CZecking heart failure in patients with advanced chronic kidney disease (Czech HF-CKD): Study protocol.

BACKGROUND: Heart failure (HF) is a frequent cause of morbidity and mortality of end-stage kidney disease (ESKD) patients on hemodialysis. It is not easy to distinguish HF from water overload. The traditional HF definition has low sensitivity and specificity in this population. Moreover, many patients on hemodialysis have exercise limitations unrelated to HF. Therefore, we postulated two new HF definitions ((1) Modified definition of the Acute Dialysis Quality Improvement working group; (2) Hemodynamic definition based on the calculation of the effective cardiac output). We hypothesize that the newer definitions will better identify patients with higher number of endpoints and with more advanced structural heart disease. METHODS: Cohort, observational, longitudinal study with recording predefined endpoints. Patients (n = 300) treated by hemodialysis in six collaborating centers will be examined centrally in a tertiary cardiovascular center every 6-12 months lifelong or till kidney transplantation by detailed expert echocardiography with the calculation of cardiac output, arteriovenous dialysis fistula flow volume calculation, bio-impedance, and basic laboratory analysis including NTproBNP. Effective cardiac output will be measured as the difference between measured total cardiac output and arteriovenous fistula flow volume and systemic vascular resistance will be also assessed non-invasively. In case of water overload during examination, dry weight adjustment will be recommended, and the patient invited for another examination within 6 weeks. A composite major endpoint will consist of (1) Cardiovascular death; (2) HF worsening/new diagnosis of; (3) Non-fatal myocardial infarction or stroke. The two newer HF definitions will be compared with the traditional one in terms of time to major endpoint analysis. DISCUSSION: This trial will differ from others by: (1) detailed repeated hemodynamic assessment including arteriovenous access flow and (2) by careful assessment of adequate hydration to avoid confusion between HF and water overload.

Population pharmacokinetics-pharmacodynamics of fondaparinux in dialysis-dependent chronic kidney disease patients undergoing chronic renal replacement therapy.

PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

Vancomycin pharmacokinetics in patients treated with intermittent haemodialysis based on therapeutic drug monitoring.

Vancomycin is frequently used in haemodialysis (HD) patients but generally accepted target serum ranges and dosing strategy are still lacking in this group. Based on retrospective analysis of data from 118 HD patients treated with vancomycin the interdialytic elimination constant (Ke), apparent volume of distribution (Vd) and dialysis efficacy were calculated. The influence of possible clinical variables on the pharmacokinetic parameters of vancomycin have been tested. The median of Ke in interdialytic periods, corresponding half-life and Vd were 0.0073 h-1, 95.0 h and 0.87 L/kg, respectively. We found significant positive correlation between time in dialysis program and Ke. The Vd correlated best with lean body mass (LBM). For high- and low flux membrane HD of 4 hours duration the decline in vancomycin levels was 20.88% and 12.86%, respectively. Based on these data loading dose for vancomycin in HD patient should be calculated as 24.483 × LBM (kg) + 455 mg. The utility of this equation for entire HD population should be also verified prospectively.

Changes in vascular access blood flow: Etiological factors and clinical implications.

METHODS: Records of 10,000 QVA measurement performed in 549 patients over 20 years were used as retrospective and anonymized data source, making ethical commission involvement unnecessary. Two approaches are used to elucidate association of QVA changes with different factors: analyses of smaller cohorts in which both the QVA and the respective factor were measured (e.g. association of QVA with cardiac output (CO)), or-in case of rare phenomena-a form of a well illustrated case reports was used (e.g. association of QVA and Kt/V). RESULTS: Significant increase in CO after permanent VA creation (3-4-fold of the QVA value) was found. Impact of intradialytic CO changes on QVA is attenuated by relatively stable VA resistance compared to systemic resistance. Blood pressure impact is much stronger and it should therefore be noted at each QVA measurement. As reproducibility of different QVA measurement methods varies, use of the same method should be preferred. Direction of the arterial needle insertion in VA affects the QVA measured, especially in synthetic grafts, too. Also patient's own QVA variability may be quite high. All this makes KDOQI/EBPG recommended acceptable QVA drops too strict, they should be revised. In re-stenoses prone patients, measurement intervals should be shortened, too. CONCLUSION: QVA values are significantly affected by many factors. Their knowledge appears essential for safe and effective VA surveillance and management.

Fallacies and Pitfalls of Dialysis Sodium Prescription and Control.

Dialysate conductivity is routinely used as a surrogate for dialysate sodium concentration. However, dialysis machine manufacturers apply different conductivity temperature correction coefficients. With the same conductivity in dialysis machines manufactured by different manufacturers, dialysate sodium may significantly differ. Also, electrolyte prescriptions are individualized (K, Ca, HCO3) and this is associated with another variation in dialysate sodium in the order of 1-5 mmol/L and both deviations are cumulative and chronic for each patient. Equivalence of the prescribed dialysate sodium and the concentration measured in it is not granted. Both variables differ and it is machine dependent! This paper analyses those variations from a technical point of view and suggests how to detect them and how to deal with or avoid them in clinical practice.

Safety aspects in patients on hemodialysis with catheters.

Central venous catheter (CVC)-related problems, risks and safety hazards are partly caused by different characteristics of the CVC-based access and their performance features. This chapter covers those issues in a chronological order, from factors related to the choice of the CVC, insertion site and insertion procedure itself, over those associated with CVC use and their monitoring up to safety hazards of interventional procedures. Not discussed are CVC infections as they are covered in a separate chapter in this book.

Immunogenicity and safety of an investigational AS02(v)-adjuvanted hepatitis B vaccine in patients with renal insufficiency who failed to respond or to maintain antibody levels after prior vaccination: results of two open, randomized, comparative trials.

An investigational AS02(v)-adjuvanted hepatitis B (HB-AS02) was compared with a licensed conventional recombinant hepatitis B vaccine (HBVAXPRO™; Sanofi Pasteur MSD, Lyon, France) in pre-dialysis, peritoneal dialysis and hemodialysis patients aged ≥18 years who had failed either to respond to prior vaccination with a conventional hepatitis B vaccine (Study A; n=251) or to maintain protective antibody concentrations after prior hepatitis B vaccination (Study B; n=181). These were open, randomized, comparative trials. Mean (range) age was 65.9 (31-92) and 64.6 (29-92) years in the two studies, respectively. In Study A, two doses of HB-AS02 given one month apart were found to be superior to two doses of the licensed vaccine in terms of seroprotection rate (76.9% versus 37.6%) and anti-HBs geometric mean antibody concentration (GMC; 139.3 versus 6.9mIU/ml), with antibody concentrations ≥100mIU/ml in 61.1% and 15.4% of subjects in the two groups, respectively. In Study B, one month after administration of a single booster dose, seroprotection rates were 89.0% in the HB-AS02 group and 90.8% in the licensed vaccine group, 81.3% and 60.9% of subjects had antibody concentrations ≥100mIU/ml, and anti-HBs GMCs were 1726.8 and 189.5mIU/ml. HB-AS02 was found to be more reactogenic than the licensed vaccine. In summary, the investigational HB-AS02 vaccine induced higher seroprotection rates and anti-HBs GMCs than a licensed conventional hepatitis B vaccine in uremic patients who had failed to respond or to maintain protective antibody titers after prior hepatitis B vaccination.

Arteriovenous fistula, blood flow, cardiac output, and left ventricle load in hemodialysis patients.

The aim of this study was to investigate an association between vascular access blood flow (QVA), cardiac output(CO), and load of left ventricle (LLV) using a simple physical model calculation based on real data, specifically inpatients with high access blood flow arteriovenous fistula(AVF). Vascular access blood flow, CO, and peripheral vascular resistance (PR) were determined by ultrasound dilution technique (HD01; Transonic Systems, Inc., Ithaca, NY). Load of left ventricle was calculated using simplified formula: LLV x PR CO2. This total load was computationally divided into the part spent to run the flow QVA through the AVF (LLVAVF) and that part ensuring the flow (CO-QVA) through the vascular system. The model calculation was first performed in a selected group of 15 patients with high access blood flow (QVA >1,300 ml/min, group 1) and later extended for comparison by another group of 40 unselected patients with access blood flow in lower range (QVA range 200-1,400 ml/min, group 2).Mean LLV in group 1 was 2.10 +/- 0.68 W. LLV(AVF) was 21.8% of total LLV. Mean LLV in group 2 was 1.2 +/- 0.5 W.LLVAVF was 11.1% of total LLV. Our computational results suggest that AVF in typical range of QVA shall not increase heart load significantly.

Obliteration Index: a simple non-invasive tool for the assessment of peripheral vascular disease in chronic kidney disease.

BACKGROUND: Peripheral artery disease (PAD) represents a major complication in chronic kidney disease (CKD) patients, but its early diagnosis is still problematic. Traditionally, ankle-arm blood pressure index (API) determined by means of a simple hand-held unidimensional Doppler device has been used for noninvasive diagnosis of PAD, with a cutoff value of 0.9. However, in CKD patients, vascular disease includes not only atherosclerosis but also arteriosclerosis with high calcification score. There, the API method often fails. DEVELOPMENT OF THE METHOD: Based on complex examination of Doppler signals recorded at 4 main arteries of both lower extremities (a. femoralis, a. poplitea, a. dorsalis pedis, a. tibialis posterior) and their semiquantitative assessment, we introduced the Obliteration Index (OI) as a novel and simple tool allowing semiquantitative assessment of PAD in CKD patients: the signal from each artery is assessed in a 6-grade scale, with each grade represented by 5 points. The sum of points allocated to all arteries constitutes the final OI value, ranging from 0 (normal finding) up to 240 (most severe PAD). VERIFICATION OF THE METHOD: Comparison of the OI method with the conventional API examined in over 100 renal patients revealed superior OI sensitivity in detection of PAD in the early stage and low-grade vessel infliction where the API still remains within the normal range. OI can also be evaluated even when API is not measurable. Very good correspondence was found between the OI and angiography. CONCLUSIONS: The OI method has now been introduced into routine use in the authors' department. Based on over 1,500 OI evaluations performed so far, it can be recommended as a simple, noninvasive, bedside tool for diagnosis of early as well as advanced PAD.

Assessing skin hydration status in haemodialysis patients using terahertz spectroscopy: a pilot/feasibility study.

Terahertz (THz) time-domain spectroscopy was used in vivo to measure the body reflectance with the aim of determining experimentally the influence of haemodialysis on the content of water in the human skin. For this purpose, an original methodology of determining the skin properties at THz frequencies from the reflectance was developed. A series of measurements were performed before and after dialysis with ten subjects. The results strongly indicate that the surface body hydration is not the main parameter determining the skin conductivity in the THz range.

Physiologic variability of vascular access blood flow for hemodialysis.

AIM: To assess the variability of blood flow (QVA) through a native arteriovenous fistula (AVF) in the long-term and to determine the QVA reduction at which an intervention is appropriate. PATIENTS AND METHODS: The study was performed in a group of 34 chronic hemodialysis patients with no history of a AVF intervention. QVA was measured using the thermodilution method (Blood Thermodilution Monitor, Fresenius). Median follow-up was 41 months and the median number of QVA measurements in each patient was 15. The coefficient of variation (CV) of QVA was calculated for each patient. RESULTS: Mean QVA was 904 +/- 334 ml/min. The mean CV was 23.3 +/- 11.2%. CONCLUSION: QVA may fluctuate during a long-term follow-up period. The detection of QVA decrease by 20-25% could be still within physiological limits. Based on the results we recommend to first repeat the measurement at a shorter interval and to refer the patient to a radiologist only when the decreasing trend is confirmed.

Ghrelin variants influence development of body mass index and plasma levels of total cholesterol in dialyzed patients.

BACKGROUND: Ghrelin is an endogenous hormone expressed predominantly in the stomach. Ghrelin controls growth hormone secretion and also affects the body's energy balance. We analyzed the association of ghrelin variants with body mass index (BMI), albumin as a marker of malnutrition and plasma lipids as risk factors for atherosclerosis in hemodialyzed patients, in whom malnutrition and accelerated atherosclerosis are common complications. METHODS: Ghrelin variants Arg51>Gln and Leu72> Met were analyzed by PCR-RFLP in 210 hemodialyzed patients, prospectively followed up for 15 months. Changes in body mass index, triglycerides, total cholesterol and albumin over time (after 3, 6, 9, 12 and 15 months of dialysis) were analyzed in subgroups divided according to ghrelin genotypes. RESULTS: Carriers of at least one of the Gln51 and Met72 alleles lost body weight more quickly than Arg51Arg/Leu72Leu homozygotes (p<0.01). Carriers of the Gln51 allele were at higher risk of developing high cholesterol levels (p<0.01). CONCLUSIONS: Common ghrelin variants may have an effect on changes in biochemical and anthropometric parameters in hemodialyzed patients over time and could be used in the future to plan individualized therapy.