Dialysis Clearance Research Articles

Age- and weight-based differences in haemodialysis prescription and delivery in children, adolescents and young adults.

Limited systematic data are available on prescription and dosing of haemodialysis (HD) in children and adolescents compared with adults. We aimed to characterize age- and weight-based differences in HD delivery in children, adolescents and young adults. This is a retrospective observational study including 1852 patients <30 years on chronic HD from childhood (53 903 HD sessions), receiving thrice weekly outpatient HD between 2004 and 2016 in the USA (6075 patient-years, of which 2535 were in patients aged 1-18 years; weight range 8.3-168 kg). Median individual prescriptions per year were calculated and overall 50% (IQR) and 90% distribution ranges over age and weight were derived. Repeated measurements analysis of variance assessed differences between age and weight groups. Prescriptions significantly differed among age and weight groups (P < 0.001). Lower weight patients (<75 kg) had higher (inter-quartile range, IQR) weight-normalized blood flow rate (highest in <25 kg: QB/kg = 6.5-9.1 mL/min/kg), urea dialytic clearance (KD/kg) and single pool Kt/V (spKt/V) (<25 kg: 1.43-1.78; 25-50 kg: 1.52-1.92; 50-75 kg: 1.43-1.74) than heavier patients (lowest in >100 kg: QB/kg = 3.1-4.0 mL/min/kg, spKt/V = 1.22-1.47, respectively). Adolescents had significantly lower QB/kg, KD/kg and spKt/V (1.34-1.71) compared with adults (1.45-1.79) and children <12 years (range of 25th percentiles: 1.37-1.44). Dialytic clearance derived from a mechanistic equation underpredicted KD in children but not in young adults. Significant growth retardation was observed, with the proportion of patients <3rd percentile (height for age) decreasing from 71% (1-2 years) to 15% (>18 years). Delivered HD treatment varies with age and weight and is more intensified in children aged <12 years, compared with adolescents and overweight young adults, who appear to be at highest risk of receiving suboptimal treatment. Still, delivery of target or higher spKt/V values did not result in appropriate growth in these children, questioning the value of spKt/V as a measure of HD adequacy in children. Provided ranges of outpatient HD prescription can help clinicians and researchers in personalizing and optimizing delivery of dialysis treatment.

β-Blocker Dialyzability in Maintenance Hemodialysis Patients: A Randomized Clinical Trial.

There is a paucity of data available to describe drug dialyzability. Of the available information, most was obtained before implementation of modern hemodialysis membranes. Our study characterized dialyzability of the most commonly prescribed β-blockers in patients undergoing high-flux hemodialysis. Patients on hemodialysis (n=8) were recruited to an open label, pharmacokinetic, four-way crossover trial. Single doses of atenolol, metoprolol, bisoprolol, and carvedilol were administered on separate days in random order to each patient. Plasma and dialysate drug concentrations were measured, and dialyzability was determined by the recovery clearance and arterial venous difference methods. Using the recovery clearance method, the dialytic clearance values for atenolol, metoprolol, bisoprolol, and carvedilol were 72, 87, 44, and 0.2 ml/min, respectively (P<0.001). Applying the arterial venous difference method, the dialytic clearance values of atenolol, metoprolol, bisoprolol, and carvedilol were 167, 114, 96, and 24 ml/min, respectively (P<0.001). Atenolol and metoprolol are extensively cleared by hemodialysis compared with the negligible dialytic clearance of carvedilol. Contrary to estimates of dialyzability on the basis of previous literature, our data indicate that bisoprolol is also dialyzable. This finding highlights the importance of conducting dialyzability studies to definitively characterize drug dialytic clearance.

Hypothermic Machine Perfusion Results in a Marginal Kidney Transplant Programme

BackgroundHypothermic machine perfusion (HMP) of deceased donor kidneys is associated with a better outcome than static cold storage, predominantly in marginal donors. Nevertheless, there is little evidence supporting whether graft centre of origin and donor category impact HMP results. ObjectiveTo identify factors impacting HMP in transplantation from marginal donors. Design, setting, and participantsAnalysis of prospectively collected cohort data of expanded criteria donor (ECD) and donor after circulatory death (DCD) categories II and III was performed. A total of 214 adult recipients of first kidney transplantation with complete data and a minimum of 6-mo follow-up were included. Outcome measurements and statistical analysisDelayed graft function (DGF) was defined as the lack of decrease in creatinine level in the first 48h. Graft loss was defined as return to dialysis or creatinine clearance <15ml/min/1.73m2. Univariate and multivariate logistic regression analyses for DGF were constructed to identify independent risk factors. Recipient and graft survival (GS) analyses were conducted by Kaplan-Meier, and univariate and multivariate Cox regression analyses. Results and limitationDGF occurred in 32.8% of imported and 20.5% of local grafts (p=0.059). Only donor category (DCD; odds ratio [OR]: 6.6, p=0.008) and haemodialysis (OR: 3.5, p=0.002) were significantly associated with DGF development. The 1-yr GS rate was 92.5% in the local donor group and 84.3% in the imported donor group (p=0.050). Multivariate analysis by Cox proportional hazards model identified only donor category (hazard ratio [HR] 10.99, p=0.001) and donor age (HR 1.07, p=0.005) as predictive variables for GS. The small sample size of the DCD group diminished the statistical power and did not permit a subgroup analysis to determine the impact of specific DCD category on HMP results. ConclusionsDCD donor category, but not donor centre of origin, impacted DGF development and GS in the HMP of deceased donor kidneys. Patient summaryCurrently, the number of donors is insufficient to meet the demand for renal grafts. Expanded criteria for donation after brain death and donation after circulatory death (DCD) programmes have been developed as strategies to minimise this problem. Hypothermic machine perfusion has previously demonstrated its usefulness in expanded criteria donation and DCD preservation. DCD type and donor age increase the risk of graft loss.

The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes.

BackgroundThere is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable.We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS.MethodsWe tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment (“isohydric dialysis”). Eight stable hemodialysis patients underwent “isohydric dialysis” for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout.ResultsWe found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of “isohydric dialysis” (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound.The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid.ConclusionThese findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration (“isohydric dialysis:”), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.

Kinetic Glomerular Filtration Rate in Routine Clinical Practice-Applications and Possibilities.

When the [creatinine] is changing, the kidney function can still be tracked with a quantitative technique called kinetic glomerular filtration rate (GFR). The equation yields useful information on the severity of acute kidney injury, the clinical course of kidney and dialysis clearances, and the timing of kidney recovery. It has been validated in at least 3 independent studies, where it performed sufficiently well in intensive care unit and kidney transplant settings, and in head-to-head comparisons with biomarkers. Because it is based on a mathematical model, the kinetic GFR faces limitations depending on the accuracy of its assumptions. As the assumptions more accurately reflect the complexities of biology, some of these limitations can be overcome in a more sophisticated model. Kinetic GFR is an easy-to-use, low-cost tool that should be more widely incorporated into medical practice.

Intensive Hemodialysis: Effects of Treatment Time and Frequency on Time-Averaged Concentrations of Solutes.

Most of chronic renal disease patients receive 4-h hemodialysis (HD) sessions thrice a week. This is the minimum therapy needed to maintain life. This conventional HD therapy protocol is, however, inadequate to prevent dialysis-related complications. On the other hand, some intensive HD therapies, such as "short daily dialysis," "quotidian dialysis," etc., are being adopted in some dialysis institutions for maximizing the beneficial effects of HD on the quality of life/activities of daily living of the patients. In this paper, the effects of dialysis treatment time and frequency on the adequacy of solute removal in these intensive HD therapies protocols were examined by kinetic modeling using a 1-compartment model. In this model, it is presupposed that urea is distributed throughout the total body fluid compartment and β2-microglobulin (β2-MG) is distributed throughout the extracellular compartment. The time-averaged concentrations (TACs) of BUN and β2-MG can be estimated by inputting the body weight, generation rate of the solute, dialyzer clearance for the solute, and the dialysis treatment time and frequency into the model. According to the results, the TACs were strongly dependent on the total dialysis time per week (T) value and to a slightly lesser degree on the dialysis frequency per week (N) value for both solutes. It is concluded that the 1-compartment model introduced in this study is valid for estimating the TACs of BUN and β2-MG in patients undergoing maintenance HD therapy, and T and N values are important factors influencing the adequacy of solute removal in patients receiving maintenance HD therapy.

Untargeted mass spectrometry discloses plasma solute levels poorly controlled by hemodialysis.

Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated.

Acetaminophen clearance during ex vivo continuous renal replacement therapies.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Filter Adsorption of Anidulafungin to a Polysulfone-Based Hemofilter During CVVHD In Vitro.

Candidemia is frequent in critically ill patients, especially in combination with an acute kidney injury (AKI). Echinocandins generally are recommended for therapy of such infections. Recent studies found no need for dosage adjustment in patients with end-stage renal disease receiving hemodialysis, or patients with AKI receiving continuous venovenous hemofiltration. The aim of this in vitro study was to examine the adsorption of anidulafungin to the surface of the hemofilter during continuous venovenous hemodialysis (CVVHD) and its effect on anidulafungin concentrations. The concentration of anidulafungin in the dialyzed fluid, and the dialysate during CVVHD in vitro was examined using three different dialyzed fluids (saline; saline with 40 g/L human albumin; and a mixture of human erythrocytes and fresh frozen plasma). After the end of dialysis, the hemofilter was opened and portions of the filter capillaries were also analyzed to determine the amount of anidulafungin adsorbed. When dialyzing saline, about 99% of the anidulafungin used adsorbed to the hemofilter capillaries; in the experiments with saline with 40 g/L albumin, about 60% adsorbed to the hemofilter's surface, and when blood was dialyzed, 35% was found adsorbed after analyzing the filter capillaries. Anidulafungin was not detectable in the dialysate of any of the experiments, consequently the dialysis clearance was 0 mL/min. In conclusion, during CVVHD in vitro we found remarkable adsorption of anidulafungin to the hemofilter's surface, yet the effect on the tissue concentration needs further examination.

Regional citrate anticoagulation for continuous renal replacement therapy in pediatric patients with liver failure.

Pediatric liver failure patients frequently develop multiple organ failure and require continuous renal replacement therapy (CRRT) as part of supportive therapy in the pediatric intensive care unit. While many centers employ no anticoagulation for fear of bleeding complications, balanced coagulation disturbance predisposes these patients to clotting as well as bleeding, making maintenance of longer circuit life to deliver adequate dialysis clearance challenging. Regional citrate anticoagulation (RCA) is an attractive option as it avoids systemic anticoagulation, but since citrate metabolism is impaired in liver failure, concerns about toxicity has limited its use. Pediatric data on RCA with liver failure is very scarce. We aimed to establish safety and efficacy of RCA in pediatric liver failure patients on CRRT. Retrospective review of pediatric patients with liver failure receiving CRRT over 30 months. Demographic data and CRRT related data were collected by chart review. Citrate accumulation (CA) was defined as total calcium (mg/dl) /ionized calcium (mmol/L) ratio >2.5 for > 48 hours. Efficacy was assessed by filter life. Safety was assessed by frequency of adverse events ((AEs) defined as bleeding, hemodynamic instability, arrhythmias). Fifty-one patients (median age 3.5 (IQR 0.75–14.2) years) received 861 CRRT days; 70% experienced at least one episode of CA, only 37% were recorded as such in the medical record. AE rate was 93/1000 CRRT days and did not differ between CA days and others. Median filter life was 66 hours (IQR 29–74); 63% filters lasted longer than 48 hrs. Though common, CA was not associated with increased AEs on in pediatric liver failure patients on CRRT receiving RCA. Filter life was adequate. RCA appears an effective anticoagulation for CRRT in pediatric liver failure. Application of a structured definition would increase recognition of CA to allow timely intervention.

How to set the stage for a full-fledged clinical trial testing 'incremental haemodialysis'.

Most people who make the transition to maintenance haemodialysis (HD) therapy are treated with a fixed dose of thrice-weekly HD (3HD/week) regimen without consideration of their residual kidney function (RKF). The RKF provides an effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life. Its preservation is instrumental to the prescription of incremental (1HD/week to 2HD/week) HD. The recently heightened interest in incremental HD has been hindered by the current limitations of the urea kinetic model (UKM), which tend to overestimate the needed dialysis dose in the presence of a substantial RKF. A recent paper by Casino and Basile suggested a variable target model (VTM), which gives more clinical weight to the RKF and allows less frequent HD treatments at lower RKF as opposed to the fixed target model, based on the wrong concept of the clinical equivalence between renal and dialysis clearance. A randomized controlled trial (RCT) enrolling incident patients and comparing incremental HD (prescribed according to the VTM) with the standard 3HD/week schedule and focused on hard outcomes, such as survival and health-related quality of life of patients, is urgently needed. The first step in designing such a study is to compute the 'adequacy lines' and the associated fitting equations necessary for the most appropriate allocation of the patients in the two arms and their correct and safe follow-up. In conclusion, the potentially important clinical and financial implications of the incremental HD render it highly promising and warrant RCTs. The UKM is the keystone for conducting such studies.

Pharmacokinetics and Dialytic Clearance of Ceftazidime-Avibactam in a Critically Ill Patient on Continuous Venovenous Hemofiltration.

Ceftazidime-avibactam administered at 1.25 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa bacteremia in a critically ill patient on continuous venovenous hemofiltration (CVVH). Prefiltration plasma drug concentrations of ceftazidime and avibactam were measured at 0, 1, 2, 4, 6, and 8 h along with postfiltration and ultrafiltrate concentrations at h 2 and h 6. Plasma pharmacokinetic parameters of ceftazidime and avibactam, respectively, were as follows: maximum plasma concentration (Cmax), 61.10 and 14.54 mg/liter; minimum plasma concentration (Cmin), 31.96 and 8.45 mg/liter; half-life (t1/2), 6.07 and 6.78 h; apparent volume of distribution at the steady state (Vss), 27.23 and 30.81 liters; total clearance at the steady state (CLss), 2.87 and 2.95 liters/h; area under the concentration-time curve from 0 to 8 h (AUC0-8), 347.87 and 85.69 mg · h/liter. Concentrations of ceftazidime in plasma exceeded the ceftazidime-avibactam MIC (6 mg/liter) throughout the 8-h dosing interval. Mean CVVH extraction ratios for ceftazidime and avibactam were 14.44% and 11.53%, respectively, and mean sieving coefficients were 0.96 and 0.93, respectively. The calculated mean clearance of ceftazidime by CVVH was 1.64 liters/h and for avibactam was 1.59 liters/h, representing 57.1% of the total clearance of ceftazidime and 54.3% of the total clearance of avibactam. Further data that include multiple patients and dialysis modes are needed to verify the optimal ceftazidime-avibactam dosing strategy during critical illness and CVVH.

Clearance of Sclerostin, Osteocalcin, Fibroblast Growth Factor 23, and Osteoprotegerin by Dialysis

Introduction: Fibroblast growth factor (FGF23), sclerostin, osteocalcin, and osteoprotegerin are important factors that control mineral bone metabolism. End-stage renal disease is associated with the pronounced dysregulation of mineral bone metabolism; however, the impact and clearance of mineral bone metabolism factors during dialysis remain largely undescribed. Methods: In a cross-sectional study, 10 chronic hemodialysis patients were treated with hemodialysis for 8 h using a high-flux filter and a dialysate bath of 50% calculated total body water continuously recycled at a rate of 500 mL/min. Plasma and dialysate concentrations of FGF23, sclerostin, osteoprotegerin, and osteocalcin were measured at 1, 2, 4, 6, and 8 h permitting the estimation of dialysis clearance. Results: Clearance of FGF23 was 7.7 mL/min, of sclerostin was 7.6 mL/min, of osteoprotegerin was 1.2 mL/min, and of osteocalcin was 19.7 mL/min. Clearance of FGF23 was correlated to sclerostin and osteoprotegerin clearance and also to the ultrafiltration rate. Although, osteocalcin blood concentrations decreased during dialysis, they rebounded within 6 h. Overall, no significant changes in blood concentrations of the measure mineral bone metabolism factors were observed. Conclusions: The intradialytic clearance of osteocalcin, FGF23, sclerostin, and osteoprotegerin occurs; however, only clearance of FGF23 is directly correlated with the ultrafiltration rate. The effects of dialytic clearance on mineral bone metabolism are, however, uncertain and intradialytic plasma concentrations of the studied substrates remained largely unchanged.

Impact of high-flux haemodialysis on the probability of target attainment for oral amoxicillin/clavulanic acid combination therapy

Clearance of small molecules such as amoxicillin and clavulanic acid is expected to increase during high-flux haemodialysis, which may result in lower concentrations and thus reduced efficacy. To date, clearance of amoxicillin/clavulanic acid (AMC) during high-flux haemodialysis remains largely unexplored. Using published pharmacokinetic parameters, a two-compartment model with first-order input was simulated to investigate the impact of high-flux haemodialysis on the probability of target attainment (PTA) of orally administered AMC combination therapy. The following pharmacokinetic/pharmacodynamic targets were used to calculate the PTA. For amoxicillin, the time that the free concentration remains above the minimum inhibitory concentration (MIC) of ≥50% of the dosing period (≥50%ƒT>MIC) was used. For clavulanic acid, the time that the free concentration was >0.1 mg/L of ≥45% of the dosing period (≥45%ƒT>0.1 mg/L) was used. Dialysis clearance reported in low-flux haemodialysis for both compounds was doubled to represent the likely clearance during high-flux haemodialysis. Monte Carlo simulations were performed to produce concentration–time profiles over 10 days in 1000 virtual patients. Seven different regimens commonly seen in clinical practice were explored. When AMC was dosed twice daily, the PTA was mostly ≥90% for both compounds regardless of when haemodialysis commenced. When administered once daily, the PTA was 20–30% for clavulanic acid and ≥90% for amoxicillin. The simulations suggest that once-daily orally administered AMC in patients receiving high-flux haemodialysis may result in insufficient concentrations of clavulanic acid to effectively treat infections, especially on days when haemodialysis occurs.

Efficacy and safety of low-dose heparin in hemodialysis.

The dose of unfractionated heparin (UFH) administered during hemodialysis (HD) varies widely. This prospective study evaluated the safety and efficacy of UFH dose de-escalation. Sixty-six prevalent patients on HD receiving UFH per standard-dose protocol (load dose [LD] 50-75 units/kg, maintenance dose [MD] 500-1000 units/hour) had heparin prescription converted to low-dose protocol (start LD 15 units/kg and MD 500 units/hour; dose adjusted in small increments based on assessments of extracorporeal blood circuit). Coagulation parameters, dialysis adequacy, dialyzer clotting, anemia management, and dialyzer reuse rates were compared based on the heparin protocol. Mean(SD) UFH dose per HD session, before and after protocol conversion, was 6178(2644) and 2913(1116) units, respectively (P < 0.0001). This corresponded to LD 52.1(16.6) units/kg and MD 615(207) units/hour with standard-dose protocol, and LD 18.3(6.5) units/kg and MD 505(27) units/hour with low-dose protocol (P < 0.0001). Mid and postdialysis aPTT was 55.3(31.2) and 35.1(7.8) seconds before, and 37.3(12.9) and 31.5(5.3) seconds after conversion (P = 0.007 and 0.003, respectively); no significant changes in D-dimer levels occurred. Low-dose UFH was associated with a small increase in URR and spKt/V (73.0 and 1.54) compared with dialysis clearance on standard-dose UFH (71.2 and 1.48, respectively, P = 0.02). Weekly dose of ESA decreased by 2388 units postconversion (P = 0.03), while hemoglobin levels and the weekly dose of intravenous iron did not change (P = 0.16 and 0.78). A small rise in the rate of moderate dialyzer clotting at the end of HD was noted with low-dose UFH (5.7% vs. 7.5%, P = 0.002); the rate of severe dialyzer clotting events did not change (P = 0.91). No change in the dialyzer reuse rate was noted (18.5 vs. 17.0 treatments, P = 0.26). Low-dose heparinization did not compromise dialysis adequacy and permitted ESA dose reduction. Our findings suggest that in prevalent patients on HD, UFH dose of 15-20 units/kg loading and 500 units/hour maintenance was medically safe and effective.

Enhancing dialyser clearance-from target to development.

Products of metabolism accumulate in kidney failure and potentially have toxic effects. Traditionally these uraemic toxins are classified as small, middle-sized and protein-bound toxins, and clearance during dialysis is affected by diffusion, convection and adsorption. As current dialysis practice effectively clears small solutes, increasing evidence supports a toxic effect for middle-sized and protein-bound toxins. Therefore, newer approaches to standard dialysis practice are required to look beyond urea clearance. Current dialysers have been developed to effectively clear small solutes and secondly to increase middle-sized toxin clearances. However, there is no ideal dialyser which can effectively clear all uraemic toxins. Advances in nanotechnology have led to improvements in manufacturing, with the production of smoother membrane surfaces and uniformity of pore size. The introduction of haemodiafiltration has led to changes in dialyser design to improve convective clearances. Both diffusional and convectional clearances can be increased by changing dialyser designs to alter blood and dialysate flows, and novel dialyser designs using microfluidics offer more efficient solute clearances. Adjusting surface hydrophilicity and charge alter adsorptive properties, and greater clearance of protein-bound toxins can be achieved by adding carbon or other absorptive monoliths into the circuit or by developing composite dialyser membranes. Other strategies to increase protein-bound toxins clearances have centred on disrupting binding and so displacing toxins from proteins. Just as the hollow fibre design replaced the flat plate dialyser, we are now entering a new era of dialyser designs aimed to increase the spectrum of uraemic toxins which can be cleared by dialysis.

The Effect of Renal Function and Hemodialysis Treatment on Plasma Vasopressin and Copeptin Levels

IntroductionCopeptin is increasingly used in epidemiological studies as a substitute for vasopressin. The effect of renal function per se on copeptin and vasopressin concentrations as well as their ratio have, however, not been well described.MethodsCopeptin and vasopressin levels were measured in 127 patients with various stages of chronic kidney disease, including 42 hemodialysis patients and 16 healthy participants in this observational study. Linear (segmental) regression analyses were performed to assess the association between renal function and copeptin, vasopressin and the C/V ratio. In addition, clearance of copeptin and vasopressin by hemodialysis was calculated.ResultsBoth copeptin and vasopressin levels were higher when renal function was lower, and both showed associations with plasma osmolality. The C/V ratio was stable across renal function in subjects with an eGFR >28 ml/min per 1.73 m2. In contrast, the C/V ratio increased with worsening renal function in patients with eGFR ≤28 ml/min per 1.73 m2. During hemodialysis, the initial decrease in vasopressin levels was greater compared with copeptin and, consequently, the C/V ratio increased. This was, at least in part, explained by a greater dialytic clearance of vasopressin compared with copeptin.DiscussionOur data indicate that copeptin is a reliable substitute for vasopressin in subjects with an eGFR >28 ml/min per 1.73 m2, whereas at an eGFR ≤28 ml/min per 1.73 m2, that is, CKD stages 4 and 5, a correction for renal function is required in epidemiological studies that use copeptin as a marker for vasopressin. Intradialytic copeptin levels do not adequately reflect vasopressin levels because vasopressin clearance by hemodialysis is higher than that of copeptin.

Role of glabridin in maintaining residual kidney function in dialysis patients

Purpose: To demonstrate the effect of glabridin on peritoneal function and residual renal function (RRF) in peritoneal dialysis (PD) patients. Methods: Twenty five patients (age range, 24 - 58 years) with a glomerular filtration rate of above 2 mL/min/1.73 m2 and on PD were subjected to glabridin therapy. The patients were treated daily with glabridin (30 mg) for 6 months. The baseline parameters for serum high-sensitivity C-reactive protein (hs-CRP), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) were compared with those found after 6 months of glabridin treatment. In addition, end-to-initial dialysate concentration of glucose (D4/D0 glucose), dialyzer clearance of urea (K), dialysis time (t), volume of distribution of urea (V), peritoneal transport status as well as dialysate cancer antigen 125 (CA125) were also compared. Results: The results revealed a significant increase in mean dialysate CA125 after glabridin treatment (25.6 ± 2.7 U/mL) compared with baseline value (19.7 ± 3.2 U/mL). However, serum hs-CRP, VEGF, TGF-β, CTGF, daily ultrafiltration, D4/D0 glucose, Kt/V, and peritoneal transport status remained unaffected. Residual glomerular filtration rate in all the patients decreased. Glabridin treatment also led to a decrease in the decline of peritoneal function, suppression of elevation of profibrotic markers, and increased mesothelial cell mass in PD patients. Conclusion: Thus, glabridin is a potent candidate for the treatment of residual kidney function in dialysis patients. Keywords: Glabridin, Residual renal function, Peritoneal function, Dialysate, Profibrotic markers, Mesothelial cell mass, Glomerular filtration rate

Functional bowel disorders and associated risk factors in hemodialysis patients in Turkey.

Functional bowel disorders (FBDs) impair the quality of life in patients with end-stage renal disease (ESRD). The aim of our study was to determine the prevalence and distribution of the subtypes of FBDs in hemodialysis (HD) patients. This prospective, cross-sectional study included 80 patients who received HD for more than 3 months (patient group) and 80 healthy controls (control group). FBDs were diagnosed according to the Rome II diagnostic criteria by excluding organic pathologies. Forty-six (57.5%) patients were males, and their average age was 62.13±12.92 (23-90) years. The mean duration of dialysis was 57.48±59.23 (3-312) months, and the mean Kt/V (K: dialyzer clearance of urea, t: dialysis time, V: volume of distrubition of urea) value was 1.53±0.31. The rate of FBDs was significantly higher in the patient group than in the control group (p=0.01). In total, 7.5% of the patients had irritable bowel syndrome, 3.8% had functional bloating, and 16.3% had functional constipation. FBDs were significantly higher in women (p=0.004). While there was no statistically significant difference between patients with and those without FBDs in terms of the presence of additional diseases, smoking, alcohol use, educational level, marital status, and resi- dential areas (p>0.05), serum phosphorus (P) levels were significantly higher in the patients with FBDs (p=0.03). FBDs and their functional constipation subtype are more common in HD patients than in the healthy population in Turkey. FBDs are most frequently observed in females and housewives with high serum P levels.

End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes.

Despite marked improvements in renal replacement therapy during the last 30 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients is still unacceptably high and comparable to that of many malignancies. Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in ESRD patients. However, traditional risk factors can only partially explain the high premature cardiovascular burden in this population. Nontraditional risk factors, including persistent low-grade inflammation, are critical in the pathogenesis of atherosclerosis, vascular calcification, and other causes of CVD and may also contribute to protein-energy wasting and other complications in chronic kidney disease (CKD) patients. Inflammatory biomarkers, such as high sensitivity C-reactive protein and interleukin-6, independently predict mortality in these patients. The causes of inflammation in CKD are multifactorial and include imbalance between increased production (due to multiple sources of inflammatory stimuli such as oxidative stress, acidosis, volume overload, co-morbidities, especially infections, genetic and epigenetic influences, and the dialysis procedure) and inadequate removal (due to decreased glomerular filtration rate or in ESRD patients, inadequate dialytic clearance) of pro-inflammatory cytokines. Though there are currently no established guidelines for the treatment of low-grade inflammation in ESRD patients, several strategies have been proposed, such as lifestyle modifications, pharmacological treatment, and optimization of dialysis. Further studies on pathways involved in pathogenic processes of inflammation in ESRD, and long-term effects of anti-inflammatory interventions targeting production or removal of cytokines or both on premature CVD and clinical outcomes in this patient group are warranted.