Rastislav Dzúrik

The isolation of an inhibitor of glucose utilization from the serum of uraemic subjects

Abstract A peptide of basic nature and probably of molecular weight 1000–1500 was isolated from the serum of patients suffering from chronic renal failure. This peptide inhibits glucose utilization in rat diaphragm, brain and kidney cortex slices as well as in human erythrocytes. It is suggested that this inhibitor is responsible for the abnormal carbohydrate metabolism in uraemia.

Effects of Long-Term Cholecalciferol Supplementation on Mineral Metabolism and Calciotropic Hormones in Chronic Kidney Disease

Background: Data on the efficacy and safety of long-term vitamin D supplementation in chronic kidney disease (CKD) are scarce. We assessed the effects of the 12-month vitamin D3 treatment on mineral metabolism and calciotropic hormones in patients with CKD stages 2–4. Methods: Eighty-seven patients (mean age 66 years, men/women 33/54) were randomized to cholecalciferol treatment with either 5,000 or 20,000 IU/week. Serum calcium, phosphate, 25(OH)D3, 1,25(OH)2D3, PTH and urinary mineral concentrations were obtained at baseline and after 4, 8 and 12 months. Results: The median serum mineral concentrations were normal and not changed throughout the study. The number of hypercalciuric patients slightly increased with higher dose, but no sustained rise in calciuria was present. Vitamin D insufficiency/deficiency was revealed in 72 (83%) patients at baseline and 37 (43%) at month 12. The 25(OH)D3 levels increased more with higher dose; a rise in 1,25(OH)2D3 was less impressive. The parathyroid hormone (PTH) concentrations were reduced, but the number of subjects with PTH below the lower limit for CKD stage 3 increased equally with both doses. Conclusions: Vitamin D insufficiency/deficiency in CKD significantly improved after the 12-month cholecalciferol treatment, with higher dose being more effective and equally safe. Further studies of vitamin D3 effects on bone metabolism are warranted.

Advanced glycation end-product levels in subtotally nephrectomized rats: beneficial effects of angiotensin II receptor 1 antagonist losartan.

The angiotensin II receptor 1 antagonist losartan (L) inhibited the advanced glycated end-products (AGEs) induced expression of transforming growth factor β1 in in vitro experiments performed on renal tubuloepithelial cells. To test the pathophysiological importance of these findings, the possible link between serum AGEs levels and angiotensin system was investigated in the model of normotensive subtotally nephrectomized rats(4/6-NX). Concentration of AGEs in serum of placebo administered 4/6-NX rats (n = 7, 1.09±0.09 U/l) increased slightly in comparison with sham-operated healthy controls (CTRL, n = 8, 0.94±0.10 U/l, p<0.02) as measured by competitive ELISA. Treatment of 4/6-NX rats with L over 12 weeks ameliorated the rise in serum AGEs concentration (1.00±0.12 U/l, n = 15 <0.005) almost to the level observed for CTRL. This effect was further corroborated by the observation, that the impaired renal excretion of AGEs in 4/6-NX-placebo rats (0.07±0.02 U/µmol creatinine) was significantly restored by L (0.09±0.02 U/µmol creatinine, <0.009) and resembled that of the CTRL (0.10±0.03 U/µmol creatinine). Administration of L to 4/6-NX rats significantly improved renal function as evaluated by a smaller rise in serum creatinine and urea concentration. In spite of the improvement in renal function, there were no differences in concentrations of transforming growth factor β1 in serum and in urine among the two groups. These effects were independent of blood pressure. Our data give first evidence, that long-term treatment with angiotensin II receptor 1 antagonist may exert salutary effects on AGEs levels in the rat remnant kidney model, probably due to improved renal function.

Effects of angiotensin-converting enzyme inhibitors on glucose and lipid metabolism in essential hypertension.

Summary Data of 52 patients, 29 women and 23 men aged 32–68 years (mean age 47 years) with essential hypertension, participating in three open therapeutic trials with either enalapril, lisinopril, or perindopril were evaluated to assess the effects of angiotensin-converting enzyme (ACE) inhibition on glucose and lipid metabolism. The 75-g oral glucose tolerance test (oGTT) was performed, and plasma glucose and insulin levels, as well as total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides levels were determined before and after the 8− to 12-week treatment. Minor differences in the blood pressure (BP)-lowering effect and metabolic response were obtained with the ACE inhibitors studied; only lisinopril improved glucose tolerance significantly; blood lipids were not changed by any drug. The entire patient population showed only a slight reduction in 1-h postload glucose after treatment. More obvious improvement in glucose tolerance was evident in hypertensive patients who were glucose intolerant and/or insulin resistant (GI/IR, 53.8% of all), however. This subgroup also showed a slight but not significant increase in HDL-cholesterol and a decrease in triglycerides levels. Only a slight change or no change in plasma glucose, insulin, and lipid values was noted in hypertensive patients with normal glucose tolerance (NGT) and insulin sensitivity. These favorable effects were expressed only after ACE inhibitor monotherapy, but not when hydrochlorothiazide was added. The results indicate that a lack of stratification of hypertensive patients with regard to glucose tolerance or insulin sensitivity could be a confounding factor in evaluation of metabolic effects of ACE inhibitors.

Inhibitor(s) of protein synthesis in uremic serum and urine: Partial purification and relationship to amino acid transport

The accumulation of an inhibitor of protein synthesis in serum of patients with CRF was found, IPS being excreted in the urine in a biologically active form. A purification procedure was elaborated, comprising GPC on Sephadex G-25, IEC on DEAE Sephadex A-25, and GPC on Sephadex G-15. At least two components of IPS inhibit labeled amino acid incorporation into rat tissues in vitro (muscle, liver, brain, kidney cortex), with the molecular weight of one component in the range 500–1000 daltons and that of the other, less than 500 daltons. In muscle IPS interferes noncompetitively and selectively with transport of [14C]AIB. In the presence of insulin, IPS does not inhibit the insulin-stimulated increase in AIB transport, but it acts independently and oppositely to insulin action. The existence of a circulating inhibitor of amino acid transport and amino acid incorporation in protein may contribute to the imbalance of the amino acid spectrum and that of protein synthesis and degradation in uremia.

Pathogenesis and Consequences of the Alteration of Glucose Metabolism in Renal Insufficiency

The decreased hyperglycemic response of patients in renal insufficiency (RI) to the applied glucagon or epinephrine and abnormal galactose tolerance test pointed to the abnormal liver glycogen metabolism and its decreased liver concentration (Cohen, 1962; Westervelt and Schreiner, 1962). However, later on the glucagon and epinephrine studies have not been confirmed and normal liver glycogen concentration was found in a group of patients with normal caloric intakte in our laboratory (Dzurik and Brixova, 1968). The liver glycogen concentration was normal even in patients with abnormal glucose tolerance test. Similar findings were published on muscle glycogen by Bergstrom (Bergstrom and Hultman, 1969). It appears now that the glycogen concentration and metabolism depend primarily on nutritional state and not on renal insufficiency. Consequently, adequate caloric intake is the best prevention of this abnormality.

Effect of Hippurate on Glucose Utilization in Rat Kidney Cortex Slices

Hippurate action on glucose utilization was evaluated in rat kidney cortex slices. Studies have shown the following. (1) Hippurate inhibits markedly basal as well as insulin-stimulated glucose utilization and basal gluconeogenesis. (2) Ca deficiency and specific Ca channel blockers diltiazem and isradipine abolish the hippurate inhibition of glucose utilization. (3) K+ channel blockers, i.e. the increased K+ concentration in incubation medium, procaine and sulfonylurea drugs also abolish the hippurate inhibition of glucose utilization. It is concluded that hippurate and benzoate operate through the ATP-dependent K+ channel.

Oxidative Stress and Plasma Concentrations of Coenzyme Q10, α-Tocopherol, and β-Carotene in Patients with a Mild to Moderate Decrease of Kidney Function

Accessible online at: www.karger.com/journals/nef Dear Sir, Oxidative stress (OS) and decreased function of the antioxidant system are apparent in dialysis patients [1] and even in ‘uremic patients’ during the predialysis phase [2, 3]. However, data on OS in predialysis patients with a just mild to moderate kidney function decrease are lacking. We have determined OS plasma concentrations of malondialdehyde (MDA), the parameter of lipid peroxidation, coenzyme Q10 (CoQ10), ·-tocopherol (·-TOC), and ß-carotene (ß-CAR) and performed standard kidney function tests in a group of 55 predialysis patients with mild (creatinine clearance 160 ml/min; n = 21), moderate (n = 25), and severe (creatinine clearance !25 ml/min; n = 9) glomerulonephritis or interstitial nephritis. The reference values were obtained from original procedures and previous studies of our group. The MDA plasma levels were increased even in a group with a mild decrease of the creatinine clearance (table 1), and no further significant MDA increase was apparent with further decreases of the creatinine clearance (r = –0.242, p = 0.078). On the other hand, the CoQ10 concentrations were decreased in patients with mildly decreased creatinine clearance, and no further decreases were apparent with further decreasing kidney function (r = 0.186, p = 0.179). A correlation was found between these two variables (r = 0.327, p = 0.018). The concentrations of ßCAR were in the normal range in patients with a mildly decreased creatinine clearance, but decreased with deteriorating kidney function (r = 0.320, p = 0.030). The ·-TOC plasma concentrations were slightly increased in patients with mildly decreased creatinine clearance, but increased further with the decreasing creatinine clearance (r = –0.364, p = 0.007). Thus, OS develops during the early phase of kidney disease (marker of OS: increased MDA levels). The changes of ·-TOC and ßCAR are opposite: while ·-TOC concentrations increase, ß-CAR concentrations decrease. This basic relationship could be modified by various factors: for instance, the highest values of MDA (p = 0.010) were found in 5 patients treated with prednisone combined with ciclosporin. It could be concluded that OS develops early in patients with kidney disease, probably with pathogenetic significance and the possibility of preventing the progression of kidney impairment. The significance of CoQ10 seems to be of outstanding interest.

Isolation of an inhibitor responsible for abnormal glucose utilization in liver disease

SummaryAn inhibitor of glucose utilization in rat diaphragm was isolated from the serum of patients suffering from liver cirrhosis. This inhibitor is suggested to contribute to abnormal carbohydrate metabolism in liver diseases. It is a low molecular weight substance, probably of pepticle nature. It is identical with the inhibitor of glucose utilization isolated from the serum and urine of patients with renal failure and from the urine of healthy subjects.

Ciprofibrate increases plasma concentration of platelet-derived growth factor AB in patients with advanced atherosclerosis and hyperlipidemia independently of its hypolipidemic effects.

Fibrates, besides their hypolipidemic action, share alternative effects, such as decreased plasma fibrinogen and uric acid levels. Because of their complex action, additional effects have been investigated. A group of 23 patients with clinical signs of atherosclerosis and hyperlipoproteinemia was randomly allocated after a 1-month washout period and treated with either 100 mg/d of ciprofibrate or 100 mg/d of aspirin for 2 months. Patients were then treated with a combination of these two agents for the next 2 months. Ciprofibrate decreased plasma concentrations of triglycerides (−29%) and very-low-density lipoprotein cholesterol (−27%) in monotherapy and a larger reduction was observed if ciprofibrate was added to the aspirin therapy: triglycerides (−39%), very-low-density lipoprotein cholesterol (−33%), total cholesterol (−18%), low-density lipoprotein cholesterol (−17%), and increased high-density lipoprotein cholesterol (+36%). Ciprofibrate increased plasma levels of platelet-derived growth factor (PDGF) AB in both monotherapy patients (+162.9 pg/ml, +297%) and in aspirin-pretreated patients (+129.8 pg/ml, +134%); the increase of PDGF AB platelet store was significant only in aspirin-pretreated patients (+11.1 ng/ml, +51%). Aspirin in monotherapy did not modulate either plasma or platelet store of PDGF AB. Ciprofibrate did not inhibit thromboxane B 2 synthesis in platelets. Aspirin did not influence plasma thromboxane B 2 concentration at all, whereas it decreased thromboxane B 2 platelet production markedly in monotherapy (−85%) and in combination with ciprofibrate (−91%). Ciprofibrate increases PDGF AB content, which is amplified by aspirin pretreatment without correlation with its hypolipidemic action. The increase of PDGF production is suggested to participate in plaque stabilization.