Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. TEES Study Group.

OBJECTIVE: To assess the antihypertensive efficacy and safety of the novel AT1 receptor antagonist, telmisartan, compared with that of enalapril in elderly patients with mild to moderate hypertension. DESIGN: A 26-week, multicenter, double-blind, parallel-group, dosage titration study. METHODS: A total of 278 patients aged > or = 65 years were randomized to eithertelmisartan or enalapril once a day. The telmisartan dosage was increased from 20 to 40-80 mg and that of enalapril from 5 to 10-20 mg at 4-week intervals until trough supine diastolic blood pressure was < 90 mmHg. After 12 weeks, hydrochlorothiazide at 12.5-25 mg once a day was added to the treatment regimen of those patients not controlled on monotherapy. RESULTS: Both treatments lowered blood pressure in a comparable and clinically meaningful manner. The adjusted mean changes from baseline in supine diastolic blood pressure at trough were -12.8 mmHg for telmisartan and -11.4 mmHg for enalapril (P = 0.074). Mean changes in supine systolic blood pressure were -22.1 mmHg for telmisartan and -20.1 mmHg for enalapril (P = 0.350). Overall, 63 and 62% of patients responded to telmisartan and enalapril, respectively, with a supine diastolic blood pressure of < 90 mmHg. Both regimens provided effective blood pressure lowering over the 24 h dosing interval, as determined by ambulatory blood pressure monitoring. Both regimens were well tolerated; however, patients on the enalapril regimen had more than double the incidence of treatment-related cough compared with those on the telmisartan regimen (16 versus 6.5%). CONCLUSIONS: These results demonstrate that telmisartan is well tolerated and is at least as effective as enalapril in treating elderly patients with mild to moderate hypertension.

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.

Monocyte and granulocyte CD11b/CD18, CD62L expression and sICAM-1 concentration in the interdialytic period.

We studied cell surface modulation of CD11b/CD18 and CD62L on monocytes and granulocytes, sICAM-1 concentrations and the responsiveness of cells to exogenous fMLP in patients in the intra- (0-4 h Cuprophan dialysis) and interdialytic period (5-28 h) and in healthy subjects (0-24 h). The high CD11b/CD18, low CD62L granulocyte phenotype occurred rapidly during dialysis. By contrast, CD62L increased on the subpopulation of monocytes in circulation initially during dialysis and CD11b/CD18 was mobilized much slower. In the interdialytic period, the CD62L/(CD11b/CD18) ratio was reduced up to 12 h after start of treatment on both monocytes and granulocytes. This ratio was significantly lower than in healthy subjects up to 8 h after start of treatment. The responsiveness of granulocytes to exogenous fMLP, in terms of CD11b/CD18 mobilization, was significantly reduced in patients during and after hemodialysis as compared to that on granulocytes obtained from healthy controls. Monocytes were more refractory to fMLP up to 4 h after dialysis. sICAM-1 was significantly increased in patients before dialysis as compared to controls and remained elevated and fairly stable throughout treatment and in the interdialytic period. The variation in the expression of adhesion molecules on monocytes and on granulocytes in the interdialytic period was not related to the presence of activating serum factors remaining in the circulation after treatment. Our findings emphasize the importance of including the interdialytic period in the evaluation of dialysis membrane biocompatibility, especially when effects on monocytes are of interest.

Effects of hemodialysis and long-term erythropoietin treatment on protein C, and on free and total protein S.

We studied 37 hemodialysis patients during hemodialysis in order to assess the effects of dialysis on endogenous plasma coagulation inhibitors (antithrombin III, protein C, free and total protein S). The patients were examined prior to erythropoietin (EPO) treatment, upon reaching target hemoglobin (Hb) and after 3 months at steady state Hb levels. The levels of protein C increased significantly during dialysis. However, EPO treatment did not affect the levels of any of the endogenous coagulation inhibitors, either upon reaching target Hb or after 3 months of steady state Hb. The sequence of change during dialysis of protein C, free and total protein S was constant when comparing respective patterns prior to EPO treatment to those at target Hb and steady state Hb respectively. In conclusion, hemodialysis seems to activate synthesis of endogenous coagulation while partial correction of anaemia with EPO does not affect the levels of these inhibitors.

Long-term effects of erythropoietin treatment on the coagulation system during standardized hemodialysis.

We studied 37 hemodialysis patients, treated with erythropoietin (EPO), prior to and upon reaching target Hb and after 3 months at steady state Hb levels. Our aim was to analyze the effects of EPO on markers of all stages of coagulation and anticoagulation during a standardized hemodialysis procedure upon reaching target Hb as well as long term effects of a stable Hb. The Hb rose from 82 +/- 9 to 111 +/- 12 g/L at target Hb (p < 0.0001) and was 108 +/- 15 g/L after 3 months of steady state. The heparin dose was individually titrated, using a whole blood activated coagulation time method (WBACT) and kept constant during the first phase of the study. The titrated heparin dose increased significantly at target Hb and this increase persisted after 3 months at steady state. Accordingly the increase in WBACT decreased significantly. There was a significant increase in platelets at target Hb and this increase persisted at steady state. beta-thromboglobulin increased significantly at target Hb and this increase persisted after 3 months at steady state. Platelet factor 4 was unchanged throughout the study period. Inhibitors of plasma coagulation: AT III, protein C and total and free protein S were unchanged throughout the study period. There was no changes in indicators of intravascular coagulation: TAT, fibrin monomers or FPA throughout the study period. There was no FPA generation during dialysis. The residual blood volume in the dialyzer was unaffected throughout the study period. There was a significant decrease in D-dimers at target Hb and after 3 months at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute symptoms during and between hemodialysis: the relative role of speed, duration, and biocompatibility of dialysis.

The relationship between hemodialysis (HD) symptoms and dialyzer membrane composition and area, blood-flow, treatment duration, urea removal, ultrafiltration volume, leukocyte activation, and complement generation (C3a) was studied in 20 patients undergoing 234 HD treatments by 12 different modes in random order using Cuprophan, hemophane, or polyamide membranes with small or large membrane areas with high Qb (400 ml/min) and short duration (2 h) or low Qb (200 ml/min) and long duration (4 h). Fewer symptoms occurred during the 2-h HD at high Qb than during the 4-h HD with low Qb (19% vs. 32%, p = 0.0351). No differences were observed between different dialyzer membranes or areas. More intradialytic symptoms occurred when urea elimination was high than it was low (p = 0.0044). Leukocyte activation (leukocyte drop) after 15 min of dialysis and complement generation did not influence symptom incidence. Blood pressure changes were mainly influenced by ultrafiltration volume (p < 0.001). Symptoms between dialyses were determined by urea removal and ultrafiltration. Membrane, area, or Qb were of no importance. Thus, duration of dialysis, urea removal, and demand for ultrafiltration, but not membrane composition, area, or biocompatability, are important for the development of HD-related symptoms.

Progressive decline in renal function induces a gradual decrease in total hemoglobin and exercise capacity.

We examined 58 patients (38 men, 20 women; mean age: 45 +/- 12 years; body mass index: 24 +/- 4 kg/m2) with a glomerular filtration rate (GFR) ranging from 3 to 32 ml/min, in order to determine the effects of a progressive decline in renal function on total hemoglobin (THb) and exercise capacity. The THb ranged from 185 to 759 g and the hemoglobin concentration ranged from 66 to 151 g/l. Maximal exercise capacity ranged from 50 to 260 W (40-143% of the expected norm). Nearly all the patients interrupted their exercise tests due to general fatigue, leg tiredness or a combination of these factors. There was a significant partial correlation between THb and GFR after sex and age had been accounted for (r = 0.39; p < 0.005). Maximal exercise capacity and THb showed a significant partial correlation after sex, age and GFR had been accounted for (r = 0.27; p < 0.05). Maximal exercise capacity showed a significant partial correlation with GFR after sex, age and THb had been accounted for (r = 0.30; P < 0.05). In conclusion, there is a gradual decline in THb and maximal exercise capacity as uremia progresses. Anemia appears to be a contributory cause responsible for the decrease in maximal exercise capacity along with other factors pertinent to uremia per se.

The influence of dialyzer geometry on blood coagulation and biocompatibility.

The influence of dialyzer geometry on blood coagulation, heparin requirement and complement activation was studied in fourteen chronic hemodialysis patients. Each patient was dialyzed with two different cuprophan dialyzers, hollow fiber GF 120M and parallel plate Lundia IC5N. Both dialyzers had a wall thickness of 11 microns, surface area of 1.2 m2 and both were sterilized with ethylene oxide. Heparin doses were individually titrated. The mean heparin dose was 6089 +/- 988 U. Platelet count decreased from 218 x 10(9)/l to 193 x 10(9)/l and from 235 x 10(9)/l to 197 x 10(9)/l respectively (hollow fiber/plate dialyzer, ns). The number of leucocytes decreased at 15 min after start of dialysis by 56% and 61% (hollow fiber/plate dialyzer, ns). The heparin requirement, measured as prolongation of whole blood activated coagulation time after identical doses of heparin, were the same in hollow fiber and plate dialysis sessions. The arterial fibrinopeptide A concentrations increased during dialysis from 5.4 to 7.1 nmol/l and 8.5 to 9.6 nmol/l respectively (hollow fiber/plate dialyzer, ns). The residual blood volume in the hollow fiber dialyzers was 1.3 +/- 1.1 ml and in the plate dialyzers 1.5 +/- 0.9 ml (ns). C3a activation, indicated by a marked arterio-venous difference, was observed at 15 min after start of dialysis with hollow fiber as well as plate dialyzers. The arterio-venous difference was less pronounced at the end of dialysis. There were no differences in C3a activation between hollow fiber and plate dialyzers at any timepoint. It is concluded that dialyzer geometry does not significantly influence platelet count, blood coagulation, heparin requirement or complement activation.

Effects of renal failure on skeletal muscle.

In this cross-sectional study, we examined biopsies from the vastus lateralis muscle of 13 predialytic uremic men (mean age 46 +/- 8 years). Their average glomerular filtration rate was 14 +/- 7 ml/min x 1.73 m2 and their maximal exercise capacity, measured by standardized exercise test on a bicycle ergometer, was 184 +/- 45 W (94% of the expected norm). The proportion of type I fibers (type I%) in the uremic group was similar to that of the reference group (42 +/- 11 vs. 41 +/- 8% NS). The proportion of type IIA fibers (type IIA%) in the uremic group was higher than in the reference group (44 +/- 10 compared to 35 +/- 9%, p < 0.05). The proportion of type IIB fibers (type IIB%) was lower than in the reference group (13 +/- 8 vs. 21 +/- 8%, p < 0.05). Type I fiber area was similar to that of the reference group (4,768 +/- 1,033 vs. 4,627 +/- 1,112 microns 2, NS). Type IIA and type IIB fiber areas tended to be smaller than those of the reference group (type IIA fiber area: 4,515 +/- 929 vs. 5,213 +/- 1,288 microns 2, NS; type IIB fiber area: 3,953 +/- 1,066 vs. 4,406 +/- 1,582 microns 2, NS) with a type IIA area/type I area ratio which was significantly lower than in the reference group. Citrate synthase activity was 0.48 +/- 0.08 mu kat/g in the uremic group and 0.50 +/- 0.08 mu kat/g in the reference group, NS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effective anticoagulation by a low molecular weight heparin (Fragmin) in hemodialysis with a highly permeable polysulfone membrane.

The efficacy and kinetics of a low molecular weight heparin fragment (LMWH-fragment, Fragmin) were studied during one hemodialysis session with a highly permeable polysulfone membrane and compared to a second dialysis session using a conventional cuprophane membrane. All patients received 5000 U of Fragmin given as an injection into the arterial line at start of dialysis. The anticoagulative efficacy was evaluated by measuring plasma fibrinopeptide A concentrations. LMWH-fragment concentrations in plasma and ultrafiltrate were determined by an amidolytic activity assay and by a radioimmunoassay using a monoclonal antibody. During hemodialysis with cuprophane and polysulfone membranes the fibrinopeptide A concentrations were low indicating adequate anticoagulation. LMWH concentrations in plasma did not differ in the two membranes at any time. The LMWH-fragment in the ultrafiltrate could neither be detected with the amidolytic assay nor with the radioimmunoassay. We conclude that a single injection of Fragmin effectively prevents clotting during hemodialysis with a highly polysulfone membrane. No significant amounts of the anticoagulant are lost over the dialysis membrane.

Blood pressure reduction during hemodialysis correlates to intradialytic changes in plasma volume.

Blood pressure alterations during hemodialysis were related to changes in body fluid in 14 patients with chronic renal failure. Changes in plasma volume (PV) and extracellular volume (ECV) were calculated from determinations of fluid volumes before and after hemodialysis, using 125I-albumin and 51Cr EDTA respectively. Reduction in body water was estimated from body weight changes. Weight loss was 3.3 +/- 0.3 kg (range 1.8-6.0 kg). The relative reduction of fluid was greater in the ECV, 21.6 +/- 3.2%, compared to plasma volume, 6.9 +/- 1.8%. The reduction in systolic blood pressure was related to both absolute (r = 0.66, p less than 0.05) and relative PV reduction (r = 0.72, p less than 0.02). There was no correlation between blood pressure reduction and weight loss or ECV changes. Only minor alterations were found in diastolic blood pressure. Plasma volume maintenance relates to blood pressure changes. Plasma volume monitoring could be useful for improving intradialytic hemodynamic control.

Binding of dietary cobalt to sarcoplasmic reticulum proteins.

It has previously been shown that cobalt accumulates in the myocardium of rats, mainly the sarcoplasmic reticulum (SR) and the mitochondrial inner membrane. In order to investigate the mode of accumulation of cobalt in the SR, rats were given a dietary cobalt supplementation of 40 mg of CoSO4 x 7H2O kg-1 body wt, after which the rats were sacrificed and the sarcoplasmic reticulum was isolated. The SR proteins were subjected to analysis by polyacrylamide gel electrophoresis followed by protein staining and determination of the content of cobalt in each protein band. The major cobalt-binding protein was found to have a molecular weight of about 100,000; a 200,000 molecular weight protein was also found to bind cobalt, although less extensively. These results suggest that cobalt is bound to the monomeric and dimeric forms of Ca(2+)-ATPase in the SR of the myocardium.

Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood--a 27-year follow-up.

In a previous report the long-term prognosis of 30 patients with renal scarring after pyelonephritis in childhood was described. In this study, we have related the extent of renal scarring present in childhood to the conditions in early adulthood. A radiological progression of scarring from childhood to adulthood was seen in one-third of the kidneys. The 7 patients with bilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate and higher plasma vasopressin at follow-up than 13 healthy controls. The 20 patients who had unilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate, higher diastolic blood pressure and higher plasma renin at follow-up than controls; 4 had hypertension. The most important finding was that children with unilateral disease are at risk of serious long-term complications. Filtration fraction at follow-up was higher in patients with extensive renal scarring in childhood compared with those with a normal renal area or small scars in childhood (r = -0.43, P less than 0.05). This may indicate glomerular hyperfiltration by remnant glomeruli. This paper emphasizes t the potential seriousness of childhood urinary tract infections especially when early infantile infections are overlooked. A follow-up of more than 4 decades may be necessary before the ultimate prognosis can be established, especially in patients with unilateral renal disease. It is advised that most patients with post-infectious renal scars are followed as high-risk patients, and that treatment continuity is established between paediatricians, nephrologists and, when required, obstetricians.

Effects of exercise training in predialytic uremic patients.

We examined the effects of physical training in 10 predialytic uremic patients (7 men, 3 women, mean age 47 +/- 8 years) with an average glomerular filtration (GFR) of 15 +/- 7 ml/min x 1.73 m2. All 10 patients participated in an exercise programme 3 times/week for 3 months and were compared to a control group of 9 patients with comparable baseline variables. The exercise group increased its maximal exercise capacity measured by standardized exercise test on a bicycle ergometer, from an average 159 +/- 49 to 174 +/- 57 W (p less than 0.01). They also showed a decrease in heart rate at equal load (138 +/- 29-123 +/- 18 beats/min, p less than 0.05). The control group did not change its exercise capacity (171 +/- 60 and 171 +/- 65 W, respectively, NS), nor its heart rate at equal load (124 +/- 24 and 123 +/- 24 beats/min, respectively, NS). Thigh muscular function assessed by static endurance increased from a median 77 s (range 27-197) to 113 s (range 66-201), p less than 0.002. Dynamic muscular endurance increased from a median number of 41 movements (range 28-105) to 93 movements (range 45-139), p less than 0.001. The corresponding figures for the controls were: static endurance 60 (range 20-209) and 47 s (range 9-203), respectively, NS; dynamic endurance 53 (range 19-190) and 43 movements (range 10-126), respectively, NS. Total hemoglobin, blood volume, GFR, blood pressure and echocardiographic variables remained unchanged during the observation period. We conclude that in predialytic uremic patients, physical training improves exercise capacity mainly due to an improved muscular function.

The intracellular distribution of cobalt in exposed and unexposed rat myocardium.

The intracellular distribution of cobalt was analysed in the myocardium of exposed and unexposed rats. The exposed rats were given a dietary cobalt supplementation of 40 mg CoSO4.7 H2O/kg body weight for 8 weeks. The mitochondrial fraction showed the greatest relative increase in cobalt: 0.09 ng/mg protein in the unexposed rats to 8.43 ng/mg protein in the exposed rats. In the exposed rats the submitochondrial particles had the highest levels of cobalt: 19.43 ng/mg protein, followed by the sarcoplasmatic reticulum: 12.3 ng/mg protein. The microsomal 44,000 g supernatant also showed an increase, although the levels remained low (0.51 ng/mg protein in the exposed animals). Apparently the calcium-storing organelles had the highest levels of cobalt. This could affect calcium flux in myocardial cells and, secondarily, tension development in cardiac muscle.

Whole body impedance measurements reflect total body water changes. A study in hemodialysis patients.

Fluid volume changes during hemodialysis was monitored by continuous whole body impedance measurements. The fluid changes recorded using this method was compared to fluid volume changes measured in plasma water (PV) using 125I-albumin, and extracellular volume (ECV) using 51Cr-EDTA before and after treatment, and total body water (TBW) changes reflected by continuous bed scale monitoring. Changes in impedance correlated to TBW changes, r = 0.80, p less than 0.001, while correlations to changes in ECV and PV were: r = 0.57 and r = 0.55, respectively, p less than 0.05. Alterations in body fluid volumes recorded with whole body impedance is best correlated to total body water changes. The use of continuous whole body impedance monitoring has been shown to offer a simple non-invasive method for recording total body water changes during hemodialysis.

Leukocyte overshoot: a new sign of bioincompatibility in fast hemodialysis.

A high blood flow of 400 ml/min induces leukocytosis after 2 hr of dialysis with leukocyte concentrations of 110-150% of predialysis values. The leukocytosis occurs with both low and high biocompatible membranes, such as Cuprophan, Hemophan, and Polyamide. Cuprophan induces the most profound leukopenia, and also induces the most pronounced leukocytosis. For treatments with a given membrane there was, however, no correlation between leukopenia and leukocytosis. Leukopenia was independent of blood flow, while leukocytosis was strongly influenced by this factor. These observations indicate that different factors cause leukopenia and leukocytosis. Although a larger area induced more leukopenia, the effect was small. Membrane area had no effect on leukocytosis. There were no acute clinical side effects during dialysis that could be related to the leukocyte overshoot. The cause and chronic clinical consequences of leukocyte overshoot are unknown.

Biocompatibility of dialysis membranes is of no importance for objective or subjective symptoms during or after hemodialysis.

The clinical importance of biocompatibility of hemodialysis membranes is a matter of controversy. The authors studied the relationship between biocompatibility and acute symptoms during hemodialysis (HD). Twenty-three patients underwent 12 different bicarbonate HD using Cuprophan, Hemophan, or Polyamide membranes for short (2 hr) and long (4 hr) treatments, with small or large membrane areas. Subjective and objective symptoms were registered during HD and 12 and 36 hours thereafter. Type of membrane, membrane area, or Kt/V were of no importance for the occurrence of subjective or objective symptoms. The patients registered fewer symptoms during 2 hr HD with high blood flow than during 4 hr HD with slow blood flow (p = 0.04). Headache was particularly more frequent during the 4 hr HD. Blood pressure, and to some extent subjective symptoms, were influenced by ultrafiltration volume but not by type of membrane. Biocompatibility is not a determinant of acute side effects of hemodialysis.

The effect of cobalt on mitochondrial ATP-production in the rat myocardium and skeletal muscle.

Cobalt has been shown to accumulate in the myocardium of uraemic patients and has been suggested as a myocardial toxin inhibiting mitochondrial respiration. In order to study the cellular effects of cobalt exposure three groups of rats (n = 12 per group) were fed a diet containing 12% protein without supplementation or with 20 mg and 40 mg CoSO4 7 H2O/kg body weight/day respectively. After 8 weeks the hearts and soleus muscles were removed. Cobalt in tissues and in four cell fractions were analysed with neutron-activation analysis (ng/g wet weight and ng/mg protein respectively). Mitochondrial respiration was analysed as ATP-production rate using pyruvate + malate and palmitoyl-carnitine + malate as substrate. The ATP-production from pyruvate + malate was unchanged in both heart and skeletal muscle in the exposed animals. With palmitate as substrate, the heart muscle showed a slightly lower ATP-production rate (p less than 0.05) after the 20 mg cobalt dose, but the rate was unchanged in the group with higher cobalt intake. No changes in ATP-production rate from palmitate was observed in soleus muscle. The microsomal (100,000 g) fraction in the myocardial cells contained significantly higher cobalt concentrations compared to the mitochondrial fraction in both the unexposed (1.4 ng/mg protein vs 0.19, p less than 0.05) and exposed rats (53.4 ng/mg protein vs 13.2, p less than 0.005). In conclusion, cobalt showed a large accumulation in myocardial cells, without significant effects on mitochondrial ATP-formation rate from oxidation of pyruvate or palmitate and with the highest cobalt content contained in the microsomal (100,000 g) fraction.