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Uremia Retention Molecules and Clinical Outcomes


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Chronic kidney disease is characterized by the accumulation of organic compounds in the bloodstream that may exert a variety of toxic effects in the body. These compounds, collectively known as uremic toxins, may be classified according to their physicochemical properties as free water-soluble low molecular weight molecules, middle molecules or protein-bound uremic toxins. Most of these retention molecules, due to either their size and/or binding to protein, constitute a complex therapeutic challenge to the nephrologist, particularly in end-stage renal disease, because of their limited removal by conventional dialysis therapies. Therefore, we review in this article the current clinical evidences that have supported the important role of uremic toxins in uremia by contributing to the adverse outcomes related to chronic kidney disease, such as increased mortality and cardiovascular events, as well as renal impairment progression that cannot be solely explained by traditional risk factors. These observations have ultimately contributed to testing new therapeutic targets, such as the gut, and the development of modern dialysis strategies to manage chronic kidney disease patients.
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Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159/000479253 )
Chronic kidney disease is characterized by the accumulation of organic compounds in the
bloodstream that may exert a variety of toxic effects in the body. These compounds, col-
lectively known as uremic toxins, may be classified according to their physicochemical
properties as free water-soluble low molecular weight molecules, middle molecules or
protein-bound uremic toxins. Most of these retention molecules, due to either their size
and/or binding to protein, constitute a complex therapeutic challenge to the nephrolo-
gist, particularly in end-stage renal disease, because of their limited removal by conven-
tional dialysis therapies. Therefore, we review in this article the current clinical evidences
that have supported the important role of uremic toxins in uremia by contributing to the
adverse outcomes related to chronic kidney disease, such as increased mortality and car-
diovascular events, as well as renal impairment progression that cannot be solely ex-
plained by traditional risk factors. These observations have ultimately contributed to test-
ing new therapeutic targets, such as the gut, and the development of modern dialysis
strategies to manage chronic kidney disease patients. © 2017 S. Karger AG, Basel
Chronic kidney disease (CKD) is associated with a high risk of mortality, par-
ticularly due to cardiovascular disease (CVD) that cannot be fully explained only
by traditional risk factors
[1] . Among the nontraditional factors, uremia reten-
tion molecules, also called uremic toxins, are of particular interest since they
represent new therapeutic targets for a better management of CKD patients.
Uremia Retention Molecules and
Clinical Outcomes
Fellype Carvalho Barreto a · Daniela Veit Barreto b ·
Maria Eugênia Fernandes Canziani
a Service of Nephrology, Department of Internal Medicine, Federal University of Paraná, and
b Hospital Marcelino Champagnat, Curitiba, and c Service of Nephrology, Department of Internal
Medicine, Federal University of São Paulo, São Paulo , Brazil
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Uremic Toxins and Outcomes 19
These molecules can be classified according to their physicochemical character-
istics and removal by dialysis into 3 classes: small water-soluble; middle mole-
cules, and protein-bound compounds ( Table1 ). Most of them, due to either
their size and/or binding to protein, constitute a therapeutic challenge to the
nephrologist, particularly in end-stage renal disease (ESRD) patients, because of
their limited removal by conventional dialysis therapies.
The importance of this concept is suggested by the fact that randomized con-
trolled trials have not been able to show any benefit of increasing Kt/V or, in
other words urea removal, on ESRD patient survival
[2] . Furthermore, it has
been suggested that estimated glomerular filtration rate (GFR) cannot be con-
sidered a good predictor for evaluating the accumulation of many solutes in the
course of CKD
[3] . Thus, investigating the contribution of different uremic
Table 1. Uremic toxins classification and characteristics
Classification Characteristics Examples
Small water-
Molecular weight <500 Da;
Easily removed by dialysis
Guanidine* (ADMA/SDMA)
Uric acid
Molecular weight >500 Da;
Need dialysis membranes with large
pores large to be removed;
Many are peptides
Complement factor D
Cystatin C
Generally of low molecular weight;
Difficult to be removed by dialysis
Hippuric acid
Indoxyl sulfate*
* Indicates the molecules considered as the prototypes of each group.
AGES, advanced glycation end-products; AOPP, advanced oxidation protein products;
ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; CMPF, 3-car-
boxy-4-methyl-5-propyl-2-furan-propanoic acid.
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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20 Barreto · Barreto · Canziani
toxins for the uremic syndrome is crucial for the better understanding of CKD
and, above all, to guide the development and implementation of novel therapeu-
tic strategies.
In the subsequent sections, we will present the current evidences derived
from clinical observational studies that support the key role of uremic toxins in
the uremia-related poor outcome, such as cardiovascular events, increased mor-
tality, and progression of CKD.
Small Water-Soluble Molecules
Symmetric Dimethylarginine and Asymmetric Dimethylarginine
Symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine
(ADMA), compounds from the group of guanidines, are derived from the me-
tabolism of L-arginine. Serum levels of methylarginines increase in CKD due to
reduced renal clearance, increased synthesis, and reduced catabolism. Despite
being structurally similar to urea, methylguanidines have a greater distribution
volume, resulting in lower removal efficiency by dialysis procedures in com-
parison to urea
[4] . Higher dialysis dose or longer sessions seem to be incapable
of further lowering ADMA or SDMA concentrations
[5] .
ADMA is an inhibitor of nitric oxide synthase, causing vasoconstriction, ar-
terial stiffness, and hypertension. Several studies have reported a strong and in-
dependent association of higher serum levels of ADMA and mortality and car-
diovascular events in general, predialysis and dialysis populations
[6–8] . Re-
cently, in a post-hoc analysis of the Hemodialysis (HEMO) study, Shafi et al.
have found an association between ADMA levels and higher risk of cardiac
death (HR 1.83; 95% CI 1.29–2.58), sudden cardiac death (HR 1.79; 95% CI
1.19–2.69), first cardiovascular event (HR 1.50; 95% CI 1.20–1.87), and any-
cause death (HR 1.44; 95% CI 1.13–1.83). Interestingly, they were also able to
demonstrate an association between SDMA levels and the risk for cardiac death
(HR 1.40; 95% CI 1.03–1.92), though it was no longer significant after adjusting
for ADMA. Studies have also reported a similar association between SDMA and
cardiovascular and cerebrovascular outcomes
[6, 9] . Taken together, these find-
ings corroborate to the current concept that SDMA is not an inert compound.
Actually, it has been demonstrated that SDMA has pro-oxidant and pro-inflam-
matory effects, and inhibits nitric oxide production
[10, 11] . Finally, a recent
meta-analysis found that higher levels of ADMA and SDMA were associated
with increased risk of all-cause mortality (RR 1.52, 95% CI 1.37–1.68; RR 1.31,
95% CI 1.18–1.46; respectively) and CVD (RR 1.33, 95% CI 1.22–1.45; RR 1.36,
95% CI 1.10–1.68; respectively)
[12] .
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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Uremic Toxins and Outcomes 21
Hyperphosphatemia usually appears in CKD patients when GFR <30 mL/
min/1.73 m
2 , being particularly common among ESRD patients due to the low
clearance of phosphate by conventional dialysis. Until the late 1990s, it was con-
ceived that the deleterious effects of hyperphosphatemia were restricted to bone
and mineral metabolism. Actually, hyperphosphatemia is closely associated
with the development of secondary hyperparathyroidism (sHPT) through direct
and indirect mechanisms that may stimulate the synthesis and secretion of para-
thyroid hormone and parathyroid cell growth. Hyperphosphatemia is also an
important stimulus for the secretion of the phosphaturic hormone, fibroblast
growth factor-23 (FGF23).
Several observational studies have reported that hyperphosphatemia is asso-
ciated with an increased risk of all-cause and cardiovascular mortalities in dialy-
sis and pre-dialysis CKD patients
[13, 14] . Hyperphosphatemia has also been
associated with vascular calcification in CKD patients as well as among people
with relatively preserved renal function
[15, 16] . Notably, in vitro experiments
have shown that phosphate may contribute to CVD by inducing endothelial dys-
function and/or by promoting vascular smooth muscle cell transdifferentiation
to osteoblast-like cells that participate in the pathogenesis of vascular calcifica-
tion. It has also been noted that a significant association exists between serum
phosphate levels near the upper limit of the normal range and the risk of all-
cause death (HR 1.27; 95% CI 1.02–1.58) and cardiovascular event, such as new
heart failure and myocardial infarction, in subjects with prior myocardial infarc-
[17] . Finally, a recent study expanded the relevance of hyperphosphatemia
as a potential modifiable risk factor to the field of kidney transplant. Merhi et al.
[18] have reported that higher serum phosphate levels may be associated with
increased risk of transplant failure (HR 1.36; 95% CI 1.15–1.62) and mortality
risk (HR 1.21; 95% CI 1.04–1.40) in a cohort of 3,138 stable kidney transplant
recipients followed up for a median time of 4.0 years.
Trimethylamine N-Oxide
Trimethylamine-N-oxide (TMAO), a circulating organic compound produced
by the metabolism of dietary L-carnitine and choline, has emerged as a novel
cardiovascular risk factor, likely due to its pro-atherogenic effect. Both L-carni-
tine and choline, abundantly present in eggs and red meat, are metabolized by
intestinal bacteria to trimethylamine which, after intestinal absorption, is oxi-
dized by flavin mono-oxygenase enzymes in the liver to form TMAO. Urinary
excretion is the most exclusive route to eliminate TMAO from the body.
It has been reported that serum levels of TMAO are inversely associated with
renal function, being markedly elevated in hemodialysis patients
[19] . TMAO
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22 Barreto · Barreto · Canziani
accumulates during the interdialytic interval, but it is efficiently removed by he-
[20] . Beyond renal function impairment, dysbiosis of the gut micro-
biota, diet seems to increase TMAO levels and might explain the great variabil-
ity in its urinary levels
[21] .
T M A O s e e m s n o t t o b e o n l y a s u r r o g a t e m a r k e r f o r r e n a l d y s f u n c t i o n , b u t
likely contributes to the risk of death in CKD patients. TMAO levels in the highest
quartile were independently associated with a 1.9-fold increase in all-cause mor-
tality at 5 years among subjects with either normal or elevated cystatin C levels
[22] . T M A O c o n c e n t r a t i o n s p r e d i c t e d t h e c o r o n a r y a t h e r o s c l e r o s i s b u r d e n a n d
long-term mortality, independent of traditional cardiac risk factors in a cohort of
patients with variable degree of renal impairment
[19] . I n a l a r g e o b s e r v a t i o n a l
study that enrolled 2,529 CKD (stages 3b and 4) patients from the CanPREDDICT
cohort, TMAO was independently associated with cardiovascular events after ad-
justing for potential risk factors. Importantly, even among those with stage 3b
CKD, TMAO levels were capable of identifying those exposed to the highest risk
for cardiovascular events, independent of kidney function
[23] . T M A O l e v e l s a l s o
seem to be associated with higher risk of cardiovascular events and any-cause
death in hemodialysis patients, an effect apparently modulated by race
[24] .
Middle Molecules
Fibroblast Growth Factor 23
FGF23 (MW 32 kDa) is a phosphaturic hormone that regulates mineral homeo-
stasis, mostly secreted by osteocytes and osteoblasts. FGF23 regulates phosphate
levels directly, by inhibiting the renal tubular reabsorption of phosphate, and
indirectly, by reducing calcitriol levels. FGF23 also inhibits the secretion of para-
thyroid hormone (PTH) by the parathyroid glands. These effects depend on the
binding of FGF23 to the complex FGF receptor (FGFR)-klotho, a co-factor that
greatly increases the affinity of FGF23 for FGFR.
Serum levels of FGF23 increase since the early stages of CKD, reaching con-
centrations of up to 1,000-fold above the normal range in patients on hemodi-
alysis. Of note, conventional hemodialysis is not capable of removing FGF23.
This increase in the FGF23 levels results from (i) an increased production to
counteract phosphate accumulation and to overcome FGF23 resistance due to
lower expression of FGFR-klotho; (ii) decreased renal clearance; and (iii) de-
creased degradation of FGF23. The cleavage of the FGF23 molecule is impaired
in uremia leading to the accumulation of the carboxy-terminal fragments that
are not considered biologically active. Interestingly, inflammation and iron de-
ficiency may contribute to the increased FGF23 concentrations noted in CKD.
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
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Uremic Toxins and Outcomes 23
Several observational studies have reported that elevated serum levels of
FGF23 are independently associated with adverse clinical outcomes. A large
prospective study that included more than 10,000 incident hemodialysis pa-
tients followed up for 12 months showed that elevated FGF23 level was asso-
ciated with almost 6-fold increase in the risk of one-year mortality
[25] . The
Homocysteine in Kidney and End-Stage Renal Disease (HOST) study ( n =
1,099; CKD stages 2–4) found that elevated FGF23 levels are independently
associated with greater risk of ESRD
[26] . High serum levels of FGF23 have
also been associated with left ventricular hypertrophy and vascular altera-
tions, such as atherosclerosis and vascular calcifications
[27, 28] . Interestingly,
the cardiac hypertrophic action of FGF23 depends on the FGF23 binding to
the FGFR4 present in the myocardium (not to the complex FGFR-klotho),
and the signaling pathway occurs through the PLCγ-calcineurin-NFAT path-
way rather than via the MAPK cascade
[29] . Higher FGF23 levels have been
associated with a greater risk of heart failure
[30] . Giving further support to
the relevance of FGF23 as a predictor of adverse outcomes, a recent meta-
analysis that evaluated 19 prospective studies showed that increased FGF23
serum levels were independently associated with a higher risk of all-cause (RR
1.68; 95% CI 1.48–1.92) and cardiovascular mortalities (RR 1.68; 95% CI 1.38–
[31] .
Parathyroid Hormone
PTH (MW 9.4 kDa) is secreted by the parathyroid glands in response to a de-
crease in the concentration of extracellular calcium. PTH is essential for the
bone and mineral homeostasis due to its action in the kidneys, where it promotes
calcium reabsorption, phosphate excretion, and stimulates the activity of
1-α-hydroxylase, the enzyme responsible for the production of calcitriol; and
bone, where it regulates bone remodeling and FGF23 production.
Increased levels of PTH are generally found since the early stages of CKD,
namely sHPT. Besides and beyond the myriad of clinical manifestations related
to sHPT that include fatigue, pruritus, psychological symptoms, and bone de-
formities, elevated serum levels of PTH have been associated with bone fracture,
cardiovascular complications, and mortality. In a large observational study that
enrolled 40,538 hemodialysis patients, PTH concentrations 600 pg/mL were
associated with an increase in the relative risk of death, all-cause, cardiovascular,
and fracture-related hospitalization
[32] . Moreover, it has been reported that
high PTH levels are associated with vascular calcification and left ventricular
[33, 34] . PTH may lead to deleterious effects on the cardiovascular
system due to the ubiquitous expression of its main receptor, PTH1R. The hy-
pertrophic effects of PTH on cardiomyocytes, and the bidirectional and
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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24 Barreto · Barreto · Canziani
stimulatory relationship between aldosterone and PTH are some of the potential
mechanisms that might, at least partly, explain why PTH may damage the car-
diovascular system
[35] .
Beta 2-microglobulin (β2M) is a polypeptide (MW 11,729 Da) found ubiqui-
tously on the surface of nucleated cells as part of the major histocompatibility
complex I. β2M is freely filtered by the glomerulus and metabolized by the tu-
bules. Hence, its levels inversely correlate with the renal function. Other condi-
tions that may increase β2M serum levels are hematologic, inflammatory, and
infectious diseases. Factors beyond β2M accumulation, such as molecular struc-
tural changes by AGES and limited proteolysis, may corroborate to its toxicity.
The classical complication related to β2M accumulation in ESRD patients is
its deposition on bone and joints leading to pain, carpal tunnel syndrome, hem-
arthrosis, and cystic bone lesions, the so-called dialysis-related amyloidosis
[36] .
More recently, there is a growing interest on the effects of β2M on the cardio-
vascular system. Higher levels of β2M have been associated with arterial stiff-
ness, vascular calcification, and higher mortality
[37] . In the HEMO study, high
serum levels of β2M was associated with an increased risk of mortality, mainly
due to infectious disease
[38] . Interestingly, in transplant recipients, the serum
levels of β2M at the moment of hospital discharge was a potent predictor of mor-
tality and loss of the renal allograft, suggesting that β2M may be a more valuable
surrogate marker for these outcomes than creatinine
[39] .
Free Light Chains
Light chains (LCs) are important components of the immunoglobulin mole-
cules synthesized by plasma cells. Both LC isotypes, the monomeric κ (MW 22.5
kDa) and the dimeric λ (MW 45 kDa), are produced more on a small scale than
the heavy chains of the immunoglobulin. This excess is normally excreted and/
or metabolized by the kidneys. Thus, free light chains (FLCs) may accumulate
as renal function declines. The development of more accurate assays capable of
detecting FLC levels below the so-called normal range have allowed the assess-
ment of the relationship between polyclonal FLC serum levels and clinical out-
Clinical studies in CKD patients have demonstrated that high FLC levels are
independently associated with overall mortality risk across different stages of
[40, 41] . Not all studies were able to demonstrate this association though
[42] . Differences on the clinical and demographic characteristics of the study
population, number of patients included, and follow-up duration may account
for these conflicting findings. FLC κ and λ levels have also been associated with
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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Uremic Toxins and Outcomes 25
inflammation, vascular calcification, and levels of other uremic toxins, such as
β2M, indoxyl sulphate, and para-cresyl sulfate, and with progression to ESRD
[40, 42] .
In conclusion, polyclonal FLC has been considered a valuable marker of in-
flammation that reflects more closely the activity of the adaptive immune system
and chronic inflammation. In addition, its independent association with mortal-
ity suggests that FLC measurement may provide additional information over
traditional markers of inflammation, such as hsRCP, and of renal function. Oth-
erwise, whether free LC may provide prognostic information over-and-above
other middle molecules, such as β2M, and its pathogenic role in uremia remains
to been demonstrated.
Protein-Bound Uremic Toxins
Indoxyl Sulfate
Indoxyl sulfate (IS; MW 212.21 Da) is the main compound of the indole group.
IS is generated in the liver from the metabolism of indole, which is produced by
intestinal microbiota from the degradation of dietary tryptophan. The kidneys
are the main route of excretion of IS by tubular secretion via organic anion trans-
porters (OAT)-1 and OAT-3 located on the basolateral membrane of epithelial
cells of the proximal tubule. As other protein-bound uremic toxins, the major
fraction of IS circulates in the body tightly bound to albumin. As expected con-
sidering its physicochemical characteristics, IS has an inverse relationship with
kidney function and is poorly removed by conventional dialysis therapies.
IS is one of the most vastly studied uremic toxins. Most clinical and experi-
mental evidences suggest that IS acts as a nephro-vascular toxin. Barreto et al.
[43] have reported that IS levels are directly associated with arterial calcification
and stiffness and with overall and cardiovascular mortality, even after adjust-
ment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic cal-
cification. A recent meta-analysis has found an association between elevated free
IS levels and increased risk of all-cause mortality (OR 1.10, 95% CI 1.03–1.17),
but not with cardiovascular events
[44] . Furthermore, IS has been independent-
ly associated with first heart failure event in hemodialysis patients
[45] . High
levels of IS were reported to be associated with dialysis graft thrombosis after
endovascular interventions, given further support to the hypothesis that IS acts
as a cardiovascular toxin
[46] .
It has been reported that serum levels of IS may also influence CKD progres-
sion and other uremic manifestations. Higher IS serum levels have been associ-
ated with renal progression (reduction in estimated GFR >50% from baseline or
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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26 Barreto · Barreto · Canziani
progression to ESRD); its predictive power, however, was reduced when para-
cresyl sulfate (pCS) was added to the model
[47] . Even though some studies have
suggested that IS may play a role in the uremia-related musculoskeletal disor-
ders, such as renal osteodystrophy
[48] , no study so far has examined the asso-
ciation between IS levels and bone-specific outcomes, such as fracture.
Para-Cresyl Sulfate
pCS (MW 188.2 Da) is a phenol compound produced from the metabolism of
tyrosine and phenylalanine by intestinal bacteria. In the distal portion of the co-
lon, these amino acids are converted into phenolic compounds, such as p-cresol,
which suffer conjugation in the liver to generate pCS, the main metabolite, and
p-cresylglucoronide (pCG). In the blood, these compounds circulate mostly
bound to albumin. pCS and pCG are excreted by the kidneys mainly via the tu-
bular secretion by OAT-1 and OAT-3.
Serum levels of pCS increase as renal function declines, particularly in the late
stages of CKD. Moreover, due to its binding to albumin, pCS is hardly removed
by traditional dialysis therapies. High serum levels of pCS have been significant-
ly associated with overall and cardiovascular mortalities independent of well-
known predictors of survival, and with renal progression
[47, 49] . The clinical
importance of pCS has been further supported by 2 recent meta-analyses that
demonstrated its association with increased risk of mortality and of cardiovas-
cular events in CKD patients
[44] . More recently, Liabeuf et al. [50] were the first
to report that pCG, the minor metabolite of p-cresol, is independently associ-
ated with overall and cardiovascular mortalities, suggesting that it may have
much the same predictive power for mortality as pCS.
The relationship between pCS with infection-related hospitalizations and
septicemia has been recently investigated in 2 cohorts of hemodialysis patients,
Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study and HEMO
study. In CHOICE, free pCS was associated with 50% higher risk of infection-
related hospitalizations in patients with no gastrointestinal disease. A significant
trend was noted between greater levels of free pCS and septicemia in both co-
horts in patients with no gastrointestinal disease
[51] .
The field of uremic toxicity has gained a lot of interest during the last years. A
number of observational studies have suggested that uremic toxins contribute
to the high cardiovascular burden and mortality observed in CKD. The obser-
vational design of these studies precludes establishing a causal relationship be-
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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Uremic Toxins and Outcomes 27
tween uremic retention solutes and clinical outcomes, particularly when analy-
ses are not adjusted for GFR. Experimental studies, both in vitro and those based
on animal models of CKD, have complemented the clinical studies providing
consistent evidences that support the role of uremic toxins in the pathogenesis
of uremic syndrome, including cardiovascular manifestations and CKD pro-
gression ( Fig.1 ). Importantly, the acquired knowledge may shift treatment par-
adigms in Nephrology. New therapeutic targets, such as the gut, have been pro-
posed and the concept of dialysis adequacy relied only on urea removal has been
questioned. The development of novel technologies on dialysis therapy aimed
to remove middle molecules and protein-bound uremic toxins seems to be an
interesting approach as an attempt to change the high cardiovascular mortality
observed in CKD.
Chronic kidney disease
Renal clearance Gut generation
Uremia retention
Oxidative stress
Endothelial dysfunction
Progression of
renal impairment
Cardiovascular events (e.g., ischemic coronariopathy)
Cerebrovascular events (e.g., stroke)
Bone fractures
End-stage renal disease
Overall and cardiovascular mortalities
Fig. 1. Schematic view of uremia retention molecules accumulation and toxicity.
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28 Barreto · Barreto · Canziani
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CHOICE and HEMO. Medicine (Baltimore)
Maria Eugênia Fernandes Canziani
Service of Nephrology, Department of Internal Medicine
Federal University of São Paulo
Rua Pedro de Toledo 282
São Paulo, SP, CEP 04039-000 (Brazil)
Ronco C (ed): Expanded Hemodialysis – Innovative Clinical Approach in Dialysis.
Contrib Nephrol. Basel, Karger, 2017, vol 191, pp 18–31 ( DOI: 10.1159 /000479253 )
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... In a rat model of chronic renal failure (CRF), the overload of PAH and indoleacetic acid accelerated the loss of kidney function, glomerular sclerosis and tubulointerstitial injury [141]. Numerous studies in patients with CRF showed that uremic toxin accumulation leads to various complications including endothelial senescence [142], atherogenesis [143], cardiovascular diseases [144,145] or increased risk of all-cause mortality [144,146]. In CRF, these toxins accumulate for very long periods, making their toxicity particularly critical. ...
... In a rat model of chronic renal failure (CRF), the overload of PAH and indoleacetic acid accelerated the loss of kidney function, glomerular sclerosis and tubulointerstitial injury [141]. Numerous studies in patients with CRF showed that uremic toxin accumulation leads to various complications including endothelial senescence [142], atherogenesis [143], cardiovascular diseases [144,145] or increased risk of all-cause mortality [144,146]. In CRF, these toxins accumulate for very long periods, making their toxicity particularly critical. ...
Full-text available
Ischemia-reperfusion (IR)-induced acute kidney injury (IRI) is an inevitable event in kidney transplantation. It is a complex pathophysiological process associated with numerous structural and metabolic changes that have a profound influence on the early and the late function of the transplanted kidney. Proximal tubular cells are particularly sensitive to IRI. These cells are involved in renal and whole-body homeostasis, detoxification processes and drugs elimination by a transporter-dependent, transcellular transport system involving Solute Carriers (SLCs) and ATP Binding Cassettes (ABCs) transporters. Numerous studies conducted mainly in animal models suggested that IRI causes decreased expression and activity of some major tubular transporters. This could favor uremic toxins accumulation and renal metabolic alterations or impact the pharmacokinetic/toxicity of drugs used in transplantation. It is of particular importance to understand the underlying mechanisms and effects of IR on tubular transporters in order to improve the mechanistic understanding of IRI pathophysiology, identify biomarkers of graft function or promote the design and development of novel and effective therapies. Modulation of transporters’ activity could thus be a new therapeutic opportunity to attenuate kidney injury during IR.
... 9,11 The vast majority of uremic toxins, including S100A12, have molecular weights (MW) above 10 kDa and cannot be eliminated by a standard HD treatment. 12 The latest development in this subject is introduction of the medium cut-off (MCO) membranes. MCO membranes have enhanced permeability, selectivity, and very high MW retention onset and cut-off close to the MW of albumin. ...
Full-text available
Introduction: Of the most remarkable molecules associated with atherosclerosis and the cardiovascular outcome are S100A12 (10,379.5 Da) and soluble receptor for advanced glycation end products (sRAGE-42,803 Da) in the hemodialysis (HD) population. We designed a study investigating the effects of the medium cut-off (MCO) dialyzers focusing on S100A12 and sRAGE in HD patients compared with low-flux and high-flux dialyzers. Methods: This single-site, prospective, observational study comprises age and sex-matched HD groups (low-flux, high-flux, and MCO). Blood samples were drawn at baseline (predialysis and postdialysis) and the sixth month (predialysis). Results: Groups had similar demographic features and laboratory parameters. Baseline S100A12 levels of the groups were similar [34.3 (±66.5), 30.9 (±42.7), and 40.6 (±29.6); p = 0.13]. Compared to their baseline, the sixth-month S100A12 levels were constant in low-flux and high-flux group and significantly lower in MCO group (p = 0.16, p = 0.33, and p = 0.004). Baseline sRAGE levels of the groups were similar at baseline [2.8 (±0.8), 2.7 (±0.6), and 2.6 (±0.7); p = 0.65], and the sixth-month [2.9 (±0.5), 2.4 (±0.7), and 2.4 (±0.8); p = 0.24]. sRAGE levels remained constant in all groups [p = 0.84, p = 0.13, and p = 0.39]. S100A12/sRAGE ratio at baseline and sixth month was constant in low-flux [22.3 (±63.7) and 18.1 (±24.8); p = 0.17] and high-flux groups [11.9 (±15.3) and 13.1 (±5.8); p = 0.26], the ratio decreased significantly in MCO group [16.5 (±11.6) to 7.8 (±5.5); p = 0.03]. Conclusion: Our study suggests that prolonged use of MCO dialyzers is associated with better S100A12 and sRAGE levels. Long-term studies with larger samples are needed to understand the effects of a better S100A12-sRAGE profile provided by MCO dialyzers on HD patients' cardiovascular outcomes.
... The vast majority of middle molecules is represented by proteins derived from endogenous metabolism (either 2 DOI: 10.1159/000512537 primary products or their metabolites) which are cleared less and/or synthesized in response to uraemic environment changes. Toxicity affects mainly the cardiovascular system, pro-fibrotic pathways and inflammation [3]. Furthermore, most of the compounds belonging to proteinbound uraemic toxins (PBUTs) are small and derive from gastrointestinal metabolism. ...
... Middle molecules are organic compounds characterized by a molecular weight >500 kDa, which can accumulate in ESRD and exert many toxic effects. The retention of middle molecules is associated with the development of cardiovascular disease, chronic inflammatory disease, chronic kidney disease-mineral and bone disorder (CKD-MBD), secondary immunodeficiency, amyloidosis and protein-energy wasting [5][6][7][8][9]. Therefore, a better clearance of these toxins could lead to improved long-term outcomes in patients with ESRD. ...
Full-text available
Background Despite significant advances in haemodialysis (HD) in recent decades, current dialysis techniques are limited by inadequate removal of uraemic solutes such as middle molecules and protein-bound uraemic toxins. Novel medium cut-off (MCO) membrane or ‘expanded haemodialysis’ (HDx) provides diffusive removal of conventional and large middle molecular weight uraemic toxins, with marginal albumin leak. Methods This prospective, open-label, controlled, cross-over pilot study compared HDx (novel MCO membrane Theranova® 400) and conventional HD in 20 prevalent HD patients. Biochemical, dialysis adequacy and safety measures (adverse events, infections and hospitalization frequency) were recorded. Ten patients underwent conventional HD high-flux dialyser and 10 patients underwent HDx for 3 months, and the patients then switched and received the other treatment for a further 3 months. Results Treatment with HDx was associated with a significant reduction in serum albumin concentration [median (interquartile range) reduction −0.45 g/dL (−0.575 to −0.05); P = 0.025]. However, median albumin levels were ≥3.5 g/dL and no patients had clinical symptoms of hypoalbuminaemia or needed intravenous albumin administration. The number of infections was lower in patients treated with HDx (n = 7/19) compared with patients treated with HD (n = 14/20; P = 0.03). Patients treated with HDx had reduced levels of interleukin (IL)-1β (from 0.06 ± 0.02 pg/mL versus 0.28 ± 0.18 pg/mL with HD) and IL-6 (6.45 ± 1.57 pg/mL versus 9.48 ± 2.15 pg/mL), while tumour necrosis factor-α levels remain unchanged. Conclusions This study demonstrates that the chronic use of the novel MCO dialyser Theranova® appears to be safe and well-tolerated, without serious side effects or hypoalbuminaemia, as well as fewer infections. These results need to be confirmed in larger randomized clinical trials.
... Elevated ADMA and SDMA are related with increased all-cause mortality and cardiovascular disease [39]. Both markers accumulate in chronic kidney disease by increased synthesis, reduced catabolism and reduced renal clearance [40]. They are small molecules (202 Da) but poorly dialyzed with a substantial rebound occurring at the end of dialysis, which is explained by extended volume of distribution [41,42]. ...
Introduction: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed. Method: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment. Results: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower β2M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α1M (p < 0.001) and λFLC (p < 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups. Conclusion: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α1M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF.
Full-text available
Introduction Medium cut-off (MCO) dialyzers were designed to provide better clearance of uremic toxins. Methods We conducted a meta-analysis comparing MCO with high-flux (HF) dialyzers for the effect on uremic toxins in maintenance hemodialysis(HD) patients. Five databases were systematically searched for relevant studies and 9 studies were identified finally. Results Reduction ratio (RR) of urea, urea, creatinine, β2-macroglobulin(β2-MG), kappa free light chain(κFLC) and lambda FLC(λFLC) levels were not significantly different between MCO and HF dialyzers. But RR of β2-MG, κFLC and λFLC were greater for MCO than HF dialyzers. MCO dialyzers could better reduce tumor necrosis factor-α(TNF-α) levels. Subgroup analysis stratified by study design indicated that in randomized controlled trial(RCT) studies, albumin levels was lower in MCO than HF dialyzers group, but the two dialyzers treatments were equivalent in non-RCT subgroup. Conclusions Compared with HF dialyzers, MCO dialyzers provided higher middle-molecules uremic toxins clearance and obviously reduced TNF-α levels. This article is protected by copyright. All rights reserved.
Chitin nanofibers were prepared from crab shell for the purpose of utilizing crab shells. After the series chemical treatment and wet pulverization treatment, a uniform fibrous substance having a width of about 10 nm was obtained. The reason why fine fibrous chitin can be obtained is the structure of the crab shell. A characteristic of chitin nanofibers is their high dispersibility in water. Therefore, processing ability is improved, and biological properties of the nanofibers can be evaluated. Chitin nanofibers whose surface is modified to chitosan can be obtained after treatment with a relatively medium concentration of sodium hydroxide. Since chitosan nanofibers have an amino group on the surface, they are positively charged in an acidic aqueous solution. Chitin and chitosan nanofibers have various physiological functions when taken or applied to the skin. Effects of oral ingestion of chitosan nanofibers on chronic kidney disease (CKD) model, non-alcoholic steatohepatitis model, and inflammatory bowel disease model were studied. Furthermore, the biological effects of chitin and chitosan nanofibers for the skin are also investigated.
Extracorporeal treatments create opportunity for removing disease causing solutes within blood. Intoxications, renal failure, and immune-mediated diseases may be managed with these treatments, often providing new hope for patients with severe or refractory disease. Understanding solute pharmacokinetics and the limitations of each type of extracorporeal technique can allow for the selection of the optimal treatment modality.
The dialyzer is the core element of the extracorporeal blood purification therapies where several processes take place depending on specific membrane characteristics. To date, the filter choice requires preliminary knowledge of all its characteristics as they cannot be easily deduced from the commercial trade name. Hence the difficulty in identifying easily equivalent dialyzers and clearly comparing single filter characteristics. The choice of improper dialyzers for a specific treatment can determine a less effective blood purification and potentially harmful treatments. We aim to propose a univocal and standardized alphanumeric string to summarize essential filter properties in the Dialyzer Identification Code (DIC). DIC clearly describes device characteristics and allows to compare different dialyzers performances without resorting to the technical data sheets. Therefore, the presence of the DIC on every device facilitates information retrieval on the dialyzer, its intended use and can facilitate matching the dialysis modality to correct dialyzers achieving a personalized renal replacement therapy. The standard filter characteristics codification by the DIC may further optimize correct extracorporeal blood purification prescriptions and the use of equivalent filters from different providers avoiding treatment inefficiency, clinical complications and improving the patient safety.
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Chronic kidney disease (CKD) patients have an increased risk of cardiovascular diseases (CVDs). The present study aimed to investigate the gut microbiota and blood trimethylamine-N-oxide concentration (TMAO) in Chinese CKD patients and explore the underlying explanations through the animal experiment. The median plasma TMAO level was 30.33 μmol/L in the CKD patients, which was significantly higher than the 2.08 μmol/L concentration measured in the healthy controls. Next-generation sequence revealed obvious dysbiosis of the gut microbiome in CKD patients, with reduced bacterial diversity and biased community constitutions. CKD patients had higher percentages of opportunistic pathogens from gamma-Proteobacteria and reduced percentages of beneficial microbes, such as Roseburia, Coprococcus, and Ruminococcaceae. The PICRUSt analysis demonstrated that eight genes involved in choline, betaine, L-carnitine and trimethylamine (TMA) metabolism were changed in the CKD patients. Moreover, we transferred faecal samples from CKD patients and healthy controls into antibiotic-treated C57BL/6 mice and found that the mice that received gut microbes from the CKD patients had significantly higher plasma TMAO levels and different composition of gut microbiota than did the comparative mouse group. Our present study demonstrated that CKD patients had increased plasma TMAO levels due to contributions from both impaired renal functions and dysbiosis of the gut microbiota.
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The uremic syndrome is attributed to progressive retention of compounds that, under normal conditions, are excreted by the healthy kidneys. p-cresol sulfate (PCS), a prototype protein-bound uremic retention solute, has been shown to exert toxic effects in vitro. Recent studies have identified relations between increased levels of PCS and indoxyl sulfate (IS) and adverse clinical outcomes in hemodialysis patients. We explored the relationship between free and total PCS and IS with infection-related hospitalizations (IH) and septicemia in 2 cohorts, Choices for Healthy Outcomes in Caring for end-stage renal disease (ESRD) Study (CHOICE) and Hemodialysis Study (HEMO). We measured free and total levels of PCS and IS in stored specimens in CHOICE, a cohort of 464 incident hemodialysis patients enrolled in 1995 to 1998 and followed for an average of 3.4 years and in a prevalent dialysis cohort of 495 patients enrolled in HEMO from 1995 to 2000 and followed for an average of 4.4 years. We measured free PCS and IS using mass spectroscopy. The 2 cohorts were linked to United States Renal Data System (USRDS) Medicare billing records to ascertain IH over follow-up. We examined the association of free and total levels of PCS and IS with IH and septicemia using multilevel Poisson regression models adjusted for demographics, comorbidities, clinical factors, and laboratory tests including residual kidney function. We stratified patients a priori based on gastrointestinal (GI) disease as PCS and IS are produced in colon. In CHOICE, highest tertile of free PCS in multivariable model was associated with 50% higher risk of IH [95% CI = 1.01–2.23] compared with lowest tertile in patients with no-GI disease. A significant trend was noted between greater levels of free PCS and septicemia in no-GI disease group in both cohorts, while no association was noted in GI disease group. Total PCS concentrations were not associated with either IH or septicemia in either cohort. No significant risk of IH or septicemia was noted with higher levels of free or total IS in either GI or no-GI disease group. These results suggest an association between higher concentrations of free PCS and infection-related and sepsis-related hospitalizations in hemodialysis patients. Better methods of dialysis should be developed to evaluate the utility of removing PCS and its effect on the outcome and also therapies to decrease gastrointestinal tract production of uremic solutes.
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Background: A growing number of studies linked elevated concentrations of circulating asymmetric (ADMA) and symmetric (SDMA) dimethylarginine to mortality and cardiovascular disease (CVD) events. To summarize the evidence, we conducted a systematic review and quantified associations of ADMA and SDMA with the risks of all-cause mortality and incident CVD in meta-analyses accounting for different populations and methodological approaches of the studies. Methods: Relevant studies were identified in PubMed until February 2015. We used random effect models to obtain summary relative risks (RR) and 95% confidence intervals (95%CIs), comparing top versus bottom tertiles. Dose-response relations were assessed by restricted cubic spline regression models and potential non-linearity was evaluated using a likelihood ratio test. Heterogeneity between subgroups was assessed by meta-regression analysis. Results: For ADMA, 34 studies (total n = 32,428) investigating associations with all-cause mortality (events = 5,035) and 30 studies (total n = 30,624) investigating the association with incident CVD (events = 3,396) were included. The summary RRs (95%CI) for all-cause mortality were 1.52 (1.37-1.68) and for CVD 1.33 (1.22-1.45), comparing high versus low ADMA concentrations. Slight differences were observed across study populations and methodological approaches, with the strongest association of ADMA being reported with all-cause mortality in critically ill patients. For SDMA, 17 studies (total n = 18,163) were included for all-cause mortality (events = 2,903), and 13 studies (total n = 16,807) for CVD (events = 1,534). High vs. low levels of SDMA, were associated with increased risk of all-cause mortality [summary RR (95%CI): 1.31 (1.18-1.46)] and CVD [summary RR (95%CI): 1.36 (1.10-1.68) Strongest associations were observed in general population samples. Conclusions: The dimethylarginines ADMA and SDMA are independent risk markers for all-cause mortality and CVD across different populations and methodological approaches.
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Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.
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Hemodialysis vascular accesses are prone to recurrent stenosis and thrombosis after endovascular interventions. In vitro data suggest that indoxyl sulfate, a protein-bound uremic toxin, may induce vascular dysfunction and thrombosis. However, there is no clinical evidence regarding the role of indoxyl sulfate in hemodialysis vascular access. From January 2010 to June 2013, we prospectively enrolled patients undergoing angioplasty for dialysis access dysfunction. Patients were stratified into tertiles by baseline serum indoxyl sulfate levels. Study participants received clinical follow-up at 6-month intervals until June 2014. Primary end points were restenosis, thrombosis, and failure of vascular access. Median follow-up duration was 32 months. Of the 306 patients enrolled, 262 (86%) had symptomatic restenosis, 153 (50%) had access thrombosis, and 25 (8%) had access failure. In patients with graft access, free indoxyl sulfate tertiles showed a negative association with thrombosis-free patency (thrombosis-free patency rates of 54%, 38%, and 26% for low, middle, and high tertiles, respectively; P=0.001). Patients with graft thrombosis had higher free and total indoxyl sulfate levels. Using multivariate Cox regression analysis, graft thrombosis was independently predicted by absolute levels of free indoxyl sulfate (hazard ratio=1.14; P=0.01) and free indoxyl sulfate tertiles (high versus low, hazard ratio=2.41; P=0.001). Results of this study provide translational evidence that serum indoxyl sulfate is a novel risk factor for dialysis graft thrombosis after endovascular interventions.
Background: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. Study design: Cohort study. Setting & participants: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. Predictor: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. Results: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). Limitations: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. Conclusions: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
Background and aims: The prognostic value of fibroblast growth factor 23 (FGF23) for mortality remains controversial. We performed a meta-analysis of cohort studies to examine the controversial relationship between FGF23 and mortality. Methods: PubMed, EMBASE, the Cochrane Library databases and reference bibliographies were searched through September 2016 to identify prospective cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) for FGF23 and mortality. A random effects model was used to pool the risk estimates. A dose-response analysis of the risk for all-cause mortality associated with FGF23 was conducted using the generalized least squares trend estimation method. Results: Nineteen prospective cohort studies were eligible for inclusion in this meta-analysis, of which 16 reported all-cause mortality and 9 reported cardiovascular mortality. During the follow-up periods ranging from 1 to 18.6 years, 5606 deaths occurred among 22,805 participants and 2458 cardiovascular deaths occurred among 28,845 participants. Elevated FGF23 was associated with an increased risk of all-cause mortality (RR 1.68; 95% CI 1.48-1.92) and cardiovascular mortality (RR 1.68; 95% CI 1.38-2.04) with moderate heterogeneity. These associations were not markedly modified by the geographic location, follow-up length, patient predisposition, FGF23 measurement or study quality. A sensitivity analysis yielded a similar effect on the pooled risk estimate. Evidence of a nonlinear relationship between FGF23 and all-cause mortality was observed in the dose-response analysis, with the risk gradually increasing as FGF23 increased. Conclusions: This meta-analysis showed that individuals with increased plasma FGF23 levels might suffer a higher risk of all-cause mortality and cardiovascular mortality.
Background: Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms, including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients. Study design: Post hoc analysis of the Hemodialysis (HEMO) Study. Setting & participants: 1,276 prevalent hemodialysis patients with available samples 3 to 6 months after randomization. Predictor: ADMA and SDMA measured in stored specimens. Outcomes: Cardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbid conditions, albumin level, and residual kidney function). Results: Mean age of patients was 57±14 (SD) years, 63% were black, and 57% were women. Mean ADMA (0.9±0.2μmol/L) and SDMA levels (4.3±1.4μmol/L) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis ADMA or SDMA concentrations. In fully adjusted models, each doubling of ADMA level was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29-2.58), sudden cardiac death (1.79; 1.19-2.69), first cardiovascular event (1.50; 1.20-1.87), and any-cause death (1.44; 1.13-1.83). Compared to the lowest ADMA quintile (<0.745 μmol/L), the highest ADMA quintile (≥1.07μmol/L) was associated with higher risk (HR; 95% CI) of cardiac death (2.10; 1.44-3.05), sudden cardiac death (2.06; 1.46-2.90), first cardiovascular event (1.75; 1.35-2.27), and any-cause death (1.56; 1.21-2.00). SDMA level was associated with higher risk for cardiac death (HR, 1.40; 95% CI, 1.03-1.92), but this was no longer statistically significant after adjusting for ADMA level (HR, 1.20; 95% CI, 0.86-1.68). Limitations: Single time-point measurement of ADMA and SDMA. Conclusions: ADMA and, to a lesser extent, SDMA levels are associated with cardiovascular outcomes in hemodialysis patients.
Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3–6months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function).Mean age of the patients was 58 years; 35%of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95%confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO($135mM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.