH or rate of ultrafiltration. BF and PIF-max were similar in uremics and controls, and no changes were observed during HD. Our study shows that the physiological flow motion is reduced in the skin microcirculation of uremics on HD. This abnormality is rapidly corrected by HD.

Activated partial thromboplastin time (aPTT) during heparin infusion in 10 patients on regular dialytic treatment was evaluated. At end-dialysis (3 hours) plasma heparinization ranged between 2000-4000 IU and from the clinical point of view dialytic performance was good. At end-dialysis aPTT was 53 +/- 14 seconds: this value is under the prescribed aPTT prolongation (1.5-2 times baseline values) to achieve a therapeutic heparin plasma level. Physiopathological implications of this aPTT "resistance" to heparin infusion are studied.

The actions of ITF 296 and isosorbide dinitrate (ISDN), 20, 70, and 200 g/kg/min, on myocardial transmural blood flow distribution during acute thrombotic occlusion of the left circumflex coronary artery (LCX) have been evaluated in seven and three anesthetized open-chest dogs, respectively, and compared with four animals receiving vehicle. Occlusion of LCX was achieved in 14 +/- 2 min by the insertion of a copper coil. This caused transmural myocardial ischemia in the LCX area, while leaving blood flow in the left anterior descending coronary artery (control area) unaffected. Infusion of ITF 296 (200 g/kg/min) increased transmural coronary flow in the border zone and in the control area without affecting blood flow in the central ischemic area. ISDN, given in the same dose, reduced systemic blood pressure but did not affect LCX blood flow. In three dogs with residual perfusion in the LCX central area ITF 296 also increased blood flow. These results confirm that ITF 296 promotes an increase of flow to the border zone, thus possibly reducing the area of myocardial infarction.

IgA nephropathy (Berger's disease) is one of the commonest forms of glomerular disease, not rarely progressing to renal failure. Hemostatic system activation may play a role in the development of glomerular injury. In a series of 12 adult patients affected with IgA nephropathy we have observed increased plasma levels of D-dimer, a stable end-product of cross-linked fibrin degradation that is considered a reliable index of blood clotting activation, as well as "in vitro" raised generation of thromboxane, the main platelet product of arachidonic acid metabolism that seems to play an important role in glomerulosclerosis. Picotamide, a novel antiplatelet drug acting as thromboxane synthase inhibitor as well as thromboxane receptor antagonist, administered for 8-12 weeks, was effective in reducing thromboxane generation. We conclude that picotamide may be useful in the management of glomerular nephropathy.

Twenty six adult patients were treated with high dose intravenous immuneglobulin (Endobulin-Immuno) for idiopathic membranous nephropathy and nephrotic syndrome.Pulse doses of 0.4 g/Kg b. wt. for 3 consecutive days were given and repeated twice after 3 weeks. Afterwards, one pulse dose every 3 weeks has been administered for a 12 months period. At the end of the study, 11 patients had a complete remission (daily proteinuria

Thirteen patients (7 males, 6 females, aged 17-68 years) affected by primary, steroid-resistant, nephrotic syndrome and normal renal function were treated with a vegan, low-protein (0.7 g/kg per day) diet supplemented with essential amino acids and Ketoanalogues (VSD) for 3.9 +/- 2.9 months. These patients were studied at the beginning (following an unrestricted protein diet (UPD) supplying about 1 g/kg per day of mixed proteins) and at the end of VSD period. Urinary protein excretion decreased from 8.7 +/- 2.6 to 5.6 +/- 2.4 g/day (P less than 0.01), serum total cholesterol from 334.6 +/- 97.1 to 275.6 +/- 49.4 mg/dl (P less than 0.05). Serum albumin, HDL-cholesterol, triglycerides, and anthropometric measurements (triceps skinfold thickness and middle arm muscle circumference) did not change. Urinary urea nitrogen decreased from 7.5 +/- 1.8 to 3.8 +/- 1.2 g/day (P less than 0.005), according to dietary prescriptions. Creatinine clearance changed from 104.4 +/- 28.7 to 89.3 +/- 16.7 ml/min (n.s.) and no correlation was found with the changes in urinary protein excretion. This data suggest that VSD reduces proteinuria and exerts favourable effects on hypercholesterolaemia. Protein malnutrition was absent in these patients, probably because of the essential amino acids and ketoanalogues supplementation.

A comprehensive study of haemostasis has been performed in a homogeneous group of 20 patients with nephrotic syndrome without renal failure. We have found unchanged number of platelets and a significant increase of platelet adhesiveness and aggregation; increased levels of activity and related antigen of fibrinogen, of factor VIII, of activity of factors II, VII and X and of antigens of factors XIII. Antithrombin III was unchanged in plasma and was detected in the urine. Euglobulin lysis times were decreased, and levels of plasminogen and its activators were increased after a venous occlusion test. At the same time urokinase inhibitors and antiplasmins were increased not only after, but also before a venous occlusion test. Fibrinogen degradation products have been found in the urine of all our patients but not in their sera.

A comprehensive study of haemostasis has been performed in a homogeneous group of 25 adult patients with conservatively treated chronic uraemia. We have found prolonged bleeding time, impaired platelet adhesiveness and aggregation, and decreased platelet factor 3 activity, increased values of fibrinogen, of factor VIII activity and related antigen, and of combined levels of factors II, VII and X. Non-significantly abnormal concentrations of factor XIII and of plasminogen and significantly lower values of plasminogen activators and higher values of urokinase inhibitors and anti-plasmin have also been found. Fibrinogen degradation products were detected in the urine of some patients.

Serum iPTH levels decreased markedly in 16 severe chronic uremic patients who changed from a standard low-protein diet to a very low-nitrogen and very low-phosphorus diet supplemented with essential a

Creatinine clearance has been repeatedly measured in three groups of chronic uremics. In the first control group (31 cases), following a conventional low-protein diet, creatinine clearance declined linearly with time. In the second group (12 cases), following very low nitrogen diet supplemented with essential amino acids and ketoanalogues, creatinine clearance remained practically constant with only one exception in which it continued to decline. In the third group of uremics (13 cases) on repeated dialysis therapy, the deterioration of creatinine clearance was markedly accelerated. The possible explanations and the practical implications of these findings are discussed.

Serum oxalic acid (sOx) was determined with a new, specific enzymatic method in 73 uremic patients and the values were plotted against serum creatinine. 41 patients received a free mixed diet, and 32 similar patients were given a low-nitrogen diet supplemented with essential amino acids, ketoanalogues, and calcium carbonate (AD). A significant correlation was found between serum creatinine and sOx levels in patients following a free mixed diet, while no correlation appeared in patients on AD: The sOx concentrations were significantly lower and even normal in this group, and a significant reduction of sOx occurred in 10 patients with chronic renal failure, who changed from a free mixed diet to the AD. The lowering of sOx concentration in patients following AD is attributed both to low intake of its metabolic precursors and to the oral calcium carbonate supplementation.

First hints that a low-protein diet (LPD) has a positive influence on uremic symptoms and on the rate of progression of CRF were found earlier this century [1]. Since the initial reports, a considerable body of evidence has been accumulated suggesting the slowing or temporary halting of the progression of CRF. The results of these studies, however, are often regarded as unconvincing, as they do not meet strict statistical rules. Also, the methods of evaluating the progression rate (slopes of reciprocal sCR or CRcl) were criticized. Today several multicenter trials are under way that are attempting to overcome this criticism. Even these trials, however, will have weak points. In this chapter, we will briefly discuss desirable design features and practical obstacles in performing such trials. Thereafter, data from the literature addressing the problem of progression of CRF under different dietary treatments will be summarized.