Switching from high-flux dialysis to hemodiafiltration: Cost-consequences for patients, providers, and payers.

Hemodiafiltration (HDF) achieves a more efficient reduction of the uremic toxic load compared to standard high-flux hemodialysis (HF-HD) by virtue of the combined diffusive and convective clearances of a broad spectrum of uremic retention solutes. Clinical trials and registry data suggest that HDF improves patient outcomes. Despite the acknowledged need to improve survival rates of dialysis patients and the survival benefit HDF offers, there is little to no utilization in some countries (such as the US) in prescribing HDF to their patients. In this analysis, we present the healthcare value-based case for HDF (relative to HF-HD) from the patient, provider, and payor perspectives. The improved survival and reduced morbidity observed in studies conducted outside the US, as well as the reduced hospitalization, are attractive for each stakeholder. We also consider the potential barriers to greater utilization of HDF therapies, including unfounded concerns regarding additional costs of HDF, e.g., for the preparation and microbial testing of quality of substitution fluids. Ultrapure fluids are easily attainable and prepared from dialysis fluids using established "online" (OL) technologies. OL-HDF has matured to a level whereby little additional effort is required to safely implement it as all modern machine systems are today equipped with the OL-HDF functionality. Countries already convinced of the advantages of HF-HD are thus well positioned to make the transition to OL-HDF to achieve further clinical and associated economic benefits. Healthcare systems struggling to cope with the increasing demand for HD therapies would therefore, like patients, be beneficiaries in the long term with increased usage of OL-HDF for end stage kidney disease patients.

Chronic Kidney Disease: Exploring Value-Based Healthcare as a Potential Viable Solution.

BACKGROUND: Increasing healthcare expenditures have triggered a trend from volume to value by linking patient outcome to costs. This concept first described as value-based healthcare (VBHC) by Michael Porter is especially applicable for chronic conditions. This article aims to explore the applicability of the VBHC framework to the chronic kidney disease (CKD) care area. METHODS: The 4 dimensions of VBHC (measure value; set and communicate value benchmarking; coordinate care; payment to reward value-add) were explored for the CKD care area. Available data was reviewed focusing on CKD initiatives in Europe to assess to what extent each of the 4 dimensions of VBHC have been applied in practice. RESULTS: Translating VBHC into value-based renal care (VBRC) seems to be initiated to a limited extent in European health systems. In most cases not all dimensions of VBHC have been utilized in the renal care initiatives. CONCLUSION: The translation of VBHC into VBRC is possible and even desirable if an optimal treatment pathway for CKD patients could be achieved. This would require an organizational change in health system set up and should include a strategy focusing on full care responsibility. The patient outcome perspective and health economic analysis need to be the centre of attention.

The case for treating refractory congestive heart failure with ultrafiltration.

Extracellular fluid retention and congestion is a fundamental manifestation of heart failure (HF) and cardiorenal syndrome (CRS). Patients are normally hospitalized and treated with diuretics, but their outcomes are often poor as severe congestion and diuretics resistance is the primary cause of HF-related hospital admissions and readmissions. Isolated ultrafiltration (UF), which can be considered as a 'mechanical diuretic and natriuretic' tool, offers promise in achieving safe and effective fluid volume removal in HF patients with CRS who are resistant to stepwise guided diuretic therapy. This paper outlines the rationale for machine-driven isolated UF in CRS and the available clinical evidence regarding its use in patients with HF. In addition, this article summarizes some future clinical perspectives for expanding the use of UF therapy in HF patients in order to improve outcomes.

Achieving high convective volumes in on-line hemodiafiltration.

On-line hemodiafiltration (OL-HDF) has established itself as a highly efficient and safe form of renal replacement therapy, providing clinical benefits for several conditions that afflict end-stage chronic kidney disease patients. Additionally, evidence now ascribes a survival benefit to OL-HDF. The first indication that mortality rates decline with high-efficiency OL-HDF was provided by the European results from the DOPPS. Since then, the RISCAVID, CONTRAST and the Turkish HDF trials have all substantiated the original findings that higher convection volumes are favorable in terms of improved survival. With the emerging concept of convection volume impacting patient survival, we examine the factors and practical approaches by which maximal convection volumes can actually be achieved and individualized for each patient treated with OL-HDF. We believe that with these factors in mind, all attempts should be made to maximize convective volume, and hence the convective dose, to enable the patient to derive the full benefits of OL-HDF over extended periods.

Emerging clinical evidence on online hemodiafiltration: does volume of ultrafiltration matter?.

Online hemodiafiltration (OL-HDF), first described in 1985, is today a widely prescribed treatment modality for end-stage chronic kidney disease (CKD) patients. Other than in the United States, prescription of the treatment modality is widespread with a steady increase since its inception. Indeed, in Western Europe, more CKD patients receive OL-HDF than peritoneal dialysis, hitherto the second most prescribed therapy after conventional hemodialysis. The rise and success of OL-HDF can be attributed to diverse clinical advantages that have been documented over the last two decades. Numerous publications attest to the beneficial effects of OL-HDF in terms of removal of a broad spectrum of uremic toxin, anemia control, phosphate reduction, increased hemodynamic stability and blood pressure control and less dialysis-related amyloidosis, to mention just a few. Significantly, the improvement in these conditions is considered to contribute to improved patient outcomes. Despite the extended worldwide clinical experience, elaborate scientific validation of the principles of the therapy and technical innovations that facilitate its prescription, a point of contention is whether OL-HDF leads to a reduction of mortality rates. A number of observational and retrospective analyses have indicated a survival benefit, while prospective investigations involving small numbers of patients but nevertheless specifically addressing survival have further supplied evidence of improved survival with OL-HDF. The quest for large-scale, multicenter prospective randomized controlled trials examining patient survival led to the CONTRAST and the Turkish OL-HDF trials. Both trials have been concluded and published recently. In this chapter, we document and assess the key investigations that have examined the impact of OL-HDF on patient outcome and survival. Based on the findings of previous analyses and of the two recently concluded trials, it appears that the volume of convection appears to be decisive towards the survival benefit accredited to OL-HDF. We consider the implications of this new evidence.

Impact of hemodialysis therapy on anemia of chronic kidney disease: the potential mechanisms.

A significant and increasing number of chronic kidney disease (CKD) patients are treated with online hemodiafiltration (OL-HDF), even in the absence of more conclusive survival data. OL-HDF affords several clinical benefits including control of anemia of CKD, a common affliction in dialysis patients. In efforts to understand the underlying mechanisms that contribute to the purported benefits of OL-HDF, we examined the potential role and impact of OL-HDF on key stages of anemia and its correction: erythropoiesis of bone marrow, circulating erythrocytes and on anemia therapy. We review evidence that indicates OL-HDF may modulate key processes of anemia and its therapy, including underlying conditions and responses of uremic toxicity and inflammation that aggravate anemia. Our assessment indicates that OL-HDF favorably impacts anemia by not only eliminating putative uremic inhibitors that suppress erythropoiesis, reducing red cell destruction and increasing iron availability, but also by mechanisms restricting underlying inflammation and endothelial dysfunction that are crucial to both CKD and anemia.

The scientific principles and technological determinants of haemodialysis membranes.

In most biological or industrial (including medical) separation processes, a membrane is a semipermeable barrier that allows or achieves selective transport between given compartments. In haemodialysis (HD), the semipermeable membrane is in a tubular geometry in the form of miniscule pipes (hollow fibres) and separation processes between compartments involve a complex array of scientific principles and factors that influence the quality of therapy a patient receives. Several conditions need to be met to accomplish the selective and desired removal of substances from blood in the inner cavity (lumen) of the hollow fibres and across the membrane wall into the larger open space surrounding each fibre. Current HD membranes have evolved and improved beyond measure from the experimental membranes available in the early developmental periods of dialysis. Today, the key functional determinants of dialysis membranes have been identified both in terms of their potential to remove uraemic retention solutes (termed 'uraemic toxins') as well subsidiary criteria they must additionally fulfill to avoid undesirable patient reactions or to ensure safety. The production of hundreds of millions of kilometres of hollow fibre membranes is truly a technological achievement to marvel, particularly in ensuring that the fibre dimensions of wall thickness and inner lumen diameter and controlled porosity-all so vital to core solute removal and detoxification functions of dialysis-are maintained for every centimetre length of the fragile fibres. Production of membranes will increase in parallel with the increase in the number of chronic kidney disease (CKD) patients expected to require HD therapies in the future. The provision of high-quality care entails detailed consideration of all aspects of dialysis membranes, as quality cannot in any way be compromised for the life-sustaining-like the natural membranes within all living organisms-function artificial dialysis membranes serve.

Flummoxed by flux: the indeterminate principles of haemodialysis.

In haemodialysis (HD), unwanted substances (uraemic retention solutes or 'uraemic toxins') that accumulate in uraemia are removed from blood by transport across the semipermeable membrane. Like all membrane separation processes, the transport requires driving forces to facilitate the transfer of molecules across the membrane. The magnitude of the transport is quantified by the phenomenon of 'flux', a finite parameter defined as the volume of fluid (or permeate) transferred per unit area of membrane surface per unit time. In HD, as transmembrane pressure is applied to facilitate fluid flow or flux across the membrane to enhance solute removal, flux is defined by the ultrafiltration coefficient (KUF; mL/h/mmHg) reflecting the hydraulic permeability of the membrane. However, in HD, the designation of flux has come to be used in a much broader sense and the term is commonly used interchangeably and erroneously with other measures of membrane separation processes, resulting in considerable confusion. Increased flux is perceived to reflect more 'porous' membranes having 'larger' pores, even though other membrane and therapy attributes determine the magnitude of flux achieved during HD. Adjectival designations of flux (low-, mid-, high-, super-, ultra-) have found indiscriminate usage in the scientific literature to qualify a parameter that influences clinical decision making and prescription of therapy modalities (low-flux or high-flux HD). Over the years the concept and definition of flux has undergone arbitrary and periodic adjustment and redefinition by authors in publications, regulatory bodies (US Food and Drug Administration) and professional association guidelines (European Renal Association, Kidney Disease Outcomes Quality Initiative), with little consensus. Industry has stretched the boundaries of flux to derive marketing advantages, justify increased reimbursement or contrive new classes of therapy modalities when in fact flux is just one of several specifications that determine membrane or dialyser performance. Membranes considered as high-flux previously are today at the lower end of the flux spectrum. Further, additional parameters unrelated to the rate of diffusive or convective transport (flux) are used in conjunction with or in place of KUF to allude to flux: clearance (mL/min, e.g. of ß2-microglobulin) or sieving coefficients (dimensionless). Considering that clinical trials in nephrology, designed to make therapy recommendations and guide policy with economic repercussions, are based on the parameter flux they merit clarification-by regulatory authorities and scientists alike-to avoid further misappropriation.

Deciphering the core elements around haemodialysis therapy.

The projected future demand for renal replacement therapies for patients with end-stage renal failure requires preparedness at different levels. The deliberations focus predominantly on the disproportionately high financial burden of care for patients on routine dialysis therapy compared with other chronic conditions. However, even today there are concerns regarding the shortage of healthcare workers in the field of nephrology. A substantial increase in trained healthcare professionals is needed for the future delivery and care of patients requiring haemodialysis (HD) that 89% of patients on dialysis receive; a sustainable health workforce is the cornerstone of any healthcare system. The multimorbid nature of chronic kidney disease as well as the complexity-especially the technical aspects-of HD are deterrents for pursuing nephrology as a career. An educational platform that critically examines the essential issues and components of HD therapy was thus considered appropriate to create or renew interest in nephrology. By providing broader and newer perspectives of some of the core principles around which HD evolves, with this set of articles we seek to facilitate a better appreciation of HD. We believe that such a reappraisal of either poorly understood or ill-defined principles, including usage of terminology that is imprecise, will help facilitate a better understanding of the functioning principles of HD.

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.

Clinical relevance of abstruse transport phenomena in haemodialysis.

Haemodialysis (HD) utilizes the bidirectional properties of semipermeable membranes to remove uraemic toxins from blood while simultaneously replenishing electrolytes and buffers to correct metabolic acidosis. However, the nonspecific size-dependent transport across membranes also means that certain useful plasma constituents may be removed from the patient (together with uraemic toxins), or toxic compounds, e.g. endotoxin fragments, may accompany electrolytes and buffers of the dialysis fluids into blood and elicit severe biological reactions. We describe the mechanisms and implications of these undesirable transport processes that are inherent to all HD therapies and propose approaches to mitigate the effects of such transport. We focus particularly on two undesirable events that are considered to adversely affect HD therapy and possibly impact patient outcomes. Firstly, we describe how loss of albumin (and other essential substances) can occur while striving to eliminate larger uraemic toxins during HD and why hypoalbuminemia is a clinical condition to contend with. Secondly, we describe the origins and mode of transport of biologically active substances (from dialysis fluids with bacterial contamination) into the blood compartment and biological reactions they elicit. Endotoxin fragments activate various proinflammatory pathways to increase the underlying inflammation associated with chronic kidney disease. Both phenomena involve the physical as well as chemical properties of membranes that must be selected judiciously to balance the benefits with potential risks patients may encounter, in both the short and long term.

Does an alteration of dialyzer design and geometry affect biocompatibility parameters?

The aim of the study was to assess the biocompatibility profile of a newly developed high-flux polysulfone dialyzer type (FX-class dialyzer). The new class of dialyzers incorporates a number of novel design features (including a new membrane) that have been developed specifically in order to enhance the removal of small- and middle-size molecules. The new FX dialyzer series was compared with the classical routinely used high-flux polysulfone F series of dialyzers. In an open prospective, randomized, crossover clinical study, concentrations of the C5a complement component, and leukocyte count in blood and various thrombogenicity parameters were evaluated before, and at 15 and 60 min of hemodialysis at both dialyzer inlet and outlet in 9 long-term hemodialysis patients using the FX60S dialyzers and, after crossover, the classical F60S, while in another 9 patients, the evaluation was made with the dialyzers used in reverse order. The comparison of dialyzers based on evaluation of the group including all procedures with the FX60S and the group including procedures with the F60S did not reveal significant differences in platelet count, activated partial thromboplastin times, plasma heparin levels, platelet factor-4, D-dimer, C5a, and leukocyte count at any point of the collecting period. Both dialyzer types showed a significant increase in the plasma levels of the thrombin-antithrombin III complexes; however, the measured levels were only slightly elevated compared with the upper end of the normal range. Biocompatibility parameters reflecting the behavior of platelets, fibrinolysis, complement activation, and leukopenia do not differ during dialysis with either the FX60S or the F60S despite their large differences in design and geometry features. Although coagulation activation, as evaluated by one of the parameters used, was slightly higher with the FX60S, it was still within the range seen with other highly biocompatible dialyzers and therefore is not indicative of any appreciable activation of the coagulation system. Thus, the incorporation of various performance-enhancing design features into the new FX class of dialyzers does not result in a deterioration of their biocompatibility profile, which is comparable to that of the classical F series of dialyzers.

Contribution of polysulfone membranes to the success of convective dialysis therapies.

The majority of patients with chronic kidney disease are currently treated with dialyzers containing synthetic membranes. Of all the dialysis membranes made from these polymers, 93% are from the parent polyarylsulfone family of which 71% are from polysulfone (PSu) and 22% from polyethersulfone. The preference of nephrologists for PSu dialyzers signifies their versatility in terms of meeting the solute and fluid removal demands for all treatment modalities (low-and high-flux dialysis, online hemodiafiltration, hemofiltration). The unprecedented success and widespread usage of PSu membranes is attributed, in addition to efficient removal of a broad spectrum of uremic toxins, to other criteria required of modern dialysis therapies. Namely, effective endotoxin retention capacity, pronounced intrinsic biocompatibility and low cytotoxicity are factors which all contribute to minimal adverse clinical sequelae. Furthermore, PSu by virtue of its high thermal stability can be sterilized with steam, the preferred mode of sterilization as it does not have the disadvantages associated with other sterilization methods. However, there are significant differences between membranes made from PSu due to differences in membrane polymer recipes and manufacturing technologies. Although PSu may be the main constituent, these membranes are blended with other polymers, e.g. hydrophilizing agents, such as polyvinylpyrrolidone to give each membrane its characteristic profile. The relative amounts of the two (or more) co-polymers as well as the spinning conditions provide a fingerprint of each membrane in terms of solute separation characteristics, biocompatibility, cytotoxicity or endotoxin retention capabilities. PSu membrane-based dialyzers thus fulfill the crucial therapy requirements of current treatment modalities to varying extents. Thereby, different effects towards patient outcomes and treatment safety are achieved.

The cardiovascular burden of the dialysis patient: the impact of dialysis technology.

There is widespread recognition that the poor survival rates of dialysis patients, attributed predominantly to cardiovascular disease, need to be addressed and improved. In this paper, we relate diverse aspects of modern dialysis technology with factors that are considered to contribute towards increased mortality and morbidity in the dialysis population. Firstly, we assess the overall cardiovascular burden of the dialysis patient: it is the sum of uraemia-related risk factors (URRF), traditional risk factors and dialysis-therapy-related factors. Secondly, we describe how key components of the dialysis procedure may be directly related to the more common URRF: the dialyser and the membrane, microbiological quality of water and dialysate, treatment modality and online monitory equipment. The judicious selection and application of these components may collectively help improve patient outcomes in hemodialysis therapy.