The membrane perspective of uraemic toxins: which ones should, or can, be removed?

Informed decision-making is paramount to the improvement of dialysis therapies and patient outcomes. A cornerstone of delivery of optimal dialysis therapy is to delineate which substances (uraemic retention solutes or 'uraemic toxins') contribute to the condition of uraemia in terms of deleterious biochemical effects they may exert. Thereafter, decisions can be made as to which of the accumulated compounds need to be targeted for removal and by which strategies. For haemodialysis (HD), the non-selectivity of membranes is sometimes considered a limitation. Yet, considering that dozens of substances with potential toxicity need to be eliminated, and targeting removal of individual toxins explicitly is not recommended, current dialysis membranes enable elimination of several molecules of a broad size range within a single therapy session. However, because HD solute removal is based on size-exclusion principles, i.e. the size of the substances to be removed relative to the mean size of the 'pores' of the membrane, only a limited degree of selectivity of removal is possible. Removal of unwanted substances during HD needs to be weighed against the unavoidable loss of substances that are recognized to be necessary for bodily functions and physiology. In striving to improve the efficiency of HD by increasing the porosity of membranes, there is a greater potential for the loss of substances that are of benefit. Based on this elementary trade-off and availability of recent guidance on the relative toxicity of substances retained in uraemia, we propose a new evidence-linked uraemic toxin elimination (ELUTE) approach whereby only those clusters of substances for which there is a sufficient body of evidence linking them to deleterious biological effects need to be targeted for removal. Our approach involves correlating the physical properties of retention solutes (deemed to express toxicity) with key determinants of membranes and separation processes. Our analysis revealed that in attempting to remove the relatively small number of 'larger' substances graded as having only moderate toxicity, uncontrolled (and efficient) removal of several useful compounds would take place simultaneously and may compromise the well-being or outcomes of patients. The bulk of the uraemic toxin load comprises uraemic toxins below <30 000 Da and are adequately removed by standard membranes. Further, removal of a few difficult-to-remove-by-dialysis (protein-bound) compounds that express toxicity cannot be achieved by manipulation of pore size alone. The trade-off between the benefits of effective removal of the bulk of the uraemic toxin load and risks (increased loss of useful substances) associated with targeting the removal of a few larger substances in 'high-efficiency' HD treatment strategies needs to be recognized and better understood. The removability during HD of substances, be they toxic, inert or beneficial, needs be revised to establish the pros and cons of current dialytic elimination strategies. .

Blood-incompatibility in haemodialysis: alleviating inflammation and effects of coagulation.

Blood-incompatibility is an inevitability of all blood-contacting device applications and therapies, including haemodialysis (HD). Blood leaving the environment of blood vessels and the protection of the endothelium is confronted with several stimuli of the extracorporeal circuit (ECC), triggering the activation of blood cells and various biochemical pathways of plasma. Prevention of blood coagulation, a major obstacle that needed to be overcome to make HD possible, remains an issue to contend with. While anticoagulation (mainly with heparin) successfully prevents clotting within the ECC to allow removal of uraemic toxins across the dialysis membrane wall, it is far from ideal, triggering heparin-induced thrombocytopenia in some instances. Soluble fibrin can form even in the presence of heparin and depending on the constitution of the patient and activation of platelets, could result in physical clots within the ECC (e.g. bubble trap chamber) and, together with other plasma and coagulation proteins, result in increased adsorption of proteins on the membrane surface. The buildup of this secondary membrane layer impairs the transport properties of the membrane to reduce the clearance of uraemic toxins. Activation of complement system-dependent immune response pathways leads to leukopenia, formation of platelet-neutrophil complexes and expression of tissue factor contributing to thrombotic processes and a procoagulant state, respectively. Complement activation also promotes recruitment and activation of leukocytes resulting in oxidative burst and release of pro-inflammatory cytokines and chemokines, thereby worsening the elevated underlying inflammation and oxidative stress condition of chronic kidney disease patients. Restricting all forms of blood-incompatibility, including potential contamination of dialysis fluid with endotoxins leading to inflammation, during HD therapies is thus still a major target towards more blood-compatible and safer dialysis to improve patient outcomes. We describe the mechanisms of various activation pathways during the interaction between blood and components of the ECC and describe approaches to mitigate the effects of these adverse interactions. The opportunities to develop improved dialysis membranes as well as implementation strategies with less potential for undesired biological reactions are discussed.

Phosphates in medications: Impact on dialysis patients
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Maintaining phosphorus balance in in-center hemodialysis (ICHD) patients is problematic despite recommended dietary restriction, dialysis, and phosphate binder use. Rarely is P content in prescribed medications considered, but this source should raise concern. Data was obtained from the Fresenius Kidney Care (FKC) electronic data warehouse Knowledge Center and MedReview-eRx accessed Surescripts, housing > 80% of US-filled prescriptions. Adult FKC ICHD patients prescribed ≥ 1 medication in the MedReview-eRx database were analyzed (695,759 prescriptions). Information collected included medication dose, dose unit, dose timing, strength, start and stop dates, refills, demographic information, admission history, and modality type. Numbers of patients, prescriptions by individual medication, and drug class were then analyzed. Medications prescribed > 100 times were reported. Median doses/day (number of tablets) were calculated for each medication (open order on randomly selected day). Phosphate content of medications taken in FKC clinics was assessed using routinely used pharmacology references, and potential resulting phosphate and pill burden were also calculated. The top five prescribed drug classes in FKC dialysis patients were calcium-channel blockers (22%), proton pump inhibitors (PPIs; 18%), acetaminophen-opioid (AO; 13%), angiotensin-converting enzyme inhibitors (ACEi; 10%), and α2-agonists (9%). The maximum phosphate added for different medications varied by manufacturer. For instance, at median daily doses, phosphate contributions from the top five medications prescribed were 112 mg for amlodipine, 116.2 mg from lisinopril, 6.7 mg from clonidine, 0 mg from acetaminophen, and 200 mg for omeprazole. Prescribing these together could increase the daily phosphate load by 428 mg, forcing the patient to exceed the recommended daily intake (RDI) with food and drink. Phosphate content in medications prescribed to HD patients can substantially contribute to the daily phosphate load and, in combination, may even exceed the daily recommended dietary phosphate intake. Healthcare providers should monitor all medications containing phosphate prescribed in order to minimize risk of uncontrolled hyperphosphatemia and poor adherence.
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Residual Renal Function and Effect of Low-Sodium Solution on Blood Pressure in Peritoneal Dialysis Patients.

Background:Residual renal function (RRF) affects sodium and fluid balance. The aim of this analysis was to examine the impact of RRF on the effect of a sodium-reduced peritoneal dialysis fluid (PDF) on blood pressure (BP).Methods:This is a post-hoc analysis of a prospective, randomized, controlled double-blind clinical trial with 82 patients on continuous ambulatory PD (CAPD) treated with a low-sodium (125 mmol/L Na) or a standard-sodium (134 mmol/L Na) PDF. Subgroups according to glomerular filtration rate (GFR) at baseline (≤ / > 6 mL/min/1.73 m2) were analyzed for BP and antihypertensive medication.Results:In the low-GFR group on low-sodium PDF (N = 26), systolic BP was reduced from 152 ± 24 mmHg at baseline to 137 ± 21 mmHg at week 12, diastolic BP from 90 ± 16 mmHg to 83 ± 11 mmHg. In the low-GFR group on standard-sodium PDF and in the high-GFR group on both PDF types, only minor changes were observed. For the low-GFR subgroup, the confounder-adjusted mean study group difference in systolic BP at week 12 between low-sodium and standard-sodium PDF was -16.9 (95% confidence interval [CI] -27.2 to -6.6) mmHg, for diastolic BP, it was -7.0 (95% CI -12.6 to -1.4) mmHg. In both GFR subgroups, more patients had a reduced daily dose of antihypertensive medication and fewer patients an increased daily dose in the low-sodium compared with the standard-sodium group at week 12.Conclusions:The reduction of BP with a sodium-reduced PDF seems to be more effective in patients with no or low RRF than in patients with residual capacity of renal sodium and fluid control.

Choosing Home Hemodialysis: A Critical Review of Patient Outcomes.

BACKGROUND/AIM: Home hemodialysis (HHD) has been associated with improved clinical outcomes vs. in-center HD (ICHD). The prevalence of HHD in the United States is still very low at 1.8%. This critical review compares HHD and ICHD outcomes for survival, hospitalization, cardiovascular (CV), nutrition, and quality of life (QoL). METHODS: Of 545 publications identified, 44 were not selected after applying exclusion criteria. A systematic review of the identified publications was conducted to compare HHD to ICHD outcomes for survival, hospitalization, CV outcomes, nutrition, and QoL. RESULTS: Regarding mortality, 10 of 13 trials reported 13-52% reduction; three trials found no differences. According to 6 studies, blood pressure and left ventricular size measurements were generally lower in HHD patients compared to similar measurements in ICHD patients. Regarding nutritional status, conflicting results were reported (8 studies); some found improved muscle mass, total protein, and body mass index in HHD vs. ICHD patients, while others found no significant differences. There were no significant differences in the rate of hospitalization between HHD and ICHD in the 6 articles reviewed. Seven studies on QoL demonstrated positive trends in HHD vs. ICHD populations. CONCLUSIONS: Despite limitations in the current data, 66% of the publications reviewed (29/44) demonstrated improved clinical outcomes in patients who chose HHD. These include improved survival, CV, nutritional, and QoL parameters. Even though HHD may not be preferred in all patients, a review of the literature suggests that HHD should be provided as a modality choice for substantially more than the current 1.8% of HHD patients in the United States.

Low-Sodium Versus Standard-Sodium Peritoneal Dialysis Solution in Hypertensive Patients: A Randomized Controlled Trial.

BACKGROUND: Peritoneal dialysis (PD) solutions with reduced sodium content may have advantages for hypertensive patients; however, they have lower osmolarity and solvent drag, so the achieved Kt/Vurea may be lower. Furthermore, the increased transperitoneal membrane sodium gradient can influence sodium balance with consequences for blood pressure (BP) control. STUDY DESIGN: Prospective, randomized, double-blind clinical trial to prove the noninferiority of total weekly Kt/Vurea with low-sodium versus standard-sodium PD solution, with the lower confidence limit above the clinically accepted difference of -0.5. SETTING & PARTICIPANTS: Hypertensive patients (≥ 1 antihypertensive drug, including diuretics, or office systolic BP ≥ 130 mmHg) on continuous ambulatory PD therapy from 17 sites. INTERVENTION: 108 patients were randomly assigned (1:1) to 6-month treatments with either low-sodium (125 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 338-491 mOsm/L) or standard-sodium (134 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 356-509 mOsm/L) PD solution. OUTCOMES: Primary end point: weekly total Kt/Vurea; secondary outcomes: BP control, safety, and tolerability. MEASUREMENTS: Total Kt/Vurea was determined from 24-hour dialysate and urine collection; BP, by office measurement. RESULTS: Total Kt/Vurea after 12 weeks was 2.53 ± 0.89 in the low-sodium group (n = 40) and 2.97 ± 1.58 in the control group (n = 42). The noninferiority of total Kt/Vurea could not be confirmed. There was no difference for peritoneal Kt/Vurea (1.70 ± 0.38 with low sodium, 1.77 ± 0.44 with standard sodium), but there was a difference in renal Kt/Vurea (0.83 ± 0.80 with low sodium, 1.20 ± 1.54 with standard sodium). Mean daily sodium removal with dialysate at week 12 was 1.188 g higher in the low-sodium group (P < 0.001). BP changed marginally with standard-sodium solution, but decreased with low-sodium PD solution, resulting in less antihypertensive medication. LIMITATIONS: Broader variability of study population than anticipated, particularly regarding residual kidney function. CONCLUSIONS: The noninferiority of the low-sodium PD solution for total Kt/Vurea could not be proved; however, it showed beneficial clinical effects on sodium removal and BP.

Home hemodialysis dose: balancing patient needs and preferences.

BACKGROUND: The aim in defining the dose of HHD is to provide sufficient dialysis required to possibly 'normalize' all abnormalities associated with renal failure in order improve patient survival and quality of life. Much progress has been made in defining the dose required to accomplish this goal, but the evidence is still far from robust. The main limitations are incomplete understanding of uremic toxins, their relative importance in causing uremic symptoms, and our inability to comprehensively assess dry weight. SUMMARY: This review provides guidance on realistic dosing of dialysis for the HHD patient based on the available evidence, where available, and alternative regimens that suit the individual's lifestyle and preferences. KEY MESSAGES: HHD can easily accommodate alternative, intensive HD prescriptions, including daily and nocturnal HD. HHD provides prescription flexibility to fulfill patient needs while taking their preferences into account.

The importance of residual renal function in peritoneal dialysis patients.

Increased peritoneal clearance can compensate for reductions in renal solute removal in patients receiving peritoneal dialysis (PD); however there is abundant evidence to suggest that renal rather than peritoneal clearance contributes to clinical outcomes. We review the evidence investigating the impact of residual renal function (RRF) and peritoneal solute clearances on survival and quality of life in PD patients. We also provide a comparison of the relative contribution of RRF and peritoneal clearance to patient survival. In addition, mechanisms of survival benefit in patients with preserved renal function, factors contributing to RRF decline, and interventions that may limit the progressive loss of RRF are discussed.

Frequent hemodialysis: a critical review.

Conventional, thrice-weekly hemodialysis (CHD) is the most commonly prescribed dialysis regimen. Despite widespread acceptance of CHD, long-term analyses of registry data have revealed an increased risk for mortality during the long 2-day interdialytic interval of thrice-weekly therapies. High mortality rates during this period suggest that there may be a role for more frequent HD in improving patient outcomes and survival through elimination of the long interdialytic period. Several regimens have been investigated including: short, daily HD, frequent nocturnal HD, and alternate-day HD. In this review, we provide an in-depth summary of current data comparing the effects of frequent and CHD modalities on survival, hospitalizations, vascular access complications, burden of therapy, quality of life, residual renal function, cardiovascular parameters, bone mineral metabolism, and anemia. Limitations of the data as well as the role of frequent dialysis in clinical practice are also discussed.

A new neutral-pH low-GDP peritoneal dialysis fluid.

BACKGROUND: Conventional peritoneal dialysis fluids (PDFs) consist of ready-to-use solutions with an acidic pH. Sterilization of these fluids is known to generate high levels of glucose degradation products (GDPs). Although several neutral-pH, low-GDP PD solutions have been developed, none are commercially available in the United States. We analyzed pH and GDPs in Delflex Neutral pH (Fresenius Medical Care North America, Waltham, MA, USA), the first neutral-pH PDF to be approved by the US Food and Drug Administration. METHODS: We evaluated whether patients (n = 26; age range: 18 - 78 years) could properly mix the Delflex Neutral pH PDF after standardized initial training. We further analyzed the concentrations of 10 different glucose degradation products in Delflex Neutral pH PDF and compared the results with similar analyses in other commercially available biocompatible PDFs. RESULTS: All pH measurements (n = 288) in the delivered Delflex Neutral pH solution consistently fell within the labeled range of 7.0 ± 0.4. Analysis of mixing errors showed no significant impact on the pH results. Delflex Neutral pH, Balance (Fresenius Medical Care, Bad Homburg, Germany), BicaVera (Fresenius Medical Care), and Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) exhibited similar low total GDP concentrations, with maximums in the 4.25% solutions of 88 µmol/L, 74 µmol/L, 74 µmol/L, and 79 µmol/L respectively; the concentration in Physioneal (Baxter Healthcare Corporation, Deerfield, IL, USA) was considerably higher at 263.26 µmol/L. The total GDP concentration in Extraneal (Baxter Healthcare Corporation) was 63 µmol/L, being thus slightly lower than the concentrations in the 4.25% glucose solutions, but higher than the concentrations in the 1.5% and 2.5% glucose solutions. CONCLUSIONS: The new Delflex Neutral pH PDF consistently delivers neutral pH with minimal GDPs.

Phosphate clearance in peritoneal dialysis: automated PD compared with continuous ambulatory PD.

Although dialytic removal of phosphate significantly contributes to the management of phosphate levels in end-stage renal disease, many patients on peritoneal dialysis (PD) still do not reach optimal phosphate control. The present review discusses the impact of PD modality--continuous ambulatory (CAPD) or automated (APD)--on phosphate removal. Relevant factors are the diffusive properties of the phosphate anion and the kinetics of phosphate distribution in various body compartments. Confounders that potentially affect comparisons of phosphate clearances in CAPD and APD are differences in residual renal function, membrane transport status, and prescribed dialysis dose. The evidence reviewed here is not strong enough to clearly determine if one modality has a clear advantage with respect to phosphate removal. In the absence of final proof the data suggest that, given the same residual renal function and dialysis dose, CAPD might be slightly more effective than APD at peritoneal phosphate clearance, especially in low transporters.

The challenges of heat sterilization of peritoneal dialysis solutions: is there an alternative?

Peritoneal dialysis (PD) solutions are currently sterilized in an autoclave using high-temperature saturated steam. Although thermal methods are an effective means of sterilization, the heating of PD solutions results in the formation of toxic glucose degradation products (GDPs). Here, we review basic concepts in the sterilization of PD solutions and discuss possible alternatives to steam sterilization, including filtration, ohmic heat, ionizing radiation, and pulsed ultraviolet light. Although the latter methods have several advantages, many also have prohibitive limitations or have not been adequately studied for use on PD solutions. Thus, in the absence of suitable alternatives, conventional heat sterilization, in combination with low-GDP manufacturing practices, remains the best option at the present time.

GDPs and AGEs: impact on cardiovascular toxicity in dialysis patients.

Glucose degradation products (GDPs) are highly reactive precursors of advanced glycation end-products (AGEs). High glucose concentrations, GDPs, and AGEs can activate specific pathways, including inflammatory and oxidative stress response pathways, which may adversely affect the cardiovascular system. This review discusses the impact and possible mechanisms of action of GDPs and AGEs with regard to cardiovascular toxicity in chronic kidney disease patients. The AGE-RAGE pathway appears to be particularly important in the pathogenesis of cardiovascular diseases in dialysis patients. In the absence of definitive proof from randomized controlled trials, mounting evidence suggests that high levels of GDPs and AGEs play a role in the pathophysiology of cardiotoxicity.

Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort.

BACKGROUND: Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far. METHODS: We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population. RESULTS: Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R² of the model = 0.57). CONCLUSIONS: The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia.

Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.

BACKGROUND: Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited. METHODS: One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. RESULTS: Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation. CONCLUSIONS: Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.

Strategies to universally improve peritonitis rates, including use of dialysis solutions with low glucose degradation products.

Despite technology advances, prevention of peritonitis remains one of the major challenges in peritoneal dialysis (PD). Several innovative developments have shown an impact on peritonitis rates. Innovative antimicrobial-coated catheter modifications have been introduced, showing promising results in vitro. Topical application of antimicrobial agents such as mupirocin to prevent exit-site infections has been successfully used. New alternative agents for topical exit-site care with reduced potential for antimicrobial resistance are under development. Flushing before fill and avoidance of spiking of solution bags have improved peritonitis rates, as have innovative connectology and double-bag systems. Automated PD seems to be superior with regard to peritonitis rates, although clinical evidence for the benefit is not always conclusive. New PD solutions with neutral pH and low concentrations of glucose degradation products (GDPs) have shown beneficial effects on cell viability and have improved peritoneal host defense. Yet despite advantageous clinical outcomes in some studies, other trials with low-GDP solutions did not show any difference in peritonitis rates. The incidence of peritonitis has markedly improved since the end of the 1980s, but the infection remains a significant complication of chronic PD. Quantifying the role of the many practices and devices in reducing complications is difficult, but their combined effect has clearly improved peritonitis outcomes.

Intact IGF-binding protein-4 and -5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions in cultured growth plate chondrocytes.

Impairment of longitudinal growth among children with chronic renal failure (CRF) may be partly attributable to the inhibition of insulin-like growth factor (IGF) activity by an excess amount of high-affinity IGF-binding proteins (IGFBP). Elevated levels of immunoreactive IGFBP-4 in CRF serum are inversely correlated with the standardized heights of these children, whereas levels of IGFBP-5, which circulates mainly as proteolyzed fragments, are positively correlated with growth parameters. To delineate the respective effects of these IGFBP on growth cartilage, the biologic effects of intact and fragmented forms of IGFBP-4 and IGFBP-5 on rat growth plate chondrocytes in primary cultures were characterized. Intact IGFBP-4 and IGFBP-5 and the amino-terminal fragment IGFBP-5(1-169) were recombinant proteins; the carboxy-terminal fragments IGFBP-5(144-252) and IGFBP-4(136-237) and the amino-terminal fragment IGFBP-4(1-122) were purified to homogeneity from CRF hemofiltrates. Intact IGFBP-4 and, to a lesser extent, IGFBP-4(1-122) inhibited IGF-I-induced cell proliferation. In contrast, intact IGFBP-5 was stimulatory in the absence or presence of exogenous IGF-I, whereas the amino-terminal fragment IGFBP-5(1-169) was inhibitory. Studies on the mechanism by which IGFBP-4 and IGFBP-5 exert opposite effects on chondrocyte proliferation demonstrated that intact IGFBP-4 prevented the binding of (125)I-IGF-I to chondrocytes, whereas intact IGFBP-5 enhanced ligand binding and was able to bind specifically to the cell membrane. These data suggest that intact IGFBP-4 and, to a lesser extent, IGFBP-4(1-122) act exclusively as growth-inhibitory binding proteins in the growth cartilage. IGFBP-5, however, can either stimulate (if it remains intact) or inhibit (if amino-terminal forms predominate) IGF-I-stimulated chondrocyte proliferation.