Unveiling the Clinical Benefits of High-Volume Hemodiafiltration: Optimizing the Removal of Medium-Weight Uremic Toxins and Beyond

Abstract

Dialysis treatment has improved the survival of patients with kidney failure. However, the hospitalization and mortality rates remain alarmingly high, primarily due to incomplete uremic toxin elimination. High-volume hemodiafiltration (HDF) has emerged as a promising approach that significantly improves patient outcomes by effectively eliminating medium and large uremic toxins, which explains its increasing adoption, particularly in Europe and Japan. Interest in this therapy has grown following the findings of the recently published CONVINCE study, as well as the need to understand the mechanisms behind the benefits. This comprehensive review aims to enhance the scientific understanding by explaining the underlying physiological mechanisms that contribute to the positive effects of HDF in terms of short-term benefits, like hemodynamic tolerance and cardiovascular disease. Additionally, it explores the rationale behind the medium-term clinical benefits, including phosphorus removal, the modulation of inflammation and oxidative stress, anemia management, immune response modulation, nutritional effects, the mitigation of bone disorders, neuropathy relief, and amyloidosis reduction. This review also analyzes the impact of HDF on patient-reported outcomes and mortality. Considering the importance of applying personalized uremic toxin removal strategies tailored to the unique needs of each patient, high-volume HDF appears to be the most effective treatment to date for patients with renal failure. This justifies the need to prioritize its application in clinical practice, initially focusing on the groups with the greatest potential benefits and subsequently extending its use to a larger number of patients.

Keywords: cardiovascular disease; dialysis; hemodiafiltration; hemodynamic tolerance; inflammation; kidney failure; mortality; oxidative stress; patient-reported outcomes; uremic toxins.

Figure 1

Phosphorus kinetics during hemodiafiltration. During hemodiafiltration, the levels of phosphate in the blood rapidly reach a plateau, below which they do not decrease. After therapy, there is a rebound effect that persists for over an hour. This can be explained by a four-compartment system with controlled kinetics, which responds to changes in the concentration of intracellular phosphate. Initially, there is a dynamic equilibrium established between the intracellular compartment (1st pool) and the extracellular compartment (2nd pool). Once the serum phosphate levels reach a critically low limit, the intravascular space receives additional phosphorus, potentially originating from a phosphate reservoir that has not yet been incorporated into the bone matrix (3rd pool). It is plausible that changes in the concentration of phosphate inside the cells trigger this control mechanism. Finally, when intracellular phosphate levels drop below a critical threshold (<0.97 mmol/L), there is an immediate release of phosphate from a fourth pool into the intracellular space. This 4th pool is believed to consist of phosphate derived from mitochondrial adenosine triphosphate (ATP). This mechanism serves to protect the intracellular environment from dangerously low concentrations of phosphate.

Figure 2

Gibbs–Donnan effect in hemodiafiltration. During conventional hemodialysis, sodium is removed by convection and diffusion until equilibrium is reached, without causing significant changes in osmotic pressure. However, in postdilutional hemodiafiltration, significant intermittent ultrafiltration occurs, resulting in secondary hemoconcentration, which causes an increase in the albumin concentration on the blood side of the membrane. When large negatively charged particles, such as albumin, cannot diffuse across a semipermeable membrane and are present in a fluid compartment such as the vascular compartment, they attract positively charged ions, especially sodium, which is the most abundant in plasma. This generates an osmotic gradient that favors the movement of fluids into the blood compartment. At Gibbs–Donnan equilibrium, this osmotic pressure reaches approximately 6–7 mmHg, which could facilitate fluid refilling from the interstitium and provide hemodynamic stability.

Figure 3

Role of hemodiafiltration in intradialytic hypotension. During hemodialysis and ultrafiltration (UF), normal compensatory responses involve activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, in addition to adequate plasma refilling. All this facilitates blood pressure maintenance through increased venous return and cardiac preload, increased cardiac output, and arteriolar vasoconstriction. When any of these compensatory mechanisms are impaired, hypotension is observed. Hemodialysis leads to an increase in core body temperature, which has been attributed to the blood–membrane interaction that generates complement activation and cytokine release. In addition, reduced heat loss through the skin due to peripheral vasoconstriction in response to UF may increase body temperature (shell phenomenon). As a consequence of this heat accumulation, loss of vascular tone may occur, resulting in hypotension. Hemodiafiltration (HDF) can improve hemodynamic stability by acting on several of these mechanisms.