Sudhir K. Bowry

Optimal convection volume for improving patient outcomes in an international incident dialysis cohort treated with online hemodiafiltration

Online hemodiafiltration (OL-HDF), the most efficient renal replacement therapy, enables enhanced removal of small and large uremic toxins by combining diffusive and convective solute transport. Randomized controlled trials on prevalent chronic kidney disease (CKD) patients showed improved patient survival with high-volume OL-HDF, underlining the effect of convection volume (CV). This retrospective international study was conducted in a large cohort of incident CKD patients to determine the CV threshold and range associated with survival advantage. Data were extracted from a cohort of adult CKD patients treated by post-dilution OL-HDF over a 101-month period. In total, 2293 patients with a minimum of 2 years of follow-up were analyzed using advanced statistical tools, including cubic spline analyses for determination of the CV range over which a survival increase was observed. The relative survival rate of OL-HDF patients, adjusted for age, gender, comorbidities, vascular access, albumin, C-reactive protein, and dialysis dose, was found to increase at about 55 l/week of CV and to stay increased up to about 75 l/week. Similar analysis of pre-dialysis β2-microglobin (marker of middle-molecule uremic toxins) concentrations found a nearly linear decrease in marker concentration as CV increased from 40 to 75 l/week. Analysis of log C-reactive protein levels showed a decrease over the same CV range. Thus, a convection dose target based on convection volume should be considered and needs to be confirmed by prospective trials as a new determinant of dialysis adequacy.

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.

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.

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.

Membranes for hemodialysis

The initiation of renal replacement therapy in chronic uremia coincides with the evolution and subsequent progression of renal disease. The decision as to the appropriate starting moment for the substitution program is still the subject of much discussion. Although specific biochemical parameters (such as the level of plasma creatinine) have been suggested to guide the decision to begin therapy, each patient must be evaluated on an individual basis; whilst specific guidelines may be helpful, they must be considered in conjunction with a large number of additional factors. Some patients may appear well, but may have high levels of creatinine, while others may have much lower creatinine levels, but nevertheless demonstrate classic signs of the uremic syndrome such as nausea, vomiting, progressive anemia, electrolytic disorders, acid—base disequilibrium or neuropathy.

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.

Hemodialysis membranes for high‐volume hemodialytic therapies: The application of nanotechnology

In recent years, much attention has been devoted to the various issues around the poor survival rates of patients on routine hemodialysis. A wealth of data now exists showing both poor patient outcomes and a poorer quality of life of dialysis patients worldwide. The challenging task to improve this bleak situation is being addressed by diverse factions of the dialysis fraternity, involving nephrologists, nurses, scientists, technicians, statisticians, and of course industry which is the provider of devices, instrumentation, as well as a whole spectrum of patient-care services. It has also become apparent that dialysis patient mortality attributed to cardiovascular events is unacceptably higher than that for the general population. Patients on maintenance dialysis have a several-fold higher risk of death from cardiovascular disease than individuals of the general population. Indeed, the fact that a 25-year-old dialysis patient has approximately the same risk of death as an 85-year-old person from the general population clearly emphasizes the predicament of all involved in the care of the dialysis patient. A number of separate issues that may influence the poor outcomes have been delineated and are being addressed in recent years. The effect of comorbid conditions, residual renal function and time of referral to dialysis, the aging dialysis population, medication and the type, duration and frequency of the hemodialysis therapy being administered are just some of the issues we are confronted with. In this paper we look at some of the aspects pertaining to the choice of the therapy modality which may further be related to the issue of patient 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.

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.

Revisiting Frontiers of Tolerability and Efficacy in Renal Replacement Therapy

Clinical outcomes associated with dialysis therapies depend on the prescribed treatment modality and conditions of treatment delivery. Prescribing dialysis therapy to patients with chronic kidney failure requires considering an impressive array of patientand technology-related factors, not to mention a variety of care practices. The study by Cornelis et al in this issue of AJKD examines the combined effects of 2 of the most widely debated and fundamental modifiable factors of the hemodialysis (HD) prescription: treatment modality and treatment duration. Most patients today are treated with high-flux rather than low-flux HD, which reflects the recognition that large, and not just small, uremic toxins must be removed to treat patients with chronic kidney failure. Hemodiafiltration (HDF), an extension of high-flux HD, is an alternative treatment modality that further increases the removal of larger uremic toxins by enhancing convective clearance. The second modifiable factor, treatment duration, has been a subject of debate since the early days of dialysis therapy, with most nephrologists of the opinion that patients derive the greatest benefit from longer and more frequent dialysis sessions. Cornelis et al explored the interaction of treatment modality and duration with a 232 factorial crossover study design that used each patient as his or her own control. Interventions included duration of the dialysis session (short [4 hours] vs long [8 hours]) and type of solute flux (diffusive flux using high-flux HD vs enhanced convective flux using HDF; in both cases, high-flux membrane dialyzers were used). The primary outcomes were hemodynamic tolerance and solute mass transfer as surrogate markers of the combined effect of time and solute flux prescription. Hemodynamic changes were used as outcome parameters for assessing the tolerability of both treatment time (short vs long) and modality (high-flux HD vs HDF). Hemodynamic assessment was performed using conventional measures such as relative blood volume changes, intermittent blood pressure, ultrafiltration, and weight loss, as well as more sophisticated markers like cardiac output, pulse wave velocity analysis, and microcirculation changes. As expected, ultrafiltration rate (in milliliters per kilogram per hour) was reduced by w50% in both modalities when long treatment times were used. Importantly, thermal balance was matched in the 4 treatment schedules, which suppressed this confounding factor in HDF. Clinical tolerance was not reported.