Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.

The focus of this study is to enhance the protein fouling resistance, hydrophilicity, biocompatibility, hemocompatibility and ability of the membranes and to reduce health complications like chronic pulmonary disease, peripheral vascular disease, cerebrovascular disease, and cardiovascular disease after dialysis, which are the great challenges in HD applications. In the current study, the PSF-based dialysis membranes are studied broadly. Significant consideration has also been provided to membrane characteristics (e.g., flowrate coefficient, solute clearance characteristic) and also on commercially available polysulfone HD membranes. PSF has gained a significant share in the development of HD membranes, and continuous improvements are being made in the process to make high flux PSF-based dialysis membranes with enhanced biocompatibility and improved protein resistance ability as the major issue in the development of membranes for HD application is biocompatibility. There has been a great increase in the demand for novel biocompatible membranes that offer the best performances during HD therapy, for example, low oxidative stress and low change ability of blood pressure.

The AGTRAP-PLOD1 locus is a conserved gene cluster containing several blood pressure regulatory genes, including CLCN6, MTHFR, NPPA, and NPPB. Previous work revealed that knockout of Clcn6 on the Dahl Salt-Sensitive (SS) rat background (SS-Clcn6) resulted in lower diastolic blood pressure compared to SS-WT rats. Additionally, a recent study found sickle cell anemia patients with mutations in CLCN6 had improved survival and reduced stroke risk. We investigated whether loss of Clcn6 would delay the mortality of Dahl SS rats on an 8% NaCl (HS) diet. No significant difference in survival was found. The ability of Clcn6 to affect mRNA expression of nearby Mthfr, Nppa, and Nppb genes was also tested. On normal salt (0.4% NaCl, NS) diets, renal Mthfr mRNA and protein expression were significantly increased in the SS-Clcn6 rats. MTHFR reduces homocysteine to methionine, but no differences in circulating homocysteine levels were detected. Nppa mRNA levels in cardiac tissue from SS-Clcn6 rat in both normotensive and hypertensive conditions were significantly reduced compared to SS-WT. Nppb mRNA expression in SS-Clcn6 rats on a NS diet was also substantially decreased. Heightened Mthfr expression would be predicted to be protective; however, diminished Nppa and Nppb expression could be deleterious and by preventing or blunting vasodilation, natriuresis, and diuresis that ought to normally occur to offset blood pressure increases. The conserved nature of this genetic locus in humans and rats suggests more studies are warranted to understand how mutations in and around these genes may be influencing the expression of their neighbors.

Protein-bound uraemic toxins (PBUTs) accumulate in patients with chronic kidney disease and impose detrimental effects on the vascular system. However, a unanimous consensus on the most optimum approach for the reduction of plasma PBUTs is still lacking.

In this systematic review, we aimed to identify the most efficient clinically available plasma PBUT reduction method reported in the literature between 1980 and 2020. The literature was screened for clinical studies describing approaches to reduce the plasma concentration of known uraemic toxins. There were no limits on the number of patients studied or on the duration or design of the studies.

Out of 1274 identified publications, 101 studies describing therapeutic options aiming at the reduction of PBUTs in CKD patients were included in this review. We stratified the studies by the PBUTs and the duration of the analysis into acute (data from a single procedure) and longitudinal (several treatment interventions) trials. Reduction ratio (RR) was used as the measure of plasma PBUTs lowering efficiency. For indoxyl sulphate and p-cresyl sulphate, the highest RR in the acute studies was demonstrated for fractionated plasma separation, adsorption and dialysis system. In the longitudinal trials, supplementation of haemodialysis patients with AST-120 (Kremezin®) adsorbent showed the highest RR. However, no superior method for the reduction of all types of PBUTs was identified based on the published studies.

Our study shows that there is presently no technique universally suitable for optimum reduction of all PBUTs. There is a clear need for further research in this field.

The levels of thiamine diphosphate (ThDP), the most active biologically form of vitamin B₁, were assessed in whole blood oflong-term haemodialysed patients (n = 50), by applying chromatographic methods based on RP-HPLC technique with isocratic elution and fluorescence detection. The target analyte, thiochrome diphosphate (ThODP), was obtained by pre-column derivatization of vitamin B₁ contained in blood samples, applying deproteination with trichloroacetic acid, following by oxidation with alkaline solution of potassium ferricyanide(III) and stabilization with DTT before assays. A simple and sensitive assay was developed, and the results were referenced to the commercially available test. Steady-state and time-resolved studies on emissive properties of ThODP enabled optimization of the proposed assay. The F-Snedecor test shown no statistically significant differences between both approaches. Assessed parameters of the proposed assay, such as linearity, precision, sensitivity, and recovery, were satisfactory if compared to the reference one. The LOQ value for ThDP in whole blood of studied group of patients was of 0.5 ng/mL and the recovery of88%. The results disclosed high individual variabilities in the interdialytic deficiencies of ThDP among the patients - ranged from afew percent to values close to 100%. A comprehensive clinical data, characterizing patients under study, were processed together, and analysed by employing achemometric discriminative tool, the Principal Components Analysis,to find interdependences among clinical data characterizing patients. The three Principal Components were disclosed, that in sum explained almost 50% of the observed variability of the clinical data set. Among the clinical parameters involved in PCs were dialyzer membrane and type, duration as well as levels of creatinine, haemoglobin, and red blood cells in patients' whole blood.

Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).

MicroRNA (miRNA) 499 is an evolutionarily conserved muscle-specific miRNA that is encoded by an intron of the myh7 gene and is likely to play a role in myosin gene regulation. It has been shown to be involved in inhibiting apoptosis and myocardial infarction induced by ischemia and anoxia. It is unknown whether levels of miRNAs are affected in patients undergoing hemodialysis.

The aim of this study was to assess circulating levels of miRNA 499 in hemodialysis patients and whether the levels are affected by dialyzer membranes (high flux vs. low flux).

The studied population consisted of 32 end stage renal disease (ESRD) patients (22 males and 10 females) with age ranged from 38% to 75% years on regular hemodialysis (4 hours, 3 times weekly) for at least 1 year duration with cardiovascular events in the last 6 months and 32 healthy controls (20 males and 12 females) with an age range from 54 to 60 years. Patients were involved into a two-stage sequential study; high-flux hemodialysis stage (stage I), then low-flux hemodialysis stage (stage II). Expressed levels of plasma miRNA 499 have been measured by Real Time-PCR. Lipid profile, serum phosphorus, serum calcium, serum creatinine, and blood urea were measured in all patients.

In this study, 2 patients with an open-heart surgery showed highly elevation in the miRNA 499, while the other patients, showing different degrees of ischemia, had different levels of elevated miRNA 499. Statistically significant higher levels of miRNA 499 in plasma were observed in all the studied patients with cardiovascular diseases compared to the levels of miRNA 499 found in healthy controls (P < 0.0001). MicroRNA 499 was found to be a dialyzable marker. A significant decrease in plasma levels of miRNA 499 was obtained after either high-flux or low-flux dialysis compared to plasma levels of miRNA 499 found before dialysis (P < 0.0001). On comparing both types of hemodialysis membranes with respect to miRNA 499 clearance, we found that low-flux membrane showed better clearance for miRNA 499 than high-flux membrane with a statistically significant difference between them (P < 0.001).

In conclusion, miRNA 499 levels are elevated in patients with ESRD with cardiovascular complications. High-flux membrane seems to be less efficient in miRNA 499 clearance in cardiac patients on hemodialysis.

People with end-stage kidney disease (ESKD) have high rates of cardiovascular events. Randomised controlled trials (RCTs) of homocysteine-lowering therapies have not shown reductions in cardiovascular event rates in the general population. However, people with kidney disease have higher levels of homocysteine and may have different mechanisms of cardiovascular disease. We performed a systematic review of the effect of homocysteine-lowering therapies in people with ESKD.

To evaluate the benefits and harms of established homocysteine lowering therapy (folic acid, vitamin B6, vitamin B12) on all-cause mortality and cardiovascular event rates in patients with ESKD.

We searched Cochrane Kidney and Transplant's Specialised Register to 25 January 2016 through contact with the Information Specialist using search terms relevant to this review.

Studies conducted in people with ESKD that reported at least 100 patient-years of follow-up and assessed the effect of therapies that are known to have homocysteine-lowering properties were included.

Two authors independently extracted data using a standardised form. The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, incident cardiovascular disease (fatal and nonfatal myocardial infarction and coronary revascularisation), cerebrovascular disease (stroke and cerebrovascular revascularisation), peripheral vascular disease (lower limb amputation), venous thromboembolic disease (deep vein thrombosis and pulmonary embolism), thrombosis of dialysis access, and adverse events. The effects of homocysteine-lowering therapies on outcomes were assessed with meta-analyses using random-effects models. Prespecified subgroup and sensitivity analyses were conducted.

We included six studies that reported data on 2452 participants with ESKD. Interventions investigated were folic acid with or without other vitamins (vitamin B6, vitamin B12). Participants' mean age was 48 to 65 years, and proportions of male participants ranged from 50% to 98%.Homocysteine-lowering therapy probably leads to little or no effect on cardiovascular mortality (4 studies, 1186 participants: RR 0.93, 95% CI 0.70 to 1.22). There was no evidence of heterogeneity among the included studies (I² = 0%). Homocysteine-lowering therapy had little or no effect on all-cause mortality or any other of this review's secondary outcomes. All prespecified subgroup and sensitivity analyses demonstrated little or no difference. Reported adverse events were mild and there was no increase in the incidence of adverse events from homocysteine-lowering therapies (3 studies, 1248 participants: RR 1.12, 95% CI 0.51 to 2.47; I(2) = 0%). Overall, studies were assessed as being at low risk of bias and there was no evidence of publication bias.

Homocysteine-lowering therapies were not found to reduce mortality (cardiovascular and all-cause) or cardiovascular events among people with ESKD.

Although convective therapies have gained popularity for the optimal removal of uremic solutes, their benefits and potential risks have not been fully elucidated. We conducted a meta-analysis of all randomized controlled trials comparing convective therapies with low-flux hemodialysis in patients with chronic kidney failure.

We performed a literature search using MEDLINE (inception-December 2012), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, scientific abstracts from meetings and bibliographies of retrieved articles. Randomized controlled trials comparing the effect of convective therapies including high-flux hemodialysis, hemofiltration or hemodiafiltration versus low-flux hemodialysis were included. Random-effects model meta-analyses were used to examine continuous and binary outcomes.

Sixty-five (29 crossover and 36 parallel-arm) trials were identified (n = 12 182). Convective therapies resulted in a decrease in all-cause mortality [relative risk (RR) 0.88; 95% confidence interval (CI) 0.76, 1.02, P = 0.09], cardiovascular mortality (RR 0.84; 95% CI 0.71, 0.98, P = 0.03), all-cause hospitalization (RR 0.91; 95% CI 0.82, 1.01; P = 0.08) and therapy-related hypotension (RR 0.55, 95% CI 0.35, 0.87, P = 0.01). Convective therapies also resulted in an increase in the clearance of several low-molecular-weight (urea, creatinine and phosphate), middle-sized (β-2 microglobulin and leptin) and protein-bound (homocysteine, advanced glycation end-products and pentosidine) solutes and a decrease in inflammatory markers (interleukin-6). There was no impact of convective therapies on cardiac morphological and functional parameters, and blood pressure and anemia parameters.

Although convective therapies are associated with improved clearance of uremic solutes, the potential long-term benefits of specific convective modalities require further study.

There is a bidirectional and complex relationship between the heart and kidneys. This interaction is physical, chemical as well as biological and is also reflected in a strong connection between renal and cardiovascular diseases. Cardiorenal syndrome type 4 (CRS type 4) is characterized by primary chronic kidney disease (CKD) leading to an impairment of cardiac function, with ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. The incidence of CKD is increasing, and CRS type 4 is becoming a major public health problem associated with a high morbidity and mortality. In this study, we briefly review the epidemiology and pathophysiology of CRS type 4, the role of biomarkers in its early identification, and its management.

Several cardiovascular (CV) risk factors may explain the high rate of CV death among patients with chronic kidney disease (CKD). Among them both traditional and uremia-related risk factors are implicated and, moreover, the presence of kidney disease represents "per se" a multiplier of CV risk. Plasma lipid and lipoprotein profiles are changed in quantitative, but above all in qualitative, structural, and functional ways, and lipoprotein metabolism is influenced by the progressive loss of renal function. Statin therapy significantly reduces cholesterol synthesis and both CV morbidity and mortality either directly, by reducing the lipid profile, or via pleiotropic effects; it is supposed to be able to reduce both the progression of CKD and also proteinuria. These observations derive from a post-hoc analysis of large trials conducted in the general population, but not in CKD patients. However, the recently published SHARP trial, including over 9200 patients, either on dialysis or pre-dialysis, showed that simvastatin plus ezetimibe, compared with placebo, was associated with a significant low-density lipoprotein cholesterol reduction and a 17% reduction in major atherosclerotic events. However, no benefit was observed in overall survival nor in preserving renal function in patients treated. These recent data reinforce the conviction among nephrologists to consider their patients at high CV risk and that lipid lowering drugs such as statins may represent an important tool in reducing atheromatous coronary disease which, however, represents only a third of CV deaths in patients with CKD. Therefore, statins have no protective effect among the remaining two-thirds of patients who suffer from sudden cardiac death due to arrhythmia or heart failure, prevalent among CKD patients. The safety of statins is demonstrated in CKD by several trials and recently confirmed by the largest SHARP trial, in terms of no increase in cancer incidence, muscle pain, creatine kinase levels, severe rhabdomyolysis, hepatitis, gallstones and pancreatitis; thus confirming the handiness of statins in CKD patients. Here we will review the latest data available concerning the effectiveness and safety of statin therapy in CKD patients.

Clinical practice guidelines regarding the use of high-flux haemodialysis membranes vary widely.

We aimed to analyse the current evidence reported for the benefits and harms of high-flux and low-flux haemodialysis.

We searched Cochrane Renal Group's specialised register (July 2012), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1948 to March 2011), and EMBASE (1947 to March 2011) without language restriction.

We included randomised controlled trials (RCTs) that compared high-flux haemodialysis with low-flux haemodialysis in people with end-stage kidney disease (ESKD) who required long-term haemodialysis.

Data were extracted independently by two authors for study characteristics (participants and interventions), risks of bias, and outcomes (all-cause mortality and cause-specific mortality, hospitalisation, health-related quality of life, carpal tunnel syndrome, dialysis-related arthropathy, kidney function, and symptoms) among people on haemodialysis. Treatment effects were expressed as a risk ratio (RR) or mean difference (MD), with 95% confidence intervals (CI) using the random-effects model.

We included 33 studies that involved 3820 participants with ESKD. High-flux membranes reduced cardiovascular mortality (5 studies, 2612 participants: RR 0.83, 95% CI 0.70 to 0.99) but not all-cause mortality (10 studies, 2915 participants: RR 0.95, 95% CI 0.87 to 1.04) or infection-related mortality (3 studies, 2547 participants: RR 0.91, 95% CI 0.71 to 1.14). In absolute terms, high-flux membranes may prevent three cardiovascular deaths in 100 people treated with haemodialysis for two years. While high-flux membranes reduced predialysis beta-2 microglobulin levels (MD -12.17 mg/L, 95% CI -15.83 to -8.51 mg/L), insufficient data were available to reliably estimate the effects of membrane flux on hospitalisation, carpal tunnel syndrome, or amyloid-related arthropathy. Evidence for effects of high-flux membranes was limited by selective reporting in a few studies. Insufficient numbers of studies limited our ability to conduct subgroup analyses for membrane type, biocompatibility, or reuse. In general, the risk of bias was either high or unclear in the majority of studies.

High-flux haemodialysis may reduce cardiovascular mortality in people requiring haemodialysis by about 15%. A large well-designed RCT is now required to confirm this finding.

The efficacy of homocysteine (Hcy)-lowering therapy in reducing the risk of CVD among patients with chronic kidney disease (CKD) remains controversial. We performed a meta-analysis to determine whether pooling the data from the few small randomised, controlled trials that address this topic would improve the statistical power of the analysis and resolve some of the inconsistencies in the results. Randomised, controlled clinical trials (RCT) were identified from MEDLINE, EMBASE, www.clinicaltrials.gov, the Cochrane Controlled Clinical Trials Register Database and Nephrology Filters. Independent extraction of articles was performed using predefined data fields. The primary outcome was relative risk (RR) of CVD, CHD, stroke and all-cause mortality for the pooled trials. A stratified analysis was planned, assessing the RR for cardiovascular events between the patients on and not on dialysis. Overall, ten studies met the inclusion criteria. The estimated RR were not significantly different for any outcomes, including CHD (RR 1·00, 95 % CI 0·75, 1·31, P = 0·97), CVD (RR 0·94, 95 % CI 0·84, 1·05, P = 0·30), stroke (RR 0·83, 95 % CI 0·57, 1·19, P = 0·31) and all-cause mortality (RR 1·00, 95 % CI 0·92, 1·09, P = 0·98). In the stratified analysis, the estimated RR were not significantly different for cardiovascular events regardless of dialysis or in combination with vitamin B therapy or the degree of reduction in Hcy levels. Our meta-analysis of RCT supports the conclusion that Hcy-lowering therapy was not associated with a significant decrease in the risk for CVD events, stroke and all-cause mortality among patients with CKD.

Both larger molecule removal and dialyzer biocompatibility have been implicated in the high-flux hemodialysis (HD)-associated favorable outcome. In an attempt to delineate the effect of membrane permeability, we performed a randomized, crossover study to compare the inflammatory biomarkers, lipid profile, and aortic pulse wave velocity (PWV) of two dialyzers that are composed of identical membranes but with different flux characteristics.

Stable patients who had anuria and were on low-flux polysulfone membrane were randomly allocated either to HD with high-flux polyamide membrane (group A; 22 patients) or to HD with low-flux polyamide membrane (group B; 24 patients) for 24 weeks, then they were started on 24 weeks of the alternative HD treatment. Apart from the dialyzer, the dialysis prescription remained unchanged.

Nineteen patients from group A and 23 patients from group B completed the study. Predialysis beta(2)-microglobulin levels decreased significantly when using the high-flux polyamide membrane. No difference between membranes was observed for serum albumin, high-sensitivity C-reactive protein, fibrinogen, IL-6, triglycerides, HDL cholesterol, LDL cholesterol, and lipoprotein(a) during the study. A significant increase in aortic PWV, a marker of aortic stiffness, was noted after patients switched from high-flux to low-flux polyamide membranes. Similarly, the rate of change in aortic PWV was significantly decreased with the use of the high-flux polyamide membrane.

Our findings suggest that dialysis with polyamide membranes with different flux characteristics did not modify the inflammatory indices and lipid profile in stable HD patients; however, a seemingly beneficial effect on aortic stiffness was noted for patients who were maintained on high-flux polyamide membrane.

Middle molecules can be defined as compounds with a molecular weight (MW) above 500 Da. An even broader definition includes those molecules that do not cross the membranes of standard low-flux dialyzers, not only because of molecular weight, but also because of protein binding and/or multicompartmental behavior. Recently, several of these middle molecules have been linked to the increased tendency of uremic patients to develop inflammation, malnutrition, and atheromatosis. Other toxic actions can also be attributed to the middle molecules. In the present publication we will consider whether improved removal of middle molecules by large pore membranes has an impact on clinical conditions related to the uremic syndrome. The clinical benefits of large pore membranes are reduction of uremia-related amyloidosis; maintenance of residual renal function; and reduction of inflammation, malnutrition, anemia, dyslipidemia, and mortality. It is concluded that middle molecules play a role in uremic toxicity and especially in the processes related to inflammation, atherogenesis, and malnutrition. Their removal seems to be related to a better outcome, although better biocompatibility of membranes might be a confounding factor.

Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo.

Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test.

Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group (n = 22 [11 pairs]; mean difference 0.63). Interim analysis at 4 wk also showed no significant difference between mesna and placebo (n = 32 [16 pairs]; placebo 26.3 micromol/L, mesna 24.5 micromol/L; mean difference 1.88). Multivariable adjustments for baseline characteristics did not alter the analysis. Plasma mesna seemed to reach steady-state concentrations by 4 wk.

It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.

There is debate on the influence of haemodialysis (HD) on lipoprotein(a).

Lp(a), apo A, apo B and high-sensitivity C-reactive protein (hs-CRP) were measured in 46 patients pre- and post-HD.

The median Lp(a) concentration significantly decreased post-HD (106 vs. 145 mg/L, p<0.001). No significant variations were observed for apo A, apo B and hs-CRP. Comparable results were observed with high- and low-flux membranes.

HD is effective in lowering Lp(a).

Plasma total homocysteine (tHcy) level is an independent risk factor for the development of atherosclerosis. The degree of risk in most of the population is decreased by using dietary vitamin supplementation; however, more than 90% of patients with end-stage renal disease have increased tHcy levels despite supplementation. Only a small fraction of tHcy is removed by hemodialysis because of extensive disulfide bonding to albumin. The objective of this study is to determine whether a single intravenous dose of mesna, a thiol-containing drug analogue of taurine, facilitates tHcy clearance during hemodialysis.

Initial in vitro thiol exchange tests were performed with mesna in plasma from dialysis patients. Mesna, 300 micromol/L (49.2 mg/L), was incubated with plasma at 37 degrees C, and free homocysteine was measured at various times. In vivo, mesna activity was tested in 10 hemodialysis patients by administering 2.5 or 5.0 mg/kg of mesna intravenously at the beginning of a treatment cycle. Blood samples were drawn throughout dialysis, and plasma tHcy levels were compared with those obtained from a previous dialysis session in which mesna was not administered.

In vitro, mesna liberated 36.5% +/- 2.5% of protein-bound homocysteine in 30 minutes. In vivo, a single 2.5-mg/kg dose of mesna was ineffective; however, at 5.0 mg/kg, it caused a 55.2% +/- 3.9% decrease in plasma tHcy levels postdialysis compared with a 34.2% +/- 5.3% decrease with dialysis alone (P < 0.001).

Intravenous mesna causes a rapid decrease in plasma tHcy levels during hemodialysis.

The management of lipid abnormalities in patients with end-stage renal disease (ESRD) remains controversial. Large, well-designed studies investigating the effects of dyslipidemia on cardiovascular (CV) morbidity and mortality and the role of cholesterol lowering drugs in reducing mortality in ESRD patients are lacking. While it seems reasonable to suspect that dyslipidemia and its treatment in ESRD patients will affect CV morbidity and mortality similar to that in the general population, recent studies have suggested that this may not be the case. Furthermore, the pharmacokinetics of lipid lowering drugs are altered in patients with ESRD and must be considered when treating this group of patients. This article reviews the major classes of drugs used to treat dyslipidemia, emphasizing their role in patients with ESRD.

Hemodialysis patients suffer from a high incidence of cardiovascular disease. Among the many predisposing factors, such as high blood pressure, dyslipidemia, and fluid overload, the accumulation of high molecular weight uremic toxins, the so-called middle molecules, may play an important role. Since convective therapies such as online hemodiafiltration have a better clearance profile for these compounds than standard hemodialysis, it has been suggested that these dialysis strategies may reduce cardiovascular morbidity and mortality. As reliable data on these issues are not available, the Dutch Convective Transport Study (CONTRAST) was recently initiated. This prospective randomized trial was designed to compare online hemodiafiltration with low-flux hemodialysis with respect to cardiovascular morbidity and mortality.

Recent studies give contradictory data regarding the role of hyperhomocysteinemia (hyperHcy) in cardiovascular (CV) morbidity and mortality in hemodialysis (HD) patients. The aims of the present study were to detect the most powerful variables associated with hyperHcy as well as to evaluate the relationship between hyperHcy and CV morbidity and mortality. The prospective follow-up study of 113 patients (52 males, aged 55.2+/-13.1 years) maintained by HD for 81.9+/-56.9 months at our Institute was carried out over 55 months. Fifty-seven (50.4%) of the examined patients were supplemented with water-soluble vitamins including folic acid and vitamin B complex pills or ampoules. Total serum Hcy level was determined by high-performance liquid chromatography, while serum folic acid and vitamin B(12) were measured by radioimmunoassay. The multivariate analysis showed HD duration (r=0.608; P=0.02) and folic acid serum level (r=-0.580; P=0.03) to be significant predictors of serum tHcy concentration. The multivariate Cox regression analysis of CV mortality revealed diabetes mellitus and heart failure as the most powerful positive predictors, while creatinine, albumin and vitamins intake therapy were negative predictors of CV mortality. Long-term supplementation with the usual doses of vitamins is followed with increased survival in hemodialysis patients. Although total serum Hcy level was not found to be a predictor of overall and CV mortality, the role of hyperHcy. as risk factor for CVD cannot be excluded in hemodialysis patients.

There are considerably fewer randomized controlled trials investigating hemodialysis (HD) than other fields of internal medicine, and no significant improvements have been observed over time. Only the National Cooperative Dialysis Study and the HEMO trial were based on hard endpoints such as morbidity and mortality, but neither considered on-line hemodiafiltration or super-flux membranes, which are thought to provide a number of advantages in terms of the cardiovascular condition of uremic patients. However, results of well-designed clinical trials showing that increasing convection may improve the clinical outcome of HD patients are still lacking. The need for maximizing removal of uremic toxins calls for more frequent HD sessions, but this may be affected by many organizational problems. Therefore, well-designed, long-term clinical trials are urgently needed to investigate which currently available therapeutic instruments can improve the clinical outcome of uremic patients.

The aim of the study was to assess plasma homocysteine concentration in peritoneal dialysis patients, and to compare the effect of different peritoneal solutions (glucose-based and icodextrin-based) on peritoneal clearance of homocysteine.

The study group comprised 10 chronic peritoneal dialysis patients; the control group comprised 15 healthy, age-matched non-obese subjects with normal renal function. Patients with vitamin B(12) or folate deficiency were excluded. In all subjects, plasma homocysteine and dialysis adequacy parameters were assessed at baseline. The clearance study was carried out with 2.27% glucose and 7.5% icodextrin solutions (12-h dwell time).

Mean dialysate concentration of homocysteine was similar for both glucose and icodextrin solutions (8.3 +/- 3.2 and 8.4 +/- 1.9 micromol/L, respectively), but homocysteine clearance was significantly higher for icodextrin than glucose solution (1.82 +/- 0.57 vs 1.39 +/- 0.53 mL/min per 1.73 m(2)P = 0.01). Net ultrafiltration after icodextrin solution was also higher than after glucose solution (599 +/- 136 mL vs 134 +/- 337 mL, P < 0.01). A correlation between total plasma level of homocysteine and its peritoneal clearance was found (r = 0.69; P = 0.03).

It appears that peritoneal elimination of homocysteine depends primarily on its plasma concentration. Icodextrin-based solution for peritoneal dialysis seems to be more efficient in homocysteine elimination than a standard glucose-based solution.

Cardiovascular disease is the major cause of death in the end-stage renal disease population. Novel risk factors such as homocysteine (Hcy) are of considerable interest in this group as hyperhomocysteinaemia is highly prevalent in the setting of renal impairment. Folic acid-vitamin B group therapies are only partially effective treatments. Hcy is highly protein-bound and thus poorly dialysed. Dialyzers with albumin-leaking properties have been shown to result in lowering of plasma Hcy. As the FX-class (Advanced Fresenius Polysulfone dialyzer) has greater clearance of larger molecular weight substances but is non-albumin-leaking, we explored the capacity of this new technology membrane to reduce plasma Hcy levels.

A prospective randomized cross-over trial in 35 prevalent haemodialysis patients, one group receiving 12 weeks dialysis using FX dialyzer then 12 weeks with standard high flux dialysis (SHF) and the other group SHF followed by FX dialyzer. All patients received vitamin B(6) 25 mg and folic acid 5 mg daily throughout the study.

The primary outcome was plasma Hcy pre-dialysis at week 12. FX vs SHF showed no significant difference, 25+/-6.6 vs 25.9+/-5.8 microg/l, Delta95% CI = -2.77 to 4.59, P = 0.31. There was a non-significant trend toward a decrease in Hcy in both groups (27.43+/-7.68 to 25.91+/-5.78 micromol/l for SHF, P = 0.23 and 26.0+/-4.58 to 25.0+/-6.61 micromol/l for FX, P = 0.28). Analysis by repeated measures method demonstrated a statistically significantly lower Hcy with FX vs SHF dialyzer (adjusted beta = -1.30, 95% CI = -2.41 to -0.19, P = 0.022). K(t)/V(urea) was higher in FX vs SHF (1.35+/-0.18 vs 1.22+/-0.2; P = 0.013). Folate and B(6) levels did not change.

The primary outcome analysis did not show any significant difference in pre-Hcy comparing FX and SHF membranes. Although our secondary analysis demonstrated a statistically significant difference between membranes, the magnitude of the difference (1.3 mumol/l) is not clinically significant. Thus the use of the FX dialyzer did not result in a clinically significant benefit in relation to improving pre-dialysis Hcy compared with standard high-flux dialysis.

This review summarizes our current understanding of the role of folate in the treatment of hyperhomocysteindemia and the prevention of cardiovascular disease in patients with chronic kidney disease and end stage renal disease. Relevant papers published between 2003 and 2004 are referenced.

With the exception of one paper, recent therapeutic studies supported previous findings that folate therapy achieves only a modest reduction in plasma homocysteine and seldom normalizes homocysteine. Large prospective studies are under way to evaluate the causal relationship between homocysteine and cardiovascular risk. Recent work supports earlier data that suggested that homocysteine inflicts its damage by oxidative stress. A newly described consequence of hyperhomocysteindemia is DNA hypomethylation and alteration of gene expression. A recent study in the general population suggested that while folate may lower homocysteine it does not improve endothelial function in individuals without cardiovascular disease.

The causes of hyperhomocysteindemia in renal failure remain obscure. The possibilities include impairment of both renal and extrarenal metabolic pathways by uraemia. Hyperhomocysteindemia is associated in some but not all studies with an increased risk for cardiovascular disease. A low homocysteine may reflect malnutrition and predict a poor outcome. Folate achieves modest reductions of homocysteine in some but not all studies. There are no data to support therapy with very high-dose folic acid. Hyperhomocysteindemia impairs endothelial function which is not adequately reversed by folate.

Hemodiafiltration (HFR) with on-line regeneration of the ultrafiltrate, a technique of hemodiafiltration in which the ultrafiltrate passes through a cartridge containing uncoated charcoal, has been shown to be safe, simple, and well tolerated and has been claimed to improve nutritional status or to prevent its deterioration while decreasing the inflammatory response via a reduced production of proinflammatory cytokines. The purpose of the present prospective study was to ascertain whether HRF improves the nutritional status, reduces microinflammation, and decreases serum beta2-microglobulin levels in patients with end-stage renal disease (ESRD).

Eight patients, four males and four females, with a mean age of 49.4 +/- 16.8 years, stable on hemodialysis over a period of 8.7 +/- 6.1 years and on standard 4-4.5 h three-times-a-week bicarbonate hemodialysis, were switched to three-times-a-week, 4-h HFR. At baseline and every two months for 12 months at mid-week, serum levels of urea, creatinine, albumin, total cholesterol, C-reactive protein, fibrinogen, complement, ferritin, beta2-microglobulin, intact parathyroid hormone (PTH), hemoglobin concentrations, and hematocrit and the EPO weekly dose were determined. At baseline and at the end of the study, the Malnutrition Inflammatory Score (MIS) was calculated.

Nutritional and inflammatory parameters remained constant during the 12-month period of the study. After 12 months of HFR, the MIS trended to be lower, but the difference was not statistically significant. Serum beta2-microglobulin and PTH levels remained constant during all time intervals. Neither hematocrit nor hemoglobin changed over the course of the study as well as the weekly EPO dose.

The change from bicarbonate hemodialysis to HFR was safe and well tolerated but was not associated with an improvement of nutritional and inflammatory parameters or a reduction of serum beta2-microglobulin levels.

Elevated concentration of plasma homocysteine (tHcy) is common in renal patients, however, the reason behind the resistance to vitamin B(12) and folate therapy are poorly understood.

We investigated vitamin B12 uptake by mononuclear cells (MC) from predialysis patients (n = 19) as compared to healthy controls (n = 15). Serum levels of tHcy, methylmalonic acid and cystathionine, holotranscobalamin (holoTC), total vitamin B12 and folate were also measured.

The uptake of vitamin B12 by MC from renal patients was lower than that by MC from controls (9.3 vs. 12.5 pg/3 x 10(6) cells; p = 0.001). Nonetheless, the receptor-binding capacity was comparable between patients and controls (6.1 vs. 6.5 pg/3 x 10(6) cells; p = 0.627). Average reduction of vitamin B12 uptake in patients as compared to the controls was 18.1%.

Our results show that vitamin B12 uptake is impaired in MC from renal patients, with no evidence that the surface receptor is down-regulated. High serum concentrations of holoTC are common in renal patients and might be related to a generalized resistance to this vitamin. Serum concentrations of vitamin B12 within the reference range are not likely to ensure vitamin delivery into the cells. Supraphysiological doses of vitamin B12 may be necessary to deliver a sufficient amount of the vitamins to the cells via mechanisms largely independent of holoTC receptor.

HFR-ON LINE (double chamber HDF with reinfusion of ultrafiltrate regenerated through a charcoal-resin cartridge) is a novel method which combines the processes of diffusion, convection, and adsorbance. We have investigated the effect of such a treatment on the homocysteine (Hcy) levels in ten patients with a mean Hcy level of 57.6 micromol/L (range 24.1-119.7 micromol/L). We have measured the Hcy, folate, and vitamin B12 predialysis and postdialysis, and in the ultrafiltrate precartridge and postcartridge at 10, 120, and 240 min. The mean Hcy levels were 57.6 and 35.3 micromol/L (range 9.9-80.3 micromol/L) (P = 0.005) predialysis and postdialysis, respectively, while folate and vitamin B12 were unchanged. Precartridge and postcartridge Hcy levels were 11.6 vs. 2.5 micromol/L (P = 0.005), 9.3 vs. 3.9 micromol/L (P = 0.005), and 7.7 vs. 4.6 micro mol/L (P = 0.012) at the three time points considered, while folate and vitamin B12 were essentially undetectable. These preliminary data, which need confirmation in a long-term study, seem to indicate that HFR-ON LINE is able to reduce Hcy levels not only through a likely reduction of uremic toxins, but also through an actual removal of Hcy by adsorbance onto the charcoal-resin cartridge.

Dyslipidaemia, inflammation and oxidative stress are prominent risk factors that potentially cause vascular disease in haemodialysis patients. Dialysis modalities affect uraemic dyslipidaemia, possibly by modifying oxidative stress, but the effects of dialyser flux and membrane material on atherogenic remnant particles and oxidized low-density lipoproteins (LDL) are unknown.

We performed a randomized crossover study in 36 patients on haemodialysis to analyse the effect of dialyser flux and membrane material on plasma lipids, apolipoproteins and markers of inflammation and oxidative stress. Stable patients on low-flux dialysis with polysulphone for >/=6 weeks were assigned to high-flux polysulphone or high-flux modified cellulose with similar dialyser surface area and permeability characteristics and crossed over twice every 6 weeks.

Thirty patients completed the study per protocol. Treatments with high-flux polysulphone and modified cellulose lowered serum triglyceride (by 20% and 10%, respectively; P<0.05) and remnant-like particle cholesterol by 32% (P<0.001) and 11% (NS) after the first 6 weeks of treatment. Oxidized LDL decreased significantly with high-flux polysulphone, but not with modified cellulose. Apolipoproteins CII and CIII were reduced, whereas the ratio CII/CIII was increased (all P<0.05). Acute-phase proteins and LDL and high-density lipoprotein cholesterol remained unaffected.

This randomized crossover study demonstrates a potent effect of high-flux haemodialysis on uraemic dyslipidaemia. Polysulphone membrane material showed superiority on oxidatively modified LDL, an indicator of oxidative stress in haemodialysis patients.

The uremic syndrome is a mix of clinical features resulting from multiple organ dysfunctions which develop when kidney failure progresses, and is attributed to the retention of solutes, which under normal conditions are excreted by the healthy kidneys into the urine. The most practical classification of uremic solutes is based on their physicochemical characteristics that influence their dialytic removal, in (1) small water soluble compounds, (2) the larger "middle molecules," and (3) the protein bound compounds. Hence, uremic retention is much more complex than originally believed. Among the small water soluble compounds, urea exerts not much toxic activity and is not very representative in its kinetic behavior for many other uremic solutes. Among the middle molecules, many have been recognized to exert biological activity and hence to contribute to the uremic syndrome. Specific dialysis strategies apply large pore membranes to remove those middle molecules and have a beneficial impact on uremic morbidity and mortality. A substantial number of uremic solutes are protein bound. Only recently, a relation between their concentration and clinical status could be demonstrated. Likewise, it was only recently possible to demonstrate more than standard removal with super-flux dialysis membranes. To further improve characterization of uremic solutes and to develop directed therapeutic approaches, further concerted action among various groups of researchers will be needed.

Hyperhomocysteinaemia is a putative risk factor for atherothrombotic cardiovascular disease in the haemodialysis population. High-dose vitamin B therapy does not entirely normalize elevated plasma total homocysteine (tHcy) levels in haemodialysis patients. Alternative therapies to reduce tHcy further are therefore required. Modifications of the dialysis regimen may result in a better removal of Hcy. We examined the effect of dialyser membrane pore size on tHcy levels in vitamin-replete chronic haemodialysis patients.

Forty-five haemodialysis patients were dialysed during 4 weeks with a low-flux, a high-flux and a super-flux membrane, in random order. Pre-dialysis tHcy was determined at baseline and every 4 weeks. In 18 patients, plasma tHcy before and after dialysis and dialysate tHcy concentrations were measured.

Pre-dialysis tHcy decreased significantly during 4 weeks super-flux dialysis (-14.6 +/- 2.8%), whereas it remained stable during high-flux (+0.5 +/- 2.4%) and low-flux dialysis (+1.7 +/- 3.2%). The homocysteine reduction ratio was not different for the three membranes: 0.39 +/- 0.03 for the super-flux, 0.47 +/- 0.02 for the high-flux and 0.39 +/- 0.02 for the low-flux dialyser. The amount of Hcy recovered in the dialysate during a single dialysis session was also similar: 117.5 +/- 3.6 micro mol during super-flux, 95.3 +/- 11.5 micro mol during high-flux and 116.5 +/- 11.6 micro mol during low-flux dialysis.

Super-flux dialysis significantly lowers tHcy in chronic haemodialysis patients. Improved removal of middle-molecule uraemic toxins with inhibitory effects on Hcy-metabolizing enzymes, rather than better dialytic clearance of Hcy itself, may explain the beneficial effect of the super-flux membrane.

Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease in end-stage renal disease (ESRD) patients. Since homocysteine (Hcy) largely binds to serum proteins (80 to 90%), in this study we investigated the possibility that polymethylmethacrylate (PMMA)-based protein-leaking dialyzers could reduce total plasma Hcy (tHcy) levels in ESRD patients.

Two matched groups of patients (N = 13) showing mild to intermediate hyperhomocysteinemia on standard hemodialysis (HD) with conventional non-protein-leaking dialyzers were included. In the control group membranes were maintained the same, while the study group was switched to protein-leaking dialyzers (BK-F series; Toray, Japan) and studied for 6 months. tHcy was measured by high performance liquid chromatography (HPLC) at baseline and after 1, 3, and 6 months. Proteins and Hcy were also measured in the spent dialysate.

The pre-HD levels of tHcy in the control group remained close to baseline values (26.6 +/- 5.0 micromol/L), while in the study group at 1, 3, and 6 months they decreased from a baseline value (in micrormol/L) of 25.3 +/- 5.9 to 21.5 +/- 4.5, 16.9 +/- 4.0, and 17.2 +/- 4.2, respectively (P < 0.01 for values at 3 and 6 months vs. baseline). The intra-HD drop of tHcy (Delta HDHcy) slightly but progressively decreased during the 3 steps on protein-leaking dialyzers and a positive correlation was found between Delta HDHcy and pre-HD levels of tHcy. In spent dialysate samples from protein-leaking dialyzer-treated patients, the amount of protein-bound Hcy (bHcy) was approximately 10 times higher than in non-protein-leaking dialyzers, but the Delta HDHcy observed in non-protein-leaking dialyzers and protein-leaking dialyzers was comparable. Serum proteins and albumin were only slightly affected by protein-leaking dialyzers.

This study demonstrates that protein-leaking dialyzers used with a pure diffusive technique significantly lower pre-HD tHcy (approximately 33% of starting levels after 3 months of treatment) in ESRD patients. A possible underlying mechanism for this effect could be the removal of large molecular weight solutes responsible for a defective metabolism of the Hcy, as the removal of bHcy with protein-leaking dialyzers seems not sufficient, per se, to explain this steady reduction of tHcy levels in pre-HD.

Progressive renal failure is accompanied by dyslipidemia, which is reflected in an abnormal apolipoprotein profile. It is characterized by increased concentrations of intact and partially metabolized triglyceride-rich apoB-containing lipoproteins. They occur preferentially in very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL) as a result of impaired metabolism and clearance. Hemodialysis can moderately attenuate the renal dyslipidemia. In contrast, peritoneal dialysis is associated with further aggravation, including an increase of cholesterol-rich apoB-containing lipoproteins.

Recently published evidence suggests that, either than folate therapy, the enhancement of homocysteine remethylation in tissues by correcting the multiple abnormalities of the remethylation pathway in chronic renal failure that extend beyond folate-related disturbances, or else the improved removal of uremic toxins and/or Hcy through intensified dialysis procedures may represent two strategies to normalize total homocysteine in uremic patients.

Mild to moderate hyperhomocysteinemia is very common among patients undergoing haemodialysis. There is sufficient evidence that hyperhomocysteinemia is an independent risk factor for cardiovascular and or atheromatous disease in end stage renal failure patients. Vitamin supplementation such as vitamin B6, B12 or folate has been proposed to correct this metabolic disturbance and it is to be proved if this intervention benefit these patients, but there is no agreement whether oral folate supplementation is capable to normalize homocysteine levels in end stage renal failure patients.

In 53 patients, undergoing haemodialysis, homocysteine levels (Hcy), folate, vitamin B12, ferritin and C-reactive protein (CRP) were estimated before and after dialysis, without folate supplementation. Thirty voluntary blood donors were used as controls to compare homocysteine levels. After four weeks of oral folate supplementation (10 mg/24 hours) the levels of homocysteine, serum folate and intra-erythrocyte folate were estimated again. Eighteen months later the survival rate of our patients was recorded and analyzed in relation to Hcy and CRP levels.

The results showed that haemodialysis patients exhibited, almost, fourfold higher homocysteine levels than controls (27.39 +/- 11.54 vs 7.38 +/- 3.5, t = -8.2, p = 0.000000). Folate levels, vitamin B12 and CRP increase significantly after haemodialysis where as homocysteine levels decrease (Hcy1 vs. Hcy2: z = 2.08, p = 0.03). Fourteen (14) patients suffered from coronary heart disease (CHD) and they exhibited the higher levels of homocysteine (Hcy1 vs. CHD: z = -3.4, p = 0.0006). All estimations performed revealed a negative correlation between homocysteine levels and plasma or intra-erythrocyte folate. No other variable exhibited any significant influence upon homocysteine levels. After folate supplementation homocysteine levels in the whole number of patients were unchanged (Hcy(before) vs. Hcy(after): 27.39 +/- 11.54 vs. 26.95 +/- 8.22, z = 0.3, p = 0.7, NS). When patients with homocysteine levels higher than 24 micromol/L were selected, a significant decrease was observed (34.77 +/- 9.32 vs. 30.0 +/- 8.05, z = 2.09, p = 0.02). Forty-two patients were treated with erythropoietin for their anemia and we found a positive correlation between C-reactive protein levels and rhu-Epo dose (CRP vs. Epo: r = 0.45, p = 0.002). Homocysteine levels did not exhibit any significant influence upon short-term survival (U = -0.37, p = 0.3, NS) where as CRP levels exhibit a significant influence upon short-term survival (U = 2.15, p = 0.005).

Homocysteine levels in haemodialysis patients are fourfold higher than healthy controls. Folate, vitamin B12 and CRP increases significantly after dialysis. Patients with coronary heart disease exhibit the highest levels of homocysteine. The homocysteine levels are inversely related with the folate levels. The exogenous folate supplementation increase the serum folate levels but decreases homocysteine only in patients with higher than mild hyperhomocysteinemia. Hcy doesn't exert any significant effect upon the short-term survival of the haemodialysis patients but CRP level is a god predictor of the short-term survival of these patients.