Abstract

Despite the significant medical and technical improvements in the field of dialytic renal replacement modalities, morbidity and mortality are excessively high among patients with end-stage kidney disease, and most interventional studies yielded disappointing results. Hemodiafiltration, a dialysis method that was implemented in clinics many years ago and that combines the two main principles of hemodialysis and hemofiltration—diffusion and convection—has had a positive impact on mortality rates, especially when delivered in a high-volume mode as a surrogate for a high convective dose. The achievement of high substitution volumes during dialysis treatments does not only depend on patient characteristics but also on the dialyzer (membrane) and the adequately equipped hemodiafiltration machine. The present review article summarizes the technical aspects of online hemodiafiltration and discusses present and ongoing clinical studies with regards to hard clinical and patient-reported outcomes.

Keywords: hemodiafiltration, performance, convection volume, end-stage kidney disease, dialysis

1. Introduction

Patients with end-stage kidney disease (ESKD) are a severely ill population with a complex comorbidity situation and high mortality rates. There is a clear need to improve these hard clinical endpoints and the quality of life of ESKD patients. Most of the patients depend on an extracorporeal renal replacement therapy, such as low- and high-flux hemodialysis (HD) or hemodiafiltration (HDF). HDF is in widespread use, especially in Europe and Asia, but less so in the United States; here, fewer HDF systems have been cleared by the Food and Drug Administration (FDA) .

HDF combines the diffusion of mainly low molecular weight uremic toxins, known from conventional HD, with the convection of soluble middle-sized toxins, such as β2-microglobulin, within the same high-flux hemodialyzer module. HDF is considered the most advanced renal replacement therapy that is currently available , as clinical studies have demonstrated its superiority in removing middle- and large-sized uremic toxins as compared to HD. Moreover, HDF offers the potential to improve hard clinical outcomes, and clinical studies have shown very promising results.

Firstly, the present review article describes the technical considerations of HDF with regards to the dialyzer and the machine to achieve the best potential of HDF. Secondly, medical considerations of HDF are discussed in this article, which summarizes the current clinical evidence on performance and hard clinical endpoints. Finally, the review article provides an outlook on ongoing clinical trials on HDF investigating hard clinical endpoints and patient-reported outcomes.

2. Technical Insights of HDF

HDF dates back to the late 1960s and has been improved continuously thereafter . It is a form of kidney replacement therapy that combines the principles of HD and hemofiltration (HF). In conventional HD, the solute removal is primarily achieved via diffusion, which is the movement of molecules along a concentration gradient between the blood and dialysate that is higher for small molecules. In contrast, solute removal in HF is based on convective transport, which depends on the ultrafiltration rate and is equal for different molecule sizes as long as they can pass through the pores of the membrane, reflecting its sieving capacity. In HDF, diffusive and convective mechanisms are combined, resulting in the high removal of small molecules while also obtaining a high removal of larger molecules. However, as diffusive and convective transports are affecting each other, the total clearance by the combination of both techniques is not as high as the sum of the clearances of each single technique alone; diffusion lowers a solute’s concentration in the blood and, thereby, the potential removal capacity via convective transport. Vice versa, a solute’s removal via convection lowers the concentration gradient between the blood and dialysate and, thereby, reduces the potential removal capacity via diffusive transport .

The following three major technological components are required to perform HDF: a substitution fluid, a hemodiafilter, and an HDF machine. The following sections review technical insights for each of these three major components and further address how synergy between the hemodiafilter and the HDF machine can help maximize the substitution volume.

2.1. The Substitution Fluid

HDF removes high plasma water volumes via ultrafiltration, which, in turn, needs to be replaced isovolumetrically with a substitution fluid. This substitute fluid is infused into the blood of the patient and, therefore, needs to be sterile and non-pyrogenic. There are several modes of replacement therapies available. Of these, the following are described in more detail: post-dilution, pre-dilution, mixed-dilution, and mid-dilution HDF.

Post-dilution HDF: The substitution fluid is infused downstream of the dialyzer into the venous side of the extracorporeal circuit. Post-dilution HDF offers high convective clearances and removal rates of soluble uremic toxins at normal or higher blood flow rates. The high ultrafiltration rate results in an increase in the serum protein concentrations due to the high water removal and, thereby, an increase in blood viscosity and oncotic pressure, which, in turn, can lead to membrane fouling . Post-dilution is the most commonly used mode of online HDF . These factors limit the filtration fraction to around 30% of the blood flow rate.

Pre-dilution HDF: The substitution fluid is infused upstream of the dialyzer into the arterial side of the extracorporeal circuit. In the pre-dilution mode, the solute concentrations in the blood are reduced, resulting in lower diffusive and convective clearance rates compared with the post-dilution mode. Pre-dilution HDF decreases the hematocrit and oncotic pressure while preserving the transmembrane pressure gradient along the capillaries, reducing the risk of clot formation and shear stress inside the capillaries; thus, it may reduce the formation of a “secondary membrane” as a polarization of proteins on the dialyzer’s inner membrane surface. This may be especially important if the membrane is prone to such accumulation, as secondary membranes change a dialyzer’s performance and characteristics. It facilitates superior convective clearances in some particular clinical conditions associated with low blood flow regimens (i.e., children, low access flow, and central venous catheters) or unfavorable hemorheological conditions (i.e., high protein concentration and high hematocrit). It requires a larger (twice as large) substitution volume to achieve equivalent solute clearances as in post-dilution HDF since it dilutes solutes entering the hemodialyzer. Pre-dilution HDF is commonly used in Japan, where traditionally applied low blood flow rates favor this modality.

Mixed-dilution HDF: In mixed-dilution HDF, the substitution fluid is infused simultaneously at different rates (typically 80/20%) before and after the dialyzer, avoiding some of the shortcomings of pre- and post-dilution HDF. It, however, requires specific blood tubing and a non-standard dialysis machine with an additional pump.

Mid-dilution HDF: Mid-dilution HDF is a non-conventional modality that requires a special dialyzer with a specific inlet port for the replacement fluid, allowing for pre- and post-dilution. The housing of this dialyzer contains two high-flux fiber bundles—an outer annular region and an inner core region—divided by a special header cap. Firstly, the blood is passed through the annular outer bundle in the post-dilution mode and is then mixed with the substitution fluid at the opposite end of the dialyzer. Secondly, the diluted blood is passed through the inner core of the dialyzer in the reverse direction to the dialyzer blood exit in the pre-dilution mode .

Of note, several factors during HDF treatments affect each other, including blood flow or convective volume, and are important determinants among the different substitution modalities to achieve the respective treatment goals. For example, in certain conditions where low blood flow is necessary, the convective volume target may nonetheless be achieved. Here, the dilution factor of the respective HDF mode plays the following important role: when compared to post-dilution HDF, the dilution factor for pre-dilution HDF is 2, 1.5 for mixed-dilution HDF, and also 1.5 for mid-dilution HDF. Thus, in pre-, mixed-, and mid-dilution HDF, higher substitution volumes are needed than in post-dilution HDF. Such higher volumes allow for increased plasma flow within the hemodiafilter and enhanced ultrafiltration flow in order to compensate for the lower solute concentrations and maintain the overall solute clearances throughout the dialysis session .

As described above, HDF requires the replacement of the fluid removed via ultrafiltration. In chronic kidney disease, this is mainly achieved via the use of online HDF . During online HDF, the substitution fluid is not provided as a bagged, ready-made sterile fluid but is prepared during the treatment “online” from the dialysate fluid. Cold sterilization of the substitution fluid is achieved via a two-stage ultrafiltration of the dialysate using sterilizing ultrafilters. The use of specifically designed HDF machines and respective quality monitoring of the disinfection process combined with strict hygienic rules are mandatory . Furthermore, HDF requires high-flux hemodiafilters with certain membrane characteristics and fiber geometry to achieve high convective clearance rates.