Telmisartan lowers albuminuria in type 2 diabetic patients treated with angiotensin enzyme inhibitors.

PURPOSE: Angiotensin-converting-enzyme inhibitors (ACEIs) provide renal protection in patients with type 2 diabetes and microalbuminuria. MATERIAL AND METHODS: In the presented study we followed 34 stable, type 2 diabetic patients with persistent albuminuria treated with maximal doses of ACEIs as a part of their anti-hypertensive treatment. Telmisartan--an angiotensin receptor blocker (ARB)--in a dose of 40 mg was added to the treatment and the patients were observed for 12 weeks. We measured creatinine clearance, 24-hour urinary albumin excretion, before and after 12 weeks of combined therapy. RESULTS: The addition of telmisartan resulted in a significant reduction of albuminuria from median 157 to 67 mg/24h. No change in creatinine clearance was observed (93 vs 97 ml/min). CONCLUSION: The addition of telmisartan to a maximum dose of ACEI is safe and results in further albuminuria decrease in patients with type 2 diabetes and incipient nephropathy.

[Effects of L-carnitine on erythropoiesis and blood platelet aggregation in patients with chronic renal failure treated with hemodialysis]. / Wplyw l-karnityny na erytropoeze i agregacje plytek krwi u chorych hemodializowanych z przewlekla niewydolnoscia nerek.

The aim of the work has to assess the effects of L-carnitine therapy on erythropoiesis and whole blood platelet aggregation. The studies were performed in 28 patients divided into 3 groups: I-group was given erythropoietin, II-group was given erythropoietin and L-carnitine, III-group was given L-carnitine. After 22 month of the therapy a statistically significant rise in hematocrit was observed in group III, improvement in muscle strength, a rise in free and total carnitine concentration was found in group II and III. There were no significant changes in urea concentration, platelet count and iron metabolism. Whole blood platelet aggregation induced by ADP, collagen and ristocetin was impaired relative to healthy volunteers. After 2 month of L-carnitine treatment of significant rise in collagen induced platelet aggregation was observed in group II.

[The influence of multiple dialyzer reuse on selected coagulation parameters]. / Wplyw wielokrotnej reutylizacji dializatorów na wybrane parametry ukladu krzepniecia.

The aim of the study was to follow effects of multiple dialyzer reuse on some coagulation parameters. In a random group of 10 patients undergoing intermittent hemodialysis treatment, platelet coagulant, fibrinogen, BTG and PF4 concentrations were determined after 1st dialyzer usage and after 2 consecutive dialysis sessions after which the dialyzer was reused by manual method with 1% Dialyne solution. An increase in fibrinogen concentration after 240 min of HD procedure was shown when dialyzer was used for 1st and 3rd time. BTG activity increased after 240 min of HI procedure when the dialyzer was used for 3rd time. There was a fall in platelet count after 30 min of HD during the 1st and the 3rd dialyzer use. The fall in platelet count lasted all dialysis session when dialyser was used for 3rd time. The PF4 activity was decreased after 30 min of HD session after the 1st and the 2nd dialyzer use.

Inverse relationships between haemoglobin and ristocetin-induced platelet aggregation in haemodialysis patients under erythropoietin therapy.

BACKGROUND: Amelioration of the anaemia of chronic renal failure and subsequent improved haemorheology result in correction of bleeding diathesis as evidenced by shortening of the skin bleeding time (BT). However, the relationship between the haematocrit and platelet-vessel wall interactions in haemodialysis (HD) patients under recombinant human erythropoietin (rHuEpo) therapy, assessed by platelet aggregation in response to ristocetin is more complex and somewhat inconsistent. METHODS: We investigated the relationship between haemoglobin (Hb) levels and whole blood ristocetin-induced platelet aggregation (electric impedance method) in 28 HD patients treated with rHuEpo, and with normal BT. The measurements were repeated in 16 subjects after having reduced platelet aggregability with orally administered ketanserin. RESULTS: Ristocetin-induced platelet aggregation in the whole group was comparable to those found in 21 age-matched healthy subjects (normals) and in 25 HD patients not treated with rHuEpo (uraemics). Interestingly, a significant inverse correlation between this aggregation and Hb concentration was found (r = -0.392, P < 0.05). In the group of 16 patients, the pre-ketanserin aggregation was more intensive than in the normals and uraemics (P < 0.05). Ketanserin produced a fall in ristocetin-induced platelet aggregation (P < 0.02), prolongation of the BT (P < 0.02) and, unexpectedly, a decrease in serum Epo concentration (P < 0.0002) and the Hb level (P < 0.001). Again, an inverse correlation between depressed ristocetin-induced platelet aggregation and lowered Hb concentration was found (r = -0.590, P < 0.02). Moreover, a strong positive correlation between the extent of preketanserin platelet aggregation and the decrease in the intensity of this process that followed the trial was observed (r = 0.919, P < 0.000005). There were no changes in other haematological parameters or arterial blood pressure. CONCLUSIONS: Considering the role of von Willebrand factor and fibrinogen in mediating ristocetin-induced platelet aggregation, and enhanced synthesis and/or release of these macromolecules in response to uraemia or inflammation, we suggest that exaggerated whole-blood platelet aggregability to ristocetin points to blunted erythropoiesis in HD patients on rHuEpo therapy.

[Exocrine pancreatic function and gastric mucosa and duodenal mucosa in patients with chronic kidney failure]. / Czynnosc zewnatrzwydzielnicza trzustki i blony sluzowej zoladka i dwunastnicy u chorych na przewlekla niewydolnosc nerek.

Uraemic pancreatopathy is frequently observed in patients with chronic renal failure. The aim of the study was to assess some parameters of exocrine pancreatic function in uraemic patients maintained on intermittent haemodialyses. Elevated serum amylase activity was found in these patients. The most significant finding was the low bicarbonate output in duodenal content after secretin-cerulein stimuli, comparable with that obtained in patients with chronic pancreatitis. It indicates pancreatic exocrine defect in uraemic patients. A fall in protein output and lower amylase activity in duodenal content was also observed in haemodialyzed patients after stimulation. Low basal acid output (BAO) and enhanced maximal (MAO) and peak (PAO) acid outputs were found in uraemic patients after pentagastrin stimulation. Gastritis and duodenitis were frequently diagnosed in endoscopic and histopathological examinations in these patients. In patients with chronic renal failure even without clinical signs of pancreatic, laboratory findings of exocrine pancreatic abnormalities are reported. It may be the cause of uraemic pancreatopathy.

Ketanserin: a new perspective in posttransplant erythrocytosis?

We have recently shown that ketanserin, an antagonist of peripheral serotonin 5-HT2 receptors lowers blood erythropoietin (Epo) levels in some chronic hemodialysis patients. Based on this finding, a preliminary study was undertaken to investigate the effect of a 3-week oral ketanserin administration on serum Epo concentration and relevant hematological parameters in 4 renal allograft recipients with posttransplant erythrocytosis (PTE). We found a marked decrease in Epo concentrations following ketanserin administration, from 48% to 76% of the abnormally elevated pretreatment values with subsequent increases at 3 weeks after discontinuation of the drug in all patients studied. In 3 of them a corresponding decrease or no rise in the erythrocyte count were noted. During the 6-week study period, the need for monthly phlebotomies was eliminated in these patients. It is hypothesized that ketanserin diminishes erythropoietin synthesis and may become a new drug in the treatment of posttransplant erythrocytosis.

Ketanserin lowers erythropoietin concentration in hemodialyzed patients treated with the hormone.

Ketanserin, an antagonist of peripheral serotonin receptors when given to hemodialyzed patients treated with recombinant human erythropoietin (rHuEpo) corrects some changes in hemostasis but also apparently delays an increase in hematocrit. We wished to elucidate the effects of oral administration of ketanserin on serum Epo, some hematological and biochemical blood parameters, arterial blood pressure (BP), and bleeding time in hemodialyzed patients receiving rHuEpo therapy. We noted a 33% decrease in Epo concentration (p < 0.05) after a 4-week ketanserin trial in patients in the initial stage of rHuEpo therapy. Although a concomitant decrease in erythrocyte count and hemoglobin did not reach statistical significance, these changes correlated positively with decreasing Epo level (r = 0.749 and 0.787, respectively). Ketanserin administered for 14 days to patients between 32 and 34 weeks of rHuEpo therapy also produced a decrease of 26% in Epo concentration (p < 0.005). This decrease correlated (r = 0.629) with a decrement in the red blood cell (RBC) count (p < 0.005). Hemoglobin concentration followed the same pattern (p < 0.005). However, the decreases in the reticulocyte count did not reach statistical significance. The decrease in hormone concentration resulted in a concomitant thrombocyte decrease (p < 0.05) only in patients who received ketanserin in the interval between 8 and 12 weeks of rHuEpo therapy. The previously normal bleeding time was significantly prolonged (p < 0.05) in both groups of patients. There were no changes in leukocyte count, iron status parameters, or calcium, phosphorus, or bilirubin concentration. Administration of ketanserin even for 4 weeks did not influence BP in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Lipid metabolism and fibrinolysis in diabetic nephropathy in the course of diabetes type II]. / Gospodarka lipidowa oraz uklad fibrynolityczny w nefropatii cukrzycowej w przebiegu cukrzycy typu II.

Disturbances in lipid metabolism and in blood fibrinolytic system may play a role in pathogenesis of vascular complications of diabetes mellitus. The aim of the study was to evaluate fibrinolytic parameters (antigen of tissue plasminogen activator-tPA, its inhibitor-PAI, tPA/PAI complexes measured by enzyme immunoassays, euglobulin clot lysis time-ECLT), cholesterol, triglycerides, lipoprotein (a) and apolipoproteins (AI, AII, B) in diabetic patients with and without diabetic nephropathy. The studies were performed in 25 patients with type II diabetes mellitus (age range 42-69), 31 patients with diabetic nephropathy (age range 46-76) and healthy volunteers (age range 31-66). There were no significant differences among the groups studies in tPA:Ag, tPA/PAI complexes, total PAI:Ag and free PAI. ECLT was slightly prolonged in patients with diabetic nephropathy when compared to controls. Cholesterol and triglycerides were significantly elevated in patient with diabetic nephropathy and without nephropathy when compared to healthy volunteers. Triglicerides levels were higher in patients with diabetic nephropathy when compared to subjects without it. Apolipoprotein AI and AII were significantly lower, whereas lipoprotein (a) and apolipoprotein B were significantly higher in patient with diabetic nephropathy when compared to healthy volunteers and diabetic subjects without nephropathy. Lipid metabolism disturbances and impairment in fibrinolysis might contribute to the progression of atherosclerosis and nephropathy in diabetic patients.

Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy.

Previous studies documented that single section examination of kidney tissue underestimates glomerulosclerosis and that three-dimensional examination of glomerular morphology improves recognition of the incidence and distribution of sclerotic changes within the glomerular capillary tuft. We have adopted this technique to evaluate the true frequency and the spatial extent of glomerulosclerosis in patients who were subjected to extensive renal mass reduction. We re-evaluated four kidney biopsies of patients with a solitary kidney who had undergone partial nephrectomy for renal-cell carcinoma. Histopathological examination aimed at detection of glomerular sclerotic lesions was performed on serial sections (from 75 to 93 serial sections for each biopsy, 3 microns thick) together with three-dimensional morphometric analysis of glomerular tuft and sclerotic areas using a computer-based image processing system. Results were compared with observations based on more conventional single section evaluation of the same biopsies. Among 65 glomeruli examined by three-dimensional morphometric analysis, only 8% were normal, 42% revealed segmental sclerosis and 51% global sclerosis. These results confirmed that single section evaluation grossly overestimates the number of normal glomeruli (37% vs. 8%, respectively), since the majority of glomeruli classified as normal are indeed affected by sclerotic changes in areas typically out of the section plane. The three-dimensional distribution of sclerosis is characterized by the appearance of multi-focal areas affecting a small capillary tuft volume (< 10%) which ultimately propagate to the entire capillary tuft. Despite the maintenance of renal function, at the time of biopsy in patients with extensive ablation of renal mass, the incidence of glomerulosclerosis affects almost the entire glomerular population.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric and pancreatic functions in haemodialyzed patients.

The aim of this work was to assess gastric acid secretion in relation to morphological and histological changes in the gastric mucosa as well as prevalence of Helicobacter pylori in chronically haemodialyzed uraemic patients. Exocrine pancreatic functions after secretin-cerulein test were also studied. In haemodialyzed patients low basal gastric acid output was found, whereas peak output after pentagastrin stimulation did not differ significantly when compared to controls. Endoscopy of gastric and duodenal mucosa revealed inflammatory changes in the majority of patients, described histologically as chronic gastritis with duodenitis. Helicobacter pylori antigen was detected in the serum of 45% of uraemic patients. Serum amylase activity was elevated in haemodialyzed patients relative to controls. Although clinically asymptomatic, haemodialyzed patients exhibited various degrees of gastrointestinal mucosal abnormalities and impairment in exocrine pancreatic functions, mainly low stimulated bicarbonate and protein output as well as low electrolyte concentrations in duodenal content.

[Ketanserin decreases erythropoietin concentration in hemodialyzed patients on rHuEPO therapy]. / Ketanseryna obniza Stezenie erytropoetyny u pacjentów hemodializowanych leczonych rHuEPO.

Serotonergic mechanisms are partially responsible for changes in haemostasis and blood pressure rise in haemodialyzed patients treated with recombinant human erythropoietin (rHuEPO). Ketanserin--an antagonist of platelet and blood vessel serotonin receptors, given concomitantly to patients on rHuEPO therapy, prevents certain changes in haemostasis. Preliminary observations suggest that ketanserin also inhibits an increase in haemoglobin and haematocrit. So far there have been no reports on ketanserin affecting erythropoiesis. We studied an influence of the 2-week oral ketanserin administration on some haematologic parameters, serum erythropoietin concentration, blood pressure and relevant biochemical blood indexes in 15 haemodialyzed patients treated with rHuEPO for 32 weeks. We found a significant fall in serum EPO concentration (p < 0.005) measured with the ELISA technique that correlated positively (r = 0.629) with a decrease in erythrocyte count (p < 0.005). Haemoglobin concentration followed the same pattern (p < 0.005). The previously normal bleeding time prolonged significantly (p < 0.02) after ketanserin therapy. There were no changes in plasma iron and ferritin concentration, total iron binding capacity, transferrin saturation index, calcium, phosphorus and bilirubin concentration nor reticulocytosis. The decrement in EPO concentration did not affect peripheral blood platelet or leukocyte counts. The 14-day treatment with ketanserin did not influence arterial blood pressure in the patients. The study shows that ketanserin administered to haemodialyzed patients on long-term rHuEPO therapy induces a decrease in erythropoietin concentration and inhibits erythropoiesis. This phenomenon seems to result from diminished endogenous hormone synthesis caused by ketanserin.

[Erythropoietin and fibrinolysis in uremic patients]. / Erytropoetyna a uklad fibrynolityczny u chorych na mocznice.

Thrombotic events sometimes complicate erythropoietin therapy. Fibrinolytic system may play a role in their pathogenesis. The studies were performed on 22 chronically hemodialyzed patients with end-stage renal failure treated with recombinant human erythropoietin (rHuEPO, Eprex, Cilag) for 12 weeks. Alpha 2 antiplasmin (alpha 2AP), antithrombin III (AT III), C1 esterase inhibitor (C1 INH), plasminogen activator inhibitor (PAI) activities, alpha 2macroglobulin (alpha 2M), fibrinogen, fibrin monomers concentration and euglobulin clot lysis time (ECLT) were measured before and after 1, 2, 4, 8 and 12 weeks of rHEPO therapy. A fall in PAI activity (p < 0.05) was found after 1 week, while alpha 2AP and C1 INH activities decreased after 12 weeks of the therapy (p < 0.001 and p < 0.05, respectively). The activity of AT III, the main inhibitor of the coagulation cascade fell after 4 weeks of the treatment with rHuEPO (p < 0.001). Fibrin monomers concentration was found to be decreased after 12 weeks of rHuEPO administration. Fibrinogen and alpha 2M concentration showed no statistically significant changes during rHuEPO therapy. A decrease in plasma fibrinolytic inhibitor activities may be considered as a protective mechanism against thrombotic tendency observed during rHuEPO therapy.

Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

Serotonergic mechanisms are involved in the hemostatic action of erythropoietin in uremic patients.

Recombinant human erythropoietin was administered to 12 patients with end-stage renal failure on long-term hemodialysis. They responded to the therapy with a shortening of the prolonged bleeding time, starting from the 1st week of therapy, before a significant increase in hemoglobin concentration was achieved. We also observed an increase in the activity of tissue plasminogen activator and a decrease in the activity of its inhibitor. There were no changes in platelet count but a significant increase in blood and platelet serotonin concentration was found. The shortening of the prolonged bleeding time before the correction of the anemia correlated with the rise in blood and platelet serotonin concentration during erythropoietin therapy. We suggest the possible involvement of an serotonergic mechanism in the hemostatic action of recombinant human erythropoietin.

[Platelet aggregation during the recombinant human erythropoietin (rHuEPO) treatment of patients with uremia]. / Agregacja plytek krwi podczas leczenia erytropoetyna (rHuEPO) pacjentów z mocznica.

Patients with uraemia have a defect haemostasis caused by severe anaemia and disturbances of platelet/vessel wall interactions. Recombinant human erythropoietin (rHuEPO) treatment not only corrects anaemia, but also shortens the bleeding time. There are few reports dealing with changes of haemostasis during the first month of rHuEPO treatment. We studied platelet function after 1, 2, 4, 8, and 12 weeks of rHuEPO treatment. Erythropoietin was given to 19 dialysed patients with chronic uraemia in a dose of 2000 u subcutaneously 3 times a week. Bleeding time showed a significant fall as early as after the first week of rHuEPO treatment (p < 0.05). After the first month the bleeding time became normal in most of the patients. A significant rise in ristocetin-induced platelet aggregation was observed from the first week of therapy. It showed a strong correlation with the shortening of the bleeding time. Collagen-induced aggregation followed the same pattern but the changes were not striking. There was not significant difference in platelet adhesion, platelet aggregation in the whole blood and those induced by ADP and arachidonic acid. Platelet serotonin concentration was also showed to increase during rHuEPO therapy. We conclude that rHuEPO improves haemostasis by influencing platelet aggregation possibly involving a serotoninergic mechanism but on the other hand may increase a tendency to thrombosis.