Accepted Manuscript Title: Cerebro-renal interactions: Impact of uremic toxins on cognitive function Author: Kimio Watanabe Tsuyoshi Watanabe Masaaki Nakayama PII: DOI: Reference:
S0161-813X(14)00105-3 http://dx.doi.org/doi:10.1016/j.neuro.2014.06.014 NEUTOX 1712
To appear in:
NEUTOX
Received date: Revised date: Accepted date:
27-3-2014 13-6-2014 27-6-2014
Please cite this article as: Watanabe K, Watanabe T, Nakayama M, Cerebro-renal interactions: Impact of uremic toxins on cognitive function., Neurotoxicology (2014), http://dx.doi.org/10.1016/j.neuro.2014.06.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title
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Cerebro-renal interactions: Impact of uremic toxins on cognitive function.
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Author names and affiliations:
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Kimio Watanabe, MD1, Tsuyoshi Watanabe, Prof1, and Masaaki Nakayama, Prof1
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1 Department of Nephrology, Hypertension, Diabetology, Endocrinology and
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Metabolism, Fukushima Medical University School of Medicine
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Corresponding author: Kimio Watanabe
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1 Hikarigaoka, Fukushima, Fukushima 960-1295, Japan.
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Phone: +81-24-547-1206; Fax: +81-24-548-3044
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Email: [email protected]
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Key words
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Uremic toxins, Cognitive Impairment, Cerebro-renal interactions
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Abstract
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Cognitive impairment (CI) associated with chronic kidney disease (CKD) has received
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attention as an important problem in recent years. Causes of CI with CKD are
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multifactorial, and include cerebrovascular disease, renal anemia, secondary
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hyperparathyroidism, dialysis disequilibrium, and uremic toxins (UTs). Among these
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causes, little is known about the role of UTs. We therefore selected 21 uremic
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compounds, and summarized reports of cerebro-renal interactions associated with UTs.
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Among the compounds, uric acid, indoxyl sulfate, p-cresyl sulfate, interleukin 1-β,
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interleukin 6, TNF-α, and PTH were most likely to affect the cerebro-renal interaction
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dysfunction; however, sufficient data have not been obtained for other UTs. Notably,
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most of the data were not obtained under uremic conditions; therefore, the impact and
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mechanism of each UT on cognition and central nervous system in uremic state remains
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unknown. At present, impacts and mechanisms of UT effects on cognition are poorly
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understood. Clarifying the mechanisms and establishing novel therapeutic strategies for
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cerebro-renal interaction dysfunction is expected to be subject of future research.
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1. Introduction
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Cognitive impairment (CI) associated with chronic kidney disease (CKD) has received
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attention as an important problem in recent years. CI accompanied by CKD occurs not
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only in end-stage renal disease (ESRD) patients but also in patients with early-stage
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CKD, and CKD is a risk factor for CI development (McQuillan and Jassal 2010). CI
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with CKD not only influences daily life and job function, but also results in longer
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hospitalization and higher risk for mortality. Bugnicourt et al. (2013) estimated a
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prevalence of CI in CKD of 30% to 60%, a value at least twice that observed in
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age-matched controls. In Japan, the number of hemodialysis (HD) patients has increased
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from 116,303 to 304,856 (from 1991 to 2011), and mean age has risen from 55.3 to 66.6
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years old (Nakai et al. 2013). Behavioral abnormalities such as restlessness during HD
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sessions, needle removal accidents, non-compliance with drug regimens, and difficulty
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with dietary restrictions are all critical issues seen in elderly dialysis patients with
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dementia.
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Cerebrovascular disease, anemia, secondary hyperparathyroidism, dialysis
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disequilibrium, and uremic toxins (UTs) have been reported as major causes of CI
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accompanied by CKD (Beard et al. 1997; Brines et al. 2000; Cerami et al. 2001; Chou
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et al. 2008; Cogan et al. 1978; Drueke et al. 2006; Erbayraktar et al. 2003; Goldstein et
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al. 1980; Goldstein and Massry 1980; Guisado et al. 1975; Lee et al. 2004; Leist et al.
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2004; Pfeffer et al. 2009; Pickett et al. 1999; Rabie and Marti 2008; Seliger et al. 2005;
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Shah et al. 2006; Singh et al. 2006; Temple et al. 1992; Zhang et al. 2009). Uremia can
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be defined as biochemical and physiologic dysfunction that increases with progression
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of CKD, resulting in variable symptomatology (Vanholder and De Smet 1999). Various
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potentially toxic compounds are accumulated in CKD patients, and these compounds
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are called “uremic retention solutes”. Such solutes that are biologically/biochemically
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active are called “uremic toxins” (Vanholder et al. 2003a; Vanholder et al. 2008). One
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hundred fifty-two UTs have been detected in the past (http://www.uremic-toxins.org/),
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and these molecules have been shown to have various negative effects, such as anorexia,
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cardiac failure, anemia, immune dysfunction, malnutrition, inflammation, and skin
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atrophy (Vanholder et al. 2008). However, the influence of UTs on CI in CKD patients
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is largely unknown. Therefore, from a collection of 152 known UTs, we selected a
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subset of 21 compounds reported (in previous research) to exhibit a relationship with
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the central nervous system (CNS). The present work summarizes the relevant literature
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for associations between UTs and cerebro-renal interactions.
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2. Material and Methods
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2.1 Review Criteria
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The information referenced in this paper was compiled by performing MEDLINE
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searches using the terms “asymmetric dimethylarginine”, “guanidino succinic acid”,
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“methylguanidine”, “hypoxanthine”, “uric acid”,
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“3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid”, “hippuric acid”, “homocysteine”,
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“indole-3-acetic acid”, “spermidine”, “putrescine”, “methylglyoxal”, “leptin”, “indoxyl
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sulfate”, “p-cresyl sulfate”, “interleukin 1-β”, “interleukin 6”, “tumor necrosis factor
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alpha”, “parathyroid hormone”, “beta-2-microglobulin”, “cystatin C”, “(chronic) kidney
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disease”, and “dialysis” in combination with the terms “cognitive impairment”,
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“dementia”, and “brain”. Further references were identified by hand-searching reports
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from recent large clinical trials or innovative basic research for the terms “cerebro-renal
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interaction” and “uremic toxin”. All cited articles were written in English.
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2.2 Cognitive impairment in CKD patients
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CI accompanied by CKD occurs not only in ESRD patients but also in patients with
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early-stage CKD, and CKD is considered a risk factor for CI development (McQuillan
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and Jassal 2010). Previous studies demonstrated the association of CI and CKD from a
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variety of perspectives. For example, patients with mild CKD or with albuminuria
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exhibited declines in memory as well as impairment in concentration and visual
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attention (Hailpern et al. 2007; Weiner et al. 2009), and CKD was associated with an
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increased prevalence of CI (odds ratio, 1.23). Patients with estimated glomerular
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filtration rates (eGFR) of less than 30 mL/min/1.73 m² exhibited a more than five-fold
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elevation in risk for CI (Khatri et al. 2009; Kurella et al. 2005b; Kurella Tamura et al.
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2008); CKD was associated with a 37% increased risk of CI over a 6-year follow-up
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interval. The increased risk of CI associated with a 15-mL/min/1.73 m² decline in eGFR
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was similar in magnitude to the effect of being 3 years older (Buchman et al. 2009;
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Kurella et al. 2005a; Seliger et al. 2004). In one study, only 13% of HD patients were
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classified as having normal cognition (Murray et al. 2006). CI accompanied by CKD
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has effects not only on daily life and job function but also on hospitalization length and
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increased risk of mortality. The average time to death in HD patients with CI was 1.09
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years, and hazard ratio (HR) for death was 1.87, which was higher than that seen in HD
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patients with cardiac disease (HR, 1.28) or stroke (HR, 1.20) (Rakowski et al. 2006).
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Memory holding errors and impaired responses due to frontal lobe dysfunction occur
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frequently in patients with CI accompanied by CKD (Lee et al. 2011; Post et al. 2010).
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Cerebrovascular disease, anemia, secondary hyperparathyroidism (SHPT), dialysis
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disequilibrium, and UTs have been reported as major causes of CI with CKD (Beard et
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al. 1997; Brines et al. 2000; Cerami et al. 2001; Chou et al. 2008; Cogan et al. 1978;
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Drueke et al. 2006; Erbayraktar et al. 2003; Goldstein et al. 1980; Goldstein and Massry
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1980; Guisado et al. 1975; Lee et al. 2004; Leist et al. 2004; Pfeffer et al. 2009; Pickett
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et al. 1999; Rabie and Marti 2008; Seliger et al. 2005; Shah et al. 2006; Singh et al.
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2006; Temple et al. 1992; Zhang et al. 2009). Hypoxia-induced deleterious effects on
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brain metabolism and/or direct effects on CNS by decreased erythropoietin (EPO) are
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considered to be mechanisms of CI resulting from renal anemia (Brines et al. 2000; Lee
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et al. 2004; Pickett et al. 1999; Temple et al. 1992). The ameliorative effects of EPO on
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cerebral hypoxia or brain tissue damage after trauma are expected to reflect the
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neurotrophic and neuroprotective effects of EPO; at the same time, EPO may elevate the
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frequency of vascular events due to increases in hemoglobin levels (Cerami et al. 2001;
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Drueke et al. 2006; Erbayraktar et al. 2003; Leist et al. 2004; Pfeffer et al. 2009; Rabie
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and Marti 2008; Singh et al. 2006; Zhang et al. 2009). SHPT is one of the major factors
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of CI with CKD patients, and several researchers have shown that cognition and
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electroencephalogram findings are improved by parathyroidectomy or vitamin D
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therapy (Chou et al. 2008; Cogan et al. 1978; Goldstein et al. 1980; Goldstein and
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Massry 1980; Guisado et al. 1975). Dialysis disequilibrium syndrome is a pathological
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condition whereby HD treatment itself impairs cognition. Rapid and short-term removal
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of body fluid by HD decreases cerebral blood circulation and oxygen supply to the brain
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(Chen et al. 2007; Hill 2001; Murray 2008; Patel et al. 2008; Prohovnik et al. 2007;
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Toyoda et al. 2005). Murray et al. reported that global cognitive function was worst
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during dialysis and best shortly before or on the day after a dialysis session (Murray et
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al. 2007); however, in a small-scale study, Vos et al. reported that short daily HD had no
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clear effect on cognitive functioning or electroencephalograms, suggesting that further
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investigation is required to confirm a link between dialysis disequilibrium and cognition
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(Suri et al. 2007; Vos et al. 2006). Kalirao et al. (2011) reported that two-thirds of
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peritoneal dialysis patients had moderate to severe CI, with severity sufficient to
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interfere with safe self-administration of dialysis and adherence to complex medication
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regimens. Verbal and visual memory are improved by kidney transplantation (Griva et
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al. 2006; Koushik et al. 2010); however, global cognition remains worse in
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post-transplant patients compared to healthy subjects (Gelb et al. 2008). Enervation,
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convulsion, and coma are observed in uremic encephalopathy patients, and these
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symptoms are partially improved by dialysis treatment (Deguchi et al. 2006). This
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improvement is thought to be an effect of UT removal by dialysis from the blood.
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2.3 The role of uremic toxins in cognitive impairment
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2.3.1 Small water-soluble solutes UTs can be divided into three groups according to molecular weight and protein binding
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rate, with the three classes designated as “small water-soluble solutes”, “protein-bound
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solutes”, and “middle molecules”. Small water-soluble solutes are characterized by
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molecular weights of less than 500 daltons and easy removal by conventional HD
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procedures (Vanholder et al. 2008). Urea and creatinine are typical UTs belonging to
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this group. We reviewed the literature regarding guanidine compounds (including
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asymmetric dimethylarginine (ADMA), guanidino succinic acid (GSA),
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methylguanidine (MG)) and purine metabolites (hypoxanthine and uric acid (UA)).
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2.3.2 Asymmetric dimethylarginine
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Asymmetric dimethylarginine (ADMA), one of the guanidine compounds, inhibits NO
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synthase activity and affects blood-pressure variability, inducing oxidative stress and
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causing vascular involvement (Hu et al. 2009). Impaired synthesis and utilization of NO
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is thought to contribute to CI through the mechanisms of development and progression
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of arteriosclerosis, vasoconstriction, abnormalities in cerebral blood flow, and decreased
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neuro-protection (Asif et al. 2013). The Framingham offspring study revealed that
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higher plasma ADMA is associated with an increased prevalence of asymptomatic
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cerebral infarction (Pikula et al. 2009), and Kielstein et al. (2006) showed that
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subpressor doses of ADMA increased vascular stiffness and decreased cerebral
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perfusion by 15% in healthy subjects. These data suggest that ADMA is an important
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contributor to CI, particularly due to impaired blood flow and vascular structure. 2.3.3 Guanidino succinic acid (GSA), Methylguanidine (MG) Guanidino succinic acid (GSA) and methylguanidine (MG) are significantly increased
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in plasma, CSF, and brain tissue in patients with uremia, and these compounds are
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thought to contribute to CI and epilepsy. The kinetics of GSA and MG vary greatly. The
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mean distributed volumes are 30.6 and 102.6 L, respectively, and removal rates by
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dialysis are 76% and 42%, respectively (Eloot et al. 2005). Hippocampal injection of
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GSA in mice has been shown to have significant dose-dependent effects on cognitive
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performance, activity, and hippocampal volume (Torremans et al. 2005), and apoptosis
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of cultured rat glial cells is induced by MG and hydrogen peroxide exposure (Marzocco
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et al. 2010). The mechanism of enhancement of CNS excitability by uremic guanidine
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compounds may be partly explained by the activation of N-methyl-D-aspartate receptors,
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along with concomitant inhibition of GABA (A) receptors (De Deyn et al. 2001).
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Transporters of UT at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid
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(CSF) barrier determine the distribution of guanidine compounds in the brain, and
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dysfunction of these transporters may cause abnormal distribution of UT and associated
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neurological problems (Tachikawa and Hosoya 2011).
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2.3.4 Hypoxanthine
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Hypoxanthine and uric acid (UA) are purine metabolites, and some studies indicate an
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influence of these compounds on CNS. In particular, intrastriatal injection of
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hypoxanthine in adult Wistar rats has been shown to impair memory formation
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(Bavaresco et al. 2008). Rat hippocampus and striatum are disrupted upon exposure to
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hypoxanthine; these effects are mediated by free radical production and elevated uric
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acid levels, which induce changes in acetylcholinesterase and butyrylcholinesterase
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activities (Wamser et al. 2013). In contrast, infusion of hypoxanthine in rabbits
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subjected to hypoxic-ischemic brain injury reduced cerebral injury and significantly
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improved somatosensory-evoked potential recovery (Mink and Johnston 2007). Levels
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of xanthine oxidase (XO), an enzyme that converts hypoxanthine to xanthine and
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xanthine to uric acid, are increased in plasma and brain in aging mice, and XO levels
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have been shown to correlate with lipid peroxidation (Vida et al. 2011). Consistent with
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this observation, brain damage and renal dysfunction are improved by XO inhibition
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(Hughes et al. 2013; Mink and Johnston 2007).
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2.3.5 Uric acid (UA)
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Higher serum levels of UA in CKD patients with eGFR less than 60 mL/min/1.73m²
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independently correlated with CI, as evaluated by the Mini Mental State Examination
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(MMSE), the most widely used screening tool for CI; elevated serum UA levels were
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associated with poorer working memory, processing speed, fluency, verbal memory, and
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greater white matter hyperintensities (Afsar et al. 2011; Vannorsdall et al. 2008). In
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contrast, higher serum UA levels were related to lower risks of CI in Chinese male
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nonagenarians and centenarians (Li et al. 2010), and also were related to a decreased
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risk of dementia and better cognitive function in a study consisting of 1724 participants
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aged 55 years and over during an 11-year follow-up (Euser et al. 2009).
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2.4 Protein-bound solutes
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Phenol and indole are categorized as “protein-bound solutes”, a class that primarily
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includes molecules with molecular weight less than 500 daltons. Removal of this type
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of UT from the blood by dialysis, even using high-flux dialysis membranes, is difficult,
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because molecules of this class bind tightly to albumin in the blood. We reviewed
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literature for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric
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acid, homocysteine (Hcy), putrescine, spermidine, indole-3-acetic acid (IAA),
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methylglyoxal (MGO), leptin, p-cresyl sulfate (PCS), and indoxyl sulfate (IS).
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2.4.1 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF)
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3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is a furan fatty acid that
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accumulates in renal tubular cells (Miyamoto et al. 2012). p-cresyl sulfate (PCS) and
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indoxyl sulfate (IS) show high protein binding rates (more than 95%) and low removal
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rates by HD (less than 35%); CMPF shows an even higher protein binding rate
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(99-100%). CMPF induced reactive oxygen species (ROS) in human renal proximal
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tubular epithelial cells and human umbilical vein endothelial cells, and inhibited cell
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growth (Itoh et al. 2012; Miyamoto et al. 2012; Niwa 2013). Intracellular accumulation
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and pro-oxidant effects of CMPF are important points; however, the role of CMPF in
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CNS remains unclear.
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2.4.2 Hippuric acid
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Salts of hippuric acid are one of the major compounds that contribute to uremic
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encephalopathy. Accumulation of UT in the brain is thought to result from UT
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transporter (rat organic anion transporter 3, rOat3) dysfunction at the BBB; this
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inhibition, which decreases efflux clearance of UTs from brain to blood (across the
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BBB), is thought to be a mechanism of uremic encephalopathy (Deguchi et al. 2006).
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Murine renal organic transporter (mOAT1), which is expressed in cerebral cortex and
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hippocampus, also has a critical role in regulation of UTs (Bahn et al. 2005). It has also
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been reported that urinary levels of hippuric acid are elevated in patients with major
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depressive disorders and in rat models of depression (Zheng et al. 2013; Zheng et al.
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2010). This pattern suggests the availability of hippuric acid as a potential marker for
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depression. However, the role of hippuric acid in cerebro-renal interaction dysfunction
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remains unclear. 2.4.3 Homocysteine (Hcy) There are several reports related to homocysteine (Hcy) and CI. Hcy was a contributing
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factor for faster rate of decline in cognition during a six-year follow up with 1076
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elderly subjects (van den Kommer et al. 2010). Hcy levels were related to episodic
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memory, executive function, and verbal expression in 274 non-demented elderly
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subjects during a seven-year follow-up (Hooshmand et al. 2012). Elevated Hcy levels
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were related to progression of ventricular enlargement and increased risk of decline in
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executive function in 663 patients with mean age of 57 during a 3.9-year follow-up
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(Jochemsen et al. 2013). Polymorphism at the 5,10-methylenetetrahydrofolate
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reductase-encoding gene, a trait related to high Hcy levels, was associated with 46%
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greater odds of CI in elderly men (Ford et al. 2012). While these data do not directly
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address the role of UTs in cerebro-renal interactions, the results do suggest that higher
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Hcy levels may influence CI, especially in elderly subjects.
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2.4.4 Putrescine and spermidine
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Putrescine, spermidine, and spermine are typical polyamines in the human body. In aged
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rats, putrescine levels were decreased in the CA1 and dentate gyrus and increased in the
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CA2/3, while spermidine levels were increased in the CA1 and CA2/3 (Liu et al. 2008b).
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Low doses of difluoromethylornithine, a potent inhibitor of putrescine synthesis,
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induced anxiety-like behavior and impaired memory in rats without affecting the
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animals' activity (Gupta et al. 2009). Spermine and spermidine levels were decreased in
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mice trained in a Morris water maze (Tiboldi et al. 2012); elevated levels of endogenous
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polyamines contributed to memory function improvement in the fruit fly Drosophila
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melanogaster (Gupta et al. 2013; Sigrist et al. 2013); and decreased
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spermidine/spermine N1-acetyltransferase activity was observed in the brains of
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humans who died of suicide (Fiori et al. 2009). These findings suggest that dysfunction
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in the polyamine system affects learning and impairs memory, but the influence of
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polyamine metabolic abnormalities on CNS function has not been characterized in
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patients with CKD.
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2.4.5 Indole-3-acetic acid (IAA)
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Indole-3-acetic acid (IAA) is a plant hormone known as a natural auxin, and plays a role
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in the mechanisms of cell growth in animals. Administration of IAA to pregnant mice
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decreased neuron formation and induced microencephaly in the fetus, effects that were
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mediated by p53 in the embryonic neuroepithelium (Furukawa et al. 2007). However,
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no data is available regarding IAA and cerebro-renal interaction. In renal proximal
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tubule epithelial cells, the toxic mechanism of IAA has been reported to include tissue
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factor production in endothelial and peripheral blood mononuclear cells by aryl
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hydrocarbon receptor (Gondouin et al. 2013), and inhibition of
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UDP-glucuronosyltransferase activity and mitochondrial activity (Mutsaers et al. 2013). 2.4.6 Methylglyoxal (MGO)
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Methylglyoxal (MGO) is a highly reactive alpha-dicarbonyl compound that binds to
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arginine and lysine residues and produces a variety of advanced glycation endproducts
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(AGEs) (Matafome et al. 2013). Higher MGO levels were associated with a faster rate
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of cognitive decline in 267 non-demented elderly patients (Beeri et al. 2011); elevated
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MGO levels also were associated with poorer memory, reduced executive function, and
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lower grey matter volume in 378 non-demented subjects with mean age 72 years
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(Srikanth et al. 2013). Exposure of rat hippocampal neurons to MGO yielded decreased
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levels of reduced glutathione while inhibiting glyoxalase and glutathione peroxidase
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activities and inducing apoptosis and increasing the expression of inflammatory
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cytokines (Di Loreto et al. 2008). Exposure of SH-SY5Y neuroblastoma cells to MGO
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induced the production of intracellular ROS and lactate, while decreasing mitochondrial
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membrane potential and intracellular ATP levels (de Arriba et al. 2007). These results
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suggest that carbonyl stress-induced loss of mitochondrial integrity contributes to the
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cytotoxicity of MGO. In in vivo studies, streptozotocin-induced diabetic rats showed CI
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in a Morris water maze (Huang et al. 2012), but normal Sprague-Dawley rats did not
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show spatial memory dysfunction despite administration of exogenous MGO (Watanabe
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et al. 2014). As to the vasculature effects, oral administration of MGO to Wistar rats
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induced a decrease of NO-dependent vasorelaxation in isolated aortic arteries (Sena et al.
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2012). Exposure of brain microvascular endothelial cells to MGO induced glycation and
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endothelial cell dysfunction, along with elevated expression of occludin, an adhesion
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protein that contributes to the formation of tight junctions (Li et al. 2013).
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2.4.7 Leptin
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Leptin is an adipose cell-derived compound that contributes to appetite control, with
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associated effects on weight gain. Higher serum leptin levels were associated with
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reduced risk for dementia or mild cognitive impairment in very old women with normal
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body mass indexes (Zeki Al Hazzouri et al. 2013). In animal experiments, leptin
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delivery to the ventral hippocampus suppressed memory consolidation for the spatial
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location of food (Kanoski et al. 2011). In the context of Alzheimer’s disease (AD),
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leptin is thought to inhibit hippocampal involvement by accumulation of amyloid-β,
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which affects cognitive decline in AD patients (Doherty et al. 2013; Martins et al. 2013).
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Plasma leptin levels are known to be increased about eight- to nine-fold in uremic
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patients compared to healthy subjects. Nonetheless, the role of leptin in CNS function
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remains unclear. 2.4.8 P-cresyl sulfate (PCS) and indoxyl sulfate (IS) The pre-dialysis concentrations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are
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41-fold and 116-fold elevated compared to those of normal subjects, and the dialytic
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clearance rates of PCS and IS are decreased (to 0.39-fold and 0.21-fold, respectively),
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yielding rates that are relatively low compared to those for urea (4.2-fold) and creatinine
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(1.3-fold) (Sirich et al. 2013). Thus, the biological effects of PCS and IS accumulation
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are of great concern. Both PCS and IS also are risk factors for CKD progression;
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because these molecules share the same albumin binding site, both compounds are
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thought to be valid markers for monitoring the behavior of protein-bound solutes during
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dialysis (Meijers et al. 2009; Wu et al. 2011). Cisplatin-administered rats showed
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increased IS concentrations in brain tissue, with associated increases in nephrotoxicity
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along with disturbances in the circadian rhythm of the transcription of the clock gene
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rPer2 (Iwata et al. 2007). IS normally is transported from brain to blood via organic
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anion transporter 3, which is located in the BBB; IS accumulates in the brains of uremic
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patients as a result of transporter dysfunction (Ohtsuki et al. 2002). Additionally, PCS
318
and IS are thought to be causative factors for endothelial cell dysfunction in HD patients,
319
and to induce renal fibrosis through accumulation in renal tubular cells (Sun et al. 2013;
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Watanabe et al. 2013). IS activates the aryl hydrocarbon receptor (AhR), which is a
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ligand-activated transcriptional factor (Watanabe et al. 2013b). Prolonged activation of
322
AhR by IS may contribute to neurotoxicity through the mechanism of endothelial
323
dysfunction (Goudouin et al. 2013; Schroeder et al. 2010).
324
2.5 Middle molecules
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UTs in the “middle molecules” group have molecular weights greater than 500 daltons
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and can be removed by large pore-size dialysis membranes. We reviewed relevant
327
literature for the following molecules: cystatin C (CyC); cytokines IL-1β, IL-6, and
328
TNF-α; parathyroid hormone (PTH); and beta-2-microglobulin (β2MG).
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2.5.1 Cystatin C (CyC)
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Cystatin C (CyC), a proteinase inhibitor, is recognized as an endogenous glomerular
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filtration rate (GFR) marker. Serum CyC levels correlated with incident CI risk (odds
332
ratio, 1.54-1.92) among 3,030 elders in the health ABC study (Yaffe et al. 2008). In a
333
study of 604 Japanese elderly, subjects with higher CyC levels tended to have more
334
lacunae and higher grades of white matter lesions (Wada et al. 2010). Elevated CyC
335
levels correlated with reduced scores in cognitive tests such as the digit symbol
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substitution test or the Stroop test of executive function in diabetic patients (Murray et
337
al. 2011). Among 738 elderly Caucasian subjects, elevated CyC levels also were
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associated with volume deficits in the white matter region, especially bilaterally in the
339
anterior limb of the internal capsule of the brain (Rajagopalan et al. 2013). On the other
340
hand, several reports have indicated a positive correlation between CyC levels and brain
341
function. Notably, a 0.1-µM decrease of CyC in elderly patients was associated with a
342
29% higher risk of incident AD (Sundelof et al. 2008), and low plasma CyC levels
343
correlated with conversion from mild-CI to AD (Ghidoni et al. 2010). Furthermore, in
344
vivo administration of CyC in an animal model of subarachnoid hemorrhage attenuated
345
early brain injury (Liu et al. 2013). Based on these results, the pathological significance
346
of CyC levels appears to differ in cerebrovascular disease compared to
347
neurodegenerative disorders such as AD. Given that CyC itself is thought to directly
348
reflect renal function, the compound may be a useful marker, especially in vascular
349
impairment of cerebro-renal interaction.
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2.5.2 Interleukin 1-β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α
351
(TNF-α)
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Several important clinical studies have suggested correlations between cytokine levels
353
and CNS function. Specifically, associations have been reported between interleukin 6
354
(IL-6) levels and memory of encoding and recall in the elderly (Elderkin-Thompson et
355
al. 2012); between plasma IL-6 concentration and cognition among 1224 subjects with
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mean age of 71 years during a 3-year follow-up (Economos et al. 2013); and between
357
elevated IL-6 levels and impaired executive cognitive function in a cross-sectional
358
analysis of 5653 participants with mean age of 75 years with 39-month follow-up
359
(Mooijaart et al. 2013). As for the cytokines and cerebro-renal interactions, when
360
secondary brain damage was incurred from kidney or intestinal ischemia-reperfusion
361
injury, TNF-α and IL-6 levels were upregulated (Hsieh et al. 2011; Liu et al. 2008a).
362
Brain inflammation, especially in microglial cells and astrocytes, was confirmed in that
363
study (Hsieh et al. 2011). DNA damage was observed in the brains of CKD model rats,
364
and this damage was mediated by the increased levels of pro-inflammatory cytokines
365
such as IL-1α, IL-1β, IL-6, and TNF-α (Hirotsu et al. 2011).
366
Mechanistically, the neurotoxicity of cytokines has been proposed to be an effect of
367
glutamate, the production of which is up-regulated by IL-1β and TNF-α (Ye et al. 2013).
368
Better understanding of the relationship between cytokines and cerebro-renal
369
interactions will be critical, given that the CNS is vulnerable to cytokine-induced DNA
370
damage.
371
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2.5.3 Parathyroid hormone (PTH)
372
Several clinical investigations have suggested a negative correlation between PTH
373
levels and brain function, as evidenced by cognition and mood. Specifically,
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parathyroidectomy in 39 HD patients with SHPT resulted in improved cognition, as
375
evaluated by the MMSE test and clinical dementia rating (Chou et al. 2008). In a
376
separate study, patients who underwent parathyroidectomy also exhibited improvements
377
in depression, anxiety, visuospatial memory, and verbal memory (Roman et al. 2011).
378
Consistent with these observations, a study in 1282 older adults aged 65 to 95 years
379
revealed an association between increased PTH levels, decreased 25-hydroxyvitamin D
380
levels, and severity of depression (Hoogendijk et al. 2008). Receptors for PTH and
381
1,25-hydroxyvitamin D are known to exist in the brain (Jorde et al. 2006), and rats with
382
CKD exhibited an increase in brain calcium content accompanied by increased levels of
383
cytosolic calcium in synaptosomes, leading to somatic, behavioral, and motor
384
dysfunctions (Smogorzewski 2001). Notably, parathyroidectomy in this animal model
385
prevented the increase in calcium levels and inhibited derangements in neurotransmitter
386
metabolism (Smogorzewski 2001).
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2.5.4 Beta-2-microglobulin (β2MG)
388
Beta-2-microglobulin (β2MG) accumulates selectively in the bones and tendons of
389
dialysis patients, inducing a type of osteoarthritis referred to as dialysis amyloidosis
390
(Yamamoto et al. 2009). There is limited information about the relation of β2MG and
391
CNS effects. Cytotoxicity was observed in SH-SY5Y neuroblastoma cells following
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exposure to β2MG at levels similar to those seen in the plasma of HD patients (Giorgetti
393
et al. 2009). However, β2MG concentration in the CSF of HD patients did not correlate
394
with plasma level, and CSF β2MG levels in these patients was below the lower limit
395
required for cytotoxicity in cell culture (Giorgetti et al. 2009). Therefore, although
396
β2MG is potentially neurotoxic, the BBB is thought to restrict CSF β2MG concentration
397
in HD patients (Giorgetti et al. 2009).
398
Literature results for the twenty-one compounds described above are summarized in
399
Table 1. And we have summarized segment of the manuscript that refer to the
400
relationship between uremic toxins and cerebro-renal interaction in Table 2. Compound
401
molecular weights and data on plasma concentrations in normal and uremic states are
402
derived from the European Uremic Solutes Database (http://www.uremic-toxins.org/;
403
Duranton et al. 2012).
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3. Discussion
406
3.1 Therapeutic strategy for uremic toxins and cerebro-renal interaction
407
Several studies have attempted to treat CI by targeting UTs. A systematic review and
408
meta-analysis was performed for 19 randomized controlled trials that attempted to lower
409
Hcy levels by supplementation with vitamins B12, B6, and folic acid; the authors of that
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meta-analysis concluded that B-vitamin supplementation did not improve cognitive
411
function (Brady et al. 2009; Ford and Almeida 2012; Hankey et al. 2013; McMahon et
412
al. 2006). In a rat model of AD, researchers administered gamma-glutathione (ψ-GSH),
413
a synthetic cofactor of glyoxalase expected to counteract the reactive carbonyl moiety of
414
MGO, and reported therapeutic efficacy of ψ-GSH as judged by spatial mnemonic and
415
long-term recall impairment (More et al. 2013). Treatment of CKD model mice with a
416
pegylated leptin receptor antagonist attenuated cachexia (body weight loss) and muscle
417
wasting, effects that were presumed to occur via appetite motivation (Cheung et al.
418
2013). MK-801, which is N-methyl-D-aspartate receptor antagonist, blocked glutamate
419
production by IL-1β and/or TNF-α and alleviated the neurotoxicity associated with
420
these cytokines (Ye et al. 2013). As to PTH, improvements of depression, anxiety,
421
visuospatial memory, and verbal memory were observed in patients who underwent
422
parathyroidectomy, effects that correlated with postoperative reductions in iPTH,
423
decreases in state anxiety, and improved visuospatial working memory (Roman et al.
424
2011). Consistent with these clinical results, parathyroidectomies in CKD model rats
425
inhibited neurotransmitter metabolism dysfunction (Smogorzewski 2001).
426
Vascular dysfunction has been recognized as a traditional factor in dementia among
427
CKD patients (Bugnicourt et al. 2013). Recently, Jourde-Chiche et al. (2011) reported
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that several UTs (including ADMA, Hcy, AGEs, PCS, and IS) contribute to dysfunction
429
of the cardiovascular system. It is estimated that the adequate management of vascular
430
risk factors might result in a 50% reduction in dementia prevalence (Asif et al. 2013), so
431
maintenance of residual renal function (that is, maintenance of UT excretion ability) is
432
thought to be an important treatment approach.
433
Nocturnal daily HD improved CI symptoms such as psychomotor efficiency, attention,
434
and working memory in a small longitudinal pilot study (Jassal et al. 2008).
435
Protein-leaking HD with a polymethylmethacrylate membrane BK-F dialyzer reduced
436
serum CMPF levels with improvement of anemia while reducing plasma levels of Hcy,
437
pentosidine, and inflammatory cytokines (Niwa 2013). Negative effects of UTs and the
438
UTs themselves are expected to be decreased by treatment with vitamin C or E, aspirin,
439
statins, ACE-inhibitors, acetyl-l-carnitine, alpha-lipoic acid, or various scavenging
440
agents (Vanholder et al. 2003). Pro-oxidants such as D-galactose and iron have been
441
shown to induce dysfunction in learning, cognition, and spatial memory in rodent
442
models (de Lima et al. 2005; Wang et al. 2009), and anti-oxidants such as vitamin E and
443
alpha-lipoic acid have been suggested to improve CI symptoms by decreasing oxidative
444
stress (Fukui et al. 2002; Liu et al. 2002; Shamoto-Nagai et al. 2003).
445
As discussed above, various research has been conducted focusing on the possible
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effects of UTs on CNS function; antagonistic agents, parathyroidectomy, vitamin
447
supplementation, and innovative dialysis methods have been employed to counter the
448
effects of UTs. In the future, systematization of treatment strategies in terms of UTs and
449
cerebro-renal interactions is expected.
450
3.2 Limitations and future perspectives
451
In this review, we considered the effects of UTs on the CNS, with an emphasis on
452
cognitive function. There is little information about the roles of UTs in cerebro-renal
453
interactions. References cited in this paper included experiments with cultured cells and
454
in animal models without renal impairment. Therefore, caution is required in extending
455
these results to human subjects with CKD. For uremic patients, various UTs accumulate
456
gradually in the blood and tissues as CKD progresses, with associated increases in basal
457
oxidative stress. Additionally, existing conditions (e.g., diabetes, cardiac failure,
458
hypertension) may result in various complications that further affect cognition.
459
Especially in animal experiments, responses to individual UTs are thought to vary
460
greatly depending on species (e.g., mouse vs. rat), strain (e.g., Dahl rat vs.
461
Sprague-Dawley rat), and background pathological condition. Results opposite from
462
those expected might occasionally be observed, depending on the experimental
463
conditions (Watanabe et al. 2014). This distinction is an important point when we
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consider the pathological significance of each UT associated with cerebro-renal
465
interactions. In terms of the future research on UTs and cerebro-renal interactions,
466
detailed examination using appropriate animal models of renal dysfunction will be
467
required to distinguish the effects of UTs on CNS compared to traditional risk factors; to
468
determine which brain regions are affected (e.g., frontal cortex, hippocampus, or
469
amygdala); and to determine which structures are disrupted (e.g., neuron, endothelial
470
cell, or vascular tissue).
471
Clarification of the pathological significance of UTs for CI accompanied by CKD is
472
expected to facilitate the establishment of specific therapies while reducing the health
473
care costs and social burden for such patients.
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4. Conclusions
476
We reviewed the literature for 21 uremic toxins, and summarized the compounds in
477
terms of uremic toxicity and cerebro-renal interaction dysfunction. Among the
478
compounds, uric acid, indoxyl sulfate, p-cresyl sulfate, interleukin 1-β, interleukin 6,
479
TNF-α, and PTH are more likely to affect the cerebro-renal interaction dysfunction;
480
however, data for other uremic toxins remain limiting. This distinction may be due to
481
differences in study populations in clinical trials, or to differences in study conditions in
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animal experiments. Unfortunately, most of the data in this paper were not obtained
483
under uremic conditions; therefore, the impact and mechanism of each uremic toxin on
484
cognition and the central nervous system in the uremic state remains unknown.
485
Clarifying the mechanisms and establishing novel therapeutic strategies for
486
cerebro-renal interaction dysfunction is expected to be the subject of future research.
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Acknowledgements: This work was supported by JADP Grant 2013-1 and JSPS
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KAKENHI Grant Number 23591196.
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Conflict of interest: The authors declare no conflict of interest.
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References
493
Afsar, B., Elsurer, R., Covic, A., Johnson, R.J. and Kanbay, M. 2011. Relationship
494
between uric acid and subtle cognitive dysfunction in chronic kidney disease. Am J
495
Nephrol 34, 49-54.
496
Asif, M., Soiza, R.L., McEvoy, M. and Mangoni, A.A. 2013. Asymmetric
497
dimethylarginine: a possible link between vascular disease and dementia. Curr
498
Alzheimer Res 10, 347-356.
499
Bahn, A., Ljubojevic, M., Lorenz, H., Schultz, C., Ghebremedhin, E., Ugele, B., Sabolic,
500
I., Burckhardt, G. and Hagos, Y. 2005. Murine renal organic anion transporters mOAT1
501
and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol.
502
Cell physiology 289, C1075-1084.
503
Bavaresco, C.S., Ben, J., Chiarani, F., Netto, C.A. and Wyse, A.T. 2008. Intrastriatal
504
injection of hypoxanthine impairs memory formation of step-down inhibitory avoidance
505
task in rats. Pharmacol Biochem Behav 90, 594-597.
506
Beard, C.M., Kokmen, E., O'Brien, P.C., Ania, B.J. and Melton, L.J., 3rd. 1997. Risk of
507
Alzheimer's disease among elderly patients with anemia: population-based
508
investigations in Olmsted County, Minnesota. Ann Epidemiol 7, 219-224.
509
Beeri, M.S., Moshier, E., Schmeidler, J., Godbold, J., Uribarri, J., Reddy, S., Sano, M.,
Ac ce
pt
ed
M
an
us
cr
ip t
492
29 Page 29 of 60
Grossman, H.T., Cai, W., Vlassara, H. and Silverman, J.M. 2011. Serum concentration
511
of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive
512
decline in elderly individuals. Mech Ageing Dev 132, 583-587.
513
Brady, C.B., Gaziano, J.M., Cxypoliski, R.A., Guarino, P.D., Kaufman, J.S., Warren,
514
S.R., Hartigan, P., Goldfarb, D.S. and Jamison, R.L. 2009. Homocysteine lowering and
515
cognition in CKD: the Veterans Affairs homocysteine study. Am J Kidney Dis 54,
516
440-449.
517
Brines, M.L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N.C., Cerami, C., Itri,
518
L.M. and Cerami, A. 2000. Erythropoietin crosses the blood-brain barrier to protect
519
against experimental brain injury. Proc Natl Acad Sci U S A 97, 10526-10531.
520
Buchman, A.S., Tanne, D., Boyle, P.A., Shah, R.C., Leurgans, S.E. and Bennett, D.A.
521
2009. Kidney function is associated with the rate of cognitive decline in the elderly.
522
Neurology 73, 920-927.
523
Bugnicourt, J.M., Godefroy, O., Chillon, J.M., Choukroun, G. and Massy, Z.A. 2013.
524
Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc
525
Nephrol 24, 353-363.
526
Cerami, A., Brines, M.L., Ghezzi, P. and Cerami, C.J. 2001. Effects of epoetin alfa on
527
the central nervous system. Semin Oncol 28, 66-70.
Ac ce
pt
ed
M
an
us
cr
ip t
510
30 Page 30 of 60
Chen, C.L., Lai, P.H., Chou, K.J., Lee, P.T., Chung, H.M. and Fang, H.C. 2007. A
529
preliminary report of brain edema in patients with uremia at first hemodialysis:
530
evaluation by diffusion-weighted MR imaging. AJNR Am J Neuroradiol 28, 68-71.
531
Cheung, W.W., Ding, W., Gunta, S.S., Gu, Y., Tabakman, R., Klapper, L.N., Gertler, A.
532
and Mak, R.H. 2013. A Pegylated Leptin Antagonist Ameliorates CKD-Associated
533
Cachexia in Mice. J Am Soc Nephrol 25, 119-128.
534
Chou, F.F., Chen, J.B., Hsieh, K.C. and Liou, C.W. 2008. Cognitive changes after
535
parathyroidectomy in patients with secondary hyperparathyroidism. Surgery 143,
536
526-532.
537
Cogan, M.G., Covey, C.M., Arieff, A.I., Wisniewski, A., Clark, O.H., Lazarowitz, V. and
538
Leach, W. 1978. Central nervous system manifestations of hyperparathyroidism. Am J
539
Med 65, 963-970.
540
de Arriba, S.G., Stuchbury, G., Yarin, J., Burnell, J., Loske, C. and Munch, G. 2007.
541
Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal
542
cells--protection by carbonyl scavengers. Neurobiol Aging 28, 1044-1050.
543
De Deyn, P.P., D'Hooge, R., Van Bogaert, P.P. and Marescau, B. 2001. Endogenous
544
guanidino compounds as uremic neurotoxins. Kidney Int Suppl 78, S77-83.
545
de Lima, M.N., Polydoro, M., Laranja, D.C., Bonatto, F., Bromberg, E., Moreira, J.C.,
Ac ce
pt
ed
M
an
us
cr
ip t
528
31 Page 31 of 60
Dal-Pizzol, F. and Schroder, N. 2005. Recognition memory impairment and brain
547
oxidative stress induced by postnatal iron administration. Eur J Neurosci 21, 2521-2528.
548
Deguchi, T., Isozaki, K., Yousuke, K., Terasaki, T. and Otagiri, M. 2006. Involvement of
549
organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. J
550
Neurochem 96, 1051-1059.
551
Di Loreto, S., Zimmitti, V., Sebastiani, P., Cervelli, C., Falone, S. and Amicarelli, F.
552
2008. Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic
553
cell death in rat hippocampal neurons. Int J Biochem Cell Biol 40, 245-257.
554
Doherty, G.H., Beccano-Kelly, D., Yan, S.D., Gunn-Moore, F.J. and Harvey, J. 2013.
555
Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by
556
amyloid beta. Neurobiol Aging 34, 226-237.
557
Drueke, T.B., Locatelli, F., Clyne, N., Eckardt, K.U., Macdougall, I.C., Tsakiris, D.,
558
Burger, H.U. and Scherhag, A. 2006. Normalization of hemoglobin level in patients
559
with chronic kidney disease and anemia. N Engl J Med 355, 2071-2084.
560
Duranton, F., Cohen, G., De Smet, R., Rodriguez, M., Jankowski, J., Vanholder, R. and
561
Argiles, A. 2012. Normal and pathologic concentrations of uremic toxins. J Am Soc
562
Nephrol 23, 1258-1270.
563
Economos, A., Wright, C.B., Moon, Y.P., Rundek, T., Rabbani, L., Paik, M.C., Sacco,
Ac ce
pt
ed
M
an
us
cr
ip t
546
32 Page 32 of 60
R.L. and Elkind, M.S. 2013. Interleukin 6 plasma concentration associates with
565
cognitive decline: the northern Manhattan study. Neuroepidemiology 40, 253-259.
566
Elderkin-Thompson, V., Irwin, M.R., Hellemann, G. and Kumar, A. 2012. Interleukin-6
567
and memory functions of encoding and recall in healthy and depressed elderly adults.
568
Am J Geriatr Psychiatry 20, 753-763.
569
Eloot, S., Torremans, A., De Smet, R., Marescau, B., De Wachter, D., De Deyn, P.P.,
570
Lameire, N., Verdonck, P. and Vanholder, R. 2005. Kinetic behavior of urea is different
571
from that of other water-soluble compounds: the case of the guanidino compounds.
572
Kidney Int 67, 1566-1575.
573
Erbayraktar, S., Grasso, G., Sfacteria, A., Xie, Q.W., Coleman, T., Kreilgaard, M., Torup,
574
L., Sager, T., Erbayraktar, Z., Gokmen, N., Yilmaz, O., Ghezzi, P., Villa, P., Fratelli, M.,
575
Casagrande, S., Leist, M., Helboe, L., Gerwein, J., Christensen, S., Geist, M.A.,
576
Pedersen, L.O., Cerami-Hand, C., Wuerth, J.P., Cerami, A. and Brines, M. 2003.
577
Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity
578
in vivo. Proc Natl Acad Sci U S A 100, 6741-6746.
579
Euser, S.M., Hofman, A., Westendorp, R.G. and Breteler, M.M. 2009. Serum uric acid
580
and cognitive function and dementia. Brain 132, 377-382.
581
Fiori, L.M., Mechawar, N. and Turecki, G. 2009. Identification and characterization of
Ac ce
pt
ed
M
an
us
cr
ip t
564
33 Page 33 of 60
spermidine/spermine N1-acetyltransferase promoter variants in suicide completers. Biol
583
Psychiatry 66, 460-467.
584
Ford, A.H. and Almeida, O.P. 2012. Effect of homocysteine lowering treatment on
585
cognitive function: a systematic review and meta-analysis of randomized controlled
586
trials. J Alzheimers Dis 29, 133-149.
587
Ford, A.H., Flicker, L., Hankey, G.J., Norman, P., van Bockxmeer, F.M. and Almeida,
588
O.P. 2012. Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism
589
and cognitive impairment: the health in men study. Mol Psychiatry 17, 559-566.
590
Fukui, K., Omoi, N.O., Hayasaka, T., Shinnkai, T., Suzuki, S., Abe, K. and Urano, S.
591
2002. Cognitive impairment of rats caused by oxidative stress and aging, and its
592
prevention by vitamin E. Ann N Y Acad Sci 959, 275-284.
593
Furukawa, S., Usuda, K., Abe, M., Hayashi, S. and Ogawa, I. 2007. Indole-3-acetic acid
594
induces microencephaly in mouse fetuses. Exp Toxicol Pathol 59, 43-52.
595
Gelb, S., Shapiro, R.J., Hill, A. and Thornton, W.L. 2008. Cognitive outcome following
596
kidney transplantation. Nephrol Dial Transplant 23, 1032-1038.
597
Ghidoni, R., Benussi, L., Glionna, M., Desenzani, S., Albertini, V., Levy, E., Emanuele,
598
E. and Binetti, G. 2010. Plasma cystatin C and risk of developing Alzheimer's disease in
599
subjects with mild cognitive impairment. J Alzheimers Dis 22, 985-991.
Ac ce
pt
ed
M
an
us
cr
ip t
582
34 Page 34 of 60
Giorgetti, S., Raimondi, S., Cassinelli, S., Bucciantini, M., Stefani, M., Gregorini, G.,
601
Albonico, G., Moratti, R., Montagna, G., Stoppini, M. and Bellotti, V. 2009.
602
beta2-Microglobulin is potentially neurotoxic, but the blood brain barrier is likely to
603
protect the brain from its toxicity. Nephrol Dial Transplant 24, 1176-1181.
604
Goldstein, D.A., Feinstein, E.I., Chui, L.A., Pattabhiraman, R. and Massry, S.G. 1980.
605
The relationship between the abnormalities in electroencephalogram and blood levels of
606
parathyroid hormone in dialysis patients. J Clin Endocrinol Metab 51, 130-134.
607
Goldstein, D.A. and Massry, S.G. 1980. Parathyroid hormone, uremia, and the nervous
608
system. Contrib Nephrol 20, 73-83.
609
Gondouin, B., Cerini, C., Dou, L., Sallee, M., Duval-Sabatier, A., Pletinck, A., Calaf, R.,
610
Lacroix, R., Jourde-Chiche, N., Poitevin, S., Arnaud, L., Vanholder, R., Brunet, P.,
611
Dignat-George, F. and Burtey, S. 2013. Indolic uremic solutes increase tissue factor
612
production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 84,
613
733-744.
614
Griva, K., Thompson, D., Jayasena, D., Davenport, A., Harrison, M. and Newman, S.P.
615
2006. Cognitive functioning pre- to post-kidney transplantation--a prospective study.
616
Nephrol Dial Transplant 21, 3275-3282.
617
Guisado, R., Arieff, A.I., Massry, S.G., Lazarowitz, V. and Kerian, A. 1975. Changes in
Ac ce
pt
ed
M
an
us
cr
ip t
600
35 Page 35 of 60
the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain
619
electrolytes. J Clin Invest 55, 738-745.
620
Gupta, N., Zhang, H. and Liu, P. 2009. Behavioral and neurochemical effects of acute
621
putrescine depletion by difluoromethylornithine in rats. Neuroscience 161, 691-706.
622
Gupta, V.K., Scheunemann, L., Eisenberg, T., Mertel, S., Bhukel, A., Koemans, T.S.,
623
Kramer, J.M., Liu, K.S., Schroeder, S., Stunnenberg, H.G., Sinner, F., Magnes, C.,
624
Pieber, T.R., Dipt, S., Fiala, A., Schenck, A., Schwaerzel, M., Madeo, F. and Sigrist, S.J.
625
2013. Restoring polyamines protects from age-induced memory impairment in an
626
autophagy-dependent manner. Nat Neurosci 16, 1453-1460.
627
Hailpern, S.M., Melamed, M.L., Cohen, H.W. and Hostetter, T.H. 2007. Moderate
628
chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third
629
National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol
630
18, 2205-2213.
631
Hankey, G.J., Ford, A.H., Yi, Q., Eikelboom, J.W., Lees, K.R., Chen, C., Xavier, D.,
632
Navarro, J.C., Ranawaka, U.K., Uddin, W., Ricci, S., Gommans, J., Schmidt, R.,
633
Almeida, O.P. and van Bockxmeer, F.M. 2013. Effect of B vitamins and lowering
634
homocysteine on cognitive impairment in patients with previous stroke or transient
635
ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled
Ac ce
pt
ed
M
an
us
cr
ip t
618
36 Page 36 of 60
trial and meta-analysis. Stroke; a journal of cerebral circulation 44, 2232-2239.
637
Hill, M.B. 2001. Dialysis disequilibrium syndrome. Nephrol Nurs J 28, 348-349.
638
Hirotsu, C., Tufik, S., Ribeiro, D.A., Alvarenga, T.A. and Andersen, M.L. 2011.
639
Genomic damage in the progression of chronic kidney disease in rats. Brain Behav
640
Immun 25, 416-422.
641
Hoogendijk, W.J., Lips, P., Dik, M.G., Deeg, D.J., Beekman, A.T. and Penninx, B.W.
642
2008. Depression is associated with decreased 25-hydroxyvitamin D and increased
643
parathyroid hormone levels in older adults. Arch Gen Psychiatry 65, 508-512.
644
Hooshmand, B., Solomon, A., Kareholt, I., Rusanen, M., Hanninen, T., Leiviska, J.,
645
Winblad, B., Laatikainen, T., Soininen, H. and Kivipelto, M. 2012. Associations
646
between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a
647
longitudinal study. J Intern Med 271, 204-212.
648
Hsieh, Y.H., McCartney, K., Moore, T.A., Thundyil, J., Gelderblom, M., Manzanero, S.
649
and Arumugam, T.V. 2011. Intestinal ischemia-reperfusion injury leads to inflammatory
650
changes in the brain. Shock 36, 424-430.
651
Hu, X., Xu, X., Zhu, G., Atzler, D., Kimoto, M., Chen, J., Schwedhelm, E., Luneburg,
652
N., Boger, R.H., Zhang, P. and Chen, Y. 2009. Vascular endothelial-specific
653
dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular
Ac ce
pt
ed
M
an
us
cr
ip t
636
37 Page 37 of 60
endothelium plays an important role in removing asymmetric dimethylarginine.
655
Circulation 120, 2222-2229.
656
Huang, X., Wang, F., Chen, W., Chen, Y., Wang, N. and von Maltzan, K. 2012. Possible
657
link between the cognitive dysfunction associated with diabetes mellitus and the
658
neurotoxicity of methylglyoxal. Brain Res 1469, 82-91.
659
Hughes, K., Flynn, T., de Zoysa, J., Dalbeth, N. and Merriman, T.R. 2013. Mendelian
660
randomization analysis associates increased serum urate, due to genetic variation in uric
661
acid transporters, with improved renal function. Kidney Int 85, 344-351.
662
Itoh, Y., Ezawa, A., Kikuchi, K., Tsuruta, Y. and Niwa, T. 2012. Protein-bound uremic
663
toxins in hemodialysis patients measured by liquid chromatography/tandem mass
664
spectrometry and their effects on endothelial ROS production. Anal Bioanal Chem 403,
665
1841-1850.
666
Iwata, K., Watanabe, H., Morisaki, T., Matsuzaki, T., Ohmura, T., Hamada, A. and Saito,
667
H. 2007. Involvement of indoxyl sulfate in renal and central nervous system toxicities
668
during cisplatin-induced acute renal failure. Pharm Res 24, 662-671.
669
Jassal, S.V., Roscoe, J., LeBlanc, D., Devins, G.M. and Rourke, S. 2008. Differential
670
impairment of psychomotor efficiency and processing speed in patients with chronic
671
kidney disease. Int Urol Nephrol 40, 849-854.
Ac ce
pt
ed
M
an
us
cr
ip t
654
38 Page 38 of 60
Jochemsen, H.M., Kloppenborg, R.P., de Groot, L.C., Kampman, E., Mali, W.P., van der
673
Graaf, Y. and Geerlings, M.I. 2013. Homocysteine, progression of ventricular
674
enlargement, and cognitive decline: the Second Manifestations of ARTerial
675
disease-Magnetic Resonance study. Alzheimers Dement 9, 302-309.
676
Jorde, R., Waterloo, K., Saleh, F., Haug, E. and Svartberg, J. 2006. Neuropsychological
677
function in relation to serum parathyroid hormone and serum 25-hydroxyvitamin D
678
levels. The Tromso study. J Neurol 253, 464-470.
679
Jourde-Chiche, N., Dou, L., Cerini, C., Dignat-George, F. and Brunet, P. 2011. Vascular
680
incompetence in dialysis patients--protein-bound uremic toxins and endothelial
681
dysfunction. Semin Dial 24, 327-337.
682
Kalirao, P., Pederson, S., Foley, R.N., Kolste, A., Tupper, D., Zaun, D., Buot, V. and
683
Murray, A.M. 2011. Cognitive impairment in peritoneal dialysis patients. Am J Kidney
684
Dis 57, 612-620.
685
Kanoski, S.E., Hayes, M.R., Greenwald, H.S., Fortin, S.M., Gianessi, C.A., Gilbert, J.R.
686
and Grill, H.J. 2011. Hippocampal leptin signaling reduces food intake and modulates
687
food-related memory processing. Neuropsychopharmacology 36, 1859-1870.
688
Khatri, M., Nickolas, T., Moon, Y.P., Paik, M.C., Rundek, T., Elkind, M.S., Sacco, R.L.
689
and Wright, C.B. 2009. CKD associates with cognitive decline. J Am Soc Nephrol 20,
Ac ce
pt
ed
M
an
us
cr
ip t
672
39 Page 39 of 60
2427-2432.
691
Kielstein, J.T., Donnerstag, F., Gasper, S., Menne, J., Kielstein, A.,
692
Martens-Lobenhoffer, J., Scalera, F., Cooke, J.P., Fliser, D. and Bode-Boger, S.M. 2006.
693
ADMA increases arterial stiffness and decreases cerebral blood flow in humans. Stroke
694
37, 2024-2029.
695
Koushik, N.S., McArthur, S.F. and Baird, A.D. 2010. Adult chronic kidney disease:
696
neurocognition in chronic renal failure. Neuropsychol Rev 20, 33-51.
697
Kurella, M., Chertow, G.M., Fried, L.F., Cummings, S.R., Harris, T., Simonsick, E.,
698
Satterfield, S., Ayonayon, H. and Yaffe, K. 2005a. Chronic kidney disease and cognitive
699
impairment in the elderly: the health, aging, and body composition study. J Am Soc
700
Nephrol 16, 2127-2133.
701
Kurella, M., Yaffe, K., Shlipak, M.G., Wenger, N.K. and Chertow, G.M. 2005b. Chronic
702
kidney disease and cognitive impairment in menopausal women. Am J Kidney Dis 45,
703
66-76.
704
Kurella Tamura, M., Wadley, V., Yaffe, K., McClure, L.A., Howard, G., Go, R., Allman,
705
R.M., Warnock, D.G. and McClellan, W. 2008. Kidney function and cognitive
706
impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke
707
(REGARDS) Study. Am J Kidney Dis 52, 227-234.
Ac ce
pt
ed
M
an
us
cr
ip t
690
40 Page 40 of 60
Lee, J.J., Chin, H.J., Byun, M.S., Choe, J.Y., Park, J.H., Lee, S.B., Choi, E.A., Chae,
709
D.W. and Kim, K.W. 2011. Impaired frontal executive function and predialytic chronic
710
kidney disease. J Am Geriatr Soc 59, 1628-1635.
711
Lee, S.Y., Lee, H.J., Kim, Y.K., Kim, S.H., Kim, L., Lee, M.S., Joe, S.H., Jung, I.K.,
712
Suh, K.Y. and Kim, H.K. 2004. Neurocognitive function and quality of life in relation to
713
hematocrit levels in chronic hemodialysis patients. J Psychosom Res 57, 5-10.
714
Leist, M., Ghezzi, P., Grasso, G., Bianchi, R., Villa, P., Fratelli, M., Savino, C., Bianchi,
715
M., Nielsen, J., Gerwien, J., Kallunki, P., Larsen, A.K., Helboe, L., Christensen, S.,
716
Pedersen, L.O., Nielsen, M., Torup, L., Sager, T., Sfacteria, A., Erbayraktar, S.,
717
Erbayraktar, Z., Gokmen, N., Yilmaz, O., Cerami-Hand, C., Xie, Q.W., Coleman, T.,
718
Cerami, A. and Brines, M. 2004. Derivatives of erythropoietin that are tissue protective
719
but not erythropoietic. Science 305, 239-242.
720
Li, J., Dong, B.R., Lin, P., Zhang, J. and Liu, G.J. 2010. Association of cognitive
721
function with serum uric acid level among Chinese nonagenarians and centenarians.
722
Exp Gerontol 45, 331-335.
723
Li, W., Maloney, R.E., Circu, M.L., Alexander, J.S. and Aw, T.Y. 2013. Acute carbonyl
724
stress induces occludin glycation and brain microvascular endothelial barrier
725
dysfunction: role for glutathione-dependent metabolism of methylglyoxal. Free Radic
Ac ce
pt
ed
M
an
us
cr
ip t
708
41 Page 41 of 60
Biol Med 54, 51-61.
727
Liu, J., Head, E., Gharib, A.M., Yuan, W., Ingersoll, R.T., Hagen, T.M., Cotman, C.W.
728
and Ames, B.N. 2002. Memory loss in old rats is associated with brain mitochondrial
729
decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or
730
R-alpha -lipoic acid. Proc Natl Acad Sci U S A 99, 2356-2361.
731
Liu, M., Liang, Y., Chigurupati, S., Lathia, J.D., Pletnikov, M., Sun, Z., Crow, M., Ross,
732
C.A., Mattson, M.P. and Rabb, H. 2008a. Acute kidney injury leads to inflammation and
733
functional changes in the brain. J Am Soc Nephrol 19, 1360-1370.
734
Liu, P., Gupta, N., Jing, Y. and Zhang, H. 2008b. Age-related changes in polyamines in
735
memory-associated brain structures in rats. Neuroscience 155, 789-796.
736
Liu, Y., Li, J., Wang, Z., Yu, Z. and Chen, G. 2013. Attenuation of Early Brain Injury
737
and Learning Deficits Following Experimental Subarachnoid Hemorrhage Secondary to
738
Cystatin C: Possible Involvement of the Autophagy Pathway. Mol Neurobiol.
739
Martins, I., Gomes, S., Costa, R.O., Otvos, L., Oliveira, C.R., Resende, R. and Pereira,
740
C.M. 2013. Leptin and ghrelin prevent hippocampal dysfunction induced by Abeta
741
oligomers. Neuroscience 241, 41-51.
742
Marzocco, S., Popolo, A., Bianco, G., Pinto, A. and Autore, G. 2010. Pro-apoptotic
743
effect of methylguanidine on hydrogen peroxide-treated rat glioma cell line. Neurochem
Ac ce
pt
ed
M
an
us
cr
ip t
726
42 Page 42 of 60
Int 57, 518-524.
745
Matafome, P., Sena, C. and Seica, R. 2013. Methylglyoxal, obesity, and diabetes.
746
Endocrine 43, 472-484.
747
McMahon, J.A., Green, T.J., Skeaff, C.M., Knight, R.G., Mann, J.I. and Williams, S.M.
748
2006. A controlled trial of homocysteine lowering and cognitive performance. N Engl J
749
Med 354, 2764-2772.
750
McQuillan, R. and Jassal, S.V. 2010. Neuropsychiatric complications of chronic kidney
751
disease. Nature reviews. Nephrology 6, 471-479.
752
Meijers, B.K., De Loor, H., Bammens, B., Verbeke, K., Vanrenterghem, Y. and
753
Evenepoel, P. 2009. p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin J
754
Am Soc Nephrol 4, 1932-1938.
755
Mink, R. and Johnston, J. 2007. The effect of infusing hypoxanthine or xanthine on
756
hypoxic-ischemic brain injury in rabbits. Brain Res 1147, 256-264.
757
Miyamoto, Y., Iwao, Y., Mera, K., Watanabe, H., Kadowaki, D., Ishima, Y., Chuang,
758
V.T., Sato, K., Otagiri, M. and Maruyama, T. 2012. A uremic toxin,
759
3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal
760
tubular cells via the generation of a radical intermediate. Biochem Pharmacol 84,
761
1207-1214.
Ac ce
pt
ed
M
an
us
cr
ip t
744
43 Page 43 of 60
Mooijaart, S.P., Sattar, N., Trompet, S., Lucke, J., Stott, D.J., Ford, I., Jukema, J.W.,
763
Westendorp, R.G. and de Craen, A.J. 2013. Circulating interleukin-6 concentration and
764
cognitive decline in old age: the PROSPER study. J Intern Med 274, 77-85.
765
More, S.S., Vartak, A.P. and Vince, R. 2013. Restoration of glyoxalase enzyme activity
766
precludes cognitive dysfunction in a mouse model of Alzheimer's disease. ACS Chem
767
Neurosci 4, 330-338.
768
Murray, A.M. 2008. Cognitive impairment in the aging dialysis and chronic kidney
769
disease populations: an occult burden. Adv Chronic Kidney Dis 15, 123-132.
770
Murray, A.M., Barzilay, J.I., Lovato, J.F., Williamson, J.D., Miller, M.E., Marcovina, S.
771
and Launer, L.J. 2011. Biomarkers of renal function and cognitive impairment in
772
patients with diabetes. Diabetes Care 34, 1827-1832.
773
Murray, A.M., Pederson, S.L., Tupper, D.E., Hochhalter, A.K., Miller, W.A., Li, Q.,
774
Zaun, D., Collins, A.J., Kane, R. and Foley, R.N. 2007. Acute variation in cognitive
775
function in hemodialysis patients: a cohort study with repeated measures. Am J Kidney
776
Dis 50, 270-278.
777
Murray, A.M., Tupper, D.E., Knopman, D.S., Gilbertson, D.T., Pederson, S.L., Li, S.,
778
Smith, G.E., Hochhalter, A.K., Collins, A.J. and Kane, R.L. 2006. Cognitive impairment
779
in hemodialysis patients is common. Neurology 67, 216-223.
Ac ce
pt
ed
M
an
us
cr
ip t
762
44 Page 44 of 60
Mutsaers, H.A., Wilmer, M.J., Reijnders, D., Jansen, J., van den Broek, P.H., Forkink,
781
M., Schepers, E., Glorieux, G., Vanholder, R., van den Heuvel, L.P., Hoenderop, J.G.
782
and Masereeuw, R. 2013. Uremic toxins inhibit renal metabolic capacity through
783
interference with glucuronidation and mitochondrial respiration. Biochim Biophys Acta
784
1832, 142-150.
785
Nakai, S., Watanabe, Y., Masakane, I., Wada, A., Shoji, T., Hasegawa, T., Nakamoto, H.,
786
Yamagata, K., Kazama, J.J., Fujii, N., Itami, N., Shinoda, T., Shigematsu, T.,
787
Marubayashi, S., Morita, O., Hashimoto, S., Suzuki, K., Kimata, N., Hanafusa, N.,
788
Wakai, K., Hamano, T., Ogata, S., Tsuchida, K., Taniguchi, M., Nishi, H., Iseki, K. and
789
Tsubakihara, Y. 2013. Overview of regular dialysis treatment in Japan (as of 31
790
December 2011). Therapeutic Apheresis and Dialysis 17, 567-611.
791
Niwa, T. 2013. Removal of protein-bound uraemic toxins by haemodialysis. Blood Purif
792
35 Suppl 2, 20-25.
793
Ohtsuki, S., Asaba, H., Takanaga, H., Deguchi, T., Hosoya, K., Otagiri, M. and Terasaki,
794
T. 2002. Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of
795
indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance
796
from the brain. J Neurochem 83, 57-66.
797
Patel, N., Dalal, P. and Panesar, M. 2008. Dialysis disequilibrium syndrome: a narrative
Ac ce
pt
ed
M
an
us
cr
ip t
780
45 Page 45 of 60
review. Semin Dial 21, 493-498.
799
Pfeffer, M.A., Burdmann, E.A., Chen, C.Y., Cooper, M.E., de Zeeuw, D., Eckardt, K.U.,
800
Feyzi, J.M., Ivanovich, P., Kewalramani, R., Levey, A.S., Lewis, E.F., McGill, J.B.,
801
McMurray, J.J., Parfrey, P., Parving, H.H., Remuzzi, G., Singh, A.K., Solomon, S.D. and
802
Toto, R. 2009. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
803
N Engl J Med 361, 2019-2032.
804
Pickett, J.L., Theberge, D.C., Brown, W.S., Schweitzer, S.U. and Nissenson, A.R. 1999.
805
Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis
806
33, 1122-1130.
807
Pikula, A., Boger, R.H., Beiser, A.S., Maas, R., DeCarli, C., Schwedhelm, E., Himali,
808
J.J., Schulze, F., Au, R., Kelly-Hayes, M., Kase, C.S., Vasan, R.S., Wolf, P.A. and
809
Seshadri, S. 2009. Association of plasma ADMA levels with MRI markers of vascular
810
brain injury: Framingham offspring study. Stroke 40, 2959-2964.
811
Post, J.B., Jegede, A.B., Morin, K., Spungen, A.M., Langhoff, E. and Sano, M. 2010.
812
Cognitive profile of chronic kidney disease and hemodialysis patients without dementia.
813
Nephron Clin Pract 116, c247-255.
814
Prohovnik, I., Post, J., Uribarri, J., Lee, H., Sandu, O. and Langhoff, E. 2007.
815
Cerebrovascular effects of hemodialysis in chronic kidney disease. J Cereb Blood Flow
Ac ce
pt
ed
M
an
us
cr
ip t
798
46 Page 46 of 60
Metab 27, 1861-1869.
817
Rabie, T. and Marti, H.H. 2008. Brain protection by erythropoietin: a manifold task.
818
Physiology 23, 263-274.
819
Rajagopalan, P., Refsum, H., Hua, X., Toga, A.W., Jack, C.R., Jr., Weiner, M.W. and
820
Thompson, P.M. 2013. Mapping creatinine- and cystatin C-related white matter brain
821
deficits in the elderly. Neurobiol Aging 34, 1221-1230.
822
Rakowski, D.A., Caillard, S., Agodoa, L.Y. and Abbott, K.C. 2006. Dementia as a
823
predictor of mortality in dialysis patients. Clin J Am Soc Nephrol 1, 1000-1005.
824
Roman, S.A., Sosa, J.A., Pietrzak, R.H., Snyder, P.J., Thomas, D.C., Udelsman, R. and
825
Mayes, L. 2011. The effects of serum calcium and parathyroid hormone changes on
826
psychological and cognitive function in patients undergoing parathyroidectomy for
827
primary hyperparathyroidism. Ann Surg 253, 131-137.
828
Schroeder, J.C., Dinatale, B.C., Murray, I.A., Flaveny, C.A., Liu, Q., Laurenzana, E.M.,
829
Lin, J.M., Strom, S.C., Omiecinski, C.J., Amin, S. and Perdew, G.H. 2010. The uremic
830
toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon
831
receptor. Biochemistry 49, 393-400.
832
Seliger, S.L., Longstreth, W.T., Jr., Katz, R., Manolio, T., Fried, L.F., Shlipak, M.,
833
Stehman-Breen, C.O., Newman, A., Sarnak, M., Gillen, D.L., Bleyer, A. and Siscovick,
Ac ce
pt
ed
M
an
us
cr
ip t
816
47 Page 47 of 60
D.S. 2005. Cystatin C and subclinical brain infarction. J Am Soc Nephrol 16,
835
3721-3727.
836
Seliger, S.L., Siscovick, D.S., Stehman-Breen, C.O., Gillen, D.L., Fitzpatrick, A., Bleyer,
837
A. and Kuller, L.H. 2004. Moderate renal impairment and risk of dementia among older
838
adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 15, 1904-1911.
839
Sena, C.M., Matafome, P., Crisostomo, J., Rodrigues, L., Fernandes, R., Pereira, P. and
840
Seica, R.M. 2012. Methylglyoxal promotes oxidative stress and endothelial dysfunction.
841
Pharmacol Res 65, 497-506.
842
Shah, R.C., Wilson, R.S., Bienias, J.L., Arvanitakis, Z., Evans, D.A. and Bennett, D.A.
843
2006. Relation of blood pressure to risk of incident Alzheimer's disease and change in
844
global cognitive function in older persons. Neuroepidemiology 26, 30-36.
845
Shamoto-Nagai, M., Maruyama, W., Kato, Y., Isobe, K., Tanaka, M., Naoi, M. and
846
Osawa, T. 2003. An inhibitor of mitochondrial complex I, rotenone, inactivates
847
proteasome by oxidative modification and induces aggregation of oxidized proteins in
848
SH-SY5Y cells. J Neurosci Res 74, 589-597.
849
Sigrist, S.J., Carmona-Gutierrez, D., Gupta, V.K., Bhukel, A., Mertel, S., Eisenberg, T.
850
and Madeo, F. 2013. Spermidine-triggered autophagy ameliorates memory during aging.
851
Autophagy 10.
Ac ce
pt
ed
M
an
us
cr
ip t
834
48 Page 48 of 60
Singh, A.K., Szczech, L., Tang, K.L., Barnhart, H., Sapp, S., Wolfson, M. and Reddan,
853
D. 2006. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J
854
Med 355, 2085-2098.
855
Sirich, T.L., Funk, B.A., Plummer, N.S., Hostetter, T.H. and Meyer, T.W. 2013.
856
Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular
857
secretion. J Am Soc Nephrol 25(3), 615-622.
858
Smogorzewski, M.J. 2001. Central nervous dysfunction in uremia. Am J Kidney Dis 38,
859
S122-128.
860
Srikanth, V., Westcott, B., Forbes, J., Phan, T.G., Beare, R., Venn, A., Pearson, S.,
861
Greenaway, T., Parameswaran, V. and Munch, G. 2013. Methylglyoxal, cognitive
862
function and cerebral atrophy in older people. J Gerontol A Biol Sci Med Sci 68, 68-73.
863
Sun, C.Y., Hsu, H.H. and Wu, M.S. 2013. p-Cresol sulfate and indoxyl sulfate induce
864
similar cellular inflammatory gene expressions in cultured proximal renal tubular cells.
865
Nephrol Dial Transplant 28, 70-78.
866
Sundelof, J., Arnlov, J., Ingelsson, E., Sundstrom, J., Basu, S., Zethelius, B., Larsson, A.,
867
Irizarry, M.C., Giedraitis, V., Ronnemaa, E., Degerman-Gunnarsson, M., Hyman, B.T.,
868
Basun, H., Kilander, L. and Lannfelt, L. 2008. Serum cystatin C and the risk of
869
Alzheimer disease in elderly men. Neurology 71, 1072-1079.
Ac ce
pt
ed
M
an
us
cr
ip t
852
49 Page 49 of 60
Suri, R.S., Garg, A.X., Chertow, G.M., Levin, N.W., Rocco, M.V., Greene, T., Beck, G.J.,
871
Gassman, J.J., Eggers, P.W., Star, R.A., Ornt, D.B. and Kliger, A.S. 2007. Frequent
872
Hemodialysis Network (FHN) randomized trials: study design. Kidney Int 71, 349-359.
873
Tachikawa, M. and Hosoya, K. 2011. Transport characteristics of guanidino compounds
874
at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural
875
disorders. Fluids Barriers CNS 8, 13.
876
Temple, R.M., Langan, S.J., Deary, I.J. and Winney, R.J. 1992. Recombinant
877
erythropoietin improves cognitive function in chronic haemodialysis patients. Nephrol
878
Dial Transplant 7, 240-245.
879
Tiboldi, A., Lentini, A., Provenzano, B., Tabolacci, C., Hoger, H., Beninati, S. and
880
Lubec, G. 2012. Hippocampal polyamine levels and transglutaminase activity are
881
paralleling spatial memory retrieval in the C57BL/6J mouse. Hippocampus 22,
882
1068-1074.
883
Torremans, A., Marescau, B., Van Dam, D., Van Ginneken, C., Van Meir, F., Van
884
Bogaert, P.P., D'Hooge, R., de Vente, J. and De Deyn, P.P. 2005. GSA: behavioral,
885
histological, electrophysiological and neurochemical effects. Physiol Behav 84,
886
251-264.
887
Toyoda, K., Fujii, K., Fujimi, S., Kumai, Y., Tsuchimochi, H., Ibayashi, S. and Iida, M.
Ac ce
pt
ed
M
an
us
cr
ip t
870
50 Page 50 of 60
2005. Stroke in patients on maintenance hemodialysis: a 22-year single-center study.
889
Am J Kidney Dis 45, 1058-1066.
890
van den Kommer, T.N., Dik, M.G., Comijs, H.C., Jonker, C. and Deeg, D.J. 2010.
891
Homocysteine and inflammation: predictors of cognitive decline in older persons?
892
Neurobiol Aging 31, 1700-1709.
893
Vanholder, R. and De Smet, R. 1999. Pathophysiologic effects of uremic retention
894
solutes. J Am Soc Nephrol 10, 1815-1823.
895
Vanholder, R., De Smet, R., Glorieux, G., Argiles, A., Baurmeister, U., Brunet, P., Clark,
896
W., Cohen, G., De Deyn, P.P., Deppisch, R., Descamps-Latscha, B., Henle, T., Jorres, A.,
897
Lemke, H.D., Massy, Z.A., Passlick-Deetjen, J., Rodriguez, M., Stegmayr, B.,
898
Stenvinkel, P., Tetta, C., Wanner, C. and Zidek, W. 2003a. Review on uremic toxins:
899
classification, concentration, and interindividual variability. Kidney Int 63, 1934-1943.
900
Vanholder, R., Glorieux, G., De Smet, R. and Lameire, N. 2003. New insights in uremic
901
toxins. Kidney Int Suppl, S6-10.
902
Vanholder, R., Van Laecke, S. and Glorieux, G. 2008. What is new in uremic toxicity?
903
Pediatr Nephrol 23, 1211-1221.
904
Vannorsdall, T.D., Jinnah, H.A., Gordon, B., Kraut, M. and Schretlen, D.J. 2008.
905
Cerebral ischemia mediates the effect of serum uric acid on cognitive function. Stroke
Ac ce
pt
ed
M
an
us
cr
ip t
888
51 Page 51 of 60
39, 3418-3420.
907
Vida, C., Corpas, I., De la Fuente, M. and Gonzalez, E.M. 2011. Age-related changes in
908
xanthine oxidase activity and lipid peroxidation, as well as in the correlation between
909
both parameters, in plasma and several organs from female mice. Journal of Physiology
910
and Biochemistry 67, 551-558.
911
Vos, P.F., Zilch, O., Jennekens-Schinkel, A., Salden, M., Nuyen, J., Kooistra, M.M., van
912
Huffelen, A.C. and Sitskoorn, M.M. 2006. Effect of short daily home haemodialysis on
913
quality of life, cognitive functioning and the electroencephalogram. Nephrol Dial
914
Transplant 21, 2529-2535.
915
Wada, M., Nagasawa, H., Kawanami, T., Kurita, K., Daimon, M., Kubota, I., Kayama, T.
916
and Kato, T. 2010. Cystatin C as an index of cerebral small vessel disease: results of a
917
cross-sectional study in community-based Japanese elderly. Eur J Neurol 17, 383-390.
918
Wamser, M.N., Leite, E.F., Ferreira, V.V., Delwing-de Lima, D., da Cruz, J.G., Wyse,
919
A.T. and Delwing-Dal Magro, D. 2013. Effect of hypoxanthine, antioxidants and
920
allopurinol on cholinesterase activities in rats. J Neural Transm 120, 1359-1367.
921
Wang, W., Li, S., Dong, H.P., Lv, S. and Tang, Y.Y. 2009. Differential impairment of
922
spatial and nonspatial cognition in a mouse model of brain aging. Life Sci 85, 127-135.
923
Watanabe, H., Miyamoto, Y., Honda, D., Tanaka, H., Wu, Q., Endo, M., Noguchi, T.,
Ac ce
pt
ed
M
an
us
cr
ip t
906
52 Page 52 of 60
Kadowaki, D., Ishima, Y., Kotani, S., Nakajima, M., Kataoka, K., Kim-Mitsuyama, S.,
925
Tanaka, M., Fukagawa, M., Otagiri, M. and Maruyama, T. 2013. p-Cresyl sulfate causes
926
renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase.
927
Kidney Int 83, 582-592.
928
Watanabe, I., Tatebe, J., Namba, S., Koizumi, M., Yamazaki, J. and Morita, T. 2013b.
929
Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte
930
chemoattractant protein-1 expression in human umbilical vein endothelial cells.
931
Circulation Journal: Official Journal of the Japanese Circulation Society 77, 224-230.
932
Watanabe, K., Okada, K., Fukabori, R., Hayashi, Y., Asahi, K., Terawaki, H., Kobayashi,
933
K., Watanabe, T. and Nakayama, M. 2014. Methylglyoxal (MG) and Cerebro-Renal
934
Interaction: Does Long-Term Orally Administered MG Cause Cognitive Impairment in
935
Normal Sprague-Dawley Rats? Toxins 6, 254-269.
936
Weiner, D.E., Bartolomei, K., Scott, T., Price, L.L., Griffith, J.L., Rosenberg, I., Levey,
937
A.S., Folstein, M.F. and Sarnak, M.J. 2009. Albuminuria, cognitive functioning, and
938
white matter hyperintensities in homebound elders. Am J Kidney Dis 53, 438-447.
939
Wu, I.W., Hsu, K.H., Lee, C.C., Sun, C.Y., Hsu, H.J., Tsai, C.J., Tzen, C.Y., Wang, Y.C.,
940
Lin, C.Y. and Wu, M.S. 2011. p-Cresyl sulphate and indoxyl sulphate predict
941
progression of chronic kidney disease. Nephrol Dial Transplant 26, 938-947.
Ac ce
pt
ed
M
an
us
cr
ip t
924
53 Page 53 of 60
Yaffe, K., Lindquist, K., Shlipak, M.G., Simonsick, E., Fried, L., Rosano, C., Satterfield,
943
S., Atkinson, H., Windham, B.G. and Kurella-Tamura, M. 2008. Cystatin C as a marker
944
of cognitive function in elders: findings from the health ABC study. Ann Neurol 63,
945
798-802.
946
Yamamoto, S., Kazama, J.J., Narita, I., Naiki, H. and Gejyo, F. 2009. Recent progress in
947
understanding dialysis-related amyloidosis. Bone 45 Suppl 1, S39-42.
948
Ye, L., Huang, Y., Zhao, L., Li, Y., Sun, L., Zhou, Y., Qian, G. and Zheng, J.C. 2013.
949
IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential
950
role for neuronal glutaminase. J Neurochem 125, 897-908.
951
Zeki Al Hazzouri, A., Stone, K.L., Haan, M.N. and Yaffe, K. 2013. Leptin, mild
952
cognitive impairment, and dementia among elderly women. J Gerontol A Biol Sci Med
953
Sci 68, 175-180.
954
Zhang, Y., Xiong, Y., Mahmood, A., Meng, Y., Qu, C., Schallert, T. and Chopp, M. 2009.
955
Therapeutic effects of erythropoietin on histological and functional outcomes following
956
traumatic brain injury in rats are independent of hematocrit. Brain Res 1294, 153-164.
957
Zheng, P., Chen, J.J., Huang, T., Wang, M.J., Wang, Y., Dong, M.X., Huang, Y.J., Zhou,
958
L.K. and Xie, P. 2013. A novel urinary metabolite signature for diagnosing major
959
depressive disorder. J Proteome Res 12(12), 5904-5911.
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54 Page 54 of 60
Zheng, S., Yu, M., Lu, X., Huo, T., Ge, L., Yang, J., Wu, C. and Li, F. 2010. Urinary
961
metabonomic study on biochemical changes in chronic unpredictable mild stress model
962
of depression. Clin Chim Acta 411, 204-209.
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960
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973 974 975 976 977 978
cerebro-renal interaction unknown. Grade C: UT that has both positive and negative data (and so is still controversial). Grade D: UT that that lacks sufficient data regarding effects on neural system. Abbreviations: NO, nitric oxide; CI, cognitive impairment; CNS, central nervous system; NMDA, N-methyl-D-aspartate; GABA, gamma-aminobutyric acid; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; BBB, blood-brain barrier; UT, uremic toxin; ROS, reactive oxygen species; AD, Alzheimer’s disease.
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Tables
Uremic toxin
Group
MW
Normal
(dalton)
Concentration
Concentration
(SD)
(SD or Range)
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S0161-813X(14)00105-3 http://dx.doi.org/doi:10.1016/j.neuro.2014.06.014 NEUTOX 1712
To appear in:
NEUTOX
Received date: Revised date: Accepted date:
27-3-2014 13-6-2014 27-6-2014
Please cite this article as: Watanabe K, Watanabe T, Nakayama M, Cerebro-renal interactions: Impact of uremic toxins on cognitive function., Neurotoxicology (2014), http://dx.doi.org/10.1016/j.neuro.2014.06.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title
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Cerebro-renal interactions: Impact of uremic toxins on cognitive function.
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Author names and affiliations:
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Kimio Watanabe, MD1, Tsuyoshi Watanabe, Prof1, and Masaaki Nakayama, Prof1
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1 Department of Nephrology, Hypertension, Diabetology, Endocrinology and
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Metabolism, Fukushima Medical University School of Medicine
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Corresponding author: Kimio Watanabe
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1 Hikarigaoka, Fukushima, Fukushima 960-1295, Japan.
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Phone: +81-24-547-1206; Fax: +81-24-548-3044
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Email: [email protected]
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Key words
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Uremic toxins, Cognitive Impairment, Cerebro-renal interactions
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Abstract
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Cognitive impairment (CI) associated with chronic kidney disease (CKD) has received
19
attention as an important problem in recent years. Causes of CI with CKD are
20
multifactorial, and include cerebrovascular disease, renal anemia, secondary
21
hyperparathyroidism, dialysis disequilibrium, and uremic toxins (UTs). Among these
22
causes, little is known about the role of UTs. We therefore selected 21 uremic
23
compounds, and summarized reports of cerebro-renal interactions associated with UTs.
24
Among the compounds, uric acid, indoxyl sulfate, p-cresyl sulfate, interleukin 1-β,
25
interleukin 6, TNF-α, and PTH were most likely to affect the cerebro-renal interaction
26
dysfunction; however, sufficient data have not been obtained for other UTs. Notably,
27
most of the data were not obtained under uremic conditions; therefore, the impact and
28
mechanism of each UT on cognition and central nervous system in uremic state remains
29
unknown. At present, impacts and mechanisms of UT effects on cognition are poorly
30
understood. Clarifying the mechanisms and establishing novel therapeutic strategies for
31
cerebro-renal interaction dysfunction is expected to be subject of future research.
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1. Introduction
33
Cognitive impairment (CI) associated with chronic kidney disease (CKD) has received
34
attention as an important problem in recent years. CI accompanied by CKD occurs not
35
only in end-stage renal disease (ESRD) patients but also in patients with early-stage
36
CKD, and CKD is a risk factor for CI development (McQuillan and Jassal 2010). CI
37
with CKD not only influences daily life and job function, but also results in longer
38
hospitalization and higher risk for mortality. Bugnicourt et al. (2013) estimated a
39
prevalence of CI in CKD of 30% to 60%, a value at least twice that observed in
40
age-matched controls. In Japan, the number of hemodialysis (HD) patients has increased
41
from 116,303 to 304,856 (from 1991 to 2011), and mean age has risen from 55.3 to 66.6
42
years old (Nakai et al. 2013). Behavioral abnormalities such as restlessness during HD
43
sessions, needle removal accidents, non-compliance with drug regimens, and difficulty
44
with dietary restrictions are all critical issues seen in elderly dialysis patients with
45
dementia.
46
Cerebrovascular disease, anemia, secondary hyperparathyroidism, dialysis
47
disequilibrium, and uremic toxins (UTs) have been reported as major causes of CI
48
accompanied by CKD (Beard et al. 1997; Brines et al. 2000; Cerami et al. 2001; Chou
49
et al. 2008; Cogan et al. 1978; Drueke et al. 2006; Erbayraktar et al. 2003; Goldstein et
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al. 1980; Goldstein and Massry 1980; Guisado et al. 1975; Lee et al. 2004; Leist et al.
51
2004; Pfeffer et al. 2009; Pickett et al. 1999; Rabie and Marti 2008; Seliger et al. 2005;
52
Shah et al. 2006; Singh et al. 2006; Temple et al. 1992; Zhang et al. 2009). Uremia can
53
be defined as biochemical and physiologic dysfunction that increases with progression
54
of CKD, resulting in variable symptomatology (Vanholder and De Smet 1999). Various
55
potentially toxic compounds are accumulated in CKD patients, and these compounds
56
are called “uremic retention solutes”. Such solutes that are biologically/biochemically
57
active are called “uremic toxins” (Vanholder et al. 2003a; Vanholder et al. 2008). One
58
hundred fifty-two UTs have been detected in the past (http://www.uremic-toxins.org/),
59
and these molecules have been shown to have various negative effects, such as anorexia,
60
cardiac failure, anemia, immune dysfunction, malnutrition, inflammation, and skin
61
atrophy (Vanholder et al. 2008). However, the influence of UTs on CI in CKD patients
62
is largely unknown. Therefore, from a collection of 152 known UTs, we selected a
63
subset of 21 compounds reported (in previous research) to exhibit a relationship with
64
the central nervous system (CNS). The present work summarizes the relevant literature
65
for associations between UTs and cerebro-renal interactions.
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2. Material and Methods
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2.1 Review Criteria
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The information referenced in this paper was compiled by performing MEDLINE
70
searches using the terms “asymmetric dimethylarginine”, “guanidino succinic acid”,
71
“methylguanidine”, “hypoxanthine”, “uric acid”,
72
“3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid”, “hippuric acid”, “homocysteine”,
73
“indole-3-acetic acid”, “spermidine”, “putrescine”, “methylglyoxal”, “leptin”, “indoxyl
74
sulfate”, “p-cresyl sulfate”, “interleukin 1-β”, “interleukin 6”, “tumor necrosis factor
75
alpha”, “parathyroid hormone”, “beta-2-microglobulin”, “cystatin C”, “(chronic) kidney
76
disease”, and “dialysis” in combination with the terms “cognitive impairment”,
77
“dementia”, and “brain”. Further references were identified by hand-searching reports
78
from recent large clinical trials or innovative basic research for the terms “cerebro-renal
79
interaction” and “uremic toxin”. All cited articles were written in English.
80
2.2 Cognitive impairment in CKD patients
81
CI accompanied by CKD occurs not only in ESRD patients but also in patients with
82
early-stage CKD, and CKD is considered a risk factor for CI development (McQuillan
83
and Jassal 2010). Previous studies demonstrated the association of CI and CKD from a
84
variety of perspectives. For example, patients with mild CKD or with albuminuria
85
exhibited declines in memory as well as impairment in concentration and visual
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attention (Hailpern et al. 2007; Weiner et al. 2009), and CKD was associated with an
87
increased prevalence of CI (odds ratio, 1.23). Patients with estimated glomerular
88
filtration rates (eGFR) of less than 30 mL/min/1.73 m² exhibited a more than five-fold
89
elevation in risk for CI (Khatri et al. 2009; Kurella et al. 2005b; Kurella Tamura et al.
90
2008); CKD was associated with a 37% increased risk of CI over a 6-year follow-up
91
interval. The increased risk of CI associated with a 15-mL/min/1.73 m² decline in eGFR
92
was similar in magnitude to the effect of being 3 years older (Buchman et al. 2009;
93
Kurella et al. 2005a; Seliger et al. 2004). In one study, only 13% of HD patients were
94
classified as having normal cognition (Murray et al. 2006). CI accompanied by CKD
95
has effects not only on daily life and job function but also on hospitalization length and
96
increased risk of mortality. The average time to death in HD patients with CI was 1.09
97
years, and hazard ratio (HR) for death was 1.87, which was higher than that seen in HD
98
patients with cardiac disease (HR, 1.28) or stroke (HR, 1.20) (Rakowski et al. 2006).
99
Memory holding errors and impaired responses due to frontal lobe dysfunction occur
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100
frequently in patients with CI accompanied by CKD (Lee et al. 2011; Post et al. 2010).
101
Cerebrovascular disease, anemia, secondary hyperparathyroidism (SHPT), dialysis
102
disequilibrium, and UTs have been reported as major causes of CI with CKD (Beard et
103
al. 1997; Brines et al. 2000; Cerami et al. 2001; Chou et al. 2008; Cogan et al. 1978;
6 Page 6 of 60
Drueke et al. 2006; Erbayraktar et al. 2003; Goldstein et al. 1980; Goldstein and Massry
105
1980; Guisado et al. 1975; Lee et al. 2004; Leist et al. 2004; Pfeffer et al. 2009; Pickett
106
et al. 1999; Rabie and Marti 2008; Seliger et al. 2005; Shah et al. 2006; Singh et al.
107
2006; Temple et al. 1992; Zhang et al. 2009). Hypoxia-induced deleterious effects on
108
brain metabolism and/or direct effects on CNS by decreased erythropoietin (EPO) are
109
considered to be mechanisms of CI resulting from renal anemia (Brines et al. 2000; Lee
110
et al. 2004; Pickett et al. 1999; Temple et al. 1992). The ameliorative effects of EPO on
111
cerebral hypoxia or brain tissue damage after trauma are expected to reflect the
112
neurotrophic and neuroprotective effects of EPO; at the same time, EPO may elevate the
113
frequency of vascular events due to increases in hemoglobin levels (Cerami et al. 2001;
114
Drueke et al. 2006; Erbayraktar et al. 2003; Leist et al. 2004; Pfeffer et al. 2009; Rabie
115
and Marti 2008; Singh et al. 2006; Zhang et al. 2009). SHPT is one of the major factors
116
of CI with CKD patients, and several researchers have shown that cognition and
117
electroencephalogram findings are improved by parathyroidectomy or vitamin D
118
therapy (Chou et al. 2008; Cogan et al. 1978; Goldstein et al. 1980; Goldstein and
119
Massry 1980; Guisado et al. 1975). Dialysis disequilibrium syndrome is a pathological
120
condition whereby HD treatment itself impairs cognition. Rapid and short-term removal
121
of body fluid by HD decreases cerebral blood circulation and oxygen supply to the brain
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(Chen et al. 2007; Hill 2001; Murray 2008; Patel et al. 2008; Prohovnik et al. 2007;
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Toyoda et al. 2005). Murray et al. reported that global cognitive function was worst
124
during dialysis and best shortly before or on the day after a dialysis session (Murray et
125
al. 2007); however, in a small-scale study, Vos et al. reported that short daily HD had no
126
clear effect on cognitive functioning or electroencephalograms, suggesting that further
127
investigation is required to confirm a link between dialysis disequilibrium and cognition
128
(Suri et al. 2007; Vos et al. 2006). Kalirao et al. (2011) reported that two-thirds of
129
peritoneal dialysis patients had moderate to severe CI, with severity sufficient to
130
interfere with safe self-administration of dialysis and adherence to complex medication
131
regimens. Verbal and visual memory are improved by kidney transplantation (Griva et
132
al. 2006; Koushik et al. 2010); however, global cognition remains worse in
133
post-transplant patients compared to healthy subjects (Gelb et al. 2008). Enervation,
134
convulsion, and coma are observed in uremic encephalopathy patients, and these
135
symptoms are partially improved by dialysis treatment (Deguchi et al. 2006). This
136
improvement is thought to be an effect of UT removal by dialysis from the blood.
137
2.3 The role of uremic toxins in cognitive impairment
138 139
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2.3.1 Small water-soluble solutes UTs can be divided into three groups according to molecular weight and protein binding
8 Page 8 of 60
rate, with the three classes designated as “small water-soluble solutes”, “protein-bound
141
solutes”, and “middle molecules”. Small water-soluble solutes are characterized by
142
molecular weights of less than 500 daltons and easy removal by conventional HD
143
procedures (Vanholder et al. 2008). Urea and creatinine are typical UTs belonging to
144
this group. We reviewed the literature regarding guanidine compounds (including
145
asymmetric dimethylarginine (ADMA), guanidino succinic acid (GSA),
146
methylguanidine (MG)) and purine metabolites (hypoxanthine and uric acid (UA)).
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2.3.2 Asymmetric dimethylarginine
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Asymmetric dimethylarginine (ADMA), one of the guanidine compounds, inhibits NO
149
synthase activity and affects blood-pressure variability, inducing oxidative stress and
150
causing vascular involvement (Hu et al. 2009). Impaired synthesis and utilization of NO
151
is thought to contribute to CI through the mechanisms of development and progression
152
of arteriosclerosis, vasoconstriction, abnormalities in cerebral blood flow, and decreased
153
neuro-protection (Asif et al. 2013). The Framingham offspring study revealed that
154
higher plasma ADMA is associated with an increased prevalence of asymptomatic
155
cerebral infarction (Pikula et al. 2009), and Kielstein et al. (2006) showed that
156
subpressor doses of ADMA increased vascular stiffness and decreased cerebral
157
perfusion by 15% in healthy subjects. These data suggest that ADMA is an important
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158 159
contributor to CI, particularly due to impaired blood flow and vascular structure. 2.3.3 Guanidino succinic acid (GSA), Methylguanidine (MG) Guanidino succinic acid (GSA) and methylguanidine (MG) are significantly increased
161
in plasma, CSF, and brain tissue in patients with uremia, and these compounds are
162
thought to contribute to CI and epilepsy. The kinetics of GSA and MG vary greatly. The
163
mean distributed volumes are 30.6 and 102.6 L, respectively, and removal rates by
164
dialysis are 76% and 42%, respectively (Eloot et al. 2005). Hippocampal injection of
165
GSA in mice has been shown to have significant dose-dependent effects on cognitive
166
performance, activity, and hippocampal volume (Torremans et al. 2005), and apoptosis
167
of cultured rat glial cells is induced by MG and hydrogen peroxide exposure (Marzocco
168
et al. 2010). The mechanism of enhancement of CNS excitability by uremic guanidine
169
compounds may be partly explained by the activation of N-methyl-D-aspartate receptors,
170
along with concomitant inhibition of GABA (A) receptors (De Deyn et al. 2001).
171
Transporters of UT at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid
172
(CSF) barrier determine the distribution of guanidine compounds in the brain, and
173
dysfunction of these transporters may cause abnormal distribution of UT and associated
174
neurological problems (Tachikawa and Hosoya 2011).
175
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2.3.4 Hypoxanthine
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Hypoxanthine and uric acid (UA) are purine metabolites, and some studies indicate an
177
influence of these compounds on CNS. In particular, intrastriatal injection of
178
hypoxanthine in adult Wistar rats has been shown to impair memory formation
179
(Bavaresco et al. 2008). Rat hippocampus and striatum are disrupted upon exposure to
180
hypoxanthine; these effects are mediated by free radical production and elevated uric
181
acid levels, which induce changes in acetylcholinesterase and butyrylcholinesterase
182
activities (Wamser et al. 2013). In contrast, infusion of hypoxanthine in rabbits
183
subjected to hypoxic-ischemic brain injury reduced cerebral injury and significantly
184
improved somatosensory-evoked potential recovery (Mink and Johnston 2007). Levels
185
of xanthine oxidase (XO), an enzyme that converts hypoxanthine to xanthine and
186
xanthine to uric acid, are increased in plasma and brain in aging mice, and XO levels
187
have been shown to correlate with lipid peroxidation (Vida et al. 2011). Consistent with
188
this observation, brain damage and renal dysfunction are improved by XO inhibition
189
(Hughes et al. 2013; Mink and Johnston 2007).
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2.3.5 Uric acid (UA)
191
Higher serum levels of UA in CKD patients with eGFR less than 60 mL/min/1.73m²
192
independently correlated with CI, as evaluated by the Mini Mental State Examination
193
(MMSE), the most widely used screening tool for CI; elevated serum UA levels were
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associated with poorer working memory, processing speed, fluency, verbal memory, and
195
greater white matter hyperintensities (Afsar et al. 2011; Vannorsdall et al. 2008). In
196
contrast, higher serum UA levels were related to lower risks of CI in Chinese male
197
nonagenarians and centenarians (Li et al. 2010), and also were related to a decreased
198
risk of dementia and better cognitive function in a study consisting of 1724 participants
199
aged 55 years and over during an 11-year follow-up (Euser et al. 2009).
200
2.4 Protein-bound solutes
201
Phenol and indole are categorized as “protein-bound solutes”, a class that primarily
202
includes molecules with molecular weight less than 500 daltons. Removal of this type
203
of UT from the blood by dialysis, even using high-flux dialysis membranes, is difficult,
204
because molecules of this class bind tightly to albumin in the blood. We reviewed
205
literature for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric
206
acid, homocysteine (Hcy), putrescine, spermidine, indole-3-acetic acid (IAA),
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methylglyoxal (MGO), leptin, p-cresyl sulfate (PCS), and indoxyl sulfate (IS).
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2.4.1 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF)
209
3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is a furan fatty acid that
210
accumulates in renal tubular cells (Miyamoto et al. 2012). p-cresyl sulfate (PCS) and
211
indoxyl sulfate (IS) show high protein binding rates (more than 95%) and low removal
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rates by HD (less than 35%); CMPF shows an even higher protein binding rate
213
(99-100%). CMPF induced reactive oxygen species (ROS) in human renal proximal
214
tubular epithelial cells and human umbilical vein endothelial cells, and inhibited cell
215
growth (Itoh et al. 2012; Miyamoto et al. 2012; Niwa 2013). Intracellular accumulation
216
and pro-oxidant effects of CMPF are important points; however, the role of CMPF in
217
CNS remains unclear.
218
2.4.2 Hippuric acid
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Salts of hippuric acid are one of the major compounds that contribute to uremic
220
encephalopathy. Accumulation of UT in the brain is thought to result from UT
221
transporter (rat organic anion transporter 3, rOat3) dysfunction at the BBB; this
222
inhibition, which decreases efflux clearance of UTs from brain to blood (across the
223
BBB), is thought to be a mechanism of uremic encephalopathy (Deguchi et al. 2006).
224
Murine renal organic transporter (mOAT1), which is expressed in cerebral cortex and
225
hippocampus, also has a critical role in regulation of UTs (Bahn et al. 2005). It has also
226
been reported that urinary levels of hippuric acid are elevated in patients with major
227
depressive disorders and in rat models of depression (Zheng et al. 2013; Zheng et al.
228
2010). This pattern suggests the availability of hippuric acid as a potential marker for
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depression. However, the role of hippuric acid in cerebro-renal interaction dysfunction
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230 231
remains unclear. 2.4.3 Homocysteine (Hcy) There are several reports related to homocysteine (Hcy) and CI. Hcy was a contributing
233
factor for faster rate of decline in cognition during a six-year follow up with 1076
234
elderly subjects (van den Kommer et al. 2010). Hcy levels were related to episodic
235
memory, executive function, and verbal expression in 274 non-demented elderly
236
subjects during a seven-year follow-up (Hooshmand et al. 2012). Elevated Hcy levels
237
were related to progression of ventricular enlargement and increased risk of decline in
238
executive function in 663 patients with mean age of 57 during a 3.9-year follow-up
239
(Jochemsen et al. 2013). Polymorphism at the 5,10-methylenetetrahydrofolate
240
reductase-encoding gene, a trait related to high Hcy levels, was associated with 46%
241
greater odds of CI in elderly men (Ford et al. 2012). While these data do not directly
242
address the role of UTs in cerebro-renal interactions, the results do suggest that higher
243
Hcy levels may influence CI, especially in elderly subjects.
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2.4.4 Putrescine and spermidine
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Putrescine, spermidine, and spermine are typical polyamines in the human body. In aged
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rats, putrescine levels were decreased in the CA1 and dentate gyrus and increased in the
247
CA2/3, while spermidine levels were increased in the CA1 and CA2/3 (Liu et al. 2008b).
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Low doses of difluoromethylornithine, a potent inhibitor of putrescine synthesis,
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induced anxiety-like behavior and impaired memory in rats without affecting the
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animals' activity (Gupta et al. 2009). Spermine and spermidine levels were decreased in
251
mice trained in a Morris water maze (Tiboldi et al. 2012); elevated levels of endogenous
252
polyamines contributed to memory function improvement in the fruit fly Drosophila
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melanogaster (Gupta et al. 2013; Sigrist et al. 2013); and decreased
254
spermidine/spermine N1-acetyltransferase activity was observed in the brains of
255
humans who died of suicide (Fiori et al. 2009). These findings suggest that dysfunction
256
in the polyamine system affects learning and impairs memory, but the influence of
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polyamine metabolic abnormalities on CNS function has not been characterized in
258
patients with CKD.
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Indole-3-acetic acid (IAA) is a plant hormone known as a natural auxin, and plays a role
261
in the mechanisms of cell growth in animals. Administration of IAA to pregnant mice
262
decreased neuron formation and induced microencephaly in the fetus, effects that were
263
mediated by p53 in the embryonic neuroepithelium (Furukawa et al. 2007). However,
264
no data is available regarding IAA and cerebro-renal interaction. In renal proximal
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tubule epithelial cells, the toxic mechanism of IAA has been reported to include tissue
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factor production in endothelial and peripheral blood mononuclear cells by aryl
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hydrocarbon receptor (Gondouin et al. 2013), and inhibition of
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UDP-glucuronosyltransferase activity and mitochondrial activity (Mutsaers et al. 2013). 2.4.6 Methylglyoxal (MGO)
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Methylglyoxal (MGO) is a highly reactive alpha-dicarbonyl compound that binds to
271
arginine and lysine residues and produces a variety of advanced glycation endproducts
272
(AGEs) (Matafome et al. 2013). Higher MGO levels were associated with a faster rate
273
of cognitive decline in 267 non-demented elderly patients (Beeri et al. 2011); elevated
274
MGO levels also were associated with poorer memory, reduced executive function, and
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lower grey matter volume in 378 non-demented subjects with mean age 72 years
276
(Srikanth et al. 2013). Exposure of rat hippocampal neurons to MGO yielded decreased
277
levels of reduced glutathione while inhibiting glyoxalase and glutathione peroxidase
278
activities and inducing apoptosis and increasing the expression of inflammatory
279
cytokines (Di Loreto et al. 2008). Exposure of SH-SY5Y neuroblastoma cells to MGO
280
induced the production of intracellular ROS and lactate, while decreasing mitochondrial
281
membrane potential and intracellular ATP levels (de Arriba et al. 2007). These results
282
suggest that carbonyl stress-induced loss of mitochondrial integrity contributes to the
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cytotoxicity of MGO. In in vivo studies, streptozotocin-induced diabetic rats showed CI
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in a Morris water maze (Huang et al. 2012), but normal Sprague-Dawley rats did not
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show spatial memory dysfunction despite administration of exogenous MGO (Watanabe
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et al. 2014). As to the vasculature effects, oral administration of MGO to Wistar rats
287
induced a decrease of NO-dependent vasorelaxation in isolated aortic arteries (Sena et al.
288
2012). Exposure of brain microvascular endothelial cells to MGO induced glycation and
289
endothelial cell dysfunction, along with elevated expression of occludin, an adhesion
290
protein that contributes to the formation of tight junctions (Li et al. 2013).
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Leptin is an adipose cell-derived compound that contributes to appetite control, with
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associated effects on weight gain. Higher serum leptin levels were associated with
294
reduced risk for dementia or mild cognitive impairment in very old women with normal
295
body mass indexes (Zeki Al Hazzouri et al. 2013). In animal experiments, leptin
296
delivery to the ventral hippocampus suppressed memory consolidation for the spatial
297
location of food (Kanoski et al. 2011). In the context of Alzheimer’s disease (AD),
298
leptin is thought to inhibit hippocampal involvement by accumulation of amyloid-β,
299
which affects cognitive decline in AD patients (Doherty et al. 2013; Martins et al. 2013).
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Plasma leptin levels are known to be increased about eight- to nine-fold in uremic
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patients compared to healthy subjects. Nonetheless, the role of leptin in CNS function
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302 303
remains unclear. 2.4.8 P-cresyl sulfate (PCS) and indoxyl sulfate (IS) The pre-dialysis concentrations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are
305
41-fold and 116-fold elevated compared to those of normal subjects, and the dialytic
306
clearance rates of PCS and IS are decreased (to 0.39-fold and 0.21-fold, respectively),
307
yielding rates that are relatively low compared to those for urea (4.2-fold) and creatinine
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(1.3-fold) (Sirich et al. 2013). Thus, the biological effects of PCS and IS accumulation
309
are of great concern. Both PCS and IS also are risk factors for CKD progression;
310
because these molecules share the same albumin binding site, both compounds are
311
thought to be valid markers for monitoring the behavior of protein-bound solutes during
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dialysis (Meijers et al. 2009; Wu et al. 2011). Cisplatin-administered rats showed
313
increased IS concentrations in brain tissue, with associated increases in nephrotoxicity
314
along with disturbances in the circadian rhythm of the transcription of the clock gene
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rPer2 (Iwata et al. 2007). IS normally is transported from brain to blood via organic
316
anion transporter 3, which is located in the BBB; IS accumulates in the brains of uremic
317
patients as a result of transporter dysfunction (Ohtsuki et al. 2002). Additionally, PCS
318
and IS are thought to be causative factors for endothelial cell dysfunction in HD patients,
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and to induce renal fibrosis through accumulation in renal tubular cells (Sun et al. 2013;
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Watanabe et al. 2013). IS activates the aryl hydrocarbon receptor (AhR), which is a
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ligand-activated transcriptional factor (Watanabe et al. 2013b). Prolonged activation of
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AhR by IS may contribute to neurotoxicity through the mechanism of endothelial
323
dysfunction (Goudouin et al. 2013; Schroeder et al. 2010).
324
2.5 Middle molecules
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UTs in the “middle molecules” group have molecular weights greater than 500 daltons
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and can be removed by large pore-size dialysis membranes. We reviewed relevant
327
literature for the following molecules: cystatin C (CyC); cytokines IL-1β, IL-6, and
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TNF-α; parathyroid hormone (PTH); and beta-2-microglobulin (β2MG).
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2.5.1 Cystatin C (CyC)
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Cystatin C (CyC), a proteinase inhibitor, is recognized as an endogenous glomerular
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filtration rate (GFR) marker. Serum CyC levels correlated with incident CI risk (odds
332
ratio, 1.54-1.92) among 3,030 elders in the health ABC study (Yaffe et al. 2008). In a
333
study of 604 Japanese elderly, subjects with higher CyC levels tended to have more
334
lacunae and higher grades of white matter lesions (Wada et al. 2010). Elevated CyC
335
levels correlated with reduced scores in cognitive tests such as the digit symbol
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substitution test or the Stroop test of executive function in diabetic patients (Murray et
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al. 2011). Among 738 elderly Caucasian subjects, elevated CyC levels also were
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associated with volume deficits in the white matter region, especially bilaterally in the
339
anterior limb of the internal capsule of the brain (Rajagopalan et al. 2013). On the other
340
hand, several reports have indicated a positive correlation between CyC levels and brain
341
function. Notably, a 0.1-µM decrease of CyC in elderly patients was associated with a
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29% higher risk of incident AD (Sundelof et al. 2008), and low plasma CyC levels
343
correlated with conversion from mild-CI to AD (Ghidoni et al. 2010). Furthermore, in
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vivo administration of CyC in an animal model of subarachnoid hemorrhage attenuated
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early brain injury (Liu et al. 2013). Based on these results, the pathological significance
346
of CyC levels appears to differ in cerebrovascular disease compared to
347
neurodegenerative disorders such as AD. Given that CyC itself is thought to directly
348
reflect renal function, the compound may be a useful marker, especially in vascular
349
impairment of cerebro-renal interaction.
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2.5.2 Interleukin 1-β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α
351
(TNF-α)
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Several important clinical studies have suggested correlations between cytokine levels
353
and CNS function. Specifically, associations have been reported between interleukin 6
354
(IL-6) levels and memory of encoding and recall in the elderly (Elderkin-Thompson et
355
al. 2012); between plasma IL-6 concentration and cognition among 1224 subjects with
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mean age of 71 years during a 3-year follow-up (Economos et al. 2013); and between
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elevated IL-6 levels and impaired executive cognitive function in a cross-sectional
358
analysis of 5653 participants with mean age of 75 years with 39-month follow-up
359
(Mooijaart et al. 2013). As for the cytokines and cerebro-renal interactions, when
360
secondary brain damage was incurred from kidney or intestinal ischemia-reperfusion
361
injury, TNF-α and IL-6 levels were upregulated (Hsieh et al. 2011; Liu et al. 2008a).
362
Brain inflammation, especially in microglial cells and astrocytes, was confirmed in that
363
study (Hsieh et al. 2011). DNA damage was observed in the brains of CKD model rats,
364
and this damage was mediated by the increased levels of pro-inflammatory cytokines
365
such as IL-1α, IL-1β, IL-6, and TNF-α (Hirotsu et al. 2011).
366
Mechanistically, the neurotoxicity of cytokines has been proposed to be an effect of
367
glutamate, the production of which is up-regulated by IL-1β and TNF-α (Ye et al. 2013).
368
Better understanding of the relationship between cytokines and cerebro-renal
369
interactions will be critical, given that the CNS is vulnerable to cytokine-induced DNA
370
damage.
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2.5.3 Parathyroid hormone (PTH)
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Several clinical investigations have suggested a negative correlation between PTH
373
levels and brain function, as evidenced by cognition and mood. Specifically,
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parathyroidectomy in 39 HD patients with SHPT resulted in improved cognition, as
375
evaluated by the MMSE test and clinical dementia rating (Chou et al. 2008). In a
376
separate study, patients who underwent parathyroidectomy also exhibited improvements
377
in depression, anxiety, visuospatial memory, and verbal memory (Roman et al. 2011).
378
Consistent with these observations, a study in 1282 older adults aged 65 to 95 years
379
revealed an association between increased PTH levels, decreased 25-hydroxyvitamin D
380
levels, and severity of depression (Hoogendijk et al. 2008). Receptors for PTH and
381
1,25-hydroxyvitamin D are known to exist in the brain (Jorde et al. 2006), and rats with
382
CKD exhibited an increase in brain calcium content accompanied by increased levels of
383
cytosolic calcium in synaptosomes, leading to somatic, behavioral, and motor
384
dysfunctions (Smogorzewski 2001). Notably, parathyroidectomy in this animal model
385
prevented the increase in calcium levels and inhibited derangements in neurotransmitter
386
metabolism (Smogorzewski 2001).
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2.5.4 Beta-2-microglobulin (β2MG)
388
Beta-2-microglobulin (β2MG) accumulates selectively in the bones and tendons of
389
dialysis patients, inducing a type of osteoarthritis referred to as dialysis amyloidosis
390
(Yamamoto et al. 2009). There is limited information about the relation of β2MG and
391
CNS effects. Cytotoxicity was observed in SH-SY5Y neuroblastoma cells following
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exposure to β2MG at levels similar to those seen in the plasma of HD patients (Giorgetti
393
et al. 2009). However, β2MG concentration in the CSF of HD patients did not correlate
394
with plasma level, and CSF β2MG levels in these patients was below the lower limit
395
required for cytotoxicity in cell culture (Giorgetti et al. 2009). Therefore, although
396
β2MG is potentially neurotoxic, the BBB is thought to restrict CSF β2MG concentration
397
in HD patients (Giorgetti et al. 2009).
398
Literature results for the twenty-one compounds described above are summarized in
399
Table 1. And we have summarized segment of the manuscript that refer to the
400
relationship between uremic toxins and cerebro-renal interaction in Table 2. Compound
401
molecular weights and data on plasma concentrations in normal and uremic states are
402
derived from the European Uremic Solutes Database (http://www.uremic-toxins.org/;
403
Duranton et al. 2012).
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3. Discussion
406
3.1 Therapeutic strategy for uremic toxins and cerebro-renal interaction
407
Several studies have attempted to treat CI by targeting UTs. A systematic review and
408
meta-analysis was performed for 19 randomized controlled trials that attempted to lower
409
Hcy levels by supplementation with vitamins B12, B6, and folic acid; the authors of that
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meta-analysis concluded that B-vitamin supplementation did not improve cognitive
411
function (Brady et al. 2009; Ford and Almeida 2012; Hankey et al. 2013; McMahon et
412
al. 2006). In a rat model of AD, researchers administered gamma-glutathione (ψ-GSH),
413
a synthetic cofactor of glyoxalase expected to counteract the reactive carbonyl moiety of
414
MGO, and reported therapeutic efficacy of ψ-GSH as judged by spatial mnemonic and
415
long-term recall impairment (More et al. 2013). Treatment of CKD model mice with a
416
pegylated leptin receptor antagonist attenuated cachexia (body weight loss) and muscle
417
wasting, effects that were presumed to occur via appetite motivation (Cheung et al.
418
2013). MK-801, which is N-methyl-D-aspartate receptor antagonist, blocked glutamate
419
production by IL-1β and/or TNF-α and alleviated the neurotoxicity associated with
420
these cytokines (Ye et al. 2013). As to PTH, improvements of depression, anxiety,
421
visuospatial memory, and verbal memory were observed in patients who underwent
422
parathyroidectomy, effects that correlated with postoperative reductions in iPTH,
423
decreases in state anxiety, and improved visuospatial working memory (Roman et al.
424
2011). Consistent with these clinical results, parathyroidectomies in CKD model rats
425
inhibited neurotransmitter metabolism dysfunction (Smogorzewski 2001).
426
Vascular dysfunction has been recognized as a traditional factor in dementia among
427
CKD patients (Bugnicourt et al. 2013). Recently, Jourde-Chiche et al. (2011) reported
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that several UTs (including ADMA, Hcy, AGEs, PCS, and IS) contribute to dysfunction
429
of the cardiovascular system. It is estimated that the adequate management of vascular
430
risk factors might result in a 50% reduction in dementia prevalence (Asif et al. 2013), so
431
maintenance of residual renal function (that is, maintenance of UT excretion ability) is
432
thought to be an important treatment approach.
433
Nocturnal daily HD improved CI symptoms such as psychomotor efficiency, attention,
434
and working memory in a small longitudinal pilot study (Jassal et al. 2008).
435
Protein-leaking HD with a polymethylmethacrylate membrane BK-F dialyzer reduced
436
serum CMPF levels with improvement of anemia while reducing plasma levels of Hcy,
437
pentosidine, and inflammatory cytokines (Niwa 2013). Negative effects of UTs and the
438
UTs themselves are expected to be decreased by treatment with vitamin C or E, aspirin,
439
statins, ACE-inhibitors, acetyl-l-carnitine, alpha-lipoic acid, or various scavenging
440
agents (Vanholder et al. 2003). Pro-oxidants such as D-galactose and iron have been
441
shown to induce dysfunction in learning, cognition, and spatial memory in rodent
442
models (de Lima et al. 2005; Wang et al. 2009), and anti-oxidants such as vitamin E and
443
alpha-lipoic acid have been suggested to improve CI symptoms by decreasing oxidative
444
stress (Fukui et al. 2002; Liu et al. 2002; Shamoto-Nagai et al. 2003).
445
As discussed above, various research has been conducted focusing on the possible
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effects of UTs on CNS function; antagonistic agents, parathyroidectomy, vitamin
447
supplementation, and innovative dialysis methods have been employed to counter the
448
effects of UTs. In the future, systematization of treatment strategies in terms of UTs and
449
cerebro-renal interactions is expected.
450
3.2 Limitations and future perspectives
451
In this review, we considered the effects of UTs on the CNS, with an emphasis on
452
cognitive function. There is little information about the roles of UTs in cerebro-renal
453
interactions. References cited in this paper included experiments with cultured cells and
454
in animal models without renal impairment. Therefore, caution is required in extending
455
these results to human subjects with CKD. For uremic patients, various UTs accumulate
456
gradually in the blood and tissues as CKD progresses, with associated increases in basal
457
oxidative stress. Additionally, existing conditions (e.g., diabetes, cardiac failure,
458
hypertension) may result in various complications that further affect cognition.
459
Especially in animal experiments, responses to individual UTs are thought to vary
460
greatly depending on species (e.g., mouse vs. rat), strain (e.g., Dahl rat vs.
461
Sprague-Dawley rat), and background pathological condition. Results opposite from
462
those expected might occasionally be observed, depending on the experimental
463
conditions (Watanabe et al. 2014). This distinction is an important point when we
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consider the pathological significance of each UT associated with cerebro-renal
465
interactions. In terms of the future research on UTs and cerebro-renal interactions,
466
detailed examination using appropriate animal models of renal dysfunction will be
467
required to distinguish the effects of UTs on CNS compared to traditional risk factors; to
468
determine which brain regions are affected (e.g., frontal cortex, hippocampus, or
469
amygdala); and to determine which structures are disrupted (e.g., neuron, endothelial
470
cell, or vascular tissue).
471
Clarification of the pathological significance of UTs for CI accompanied by CKD is
472
expected to facilitate the establishment of specific therapies while reducing the health
473
care costs and social burden for such patients.
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4. Conclusions
476
We reviewed the literature for 21 uremic toxins, and summarized the compounds in
477
terms of uremic toxicity and cerebro-renal interaction dysfunction. Among the
478
compounds, uric acid, indoxyl sulfate, p-cresyl sulfate, interleukin 1-β, interleukin 6,
479
TNF-α, and PTH are more likely to affect the cerebro-renal interaction dysfunction;
480
however, data for other uremic toxins remain limiting. This distinction may be due to
481
differences in study populations in clinical trials, or to differences in study conditions in
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animal experiments. Unfortunately, most of the data in this paper were not obtained
483
under uremic conditions; therefore, the impact and mechanism of each uremic toxin on
484
cognition and the central nervous system in the uremic state remains unknown.
485
Clarifying the mechanisms and establishing novel therapeutic strategies for
486
cerebro-renal interaction dysfunction is expected to be the subject of future research.
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Acknowledgements: This work was supported by JADP Grant 2013-1 and JSPS
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KAKENHI Grant Number 23591196.
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Conflict of interest: The authors declare no conflict of interest.
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References
493
Afsar, B., Elsurer, R., Covic, A., Johnson, R.J. and Kanbay, M. 2011. Relationship
494
between uric acid and subtle cognitive dysfunction in chronic kidney disease. Am J
495
Nephrol 34, 49-54.
496
Asif, M., Soiza, R.L., McEvoy, M. and Mangoni, A.A. 2013. Asymmetric
497
dimethylarginine: a possible link between vascular disease and dementia. Curr
498
Alzheimer Res 10, 347-356.
499
Bahn, A., Ljubojevic, M., Lorenz, H., Schultz, C., Ghebremedhin, E., Ugele, B., Sabolic,
500
I., Burckhardt, G. and Hagos, Y. 2005. Murine renal organic anion transporters mOAT1
501
and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol.
502
Cell physiology 289, C1075-1084.
503
Bavaresco, C.S., Ben, J., Chiarani, F., Netto, C.A. and Wyse, A.T. 2008. Intrastriatal
504
injection of hypoxanthine impairs memory formation of step-down inhibitory avoidance
505
task in rats. Pharmacol Biochem Behav 90, 594-597.
506
Beard, C.M., Kokmen, E., O'Brien, P.C., Ania, B.J. and Melton, L.J., 3rd. 1997. Risk of
507
Alzheimer's disease among elderly patients with anemia: population-based
508
investigations in Olmsted County, Minnesota. Ann Epidemiol 7, 219-224.
509
Beeri, M.S., Moshier, E., Schmeidler, J., Godbold, J., Uribarri, J., Reddy, S., Sano, M.,
Ac ce
pt
ed
M
an
us
cr
ip t
492
29 Page 29 of 60
Grossman, H.T., Cai, W., Vlassara, H. and Silverman, J.M. 2011. Serum concentration
511
of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive
512
decline in elderly individuals. Mech Ageing Dev 132, 583-587.
513
Brady, C.B., Gaziano, J.M., Cxypoliski, R.A., Guarino, P.D., Kaufman, J.S., Warren,
514
S.R., Hartigan, P., Goldfarb, D.S. and Jamison, R.L. 2009. Homocysteine lowering and
515
cognition in CKD: the Veterans Affairs homocysteine study. Am J Kidney Dis 54,
516
440-449.
517
Brines, M.L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N.C., Cerami, C., Itri,
518
L.M. and Cerami, A. 2000. Erythropoietin crosses the blood-brain barrier to protect
519
against experimental brain injury. Proc Natl Acad Sci U S A 97, 10526-10531.
520
Buchman, A.S., Tanne, D., Boyle, P.A., Shah, R.C., Leurgans, S.E. and Bennett, D.A.
521
2009. Kidney function is associated with the rate of cognitive decline in the elderly.
522
Neurology 73, 920-927.
523
Bugnicourt, J.M., Godefroy, O., Chillon, J.M., Choukroun, G. and Massy, Z.A. 2013.
524
Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc
525
Nephrol 24, 353-363.
526
Cerami, A., Brines, M.L., Ghezzi, P. and Cerami, C.J. 2001. Effects of epoetin alfa on
527
the central nervous system. Semin Oncol 28, 66-70.
Ac ce
pt
ed
M
an
us
cr
ip t
510
30 Page 30 of 60
Chen, C.L., Lai, P.H., Chou, K.J., Lee, P.T., Chung, H.M. and Fang, H.C. 2007. A
529
preliminary report of brain edema in patients with uremia at first hemodialysis:
530
evaluation by diffusion-weighted MR imaging. AJNR Am J Neuroradiol 28, 68-71.
531
Cheung, W.W., Ding, W., Gunta, S.S., Gu, Y., Tabakman, R., Klapper, L.N., Gertler, A.
532
and Mak, R.H. 2013. A Pegylated Leptin Antagonist Ameliorates CKD-Associated
533
Cachexia in Mice. J Am Soc Nephrol 25, 119-128.
534
Chou, F.F., Chen, J.B., Hsieh, K.C. and Liou, C.W. 2008. Cognitive changes after
535
parathyroidectomy in patients with secondary hyperparathyroidism. Surgery 143,
536
526-532.
537
Cogan, M.G., Covey, C.M., Arieff, A.I., Wisniewski, A., Clark, O.H., Lazarowitz, V. and
538
Leach, W. 1978. Central nervous system manifestations of hyperparathyroidism. Am J
539
Med 65, 963-970.
540
de Arriba, S.G., Stuchbury, G., Yarin, J., Burnell, J., Loske, C. and Munch, G. 2007.
541
Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal
542
cells--protection by carbonyl scavengers. Neurobiol Aging 28, 1044-1050.
543
De Deyn, P.P., D'Hooge, R., Van Bogaert, P.P. and Marescau, B. 2001. Endogenous
544
guanidino compounds as uremic neurotoxins. Kidney Int Suppl 78, S77-83.
545
de Lima, M.N., Polydoro, M., Laranja, D.C., Bonatto, F., Bromberg, E., Moreira, J.C.,
Ac ce
pt
ed
M
an
us
cr
ip t
528
31 Page 31 of 60
Dal-Pizzol, F. and Schroder, N. 2005. Recognition memory impairment and brain
547
oxidative stress induced by postnatal iron administration. Eur J Neurosci 21, 2521-2528.
548
Deguchi, T., Isozaki, K., Yousuke, K., Terasaki, T. and Otagiri, M. 2006. Involvement of
549
organic anion transporters in the efflux of uremic toxins across the blood-brain barrier. J
550
Neurochem 96, 1051-1059.
551
Di Loreto, S., Zimmitti, V., Sebastiani, P., Cervelli, C., Falone, S. and Amicarelli, F.
552
2008. Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic
553
cell death in rat hippocampal neurons. Int J Biochem Cell Biol 40, 245-257.
554
Doherty, G.H., Beccano-Kelly, D., Yan, S.D., Gunn-Moore, F.J. and Harvey, J. 2013.
555
Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by
556
amyloid beta. Neurobiol Aging 34, 226-237.
557
Drueke, T.B., Locatelli, F., Clyne, N., Eckardt, K.U., Macdougall, I.C., Tsakiris, D.,
558
Burger, H.U. and Scherhag, A. 2006. Normalization of hemoglobin level in patients
559
with chronic kidney disease and anemia. N Engl J Med 355, 2071-2084.
560
Duranton, F., Cohen, G., De Smet, R., Rodriguez, M., Jankowski, J., Vanholder, R. and
561
Argiles, A. 2012. Normal and pathologic concentrations of uremic toxins. J Am Soc
562
Nephrol 23, 1258-1270.
563
Economos, A., Wright, C.B., Moon, Y.P., Rundek, T., Rabbani, L., Paik, M.C., Sacco,
Ac ce
pt
ed
M
an
us
cr
ip t
546
32 Page 32 of 60
R.L. and Elkind, M.S. 2013. Interleukin 6 plasma concentration associates with
565
cognitive decline: the northern Manhattan study. Neuroepidemiology 40, 253-259.
566
Elderkin-Thompson, V., Irwin, M.R., Hellemann, G. and Kumar, A. 2012. Interleukin-6
567
and memory functions of encoding and recall in healthy and depressed elderly adults.
568
Am J Geriatr Psychiatry 20, 753-763.
569
Eloot, S., Torremans, A., De Smet, R., Marescau, B., De Wachter, D., De Deyn, P.P.,
570
Lameire, N., Verdonck, P. and Vanholder, R. 2005. Kinetic behavior of urea is different
571
from that of other water-soluble compounds: the case of the guanidino compounds.
572
Kidney Int 67, 1566-1575.
573
Erbayraktar, S., Grasso, G., Sfacteria, A., Xie, Q.W., Coleman, T., Kreilgaard, M., Torup,
574
L., Sager, T., Erbayraktar, Z., Gokmen, N., Yilmaz, O., Ghezzi, P., Villa, P., Fratelli, M.,
575
Casagrande, S., Leist, M., Helboe, L., Gerwein, J., Christensen, S., Geist, M.A.,
576
Pedersen, L.O., Cerami-Hand, C., Wuerth, J.P., Cerami, A. and Brines, M. 2003.
577
Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity
578
in vivo. Proc Natl Acad Sci U S A 100, 6741-6746.
579
Euser, S.M., Hofman, A., Westendorp, R.G. and Breteler, M.M. 2009. Serum uric acid
580
and cognitive function and dementia. Brain 132, 377-382.
581
Fiori, L.M., Mechawar, N. and Turecki, G. 2009. Identification and characterization of
Ac ce
pt
ed
M
an
us
cr
ip t
564
33 Page 33 of 60
spermidine/spermine N1-acetyltransferase promoter variants in suicide completers. Biol
583
Psychiatry 66, 460-467.
584
Ford, A.H. and Almeida, O.P. 2012. Effect of homocysteine lowering treatment on
585
cognitive function: a systematic review and meta-analysis of randomized controlled
586
trials. J Alzheimers Dis 29, 133-149.
587
Ford, A.H., Flicker, L., Hankey, G.J., Norman, P., van Bockxmeer, F.M. and Almeida,
588
O.P. 2012. Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism
589
and cognitive impairment: the health in men study. Mol Psychiatry 17, 559-566.
590
Fukui, K., Omoi, N.O., Hayasaka, T., Shinnkai, T., Suzuki, S., Abe, K. and Urano, S.
591
2002. Cognitive impairment of rats caused by oxidative stress and aging, and its
592
prevention by vitamin E. Ann N Y Acad Sci 959, 275-284.
593
Furukawa, S., Usuda, K., Abe, M., Hayashi, S. and Ogawa, I. 2007. Indole-3-acetic acid
594
induces microencephaly in mouse fetuses. Exp Toxicol Pathol 59, 43-52.
595
Gelb, S., Shapiro, R.J., Hill, A. and Thornton, W.L. 2008. Cognitive outcome following
596
kidney transplantation. Nephrol Dial Transplant 23, 1032-1038.
597
Ghidoni, R., Benussi, L., Glionna, M., Desenzani, S., Albertini, V., Levy, E., Emanuele,
598
E. and Binetti, G. 2010. Plasma cystatin C and risk of developing Alzheimer's disease in
599
subjects with mild cognitive impairment. J Alzheimers Dis 22, 985-991.
Ac ce
pt
ed
M
an
us
cr
ip t
582
34 Page 34 of 60
Giorgetti, S., Raimondi, S., Cassinelli, S., Bucciantini, M., Stefani, M., Gregorini, G.,
601
Albonico, G., Moratti, R., Montagna, G., Stoppini, M. and Bellotti, V. 2009.
602
beta2-Microglobulin is potentially neurotoxic, but the blood brain barrier is likely to
603
protect the brain from its toxicity. Nephrol Dial Transplant 24, 1176-1181.
604
Goldstein, D.A., Feinstein, E.I., Chui, L.A., Pattabhiraman, R. and Massry, S.G. 1980.
605
The relationship between the abnormalities in electroencephalogram and blood levels of
606
parathyroid hormone in dialysis patients. J Clin Endocrinol Metab 51, 130-134.
607
Goldstein, D.A. and Massry, S.G. 1980. Parathyroid hormone, uremia, and the nervous
608
system. Contrib Nephrol 20, 73-83.
609
Gondouin, B., Cerini, C., Dou, L., Sallee, M., Duval-Sabatier, A., Pletinck, A., Calaf, R.,
610
Lacroix, R., Jourde-Chiche, N., Poitevin, S., Arnaud, L., Vanholder, R., Brunet, P.,
611
Dignat-George, F. and Burtey, S. 2013. Indolic uremic solutes increase tissue factor
612
production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int 84,
613
733-744.
614
Griva, K., Thompson, D., Jayasena, D., Davenport, A., Harrison, M. and Newman, S.P.
615
2006. Cognitive functioning pre- to post-kidney transplantation--a prospective study.
616
Nephrol Dial Transplant 21, 3275-3282.
617
Guisado, R., Arieff, A.I., Massry, S.G., Lazarowitz, V. and Kerian, A. 1975. Changes in
Ac ce
pt
ed
M
an
us
cr
ip t
600
35 Page 35 of 60
the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain
619
electrolytes. J Clin Invest 55, 738-745.
620
Gupta, N., Zhang, H. and Liu, P. 2009. Behavioral and neurochemical effects of acute
621
putrescine depletion by difluoromethylornithine in rats. Neuroscience 161, 691-706.
622
Gupta, V.K., Scheunemann, L., Eisenberg, T., Mertel, S., Bhukel, A., Koemans, T.S.,
623
Kramer, J.M., Liu, K.S., Schroeder, S., Stunnenberg, H.G., Sinner, F., Magnes, C.,
624
Pieber, T.R., Dipt, S., Fiala, A., Schenck, A., Schwaerzel, M., Madeo, F. and Sigrist, S.J.
625
2013. Restoring polyamines protects from age-induced memory impairment in an
626
autophagy-dependent manner. Nat Neurosci 16, 1453-1460.
627
Hailpern, S.M., Melamed, M.L., Cohen, H.W. and Hostetter, T.H. 2007. Moderate
628
chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third
629
National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol
630
18, 2205-2213.
631
Hankey, G.J., Ford, A.H., Yi, Q., Eikelboom, J.W., Lees, K.R., Chen, C., Xavier, D.,
632
Navarro, J.C., Ranawaka, U.K., Uddin, W., Ricci, S., Gommans, J., Schmidt, R.,
633
Almeida, O.P. and van Bockxmeer, F.M. 2013. Effect of B vitamins and lowering
634
homocysteine on cognitive impairment in patients with previous stroke or transient
635
ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled
Ac ce
pt
ed
M
an
us
cr
ip t
618
36 Page 36 of 60
trial and meta-analysis. Stroke; a journal of cerebral circulation 44, 2232-2239.
637
Hill, M.B. 2001. Dialysis disequilibrium syndrome. Nephrol Nurs J 28, 348-349.
638
Hirotsu, C., Tufik, S., Ribeiro, D.A., Alvarenga, T.A. and Andersen, M.L. 2011.
639
Genomic damage in the progression of chronic kidney disease in rats. Brain Behav
640
Immun 25, 416-422.
641
Hoogendijk, W.J., Lips, P., Dik, M.G., Deeg, D.J., Beekman, A.T. and Penninx, B.W.
642
2008. Depression is associated with decreased 25-hydroxyvitamin D and increased
643
parathyroid hormone levels in older adults. Arch Gen Psychiatry 65, 508-512.
644
Hooshmand, B., Solomon, A., Kareholt, I., Rusanen, M., Hanninen, T., Leiviska, J.,
645
Winblad, B., Laatikainen, T., Soininen, H. and Kivipelto, M. 2012. Associations
646
between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a
647
longitudinal study. J Intern Med 271, 204-212.
648
Hsieh, Y.H., McCartney, K., Moore, T.A., Thundyil, J., Gelderblom, M., Manzanero, S.
649
and Arumugam, T.V. 2011. Intestinal ischemia-reperfusion injury leads to inflammatory
650
changes in the brain. Shock 36, 424-430.
651
Hu, X., Xu, X., Zhu, G., Atzler, D., Kimoto, M., Chen, J., Schwedhelm, E., Luneburg,
652
N., Boger, R.H., Zhang, P. and Chen, Y. 2009. Vascular endothelial-specific
653
dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular
Ac ce
pt
ed
M
an
us
cr
ip t
636
37 Page 37 of 60
endothelium plays an important role in removing asymmetric dimethylarginine.
655
Circulation 120, 2222-2229.
656
Huang, X., Wang, F., Chen, W., Chen, Y., Wang, N. and von Maltzan, K. 2012. Possible
657
link between the cognitive dysfunction associated with diabetes mellitus and the
658
neurotoxicity of methylglyoxal. Brain Res 1469, 82-91.
659
Hughes, K., Flynn, T., de Zoysa, J., Dalbeth, N. and Merriman, T.R. 2013. Mendelian
660
randomization analysis associates increased serum urate, due to genetic variation in uric
661
acid transporters, with improved renal function. Kidney Int 85, 344-351.
662
Itoh, Y., Ezawa, A., Kikuchi, K., Tsuruta, Y. and Niwa, T. 2012. Protein-bound uremic
663
toxins in hemodialysis patients measured by liquid chromatography/tandem mass
664
spectrometry and their effects on endothelial ROS production. Anal Bioanal Chem 403,
665
1841-1850.
666
Iwata, K., Watanabe, H., Morisaki, T., Matsuzaki, T., Ohmura, T., Hamada, A. and Saito,
667
H. 2007. Involvement of indoxyl sulfate in renal and central nervous system toxicities
668
during cisplatin-induced acute renal failure. Pharm Res 24, 662-671.
669
Jassal, S.V., Roscoe, J., LeBlanc, D., Devins, G.M. and Rourke, S. 2008. Differential
670
impairment of psychomotor efficiency and processing speed in patients with chronic
671
kidney disease. Int Urol Nephrol 40, 849-854.
Ac ce
pt
ed
M
an
us
cr
ip t
654
38 Page 38 of 60
Jochemsen, H.M., Kloppenborg, R.P., de Groot, L.C., Kampman, E., Mali, W.P., van der
673
Graaf, Y. and Geerlings, M.I. 2013. Homocysteine, progression of ventricular
674
enlargement, and cognitive decline: the Second Manifestations of ARTerial
675
disease-Magnetic Resonance study. Alzheimers Dement 9, 302-309.
676
Jorde, R., Waterloo, K., Saleh, F., Haug, E. and Svartberg, J. 2006. Neuropsychological
677
function in relation to serum parathyroid hormone and serum 25-hydroxyvitamin D
678
levels. The Tromso study. J Neurol 253, 464-470.
679
Jourde-Chiche, N., Dou, L., Cerini, C., Dignat-George, F. and Brunet, P. 2011. Vascular
680
incompetence in dialysis patients--protein-bound uremic toxins and endothelial
681
dysfunction. Semin Dial 24, 327-337.
682
Kalirao, P., Pederson, S., Foley, R.N., Kolste, A., Tupper, D., Zaun, D., Buot, V. and
683
Murray, A.M. 2011. Cognitive impairment in peritoneal dialysis patients. Am J Kidney
684
Dis 57, 612-620.
685
Kanoski, S.E., Hayes, M.R., Greenwald, H.S., Fortin, S.M., Gianessi, C.A., Gilbert, J.R.
686
and Grill, H.J. 2011. Hippocampal leptin signaling reduces food intake and modulates
687
food-related memory processing. Neuropsychopharmacology 36, 1859-1870.
688
Khatri, M., Nickolas, T., Moon, Y.P., Paik, M.C., Rundek, T., Elkind, M.S., Sacco, R.L.
689
and Wright, C.B. 2009. CKD associates with cognitive decline. J Am Soc Nephrol 20,
Ac ce
pt
ed
M
an
us
cr
ip t
672
39 Page 39 of 60
2427-2432.
691
Kielstein, J.T., Donnerstag, F., Gasper, S., Menne, J., Kielstein, A.,
692
Martens-Lobenhoffer, J., Scalera, F., Cooke, J.P., Fliser, D. and Bode-Boger, S.M. 2006.
693
ADMA increases arterial stiffness and decreases cerebral blood flow in humans. Stroke
694
37, 2024-2029.
695
Koushik, N.S., McArthur, S.F. and Baird, A.D. 2010. Adult chronic kidney disease:
696
neurocognition in chronic renal failure. Neuropsychol Rev 20, 33-51.
697
Kurella, M., Chertow, G.M., Fried, L.F., Cummings, S.R., Harris, T., Simonsick, E.,
698
Satterfield, S., Ayonayon, H. and Yaffe, K. 2005a. Chronic kidney disease and cognitive
699
impairment in the elderly: the health, aging, and body composition study. J Am Soc
700
Nephrol 16, 2127-2133.
701
Kurella, M., Yaffe, K., Shlipak, M.G., Wenger, N.K. and Chertow, G.M. 2005b. Chronic
702
kidney disease and cognitive impairment in menopausal women. Am J Kidney Dis 45,
703
66-76.
704
Kurella Tamura, M., Wadley, V., Yaffe, K., McClure, L.A., Howard, G., Go, R., Allman,
705
R.M., Warnock, D.G. and McClellan, W. 2008. Kidney function and cognitive
706
impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke
707
(REGARDS) Study. Am J Kidney Dis 52, 227-234.
Ac ce
pt
ed
M
an
us
cr
ip t
690
40 Page 40 of 60
Lee, J.J., Chin, H.J., Byun, M.S., Choe, J.Y., Park, J.H., Lee, S.B., Choi, E.A., Chae,
709
D.W. and Kim, K.W. 2011. Impaired frontal executive function and predialytic chronic
710
kidney disease. J Am Geriatr Soc 59, 1628-1635.
711
Lee, S.Y., Lee, H.J., Kim, Y.K., Kim, S.H., Kim, L., Lee, M.S., Joe, S.H., Jung, I.K.,
712
Suh, K.Y. and Kim, H.K. 2004. Neurocognitive function and quality of life in relation to
713
hematocrit levels in chronic hemodialysis patients. J Psychosom Res 57, 5-10.
714
Leist, M., Ghezzi, P., Grasso, G., Bianchi, R., Villa, P., Fratelli, M., Savino, C., Bianchi,
715
M., Nielsen, J., Gerwien, J., Kallunki, P., Larsen, A.K., Helboe, L., Christensen, S.,
716
Pedersen, L.O., Nielsen, M., Torup, L., Sager, T., Sfacteria, A., Erbayraktar, S.,
717
Erbayraktar, Z., Gokmen, N., Yilmaz, O., Cerami-Hand, C., Xie, Q.W., Coleman, T.,
718
Cerami, A. and Brines, M. 2004. Derivatives of erythropoietin that are tissue protective
719
but not erythropoietic. Science 305, 239-242.
720
Li, J., Dong, B.R., Lin, P., Zhang, J. and Liu, G.J. 2010. Association of cognitive
721
function with serum uric acid level among Chinese nonagenarians and centenarians.
722
Exp Gerontol 45, 331-335.
723
Li, W., Maloney, R.E., Circu, M.L., Alexander, J.S. and Aw, T.Y. 2013. Acute carbonyl
724
stress induces occludin glycation and brain microvascular endothelial barrier
725
dysfunction: role for glutathione-dependent metabolism of methylglyoxal. Free Radic
Ac ce
pt
ed
M
an
us
cr
ip t
708
41 Page 41 of 60
Biol Med 54, 51-61.
727
Liu, J., Head, E., Gharib, A.M., Yuan, W., Ingersoll, R.T., Hagen, T.M., Cotman, C.W.
728
and Ames, B.N. 2002. Memory loss in old rats is associated with brain mitochondrial
729
decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or
730
R-alpha -lipoic acid. Proc Natl Acad Sci U S A 99, 2356-2361.
731
Liu, M., Liang, Y., Chigurupati, S., Lathia, J.D., Pletnikov, M., Sun, Z., Crow, M., Ross,
732
C.A., Mattson, M.P. and Rabb, H. 2008a. Acute kidney injury leads to inflammation and
733
functional changes in the brain. J Am Soc Nephrol 19, 1360-1370.
734
Liu, P., Gupta, N., Jing, Y. and Zhang, H. 2008b. Age-related changes in polyamines in
735
memory-associated brain structures in rats. Neuroscience 155, 789-796.
736
Liu, Y., Li, J., Wang, Z., Yu, Z. and Chen, G. 2013. Attenuation of Early Brain Injury
737
and Learning Deficits Following Experimental Subarachnoid Hemorrhage Secondary to
738
Cystatin C: Possible Involvement of the Autophagy Pathway. Mol Neurobiol.
739
Martins, I., Gomes, S., Costa, R.O., Otvos, L., Oliveira, C.R., Resende, R. and Pereira,
740
C.M. 2013. Leptin and ghrelin prevent hippocampal dysfunction induced by Abeta
741
oligomers. Neuroscience 241, 41-51.
742
Marzocco, S., Popolo, A., Bianco, G., Pinto, A. and Autore, G. 2010. Pro-apoptotic
743
effect of methylguanidine on hydrogen peroxide-treated rat glioma cell line. Neurochem
Ac ce
pt
ed
M
an
us
cr
ip t
726
42 Page 42 of 60
Int 57, 518-524.
745
Matafome, P., Sena, C. and Seica, R. 2013. Methylglyoxal, obesity, and diabetes.
746
Endocrine 43, 472-484.
747
McMahon, J.A., Green, T.J., Skeaff, C.M., Knight, R.G., Mann, J.I. and Williams, S.M.
748
2006. A controlled trial of homocysteine lowering and cognitive performance. N Engl J
749
Med 354, 2764-2772.
750
McQuillan, R. and Jassal, S.V. 2010. Neuropsychiatric complications of chronic kidney
751
disease. Nature reviews. Nephrology 6, 471-479.
752
Meijers, B.K., De Loor, H., Bammens, B., Verbeke, K., Vanrenterghem, Y. and
753
Evenepoel, P. 2009. p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin J
754
Am Soc Nephrol 4, 1932-1938.
755
Mink, R. and Johnston, J. 2007. The effect of infusing hypoxanthine or xanthine on
756
hypoxic-ischemic brain injury in rabbits. Brain Res 1147, 256-264.
757
Miyamoto, Y., Iwao, Y., Mera, K., Watanabe, H., Kadowaki, D., Ishima, Y., Chuang,
758
V.T., Sato, K., Otagiri, M. and Maruyama, T. 2012. A uremic toxin,
759
3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal
760
tubular cells via the generation of a radical intermediate. Biochem Pharmacol 84,
761
1207-1214.
Ac ce
pt
ed
M
an
us
cr
ip t
744
43 Page 43 of 60
Mooijaart, S.P., Sattar, N., Trompet, S., Lucke, J., Stott, D.J., Ford, I., Jukema, J.W.,
763
Westendorp, R.G. and de Craen, A.J. 2013. Circulating interleukin-6 concentration and
764
cognitive decline in old age: the PROSPER study. J Intern Med 274, 77-85.
765
More, S.S., Vartak, A.P. and Vince, R. 2013. Restoration of glyoxalase enzyme activity
766
precludes cognitive dysfunction in a mouse model of Alzheimer's disease. ACS Chem
767
Neurosci 4, 330-338.
768
Murray, A.M. 2008. Cognitive impairment in the aging dialysis and chronic kidney
769
disease populations: an occult burden. Adv Chronic Kidney Dis 15, 123-132.
770
Murray, A.M., Barzilay, J.I., Lovato, J.F., Williamson, J.D., Miller, M.E., Marcovina, S.
771
and Launer, L.J. 2011. Biomarkers of renal function and cognitive impairment in
772
patients with diabetes. Diabetes Care 34, 1827-1832.
773
Murray, A.M., Pederson, S.L., Tupper, D.E., Hochhalter, A.K., Miller, W.A., Li, Q.,
774
Zaun, D., Collins, A.J., Kane, R. and Foley, R.N. 2007. Acute variation in cognitive
775
function in hemodialysis patients: a cohort study with repeated measures. Am J Kidney
776
Dis 50, 270-278.
777
Murray, A.M., Tupper, D.E., Knopman, D.S., Gilbertson, D.T., Pederson, S.L., Li, S.,
778
Smith, G.E., Hochhalter, A.K., Collins, A.J. and Kane, R.L. 2006. Cognitive impairment
779
in hemodialysis patients is common. Neurology 67, 216-223.
Ac ce
pt
ed
M
an
us
cr
ip t
762
44 Page 44 of 60
Mutsaers, H.A., Wilmer, M.J., Reijnders, D., Jansen, J., van den Broek, P.H., Forkink,
781
M., Schepers, E., Glorieux, G., Vanholder, R., van den Heuvel, L.P., Hoenderop, J.G.
782
and Masereeuw, R. 2013. Uremic toxins inhibit renal metabolic capacity through
783
interference with glucuronidation and mitochondrial respiration. Biochim Biophys Acta
784
1832, 142-150.
785
Nakai, S., Watanabe, Y., Masakane, I., Wada, A., Shoji, T., Hasegawa, T., Nakamoto, H.,
786
Yamagata, K., Kazama, J.J., Fujii, N., Itami, N., Shinoda, T., Shigematsu, T.,
787
Marubayashi, S., Morita, O., Hashimoto, S., Suzuki, K., Kimata, N., Hanafusa, N.,
788
Wakai, K., Hamano, T., Ogata, S., Tsuchida, K., Taniguchi, M., Nishi, H., Iseki, K. and
789
Tsubakihara, Y. 2013. Overview of regular dialysis treatment in Japan (as of 31
790
December 2011). Therapeutic Apheresis and Dialysis 17, 567-611.
791
Niwa, T. 2013. Removal of protein-bound uraemic toxins by haemodialysis. Blood Purif
792
35 Suppl 2, 20-25.
793
Ohtsuki, S., Asaba, H., Takanaga, H., Deguchi, T., Hosoya, K., Otagiri, M. and Terasaki,
794
T. 2002. Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of
795
indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance
796
from the brain. J Neurochem 83, 57-66.
797
Patel, N., Dalal, P. and Panesar, M. 2008. Dialysis disequilibrium syndrome: a narrative
Ac ce
pt
ed
M
an
us
cr
ip t
780
45 Page 45 of 60
review. Semin Dial 21, 493-498.
799
Pfeffer, M.A., Burdmann, E.A., Chen, C.Y., Cooper, M.E., de Zeeuw, D., Eckardt, K.U.,
800
Feyzi, J.M., Ivanovich, P., Kewalramani, R., Levey, A.S., Lewis, E.F., McGill, J.B.,
801
McMurray, J.J., Parfrey, P., Parving, H.H., Remuzzi, G., Singh, A.K., Solomon, S.D. and
802
Toto, R. 2009. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
803
N Engl J Med 361, 2019-2032.
804
Pickett, J.L., Theberge, D.C., Brown, W.S., Schweitzer, S.U. and Nissenson, A.R. 1999.
805
Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis
806
33, 1122-1130.
807
Pikula, A., Boger, R.H., Beiser, A.S., Maas, R., DeCarli, C., Schwedhelm, E., Himali,
808
J.J., Schulze, F., Au, R., Kelly-Hayes, M., Kase, C.S., Vasan, R.S., Wolf, P.A. and
809
Seshadri, S. 2009. Association of plasma ADMA levels with MRI markers of vascular
810
brain injury: Framingham offspring study. Stroke 40, 2959-2964.
811
Post, J.B., Jegede, A.B., Morin, K., Spungen, A.M., Langhoff, E. and Sano, M. 2010.
812
Cognitive profile of chronic kidney disease and hemodialysis patients without dementia.
813
Nephron Clin Pract 116, c247-255.
814
Prohovnik, I., Post, J., Uribarri, J., Lee, H., Sandu, O. and Langhoff, E. 2007.
815
Cerebrovascular effects of hemodialysis in chronic kidney disease. J Cereb Blood Flow
Ac ce
pt
ed
M
an
us
cr
ip t
798
46 Page 46 of 60
Metab 27, 1861-1869.
817
Rabie, T. and Marti, H.H. 2008. Brain protection by erythropoietin: a manifold task.
818
Physiology 23, 263-274.
819
Rajagopalan, P., Refsum, H., Hua, X., Toga, A.W., Jack, C.R., Jr., Weiner, M.W. and
820
Thompson, P.M. 2013. Mapping creatinine- and cystatin C-related white matter brain
821
deficits in the elderly. Neurobiol Aging 34, 1221-1230.
822
Rakowski, D.A., Caillard, S., Agodoa, L.Y. and Abbott, K.C. 2006. Dementia as a
823
predictor of mortality in dialysis patients. Clin J Am Soc Nephrol 1, 1000-1005.
824
Roman, S.A., Sosa, J.A., Pietrzak, R.H., Snyder, P.J., Thomas, D.C., Udelsman, R. and
825
Mayes, L. 2011. The effects of serum calcium and parathyroid hormone changes on
826
psychological and cognitive function in patients undergoing parathyroidectomy for
827
primary hyperparathyroidism. Ann Surg 253, 131-137.
828
Schroeder, J.C., Dinatale, B.C., Murray, I.A., Flaveny, C.A., Liu, Q., Laurenzana, E.M.,
829
Lin, J.M., Strom, S.C., Omiecinski, C.J., Amin, S. and Perdew, G.H. 2010. The uremic
830
toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon
831
receptor. Biochemistry 49, 393-400.
832
Seliger, S.L., Longstreth, W.T., Jr., Katz, R., Manolio, T., Fried, L.F., Shlipak, M.,
833
Stehman-Breen, C.O., Newman, A., Sarnak, M., Gillen, D.L., Bleyer, A. and Siscovick,
Ac ce
pt
ed
M
an
us
cr
ip t
816
47 Page 47 of 60
D.S. 2005. Cystatin C and subclinical brain infarction. J Am Soc Nephrol 16,
835
3721-3727.
836
Seliger, S.L., Siscovick, D.S., Stehman-Breen, C.O., Gillen, D.L., Fitzpatrick, A., Bleyer,
837
A. and Kuller, L.H. 2004. Moderate renal impairment and risk of dementia among older
838
adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 15, 1904-1911.
839
Sena, C.M., Matafome, P., Crisostomo, J., Rodrigues, L., Fernandes, R., Pereira, P. and
840
Seica, R.M. 2012. Methylglyoxal promotes oxidative stress and endothelial dysfunction.
841
Pharmacol Res 65, 497-506.
842
Shah, R.C., Wilson, R.S., Bienias, J.L., Arvanitakis, Z., Evans, D.A. and Bennett, D.A.
843
2006. Relation of blood pressure to risk of incident Alzheimer's disease and change in
844
global cognitive function in older persons. Neuroepidemiology 26, 30-36.
845
Shamoto-Nagai, M., Maruyama, W., Kato, Y., Isobe, K., Tanaka, M., Naoi, M. and
846
Osawa, T. 2003. An inhibitor of mitochondrial complex I, rotenone, inactivates
847
proteasome by oxidative modification and induces aggregation of oxidized proteins in
848
SH-SY5Y cells. J Neurosci Res 74, 589-597.
849
Sigrist, S.J., Carmona-Gutierrez, D., Gupta, V.K., Bhukel, A., Mertel, S., Eisenberg, T.
850
and Madeo, F. 2013. Spermidine-triggered autophagy ameliorates memory during aging.
851
Autophagy 10.
Ac ce
pt
ed
M
an
us
cr
ip t
834
48 Page 48 of 60
Singh, A.K., Szczech, L., Tang, K.L., Barnhart, H., Sapp, S., Wolfson, M. and Reddan,
853
D. 2006. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J
854
Med 355, 2085-2098.
855
Sirich, T.L., Funk, B.A., Plummer, N.S., Hostetter, T.H. and Meyer, T.W. 2013.
856
Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular
857
secretion. J Am Soc Nephrol 25(3), 615-622.
858
Smogorzewski, M.J. 2001. Central nervous dysfunction in uremia. Am J Kidney Dis 38,
859
S122-128.
860
Srikanth, V., Westcott, B., Forbes, J., Phan, T.G., Beare, R., Venn, A., Pearson, S.,
861
Greenaway, T., Parameswaran, V. and Munch, G. 2013. Methylglyoxal, cognitive
862
function and cerebral atrophy in older people. J Gerontol A Biol Sci Med Sci 68, 68-73.
863
Sun, C.Y., Hsu, H.H. and Wu, M.S. 2013. p-Cresol sulfate and indoxyl sulfate induce
864
similar cellular inflammatory gene expressions in cultured proximal renal tubular cells.
865
Nephrol Dial Transplant 28, 70-78.
866
Sundelof, J., Arnlov, J., Ingelsson, E., Sundstrom, J., Basu, S., Zethelius, B., Larsson, A.,
867
Irizarry, M.C., Giedraitis, V., Ronnemaa, E., Degerman-Gunnarsson, M., Hyman, B.T.,
868
Basun, H., Kilander, L. and Lannfelt, L. 2008. Serum cystatin C and the risk of
869
Alzheimer disease in elderly men. Neurology 71, 1072-1079.
Ac ce
pt
ed
M
an
us
cr
ip t
852
49 Page 49 of 60
Suri, R.S., Garg, A.X., Chertow, G.M., Levin, N.W., Rocco, M.V., Greene, T., Beck, G.J.,
871
Gassman, J.J., Eggers, P.W., Star, R.A., Ornt, D.B. and Kliger, A.S. 2007. Frequent
872
Hemodialysis Network (FHN) randomized trials: study design. Kidney Int 71, 349-359.
873
Tachikawa, M. and Hosoya, K. 2011. Transport characteristics of guanidino compounds
874
at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural
875
disorders. Fluids Barriers CNS 8, 13.
876
Temple, R.M., Langan, S.J., Deary, I.J. and Winney, R.J. 1992. Recombinant
877
erythropoietin improves cognitive function in chronic haemodialysis patients. Nephrol
878
Dial Transplant 7, 240-245.
879
Tiboldi, A., Lentini, A., Provenzano, B., Tabolacci, C., Hoger, H., Beninati, S. and
880
Lubec, G. 2012. Hippocampal polyamine levels and transglutaminase activity are
881
paralleling spatial memory retrieval in the C57BL/6J mouse. Hippocampus 22,
882
1068-1074.
883
Torremans, A., Marescau, B., Van Dam, D., Van Ginneken, C., Van Meir, F., Van
884
Bogaert, P.P., D'Hooge, R., de Vente, J. and De Deyn, P.P. 2005. GSA: behavioral,
885
histological, electrophysiological and neurochemical effects. Physiol Behav 84,
886
251-264.
887
Toyoda, K., Fujii, K., Fujimi, S., Kumai, Y., Tsuchimochi, H., Ibayashi, S. and Iida, M.
Ac ce
pt
ed
M
an
us
cr
ip t
870
50 Page 50 of 60
2005. Stroke in patients on maintenance hemodialysis: a 22-year single-center study.
889
Am J Kidney Dis 45, 1058-1066.
890
van den Kommer, T.N., Dik, M.G., Comijs, H.C., Jonker, C. and Deeg, D.J. 2010.
891
Homocysteine and inflammation: predictors of cognitive decline in older persons?
892
Neurobiol Aging 31, 1700-1709.
893
Vanholder, R. and De Smet, R. 1999. Pathophysiologic effects of uremic retention
894
solutes. J Am Soc Nephrol 10, 1815-1823.
895
Vanholder, R., De Smet, R., Glorieux, G., Argiles, A., Baurmeister, U., Brunet, P., Clark,
896
W., Cohen, G., De Deyn, P.P., Deppisch, R., Descamps-Latscha, B., Henle, T., Jorres, A.,
897
Lemke, H.D., Massy, Z.A., Passlick-Deetjen, J., Rodriguez, M., Stegmayr, B.,
898
Stenvinkel, P., Tetta, C., Wanner, C. and Zidek, W. 2003a. Review on uremic toxins:
899
classification, concentration, and interindividual variability. Kidney Int 63, 1934-1943.
900
Vanholder, R., Glorieux, G., De Smet, R. and Lameire, N. 2003. New insights in uremic
901
toxins. Kidney Int Suppl, S6-10.
902
Vanholder, R., Van Laecke, S. and Glorieux, G. 2008. What is new in uremic toxicity?
903
Pediatr Nephrol 23, 1211-1221.
904
Vannorsdall, T.D., Jinnah, H.A., Gordon, B., Kraut, M. and Schretlen, D.J. 2008.
905
Cerebral ischemia mediates the effect of serum uric acid on cognitive function. Stroke
Ac ce
pt
ed
M
an
us
cr
ip t
888
51 Page 51 of 60
39, 3418-3420.
907
Vida, C., Corpas, I., De la Fuente, M. and Gonzalez, E.M. 2011. Age-related changes in
908
xanthine oxidase activity and lipid peroxidation, as well as in the correlation between
909
both parameters, in plasma and several organs from female mice. Journal of Physiology
910
and Biochemistry 67, 551-558.
911
Vos, P.F., Zilch, O., Jennekens-Schinkel, A., Salden, M., Nuyen, J., Kooistra, M.M., van
912
Huffelen, A.C. and Sitskoorn, M.M. 2006. Effect of short daily home haemodialysis on
913
quality of life, cognitive functioning and the electroencephalogram. Nephrol Dial
914
Transplant 21, 2529-2535.
915
Wada, M., Nagasawa, H., Kawanami, T., Kurita, K., Daimon, M., Kubota, I., Kayama, T.
916
and Kato, T. 2010. Cystatin C as an index of cerebral small vessel disease: results of a
917
cross-sectional study in community-based Japanese elderly. Eur J Neurol 17, 383-390.
918
Wamser, M.N., Leite, E.F., Ferreira, V.V., Delwing-de Lima, D., da Cruz, J.G., Wyse,
919
A.T. and Delwing-Dal Magro, D. 2013. Effect of hypoxanthine, antioxidants and
920
allopurinol on cholinesterase activities in rats. J Neural Transm 120, 1359-1367.
921
Wang, W., Li, S., Dong, H.P., Lv, S. and Tang, Y.Y. 2009. Differential impairment of
922
spatial and nonspatial cognition in a mouse model of brain aging. Life Sci 85, 127-135.
923
Watanabe, H., Miyamoto, Y., Honda, D., Tanaka, H., Wu, Q., Endo, M., Noguchi, T.,
Ac ce
pt
ed
M
an
us
cr
ip t
906
52 Page 52 of 60
Kadowaki, D., Ishima, Y., Kotani, S., Nakajima, M., Kataoka, K., Kim-Mitsuyama, S.,
925
Tanaka, M., Fukagawa, M., Otagiri, M. and Maruyama, T. 2013. p-Cresyl sulfate causes
926
renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase.
927
Kidney Int 83, 582-592.
928
Watanabe, I., Tatebe, J., Namba, S., Koizumi, M., Yamazaki, J. and Morita, T. 2013b.
929
Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte
930
chemoattractant protein-1 expression in human umbilical vein endothelial cells.
931
Circulation Journal: Official Journal of the Japanese Circulation Society 77, 224-230.
932
Watanabe, K., Okada, K., Fukabori, R., Hayashi, Y., Asahi, K., Terawaki, H., Kobayashi,
933
K., Watanabe, T. and Nakayama, M. 2014. Methylglyoxal (MG) and Cerebro-Renal
934
Interaction: Does Long-Term Orally Administered MG Cause Cognitive Impairment in
935
Normal Sprague-Dawley Rats? Toxins 6, 254-269.
936
Weiner, D.E., Bartolomei, K., Scott, T., Price, L.L., Griffith, J.L., Rosenberg, I., Levey,
937
A.S., Folstein, M.F. and Sarnak, M.J. 2009. Albuminuria, cognitive functioning, and
938
white matter hyperintensities in homebound elders. Am J Kidney Dis 53, 438-447.
939
Wu, I.W., Hsu, K.H., Lee, C.C., Sun, C.Y., Hsu, H.J., Tsai, C.J., Tzen, C.Y., Wang, Y.C.,
940
Lin, C.Y. and Wu, M.S. 2011. p-Cresyl sulphate and indoxyl sulphate predict
941
progression of chronic kidney disease. Nephrol Dial Transplant 26, 938-947.
Ac ce
pt
ed
M
an
us
cr
ip t
924
53 Page 53 of 60
Yaffe, K., Lindquist, K., Shlipak, M.G., Simonsick, E., Fried, L., Rosano, C., Satterfield,
943
S., Atkinson, H., Windham, B.G. and Kurella-Tamura, M. 2008. Cystatin C as a marker
944
of cognitive function in elders: findings from the health ABC study. Ann Neurol 63,
945
798-802.
946
Yamamoto, S., Kazama, J.J., Narita, I., Naiki, H. and Gejyo, F. 2009. Recent progress in
947
understanding dialysis-related amyloidosis. Bone 45 Suppl 1, S39-42.
948
Ye, L., Huang, Y., Zhao, L., Li, Y., Sun, L., Zhou, Y., Qian, G. and Zheng, J.C. 2013.
949
IL-1beta and TNF-alpha induce neurotoxicity through glutamate production: a potential
950
role for neuronal glutaminase. J Neurochem 125, 897-908.
951
Zeki Al Hazzouri, A., Stone, K.L., Haan, M.N. and Yaffe, K. 2013. Leptin, mild
952
cognitive impairment, and dementia among elderly women. J Gerontol A Biol Sci Med
953
Sci 68, 175-180.
954
Zhang, Y., Xiong, Y., Mahmood, A., Meng, Y., Qu, C., Schallert, T. and Chopp, M. 2009.
955
Therapeutic effects of erythropoietin on histological and functional outcomes following
956
traumatic brain injury in rats are independent of hematocrit. Brain Res 1294, 153-164.
957
Zheng, P., Chen, J.J., Huang, T., Wang, M.J., Wang, Y., Dong, M.X., Huang, Y.J., Zhou,
958
L.K. and Xie, P. 2013. A novel urinary metabolite signature for diagnosing major
959
depressive disorder. J Proteome Res 12(12), 5904-5911.
Ac ce
pt
ed
M
an
us
cr
ip t
942
54 Page 54 of 60
Zheng, S., Yu, M., Lu, X., Huo, T., Ge, L., Yang, J., Wu, C. and Li, F. 2010. Urinary
961
metabonomic study on biochemical changes in chronic unpredictable mild stress model
962
of depression. Clin Chim Acta 411, 204-209.
ip t
960
Ac ce
pt
ed
M
an
us
cr
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55 Page 55 of 60
973 974 975 976 977 978
cerebro-renal interaction unknown. Grade C: UT that has both positive and negative data (and so is still controversial). Grade D: UT that that lacks sufficient data regarding effects on neural system. Abbreviations: NO, nitric oxide; CI, cognitive impairment; CNS, central nervous system; NMDA, N-methyl-D-aspartate; GABA, gamma-aminobutyric acid; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; BBB, blood-brain barrier; UT, uremic toxin; ROS, reactive oxygen species; AD, Alzheimer’s disease.
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ip t
Tables
Uremic toxin
Group
MW
Normal
(dalton)
Concentration
Concentration
(SD)
(SD or Range)
202
