Microparticles at the crossroads of the gut-kidney axis: Mechanistic drivers and therapeutic horizons in hemodialysis

Abstract

Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) pose significant global health challenges, with hemodialysis serving as a vital treatment for ESKD patients. Despite its life-sustaining role, hemodialysis is associated with elevated cardiovascular morbidity and mortality, driven in part by the accumulation of uremic toxins. Recent research underscores the gut-kidney axis as a pivotal contributor to CKD progression and its complications, with gut microbiota dysbiosis amplifying uremic toxin production. Microparticles (MPs)-small extracellular vesicles released from cells-have emerged as key mediators in intercellular communication, inflammation, and vascular dysfunction. This review examines the role of MPs in the gut-kidney axis, with a focus on their contribution to uremic toxicity and clinical outcomes in hemodialysis patients. We explore how MPs, originating from endothelial cells, platelets, and gut microbiota, transport bioactive molecules, intensify inflammation, and impair endothelial function, thereby heightening cardiovascular risk. Furthermore, we assess their potential as biomarkers of disease severity and as novel therapeutic targets. By integrating current evidence, this review elucidates the intricate interplay between MPs, the gut-kidney axis, and uremic toxicity, offering fresh insights into improving outcomes for hemodialysis patients.

Key Words: Microparticles; Gut-kidney axis; Hemodialysis; Uremic toxins; Chronic kidney disease

Core Tip: Microparticles (MPs) are increasingly recognized as pivotal mediators in the gut-kidney axis, particularly in hemodialysis patients. This review elucidates how gut dysbiosis triggers the release of host and microbial MPs, which transport uremic toxins and pro-inflammatory cargo to drive endothelial dysfunction and cardiovascular complications. By synthesizing current evidence on MP biogenesis and their role as biomarkers, we highlight novel therapeutic horizons, including microbiota modulation and MP-targeted interventions, aimed at disrupting this pathogenic dialogue to improve clinical outcomes in end-stage kidney disease.

INTRODUCTION

Chronic kidney disease (CKD) is a global health burden, affecting over 850 million people worldwide, with end-stage kidney disease (ESKD) representing its most severe form[1]. Hemodialysis, the primary treatment modality for ESKD, sustains life but is associated with significant complications, particularly cardiovascular disease (CVD), which accounts for nearly half of all deaths in this population[2]. The high cardiovascular mortality in hemodialysis patients is driven, in part, by the retention of uremic toxins-waste products that accumulate due to impaired renal clearance[3]. Among these, protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (p-CS) are particularly problematic, as they are poorly removed by dialysis and contribute to endothelial dysfunction, oxidative stress, and inflammation[4].

Emerging evidence highlights the gut-kidney axis as a critical pathway in CKD progression and uremic toxicity[5]. The gut microbiota, a diverse community of microorganisms, plays a pivotal role in metabolizing dietary components into precursors of uremic toxins[6]. In CKD and ESKD, dysbiosis-an imbalance in gut microbiota composition-exacerbates the production of these toxins, further amplifying their systemic effects[7]. However, the mechanisms linking gut-derived uremic toxins to distal organ damage, particularly the cardiovascular system, remain incompletely understood.

Microparticles (MPs), small extracellular vesicles (EVs) (0.1-1 μm) released from various cell types, including endothelial cells, platelets, and leukocytes, have recently garnered attention for their role in intercellular communication and disease pathogenesis[8]. These vesicles carry bioactive molecules such as proteins, lipids, and nucleic acids, and can transfer these cargoes to target cells, influencing inflammation, coagulation, and vascular function[9]. In the context of CKD and hemodialysis, elevated levels of circulating MPs, particularly endothelial-derived MPs (EMPs), have been associated with vascular injury and inflammation[10]. Moreover, recent studies suggest that metabolites or MPs may also originate from gut microbiota, potentially serving as vehicles for the transport of microbial products, including uremic toxin precursors[11].

This review explores the hypothesis that MPs act as mediators in the gut-kidney axis, linking gut microbiota dysbiosis, uremic toxin production, and adverse clinical outcomes in hemodialysis patients. We examine the dual origin of MPs-from host cells and the microbiota-and their potential to transport or amplify the effects of uremic toxins, thereby contributing to systemic inflammation and cardiovascular complications. Additionally, we assess the utility of MPs as biomarkers for disease severity and their potential as therapeutic targets. By synthesizing current evidence, this review aims to provide a comprehensive understanding of the role of MPs in uremic toxicity and to highlight novel avenues for improving outcomes in hemodialysis patients.

GUT-KIDNEY AXIS: A CRITICAL INTERFACE IN RENAL HEALTH AND DISEASE

The gut-kidney axis refers to the bidirectional relationship between the gastrointestinal tract and the kidneys, where each organ system influences the function and health of the other[5]. This axis has gained increasing recognition as a critical factor in the pathogenesis and progression of CKD and its complications, particularly in patients with ESKD requiring hemodialysis[2].

In health, the gut microbiota plays a vital role in metabolizing dietary components, producing beneficial metabolites such as short-chain fatty acids (SCFAs) that support gut barrier integrity and immune regulation[12]. However, in CKD, this symbiotic relationship is disrupted. The uremic environment alters gut microbiota composition, leading to dysbiosis characterized by an overgrowth of pathogenic bacteria and a reduction in beneficial species[6]. Conversely, the altered gut microbiota contributes to the production of uremic toxins, such as IS and p-CS, which are derived from bacterial metabolism of tryptophan and tyrosine, respectively[4]. These toxins, in turn, exacerbate kidney damage and contribute to systemic inflammation and CVD[3].

Uremic toxins are a diverse group of compounds that accumulate in the blood as renal function declines. Among them, protein-bound toxins like IS and p-CS are particularly problematic because they are poorly removed by conventional hemodialysis due to their high affinity for plasma proteins[13]. These toxins originate from the gut, where specific bacterial species metabolize amino acids into precursors that are further processed by the liver into the final toxic compounds[14]. Once in circulation, IS and p-CS induce oxidative stress, endothelial dysfunction, and fibrosis in the kidneys and other organs, thereby accelerating CKD progression and increasing the risk of cardiovascular events[15].

In hemodialysis patients, the gut-kidney axis takes on added significance. The persistent elevation of uremic toxins, despite regular dialysis, contributes to the high burden of CVD and mortality in this population[2]. Moreover, the hemodialysis procedure itself may further disrupt gut microbiota, creating a vicious cycle of dysbiosis and toxin production[16]. Understanding and targeting the gut-kidney axis offers a promising avenue for therapeutic interventions, such as probiotics, prebiotics, or adsorbents, aimed at reducing uremic toxin levels and improving clinical outcomes[17].

MICROBIOTA-DERIVED UREMIC TOXINS: PRODUCTION, ACCUMULATION, AND SYSTEMIC EFFECTS

Uremic toxins are a diverse group of compounds that accumulate in the blood and tissues due to impaired kidney function, contributing to the uremic syndrome in CKD and ESKD patients[3,18]. Among these, microbiota-derived uremic toxins, such as IS and p-CS, are protein-bound solutes that play a critical role in systemic complications, particularly in hemodialysis patients[4].

Production of microbiota-derived uremic toxins

The gut microbiota initiates the production of uremic toxins by metabolizing dietary amino acids into precursor compounds[14]. Key examples include IS generated from tryptophan metabolism by gut bacteria such as Escherichia coli and Clostridium species. These microbes convert tryptophan into indole, which is absorbed and subsequently oxidized in the liver to form IS[19]. Likewise, p-CS is derived from the fermentation of tyrosine and phenylalanine by bacteria like Bacteroides and Clostridium species. The resulting p-cresol is sulfated in the liver to produce p-CS[20].

In healthy individuals, these toxins are efficiently cleared by the kidneys. However, in CKD and ESKD, reduced glomerular filtration rate leads to their retention[18]. Additionally, CKD-associated dysbiosis amplifies toxin production by shifting the microbial balance toward toxin-generating species, influenced by factors such as low dietary fiber, elevated colonic pH, and the uremic environment[6,21].

Accumulation in hemodialysis patients

Hemodialysis is notably ineffective at removing protein-bound uremic toxins like IS and p-CS due to their strong binding to plasma proteins, such as albumin, which limits their free fraction and dialytic clearance[22]. Research indicates standard hemodialysis removes only 20%-30% of IS and p-CS, compared to over 70% for small, water-soluble toxins like urea[23]. As a result, hemodialysis patients exhibit serum IS and p-CS levels 10- to 100-fold higher than healthy individuals[15]. Persistent dysbiosis sustains toxin production, perpetuating a cycle of accumulation and microbial imbalance[7].

Systemic effects of uremic toxins

Microbiota-derived uremic toxins exert profound systemic effects, significantly contributing to morbidity and mortality in hemodialysis patients. CVD is the predominant cause of mortality in CKD and hemodialysis patients, responsible for approximately 50% of deaths[24]. Uremic toxins play a critical role in CVD pathogenesis by inducing oxidative stress, endothelial dysfunction, and vascular calcification[15,25]. Furthermore, these toxins promote cardiac fibrosis and left ventricular hypertrophy, amplifying cardiovascular risk[26]. These mechanisms collectively underscore the profound impact of uremic toxicity on the cardiovascular system and mortality[27]. Another notable impact involves the renal system; these toxins hasten CKD progression by triggering renal fibrosis, tubular damage, and inflammation, with IS activating the renin-angiotensin system and epithelial-to-mesenchymal transition[28,29]. In addition, IS and p-CS disrupt immune function by enhancing leukocyte activation and cytokine release, fueling chronic inflammation and infection risk[30-32]. This chronic inflammatory state accelerates atherosclerosis and impairs erythropoiesis[33]. Additionally, it has been linked to cognitive decline and peripheral neuropathy[34,35]. The inflammation also exacerbates muscle wasting and malnutrition while heightening infection risk, all of which compound patient morbidity[36]. Regarding bone and mineral metabolism, both impair bone turnover by inhibiting osteoblast activity and stimulating osteoclasts, worsening CKD-mineral and bone disorder[37,38]. To sum up, the clinical consequences of uremic toxicity in hemodialysis patients extend well beyond renal impairment leading to CVD, chronic inflammation, and other systemic complications. These effects significantly influence patient outcomes, emphasizing the need for targeted therapeutic strategies to mitigate their impact.

MPS: EMERGING PLAYERS IN THE GUT-KIDNEY DIALOGUE

EVs are membrane-bound structures released from cells, comprising two main subtypes: MPs and exosomes (Figure 1). MPs are typically submicron-sized vesicles (ranging from 100 nm to 1000 nm), whereas exosomes are smaller, nanometer-scale vesicles (< 150 nm). Both carry a variety of intracellular cargos, including RNAs, proteins, and lipids derived from their parent cells, and are commonly released in response to cellular activation, stress, or apoptosis. Indeed, MPs are small vesicles generated through outward blebbing of the plasma membrane, a process where the membrane bulges outward and pinches off. This formation occurs selectively in lipid-rich microdomains, such as lipid rafts or caveolae, within the membrane. The process involves several key mechanisms including cytoskeletal reorganization, wherein changes in the cell’s structural framework facilitate the blebbing, alterations in phospholipid symmetry, and enzyme and calcium dependence. Outward blebbing is influenced by various enzymes and an influx of calcium ions, originates from direct outward budding of the plasma membrane, and is shed by diverse cell types such as endothelial cells, platelets, and even bacteria during physiological or pathological stimuli[39], making them critical mediators of intercellular communication[39,40]. In the context of kidney disease, MPs are increasingly implicated in driving pathological processes such as inflammation, endothelial dysfunction, and fibrosis, thereby exacerbating disease progression. The gut-kidney axis, a bidirectional communication pathway between the gut microbiota and renal system, has emerged as a significant area of interest, with MPs potentially serving as novel mediators in this dialogue.

Figure 1 Biogenesis and functional roles of extracellular vesicles. Exosomes (depicted in yellow; 30-100 nm in diameter) are generated within multivesicular bodies (MVBs) as intraluminal vesicles and are secreted upon fusion of the MVB with the plasma membrane. In contrast, microparticles [microparticles (MPs); shown in blue; 100-1000 nm] arise through direct outward budding of the plasma membrane and are enriched in cytosolic content and phospholipid components. Both classes of extracellular vesicles (EVs) contribute to intercellular communication by facilitating antigen presentation (via major histocompatibility complex peptide complexes), transferring surface receptors, or directly modulating signaling pathways. Additionally, EVs act as carriers for functional cargo such as proteins, transcription factors, and regulatory RNAs (including microRNAs and messenger RNAs). The precise mechanisms underlying EV uptake remain incompletely characterized, but may involve: (1) Receptor binding; (2) Endocytosis or micropinocytosis; and (3) Direct membrane fusion-mediated signaling. Created by BioRender. MVB: Multivesicular bodies.

Expanded role of MPs in the gut-kidney axis

Emerging evidence underscores the significance of MPs as mediators within the gut-kidney axis, particularly in CKD. Gut dysbiosis, a hallmark of CKD, disrupts intestinal barrier integrity, facilitating the translocation of bacterial products-including MPs-into the systemic circulation[5]. These bacterial MPs, laden with pathogen-associated molecular patterns such as lipopolysaccharide, can engage toll-like receptors on renal cells, initiating inflammatory cascades that exacerbate kidney injury[41]. Additionally, MPs shed from stressed intestinal epithelial cells may encapsulate microRNAs or proteins that influence renal cell behavior. For instance, a study demonstrated that MPs carrying miR-155 from gut epithelial cells could modulate pro-fibrotic gene expression in renal tubular cells, suggesting a direct link between gut-derived MPs and kidney pathophysiology[42]. This crosstalk positions MPs as critical vectors transmitting gut microenvironment signals to the kidneys, amplifying disease progression.

Mechanisms of MP-mediated kidney pathology

Within the renal microenvironment, MPs exert multifaceted effects that drive hallmark pathological processes of kidney disease, including inflammation, endothelial dysfunction, and fibrosis. Endothelial MPs, which are elevated in CKD, impair nitric oxide (NO) bioavailability and heighten oxidative stress, compromising endothelial function and contributing to microvascular rarefaction[43]. Concurrently, MPs from activated leukocytes deliver pro-inflammatory cytokines and chemokines to the renal parenchyma, intensifying local inflammation[44]. Fibrosis is further propelled by MPs; platelet-derived MPs, for example, have been shown to transfer growth factors that stimulate fibroblast proliferation and collagen deposition[45]. Moreover, MPs can enhance thrombotic tendencies by serving as a scaffold for coagulation factor assembly, a complication frequently observed in advanced CKD[46]. These diverse mechanisms highlight the complex role of MPs in renal pathology and their potential as both biomarkers and therapeutic targets in the gut-kidney dialogue.

CHRONIC LOW-GRADE INFLAMMATION AND ENDOTHELIAL ACTIVATION IN CKD

Chronic low-grade inflammation is a well-established driver of CKD progression and a hallmark of the uremic environment. Impaired renal clearance leads to systemic accumulation of proinflammatory cytokines, including interleukin-6 (IL-6), interleukin-1beta, and tumor necrosis factor alpha (TNF-α), which exacerbate vascular injury through endothelial dysfunction. These cytokines reduce eNOS expression and impair NO bioavailability, thereby increasing endothelial permeability and leukocyte adhesion via pathways such as STAT3 and NF-κB signaling[47-49]. Circulating inflammatory markers including high sensitivity C-reactive protein and IL-6 independently predict cardiovascular outcomes in CKD patients[50,51]. Notably, MPs derived from activated leukocytes and intestinal epithelial cells may act as carriers of these cytokines or microRNAs, enabling remote modulation of endothelial behavior in the kidney[52].

OXIDATIVE STRESS AND THE ROLE OF MPS

Oxidative stress, primarily driven by NOX family activation, is another major contributor to endothelial injury in CKD. Uremic toxins such as IS and p-CS stimulate NADPH oxidases (NOX1, NOX2, NOX4), resulting in excessive reactive oxygen species (ROS) and eNOS uncoupling, a process further exacerbated by altered high-density lipoprotein and low-density lipoprotein particles due to posttranslational modifications[53-55]. MPs, especially those originating from oxidative-stressed cells, can propagate this dysfunction through vesicular transport of oxidized proteins and ROS-inducing cargo[56]. This MP-mediated signaling may amplify endothelial injury and vascular calcification, thus linking local gut disturbances to systemic vascular pathology.

UREMIC TOXINS, MPS, AND ENDOTHELIAL INJURY

Uremic toxins themselves directly contribute to endothelial dysfunction by activating signaling pathways such as MAPK/NF-κB, CREB/ATF1, RAGE, and AhR, leading to proinflammatory cytokine release and reduced antioxidant defenses[56-59]. MPs act as intermediaries in this axis by encapsulating and delivering these toxins or related proinflammatory molecules to the endothelium. Evidence indicates that exposure of endothelial cells to uremic serum or specific toxins induces structural glycocalyx degradation, increased stiffness, and apoptosis-all of which are mechanistically linked to MP activity[60-62]. These observations suggest MPs are not merely byproducts of cellular damage but active conveyors of pathogenic signals in CKD.

METABOLIC ACIDOSIS AND SYMPATHETIC ACTIVATION ENHANCE MP-MEDIATED DAMAGE

Further contributing to the pathogenesis are metabolic acidosis and heightened sympathetic nerve activity. Acidic stress induces GPR4-mediated NF-κB activation and reduces NO/prostacyclin release from endothelial cells[63-65]. Simultaneously, increased sympathetic tone elevates catecholamines that disrupt endothelial integrity through adrenergic receptor stimulation, promoting glycocalyx loss[66,67]. These conditions are known to augment MP shedding, particularly from stressed vascular and intestinal cells[67]. Thus, MPs may integrate multiple upstream insults-microbiota-derived toxins, inflammatory cytokines, oxidative stress, and neurohumoral activation-into a unified pathogenic stream that culminates in endothelial dysfunction and cardiovascular risk in CKD.

To sum up, as shown in Figure 2, EVs, particularly MPs, are increasingly recognized as key mediators in the gut-kidney axis, driving pathological processes in CKD. Ranging from 100 nm to 1000 nm, MPs are shed from cells like endothelial cells, platelets, and bacteria, carrying cargos such as RNAs, proteins, and lipids that influence intercellular communication. In CKD, gut dysbiosis compromises intestinal barrier integrity, allowing bacterial MPs laden with pathogen-associated molecular patterns to enter the circulation and trigger renal inflammation via toll-like receptor activation. MPs from stressed intestinal epithelial cells further contribute by delivering microRNAs and proteins that modulate renal cell behavior, linking gut signals to kidney pathology. Within the kidney, MPs exacerbate endothelial dysfunction by reducing NO bioavailability and increasing oxidative stress, while leukocyte- and platelet-derived MPs intensify inflammation and fibrosis by transferring pro-inflammatory cytokines and growth factors. Uremic toxins, oxidative stress, metabolic acidosis, and sympathetic activation amplify MP shedding and effects, converging to heighten cardiovascular risk in CKD.

Figure 2 Role of microparticles in the gut-kidney axis in chronic kidney disease. This schematic diagram illustrates the pivotal role of microparticles (MPs) in mediating the gut-kidney dialogue in chronic kidney disease (CKD). It depicts how gut dysbiosis compromises the intestinal barrier, leading to a “leaky gut” that facilitates the translocation of bacterial MPs and lipopolysaccharide into the circulation. These gut-derived MPs, along with uremic toxins (e.g., indoxyl sulfate, p-cresyl sulfate) produced by the kidney contribute to systemic pathology. The figure further shows MPs shed from endothelial cells, platelets, and leukocytes, carrying pro-inflammatory cytokines, oxidized lipids, and other pathogenic cargos. These MPs drive endothelial dysfunction, renal inflammation, oxidative stress, and fibrosis, amplifying CKD progression. The diagram highlights the amplifying effects of uremic toxins, metabolic acidosis, and sympathetic activation on MP-mediated damage, culminating in increased cardiovascular risk. Created by BioRender. LPS: Lipopolysaccharide; ROS: Reactive oxygen species.

MPs as biomarkers in CKD and hemodialysis

Diagnostic potential: MPs as indicators of disease severity and cardiovascular risk. MPs, particularly those originating from endothelial cells and platelets, have gained significant attention as biomarkers for assessing disease severity and cardiovascular risk in CKD and hemodialysis patients. Elevated circulating levels of EMPs correlate strongly with endothelial dysfunction and increased cardiovascular morbidity[10]. EMPs, identified by surface markers such as CD31 and CD144, reflect vascular injury and inflammation and have been consistently linked to disease progression and severity[44]. Furthermore, platelet-derived MPs expressing markers such as CD41 and CD62P have shown promise as indicators of heightened thrombotic risk, a critical concern in hemodialysis patients due to their elevated cardiovascular event rates[46].

Prognostic value: Correlation with mortality and dialysis outcomes

MPs not only serve diagnostic purposes but also provide prognostic information regarding patient outcomes. Several studies have demonstrated a robust correlation between high levels of MPs and increased all-cause and cardiovascular mortality in CKD and hemodialysis patients. For example, circulating EMP levels have been independently associated with mortality risk, highlighting their utility in identifying patients at greatest risk for adverse outcomes[9,10]. Additionally, MP levels appear predictive of dialysis efficacy and complications, as they inversely correlate with dialysis adequacy parameters like Kt/V and directly correlate with inflammatory markers such as C-reactive protein and IL-6[44]. Thus, MPs represent valuable prognostic markers that can enhance clinical decision-making and patient stratification.

Technical challenges: Standardization of detection methods

Despite promising clinical implications, the translation of MP measurements into routine clinical practice faces several technical challenges, primarily the lack of standardized detection methods. Flow cytometry, the most common technique for MP quantification, suffers from variability in protocols, instrument sensitivity, and data interpretation[45]. Moreover, inconsistencies in pre-analytical variables, including sample collection, storage, and processing, significantly affect the reproducibility and comparability of MP studies. Efforts toward standardizing methods, such as the use of calibrated beads for size and fluorescence intensity, uniform gating strategies, and consensus-driven reporting standards, are essential to overcome these limitations and facilitate clinical adoption[44,45].

THERAPEUTIC TARGETING OF MPS AND THE GUT-KIDNEY AXIS IN CKD

The gut-kidney axis and MPs represent critical therapeutic targets in CKD, particularly for hemodialysis patients where uremic toxicity drives poor clinical outcomes. The interplay between gut microbiota dysbiosis, uremic toxin production, and MP-mediated systemic effects amplifies inflammation, endothelial dysfunction, and cardiovascular risk[5,9]. Below, we explore current strategies, emerging therapies, and future directions for addressing these pathways, aiming to reduce uremic toxin burden and MP-related pathology.

Current strategies

Current therapeutic approaches primarily target the gut-kidney axis to limit the production and systemic impact of uremic toxins, such as IS and p-CS, which are poorly cleared by hemodialysis[13]. These toxins, derived from microbial metabolism of dietary amino acids, exacerbate CKD progression and cardiovascular complications[15]. Strategies as follows.

Probiotics and prebiotics: These interventions seek to restore gut microbiota homeostasis, reducing dysbiosis and subsequent uremic toxin production. Probiotics introduce beneficial bacteria (e.g., Lactobacillus or Bifidobacterium), while prebiotics (e.g., inulin or fructooligosaccharides) promote their growth, shifting microbial metabolism away from toxin-generating pathways[5]. Clinical trials, such as the SYNERGY study, have demonstrated that synbiotic therapy (combined probiotics and prebiotics) can lower serum p-CS levels in CKD patients, suggesting a potential reduction in uremic toxicity[17]. By enhancing the production of SCFAs and reinforcing gut barrier integrity, these agents may also indirectly limit MP release from stressed intestinal epithelial cells[12].

Adsorbents: Oral adsorbents like AST-120 (an activated charcoal derivative) bind uremic toxin precursors, such as indole and p-cresol, in the gastrointestinal tract, preventing their absorption and hepatic conversion into IS and p-CS[17]. Randomized controlled trials have shown that AST-120 reduces serum IS levels and may slow CKD progression by alleviating oxidative stress and inflammation[22]. Although not directly targeting MPs, this approach mitigates the downstream inflammatory and endothelial effects that MPs amplify, offering a practical, albeit indirect, strategy to disrupt the gut-kidney-MP axis[15]. These interventions, while promising, are limited by variability in patient response, likely due to differences in baseline microbiota composition and toxin clearance efficacy during hemodialysis[6].

Emerging therapies

Emerging therapies aim to directly address MPs or their pathogenic cargos, offering novel ways to interrupt their role in uremic toxicity and vascular dysfunction. These approaches as follows.

Drugs inhibiting MP release: Statins, widely used for their lipid-lowering properties, also exhibit pleiotropic effects that reduce MP shedding from endothelial cells and platelets[43]. By stabilizing cell membranes and modulating cytoskeletal dynamics, statins decrease the release of proinflammatory and prothrombotic MPs in CKD patients[9]. Preclinical studies suggest that atorvastatin, for instance, reduces circulating endothelial MP levels, correlating with improved endothelial function and reduced cardiovascular risk[43]. This dual action-targeting both lipid metabolism and MP dynamics-positions statins as a promising therapeutic tool in hemodialysis patients, where cardiovascular mortality remains a leading concern[24].

Neutralizing proinflammatory cargo: MPs act as carriers of bioactive molecules, including cytokines (e.g., IL-6, TNF-α), microRNAs (e.g., miR-155), and oxidized lipids, which exacerbate inflammation and endothelial injury[44,45]. Emerging strategies focus on neutralizing or blocking these cargos to prevent their deleterious effects. For example, monoclonal antibodies or small-molecule inhibitors targeting specific MP-associated cytokines could dampen systemic inflammation[44]. Bioactive molecules like Annexin V, which bind phosphatidylserine residues on MPs, and integrin αvβ3 antagonists effectively prevent MP uptake and subsequent cellular activation in preclinical studies[10]. Novel extracorporeal techniques, including high-flux dialysis membranes or specialized adsorption columns, are also under investigation for physically removing MPs from circulation, potentially decreasing systemic inflammation during dialysis treatments[13,20]. Alternatively, RNA-based therapies (e.g., antisense oligonucleotides) might silence pathogenic microRNAs within MPs, a concept supported by studies showing miR-155’s role in renal fibrosis[42]. While still in early development, these precision approaches hold potential to disrupt MP-mediated signaling in the gut-kidney axis. These therapies represent a shift toward directly addressing MP biology, moving beyond the indirect effects of gut-focused interventions. However, their clinical translation requires further validation in CKD-specific populations.

Future directions

The future of therapeutic targeting in this domain lies in personalized, mechanism-driven strategies that account for individual variability in gut microbiota and MP profiles. Key directions as follows.

Personalized microbiota-based interventions: Advances in metagenomic sequencing enable detailed profiling of a patient’s gut microbiota, revealing specific dysbiotic patterns linked to uremic toxin production and MP release[6]. Tailored probiotic or prebiotic regimens, designed to correct these imbalances, could optimize therapeutic efficacy. For instance, patients with enriched Clostridium species-key producers of p-cresol-might benefit from targeted prebiotics that favor SCFA-producing bacteria instead[21]. Early evidence suggests that such personalized interventions could reduce toxin levels more effectively than generic approaches, potentially decreasing MP-mediated inflammation[17]. Clinical trials integrating microbiota profiling with therapeutic outcomes are needed to establish feasibility and efficacy.

Targeting MP-mediated pathways: A deeper understanding of MP cargo and signaling pathways offers opportunities for precision therapies. For example, inhibiting specific MP-derived microRNAs (e.g., miR-155) or blocking receptors (e.g., toll-like receptors) activated by bacterial MPs could interrupt proinflammatory and profibrotic cascades in the kidney[41,42]. Similarly, disrupting MP interactions with endothelial cells-via antagonists of adhesion molecules or scavenger receptors-might mitigate vascular dysfunction[43]. Advances in nanotechnology, such as engineered nanoparticles that sequester MPs or their cargos, could further enhance specificity[39]. Engineered EVs loaded with therapeutic molecules or small interfering RNA (siRNA), targeted specifically to renal or vascular cells, offer a highly precise method for mitigating MP-driven pathology[40]. Additionally, MP-targeted immunomodulation, such as monoclonal antibodies against proinflammatory cargo carried by MPs or infusion of tolerogenic regulatory cell-derived MPs, holds potential to specifically counteract MP-induced inflammation[8]. These strategies, while speculative, leverage the growing molecular insights into MP biology and promise to address the root causes of uremic toxicity in hemodialysis patients.

Integration and clinical implications

The integration of these therapeutic approaches-current, emerging, and future-offers a multi-pronged strategy to tackle the gut-kidney-MP axis in CKD. Current interventions like probiotics and AST-120 provide immediate, accessible options to reduce uremic toxin production, while emerging therapies like statins and cargo-neutralizing agents target MP dynamics directly. Future personalized and pathway-specific strategies hold the potential to transform care by addressing individual disease drivers. For hemodialysis patients, where cardiovascular mortality remains stubbornly high[2], these therapies could improve quality of life and survival by alleviating the systemic burden of uremic toxins and MP-mediated pathology. However, challenges remain, including the need for large-scale clinical trials, standardized MP detection methods, and cost-effective personalization frameworks[44].

In conclusion, as summarized in Table 1, therapeutic approaches targeting MPs and the gut-kidney axis represent a frontier in CKD management. By bridging gut microbiota modulation with MP-focused therapies, we can address the intertwined mechanisms of uremic toxicity and vascular dysfunction, paving the way for innovative treatments that enhance outcomes in hemodialysis patients.

Table 1 Therapeutic approaches targeting microparticles and the gut-kidney axis in chronic kidney disease.

Therapeutic class	Mechanism of action	Representative agents or interventions	Clinical status
Probiotics & synbiotics	Rebalance gut microbiota, reduce uremic toxins	Lactobacillus, Bifidobacterium	Clinical use; evidence from randomized controlled trials
Adsorbents	Bind and reduce gut-derived toxin precursors	AST-120	Clinical use; mixed evidence, beneficial subsets
Statins	Inhibit cellular release of MPs	Atorvastatin, rosuvastatin	Clinical use; proven reduction in MPs
MP signaling blockers	Block MP cellular interactions and inflammatory signaling	Annexin V, integrin αvβ3 antagonists	Preclinical; promising early data
Extracorporeal MP removal	Remove MPs from circulation through filtration or adsorption	High-flux dialysis, adsorption columns	Experimental; preliminary data
Personalized microbiome therapy	Individualized microbiome correction, engineered probiotics	Fecal microbiota transplantation, engineered probiotics	Experimental; ongoing clinical research
EV-based therapies	Therapeutic EVs delivering anti-inflammatory or regenerative factors	Mesenchymal stem cell EVs, engineered EVs	Preclinical; highly promising results
MP-targeted immunomodulation	Immunological modulation to reduce MP-induced inflammation	Regulatory MPs, monoclonal antibodies	Experimental; concept development

EVs: Extracellular vesicles; MPs: Microparticles.

Comprehensive biomarker validation

MPs represent a promising avenue for biomarker development in CKD and hemodialysis, offering insights into vascular dysfunction and disease progression; however, their transition from research tools to clinically actionable biomarkers requires rigorous validation[44]. To be deemed robust, MPs must fulfill several critical criteria tailored to their unique properties as small, heterogeneous EVs. These criteria include high sensitivity and specificity to distinguish CKD-related pathological states from healthy conditions, reproducibility across laboratories and time points, and demonstrable clinical relevance for diagnosis, prognosis, or therapeutic decision-making[68]. The complexity of MP detection, stemming from their nanoscale size and diverse cellular origins, necessitates standardized methodologies and comprehensive validation frameworks to ensure reliability and applicability in clinical settings[8].

Standardized detection methods form the cornerstone of MP biomarker development. Flow cytometry remains the most widely adopted technique due to its ability to quantify and characterize MPs based on size, surface markers, and fluorescence[69]. However, its limitations-such as variability in instrument sensitivity, lack of consensus on gating strategies, and challenges in detecting particles below 500 nm-underscore the need for standardization[8]. The International Society on Thrombosis and Haemostasis has proposed guidelines to address these issues, advocating for the use of calibrated beads (e.g., Megamix beads) to define size gates, standardized antibody panels for phenotyping, and optimized pre-analytical protocols to minimize artefactual MP generation[70]. Complementary methods, such as nanoparticle tracking analysis, provide high-resolution sizing and concentration data but fall short in distinguishing MPs from other nanoparticles due to limited specificity[71]. Emerging technologies, including resistive pulse sensing and advanced imaging flow cytometry, hold potential but require further validation for routine use[72]. Achieving methodological consensus is critical to enable cross-study comparisons and establish MP reference ranges in CKD and hemodialysis populations[73].

Validation frameworks for MPs must integrate analytical and clinical dimensions to bridge the gap between laboratory measurement and patient care. Analytical validation focuses on the technical performance of detection methods, requiring the establishment of key parameters: The limit of detection to identify low-abundance MPs, precision (both intra-assay and inter-assay) to ensure consistent results, and accuracy against known standards or orthogonal methods[74]. For example, precision studies might assess variability in MP counts across repeated measurements, while accuracy could be validated by comparing flow cytometry results with electron microscopy[75]. Clinical validation, in contrast, evaluates the biomarker’s utility in CKD and hemodialysis contexts, necessitating prospective, longitudinal studies to confirm that MP levels-or specific MP subpopulations (e.g., EMPs)-independently predict outcomes such as cardiovascular events, dialysis efficacy, or mortality[76]. These studies should account for confounders like age, comorbidities, and dialysis modality, and they must validate findings across diverse ethnic and disease-stage cohorts to ensure generalizability[77].

Regulatory approval from bodies like the United States Food and Drug Administration and the European Medicines Agency further demands a structured qualification process, integrating analytical and clinical data into a cohesive dossier[78]. This includes defining standardized thresholds (e.g., MP concentration cutoffs for risk stratification) and demonstrating added value over existing biomarkers like albuminuria or C-reactive protein[10]. Current evidence highlights elevated MP levels in CKD patients, with studies linking endothelial and platelet-derived MPs to vascular calcification and inflammation; however, inconsistencies in detection protocols and small sample sizes limit their immediate clinical adoption[79]. Future efforts must prioritize multi-center trials, harmonized detection standards, and the integration of MPs into composite biomarker panels to enhance prognostic precision in CKD and hemodialysis[80].

Economic and ethical considerations

Novel microbiota and MP-targeted therapies represent a frontier in CKD management, yet their economic and ethical implications are profound and multifaceted[81]. Economically, CKD exerts a staggering burden, with hemodialysis costs surpassing $90000 annually per patient in the United States[2]. Therapies such as microbiota modulation via probiotics or MP-sequestering nanoparticles could mitigate this by reducing disease progression and dialysis dependency, potentially yielding long-term savings[82]. However, the high initial investment-spanning research, clinical trials, and scalable production-poses challenges, particularly for therapies leveraging metagenomics or nanotechnology, which demand advanced infrastructure[83,84]. For a high-impact readership, it’s critical to note that these costs may shift economic priorities, diverting funds from conventional care and risking inequitable access, especially in low-income regions where CKD prevalence is rising[85]. Market incentives for pharmaceutical innovation further complicate cost structures, potentially inflating prices and limiting adoption[86].

Ethically, these therapies raise pressing questions of justice, autonomy, and societal impact. Personalized interventions, while groundbreaking, could deepen health disparities if access remains stratified by socioeconomic status[87]. Inclusive clinical trials across diverse populations are essential to ensure efficacy and fairness, yet such efforts are often underfunded[88]. Ethical considerations, particularly concerning patient autonomy, are heightened in the context of experimental treatments like siRNA-loaded EVs. Patients must carefully deliberate on whether to pursue these treatments, balancing the potential for uncertain benefits against the associated risks. This uncertainty underscores the need for rigorous ethical standards in clinical applications. Furthermore, the societal implications of prioritizing resource allocation toward cutting-edge therapeutic interventions, such as MP-based treatments, over the provision of basic healthcare services merit critical examination. This tension poses a significant challenge for policymakers, who must balance the advancement of innovation with the imperative of ensuring equitable access to healthcare[89]. To address these complexities, the development of robust regulatory frameworks and the transparent communication of risks and benefits associated with these therapies are essential[89]. Such measures are critical not only for safeguarding patient welfare but also for fostering public trust in these emerging biomedical advancements. Ongoing research and interdisciplinary dialogue will be vital to refining these approaches and mitigating potential disparities in healthcare delivery.

CONCLUSION

CKD creates a vicious triad of gut dysbiosis, uremic toxin overload and MP dysregulation that conventional dialysis cannot correct. MPs emerge as central couriers-shuttling microbial, inflammatory and pro-thrombotic signals from the intestine to the vasculature and kidney, thereby fueling cardiovascular mortality in hemodialysis. Deciphering MP cargo with next-generation omics, standardizing their measurement and designing interventions that either curb their release (e.g., statins, membrane innovations) or neutralize their payload (e.g., antibody sequestration, engineered EV traps) now constitute a tangible translational frontier. Addressing these avenues-while accounting for dialysis modality, complement crosstalk and patient heterogeneity-could finally convert mechanistic insight into measurable survival gains for almost three million people worldwide who rely on hemodialysis.