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Chronic kidney disease (CKD) leads to Astrocytosis in mice brain. Representative photographs of Glial fibrillary acidic protein (GFAP)-immunohistochemistry in the brain of control (A,C,E,G) and CKD (B,D,F,H) mice. Note the increased GFAP-reactivity in the cortex (B-i,ii), striatum (D-i,ii), hippocampal CA1 (F-ii) hippocampal CA3 (F-iii), hippocampal DG (F-iv) and substantia nigra (H-i,ii) regions in CKD mice, compared to the corresponding regions of control mice. The photographs A-i, B-i, C-i, D-i, E-i, F-i, G-i, and H-i were taken at 4× magnification, while the remaining photographs A-ii, B-ii, C-ii, D-ii, E-ii-iv, F-ii-iv, G-ii, and H-ii were taken at 20× magnification under bright field illumination. CA = Cornus ammonis; DG = Dentate Gyrus.
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With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cogniti...
Citations
... Depletion in the activity of AChE is one of the early and consistent findings in Alzheimer's disease (AD) patients with dementia and cognitive impairment [10,25]. In agreement with the previous reports, the results of our study indicated a decrease in the activity of AChE in CKD patients [26,27]. The mechanism underlying the cognitive loss in CKD may thus be explained by the fact that dementia and cognitive impairment in AD patients have been linked to decreased AChE activity in the brain's cortex and hippocampus. ...
... The mechanism underlying the cognitive loss in CKD may thus be explained by the fact that dementia and cognitive impairment in AD patients have been linked to decreased AChE activity in the brain's cortex and hippocampus. In vitro study by Prall et al. further showed increased AChE activity in red blood cells (RBCs) of patients with CRF, however, the results were insignificantly different in the various density-based age subfractions of RBCs in both CRF patients and controls [27]. However, although treatment of AD has been dominated by the use of AChE inhibitors, research shows that AChE itself has been implicated in the pathogenesis of AD, so it appears that AChE may directly interact with Aβ in a manner that increases the deposition of this peptide into insoluble plaques [28]. ...
Introduction: Chronic kidney disease (CKD) patients suffer from several neurological complications due to the retention of uremic toxins, electrolytes, and water and the resultant metabolic disturbances. Therefore, the aim of this research is to assess neuropeptide Y (NPY), amyloid beta (Aβ), P-Tau-181, acetylcholinesterase (AChE) and peptidyl-prolyl cis-trans isomerase1 (Pin1) that play important role in neural dysfunction. Methods: This study was performed on 20 CKD patients and 20 healthy controls who were referred to the hospital. The circular levels of NPY, Aβ, and P-Tau-181 were determined by specific ELISA kits. While, the levels of Pin1 and AChE were determined by western blot analysis in blood samples. Results and discussion: The obtained results show that NPY was significantly lower (P<0.001) and p-tau-181 and Aβ-40 were significantly higher in CKD patients than control subjects (P<0.001). CKD patients showed no significant changes in circular AChE content while activity of this enzyme increased remarkably that confirmed cholinergin abnormalities in hyperuricemia condition. Also, based on western blot analysis, the Pin-1 level is significantly lower in CKD patients (P<0.05). Conclusion: In this research, elevated p-tau181, AChE, and Aβ-40 and reduced Pin1 and NPY were associated with renal impairment. Although increased in the activity of AChE is associated with dementia and cognitive impairment, AChE may directly interact with Aβ and cause its deposition. Accordingly, kidney dysfunction could be considered an effective risk factor for dementia development.
... Nella CKD tuttavia, oltre all'età, altri fattori influenzano la memoria. Evidenze sperimentali suggeriscono come modifiche delle sinapsi colinergiche neuronali siano implicate nei deficit della memoria che si osservano in corso di CKD (24). Per le funzioni esecutive invece la patologia cerebrovascolare sembra essere quella più strettamente connessa con il deficit nelle funzioni esecutive. ...
Chronic kidney disease (CKD or CKD [Chronic Kidney Disease]) is present in approximately 7% of the world population: several studies have highlighted socio-cultural discrimination, to the detriment of women, in referral to specialist nephrological care and access to dialysis and transplantation. Globally, gender discrimination limits the possibility of access to education, medical care and involvement in clinical trials. Women on dialysis have different comorbidities than men; the choice to follow a predialysis process and the subsequent orientation towards dialysis treatment are certainly influenced by gender as is the choice of dialysis access. As regards kidney transplantation, women are more likely to offer themselves as donors rather than to be beneficiaries. Conventional knowledge supports the belief that there are gender differences in the acquisition, preparation and consumption of food, for this reason it is essential to consider the variables that come into play when defining and agreeing treatment paths, in particular in taking care of people with chronic diseases such as CKD
... Our results are in accordance with Berini et al., 2015 [57] they reported the effect of calcium oxalate on brain structure and function discussing the mechanisms causing nerve injury in hyperoxaluria. Many researches focused on the brain status during the existence of acute kidney disease in the long run [58,59] and the effect of the accumulated blood wastes on the brain due to kidney malfunction. But in the present study the blood wastes were not yet increased significantly So we can attribute these accelerated distortions in the brain tissue in our study to performing the experiment on male aged rats as the brain of aged males may be more susceptible to oxalate effect than young ones. ...
HYPEROXALURIA is considered the real cause of the kidney oxalate stones. The present work is considered as an exploratory study which is continued with an original research work to evaluate the efficacy of the aqueous extract of Rosmarinus officinalis Linn on oxalate fragmentation in rat tissues. This work was divided into two different studies an in vivo and an in vitro one. Rats in the in vivo study were divided into two groups: Group (1) represented the control group while in group (2) rats were injected with sodium oxalate to trace the oxalate impact and oxalate stones formation in rat tissues. The in vitro study was performed by adding sodium oxalate in human urine with or without the addition of different concentrations of the grinded leaves of Rosmarinus officinalis Linn. Results showed mild significant changes in some of the serum biochemical parameters in the oxalate treated group. On the other hand, the histopathological examinations showed that hyperoxaluria exhibited many tissue distortions in the kidneys, the bone marrow and the brain more than those found in the liver and the spleen compared to the control group. Oxalate crystals were noticed in rats' urine in the oxalate injected group and no stones were observed in kidneys or in other tested tissue. The in vitro study results showed that the plant leaves displayed highly fragmentation impact on oxalate crystals in human urine at a certain dose range concentration which when increased showed no effect on oxalate crystals fragmentation. It was concluded that Rosmarinus officinalis Linn had a great influence on oxalate fragmentation at a certain dose range.
... Our results are in accordance with Berini et al., 2015 [57] they reported the effect of calcium oxalate on brain structure and function discussing the mechanisms causing nerve injury in hyperoxaluria. Many researches focused on the brain status during the existence of acute kidney disease in the long run [58,59] and the effect of the accumulated blood wastes on the brain due to kidney malfunction. But in the present study the blood wastes were not yet increased significantly So we can attribute these accelerated distortions in the brain tissue in our study to performing the experiment on male aged rats as the brain of aged males may be more susceptible to oxalate effect than young ones. ...
HYPEROXALURIA is considered the real cause of the kidney oxalate stones. The present work is considered as an exploratory study which is continued with an original research work to evaluate the efficacy of the aqueous extract of Rosmarinus officinalis Linn on oxalate fragmentation in rat tissues. This work was divided into two different studies an in vivo study and an in vitro one. Rats in the in vivo study were divided into two groups: Group (1) represented the control group while in group (2) rats were injected with sodium oxalate to trace the oxalate impact and oxalate stones formation in rat tissues. The in vitro study was performed by adding sodium oxalate in human urine with or without the addition of different concentrations of the grinded leaves of Rosmarinus officinalis Linn.
Results showed mild significant changes in some of the serum biochemical parameters in the oxalate treated group. On the other hand, the histopathological examinations showed that hyperoxaluria exhibited many tissue distortions in the kidneys, the bone marrow and the brain more than those found in the liver and the spleen compared to the control group. Oxalate crystals were noticed in rats’ urine in the oxalate injected group and no stones were observed in kidneys or in other tested tissue. The in vitro study results showed that the plant leaves displayed highly fragmentation impact on oxalate crystals in human urine at a certain dose range concentration which when increased showed no effect on oxalate crystals fragmentation.
It was concluded that Rosmarinus officinalis Linn had a great influence on oxalate fragmentation at a certain dose range.
... Les travaux de Mazumder et al. ont mis en évidence plusieurs atteintes neurocomportementales et thymiques au cours d'un modèle de MRC par régime enrichi en adénine à 0,3 % chez la souris : les auteurs ont décrit une atteinte de la mémoire de travail, de la mémoire spatiale, un phénotype de type dépressif, ainsi qu'un phénotype anxieux chez les animaux MRC, en lien avec une inflammation cérébrale, une augmentation du stress oxydatif, et une dysfonction mitochondriale cérébrale, ainsi qu'une diminution de l'activité d'acétylcholinestérase neuronale [26,29]. Des atteintes de la mémoire spatiale, de la mémoire de travail et de la coordination motrice, ainsi que des phénotypes anxieux et dépressifs ont également été retrouvés dans les travaux de Fujisaki et al. [25,27,30], notamment en lien avec une augmentation du stress oxydatif. ...
... Les travaux d'Adesso et al. ont rapporté un lien entre IS et neuro-inflammation chez la souris, potentiellement réversible sous AST-120 [40,42]. Des phénomènes d'astrocytose ont été mis en évidence dans des modèles de MRC par Mazumder et al. chez la souris après un régime enrichi en adénine [29]. ...
Patients with chronic kidney disease (CKD) have an increased risk of cognitive disorders, presenting as vascular dementia, compared with the general population. These cognitive disorders occur early during the course of the kidney disease and evolve in parallel with the decline in glomerular filtration rate. They affect 30 to 80 % of patients with stage 5 CKD. Kidney transplantation only partially improves cognitive impairment. In this narrative review, we summarize the epidemiology and recent clinical and experimental data on cognitive impairment in CKD and discuss the potential specific mechanisms. Among the factors associated with cognitive impairment, the accumulation of uremic toxins such as indoxyl sulfate appears to be a specific risk factor for cognitive decline. These toxins have an endothelial toxicity that can disrupt the cerebral endothelium. The rupture of the blood-brain barrier (BBB) is a mechanism implicated in several neurodegenerative pathologies and systemic diseases with cerebral tropism. Recent experimental findings in CKD indicate that disruption of the BBB appears to be an important mechanism behind cognitive impairment in CKD. In murine models of CKD, increased BBB permeability is linked to memory impairment and aryl hydrocarbon receptor activation following accumulation of circulating indoxyl sulfate. This disruption of the BBB could also have harmful consequences for stroke susceptibility and drug neurotoxicity in CKD patients.
... The lack of a predictable association between AVF-induced hemodynamic perturbations and ARHD further contributes to the inability to accurately identify high-risk patients which has a significant negative impact on quality of life. A defining metabolic feature of ESKD is presence of a toxic systemic milieu driven by uremic metabolite accumulation, metabolic acidosis, and inflammation [5][6][7][8][9][10][11][12] . However, whether these factors contribute to the development of ARHD is unknown. ...
For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and 6-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry (P < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation.
... CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. Further, peripheral nervous system, have been suggested to impair neurotransmission, and thereby contribute to the neurological complications in CKD that are warranted for investigating the role of individual uremic toxins in causing the neurological complications [14]. In addition, elemental toxic zinc status in CKD development is under without Zn deficiency and Zn excess that plasma zinc levels and serum zinc levels are 0.82 ±0.04μg/mL, 43.4 mg/dL (lower serum zinc levels), respectively, in which low plasma zinc levels in CKD patients and abnormal blood-zinc level are the result of anemia [15]. ...
Zinc(Ⅱ) supplementation with 30 mg/day should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications. Zinc induced neuroimmunological suppressive CKD progression with Stage 2 ～ 3A, 3B, zinc supplementation (30 mg/day) may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4-5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction. Thus, zinc intake of 30 mg/day and serum zinc level of 60～76 μg/dL could slow down CKD Stage 4 progression. Zinc induced CKD Stage 5 (eGFR < 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is partly caused by renal losses of zinc, becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Serum zinc and serum albumin levels are 37.4 ± 5.4 and 2.6 ± 0.6 µg/dL, respectively, for as eGFR 6.6 (5.2–8.3). Zn intake of 45-75 mg/day and serum zinc level of ≤78.3 µg/dL are beneficial for HD and maintenance hemodialysis (MHD) patients, in which Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD(P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•), and in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions-several protein complexes coordinated binding model of ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.
... A de ning metabolic feature of ESKD is presence of a toxic systemic milieu driven by uremic metabolite accumulation, metabolic acidosis, and in ammation [5][6][7][8][9][10][11][12] . However, whether these factors contribute to the development of ARHD is unknown. ...
For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and six-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry ( P < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation.
... Calcification in vasculature is widely categorised into two types-intimal and medial calcification depending on the location of mineral deposits in the blood vessels (Valdivielso et al. 2012). Generally, the intimal calcification is associated with the development of atherosclerotic plaques on the vascular intimal layer caused due to obesity and high-fat diet consumption (Nakagami et al. 2011), whereas medial calcification is found to be prevalent in medical conditions such as Chronic kidney disease (Mazumder et al. 2019), diabetes (Jeffcoate et al. 2009) and aging (Rocha-Singh et al. 2014). Previous studies have shown that both intimal and medial calcification has adverse impact on cerebral health (Mazumder et al. 2019;Bos et al. 2012) but how this can affect the outcome of IR injury in brain tissues and its management remains unclear. ...
... Generally, the intimal calcification is associated with the development of atherosclerotic plaques on the vascular intimal layer caused due to obesity and high-fat diet consumption (Nakagami et al. 2011), whereas medial calcification is found to be prevalent in medical conditions such as Chronic kidney disease (Mazumder et al. 2019), diabetes (Jeffcoate et al. 2009) and aging (Rocha-Singh et al. 2014). Previous studies have shown that both intimal and medial calcification has adverse impact on cerebral health (Mazumder et al. 2019;Bos et al. 2012) but how this can affect the outcome of IR injury in brain tissues and its management remains unclear. ...
Cerebral ischemia reperfusion injury (CIR) is one of the clinical manifestations encountered during the management of stroke. High prevalence of intracranial arterial calcification is reported in stroke patients. However, the impact of vascular calcification (VC) in the outcome of CIR and the efficacy of mechanical preconditioning (IPC) and pharmacological conditioning with sodium thiosulphate (STS) in ameliorating IR remains unclear. Two experimental models namely carotid artery occlusion (n = 36) and brain slice models (n = 18) were used to evaluate the efficacy of STS in male Wistar rats. IR was inflicted in rat by occluding carotid artery for 30 min followed by 24-h reperfusion after STS (100 mg/kg) administration. Brain slice model was used to reconfirm the results to account blood brain barrier permeability. Further, brain slice tissue was utilised to evaluate the efficacy of STS in VC rat brain by measuring the histological alterations and biochemical parameters. Pre-treatment of STS prior to CIR in intact animal significantly reduced the IR-associated histopathological alterations in brain, declined oxidative stress and improved the mitochondrial function found to be similar to IPC. Brain slice model data also confirmed the neuroprotective effect of STS similar to IPC in IR challenged tissue slice. Higher tissue injury was noted in VC brain IR tissue than normal IR tissue. Therapeutic efficacy of STS was evident in VC rat brain tissues and normal tissues subjected to IR. On the other hand, IPC-mediated protection was noted only in IR normal and adenine-induced VC brain tissues not in high-fat diet (HFD) induced VC brain tissues. Based on the results, we concluded that similar to IPC, STS was effective in attenuating IR injury in CIR rat brain. Vascular calcification adversely affected the recovery protocol of brain tissues from ischemic insult. STS was found to be an effective agent in ameliorating the IR injury in both adenine and HFD induced vascular calcified rat brain, but IPC-mediated neuroprotection was absent in HFD-induced VC brain tissues.
... 57 Certain protein-bound toxins and large middle compounds that are poorly removed during dialysis cause neurotoxicity through vascular effects. 58 Studies in murine CKD models have reported blood-brain-barrier disruption, oxidative stress, inflammation, and mitochondrial dysfunction in the mouse brain, which are fundamental causes of neurochemical and histological abnormalities. 59 The uremic milieu compromises the blood-brain-barrier, as demonstrated by changes in the levels of brain-specific proteins neuron-specific enolase and brain-derived neurotrophic factor in the peripheral circulation. ...
The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population.
