Biocompatibility in hemodialysis: artificial membrane and human blood interactions.

Introduction

Chronic kidney disease (CKD) stage 5 is an increasing global health concern, affecting 3.4 million individuals worldwide [ 1 ]. Kidney transplantation is widely regarded as the preferred treatment option among renal replacement therapies (RRTs); however, its availability is limited [ 2 ]. As a consequence, the majority of individuals at this stage of CKD rely on RRTs and primarily dialysis, either hemodialysis (HD) or peritoneal dialysis, as a crucial life-supporting therapy. Hemodialysis, an artificial extracorporeal system, utilizes a semipermeable polymeric membrane to depurate the blood through countercurrent filtration against dialysate fluid (Fig. 1 a). Filtration membranes remove uremic solutes and fluid through diffusion, convection, and adsorption, depending on their architecture. The relative contribution of these mechanisms varies depending on the type of membrane used.

Based on Thomas Graham’s foundational studies on gas and fluid diffusion, John Abel’s research on substance diffusion in the bloodstream, and Georg Haas’s pioneering work on the first human dialysis—along with contributions from other notable researchers—Willem Johan Kolff designed the world’s first artificial organ, the artificial kidney, in the 1940s in the Netherlands [ 3 ]. The success of his invention was partly attributed to the use of heparin, which addressed the issue of clot formation in the extracorporeal system [ 4 ]. Despite the passage of years, the problem identified by Kolff persists in current hemodialysis practice, resulting from the body’s exposure to biomaterials.

The interaction between blood and dialysis membrane holds significant clinical interest, as it delineates the membrane’s biocompatibility. A membrane inducing adverse effects upon interaction with blood is termed bioincompatible [ 5 ]. On the other hand, the term biocompatibility is widely discussed in the literature, referring to a material’s capacity to function appropriately in a specific application without triggering an inappropriate response from the host organism or compromising its intended function [ 6 ]. In hemodialysis, bioincompatibility refers to membrane protein adsorption, reducing therapy efficacy [ 7 , 8 ].

Bioincompatibility is divided into two aspects: tissue compatibility and hemocompatibility. The latter involves the artificial surface contacting blood, a complex tissue composed of 44% erythrocytes, 1% leukocytes and platelets, and 55% plasma. Therefore, the resulting biological response from this interaction partly also depends on physical dimension, such as on blood rheology and device geometry [ 8 ].

Biocompatibility phenomena related to the interaction of blood with an artificial material are not solely confined to the filtration membrane but also encompass all system components associated with the therapy, including the manufacturing process (e.g., associated to bisphenol A), sterilization methods, HD circuit tubing, air microbubbles, connection needles, among others [ 9 ]. Given that hemodialysis is a repetitive procedure, even brief interactions can trigger a long-term response from the body, leading to cardiovascular and infectious events, contributing to the pathogenesis of chronic inflammation in chronic kidney disease [ 10 , 11 ].

In this review, we will focus on biocompatibility in hemodialysis membranes, examining the specific characteristics of these biomaterials. This includes the initial interaction between blood and the membrane, beginning with protein adsorption and progressing through the subsequent pathophysiological processes that arise from this interaction, both at the cellular and acellular levels. Additionally, we will address the clinical implications of bioincompatibility in patients with chronic kidney disease undergoing hemodialysis and conclude with an overview of current treatments and innovations to mitigate bioincompatibility related effects.

T raditional classification of dialysis membranes

Traditionally, hemodialysis membranes have been classified according to their composition into three main categories. Initially, the dialysis membranes consisted of flat cellulose sheets, such as Cuprophan, it was made from cotton and was effective in purifying small solutes (molecular weight < 500 Da [ 12 ]; subsequently, membranes with hollow fibers of modified cellulose were developed, and currently, membranes based on synthetic polymers are manufactured [ 7 , 13 ].

Cellulose membranes

These are made of repetitive units of polysaccharides containing hydroxyl groups, similar to those found in bacterial cell walls [ 14 , 15 ]. These free hydroxyl groups can trigger complement activation upon interaction with blood (Fig. 2 a-b). Conversely, modified cellulose membranes replace up to 80% of hydroxyl groups with acetate, such as diacetate or triacetate, aromatic benzyl groups, or tertiary amines, which reduce complement activation and make the membranes more biocompatible [ 13 , 16 ].

Synthetic membranes

Synthetic polymer membranes are constructed from polymers such as polyester, polycarbonate (PC), polysulfone (PSU), polyethersulfone (PES), polyacrylonitrile (PAN), acrylonitrile ethylene sulfate (PAN/AN69), polymethylmethacrylate (PMMA), among others. Unlike cellulose membranes, which have a symmetric structure with uniform pore size throughout their thickness, synthetic polymeric membranes exhibit an asymmetric architecture. The outer layer is a mechanical support for the fiber, typically featuring a sponge-like or finger-like structure. In contrast, the inner layer is characterized by a high-density selective barrier, which directly contacts blood components and regulates molecular transport across the membrane [ 12 ]. By masking hydroxyl groups, synthetic polymers reduce complement activation and enhance biocompatibility (Fig. 2 a) [ 16 , 17 ]. Synthetic membranes are the most widely used and exhibit distinct features, with pores of varied sizes allowing for various dialysis therapy modalities. These synthetic membranes are constantly being developed, with new applications and modifications [ 18 ].

However, the main disadvantage of synthetic membranes compared to cellulose-based membranes is their extreme hydrophobicity, which is associated with increased protein adsorption, membrane fouling, and reduced biocompatibility [ 12 , 19 , 20 ].

Characteristics of hemodialysis membranes

The hemodialysis membrane possesses various structural characteristics, including water interaction (hydrophilicity) [ 21 ], pore size, quantity, distribution, porosity, pore symmetry, thickness, surface area, polarity, Zeta potential, and chemical composition. The result of the combination of these structural attributes defines the specific functional properties of each membrane. Some of the relevant characteristics related to biocompatibility will be described [ 22 , 23 ].

Dialysis membranes by hydrophilicity

Hydrophilic: Absorb water with lower protein adsorption. Cellulose-based filters are inherently hydrophilic due to the chemical structure of cellulose, which contains numerous hydroxyl groups (-OH) along its polymeric chain. These groups form hydrogen bonds with water molecules, giving cellulose a high affinity for water and an exceptional absorption capacity. Being hydrophilic, these surfaces are often “coated” with a stable water layer that acts as a physical barrier, preventing direct interaction with proteins and cells. Hydrophilic membranes exhibit enhanced interactions with water and other fluids, facilitating the passage of small molecules (such as urea and creatinine) while minimizing the entrapment of larger proteins like albumin [ 24 ].

Hydrophobic: These membranes do not interact with water and are more prone to protein adsorption. They are more porous and have a high ultrafiltration coefficient, which increases the tendency to promote thrombi.

One commonly used technique to assess the membrane’s hydrophilicity is the water contact angle (Fig. 1 d), which reveals the wetting properties of the membrane surface.

Dialysis membranes by permeability to solutes and water

Plasma proteins form colloids that influence oncotic pressure, membrane selectivity, and adsorption in hemodialysis [ 25 ].

Solute Permeability: Dissolved solutes move by diffusion or convection. There is probably always a mixture of these phenomena. Smaller solutes tend to be dissolved and move by diffusion; larger ones tend to be convection only. It is possible to measure the “diffusive capacity”, preferably by transferring “urea” (a small dissolved solute). It can be assessed by Ko, a parameter used to describe the diffusion coefficient of the membrane in the presence of ideally unlimited blood and dialysate flows. The final characteristics of a membrane must be indexed by surface area, leading to the definition of a parameter called KoA, which measures diffusive purification efficiency (applied explicitly to urea) [ 25 ]. It is considered to have a low purification efficiency when KoA < 500. KoA is influenced by pore size, membrane porosity and thickness, while depending on solute size, blood flow and dialysis fluid [ 12 , 18 , 26 , 27 ].

Water Permeability: Water moves by osmosis or ultrafiltration. Water permeability in filters is measured by ultrafiltration capacity. Ultrafiltration coefficient (KUf) is a functional filter property that measures permeability according to its capacity to ultrafilter water. The definition of high-flux dialyzers has evolved in response to developing new membranes and surface modifications [ 28 , 29 ]. The current definition of high-flux membranes includes a water permeability of 20 to 40 mL/h/mmHg/m², a sieving coefficient (SC) for β-2-microglobulin—defined as the ratio of a solute concentration in the ultrafiltrate compared to its concentration in plasma—of 0.7 to 0.8, and an albumin loss of less than 0.5 g over a 4-hour hemodialysis session [ 12 , 18 , 26 , 27 ].

Additionally, solute transport across a membrane can be assessed using the sieving coefficient (SC). SC measures the membrane’s permeability for a specific solute, representing the ratio between the solute’s concentration in the ultrafiltrate and the plasma. Unlike global clearance measures, SC focuses on individual solutes, bypassing the distinction between diffusion and convection as transport mechanisms. However, it is primarily associated with convective transport, as it is typically assessed under ultrafiltration conditions. The SC ranges from 0 (no transport) to 1 (unrestricted transport). The SC is used to define the Molecular Weight Retention Onset (MWRO), which corresponds to the molecular weight at an SC of 0.9, and the Molecular Weight Cut-Off (MWCO), which is defined at an SC of 0.1 (indicating 10% permeability). The MWRO provides insight into the pore size distribution, while the MWCO reflects the average pore size of the membrane [ 12 ].

It is important to highlight that water permeability and water affinity are distinct concepts. For example, cellulose-based filters such as Cuprophan are hydrophilic, meaning the membrane has an affinity for water—it can attract and “wet” easily. However, these are low-flux filters (low KUf), as their small and dense pore structure limits their capacity to allow the passage of large volumes of water and solutes via convection. Additionally, their limited mechanical resistance means they cannot withstand the high transmembrane pressures (TMP) required to generate the water flow necessary for convective therapies.

Dialysis membranes by polarity and Z-potential

Membranes possessing a charge on their surface are considered polar. This polarity partially contributes to diffusive transport. All membranes’ charge or surface potential is negative, while the values vary among membranes. For example, AN69 has a surface potential of -100 mV and polysulfone of -20 mV. Membranes with a strong negative charge on their surface, such as AN69 and, to a lesser extent, PMMA, have been associated with increased bradykinin generation, potentially leading to severe anaphylactoid reactions [ 9 , 30 ].

On the other hand, Zeta potential describes the electrical potential at the interface between blood and the dialysis membrane surface. This electrical potential arises due to the presence of electronegative charges on the membrane’s surface layer, generated by the chemical composition of the polymer and polymerization processes. From a functional point of view, Zeta potential measures the intensity of the electrostatic repulsion between the membrane and similarly charged particles in the blood (such as proteins and cells) or the attraction of oppositely charged molecules. The membrane’s surface charge has a direct impact on biocompatibility. A highly negative Z potential favors the adsorption of positively charged proteins and complement activation.

Membrane roughness

The dialysis membranes aim to eliminate toxins while preventing the loss of beneficial proteins. Multilayer membranes with a hydrophilic inner layer have been designed, allowing solute selectivity. A second outer layer provides support, composed of interconnected nanoporous structures offering pathways for removing excess water and toxins. The roughness of the inner surface plays a significant role in the integration between blood components and the surface, but also, as greater the roughness greater will be the shear stress on blood components flowing near the membrane [ 18 , 31 ].

Membrane biocompatibility

Protein adsorption—a key biocompatibility event—is a dynamic interaction between blood and the membrane, marked by continuous adsorption and desorption of plasma proteins. Adsorbed proteins change their orientation from an initial state to a new state, where they lose free energy by reducing the attractive forces towards the surface and gain free energy due to less repulsive forces between adjacent proteins due to differences in polarity and changes in surface density [ 32 – 34 ].

The protein adsorption process is influenced by several factors, including:

The properties of the proteins, including size, isoelectric point, and structural stability.

The membrane’s characteristics include its roughness, porosity, thickness, wettability, and composition [ 35 – 41 ].

Membrane-protein or protein-protein interactions, these interactions include hydrophobic and hydrophilic interactions, as well as surface tension [ 42 , 43 ], contact time with the surface [ 38 ], ionic strength of the molecules [ 44 – 46 ], pH of the medium where the proteins are located [ 47 ], presence of hydrogen bonds, and Van der Waals forces.

The concentration of salts plays a critical role in modulating protein solubility through the “salting out” effect. At high salt concentrations, ions compete with proteins for water molecules, decreasing the availability of free water to stabilize protein solubility, which can lead to protein aggregation and precipitation. Salts are classified as kosmotropes or chaotropes based on their ability to stabilize or destabilize protein structures, respectively, a distinction described by the Hofmeister series. For example, kosmotropes such as calcium (Ca 2+ ) and magnesium (Mg 2+ ) may promote protein precipitation by potentially enhancing structural stability and reducing solubility. In contrast, ions like citrate could act as chaotropes, potentially destabilizing proteins, reducing their adsorption to surfaces, and thereby mitigating inflammatory responses. While these effects are theoretically plausible, further investigation is needed to confirm their specific impact in the context of dialysis [ 48 – 50 ].

Operating conditions of the dialyzer, the shear stress generated by blood flow, and temperature [ 51 – 57 ].

The process begins almost immediately upon contact with the membrane, triggering a sequence of bioincompatibility events that follow a sequence according to the Vroman model [ 58 , 59 ]. In the initial minutes, fibrinogen, albumin, and immunoglobulin G adhere to the biomaterial surface, gradually replaced by less abundant proteins but with a higher affinity for the surface, such as high molecular weight kininogen (HMWK), plasminogen, and factor XII, which bind competitively and sequentially [ 8 , 60 ]. Subsequently, small and medium-sized plasma proteins exhibit increased interaction with the surface, leading to reversible or irreversible, non-selective bindings occurring within seconds [ 9 , 61 ]. While the Vroman model has been generally validated, several other kinetic mathematical models for protein adsorption have been developed to address different aspects of this phenomenon. For instance, the Langmuir model describes adsorption as a reversible process at discrete surface sites. In contrast, the Random Sequential Adsorption model accounts for the random nature of protein adsorption and surface saturation. Cooperative models incorporate interactions between adsorbed proteins, explaining positive or negative cooperative effects and dynamic models capture conformational changes, rearrangements, and multilayer formation on surfaces. These models complement the Vroman model, offering a more comprehensive understanding of protein adsorption dynamics under varying conditions [ 32 , 62 – 70 ].

The irreversible adsorption of proteins on dialysis membranes is governed by changes in the Gibbs free energy (ΔG), where ΔG = ΔH-TΔS. Specifically, during this process, ΔG tends to decrease, which is achieved by reducing enthalpy (ΔH) and increasing entropy (ΔS) at constant temperature (T). Protein-membrane contact releases water and ions, increasing entropy and favoring hydrophobic interactions. This phenomenon favors additional protein adsorption, which increases enthalpy and denaturation; however, the net result is the reduction of ΔG [ 71 ].

Conformational changes during protein adsorption have macroscopic effects, including a reduction in the quantity of adsorbed proteins, alterations in the secondary structure of proteins, and increased resistance to elution. For example, after conformational changes, fibrinogen or von Willebrand factor exposes more binding domains to leukocytes and platelets [ 72 ].

Protein adsorption is a central event in bioincompatibility during the interaction between dialysis membranes and blood. Membrane properties and hydrodynamic conditions near the surface primarily influence adsorption. Secondary adsorption depends on interactions between proteins, the membrane, and individual proteins. Over time, the system reaches a dynamic equilibrium in which the properties of the adsorbed layer change gradually [ 8 , 59 ].

The hydrophilic nature of membranes facilitates the formation of a water layer on their surface, which hinders protein adsorption (Fig. 1 b-d). Furthermore, hydrophilic functional groups in hydrophilic membranes can repel or minimize interaction with proteins [ 8 ]. Therefore, hydrophobic surfaces activate the complement system more than hydrophilic surfaces [ 73 ].

Although Cuprophan membranes are hydrophilic, they are not inherently biocompatible. Cuprophan is a modified (acetylated) cellulose material with an irregular surface containing reactive groups that expose numerous hydroxyl groups (-OH) on its surface. While these membranes are hydrophilic, their chemical structure, surface roughness, and reactivity promote complement activation and other mechanisms of bioincompatibility.

Protein adsorption not only determines the formation of the protein pseudo-layer but also generates secondary interactions among the initially adsorbed proteins and other circulating proteins, gradually reducing the surface area of the exposed membrane and decreasing the deposition of adsorbed proteins until reaching a critical packing density [ 23 , 33 ]. The structure of the pseudo-layer can vary from a dense or loose monolayer of approximately 8 nm to a multilayer, depending on the conditions of attraction or repulsion among the proteins comprising it [ 34 , 74 , 75 ].

Surface roughness and electrostatic charge have a significant influence on the kinetics and selectivity of protein adsorption on dialysis membranes. Synthetic membranes such as PAES: PVP exhibit higher roughness (Ra ≈ 10.4–15.3 nm) and a more negative surface charge (− 68 mV), favoring the progressive and largely irreversible adsorption of fibrinogen and other plasma proteins. In contrast, cellulose triacetate (CTA) membranes exhibit smoother surfaces (Ra ≈ 5.4–7.5 nm) and a moderately negative charge (− 34 mV), resulting in faster but more reversible protein adsorption. Notably, fibrinogen retention is higher in PAES: PVP (Ci/Co ≈ 0.62 at 25 min) than in CTA (Ci/Co ≈ 0.45, equilibrium at 3 min) [ 18 , 76 ]. Although early unmodified cellulose membranes such as cuprophan were strongly bioincompatible (activating the alternative complement pathway via sustained C3 convertase activity and poor regulation by factor H [ 77 , 78 ], chemically modified cellulose membranes such as CTA represent a substantial improvement. CTA binds significantly more factor H and fewer APC-activating proteins (e.g., factor B), thus attenuating complement activation and mimicking the regulatory balance of plasma [ 77 ]. Furthermore, their enhanced hydrophilic surfaces reduce non-specific protein adhesion, contributing to a more selective and biocompatible adsorption profile [ 77 ]. Comparative proteomic studies confirm that CTA and similar modified cellulose membranes adsorb fewer pro-inflammatory proteins and trigger lower IL-1β and IL-6 responses after dialysis, compared to synthetic membranes such as Helixone [ 18 ].

Study of protein adsorption

In assessing the biocompatibility of these membranes, it is crucial to evaluate the complex phenomenon of protein adsorption. To achieve this, various experimental techniques have been used [ 70 , 79 – 89 ]. Proteomics has allowed for a detailed analysis of the adsorption potential of dialysis membranes in recent years, enabling the quantification and identification of proteins present in the dialyzer eluate, as well as the characterization of metabolic pathways and biological networks affected by the identified proteins using bioinformatics tools.

A comparative proteomics study between cellulose triacetate membranes and Helixone dialyzers demonstrated that both membranes adsorb specific proteins. In another study comparing high-flux and low-flux membranes, 668 proteins were detected using liquid chromatography-mass spectrometry, with 177 proteins retained in high-flux membranes and 320 proteins retained in low-flux membranes. Another interesting study, assessing the eluates of hemodialysis membranes, revealed distinct adsorbed proteome profiles between patients and within patients using various types of membranes [ 90 ].

Comparative proteomic studies have revealed that different dialysis membranes exhibit distinct protein adsorption profiles, which in turn modulate key biological pathways such as complement activation, coagulation, and immune response. For example, helixone membranes tend to adsorb more proinflammatory and complement-related proteins (e.g., ficolin-2, serum amyloid A), thereby signaling for the growth and differentiation of vascular endothelial cells, lymphatic cells, and cell-extracellular matrix interactions, which are associated with cell migration, adhesion, growth, and differentiation, with greater activation of the coagulation cascade and platelet activation; whereas CTA membranes preferentially bind transport and humoral defense proteins, such as HDL-associated apolipoproteins and immunoglobulins [ 76 ]. These “proteomic signatures” reflect membrane-specific biocompatibility profiles that could be translated into tools for clinical decision-making. Advances in this field suggest that dialysis membranes can serve as platforms for biological sampling, enabling the identification of adsorbed proteins as biomarkers not only of membrane interaction but also of systemic pathological processes such as autoimmune diseases or hematological conditions like multiple myeloma [ 90 ].

While no validated biomarker panels or machine learning models are currently applied in clinical nephrology, recent in silico studies employing algorithms such as Random Forest and XGBoost have demonstrated high predictive performance of membrane-protein binding affinity using molecular descriptors. These models can be inverted to associate individual plasma proteomes with membranes optimized to minimize adsorption of high-risk proteins (e.g., fibrinogen, β2-microglobulin, SAA). The clinical utility of this approach lies not in the discovery of new biomarkers, but in the integration of known sentinel proteins into robust and practical panels to guide membrane selection and personalize treatment, particularly for patients at high thrombotic or inflammatory risk [ 91 – 93 ].

Interaction between dialysis membrane and blood

The interactions of the membrane with blood can be categorized based on their interaction with cellular and non-cellular components, such as complement activation, systemic inflammation, and coagulation (Fig. 3 ) [ 94 ].

Non-cellular components of the interaction

Complement system

A typical biological response to foreign structures within the body is the activation of the complement system. This intricate cascade entails a multitude of proteins circulating either in inactive form or tethered to cells, meticulously regulated and entrenched within the realm of the innate immune system, devoted to discerning self from non-self within the corporeal landscape [ 95 ]. How complement activation occurs may involve either direct or indirect mechanisms, depending on the specific biomaterial, and affect the established pathways of the classical, lectin, and alternative routes, focusing on the latter two. Direct activation occurs by binding complement components to the biomaterial’s surface. Conversely, the indirect pathway encompasses the binding of immunoglobulin G to the biomaterial’s surface, thereby facilitating classical pathway initiation; the presence of carbohydrates or acetylated moieties on the membrane, activating the lectin pathway; and the induction of the alternative pathway, mediated by the adsorption of plasma proteins onto the membrane. Irrespective of the activation pathway, these cascades result in the cleavage of C3, yielding C3a and C3b, and the birth of C5 convertase, which cleaves C5 into C5a and C5b. C3a and C5a operate as anaphylotoxins, while C5b docks onto the surface, interacting with C6-C9, forming the membrane attack complex (MAC/C5b-9). Soluble C5b-9 (sC5b-9) levels and the C3d/C3 ratios in plasma may increase by up to 70% throughout a single HD session. However, this estimate could be underestimated, as it only encompasses the fluid phase of complement activation (12). Furthermore, HD membranes exert complex effects on complement regulators, including factor H and the C1q inhibitor [ 8 , 94 ].

Complement activation fosters thrombogenic and inflammatory milieu, unleashing reactive oxygen species (ROS), cytokines, and adhesion molecules like P-selectin, chemokines, elastase, myeloperoxidase, and the anaphylatoxins (C3a, C5a), which serve as chemoattractants, recruiting and activating neutrophils. The most extreme event was observed in the early experiences of hemodialysis with Cuprophan cellulose fiber [ 77 , 96 – 99 ], marking the onset of identifying immune system implications and subsequent research. Complement activation results in the upregulation of adhesion molecules on leukocytes, notably complement receptor 3 (CR3). Leukocytes activated with C5a subsequently bind to C3 fragments (iC3b) deposited on the membrane via CR3, potentially causing systemic transient leukopenia, with leukocyte sequestration in pulmonary capillaries, culminating in respiratory failure, a scenario less observed with current synthetic dialyzers compared to previous cellulose filters [ 5 , 75 , 100 ].

Lectin pathway

The primary event in complement activation through the lectin pathway is the binding of ficolin-2 and mannose-binding lectin (MBL) to the membrane. Proteomic analyses have revealed that during a hemodialysis session, plasma levels of ficolin-2 decrease by 41% due to its excessive adsorption onto the membrane, which is associated with the production of C5a and leukopenia [ 94 , 101 ].

Alternative pathway

Concurrently with lectin pathway activation, properdin and/or C3b adhere to the membrane, resulting in alternative pathway activation. C3 activation occurs early during the HD session, typically within 10–15 min, while terminal complement pathway activation, C5a, and C5b-9, occurs at a later stage. In older cellulose membranes like Cuprophan, free hydroxyl groups on their surface tend to promote C3b deposition and covalent binding and association with factor B, initiating the alternative pathway cascade with the generation of C3bBb convertase and the common pathway C5 convertase. The generation of anaphylatoxins C3a and C5a facilitates this process, inducing vasoconstriction, increased vascular permeability, and histamine release from mast cells.

In addition, factor H and clusterin adsorption have been shown to suppress complement activation. Factor H acts at multiple levels by inhibiting C3b binding, destabilizing the C3bBb (C3 convertase) and C3bBbC3b (C5 convertase) complexes, and promoting their inactivation through interaction with polyanionic substances on the plasma membrane; on the other hand, clusterin inhibits the formation of C5a and the common terminal pathway C5b-9. Factor H polymorphisms, such as the Y402H polymorphism affecting heparin and C-reactive protein binding sites, have increased cardiovascular mortality in hemodialysis patients [ 71 , 94 , 102 – 105 ].

Factor D limits the speed of alternative pathway activation, and in patients with CKD, it is elevated up to tenfold, favoring pathway activation. In vivo studies have shown that blocking factor D alters alternative pathway activation, suggesting that factor D adsorption on dialysis membranes could be beneficial in inhibiting complement activation. In this regard, PAN/AN69 and PMMA membranes remove substantial amounts of factor D, around 80% and 50%, respectively, while cellulose membranes remove it by 10%. Moreover, the adsorption of complement inhibitors like factor H and clusterin also occurs, stimulating complement activation [ 94 , 106 ].

Classical pathway

The role of the classical pathway in the formation of the membrane attack complex has been investigated, and it was found that concentrations of the C4d fragment remained unchanged during hemodialysis. C4d, a product of C4 activation, may help assess the involvement of the classical pathway in the process. This complement activation pathway appears to have a minor contribution to the process [ 107 , 108 ].

Although the alternative and lectin pathways are the predominant routes of complement activation in hemodialysis, recent evidence suggests that the classical pathway may also play a contributing role under specific conditions. Synthetic membranes, due to their hydrophobic nature, preferentially adsorb abundant plasma proteins such as albumin, fibrinogen, and IgG [ 75 , 109 ]. Adsorbed IgG molecules may undergo transient conformational changes that allow limited activation of the classical pathway. Although this activation appears to be self-limiting and insufficient to propagate the classical cascade fully, it can nonetheless potentiate the amplification loop of the alternative pathway. In contrast, historical cellulose-based membranes, despite their hydrophilic nature, exposed free hydroxyl (OH) groups that directly bind to C3b, favoring robust activation of the alternative pathway [ 75 ]. These mechanistic differences highlight how membrane composition and surface chemistry influence both the pathway and the intensity of complement activation.

Complement is a critical component in the response to a biomaterial; in an animal model of hemodialysis, inhibition of complement system activation was observed to attenuate the inflammatory response and also resulted in increased production of the anti-inflammatory cytokine interleukin-10 [ 94 , 95 ].

Coagulation

In the 1950s, the first effects of blood contact with an external surface, such as glass, were observed with the discovery of the Hagemann factor (known as factor XII of coagulation) [ 110 ]. All artificial extracorporeal membranes and circuits used in hemodialysis, which come into direct contact with blood, trigger coagulation, resulting in thrombus formation. This phenomenon involves cellular and molecular processes [ 5 ], clinically manifesting a loss of depurative efficiency, blood entrapment, and long-term atherosclerosis, fibrosis, and thromboembolic events. Therefore, anticoagulants like heparin are commonly used to prevent this complication during hemodialysis sessions; however, this exposes the patient to the risk of hemorrhage [ 111 , 112 ].

The phenomenon of bioincompatibility involves both primary and secondary hemostasis. As mentioned, the process begins with protein adsorption, followed by conformational changes, and is exacerbated by other factors such as shear stress from the flow in the hemodialysis pump [ 113 – 115 ].

Primary hemostasis

Adsorbed proteins promote platelet adhesion by binding to glycoprotein IIb/IIIa receptors, followed by platelet activation with morphological changes and pseudopod generation, release of phosphatidylserine and choline via the flip-flop mechanism, secretion of granular content (β-thrombomodulin, platelet factor-4, and prostaglandins), facilitating binding to coagulation factors and increased platelet aggregation.

Secondary hemostasis

Thrombin generation is predisposed through the intrinsic pathway, which initiates near the extracorporeal surface via the contact-kinin system, with the binding of factor XII, factor XI, prekallikrein, and high molecular weight kininogen (HMWK) to the negatively charged surface [ 73 ]. The conformational change of factor XII upon binding to the membrane surface releases the active form (B-FXIIa) through two pathways: one pathway utilizes HMWK as a cofactor, cleaving prekallikrein to generate kallikrein, which, in turn, produces more kallikrein, thus amplifying a chain of factor XII autoactivation. This process may generate bradykinin, a potent vasodilator and inducer of endothelial permeability, with proinflammatory consequences. The second pathway uses HMWK to activate factor XI, which, via the intrinsic coagulation pathway, leads to factor X activation and thrombin generation. Thrombin catalyzes fibrinogen polymerization to fibrin and successive polymers, leading to platelet activation and insoluble clot formation. The electronegativity of the membrane, assessed by Zeta potential, is associated with contact system activation within the first 5 min of hemodialysis initiation [ 8 , 18 , 23 , 111 , 116 ]. Upon fibrinogen and/or von Willebrand factor (vWF) adsorption, these undergo conformational changes, exposing domains further enhancing platelet adhesion [ 71 ]. Additionally, complement system activation may lead to tissue factor generation from monocytes, resulting in extrinsic pathway activation [ 73 ].

Unlike other bioincompatibility processes, hemodialysis involves a hemodynamic physical dimension known as shear stress, a result of the blood flow generated by the blood pump, typically from 100 ml/min to 500 ml/min [ 117 ]. This factor promotes platelet adhesion and aggregation on the membrane through different pathways. On the one hand, with a shear rate below 1000 s − 1 , aggregation is primarily due to the αIIbβ3-fibronectin interaction; on the other hand, with a shear rate above 10,000 s − 1 , aggregation is regulated by the GPIbα-vWF interaction, even in the absence of platelet activation by αIIbβ3 [ 71 , 118 , 119 ].

Many other stimuli contribute to the procoagulant phenomenon, such as complement activation, leukocytes, protein adsorption, venous punctures, tubing, and traumas caused by the blood pump, with hemolysis releasing adenosine diphosphate (ADP). In these bubble traps, foam denatures proteins. Furthermore, the activation of coagulation is enhanced by the activation of anaphylatoxins C5a, stimulating granulocytes to generate tissue factor. Complement activation also positively regulates leukocyte adhesion molecules, especially complement receptor 3 (CR3), which is also crucial for platelet-neutrophil complex formation, contributing to inflammation and thrombosis.

Furthermore, proteomic analyses have revealed that different dialysis membranes exhibit distinct protein adsorption patterns, which may influence coagulation and inflammatory responses. Cellulose triacetate tends to adsorb more plasma proteins, including immunoglobulins, albumin, and complement factors, whereas synthetic polysulfone membranes preferentially retain cytoskeletal and intracellular proteins. These adsorption differences may impact thrombin generation and platelet activation, contributing to variations in bioincompatibility profiles. Neutrophil elastase—a protease involved in plasma protein degradation and coagulation activation—displays higher adsorption on polysulfone membranes than on CTA. This selective retention may affect the initiation of the intrinsic coagulation pathway by modulating factor XII activation [ 76 ].

Inflammation

Neutrophils become activated, releasing inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, TNF-α, monocyte chemoattractant protein-1 (MCP-1), and various myeloperoxidases. The rise in various cytotoxic inflammatory mediators encourages a state of chronic inflammation that exacerbates inflammation beyond that of CKD itself [ 18 ].

The permeability of the dialysis membranes can impact biocompatibility. For instance, high-flux membranes tend to activate complement, coagulation, and inflammation to a lesser extent. However, these membranes possess larger pores, potentially leading to back-filtration, whereby dialysate fluid passes from the dialysate compartment into the bloodstream, carrying toxins into the systemic circulation, thereby contributing to bioincompatibility and inflammation. In such scenarios, ensuring the availability of ultrapure water is essential to reduce this risk [ 18 , 26 , 120 ].

The majority of mediators produced in the bloodstream, including anaphylatoxins C3a and C5a, interleukin-1, and factor D, can be simultaneously removed during high-flux therapies due to their relatively low molecular weights (8.9, 11, 17, and 23 kDa, respectively). On the other hand, high molecular weight components such as the C3b fragment (189 kDa) [ 10 , 121 ] and the membrane attack complex sC5b-9 (> 1,000 kDa) are not expected to be significantly removed, even by high-flux hemodialysis membranes [ 94 , 121 ].

Cellular components of the interaction

Cellular components, including neutrophils, monocytes, lymphocytes, platelets, and erythrocytes, are activated following interaction with the hemodialysis membrane [ 13 ].

Leukocytes

Contact with the blood membrane results in increased leukocyte activation, leading to the production of reactive oxygen species, the release of elastases, and the formation of neutrophil extracellular traps (NETs) through NETosis, which is a network of neutrophil chromatin to which histones, myeloperoxidases, and elastases adhere, promoting inflammation and thrombosis [ 73 , 122 ].

Both neutrophils and monocytes can adhere to and become activated on the biomaterial, triggered by adherent platelets and primarily by adherent proteins such as fibrinogen, fibronectin, and iC3b. This activation occurs at both local and systemic levels. Clinically, leukocyte activation can result in leukocyte sequestration in the capillary bed of the lungs, due to complement activation following exposure to Cuprophan, resulting in respiratory failure and leukopenia in an ovine model of hemodialysis [ 5 , 96 ].

Similar to complement activation, which peaks 15 min after starting dialysis, a simultaneous reduction in peripheral blood leukocytes has been observed during the same period, proportional to the elimination of ficolin-2. A multivariable model has demonstrated that decreased ficolin-2 concentration and complement C5a independently predict changes in leukocyte count [ 13 ].

Recent findings indicate that CD4 + T lymphocytes undergo premature activation during hemodialysis (HD), likely driven by heightened innate immune responses. Notably, a significant reduction in the percentage of CD8 + HLA-DR + , CD8 + CD69 + , and CD8 + CD95 + T cells was observed following a single HD session. Concurrently, there was an increase in CD4 + CD95 + T cells, resulting in an elevated CD4 + /CD8 + ratio. This immune modulation may stem from complement system activation during HD, with CD95 + expression suggesting T-cell activation [ 123 ]. Such repetitive immune stimulation could lead to T-cell exhaustion, potentially explained by stress-induced premature senescence (SIPS)—a phenomenon associated with telomere shortening observed in HD patients [ 124 ]. Although these changes underline the immunomodulatory effects of HD, further research is essential to confirm the role of membrane biocompatibility in driving these alterations.​

Platelets

Exposure of the biomaterial to blood triggers platelet activation, which begins rapidly (180 ms) after protein adsorption [ 125 ]. Platelets adhere through fibrinogen, vWF, fibronectin, and vitronectin via the most abundant integrin receptor, GP IIb/IIIa, which activates the platelet. This process is facilitated by conformational changes experienced by adsorbed fibrinogen. Once activated, platelets release their alpha granules containing hemostatic proteins such as vWF, fibrinogen, factor V, factor IX, chemokines (platelet factor 4, among others), growth factors: vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), plasminogen, P-selectin that can activate neutrophils, in addition to β-thromboglobulin that aids in leukocyte recruitment. The content of dense granules is also released, containing pro-aggregants such as histamine, serotonin, bivalent cations Mg + 2 and Ca + 2 , as well as polyphosphates, which can activate factor XII, triggering the intrinsic coagulation pathway, along with adenosine triphosphate (ATP) and ADP that can activate neighboring platelets by binding to purinergic receptors P2Y1 and P2Y12. The resulting platelet degranulation leads to increased platelet adhesion and aggregation in the vicinity, a non-uniform process with inactive, partially activated, and fully activated platelets at different intensity levels intensity [ 73 ]. This results in the conformational change of the platelet, with the extension of pseudopods, while exposing additional procoagulant phospholipids such as phosphatidylserine and phosphatidylcholine on its membrane, which subsequently bind to plasma coagulation factors in secondary hemostasis, culminating in thrombus formation stabilized by fibrin [ 5 ].

Erythrocytes

Red blood cells are the stiffest blood cells and are prone to rupture and hemolysis due to shear stress and osmotic changes [ 73 ]. During hemodialysis, red blood cells are forced to pass through narrow pores or channels, exposing them to turbulence and significant stresses, with differential forces and shear stress between central laminar flows and flows at the edges [ 126 ]. Additionally, patients undergoing dialysis experience elevated oxidative stress associated with various cardiovascular events, anemia, and malnutrition. This oxidative stress has been linked to lipid peroxidation of the red blood cell membrane, making them more susceptible to hemolysis. Hemolysis can lead to severe clinical conditions, reducing oxygen transport to tissues, and the released hemoglobin can induce renal toxicity, altering residual function in patients who still retain it [ 73 , 127 ]. Other aspects of hemolysis related to the extracorporeal technique, such as needles and tubing, must be considered. However, nowadays, the risk of hemolysis due to the specific interaction of red blood cells with the dialysis membrane is rare, thanks to modifications in its construction with smooth and flat surfaces, as well as strict quality controls, reducing rough surfaces and, therefore, shear stress (Fig. 1 e) [ 126 ].

Modifications of dialysis membranes: strategies to mitigate bio-incompatibility

Given artificial membranes’ limitations in biocompatibility, several membrane modifications, physical-chemical and biological, have been developed. These modifications aim to optimize membrane biocompatibility by reducing protein adsorption, following Whitesides’ principles for the design of antifouling surfaces. A key approach involves increasing the membrane’s hydrophilicity, among other physicochemical properties, to minimize unwanted interactions with blood components [ 71 ].

The production of dialysis membranes is a highly specialized process that integrates material engineering and advanced manufacturing techniques to optimize biocompatibility and filtration efficiency (Table 1 ). The process begins with selecting a base polymer, then the preparation of a polymer solution, extrusion and hollow fiber formation, surface modifications to enhance performance and hemocompatibility, and finally, the assembly of the dialyzer, drying, sterilization, and quality control.

The transformation of polymers into fibers is known as spinning, a process in which the polymer is extruded through a spinneret and subsequently solidified to form the final membrane structure. Melt extrusion was the primary manufacturing method in earlier generations of dialysis filters. This solvent-free technique involved heating the polymer above its melting point and extruding it into a thin sheet, which was then stretched to introduce porosity. However, the membranes produced in this way were structurally symmetrical and had relatively low permeability.

In contrast, modern dialysis filters are made mainly by phase inversion, which allows for forming asymmetric membranes. These membranes feature a dense surface layer that provides selective filtration, while an underlying porous structure enhances permeability. In this process, the polymer solution is extruded into a coagulation bath containing a non-solvent (usually water or aqueous solutions), triggering phase separation and the development of the membrane’s porous architecture. The rate of polymer precipitation significantly influences the internal structure: fast precipitation leads to a finger-like morphology with large interconnected macropores, whereas slower precipitation results in a sponge-like configuration with a more uniform porous network (Fig. 2 d-e). The latter tends to be less hydrophobic than finger-like structures, improving water retention and reducing protein adhesion [ 27 , 71 , 128 , 129 ].

Given the biocompatibility limitations of artificial membranes, several membrane modifications have been developed. These strategies enhance membrane biocompatibility by reducing protein adsorption, in line with Whitesides’ antifouling principles. A key approach involves increasing the membrane’s hydrophilicity, among other physicochemical properties, to minimize unwanted interactions with blood components [ 71 ].

Physical and chemical modifications

Surface modifications involve altering the physical, chemical, or biological characteristics of a membrane’s surface while preserving the bulk properties of the polymeric material. Physical and chemical modifications are the most widely employed strategies, offering effective means to improve biocompatibility and performance in hemodialysis applications (Table 2 ) [ 71 , 150 ].

Hydrophilic surface modification of synthetic dialysis membranes with PVP has demonstrated a dual impact, improving biocompatibility and influencing solute transport parameters. PVP reduces protein adsorption and membrane fouling, while increasing water permeability by modulating pore size and distribution. In membranes composed of polyethersulfone or polysulfone, the addition of PVP produces enlarged, finger-like or channel-like pore structures that promote convective transport. Studies have shown that, at specific polymer concentrations, the incorporation of PVP improves the clearance of uremic toxins by facilitating water flux through the membrane. Although direct comparative data on KoA or KUf changes remain limited, morphometric and functional analyses suggest that PVP-modified membranes can achieve solute clearance comparable to high-efficiency membranes such as EVAL- or PAN-based membranes. However, PVP elution during storage or post-sterilization (e.g., gamma radiation, steam) may contribute to adverse reactions such as thrombocytopenia or acute intradialytic symptoms. Therefore, while PVP improves hydrophilicity and biocompatibility, its concentration, stability, and retention within the membrane matrix must be carefully optimized to avoid compromising dialysis safety or performance [ 151 – 153 ].

Biological modifications

Biological modifications can be categorized based on their therapeutic objectives: antithrombotic, anti-inflammatory, which generally begin by reducing protein adsorption.

Antithrombotic membrane modifications

Heparin-coated surfaces

The HepZero study, a randomized controlled trial involving high-bleeding-risk patients, evaluated the noninferiority of a heparin-grafted dialyzer (Evodial ® ) compared to the standard practice of saline rinses without systemic heparin. While the results demonstrated noninferiority, it is essential to note that the comparator, saline rinses is a widely used, economical, and simple technique [ 154 ].

Another approach has involved membranes modified with heparin mimetics. Polyurethanes (PU) designed to mimic heparin were synthesized in a mixed solution of dimethyl sulfoxide (DMSO) and water, reducing the use of organic solvents. These PU materials were blended with polyethersulfone (PES) to fabricate PES membranes with enhanced hydrophilicity, lower protein adsorption, reduced complement activation, and leukocyte and platelet inflammatory activation [ 155 ].

Direct thrombin inhibitors

In experimental models, membranes modified with argatroban, a direct thrombin inhibitor, have shown reduced platelet adhesion and complement activation [ 23 ].

Calcium-chelating surfaces

Membranes with calcium-chelating properties, inspired by regional citrate anticoagulation, have been developed. A hydrogel of poly (sodium alginate-acrylic acid) was applied to polysulfone membranes, demonstrating reduced filter clotting in an animal model of one-hour dialysis [ 156 ].

Albumin coatings

Polysulfone membranes coated with heparin and albumin have shown improved hydrophilicity, reduced protein adsorption, and decreased platelet adhesion, enhancing overall biocompatibility [ 157 ].

To enhance the anticoagulant properties of membranes, their hydrophilicity can be modified to reduce protein adsorption or calcium concentration. However, as mentioned earlier, the activation process of both hemostasis pathways differs from the classic physiological one, so common anticoagulants like low molecular weight heparin cannot block all the involved pathological pathways [ 23 , 112 , 158 , 159 ].

Anti-Inflammatory membrane modifications

Vitamin E-coated membranes

Vitamin E is a lipophilic antioxidant, it’s one of the most extensively studied modifications. A systematic review of 60 studies revealed its association with reduced erythropoiesis resistance index and lower systemic inflammation, as evidenced by decreased IL-6 levels. However, no significant effects were observed on lipid profiles, dialysis adequacy, or anemia control [ 160 ].

Lipoic acid-modified membranes

Lipoic acid is a fat-soluble antioxidant. PS membranes enriched with α-lipoic acid and α-tocopherol tended to reduce oxidative stress in vivo [ 12 ].

Endothelialization of membranes

Reconstruction of the membrane’s surface to mimic the endothelial basement membrane has been explored. Hyaluronic acid, collagen IV, and laminin were applied to modulate the interaction between blood and the membrane using shear stress-generated patterns. This approach reduces platelet deposition and inflammation but faces challenges in sterilizing the modified filters for clinical use [ 161 ].

Neutrophil elastase inhibitor-Modified membranes

Neutrophil elastase (NE) is a proteinase secreted by neutrophils and macrophages, which acts to destroy bacteria. An in vitro study was carried out to reduce the increased concentration of elastase produced during hemodialysis. NE inhibitors were immobilized, trapping active elastase and reducing its concentration in blood, which could mitigate the inflammatory response and improve biocompatibility [ 162 ].

Nitric oxide-releasing membranes

Materials capable of releasing nitric oxide (NO) have been investigated in vitro and animal models. NO inhibits platelet adhesion and activation, reduces leukocyte chemotaxis, and prevents smooth muscle cell proliferation, potentially minimizing vascular prosthesis thrombosis. However, limitations include uncertainty of NO concentrations in target tissues, lack of efficient storage materials, and the need for clinical tailoring of dialysis filters [ 163 ].

Other modifications

Mixed matrix membranes (MMM)

These are asymmetric membranes composed of an internal layer made of a PES/PVP blend and an external layer embedded with microparticles of activated carbon. The inner layer functions as a selective transport barrier, while the outer layer enhances the concentration gradient of toxins between the blood and dialysate compartments, facilitating diffusive clearance. This design improves biocompatibility by reducing protein adsorption and minimizing complement activation. Additionally, these membranes have been shown to remove ten times more endotoxins from the dialysate compartment than conventional membranes [ 12 , 164 ].

Super-hydrophobic membranes

Following the precept of avoiding the initial phenomenon of bioincompatibility, i.e. protein adsorption, the trend has been to generate membranes with hydrophilic properties. However, inspired by the nature of the lotus flower, gecko skin, among others, a paradigm shift was evaluated, generating membranes with highly hydrophobic properties, through modifications of the relief of the membrane surface that allow the generation of a thin layer of air, acting as a barrier to protein adsorption [ 165 ]. This theory was evaluated in an in vitro model, demonstrating lower hemolysis [ 166 ].

A critical aspect to consider when selecting a membrane modification is its potential adverse effects. One of the most important factors is the phenomenon of leaching, which occurs when membrane components, such as polymers, additives, or coatings, dissolve and migrate into the dialysis fluid or, in some cases, enter the patient’s bloodstream. This process can compromise the biocompatibility and safety of the membrane, as unwanted materials may come into contact with the patient. For example, the incorporation of PVP into polymeric membranes has enhanced their biocompatibility; however, its potential harmful effects must also be considered. During hemodialysis, PVP can be eluted from the membrane and enter the dialysis fluid; even small amounts can pass into the patient’s bloodstream. This has been linked to the occurrence of hypersensitivity reactions during dialysis [ 167 , 168 ]. Also, this loss of PVP from the membrane surface can compromise its hydrophilic coating, reducing biocompatibility and increasing the risk of protein adsorption. Eventually, accumulated PVP can contribute to chronic inflammation or immune activation in the bloodstream, particularly during long-term dialysis [ 169 , 170 ]. The real clinical impact of membrane component leaching has been poorly investigated. Further research is needed to determine the concentration of polymeric or other elements that enter the bloodstream after detaching (eluting) from the dialysis membrane in hemodialysis patients.

Influence of blood flow on biocompatibility

Dialyzer design is key in blood flow distribution, directly influencing purification efficiency and membrane biocompatibility. The presence of turbulence increases the shear on blood components, which can induce platelet and coagulation activation. A model that generates turbulent flow over a porous medium tends to generate a boundary layer that thickens and penetrates up to 7% of the thickness of the porous fiber diameter. In addition, vortices and velocity fluctuations generate low-velocity zones near the membrane surface, promoting protein and cell adhesion, which increases the risk of thrombus formation and inflammatory responses [ 171 ].

In conventional designs, blood is introduced through a central port, which concentrates the flow on the inner capillary fibers. This reduces the effective diffusion area and increases the risk of clotting in the outer fibers due to slower blood flow, which can compromise biocompatibility by promoting cellular and coagulation system activation.

Structural modifications have been implemented to counteract this limitation, such as incorporating an “O”-shaped inner ring or redesigning the dialyzer’s outer casing with a cone in the middle segment. These improvements generate a vortex effect that increases the flow velocity in the outer fibers, decreases the drag force on the hollow fibers, and reduces downstream turbulence. As a result, a more uniform distribution of blood is achieved, which contributes to minimizing inflammatory and thrombotic activation [ 151 , 172 ].

In addition, the diameter of the capillary fibers is crucial. In conventional dialyzers, narrow fibers maximize the surface area for diffusion, but in convective therapies, this design increases blood viscosity and internal pressure, increasing the risk of bioincompatibility. Therefore, larger diameter fibers are preferred, facilitating convective transport without generating high pressures [ 173 ].

When high blood flow cannot be achieved, predilution hemodiafiltration is used, which dilutes the blood before it enters the dialyzer, reducing viscosity and internal pressure. Even in diffusive modes, modern membranes, having high hydraulic permeability, allow internal filtration whose degree depends on the transmembrane pressure, the diameter of the fibers, and the intrinsic properties of the membrane, being more significant in those with high permeability [ 151 ].

Other therapies

This review does not aim to discuss anticoagulants used in hemodialysis therapies. However, two notable aspects warrant attention. Heparin remains the standard anticoagulant in hemodialysis, primarily to prevent clotting within the dialyzer and circuit [ 174 – 176 ]. Beyond this conventional role, its potential to modulate complement activation has been explored.

Interestingly, regional citrate anticoagulation (RCA) has been shown to reduce complement activation, measured by C3a levels by up to 50% more than heparin [ 94 , 177 ], though conflicting results have been reported with cellulose membranes [ 178 ]. In another study, RCA was associated with a trend toward lower complement activation during hemodialysis, particularly at higher citrate concentrations, though the difference between the two citrate groups did not reach statistical significance [ 179 ]. Additional studies have highlighted similar benefits, including reduced platelet and leukocyte adhesion [ 180 ], decreased neutrophil degranulation [ 181 ], and lower oxidative stress and inflammation [ 182 ]. However, this therapy is not without risks, particularly potential disturbances in acid-base balance [ 183 , 184 ].

Regional citrate anticoagulation has been shown to enhance the overall biocompatibility of the hemodialysis procedure, acting independently of membrane material. In a randomized crossover trial involving 32 chronic HD patients undergoing expanded hemodialysis with Theranova R membranes, the use of RCA significantly reduced markers of bioincompatibility—including C3a, myeloperoxidase, and PF-4 —compared to unfractionated heparin, with no significant increases observed during the RCA sessions. Mechanistically, RCA mitigates contact and complement activation not only by preventing calcium-dependent coagulation, but also by chelating ionized magnesium, a critical cofactor in the alternative complement pathway. This dual ionic modulation inhibits early inflammatory and prothrombotic responses triggered by blood–membrane contact, thus supporting RCA as a membrane-independent strategy to reduce bioincompatibility during hemodialysis [ 185 , 186 ].

Complement blockade has emerged as a promising strategy to enhance biocompatibility in hemodialysis. Among the approaches investigated, heparinoids have demonstrated in vitro complement inhibition through C1-inhibitor activity [ 187 ]. Additionally, C3 and C5 inhibitors have shown efficacy in preclinical models, with Compstatin effectively reducing complement activation in hemodialysis [ 188 , 189 ], while eculizumab blocks C5a and C5b-9 but presents limitations due to its high cost and prolonged half-life [ 190 ].

Alternatively, C5a receptor antagonists (C5aRA), such as PMX-53 [ 191 ], offer a more accessible option, although their application in hemodialysis requires clinical validation. Another innovative strategy involves coating dialysis membranes with complement inhibitors, such as the 5C6 peptide, which binds to factor H and prevents complement activation without altering its regulatory function. However, further research is needed to assess its feasibility in biomaterials and its long-term safety in clinical settings [ 94 , 192 , 193 ].

Clinical results of membrane biocompatibility interaction

The interaction between blood and the hemodialyzer biomaterial can be conceptualized as a bioreactor, initiating a cascade of cellular and acellular biological reactions. These previously described interactions translate clinically into inflammatory processes and a spectrum of clinical manifestations (Fig. 4 ). This exposure’s intensity, frequency, and duration may critically influence the degree of morbidity and mortality associated with hemodialysis [ 5 , 194 ]. Figure 5 presents a summary recommendation of the filter to be used, depending on the patient’s phenotype.

Cardiovascular disease

Cardiovascular disease and chronic inflammation are the leading causes of high mortality in patients with CKD [ 195 , 196 ]. Given the impact of the repeated interaction between the dialysis membrane and blood, improvements have been developed to remove toxins and increase biocompatibility, thereby reducing inflammation. However, determining the specific contribution of dialysis membrane bioincompatibility in CKD patients is challenging, as CKD itself is inflammatory [ 95 , 197 , 198 ].

The anaphylatoxins C3a and C5a, along with the subsequent activation of the complement’s membrane attack complex, play a fundamental role in chronic inflammation [ 199 ]. The standard treatment involves synthetic membranes due to their better biocompatibility profile. One study compared the biocompatibility of various synthetic dialysis membranes, such as polysulfone, polyethersulfone, and cellulose membranes. The activation of C3a, C5a, and the membrane attack complex was evaluated, along with the albumin sieving coefficients, as an indicator of protein pseudo-layer formation. It was concluded that polysulfone membranes with internal surface modification, adding polyvinylpyrrolidone to increase hydrophilicity, reduced albumin adsorption, and complement activation [ 55 ].

Emerging longitudinal evidence suggests a clinically relevant association between complement activation and adverse cardiovascular outcomes in patients undergoing hemodialysis. Prospective studies have demonstrated that elevated baseline levels of complement components and activation markers—such as C3, C4, C3d, the C3d/C3 ratio, and the terminal complement complex sC5b-9—are independent predictors of cardiovascular mortality in this population [ 200 – 202 ]. These biomarkers reflect persistent immune activation and endothelial injury, which may contribute to accelerated atherosclerosis, vascular calcification, and left ventricular dysfunction. As such, complement activation serves not only as a mechanistic link to bioincompatibility but also as a measurable risk factor with prognostic significance.

A 45-month prospective follow-up study was conducted on patients undergoing conventional hemodialysis with low-flux polysulfone membranes. Patients who experienced cardiovascular events were compared to those who did not. It was found that patients with cardiovascular events had significantly higher levels of the C3d/C3 ratio and IL-6/IL-10 during hemodialysis sessions and a more significant increase in TNF-α and von Willebrand factor levels at the end of the session [ 201 ]. Other studies have shown that increased inflammation markers, such as C-reactive protein, during hemodialysis are independently associated with a higher risk of cardiovascular events and mortality [ 95 , 203 ].

The decrease in leukocyte count, a consequence of complement activation, thrombosis, and inflammation phenomena during dialysis, is associated with a higher cardiovascular risk and morbidity/mortality [ 95 , 122 ]. Transient neutropenia was more common with less biocompatible membranes, such as cellulose ones, than current synthetic membranes. For instance, with membranes like Cuprophan, patients experienced a marked depletion of neutrophils within 15 min of starting dialysis, complement activation, and symptoms such as hypoxemia due to leukocyte aggregation, chest pain, and back pain [ 98 ]. Similarly, due to complement system activation, a transient decrease in platelet count has been observed during the first 15 to 30 min of hemodialysis, with greater activation seen in cell-based membranes compared to current synthetic membranes [ 204 ]. The specific clinical consequences of this transient reduction in leukocytes and platelets, with the formation of leukocyte-leukocyte, platelet-platelet, or platelet-leukocyte aggregates in patients with chronic hemodialysis due to repeated exposures to membrane-blood interactions and successive complement system and inflammation activations, are unknown but could predispose to a higher risk of infections, thrombotic events, and long-term cardiovascular complications, contributing to the observed morbidity and mortality in these patients [ 95 , 98 , 204 ].

Anemia

Neutrophil elastase is considered important in inflammation during hemodialysis [ 205 , 206 ]. This enzyme is elevated and has been associated with anemia due to the reduction in the lifespan of red blood cells [ 207 ], and a diminished response to treatment with recombinant human erythropoietin [ 208 ].

Oxidative stress

Hemodialysis has been associated with increased oxidative stress due to the rise in reactive oxygen species [ 209 ] and the loss of water-soluble antioxidants such as vitamin C across the membrane [ 210 ]. Oxidative stress is not only a consequence of bioincompatibility but also plays a causative role in inflammation among HD patients with CKD [ 211 ]. This leads to a heightened risk of cardiovascular issues, heart failure, myocardial infarction, vascular calcification [ 212 , 213 ], anemia, endothelial dysfunction [ 95 ], and malnutrition [ 209 ].

In diabetic patients on hemodialysis, the Toraylight NV membrane, designed to enhance biocompatibility, demonstrated a protective effect against oxidative stress in dialysis patients. In contrast to conventional PSU membranes, NV was associated with stable serum pentosidine levels, whereas pentosidine levels significantly increased in the PSU group over time. Given that pentosidine is a well-established marker of oxidative stress and is linked to the progression of atherosclerosis, this finding suggests that the lower activation of blood cells observed with NV contributes to reduced oxidative stress [ 214 ].

Anaphylactoid reactions

Previously referred to as “first-use syndrome” due to its occurrence mainly with new dialyzers [ 215 ], these reactions are now classified as dialyzer reactions, specifically anaphylactoid reactions [ 216 ], further categorized into type A and type B.

Type A reactions occur in approximately 4 out of every 100,000 dialysis treatments, typically within the first few minutes of the session. Symptoms range from mild manifestations such as pruritus, urticaria, flushing, cough, wheezing, chest or abdominal pain, diarrhea, and chills to severe complications including laryngeal edema, dyspnea, bradycardia, hypotension, cardiorespiratory arrest, and even death [ 215 ]. The etiology is primarily linked to leachable substances from the dialyzer or bacterial peptide contamination, with the main culprit historically being ethylene oxide used in dialyzer sterilization. However, its presence in modern filters has significantly declined. Patients at higher risk include those with eosinophilia, as specific IgE antibodies against ethylene oxide have been detected in the most severe cases [ 217 ].

As previously mentioned, highly electronegative membranes, such as the AN69 membrane, may trigger type A anaphylactoid reactions. Concurrent use of angiotensin-converting enzyme inhibitors (ACEi) increases the risk of these reactions. It is important to note that the causes of these reactions are not limited to the activation of the kallikrein-kinin system with bradykinin release due to membrane interaction but also include other dialysis related causes such as the use of formaldehyde and heparin, as well as IgE-mediated allergic reactions such as latex and hypersensitivity to chlorhexidine [ 218 ]. Modifications have been made to AN69 membranes by neutralizing electronegativity with a layer of polyethylenimine (AN69 ST), reducing the risk of this reaction. These highly adsorbent membranes have also been evaluated for cytokine and endotoxin removal in sepsis patients [ 9 ].

Type B reactions are more common, occurring in up to 5% of dialysis treatments. They are more prevalent in cellulose-based membranes compared to more biocompatible synthetic alternatives [ 215 ]. Symptoms typically appear later, between 15 and 30 min into the session, and may improve with continued dialysis [ 219 ]. The pathogenesis involves complement system activation, leading to neutrophil sequestration in the pulmonary capillaries, mediated by C5a. This process results in a transient leukocyte reduction within the first hour of therapy, followed by a return to baseline or increased leukocyte levels [ 220 ].

Both type A and B anaphylactoid reactions can be mitigated by pre-rinsing the dialyzer before use, ensuring proper sterilization techniques, avoiding AN69 membranes in patients with eosinophilia or concurrent ACE inhibitor use, and opting for more biocompatible membranes. Dialyzer reuse may also provide a protective effect due to forming a protein layer that coats free hydroxyl groups, reducing the risk of reactions. Management is generally supportive. Type A reactions require immediate discontinuation of hemodialysis, while type B symptoms typically resolve over the course of treatment [ 221 ].

Infections

Hemodialysis patients are particularly susceptible to infections due to invasive vascular access and impaired phagocytic function, limiting their ability to combat pathogens [ 222 – 224 ]. Additionally, even after completing antibiotic treatment for sepsis, mortality rates remain elevated [ 225 ]. The type of dialysis membrane used may further influence the inflammatory and immune response, as higher membrane biocompatibility is associated with reduced complement activation. This may contribute to lower infection risk and improved survival when comparing conventional cellulose-based filters to high-flux synthetic polymer membranes [ 226 , 227 ].

Beyond the mechanical factors, inflammatory markers such as C-reactive protein (CRP), ferritin, and fibrinogen are often elevated in uremic patients, signaling acute inflammation and an increased cardiovascular risk. Conversely, negative acute-phase reactants like albumin and transferrin tend to decline in dialysis patients, reflecting an altered immune and nutritional status.

Patients treated with bioincompatible membranes, such as Cuprophan, exhibit higher complement activation, increased neutrophil degranulation, and more significant suppression of phagocyte function, all of which may contribute to immune dysfunction and heightened infection risk. In contrast, synthetic membranes generally induce a lower inflammatory response, with PMMA based membranes showing the least complement activation while simultaneously promoting a more favorable acute-phase response. Interestingly, PMMA membranes have also been shown to clear soluble CD40, a molecule critical for B-cell function, potentially improving vaccine response in dialysis patients [ 227 , 228 ].

Mineral bone disorder

Chronic kidney disease–mineral bone disorders encompass biochemical and hormonal alterations that are part of the complications linked to CKD progression. These disorders result from a complex interaction of several factors regulating bone formation and resorption.

To investigate the potential impact of the dialysis filter on the pathogenesis of bone disorders in CKD, a prospective study was conducted involving 24 patients. These patients were randomly assigned to one of two groups: one undergoing hemodialysis with a cellulose filter and the other with a synthetic filter (polyacrylonitrile) over nine months. Although both groups started with similar parathyroid hormone levels, significant differences were observed during follow up. Specifically, in the group with the synthetic filter, a significant decrease in plasma insulin-like growth factor I (IGF-1) levels was recorded (associated with a reduction in bone turnover), along with a decrease in the surface area of osteoblasts and osteoclasts, as well as in the number of osteoclasts. Additionally, a non-significant decrease of 31% in the rate of bone formation was observed (in contrast to a 50% increase in the cellulose filter group). These findings indicate an increase in the number and activity of bone cells, resulting in increased bone turnover in patients treated with cellulose membranes compared to synthetic membranes, which could be explained by biocompatibility phenomena generated by the HD membrane [ 229 – 231 ].

Nutritional status

Hypoalbuminemia has been linked to increased morbidity and mortality in hemodialysis patients with CKD. However, this association can be confounding, as it serves as a marker for malnutrition and inflammation, which are the true underlying causes of this relationship [ 232 ]. Although hypoalbuminemia may partly reflect the chronic inflammation caused by the bioincompatibility of the hemodialysis membrane and/or the loss of plasma albumin during the process, either by adsorption or filtration (although this occurs to a lesser extent with most conventional membranes due to their larger molecular size). Regarding nutritional status, a study in healthy individuals simulating blood passage through a dialyzer for 150 min found increased protein catabolism with synthetic membranes (polyacrylonitrile) compared to cellulose membranes [ 233 ]. Studies suggest that patients treated with more biocompatible membranes exhibit higher plasma albumin levels, increased IGF-1 concentrations, and more significant body mass gain over 18 months than those using bioincompatible membranes​. Additionally, while high-flux membranes enhance toxin clearance, they may also lead to increased amino acid losses, potentially impacting protein metabolism​ [ 234 , 235 ].

Like albumin, transferrin is a negative acute phase protein whose synthesis is suppressed by the inflammatory response. Hypotransferrinemia is common in hemodialysis patients and is another cause of anemia in CKD patients. Transferrin is also adsorbed by the dialysis membrane, as described in the Vroman model [ 59 ].

Dialyzer reuse

Dialyzer reuse, defined as the repeated use of the same dialyzer for multiple hemodialysis sessions in a patient, began in the 1960s, and although less common today, it is still practiced in resource limited settings [ 236 ]. In the past, reuse was justified due to purported increased biocompatibility, as seen in studies showing lower complement activation with the reuse of Cuprophan membranes, attributing this to the formation of a protein pseudo-layer that disrupted the biomaterial’s contact with the blood complement system [ 98 ]. However, this protein layer also contributes to membrane fouling. Evidence shows that clearance values ​​for α1-microglobulin decrease gradually and those for albumin decrease abruptly with time, mainly due to membrane plugging by proteins [ 237 ].

Additionally, reuse also reduces the risks of first-use syndrome, which is due to a type A IgE-mediated allergic reaction associated with sensitization to ethylene oxide, a sterilizing agent used in the manufacture of current dialyzers that deposits in the polyurethane filler used to secure the hollow fibers within the dialyzer. Contrary to the aforementioned, biocompatibility is a multifactorial concept involving the selection of more suitable biomaterials, such as current synthetic polymer filters instead of cellulose. Reuse is considered detrimental and may trigger adverse events, such as infections by gram negative bacteria and antibody induced anaphylactic reactions due to exposure to germicides [ 151 , 236 ].

A growing concern in hemodialysis is the potential exposure of patients to high levels of microplastics and nanoplastics (1 nm to < 5 mm). Research has indicated that people undergoing hemodialysis may accumulate more microplastics than the general population, raising questions about the origin of these particles. Among these, dialyzers are composed of plastic polymeric materials. It can also be caused by deteriorated reverse osmosis (RO) membranes or the degradation of synthetic RO membranes. Other sources include plastic pipes used to transport water, plastic storage tanks, and leaching from plastic containers containing acid concentrates and bicarbonate solutions may contribute to microplastic release, particularly since sterilization techniques such as irradiation may alter polymer integrity and plasticizer stability. Furthermore, reuse of the dialyzer could further compromise membrane integrity, potentially increasing the risk of microplastic exposure [ 238 ]. While this remains a theoretical risk, it has not yet been systematically explored in the literature. Nevertheless, no randomized studies have demonstrated adverse clinical outcomes. A systematic review based on observational studies concluded no difference in mortality between reuse and single use hemodialysis filters. The current trend favors single-use dialysis, promoting continuous improvement and innovation in biomaterials increasingly compatible with the organism [ 236 , 239 ].

Biocompatibility in acute kidney injury

In contrast to the clinical evidence in patients with chronic kidney disease, evidence regarding the use of biocompatible membranes in acute kidney injury (AKI) appears contradictory [ 240 – 242 ]. In an animal model of AKI, exposure to Cuprophan versus synthetic polymeric hemodialysis membranes resulted in neutrophil infiltration within the glomeruli and a delayed recovery of renal function [ 243 ]. Initial studies assessing the effects of biocompatible membranes in AKI showed significant renal function recovery and a trend towards improved survival [ 194 , 244 , 245 ]. However, a systematic review of 1100 adults with AKI comparing the use of biocompatible membranes (primarily synthetic) versus bioincompatible membranes (defined by their cellulose derived composition) found no significant differences in mortality (RR 0.93; 95% CI: 0.81 to 1.07) or renal function recovery (RR 1.09; 95% CI: 0.90 to 1.31). In the same study, there were no differences by type of dialyzer (high vs. low-flux) in subgroup analysis [ 242 ].

Several methodological and clinical factors can explain the conflicting evidence on the impact of biocompatible membranes on AKI. Many studies have limitations, including small sample sizes, the lack of standardized protocols, and inadequate blinding. Furthermore, there is no universally accepted definition of “biocompatible” versus “bioincompatible” membranes, making cross-study comparisons difficult. Patient heterogeneity also plays an important role: clinical conditions such as sepsis, ischemia, oliguria, and various comorbidities influence both the inflammatory response and renal recovery. Likewise, technical parameters such as membrane surface area, modality (diffusive versus convective), session duration, KuF, KoA, and sterilization method can critically affect the biological response to dialysis. These combined variables contribute to the heterogeneity of the results and highlight the need for rigorously designed randomized studies with well-characterized AKI populations and standardized treatment protocols to accurately assess the clinical relevance of membrane biocompatibility in this setting [ 242 , 246 ].

Residual kidney function

Biocompatible membranes may help preserve residual renal function in chronic HD patients [ 247 – 251 ], although some studies suggest otherwise [ 252 ]. One study demonstrated that after 12 months, biocompatible membranes, compared to cellulose based ones, were more effective in maintaining residual urine output and slowing the decline in creatinine clearance [ 253 ].

Mortality associated with bioincompatible membranes

Although there are no prospective randomized studies on biocompatible membranes in patients with CKD on hemodialysis, several studies have shown better outcomes using synthetic filters. One study found lower mortality among patients using high-flux polysulfone membranes than cellulose membranes (7% vs. 20%), with no differences in hospital admissions [ 226 ].

Compared with more biocompatible synthetic polymer membranes, bioincompatible membranes, such as cellulose-based filters, appear to be associated with an increased risk of dialysis related amyloidosis. This condition is characterized by the accumulation and tissue deposition of amyloid fibrils composed of beta-2 microglobulin, primarily affecting bone, periarticular structures, and visceral organs in patients with end-stage renal disease [ 248 , 254 – 256 ].

In a post hoc analysis of the 4D study, which compared four different types of dialysis membranes, low-flux cellulose derived membranes showed significantly higher mortality than semi synthetic low-flux membranes [ 257 ].

Perspectives for future research

This review has primarily focused on membrane biocompatibility; however, membrane clearance properties are also critical, as they directly influence biocompatibility. One such factor is the boundary layer effect, a mass and fluid transport phenomenon in dialysis membranes. This effect forms a stationary or slow-moving fluid layer at the interface between the flowing liquid and the membrane surface. Within this boundary layer, solute movement is significantly reduced due to the lower flow velocity, creating an additional resistance to substance exchange.

A thick boundary layer can have dual negative effects: first, it can establish a concentration gradient that impairs solute diffusion from the blood to the dialysate—a phenomenon known as concentration polarization—ultimately reducing dialysis efficiency. Second, it can promote protein adsorption onto the membrane surface, contributing to fouling and triggering bioincompatibility-related processes [ 12 , 54 , 258 , 259 ].

Furthermore, purification allows for a decrease in uremic toxins, which favors a decrease in the inflammatory state, an improvement in the quality of life, and a decrease in mortality [ 260 , 261 ]. However, the intrinsic biocompatibility of the membrane remains a key determinant of blood-material interactions [ 12 , 262 ].

A greater understanding of the pathophysiological processes involved in biocompatibility could reduce the risks associated with the subsequent activation of inflammation and coagulation, not only in relation to hemodialysis therapy, since the protein adsorption process is a common event in the interaction between any medical device that interacts with blood.

There are areas of knowledge gaps to investigate. In clinical practice, renal replacement therapy (RRT) encompasses a diverse range of modalities (Fig. 6 ), each defined by critical factors such as the primary transport mechanism between compartments—whether diffusion, convection, adsorption, or a combination thereof—along with blood flow rates (Q b ), dialysate flow (Q d ), and ultrafiltration rates (Q uf ). Additionally, the duration of therapy (Q t ) varies significantly, spanning from intermittent therapies (3–4 h) to prolonged intermittent (8–12 h) and continuous therapies “CRRT” (≥ 24 h). Generally, though not exclusively, specific modalities are employed for chronic kidney disease patients, such as intermittent hemodialysis (IHD) and hemodiafiltration (HDF), which combine diffusive and convective transport. In contrast, acute kidney injury or critically ill patients often require other RRT modalities, including slow continuous ultrafiltration (SCUF), continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemodiafiltration (CVVHDF), sustained low-efficiency dialysis (SLED), therapeutic plasma exchange (TPE), hemoperfusion (HP), continuous plasma filtration coupled with adsorption (CPFA), and high-volume hemofiltration (HVHF)(Fig. 6 ) [ 263 – 266 ].

Some evaluations of membrane biocompatibility within hemodiafiltration (HDF) have revealed that predilution HDF exhibits more excellent biocompatibility than postdilution HDF. This conclusion is based on the observation of reduced platelet activation in predilution HDF, where the dilution of blood leads to lower viscosity and, consequently, diminished shear stress, thereby decreasing cellular activation. Additionally, the dilution effect mitigates the production of hydroxyl radicals, resulting in lower inflammation and enhanced biocompatibility in this modality [ 263 ].

Extracorporeal adsorption techniques, such as hemoperfusion (HP) and plasma filtration adsorption (PFAD), represent distinct modalities of renal replacement therapy (RRT) that, unlike other therapies, employ adsorbent materials to remove specific molecules from the blood. They are manufactured from materials including activated charcoal, ion exchange resins, and polymyxin B, which are packaged in cartridges designed with a tortuous path to maximize contact with blood or another fluid phase such as plasma and the adsorbent, thereby facilitating effective removal of target solutes. These solute removal modalities have been used to treat endotoxins and cytokines in infections, sepsis, poisoning, and immunoregulation conditions. Early trials of these techniques have been associated with bioincompatibility events, including thrombocytopenia, leukopenia, hypoglycemia, hypocalcemia, and aluminum leaching. Modern adsorbents are designed to improve biocompatibility through specific coatings that encase the particles with biocompatible layers. In addition, bioincompatibility can be further prevented by separating plasma from blood prior to circulation through the adsorbent bed. After passage through the adsorbent cartridge, blood and plasma components are recombined again, effectively preventing cellular bioincompatibility reactions [ 24 , 267 ].

No randomized study has rigorously compared changes in biocompatibility by RRT modality. The existing research predominantly focuses on diffusive therapies, such as intermittent hemodialysis. In general, while existing studies assess the clinical outcomes associated with various RRT modalities, they fall short of thoroughly exploring the intricate interactions between blood components and the artificial membrane—specifically, the phenomena of biocompatibility or bioincompatibility that arise as a consequence of the RRT modality employed.

It is important to mention that research and innovation are also required for a quantitative evaluation at a clinical level of the biocompatibility phenomenon, such as the development of real-time biosensors or a biomarker representative of the activation of pathological processes in the membrane, such as Kt/V for the evaluation of the effectiveness of the clearance of uremic toxins. However, the latter has important limitations, it has allowed comparisons and clinical studies, which, by taking it to the study of biocompatibility, will allow progress towards the personalization of dialysis therapy.

Artificial intelligence-based models are currently used to study protein adsorption and biocompatibility [ 90 , 268 – 271 ]. These experimental tools provide insights into the interactions between the artificial membrane material and blood supporting the development of next-generation biomaterials. Such biomaterials may mimic natural structural assembly, adapting to the spatial and temporal relationships of molecular events experienced by patients undergoing hemodialysis [ 5 , 91 , 272 ]. For instance, a recent study applied machine learning to predict protein-membrane interactions, identifying binding affinity as a key determinant of hemocompatibility. Using molecular docking data from 916 records, Random Forest Regression demonstrated the highest predictive accuracy (R² = 0.8987) in modeling plasma protein adsorption. The findings emphasize how surface properties—hydrophilicity, charge, and roughness—modulate protein interactions, thrombin generation, and immune activation. This machine learning-driven approach is cost-effective for optimizing membrane design and minimizing reliance on trial-and-error testing [ 93 ].

Despite significant advances in improving membrane biocompatibility, the development of real-time biosensors integrated into dialysis systems remains a largely unexplored but promising frontier. Current innovations have focused on membrane engineering and proteomic profiling to predict protein adsorption patterns and inform the customization of membrane selection. Although the adsorption of plasma proteins—particularly following the Vroman effect, plays a key role in initiating blood membrane interactions, its direct translation into clinical consequences in dialysis patients remains unclear and insufficiently demonstrated in current literature. Further studies are needed to elucidate this potential link and its relevance in long-term outcomes. However, future dialysis systems could benefit from integrated biosensor platforms capable of monitoring key biocompatibility indicators, such as complement activation products, platelet activation markers, or oxidative stress, in real time. Beyond specific membrane improvements, the field of renal replacement therapy is advancing toward transformative technologies such as bioartificial kidneys (BAKs) and wearable or implantable artificial kidneys (WAKs/IAKs). These systems, exemplified by the KidneyX initiative, seek to replicate the excretory and endocrine functions of native kidneys. Notably, BAK models incorporating conditionally immortalized human proximal tubular cells (ciPTEC) have shown promise for secretory clearance, albumin reabsorption, and hormonal regulation. However, a common challenge for these technologies is controlling the immune response. Whether through material selection, cell encapsulation, or biosensing, future innovations must integrate immunomodulatory strategies to ensure safety and efficacy in both acute and chronic settings [ 273 ].

Conclusions

The interaction between cellular and non-cellular components of blood with the hemodialysis membrane is a critical factor that significantly influences dialysis therapy’s biocompatibility and overall effectiveness [ 274 ]. Structural characteristics of the membranes play a pivotal role in protein adsorption, which is central to the pathological processes associated with bioincompatibility.

While emerging technologies, such as superhydrophilic or AI-optimized membranes, hold promise for improving biocompatibility and personalized therapy, their long-term safety profiles must be critically evaluated. Synthetic dialyzers, particularly those based on PES, PSU, and PVP, can degrade over time or under certain conditions (e.g., sterilization, storage, chemical exposure), potentially releasing harmful byproducts. For example, loss of PVP has been associated with decreased membrane performance, complement activation, and potential albumin leakage. Furthermore, regulatory agencies such as the US FDA have raised concerns about the leaching of microplastics or chemicals into dialysis systems, including the detection of non-dioxin-like polychlorinated biphenyl acids (NDL-PCBAs) in components such as silicone tubing. While manufacturers have taken steps to replace such materials with safer alternatives (e.g., platinum-catalyzed silicone), comprehensive preclinical and clinical testing remains limited. Furthermore, reuse protocols, sterilization methods, and environmental factors can further influence membrane integrity. As new materials and intelligent systems are introduced, rigorous long-term evaluations will be essential to balance innovation with safety, especially in vulnerable populations such as patients with chronic kidney disease [ 275 , 276 ].

As the field of dialysis advances toward more biocompatible and personalized therapies, environmental sustainability must become a parallel priority. Hemodialysis therapies carry a substantial ecological burden, with each session consuming between 120 and 500 L of water and generating approximately 2.5 kg of clinical waste—38% of which is plastic—resulting in up to 72,000 L of water used and 390 kg of waste produced annually per patient [ 273 , 277 ]. Beyond resource consumption, concerns have emerged regarding potential microplastic and chemical contamination of water sources from discarded dialyzers. Therefore, innovation in renal replacement therapies must not only ensure patient safety and therapeutic efficacy, but also incorporate environmentally responsible practices across the full life cycle of the dialyzer—from manufacturing and sterilization to clinical use and disposal.

The constant development of dialysis membranes has allowed for improvement in the clinical results of patients with chronic kidney disease, from the first artificial kidney by W. Kolff, a perfect example of continuous innovation, through the beginnings, with the surprising use of sausage casing as the first dialysis membrane, to current filters. Biocompatibility is the key concept to address for the development of future artificial organs.

Acknowledgements

We thank Dr. Juan Andrés Orellana R., PhD, Associate Professor at Pontificia Universidad Católica de Chile, for his valuable support in understanding cellular interaction mechanisms.

Abbreviations

Adenosine Diphosphate

Adenosine Triphosphate

Continuous Plasma Filtration with Adsorption

Continuous Renal Replacement Therapy

Cellulose Triacetate

Continuous Veno–Venous Hemofiltration

Continuous Veno–Venous Hemodialysis

Continuous Veno–Venous Hemodiafiltration

Hemodiafiltration

High Molecular Weight Kininogen

Hemoperfusion

High–Volume Hemofiltration

Intermittent Hemodialysis

1–Insulin–like Growth Factor 1

Membrane Attack Complex

Platelet–Derived Growth Factor

4–Platelet Factor 4

Blood Flow Rate

Dialysis Flow Rate

Effluent Flow Rate

R–Replacement Plasma Flow Rate

UF–Plasma Ultrafiltration Flow Rate

Therapy Time

Ultrafiltration Rate

Reverse Osmosis

Reactive Oxygen Species

Renal Replacement Therapy

Slow Continuous Ultrafiltration

Stress–Induced Premature Senescence

Sustained Low–Efficiency Dialysis

Therapeutic Plasma Exchange

Vascular Endothelial Growth Factor

Author contributions

Conception: Eduardo Avila; Literature, analysis and paper writing: E.A. and D.H. ; R.S. and J.R. critically reviewed the manuscript. All authors read and agreed on the final version of the paper.

Funding

D.H. Acknowledges the support from Agencia Nacional de Investigación y Desarrollo/ Fondecyt de Iniciación 11240633. E.A Acknowledges the support Agencia Nacional de Investigación y Desarrollo/ Beca Doctorado Nacional ANID N°21231166. J.R. Acknowledges the support from Agencia Nacional de Investigación y Desarrollo/ Fondecyt Regular 1241897.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.