Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney disease: focused on β2-microglobulin-related amyloidosis and indoxyl sulfate-induced atherosclerosis—Oshima Award Address 2016

Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney... Uremic toxins are linked to chronic kidney disease (CKD)-related systemic diseases. β -Microglobulin (β -m), a water-solu- 2 2 ble, middle-sized molecule, is associated with mortality and dialysis-related amyloidosis (DRA). DRA occurs in long-term dialysis patients, with β -m amyloid deposited mainly in osteoarticular tissues. We investigated a model of β -m amyloid 2 2 fibril extension at neutral pH in the presence of trifluoroethanol or sodium dodecyl sulfate. Using this model, some biologi- cal molecules, including glycosaminoglycans and lysophospholipids, were found to be chaperones for β -m amyloid fibril extension. Several protein-bound solutes, such as indoxyl sulfate (IS) and p-cresyl sulfate, are independent risk factors for cardiovascular disease in CKD patients, especially those undergoing dialysis. We investigated kidney injury-induced accel- eration of atherosclerosis in association with macrophage phenotypic change to a proinflammatory state as well as increased IS deposition in lesions in an animal model. IS directly induced macrophage inflammation and impaired cholesterol efflux to high-density lipoprotein (HDL) in vitro. In addition, a clinical study showed that HDL isolated from CKD patients induced proinflammatory reactions and impaired cholesterol efflux to macrophages. These findings suggest that protein-bound solutes, including IS, will induce dysfunction of both macrophages and HDL in atherosclerotic lesions. To remove uremic toxins efficiently, we demonstrated the potential efficacy of oral charcoal adsorbent and hexadecyl-immobilized cellulose beads in hemodialysis patients. These findings suggest that uremic toxins induce various CKD-related systemic disorders, and further therapeutic strategies will be needed to reduce uremic toxins enough and improve life expectancy in CKD patients. Keywords Uremic toxins · β -Microglobulin · Dialysis-related amyloidosis · Indoxyl sulfate · Atherosclerosis · Macrophages Uremic toxins and systemic disease others. The frequency and severity are enhanced with the in chronic kidney disease patients progression of CKD, especially end-stage kidney disease with dialysis treatment [1]. CKD-related systemic disease Advanced chronic kidney disease (CKD) induces various not only worsens survival, but also impairs activities of daily systemic diseases including cardiovascular disease (CVD), living (ADL) and quality of life (QOL). Thus, greater under- osteoarticular disorders, infections, malignant disease, and standing of the mechanism of these disorders and investiga- tion of therapeutic strategies is necessary. An accumulation of uremic toxins is a CKD-specific factor in the development This article was presented as the Oshima Award memorial lecture of CKD-related systemic disease. Despite recent progress at the 59th annual meeting of the Japanese Society of Nephrology, held at Yokohama, Japan in 2016. in dialysis treatment and the preservation of kidney func- tion [2], survival and ADL/QOL in CKD patients have not * Suguru Yamamoto improved enough. yamamots@med.niigata-u.ac.jp My collaborators and I have studied the pathophysiol- Division of Clinical Nephrology and Rheumatology, Niigata ogy of uremic toxin-related systemic disorders, especially University Graduate School of Medical and Dental Sciences, dialysis-related amyloidosis (DRA) and atherosclerosis, with 1-757 Asahimachi-dori, Niigata 951-8510, Japan Vol.:(0123456789) 1 3 Clinical and Experimental Nephrology a focus on β -microglobulin (β -m) and indoxyl sulfate (IS), extension of amyloid fibrils according to a first-order kinetic 2 2 respectively, and tried to identify therapeutic strategies to model [12, 14]. In the mechanism of amyloidogenesis of improve survival and ADL/QOL in CKD patients. natively folded proteins as well as β -m, partial unfolding is Progressive kidney disease induces uremic syndrome, believed to be a prerequisite to assembly into amyloid fibrils, with the retention of various solutes that are normally both in vitro and in vivo. In this process, conformational excreted by the kidney. Solutes with biological toxicity, change of β -m with biological molecules is necessary [12, direct or indirect, are called “uremic toxins.” 15]. The extension of β -m-related amyloid fibrils, as well Requirements for a uremic toxin are include the follow- as the formation of the fibrils from β -m, is greatly depend- ing [3–5]: ent on the pH of the reaction mixture, with the optimum pH being around 2.0–3.0 [15, 16]. On the other hand, the 1. The toxin is a unique chemical entity. fibrils readily depolymerize into monomeric β -m at pH 7.5 2. Quantitative analysis of the toxin in biological fluids is [17]. Thus, to observe the extension of β -m-related amyloid possible. fibrils at neutral pH, we need to unfold the compact struc- 3. The levels of the toxin in biological fluids increase with ture of β -m monomer to an amyloidogenic conformer, and deterioration of kidney function. stabilize the extended fibrils by adding other factors. We 4. A positive relationship between toxin level in biological investigated the effect of low concentrations of 2,2,2-trif- fluids and manifestations of uremic syndrome is present. luoroethanol (TFE) and sodium dodecyl sulfate (SDS) on 5. Administration of the toxin at a concentration seen in the extension of β -m-related amyloid fibrils at neutral pH patients with kidney disease shows toxic effects related in vitro [18, 19]. TFE at concentrations of up to 20% (v/v) or to uremic syndrome, both in vivo and in vitro. SDS at a critical micelle concentration caused amyloid fibril extension by inducing a subtle change in the tertiary struc- A literature search identified 88 uremic toxins in 621 arti- ture of β -m, and stabilizing the fibrils at neutral pH. TFE- cles. These were classified into groups according to molecu- induced amyloid fibril extension at neutral pH was enhanced lar weight and protein-bound properties, and were water-sol- by several kinds of glycosaminoglycans, especially heparin uble low molecular weight, middle sized, and protein-bound [18]. In these reactions, glycosaminoglycans bound directly molecules [3]. to the amyloid fibrils. In another study, depolymerization of amyloid fibrils at pH 7.5 was inhibited dose-dependently by the presence of apolipoprotein E, some glycosaminogly- β ‑Microglobulin and dialysis‑related cans, or proteoglycans [17, 20]. The results suggested that amyloidosis those biological molecules could enhance the deposition of β -m-related amyloid fibrils in vivo, possibly by bind- A representative, water-soluble middle sized molecule, β -m ing directly to the surface of the fibrils and stabilizing the (11.8 kDa), is associated with survival in dialysis patients conformation of β -m in the fibrils [12]. Using an in vitro [6–8]. For example, the randomized Hemodialysis (HEMO) β -m amyloid fibril formation model, other studies showed Study showed that predialysis serum β -m levels were asso- that several other biological molecules including lysophos- ciated with all-cause mortality [8], as well as mortality pholipids [21] and various non-esterified fatty acids [22] are owing to infections in dialysis patients [9]. In CKD-related enhancing-factor candidates for β -m-related amyloid fibril osteoarticular disorders, β -m is a precursor protein for DRA deposition in vivo. Thus, deposition of β -m-related amyloid 2 2 [10]. β -m-related amyloid fibrils are formed and deposited requires β -m conformational change and stabilization of 2 2 primarily in osteoarticular joint tissues, resulting in various amyloid fibrils with some biological molecules (Fig.  1). In osteoarticular disorders, such as carpal tunnel syndrome, contrast, recent findings showed that extracellular chaper - destructive spondyloarthropathy, and bone cysts in dialysis ones including α -macroglobulin may inhibit amyloid fibril patients [11]. Accumulation of β -m and the interactions formation by capturing unfolded and misfolded β -m [23]. 2 2 between β -m and other biological molecules are thought Further clinical studies will be needed to verify the in vivo to be needed for amyloid fibril formation in vivo [ 12, 13]. roles of these molecules in DRA. The β -m-related amyloid The β -m-related amyloid fibril formation and extension fibrils deposited in tissues induce cellular interactions that occurs according to a nucleation-dependent polymerization are associated with DRA symptoms, such as carpal tunnel model [12, 14]. This model consists of a nucleation phase syndrome and destructive spondyloarthropathy. When syno- and an extension phase. Nucleus formation requires a series vial fibroblast cells were reacted with extended β -m-related of monomer association steps, which represent the rate- amyloid fibrils in vitro, cellular survival were impaired by limiting step in amyloid fibril formation. Once the nucleus disrupting endosomal/lysosomal membranes [24]. This reac- (n-mer) has been formed, further addition of monomers tion may be associated with the development of carpal tun- becomes thermodynamically favorable, resulting in the rapid nel syndrome in CKD patients. Macrophages in spine lesions 1 3 Clinical and Experimental Nephrology Fig. 1 Pathogenesis of dialysis-related amyloidosis. β -Microglobulin (β -m), a 2 2 water-soluble, middle sized uremic toxin, increases with the deterioration of kidney function. Some biological molecules, such as glycosaminoglycans and proteoglycans, change the conformation of β -m and stabilize and extend the amyloid fibrils. In contrast, extracel- lular chaperones including α -macroglobulin may inhibit amyloid fibril formation by cap- turing unfolded and misfolded β -m are thought to be activated by deposited amyloid fibrils, and and multivariate analysis showed that IAA, but not IS or activated macrophages may accelerate destruction of spine p-cresyl sulfate, remained a significant predictor of mor - with long-term dialysis treatment [25]. tality and cardiovascular events [26]. In animal models, subtotal nephrectomy accelerated atherosclerosis as well as plaque formation in apolipoprotein E knockout mice [31]. Indoxyl sulfate and atherosclerosis In atherosclerotic lesions, renal injury induced macrophage phenotypic change, with an increase in proinflammatory CKD is one of the strongest risk factors for CVD owing to M1 as well as a decrease in anti-inflammatory M2 [32, 33]. progressive atherosclerosis as well as vascular calcification. Our research suggested that kidney injury-induced accel- Accumulation of protein-bound uremic toxins is associated eration of atherosclerosis is associated with IS [31], the with cardiovascular mortality in CKD patients [26–28]. renin-angiotensin-aldosterone system [32], and peroxisome Serum levels of IS increase with the progression of CKD, proliferator-activated receptor-γ [33]. These clinical and particularly in patients undergoing dialysis. Production of basic studies suggested that protein-bound uremic toxins, indole, precursor of IS, by intestinal flora is enhanced with especially IS, act as major CKD-specific factors in CKD- kidney disease setting, animal models suggested that use induced acceleration of atherosclerosis. When macrophages of Lubiprostone modulated kidney damage-induced pertur- differentiated from THP-1 cells were exposed to IS in vitro, bation of microbiota and reduced IS production [29, 30]. IS decreased cell viability but promoted macrophage IS was associated with increased cardiovascular mortality, inflammatory cytokine production as well as reactive oxy - aortic calcification, and pulse wave velocity in CKD patients gen species production [34]. In this process, IS-inducing [28]. Indole acetic acid (IAA) showed trends similar to IS, inflammation in macrophages results from accelerating aryl 1 3 Clinical and Experimental Nephrology hydrocarbon receptor-NF-κΒ/MAPK cascades, but not the especially end-stage kidney disease, removal of uremic NLRP3 inflammasome [35]. These reactions may restrict toxins with medication and blood purification therapy mature IL-1β production, which may explain sustained will be another option for the prevention of CKD-related chronic inflammation in CKD patients. IS also reduced systemic disease. An oral charcoal adsorbent (AST-120) macrophage cholesterol efflux and decreased ATP-binding reduces serum levels of IS [40, 41] and can be used in cassette transporter G1 expression [34]. Thus, direct inter- advanced CKD patients for the preservation of kidney actions of IS with macrophages induces macrophage foam function while some large interventional clinical stud- cell formation, which leads to atherosclerosis acceleration ies did not show clear effect on it [42– 46]. Reduction of in patients with CKD (Fig. 2). We also found that HDL from uremic toxins with AST-120 may be associated with bet- CKD patients but not from non-CKD subjects impaired mac- ter outcomes in CKD-related systemic disease. In fact, rophage cholesterol efflux [36]. Although HDL is known kidney damage-induced acceleration of atherosclerosis to have anti-inflammatory activity, uremic HDL enhanced was modulated with administration of AST-120, with less macrophage inflammation as well as migration [36]. These aortic deposition of IS and aortic expression of inflamma- results suggest that uremic toxins may induce functional tory cytokines [31]. Another study showed that AST-120 abnormalities in macrophages and HDL that enhance mac- modulated CKD-induced cardiac damage, with decreased rophage foam cell formation in atherosclerotic lesions in serum/urine levels of IS and oxidative stress markers, CKD patients (Fig. 2) [37]. IS or uremic HDL also induced such as 8-hydroxy-2′-deoxyguanosine and acrolein, in a functional abnormalities of not only macrophages but other rat model [47]. IS strongly bound to high molecular weight atherosclerosis-associated cells including endothelial cells protein and is difficult to remove with conventional dialy - [38, 39]. Thus, systemic removal of uremic toxins will be sis treatment. A clinical study showed that IS in serum is effective to prevent CKD-induced disorders. 97.7% protein-bound and is only reduced by 31.8% with standard hemodialysis [4]. Recent findings showed that a longer hemodialysis treatment session [48], use of large- Strategies to remove uremic toxins pore, super-flux cellulose triacetate membranes [49], and hemodiafiltration [50] increased the removal of protein- To prevent CKD-related systemic disease including CVD, bound uremic toxins; however, these changes are thought preservation of kidney function, including treatment for to be insufficient to prevent CKD-related complications. glomerulonephritis and diabetic nephropathy, is essential Additional therapy with conventional dialysis is needed to avoid accumulation of uremic toxins. In advanced CKD, to adequately remove protein-bound uremic toxins. For example, when anuric patients undergoing maintenance hemodialysis used AST-120 6 g/day for 2 weeks, serum IS, p-cresyl sulfate, and phenyl sulfate levels in the predi- alysis session decreased significantly [51], as did oxidative stress markers including oxidized albumin and 8-isopros- tane [51]. The Lixelle column contains porous hexadecyl- immobilized cellulose beads and was developed for direct hemoperfusion of blood β -m with hydrophobic inter- actions [52, 53]. Recent research found that hexadecyl- immobilized cellulose beads adsorbed protein-unbound free IS, p-cresyl sulfate, phenyl sulfate, and IAA to some degree [54]. These interventions are problematic in clini- cal use, and further clinical investigation will be necessary to adequately reduce uremic toxins. Methods for reduction include targeting of intestinal flora that produce uremic toxins, removal of circulating uremic toxins, and others (Fig.  3). Treatments at each stage will decrease uremic toxins and prevent CKD-related systemic disorders. In Fig. 2 Indoxyl sulfate induces macrophage foam cell formation in addition, adequate removal of protein-bound uremic tox- atherosclerotic lesions. Indoxyl sulfate, a protein-bound uremic toxin, ins should be recommended when the interventions can reacts directly with macrophages and induces production of inflam- matory cytokines as well as impairment of cholesterol efflux to high- improve survival and ADL/QOL in CKD patients. density lipoprotein, leading to macrophage foam cell formation. ABCG1 ATP-binding cassette transporter G1, CKD chronic kidney disease, FC free cholesterol, LDL low-density lipoprotein, HDL high- density lipoprotein 1 3 Clinical and Experimental Nephrology Fig. 3 Therapeutic strategies for uremic toxin-related systemic disorders. Therapeutic strategies for the reduction of uremic toxins should include (A) preservation of kidney function, (B) inhibition of uremic toxin production, (C) prevention of the interaction between uremic toxins and tissues/cells, and (D) removal of uremic toxins with medication or blood purification therapy Conclusion References 1. Levey AS, Coresh J. Chronic kidney disease. Lancet. 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Molecular mechanisms underlying uremic toxin-related systemic disorders in chronic kidney disease: focused on β2-microglobulin-related amyloidosis and indoxyl sulfate-induced atherosclerosis—Oshima Award Address 2016

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Abstract

Uremic toxins are linked to chronic kidney disease (CKD)-related systemic diseases. β -Microglobulin (β -m), a water-solu- 2 2 ble, middle-sized molecule, is associated with mortality and dialysis-related amyloidosis (DRA). DRA occurs in long-term dialysis patients, with β -m amyloid deposited mainly in osteoarticular tissues. We investigated a model of β -m amyloid 2 2 fibril extension at neutral pH in the presence of trifluoroethanol or sodium dodecyl sulfate. Using this model, some biologi- cal molecules, including glycosaminoglycans and lysophospholipids, were found to be chaperones for β -m amyloid fibril extension. Several protein-bound solutes, such as indoxyl sulfate (IS) and p-cresyl sulfate, are independent risk factors for cardiovascular disease in CKD patients, especially those undergoing dialysis. We investigated kidney injury-induced accel- eration of atherosclerosis in association with macrophage phenotypic change to a proinflammatory state as well as increased IS deposition in lesions in an animal model. IS directly induced macrophage inflammation and impaired cholesterol efflux to high-density lipoprotein (HDL) in vitro. In addition, a clinical study showed that HDL isolated from CKD patients induced proinflammatory reactions and impaired cholesterol efflux to macrophages. These findings suggest that protein-bound solutes, including IS, will induce dysfunction of both macrophages and HDL in atherosclerotic lesions. To remove uremic toxins efficiently, we demonstrated the potential efficacy of oral charcoal adsorbent and hexadecyl-immobilized cellulose beads in hemodialysis patients. These findings suggest that uremic toxins induce various CKD-related systemic disorders, and further therapeutic strategies will be needed to reduce uremic toxins enough and improve life expectancy in CKD patients. Keywords Uremic toxins · β -Microglobulin · Dialysis-related amyloidosis · Indoxyl sulfate · Atherosclerosis · Macrophages Uremic toxins and systemic disease others. The frequency and severity are enhanced with the in chronic kidney disease patients progression of CKD, especially end-stage kidney disease with dialysis treatment [1]. CKD-related systemic disease Advanced chronic kidney disease (CKD) induces various not only worsens survival, but also impairs activities of daily systemic diseases including cardiovascular disease (CVD), living (ADL) and quality of life (QOL). Thus, greater under- osteoarticular disorders, infections, malignant disease, and standing of the mechanism of these disorders and investiga- tion of therapeutic strategies is necessary. An accumulation of uremic toxins is a CKD-specific factor in the development This article was presented as the Oshima Award memorial lecture of CKD-related systemic disease. Despite recent progress at the 59th annual meeting of the Japanese Society of Nephrology, held at Yokohama, Japan in 2016. in dialysis treatment and the preservation of kidney func- tion [2], survival and ADL/QOL in CKD patients have not * Suguru Yamamoto improved enough. yamamots@med.niigata-u.ac.jp My collaborators and I have studied the pathophysiol- Division of Clinical Nephrology and Rheumatology, Niigata ogy of uremic toxin-related systemic disorders, especially University Graduate School of Medical and Dental Sciences, dialysis-related amyloidosis (DRA) and atherosclerosis, with 1-757 Asahimachi-dori, Niigata 951-8510, Japan Vol.:(0123456789) 1 3 Clinical and Experimental Nephrology a focus on β -microglobulin (β -m) and indoxyl sulfate (IS), extension of amyloid fibrils according to a first-order kinetic 2 2 respectively, and tried to identify therapeutic strategies to model [12, 14]. In the mechanism of amyloidogenesis of improve survival and ADL/QOL in CKD patients. natively folded proteins as well as β -m, partial unfolding is Progressive kidney disease induces uremic syndrome, believed to be a prerequisite to assembly into amyloid fibrils, with the retention of various solutes that are normally both in vitro and in vivo. In this process, conformational excreted by the kidney. Solutes with biological toxicity, change of β -m with biological molecules is necessary [12, direct or indirect, are called “uremic toxins.” 15]. The extension of β -m-related amyloid fibrils, as well Requirements for a uremic toxin are include the follow- as the formation of the fibrils from β -m, is greatly depend- ing [3–5]: ent on the pH of the reaction mixture, with the optimum pH being around 2.0–3.0 [15, 16]. On the other hand, the 1. The toxin is a unique chemical entity. fibrils readily depolymerize into monomeric β -m at pH 7.5 2. Quantitative analysis of the toxin in biological fluids is [17]. Thus, to observe the extension of β -m-related amyloid possible. fibrils at neutral pH, we need to unfold the compact struc- 3. The levels of the toxin in biological fluids increase with ture of β -m monomer to an amyloidogenic conformer, and deterioration of kidney function. stabilize the extended fibrils by adding other factors. We 4. A positive relationship between toxin level in biological investigated the effect of low concentrations of 2,2,2-trif- fluids and manifestations of uremic syndrome is present. luoroethanol (TFE) and sodium dodecyl sulfate (SDS) on 5. Administration of the toxin at a concentration seen in the extension of β -m-related amyloid fibrils at neutral pH patients with kidney disease shows toxic effects related in vitro [18, 19]. TFE at concentrations of up to 20% (v/v) or to uremic syndrome, both in vivo and in vitro. SDS at a critical micelle concentration caused amyloid fibril extension by inducing a subtle change in the tertiary struc- A literature search identified 88 uremic toxins in 621 arti- ture of β -m, and stabilizing the fibrils at neutral pH. TFE- cles. These were classified into groups according to molecu- induced amyloid fibril extension at neutral pH was enhanced lar weight and protein-bound properties, and were water-sol- by several kinds of glycosaminoglycans, especially heparin uble low molecular weight, middle sized, and protein-bound [18]. In these reactions, glycosaminoglycans bound directly molecules [3]. to the amyloid fibrils. In another study, depolymerization of amyloid fibrils at pH 7.5 was inhibited dose-dependently by the presence of apolipoprotein E, some glycosaminogly- β ‑Microglobulin and dialysis‑related cans, or proteoglycans [17, 20]. The results suggested that amyloidosis those biological molecules could enhance the deposition of β -m-related amyloid fibrils in vivo, possibly by bind- A representative, water-soluble middle sized molecule, β -m ing directly to the surface of the fibrils and stabilizing the (11.8 kDa), is associated with survival in dialysis patients conformation of β -m in the fibrils [12]. Using an in vitro [6–8]. For example, the randomized Hemodialysis (HEMO) β -m amyloid fibril formation model, other studies showed Study showed that predialysis serum β -m levels were asso- that several other biological molecules including lysophos- ciated with all-cause mortality [8], as well as mortality pholipids [21] and various non-esterified fatty acids [22] are owing to infections in dialysis patients [9]. In CKD-related enhancing-factor candidates for β -m-related amyloid fibril osteoarticular disorders, β -m is a precursor protein for DRA deposition in vivo. Thus, deposition of β -m-related amyloid 2 2 [10]. β -m-related amyloid fibrils are formed and deposited requires β -m conformational change and stabilization of 2 2 primarily in osteoarticular joint tissues, resulting in various amyloid fibrils with some biological molecules (Fig.  1). In osteoarticular disorders, such as carpal tunnel syndrome, contrast, recent findings showed that extracellular chaper - destructive spondyloarthropathy, and bone cysts in dialysis ones including α -macroglobulin may inhibit amyloid fibril patients [11]. Accumulation of β -m and the interactions formation by capturing unfolded and misfolded β -m [23]. 2 2 between β -m and other biological molecules are thought Further clinical studies will be needed to verify the in vivo to be needed for amyloid fibril formation in vivo [ 12, 13]. roles of these molecules in DRA. The β -m-related amyloid The β -m-related amyloid fibril formation and extension fibrils deposited in tissues induce cellular interactions that occurs according to a nucleation-dependent polymerization are associated with DRA symptoms, such as carpal tunnel model [12, 14]. This model consists of a nucleation phase syndrome and destructive spondyloarthropathy. When syno- and an extension phase. Nucleus formation requires a series vial fibroblast cells were reacted with extended β -m-related of monomer association steps, which represent the rate- amyloid fibrils in vitro, cellular survival were impaired by limiting step in amyloid fibril formation. Once the nucleus disrupting endosomal/lysosomal membranes [24]. This reac- (n-mer) has been formed, further addition of monomers tion may be associated with the development of carpal tun- becomes thermodynamically favorable, resulting in the rapid nel syndrome in CKD patients. Macrophages in spine lesions 1 3 Clinical and Experimental Nephrology Fig. 1 Pathogenesis of dialysis-related amyloidosis. β -Microglobulin (β -m), a 2 2 water-soluble, middle sized uremic toxin, increases with the deterioration of kidney function. Some biological molecules, such as glycosaminoglycans and proteoglycans, change the conformation of β -m and stabilize and extend the amyloid fibrils. In contrast, extracel- lular chaperones including α -macroglobulin may inhibit amyloid fibril formation by cap- turing unfolded and misfolded β -m are thought to be activated by deposited amyloid fibrils, and and multivariate analysis showed that IAA, but not IS or activated macrophages may accelerate destruction of spine p-cresyl sulfate, remained a significant predictor of mor - with long-term dialysis treatment [25]. tality and cardiovascular events [26]. In animal models, subtotal nephrectomy accelerated atherosclerosis as well as plaque formation in apolipoprotein E knockout mice [31]. Indoxyl sulfate and atherosclerosis In atherosclerotic lesions, renal injury induced macrophage phenotypic change, with an increase in proinflammatory CKD is one of the strongest risk factors for CVD owing to M1 as well as a decrease in anti-inflammatory M2 [32, 33]. progressive atherosclerosis as well as vascular calcification. Our research suggested that kidney injury-induced accel- Accumulation of protein-bound uremic toxins is associated eration of atherosclerosis is associated with IS [31], the with cardiovascular mortality in CKD patients [26–28]. renin-angiotensin-aldosterone system [32], and peroxisome Serum levels of IS increase with the progression of CKD, proliferator-activated receptor-γ [33]. These clinical and particularly in patients undergoing dialysis. Production of basic studies suggested that protein-bound uremic toxins, indole, precursor of IS, by intestinal flora is enhanced with especially IS, act as major CKD-specific factors in CKD- kidney disease setting, animal models suggested that use induced acceleration of atherosclerosis. When macrophages of Lubiprostone modulated kidney damage-induced pertur- differentiated from THP-1 cells were exposed to IS in vitro, bation of microbiota and reduced IS production [29, 30]. IS decreased cell viability but promoted macrophage IS was associated with increased cardiovascular mortality, inflammatory cytokine production as well as reactive oxy - aortic calcification, and pulse wave velocity in CKD patients gen species production [34]. In this process, IS-inducing [28]. Indole acetic acid (IAA) showed trends similar to IS, inflammation in macrophages results from accelerating aryl 1 3 Clinical and Experimental Nephrology hydrocarbon receptor-NF-κΒ/MAPK cascades, but not the especially end-stage kidney disease, removal of uremic NLRP3 inflammasome [35]. These reactions may restrict toxins with medication and blood purification therapy mature IL-1β production, which may explain sustained will be another option for the prevention of CKD-related chronic inflammation in CKD patients. IS also reduced systemic disease. An oral charcoal adsorbent (AST-120) macrophage cholesterol efflux and decreased ATP-binding reduces serum levels of IS [40, 41] and can be used in cassette transporter G1 expression [34]. Thus, direct inter- advanced CKD patients for the preservation of kidney actions of IS with macrophages induces macrophage foam function while some large interventional clinical stud- cell formation, which leads to atherosclerosis acceleration ies did not show clear effect on it [42– 46]. Reduction of in patients with CKD (Fig. 2). We also found that HDL from uremic toxins with AST-120 may be associated with bet- CKD patients but not from non-CKD subjects impaired mac- ter outcomes in CKD-related systemic disease. In fact, rophage cholesterol efflux [36]. Although HDL is known kidney damage-induced acceleration of atherosclerosis to have anti-inflammatory activity, uremic HDL enhanced was modulated with administration of AST-120, with less macrophage inflammation as well as migration [36]. These aortic deposition of IS and aortic expression of inflamma- results suggest that uremic toxins may induce functional tory cytokines [31]. Another study showed that AST-120 abnormalities in macrophages and HDL that enhance mac- modulated CKD-induced cardiac damage, with decreased rophage foam cell formation in atherosclerotic lesions in serum/urine levels of IS and oxidative stress markers, CKD patients (Fig. 2) [37]. IS or uremic HDL also induced such as 8-hydroxy-2′-deoxyguanosine and acrolein, in a functional abnormalities of not only macrophages but other rat model [47]. IS strongly bound to high molecular weight atherosclerosis-associated cells including endothelial cells protein and is difficult to remove with conventional dialy - [38, 39]. Thus, systemic removal of uremic toxins will be sis treatment. A clinical study showed that IS in serum is effective to prevent CKD-induced disorders. 97.7% protein-bound and is only reduced by 31.8% with standard hemodialysis [4]. Recent findings showed that a longer hemodialysis treatment session [48], use of large- Strategies to remove uremic toxins pore, super-flux cellulose triacetate membranes [49], and hemodiafiltration [50] increased the removal of protein- To prevent CKD-related systemic disease including CVD, bound uremic toxins; however, these changes are thought preservation of kidney function, including treatment for to be insufficient to prevent CKD-related complications. glomerulonephritis and diabetic nephropathy, is essential Additional therapy with conventional dialysis is needed to avoid accumulation of uremic toxins. In advanced CKD, to adequately remove protein-bound uremic toxins. For example, when anuric patients undergoing maintenance hemodialysis used AST-120 6 g/day for 2 weeks, serum IS, p-cresyl sulfate, and phenyl sulfate levels in the predi- alysis session decreased significantly [51], as did oxidative stress markers including oxidized albumin and 8-isopros- tane [51]. The Lixelle column contains porous hexadecyl- immobilized cellulose beads and was developed for direct hemoperfusion of blood β -m with hydrophobic inter- actions [52, 53]. Recent research found that hexadecyl- immobilized cellulose beads adsorbed protein-unbound free IS, p-cresyl sulfate, phenyl sulfate, and IAA to some degree [54]. These interventions are problematic in clini- cal use, and further clinical investigation will be necessary to adequately reduce uremic toxins. Methods for reduction include targeting of intestinal flora that produce uremic toxins, removal of circulating uremic toxins, and others (Fig.  3). Treatments at each stage will decrease uremic toxins and prevent CKD-related systemic disorders. In Fig. 2 Indoxyl sulfate induces macrophage foam cell formation in addition, adequate removal of protein-bound uremic tox- atherosclerotic lesions. Indoxyl sulfate, a protein-bound uremic toxin, ins should be recommended when the interventions can reacts directly with macrophages and induces production of inflam- matory cytokines as well as impairment of cholesterol efflux to high- improve survival and ADL/QOL in CKD patients. density lipoprotein, leading to macrophage foam cell formation. ABCG1 ATP-binding cassette transporter G1, CKD chronic kidney disease, FC free cholesterol, LDL low-density lipoprotein, HDL high- density lipoprotein 1 3 Clinical and Experimental Nephrology Fig. 3 Therapeutic strategies for uremic toxin-related systemic disorders. Therapeutic strategies for the reduction of uremic toxins should include (A) preservation of kidney function, (B) inhibition of uremic toxin production, (C) prevention of the interaction between uremic toxins and tissues/cells, and (D) removal of uremic toxins with medication or blood purification therapy Conclusion References 1. Levey AS, Coresh J. Chronic kidney disease. Lancet. 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Clinical and Experimental NephrologySpringer Journals

Published: Jun 5, 2018

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