Viktoriya Kuntsevich

Metabolic effects of dialyzate glucose in chronic hemodialysis: results from a prospective, randomized crossover trial

BACKGROUND There is no agreement concerning dialyzate glucose concentration in hemodialysis (HD) and 100 and 200 mg/dL (G100 and G200) are frequently used. G200 may result in diffusive glucose flux into the patient, with consequent hyperglycemia and hyperinsulinism, and electrolyte alterations, in particular potassium (K) and phosphorus (P). This trial compared metabolic effects of G100 versus G200. METHODS Chronic HD patients participated in this randomized, single masked, controlled crossover trial (www.clinicaltrials.gov: #NCT00618033) consisting of two consecutive 3-week segments with G100 and G200, respectively. Intradialytic serum glucose (SG) and insulin concentrations (SI) were measured at 0, 30, 60, 120, 180, 240 min and immediately post-HD; P and K were measured at 0, 120, 180 min and post-HD. Hypoglycemia was defined as an SG<70 mg/dL. Mean SG and SI were computed as area under the curve divided by treatment time. RESULTS Fourteen diabetic and 15 non-diabetic subjects were studied. SG was significantly higher with G200 as compared to G100, both in diabetic {G200: 192.8±48.1 mg/dL; G100: 154.0±27.3 mg/dL; difference 38.8 [95% confidence interval (CI): 21.2-56.4] mg/dL; P<0.001} and non-diabetic subjects [G200: 127.0±11.2 mg/dL; G100 106.5±10.8 mg/dL; difference 20.6 (95% CI: 15.3-25.9) mg/dL; P<0.001]. SI was significantly higher with G200 in non-diabetic subjects. Frequency of hypoglycemia, P and K serum levels, interdialytic weight gain and adverse intradialytic events did not differ significantly between G100 and G200. CONCLUSION G200 may exert unfavorable metabolic effects in chronic HD patients, in particular hyperglycemia and hyperinsulinism, the latter in non-diabetic subjects.

Fatigue in Hemodialysis Patients With and Without Diabetes: Results From a Randomized Controlled Trial of Two Glucose-Containing Dialysates

In hemodialysis (HD), dialysate glucose concentrations differ worldwide between 0 and 200 mg/dl and can, if above the serum glucose levels, lead to diffusive glucose shifts into the patient (1). The effects of glucose (2) and insulin (3) on the autonomic nervous system, as well as during HD with different glucose concentrations, (4) have been reported. However the effect of dialysate glucose on fatigue has not been studied. This study investigated fatigue in chronic HD subjects treated with 100 mg/dl (G100) versus 200 mg/dl dialysate glucose (G200). In this randomized, crossover, multicenter study (www.clinicaltrials.gov, NCT00618033), diabetic and nondiabetic patients were enrolled in a 1:1 fashion. Diabetes was defined as either requiring oral antidiabetic medication or insulin or having random blood glucose levels above 200 mg/dl during the preceding 12 months. The study protocol …

Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients

Background/Aims: In hemodialysis (HD) patients the endothelial and erythrocyte glycocalyx is impaired which in turn correlates with elevated erythrocyte sodium sensitivity (ESS). Additionally, apoptotic erythrocyte death (eryptosis), characterized by phosphatidylserine (PS) exposure on the cell surface, is increased in this population. We aimed to explore the relationship of ESS and eryptosis. Methods: Blood samples were collected from 11 healthy controls and 20 chronic HD patients before and after midweek HD. ESS was quantified by the salt blood test. PS-exposure, intracellular reactive oxygen species (ROS) of erythrocytes and reticulocytes were assessed by flow cytometry. Results: Compared to controls ESS was significantly higher in HD patients preHD and did not change during treatment. The percentage of eryptotic cells did not differ between controls and patients preHD. However, eryptosis decreased during HD. ESS and eryptosis were uncorrelated, while eryptosis was positively correlated with intracellular ROS and percent reticulocytes. Conclusions: Higher ESS levels in HD patients indicate a pathologic glycocalyx. ESS and eryptosis were not correlated. The decreased eryptosis postHD may possibly be related to dialytic uremic toxin removal, but is likely multifactorial. The relationship between eryptosis and intracellular ROS warrants further research.

Plasma Gelsolin and Its Association with Mortality and Hospitalization in Chronic Hemodialysis Patients

Background: Human plasma gelsolin (pGSN) is an actin-binding protein that is secreted into the extracellular fluid, with the skeletal muscle and myocardial tissues being its major source. Depletion of pGSN has been shown to be related to a variety of inflammatory and clinical conditions. Methods: pGSN levels were prospectively determined in prevalent maintenance hemodialysis (HD) patients from 3 U.S. dialysis centers. Demographics (age, time since dialysis initiation, race, gender, body height and weight, comorbidities), inflammatory markers (C reactive protein, CRP; interleukin 6, IL-6), free triiodothyronine (fT3), and routine laboratory parameters were obtained. We performed Kaplan-Meier and Cox proportional hazard survival analysis for all-cause and cardiovascular mortality, and recurrent event survival analysis for hospitalization. Results: We studied 153 patients; mean age was 60.5 ± 14.7; 52% were males. The mean pGSN level was 6,617 ± 1,789 mU/ml. In univariate analysis, pGSN was positively correlated with body mass index (r = 0.2, p = 0.01), pre-HD serum albumin (r = 0.247, p = 0.002), and pre-HD serum creatinine (r = 0.381, p < 0.001), and inversely with age (r = -0.286, p < 0.001), CRP (r = -0.311, p < 0.001), and IL-6 (r = -0.317, p < 0.001). In the adjusted analysis, the associations with CRP and creatinine were retained. pGSN levels tended to be lower in patients who died (p = 0.08). There was no association with all-cause or cardiovascular mortality, or all-cause hospitalization. Of note, fT3 was lower in patients who died (p = 0.001). Conclusions: Even though pGSN was inversely correlated with age, CRP and IL-6, suggesting that inflammation may influence pGSN, lower pGSN levels were not associated with hospitalization, all-cause and cardio-vascular mortality in this patient population.

Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways

It is hypothesized that the uremic toxin indoxyl sulfate (IS) plays a role in the pathogenesis of renal anemia. To further explore that hypothesis, we examined the effects of IS on reactive oxygen species (ROS) production, levels of reduced glutathione (GSH), and erythrocyte death (eryptosis) in red blood cells (RBC) from healthy controls (CON-RBC) and hemodialyzed patients (HD-RBC), respectively. RBC were incubated either in either TRIS-Glc-BSA buffer or IS at concentrations of 0.01, 0.09, and 0.17 mM, respectively. We measured ROS generation (expressed as % of DCFH-DA positive RBC), eryptosis (expressed as % of annexin-V positive RBC), and GSH levels after 6, 12, and 24 h. When incubated in buffer, ROS production was approximately seven-fold higher at all time points HD-RBC when compared to CON-RBC. Incubation with IS increased ROS production in CON-RBS dose-dependently up to 10-fold. Eryptosis in buffer-incubated HD-RBC was up to seven-fold higher as compared to COB-RBC. Incubation of CON-RBC with IS increased the eryptosis rate dose-dependently up to 6-fold. Pretreatment of CON-RBC with the organic anion transporter 2 (OAT2) specific inhibitor ketoprofen or with NADPH oxidase inhibitor diphenyleneiodonium-Cl blunted the IS effect on both ROS production and eryptosis induction. While GSH levels in HD-RBC were reduced when compared to CON-RBC, they were not affected by IS incubation. In summary, IS increases ROS generation and eryptosis in CON-RBC by an activity dependent of the IS influx through OAT2, and NADPH oxidase activity-dependent, and a GSH-independent mechanism. These findings lend support to a putative role of IS in the pathogenesis of renal anemia.

Inflammatory Response to Sorbent Hemodialysis.

Inflammation is common and associated with morbidity and mortality in hemodialysis (HD) patients. Exposure to endotoxin contained in the dialysate may trigger inflammation. Dialysate volume is substantially reduced in sorbent HD compared with standard single-pass dialysis. In this prospective study (Clinicaltrials.gov, number: NCT00788905), we compared the inflammatory response to single-pass and sorbent HD. Patients receiving single-pass HD were studied during 1 week of sorbent HD (Allient system; Renal Solutions, Warrendale, PA) and 1 week of single-pass HD. Patients were dialyzed using high-flux polysulfone dialyzers. Midweek pre- and post-HD serum levels of high-sensitivity C-reactive protein, interleukin (IL)-1&bgr;, IL-6, IL-10, interferon gamma, tumor necrosis factor alpha (TNF-&agr;), and eotaxin were determined and their intradialytic change corrected for hemoconcentration during single-pass HD and sorbent HD compared by paired t-test. We enrolled 18 patients, nine completed the study. Although TNF-&agr; decreased during both single-pass and sorbent HD (p < 0.001), none of the other biomarkers changed significantly during HD. We observed no difference between single-pass and sorbent HD. For the markers investigated in this study, there was no difference in the acute intradialytic inflammatory response to single-pass or sorbent HD.