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Circulation  (2021)

Cardiovascular Disease in Chronic Kidney Disease
Jankowski J, Floege J, Fliser D, Böhm M, Marx N.

Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1–3) compared with the general population, patients with advanced CKD stages (CKD stages 4–5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.

J Am Soc Nephrol (2012)

Normal and Pathologic Concentrations of Uremic Toxins
Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A.

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of b2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations , although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.

J Am Soc Nephrol (2008)
A bench to bedside view of uremic toxins.
Vanholder R, Baurmeister U, Brunet P, Cohen G, Glorieux G, Jankowski J.

Reviewing the current picture of uremic toxicity reveals its complexity. Focusing on cardiovascular damage as a model of uremic effects resulting in substantial morbidity and mortality, most molecules with potential to affect the function of a variety of cell types within the vascular system are difficult to remove by dialysis. Examples are the larger middle molecular weight molecules and protein-bound molecules. Recent clinical studies suggest that enhancing the removal of these compounds is beneficial for survival. Future therapeutic options are discussed, including improved removal of toxins and the search for pharmacologic strategies blocking responsible pathophysiologic pathways.

Nephrol Dial Transplant; 22: 3115-3121, 2007
Review on uraemic solutes II-variability in reported concentrations: causes and consequences.
Vanholder R, Meert N, Schepers E et al.

The aim of this manuscript is to initiate a constructive discussion about deviations in measured concentrations of uraemic solutes; these deviations, if not perceived or handled appropriately, may lead to incorrect interpretations of the pathophysiological role of uraemic solutes and/or to erroneous therapeutic decisions. To come to an objective approach towards this problem, variability analysis of reported concentrations may be of help. Striking outliers should either be discarded or considered together with other values which are more consistent with the majority of reported data.

Nephrol Dial Transplant; 22: 3381-3390, 2007
Review on uraemic toxins III: recommendations for handling uraemic retention solutes in vitro–towards a standardized approach for research on uraemia.
Cohen G, Glorieux G, Thornalley P et al.

No abstract

Artif Organs 31: 600-611, 2007
Inconsistency of reported uremic toxin concentrations.
Meert N, Schepers E, De Smet R et al.

Discrepancies in reported uremic toxin concentrations were evaluated for 78 retention solutes. For this analysis, 378 publications were screened. Up to eight publications per toxin were retained. The highest and the lowest reported concentrations, as well as the median reported concentration were registered. The ratio between the highest and the lowest (H/L) concentrations and, for some solutes, also the ratio between the highest and the median (H/M) concentrations were calculated. The compounds were arbitrarily subdivided into three groups based on their H/L ratio: group A, H/L < 3 (n = 33); group B, 3 < H/L < 8.5 (n = 20); and group C, H/L > 8.5 (n = 25). Solutes of groups A and B showed a low to intermediate scatter, suggesting a homogeneity of reported data. Group C showed a more substantial scatter. For at least 10 compounds of group C, extremely divergent concentrations were registered (H/M > 5.5) using scatter plot analysis. For all solutes of groups A and B, the highest reported concentration could be used as a reference. For some solutes of group C and for the compounds showing a divergent scatter analysis, however, more refined directives should be followed.

Artif Organs. 2005 Jun;29(6):498-506.
The European artificial organ scene: present status.
Vanholder R, del Canizo JF, Sauer IM, Stegmayr B.
Nephrology Section, Department of Internal Medicine, University Hospital, Gent, Belgium .

This article summarizes the current evolutions regarding artificial organs in Europe. The review emanates from the activities by four of the work groups of the European Society for Artificial Organs (ESAO) and is essentially based on the reports by these work groups at the latest ESAO meeting in Warsaw, Poland (2004). The topics are: apheresis, heart support, liver support, uremic toxins.

DNephrol Dial Transplant. 2005 Jun;20(6):1048-56. Epub 2005 Apr 6
Chronic kidney disease as cause of cardiovascular morbidity and mortality.
Vanholder R etal NDT 2005 pp 1048-56 PDF
Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N; European Uremic Toxin Work Group.
Nephrology Section, 0K12, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.

Vanholder R  NDT 2005 pp 1048-56 PDF

To make an evidence-based evaluation of the relationship between kidney failure and cardiovascular risk, we reviewed the literature obtained from a PubMed search using pre-defined keywords related to both conditions and covering 18 years (1986 until end 2003). Eighty-five publications, covering 552 258 subjects, are summarized. All but three studies support a link between kidney dysfunction and cardiovascular risk. More importantly, the association is observed very early during the evolution of renal failure: an accelerated cardiovascular risk appears at varying glomerular filtration rate (GFR) cut-off values, which were >/=60 ml/min in at least 20 studies. Many studies lacked a clear definition of cardiovascular disease and/or used a single determination of serum creatinine or GFR as an index of kidney function, which is not necessarily corresponding to well-defined chronic kidney disease. In six studies, however, chronic kidney dysfunction and cardiovascular disease were well defined and the results of these confirm the impact of kidney dysfunction. It is concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk and that the presence of even subtle kidney dysfunction should be considered as one of the conditions necessitating intensive prevention of this cardiovascular risk.

Contrib Nephrol. 2005;149:315-24.
New insights in uremic toxicity.
Vanholder R, Glorieux G, Lameire N.
Nephrology Section, Department of Internal Medicine, University Hospital, Ghent, Belgium .

The uremic syndrome is characterised by the retention of a host of compounds that in healthy subjects are secreted by the kidneys into normal urine. These compounds disturb many physiologic functions, resulting in toxicity. Many of the responsible compounds remain unknown, however, as well as many patho-physiologic actions of the known retention solutes. In this publication, we review recent new information regarding uremic toxicity. Especially difficult to remove compounds, such as protein bound and larger molecules, seem to play a role. New strategies enhancing their removal might be highly useful.

Kidney International, Vol. 63 (2003), pp. 1934–1943
Review on uremic toxins: Classification, concentration, and interindividual variability
Vanholder R, EUTox – ESOAO 2004
Raymond Vanholder, Rita de Smet, Griet Glorieux, Angel Argile´s, Ulrich Baurmeister, Philippe Brunet, William Clark, Gerald Cohen, Peter Paul de Deyn, Reinhold Deppisch, Beatrice Descamps-Latscha, Thomas Henle, Achim Jörres, Horst Dieter Lemke, Ziad A. Massy, Jutta Passlick-Deetjen, Mariano Rodriguez, Bernd Stegmyr, Peter Stenvinkel, Ciro Tetta, Christoph Wanner, and Walter Zidek, for the European Uremic Toxin Work Group (EUTOX)

Nephrol Dial Transplant 18:463-466, 2003
Uraemic toxins and cardiovascular disease.
Full Paper
Vanholder R, Glorieux G, Lameire N:

Kidney Int Suppl. Vol.63 (2003) Supl 84, :pp. 6-10
New insights in uremic toxins.
Full Paper
Vanholder R, Glorieux G, De Smet R, Lameire N; European Uremic Toxin Work Group.
Nephrology Section, Department of Internal Medicine, University Hospital, Gent, Belgium .

The retention in the body of compounds, which normally are secreted into the urine results in a clinical picture, called the uremic syndrome. The retention compounds responsible for the uremic syndrome are called uremic toxins. Only a few of the uremic retention solutes fully conform to a true definition of uremic toxins. Uremic patients develop atheromatotic vascular disease more frequently and earlier than the general population. The classical risk factors seem to be less important. Other factors have been suggested to be at play, and among those uremic toxins are mentioned as potential culprits. The identification, classification and characterization of the solutes responsible for vascular problems seems of utmost importance but is far from complete due to a lack of standardization and organization. The European Uremic Toxin Work Group (EUTox) has as a primary aim to discuss, analyze and offer guidelines in matters related to the identification, characterization, analytical determination and evaluation of biological activity of uremic retention solutes. The final aim remains the development of new strategies to reduce the concentration of the most active uremic solutes. These activities will at first be concentrated on reducing factors influencing cardiovascular morbidity and mortality.

Int J Artif Organs 2001 Oct;24(10):695-725
Uremic toxicity: present state of the art.
Vanholder R, Argiles A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jorres A, Massy ZA, Rodriguez M, Stegmayr B, Stenvinkel P, Wratten ML. Department of Internal Medicine, University Hospital, Gent, Belgium .

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Reproduced with permission of Editore Medical Publisher who copyright all contents published in
The international Journal of Artificial Organs.


The following PhD Students sucessfully completed their thesis within the EUTox Work group:


B. Näsström: Lipoprotein lipase in hemodialysis patients and healthy controls: effects of heparin.


V. Jankowski: Isolation, identification and characterization of vasoactive substances from endothelial cells, platelets and mononuclear cells.


P. Jonsson: Safety and biological aspects of present techniques of haemodialysis.


E. Schepers: In vitro research for the pathophysiological mechanisms of uremic retention solutes on leukocytes in relation to chronic inflammation and accelerated atheromatosis in chronic kidney diseases.


T. Guenthner:Angioprotectin”: a vasoprotective angiotensin peptide.

M. Koehler: Contribution of known uremic retention solutes to the development of cardiovascular diseases in patients with chronic kidney disease.

E. Houthuys: Transcriptome analysis of monocytes and macrophages in mycobactrial infection and chronic kidney disease.

M. Luman: Dialysis Dose and Nutrition Assessment by an Optical Method.


N. Meert: Optimisation of removal of uremic retention solutes by haemodialysis strategies.


S. Salem: Isolation and identification of vasomodulating biomolecules

A. Pletinck: The peritoneal membrane as a window for microvascular pathophysiology in chronic kidney disease.


F. Duranton: Natural history of chronic kidney disease. Analysis of pathophysiological and prognostic factors of renal failure and its complications.

J. Holmar: Optical Method for Uric Acid Removal Assessment During Dialysis.

B. Holmberg: Analysis of risk factors in patients with severe chronic kidney disease. The role of atovastatin.

D. Mahmood: Lipoprotein lipase activity is reduced in dialysis patients. Studies on possible causal factors.

U. Forsberg: Presence of microemboli during haemodialysis and methods to reduce the exposure to microbubbles.


F. Böhringer: Development of clinical methods for increased removal of protein-bound uremic toxins in the context of an extracorporeal therapy.

J. Boelaert: Development of metabolic analytical platforms for the characterization of uremic retention compounds.


N. Neirynck: Micro-inflammation and cardiovascular disease in chronic kidney disease: role of uremic peptides,

J. Siwy: Validation of an urinary classifier for diagnosis of diabetic nephropathy.


M. Rueth: Hydrophobe Metabolite: Proteinaffinität, Quantifizierung und Methodische Ansätze zur Untersuchung vaskulärer Effekte. Major Chromophores and Fluorophores in the Spent Dialysate as Cornerstones for Optical Monitoring of Kidney Replacement Therapy.

J. Arund: Major Chromophores and Fluorophores in the Spent Dialysate as Cornerstones for Optical Monitoring of Kidney Replacement Therapy.

A. Bhat: Bioinformatics Modeling of Proteomics changes in Muscle Invasive Bladder Cancer.

A. Latosinska: Optimizing methodologies for clinical proteomics.

M. Pejchinovski: The role of urinary peptide markers in diagnosis and prognosis of servere renal diseases.

S. Filip: Identification of protein biomarkers for chronic kidney disease progression using state-of-the-art proteomics approaches.

O. A. Deif: Documentation and evaluation of uremic retention solutes through an interactive database


C. Pontillo: Clinical peptidomics of non-invasive diagnosis and prognosis of renal diseases.

R. Tomson: Urea- and Creatinine-Based Parameters in the Optical Monitoring of Dialysis: The Case of Lean Body Mass and Urea Rebound Assissment.

N. Chevtchik: Development of an upscaled bioatificial kidney.


D. Pavlenko: Towards Improved Removal of Uremic Toxins from Human Plasma

S. Kalle: Optical Monitoring of Uremic Metabolites-Fluorophores during Dialysis: the Case of ß2-microglobulin, Pentosidine, and 4-Pyridoxic Acid.

O. Deltombe: Kinetics of protein-bound uremic toxins in chronic kidney disease.


I. Belczacka: Urinary proteomic analysis in the context of cancer biomarkers.


T. Gryp: The gut-kidney axis: Colon derived protein-bound uremic toxins in chronic kidney disease.


M. Sternkopf: From the pathophysiology of cardiovascular disease to new therapeutic approaches.

T. He: Urinary Proteomics of patients suffering from cardiorenal syndrome.

A. Artmeyer: Posttranslationale Guanidinylierungen des Apolipoprotein A-1 chronisch niereninsuffizienter Patienten

A. A. Garrido: The role of calprotectin in vascular calcification associated with chronic kidney disease


S. Bhargava: Identifcation and charaterization of the mediators of the calcification paradox

J. Hermann: MALDI mass spectrometric imaging methods for localization and identification of pathophysiological relevant regulators in tissue samples

Ch. Hemmers: Chronic kidney disease and associated cardiovascular disease: molecular alterations as biomarkers or mediators of disease


J. Wollenhaupt: Uremia-induced effects on cardioregulatory mechanisms in the context of the cardiorenal syndrome

S. de la Puente-Secades: Vascular calcification in chronic kidney disease: vitamin K deficiency and new mediators

E. Harlacher: Increased cardiovascular risk in patients with chronic kidney disease: Insight into mechanisms and mediators of kidney-heart crosstalk

P. Bartochowski: Changes in the gut barrier and gut microbiota in animal models of chronic kidney disease and vascular calcification.

Y. Garcia-Martinez: Sulfur
metabolic alterations in chronic kidney disease: unravelling the impact of gut
microbiota dysbiosis and uremic toxicity.


C. Favero: Butyrate treatment for acute kidney injury.