Hemodialysis decreases serum brain-derived neurotrophic factor concentration in humans.

In the present study we have evaluated the effect of a single hemodialysis session on the brain-derived neurotrophic factor levels in plasma [BDNF](pl) and in serum [BDNF](s) as well as on the plasma isoprostanes concentration [F(2) isoprostanes](pl), plasma total antioxidant capacity (TAC) and plasma cortisol levels in chronic kidney disease patients. Twenty male patients (age 69.8 ± 2.9 years (mean ± SE)) with end-stage renal disease undergoing maintenance hemodialysis on regular dialysis treatment for 15-71 months participated in this study. A single hemodialysis session, lasting 4.2 ± 0.1 h, resulted in a decrease (P = 0.014) in [BDNF](s) by ~42 % (2,574 ± 322 vs. 1,492 ± 327 pg ml(-1)). This was accompanied by an increase (P < 10(-4)) of [F(2)-Isoprostanes](pl) (38 ± 3 vs. 116 ± 16 pg ml(-1)), decrease (P < 10(-4)) in TAC (1,483 ± 41 vs. 983 ± 35 trolox equivalents, µmol l(-1)) and a decrease (P = 0.004) in plasma cortisol level (449.5 ± 101.2 vs. 315.3 ± 196.3 nmol l(-1)). No changes (P > 0.05) in [BDNF](pl) and the platelets count were observed after a single dialysis session. Furthermore, basal [BDNF](s) in the chronic kidney disease patients was significantly lower (P = 0.03) when compared to the age-matched control group (n = 23). We have concluded that the observed decrease in serum BDNF level after hemodialysis accompanied by elevated [F(2)-Isoprostanes](pl) and decreased plasma TAC might be caused by enhanced oxidative stress induced by hemodialysis.

Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients.

BACKGROUND AND OBJECTIVES: Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks). RESULTS: Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population. CONCLUSIONS: This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.

Thiol levels, protein carbonylation and anaerobic sulfur metabolism in erythrocytes of peritoneal dialysis and predialysis patients.

AIM: The goal of the present study was to investigate the changes in sulfur metabolism in erythrocytes of end-stage renal failure patients. METHODS: The following substances were determined in erythrocytes of chronic kidney disease patients before dialysis, patients treated with continuous ambulatory peritoneal dialysis, and in a group of healthy volunteers: (i) sulfane sulfur level and activity of the enzymes involved in its metabolism and in cyanide detoxification; (ii) concentration of total and non-protein sulfhydryl groups -SH; and (iii) protein carbonylation rate. RESULTS: Erythrocytes of chronic kidney disease patients in predialysis period contained lower levels of sulfane sulfur, non-protein thiols, total thiols and 3-mercaptopyruvate sulfotransferase. On the other hand, in erythrocytes of end-stage renal failure patients treated with continuous ambulatory peritoneal dialysis, sulfane sulfur, non-protein thiols, total thiols and 3-mercaptopyruvate sulfotransferase activity remained at the level observed in healthy controls. These changes indicate a disturbed thiol balance and anaerobic cysteine metabolism in non-dialysis patients, whereas continuous ambulatory peritoneal dialysis patients did not show these disorders. γ-Cystathionase activity was equally elevated in predialysis period and in peritoneal dialysis patients, which means that chronic kidney disease pathology is accompanied by an increased expression of this enzymatic activity in erythrocytes. Erythrocytic rhodanese activity was unchanged and stayed at the control level in both groups. Protein carbonylation rate was equally enhanced in both patient groups, which indicated acceleration of oxidative processes and inability of continuous ambulatory peritoneal dialysis to correct these changes in erythrocytes. CONCLUSION: The CAPD as a replacement therapy helps to preserve thiol levels and anaerobic sulfur metabolism in erythrocytes.

Predicting kidney function from renal biopsy. Semiquantitative versus quantitative approach.

The term glomerulonephritis encompass a heterogeneous group of diseases; these are a important cause of end stage renal disease. Although several evidence exist, that the main prognostic factors are extraglomerular lesions, no quantitative assessment is usually done. In nephropathological practice a semiquantitative approach is preferred. However, most of work on extraglomerular lesions significance was done with quantitative methods. The aim of the study was to compare the effects of quantitative and semiquantitative assessment of extraglomerular lesions in glomerulonephritis. The material consisted of 120 renal biopsies. On inspection, percentage of sclerosed glomeruli, degree of interstitial fibrosis, degree of interstitial infiltration, degree of tubular atrophy were and degree of mesangial matrix expansion assessed. For quantitative measurements AnalySIS 3.0 pro image analysis system was used. Relative interstitial volume, volume of interstitial infiltrate, with their variability--ross sectional areas of proximal and distal tubules were assessed by point counting method. Relative interstitial volume was significantly correlated to percentage of sclerosed glomeruli (R = 0.33 p < 0.001), degree of tubular atrophy (gamma = 0.57 p < 0.00001), degree interstitial fibrosis (gamma = 0.31 p < 0.0002) and mesangial matrix expansion (gamma = 0.24 p < 0.001). Semiquantitative and quantitative assessment of interstitial infiltrate was significantly correlated as well (gamma = 0.81 p < 0.001). Semiquantitatively assessed degree of tubular atrophy showed significant relation to total proximal tubular area (gamma = -0.30 p = 0,004). Percentage of sclerosed glomeruli was significantly correlated to creatinine level (R = 0.24 p = 0.03), but not to urea level (R = 0.09, NS). Semiquantitatively assessed degree of interstitial fibrosis showed only marginal correlation to creatinine level (gamma = 0.18 NS), however degree of interstitial infiltration was significantly correlated to creatinine (gamma = 0.34 p = 0.002) and urea level (gamma = 0.22 p = 0.06). Degree of tubular atrophy was significantly correlated to creatinine (gamma = 0.43 p < 0.001) and urea level (gamma = 0.28 p = 0.015). Relative interstitial volume was the very most important correlate of creatinine (R = 0.47 p < 0.0001) and urea level (R = 0.30 p < 0.01). In conclusion, it was confirmed, that the strongest correlate of renal function is relative interstitial volume. Some, but not all of semiquantitative parameters are also significantly correlated to kidney function.

Interstitial, tubular and vascular factors in progression of primary glomerulonephritis.

Glomerulonephritis is one of the diseases leading to chronic renal failure and need of renal replacement therapy. Changes in extraglomerular compartments, especially in the interstitium, are thought to play a major role in progression. However, the exact relationships between renal interstitium, tubules and vessels and their prognostic impact are less well understood. The material consisted of 111 biopsies with primary glomerulonephritis. Normal renal tissue from surgically removed kidneys served as controls. Relative interstitial volume (RIV), its variability, volume of interstitial infiltrate, cross-sectional tubular area were measured with the point-counting method. A number of vascular parameters were also measured. The assessed interstitial and tubular parameters were strongly correlated to creatinine level. The strongest correlation was seen for RIV, also on multiple regression. In patients with renal failure, increased RIV, more pronounced vascular lesions and interstitial infiltrates were seen. Survival analysis showed that interstitial expansion is the most important factor leading to renal failure. Tubulointerstitial and vascular factors are interrelated and linked to renal function. RIV has strongest impact on renal function and survival, even taking into account other factors.

A comparison of dosing regimens of paricalcitol capsule for the treatment of secondary hyperparathyroidism in CKD stages 3 and 4.

BACKGROUND: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. METHODS: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. RESULTS: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive > or = 30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca x P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. CONCLUSIONS: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive > or = 30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca x P product as compared with placebo or intermittent dosing.

Disruption of thiol homeostasis in plasma of terminal renal failure patients.

BACKGROUND: The aim of the present studies was to investigate the changes in concentrations of different forms of thiols in plasma of terminal renal failure patients before and after hemodialysis. METHODS: Total concentrations of thiols, their free forms and the level of their mixed disulfides with proteins were determined with HPLC. RESULTS: In terminal renal failure patients before dialysis, total concentrations of cysteine, homocysteine and cysteinylglycine and their free and protein-bound fractions increased while level of all such forms of glutathione dropped. A single dialysis session caused short-lasting return of concentrations of all forms of thiols to the level equal or close to the control group. The changes observed in non-dialyzed patients were similar to those observed in dialyzed patients before single dialysis procedure. CONCLUSIONS: The obtained results showed severe disturbance of thiol homeostasis in plasma of terminal renal failure patients. The following changes have to be emphasized: (1) high level of free cysteine (cystine) fraction, (2) strong tendency of homocysteine to form mixed disulfides with proteins, (3) drop of glutathione level. These observations confirm a suggestion that atherogenic action of homocysteine can be a result of S-homocysteinylation and N-homocysteinylation reactions, whereas toxic action of cysteine can result from auto-oxidation reaction.

Relative interstitial volume is correlated with renal function even in non-representative biopsy.

An useful renal biopsy should be representative, that is should contain a sufficient number of glomeruli. However, a non-representative biopsy could possibly provide some information. The aim of the study was to evaluate the relationship between interstitial expansion, glomerular sclerosis and renal function in such material. The material consisted of 28 renal biopsies containing less than 5 non-sclerosed glomeruli. For each case the percentage of completely sclerosed glomeruli was recorded. The relative interstitial volume was evaluated by point counting method. Clinical data as sex, age, serum creatinine and urea levels were included into analysis. The mean percentage of completely sclerosed glomeruli was 39.6%; mean relative interstitial volume was 29.6%. Creatinine level was strongly correlated to relative interstitial volume (R = 0.70), but the correlation of creatinine level to percentage of sclerosed glomeruli was much weaker (R = 0.38). The relationship between interstitial expansion and renal function is seen also in deficient biopsy material. The correlation of renal function with interstitial expansion is stronger the correlation of renal function with glomerular sclerosis. These findings can indicate that the better representation is responsible for stronger prognostic impact of interstitial lesions

[Motor and endocrine function disturbances of the gastrointestinal tract in patients with chronic renal failure (CRF)]. / Zaburzenia czynnosci motorycznej oraz endokrynnej przewodu pokarmowego u chorych z przewlekla niewydolnoscia nerek (PNN).

In the chronic renal failure (CRF) there are several upper gastrointestinal symptoms, which result from both disturbed motor function (associated with the delayed gastric emptying) and myoelectrical one (associated with abnormal electrogastrography registration). In patients suffering from CRF, disturbances of the endocrine digestive system function were also demonstrated, which are related to the observations of many gastrointestinal hormones increased levels.

Deformability and enzymes activities of red blood cells in hemodialysed and peritoneal dialysed patients with chronic renal disease.

These studies were focused on the influence of two treatment methods of patients with chronic renal disease on RBC deformability. In peritoneal dialysed-patients (PD) erythrocytes exhibited a decrease in their deformability as compared to control subjects whereas this parameter in RBC deriving from hemodialysed patients (HD) was not altered. The alleviating effect of plasma components on deformability of erythrocytes was confirmed after the isolation of a pure faction of these cells as the parameter became worse. The activity of studied enzymes: acetylcholinesterase (Ache), dehydrogenase glucose-6-phosphate (G-6-PD) and glutathione reductase (GR) maintained their physiological values in both dialysis groups.

Alteration in plasma levels of nonprotein sulfhydryl compounds and S-nitrosothiols in chronic renal failure patients.

BACKGROUND: Uremia is accompanied by the elevated nitric oxide (NO) synthesis, and it has not yet been established how this influences the levels of nonprotein sulfhydryl compounds (NPSH) and formation of S-nitrosothiols (SNT). METHODS: Our study was designed to determine plasma levels of SNT and NPSH in chronic renal failure (CRF) patients, who were hemodialysed (HD) or were not on hemodialysis treatment (ND), and in the control group. RESULTS: In ND patients, the plasma levels of SNT were significantly increased (11.25+/-2.08 nmol/ml, p<0.01), while NPSH levels were simultaneously decreased (66.67+/-15.0 nmol/ml, p<0.05) in comparison with the control subjects (SNT: 8.75+/-2.08 nmol/ml, NPSH: 86.66 nmol/ml). In HD patients, plasma concentration of SNT before hemodialysis was significantly lower than in the control group (0.150+/-0.042 nmol/mg protein vs. control: 0.175+/-0.075 nmol/mg protein), and no significant change was observed after dialysis (0.142+/-0.058 nmol/mg protein, p<0.05). The level of NPSH in HD patients before dialysis was significantly decreased in comparison with the control subjects, both, when the results were calculated per 1 ml of plasma (45.96+/-17.87 nmol/ml) and per 1 mg of protein (0.70+/-0.25 nmol/mg protein). In the postdialysis samples, NPSH rose (79.15+/-22.9 nmol/ml, p<0.001 which corresponds to 1.30+/-0.55 nmol/mg protein, p<0.001) as compared to the level before dialysis. CONCLUSIONS: Firstly, plasma SNT level was found to be increased in CRF patients who were not treated with hemodialysis, while in HD patients, it dropped below the control values. It indicates that hemodialysis disturbs an equilibrium of reactions involved in S-nitrosothiols formation most probably by removing low molecular weight S-nitrosylating compounds. Secondly, the increased level of NPSH after each hemodialysis session indicates reestablished antioxidant capacity of plasma and suggests the existence of dialysable compounds, which via unknown mechanism become responsible for the decreased level of thiols.

Effects of phenylhydrazine or recombinant human erythropoietin on deformability and activity of dehydrogenase glucose-6-phosphate and acetylcholinesterase in Wistar rats blood enriched in reticulocytes.

Deformability and activity of the enzymes: acetylcholinesterase (AChE) and dehydrogenase glucose-6-phosphate (G-6-PD), were assayed for RBC enriched in immature reticulocytes. Reticulocytosis was evoked by administration of two different drugs: recombinant human erythropoietin (rHuEPO) and phenylhydrazine (PHZ) to two groups of Wistar rats. After treatment with the former compound, a group of animals exhibited 17.33% reticulocytes in blood whereas a group of rats treated with the latter drug reached 57.66% of these cells in blood. A marked decrease in RBC deformability was found in both groups of animals. AChE did not significantly change activity neither in PHZ-treated nor in rHuEPO-treated rats, whereas G-6-PD activity was significantly decreased in the PHZ-treated group.

The gamma-glutamyltransferase activity and non-protein sulfhydryl compounds levels in rat kidney of different age groups.

The present work was aimed to obtain information about age-dependent changes of gamma-glutamyltransferase (GGT) activity and the levels of non-protein sulfhydryl compounds (NPSH) in rat kidneys. In addition, protein-bound cysteine (PB-Cys), sulfane sulfur compounds and reactive oxygen species (ROS) were estimated. The results indicate that the activity of GGT and NPSH levels in the kidneys are reduced with age. At the same time, a significant increase in the level of protein-bound cysteine was observed. Simultaneously, the content of sulfane sulfur compounds was increased in the group of the oldest animals. These findings indicate that the capacity for extracellular glutathione degradation and, in consequence, the availability of cysteine for intracellular glutathione biosynthesis may be impaired. The increased PB-Cys level indicates potentiation of the thiolation reaction, i.e. development of protein-mixed disulfides. These results reveal age dependent disturbances in the thiol-disulfide equilibrium in the kidneys which leads to an imbalance between pro- and antioxidatory processes.

Rheological and biochemical examination of red blood cells after treatment with different pharmacological and toxic substances.

Rheological and enzymatic properties of red blood cells (RBC) were investigated in vitro after the treatment with vasoactive drug - buflomedil (bfl) and toxic substance - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies with bfl included two different concentrations of the drug: 90 microg/ml of blood and 10 microg/ml of blood. The former concentration of the drug corresponds to the amount of bfl which is taken daily by a patient, the latter one is the highest peak of this drug in plasma. The dosage of dioxin was 32 microg/ml of blood and 32 ng/ml of blood. Only the smaller dosage of this compound appears in the environment but the higher one may occur in human organs because of its cumulation. Rheological properties of erythrocytes were examined using a laser diffractometer Rheodyne SSD (Myrenne). The deformability of RBC was expressed as an elongation index IE which was counted from the equation: EI=(L-W)/(L+W) where L is the length of cell and W is the width of cell. As far as the impact of bfl on RBC rheology is concerned studies were conducted in two different ways: (1) RBC were incubated with bfl directly, (2) RBC before incubation with bfl were treated with diamide to cause their rigidity. The action of bfl seems to be not efficient enough as data are not statistically significant in those two cases. Enzymatic properties of RBC were investigated using the methods of Beutler [7]. The activity of three enzymes was measured (acetylcholinesterase - Ache, dehydrogenase glucoso-6-phosphate - G-6-PD and gluthatione reductase - GR) for both bfl and TCDD-treated RBC. For TCDD-treated RBC additionally malonyldialdehyde (MDA) level was assessed.