Mental health and professional outcomes in parents of children with chronic kidney disease.

BACKGROUND: This study evaluated parenting stress, anxiety, and depression symptoms and their associated factors in parents of children with chronic kidney disease (CKD). METHODS: This cross-sectional study compared parents of patients with CKD (0-18 years) with a matched control group of parents of healthy children. Both groups completed the Parenting Stress Index - Short Form, the Hospital Anxiety and Depression Scale, and a sociodemographic questionnaire. RESULTS: The study group consisted of 45 parents (median age 39; 32 mothers) of CKD patients (median age 8; 36% female). Nearly 75% of children had CKD stages 2, 3, or 4, and 44.5% had congenital anomaly of the kidney and urinary tract. Five children (11%) were on dialysis, and 4 (9%) had a functioning kidney graft. Compared with parents of healthy children, more stress and anxiety symptoms were reported. Since the CKD diagnosis, 47% of parents perceived a deterioration of their own health, and 40% reduced work on a structural basis. Higher levels of stress, anxiety, and depression symptoms were associated with a more negative perception of own health, and more child medical comorbidities and school absence. CONCLUSIONS: This study showed higher levels of parenting stress and anxiety symptoms in parents of children with CKD compared with parents of healthy children. This was associated with a less positive perception of their own health, especially if the child had more medical comorbidities or more absence from school. Psychosocial interventions to reduce the parental burden should be integrated in the standard care of pediatric nephrology departments.

Illness-related parental stress and quality of life in children with kidney diseases.

BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Validity and reliability of the Dutch version of the PedsQL™ 3.0 End Stage Renal Disease Module in children with chronic kidney disease in Belgium.

BACKGROUND: Children with chronic kidney disease (CKD) have a low quality of life (QoL). The PedsQL™ 4.0 Generic Core Scales are widely used to assess general QoL in children. The aim of this cross-sectional study was to translate the original version of the CKD-specific PedsQL™ 3.0 End Stage Renal Disease Module into a Dutch version and to evaluate its validity and reliability. METHODS: The forward-backward translation method based on the guidelines from the original developer was used to produce the Dutch version of the PedsQL™ 3.0 ESRD Module. Fifty-eight CKD patients (aged 8-18 years) and their parents (n = 31) filled in both generic and disease-specific modules. The non-clinical control group consisted of the same number of healthy children (matched for gender and age) and their parents. RESULTS: Cronbach's alpha coefficients (α's) for the PedsQL™ 3.0 ESRD Module demonstrated excellent reliability for the Total Scale scores. For all 7 subscales, α's were greater than 0.60, except for Perceived Physical Appearance. Overall, intercorrelations with the PedsQL™ 4.0 Generic Core Scales were in the medium to large range, supporting construct validity. Parent proxy reports showed lower generic QoL for all domains in CKD patients compared to healthy children. Child self-reports only demonstrated lower QoL on the domain School Functioning in children with CKD compared to healthy children. CONCLUSIONS: This study shows good validity and reliability for the Dutch version of the PedsQL™ 3.0 ESRD Module. However, testing with a larger study group is recommended in order to make final conclusions about the psychometric qualities of this measure. A higher resolution version of the Graphical abstract is available as Supplementary information.

Potassium and fiber: a controversial couple in the nutritional management of children with chronic kidney disease.

BACKGROUND: Fruit and vegetable intake is commonly discouraged in children with chronic kidney disease (CKD) to avoid hyperkalemia. However, direct evidence in support of this widespread practice is lacking. Furthermore, the resultant restricted fiber exposure may deprive CKD patients from potential health benefits associated with the latter. Therefore, we investigated associations between dietary potassium intake, fiber intake, and serum potassium levels in pediatric CKD. METHODS: This study is a longitudinal analysis of a 2-year, prospective, multi-institutional study, following children with CKD at 3-month intervals. At each visit, dietary potassium and fiber intake were assessed, using 24-h recalls and 3-day food records. On the same occasion, serum potassium concentrations were determined. Associations between dietary potassium intake, dietary fiber intake, and serum potassium concentrations were determined using linear mixed models. RESULTS: Fifty-two CKD patients (7 transplant recipients, none on dialysis) aged 9 [4;14] years with an estimated glomerular filtration rate (eGFR) of 49 [25;68] mL/min/1.73 m2 were included. For every g/day decrease in dietary potassium intake, the estimated mean daily fiber intake was 5.1 g lower (95% confidence interval (CI), 4.3-5.9 g/day; p < 0.001). Neither dietary potassium intake (p = 0.40) nor dietary fiber intake (p = 0.43) was associated with circulating potassium in a model adjusted for time point, eGFR, treatment with a renin-angiotensin-aldosterone system blocker, serum bicarbonate concentration, and body surface area. CONCLUSIONS: Dietary potassium and fiber intake are closely related but were not associated with circulating potassium levels in pediatric CKD. A higher-resolution version of the graphical abstract is available as Supplementary information.

Dietary fibre intake is low in paediatric chronic kidney disease patients but its impact on levels of gut-derived uraemic toxins remains uncertain.

BACKGROUND: Chronic kidney disease (CKD) in children is a pro-inflammatory condition leading to a high morbidity and mortality. Accumulation of organic metabolic waste products, coined as uraemic toxins, parallels kidney function decline. Several of these uraemic toxins are protein-bound (PBUT) and gut-derived. Gut dysbiosis is a hallmark of CKD, resulting in a state of increased proteolytic fermentation that might be counteracted by dietary fibre. Data on fibre intake in children with CKD are lacking. We aimed to assess dietary fibre intake in a paediatric CKD cohort and define its relationship with PBUT concentrations. METHODS: In this multi-centre, cross-sectional observational study, 61 non-dialysis CKD patients (9 ± 5 years) were included. Dietary fibre intake was assessed through the use of 24-h recalls or 3-day food records and coupled to total and free levels of 4 PBUTs (indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG) and indole acetic acid (IAA). RESULTS: In general, fibre intake was low, especially in advanced CKD: 10 ± 6 g/day/BSA in CKD 4-5 versus 14 ± 7 in CKD 1-3 (p = 0.017). Lower concentrations of both total (p = 0.036) and free (p = 0.036) pCG were observed in the group with highest fibre intake, independent of kidney function. CONCLUSIONS: Fibre intake in paediatric CKD is low and is even worse in advanced CKD stages. Current dietary fibre recommendations for healthy children are not being achieved. Dietary management of CKD is complex in which too restrictive diets carry the risk of nutritional deficiencies. The relation of fibre intake with PBUTs remains unclear and needs further investigation. Graphical abstract.

Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

Haemodiafiltration does not lower protein-bound uraemic toxin levels compared with haemodialysis in a paediatric population.

BACKGROUND: Haemodiafiltration (HDF) is accepted to effectively lower plasma levels of middle molecules in the long term, while data are conflicting with respect to the additive effect of convection on lowering protein-bound uraemic toxins (PBUTs). Here we compared pre-dialysis ß2-microglobulin (ß2M) and PBUT levels and the percentage of protein binding (%PB) in children on post-dilution HDF versus conventional high- (hf) or low-flux (lf) haemodialysis (HD) over 12 months of treatment. METHODS: In a prospective multicentre, non-randomized parallel-arm intervention study, pre-dialysis levels of six PBUTs and ß2M were measured in children (5-20 years) on post-HDF (n = 37), hf-HD (n = 42) and lf-HD (n = 18) at baseline and after 12 months. Analysis of variance was used to compare levels and %PB in post-HDF versus conventional hf-HD and lf-HD cross-sectionally at 12 months and longitudinal from baseline to 12 months. RESULTS: For none of the PBUTs, no difference was found in either total and free plasma levels or %PB between post-HDF versus the hf-HD and lf-HD groups. Children treated with post-HDF had lower pre-dialysis ß2M levels [median 23.2 (21.5; 26.6) mg/dL] after 12 months versus children on hf-HD [P<0.01; 35.2 (29.3; 41.2) mg/dL] and children on lf-HD [P<0.001; 47.2 (34.3; 53.0) mg/dL]. While ß2M levels remained steady in the hf-HD and lf-HD group, a decrease in ß2M was demonstrated for children on post-HDF (P<0.01). CONCLUSIONS: While post-HDF successfully decreased ß2M, no additive effect on PBUT over 12 months of treatment was found. PBUT removal is complex and hampered by several factors. In children, these factors might be different from adults and should be explored in future research.

Associations between the measures of physical function, risk of falls and the quality of life in haemodialysis patients: a cross-sectional study.

BACKGROUND: Impaired physical function due to muscle weakness and exercise intolerance reduces the ability to perform activities of daily living in patients with end-stage kidney disease, and by consequence, Health-Related Quality of Life (HRQoL). Furthermore, the risk of falls is an aggregate of physical function and, therefore, could be associated with HRQoL as well. The present study examined the associations between objective and subjective measures of physical function, risk of falls and HRQoL in haemodialysis patients. METHODS: This cross-sectional multicentre study included patients on maintenance haemodialysis. Physical function (quadriceps force, handgrip force, Sit-to-Stand, and six-minute walking test), the risk of falls (Tinetti, FICSIT-4, and dialysis fall index) and HRQoL (PROMIS-29 and EQ-5D-3 L) were measured and analysed descriptively, by general linear models and logistic regression. RESULTS: Of the 113 haemodialysis patients (mean age 67.5 ± 16.1, 57.5% male) enrolled, a majority had impaired quadriceps force (86.7%) and six-minute walking test (92%), and an increased risk of falls (73.5%). Whereas muscle strength and exercise capacity were associated with global HRQoL (R2 = 0.32) and the risk of falls, the risk of falls itself was related to psycho-social domains (R2 = 0.11) such as depression and social participation, rather than to the physical domains of HRQoL. Objective measures of physical function were not associated with subjective fatigue, nor with subjective appreciation of health status. CONCLUSIONS: More than muscle strength, lack of coordination and balance as witnessed by the risk of falls contribute to social isolation and HRQoL of haemodialysis patients. Mental fatigue was less common than expected, whereas, subjective and objective physical function were decreased.

Evaluation with micro-CT of different anticoagulation strategies during hemodialysis in patients with thrombocytopenia: A randomized crossover study.

In patients with enhanced risk for bleeding, heparin-free hemodialysis (HD) with conventional dialyzers is routinely used. To explore the potential benefit of using heparin-coated dialyzers, we used a reference CT-scanning technique and registered different clotting parameters to quantify coagulation with heparin-coated versus non-coated dialyzers. Six HD patients with thrombocytopenia were dialyzed 240 min in a randomized crossover study with Evodial 1.3 or FX600 Cordiax, each without anticoagulation. Blood samples were taken from the vascular access predialysis, and from the dialyzer inlet and outlet at 5 and 240 min after dialysis start. Predialysis blood samples were analyzed for hemoglobin, hematocrit, thrombocytes, fibrinogen, and activated partial thromboplastin time. On dialyzer inlet and outlet blood samples, a viscoelastic measurement of blood coagulation was performed using a Sonoclot analyzer. After dialysis, dialyzers were visually scored, subsequently dried for 24 h, weighed, and scanned with micro-CT at a resolution of 25 µm. After image reconstruction, the open, non-coagulated fibers were counted in a representative cross-section at the dialyzer outlet. No sessions were terminated prematurely for circuit clotting. Heparin-coated dialyzers had more patent fibers on micro-CT versus non-coated dialyzers and also had a better score of subjective visual assessment of fiber clotting. There was no difference in subjective assessment of clotting at the venous drip chamber. With both dialyzers, all ACT values remained in the normal range, and were lower at the dialyzer outlet versus inlet. In conclusion, dialysis with a heparin-coated versus non heparin-coated membrane results in substantially less coagulated fibers during 4 h hemodialysis without systemic anticoagulation. Eventual leaching of heparin, immobilized on the fiber membrane, does not result in measurable systemic anticoagulation.

Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population.

Background: Chronic kidney disease (CKD) in childhood is poorly explained by routine markers (e.g. urea and creatinine) and is better depicted in adults by other uraemic toxins. This study describes concentrations of representative uraemic toxins in non-dialysis CKD versus healthy children. Methods: In 50 healthy children and 57 children with CKD Stages 1-5 [median estimated glomerular filtration rate 48 (25th-75th percentile 24-71) mL/min/1.73 m2; none on dialysis], serum concentrations of small solutes [symmetric and asymmetric dimethyl-arginine (SDMA and ADMA, respectively)], middle molecules [ß2-microglobuline (ß2M), complement factor D (CfD)] and protein-bound solutes [p-cresylglucuronide (pCG), hippuric acid (HA), indole-acetic acid (IAA), indoxyl sulphate (IxS), p-cresyl sulphate (pCS) and 3-carboxy-4-methyl-5-propyl-furanpropionic acid (CMPF)] were measured. Concentrations in the CKD group were expressed as z-score relative to controls and matched for age and gender. Results: SDMA, CfD, ß2M, IxS, pCS, IAA, CMPF and HA concentrations were higher in the overall CKD group compared with controls, ranging from 1.7 standard deviations (SD) for IAA and HA to 11.1 SD for SDMA. SDMA, CfD, ß2M, IxS and CMPF in CKD Stages 1-2 with concentrations 4.8, 2.8, 4.5, 1.9 and 1.6 SD higher, respectively. In contrast, pCS, pCG and IAA concentrations were only higher than controls from CKD Stages 3-4 onwards, but only in CKD Stage 5 for ADMA and HA (z-score 2.6 and 20.2, respectively). Conclusions: This is the first study to establish reference values for a wide range of uraemic toxins in non-dialysis CKD and healthy children. We observed an accumulation of multiple uraemic toxins, each with a particular retention profile according to the different CKD stages.

Binding of bromocresol green and bromocresol purple to albumin in hemodialysis patients.

BACKGROUND: Colorimetric albumin assays based on binding to bromocresol purple (BCP) and bromocresol green (BCG) yield different results in chronic kidney disease. Altered dye binding of carbamylated albumin has been suggested as a cause. In the present study, a detailed analysis was carried out in which uremic toxins, acute phase proteins and Kt/V, a parameter describing hemodialysis efficiency, were compared with colorimetrically assayed (BCP and BCG) serum albumin. METHODS: Albumin was assayed using immunonephelometry on a BN II nephelometer and colorimetrically based on, respectively, BCP and BCG on a Modular P analyzer. Uremic toxins were assessed using high-performance liquid chromatography. Acute phase proteins (C-reactive protein and α1-acid glycoprotein) and plasma protein α2-macroglobulin were assayed nephelometrically. In parallel, Kt/V was calculated. RESULTS: Sixty-two serum specimens originating from hemodialysis patients were analyzed. Among the uremic toxins investigated, total para-cresyl sulfate (PCS) showed a significant positive correlation with the BCP/BCG ratio. The serum α1-acid glycoprotein concentration correlated negatively with the BCP/BCG ratio. The BCP/BCG ratio showed also a negative correlation with Kt/V. CONCLUSIONS: In renal insufficiency, the BCP/BCG ratio of serum albumin is affected by multiple factors: next to carbamylation, uremic toxins (total PCS) and α1-acid glycoprotein also play a role.

Accumulation of uraemic toxins is reflected only partially by estimated GFR in paediatric patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) in childhood is characterised by the accumulation of uraemic toxins resulting in a multisystem disorder that has a negative impact on quality of life. Childhood CKD is predominantly defined by a decrease in glomerular filtration rate, estimated (eGFR) by a single serum measurement of endogenous biomarkers, e.g. creatinine. The objective of this study was to evaluate how accurately eGFR predicts the concentration of uraemic toxins in a paediatric CKD cohort. METHODS: In 65 children (10.8 [5.1; 14.7] years) with CKD (eGFR 44 [20; 64] mL/min/1.73 m2), serum concentrations were determined of small solutes (uric acid [UA], urea, symmetric dimethylarginine [SDMA], asymmetric dimethylarginine [ADMA]), middle molecules (ß2-microglobulin [ß2M], complement factor D [CfD]) and protein-bound solutes (p-cresylglucuronide [pCG], hippuric acid, indole acetic acid, indoxyl sulphate [IxS], p-cresylsulfate [pCS] and 3-carboxy-4-methyl-5-propyl-furanpropionic acid [CMPF]). Spearman's correlation coefficients (r) were calculated to correlate uraemic toxin concentrations with three different eGFR equations, based on either serum creatinine or ß2M. RESULTS: Updated Schwartz eGFR was correlated reasonably well with concentrations of creatinine (r = -0.98), urea (rs = -0.84), SDMA (r = -0.82) and middle molecules CfD and ß2M (both rs = -0.90). In contrast, poor correlation coefficients were found for CMPF (rs = -0.32), UA (rs = -0.45), ADMA (rs = -0.47) and pCG (rs = -0.48). The other toxins, all protein-bound, had rs between -0.75 and -0.57. Comparable correlations were found between the three evaluated eGFR equations and uraemic toxin concentrations. CONCLUSIONS: This study demonstrates that eGFR poorly predicts concentrations of protein-bound uraemic toxins, UA and ADMA in childhood CKD. Therefore, eGFR only partially reflects the complexity of the accumulation pattern of uraemic toxins in childhood CKD.

Transport of neutral IgG2 versus anionic IgG4 in PD: implications on the electrokinetic model.

BACKGROUND: It is debated whether transperitoneal membrane transport of larger (charged) molecules in peritoneal dialysis can be partially governed by the electrokinetic model. In this model, it is postulated that streaming potentials are generated across the capillary wall by forced filtration of an ionic solution, for example transcapillary ultrafiltration induced by osmotic forces as in peritoneal dialysis. We investigated the presence of streaming potentials in the process of transperitoneal transport in Peritoneal Dialysis (PD) patients by measuring ratios of dialysate concentrations of IgG2 (neutral) and IgG4 (negative), both 150kD, under different conditions of transcapillary ultrafiltration. METHODS: Adult PD patients randomly got two consecutive dwells of 120 min each, with either 2 L Physioneal 1.36% or 3.86% glucose dialysis fluid (Baxter, USA) as their first dwell. A blood sample was taken at the test start, and dialysate samples were taken at 5, 15, 30, 60 and 120 min. IgG2 and IgG4 concentrations were measured (ELISA) and ratios calculated. RESULTS: In 10 patients (65 ± 17 years, 20 ± 17 months on dialysis), drained volume after 120 min was different between the 1.36% (1950 [1910; 2020] mL) and 3.86% (2540 [2380; 2800] mL) glucose dwells (P = 0.007). At none of the time points and irrespective of glucose concentration, a significant difference was found between the IgG2/IgG4 ratios at any time point. CONCLUSION: Our data failed to demonstrate a difference in the transport ratios of two macromolecules with same molecular weight but different charge, as would be expected by the electrokinetic model, and this despite sufficient differences in transcapillary ultrafiltration. CLINICAL TRIAL REGISTRY: Belgian Registration Number B670201523397 (20/1/2015); prospective randomized trial.

Assessment of the association between increasing membrane pore size and endotoxin permeability using a novel experimental dialysis simulation set-up.

BACKGROUND: Membranes with increasing pore size are introduced to enhance removal of large uremic toxins with regular hemodialysis. These membranes might theoretically have higher permeability for bacterial degradation products. In this paper, permeability for bacterial degradation products of membranes of comparable composition with different pore size was investigated with a new in vitro set-up that represents clinical flow and pressure conditions. METHODS: Dialysis was simulated with an AK200 machine using a low-flux, high-flux, medium cut-off (MCO) or high cut-off (HCO) device (n = 6/type). A polyvinylpyrrolidone-solution (PVP) was recirculated at blood side. At dialysate side, a challenge solution containing a filtrated lysate of two water-borne bacteria (Pseudomonas aeruginosa and Pelomononas saccharophila) was infused in the dialysate flow (endotoxin ≥ 4EU/ml). Blood and dialysate flow were set at 400 and 500 ml/min for 60 min. PVP was sampled before (PVPpre) and after (PVPpost) the experiment and dialysate after 5 and 55 min. Limulus Amebocyte Lysate (LAL) test was performed. Additionally, samples were incubated with a THP-1 cell line (24 h) and IL-1ß levels were measured evaluating biological activity. RESULTS: The LAL-assay confirmed presence of 9.5 ± 7.4 EU/ml at dialysate side. For none of the devices the LAL activity in PVPpre vs. PVPpost was significantly different. Although more blood side PVP solutions had a detectable amount of endotoxin using a highly sensitive LAL assay in the more open vs traditional membranes, the permeability for endotoxins of the 4 tested dialysis membranes was not significantly different but the number of repeats is small. None of the PVP solutions induced IL-1ß in the THP-1 assay. CONCLUSIONS: A realisitic in vitro dialysis was developed to assess membrane translocation of bacterial products. LAL activity on the blood side after endotoxin exposure did not change for all membranes. Also, none of the PVPpost solutions induced IL-1ß in the THP-1 bio-assay.

Low flow extracorporeal CO2 removal in ARDS patients: a prospective short-term crossover pilot study.

BACKGROUND: Lung protective mechanical ventilation (MV) is the corner stone of therapy for ARDS. However, its use may be limited by respiratory acidosis. This study explored feasibility of, effectiveness and safety of low flow extracorporeal CO2 removal (ECCO2R). METHODS: This was a prospective pilot study, using the Abylcap® (Bellco) ECCO2R, with crossover off-on-off design (2-h blocks) under stable MV settings, and follow up till end of ECCO2R. Primary endpoint for effectiveness was a 20% reduction of PaCO2 after the first 2-h. Adverse events (AE) were recorded prospectively. We included 10 ARDS patients on MV, with PaO2/FiO2 < 150 mmHg, tidal volume ≤ 8 mL/kg with positive end-expiratory pressure ≥ 5 cmH2O, FiO2 titrated to SaO2 88-95%, plateau pressure ≥ 28 cmH2O, and respiratory acidosis (pH <7.25). RESULTS: After 2-h of ECCO2R, 6 patients had a ≥ 20% decrease in PaCO2 (60%); PaCO2 decreased 28.4% (from 58.4 to 48.7 mmHg, p = 0.005), and pH increased (1.59%, p = 0.005). ECCO2R was hemodynamically well tolerated. During the whole period of ECCO2R, 6 patients had an AE (60%); bleeding occurred in 5 patients (50%) and circuit thrombosis in 3 patients (30%), these were judged not to be life threatening. CONCLUSIONS: In ARDS patients, low flow ECCO2R significantly reduced PaCO2 after 2 h, Follow up during the entire ECCO2R period revealed a high incidence of bleeding and circuit thrombosis. TRIAL REGISTRATION: https://clinicaltrials.gov identifier: NCT01911533 , registered 23 July 2013.

Future Avenues to Decrease Uremic Toxin Concentration.

In this article, we review approaches for decreasing uremic solute concentrations in chronic kidney disease and in particular, in end-stage renal disease (ESRD). The rationale to do so is the straightforward relation between concentration and biological (toxic) effect for most toxins. The first section is devoted to extracorporeal strategies (kidney replacement therapy). In the context of high-flux hemodialysis and hemodiafiltration, we discuss increasing dialyzer blood and dialysate flows, frequent and/or extended dialysis, adsorption, bioartificial kidney, and changing physical conditions within the dialyzer (especially for protein-bound toxins). The next section focuses on the intestinal generation of uremic toxins, which in return is stimulated by uremic conditions. Therapeutic options are probiotics, prebiotics, synbiotics, and intestinal sorbents. Current data are conflicting, and these issues need further study before useful therapeutic concepts are developed. The following section is devoted to preservation of (residual) kidney function. Although many therapeutic options may overlap with therapies provided before ESRD, we focus on specific aspects of ESRD treatment, such as the risks of too-strict blood pressure and glycemic regulation and hemodynamic changes during dialysis. Finally, some recommendations are given on how research might be organized with regard to uremic toxins and their effects, removal, and impact on outcomes of uremic patients.

Once upon a time in dialysis: the last days of Kt/V?

After its proposal as a marker of dialysis adequacy in the eighties of last century, Kt/V(urea) helped to improve dialysis efficiency and to standardize the procedure. However, the concept was developed when dialysis was almost uniformly short and was applied thrice weekly with small pore cellulosic dialyzers. Since then dialysis evolved in the direction of many strategic alternatives, such as extended or daily dialysis, large pore high-flux dialysis, and convective strategies. Although still a useful baseline marker, Kt/V(urea) no longer properly covers up for most of these modifications so that urea kinetics are hardly if at all representative for those of other solutes with a deleterious effect on morbidity and mortality of uremic patients. This is corroborated in several clinical studies showing a dissociation between removal of urea and that of other uremic toxins. In addition, randomized controlled trials showed no benefit of increasing Kt/V(urea). Finally, this parameter also hardly is evocative for metabolic or intestinal generation of toxins, for their removal by residual renal function and for the complex interaction of dialysis length with removal pattern and patient outcomes. We conclude that apart from being a baseline parameter of dialysis adequacy, Kt/V(urea) insufficiently represents all novel strategic changes of modern dialysis. Kt/V(urea) is too simple a concept for the complexities of uremia and of today's dialysis.

Protein-bound uraemic toxins, dicarbonyl stress and advanced glycation end products in conventional and extended haemodialysis and haemodiafiltration.

BACKGROUND: Protein-bound uraemic toxins (PBUT), dicarbonyl stress and advanced glycation end products (AGEs) associate with cardiovascular disease in dialysis. Intensive haemodialysis (HD) may have significant clinical benefits. The aim of this study was to evaluate the acute effects of conventional and extended HD and haemodiafiltration (HDF) on reduction ratio (RR) and total solute removal (TSR) of PBUT, dicarbonyl stress compounds and AGEs. METHODS: Thirteen stable conventional HD patients randomly completed a single study of 4-h HD (HD4), 4-h HDF (HDF4), 8-h HD (HD8) and 8-h HDF (HDF8) with a 2-week interval between the study sessions. RR and TSR of PBUT [indoxyl sulphate (IS), p-cresyl sulphate (PCS), p-cresyl glucuronide, 3-carboxyl-4-methyl-5-propyl-2-furanpropionic acid (CMPF), indole-3-acetic acid (IAA) and hippuric acid] of free and protein-bound AGEs [N(ε)-(carboxymethyl)lysine (CML), N(ε)-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine, pentosidine], as well as of dicarbonyl compounds [glyoxal, methylglyoxal, 3-deoxyglucosone], were determined. RESULTS: Compared with HD4, HDF4 resulted in increased RR of total and/or free fractions of IAA and IS as well as increased RR of free CML and CEL. HD8 and HDF8 showed a further increase in TSR and RR of PBUT (except CMPF), as well as of dicarbonyl stress and free AGEs compared with HD4 and HDF4. Compared with HD8, HDF8 only significantly increased RR of total and free IAA and free PCS, as well as RR of free CEL. CONCLUSIONS: Dialysis time extension (HD8 and HDF8) optimized TSR and RR of PBUT, dicarbonyl stress and AGEs, whereas HDF8 was superior to HD8 for only a few compounds.

New methods and technologies for measuring uremic toxins and quantifying dialysis adequacy.

This publication reviews the currently available methods to identify uremic retention solutes, to determine their biological relevance and to quantify their removal. The analytical methods for the detection of uremic solutes have improved continuously, allowing the identification of several previously unknown solutes. Progress has been accelerated by the development of comprehensive strategies such as genomics, proteomics and the latest "omics" area, metabolomics. Those methodologies will be further refined in future. Once the concentration of solutes of interest is known based on targeted analysis, their biological relevance can be studied by means of in vitro, ex vivo, or animal models, provided those are representative for the key complications of the uremic syndrome. For this to come to pass, rigid protocols should be applied, e.g., aiming at free solute concentrations conform those found in uremia. Subsequently, the decrease in concentration of relevant solutes should be pursued by nondialysis (e.g., by influencing nutritional intake or intestinal generation, using sorbents, modifying metabolism, or preserving renal function) and dialysis methods. Optimal dialysis strategies can be sought by studying solute kinetics during dialysis. Clinical studies are necessary to assess the correct impact of those optimized strategies on outcomes. Although longitudinal studies of solute concentration and surrogate outcome studies are first steps in suggesting the usefulness of a given approach, ultimately hard outcome randomized controlled trials are needed to endorse evidence-based therapeutic choices. The nonspecificity of dialysis removal is however a handicap limiting the chances to provide proof of concept that a given solute or group of solutes has definite biological impact.