No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Cardiorenal Syndrome: Role of Protein-Bound Uremic Toxins
Abstract
Renal impairment is a strong independent risk factor associated with poor prognosis in cardiovascular disease patients. Renal dysfunction is likely contributed by progressive renal structural damage. Accurate detection of kidney injury in a timely manner as well as increased knowledge of the pathophysiology and mechanisms underlying this injury is of great importance in developing therapeutic interventions for combating renal complications at an early stage. Regarding the role of uremic solutes in the pathophysiology of cardiorenal syndrome, a number of further studies are warranted. There may be uremic solutes discovered from proteomics not yet chemically identified or tested for biological activity. Beyond Protein-bound uremic toxins, uremic solutes in other classes (according to the European Uraemic Toxin Work Group classification) may have adverse cardiorenal effects. Although most small water-soluble solutes and middle molecules can be satisfactorily removed by either conventional or newly developed dialysis strategies, targeting uremic toxins with cardiorenal toxicity at predialysis stage of chronic kidney disease may retard or prevent incident dialysis as well as the initiation/progression of cardiorenal syndrome.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
... CRS 2 differs in that it starts with chronic HF leading to kidney failure, whereas CRS 4 originates from chronic kidney disease causing subsequent HF. CRS type 5 (CRS 5) includes concomitant renal and cardiovascular disease caused by systemic disease (such as obesity, diabetes, metabolic syndrome, hypertension) since it presents the simultaneous involvement of the kidneys and the heart through organ damage or dysfunction (Table 1, Ref. [2,[4][5][6][7][8][9][10][11][12][13][14][15]). ...
... [4,5,11] Type 2 Chronic CRS Heart Kidney Hypoxia and low cardiac output in chronic heart failure increase sympathetic nervous system activity, activate the RAAS, increase renal oxidative stress leading to renal fibrosis, functional loss, and permanent chronic kidney damage. [6,7,15] Type 3 Acute RCS Kidney Heart Renal failure generates excessive hemodynamic pressure, responsible for left ventricular hypertrophy (LVH) that triggers the syndrome's heart problems. Leukocyte accumulation and increase in proinflammatory cytokines in acute renal failure lead to often fatal cardiac myocyte apoptosis. ...
... Their low molecular weight and binding to serum albumin do not allow the elimination of these toxins by either normal or dialysis routes. Within this group of toxins, IS and PCS appear as two of the main toxins linked to CRS [15,32]. ...
The pathologies of the kidney and heart have instigated a large number of researchers around the world to try to better understand what the exact connectors responsible for the emergence and establishment of these diseases are. The classification of these pathologies into different types of cardiorenal syndromes (CRSs) over the last 15 years has greatly contributed to understanding pathophysiological and diagnostic aspects, as well as treatment strategies. However, with the advent of new technologies classified as “Omics”, a new range of knowledge and new possibilities have opened up in order to effectively understand the intermediaries between the kidney-heart axis. The universe of micro-RNAs (miRNAs), epigenetic factors, and components present in extracellular vesicles (EVs) have been protagonists in studying different types of CRSs. Thus, the new challenge that is imposed is to select and link the large amount of information generated from the use of large-scale analysis techniques. The present review seeks to present some of the future perspectives related to understanding CRSs, with an emphasis on CRS type 3.
... (5)(6)(7) Grupul de experţi EUTox a propus clasificarea toxinelor uremice, pe baza particularităţilor fizicochimice şi a comportamentului acestora la dializă convenţională, în trei grupe principale: compuşi uremici cu greutate moleculară mică solubili în apă, compuşi cu greutate moleculară medie şi compuşi uremici hidrosolubili sau liposolubili legaţi de proteine transportoare. (1)(2)(3)(4)(5)(6)(7)(8) Toxinele uremice cu greutate moleculară scăzută prezintă următoarele caracteristici: sunt hidrosolubile, au greutatea moleculară sub 0,5 KDa, sunt uşor de îndepărtat prin dializă, nu prezintă efecte nocive demonstrate asupra organismului. Moleculele reprezentative pentru această clasă sunt: ureea, creatinina, guanidina, oxalat, fosfor, acid uric, guanidinoacetat, guanidinosuccinat, acid hialuronic, oxalat, acid uric, fosfat anorganic, ADMA (dimetilarginina asimetrică), SDMA (dimetilarginina simetrică), MMA (monometil arginină). ...
... O serie de observaţii epidemiologice şi experimentale coroborate (1,2,5,6,8,10,11,17,(22)(23)(24)(25) au permis sistematizarea următoarelor acţiuni ale toxinelor uremice asupra organismului: ...
... -Rinichi: insuficienţă funcţională, inflamaţie renală, creşterea expresiei genice a citokinelor proinflamatorii, glomeruloscleroză, fibroză interstiţială, consolidarea stresului oxidativ, tumorigeneză în tubii renali, alterarea producţiei de eritropoietină, generarea de factori antieritrogeni, perturbarea homeostaziei calciului, PTH, vitaminei D, activarea necorespunzătoare a sistemului renină-angio tensină, scăderea producţiei de NO, inactivarea NOS, stimularea recrutării leucocitelor, accelerarea sintezei speciilor reactive de oxigen în celulele tu bulare renale şi în celulele mezangiale, reducerea sistemelor antioxidante, rol inhibitor asupra de iodinazei-1, afectări cvasodilataţie, agregarea plachetelor, adeziunea neutrofilelor, tonusul vacular, progresia aterogenezei, reducerea clearance-ului renal la citokine, acumularea AGE, hiperhomocisteinemie, promovarea semnalizării prin AhR, NFkB, AP-1, CREB. (1,2,(4)(5)(6)(7)(8)10,12,13,15,16,19,20) -Sistem cardiac: creşterea sintezei de colagen, alterarea structurii şi funcţiei joncţiunilor gap, suprimarea contractilităţii muşchiului cardiac, ateromatoza, arterioscleroza, pericardita, hipo/hiper tensiune, remodelarea cardiacă, activarea p38MAPK, Rho, p44/p42MAPK (1,2,4,5,6,8). ...
Progressive accumulation of uremic toxins in the body exerts a variety of adverse effects on all organs, tissues and systems. The elimination of these compounds from the body is a major goal in the international scientific community. The objectives of this study are: uremic toxins classification, presentation of nocive effects of uremic toxins in human body. This paper is focused on identifying the disorders induced by uremic toxins on metabolism and microcirculation and on finding new therapeutic strategies to prevent the development of complications in uremic patients.
... One distinct feature of chronic kidney disease (CKD) is systemic retention and accumulation of uremic toxins [6]. Indoxyl sulfate (IS) and p-cresol sulfate (PCS) are extensively studied due to their tendency to bind to albumin, thereby forming large protein complexes that are undialyzable through the pores of the dialysis membrane [6,7]. ...
... One distinct feature of chronic kidney disease (CKD) is systemic retention and accumulation of uremic toxins [6]. Indoxyl sulfate (IS) and p-cresol sulfate (PCS) are extensively studied due to their tendency to bind to albumin, thereby forming large protein complexes that are undialyzable through the pores of the dialysis membrane [6,7]. In dialysis patients, serum levels of IS and PCS are elevated by 54 and 17 times, respectively, whereas their amounts are undetectable in healthy individuals [5]. ...
... Both RWJ-67657 and U0126 have been widely used to inhibit p38MAPK and ERK1/2 in various disease settings. Probenecid is a potent OAT1/3 inhibitor mainly used for the treatment of gout in the clinic [6] and has been extensively used to study renal-related functions as well as its functional relevance with uremic toxins such as IS and PCS [19][20][21]. The stock solution of G226, U0126, RWJ-67657 and Probenecid was prepared in dimethyl sulfoxide and kept in -20˚C until needed. ...
Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by ³H-leucine and ³H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.
... For example, creatinine and urea were observed to cause cardiomyocyte contractile injury, as well as increase cardiac oxygen consumption by lowering norepinephrine and cause insulin resistance (Lekawanvijit and Krum, 2015). Uric acid is also associated to heart injury as it is increased during hypertension, atrial fibrillation and heart failure (Tamariz et al., 2014). ...
... The most known outcome of their accumulation is inflammation. IS in cardiomyocytes increases the production of inflammatory cytokines such as interleukin 1 beta (IL1-β), IL-6, and TNF-α (Lekawanvijit and Krum, 2015). This is shown by the previously cited NF-kB interaction. ...
The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called “uremic retention solutes” or “uremic toxins,” accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient’s therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.
... Indoxyl sulfate has garnered a great deal of attention, both because of its likely importance as a uremic toxin and because of its intriguing biology. Indoxyl sulfate is one of the acidic uremic toxins highly bound to plasma protein [216] and is thus not easily removed through hemodialysis. It is believed to be associated with the progression of CKD and cardiovascular disease [2,[216][217][218]. ...
... Indoxyl sulfate is one of the acidic uremic toxins highly bound to plasma protein [216] and is thus not easily removed through hemodialysis. It is believed to be associated with the progression of CKD and cardiovascular disease [2,[216][217][218]. Indole is created in the lumen of the gut, via the metabolism of tryptophan by the gut microbiota, and absorbed across the gut wall into the blood. ...
Introduction
The solute carrier (SLC) and the ATP-binding cassette (ABC) transporter superfamilies play essential roles in the disposition of small molecules (endogenous metabolites, uremic toxins, drugs) in the blood, kidney, liver, intestine, and other organs. In chronic kidney disease (CKD), the loss of renal function is associated with altered function of remote organs. As renal function declines, many molecules—including protein-bound uremic toxins and cytokines–accumulate in the plasma. Many studies now support the view that ABC and SLC transporters as well as drug metabolizing enzymes (DMEs) in renal and non-renal tissues are directly or indirectly affected by the presence of various types of uremic toxins, including those derived from the gut microbiome; this can lead to aberrant inter-organ communication.
Areas covered
Here, the expression, localization and/or function of various SLC and ABC transporters- as well as DMEs in the kidney and other organs are discussed in the context of CKD and systemic pathophysiology.
Expert opinion
According to the Remote Sensing and Signaling Theory (RSST), the remote sensing and signaling system—a transporter and DME-centric network that optimizes local and systemic metabolism–maintains homeostasis in the steady state and resets homeostasis following perturbations due to renal dysfunction. The implications of this view for pharmacotherapy of CKD are also discussed.
... In CKD patients, uremic toxins were accumulated in the body, and so far the known varieties of uremic toxins were N 90 (Vanholder et al., 2003). Indoxyl sulfate (IS) is one of acidic uremic toxins highly bound to plasma protein (Lekawanvijit and Krum, 2015), and cannot removed through hemodialysis. Therefore, the IS in blood was also accumulated in those patients undergoing hemodialysis treatment (Herget-Rosenthal et al., 2009;Muting, 1965). ...
... Therefore, the IS in blood was also accumulated in those patients undergoing hemodialysis treatment (Herget-Rosenthal et al., 2009;Muting, 1965). Recent studies reported that the blood IS concentration was associated with the progression of CKD, cardiovascular disease (CVD) and mortality (Barreto et al., 2009;Lekawanvijit and Krum, 2015;Lin et al., 2012;Wu et al., 2011). Owing to the strong acidity, IS exists totally as anion under physiological pH in the systemic circulation, and the uptake transport of IS into the cells of renal proximal tubules was mediated by organic anion transporters (OAT) 1 and OAT 3 (Deguchi et al., 2004;Enomoto et al., 2002;Peng et al., 2015). ...
Chronic kidney disease (CKD) is a health problem worldwide. Indoxyl sulfate (IS) is a nephro-cardiovascular toxin accumulated in CKD patients and cannot be removed through hemodialysis. The renal excretion of IS was mediated by organic anion transporters (OATs) OAT 1 and OAT 3. Because a number of nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to inhibit OATs, we hypothesize that NSAIDs might inhibit the renal excretion of IS. Rats were intravenously injected IS with and without diclofenac, ketoprofen or salicylic acid, individually. Blood samples were collected at predetermined time points and the concentrations of IS were determined by HPLC method. The results showed that diclofenac and ketoprofen at 10.0 mg/kg significantly decreased the systemic clearance of IS by 71% and 82%, and increased the MRT of IS by 106% and 105%, respectively, whereas salicylic acid did not exhibit significant effects. Cell studies indicated that diclofenac and ketoprofen inhibited the uptake of IS mediated by OAT 1 and OAT3. In conclusion, diclofenac and ketoprofen inhibited the excretion of IS through inhibition on OAT1 and OAT3.
... This leads to a prothrombotic state through the activation of prothrombotic factors such as tissue factor and factor Xa [34], and the formation of endothelial microparticles. -Cardiorenal Syndrome: The accumulation of PBUTs, particularly IS, in cardiomyocytes is linked to increased production of inflammatory cytokines such as IL1, IL6, and TNF-α [38]. These toxins have been associated with pro-arrhythmogenic effects and atrial fibrillation [35]. ...
Uremic toxins (UTs), particularly protein-bound uremic toxins (PBUTs), accumulate in chronic kidney disease (CKD) patients, causing significant health complications like uremic syndrome, cardiovascular disease, and immune dysfunction. The binding of PBUTs to plasma proteins such as albumin presents a formidable challenge for clearance, as conventional dialysis is often insufficient. With advancements in the classification and understanding of UTs, spearheaded by the European Uremic Toxins (EUTox) working group, over 120 molecules have been identified, prompting the development of alternative therapeutic strategies. Innovations such as online hemodiafiltration aim to enhance the removal process, while novel adsorptive therapies offer a means to address the high affinity of PBUTs to plasma proteins. Furthermore, the exploration of molecular displacers, designed to increase the free fraction of PBUTs, represents a cutting-edge approach to facilitate their dialytic clearance. Despite these advancements, the clinical application of displacers requires more research to confirm their efficacy and safety. The pursuit of such innovative treatments is crucial for improving the management of uremic toxicity and the overall prognosis of CKD patients, emphasizing the need for ongoing research and clinical trials.
... Потенциальная опасность белок-ассоциированных уремических комплексов, связанная с увеличением заболеваемости и смертности пациентов с ТПН, привела к более широкому применению высокопроницаемых ГМД [65][66][67][68][69]. Потеря белков крови во время ГД происходит не только путем диффузии и/ или конвекции в диализат, но и посредством их адсорбции на поверхности ГМД. ...
The article deals with the issues of renal replacement therapy (RRT) taking into account the latest knowledge in the field of physics and chemistry of polymeric dialysis membranes. Existing and historical information about the classification of membranes for hemodialysis is given. The review also discusses the classification of dialysis membranes, based on the appropriateness of their use for a particular clinical situation, in order to achieve more effective hemodialysis and its modifications, as well as increase the safety of the procedure and reduce episodes of bioincompatibility reactions. the effect of albumin loss during the use of various methods of extracorporeal apparatus detoxification and peritoneal dialysis on the quality of life and survival of patients with end-stage renal disease was evaluated. The mechanisms of protein loss during rrt by adsorption on the hemodialyzer membrane, convective transfer, and elimination into the dialysate are described. in addition, the possibilities of analyzing adsorbed protein fractions under various pathological conditions are presented. The issues of the potentiating effect of hypoalbuminemia as an independent risk factor for adverse outcomes in patients receiving rrt are discussed. determination of the albumin level and its loss during the procedures for replacing the lost kidney function seems to be a routine method that allows indirect control of basal and energy metabolism, determining the prognosis of treatment with extracorporeal detoxification methods.
... Moreover, it is responsible for a pro-thrombotic state by promoting tissue factor production [63,64]. A number of studies have also shown the toxicity of IS for the heart, with cardiac pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects associated with the induction of oxidative stress [65][66][67][68][69][70]. However, in the specific context of AKI, its role in vascular and cardiac dysfunction is poorly understood. ...
Acute kidney injury (AKI) is a frequent disease encountered in the hospital, with a higher incidence in intensive care units. Despite progress in renal replacement therapy, AKI is still associated with early and late complications, especially cardiovascular events and mortality. The role of gut-derived protein-bound uremic toxins (PBUTs) in vascular and cardiac dysfunction has been extensively studied during chronic kidney disease (CKD), in particular, that of indoxyl sulfate (IS), para-cresyl sulfate (PCS), and indole-3-acetic acid (IAA), resulting in both experimental and clinical evidence. PBUTs, which accumulate when the excretory function of the kidneys is impaired, have a deleterious effect on and cause damage to cardiovascular tissues. However, the link between PBUTs and the cardiovascular complications of AKI and the pathophysiological mechanisms potentially involved are unclear. This review aims to summarize available data concerning the participation of PBUTs in the early and late cardiovascular complications of AKI.
... The most notable molecules in the class of water-soluble compounds that play an important role in CRS are urea, creatinine, uric acid, and inorganic phosphorus. The renal injury markers creatinine and urea are related to cardiomyocyte contractile injury and lead to an increase in cardiac oxygen consumption by lowering norepinephrine and causing insulin resistance [97]. Uric acid is also correlated with atrial fibrillation, HF, and hypertension [98]. ...
Almost 200 years ago, the first evidence described by Robert Bright (1836) showed the strong interaction between the kidneys and heart and, since then, the scientific community has dedicated itself to better understanding the mechanisms involved in the kidney–heart relationship, known in recent decades as cardiorenal syndrome (CRS). This syndrome includes a wide clinical variety that affects the kidneys and heart, in an acute or chronic manner. Moreover, it is well established in the literature that the immune system, the sympathetic nervous system, the renin–angiotensin–aldosterone, and the oxidative stress actively play a strong role in the cellular and molecular processes present in CRS. More recently, uremic molecules and epigenetic factors have been also shown to be key mediators in the development of syndrome. The present review intends to present the state of the art regarding CRS and to show the paths known, until now, in the long road between the kidneys and heart.
... Anyway, a possible negative impact of CKD when it complicates the course of CLD, can be readily anticipated, due to the expected contribution of CKD on increasing cardiovascular (CV) and metabolic risk factors, secondary to the retention of a high number of uremic toxins, increasing the levels of many pro-inflammatory and oxidative mediators, inducing intestinal microbiota dysbiosis, altering the control of electrolyte levels, and, not least, modifying the drug disposal which may strongly affect the therapeutic handling of CLD patients [142][143][144][145] . ...
Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs.
A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system.
The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment.
... Индоксил сульфат (ИС) -один из уремических токсинов, которые накапливаются в крови и тканях организма при ХПН. Увеличение концентрации ИС в сыворотке крови ассоциировано с прогрессированием ХПН, а также с риском развития кардиоваскулярных заболеваний и летального исхода [37]. ИС элиминируется из организма путем канальцевой секреции с помощью ОАТ1 и ОАТ3 в проксимальных и дистальных почечных канальцах [38]. ...
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used worldwide as pain relievers, antipyretics, and anti-inflammatory drugs. Failure to comply with the instructions for medical use of this group of drugs increases the risk of serious adverse reactions on the part of different organs and systems. From 5 to 18% of patients taking NSAIDs develop adverse reactions associated with impaired renal function. Organic anion transporter (OAT) proteins, which mediate the drug excretion with urine, have an important role to play in the NSAIDs adverse effect on kidneys. The aim of the study was to analyse and systematize scientific literature on the role of OATs in nephrotoxicity development in the context of NSAIDs use. It was revealed that adverse kidney reactions associated with NSAIDs are determined by several mechanisms, including inhibition of prostaglandin synthesis due to cyclooxeganse-1 and/or cyclooxeganse-2 blockade, and direct toxic effect on renal tubule epithelium followed by tubular necrosis due to NSAIDs interaction with OATs. Moreover, by suppressing OAT1 and OAT3, NSAIDs can not only enhance, but also reduce nephrotoxic effects of other medicines (when used together) and endogenous/exogenous toxins. Considering that NSAIDs are widely used in the treatment of various diseases (including in elderly patients and patients with concomitant renal diseases), it is still relevant to study mechanisms of adverse kidney reactions associated with drug transporters.
... Although traditional coronary risk factors are prevalent in the dialysis population [11,12], it is suggested that only a combination of traditional and uremia-specific risk factors can fully explain the extraordinarily high incidence of AMI in dialysis patients [13]. Among these uremia-specific risk factors, it is speculated that dialysis modality may result in different degrees of susceptibility to the development of AMI because of the differences in hemodynamic stability during dialysis procedures, solute clearance, remodeling of left ventricular hypertrophy, endothelial dysfunction, and myocardial injury [14][15][16][17][18][19]. To date, only a few studies have compared cardiovascular (CV) outcomes, including CV-related mortality or composite CV endpoints, between hemodialysis (HD) and peritoneal dialysis (PD) therapies [5,20,21]. ...
Background and aims
Acute myocardial infarction (AMI) remains the major cause of morbidity and mortality in the dialysis population. Traditional cardiovascular (CV) risk factors are unable to fully account for the high incidence of AMI in the dialysis population. In this study, we investigated whether dialysis modalities could be one of the uremia-specific risk factors for AMI.
Methods
Using the National Health Insurance Research Database, we recruited all incident dialysis patients from the period January 1, 1998 to December 31, 2010. The propensity score matching method was applied to form the matched pairs of hemodialysis (HD) and peritoneal dialysis (PD) patients. Incidence rate (IR), cumulative incidence rate (CIR) and multivariable subdistribution hazards models were employed to compare the risk of AMI in the HD and PD groups.
Results
Of the 86,215 incident dialysis patients, 5,513 matched pairs of HD and PD patients were identified. The HD patients had a higher IR of AMI than the PD patients (9.71 vs. 8.35 per 1000 patient-years, respectively, p=0.01). The CIR was also higher in the HD patients than in the PD patients (0.09 vs. 0.05), especially 4 years after dialysis therapy was initiated (p=0.04). In the subdistribution hazards models, HD was still significantly associated with a higher risk of developing AMI (adjusted hazard ratio:1.30, 95% confidence interval:1.02–1.65). The results remained unchanged in various stratifications as well as in the analysis of the unmatched cohorts.
Conclusions
Compared to PD, HD was significantly associated with higher risk of developing AMI, especially after 4 years since dialysis was initiated. Prevention and routine surveillance programs for AMI should be individualized according to dialysis modalities and vintage.
... The development of CHF in the dialysis population results in further increases in health-care and financial burdens [4][5][6][7] as well as a higher frequency of hospitalization [1,8,9]. It is speculated that the choice of dialysis modality might lead to different degrees of susceptibility to the development of CHF mainly because hemodialysis (HD) and peritoneal dialysis (PD) are quite different with respect to uremic toxin clearance [10], hemodynamic stability during the dialysis process [11], and preservation of residual renal function [12], all of which may differentially affect the incidence of CHF. In Taiwan, the PD utilization rate increased gradually from 6.8% in 2000 to 8.8-9.5% during 2011-2015. ...
Introduction
Congestive heart failure (CHF) is associated with high mortality and a heavy financial and healthcare burden in the dialysis population. Determining which dialysis modality is associated with a higher risk of developing CHF might facilitate clinical decision making and surveillance programs in the dialysis population.
Methods
Using the Taiwan National Health Insurance Database, we recruited all incident dialysis patients during the period from January 1, 1998 to December 31, 2010. The propensity score matching method was applied to establish the matched hemodialysis (HD) and peritoneal dialysis (PD) cohort. Incidence rates and cumulative incidence rates of CHF-related hospitalization were first compared for the HD and PD patients. Multivariable subdistribution hazards models were then constructed to control for potential confounders.
Results
Among a total of 65,899 enrolled dialysis patients, 4,754 matched pairs of HD and PD patients were identified. The incidence rates of CHF in the matched HD and PD patients were 25.98 and 19.71 per 1000 patient-years, respectively (P = 0.001). The cumulative incidence rate of CHF was also higher in the matched HD patients (0.16, 95% confidence interval (CI)(0.12–0.21)] than in the corresponding PD patients (0.09, 95% CI [0.08–0.11])(P<0.0001). HD was consistently associated with an increased subdistribution hazard ratio (HR) of CHF compared with PD in the matched cohort (HR: 1.45, 95% CI [1.23–1.7]). Similar phenomenons were observed in either the subgroup analysis stratified by selected confounders or in the HD and PD group without matching.
Conclusions
HD is associated with a higher risk of developing CHF-related hospitalization than PD. The surveillance program for CHF should differ in patients receiving different dialysis modalities.
... Current treatment for PBUTs can be summarized into four categories: via dietary manipulation, removal enhancement, abrogation of PBUT production, and inhibition of toxic effects exerted by PBUTs (Ito and Yoshida, 2014;Lekawanvijit et al., 2012b). There are many reviews in the literature discussing each aspect of therapeutic measures mentioned (Lekawanvijit, 2015;Lekawanvijit et al., 2016;Lekawanvijit and Krum, 2015), therefore will not be discussed again in this review. However, we would like to highlight that these measures are still met with drawbacks. ...
Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.
... 6,7 CKD patients have high levels of uremic toxins because of their increased production and because of the damaged kidney's inability to eliminate them from the bloodstream via urine, and later via dialytic treatment. 4,[8][9][10] Exacerbation of uremic toxins in the bloodstream worsens inflammation and oxidative stress, [10][11][12][13][14][15][16] while also contributing to endothelial dysfunction and atherosclerotic processes. 10,12,17 Therefore, strategies capable of reducing the generation of these toxins are needed. ...
An imbalance of gut microbiota is considered a new cardiovascular risk factor for chronic kidney disease (CKD) patients, since it is directly associated with increased uremic toxin production, inflammation and oxidative stress. Strategies such as prebiotic supplementation have been suggested to mitigate these complications. We hypothesized that prebiotic-resistant starch could ameliorate uremic toxins levels, oxidative stress, and inflammatory states in hemodialysis (HD) patients. This pilot study evaluated 31 HD patients assigned to either resistant starch (16 g of resistant starch Hi-Maize® 260) or placebo (manioc flour) supplementation, which they received for 4 weeks on alternate days through cookies on dialysis days and powder in a sachet on non-dialysis days. Levels of interleukin (IL)-6, C-reactive protein, thiobarbituric acid reactive substances plasma (TBARS), protein carbonylation, indoxyl sulfate (IS) and p-cresyl sulfate were measured. Anthropometric and biochemical parameters, as well as, food intake were also evaluated. As expected, resistant starch group increased fiber intake (p˃0.01), in addition the prebiotic supplementation reduced IL-6 (p=0.01), TBARS (p˃0.01), and IS (p˃0.01) plasma levels. No significant differences were evident in the placebo group. Prebiotic-resistant starch supplementation seems to be a promising nutritional strategy to improve inflammation, oxidative stress and to reduce IS plasma levels in CKD patients on HD.
... The relationship between CVD and RD is now known as cardiorenal syndrome, in which the func- tional deterioration of the two organs is highly inter- connected 30,31) . Notably, IS is one of the uremic toxins that were reported to contribute to the development of CVD in patients with RD 32,33) . Particularly, inves- tigations of the relationship between IS and coronary artery disease have been reported. ...
Aim:
We investigated whether indoxyl sulfate (IS), a protein-bound uremic toxin, predicts prognosis after acute coronary syndrome (ACS).
Methods:
Serum IS level was determined prospectively in 98 patients who underwent successful primary percutaneous coronary intervention for ACS. Patients on hemodialysis were excluded. The endpoint of this study was six-month composite events including death, nonfatal myocardial infarction, heart failure requiring hospitalization, and adverse bleeding events.
Results:
During the mean follow-up period of 168 days, composite events occurred in 13.3% of cases. Serum IS level was significantly higher in subjects who developed composite events than in those without events (0.14±0.11 mg/dl vs. 0.06±0.04 mg/dl; p＜0.001). After adjusting for confounding factors, a Cox proportional hazard analysis revealed that the IS level (hazard ratio (HR): 10.6; 95% confidence interval (CI): 1.63-69.3, p=0.01), hemoglobin level (HR: 0.61; 95% CI: 0.43-0.87; p＜0.01), and left ventricular ejection fraction (LVEF) (HR: 0.95; 95% CI: 0.91-0.99; p=0.03) were independent predictive factors of composite events. Furthermore, IS level significantly conferred additional value to the combined established risks of LVEF and hemoglobin level for predicting the incidence of composite events (area under the curve: 0.82 vs. 0.88, p=0.01; net reclassification improvement: 0.67, p=0.01; and integrated discrimination improvement: 0.15, p＜0.01).
Conclusions:
The assessment of serum IS level has prognostic utility for the management of ACS.
... Recognition that medium-high molecular weight (MW) solutes, including several proteins 1,3 and protein-bound molecules, 4 are potentially toxic has led to the development of more permeable membranes, in order to ameliorate the morbidity and mortality of dialysis patients. 5,6 However, along with high removal of middle or large MW solutes, there may be loss of proteins important for the patient's health, such as albumin, transferrin, or vitamin D-binding protein -a loss which should be restricted if we need to avoid blood deficiency. ...
Mario Bonomini,1 Luisa Pieroni,2 Lorenzo Di Liberato,1 Vittorio Sirolli,1 Andrea Urbani2,3 1Department of Medicine, G. d’Annunzio University, Chieti, 2Proteomic and Metabonomic Units, IRCCS S. Lucia Foundation, Rome, 3Faculty of Medicine, Biochemistry and Clinical Biochemistry Institute, Catholic University of the “Sacred Heart”, Rome, Italy Abstract: The success and the quality of hemodialysis therapy are mainly related to both clearance and biocompatibility properties of the artificial membrane packed in the hemodialyzer. Performance of a membrane is strongly influenced by its interaction with the plasma protein repertoire during the extracorporeal procedure. Recognition that a number of medium–high molecular weight solutes, including proteins and protein-bound molecules, are potentially toxic has prompted the development of more permeable membranes. Such membrane engineering, however, may cause loss of vital proteins, with membrane removal being nonspecific. In addition, plasma proteins can be adsorbed onto the membrane surface upon blood contact during dialysis. Adsorption can contribute to the removal of toxic compounds and governs the biocompatibility of a membrane, since surface-adsorbed proteins may trigger a variety of biologic blood pathways with pathophysiologic consequences. Over the last years, use of proteomic approaches has allowed polypeptide spectrum involved in the process of hemodialysis, a key issue previously hampered by lack of suitable technology, to be assessed in an unbiased manner and in its full complexity. Proteomics has been successfully applied to identify and quantify proteins in complex mixtures such as dialysis outflow fluid and fluid desorbed from dialysis membrane containing adsorbed proteins. The identified proteins can also be characterized by their involvement in metabolic and signaling pathways, molecular networks, and biologic processes through application of bioinformatics tools. Proteomics may thus provide an actual functional definition as to the effect of a membrane material on plasma proteins during hemodialysis. Here, we review the results of proteomic studies on the performance of hemodialysis membranes, as evaluated in terms of solute removal efficiency and blood–membrane interactions. The evidence collected indicates that the information provided by proteomic investigations yields improved molecular and functional knowledge and may lead to the development of more efficient membranes for the potential benefit of the patient. Keywords: mass spectrometry, hemodialysis, end-stage renal disease, protein adsorption, biocompatibility, uremic toxin
... In 2003, The European Uremic Toxin Working Group (EUTox-group) classified 90 retention solutes; of these, 22 were middle molecules (12 having a M W > 12 kDa), while 25 solutes, essentially small solutes, were protein bound [7]. Protein-bound uremic toxins may contribute to the pathophysiology of cardiorenal syndrome [8]. ...
The retention of a number of solutes that may cause adverse biochemical/biological effects, called uremic toxins, characterizes uremic syndrome. Uremia therapy is based on renal replacement therapy, hemodialysis being the most commonly used modality. The membrane contained in the hemodialyzer represents the ultimate determinant of the success and quality of hemodialysis therapy. Membrane’s performance can be evaluated in terms of removal efficiency for unwanted solutes and excess fluid, and minimization of negative interactions between the membrane material and blood components that define the membrane’s bio(in)compatibility. Given the high concentration of plasma proteins and the complexity of structural functional relationships of this class of molecules, the performance of a membrane is highly influenced by its interaction with the plasma protein repertoire. Proteomic investigations have been increasingly applied to describe the protein uremic milieu, to compare the blood purification efficiency of different dialyzer membranes or different extracorporeal techniques, and to evaluate the adsorption of plasma proteins onto hemodialysis membranes. In this article, we aim to highlight investigations in the hemodialysis setting making use of recent developments in proteomic technologies. Examples are presented of why proteomics may be helpful to nephrology and may possibly affect future directions in renal research.
Uremic toxins are defined as substances, organic or inorganic, that accumulate in the body fluids of subjects with acute or chronic kidney disease and impaired kidney function. They collectively contribute to the diverse clinical manifestations of the uremic syndrome. They can be classified according to physicochemical properties, especially with regard to molecular size and protein binding, and organ tropism for their adverse effects. Many such substances have been identified. A substantial number of uremic toxins are the product of protein metabolism and are influenced by colonic microbiota and enterohepatic circulation. The composition of the diet, particularly the contributions of animal versus vegetable proteins, influences the generation of certain uremic toxins. Many low- and middle-molecular-weight toxins are generally removed from the body by glomerular filtration, while protein-bound uremic toxins utilize tubular secretion as a removal pathway. Some uremic toxins are elaborated endogenously by dysregulated secretion (e.g., parathyroid hormone). Dialysis is efficient for the removal of low-molecular-weight uremic toxins, but very inefficient for the removal of high-molecular-weight or protein-bound uremic toxins. This chapter provides an integrated overview of the present status of the biology and clinical significance of uremic toxins.
Protein-bound uremic toxins (PBUTs), the presence of which in the blood is an important risk factor for the progression of chronic kidney disease (CKD), have not been cleared efficiently via traditional hemodialysis methods until now. In this study, biosafe and efficient nitrogen-containing porous carbon adsorbent (NPCA) beads for the clearance of PBUTs were prepared from porous acrylonitrile/divinylbenzene cross-linked copolymer beads followed by pyrolysis. The resulting NPCA beads were characterized via SEM, XPS and nitrogen adsorption/desorption tests. The results demonstrated that the NPCA beads possessed a mesoporous/microporous hierarchical structure with rich nitrogen functional groups on their surfaces and realized efficient PBUTs adsorption in human plasma. More importantly, the efficacy of PBUTs removal was substantially higher than those of commercial adsorbents that are commonly used in clinical uremia treatments. The NPCA beads also exhibited satisfactory removal efficacy towards middle-molecular-weight uremic toxins. The PBUTs removal mechanism of the NPCA beads is ascribed to effective competition between nitrogen-containing NPCA and proteins for PBUT binding. According to hemocompatibility assays, the NPCA beads possessed satisfactory in vitro hemocompatibility. This nitrogen-containing porous carbon adsorbent is an attractive and promising material for blood purification applications in the treatment of clinical uremia.
Growing evidence has emerged about the role of dietary patterns and components in heart failure (HF) incidence and severity. The objective here is to provide a comprehensive summary of the current evidence regarding dietary patterns/components and HF. A comprehensive search of online databases was conducted using multiple relevant keywords to identify relevant human studies. The Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets have consistently been associated with decreased HF incidence and severity. Regarding specific dietary components, fruit, vegetables, legumes and whole grains appear beneficial. Current evidence suggests that red/processed meats, eggs and refined carbohydrates are harmful, while fish, dairy products and poultry remain controversial. However, there is a notable lack of human intervention trials. The existing but limited observational and interventional evidence from human studies suggests that a plant-based dietary pattern high in antioxidants, micronutrients, nitrate and fibre but low in saturated/ trans -fat and Na may decrease HF incidence/severity. Potential mechanisms include decreased oxidative stress, homocysteine and inflammation but higher antioxidant defence and NO bioavailability and gut microbiome modulation. Randomised, controlled trials are urgently required.
Evidence supporting the role of nutrition in heart failure (HF) incidence and severity is growing. A comprehensive search of online databases was conducted using relevant keywords to identify human studies including diet and HF. Several plant-based diets have consistently been associated with decreased HF incidence and severity, notably the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets. Several other plant-based dietary patterns, including low-fat diets and the rice diet, also show promise. Higher dietary quality, as assessed using different scores, seems to provide protective qualities. Fruit, vegetables, legumes and wholegrains appear to be beneficial, whereas red/processed meats, eggs and refined carbohydrates appear harmful. Some evidence suggests detrimental effects of dairy products and poultry, but more research is needed. There is observational and interventional evidence that a plant-based diet high in antioxidants, micronutrients, nitrate and fibre but low in saturated/trans fats may decrease the incidence and severity of HF. Potential mechanisms for this include decreased oxidative stress, homocysteine and inflammation levels, as well as higher antioxidant defence and nitric oxide bioavailability with gut microbiome modulation. Well-designed randomised, controlled nutrition intervention trials specific to HF are urgently required.
An accelerated progressive decline in renal function is a frequent accompaniment of myocardial infarction (MI). Indoxyl sulfate (IS), a uremic toxin that accumulates from the early stages of chronic kidney disease (CKD), is contributory to both renal and cardiac fibrosis. IS levels can be reduced by administration of the oral adsorbent AST-120, which has been shown to ameliorate pathological renal and cardiac fibrosis in moderate to severe CKD. However, the cardiorenal effect of AST-120 on less severe renal dysfunction in the post-MI setting has not previously been well studied. MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (MI+AST-120) or were untreated (MI+Vehicle) for 16 weeks. Serum IS levels were measured at baseline, 8 and 16 weeks. Echocardiography and glomerular filtration rate (GFR) were assessed prior to sacrifice. Renal and cardiac tissues were assessed for pathological changes using histological and immunohistochemical methods, Western blot analysis and real-time PCR. Compared with sham, MI+Vehicle animals had a significant reduction in left ventricular ejection fraction (by 42%, p
Background:
Vascular calcification is associated with mortality and cardiovascular events in patients with chronic kidney disease. AST-120, which adsorbs uremic toxins, is reported to reduce the risk of cardiovascular disease and death in chronic kidney disease patients. The aim of the current study was to investigate the association between abdominal aortic calcification and the use of AST-120 in predialysis chronic kidney disease patients.
Methods:
A retrospective analysis was conducted including 199 predialysis chronic kidney disease patients (stages 4 and 5) who underwent abdominal plain computed tomography in our institution between 2005 and 2010. Abdominal aortic calcification was assessed by aortic calcification index (ACI). Patients were divided into two groups based on whether or not AST-120 was administered for at least six months, and ACI was compared between the two groups.
Results:
The aortic calcification index was significantly lower in patients taking AST-120 [12.2 (2.5-30.3) vs. 25.7 (13.4-45.3) %, P < 0.001]. According to multivariate linear regression analysis, the use of AST-120 was independently and significantly correlated with ACI after adjusting for confounding factors.
Conclusions:
The use of AST-120 was independently associated with less aortic calcification in predialysis chronic kidney disease patients.
Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n=13) or no treatment (vehicle, n=17) for 12 weeks. Sham operated rats (n=12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A' waves] and a decrease of E/A and E'/A' ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120=227 ± 11 vs vehicle =224 ± 8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.
The mortality rate of elderly hemodialysis (HD) patients is high. Serum p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are associated with cardiovascular (CV) disease and mortality in renal patients. The association between such biomarkers and mortality in elderly HD patients has a high clinical value but remains unclear.
This prospective cohort study investigated the association of serum IS and PCS with all-cause and CV mortality in elderly HD patients. Multivariate Cox regression analysis was used to estimate the risk of all-cause and CV mortality in this prospective cohort.
Of 112 patients, 45 deaths (18 CV deaths) were identified after a mean follow-up of 33.2 months. The cumulative and CV survival of patients with lower free PCS was significantly better than high free PCS patients. In multivariate Cox regression analysis, serum free PCS was associated with all-cause and CV mortality after various adjustments, including age, gender and diabetes status (Model 1), albumin (Model 2), Ca × P product and intact parathyroid hormone (Model 3), hemoglobin and high-sensitivity C-reactive protein (Model 4) and hierarchically selected covariates (age, diabetes status and albumin, Model 5).
Serum free PCS levels may help in predicting risk of all-cause and CV mortality in elderly HD patients beyond traditional and uremia related risk factors.
Endothelial dysfunction and oxidative stress are matters of concern in patients with chronic renal failure (CRF). Uremic solutes retained in these patients could be involved in these processes. Notably, the protein-bound uremic solute indoxyl sulfate induces endothelial dysfunction in vitro, and has shown pro-oxidant effects.
To demonstrate that indoxyl sulfate is a potential mediator of oxidative stress in endothelial cells in vitro.
Indoxyl sulfate-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) was studied by measuring reactive oxygen specie (ROS) production by cytofluorimetry, by analyzing the involvement of the pro-oxidative enzymes NAD(P)H oxidase, xanthine oxidase, and NO synthase, and by measuring the levels of the non-enzymatic antioxidant glutathione.
We showed that indoxyl sulfate induced a significant production of ROS in HUVEC, with or without human serum albumin. We then investigated the role of pro-oxidative enzymes and measured the levels of the antioxidant glutathione. The NAD(P)H oxidase inhibitors, DPI, and apocynin, inhibited ROS production, whereas inhibitors of xanthine oxidase, NO synthase, and mitochondrial ROS had no effect. Interestingly, indoxyl sulfate strongly decreased the levels of glutathione, one of the most active antioxidant systems of the cell. In addition, the ROS production mediated by indoxyl sulfate was inhibited by the antioxidants vitamin C, vitamin E, and NAC.
The uremic solute indoxyl sulfate enhances ROS production, increases NAD(P)H oxidase activity, and decreases glutathione levels in endothelial cells. Thus, indoxyl sulfate induces oxidative stress by modifying the balance between pro- and antioxidant mechanisms in endothelial cells.
Cardiovascular disease (CVD) is a leading cause of death in chronic kidney disease (CKD) patients. One of the proposed mechanisms assumes that accumulated uremic toxins play an important role in the progression of CVD in CKD. Recently, it has been reported that AST-120 may attenuate progression of CVD through absorption of uremic toxins. In this study, we examined the association between the use of AST-120 and cardiac abnormalities in CKD patients.
This was a cross-sectional study of predialysis CKD patients hospitalized in our institution between April 2008 and October 2009. We divided 107 patients into two groups based on whether AST-120 had been administered for more than 6 months (AST-120 group: n = 43) or not (control group: n = 64). Echocardiography and laboratory tests were performed for all patients; we examined the relationship between clinical characteristics and cardiac abnormalities.
The number of patients with left ventricular (LV) concentric change was significantly smaller in the AST-120 group than in the control group. In multivariable analysis, the administration of AST-120, gender, and pulse pressure were significantly correlated with LV concentric change.
Our findings suggest that AST-120 prevents the development of LV concentric change in predialysis CKD patients.
Accelerated atherosclerosis and increased cardiovascular events are not only more common in chronic kidney disease (CKD) but are more resistant to therapeutic interventions effective in the general population. The oral charcoal adsorbent, AST-120, currently used to delay start of dialysis, reduces circulating and tissue uremic toxins, which may contribute to vasculopathy, including atherosclerosis. We, therefore, investigated whether AST-120 affects CKD-induced atherosclerosis.
Apolipoprotein E-deficient mice, a model of atherosclerosis, underwent uninephrectomy, subtotal nephrectomy or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation. Atherosclerosis and its characteristics were assessed at 25 weeks of age.
Uninephrectomy and subtotal nephrectomised mice had significantly increased acceleration of atherosclerosis. AST-120 treatment dramatically reduced the atherosclerotic burden in mice with kidney damage, while there was no beneficial effect in sham-operated mice. The benefit was independent of blood pressure, serum total cholesterol or creatinine clearance. AST-120 significantly decreased necrotic areas and lessened aortic deposition of the uremic toxin indoxyl sulfate without affecting lesional macrophage or collagen content. Furthermore, AST-120 lessened aortic expression of monocyte chemoattractant protein-1, tumor necrosis factor-α and interleukin-1β messenger RNA.
AST-120 lessens the extent of atherosclerosis induced by kidney injury and alters lesion characteristics in apolipoprotein E-deficient mice, resulting in plaques with a more stable phenotype with less necrosis and reduced inflammation.
Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients.
This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months.
Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model.
In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.
Cardiovascular disease is highly prevalent in chronic kidney disease. Traditional risk factors are insufficient to explain the high cardiovascular disease prevalence. Free p-cresol serum concentrations, mainly circulating as its derivative p-cresyl sulfate, are associated with cardiovascular disease in hemodialysis patients. It is not known if p-cresol is associated with cardiovascular disease in patients with chronic kidney disease not yet on dialysis.
In a prospective observational study in 499 patients with mild-to-moderate kidney disease, we examined the multivariate association between p-cresol free serum concentrations and cardiovascular events.
After a mean follow-up of 33 mo, 62 patients reached the primary end point of fatal or nonfatal cardiovascular events. Higher baseline concentrations of free p-cresol were directly associated with cardiovascular events (univariate hazard ratio [HR] 1.79, P<0.0001). In multivariate analysis, p-cresol remained a predictor of cardiovascular events, independent of GFR and independent of Framingham risk factors (full model, HR 1.39, P=0.04).
These findings suggest that p-cresol measurements may help to predict cardiovascular disease risk in renal patients over a wide range of residual renal function, beyond traditional markers of glomerular filtration. Whether p-cresol is a modifiable cardiovascular risk factor in CKD patients remains to be proven.
Indoxyl sulfate (IS) is a uraemic toxin found at high concentration in patients with chronic kidney disease (CKD) co-morbid with chronic heart failure (CHF). The aim of this study was to determine direct effects of IS on cardiac cells as well as the pro-inflammatory effect of IS.
Indoxyl sulfate significantly increased neonatal rat cardiac fibroblast collagen synthesis (by 145.7% vs. control, P < 0.05) and myocyte hypertrophy (by 134.5% vs. control, P < 0.001) as determined by (3)H-proline or (3)H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1beta mRNA expression in THP-1 cells as quantified by RT-PCR. Both p38 (RWJ-67657) and MEK1/2 (U0126) inhibitors suppressed all these effects by IS. Furthermore, western blot analysis showed that IS activated mitogen-activated protein kinase (MAPK) (p38, p42/44) and nuclear factor-kappa B (NFkappaB) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability.
This study has, for the first time, demonstrated that IS has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects, indicating that IS might play an important role in adverse cardiac remodelling mediated via activation of the p38 MAPK, p42/44 MAPK, and NFkappaB pathways. Targeting reduction of IS and/or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.
As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients.
One-hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled.
Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 +/- 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification.
The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.
Although a majority of patients with pouchitis respond favorably to antibiotic therapy, many relapse frequently, and nonabsorbable and non-antibiotic-based agents are desirable for reducing bacterial resistance and the systemic adverse effects associated with long-term antibiotic exposure. AST-120 (a spherical carbon adsorbent) comprises highly adsorptive, porous carbon microspheres with the ability to adsorb small-molecular-weight toxins, inflammatory mediators,and harmful bile acids. The aim of this pilot trial was to evaluate the efficacy and tolerability of AST-120 in the treatment of active pouchitis.
Eligible patients were recruited from two subspecialty pouchitis clinics. Inclusion criteria were(i) ileal pouch-anal anastomosis performed for ulcerative colitis; (ii) active pouchitis with Pouchitis Disease Activity Index (PDAI) scores > or =7; and (iii) discontinuation of antibiotic therapy for at least 2 weeks. Exclusion criteria included Crohn's disease of the pouch, isolated cuffitis, pouch strictures, abscess, and sinuses. All eligible patients received AST-120 in 2-g sachets (oral) open label, thrice a day for 4 weeks. The primary efficacy end point was remission as defined by a PDAI score of < 7 points; the main secondary end point was clinical response, defined by a reduction of the PDAI score of > or =3 points.
Nineteen of 20 patients completed the trial. Eleven patients (55.0 % ) had a clinical response to the therapy and 10 patients (50.0 % ) entered remission. Median reduction in the PDAI symptom, endoscopy, and histology subscores, and PDAI total scores after 4 weeks were -2( P = 0.002), -2 ( P = 0.003), 0 ( P = 0.32), and -4 ( P = 0.001) points, respectively. The agent was well tolerated; one patient experienced transient mild elevation of alkaline phosphatase of uncertain significance and one patient experienced an upper respiratory infection after taking one dose of AST-120 and was excluded from the fi nal analysis for the calculation of pre- and post-trial PDAI scores.
AST-120 seems to be effective and well tolerated in treating patients with active pouchitis.A randomized, placebo-controlled trial is warranted for assessing the long-term efficacy and safety of AST-120 in the disease.
The oral adsorbent AST-120 has been widely used in Japan to delay the initiation of dialysis therapy in patients with chronic renal failure. This study evaluated the long-term effects of AST-120 in patients with chronic renal failure who had not previously undergone dialysis. One hundred out-patients were prospectively enrolled and prescribed 6 g/day oral AST-120 for >or= 1 year. The clinical effectiveness of AST-120 was evaluated by comparing changes in the slope of the reciprocal serum creatinine-time plot (1/sCr slope) before and after AST-120 administration. The 1/sCr slope improved significantly after >or= 1 year of AST-120 treatment and greatest improvement was observed in patients with the longest AST-120 administration period (> 30 months). The results suggest that long-term treatment with AST-120 may be beneficial for chronic renal failure patients in the pre-dialysis stage.
Background. Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD). Increased oxidative stress plays a role in the pathogenesis of CVD in CKD patients. The oral charcoal adsorbent AST-120 attenuates the progression of CKD possibly by removing uraemic toxins such as indoxyl sulfate (IS), and reduces oxidative stress. We investigated the relationship between oxidative stress and cardiac damage in CKD and its prevention by AST-120.
Methods. Male Lewis rats were administered adriamycin at 8 weeks of age, and the right kidney was removed at 12 weeks of age. From 14 weeks of age, the rats were treated daily with AST-120 ( n = 8) or were untreated (control group, n = 8). At 34 weeks of age, the rats were killed and urinary and blood biochemical tests as well as cardiac histological analyses were performed.
Results. At 14 weeks of age, there were no significant differences in blood pressure, renal function (creatinine clearance: 1.54 ± 0.28 mL/min versus 1.60 ± 0.22 mL/min), oxidative stress markers or other biochemical data between the control and AST-120 groups. At 34 weeks, despite similar blood pressure and renal function (creatinine clearance: 0.78 ± 0.46 mL/min versus 0.75 ± 0.54 mL/min), serum concentrations of IS and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), acrolein and IS were significantly lower in the AST-120 group than in the control group. Heart volume, left ventricular volume and cardiac fibrosis were significantly smaller in the experimental AST-120 group than in the control group. Immunohistological analysis revealed that the numbers of 8-OHdG- and acrolein-positive cardiomyocytes and the degrees of myocardial and perivascular fibrosis were ameliorated by AST-120 administration. The myocardial fibrosis score was significantly associated with the 8-OHdG- ( r = 0.848, P < 0.001) and acrolein-positive ( r = 0.812, P < 0.001) cell scores. The perivascular fibrosis score was also significantly associated with the 8-OHdG- ( r = 0.906, P < 0.0001) and acrolein-positive ( r = 0.789, P < 0.001) cell scores.
Conclusions. Oxidative stress is suggested to play a key role in the development of cardiac hypertrophy and fibrosis in CKD. AST-120 may suppress oxidative stress and reduce cardiac damage in CKD.
Previously, we demonstrated that indoxyl sulphate (IS), a uraemic toxin, induced aortic calcification in hypertensive rats. This study aimed to determine if IS induces the production of reactive oxygen species (ROS) and the expression of osteoblast-specific proteins in human aortic smooth muscle cells (HASMCs).
In order to achieve these goals, HASMCs were incubated with IS. ROS were detected using probes with a fluorescence detector. The expression of alkaline phosphatase (ALP), osteopontin and organic anion transporters (OAT1, OAT3) was studied by western blotting. The expression of core binding factor 1 (Cbfa1), ALP, osteopontin and NADPH oxidases (Nox1, Nox2 and Nox4) was analysed by reverse transcription-polymerase chain reaction (RT-PCR). Knockdown of Nox4 was performed by RNA interference (RNAi).
IS induced ROS generation and the expression of Nox4, Cbfa1, ALP and osteopontin in HASMCs. A NADPH oxidase inhibitor and antioxidants inhibited IS-induced ROS production and mRNA expression of Cbfa1 and ALP. Knockdown of Nox4 using small interfering RNA (siRNA) inhibited IS-induced ROS production and mRNA expression of Cbfa1, ALP and osteopontin. OAT3 was expressed in HASMCs.
IS induces ROS generation by upregulating Nox4, and the expression of osteoblast-specific proteins such as Cbfa1, ALP and osteopontin in HASMCs.
We reviewed the records of 44 dialysis patients who had undergone one or more coronary angiograms to determine the frequency with which symptomatic ischemic heart disease (IHD) and significant coronary artery narrowing coincided and to determine those factors which were associated with the coronary atherosclerotic process. Thirty-four patients were catheterized for angina pectoris or myocardial infarction. Of this group, 53% were found to have significant narrowing of coronary arteries. This group was older than the group with trivial or no coronary artery occlusion and their duration of dialysis was shorter. All the patients with significant coronary occlusion were white and the majority were adult males. Discriminant function analysis revealed that the presence of significant coronary artery occlusion could be predicted with high sensitivity and specificity by the following variables: older age, white race, male sex, the presence of symptomatic IHD prior to the onset of dialysis, increased total serum cholesterol, abnormal left ventricular wall motion, and reduced alkaline phosphatase. We also found that the occurrence of symptomatic IHD far exceeded the presence of significant atherosclerotic coronary artery narrowing. We suggest that this may result from several dialysis-associated alterations in oxygen delivery and myocardial oxygen consumption.
Chronic kidney disease1 (CKD) is a worldwide public health problem. In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. The number of individuals with kidney failure treated by dialysis and transplantation exceeded 320 000 in 1998 and is expected to surpass 650 000 by 2010.1,2 There is an even higher prevalence of earlier stages of CKD (Table 1).1,3 Kidney failure requiring treatment with dialysis or transplantation is the most visible outcome of CKD. However, cardiovascular disease (CVD) is also frequently associated with CKD, which is important because individuals with CKD are more likely to die of CVD than to develop kidney failure,4 CVD in CKD is treatable and potentially preventable, and CKD appears to be a risk factor for CVD. In 1998, the National Kidney Foundation (NKF) Task Force on Cardiovascular Disease in Chronic Renal Disease issued a report emphasizing the high risk of CVD in CKD.5 This report showed that there was a high prevalence of CVD in CKD and that mortality due to CVD was 10 to 30 times higher in dialysis patients than in the general population (Figure 1 and Table 2).6–18 The task force recommended that patients with CKD be considered in the “highest risk group” for subsequent CVD events and that treatment recommendations based on CVD risk stratification should take into account the highest-risk status of patients with CKD.
View this table:
TABLE 1. Stages of CKD
Figure 1. Cardiovascular mortality defined by death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema in general population (GP; National Center for Health Statistics [NCHS] multiple cause of mortality data files International Classification of Diseases, 9th Revision [ICD 9] codes 402, 404, 410 to 414, and …
Background:
Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD.
Scope:
This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized.
Findings:
Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available.
Conclusion:
Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents.
The pathological role of the non-enzymatic modification of proteins by reducing sugars has become increasingly evident in various disorders. It is now well established that early glycation products undergo progressive modification over time in vivo to the formation of irreversible cross-links, after which these molecules are termed "AGEs (advanced glycation end products)". AGEs have been implicated in the development of many of the pathological sequelae of diabetes and aging, such as diabetic microangiopathy, ischemic heart disease and neurodegenerative diseases. Recently, digested food-derived AGEs are also found to play an important role in the pathogenesis of AGE-related disorders. Diet is a major environmental source of pro-inflammatory AGEs. Indeed, restriction of dietary glycotoxins decreases excessive AGE levels and subsequently reduces the inflammatory responses in patients with diabetes. These observations suggest that inhibition of absorption of dietary AGEs may be a novel target for therapeutic intervention in the above-mentioned AGE-related disorders. AST-120 (Kremezin) is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) by removing uremic toxins. We have recently found that AST-120 binds to carboxymethyllysine (CML), one of the well-characterized, digested food-derived AGEs in vitro and that administration of AST-120 decreases serum levels of AGEs in non-diabetic CRF patients. These findings suggest that digested food-derived AGEs such as CML may be a novel molecular target for oral adsorbent AST-120 and that AST-120 could exert beneficial effects on CRF patients by adsorbing diet-derived AGEs and subsequently decreasing serum AGE levels. If our speculation is correct, AST-120 may have therapeutic potentials for the treatment of patients with various AGE-related disorders as well. In this paper, we would like to propose the possible ways of testing our hypotheses. Does the long-term treatment of AST-120 decrease serum and tissue levels of AGEs in diabetic patients? Does this treatment also reduce the risk for the development and progression of diabetic vascular complications such as diabetic retinopathy or ischemic heart disease? If the answers are yes, do the serum and/or tissue levels of AGEs after AST-120 treatment predict its beneficial effects on diabetic vascular complications? How about the effects of AST-120 on Alzheimer's disease, another AGE-related neurodegenerative disorder? Does the treatment of AST-120 reduce the risk for Alzheimer's disease and/or improve the cognitive impairment of patients with this disorder? These prospective studies will provide further valuable information whether the inhibition of absorption of dietary AGEs by AST-120 could be clinically relevant.
Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate-induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.
The aim of the present study was to determine if treatment with an oral adsorbent (AST-120, Kremezin) might decrease the urinary albumin excretion and serum indoxyl sulfate (s-IS), and prevent glomerular sclerosis in early-stage renal failure, i.e. 0.9-1.2 mg/dl of serum creatinine (s-Cr) and 60-95 mg/dl of blood urea nitrogen (BUN), in subtotal (3/4) nephrectomized rats. Levels of s-Cr and s-IS in the AST-120-treated rats were significantly lower than those in the untreated control rats. The AST-120-treated rats showed an increase of creatinine clearance. Urinary protein and indoxyl sulfate excretion in the AST-120-treated rats were also significantly lower than those in the untreated control rats. The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the AST-120-treated rats was significantly lower than that in the untreated control rats. The degree of glomerular sclerosis and tubulointerstitial fibrosis in the AST-120-treated rats was significantly lower than that in the untreated control rats. Furthermore, there was a significant relationship among the degree of GT/BC, glomerular sclerosis, tubulointerstitial fibrosis and the levels of urinary protein excretion. It appears that AST-120 might decrease the accumulation of s-Cr and s-IS, and prevent glomerular sclerosis in early stage renal failure in the subtotal nephrectomized rats.
In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.
Monocyte chemotactic protein-1 (MCP-1) plays an important role in recruiting monocytes/macrophages to injured tubulointerstitial tissue. The present study examined whether indoxyl sulfate, a uremic toxin, regulates renal expression of MCP-1.
The effect of indoxyl sulfate on the expression of MCP-1 was determined using human proximal tubular cells (HK-2 cells) and following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS).
DN+IS, DH, and DH+IS rats showed significantly increased mRNA expression of MCP-1 in the kidneys compared with DN rats. DH+IS rats tended to show increased mRNA expression of MCP-1 in the kidneys compared with DH rats. Immunohistochemistry demonstrated the stimulatory effects of indoxyl sulfate on MCP-1 expression and monocyte/macrophage infiltration in the kidneys. Indoxyl sulfate upregulated mRNA and protein expression of MCP-1 in HK-2 cells. Indoxyl sulfate induced activation of ERK, p38, and JNK as well as of NF-κB and p53 in HK-2 cells. An antioxidant, and inhibitors of NF-κB, p53, ERK pathway (MEK1/2), and JNK suppressed indoxyl sulfate-induced mRNA expression of MCP-1 in HK-2 cells.
Indoxyl sulfate upregulates renal expression of MCP-1 through production of reactive oxygen species (ROS), and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells. Thus, accumulation of indoxyl sulfate in chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of MCP-1 in the kidneys.
We previously demonstrated that indoxyl sulfate induces senescence and dysfunction of proximal tubular cells by activating p53 expression. However, little is known about the role of nuclear factor (NF)-κB in these processes. The present study examines whether activation (phosphorylation) of NF-κB by indoxyl sulfate promotes senescence and dysfunction in human proximal tubular cells (HK-2 cells). Indoxyl sulfate induced phosphorylation of NF-κB p65 on Ser-276, which was suppressed by N-acetylcysteine, an antioxidant. Furthermore, indoxyl sulfate induced NF-κB p65 expression. Inhibitors of NF-κB (pyrrolidine dithiocarbamate and isohelenin) and NF-κB p65 small interfering RNA (siRNA) suppressed indoxyl sulfate-induced senescence-associated β-galactosidase activity and expression of p53, transforming growth factor (TGF)-β1, and α-smoothe muscle actin (SMA). The induction of p53 expression and p53 promoter activity by indoxyl sulfate were inhibited by pifithrin-α, p-nitro, an inhibitor of p53, whereas p53-transfected cells showed enhanced p53 promoter activity. NF-κB inhibitors suppressed indoxyl sulfate-induced p21 expression, whereas NF-κB p65 siRNA enhanced its expression. NF-κB inhibitors partially alleviated indoxyl sulfate-induced inhibition of cellular proliferation. NF-κB p65 siRNA-transfected cells showed less proliferation in the presence of indoxyl sulfate than control cells. Phosphorylated NF-κB p65 was expressed and colocalized with p53, p21, β-galactosidase, TGF-β1, and α-SMA in the kidneys of chronic renal failure (CRF) rats. AST-120, which reduces serum indoxyl sulfate level, suppressed their expression in the CRF rat kidneys. Taken together, NF-κB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. More notably, indoxyl sulfate accelerates proximal tubular cell senescence with progression of CRF through reactive oxygen species-NF-κB-p53 pathway.
Chronic kidney disease (CKD) and ESRD, treated with conventional hemo- or peritoneal dialysis are both associated with a high prevalence of an increase in left ventricular mass (left ventricular hypertrophy [LVH]), intermyocardial cell fibrosis, and capillary loss. Cardiac magnetic resonance imaging is the best way to detect and quantify these abnormalities, but M-Mode and 2-D echocardiography can also be used if one recognizes their pitfalls. The mechanisms underlying these abnormalities in CKD and ESRD are diverse but involve afterload (arterial pressure and compliance), preload (intravascular volume and anemia), and a wide variety of afterload/preload independent factors. The hemodynamic, metabolic, cellular, and molecular mediators of myocardial hypertrophy, fibrosis, apoptosis, and capillary degeneration are increasingly well understood. These abnormalities predispose to sudden cardiac death, most likely by promotion of electrical instability and re-entry arrhythmias and congestive heart failure. Current treatment modalities for CKD and ESRD, including thrice weekly conventional hemodialysis and peritoneal dialysis and metabolic and anemia management regimens, do not adequately prevent or correct these abnormalities. A new paradigm of therapy for CKD and ESRD that places prevention and reversal of LVH and cardiac fibrosis as a high priority is needed. This will require novel approaches to management and controlled interventional trials to provide evidence to fuel the transition from old to new treatment strategies. In the meantime, key management principles designed to ameliorate LVH and its complications should become a routine part of the care of the patients with CKD and ESRD.
Cardiac disease is the leading cause of death in uremic patients. In contrast to previous opinion, coronary events account for a relatively small proportion of cardiac deaths, the most common causes being sudden death and heart failure. Against this background the current text will discuss noncoronary cardiac pathology, specifically the pathogenesis and the morphological findings caused by (pathological) cardiac hypertrophy, cardiac interstitial fibrosis and microvascular disease.
Klotho, an anti-aging gene, is expressed in the kidneys, and its renal expression is decreased in chronic kidney disease (CKD). The present study aimed to examine whether renal expression of Klotho is regulated by indoxyl sulfate, a uremic toxin, using rat kidneys and human proximal tubular cells (HK-2).
The effect of indoxyl sulfate on renal expression of Klotho was examined using (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). The effects of indoxyl sulfate, inhibitors of nuclear factor-κB (NF-κB) and an antioxidant on the expression of Klotho in HK-2 cells were examined.
DH+IS and DN+IS rats showed decreased expression of Klotho mRNA in the kidneys as compared with DH and DN rats, respectively. Indoxyl sulfate suppressed the expression of Klotho mRNA and protein in HK-2 cells, whereas an antioxidant, N-acetylcysteine, and NF-κB inhibitors, pyrrolidine dithiocarbamate and isohelenin, alleviated these effects.
Indoxyl sulfate downregulates Klotho expression in kidneys through production of reactive oxygen species and activation of NF-κB in proximal tubular cells. Indoxyl sulfate may be involved in reduced renal expression of Klotho in CKD.
Since human serum albumin has one sulfhydryl group and 17 disulfides, reactive sulfhydryl groups give rise to heterogeneity. The present paper presents a comparison of sulfhydryl heterogeneity in human serum albumin and recombinant human serum albumin for clinical use. Low molecular weight sulfhydryl compounds were identified from both sources. The recombinant albumin had a much higher sulfhydryl content than plasma serum albumin.
Recent data suggest indoxyl sulfate (IS), one of the uremic toxins that accelerate the progression of chronic kidney disease (CKD), may also be responsible for vascular disease via an induction of oxidative stress. The role of IS in endothelial dysfunction in CKD and potential mechanisms of IS-induced endothelial dysfunction were investigated.
A prospective observational study in 40 CKD patients was performed. Flow-mediated endothelium-dependent vasodilatation (FMD) and its reaction time before and 24 weeks after an oral adsorbent of IS were evaluated. Plasma levels of IS and markers of oxidative stress were also measured. The proliferation, senescence, and production of nitric oxide and reactive oxygen species from human umbilical vein endothelial cells (HUVEC) were evaluated and the effect of antioxidants, N-acetylcysteine, rotenone, and apocynin was examined to explore the mechanism of IS-induced endothelial dysfunction.
AST-120 treatment for 24 weeks resulted in a significant increase in FMD with a decrease in IS and oxidized/reduced glutathione ratio. The presence of diabetes and high-sensitivity C-reactive protein were the independent predictors for an improved FMD. IS induced a production of reactive oxygen species in HUVEC, and pretreatment with antioxidants ameliorated IS-induced inhibition of proliferation and nitric oxide production and inhibited a senescence of HUVEC.
IS may play an important role in endothelial dysfunction via generation of oxidative stress with an induction of endothelial senescence. AST-120 improved endothelial dysfunction in patients with CKD associated with a decrease in IS and a restoration of antioxidant reserve.
An oral sorbent AST-120 composed of spherical porous carbon particles has superior adsorption ability for certain small-molecular-weight organic compounds known to accumulate in patients with chronic renal failure (CRF). A metabolomic approach was applied to search for uremic toxins as possible indicators of the effect of AST-120. Serum metabolites in normal and CRF rats before and after administration of AST-120 for 3 days were analyzed by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) and principal component analysis. Further, serum and urine levels of the indicators were quantified by selected reaction monitoring of LC/ESI-MS/MS. Indoxyl sulfate was the first principal serum metabolite, which could differentiate CRF from both normal and AST-120-administered CRF rats, followed by hippuric acid, phenyl sulfate and 4-ethylphenyl sulfate. CRF rats showed increased serum levels of indoxyl sulfate, hippuric acid, phenyl sulfate, 4-ethylphenyl sulfate and p-cresyl sulfate. Administration of AST-120 for 3 days to the CRF rats reduced the serum and urine levels of these metabolites. In conclusion, indoxyl sulfate is the best indicator of the effect of AST-120 in CRF rats. Hippuric acid, phenyl sulfate and 4-ethylphenyl sulfate are suggested as the additional indicators. 4-Ethylphenyl sulfate is a newly identified uremic substance.
Various uremic toxins accumulate in patients with chronic renal failure (CRF) and one of them is indoxyl sulfate, which accelerates the progression of CRF through unknown mechanisms. The present study investigates how indoxyl sulfate promotes CRF using the proximal tubular cell line HK-2 and CRF rats. Indoxyl sulfate inhibited serum-induced cell proliferation and promoted the activation of senescence-associated β-galactosidase, a marker of cellular senescence, and the expression of α-smooth muscle actin (α-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation. Pifithrin-α, p-nitro, a p53 inhibitor, blocked these effects. Indoxyl sulfate evoked reactive oxygen species (ROS), and the antioxidant N-acetylcysteine inhibited indoxyl sulfate-induced p53 expression and phosphorylation, as well as indoxyl sulfate-induced α-SMA expression. We previously demonstrated that although cellular senescence and fibrosis are detectable in the kidneys of CRF rats, the oral adsorbent AST-120 repressed these effects. Here, we found that β-galactosidase, p53 and α-SMA were expressed and colocalized in the renal tubules of CRF rats, whereas AST-120 decreased the expression of these genes. Taken together, these findings indicate that indoxyl sulfate induces the expression and phosphorylation of p53 though ROS production, thus inhibiting cell proliferation and promoting cellular senescence and renal fibrosis.
AST-120, an oral adsorbent currently on-label only in Asian countries with phase III trials ongoing in the US, slows renal disease progression in patients with diabetes and advanced-stage chronic kidney disease (CKD). The objective of this study is to evaluate the cost-effectiveness of using AST-120 to treat patients with type 2 diabetes and advanced-stage CKD.
We used Markov model simulating the progression of diabetic nephropathy. Data were obtained from randomized trials estimating the progression of diabetic nephropathy with and without AST-120, and published literature. The base population was patients 60 years of age with type 2 diabetes and Stages 3 and 4 CKD.
Treating patients with diabetes and advanced-stage CKD was found to be a dominant strategy, and quality of life improved further and more money was saved (0.22 quality-adjusted life years [QALYs] and $15,019 per patient) using AST-120 than the control strategy. Sensitivity analysis results were robust with regard to cost, adherence, and quality of life associated with AST-120 therapy, as well as age at diagnosis. The model was relatively sensitive to the effectiveness of AST-120.
Treating patients with type 2 diabetes and advanced-stage CKD with AST-120 appears to extend life and reduce costs.
We demonstrated that administration of indoxyl sulfate, a uremic toxin, promotes aortic calcification in hypertensive rats. This study aimed to clarify if indoxyl sulfate could contribute to cell senescence in the aorta of hypertensive rats. The rat groups consisted of (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). After 32weeks, their arcuate aortas were excised for histological and immunohistochemical analysis. Cell senescence was evaluated by immunohistochemistry of senescence-associated beta-galactosidase (SA-beta-gal), and senescence-related proteins such as p16(INK4a), p21(WAF1/CIP1), p53 and retinoblastoma protein (Rb). Both DH and DH+IS rats showed significantly higher systolic blood pressure than DN and DN+IS rats, respectively. Serum indoxyl sulfate levels were significantly higher in DN+IS and DH+IS rats than in DN and DH rats, respectively. In aorta, DH rats showed significantly increased aortic calcification and wall thickness, and increased expression of SA-beta-gal, p16(INK4a), p21(WAF1/CIP1), p53 and Rb in the calcification area of arcuate aorta as compared with DN rats. More notably, DH+IS rats showed significantly increased aortic calcification and wall thickness, and significantly increased expression of SA-beta-gal, p16(INK4a), p21(WAF1/CIP1), p53 and Rb in the cells embedded in the calcification area as compared with DH rats. In conclusion, indoxyl sulfate promotes cell senescence with aortic calcification and expression of senescence-related proteins in hypertensive rats.
The detailed mechanisms and treatment methods of chronic kidney disease (CKD) in patients with chronic heart failure (CHF) are not fully understood. We conducted a prospective study in CHF patients manifesting CKD to examine if AST-120 (Kremezin) improves cardiac and renal functions.
Twenty outpatients with CHF manifesting moderate CKD (serum creatinine 1.3-2.0 mg/dL) were studied. The patients had received AST-120 at a dosage of 6 g/day in combination with existing medications for 24 months. Some parameters of kidney and heart function were monitored. Also the cumulative length of hospital stay and number of admissions for the 2-year periods before and after initiation of AST-120 treatment were calculated.
Results of renal function tests, atrial natriuretic peptide, edema, cardiothoracic ratio and hospital stay indicated significant improvements in patients treated with AST-120. The length of hospital stay and number of admissions both decreased significantly during the 2 years of AST-120 treatment compared with the 2 years before treatment, from 39.7 ± 12.9 days to 4.14 ± 2.5 days, and from 0.79 ± 0.21 admissions to 0.21 ± 0.11 admissions, respectively.
AST-120 contributes to the improvement of cardiac and renal functions, and consequently improves the quality of life of patients.
The carbonaceous oral adsorbent AST-120 slows the deterioration of kidney function in patients with advanced chronic kidney disease (CKD). However, information about AST-120 in patients with less severe stages of CKD is lacking.
Randomized controlled trial.
75 medical facilities, 460 patients with CKD with serum creatinine (sCr) concentrations less than 5.0 mg/dL (not undergoing dialysis).
Random assignment to either a low-protein diet and antihypertensive medication in the control group or that treatment combined with AST-120 (6 g/d).
Composite primary end point: doubling of sCr level, increase in sCr level to 6.0 mg/dL or more, need for dialysis or transplantation, or death. Secondary outcomes: adverse events and changes in estimated creatinine clearance (CCr) rate, proteinuria (protein in milligrams per day), and quality of life.
Mean sCr level was 2.66 mg/dL and estimated CCr was 22.4 mL/min in both groups. During 56 weeks, numbers of primary end-point events (43 for control versus 42 for AST-120) and event-free survival (P = 0.9) did not differ between groups. Gastrointestinal adverse events were less common in the control group than the AST-120 group (2 versus 32 events). Estimated CCr decreased more in the control group than in the AST-120 group (-15% per year versus -12% per year, relative to the baseline value; [corrected] P = 0.001). Median proteinuria changed from protein of 1,162 to 1,167 mg/d in the control group versus 1,102 to 906 mg/d in the AST-120 group (P = 0.2).
Infrequent primary end-point events.
AST-120 did not substantially slow the progression of kidney disease in patients with moderate to severe CKD during 1 year.
Cardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p-cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated.
(1) Prospective observational study of humans and (2) in vitro study in human umbilical vein endothelial cells.
Hemodialysis patients.
p-Cresol and its main derivative p-cresyl sulfate.
Endothelial dysfunction.
We studied: (1) the relation between p-cresol and blood markers of endothelial dysfunction, including soluble P-selectin and endothelial microparticles; and (2) direct effects of p-cresol and p-cresyl sulfate on endothelial cell cultures.
(1) In a cohort of 100 maintenance hemodialysis patients, free serum p-cresol concentrations (median, 11.7 micromol/L; interquartile range, 15.2) were directly associated with circulating endothelial microparticles (P = 0.007), but not with soluble P-selectin (mean, 37.7 +/- 14.4 [SD] pg/mL). Other independent determinants of the degree of circulating microparticles were greater serum phosphorus (mean, 4.8 +/- 1.5 mg/dL; P = 0.008) and serum calcium concentrations (mean, 9.3 +/- 0.8 mg/dL; P = 0.03), whereas treatment with active vitamin D (P = 0.008) and vintage (median, 25 months; P = 0.04) were inversely associated. (2) In vitro, p-cresyl sulfate induced a dose-dependent increase in the shedding of endothelial microparticles (P < 0.001) by human umbilical vein endothelial cells. Shedding was reduced, but not completely aborted, in the presence of albumin, whereas the selective Rho kinase inhibitor Y-27632 abrogated the p-cresyl sulfate-induced generation of endothelial microparticles.
The relationship between p-cresyl sulfate and shedding of endothelial microparticles in vivo was not mechanistically explored.
p-Cresyl sulfate induces shedding of endothelial microparticles in the absence of overt endothelial damage in vitro and is independently associated with the number of endothelial microparticles in hemodialysis patients. These findings suggest that p-cresyl sulfate alters endothelial function in hemodialysis patients.
An oral adsorbent, AST-120, has been shown to retard the deterioration of renal function in patients with chronic kidney disease (CKD) by decreasing serum nephrotoxic substances such as indoxyl sulfate. Recent studies have suggested that a high level of serum indoxyl sulfate may be one of the mechanisms underlying the progression of atherosclerotic lesion, which is the leading cause of cardiovascular event or death in dialysis patients. In this study, we examined retrospectively whether AST-120 given to patients in the pre-dialysis period influences the prognosis after the initiation of dialysis.
One hundred and ninety-two CKD patients on dialysis were studied. The survival and causes of death after the initiation of dialysis were compared between patients who were administrated AST-120 (AST-120 group, n = 101) and those not administrated AST-120 (non-AST-120 group, n = 91) prior to the initiation of dialysis.
The five-year survival rate was 72.6% in the AST-120 group and 52.6% in the non-AST-120 group, and was significantly higher in the AST-120 group (p = 0.018). The risk of death was increased 1.91-fold in the non-AST-120 group. However, no difference in the causes of death was observed between two groups.
This study suggests that AST-120 given prior to the initiation of dialysis improves the prognosis of CKD patients under dialysis, although there is no association between AST-120 treatment and death caused by cardiovascular diseases such as heart failure, myocardial infarction, and cerebral hemorrhage. Further studies are needed to elucidate the effect of AST-120 on cardiovascular events and the prognosis in dialysis patients.
The survival experience of 39 patients receiving long-term regular hemodialysis in Seattle since 1960 was studied with particular reference to mortality and morbidity from arteriosclerotic cardiovascular complications. Mean age (± 1 S.D.) was 37.0 ± 9.5 years for the group at the start of dialysis. Mean duration of treatment was 6.5 years (range, one to 13). Overall mortality was 56.4 per cent at the end of the 13-year follow-up period, and 14 of 23 deaths could be attributed to arteriosclerotic complications: myocardial infarction was responsible for eight, strokes for three, and refractory congestive heart failure for three deaths. The incidence of these complications was many times higher than for normal and hypertensive groups of comparable age, and similar to rates found in Type 2 hyperlipoproteinemia. These results indicate that accelerated atherosclerosis is a major risk to long-term survivors on maintenance hemodialysis. (N Engl J Med 290:697–701, 1974)
Striking alterations of the structure of arterial vessels of different caliber are a well-known feature of renal failure, but it is currently unknown to what extent they are a reflection of hypertension or of uremia per se. To address this issue further we studied subtotally nephrectomized rats, sham-operated and pair-fed with matched controls. After uremia of 14 days' duration, stereologic measurements were carried out on perfusion-fixed tissue. To eliminate a potential influence of hypertension, subgroups of animals received furosemide and hydralazine in the drinking fluid to yield daily doses of 15 mg/kg and 20 mg/kg, respectively. At the end of the experiment, systolic blood pressure (tail plethysmography) was 110 +/- 13.3 (mean +/- SD) mm Hg and 99.4 +/- 8.1 mm Hg in untreated and treated controls, respectively, and 132 +/- 20.7 mm Hg and 103 +/- 13.0 mm Hg in untreated and treated uremic animals, respectively (n = 5 to 10 animals per group). The wall:lumen ratio of intramyocardial small arteries was 0.056 +/- 0.011 and 0.052 +/- 0.006 in untreated and treated controls, respectively. In untreated and treated uremic animals, the corresponding values were 0.077 +/- 0.011 and 0.066 +/- 0.007 (P < .01; control v uremia, ANOVA). A similar increase, unaffected by blood pressure treatment, was found for wall thickness of intramyocardial arteries. Analogous changes were also noted in mesenteric arterioles and veins. Finally, aorta media thickness was significantly (P < .005) higher in uremic animals than in controls (138 +/- 29 micrometers v 103 +/- micrometers).(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the role of indoxyl sulfate in the progression of glomerular sclerosis, the serum level of indoxyl sulfate was measured in patients with uremia, and the effect of oral administration of indoxyl sulfate on renal function and renal histology was studied in subtotally nephrectomized uremic rats. Further, the effects of a low-protein diet and oral sorbent (AST-120) administration on the serum and urine levels of indoxyl sulfate were studied in different groups of subtotally nephrectomized uremic rats. We noted a marked elevation of serum level of indoxyl sulfate in the patients with uremia. The oral administration of indoxyl sulfate to the uremic rats increased the serum creatinine and blood urea nitrogen levels and decreased creatinine clearance, inulin clearance, and p-aminohippuric acid clearance. The glomerular sclerosis index in the indoxyl sulfate-administered uremic rats was higher than in the control uremic rats. A low-protein diet and AST-120 administration decreased the serum and urine levels of indoxyl sulfate, the blood urea nitrogen level, the urinary protein level, and the glomerular sclerosis index in the uremic rats as compared with those on a high-protein diet. Thus, indoxyl sulfate, a circulating uremic toxin, stimulated the progression of glomerular sclerosis in the uremic model. A low-protein diet and AST-120 reduced the serum and urine levels of indoxyl sulfate and suppressed the progression of glomerular sclerosis.
We have recently demonstrated that indoxyl sulfate promotes the progression of glomerular sclerosis in uremic rats. In the present study, we determined whether an oral adsorbent (AST-120) could reduce the serum and urine levels of indoxyl sulfate and suppress the progression of chronic renal failure (CRF) in undialyzed uremic patients. Twenty-five undialyzed uremic patients were given AST-120 at a dose of 6 g/day for 6 months, while 10 undialyzed uremic patients were not given AST-120. The effects of the oral adsorbent on the slope of the 1/serum creatinine (Scr)-time plot, and the serum and urine levels of indoxyl sulfate were evaluated. Administration of AST-120 significantly decreased the serum and urine levels of indoxyl sulfate, and tended to improve the slope of the 1/SCr-time plot in the CRF patients. Among the patients in whom urinary excretion of indoxyl sulfate was reduced by AST-120, the oral adsorbent significantly improved the slope of the 1/SCr-time plot. The change in the slope of the 1/SCr-time plot showed a significant negative correlation with the change in the urine level of indoxyl sulfate. Thus, patients who showed a greater decrease of urinary indoxyl sulfate also showed more marked suppression of the progression of CRF. These results support the notion that indoxyl sulfate, a protein metabolite, is involved in the progression of CRF, and that an oral adsorbent can delay progression at least partly by reducing the serum and urine levels of indoxyl sulfate.
We have previously demonstrated that indoxyl sulfate is a stimulating factor for the progression of glomerular sclerosis in uremic rats. In this study we determined if a low-protein diet or oral sorbent (AST-120) could reduce the serum and urine levels of indoxyl sulfate in 5/6-nephrectomized uremic rats and undialyzed uremic patients. The uremic rats were treated by fasting or AST-120 for 2 days. The serum and urine levels of indoxyl sulfate dramatically decreased 1-2 days after fasting or AST-120 treatment. We then measured the serum and urine levels of indoxyl sulfate and calculated protein intake from urinary amounts of urea nitrogen using Maroni's equation in 80 undialyzed uremic patients with creatinine clearance less than 30 ml/min. The serum and urine levels of indoxyl sulfate were significantly lower in the patients on a low-protein diet than in those in the normal-protein diet group. Administration of AST-120 significantly decreased serum and urine levels of indoxyl sulfate in 22 undialyzed uremic patients. In conclusion, a low-protein diet or AST-120 reduced the serum and urine levels of indoxyl sulfate, a stimulating factor for glomerular sclerosis, in both uremic rats and undialyzed uremic patients.
This prospective, randomized controlled study was designed to examine the effects of oral adsorbent AST-120 on the progression of chronic renal failure (CRF) in patients on a strict low protein diet (LPD). Twenty-six patients with CRF (serum creatinine 3.0 to 8.6 mg/dl) on a LPD were randomly assigned to a control group (N = 13) or an AST-120 group (N = 13). The 1/Cr slope and creatinine clearance (CCr) slope were used to estimate the progression rate of CRF; uremic toxins, serum and urinary indoxyl sulfate (IS), peak 2a and guanidino substrates (GS) measured by HPLC. Comparisons were made between the baseline observation period for 6 to 12 months and the treatment period (0.6 g/kg/day of LPD alone or concurrent with 6 g/day of AST-120, for the control and the AST-120 groups, respectively) for 12 to 24 months in both groups. Both the 1/Cr slope and CCr slope were significantly lessened in the treatment period only in the AST-120 group. Serum and urinary IS, but neither peak 2a nor GS were significantly decreased in the treatment period only in the AST-120 group. We conclude that AST-120 administration concurrent with LPD may be superior to LPD alone in retarding the progression of CRF by inhibiting accumulation of indoxyl sulfate.
Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes.
In all, 167 patients (93 men, 74 women; mean age, 56.3+/-14.7 years) were followed for a mean duration of 17.4+/-6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0+/-48.6 versus 26.9+/-14.9 micromol/L, P=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per micromol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01).
These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per micromol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.
Homocysteine at abnormally high levels is an independent risk factor for atherosclerosis and may be a key factor in atherogenesis. Since homocysteine (Hcys) has been shown to promote cell proliferation and induction of the gene transcription factor c-fos in vascular smooth muscle cells (VSMCs), effects which can be mediated by MAP kinase, we hypothesized that homocysteine activates a MAP kinase-dependent signal transduction pathway. In this study, we find that homocysteine transiently activates MAP kinase (ERK2 isoform) in cultured VSMCs from chick embryos. Homocysteine activation of ERK2 is dose-dependent with an EC50 of approximately 500 nM and blocked by the MAP/Erk kinase (MEK) inhibitor PD98059. VSMC embryonic lineage is another determinant of homocysteine sensitivity. These findings demonstrate that homocysteine activates the MAP kinase signal transduction pathway and thus support the hypothesis that homocysteine may promote atherosclerosis by stimulation of growth promoting signal transduction pathways.
Three major groups of uremic solutes can be characterized: the small water-soluble compounds, the middle molecules, and the protein-bound compounds. Whereas small water-soluble compounds are quite easily removed by conventional hemodialysis, this is not the case for many other molecules with different physicochemical characteristics. Continuous ambulatory peritoneal dialysis (CAPD) is often characterized by better removal of those compounds. Urea and creatinine are small water-soluble compounds and the most current markers of retention and removal, but they do not exert much toxicity. This is also the case for many other small water-soluble compounds. Removal pattern by dialysis of urea and creatinine is markedly different from that of many other uremic solutes with proven toxicity. Whereas middle molecules are removed better by dialyzers containing membranes with a larger pore size, it is not clear whether this removal is sufficient to prevent the related complications. Larger pore size has virtually no effect on the removal of protein-bound toxins. Therefore, at present, the current dialytic methods do not offer many possibilities to remove protein-bound compounds. Nutritional and environmental factors as well as the residual renal function may influence the concentration of uremic toxins in the body fluids.