Risk factors for developing hyperoxaluria in children with Crohn's disease.

BACKGROUND: For the purpose of a better understanding of enteric hyperoxaluria in Crohn's disease (CD) in children and adolescents, we investigated the occurrence and risk factors for development of hyperoxaluria in those patients. METHODS: Forty-five children with CD and another 45 controls were involved in this cross-sectional study. Urine samples were collected for measurement of spot urine calcium/creatinine (Ur Ca/Cr), oxalate/creatinine (Ur Ox/Cr), and citrate/creatinine (Ur Citr/Cr) ratios. Fecal samples were also collected to detect the oxalyl-CoA decarboxylase of Oxalobacter formigenes by PCR. Patients were classified into 2 groups: group A (with hyperoxaluria) and group B (with normal urine oxalate excretion). The disease extent was assessed, and the activity index was calculated. RESULTS: According to the activity index, 30 patients (66.7%) had mild disease and 13 patients (28.9%) had moderate disease. There was no significant difference in Ur Ox/Cr ratio regarding the disease activity index. O. formigenes was not detected in 91% of patients in group A while it was detected in all patients in group B (p < 0.001). By using logistic regression analysis, the overall model was statistically significant when compared to the null model, (χ2 (7) = 52.19, p < 0.001), steatorrhea (p = 0.004), frequent stools (p = 0.009), and O. formigenes (p < 0.001). CONCLUSION: Lack of intestinal colonization with O. formigenes, steatorrhea, and frequent stools are the main risk factors for development of enteric hyperoxaluria in CD patients. Identifying risk factors facilitates proper disease management in future studies. A higher resolution version of the Graphical abstract is available as Supplementary information.

Comparing different markers of tubular dysfunction in transfusion-dependent thalassemia patients.

BACKGROUND: Renal tubular dysfunction was reported in transfusion-dependent thalassemia (TDT) patients and ranges from mild to severe. The objectives of our study were identification of the best marker of early renal tubular dysfunction in TDT patients among the three most commonly used urinary biomarkers, named neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and N-acetyl-D-glucosaminidase (NAG) and correlation of these biomarkers with different patient variables. METHODOLOGY: Sixty-one TDT patients and another 62 healthy children were enrolled in a cross-sectional study. Morning urine samples were taken for measurement of calcium, phosphorus, creatinine, microalbumin and markers of tubular dysfunction (NGAL, NAG and RBP). Urine NGAL/creatinine (UrNGAL/Cr), urine NAG/creatinine (UrNAG/Cr) and urine RBP/creatinine (UrRBP/Cr) ratios were used for accuracy. Patients were classified into 2 groups: group A, with tubular dysfunction and group b, without tubular dysfunction. RESULTS: Group A showed statistically significant higher UrNGAL/Cr (p < 0.001), UrRBP/Cr (p < 0.001) and UrNAG/Cr (p <0.001) than group B. In group A, microalbuminuria was detected only in 7 patients (28%) while it was detected in 12 patients (33.3%) in group B. By using ROC curve analysis, the diagnostic cutoff values for UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr were 3713.38, 1614.85 and 56.56 ng/g, respectively. We found a statistically significant superiority of UrNGAL/Cr over UrRBP/Cr (p < 0.001) and UrRBP/Cr over UrNAG/Cr (p < 0.001). CONCLUSION: Evaluation of UrNGAL/Cr, UrRBP/Cr and UrNAG/Cr could early discriminate tubular dysfunction TDT patients from those with normal tubular function. UrNGAL/Cr is more accurate in early detection of tubular dysfunction when compared with the other two biomarkers.

Native vs. active vitamin D in children with chronic kidney disease: a cross-over study.

BACKGROUND: The rationale for the prescription of vitamin D analogues in patients with chronic kidney disease (CKD) is still a matter of debate. We aimed to compare native vs. active forms of vitamin D on pre-dialysis children with CKD and evaluate effects on calcium (Ca), phosphorus (P), and parathyroid hormone (PTH). METHODS: Thirty children with pre-dialysis CKD were enrolled in a prospective cross-over study. Patients were randomly classified into two groups. Group A received native cholecalciferol while group B received alfacalcidol for 3 months. After 1 month (washout period), patients were switched to receive the opposite form for another 3 months. Serum Ca, P, alkaline phosphatase (ALP), PTH, and 25(OH)D3 were measured at study start (BL-1), end of first period (FU-1), before second period (BL-2), and after second period (FU-2). RESULTS: There was significant increase in levels of 25(OH)D3 after administration of either native or active vitamin D in the first period in both groups (p < 0.001 and < 0.001, respectively) and also in the second period for both groups (p = 0.02 and < 0.001, respectively). There was no significant difference between both groups regarding changes in serum Ca (1st period; p = 0.770 and 2nd period; p = 0.412), serum P (1st period; p = 0.835, 2nd period; p = 0.052), and serum PTH (1st period; p = 0.250, 2nd period; p = 0.539). CONCLUSION: Alfacalcidol and native vitamin D3 were equally effective in decreasing PTH levels and increasing serum 25(OH)D3 in pre-dialysis CKD patients. There was no significant difference between the two forms regarding changes in serum Ca or P. Graphical abstract.

Sleep disorders in children and adolescents on regular hemodialysis.

Sleep disorders in children with chronic kidney disease have been assessed in a limited number of studies. Our aim was to characterize the types of sleep disorders in children on regular hemodialysis and to detect the predictors of sleep efficiency in those children. Forty children and adolescents on regular hemodialysis and another 40 age- and gender-matched control groups were interviewed to answer a questionnaire-based survey, a modified Epworth Sleepiness Scale, to assess excess daytime sleepiness. Also, they underwent an overnight in-laboratory polysomnography to assess total sleep time, sleep efficiency, sleep staging, apnea/hypopnea index, and periodic limb movement index. We found poor sleep efficiency in 20% of cases, and periodic limb movement index higher than 5 in 45%, and apnea/hypopnea index higher than 5 in 40%. There was significant negative correlation between sleep efficiency on one hand, and serum potassium, serum creatinine, and sleep onset on other hand (p < 0.001, p < 0.001, and p < 0.001, respectively). There was significant decrease in hemoglobin, serum iron, and transferrin saturation in patients with excess daytime sleepiness (p < 0.001, p = 0.003, and p = 0.010, respectively). By using multivariate linear regression analysis, we found that serum creatinine was the single independent predictor of sleep efficiency.Conclusion: Poor sleep quality is not uncommon in hemodialysis children. Our results show a lower frequency of sleep disorders in comparison with previous studies. There is a strong association between kidney dysfunction and poor sleep quality in HD children.What is known:• Sleep disturbances can adversely affect a child's daytime performance.• Sleep disorders in children with chronic kidney disease have been assessed in only a limited number of studies.What is new:• Poor sleep quality is not uncommon in hemodialysis children.• There is a strong association between kidney dysfunction and poor sleep quality in hemodialysis children.

Randomized controlled trial on immunomodulatory effects of azithromycin in children with steroid-dependent nephrotic syndrome.

BACKGROUND: Azithromycin (AZM) is a macrolide antibiotic with anti-inflammatory and immunomodulatory effects. Our aim was to compare the immunomodulatory effects of AZM combined with steroid therapy with that of steroid therapy alone in children with steroid-dependent nephrotic syndrome (SDNS). METHODS: We enrolled 57 patients with SDNS in a multicenter randomized control trial. Patients were classified into two groups: group A (intervention group, N = 29) and group B (control group, N = 28). After achievement of remission with full-dose daily prednisone, patients in group A received AZM in conjunction with steroids which was tapered gradually, while patients in group B received steroids alone. Urine protein creatinine ratio (uPCR) and TNF-α were measured at different points of follow-up throughout the study period (5 months after achieving remission). RESULTS: After achievement of remission by full-dose steroids, there were significant differences of TNF-α between the two groups after 1-, 3- and 5-month follow-up (p < 0.001, 0.003, and 0.001, respectively). Also, there was significant difference of TNF-α in both intervention and control groups after exclusion of the relapsed cases at 3- and 5-month follow-up (, p = 0.031 and p = 0.003, respectively). There was significant difference between both groups after 5-month follow-up as regards the number of relapsed patients (group A = 4, group B = 11, p = 0.015). CONCLUSION: AZM was capable of reducing serum TNF-α which is one of the inflammatory cytokines implicated in the pathogenesis of NS.

Transforming growth factor-ß1 in children with diabetic nephropathy.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine that has numerous biological processes. Earlier research indicates that protein and mRNA production of TGF-ß1 are enhanced in the renal tissues of patients with diabetic nephropathy (DN). Our aim was to evaluate the role of TGF-ß1 in early prediction of DN in children with type 1 diabetes mellitus (T1DM). METHODS: Fifty patients with T1DM were enrolled in an observational study. Patients were eligible to participate if at least 3 years had passed since T1DM diagnosis. Patients were classified into two groups (A and B) according to the presence or absence of microalbuminuria, respectively. Serum TGF-ß1 was measured by ELISA in the patients. RESULTS: Out of the 50 studied patients with T1DM, there were 23 (46%) patients with microalbuminuria. There was a significant difference between patients in group A and B as regards TGF-ß1 (p < 0.001). HbA1c had very little influence in controlling for the relationship between TGF-ß1 and disease duration. Diagnostic cutoff value of TGF-ß1 was 358.5 pg/ml with sensitivity and specificity of 100%. CONCLUSION: TGF-ß1 was significantly higher in children with DN in comparison with children without. It could be used as an early indicator of DN in children with T1DM with high sensitivity and specificity.

Foreign body ingestion in Egyptian children: a 10-year experience of endoscopic intervention in a tertiary hospital.

BACKGROUND: There is paucity of data regarding foreign body (FB) ingestion among Middle-Eastern children. We conducted a retrospective analysis of FB ingestion among Egyptian children and determined the predictors that affect the occurrence of complications. METHODS: This retrospective study was carried out on 1546 patients aged 13 years or younger presenting with FB ingestion and in need of endoscopic FB removal. RESULTS: There were 711 males (46%) and 835 females (54%) (mean age 4.56±2.26 years). Symptoms were present in 1414 patients (91.5%) while complications were present in 137 patients (8.9%). There was a significant difference between complicated and non-complicated cases with regard to higher age group, duration of impaction, site of impaction and type of FB (P=0.001, P=0.001, P=0.001, and P<0.001, respectively). CONCLUSIONS: The highest rate of complications was observed in FB impacted in duodenum and those without symptoms while symptomatic cases and impaction in upper esophagus were associated with higher success rate of removal.

Role of Early Onset Neutropenia in Development of Candidemia in Premature Infants.

Background: The aim of the study was to assess the effect of early-onset neutropenia (EON) on the development of candidemia in premature infants and evaluate other risk factors. Materials and Methods: This prospective study was carried out in a neonatal intensive care unit of Cairo University Hospital. Fifty neutropenic premature infants were matched to 50 non-neutropenics. Subjects were then regrouped into candidemics and non-candidemics to study other risk factors such as central venous catheters, mechanical ventilation, parenteral nutrition, drugs as corticosteroids and others. Candidemia was assessed by Bactec and then seminested polymerase chain reaction for culture negatives. Results: Candidemia developed in 28 neutropenic preterms and in 8 non-neutropenics (odds ratio = 6.68, 95% confidence interval = 2.61-17.1, p <0.001). Risk factors for invasive fungal infection in univariate analysis included bacterial septicemia, mechanical ventilation, parenteral nutrition and steroid therapy. Independent predictors of candidemia in multivariate regression analysis included EON, mechanical ventilation and steroid therapy. Conclusion: EON is an independent risk factor for candidemia in premature infants.

Renal ultrasound and Doppler parameters as markers of renal function and histopathological damage in children with chronic kidney disease.

AIM: Doppler ultrasonography can be used to assess the progression of vascular (arterial sclerosis) and parenchymal (glomerular sclerosis and crescents) renal damage. The aim of this study was to evaluate the significance of some sonographic and Doppler parameters as non-invasive markers of glomerular filtration rate (GFR) and renal histopathological damage in children. METHODS: A cohort of 84 children were enrolled in a case-control study (42 with CKD stages 2-5 and 42 healthy children). GFR was assessed using new improved equation using serum creatinine and cystatin C. Sonar guided renal specimen was obtained and evaluated for the severity of global sclerosis (GS), segmental sclerosis (SS), tubular atrophy (TA), interstitial fibrosis (IF), arterial sclerosis (AS) and arteriolar hyalinosis (AH). The following sonographic and Doppler parameters were assessed in both patients and control group: resistivity index (RI), pulsatility index (PI), atrophic index (AI), mean renal volume, mean renal density, time average velocity (TAV) and body surface area related volume perfusion (BSARVP). RESULTS: There was significant difference in renal density (P < 0.001), RI (P < 0.001), PI (P = 0.021), TAV (P < 0.001) and BSARVP (P < 0.001) between patients and control group. The cutoff value of RI was 63.5% (sensitivity 83% and specificity 64%). Multivariate analysis revealed that renal density and RI were significant predictors of worsening of estimated GFR (eGFR) in CKD patients. CONCLUSION: Any increase in the RI and PI values must arouse alarm to the possibility of advancing renal damage. Moreover, RI and PI could fairly predict the degree of glomerular sclerosis and interstitial fibrosis.

Novel marker for the detection of sickle cell nephropathy: soluble FMS-like tyrosine kinase-1 (sFLT-1).

BACKGROUND: Given the burden and poor outcome of end-stage renal disease in sickle cell disease (SCD), early markers of sickle cell nephropathy (SN) are desirable. Disordered angiogenesis underlies many complications of SCD. We aimed to determine the relationship between serum FMS-like tyrosine kinase-1 (sFLT-1) and other biomarkers of renal damage for the early diagnosis of SN. METHODS: Forty-seven SCD patients and 49 healthy controls were enrolled. Microalbuminuria was determined in patient urine samples. Blood samples were tested for sFLT-1, serum creatinine, and various hemolysis and inflammation markers. Peripheral blood monocyte expression of sFLT-1 was measured using real-time polymerase chain reaction (PCR). RESULTS: The serum level of sFLT-1 (pg/ml) in SCD patients was higher than controls (median/range/IQR = 142/ 60-1300/61 pg/ml vs. 125/ 110-187/52 pg/ml, respectively) (p = 0.006). Median (range) of sFLT-1 level was higher in SCD patients with microalbuminuria compared to SCD patients with normoalbuminuria, 185 (140-1300) vs. 125 (60-189) mg/g, respectively) (p = 0.004). There was a significant positive correlation between serum sFLT-1 and microalbuminuria, lactate dehydrogenase (LDH), and indirect bilirubin (r = 0.59, 0.39, 0.30, and p = <0.001, 0.007, 0.041, respectively). sFLT-1 sensitivity in early detection of renal affection in SCD was 93.6%, while specificity was 68.6%. Finally, peripheral blood monocytes (PBM) sFLT-1 expression was significantly higher in SCD patients compared to controls (p = 0.05). CONCLUSIONS: sFLT-1 may contribute to pathogenesis of albuminuria in SCD patients and constitute a novel renal biomarker of SN.

Use of lung ultrasound in detection of complications of respiratory distress syndrome.

Repeated chest radiography is required for the diagnosis and follow-up of neonates with respiratory distress syndrome (RDS) and carries the risk of radiation hazards. Lung ultrasound (LUS) is a non-invasive bedside diagnostic tool that has proven to be effective in the diagnosis of RDS. Our aim was to assess the role of LUS with respect to the standard chest X-ray (CXR) in the detection of complications of RDS in neonates. Ninety premature newborns of both genders with RDS (mean gestational age = 29.91 ± 1.33 wk) and 40 premature babies as a control group were involved in this study. All patients underwent initial clinical assessment as well as CXR and LUS. Those who presented with respiratory distress and/or exhibited deterioration of oxygenation parameters were followed by CXR and, within 4 h, by LUS. Alveolo-interstitial syndrome and pleural line abnormalities were detected in all cases (100%) in the initial assessment, patchy consolidation was detected in 34 cases and white lung was detected in 80 cases. Alveolo-interstitial syndrome was detected in 19 controls. In follow-up of the patients, LUS was superior to CXR in detection of consolidation and sub-pleural atelectasis, but not in detection of pneumothorax. We concluded that bedside LUS is a good non-hazardous alternative tool in the early detection and follow-up of RDS in the neonatal intensive care unit; it could be of value in reducing exposure to unnecessary radiation.

Effect of On-Line Hemodiafiltration on P-Wave Dispersion in Children.

P-wave dispersion (PWD) (difference between the maximum and minimum P-wave duration), has been proposed as a useful predictor of paroxysmal atrial fibrillation (AF). The consequences of hemodialysis (HD) on PWD and P-wave duration have not been unequivocally documented and understood, and may be complex. We aimed in this work to demonstrate the effects of online hemodiafiltration (OL-HDF) on the risk of developing AF through assessment of PWD. Thirty-three pediatric patients (14 males and 19 females with mean age of 11.66 ± 2.93 years) on conventional HD for at least 6 months underwent echocardiography, 12-lead electrocardiogram and PWD calculation. Then they were switched to OL-HDF for another 6 months and same parameters were reassessed. Thirty sex- and aged-matched healthy children, served as controls. PWD significantly decreased upon switching to OL-HDF (P < 0.001) and fractional shortening significantly improved (P < 0.001). Mean PWD of controls (24 ± 6 ms) was significantly less than PWD before and after OL-HDF (P < 0.001 and <0.001, respectively). Online HDF significantly decreased PWD and hence also the potential of AF development, which may invite a higher consideration of this renal replacement modality in a pediatric population.

Serum klotho: relation to fibroblast growth factor-23 and other regulators of phosphate metabolism in children with chronic kidney disease.

FGF23 and Klotho synergize to regulate phosphate homeostasis by promoting renal phosphate excretion. Chronic kidney disease (CKD) may be viewed as a state of FGF23 resistance caused by Klotho deficiency. This viewpoint explains several observations on phosphate metabolism in CKD that lack mechanistic insights. Our objectives were to correlate serum klotho and FGF-23 with other variables that regulate phosphate metabolism. We studied 40 patients with CKD on conservative treatment (group A), 44 patients with end-stage renal disease (ESRD) on regular hemodialysis (group B), 40 kidney transplant recipients (KTR) (group C) and 40 healthy controls for measuring serum klotho and FGF-23. Blood samples were withdrawn for measuring the levels of serum Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), 1,25 (OH)2 D3, intact parathyroid hormone (PTH), FGF-23 and α klotho. The mean levels of FGF-23 and α klotho in control group were 225.78 ± 111.05 pg/ml (range: 102.4, 418.5) and 6.78 ± 1.90 ng/ml (range: 4, 11), respectively. The mean levels of FGF-23 in the 3 studied groups were 1,034.2 ± 84.6, 1,288.7 ± 131.4 and 1,008.7 ± 117.6 pg/ml, respectively. The median levels of s-klotho in the 3 studied groups were 3.15, 2.3 and 2.95, respectively. It was found that FGF-23 was significantly increased and α klotho was significantly decreased in all patients when compared with those in the control group (p < 0.001, <0.001, respectively). We found that there was a significant inverse correlation between serum Ca and α klotho in the studied groups. There was no significant correlation between FGF-23 and α klotho in the studied groups (p > 0.05). We have shown that circulating s-klotho was not related to FGF-23 in CKD, dialysis and KTR patients. In addition, we demonstrated a novel association between serum Ca and s-klotho that needs to be further studied.

Do term newborns respond similarly to different painful procedures?

OBJECTIVE: Although many methods for pain assessment in newborns are available, none of them are widely accepted. Our aim was to answer the question: do newborns respond similarly to different painful procedures? METHODS: Sixty term newborns were involved in non-randomized prospective study. They were classified into 2 groups: Group A (n=30) who needed intubation and Group B (n=30) who necessitated umbilical vein catheterization. Close observation prior to and 10 minutes after the painful procedures was performed for recording of physiological and behavioral indicators. Plasma renin activity (PRA) was measured before and 10 minutes after the painful procedures. FINDINGS: There was statistically significant difference between the 2 groups as regards physiological and hormonal responses to pain (P<0.05). Apart from palmar sweating and crying, there was no significant difference in behavioral response (P>0.05). The median pre- and post-intubation levels of PRA were 3.04 and 12.05 ng/ml/hour, respectively. There was significant (P<0.001) increase of PRA after intubation. On the other hand, the median pre- and post-catheterization levels of PRA were 5.21 and 9.19 ng/ml/hour, respectively. There was significant (P<0.001) increase of PRA after umbilical vein catheterization. We found that PRA was the only indicator of pain in group A (P=0.047). On the other hand, we did not find any indicator of pain in group B. CONCLUSION: We concluded that full-term newborns vary in their physiological and hormonal responses to different painful procedures but their behavioral response is the same.

High-flux and low-flux dialysis membranes and levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in children with chronic kidney failure.

INTRODUCTION: During hemodialysis, the expression of different adhesion molecules changes, thus serving as markers of biocompatibility of dialysis membranes. Our aim was to investigate whether low-flux and high-flux dialysis membranes have different effects on the concentration of adhesion molecules and their association with leukocytes and pro-inflammatory cytokines. MATERIALS AND METHODS: We enrolled 80 pediatric patients on hemodialysis. Baseline levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. The patients were classified into 2 groups to use either low-flux filters or high-flux filters for 3 months. At the end of the 3 months, predialysis samples were obtained for measurement of ICAM-1, VCAM-1, TNF-alpha and interleukin-1. Post-dialysis samples were collected for measurement of CBC, ICAM-1, VCAM-1, TNF-alpha, and interleukin-1. Forty volunteers were involved as a control group. RESULTS: Both TNF- ? and IL-1 were higher in the patients compared to the control group (P < .001). Compared to the control group, there was a significant increase in ICAM-1 and VCAM-1 (P < .001) in both groups predialysis and postdialysis. The postdialysis increments of ICAM-1 with the high-flux membranes were significantly less compared to the low-flux membranes (P < .001). Serum ICAM-1 and VCAM-1 significantly correlated with TNF-? and interleukin-1 in all groups. CONCLUSIONS: The postdialysis increments of the adhesion molecules are due to the effect of dialysis membranes, which is less with the use of high-flux filters.

Double-blind, placebo-controlled trial on the effect of piracetam on breath-holding spells.

Breath-holding spells (BHS) are apparently frightening events occurring in otherwise healthy children.The aim of this study was to evaluate the efficacy of piracetam in the treatment of breath-holding spells. Forty patients with BHS (who were classified into two groups)were involved in a double-blinded placebo-controlled prospective study. Piracetam was given to group A while group B received placebo. Patients were followed monthly for a total period of 4 months. The numbers of attacks/month before and monthly after treatment were documented, and the overall number of attacks/month after treatment was calculated in both groups. The median number of attacks/month before treatment in the two groups was 5.5 and 5,respectively, while after the first month of treatment, it was 2 and 5, respectively. The median overall number of attacks/month after treatment in both groups was 1 and 5, respectively.There was a significant decline of number of attacks after piracetam treatment compared to placebo (p value<0.001). There were no reported side effects of the piracetam throughout the study period. In conclusion, piracetam is a safe and effective drug for the treatment of breath-holding spells in children.

Effect of high-flux versus low-flux dialysis membranes on parathyroid hormone.

INTRODUCTION. Hyperparathyroidism is a common finding in patients with renal insufficiency and parathyroid hormone (PTH) is considered a uremic toxin responsible for many of the abnormalities of the uremic state and bone disease. The aim of this study was to investigate the influence of permeability of low-flux versus high-flux dialysis membranes on intact PTH during hemodialysis in children. MATERIALS AND METHODS. Forty-four children aged between 4 and 13 years old on regular hemodialysis were enrolled in a prospective study. Low-flux polysulfone membranes were used for at least 6 months and then the patients were switched to use high-flux polysulfone membranes for 3 months. Serum electrolytes and intact PTH before and after dialysis were compared before and after changes in dialysis membrane. RESULTS. At the end of the 3-month use of high-flux filters, predialysis intact PTH level (49.40 ± 19.64 ng/dL) showed a highly significant decline (P < .001) compared to the predialysis intact PTH (21.67 ± 4.85 ng/dL) with low-flux membranes at the start of the study. Intact PTH level correlated negatively with serum ionized calcium and positively with serum phosphorus levels only in the predialysis samples with the use of low-flux but not high-flux filters. CONCLUSIONS. In children, high-flux dialysis membranes are more efficient in removal of intact PTH, one of the middle-sized uremic toxins, than low-flux membranes.