Sunny Eloot

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.

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

BACKGROUND & OBJECTIVES Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)-κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. RESULTS Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). CONCLUSIONS The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.

An update on uremic toxins

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins.

BACKGROUND AND OBJECTIVES The degree of chronic kidney disease (CKD) is currently expressed in terms of GFR, which can be determined directly or estimated according to different formulas on the basis of serum creatinine and/or cystatin C measurements (estimated GFR [eGFR]). The purpose of this study was to investigate whether eGFR values are representative for uremic toxin concentrations in patients with different degrees of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Associations between eGFR based on serum cystatin C and different uremic solutes (mol wt range 113 to 240 D; determined by colorimetry, HPLC, or ELISA) were evaluated in 95 CKD patients not on dialysis (CKD stage 2 to 5). The same analysis was also applied for six other eGFR formulas. RESULTS There was a substantial disparity in fits among solutes. In linear regression, explained variance of eGFR was extremely low for most solutes, with eGFR > 0.4 only for creatinine. The other eGFR formulations gave comparably disappointing results with regard to their association to uremic solutes. Relative similarity in R(2) values per solute for the different eGFR values and the strong disparity in values between solutes suggest that the differences in R(2) are mainly due to discrepancies in solute handling apart from GFR. CONCLUSIONS eGFR is poorly associated with concentrations of all studied uremic toxins in patients with different degrees of CKD, correlates differently with each individual solute, and can thus not be considered representative for evaluating the accumulation of solutes in the course of CKD.

Acute Hemodynamic Response and Uremic Toxin Removal in Conventional and Extended Hemodialysis and Hemodiafiltration: A Randomized Crossover Study

BACKGROUND Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. STUDY DESIGN Randomized crossover trial. SETTINGS & PARTICIPANTS Stable patients with end-stage renal disease undergoing conventional HD. INTERVENTION 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. OUTCOMES Acute hemodynamic effects and uremic toxin clearance. MEASUREMENTS Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. RESULTS Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. LIMITATIONS Small sample size, only acute effects were studied. CONCLUSIONS Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.

Guanidino compounds as uremic (neuro)toxins.

Neurological and vascular impairment are important sources of morbidity in patients with renal failure. A portion of patients still suffers from uremic encephalopathy or other signs of nervous system impairment. Several reports demonstrate increased incidence of cardiac infarction and cerebrovascular accidents in chronic renal failure patients, even in those otherwise adequately dialyzed. Epileptic and cognitive symptoms are among the most typical manifestations of uremic encephalopathy. Several guanidino compounds (GCs) may play an important role in the etiology of uremic encephalopathy. Four GCs appeared to be substantially increased as well in serum, cerebrospinal fluid, and brain of uremic patients. These compounds, “uremic” GCs, are creatinine, guanidine (G), guanidinosuccinic acid (GSA), and methylguanidine. All four compounds are experimental convulsants in concentrations similar to those found in uremic brain. We described a possible mechanism for the contribution of GCs to uremic hyperexcitability, referring to the in vitro effects of uremic GCs on inhibitory and excitatory amino acid receptors. It was demonstrated that the excitatory effects of uremic GCs on the central nervous system can be explained by the activation of N‐methyl‐d‐aspartate receptors by GSA, concomitant inhibition of γ‐aminobutyric acid type A receptors by uremic GCs, and other depolarizing effects. These effects might also indicate the putative contribution of uremic GCs to the etiology of uremic encephalopathy. In this article, we review the uremic GCs with particular attention to their neurotoxicity. We elaborate in detail on the mechanisms of action of the neurotoxic uremic GCs and summarize the kinetics of these toxins.

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.

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

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.