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Comorbidities in Chronic Kidney Disease (CKD)

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 73331

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Special Issue Editors

Prof. Dr. Joachim Jankowski

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Guest Editor

Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, University Hospital Aachen, 52074 Aachen, Germany
Interests: chronic renal failure; hypertension; proteomics; mediator identification; mass-spectrometry; chromatography; pathophysiology of kidney diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Heidi Noels

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Guest Editor

University hospital RWTH, Aachen (Germany); Institute for Molecular Cardiovascular Research
Interests: pathophysiology of cardiovascular disease

Special Issue Information

Dear Colleagues,

Cardiovascular disease causes 47% of all deaths in Europe, 10% of Europeans suffer from chronic kidney disease, and 5–8% of elderly aged 60 years or older have to live with cognitive impairment. This disease trio is associated with end-organ damage in the kidney, heart, vasculature, and brain and displays as highly frequent comorbidities. Specifically, ~45% of patients with chronic kidney disease stage 4–5 die from cardiovascular disease, and chronic kidney disease and cardiovascular disease raise the risk of cognitive impairment 2–2.5-fold. Of note, risks of cardiovascular disease and cognitive impairment increase with chronic kidney disease severity but are already significantly higher in early chronic kidney disease compared to non-chronic kidney disease.

Chronic kidney disease, cardiovascular disease, and cognitive impairment are most likely triggered by common pathological molecular mechanisms, with chronic kidney disease further amplifying pathological triggers for co-developing cardiovascular disease and cognitive impairment, which is already present at an early stage (chronic kidney disease stage 1–3). This Special Issue will focus on both causative molecular and cellular mechanisms for diagnosis and prognosis of cardiovascular disease and cognitive impairment in chronic kidney disease, as well as biomarkers for diagnosis, prognosis, and monitoring of comorbid patients.

Prof. Dr. Joachim Jankowski
Dr. Heidi Noels
Guest Editors

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Keywords

Cardiovascular disease
Chronic renal failure
Cognitive impairment
Molecular mechanisms
Molecular mediators
Pathway analyses
Age and gender aspects
In vitro/ex vivo analyses
Proteomics
Therapy

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

5 pages, 224 KiB

Open AccessEditorial

Editorial on the Special Issue “Comorbidities in Chronic Kidney Disease”

by Heidi Noels and Joachim Jankowski

Toxins 2020, 12(6), 384; https://doi.org/10.3390/toxins12060384 - 11 Jun 2020

Cited by 5 | Viewed by 2521

Abstract

With a mean worldwide prevalence of 13 [...] Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

Research

Jump to: Editorial, Review

9 pages, 408 KiB

Open AccessEditor’s ChoiceArticle

Serum P-Cresyl Sulfate Is a Predictor of Central Arterial Stiffness in Patients on Maintenance Hemodialysis

by Yu-Hsien Lai, Chih-Hsien Wang, Chiu-Huang Kuo, Yu-Li Lin, Jen-Pi Tsai and Bang-Gee Hsu

Toxins 2020, 12(1), 10; https://doi.org/10.3390/toxins12010010 - 21 Dec 2019

Cited by 18 | Viewed by 2731

Abstract

Arterial stiffness (AS) has an important impact on the outcomes of patients on hemodialysis (HD), and p-cresyl sulfate (PC) can mediate the process of vascular damage. We aimed to investigate the relationship between carotid–femoral pulse wave velocity (cfPWV) and the level of PCs in HD patients. Serum PCs were quantified using liquid chromatography mass spectrometry. Patients who were on standard HD for more than 3 months were enrolled and categorized according to the cfPWV into the high AS (>10 m/s) and control (≤10 m/s) groups. Forty-nine (41.5%) patients belonged to the high AS group and had a higher incidence of diabetes mellitus (DM) and increased systolic blood pressure, serum C-reactive protein, and PC levels but had lower creatinine, compared with those in the control group. In HD patients, the risk for developing high AS increased in the presence of DM (OR 4.147, 95% confidence interval (CI) 1.497–11.491) and high PCs (OR 1.067, 95% CI 1.002–1.136). Having DM (r = 0.446) and high PC level (r = 0.174) were positively associated with cfPWV. The most optimal cutoff value of PC for predicting AS was 18.99 mg/L (area under the curve 0.661, 95% CI 0.568–0.746). We concluded that DM and PCs were promising predictors of high AS in patients on maintenance HD. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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Review

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18 pages, 665 KiB

Open AccessEditor’s ChoiceReview

The Role of Gut Dysbiosis in the Bone–Vascular Axis in Chronic Kidney Disease

by Pieter Evenepoel, Sander Dejongh, Kristin Verbeke and Bjorn Meijers

Toxins 2020, 12(5), 285; https://doi.org/10.3390/toxins12050285 - 29 Apr 2020

Cited by 23 | Viewed by 4318

Abstract

Patients with chronic kidney disease (CKD) are at increased risk of bone mineral density loss and vascular calcification. Bone demineralization and vascular mineralization often concur in CKD, similar to what observed in the general population. This contradictory association is commonly referred to as the ‘calcification paradox’ or the bone–vascular axis. Mounting evidence indicates that CKD-associated gut dysbiosis may be involved in the pathogenesis of the bone–vascular axis. A disrupted intestinal barrier function, a metabolic shift from a predominant saccharolytic to a proteolytic fermentation pattern, and a decreased generation of vitamin K may, alone or in concert, drive a vascular and skeletal pathobiology in CKD patients. A better understanding of the role of gut dysbiosis in the bone–vascular axis may open avenues for novel therapeutics, including nutriceuticals. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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21 pages, 848 KiB

Open AccessEditor’s ChoiceReview

Inflammation and Premature Ageing in Chronic Kidney Disease

by Thomas Ebert, Sven-Christian Pawelzik, Anna Witasp, Samsul Arefin, Sam Hobson, Karolina Kublickiene, Paul G. Shiels, Magnus Bäck and Peter Stenvinkel

Toxins 2020, 12(4), 227; https://doi.org/10.3390/toxins12040227 - 4 Apr 2020

Cited by 145 | Viewed by 10559

Abstract

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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16 pages, 1517 KiB

Open AccessEditor’s ChoiceReview

Parathyroid Hormone: A Uremic Toxin

by Eduardo J. Duque, Rosilene M. Elias and Rosa M. A. Moysés

Toxins 2020, 12(3), 189; https://doi.org/10.3390/toxins12030189 - 17 Mar 2020

Cited by 42 | Viewed by 10903

Abstract

Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]₂D₃). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]₂D₃ production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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17 pages, 682 KiB

Open AccessEditor’s ChoiceReview

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease

by Juan Rafael Muñoz-Castañeda, Cristian Rodelo-Haad, Maria Victoria Pendon-Ruiz de Mier, Alejandro Martin-Malo, Rafael Santamaria and Mariano Rodriguez

Toxins 2020, 12(3), 185; https://doi.org/10.3390/toxins12030185 - 16 Mar 2020

Cited by 61 | Viewed by 7759

Abstract

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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18 pages, 1534 KiB

Open AccessEditor’s ChoiceReview

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

by Anika Himmelsbach, Carina Ciliox and Claudia Goettsch

Toxins 2020, 12(3), 181; https://doi.org/10.3390/toxins12030181 - 14 Mar 2020

Cited by 21 | Viewed by 7903

Abstract

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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16 pages, 354 KiB

Open AccessEditor’s ChoiceReview

Cardiac Remodeling in Chronic Kidney Disease

by Nadine Kaesler, Anne Babler, Jürgen Floege and Rafael Kramann

Toxins 2020, 12(3), 161; https://doi.org/10.3390/toxins12030161 - 5 Mar 2020

Cited by 90 | Viewed by 10114

Abstract

Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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Graphical abstract

18 pages, 1064 KiB

Open AccessReview

Chronodisruption: A Poorly Recognized Feature of CKD

by Sol Carriazo, Adrián M Ramos, Ana B Sanz, Maria Dolores Sanchez-Niño, Mehmet Kanbay and Alberto Ortiz

Toxins 2020, 12(3), 151; https://doi.org/10.3390/toxins12030151 - 28 Feb 2020

Cited by 18 | Viewed by 4026

Abstract

Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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23 pages, 1252 KiB

Open AccessReview

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

by Merita Rroji, Andreja Figurek and Goce Spasovski

Toxins 2020, 12(3), 140; https://doi.org/10.3390/toxins12030140 - 25 Feb 2020

Cited by 9 | Viewed by 5440

Abstract

Cardiovascular (CV) disease is highly prevalent in the population with chronic kidney disease (CKD), where the risk of CV death in early stages far exceeds the risk of progression to dialysis. The presence of chronic kidney disease-mineral and bone disorder (CKD-MBD) has shown a strong correlation with CV events and mortality. As a non-atheromatous process, it could be partially explained why standard CV disease-modifying drugs do not provide such an impact on CV mortality in CKD as observed in the general population. We summarize the potential association of CV comorbidities with the older (parathyroid hormone, phosphate) and newer (FGF23, Klotho, sclerostin) CKD-MBD biomarkers. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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12 pages, 913 KiB

Open AccessEditor’s ChoiceReview

Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate

by Britt Opdebeeck, Patrick C. D’Haese and Anja Verhulst

Toxins 2020, 12(1), 58; https://doi.org/10.3390/toxins12010058 - 19 Jan 2020

Cited by 42 | Viewed by 5854

Abstract

The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Kidney Disease (CKD))

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