Abstracts
Chronic kidney disease is characterized by a progressive reduction of glomerular filtration rate and/or the appearance of proteinuria, and subsequently the progressive retention of organic waste compounds called uremic toxins (UT). Over the last decades, a large number of such compounds have been identified and their effects on organs and tissues, especially the cardiovascular system, has been demonstrated. In this review, we present the current classification of UT, as proposed by the EUTox Group, and the effects of some of the probably most important UTs, such as phosphate, FGF-23, PTH, AGEs, indoxyl sulfate and para-cresyl sulfate. We provide an overview on therapeutic approaches aimed to increase their extracorporeal removal via convective and/or adsorptive strategies and to lower their intestinal production/ absorption via dietetic and pharmacological interventions. The recognition that multiple toxins contribute to the uremia supports the need for new therapeutic targets, with a potentially positive impact on CKD progression and survival.
cardiovascular diseases; dialysis; kidney failure, chronic; uremia
A doença renal crônica (DRC) caracteriza-se pela redução progressiva da filtração glomerular e/ou presença de proteinúria, e subsequente retenção progressiva de compostos orgânicos, denominados toxinas urêmicas. Nas últimas décadas, um grande número destes compostos foi identificado, assim como seus efeitos adversos no organismo, sobretudo no sistema cardiovascular. Nesta revisão, apresentamos a classificação das toxinas urêmicas, proposta pelo grupo europeu de estudo em toxinas urêmicas (EUTox), e discutiremos os efeitos de algumas das principais toxinas, como ADMA, fosfato, FGF-23, PTH, AGEs, indoxil sulfato e para-cresil sulfato. Além disso, abordaremos as principais estratégias terapêuticas para aumentar a remoção das toxinas urêmicas por métodos convectivos e/ou adsortivos; e para diminuir a produção e absorção intestinal dessas toxinas por meio de intervenções dietéticas e farmacológicas, respectivamente. A compreensão de que múltiplas toxinas contribuem para a uremia expõe a necessidade de novos alvos-terapêuticos, com potencial impacto positivo na progressão da DRC e na sobrevida dos pacientes.
diálise; doenças cardiovasculares; falência renal crônica; uremia
Introduction
In the last two decades, renewed interest has emerged about the uremic syndrome and
its negative impact on chronic kidney disease (CKD) patient outcomes. The syndrome
is primarily caused by the progressive decline in kidney function that leads to an
accumulation of organic waste products.11. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007;357:1316- 25.
PMID: 17898101 DOI: http://dx.doi.org/10.1056/NEJMra071313
http://dx.doi.org/10.1056/NEJMra071313...
These waste products, not all identified as yet, are called "uremic toxins" or
"uremic retention solutes". Under normal conditions, they are excreted by the
kidneys. Thus, their concentrations increase progressively with the progression of
CKD, interacting negatively with various biological functions. The clinical spectrum
of this pathophysiological phenomenon is generally known as uremia (literally,
"urine in the blood") and at present more frequently designed as the uremic
state.22. Vanholder R. Uremic toxins. Nephrologie
2003;24:373-6.,33. Glassock RJ. Uremic toxins: what are they? An integrated overview
of pathobiology and classification. J Ren Nutr 2008;18:2-6. DOI:
http://dx.doi.org/10.1053/j.jrn.2007.10.003
http://dx.doi.org/10.1053/j.jrn.2007.10....
The first publication in this field is from 1877,44. Mahomed FA. On the Pathology of Uraemia and the Socalled Uraemic
Convulsions. Br Med J 1877;2:10-2. DOI:
http://dx.doi.org/10.1136/bmj.2.862.10
http://dx.doi.org/10.1136/bmj.2.862.10...
and little was known regarding the nature of uremic toxins before the
introduction of hemodialysis (HD) into clinical practice in the 1960s. The concept
of uremic toxins has thus been developed at that time, and their identification and
biological activities were actively investigated subsequently by a small number of
research groups (Man and Funck-Brentano in France, Bergström in Sweden, etc). These
research activities led to the "middle molecule" hypothesis.55. Man NK, Terlain B, Paris J, Werner G, Sausse A, Funck-Brentano
JL. An approach to "middle molecules" identification in artificial kidney
dialysate, with reference to neuropathy prevention. Trans Am Soc Artif Intern
Organs 1973;19:320-4.,66. Babb AL, Johansen PJ, Strand MJ, Tenckhoff H, Scribner BH.
Bi-directional permeability of the human peritoneum to middle molecules. Proc
Eur Dial Transplant Assoc 1973;10:247-62. However,
studies in this field ceased subsequently because no convincing demonstration of
their role in the uremic syndrome could be made at that time. The topic was
resuscitated later on, in the early 1990ies, by the nephrology group in Gent,
Belgium (Ringoir, Vanholder). They were able to provide new, scientifically valid
evidence in favor of the biological activity of several uremic toxins. Finally, in
1999 Vanholder's group, together with other researchers in Europe, launched the
European Uremic Toxins (EUTox) Work Group, which contributed substantially to the
acceptance of the concept and the demonstration of the role of uremic toxins.
Subsequently, the idea disseminated worldwide, as reflected by a remarkable increase
in published reports devoted to this field.
According to EUTox, a compound can be considered as a uremic toxin if it fits a
postulate, similar to Koch's postulate, as modified by Massry et al. in 1977 (Table 1).33. Glassock RJ. Uremic toxins: what are they? An integrated overview
of pathobiology and classification. J Ren Nutr 2008;18:2-6. DOI:
http://dx.doi.org/10.1053/j.jrn.2007.10.003
http://dx.doi.org/10.1053/j.jrn.2007.10....
,77. Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U,
Brunet P, et al.; European Uremic Toxin Work Group (EUTox). Review on uremic
toxins: classification, concentration, and interindividual variability. Kidney
Int 2003;63:1934-43. PMID: 12675874 At present, there
are 152 solutes listed in the EUTox database (http://eutoxdb.odeesoft.com/index.php) and certainly an increase in
this number in the following years can be expected.
Requirements for a given compound be considered as a uremic toxin44. Mahomed FA. On the Pathology of Uraemia and the Socalled Uraemic Convulsions. Br Med J 1877;2:10-2. DOI: http://dx.doi.org/10.1136/bmj.2.862.10
http://dx.doi.org/10.1136/bmj.2.862.10...
The proper identification of new compounds that fulfill the criteria of uremic toxins has at least three main implications: firstly, to be able to explore the unknown pathophysiologic mechanisms of the uremic syndrome; secondly, to use a specific uremic toxin as a biomarker of a specific pathophysiologic process in CKD and thirdly, to explore clinical interventions directed to modulate the total body/plasma levels of uremic toxins.
Uremic toxins can be classified according to their physico-chemical characteristics and removal by dialysis into the following 3 classes:
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Small water-soluble: compounds with a maximum molecular weight (MW) of 500 Daltons (Da). The main molecules in this group include urea, creatinine and guanidines, which are easily removed by dialysis. They do not necessarily have toxic effects.
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Middle molecules: Compounds of moderately elevated MW (> 500 Da), with β2-microglobulin and leptin as prototypes. They can only be removed by dialysis membranes with pores large enough to allow their passage. Many of these compounds are peptides. They affect a large number of organs and systems.
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Protein-bound compounds: They are generally of low MW. The prototypes of this group are phenols and indoles. They exert a variety of toxic effects and are difficult to remove by dialysis.
A large number of uremic toxins have deleterious effects on various organs and tissues in the body, mainly the cardiovascular system (Figure 1). The pathophysiological mechanisms involved are complex and far from being completely understood. They include reactive oxidative stress, inflammation, protein glycation and cellular transdifferentiation. In this review, we present the main toxin prototype groups, based on physico-chemical characteristics, clinical effects, and current or potential interventions aimed to modulate their concentration through extracorporeal removal methods and/or pharmacological approaches capable of opposing their toxic effects.
Small water-soluble compounds
Guanidines
An important group of small water-soluble compounds consists of guanidine
compounds, metabolites of L-arginine that have long been known for their
neurotoxic effects.88. D'Hooge R, Pei YQ, Marescau B, De Deyn PP. Convulsive action and
toxicity of uremic guanidino compounds: behavioral assessment and relation to
brain concentration in adult mice. J Neurol Sci 1992;112:96-105. PMID: 1469446
DOI: http://dx.doi.org/10.1016/0022-510X(92)90138-B
http://dx.doi.org/10.1016/0022-510X(92)9...
There are three
types of methylated arginine residues: monomethyl arginine (MMA), symmetric
dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA), the latter
being the most abundant one. Several studies have shown an increase in serum
ADMA levels in CKD, which may be particularly relevant to the presence of
nephrotic proteinuria, although its correlation with glomerular filtration
rate (GFR) has been found to be poor.99. Eloot S, Schepers E, Barreto DV, Barreto FC, Liabeuf S, Van
Biesen W, et al. Estimated glomerular filtration rate is a poor predictor of
concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol
2011;6:1266-73. DOI: http://dx.doi.org/10.2215/CJN.09981110
http://dx.doi.org/10.2215/CJN.09981110...
,1010. Kielstein JT, Böger RH, Bode-Böger SM, Frölich JC, Haller H,
Ritz E, et al. Marked increase of asymmetric dimethylarginine in patients with
incipient primary chronic renal disease. J Am Soc Nephrol
2002;13:170-6.
Initially, it was assumed that this increase was the result of lower renal
clearance. Later studies, however, suggested that the increase was due to
both augmented synthesis and reduced catabolism of these compounds.1111. Baylis C. Nitric oxide deficiency in chronic kidney disease. Am
J Physiol Renal Physiol 2008;294:F1-9. PMID: 17928410 Of note, even though guanidines and
urea are structurally similar, the distribution volume of the former is
significantly greater, which results in a decrease in removal efficiency by
dialysis procedures.1212. Eloot S, van Biesen W, Dhondt A, de Smet R, Marescau B, De Deyn
PP, et al. Impact of increasing haemodialysis frequency versus haemodialysis
duration on removal of urea and guanidino compounds: a kinetic analysis. Nephrol
Dial Transplant 2009;24:2225-32. DOI:
http://dx.doi.org/10.1093/ndt/gfp059
http://dx.doi.org/10.1093/ndt/gfp059...
ADMA has long been associated with endothelial dysfunction. In 1992, Vallence
et al.1313. Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous
dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc
Pharmacol 1992;20:S60-2. PMID: 1282988 DOI:
http://dx.doi.org/10.1097/00005344-199204002-00018
http://dx.doi.org/10.1097/00005344-19920...
identified MMA and ADMA as endogenous inhibitors of nitric oxide synthase
(eNOS). However, the intracellular concentration of MMA is very small,
whereas ADMA is the most abundant eNOS inhibitor. ADMA has been further
linked to cardiovascular disease (CVD) and mortality in both the general and
CKD population ever since.1414. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O,
et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial
dysfunction: its role in hypercholesterolemia. Circulation 1998;98:1842-7. PMID:
9799202,1515. Zoccali C, Bode-Böger S, Mallamaci F, Benedetto F, Tripepi G,
Malatino L, et al. Plasma concentration of asymmetrical dimethylarginine and
mortality in patients with end-stage renal disease: a prospective study. Lancet
2001;358:2113-7. PMID: 11784625 DOI:
http://dx.doi.org/10.1016/S0140-6736(01)07217-8
http://dx.doi.org/10.1016/S0140-6736(01)...
SDMA, the structural counterpart of ADMA, was considered inert until
recently. However, it is currently recognized as a pro-inflammatory and a
pro-oxidant agent.1616. Bode-Böger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J,
Breithardt G, Fobker M, et al. Symmetrical dimethylarginine: a new combined
parameter for renal function and extent of coronary artery disease. J Am Soc
Nephrol 2006;17:1128-34. DOI:
http://dx.doi.org/10.1681/ASN.2005101119
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,1717. Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto
FC, et al. Symmetric dimethylarginine as a proinflammatory agent in chronic
kidney disease. Clin J Am Soc Nephrol 2011;6:2374- 83. DOI:
http://dx.doi.org/10.2215/CJN.01720211
http://dx.doi.org/10.2215/CJN.01720211...
Unlike ADMA, SDMA was demonstrated
to be capable of increasing TNF-α and interleukine-6 (IL-6) expression, and
enhancing NFkB activation, in human monocytic cell line THP-1. In line with
this in vitro data, SDMA has been associated with
inflammatory markers, including TNF-α and IL-6, in pre-dialysis patients at
different stages of CKD.1717. Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto
FC, et al. Symmetric dimethylarginine as a proinflammatory agent in chronic
kidney disease. Clin J Am Soc Nephrol 2011;6:2374- 83. DOI:
http://dx.doi.org/10.2215/CJN.01720211
http://dx.doi.org/10.2215/CJN.01720211...
Uric acid
Uric acid (MW: 168 Da) is considered a uremic toxin since a considerable body
of evidence suggests that supraphysiologic uric acid concentrations have
deleterious effects on the kidney and on the cardiovascular system. In CKD,
factors like reduced GFR, increased renal vascular resistance and
co-existent insulin resistance as well as the use of diuretics can lead to
hyperuricemia, defined as the accumulation of serum uric acid beyond its
solubility point in water (6.8 mg/dL).1818. Jalal DI, Chonchol M, Chen W, Targher G. Uric acid as a target
of therapy in CKD. Am J Kidney Dis 2013;61:134-46. DOI:
http://dx.doi.org/10.1053/j.ajkd.2012.07.021
http://dx.doi.org/10.1053/j.ajkd.2012.07...
Other factors such as high purine/protein diet, alcohol
consumption and high cell turnover can also contribute to increase its serum
concentration.
Classically, hyperuricemia could lead to hyperuricosuria and deposition of
uric acid crystals in the kidney, increasing the risk of nephrolithiasis,
renal inflammation and decrease of GFR by intraluminal obstruction and
increased concentration of urate anion in renal tissue.1919. Umekawa T, Chegini N, Khan SR. Increased expression of monocyte
chemoattractant protein-1 (MCP-1) by renal epithelial cells in culture on
exposure to calcium oxalate, phosphate and uric acid crystals. Nephrol Dial
Transplant 2003;18:664-9. DOI:
http://dx.doi.org/10.1093/ndt/gfg140
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,2020. Spencer HW, Yarger WE, Robinson RR. Alterations of renal
function during dietary-induced hyperuricemia in the rat. Kidney Int
1976;9:489-500. DOI: http://dx.doi.org/10.1038/ki.1976.63
http://dx.doi.org/10.1038/ki.1976.63...
On the other hand, non-crystal dependent effects of uric acid have been
proposed, but this remains a matter of debate. Though urate anion, the
predominant form of uric acid under physiologic pH, has long been considered
a powerful antioxidant at physiologic concentrations, experimental data have
shown that at higher concentrations this anion can lead to endothelial
dysfunction, increased systemic cytokine production, activation of the
renin-angiotensin-aldosterone system and last, not least, glomerular
lesions.2121. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S,
et al. Is there a pathogenetic role for uric acid in hypertension and
cardiovascular and renal disease? Hypertension 2003;41:1183-90.
In the clinical setting, observational studies have reported conflicting
results. In the Cardiovascular Health Study, no association was observed
between serum uric acid level and the incidence of CKD.2222. Chonchol M, Shlipak MG, Katz R, Sarnak MJ, Newman AB, Siscovick
DS, et al. Relationship of uric acid with progression of kidney disease. Am J
Kidney Dis 2007;50:239-47. PMID: 17660025 DOI:
http://dx.doi.org/10.1053/j.ajkd.2007.05.013
http://dx.doi.org/10.1053/j.ajkd.2007.05...
Similarly, in the patient cohort of the MDRD Study,
uric acid was not found to be an independent risk factor for CKD
progression.2323. Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, et al.
Uric acid and long-term outcomes in CKD. Am J Kidney Dis 2009;53:796-803. DOI:
http://dx.doi.org/10.1053/j.ajkd.2008.12.021
http://dx.doi.org/10.1053/j.ajkd.2008.12...
In contrast, Hsu
et al. evaluated a cohort of 177,570 participants
followed over 25-years and found that increased serum uric acid levels were
independently associated with an increased risk of end-stage kidney disease
(ESKD).2424. Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk
factors for end-stage renal disease: 25-year follow-up. Arch Intern Med
2009;169:342-50. PMID: 19237717 DOI:
http://dx.doi.org/10.1001/archinternmed.2008.605
http://dx.doi.org/10.1001/archinternmed....
A hypothesis to explain
these apparent inconsistencies is that uric acid clearance is impaired in
CKD, which in turn can act as a confounding factor.2121. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S,
et al. Is there a pathogenetic role for uric acid in hypertension and
cardiovascular and renal disease? Hypertension 2003;41:1183-90. Taking into account interventional studies aimed to
decrease serum uric acid levels in CKD, the results, although
encouraging,2525. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero
J, Rincón A, et al. Effect of allopurinol in chronic kidney disease progression
and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-93. DOI:
http://dx.doi.org/10.2215/CJN.01580210
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are not strong
enough to systematically recommend allopurinol as a therapy for halting or
decreasing CKD progression.
Inorganic phosphate (Pi)
The regulatory mechanisms responsible for Pi homeostasis, such as
1,25(OH)2-vitamin D, parathyroid hormone (PTH) and fibroblast
growth factor-23 (FGF23), together with Klotho,26 are disrupted in the CKD
setting. Pi overload may occur early on in the course of CKD, while
hyperphosphatemia appears only when GFR falls below 30 ml/min/1.73
m2 of body surface.2727. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA,
et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in
patients with chronic kidney disease: results of the study to evaluate early
kidney disease. Kidney Int 2007;71:31-8. DOI:
http://dx.doi.org/10.1038/sj.ki.5002009
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When CKD progresses and dialysis treatment is required, the positive balance
of Pi becomes more pronounced due to (i) loss of kidney function and (ii)
insufficient removal by conventional hemodialysis (HD) or peritoneal
dialysis (PD) (Table 2). A detailed
discussion of Pi homeostasis and hyperphosphatemia treatment can be found
elsewhere.2626. Uribarri J. Phosphorus homeostasis in normal health and in
chronic kidney disease patients with special emphasis on dietary phosphorus
intake. Semin Dial 2007;20:295-301. DOI:
http://dx.doi.org/10.1111/j.1525-139X.2007.00309.x
http://dx.doi.org/10.1111/j.1525-139X.20...
,2828. Barreto FC, de Oliveira RA, Oliveira RB, Jorgetti V.
Pharmacotherapy of chronic kidney disease and mineral bone disorder. Expert Opin
Pharmacother 2012;12:2627-40. DOI:
http://dx.doi.org/10.1517/14656566.2011.626768
http://dx.doi.org/10.1517/14656566.2011....
Hyperphosphatemia has been classically linked to the pathogenesis of
secondary hyperparathyroidism (sHPT).2929. Sampaio EA, Lugon JR, Barreto FC. Fisopatologia do
hiperparatireoidismo secundário J Bras Nefrol 2008;30:6-10. Furthermore, since the end of the 1990's, the role of Pi in
uremia-related cardiovascular complications and mortality has gained growing
interest. Several observational studies showed an association of
hyperphosphatemia with overall and cardiovascular mortality, both in
dialysis and pre-dialysis patients.3030. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of
serum phosphorus and calcium x phosphate product with mortality risk in chronic
hemodialysis patients: a national study. Am J Kidney Dis 1998;31:607-17. DOI:
http://dx.doi.org/10.1053/ajkd.1998.v31.pm9531176
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,3131. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL,
Young B, et al. Serum phosphate levels and mortality risk among people with
chronic kidney disease. J Am Soc Nephrol 2005;16:520-8. DOI:
http://dx.doi.org/10.1681/ASN.2004070602
http://dx.doi.org/10.1681/ASN.2004070602...
Vascular
calcification (VC) has been proposed as one of the possible mechanisms
linking hyperphosphatemia to mortality. In vitro studies
have shown that Pi enters vascular smooth muscle cells (VSMCs) through
sodium-phosphate co-transporter type III (PiT-1), activate Cbfa-1/Runx-2
genes and thereby promote VSMC transdifferentiation into
osteoblast/osteochondrocyte-like cells.3232. Giachelli CM. Vascular calcification: in vitro evidence for the
role of inorganic phosphate. J Am Soc Nephrol 2003;14:S300-4. DOI:
http://dx.doi.org/10.1097/01.ASN.0000081663.52165.66
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Even though animal studies have demonstrated very clearly
that lowering serum Pi can decrease the progression of VC,33,34 this remains
yet to be confirmed by appropriate clinical trials in patients with
CKD.3535. Barreto DV, Barreto Fde C, de Carvalho AB, Cuppari L, Draibe SA,
Dalboni MA, et al. Phosphate binder impact on bone remodeling and coronary
calcification-results from the BRiC study. Nephron Clin Pract 2008;110:c273-83.
DOI: http://dx.doi.org/10.1159/000170783
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,3636. Chertow GM, Burke SK, Raggi P; Treat to Goal Working Group.
Sevelamer attenuates the progression of coronary and aortic calcification in
hemodialysis patients. Kidney Int 2002;62:245-52. DOI:
http://dx.doi.org/10.1046/j.1523-1755.2002.00434.x
http://dx.doi.org/10.1046/j.1523-1755.20...
More recently, the role of Pi as a potential cardiovascular toxin has
received further support. Several observational studies have suggested that
high Pi levels, even within the normal range, may be associated with an
increased risk of incident CVD,3737. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D'Agostino RB Sr,
Gaziano JM, et al. Relations of serum phosphorus and calcium levels to the
incidence of cardiovascular disease in the community. Arch Intern Med
2007;167:879-85. PMID: 17502528 DOI:
http://dx.doi.org/10.1001/archinte.167.9.879
http://dx.doi.org/10.1001/archinte.167.9...
left ventricular hypertrophy (LVH) and increased risk of heart failure,3838. Dhingra R, Gona P, Benjamin EJ, Wang TJ, Aragam J, D'Agostino RB
Sr, et al. Relations of serum phosphorus levels to echocardiographic left
ventricular mass and incidence of heart failure in the community. Eur J Heart
Fail 2010;12:812-8. DOI:
http://dx.doi.org/10.1093/eurjhf/hfq106
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coronary disease,3939. Cancela AL, Santos RD, Titan SM, Goldenstein PT, Rochitte CE,
Lemos PA, et al. Phosphorus is associated with coronary artery disease in
patients with preserved renal function. PLoS One 2012;7:e36883. DOI:
http://dx.doi.org/10.1371/journal.pone.0036883
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and higher mortality4040. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And
Recurrent Events Trial Investigators. Relation between serum phosphate level and
cardiovascular event rate in people with coronary disease. Circulation
2005;112:2627-33. PMID: 16246962 in the general population.
Experimental studies have shed some light on the mechanisms by which Pi acts
as a cardiovascular toxin, above and beyond the promotion of VC.
Apolipoprotein E knockout mice fed an atherogenic diet with high (1.6%) Pi
content had significantly more atheroma at the site of the aortic sinus than
mice fed a low (0.2%) or standard (0.6%) Pi diet, while lipid profile and
blood pressure were not affected.4141. Ellam T, Wilkie M, Chamberlain J, Crossman D, Eastell R, Francis
S, et al. Dietary phosphate modulates atherogenesis and insulin resistance in
apolipoprotein E knockout mice-brief report. Arterioscler Thromb Vasc Biol
2011;31:1988-90. DOI:
http://dx.doi.org/10.1161/ATVBAHA.111.231001
http://dx.doi.org/10.1161/ATVBAHA.111.23...
Furthermore, it has been demonstrated in two different mouse models of CKD
that lowering serum Pi levels with sevelamer, a phosphate-binding agent,
improved VC and atherosclerotic lesions,3434. Phan O, Ivanovski O, Nikolov IG, Joki N, Maizel J, Louvet L, et
al. Effect of oral calcium carbonate on aortic calcification in apolipoprotein
E-deficient (apoE-/-) mice with chronic renal failure. Nephrol Dial Transplant
2008;23:82-90. DOI: http://dx.doi.org/10.1093/ndt/gfm699
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aortic stiffness, diastolic dysfunction and prevented
ventricular hypertrophy.4242. Maizel J, Six I, Dupont S, Secq E, Dehedin B, Barreto FC, et al.
Effects of sevelamer treatment on cardiovascular abnormalities in mice with
chronic renal failure. Kidney Int 2013;84:491-500. DOI:
http://dx.doi.org/10.1038/ki.2013.110
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In vivo studies have demonstrated that Pi overload may lead
to endothelial dysfunction, by inducing apoptosis,4343. Di Marco GS, Hausberg M, Hillebrand U, Rustemeyer P, Wittkowski
W, Lang D, et al. Increased inorganic phosphate induces human endothelial cell
apoptosis in vitro. Am J Physiol Renal Physiol 2008;294:F1381-7. PMID: 18385273
DOI: http://dx.doi.org/10.1152/ajprenal.00003.2008
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impaired acethylcholine-induced vasodilation,4444. Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M, et
al. Dietary phosphorus acutely impairs endothelial function. J Am Soc Nephrol
2009;20:1504-12. DOI: http://dx.doi.org/10.1681/ASN.2008101106
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,4545. Six I, Maizel J, Barreto FC, Rangrez AY, Dupont S, Slama M, et
al. Effects of phosphate on vascular function under normal conditions and
influence of the uraemic state. Cardiovasc Res 2012;96:130-9. PMID: 22822101
DOI: http://dx.doi.org/10.1093/cvr/cvs240
http://dx.doi.org/10.1093/cvr/cvs240...
inhibition of nitric oxide production4444. Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M, et
al. Dietary phosphorus acutely impairs endothelial function. J Am Soc Nephrol
2009;20:1504-12. DOI: http://dx.doi.org/10.1681/ASN.2008101106
http://dx.doi.org/10.1681/ASN.2008101106...
and downregulation of annexin
II.4646. Di Marco GS, König M, Stock C, Wiesinger A, Hillebrand U,
Reiermann S, et al. High phosphate directly affects endothelial function by
downregulating annexin II. Kidney Int 2013;83:213-22. DOI:
http://dx.doi.org/10.1038/ki.2012.300
http://dx.doi.org/10.1038/ki.2012.300...
Interestingly, lowering
serum Pi levels (at least in animal models of CKD) by either dietary Pi
restriction or sevelamer administration ameliorates endothelial
dysfunction.4343. Di Marco GS, Hausberg M, Hillebrand U, Rustemeyer P, Wittkowski
W, Lang D, et al. Increased inorganic phosphate induces human endothelial cell
apoptosis in vitro. Am J Physiol Renal Physiol 2008;294:F1381-7. PMID: 18385273
DOI: http://dx.doi.org/10.1152/ajprenal.00003.2008
http://dx.doi.org/10.1152/ajprenal.00003...
,4747. Van TV, Watari E, Taketani Y, Kitamura T, Shiota A, Tanaka T, et
al. Dietary phosphate restriction ameliorates endothelial dysfunction in
adenine-induced kidney disease rats. J Clin Biochem Nutr 2012;51:27-32. DOI:
http://dx.doi.org/10.3164/jcbn.11-96
http://dx.doi.org/10.3164/jcbn.11-96...
A major limitation in the interpretation of Pi effects in
vivo is the difficulty to know whether they are the result of a
direct action of Pi or rather due to indirect mechanisms, e.g. via an
increase in serum PTH levels. In two studies using a rat model of CKD, in
which the animals underwent parathyroidectomy and continuous controlled
infusion of PTH, the authors were able to demonstrate a direct Pi effect on
the heart, inducing myocardial hypertrophy, cardiomyocyte hyperplasia and
interstitial fibrosis, and vessels in the absence of changes in serum PTH
concentration.4848. Neves KR, Graciolli FG, dos Reis LM, Pasqualucci CA, Moysés RM,
Jorgetti V. Adverse effects of hyperphosphatemia on myocardial hypertrophy,
renal function, and bone in rats with renal failure. Kidney Int 2004;66:2237-44.
PMID: 15569312 DOI:
http://dx.doi.org/10.1111/j.1523-1755.2004.66013.x
http://dx.doi.org/10.1111/j.1523-1755.20...
49. Custódio MR, Koike MK, Neves KR, dos Reis LM, Graciolli FG,
Neves CL, et al. Parathyroid hormone and phosphorus overload in uremia: impact
on cardiovascular system. Nephrol Dial Transplant 2012;27:1437-45. DOI:
http://dx.doi.org/10.1093/ndt/gfr447
http://dx.doi.org/10.1093/ndt/gfr447...
-5050. Graciolli FG, Neves KR, dos Reis LM, Graciolli RG, Noronha IL,
Moysés RM, et al. Phosphorus overload and PTH induce aortic expression of Runx2
in experimental uraemia. Nephrol Dial Transplant 2009;24:1416-21. DOI:
http://dx.doi.org/10.1093/ndt/gfn686
http://dx.doi.org/10.1093/ndt/gfn686...
Recent clinical evidence attributing Pi an important role as a culprit in CVD in both CKD and general population has brought this compound to the forefront of uremic toxins. It is also worth mentioning that the amount of Pi in Western diet, especially due to its use as a food additive, is probably much higher than the one recommended by health authorities, resulting in the excessive exposure to a continuous Pi overload. Therefore, given the increased CVD and mortality risk associated with hyperphosphatemia, the proposition has been made to label food products with high Pi content in the interest of public health, similarly to what is currently recommended for food NaCl content.
Middle molecules
Fibroblast growth factor-23
FGF23 was described more than 10 years ago by two independent groups.5151. Yamashita T, Yoshioka M, Itoh N. Identification of a novel
fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral
thalamic nucleus of the brain. Biochem Biophy Res Comm 2000;277:494-8. DOI:
http://dx.doi.org/10.1006/bbrc.2000.3696
http://dx.doi.org/10.1006/bbrc.2000.3696...
,5252. ADHR Consortium. Autossomal dominant hypophosphataemic rickets
is associated with mutations in FGF23. Nat Genet 2000; 26:345-8. DOI:
http://dx.doi.org/10.1038/81664
http://dx.doi.org/10.1038/81664...
This hormone, secreted by osteocytes and
osteoblasts, is a protein constituted by 251-amino-acids (MW: 30,000 Da).
Its major function is the control of mineral metabolism, particularly serum
Pi and calcitriol levels, through inhibition of renal tubular Pi
reabsorption and 1α-hydroxylase activity. FGF23 also acts on the parathyroid
gland inhibiting PTH secretion. All these actions are mediated by FGF23
binding to FGF receptors (FGFR) and its co-receptor Klotho, which greatly
increases the binding affinity of FGF23 for FGFR.5353. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K,
et al. Klotho converts canonical FGF receptor into a specific receptor for
FGF23. Nature 2006;444:770-4. PMID: 17086194 DOI:
http://dx.doi.org/10.1038/nature05315
http://dx.doi.org/10.1038/nature05315...
,5454. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M,
Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin
Invest 2007;117:4003-8. PMID: 17992255
The serum FGF23 level increases early in the course of CKD, probably due to a
state of primary FGF23 excess, resulting from a combination of increased
production and decreased degradation.5555. Larsson T, Nisbeth U, Ljunggren O, Jüppner H, Jonsson KB.
Circulating concentration of FGF-23 increases as renal function declines in
patients with chronic kidney disease, but does not change in response to
variation in phosphate intake in healthy volunteers. Kidney Int 2003;64:2272-9.
PMID: 14633152 DOI:
http://dx.doi.org/10.1046/j.1523-1755.2003.00328.x
http://dx.doi.org/10.1046/j.1523-1755.20...
As GFR declines, FGF23 increases and can reach levels >
1,000-fold above normal in patients with CKD stage 5D. Furthermore, residual
clearance by the kidney and removal by dialysis do not appear to modify
serum FGF23 to a significant extent.5656. Isakova T, Xie H, Barchi-Chung A, Vargas G, Sowden N, Houston J,
et al. Fibroblast growth factor 23 in patients undergoing peritoneal dialysis.
Clin J Am Soc Nephrol 2011;6:2688-95. DOI:
http://dx.doi.org/10.2215/CJN.04290511
http://dx.doi.org/10.2215/CJN.04290511...
Numerous reports showed a positive association between elevated FGF23 levels
and adverse clinical outcomes, such as CKD progression,5757. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel
A, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic
kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc
Nephrol 2007;18:2600-8. DOI:
http://dx.doi.org/10.1681/ASN.2006080936
http://dx.doi.org/10.1681/ASN.2006080936...
,5858. Titan SM, Zatz R, Graciolli FG, dos Reis LM, Barros RT, Jorgetti
V, et al. FGF-23 as a predictor of renal outcome in diabetic nephropathy. Clin J
Am Soc Nephrol 2011;6:241-7. DOI:
http://dx.doi.org/10.2215/CJN.04250510
http://dx.doi.org/10.2215/CJN.04250510...
LVH,5959. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of
left ventricular hypertrophy in hemodialysis patients. Am J Med Sci
2009;337:116-22. PMID: 19214027 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e3181815498
http://dx.doi.org/10.1097/MAJ.0b013e3181...
VC6060. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD,
Choukroun G, et al.; European Uremic Toxin (EUTox) Work Group. FGF23 is
independently associated with vascular calcification but not bone mineral
density in patients at various CKD stages. Osteoporos Int 2012;23:2017-25. PMID:
22109743 and mortality in pre-dialysis and dialysis CKD
populations.6161. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H,
Shah A, et al. Fibroblast growth factor 23 and mortality among patients
undergoing hemodialysis. N Engl J Med 2008;359:584-92. PMID: 18687639 DOI:
http://dx.doi.org/10.1056/NEJMoa0706130
http://dx.doi.org/10.1056/NEJMoa0706130...
,6262. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, et al.
Fibroblast growth factor 23 and risks of mortality and end-stage renal disease
in patients with chronic kidney disease. JAMA 2011;305:2432-9. PMID: 21673295
DOI: http://dx.doi.org/10.1001/jama.2011.826
http://dx.doi.org/10.1001/jama.2011.826...
Considering the above effects of
FGF23 on biological functions, one might expect to see evidence in support
of a causal relationship in this respect. However, available experimental
findings do not allow a clear conclusion. For example, complete
neutralization of FGF23 action by a specific antibody has been shown to be
harmful since it aggravated hyperphosphatemia, VC, and mortality in a rat
model of CKD and mineral bone disorder (MBD).6363. Shalhoub V, Shatzen EM, Ward SC, Davis J, Stevens J, Bi V, et
al. FGF23 neutralization improves chronic kidney disease-associated
hyperparathyroidism yet increases mortality. J Clin Invest 2012;122:2543-53.
PMID: 22728934 DOI: http://dx.doi.org/10.1172/JCI61405
http://dx.doi.org/10.1172/JCI61405...
This observation suggests that FGF23, like PTH, exerts
beneficial effects in early stages of CKD but that its excessive rise with
the progression of CKD to ESKD is a maladaptation syndrome with highly
deleterious consequences.
Regarding LVH, convincing experimental evidence has recently been provided by
Faul et al. in favor of a direct noxious effect of
FGF23.6464. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al.
FGF23 induces left ventricular hypertrophy. J Clin Invest 2011;121:4393-408.
PMID: 21985788 DOI: http://dx.doi.org/10.1172/JCI46122
http://dx.doi.org/10.1172/JCI46122...
The authors showed that
the intramyocardial or intravenous injection of FGF23 in wild-type mice
induced LVH, independent of Klotho which is not expressed in the
myocardium.6464. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al.
FGF23 induces left ventricular hypertrophy. J Clin Invest 2011;121:4393-408.
PMID: 21985788 DOI: http://dx.doi.org/10.1172/JCI46122
http://dx.doi.org/10.1172/JCI46122...
In addition, the
authors reported that elevated FGF23 levels were independently associated
with LVH in a large, racially diverse CKD cohort, in line with findings by
others in the general population.6565. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact
FGF23 associate with left ventricular mass, hypertrophy and geometry in an
elderly population. Atherosclerosis 2009;207:546-1. DOI:
http://dx.doi.org/10.1016/j.atherosclerosis.2009.05.013
http://dx.doi.org/10.1016/j.atherosclero...
However, not all authors have been able to find an association of high FGF23
levels with vascular calcification6666. Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel
MH, et al. Fibroblast growth factor 23 is not associated with and does not
induce arterial calcification. Kidney Int 2013;83:1159-68. DOI:
http://dx.doi.org/10.1038/ki.2013.3
http://dx.doi.org/10.1038/ki.2013.3...
or mortality5959. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of
left ventricular hypertrophy in hemodialysis patients. Am J Med Sci
2009;337:116-22. PMID: 19214027 DOI:
http://dx.doi.org/10.1097/MAJ.0b013e3181815498
http://dx.doi.org/10.1097/MAJ.0b013e3181...
,6767. Olauson H, Qureshi AR, Miyamoto T, Barany P, Heimburger O,
Lindholm B, et al. Relation between serum fibroblast growth factor-23 level and
mortality in incident dialysis patients: are gender and cardiovascular disease
confounding the relationship? Nephrol Dial Transplant
2010;25:3033-8. Apparent inconsistencies can be
explained by small sample size, different approaches to adjust for
confounding factors, imaging of different arterial beds, lack of prospective
data, and finally, different FGF23 mechanisms of toxicity.
Therefore, it is not yet clear if FGF23 is only a surrogate marker of
CKD-MBD, CKD progression and cardiovascular disease or whether it is also an
active player and hence a potential therapeutic target. For a more detailed
review of FGF23 the reader should refer to recent comprehensive
reviews.6868. Oliveira RB, Moysés RM. FGF-23: state of the art . J Bras Nefrol
2010;32:323-1. DOI:
http://dx.doi.org/10.1590/S0101-28002010000300015
http://dx.doi.org/10.1590/S0101-28002010...
,6969. Wolf M. Update on fibroblast growth factor 23 in chronic kidney
disease. Kidney Int 2012;82:737-47. PMID: 22622492 DOI:
http://dx.doi.org/10.1038/ki.2012.176
http://dx.doi.org/10.1038/ki.2012.176...
Leptin
The hormone leptin is a 167-amino-acid secreted protein (MW: 16,000 Da),
expressed mainly in adipose tissue. It was originally proposed to be an
antiobesity factor. However, the majority of obese healthy individuals have
elevated serum leptin levels. Therefore, the hypothesis of leptin resistance
in human obesity emerged.7070. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW,
Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and
obese humans. N Engl J Med 1996;334:292-5. PMID: 8532024 DOI:
http://dx.doi.org/10.1056/NEJM199602013340503
http://dx.doi.org/10.1056/NEJM1996020133...
The
classical actions of leptin include the control of feeding behavior, energy
balance, fertility and immune function. Recently, other actions of leptin
have been described, such as its influence on bone mass and the
cardiovascular system.7171. Friedman JM, Halaas JL. Leptin and the regulation of body weight
in mammals. Nature 1998;395:763-70. PMID: 9796811 DOI:
http://dx.doi.org/10.1038/27376
http://dx.doi.org/10.1038/27376...
At the
cellular level, leptin stimulates alkaline phosphatase activity, as well as
the proliferation, migration and calcification of VSMCs.7272. Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin
enhances the calcification of vascular cells: artery wall as a target of leptin.
Circ Res 2001;88:954-60. PMID: 11349006 DOI:
http://dx.doi.org/10.1161/hh0901.090975
http://dx.doi.org/10.1161/hh0901.090975...
,7373. Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic
smooth muscle cell proliferation and migration. Kobe J Med Sci 2001;47:141-50.
PMID: 11729375
Although clinical studies in the general population have shown a link between
leptin and CVD,7474. Singhal A, Farooqi IS, Cole TJ, O'Rahilly S, Fewtrell M,
Kattenhorn M, et al. Influence of leptin on arterial distensibility: a novel
link between obesity and cardiovascular disease? Circulation 2002;106:1919-24.
PMID: 12370213,7575. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A,
et al. Plasma leptin and the risk of cardiovascular disease in the west of
Scotland coronary prevention study (WOSCOPS). Circulation 2001;104:3052-6. PMID:
11748099 DOI: http://dx.doi.org/10.1161/hc5001.101061
http://dx.doi.org/10.1161/hc5001.101061...
leptin's role in CKD seems to be
more complex. A group of authors have suggested that dialysis patients with
high, rather that low, serum leptin levels have better outcomes,7676. Scholze A, Rattensperger D, Zidek W, Tepel M. Low serum leptin
predicts mortality in patients with chronic kidney disease stage 5. Obesity
(Silver Spring) 2007;15:1617-22. DOI:
http://dx.doi.org/10.1038/oby.2007.191
http://dx.doi.org/10.1038/oby.2007.191...
However, there was no association
between serum leptin and body mass index (BMI). Clearly, the relation
between serum leptin and BMI is complex in ESKD, and other group did not
find any survival advantage in obese HD patients as compared to lean HD
patients.7777. de Mutsert R, Snijder MB, van der Sman-de Beer F, Seidell JC,
Boeschoten EW, Krediet RT, et al. Association between body mass index and
mortality is similar in the hemodialysis population and the general population
at high age and equal duration of follow-up. J Am Soc Nephrol 2007;18:967-74.
DOI: http://dx.doi.org/10.1681/ASN.2006091050
http://dx.doi.org/10.1681/ASN.2006091050...
Apart from the unsolved issue of the role of leptin in clinical outcomes of
CKD patients, leptin appears to be related to the metabolic syndrome. In a
clinical study of 142 patients with CKD stages 2-5D, followed for a minimum
of 20 months, plasma leptin was an independent predictor of metabolic
syndrome but not of clinical outcomes. Interestingly, PTH was an independent
predictor of plasma leptin levels.7878. de Oliveira RB, Liabeuf S, Okazaki H, Lenglet A, Desjardins L,
Lemke HD, et al. The clinical impact of plasma leptin levels in a cohort of
chronic kidney disease patients. Clin Kidney J 2013;6:63-70. DOI:
http://dx.doi.org/10.1093/ckj/sfs176
http://dx.doi.org/10.1093/ckj/sfs176...
Taking into account these two findings, one could speculate that leptin is
related to factors that exert a more close impact on the clinical outcomes
of CKD patients, such as mineral disturbances and metabolic factors. This
hypothesis remains to be proven in future clinical long-term studies.
Parathyroid hormone
Secondary hyperparathyroidism, characterized by an increase in PTH (MW: 9.4
kDa) synthesis and secretion and by parathyroid gland hyperplasia, is a
common complication of CKD. Elevated PTH levels are generally found since
the early stages of CKD (GFR > 60 ml/min/1.73 m2), in any case
much sooner than hyperphosphatemia.2727. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA,
et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in
patients with chronic kidney disease: results of the study to evaluate early
kidney disease. Kidney Int 2007;71:31-8. DOI:
http://dx.doi.org/10.1038/sj.ki.5002009
http://dx.doi.org/10.1038/sj.ki.5002009...
As one of the most important regulators of bone metabolism, PTH in excess
induces significant changes in bone structure and function, leading to the
development of high turnover bone disease which, in association with CKD, is
called osteitis fibrosa.2929. Sampaio EA, Lugon JR, Barreto FC. Fisopatologia do
hiperparatireoidismo secundário J Bras Nefrol 2008;30:6-10.,7979. Mac Way F, Lessard M, Lafage-Proust MH. Pathophysiology of
chronic kidney disease-mineral and bone disorder. Joint Bone Spine
2012;79:544-9. PMID: 23177912 DOI:
http://dx.doi.org/10.1016/j.jbspin.2012.09.014
http://dx.doi.org/10.1016/j.jbspin.2012....
It is
characterized by increased bone fragility, which may explain, at least in
part, the association between sHPT and increased fracture risk.8080. Jadoul M, Albert JM, Akiba T, Akizawa T, Arab L, Bragg-Gresham
JL, et al. Incidence and risk factors for hip or other bone fractures among
hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.
Kidney Int 2006;70:1358- 66. PMID: 16929251 DOI:
http://dx.doi.org/10.1038/sj.ki.5001754
http://dx.doi.org/10.1038/sj.ki.5001754...
In addition, sHPT may cause bone
marrow fibrosis and impair erythropoiesis. It has been suggested that very
high PTH levels contribute to the polyneuropathy, glucose intolerance,
dyslipidemia and inflammation of the uremic state.8181. Rodriguez M, Lorenzo V. Parathyroid hormone, a uremic toxin.
Semin Dial 2009;22:363-8. DOI:
http://dx.doi.org/10.1111/j.1525-139X.2009.00581.x
http://dx.doi.org/10.1111/j.1525-139X.20...
It is important to recognize that toxic PTH levels may lead to deleterious
effects on many other organs and tissues due to the ubiquitous expression of
its main receptor, PTH1R, including the cardiovascular system. Observational
studies have found associations between high PTH levels and CVD in the
setting of CKD, such as VC,8282. Hernandes FR, Barreto FC, Rocha LA, Draibe SA, Canziani ME,
Carvalho AB. Evaluation of the role of severe hyperparathyroidism on coronary
artery calcification in dialysis patients. Clin Nephrol 2007;67:89-95. PMID:
17338428 DOI: http://dx.doi.org/10.5414/CNP67089
http://dx.doi.org/10.5414/CNP67089...
disturbed left ventricular function8383. Drüeke T, Fauchet M, Fleury J, Lesourd P, Toure Y, Le Pailleur
C, et al. Effect of parathyroidectomy on left-ventricular function in
haemodialysis patients. Lancet 1980;1:112-4. DOI:
http://dx.doi.org/10.1016/S0140-6736(80)90602-9
http://dx.doi.org/10.1016/S0140-6736(80)...
and mortality.8484. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow
GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J
Am Soc Nephrol 2004;15:2208-18. DOI:
http://dx.doi.org/10.1097/01.ASN.0000133041.27682.A2
http://dx.doi.org/10.1097/01.ASN.0000133...
Observational
studies have pointed toward an association between PTH and cardiovascular
mortality in the general population as well.8585. van Ballegooijen AJ, Reinders I, Visser M, Dekker JM, Nijpels G,
Stehouwer CD, et al. Serum parathyroid hormone in relation to all-cause and
cardiovascular mortality: the Hoorn study. J Clin Endocrinol Metab
2013;98:E638-45. DOI: http://dx.doi.org/10.1210/jc.2012-4007
http://dx.doi.org/10.1210/jc.2012-4007...
CKD patients with severe sHPT often develop severe VC, which
are particularly located in the arterial media such as the ones observed in
digitial arteries of the hands and the feet, and which can entirely regress
after surgical parathyroidectomy.8686. Rostand SG, Drüeke TB. Parathyroid hormone, vitamin D, and
cardiovascular disease in chronic renal failure. Kidney Int 1999;56:383-92.
PMID: 10432376 DOI:
http://dx.doi.org/10.1046/j.1523-1755.1999.00575.x
http://dx.doi.org/10.1046/j.1523-1755.19...
The effect of PTH on the CV system is an issue under continuous
investigation. Experimental studies using a rat model of CKD (5/6
nephrectomy) in which the animals underwent parathyroidectomy, the
continuous infusion of supraphysiological rates of synthetic PTH was
associated with the development of extensive VC - independently of serum Pi
levels or the presence of uremia.4848. Neves KR, Graciolli FG, dos Reis LM, Pasqualucci CA, Moysés RM,
Jorgetti V. Adverse effects of hyperphosphatemia on myocardial hypertrophy,
renal function, and bone in rats with renal failure. Kidney Int 2004;66:2237-44.
PMID: 15569312 DOI:
http://dx.doi.org/10.1111/j.1523-1755.2004.66013.x
http://dx.doi.org/10.1111/j.1523-1755.20...
In another study using the same CKD rat model, higher PTH levels were
associated with myocardial hypertrophy and fibrosis along with higher
myocardial expression of inflammation markers and oxidative stress.4949. Custódio MR, Koike MK, Neves KR, dos Reis LM, Graciolli FG,
Neves CL, et al. Parathyroid hormone and phosphorus overload in uremia: impact
on cardiovascular system. Nephrol Dial Transplant 2012;27:1437-45. DOI:
http://dx.doi.org/10.1093/ndt/gfr447
http://dx.doi.org/10.1093/ndt/gfr447...
Furthermore, studies have reported
the interplay between PTH on the one hand and aldosterone and norepinephrine
release on the other, suggesting additional pathophysiologic pathways by
which sHPT may lead to cardiovascular damage.8787. Tomaschitz A, Ritz E, Pieske B, Fahrleitner-Pammer A, Kienreich
K, Horina JH, et al. Aldosterone and parathyroid hormone: a precarious couple
for cardiovascular disease. Cardiovasc Res 2012;94:10-9. PMID: 22334595 DOI:
http://dx.doi.org/10.1093/cvr/cvs092
http://dx.doi.org/10.1093/cvr/cvs092...
,8888. Potthoff SA, Janus A, Hoch H, Frahnert M, Tossios P, Reber D, et
al. PTH-receptors regulate norepinephrine release in human heart and kidney.
Regul Pept 2011;171:35-42. PMID: 21756942 DOI:
http://dx.doi.org/10.1016/j.regpep.2011.06.002
http://dx.doi.org/10.1016/j.regpep.2011....
Finally, there is increasing evidence that circulating fragments of PTH,
which are elevated in the uremic state, are hormonally active, exerting
partially opposing effects to those of intact PTH. Thus, it has been
suggested that 7-84 PTH fragments may be involved in the skeletal resistance
to PTH observed in CKD.8989. Iwasaki Y, Yamato H, Nii-Kono T, Fujieda A, Uchida M, Hosokawa
A, et al. Insufficiency of PTH action on bone in uremia. Kidney Int Suppl
2006:S34-6. DOI: http://dx.doi.org/10.1038/sj.ki.5001600
http://dx.doi.org/10.1038/sj.ki.5001600...
There is an intricate relationship between PTH and other factors involved in
the disturbances of mineral metabolism in CKD, which may fog the importance
of PTH per se as a risk factor for uremia-related complications. The
inconclusive, non-definitive results of the recent EVOLVE trial have further
contributed to this uncertainty, since in intent-to-treat analysis there was
no significant advantage of cinacalcet treatment over best presently
available standard treatment in the combined primary endpoint
(cardiovascular events plus death) despite a marked decrease in serum
PTH.9090. EVOLVE Trial Investigators; Chertow GM, Block GA, Correa-Rotter
R, Drüeke TB, Floege J, Goodman WG, et al. Effect of cinacalcet on
cardiovascular disease in patients undergoing dialysis. N Engl J Med
2012;367:2482-94. PMID: 23121374 DOI:
http://dx.doi.org/10.1056/NEJMoa1205624
http://dx.doi.org/10.1056/NEJMoa1205624...
However, when performing
prespecified corrections of major confounders such as age and study drug
discontinuation the better control of hyperparathyroidism was associated
with a nominally significant superiority in hard outcomes. Of note, numerous
previous clinical and experimental studies support the hypothesis that PTH
acts as a systemic uremic toxin, with direct and indirect effects on a
variety of tissues and organs, and severe sHPT is a major threat to CKD
patient outcomes. Therefore, PTH remains an important therapeutic target to
avoid bone and cardiovascular complications in such patients.
Advanced glycation end products (AGEs) and advanced oxidized protein products (AOPPs)
AGEs are a heterogeneous group of molecules formed by non-enzymatic
glycosylation reactions with sugars, lipids and nucleic acids. Humans are
exposed to two main sources of AGEs. The exogenous forms come from diet
whereas the endogenous ones are formed in the body. AGE transformation of
nutrients occurs when foods are processed at high temperature. In contrast,
endogenous transformation results from exposure to high glucose levels such
as in diabetic patients, from aging, and from uremia.9191. Semba RD, Nicklett EJ, Ferrucci L. Does accumulation of advanced
glycation and products contribute to the aging phenotype? J Gerontol A Biol Sci
Med Sci 2010;65:963-75. PMID: 20478906,9292. Schwedler S, Schinzel R, Vaith P, Wanner C. Inflammation and
advanced glycation end products in uremia: simple coexistence, potentiation or
causal relationship? Kidney Int Suppl 2001;78:S32-6. PMID: 11168979
AGEs result in a first step from non-enzymatic glycation of proteins by
aldehyde and ketones to form a Schiff base. After rearrangement of the these
structures, the intermediary products are formed (Amadori products), and
finally, AGEs in a second step.9393. Piperi C, Adamopoulos C, Dalagiorgou G, Diamanti-Kandarakis E,
Papavassiliou AG. Crosstalk between advanced glycation and endoplasmic reticulum
stress: emerging therapeutic targeting for metabolic diseases. J Clin Endocrinol
Metab 2012;97:2231-42. PMID: 22508704 DOI:
http://dx.doi.org/10.1210/jc.2011-3408
http://dx.doi.org/10.1210/jc.2011-3408...
There are more than 20 AGE compounds, including 1,2-dicarbonyl precursor
compounds glyoxal, methylglyoxal, and the end products,
N-carboxymethyl-lysine, pentosidine, and hydroimidazolone as the best
characterized compounds, which serve as markers of AGE accumulation in a
range of tissues.9494. Thornalley PJ, Rabbani N. Highlights and hotspots of protein
glycation in end-stage renal disease. Semin Dial 2009;22:400-4. DOI:
http://dx.doi.org/10.1111/j.1525-139X.2009.00589.x
http://dx.doi.org/10.1111/j.1525-139X.20...
AGEs main pathway
of elimination from the body is through the urine, or through dialysis in
case of renal function replacement.9595. Alhamdani MS, Al-Azzawie HF, Abbas FK. Decreased formation of
advanced glycation end-products in peritoneal fluid by carnosine and related
peptides. Perit Dial Int 2007;27:86-9.
Patients under PD are more susceptible than HD patients to systemic and
local formation of AGEs, not only as a result of the uremic state but also
of the constant exposure of the peritoneum to high levels of glucose and
glucose degradation products generated during sterilization of dialysis
fluid by heat.9595. Alhamdani MS, Al-Azzawie HF, Abbas FK. Decreased formation of
advanced glycation end-products in peritoneal fluid by carnosine and related
peptides. Perit Dial Int 2007;27:86-9. Moreover, AGEs
accumulate progressively in the peritoneal mesothelial layer with increasing
dialysate dwell time.9696. Brunkhorst R, Kruse M, Ehlerding G, Mahiout A. Advanced
glycosylated end-products (AGEs) in non-diabetic patients undergoing dialysis.
Clin Nephrol 1996;46:265-6. Another cause
of increased AGE formation in the uremic state is oxidative stress,
generated by an imbalance between pro-oxidant forces (such as an increase in
the ratio of oxidized glutathione to reduced glutathione) and anti-oxidant
defense system (such as reduced superoxide dismutase/peroxidase
activity).
AGEs exert several potentially deleterious effects in the body. In the
cardiovascular system, their accumulation contributes to myocardial changes,
endothelial dysfunction, arterial stiffness, and atherosclerotic plaque
formation. When these molecules bind to collagen and elastin, they
accumulate in the matrix of blood vessels in a non functional and disorderly
way, changing endothelial vasomotor tone modulation, platelet adhesion, and
cell proliferation.9797. Zieman S, Kass D. Advanced glycation end product cross-linking:
pathophysiologic role and therapeutic target in cardiovascular disease. Congest
Heart Fail 2004;10:144-9. DOI:
http://dx.doi.org/10.1111/j.1527-5299.2004.03223.x
http://dx.doi.org/10.1111/j.1527-5299.20...
AGEs exert
their actions in the vascular system by binding to a specific receptor,
called RAGE. Activation of RAGE induces an inflammatory response, leading to
the effects described above and also increasing the production of adhesion
molecules, increasing proliferation of the vessel intimal layer,
angiogenesis and oxidative stress.9898. Xu Y, Wang S, Feng L, Zhu Q, Xiang P, He B. Blockade of PKC-beta
protects HUVEC from advanced glycation end products induced inflammation. Int
Immunopharmacol 2010;10:1552-9. DOI:
http://dx.doi.org/10.1016/j.intimp.2010.09.006
http://dx.doi.org/10.1016/j.intimp.2010....
RAGE is expressed in all cells involved in atherogenesis, including
monocytes, macrophages, endothelial cells and VSMC. Interestingly, these
cells do not express significant amounts of RAGE under physiological
conditions, but can be induced to express RAGE more vigorously in conditions
where their ligands and/or transcription factors accumulate, like in
uremia.9999. Figarola JL, Shanmugam N, Natarajan R, Rahbar S.
Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90
in human monocytes. Diabetes 2007;56:647-55. PMID: 17327432 DOI:
http://dx.doi.org/10.2337/db06-0936
http://dx.doi.org/10.2337/db06-0936...
Advanced oxidation protein products (AOPPs) are a class of
dityrosine-containing protein products, which arise from the reaction
between chlorinated oxidants and plasma proteins. Increased levels of AOPPs
are detected in uremic serum since predialysis stage. AOPPs have been
suggested to be not only reliable markers of oxidative stress but also
mediators of inflammation, by triggering monocyte activation.100100. Witko-Sarsat V, Friedlander M, Capeillère-Blandin C,
Nguyen-Khoa T, Nguyen AT, Zingraff J, et al. Advanced oxidation protein products
as a novel marker of oxidative stress in uremia. Kidney Int 1996;49:1304-13.
PMID: 8731095 DOI: http://dx.doi.org/10.1038/ki.1996.186
http://dx.doi.org/10.1038/ki.1996.186...
They have been associated with
podocyte injury,101101. Zhou LL, Hou FF, Wang GB, Yang F, Xie D, Wang YP, et al.
Accumulation of advanced oxidation protein products induces podocyte apoptosis
and deletion through NADPH-dependent mechanisms Kidney Int 2009;76:1148-60.
PMID: 19727064 incident
thrombo-occlusive atherosclerotic CV events in the pre-dialysis setting102102. Descamps-Latscha B, Witko-Sarsat V, Nguyen-Khoa T, Nguyen AT,
Gausson V, Mothu N, et al. Advanced oxidation protein products as risk factors
for atherosclerotic cardiovascular events in nondiabetic predialysis patients.
Am J Kidney Dis 2005;45:39- 47. PMID: 15696442 DOI:
http://dx.doi.org/10.1053/j.ajkd.2004.09.011
http://dx.doi.org/10.1053/j.ajkd.2004.09...
and carotid atherosclerosis in
ESKD patients.103103. Drüeke T, Witko-Sarsat V, Massy Z, Descamps-Latscha B, Guerin
AP, Marchais SJ, et al. Iron therapy, advanced oxidation protein products, and
carotid artery intima-media thickness in end-stage renal disease. Circulation
2002;106:2212- 7. PMID: 12390950 DOI:
http://dx.doi.org/10.1161/01.CIR.0000035250.66458.67
http://dx.doi.org/10.1161/01.CIR.0000035...
These findings
support the hypothesis that AOPPs should be considered as uremic toxins.
Protein-bound uremic toxins
Indoxyl sulfate
Indoxyl sulfate (IS) is a low-MW (213.21 Da) uremic toxin derivated from
dietary protein. It is an indol derived from the amino acid tryptophan by
action of intestinal bacteria.104104. Niwa T. Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci
2010;72:1-11. It
is normally excreted into the urine, with its mean urinary excretion rate
ranging from 50-70 mg/day in healthy persons. In CKD patients, as renal
function declines it accumulates in serum due to its reduced renal
clearance.105105. Bolati D, Shimizu H, Yisireyili M, Nishijima F, Niwa T. Indoxyl
sulfate, a uremic toxin, downregulates renal expression of Nrf2 through
activation of NF-κB. BMC Nephrol 2013;14:56. DOI:
http://dx.doi.org/10.1186/1471-2369-14-56
http://dx.doi.org/10.1186/1471-2369-14-5...
The main part of
IS in the blood of CKD patients is bound to serum albumin, which means that
its urinary excretion occurs mainly by tubular secretion, mainly by proximal
tubular cells, and secondarily by glomerular filtration. Organic anion
transporter (OAT) 1, the prototypic para-amino hippurate transporter, is
localized in renal tubular cells and interacts with a wide range of small
endogenous substances, including IS. IS is taken up from the blood by OAT1
and OAT3 at the basolateral membrane of tubular cells and accumulates in the
cells at high concentrations.106106. Taki K, Nakamura S, Miglinas M, Enomoto A, Niwa T. Accumulation
of indoxyl sulfate in OAT1/3-positive tubular cells in kidneys of patients with
chronic renal failure. J Ren Nutr 2006;16:199-203. DOI:
http://dx.doi.org/10.1053/j.jrn.2006.04.020
http://dx.doi.org/10.1053/j.jrn.2006.04....
Several studies have shown an impact of IS accumulation in CKD patients.
Increased IS concentrations compete for protein binding or excretion with
other molecules. IS probably mediates its toxicity by direct induction of a
host of genes involved in inflammation and fibrosis.107107. Lowenstein J. The anglerfish and uremic toxins. FASEB J
2011;25:1781-5. DOI: http://dx.doi.org/10.1096/fj.11-0602ufm
http://dx.doi.org/10.1096/fj.11-0602ufm...
IS plays a key role in endothelial damage and
triggers the production of pro-inflammatory molecules, inhibition of
endothelial regeneration and repair, and endothelial free radical
production.108108. Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R, et
al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial
proliferation and wound repair. Kidney Int 2004;65:442-51. DOI:
http://dx.doi.org/10.1111/j.1523-1755.2004.00399.x
http://dx.doi.org/10.1111/j.1523-1755.20...
In addition, the
participation of IS in VC, endothelial microparticle release, disruption of
adherent junctions of endothelial cells, proliferation of VSMCs, renal and
cardiac fibrosis, and impairement of osteoclast differentiation and function
has been reported as well.109109. Bammens B, Evenepoel P, Verbeke K, Vanrenterghem Y. Removal of
middle molecules and protein-bound solutes by peritoneal dialysis and relation
with uremic symptoms. Kidney Int 2003;64:2238-43. DOI:
http://dx.doi.org/10.1046/j.1523-1755.2003.00310.x
http://dx.doi.org/10.1046/j.1523-1755.20...
110. Neirynck N, Vanholder R, Schepers E, Eloot S, Pletinck A,
Glorieux G. An update on uremic toxins. Int Urol Nephrol 2013;45:139-50. DOI:
http://dx.doi.org/10.1007/s11255-012-0258-1
http://dx.doi.org/10.1007/s11255-012-025...
111. Mozar A, Louvet L, Godin C, Mentaverri R, Brazier M, Kamel S,
et al. Indoxyl sulphate inhibits osteoclast differentiation and function.
Nephrol Dial Transplant 2012;27:2176-81. DOI:
http://dx.doi.org/10.1093/ndt/gfr647
http://dx.doi.org/10.1093/ndt/gfr647...
-112112. Mozar A, Louvet L, Morlière P, Godin C, Boudot C, Kamel S, et
al. Uremic toxin indoxyl sulfate inhibits human vascular smooth muscle cell
proliferation. Ther Apher Dial 2011;15:135-9. DOI:
http://dx.doi.org/10.1111/j.1744-9987.2010.00885.x
http://dx.doi.org/10.1111/j.1744-9987.20...
It
has been proposed that IS may affect the remnant nephrons, especially
proximal tubular cells, and stimulate tubulointerstitial fibrosis,
glomerular sclerosis, and the progression of CKD by increasing the gene
expression of TGF-β1, TIMP-1, and pro-α1collagen, leading to a further loss
of nephrons, completing the vicious circle of progressive renal injury.104104. Niwa T. Uremic toxicity of indoxyl sulfate. Nagoya J Med Sci
2010;72:1-11. Several clinical studies have
shown that high IS levels are associated with high IL-6 levels, coronary
artery disease, vascular damage, progression of CKD and mortality (Figure 2).112112. Mozar A, Louvet L, Morlière P, Godin C, Boudot C, Kamel S, et
al. Uremic toxin indoxyl sulfate inhibits human vascular smooth muscle cell
proliferation. Ther Apher Dial 2011;15:135-9. DOI:
http://dx.doi.org/10.1111/j.1744-9987.2010.00885.x
http://dx.doi.org/10.1111/j.1744-9987.20...
113. Lee CT, Kuo CC, Chen YM, Hsu CY, Lee WC, Tsai YC, et al.
Factors associated with blood concentrations of indoxyl sulfate and p-cresol in
patients undergoing peritoneal dialysis. Perit Dial Int 2010;30:456-63. DOI:
http://dx.doi.org/10.3747/pdi.2009.00092
http://dx.doi.org/10.3747/pdi.2009.00092...
114. Chiu CA, Lu LF, Yu TH, Hung WC, Chung FM, Tsai IT, et al.
Increased levels of total P-Cresylsulphate and indoxyl sulphate are associated
with coronary artery disease in patients with diabetic nephropathy. Rev Diabet
Stud 2010;7:275-84. DOI:
http://dx.doi.org/10.1900/RDS.2010.7.275
http://dx.doi.org/10.1900/RDS.2010.7.275...
115. Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar
M, et al.; European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is
associated with vascular disease and mortality in chronic kidney disease
patients. Clin J Am Soc Nephrol 2009;4:1551-8. DOI:
http://dx.doi.org/10.2215/CJN.03980609
http://dx.doi.org/10.2215/CJN.03980609...
-116116. Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, et al. p-Cresyl
sulphate and indoxyl sulphate predict progression of chronic kidney disease.
Nephrol Dial Transplant 2010;26:938-47.
Kaplan-Meyer estimates of several survival probability for CKD patients as a function of tertiles of serum indoxyl sulfate levels. Footnote: reprinted with permission from Barreto FC (ref.115).
Para-cresol (P-cresol) and P-cresyl sulFate (PCS)
P-cresol (4-methylphenol) is another uremic toxin (MW: 108 Da) linked to
serum proteins, with various deleterious effects. This molecule originates
from tyrosine and phenylalanine metabolism by bacterial microbiota
fermentation in the large intestine. During its passage through the colonic
mucosa and the liver, it is metabolized by conjugation processes (sulfation
and glucuronidation) forming two compounds, PCS and ρ-cresylglucoronidate.
In patients with CKD it is possible to find these two derivatives of
ρ-cresol, both in conjugated and unconjugated form.117117. de Loor H, Bammens B, Evenepoel P, De Preter V, Verbeke K. Gas
chromatographic-mass spectrometric analysis for measurement of p-cresol and its
conjugated metabolites in uremic and normal serum. Clin Chem 2005;51:1535-8.
DOI: http://dx.doi.org/10.1373/clinchem.2005.050781
http://dx.doi.org/10.1373/clinchem.2005....
The earliest studies with phenol compounds
involved ρ-cresol; however, it was discovered subsequently that this
compound is found in only tiny concentrations in the body since it is
rapidly metabolized to its conjugates by the intestinal microbiota. Of note,
it has been shown that the biochemical impact of ρ-cresol is not necessarily
the same as the impact of its conjugates.118118. Vanholder R, Van Laecke S, Glorieux G. What is new in uremic
toxicity? Pediatr Nephrol 2008;23:1211-21. Previous studies have demonstrated that these uremic toxins
are first taken up by the kidneys, blood vessels, bones, and across the
blood-brain barrier via OATs and then induce the production of oxygen free
radicals and inflammatory cytokines in the respective organs.119119. Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S,
et al. Major role of organic anion transporter 3 in the transport of indoxyl
sulfate in the kidney. Kidney Int 2002;61:1760-8. PMID: 11967025 DOI:
http://dx.doi.org/10.1046/j.1523-1755.2002.00318.x
http://dx.doi.org/10.1046/j.1523-1755.20...
120. Tsutsumi Y, Deguchi T, Takano M, Takadate A, Lindup WE, Otagiri
M. Renal disposition of a furan dicarboxylic acid and other uremic toxins in the
rat. J Pharmacol Exp Ther 2002;303:880-7. DOI:
http://dx.doi.org/10.1124/jpet.303.2.880
http://dx.doi.org/10.1124/jpet.303.2.880...
121. Enomoto A, Niwa T. Roles of organic anion transporters in the
progression of chronic renal failure. Ther Apher Dial 2007;1:S27- 31. DOI:
http://dx.doi.org/10.1111/j.1744-9987.2007.00515.x
http://dx.doi.org/10.1111/j.1744-9987.20...
-122122. Miyamoto Y, Watanabe H, Noguchi T, Kotani S, Nakajima M,
Kadowaki D, et al. Organic anion transporters play an important role in the
uptake of p-cresyl sulfate, a uremic toxin, in the kidney. Nephrol Dial
Transplant 2011;26:2498-502. DOI:
http://dx.doi.org/10.1093/ndt/gfq785
http://dx.doi.org/10.1093/ndt/gfq785...
ρ-cresol affects the inflammatory response,
interfering with the activation of polymorphonuclear leukocytes and
endothelial response to cytokines.123123. Dou L, Cerini C, Brunet P, Guilianelli C, Moal V, Grau G, et
al. P-cresol, a uremic toxin, decreases endothelial cell response to
inflammatory cytokines. Kidney Int 2002;62:1999-2009. PMID: 12427124 DOI:
http://dx.doi.org/10.1046/j.1523-1755.2002.t01-1-00651.x
http://dx.doi.org/10.1046/j.1523-1755.20...
However, neither in uremic patients nor in normal people
this molecule can be detected in the circulation in its unconjugated form,
in contrast to PCS.124124. Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G,
Schepers E, et al.; European Uraemic Toxin Work Group (EUTox). Free
p-cresylsulphate is a predictor of mortality in patients at different stages of
chronic kidney disease. Nephrol Dial Transplant 2010;25:1183-91. DOI:
http://dx.doi.org/10.1093/ndt/gfp592
http://dx.doi.org/10.1093/ndt/gfp592...
Meijers
et al. demonstrated that PCS induces the release of
endothelial microparticles, even in the absence of endothelial injury,
suggesting that this toxin is involved in endothelial dysfunction.125125. Meijers BK, Van Kerckhoven S, Verbeke K, Dehaen W,
Vanrenterghem Y, Hoylaerts MF, et al. The uremic retention solute p-cresyl
sulfate and markers of endothelial damage. Am J Kidney Dis 2009;54:891-901.
PMID: 19615803 DOI:
http://dx.doi.org/10.1053/j.ajkd.2009.04.022
http://dx.doi.org/10.1053/j.ajkd.2009.04...
Furthermore, Schepers et
al. observed a pro-inflammatory effect of PCS, measured by
increased formation of free radicals produced by leukocytes, contributing to
vascular damage in patients with CKD.126126. Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J,
Vanholder R. P-cresylsulphate, the main in vivo metabolite of p-cresol,
activates leucocyte free radical production. Nephrol Dial Transplant
2007;22:592-6. DOI: http://dx.doi.org/10.1093/ndt/gfl584
http://dx.doi.org/10.1093/ndt/gfl584...
Importantly, high PCS levels have been associated with
mortality in CKD.124124. Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G,
Schepers E, et al.; European Uraemic Toxin Work Group (EUTox). Free
p-cresylsulphate is a predictor of mortality in patients at different stages of
chronic kidney disease. Nephrol Dial Transplant 2010;25:1183-91. DOI:
http://dx.doi.org/10.1093/ndt/gfp592
http://dx.doi.org/10.1093/ndt/gfp592...
In addition,
Koppe et al. observed that normal mice treated with PCS for
4 weeks, developed insulin resistance, loss of fat mass, and ectopic
redistribution of lipid in muscle and liver, mimicking features associated
with CKD.127127. Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert
S, et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am
Soc Nephrol 2013;24:88-99. DOI:
http://dx.doi.org/10.1681/ASN.2012050503
http://dx.doi.org/10.1681/ASN.2012050503...
Therapeutic strategies
As discussed above, the uremic syndrome is a complex condition resulting from the effects of wide variety of toxins. Current strategies aimed to decrease their serum concentration are dietary and pharmacological interventions, mainly via modulation of intestinal absorption capacity through binding effects and/or reduction of ingested amounts of the toxins or their precursors, and extra-corporeal removal via PD and HD. Notably, removal of middle and protein-bound uremic toxins by conventional HD and PD is insufficient. The main therapeutic strategies aimed to reduce the level of these compounds and possible advantages are briefly discussed below.
Dietary intervention
Protein-bound uremic toxins are generally produced from the metabolism of amino
acids in the intestine. Thus, low-protein diet is often considered as a possible
dietary approach to reduce the serum concentration of these toxins. Animal
experiments have shown that rats fed a low-protein diet had lower concentration
of protein-bound solutes.128128. Brunet P, Dou L, Cerini C, Berland Y. Protein-bound uremic
retention solutes. Adv Ren Replace Ther 2003;10:310-20. DOI:
http://dx.doi.org/10.1053/j.arrt.2003.08.002
http://dx.doi.org/10.1053/j.arrt.2003.08...
Recently,
it was demonstrated that a reduced protein and Pi intakes associated with a very
low protein diet, supplemented with ketoanalogues and essential amino acids,
significantly lowered IS in CKD patients.129129. Marzocco S, Dal Piaz F, Di Micco L, Torraca S, Sirico ML,
Tartaglia D, et al. Very low protein diet reduces indoxyl sulfate levels in
chronic kidney disease. Blood Purif 2013;35:196-201. DOI:
http://dx.doi.org/10.1159/000346628
http://dx.doi.org/10.1159/000346628...
However, nephrologists should be aware of the fact that reducing
protein intake excessively may deteriorate the nutritional status of CKD
patients and that continuous nutritional evaluations by an expert dietitian are
required. Another interesting issue that needs further investigation is the
influence of vegetarian diets on the production of uremic toxins. The urinary
excretion of PCS and IS was 62% and 59% lower, respectively, in vegetarians than
in participants consuming an unrestricted diet, which was associated with higher
fiber intake and lower protein intake.130130. Patel KP, Luo FJ, Plummer NS, Hostetter TH, Meyer TW. The
production of p-cresol sulfate and indoxyl sulfate in vegetarians versus
omnivores. Clin J Am Soc Nephrol 2012;7:982-8. DOI:
http://dx.doi.org/10.2215/CJN.12491211
http://dx.doi.org/10.2215/CJN.12491211...
Finally, the use of pre and probiotics has been suggested as
interesting approach to reduce IS and PCS serum levels as well.131131. Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel
P. p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced
by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant
2010;25:219-24. DOI: http://dx.doi.org/10.1093/ndt/gfp414
http://dx.doi.org/10.1093/ndt/gfp414...
,132132. Rossi M, Klein K, Johnson DW, Campbell KL. Pre-, pro-, and
synbiotics: do they have a role in reducing uremic toxins? A systematic review
and meta-analysis. Int J Nephrol 2012;2012:673631. PMID: 23316359
Pharmacological intervention
The rationale for using oral sorbents to achieve a reduction of protein-bound
toxins in the circulation is that they are derived from the intestinal
metabolism of amino acids. Clinical studies have demonstrated that the oral
sorbent AST-120 (Kremezin® ) is associated with lower levels of
IS,133133. Schulman G, Agarwal R, Acharya M, Berl T, Blumenthal S, Kopyt
N. A multicenter, randomized, double-blind, placebo-controlled, dose-ranging
study of AST- 120 (Kremezin) in patients with moderate to severe CKD. Am J
Kidney Dis 2006;47:565-77. PMID: 16564934 DOI:
http://dx.doi.org/10.1053/j.ajkd.2005.12.036
http://dx.doi.org/10.1053/j.ajkd.2005.12...
slower progression of
CKD134134. Shimizu H, Okada S, Shinsuke OI, Mori M. Kremezin (AST-120)
delays the progression of diabetic nephropathy in Japanese type 2 diabetic
patients. Diabetes Care 2005;28:2590. DOI:
http://dx.doi.org/10.2337/diacare.28.10.2590
http://dx.doi.org/10.2337/diacare.28.10....
and improved survival after
dialysis was started.135135. Ueda H, Shibahara N, Takagi S, Inoue T, Katsuoka Y. AST-120
treatment in pre-dialysis period affects the prognosis in patients on
hemodialysis. Ren Fail 2008;30:856-60. DOI:
http://dx.doi.org/10.1080/08860220802356531
http://dx.doi.org/10.1080/08860220802356...
Experimental
studies had also shown potentially useful therapeutic effects of AST-120 in
preventing IS-induced pathological alterations, such as VC.136136. Fujii H, Nishijima F, Goto S, Sugano M, Yamato H, Kitazawa R,
et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage
in chronic kidney disease through suppression of oxidative stress. Nephrol Dial
Transplant 2009;24:2089-95. DOI:
http://dx.doi.org/10.1093/ndt/gfp007
http://dx.doi.org/10.1093/ndt/gfp007...
,137137. Iwasaki Y, Yamato H, Nii-Kono T, Fujieda A, Uchida M, Hosokawa
A, et al. Administration of oral charcoal adsorbent (AST-120) suppresses
low-turnover bone progression in uraemic rats. Nephrol Dial Transplant
2006;21:2768-74. DOI: http://dx.doi.org/10.1093/ndt/gfl311
http://dx.doi.org/10.1093/ndt/gfl311...
Results of two EPPIC trials, that evaluated the effectiveness of AST-120 added
to standard-of-care therapy in moderate to severe CKD, did not support efficacy
of this drug in slowing CKD progression. However, a subgroup analysis indicated
a trend for AST-120 associated reduction of CKD progression in compliant
patients with rapid decline of renal function.138138. Schulman G, Bel T, Beck GJ, Remuzzi G, Ritz E. EPPIC
(Evaluating Prevention of Progression in Chronic Kidney Disease): Results from 2
Phase III, Randomized, Placebo-Controlled, Double-Blind Trials of AST-120 in
Adults with CKD (Abstract). J Am Soc Nephrol 2012;23:7. Further trials are required to confirm the reality of this
trend.
The use of specific types of phosphate binders has also been proposed as a
possible means to decrease the concentrations of several uremic toxins, apart
from their main therapeutic utilization in the control of hyperphosphatemia.
Recently, two small clinical studies pointed to the possibility of achieving a
pharmacologic modulation of leptin139139. de Oliveira RB, Graciolli FG, dos Reis LM, Cancela AL, Cuppari
L, Canziani ME, et al. Disturbances of Wnt/ß-catenin pathway and energy
metabolism in early CKD: effect of phosphate binders. Nephrol Dial Transplant
2013;28:2510-7. DOI: http://dx.doi.org/10.1093/ndt/gft234
http://dx.doi.org/10.1093/ndt/gft234...
and FGF23140140. Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA,
Cuppari L, et al. Early control of PTH and FGF23 in normophosphatemic CKD
patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol
2010;5:286-91. levels in a cohort of early
stage CKD patients via the use of sevelamer. Moreover, Vlassara et
al. demonstrated in patients with diabetes and early CKD that
sevelamer reduced markers of inflammantion and oxidative stress, independently
of changes in Pi, possibly due to sevelamer's capacity to bind AGEs in the
intestinal lumen.141141. Vlassara H, Uribarri J, Cai W, Goodman S, Pyzik R, Post J, et
al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation and
products in diabetic kidney disease. Clin J Am Soc Nephrol 2012;7:934-42. DOI:
http://dx.doi.org/10.2215/CJN.12891211
http://dx.doi.org/10.2215/CJN.12891211...
In a recent
observational cross-sectional study, in PD patients, sevelamer use was
associated with lower levels of ρ-cresol as well.142142. Guida B, Cataldi M, Riccio E, Grumetto L, Pota A, Borrelli S,
et al. Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis
patients: evidence from a Cross-Sectional Observational Study. PLoS One
2013;8:e73558. DOI:
http://dx.doi.org/10.1371/journal.pone.0073558
http://dx.doi.org/10.1371/journal.pone.0...
In a pilot study in healthy volunteers treatment with
acarbose, an alpha-glucosidase inhibitor, decreased the generation and serum
concentrations of the protein bound uremic solute ρ-cresol.143143. Evenepoel P, Bammens B, Verbeke K, Vanrenterghem Y. Acarbose
treatment lowers generation and serum concentrations of the protein-bound solute
p-cresol: a pilot study. Kidney Int 2006;70:192-8. PMID: 16688114 DOI:
http://dx.doi.org/10.1038/sj.ki.5001523
http://dx.doi.org/10.1038/sj.ki.5001523...
Whether these actions may lead to an improvement of
specific uremia-related complications and overall outcome of patients with CKD
has yet to be shown.
Hemodialysis with high-flux membranes
Several randomized controlled trials (RCT) aimed to demonstrate that an increase
in the clearance of higher weight molecules via the use of high-flux dialysis
membranes led to a survival benefit as compared to standard low-flux membranes.
The first large-scale RCT was the HEMO study.144144. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek
JW, et al.; Hemodialysis (HEMO) Study Group. Hemodialysis (HEMO) Study Group.
Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J
Med 2002;347:2010-9. DOI:
http://dx.doi.org/10.1056/NEJMoa021583
http://dx.doi.org/10.1056/NEJMoa021583...
It failed to find a difference in mortality between the two
groups. It also was unable to demonstrate a benefit of high dialysis dose as
compared to standard dialysis dose. Post hoc secondary analyses of the HEMO
study pointed to a benefit of using high-flux membranes in terms of cardiac
outcomes,145145. Cheung AK, Levin NW, Greene T, Agodoa L, Bailey J, Beck G, et
al. Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO
study. J Am Soc Nephrol 2003;14:3251-63. DOI:
http://dx.doi.org/10.1097/01.ASN.0000096373.13406.94
http://dx.doi.org/10.1097/01.ASN.0000096...
and decreased
cerebro-vascular disease mortality in patient subcategories,145145. Cheung AK, Levin NW, Greene T, Agodoa L, Bailey J, Beck G, et
al. Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO
study. J Am Soc Nephrol 2003;14:3251-63. DOI:
http://dx.doi.org/10.1097/01.ASN.0000096373.13406.94
http://dx.doi.org/10.1097/01.ASN.0000096...
possibly as the result of better
middle molecule removal due to the larger pore size of this type of membrane. It
is worth mentioning that high-flux HD has no effect on protein-bound uremic
toxin levels. Similarly to the HEMO trial, the subsequently done MPO trial also
failed to demonstrate a survival advantage with the use of high-flux as compared
to low-flux dialysis membranes.146146. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A,
Papadimitriou M, Wizemann V, et al.; Membrane Permeability Outcome (MPO) Study
Group. Effect of membrane permeability on survival ofhemodialysis patients. J Am
Soc Nephrol 2009;20:645- 54. DOI:
http://dx.doi.org/10.1681/ASN.2008060590
http://dx.doi.org/10.1681/ASN.2008060590...
It
must be pointed out that positive results obtained by secondary analyses may
strengthen, but do not prove, the hypothesis that high-flux treatment may
improve cardiovascular events and survival in certain subpopulations of HD
patients.
Convective strategies (hemofiltration or hemodiafiltration)
It has been demonstrated that convective strategies improve the removal of middle
molecules and protein-bound uremic toxins.147147. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A
comparison of on-line hemodiafiltration and high-flux hemodialysis: a
prospective clinical study. J Am Soc Nephrol 2000;11:2344-50.,148148. Meert N, Eloot S, Waterloos MA, Van Landschoot M, Dhondt A,
Glorieux G, et al. Effective removal of protein-bound uraemic solutes by
different convective strategies: a prospective trial. Nephrol Dial Transplant
2009;24:562-70. DOI: http://dx.doi.org/10.1093/ndt/gfn522
http://dx.doi.org/10.1093/ndt/gfn522...
By
comparing three main convective strategies in parallel, named pre-dilution
hemodiafiltration (HDF), post-dilution HDF and pre-hemofiltration (HF), Meert
et al. reported that under similar convective volumes,
post-and pre-dilution HDF had similar effects on protein-bound molecules
removal, though the former appeared to be better for small water soluble
compounds and β2-microgobulin. Pre-HF was superior to pre-HDF only for
β2-microgobulin removal and not at all superior to post-HDF.148148. Meert N, Eloot S, Waterloos MA, Van Landschoot M, Dhondt A,
Glorieux G, et al. Effective removal of protein-bound uraemic solutes by
different convective strategies: a prospective trial. Nephrol Dial Transplant
2009;24:562-70. DOI: http://dx.doi.org/10.1093/ndt/gfn522
http://dx.doi.org/10.1093/ndt/gfn522...
In summary, post-HDF was found to be
the most effective convective strategy for solute removal. Mid-dilution HDF, a
new strategy that allows simultaneous infusion in a pre- and post-dilution
fashion, appears to be as efficient as post-dilution HDF for small water-soluble
and protein-bound solutes removal.149149. Eloot S, Dhondt A, Van Landschoot M, Waterloos MA, Vanholder R.
Removal of water-soluble and protein-bound solutes with reversed mid-dilution
versus post-dilution haemodiafiltration. Nephrol Dial Transplant 2012;27:3278-
83. DOI: http://dx.doi.org/10.1093/ndt/gfs060
http://dx.doi.org/10.1093/ndt/gfs060...
A beneficial impact of convective therapies on hard clinical outcomes is however
far from being firmly established. Although benefit has been suggested by
observational studies,150150. Canaud B, Bragg-Gresham JL, Marshall MR, Desmeules S, Gillespie
BW, Depner T, et al. Mortality risk for patients receiving hemodiafiltration
versus hemodialysis: European results from the DOPPS. Kidney Int
2006;69:2087-93. PMID: 16641921 DOI:
http://dx.doi.org/10.1038/sj.ki.5000447
http://dx.doi.org/10.1038/sj.ki.5000447...
,151151. Vilar E, Fry AC, Wellsted D, Tattersall JE, Greenwood RN,
Farrington K. Long-term outcomes in online hemodiafiltration and high-flux
hemodialysis: a comparative analysis. Clin J Am Soc Nephrol 2009;4:1944-53. DOI:
http://dx.doi.org/10.2215/CJN.05560809
http://dx.doi.org/10.2215/CJN.05560809...
the
results obtained in recent RCTs are less clear.152152. Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der
Weerd NC, Mazairac AH, et al.; CONTRAST Investigators. Effect of online
hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc
Nephrol 2012;23:1087-96. DOI:
http://dx.doi.org/10.1681/ASN.2011121140
http://dx.doi.org/10.1681/ASN.2011121140...
,153153. Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, et al.;
Turkish Online Haemodiafiltration Study. Mortality and cardiovascular events in
online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results
from the Turkish OL-HDF Study. Nephrol Dial Transplant 2013;28:192-202. DOI:
http://dx.doi.org/10.1093/ndt/gfs407
http://dx.doi.org/10.1093/ndt/gfs407...
Thus,
Grooteman et al. found in a recent multicenter RCT that
dialysis patients assigned to high-efficiency post-dilution on-line HDF had less
cardiovascular events but there was no difference between the two groups in the
primary endpoint, namely all-cause mortality.152152. Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der
Weerd NC, Mazairac AH, et al.; CONTRAST Investigators. Effect of online
hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc
Nephrol 2012;23:1087-96. DOI:
http://dx.doi.org/10.1681/ASN.2011121140
http://dx.doi.org/10.1681/ASN.2011121140...
Ok et al. set up an RCT comparing the effect of
on-line HDF to that of high-flux HD.153153. Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, et al.;
Turkish Online Haemodiafiltration Study. Mortality and cardiovascular events in
online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results
from the Turkish OL-HDF Study. Nephrol Dial Transplant 2013;28:192-202. DOI:
http://dx.doi.org/10.1093/ndt/gfs407
http://dx.doi.org/10.1093/ndt/gfs407...
The primary outcome (composite of death from any cause and nonfatal
cardiovascular events) was not different between the two groups. However, in
adjusted Cox-regression analysis treatment with high-efficiency on-line HD was
associated with a 46% risk reduction for overall mortality. In a very recent
RCT, Asci et al. failed to find an advantage in fatal or
non-fatal cardiovascular event-free survival with high flux HD as compared to
standard HD treatment.154154. Asci G, Tz H, Ozkahya M, Duman S, Demirci MS, Cirit M, et al.;
EGE Study Group. The impact of membrane permeability and dialysate purity on
cardiovascular outcomes. J Am Soc Nephrol 2013;24:1014-23. DOI:
http://dx.doi.org/10.1681/ASN.2012090908
http://dx.doi.org/10.1681/ASN.2012090908...
Only Maduell
et al. were able to demonstrate that dialysis patients
randomized to on-line HDF had a better survival than those randomized to
standard HD.155155. Maduell F, Moreso F, Pons M, Ramos R, Mora-Macià J, Carreras J,
et al.; ESHOL Study Group. High-efficiency postdilution online hemodiafiltration
reduces all-cause mortality in hemodialysis patients. J Am Soc Nephrol
2013;24:487-97. DOI: http://dx.doi.org/10.1681/ASN.2012080875
http://dx.doi.org/10.1681/ASN.2012080875...
Whether the superiority
of HDF was due to a better clearance of uremic toxins in the middle-to-large MW
range remains to be demonstrated.
Adsorption
Other possible therapeutic strategies that could be used to improve dialysis
removal of protein-bound uremic toxins are: addition of activated charcoal or 5%
albumin to the dialysate; use of highly permeable dialysis membranes to promote
albumin leakage; fractionated plasma separation and adsorption.156156. Neirynck N, Glorieux G, Schepers E, Pletinck A, Dhondt
A,Vanholder R. Review of protein-bound toxins, possibility for blood
purification therapy. Blood Purif 2013;35:45-50. DOI:
http://dx.doi.org/10.1159/000346223
http://dx.doi.org/10.1159/000346223...
They have not yet been used in large
clinical trials, though. The risk of aggravating malnutrition, limited
effectiveness due to saturation of adsorption sites and thrombotic complications
are potential limitations of these therapies.157157. Meijers BK, Verhamme P, Nevens F, Hoylaerts MF, Bammens B,
Wilmer A, et al. Major coagulation disturbances during fractionated plasma
separation and adsorption. Am J Transplant 2007;7:2195- 9. DOI:
http://dx.doi.org/10.1111/j.1600-6143.2007.01909.x
http://dx.doi.org/10.1111/j.1600-6143.20...
Additional studies are required before recommending these
strategies in routine clinical use.
Peritoneal dialysis
Data on uremic toxins in PD is scarce. In spite of the serum concentration of
protein-bound uremic toxins being lower in PD compared to HD patients, their
removal is worse in the former group.158158. Pham NM, Recht NS, Hostetter TH, Meyer TW. Removal of the
protein-bound solutes indican and p-cresol sulfate by peritoneal dialysis. Clin
J Am Soc Nephrol 2008;3:85-90. DOI:
http://dx.doi.org/10.2215/CJN.02570607
http://dx.doi.org/10.2215/CJN.02570607...
These observations suggest that factors beyond the dialysis method, such as
intestinal generation and/or metabolism, may play a role to determine their
serum levels.
Although several studies have suggested a benefit of therapeutic intervention on middle and protein-bound uremic toxins levels, most of these data came from pos hoc analysis or small studies. Larger, prospective, well-designed RCT aimed to identify the impact of reducing the levels of different uremic toxins on hard outcomes, such as overall and cardiovascular mortality, are required.
General conclusions
The study of uremic toxins is of growing interest in nephrology. Evidence from
clinical and experimental studies have demonstrated the impact of these compounds on
a variety of organs and systems. Notably, uremic toxins have recently been claimed
as new cardiovascular risk factors, attracting interest from other fields of
medicine.159159. Massy ZA, Barreto DV, Barreto FC, Vanholder R. Uraemic toxins
for consideration by the cardiologist-Beyond traditional and non-traditional
cardiovascular risk factors. Atherosclerosis 2010;211:381-3. PMID: 20471651 DOI:
http://dx.doi.org/10.1016/j.atherosclerosis.2010.04.010
http://dx.doi.org/10.1016/j.atherosclero...
Understanding the effects
of uremic toxins may provide a more comprehensive view of CKD and its complications
and, most likely, new therapeutic targets to retard the progression of CKD and to
counteract its cardiovascular complications.
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Publication Dates
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Publication in this collection
Apr-Jun 2014
History
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Received
18 Feb 2014 -
Accepted
07 Mar 2014