Nephrol Dial Transplant (2003) 18: Editorial Comments Nephrol Dial Transplant (2003) 18: 463–466 Uraemic toxins and cardiovascular disease Raymond Vanholder, Griet Glorieux, Norbert Lameire and for the European Uremic Toxin WorkGroup (EUTox) Nephrology Section, Department of Internal Medicine, University Hospital, Ghent, Belgium Keywords: cardiovascular disease; uraemic toxins Cardiovascular disease as an inflammatorydisorder Traditionally, atherosclerosis has been considered as a degenerative disease, but more recently it has beenrecognized that it is, at least in part, an inflammatory When renal failure develops, uraemic retention solutes disorder [7]. A key role in this process is played by the are retained which are normally excreted by the healthy adhesion of activated leukocytes to the vascular endo- kidneys. If these retention solutes exert biochemical thelium, causing vascular damage by products of biological activity, they are called uraemic toxins.
inflammation, such as free radicals.
According to their physico-chemical characteristics, A large proportion of uraemic patients suffer from they can be subdivided into [1]: (i) small water-soluble inflammation [8]. Several authors demonstrated a cor- compounds (-500 Da, prototype urea); (ii) the larger relation between such inflammation and vascular disease so-called middle molecules ()500 Da, prototype [8–10], and a third clinical feature, malnutrition [8,9].
b2-microglobulin); and (iii) the protein bound solutes.
The retention of these uraemic solutes results in the progressive failure of virtually every organ system,in parallel with the failing function of the kidneys.
The resulting clinical picture is the uraemic syndrome.
The role of uraemic solutes in the development ofthe uraemic syndrome has recently been reviewed [1,11].
In this concise editorial we summarize the availableevidence concerning the most important toxins, which Cardiovascular disease as an integral part of the play a potential role in the genesis of vascular disease.
We also point to some pitfalls that may interfere withscientific progress in this area, and draw attention to The incidence of vascular disease and the morbidity therapeutic possibilities, which may result from better and mortality related to it are extremely high in the population of uraemic patients [2]. Atheromatosis fre- Space limitations prevent discussion of a number quently causes ischaemic problems such as angina of compounds, which are potentially important, pectoris, myocardial infarction, cerebrovascular acci- such as angiogenin, immunoglobulin light chains, dents and ischaemia of the lower limbs. Vascular dis- b2-microglobulin, leptin, guanidines and oxalate. The ease occurs much earlier than in the general population reader is referred to more extensive reviews [1,11].
[3] and affects subjects who are normally at low risk,such as women and young adults [2,3]. In a recentsurvey of adolescents and young adults with a long- The calcium–phosphate–parathyroid hormone axis term history of end-stage renal disease, coronarycalcifications were present even at an age of 20 years [4].
In uraemia, classical risk factors (hypertension, dys- lipidaemia, obesity, smoking) may be less important In a cohort study using multivariate analysis with than in the general population [5]. Presumably, other adjustments for comorbid conditions, Block et al. [12,13] factors are at play, and among these, uraemic toxins demonstrated a progressive increase in overall and are considered of prime importance [6]. The same cardiovascular mortality once serum phosphate and compounds might even be relevant in the general calcium–phosphorus product exceeded 5.5 mgudl and population, but their effect may be masked by the 55 mg2udl2, respectively. These findings were interpreted to suggest a role for the deposition of calcium in thevessel walls. The role of vascular calcium depositionwas further corroborated by the demonstration of Correspondence and offprint requests to: R. Vanholder, Nephrology pathophysiologically significant amounts of calcium Section, Department of Internal Medicine, University Hospital, in the coronaries of young adults, after prolonged De Pintelaan, 185, B-9000 Gent, Belgium.
Email: [email protected] dialysis treatment, from the age of 20 on [4].
# 2003 European Renal Association–European Dialysis and Transplant Association Nephrol Dial Transplant (2003) 18: Editorial Comments such inflammation-related stimuli. Such leukocyte dys-function may contribute to the susceptibility of uraemic Not only the calcium–phosphorus axis, but also secon- dary hyperparathyroidism plays a relevant role in In most studies, AGE-modified proteins were pre- the deposition of calcium in the vessel walls [14].
pared artificially in vitro. This raises the question whe- Hyperphosphataemia, either directly or by inducing ther such artificial AGEs are representative for the AGEs hypocalcaemia, is one of the main causes of hyperpara- retained in vivo [25]. Indeed it has not yet been resolved thyroidism. After parathyroidectomy, calcium deposits which of the AGEs identified in uraemia actually may disappear from the small muscular arteries [15], have toxic actions [11]. Remarkably enough, an inverse correlation was observed in a recent study between theconcentration of certain AGEs and the development of cardiovascular disease in haemodialysed patients [26].
A fourth player in the field is the active vitamin Dmetabolite, calcitriol [16], which suppresses parathy- Advanced oxidation protein products (AOPP) roid hormone production, but also favours depositionof calcium in the vessel wall, at least in part because ofits hypercalcaemic effects.
In analogy with the AGEs, oxidative metabolites The uraemic state is characterized not only by an of albumin with inflammatory potential have been inadequate production of calcitriol due to reduced renal demonstrated by the group of Witko-Sarsat et al. [23] mass, but also by calcitriol resistance related to retained in the plasma of uraemic patients. Of note, plasma uraemic ‘toxins’ [17]. Hence, calcitriol repletion per se concentration of AOPP has been shown recently to be might not suffice to control hyperparathyroidism.
correlated with common carotid artery intima-media A role of vitamin D is also suggested by recent findings, showing that overall mortality and particularlycardiovascular mortality are influenced by vitamin D High concentrations of cytokines with an immune activating potential are present in the plasma of In the general population, a correlation is found bet- uraemic patients [11]. The concentration of interleukin- ween homocysteine concentration and cardiovascular 6 has been related to carotid artery stenosis [28].
mortality [19]. The concentration of total homocys- Moreover, several pro-inflammatory cytokines were teine is elevated in the sera of uraemic patients. Instead correlated with overall mortality in the dialysed of being generated from methionine, homocysteine can population [29]. It is still an unanswered question be transformed into methionine after administration of whether they activate leukocyte function at the folic acid anduor vitamin B12 [19]. This is an example concentrations found in uraemia, and whether such illustrating that in the evaluation of a concentration cytokines are culprits or only markers.
of uraemic metabolites, one has to consider not onlyimpaired renal excretion and extracorporeal removal, but also generation via intermediate metabolism.
Unfortunately, so far evidence is not available that ADMA is an arginine analogue with a guanidine reduction of homocysteine concentration has a bene- structure, which blocks the arginine-induced vasopro- ficial effect on cardiovascular endpoints [20,21]. It is tective and vasodilatory effects of nitric oxide. In possible that reduction of homocysteine concentration elegant multivariate analyses, Zoccali et al. [30] demon- in the available series had been attempted too late to strated that in uraemic patients a relation exists between ADMA on the one hand, and cardiovascularevents on the other hand. Furthermore, a correlationwas found between ADMA concentration and carotid AGEs result from the irreversible modification of aminoacids, proteins or peptides by carbohydrates and other metabolites. Whereas in diabetes these compoundspredominantly result from excess glucose concentration, Research efforts trying to unravel the mechanisms in uraemia oxidative stress and carbamoylation seem underlying vascular disease in uraemia have often to be important alternative sources. In many con- focused on a single solute. Data comparing the stellations, AGEs are the result of inflammation [22].
effect of a hypothetical toxin with known toxins have Conversely, however, AGEs may also induce inflam- usually not been presented. Several studies examined mation in vitro [23,24]. In a recent study, leukocytes only one organ or cell system. Frequently, experiments were activated at baseline, but the response to stimu- were performed at concentrations, which did not lation was attenuated [24], presumably as the result of correspond to what is found in uraemia. One example Nephrol Dial Transplant (2003) 18: Editorial Comments of the current confusion is the discrepancy between Germany; ZA Massy, Division of Nephrology, CH-Beauvais, and the lowest and the highest ever reported concentrations INSERM Unit 507, Necker Hospital, Paris, France; J. Passlick-Deetjen, for solutes such as ADMA [32,33] interleukin-6 [29, M. Rodriguez, University Hospital Reina Sofia, Research Institute, 34] and 3-deoxyglucosone [35,36]. A broad initiative Cordoba, Spain; B. Stegmayr, Norrlands University Hospital, is needed, involving cooperation between several Division of Nephrology, Department of Medicine, Umea, Sweden; laboratories, to work out at a standardized approach.
In an attempt to enable such a standardized approach Huddinge, Sweden; C Tetta, Frenius Medical Care, Bad Homburg,Germany; R. Vanholder, Nephrology Section, Department of and to reduce methodological bias, the European Internal Medicine, University Hospital, Gent, Belgium; C. Wanner, Uremic Toxin Work Group (EUTox) has recruited Division of Nephrology, University Hospital, Wu¨rzburg, Germany; members from several European groups that are V. Witko-Sarsat, INSERM Unit 507, Necker Hospital, Paris, France; involved in toxin research. More information on the W. Zidek, University Hospital Benjamin Franklin, Berlin, Germany.
structure, aims and activities can be found on thewebsite (www.uremic-toxins.org).
1. Vanholder R, De Smet R. Pathophysiologic effects of uremic retention solutes. J Am Soc Nephrol 1999; 10: 1815–1823 2. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardio- Clinical studies attempting to remove solutes, espe- vascular disease in chronic renal disease. J Am Soc Nephrol 1998; cially middle molecules, should be performed. While obviously parathyroid hormone concentrations and 3. Iseki K, Fukiyama K. Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis.
Ca 3 P product should be optimized, most of the cur- The Okinawa Dialysis Study Group. Am J Kidney Dis 2000; rently available methods, such as the administration of calcium salts and classical vitamin D analogues, induce 4. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery hypercalcaemia. Calcimimetics and new vitamin D ana- calcification in young adults with end-stage renal disease who are logues might offer new solutions. Measures to combat undergoing dialysis. N Engl J Med 2000; 342: 1478–1483 inflammation such as use of ultrapure dialysate and 5. Fleischmann EH, Bower JD, Salahudeen AK. Are conventional cardiovascular risk factors predictive of two-year mortality in biocompatible membranes, as well as administration hemodialysis patients? Clin Nephrol 2001; 56: 221–230 of vitamin C, vitamin E, statins, ACE-inhibitors, 6. Cheung AK, Sarnak MJ, Yan G et al. Atherosclerotic aspirin or radical scavengers might prove useful and cardiovascular disease risks in chronic hemodialysis patients.
should be studied in controlled studies. Some inter- 7. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med remove unwanted substances such as homocysteine by 8. Stenvinkel P, Wanner C, Metzger T et al. Inflammation and promoting removal via intermediary metabolism. It outcome in end-stage renal disease: impact of gender. Kidney Int should also be examined whether it is not possible to inhibit uptake of toxins and their precursors from the 9. Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-Reactive intestine by appropriate measures, e.g. sorption.
protein predicts all-cause and cardiovascular mortality inhemodialysis patients. Am J Kidney Dis 2000; 35: 469–476 A concerted multicentric and multifocused research 10. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C.
programme in conjunction with pharmaceutical and Inflammation enhances cardiovascular risk and mortality in extracorporeal removal industries will be necessary to hemodialysis patients. Kidney Int 1999; 55: 648–658 make further progress in this area. New approaches 11. Vanholder R, Argiles A, Baurmeister U et al. Uremic should be tried such as proteomeugenome analysis, toxicity: present state of the art. Int J Artif Organs 2001; 24: 695–725 high throughput analysis, adsorption technologies and 12. Block GA, Port FK. Re-evaluation of risks associated with patients: recommendations for a change in management. Am JKidney Dis 2000; 35: 1226–1237 13. Block GA, Hulbert-Shearon TE, Levin NW, Port FK.
Members of EUTox: A. Argile´s, Institute of Association of serum phosphorus and calcium 3 phosphate Human Genetics, IGH-CNRS UPR 1142, Montpellier, France; product with mortality risk in chronic hemodialysis patients: a U. Baurmeister, MAT Adsorption Technologies, Obernburg, Germany; national study. Am J Kidney Dis 1998; 31: 607–617 P. Brunet, Nephrology, Internal Medicine, Ste Marguerite Hospital, 14. Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium- Marseille, France; J. Beige, University Hospital Benjamin Franklin,Berlin, Germany; B. Lindholm, Baxter Healthcare Corporation, phosphate product and bone-associated proteins on vascular Stockholm, Sweden; G. Cohen, Division of Nephrology, Department calcification in renal failure. J Am Soc Nephrol 2001; of Medicine, University of Vienna, Vienna, Austria; P. P. De Deyn, Department of Neurology, Middelheim Hospital, Laboratory of 15. Rostand SG, Drueke TB. Parathyroid hormone, vitamin D, and Neurochemistry and Behaviour, University of Antwerp, Belgium; cardiovascular disease in chronic renal failure. Kidney Int 1999; R. Deppisch, Gambro Corporate Research, Hechingen, Germany; B. Descamps-Latscha, INSERM Unit 507, Necker Hospital, Paris, 16. Feinfeld DA, Sherwood LM. Parathyroid hormone and France; A. Finn, Nephrology and Medical Intensive Care, UK 1,25(OH)2D3 in chronic renal failure. Kidney Int 1988; Charite´, Campus Virchow-Klinikum, Medical Faculty of Humboldt- University, Berlin, Germany; T. Henle, Institute of Food Chemistry, 17. Glorieux G, Hsu CH, De Smet R et al. Inhibition of calcitriol- Technical University, Dresden, Germany; J. Jankowski, University induced monocyte CD14 expression by uremic toxins: role of purines. J Am Soc Nephrol 1998; 9: 1826–1831 Nephrology and Medical Intensive Care, UK Charite´, Campus 18. Marco MP, Craver L, Betriu A, Fibla J, Fernandez E. Influence of vitamin D receptor gene polymorphisms on mortality risk in Berlin, Germany; H. D. Lemke, Membrana GmbH, Obernburg, hemodialysis patients. Am J Kidney Dis 2001; 38: 965–974 Nephrol Dial Transplant (2003) 18: Editorial Comments 19. Massy ZA. Importance of homocysteine, lipoprotein (a) and 28. Stenvinkel P, Heimburger O, Jogestrand T. Elevated interleukin- 6 predicts progressive carotid artery atherosclerosis in dialysis advanced glycation end-products) for atherogenesis in uraemic patients: association with Chlamydia pneumoniae seropositivity.
patients. Nephrol Dial Transplant 2000; 15 [Suppl 5]: 81–91 20. van Guldener C, Janssen MJ, Lambert J et al. No change in 29. Kimmel PL, Phillips TM, Simmens SJ et al. Immunologic impaired endothelial function after long-term folic acid therapy function and survival in hemodialysis patients. Kidney Int 1998; of hyperhomocysteinaemia in haemodialysis patients. Nephrol 30. Zoccali C, Bode-Boger S, Mallamaci F et al. Plasma concentra- 21. Thambyrajah J, Landray MJ, McGlynn FJ et al. Does folic acid tion of asymmetrical dimethylarginine and mortality in patients decrease plasma homocysteine and improve endothelial function with end-stage renal disease: a prospective study. Lancet 2001; in patients with predialysis renal failure? Circulation 2000; 31. Zoccali C, Benedetto FA, Maas R et al. Asymmetric dimethy- 22. Miyata T, Kurokawa K, van Ypersele DS. Advanced glycation larginine, C-reactive protein, and carotid intima- media thick- and lipoxidation end products: role of reactive carbonyl com- ness in end-stage renal disease. J Am Soc Nephrol 2002; pounds generated during carbohydrate and lipid metabolism.
32. Marescau B, Nagels G, Possemiers I et al. Guanidino 23. Witko-Sarsat V, Friedlander M, Nguyen KT et al. Advanced compounds in serum and urine of nondialyzed patients with oxidation protein products as novel mediators of inflammation chronic renal insufficiency. Metabolism 1997; 46: 1024–1031 and monocyte activation in chronic renal failure. J Immunol 33. Kang ES, Tevlin MT, Wang YB et al. Hemodialysis hypoten- 24. Bernheim J, Rashid G, Gavrieli R, Korzets Z, Wolach B. In vitro sion: interaction of inhibitors, iNOS, and the interdialytic period.
effect of advanced glycation end-products on human polymor- phonuclear superoxide production. Eur J Clin Invest 2001; 34. Kaizu Y, Kimura M, Yoneyama T et al. Interleukin-6 may mediate malnutrition in chronic hemodialysis patients. Am J 25. Glorieux G, Vanholder R, Lameire N. Advanced glycation and the immune system: stimulation, inhibition or both? Eur J Clin 35. Odani H, Shinzato T, Matsumoto Y, Usami J, Maeda K.
Increase in three alpha,beta-dicarbonyl compound levels in 26. Schwedler SB, Metzger T, Schinzel R, Wanner C. Advanced human uremic plasma: specific in vivo determination of inter- glycation end products and mortality in hemodialysis patients.
mediates in advanced Maillard reaction. Biochem Biophys Res ¨ eke T, Witko-Sarsat V, Massy Z et al. Iron therapy, advanced 36. Niwa T, Katsuzaki T, Momoi T et al. Modification of beta 2m oxidation protein products and carotid artery intima-media with advanced glycation end products as observed in dialysis- related amyloidosis by 3-DG accumulating in uremic serum.

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