Applying Proteomics and Integrative “Omics” Strategies to Decipher the Chronic Kidney Disease-Related Atherosclerosis

Patients with chronic kidney disease (CKD) are at increased risk of atherosclerosis and premature mortality, mainly due to cardiovascular events. However, well-known risk factors, which promote “classical” atherosclerosis are alone insufficient to explain the high prevalence of atherosclerosis-related to CKD (CKD-A). The complexity of the molecular mechanisms underlying the acceleration of CKD-A is still to be defied. To obtain a holistic picture of these changes, comprehensive proteomic approaches have been developed including global protein profiling followed by functional bioinformatics analyses of dysregulated pathways. Furthermore, proteomics surveys in combination with other “omics” techniques, i.e., transcriptomics and metabolomics as well as physiological assays provide a solid ground for interpretation of observed phenomena in the context of disease pathology. This review discusses the comprehensive application of various “omics” approaches, with emphasis on proteomics, to tackle the molecular mechanisms underlying CKD-A progression. We summarize here the recent findings derived from global proteomic approaches and underline the potential of utilizing integrative systems biology, to gain a deeper insight into the pathogenesis of CKD-A and other disorders.

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FO064INTEGRATIVE BIOINFORMATICS ANALYSIS PROVIDES INSIGHT INTO THE MOLECULAR MECHANISMS OF CHRONIC KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy104.fo064 ◽

2018 ◽

Vol 33 (suppl_1) ◽

pp. i45-i46

Author(s):

Le-Ting Zhou ◽

Lin-Li Lv ◽

Shen Qiu ◽

Hong Liu ◽

Ri-Ning Tang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Insight Into

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Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms23010531 ◽

2022 ◽

Vol 23 (1) ◽

pp. 531

Author(s):

Eva Harlacher ◽

Julia Wollenhaupt ◽

Constance C. F. M. J. Baaten ◽

Heidi Noels

Keyword(s):

Systematic Review ◽

Chronic Kidney Disease ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Molecular Mechanisms ◽

Uremic Toxins ◽

Uremic Toxin ◽

Thrombotic Risk ◽

Increased Risk ◽

Uremic Serum

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

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Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease

Kidney & Blood Pressure Research ◽

10.1159/000488830 ◽

2018 ◽

Vol 43 (2) ◽

pp. 568-581 ◽

Cited By ~ 9

Author(s):

Le-Ting Zhou ◽

Shen Qiu ◽

Lin-Li Lv ◽

Zuo-Lin Li ◽

Hong Liu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Insight Into

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Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Toxins ◽

10.3390/toxins10070300 ◽

2018 ◽

Vol 10 (7) ◽

pp. 300 ◽

Cited By ~ 33

Author(s):

Esmeralda Castillo-Rodriguez ◽

Raul Fernandez-Prado ◽

Raquel Esteras ◽

Maria Perez-Gomez ◽

Carolina Gracia-Iguacel ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Molecular Mechanisms ◽

Kidney Diseases ◽

Toxin Production ◽

Uremic Toxins ◽

Uremic Toxin ◽

Ckd Progression ◽

Increased Risk

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

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Chronic kidney disease: the most prevalent risk factor and the risk factor that increases most the risk for lethal COVID-19

ANALES RANM ◽

10.32440/ar.2020.137.03.rev02 ◽

2020 ◽

Vol 137 (137(03)) ◽

pp. 270-275

Author(s):

Alberto Ortiz ◽

Maria Dolores Sanchez-Niño

Keyword(s):

Chronic Kidney Disease ◽

Risk Factor ◽

Kidney Disease ◽

Premature Death ◽

Chronic Heart Disease ◽

Risk Of Mortality ◽

Increased Risk ◽

High Prevalence ◽

Risk Of Progression ◽

Kidney Replacement Therapy

Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 or evidence of kidney damage, such as albuminuria greater than 30 mg/g creatinuria, which persists more than 3 months. These cut-off points mark an increased risk of progression to the need for kidney replacement therapy and of the risk of premature death. Coronavirus disease-2019 (COVID-19) is no exception. The Global Burden of Disease collaboration identified CKD as the global most prevalent risk factor for severe COVID-19. The OpenSAFELY project analyzed the factors associated with death from COVID-19 in 17 million persons. Dialysis (adjusted hazard ratio [aHR] 3.69), organ transplantation (aHR 3.53) and CKD not on dialysis (aHR 2.52 for patients with eGFR <30 ml/min/1.73 m2) represent three of the four comorbidities associated with the highest risk of mortality from COVID-19. The risk associated with CKD is greater than the risk associated with diabetes mellitus (range aHR 1.31-1.95, depending on glycemic control) or chronic heart disease (aHR 1.17), whereas hypertension is not an independent risk factor for death from COVID-19 (aHR 0.89). The high prevalence of CKD, combined with the high risk of mortality from COVID-19 in CKD, requires urgent action to protect CKD patients from COVID-19 by offering the opportunity to participate in clinical trials of vaccines and treatments for COVID-19.

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Atherosclerosis in Chronic Kidney Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.312705 ◽

2019 ◽

Vol 39 (10) ◽

pp. 1938-1966 ◽

Cited By ~ 19

Author(s):

José M. Valdivielso ◽

Diego Rodríguez-Puyol ◽

Julio Pascual ◽

Clara Barrios ◽

Marcelino Bermúdez-López ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

General Population ◽

Subclinical Atherosclerosis ◽

Premature Mortality ◽

Atherosclerosis Progression ◽

Relative Contribution ◽

Increased Risk ◽

Vitamin D Levels ◽

Ckd Stage

Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study (Observatorio Nacional de Atherosclerosis en NEFrologia) prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.

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Hyperprolactinemia in patients with chronic kidney disease

Ukrainian Journal of Nephrology and Dialysis ◽

10.31450/ukrjnd.1(69).2021.09 ◽

2021 ◽

pp. 61-66

Author(s):

І.О. Dudar ◽

V.M. Savchuk ◽

О.М. Loboda ◽

E.K. Krasiuk

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Outcomes ◽

Cardiovascular Events ◽

Therapeutic Interventions ◽

Urgent Problem ◽

Rapid Progress ◽

Clinical Events ◽

Increased Risk ◽

High Prevalence

Despite rapid progress in improving dialysis technology in recent years, mortality in hemodialysis (HD) patients remains quite high. The main reasons are cardiovascular disease. The search of factors that are associated with an increased risk of adverse clinical events in patients with chronic kidney disease (CKD) is an urgent problem of modern nephrology. Prolactin (PL) is a unique hormone that can perform the functions of both a hormone and a neuropeptide. Among patients with CKD, the frequency of hyperprolactinemia (HPL) increases with decreasing glomerular filtration rate (GFR). There is a moderate HPL due to impaired degradation of PL in the kidneys. Hemodialysis does not affect the level of PL. A negative correlation between the levels of PL and GFR, PL and albumin levels and PL and Hb levels are shown in the studies. Serum PL is positively correlated with blood pressure and the risk of cardiovascular events. Despite the relatively high prevalence of HPL in patients with CKD, particularly in the dialysis population, there is uncertainty about the consequences of this condition for this cohort of patients. Further studies are needed to study the effects of HPL on clinical outcomes in patients with CKD. If a causal relationship between HPL and clinical outcomes, in particular cardiovascular events, is shown, HPL may be a potential target for therapeutic interventions.

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Stroke in chronic renal failure

Orvosi Hetilap ◽

10.1556/oh.2008.28292 ◽

2008 ◽

Vol 149 (15) ◽

pp. 691-696

Author(s):

Dániel Bereczki

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Disease ◽

Chronic Renal Disease ◽

Kidney Diseases ◽

Cerebrovascular Diseases ◽

Lipid Lowering ◽

Increased Risk ◽

Intracerebral Hemorrhages

Chronic kidney diseases and cardiovascular diseases have several common risk factors like hypertension and diabetes. In chronic renal disease stroke risk is several times higher than in the average population. The combination of classical risk factors and those characteristic of chronic kidney disease might explain this increased risk. Among acute cerebrovascular diseases intracerebral hemorrhages are more frequent than in those with normal kidney function. The outcome of stroke is worse in chronic kidney disease. The treatment of stroke (thrombolysis, antiplatelet and anticoagulant treatment, statins, etc.) is an area of clinical research in this patient group. There are no reliable data on the application of thrombolysis in acute stroke in patients with chronic renal disease. Aspirin might be administered. Carefulness, individual considerations and lower doses might be appropriate when using other treatments. The condition of the kidney as well as other associated diseases should be considered during administration of antihypertensive and lipid lowering medications.

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