[Chronic kidney disease and cellular calcium homeostasis]. / Chronické ochorenie obliciek a vápniková homeostáza bunky.

Free intracellular calcium represents a critical signaling mediator in a number of biological systems. Calcium cations (Ca2+) are an important ubiquitous messenger, controlling a broad range of cellular processes. Free cytosolic calcium concentration ([Ca2+]i) is controlled by mechanisms that regulate Ca2+ entry from the extracellular space and Ca2+ release from intracellular stores, and by the activity of ATP-dependent Ca2+ pumps and antiporters that move Ca2+ back into stores or out of cells. Chronic kidney disease is associated with a significant elevation in [Ca2+]i which is toxic to the cells and may be responsible for a multiple organ dysfunction. Disturbances in cellular calcium homeostasis in patients with chronic kidney disease represent a complex process. Our studies elucidate pathophysiological mechanisms of altered cellular calcium homeostasis in the peripheral blood mononuclear cells which represent the model of nonexcitable cells in patients with chronic kidney disease. The results demonstrate that [Ca2+]i is significantly increased in peripheral blood mononuclear cells already in early stages of chronic kidney disease. The calcium concentration of intracellular stores and the capacitative calcium entry into the cells of these patients are significantly higher in comparison with healthy volunteers. Also the pore-forming P2X7 receptors participate in increased [Ca2+]i in peripheral blood mononuclear cells of patients with chronic kidney disease. An altered P2X7 receptor function and increased P2X7 receptor expression may contribute to the complex disturbances in intracellular calcium homeostasis in chronic kidney disease. On the other hand, the activity of plasmatic membrane Ca2+-ATPases which is responsible for removing excessive calcium out of the cell, was found to be decreased by 25 % when compared to healthy subjects. It means that not only the mechanisms of entry, but also of the removal are impaired by the disease. All these alterations in calcium signaling are contributing very likely to the elevated [Ca2+]i from early stages of chronic kidney disease.

Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3.

Vitamin D status and the relationship between serum 25(OH) vitamin D concentrations and the components of insulin resistance were examined in 120 patients with chronic kidney disease stage 2 and 3. Insulin sensitivity/resistance was calculated by the quantitative insulin sensitivity check index (QUICKI). In this analysis, the prevalence of insulin resistance was 42 %. Only 17 % of patients had serum 25(OH) vitamin D concentration in the recommended range (>/=30 ng/ml), 42 % suffered from vitamin D insufficiency and 41 % had moderate vitamin D deficiency. Insulin resistance significantly correlated with serum 25(OH)D and 1,25(OH)(2)D concentrations, renal function and protein excretion rate. Our results support the increasing evidence that vitamin D deficiency may be one of the factors participating in the development of insulin resistance already in the early stages of chronic kidney disease.

Mitochondria and mitochondrial nitric oxide synthase alterations participate in energetical dysbalance, aging and age-related diseases.

Nitric oxide (NO) is a unique mediator of cellular regulations synthesized by nitric oxide synthases (NOS) present in cytoplasm of various cells. An additional Ca-dependent mitochondrial NOS (mtNOS) detected just recently synthesizes also NO inhibiting oxidative phosphorylation, i.e. mitochondrial energy producing metabolic process and protects mitochondria from oxygen radicals. Mitochondrial membrane possesses electrogenic uniporter transporting Ca into mitochondria (stimulation of mtNOS), while Na+/Ca2+ exchanger removes Ca from mitochondria. Mitochondrial disorders with low mtNOS activity participate in accelerated aging and age-related diseases. The direct NO balance determination is outside of the standard clinical facilities; Indirect alternatives, such as insulin resistance determination are accessible. Pharmacotherapy exploits effective therapeutic and preventive measures (NO donors, ACEI inhibitors, etc.) and pharmaceutical approach (development of mitochondriotropic drugs). We suggest, that mitochondrial disorders participate in aging and age related diseases and propose that the early diagnostics, preventive and therapeutic measures could prevent and even correct at least partially the development of age-related diseases (Tab. 4, Ref. 81).

Nitric oxide modulation of metabolic and haemodynamic balance.

Nitric oxide (NO) belongs to signal molecules and modulates notably rapid and dynamic processes. Interests are focused on the decreased NO synthesis by endothelial and mitochondrial nitric oxide synthases with the metabolic (i.e. insulin resistance, diabetes, energetical dysbalance) and vascular (i.e. hypertension, atheroslerosis) consequences. A significant source of NO are NO-donors (i.e. organic nitrates). A number of antihypertensive drugs stimulates NO production or inhibits the production of its antagonists (angiotensin II, catecholamines), other drugs (i.e. glucocorticoids) inhibit NO production. These interferences are targets of an intensive research with the aim of NO dysbalance prevention, hypertension and metabolic dysbalances correction. While the clinical research concentrates on NO and insulin resistance, the molecular biological research concentrates on "mitochondrial medicine" with the ambition to formulate a new theory of aging, carcinoma, and other fundamental biological processes (Fig. 1, Ref. 47).

Calcitriol load test in postmenopausal osteoporosis: a pilot study.

BACKGROUND: Calcium and vitamin D balance is of critical importance in both, prevention and treatment of osteoporosis. The evaluation of this balance is difficult under steady state conditions, therefore the effect of a single oral calcitriol load in postmenopausal women with osteopenia/osteoporosis was used. METHODS: Mineral and hormone concentrations were determined under basal conditions and after the administration of a single 0.5 microg calcitriol dose (Rocaltrol, Roche). RESULTS: Single oral calcitriol dose was administered to 36 postmenopausal women. Increased calciuria (p < 0.001) and calcium fractional excretion (p < 0.001) 24 hours after drug administration indicated kidney participation in calcium homeostasis. Urinary calcium excretion after the calcitriol load correlated with basal urinary calcium excretion (r = 0.772; p < 0.001). On the basis of calciuric response, women could be separated to responders and non-responders; in responders, increase in calciuria was >1.0 mmol/d, while in non-responders < 1.0 mmol/d (p < 0.001). Neither plasma calcium nor plasma 25-hydroxycholecalciferol concentrations increased after the calcitriol load. Both basal (r = -0.361; p < 0.03) and calcitriol stimulated urinary calcium excretion correlated inversely with age (r = -0.425; p < 0.01). No significant changes in measured mineral and hormone parameters were found in women with osteopenia in comparison to women with osteoporosis, with the exception of plasma intact parathormone concentration, which was significantly higher in osteoporotic women (p < 0.05) and significantly decreased (p < 0.001) after the calcitriol load. CONCLUSION: Postmenopausal women suffered from calcium and vitamin D imbalance which could be elucidated by a simple calcitriol test. The reference range, significance and differentiation from other abnormalities are to be defined in an extensive study. (Tab. 4, Ref. 19.).

[Vitamin D: synthesis, metabolism, regulation, and an assessment of its deficiency in patients with chronic renal disease]. / Vitamin D: syntéza, metabolizmus, regulácie a hodnotenie deficitu u pacientov s chronickým ochorením obliciek.

The main source of vitamin D in a man is its synthesis in human skin. 7-Dehydrocholesterol converts into cholecalciferol--vitamin D3--as a result of UV radiation. Cholecalciferol hydroxylates in liver into 25-hydroxyvitamin D3 [25(OH)D, calcidiol], which concentration in blood is a relevant indicator of the total of vitamin D in a human body. 25(OH)D hydroxylates in kidneys into 1,25-dihydroxyvitamin D3 [1,25(OH)2D, calcitriol], which is considered an active metabolite of vitamin D. Epidemiological studies showed high prevalence of low concentrations of 25(OH)D especially in older population and people with chronic diseases. 25(OH)D concentrations were defined at which rise parathormone levels, increases bone conversion, impairs bone mineralization and develops osteomalacia. Based on these results a deficiency of vitamin D was defined. Patients with chronic renal disease experience development of serious bone impairments described as renal osteodystrophy. These disorders are caused by secondary hyperparathyroidism which develops as a result of mineral metabolism impairment, especially of hypocalemia, 25(OH)D deficiency, and insufficient synthesis of 1,25(OH)2D. Presently published guidelines K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification define processes of vitamin D supplementation, particularly 1,25(OH)2D according to a degree of renal disease. Early prevention and treatment of hypovitaminosis D is a treatment goal in order to reduce or stop development of secondary hyperparathyroidism with its consequences for bone metabolism.

[Intensive vitamin D supplementation in the treatment of osteoporosis]. / Intenzifikovaná suplementácia vitamínom D v liecbe osteoporózy.

Vitamin D deficiency is not possible to correct with the nutritional vitamin D doses in postmenopausal women with decreased bone mineral density. The aim of study was to evaluated the effectivity and safety of 15,000 IU/week vitamin D administrated in 52 postmenopausal women with osteopenia or osteoporosis. Patients were divided into two groups. Treated group was supplemented by calcium 0.5 g/d and 25-hydroxycholecalciferol 15,000 IU/week and control group was supplemented by calcium and placebo for two months. Plasma calcium concentration did not change in the vitamin D treated group while it decreased (p < 0.001) in the control group. Neither calciuria nor fractional excretion of calcium changed during the treatment period. Plasma inorganic phosphate concentration did not change in any group, but urinary inorganic phosphate excretion increased in the vitamin D treated group (p < 0.001). The starting 25-hydroxycholecalciferol plasma concentrations were almost at the deficiency range in both groups. The 25-hydroxycholecalciferol plasma concentration increased substantially (p < 0.001) in the treated group, but it remained at the starting level in control group during the treatment period. Similar plasma concentration increase (p < 0.001) was apparent also in 1.25-dihydroxycholecalciferol. Plasma intact parathormone concentration did not change in the vitamin D treated patients, while it increased (p < 0.01) in the control group. None of the vitamin D treated women suffered from hypercalcemia and mild hypercalciuria was observed in one patient. In conclusion, the study presents an evidence on the effectiveness and safety of 15,000 IU/week 25-hydroxycholecalciferol dosage schedule.

Insulin resistance in kidney disease patients with mild to moderate kidney disease.

BACKGROUND: Insulin resistance is a very early sign of atherosclerosis and an increased risk of cardiovascular morbidity and mortality. Insulin resistance detection by the fasting plasma insulin and glucose determination enables early detection, follow-up, treatment and the search for accelerating factors in kidney disease patients threatened by atherosclerosis. PATIENTS AND METHODS: Insulin resistance was evaluated by the Quantitative Insulin Sensitivity Check Index from fasting glucose and insulin plasma concentrations in 66 kidney disease patients with a mild to moderate decrease in kidney function. RESULTS: Forty patients were insulin sensitive and 26 suffered from insulin resistance. These groups of patients did not differ significantly in age, gender, clearance of creatinine and cholesterol concentrations. However, patients with insulin resistance suffered from increased BMI (p < 0.001), fasting plasma glucose (p < 0.01), insulin (p < 0.001) and triglyceride (p < 0.01) concentrations. Insulin resistance correlated with BMI (r = -0.417, p < 0.001) and with plasma triglycerides concentration (r = -0.307, p < 0.01). The absent relationship between insulin resistance and age (r = -0.154, NS) or creatinine clearance (r = -0.061, NS) suggests the need for screening of insulin resistance even in young patients with mild kidney function reduction. CONCLUSION: A considerable number of renal patients in the early stages of kidney function reduction suffers from insulin resistance. They need to improve their life style and take medication (i.e. antihypertensive drugs) improving insulin sensitivity and to omit medications which harm it. (Fig. 2, Tab. 1, Ref. 20.)

[Nephrogenic metabolic acidosis]. / Nefrogénna metabolická acidóza.

Metabolic acidosis is a major risk factor of kidney disease progression as a consequence of impaired H+ urinary excretion by the decreased kidney NH3 synthesis. Two key enzymes participate: a) Phosphate-dependent glutaminase under the genomic control of metabolic acidosis and b) Phosphate independent glutaminase localized on proximal tubule microvili under the nongenomic control. Two types of kidney disease metabolic acidoses are dominant: a) Hyperchloremic metabolic acidosis usually on the basis of hereditary or toxic alterations, isolated or as a part of Fanconi syndrome. b) Hyperphosphatemic metabolic acidosis of renal insufficiency. Metabolic acidosis shares serious consequences: metabolic acidosis increases protein catabolism of amino acids, inhibits proteosynthesis (albumin!), accelerates renal osteodystrophy development, modulates calcidiol and parathormone plasma levels and evokes insulin resistance. The present therapy requires full correction of metabolic acidosis!

[Atherosclerotic nephropathy in renal artery stenosis--from randomized studies to individualized therapy]. / Aterosklerotická nefropatia pri stenóze renálnej artérie--od randomizovaných stúdií k individualizácii terapie.

Randomized trials in hypertensive patients with atherosclerotic renal artery stenosis (ARAS) mostly did not reveal any significant difference between antihypertensive treatment and revascularization (by angioplasty or bypass surgery) in their effects on blood pressure or glomerular filtration rate. This unexpected conclusion reflects a fact that in addition to potentially reversible ischemia, some other factors which are not eliminated by technically successful revascularization take part in the decrease of renal function in ARAS, including cholesterol microemboli from atherosclerotic plaques, secondary focal segmental glomerulosclerosis and hypertensive nephroangiosclerosis. Moreover, these changes have been also found in the contralateral kidney without any stenosis. Scintigraphic studies confirmed that the individual kidney function was not related to the presence of ARAS, i.e., the glomerular filtration rate in the stenotic kidney was often equal to, or paradoxically even better than that in the kidney with normal renal artery. This has obviously important consequences for the indication of revascularization which should be based on measurement of the individual kidney function rather than overall renal function. A conservative treatment of ARAS should comprise ACE inhibitors or angiotensin II receptor antagonists, statins and acetylsalicylic acid. The long-term effect of such treatment on the progression of atherosclerotic nephropathy is now being evaluated in randomized trials.

Effects of ramipril in nondiabetic nephropathy: improved parameters of oxidatives stress and potential modulation of advanced glycation end products.

Enhanced oxidative stress is involved in the progression of renal disease. Since angiotensin converting enzyme inhibitors (ACEI) have been shown to improve the antioxidative defence, we investigated, in patients with nondiabetic nephropathy, the short-term effect of the ACEI ramipril on parameters of oxidative stress, such as advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), homocysteine (Hcy), and lipid peroxidation products. Ramipril (2.5-5.0 mg/day) was administered to 12 newly diagnosed patients for 2 months and data compared with a patient group under conventional therapy (diuretic/beta-blockers) and with age- and sex-matched healthy subjects (CTRL). Patients had mild to moderate renal insufficiency and showed, in the plasma, higher fluorescent AGE and carboxymethyllysine (CML) levels, as well as elevated concentrations of AOPPs, lipofuscin and Hcy when compared with CTRL. Basal data of the patients on conventional therapy did not differ significantly from the ramipril group, except for higher Hcy levels in the latter. Administration of ramipril resulted in a drop in blood pressure and proteinuria, while creatinine clearance remained the same. The fluorescent AGEs exhibited a mild but significant decline, yet CML concentration was unchanged. The AOPP and malondialdehyde concentrations decreased, while a small rise in neopterin levels was evident after treatment. The mentioned parameters were not affected significantly in the conventionally treated patients. Evidence that ramipril administration results in a mild decline of fluorescent AGEs is herein presented for the first time. The underlying mechanism may be decreased oxidative stress, as indicated by a decline in AOPPs and malondialdehyde.

Kidney function and age related mineral imbalance in postmenopausal women with osteopenia/osteoporosis.

BACKGROUND: Negative mineral balance in postmenopausal women appears to be an important risk factor for osteoporosis and subsequent bone fractures. Its pathogenesis has not been elucidated. OBJECTIVES: To elucidate the participation of the kidney and ageing on mineral balance in postmenopausal women. METHODS: 36 postmenopausal women with osteopenia or osteoporosis, aged 46-75 years were evaluated by determination of mineral balance, kidney functions, 25(OH)-cholecalciferol [25(OH)D], 1,25(OH)2-cholecalciferol [1,25(OH)2D] and intact parathormone plasma levels. RESULTS: Plasma calcium (Ca) concentrations were low and they did not decrease further with ageing. Urinary Ca excretion decreased (r = -0.425, p < 0.01) with age without changes in the fractional excretion of Ca. A similar decrease of urinary excretion was found in the urinary excretion of phosphorus (Pi) (r = -0.335; p < 0.03) and magnesium (Mg) (r = -0.355; p < 0.03). All patients' kidney functions were in the age-related reference range. Plasma 25(OH)D concentrations were in the range of moderate to severe deficiency, related inversely to age (r = -0.357; p < 0.03) and Ca urinary excretion (r = 0.343; p < 0.04) and to plasma creatinine concentration (r = 0.381; p < 0.02). Plasma 1,25(OH)2D concentrations were also low, they did not change with age and were highly correlated with Ca urinary excretion (r = 0.458; p < 0.005). The intact parathormone (iPTH) plasma concentrations were in the reference range, without any changes during aging. CONCLUSIONS: Pi, Mg and dominantly Ca imbalance in postmenopausal women with osteopenia or osteoporosis accentuates with age and besides their insufficient intake the vitamin D deficiency takes part. These data support the need for increased supplementation of Ca and vitamin D with increasing age. (Tab. 3, Fig. 4, Ref. 18.).

Serum ex vivo lipoprotein oxidizability in patients with ischemic heart disease supplemented with vitamin E.

The decreased oxidizability of plasma lipoproteins is related to the increased vitamin E intake and its association with a relatively lower incidence of coronary heart disease has been proposed. We investigated the effect of the in vivo vitamin E supplementation on the oxidizability of serum lipids in patients with ischemic heart disease and a moderate hypercholesterolemia. Thirty-two patients (16 males and 16 postmenopausal women) participated in this placebo-controlled, randomized trial. They were treated with 400 mg vitamin E/day for 6 weeks. The copper-induced serum lipid oxidizability ex vivo was assessed by measuring conjugated diene formation at 245 nm. We also measured vitamin E, malondialdehyde (MDA) and uric acid concentrations in the plasma. Because of observed significant differences in parameters of serum lipid oxidizability (lag time and maximal rate of oxidation), plasma alpha-tocopherol and MDA levels between male patients and postmenopausal women supplemented with vitamin E, the results were compared between both genders. Six weeks of vitamin E supplementation significantly increased plasma vitamin E levels (by 87 %) in male patients but in postmenopausal women only by 34 %. Concomitantly with increased plasma levels of vitamin E the decrease in plasma MDA levels was observed in male patients (decrease by 20 %; p=0.008), but in postmenopausal women the decrease did not attain statistical significance. Plasma uric acid levels were not apparently changed in placebo or vitamin E supplemented groups of patients. The changes in ex vivo serum lipid oxidizability after vitamin E, supplementation have shown a significantly prolonged lag time (by 11 %; p=0.048) and lowered rate of lipid oxidation (by 21 %; p=0.004) in male patients in comparison with postmenopausal women. Linear regression analysis revealed a significant correlation between plasma vitamin E levels and the lag time (r=0.77; p=0.03) and the maximal rate of serum lipid oxidation (r=-0.70; p=0.05) in male patients. However, in postmenopausal women the correlations were not significant. We conclude that 400 mg vitamin E/day supplementation in patients with ischemic heart disease and a moderate hypercholesterolemia influenced favorably ex vivo serum lipid oxidation of male patients when compared with postmenopausal women. The observed differences between both genders could be useful in the selection of the effective vitamin E doses in the prevention of coronary heart disease.

Does magnesium dysbalance participate in the development of insulin resistance in early stages of renal disease?

We investigated the potential role of magnesium (Mg) dysbalance in the pathogenesis of insulin resistance (IR) in patients with mildly-to-moderately decreased renal function (creatinine: 142.8+/-11.0 mmol/l). The data were compared to those of 8 age- and sex-matched healthy controls (CTRL). The standard oral glucose tolerance test (oGTT) was performed in 61 patients. Twenty-two patients were classified as IR according to their values on fasting and after-load immunoreactive insulin concentrations. Serum and total erythrocyte Mg (tErMg) (atomic absorption spectro-photometry) and free erythrocyte Mg (fErMg) concentrations ((31) P NMR spectroscopy) were determined prior to and two hours after the glucose load. Ten out of 39 insulin-sensitive (IS) patients, but only one out of 22 insulin-resistant (IR) patients, had a low basal fErMg concentration (<162.2 micromol/l, chi2, p<0.01). IR patients had higher serum Mg, total erythrocyte Mg and bound erythrocyte Mg (bErMg) concentrations (both before and after glucose load) when compared with the IS group. Both groups responded to the glucose load with a significant decrease in serum Mg concentration (within the normal range), while the IR group also exhibited a decline in tErMg and bErMg. The mean sum of insulin needed to metabolize the same glucose load correlated positively with tErMg (r=0.545, p<0.01) and bErMg (r=0.560, p<0.01) in the IR patients. It is concluded that, at an early stage of renal dysfunction, IR is not associated with the decline in free erythrocyte Mg concentration, but the magnesium handling in red blood cells is altered.

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.

[Effect of coenzyme Q10 in patients with kidney diseases]. / Ucinok koenzýmu Q10 u pacientov s ochoreniami obliciek.

BACKGROUND: Coenzyme Q10 belongs to important antioxidants and it has a key role in the synthesis of adenosinetriphosphate. Its beneficial effect was proved in several diseases, e.g. in mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial cardiomyopathy. MATERIAL AND METHODS: All 15 patients of the studied group (5 with tubulopathy and 10 with chronic tubulointersticial nephritis) received antioxidative therapy for three months (E vitamin, C vitamin, riboflavin) and for the last two months coenzyme Q10 was added. Renal functions, spectrum of lipids, parameters of lipid peroxidation (malondialdehyde), levels of alpha-tocopherol, beta-carotene, coenzyme Q10. RESULTS: Before the substitutive antioxidative treatment, coenzyme Q10 levels reached in blood 0.11 +/- 0.03 mumol/l and 0.15 +/- 0.04 mumol/l in plasma. These values were well below the reference range (rr) is 0.4 +/- 1.0 mumol/l). After the substitution coenzyme Q10 levels significantly increased (p < 0.001) to the values of 1.66 +/- 0.16 mumol/l in blood and to 1.78 +/- 0.27 mumol/l in plasma. Plasma levels of beta-carotene increased from the markedly subnormal values 0.25 +/- 0.07 mumol/l (rr > 0.8 mumol/l) to 0.56 +/- 0.02 mumol/l (no statistical difference). Plasma levels of alpha-tocopherol remained within the reference range 32.15 +/- 4.73 mumol/l (rr 15-30 mumol/l) and they increased up to the plasma level of 44.83 +/- 5.82 mumol/l during the period of testing. Malondialdehyde levels did not significantly change within the testing period. No changes in renal functions and parameters of lipid metabolism were described. Patients well tolerated the treatment and no adverse effects were seen during the period of observation. CONCLUSIONS: Our results ascertained that levels of antioxidant CoQ10 were lower in patients with nephropathy who underwent conservative treatment with peroral substation. Such deficit can be amended by CoQ10 administration, which could be therefore taken as complementary treatment of nephrology.

DNA damage of lymphocytes in experimental chronic renal failure: beneficial effects of losartan.

BACKGROUND: Kidney diseases are associated with the accumulation of various uremic toxins increasing the oxygen free radical (OFR) activity with a number of serious consequences. One of them could be the impairment of DNA stability with the increased formation of DNA breaks. METHODS: The study was performed in 4/6 kidney ablation rat nephropathy lasting for three months. The results of sham-operated (Sham), remnant kidney (Nx), and Nx treated by losartan (NxL) were compared. RESULTS: Nx significantly increased blood pressure, plasma creatinine, urea, hippurate, malondialdehyde (MDA), lipofuscin (LF), and the number of DNA breaks of lymphocytes. Losartan decreased the rise of blood pressure and inhibited the rise of creatinine plasma concentration but not of other variables, while it markedly inhibited the number of DNA breaks (Sham 15.9 +/- 1.1, Nx 54.5 +/- 1.7, P < 0.001; Nx/Sham, NxL 23.3 +/- 2.6 P < 0.001, NxL/Sham and P < 0.001 NxL/Nx). CONCLUSIONS: The 4/6 kidney ablation nephropathy increases the susceptibility of lymphocyte DNA to breaks, and losartan inhibits the number of breaks by a mechanism independent on glomerular filtration, accumulation of MDA or LF (markers of oxidative stress), and hippurate (marker of the accumulation of middle molecular substances). An independent mechanism, probably the interference with proliferation, is suggested.

Hippurate participates in the correction of metabolic acidosis.

Hippurate (Hip), an endogenous conjugate, belongs to the group of uremic toxins. Hip stimulates P-independent glutaminase (PIG) localized at the proximal luminal membrane, desamidating glutamine with the formation of ammonia, a dominant and adaptive elimination product of H+. This appears to be important because metabolic acidosis (MAC) does not stimulate PIG. Moreover, Hip inhibits ammonia production by P-dependent mitochondrial glutaminase (PDG) that is primarily stimulated by MAC. By this mechanism, it shifts the ammonia production from mitochondria to proximal tubular lumen. MAC stimulates Hip synthesis in the liver and kidney and increases Hip plasma concentration and even fractional excretion by the kidney, which creates an effective regulatory loop of ammoniagenesis. Thus, it appears that Hip by its participation in the correction of MAC possesses the modulatory function.