Annemieke Dhondt

Effective removal of protein-bound uraemic solutes by different convective strategies: a prospective trial

BACKGROUND Although different on-line convective removal strategies are available, there are no studies comparing the efficiency of solute removal for the three main options [post-dilution haemodiafiltration (post-HDF), pre-dilution haemodiafiltration (pre-HDF) and pre-dilution haemofiltration (pre-HF)] in parallel. METHODS In this study, we compared post-HDF (Polyflux 170), pre-HDF (Polyflux 170) and pre-HF (Polyflux 210) in 14 patients. Parallelism of the evaluation protocols consisted in applying the same blood flow, dialysis time and effective convection (22.9 +/- 1.7 versus 22.2 +/- 2.0 L, P = NS) in pre-HDF versus post-HDF, and the same blood flow and dialysis time while comparing pre-HDF and pre-HF (1:1 dilution). With pre-HF, ultrafiltration was maximized and resulted in an effective convective volume of 28.5 L. We studied water-soluble compounds (urea, creatinine, uric acid), protein-bound compounds (hippuric acid, indole acetic acid, indoxylsulfate and p-cresylsulfate) and beta(2)-microglobulin (beta(2)M). RESULTS Post-HDF was superior to pre-HDF for water-soluble compounds and beta(2)M, whereas there was no difference for protein-bound compounds. Pre-HDF was superior to pre-HF for water-soluble compounds and protein-bound compounds. In contrast, removal of beta(2)M for pre-HF was higher than for pre-HDF, but it did not differ from that obtained with post-HDF. CONCLUSIONS It is concluded that post-dilution is superior to pre-dilution HDF under conditions of similar convective volume, and that HDF is superior to HF in pre-dilution, with the exception of removal of beta(2)M. Overall, post-HDF is the most efficient convective strategy among those tested.

Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes.

BACKGROUND The guanidines asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, and its counterpart symmetric dimethylarginine (SDMA), considered inert, are accumulated in chronic kidney disease (CKD). The present study evaluates their effect on monocyte function, since previous data demonstrated leukocyte activation by other guanidino compounds. METHODS The effect of ADMA and SDMA on reactive oxygen species (ROS) production in human whole blood at baseline and after N-formyl-methionine-leucine-phenylalanine (fMLP) stimulation was evaluated. By using the fluorescent probe Fluo3-AM, the role of changes in monocytic cytoplasmic calcium ([Ca2+]i) was studied. Thapsigargin, and removal followed by addition of extracellular Ca2+ (Ca2+(ex)), was used to investigate the contribution of store-operated Ca2+-channels (SOCs). SKF96365 was used as a selective inhibitor of the SOCs. A pharmacologic intervention with captopril, known to affect Ca2+ influx, was tested. RESULTS SDMA enhanced ROS production in fMLP-stimulated monocytes using heparinized blood, and this effect was abolished in EDTA-anticoagulated blood. In the presence of SDMA, an increased Ca2+ entry from the extracellular milieu resulted in an elevated amplitude of the peak [Ca2+]i change triggered by fMLP. None of these effects were seen with ADMA. Depletion of the intracellular stores with thapsigargin in the absence of Ca2+(ex), followed by re-addition of Ca2+(ex) triggered a significantly larger Ca2+ entry after SDMA treatment versus saline. This effect was prevented with SKF96365, as was the SDMA-enhanced oxidative burst after fMLP. Pre-incubation with captopril also reduced the increased ROS production seen with SDMA. CONCLUSIONS SDMA, a uraemic retention solute considered inert, stimulates ROS production of monocytes by acting on Ca2+ entry via SOCs. This pro-inflammatory effect may trigger vascular pathology and may be involved in altering the prevalence of cardiovascular disease in CKD.

Intradialytic Parenteral Nutrition in Malnourished Hemodialysis Patients: A Prospective Long-Term Study

BACKGROUND Malnutrition is a frequent problem of patients on intermittent hemodialysis and substantially contributes to their morbidity and mortality. METHODS In 26 hemodialysis patients who, despite dietary advice and oral nutritional supplements, still had malnutrition, the feasibility and effects of a specific intradialytic parenteral nutritional (IPN) regimen were evaluated during a 9-month study period. An IPN solution consisting of 250 mL glucose 50%, 250 mL lipids 20%, and 250 mL amino acids 7% was infused i.v. three times a week during the dialysis session. At the end of each dialysis session an additional volume of 250 mL amino acids was infused as a rinsing fluid. Insulin was administered i.v. before dialysis. RESULTS Of the 26 enrolled patients, 16 completed the study. The remaining 10 patients withdrew mainly because of muscle cramps and nausea during the initiation phase of the treatment, when sodium was not present in the IPN fluid but was supplemented intermittently. In the 16 treated patients, body weight, which had decreased in the pretreatment period from 58.2+/-1.3 kg (-6 months) to 54.8+/-10.1 kg at the start of the study, increased again up to 57.1+/-10.7 kg after 9 months IPN (p < .05). Serum transferrin and prealbumin rose from 1.7+/-0.4 to 2.0+/-0.4 g/L and from 0.23+/-0.05 to 0.27+/-0.10 g/L, respectively. Bone densitometry showed an increase of tissue mass, mostly related to a rise in fat tissue. Triceps skinfold (p < .05) and arm muscle compartment of the midarm (p = .07) increased as well. No such changes were observed in the patients who withdrew from treatment. CONCLUSIONS An i.v. hyperalimentation regimen applied to malnourished hemodialysis patients results in a rise of body weight and in a limited, but significant, change of some parameters of nutritional status. The rise in body weight is at least in part attributable to an increase of body fat, without changes in plasma lipid levels.

Novel method for simultaneous determination of p-cresylsulphate and p-cresylglucuronide: clinical data and pathophysiological implications

BACKGROUND The uraemic retention solutes p-cresylsulphate (pCS) and p-cresylglucuronide (pCG), two conjugates of p-cresol, were never determined simultaneously. In the present paper, a high-performance liquid chromatography (HPLC) method was developed and used to quantify both compounds in parallel in an in vivo observational study and their in vitro effect was evaluated by flow cytometry. METHODS pCS and pCG were determined in serum. For the validation specificity, linearity, recovery, precision and the quantification limit were evaluated. In vivo, concentrations of both compounds were determined in 15 controls and 77 haemodialysis patients, as well as protein binding in the dialysed group and the reduction ratios during haemodiafiltration. In addition, the in vitro effect of the solutes on leucocyte free radical production at measured concentrations was assessed. RESULTS A fast and accurate HPLC method was developed to simultaneously quantify pCS and pCG. Both conjugates are retained in uraemia with a substantially higher total serum pCS in comparison to pCG (31.4 ± 15.8 versus 7.3 ± 6.5 mg/L) but also a substantial difference in protein binding (92.4 ± 3.0 versus 8.3 ± 4.4%) and in reduction ratio during post-dilution haemodiafiltration (37.4 ± 7.1 versus 78.6 ± 6.4%). pCG per se has no effect on leucocyte oxidative burst activity, whereas in combination with pCS, a synergistic activating effect was observed. CONCLUSIONS Serum concentrations of pCS and pCG are elevated in uraemia. Both conjugates show a different protein binding, resulting in a different dialytic behaviour. Biologically, both conjugates are synergistic in activating leucocytes.

Comparison of removal capacity of two consecutive generations of high-flux dialysers during different treatment modalities

BACKGROUND Innovative modifications have been introduced in several types of dialyser membranes to improve adequacy and permselectivity. Which aspects of removal are modified and how this relates to different diffusive or convective strategies has, however, been insufficiently investigated. METHODS In a prospective cross-over study, 14 chronic kidney disease (Stage 5D) patients were dialysed with a second-generation high-flux dialyser (Polynephron) in comparison to a first-generation type (DIAPES-HF800). Both dialysers were assessed in haemodialysis, in online pre-dilution and in post-dilution haemodiafiltration. Reduction ratio (RR, %) of small water-soluble compounds (urea and uric acid), low-molecular weight proteins (LMWPs) (β(2)-microglobulin, cystatin C, myoglobin and retinol-binding protein) and protein-bound solutes (hippuric acid, indole acetic acid, indoxylsulphate and p-cresylsulphate) was assessed, together with albumin losses into the dialysate. RESULTS Comparing the two types of membranes, the second-generation dialyser demonstrated a higher RR for LMWPs, whilst at the same time exhibiting lower albumin losses but only during post-dilution haemodiafiltration. No differences in RR were detected for both the small water-soluble and the protein-bound compounds. Comparing dialysis strategies, convection removed the same amount of solute or more as compared to diffusion. CONCLUSIONS The second-generation membrane resulted in a higher removal of LMWPs compared to the first-generation membrane, but for the other solutes, differences were less prominent. Convection was superior in removal of a broad range of uraemic retention solutes especially with the first-generation membrane.

Prospective Evaluation of the Change of Predialysis Protein-Bound Uremic Solute Concentration With Postdilution Online Hemodiafiltration

Although protein-bound uremic compounds have been related to outcome in observational studies, few current dialysis strategies provide more removal of those compounds than standard hemodialysis. We evaluated the evolution of protein-bound uremic solutes after a switch from high-flux hemodialysis to postdilution hemodiafiltration (n = 13). We compared predialysis solute concentration at 4, 5, and 9 weeks versus baseline for several protein-bound compounds and water-soluble solutes, as well as for beta(2)-microglobulin. After 9 weeks of postdilution hemodiafiltration, a significant decrease versus baseline could be detected for total concentration of protein-bound solutes: p-cresylsulfate (3.98 +/- 1.51-3.17 +/- 1.77 mg/dL, -20%, P < 0.01) and 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid (0.72 +/- 0.52-0.64 +/- 0.46 mg/dL, -11%, P < 0.01). For the other protein-bound solutes, hippuric acid, indoleacetic acid, and indoxylsulfate, no change in total concentration could be detected. The concentration of the middle molecule, beta(2)-microglobulin, decreased as well after 9 weeks of postdilution hemodiafiltration (24.7 +/- 9.3-18.1 +/- 6.7 mg/L, -27%, P < 0.01). For water-soluble compounds, no significant change of concentration was found. Postdilution hemodiafiltration in comparison to high-flux hemodialysis provided significant reduction of predialysis concentration of protein-bound compounds, especially those with the highest protein binding, and of beta(2)-microglobulin, by -11 to -27% in 9 weeks.

Epidemiology of infection in critically ill patients with acute renal failure

Objectives: Critically ill patients with infection are at increased risk for developing acute renal failure (ARF), and ARF is associated with an increased risk for infection. Both conditions are associated with prolonged length of stay (LOS) and worse outcome; however, little data exist on the epidemiology of infection in this specific cohort. Therefore, we investigated the occurrence of infection in a cohort of critically ill patients with ARF treated with renal replacement therapy (RRT). In addition, we assessed whether this infection worsened outcome. Design: Retrospective cohort study. Setting: General intensive care unit (ICU) in an academic tertiary care center comprising a 22-bed surgical ICU, eight-bed cardiac surgery ICU, 14-bed medical ICU, and six-bed burn center. Patients: Six hundred forty-seven consecutive critically ill patients with ARF treated with RRT, admitted between 2000 and 2004. Interventions: None. Measurements and Main Results: total of 519 (80.2%), 193 (29.8%), 66 (10.2%), and ten (1.5%) patients developed one, two, three, and four episodes of infection, respectively. Of 788 episodes of infection observed, 364 (46.2%) occurred before, 318 (40.3%) during, and 106 (13.4%) after discontinuation of RRT. Pneumonia (54.3%) was most frequent, followed by intra-abdominal (11.9%) and urinary tract infections (9.7%). Infections were caused by Gram-negative organisms in 33.7%, Gram-positive organisms in 21.6%, and yeasts in 9.8%. Patients with infection had higher mortality (p = 0.04) and longer ICU and hospital LOS. They needed more vasoactive therapy and spent more time on mechanical ventilation and RRT (all p < 0.001) than patients without infection. After adjustment for potential confounders, Acute Physiology and Chronic Health Evaluation II score, age, mechanical ventilation, and vasoactive therapy were associated with worse outcome, but infection was not. Conclusions: Infection occurred in four fifths of critically ill patients with ARF treated with RRT and was in an unadjusted analysis associated with longer LOS and higher mortality. After correction for other covariates, infection was no longer associated with in-hospital mortality.

Impact of increasing haemodialysis frequency versus haemodialysis duration on removal of urea and guanidino compounds: a kinetic analysis

BACKGROUND Patients with renal failure retain a large variety of uraemic solutes, characterized by different kinetic behaviour. It is not entirely clear what the impact is of increasing dialysis frequency and/or duration on removal efficiency, nor whether this impact is the same for all types of solutes. METHODS This study was based on two-compartmental kinetic data obtained in stable haemodialysis patients (n = 7) for urea, creatinine (CREA), guanidinosuccinic acid (GSA) and methylguanidine (MG). For each individual patient, mathematical simulations were performed for different dialysis schedules, varying in frequency, duration and intensity. For each dialysis schedule, plasmatic and extraplasmatic weekly time-averaged concentrations (TAC) were calculated, as well as their %difference to weekly TAC of the reference dialysis schedule (three times weekly 4 h). RESULTS Increasing dialysis duration was most beneficial for CREA and MG, which are distributed in a larger volume (54.0 +/- 5.9 L and 102.6 +/- 33.9 L) than urea (42.7 +/- 6.0 L) [plasmatic weekly TAC decrease of 31.5 +/- 3.2% and 31.8 +/- 3.8% for CREA and MG with Q(B) of 200 mL/min, compared to 25.7 +/- 3.2% for urea (P = 0.001 and P < 0.001)]. Increasing dialysis frequency resulted only in a limited increase in efficiency, most pronounced for solutes distributed in a small volume like GSA (30.6 +/- 4.2 L). Increasing both duration and frequency results in weekly TAC decreases of >65% for all solutes. Comparable results were found in the extraplasmatic compartment. CONCLUSION Prolonged dialysis significantly reduces solute concentration levels, especially for those solutes that are distributed in a larger volume. Increasing both dialysis frequency and duration is the superior dialysis schedule.

Does the Adequacy Parameter Kt/Vurea Reflect Uremic Toxin Concentrations in Hemodialysis Patients?

Hemodialysis aims at removing uremic toxins thus decreasing their concentrations. The present study investigated whether Kt/Vurea, used as marker of dialysis adequacy, is correlated with these concentrations. Predialysis blood samples were taken before a midweek session in 71 chronic HD patients. Samples were analyzed by colorimetry, HPLC, or ELISA for a broad range of uremic solutes. Solute concentrations were divided into four groups according to quartiles of Kt/Vurea, and also of different other parameters with potential impact, such as age, body weight (BW), Protein equivalent of Nitrogen Appearance (PNA), Residual Renal Function (RRF), and dialysis vintage. Dichotomic concentration comparisons were performed for gender and Diabetes Mellitus (DM). Analysis of Variance in quartiles of Kt/Vurea did not show significant differences for any of the solute concentrations. For PNA, however, concentrations showed significant differences for urea (P<0.001), uric acid (UA), p-cresylsulfate (PCS), and free PCS (all P<0.01), and for creatinine (Crea) and hippuric acid (HA) (both P<0.05). For RRF, concentrations varied for β2-microglobulin (P<0.001), HA, free HA, free indoxyl sulfate, and free indole acetic acid (all P<0.01), and for p-cresylglucuronide (PCG), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), free PCS, and free PCG (all P<0.05). Gender and body weight only showed differences for Crea and UA, while age, vintage, and diabetes mellitus only showed differences for one solute concentration (UA, UA, and free PCS, respectively). Multifactor analyses indicated a predominant association of concentration with protein intake and residual renal function. In conclusion, predialysis concentrations of uremic toxins seem to be dependent on protein equivalent of nitrogen appearance and residual renal function, and not on dialysis adequacy as assessed by Kt/Vurea. Efforts to control intestinal load of uremic toxin precursors by dietary or other interventions, and preserving RRF seem important approaches to decrease uremic solute concentration and by extension their toxicity.

Why do patients on peritoneal dialysis have low blood levels of protein-bound solutes?

Lower blood concentrations of protein-bound solutes have been directly linked to better outcomes in patients on dialysis. Studies indicate that clearance of protein-bound solutes is more efficient in patients on hemodialysis than in those on peritoneal dialysis; however, paradoxically, the circulating levels of these solutes are lower in patients on peritoneal dialysis. Vanholder and colleagues consider possible explanations for this discrepancy, such as differences in intestinal generation or metabolism of these molecules.