Clinical management of the uraemic syndrome in chronic kidney disease

1. www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4 1
Review
Lancet Diabetes Endocrinol 2016
Published Online
March 2, 2016
http://dx.doi.org/10.1016/
S2213-8587(16)00033-4
Nephrology Section,
Department of Internal
Medicine, Ghent University
Hospital, Ghent, Belgium
(Prof RVanholder MD,
Prof G Glorieux PhD);
Department of Nephrology-
Nutrition-Dialysis, Centre
Hospitalier Lyon Sud,
Carmen-CENS, Université
Claude Bernard Lyon 1, Lyon,
France; F-CRIN-INI-CRCT,
France (Prof D Fouque MD);
Department of Internal
Medicine IV, Saarland
University Medical Centre,
Homburg, Germany
(Prof G H Heine MD);
Department of Medicine,
Division of Nephrology, Koc
University School of Medicine,
Istanbul,Turkey
(Prof M Kanbay MD);
Nephrology, Dialysis and
Transplantation Unit, and
CNR-IFC Clinical Epidemiology
and Pathophysiology of Renal
Diseases and Hypertension,
Ospedali Riuniti, Reggio
Calabria, Italy
(Prof F Mallamaci MD,
Prof C Zoccali MD); Division of
Nephrology, Ambroise Paré
University Hospital (APHP),
University of Paris Ouest,
Versailles-Saint-Quentin-en-
Yvelines (UVSQ),
Boulogne-Billancourt, Paris,
France (Prof Z A Massy MD);
INSERM U1018, Research
Centre in Epidemiology and
Population Health (CESP),
UVSQ,Villejuif, France
(Prof Z A Massy); Division of
Nephrology, IIS-Fundacion
Jimenez Diaz, Madrid, Spain
(Prof A Ortiz MD); INSERM
Centre d’Investigations
Cliniques (CIC)-1433, and
INSERM U1116, Nancy, France
(Prof P Rossignol MD); Institut
Lorrain du Cœur et des
Vaisseaux, CHU Nancy,
Vandoeuvre lès Nancy, France
(Prof P Rossignol); Université de
Clinical management of the uraemic syndrome in chronic
kidney disease
RaymondVanholder, Denis Fouque, Griet Glorieux, Gunnar H Heine, Mehmet Kanbay, Francesca Mallamaci, Ziad A Massy, Alberto Ortiz,
Patrick Rossignol, AndrzejWiecek, Carmine Zoccali, Gérard Michel London, for the European Renal Association European Dialysis and
Transplant Association (ERA-EDTA) European Renal and Cardiovascular Medicine (EURECA-m) working group
The clinical picture of the uraemic syndrome is a complex amalgam of accelerated ageing and organ dysfunction,
which progress in parallel to chronic kidney disease. The uraemic syndrome is associated with cardiovascular disease,
metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and
endocrine dysfunction. In this Review, we summarise specific, modern management options for the uraemic
syndrome in chronic kidney disease. Although large randomised controlled trials are scarce, based on data from
randomised controlled trials and observational studies, as well as pathophysiological reasoning, a therapeutic
algorithm can be developed for this complex and multifactorial condition, with interventions targeting several
modifiable factors simultaneously.
Introduction
Kidney failure is associated with deterioration of body
functions. The clinical picture as a whole—the uraemic
syndrome—is named after urea, the most abundant
metabolite retained in kidney failure and the first uraemic
retention product identified. The uraemic syndrome can
be caused by chronic kidney disease or acute kidney
injury, and affects almost every organ system (panel 1).1
The syndrome results from the biological effects of
metabolites that are not excreted or metabolised by the
kidneys and are retained within the body.2
Such
metabolites are named uraemic retention products, or
uraemic toxins if they exert biological or toxic effects. The
deterioration of renal endocrine function (production of
erythropoietin, active vitamin D, or renin), the
deregulation of kidney electrolyte homoeostasis, and
functional alterations resulting from chronic kidney
disease and its causes (eg, diabetes, autoimmune
disorders) also contribute to the syndrome. The clinical
picture worsens with kidney failure, with coma and death
(end-stage kidney disease; table 1) the ultimate result if the
patient is left untreated. However, since the 1940s, renal
replacement therapies (dialysis or transplantation) have
extended the life expectancy of patients with this
potentially fatal condition.
Although dialysis and transplantation extend the life
expectancy of patients with uraemia, mortality remains
substantially higher than in age-matched populations
with normal kidney function;3,4
general and cardiovascular
mortality tend to rise even before patients need dialysis.5,6
In this Review, we discuss several therapeutic options to
treat the consequences of the uraemic syndrome in
chronic kidney disease, based on the pathophysiology of
the uraemic syndrome and taking into account newly
detected, pathological pathways.
Although we have followed the principles of evidence-
based medicine as much as possible in this Review,
much of the data cited are from observation studies.
Randomised controlled trials in kidney disease are
scarce,7
and many studies have had negative results.8
This fact is largely attributable to the complex and
multifactorial nature of the disease, which makes it
difficult to recruit large patient groups with uniform
pathophysiological backgrounds. Additionally, because
of multi-layered pathophysiology, the effect of
therapeutic options that correct one aspect of disease
(eg, hypercholesterolaemia) can be masked by the effect
of other factors (eg, hypertension, fluid overload) on
outcome measures.
Traditional and non-traditional risk factors
Cardiovascular and non-cardiovascular mortality contri-
bute equally to the high mortality seen in people with
chronic kidney disease.9
Socioeconomic and
geographical factors, including access to therapy,
explain the variable mortality in chronic kidney disease
and end-stage kidney disease populations.10
Cardio-
vascular disease in patients with chronic kidney disease
is characterised by immunity-driven inflammatory
changes that cause vessel wall stiffening, arteriopathy,
and cardiomyopathy leading to heart failure,
arrhythmia, and cardiac arrest. Risk factors span from
traditional (Framingham) factors to an expanding list of
non-traditional risk factors (panel 2).8
Among non-
cardiovascular causes of death, infection, cancer,
cachexia, suicide, and refusal of treatment account for
the largest share of fatalities.9
The gap between the predictive value of traditional
risk factors and real cardiovascular mortality in chronic
kidney disease11
is to a large extent shown by indicators
of kidney dysfunction, such as estimated glomerular
filtration rate (eGFR) and albuminuria.12
Hence, factors
related to a decline in kidney function, such as
subclinical volume expansion and uraemic solute
retention, might play a part in this process. Many factors
that are affected by the uraemic status have been
associated with causes of cardiovascular damage, such
as inflammation, oxidative stress, macrophage
infiltration, endothelial dysfunction, thrombogenesis,
arterial calcification, or osteodystrophy.

2. 2 www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
Review
Lorraine, Nancy, France
(Prof P Rossignol); Association
Lorraine pour leTraitement de
l’Insuffisance Rénale,
Vandoeuvre lès Nancy, France
(Prof P Rossignol); Department
of Nephrology,Transplantation
and Internal Medicine, Medical
University of Silesia, Katowice,
Poland (Prof AWiecek MD); and
INSERM U970, Hôpital
Européen Georges Pompidou,
Paris (Prof G M London MD)
Correspondence to:
Prof RaymondVanholder,
Nephrology Section, University
Hospital, De Pintelaan
185, B9000 Ghent, Belgium
raymond.vanholder@ugent.be
See Online for appendix
Uraemic retention products
Information about uraemic retention products has
increased continuously in the past few decades. At least
150 uraemic retention products have been described so
far,13,14
and with developments in metabolomics and
proteomics in the past decade, each new study has the
potential to add dozens of new substances to this list.
The idea that removal of one single solute would be
sufficient to solve the problem of uraemic toxicity has
long since been abandoned. By contrast, the notion that
all these molecules interact is developing.15,16
In the past 30 years, based on the physicochemical
characteristics that affect their elimination during
dialysis (the main removal strategy until now), uraemic
retention products have been divided into three major
categories: small, water-soluble compounds; protein-
bound compounds; and larger, middle molecules.13
The
characteristics of these classes and some of the main
compounds in the groups are summarised in the appendix.
Pathophysiology
Scope of Review
Since the pathophysiology of the uraemic syndrome
affects the function of almost every organ (panel 1), this
Review is restricted to elements for which relevant
information is available and that imply specific therapeutic
approaches. Definition of which pathophysiological events
are directly caused by uraemic retention products and
which, as a whole or in part, are caused by other aspects of
kidney dysfunction is not always easy. We will summarise
which elements are linked to uraemic retention and which
ones to kidney dysfunction. Since the links are sometimes
very complex, we can only focus on what we deem the
most important aspects.
Progression of kidney failure
Progression of chronic kidney disease varies depending
on the underlying cause, disease-specific pathology, and
predisposing risk factors (figure 1).17
Independent of the
initial cause, any loss of functional kidney parenchyma
leads to compensatory hyperfiltration and intraglomerular
hypertension of the remaining nephrons, which causes
fibrosis and progressive decline in kidney function.
Furthermore, uraemia-specific and non-specific nephro-
toxins, inflammation, tissue ischaemia, and pro-coagulant
mechanisms damage glomeruli and tubules. Proteinuria
increases the risk of chronic kidney disease progression
by causing tubular injury that leads to inflammatory
macrophage infiltration and tubulointerstitial fibrosis.
Angiotensin II release increases intraglomerular pressure
and oxidative stress, which alters podocyte function and
promotes synthesis of chemokines and cytokines.18
Several uraemic retention products have been linked to
progression of kidney disease such as indoxyl sulfate,
p-cresyl sulfate, asymmetrical dimethylarginine (ADMA),
and several cytokines. Factors not linked to uraemic toxins
are exacerbations of primary kidney disease, acute kidney
injury, proteinuria, hyperglycaemia, external nephrotoxic
agents (radiocontrast, non-steroidals), compensatory
hyperfiltration, and ischaemia. Hypertension is a partly
retention-independent factor—ie, it can be caused by
uraemic toxins or by other factors (figure 1).
Inflammation, metabolic bone disease, and
cardiovascular disease
Non-traditional risk factors, such as low-grade
inflammation and oxidative stress play a fundamental part
in chronic kidney disease-associated cardiovascular
complications, and to a larger extent than in the general
population.19
A key element in this proinflammatory
status is the activation of the redox-sensitive nuclear
transcription factor kappa B (NF-κB) (figure 2), in response
to several factors including oxidative stress (reactive
oxygen species [ROS]), mitochondrial dysfunction,
Panel 1: Consequences of the uraemic syndrome
Cardiovascular
Hypertension, fluid overload, cardiac decompensation,
vascular damage and stiffness, cardiovascular events,
pericarditis
Haematological
Anaemia, erythrocyte fragility, immune dysfunction
(susceptibility to infections, low response to vaccination),
inflammation, hypercoagulability, bleeding tendency
Endocrine
Hyperparathyroidism, insulin resistance, impotence,
infertility, thyroid dysfunction, hyperaldosteronism, growth
disturbance, adipokine dysbalance, klotho deficiency and
FGF-23 excess, active vitamin D deficiency
Osteoarticular problems
Osteomalacia, osteodystrophy, adynamic bone disease,
β2-microglobulin amyloidosis, muscle weakness, fractures,
bone pain, calciphylaxis and cardiovascular calcification
Neurological
Polyneuropathy, coordination disturbances, tremor, cognitive
dysfunction, decreased attention span, coma
Gastrointestinal
Anorexia, gastroparesis, nausea, vomiting
Dermatological
Skin atrophy, pruritus, calciphylaxis
Stomatological
Periodontitis, stomatitis
Nephrological
Renal tubular damage, progression of kidney failure
Other
Malnutrition, changes in drug protein binding, changes in
metabolism, hyperkalaemia, metabolic acidosis

3. www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4 3
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several uraemic retention products, infection, vasoactive
substances, dyslipidaemia, and inflammation. Activation
of NF-κB is associated with the release of proinflammatory
cytokines (tumour necrosis factor α, interleukin 1β,
interleukin 6, soluble tumour necrosis factor-like weak
inducer of apoptosis) and activation of monocyte
chemoattractant protein-1 and profibrotic transforming
growth factor β1.
Inflammation and oxidative stress are tightly
interconnected. NF-κB activation initiates production of
ROS and vice versa, but under normal conditions,
nuclear factor-erythroid-2-related factor 2 (a regulator of
resistance to oxidants via expression of antioxidants
and cytoprotective agents) is also activated. This balance
might be disrupted in chronic kidney disease.20
A substantial number of uraemic toxins (eg, indoxyl
sulfate, p-cresyl sulfate, the cytokines, advanced glycation
end products, trimethylamine N-oxide) are pro-
inflammatory, as are compounds that until 5 years ago
were thought to be inert, like urea (for a more
comprehensive list, see appendix). Furthermore, several
other factors that are inflammatory are partly or entirely
unrelated from uraemic retention products: infection,
dialysis fluid contamination, dialysis bioincompatibility,
concomitant diseases (eg, autoimmune disorders), and
vasoactive agents (figure 2).
Cardiac and arterial complications are the principal
complications of the uraemic syndrome. The
cardiomyopathy in chronic kidney disease is characterised
by left ventricular hypertrophy, capillary rarefaction, and
interstitial fibrosis, with predominant diastolic dys-
function. Arrhythmias, sudden death, and heart failure
are the main consequences of these cardiac com-
plications. NF-κB activation by vasoactive substances
affects cardiomyocyte growth, fibrosis, and apoptosis,
inducing hypertrophy.19
In addition to the proinflammatory factors mentioned
above, some uraemic toxins and several factors that are
independent of uraemic toxins are damaging for heart
and vessels: indoxyl sulfate, ADMA, endothelin, oxalate
(uraemic retention products), hypertension, sodium and
fluid retention, primary diseases (eg, amyloidosis),
infections (endocarditis).
Compared with the general population, arterial disease
in populations with chronic kidney disease is premature,
and characterised by endothelial dysfunction, arterial
remodelling with arterial calcifications (figure 3A, 3B),
vascular stiffness, and the transition of the vascular
smooth muscle cells to an osseous phenotype.21
Vascular
stiffness, which is closely linked to endothelial
dysfunction, precedes arterial calcifications that further
exacerbate stiffening.22
Arterial calcifications are due to an
GFR* Definition Therapeutic approaches Pathophysiological changes Mortality
Stage 1 >90 Normal kidney function, but
urine abnormalities (eg,
haematuriaor
albuminuria†), proven
structural kidneydamage,
or genetictrait
Observation, blood pressure and
cardiovascular risk factor control,
preventionof cardiovasculardisease
Klothodeficiency Increasedoverall and
cardiovascular
mortality +
Stage 2 60–89 Mildly reduced kidney
function associatedwith
other findings (as in stage 1)
Observation, blood pressure and
cardiovascular risk factor control,
preventionof cardiovasculardisease
Klothodeficiency, elevated FGF-23 Increasedoverall and
cardiovascular
mortality +
Stage 3A
Stage 3B
45–59;
30–44
Moderately reduced kidney
function
Observation, blood pressure and
cardiovascular risk factor control,
preventionof cardiovasculardisease,
treatmentof anaemia and metabolic bone
disease, preventionof chronic kidney
disease progression
Klothodeficiency, elevated FGF-23
and PTH, malnutrition, hypertension,
left ventricular hypertrophy, anaemia
Increasedoverall and
cardiovascular
mortality ++
Stage 4 15–29 Severely reduced kidney
function
Planning for renal replacementtherapy,
blood pressure and cardiovascular risk
factor control, preventionof cardiovascular
disease,treatmentof anaemia and
metabolic bonedisease, preventionof
chronic kidneydisease progression
Klothodeficiency, elevated FGF-23
and PTH, malnutrition, hypertension,
left ventricular hypertrophy, anaemia,
hypertriglyceridaemia,
hyperphosphataemia, metabolic
acidosis, hyperkalaemia
Increasedoverall and
cardiovascular
mortality +++
Stage 5 <15 Very severe kidney failureor
end-stage kidneydisease
Renal replacementtherapyor conservative
approach, blood pressure and
cardiovascular risk factor control,
preventionof cardiovasculardisease,
treatmentof anaemia and metabolic bone
disease
Klothodeficiency, elevated FGF-23
and PTH, malnutrition, hypertension,
left ventricular hypertrophy, anaemia,
hypertriglyceridaemia,
hyperphosphataemia, metabolic
acidosis, hyperkalaemia, need for
renal replacementtherapy
Increasedoverall and
cardiovascular
mortality ++++
FGF-23=fibroblast growth factor-23. GFR=glomerular filtration rate (mL/min per 1·73 m²). PTH=parathyroid hormone. *GFR can be directly measured (eg, clearance of inulin,
iothalamate, or ethylene diamino acetic acid), or calculated based on serum markers, such as creatinine, cystatin C, or both and anthropometric parameters (estimated GFR–
eGFR). †Albuminuria is classified as moderately increased (30–300 mg/g or 3–30 mg/mmol creatinine) and severely increased (>300 mg/g or >30 mg/mmol) and increases
risk by one level unless the highest risk category has been reached. Severity of mortality is indicated as mild (+), mild-moderate (++), moderate (+++), and severe (++++).
Table 1: Chronic kidney disease stages and their implications

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imbalance of calcification inducers and inhibitors, and
development of a senescence-associated secretory
phenotype (SASP) in vascular smooth muscle cells.23
Inducers of arterial calcifications and SASP are all linked
to secretion of proinflammatory cytokines. Inflammation
activates the BMP2:BMP4, Msx2, and Wnt pathways,
which promote increased transcription of genes associated
with conversion of vascular smooth muscle cells to the
osteochondrogenic phenotype (Runx2, osterix, Sox9).24
Several chronic kidney disease-linked and biochemical
changes related to mineral bone disorder (figure 3C), such
as hyperphosphataemia, are associated with arterial
calcifications. Hyperphosphataemia also stimulates the
production of ROS and thereby activation of NF-κB. The
resultant inflammation decreases the concentration of
calcification inhibitors and reduces klotho expression,
which induces resistance to the phosphaturic effect
of fibroblast growth factor 23 (FGF-23),25
bone resistance
to parathyroid hormone (PTH), secondary hyperpara-
thyroidism,26
and accelerated ageing.27
Telomere
shortening, which is typical for ageing, is associated with
cardiovascular disease manifestations.28
Inflammatory
epigenetic changes, which, in part, involve inhibited gene
methylation of s-adenosinemethionine, also contribute to
inflammation and cardiovascular lesions.29,30
Uraemic bone disease is mainly triggered by increased
concentrations of the uraemic toxin phosphate, which
results in the enhanced generation of several
compensatory factors to maintain serum phosphate con-
centration, such as FGF-23 and PTH, at the cost of loss of
bone structure and function. Independent of metabolite
retention, ageing, inflammation, bone ischaemia, and
inadequate renal production of active vitamin D
metabolites further enhance bone degradation. Some
patients develop adynamic bone disease, whereby low
PTH hinders calcium deposition in the bone, favouring
vascular calcification. In rare cases, patients develop
calciphylaxis—a severe syndrome consisting of vascular
calcification, thrombosis, and skin necrosis.
In summary, inflammation, oxidative stress, and bone
disease show specific features linked to chronic kidney
disease and uraemia resulting in accelerated vascular
damage and ageing.
Malnutrition and dysbiosis
Malnutrition and dysbiosis are two features of the
uraemic syndrome that relate to digestive function
(figure 4). Some uraemic retention products (such as
cytokines leptin, ghrelin, and neuropeptide Y) can be
implicated in reduced appetite and nutrient intake.
p-cresyl sulfate causes insulin resistance, disturbances of
lipid metabolism, and aberrant distribution of fat cells
throughout the body. Inflammation—a common epi-
phenomenon of chronic kidney disease—is associated
with reduced appetite, at all chronic kidney disease stages,
including chronic kidney disease stage 5 on dialysis.31
Other factors implicated in reduced appetite, independent
of solute retention, are changes in taste and smell
perception, reduced intestinal motility and absorption
capacity, depression, and loss of aminoacids and protein
via dialysis (figure 4). Consequently, patients might have a
spontaneous reduction in energy intake, which can
induce protein energy wasting even before starting
dialysis (figure 3D). Although decreased protein intake
could reduce generation of uraemic retention products,
Panel 2: Non-traditional risk factors in the uraemic syndrome5
• Anaemia
• Volume overload
• Metabolic bone disorder and related mediators
• Hyperphosphataemia
• High levels of FGF-23
• Low expression of the anti-ageing factor α-klotho
• Secondary hyperparathyroidism
• Active vitamin D deficiency
• Low grade inflammation
• Oxidative stress
• Uraemic retention products*
• Post-translational protein modifications
• Accumulation of atherogenic remnant lipoproteins
• Endogenous nitric oxide synthase (NOS) inhibitors
• High sympathetic activity
• Insulin resistance
• Exposure to bioincompatible dialysis conditions
• Immune response activating membranes
• Contaminated haemodialysate
• Peritoneal dialysate containing glycation products
• Haemodynamic instability during haemodialysis
• Infections
• General
• Vascular access: arteriovenous fistula, catheters, and arteriovenous grafts
• Dyskalaemia (hypokalaemia and hyperkalaemia)
*For details, see appendix.
Figure 1: Role of progression of kidney failure in defining the uraemic syndrome
↑ Angiotensin II
↑ Catecholamines
↑ Endothelin
Glomerular hypertension
and hyperfiltration
Podocyte injury and
proteinuria
Glomerular and
tubulo-interstitial
fibrosis
Progressive kidney
dysfunction
Inflammation
Uraemic retention products
Chronic
kidney
disease

5. www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4 5
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muscle protein catabolism, indirectly caused by acidosis
and inflammation, might enhance the accumulation of
toxic metabolites. Thus, a diet containing the appropriate
nutrients in the appropriate quantity and balance is
crucial for wellbeing and to reduce metabolic poisoning
in patients with chronic kidney disease.
The intestinal microbiota plays an important part in
regulating the host’s nutritional status, metabolism, and
different aspects of immunity. Dysbiosis has been linked
to several chronic diseases. The few studies of dysbiosis
in patients with chronic kidney disease suggest changes
in the abundance and metabolic characteristics of
intestinal microbiota as compared with healthy
individuals.32
These changes induce the preferential and
abundant generation of uraemic retention products with
toxic effects. Additionally, chronic kidney disease and
uraemic retention cause structural and functional
changes of the intestinal epithelial barrier, inducing
inflammation via different pathways.33
Although
progression of kidney disease is clearly linked to changes
in intestinal microbiota, whether or not uraemic
retention products play a part in these changes is not
clear. Other conditions that are associated with kidney
disease could also affect intestinal microbiota—eg,
ageing, diabetes, obesity, changes in nutrient intake and
diet, and antibiotic intake.
Anaemia
Kidney dysfunction is associated with decreased
concentrations of haemoglobin in blood, mainly due to
deficiency of and resistance to erythropoietin and absolute
and relative iron deficiency (figure 5). The kidneys
Figure 2: Key factors in the microinflammatory condition of chronic kidney disease
All elements lead to the activation of NF-κB and the expression of several proinflammatory factors. ROS=reactive oxygen species. AGEs=advanced glycation end products. ADMA=asymmetrical
dimethylarginine. IS=indoxyl sulfate. pCS=p-cresyl sulfate.TMAO=trimethylamine-N-oxide. LPS=lipopolysaccharide. NF-κB=nuclear factor kappa B. OxLDL=oxidised low density lipoprotein.
MCP-1=monocyte chemoattractant protein-1.TGF-β=transforming growth factor β.
ROS Uraemic retention
products
AGEs, ADMA, IS, pCS,
TMAO, phosphate
Infectious agents
Infection,
endotoxin (LPS),
bacterial DNA,
peptidoglycan
Vasoactive agents
Angiotensin II,
noradrenaline,
endothelin I,
aldosterone
Cytokines and chemokines
Proinflammatory (eg, interleukin 6, MCP-1),
profibrotic (eg,TGF-β)
↑NF-κB
Mitochondrial
dysfunction
Dialysis-related
factors
Bioincompatibility,
dialysis fluid impurities
Dyslipidaemia
OxLDL
Figure 3:Typical clinical problems related to the uraemic syndrome
Vascular calcifications (A, B); rugger-jersey spine: alternating osteosclerosis and osteopenia (C); uraemic malnutrition (D); central lesions: silent infarctions (E),
microbleeds (F); white matter lesions (G).
A B C
E F G
D

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respond to low tissue oxygen by increasing erythropoietin
production, which induces erythropoiesis. Decline in
kidney function impedes this mechanism. Iron deficiency
is primarily attributable to ineffective intestinal iron
absorption, because inflammation associated with
chronic kidney disease elevates hepcidin, an inhibitor of
iron export from enterocytes to plasma. Insufficient oral
iron intake and blood loss from occult gastrointestinal or
urogenital bleeding, repetitive blood sampling, and
dialysis further drive iron deficiency. Finally, vitamin B12
and folate deficiency, shortened erythrocyte lifespan, and
frequent infections are also contributing factors.34
Erythropoietin and iron deficiencies are the main
drivers of renal anaemia, and these effects are largely
independent of uraemic retention; however, uraemic
toxins can affect erythrocyte production, solidity, and
survival (figure 5).
Neurological dysfunction
High incidence of cerebrovascular diseases (such as
stroke, white matter lesions, and intracerebral
microbleeds; figure 3E–G) and cognitive disorders
(linked to vascular abnormalities, neurodegenerative
abnormalities, or both; figure 6) have been reported in
chronic kidney disease.35
Cerebrovascular disorders
could be linked to traditional and non-traditional
cardiovascular risk factors, such as oxidative stress,
chronic inflammation, endothelial dysfunction, vascular
calcification, anaemia, dialysis-related haemodynamic
instability, and uraemic retention products.36
Uraemic
toxins could affect cerebrovascular diseases or cognition
either by direct functional effects or by modulation of
other factors (such as inflammation and oxidative
stress). β2-microglobulin—a typical uraemic toxin—
was shown to impair cognitive function and act as a
systemic, pro-ageing factor.37
Other uraemic retention
products frequently associated with neurological
dysfunction are guanidines. Phenols and indoles have
also been linked to neurological disturbances. Further
contributing factors that are partly linked to retention
are inflammation, vascular disease, and hypertension.
Factors that are more or less independent of solute
retention are depression, enhanced activity of drugs that
treat psychiatric disorders or have psychological effects
(eg, sleeping pills), and blood pressure changes related
or not to dialysis (figure 6).
Management
The studies, guidelines, position statements, and reviews
referred to in this section are summarised in the
appendix. Treatment aimed at modifying risk factors will
be discussed in broad terms independently of underlying
intermediate mechanisms. Of note, positive interventions
in the general population, could counterintuitively cause
or amplify complications in chronic kidney disease. This
section on management includes 56 original studies
(appendix), of which only 35 (63%) are randomised
controlled trials or meta-analyses. Only six (11%) of these
randomised controlled trials or meta-analyses have an
unambiguously positive intervention in a study taking
into account more than 1000 patients (all but one of these
six are meta-analyses).
Lifestyle
Emphasis is often laid on pharmacological drug
interventions in cardiovascular and kidney protection in
chronic kidney disease, of which the benefit is not
necessarily unequivocal. Several general lifestyle
measures could also be beneficial, and need negligible
societal investment, except for educational initiatives.
In a large meta-analysis, regular exercise training was
associated with improved outcomes in chronic kidney
disease. However, risk of bias of the included studies was
high.38
In a single-centre, observational study, heavy
smoking was associated with increased risk of
progression of chronic kidney disease, especially in
patients with hypertensive and diabetic nephropathy.39
In
a large, cross-sectional follow-up study, no significant
Figure 4: Role of malnutrition and dysbiosis and chronic kidney disease in defining the uraemic syndrome
Figure 5: Role of renal anaemia and chronic kidney disease in defining the uraemic syndrome
↓ Nutritional status
↑ InflammationUraemic
retention products
Chronic kidney
disease
Protein energy wasting
Intestinal modifications
and translocation
↑ Hepcidin
production
↓ Erythropoietin
generation
Iron deficiency
Inflammation,
infection
Deficient iron
intake, blood loss
Anaemia Deficiency of folic acid
and vitamin B12,
erythrocyte fragility
Chronic kidney disease
Figure 6: Role of neurological dysfunction and chronic kidney disease in defining the uraemic syndrome
Cognitive
dysfunction
Neurological
damage
Oxidative stress, inflammation,
endothelial dysfunction,
vascular calcification,
dialysis-related haemodynamic
instability
Uraemic retention
products
Chronic kidney
disease
Cerebrovascular
disease

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association was recorded between pre-dialysis obesity
and progression of chronic kidney disease.40
Another
cohort study,41
however, showed a clear association
between BMI more than 30 kg/m² and progression of
kidney disease, especially from the age of 40 years on.
The relative survival advantage in patients who are
overweight and on dialysis (obesity paradox) is
remarkable, but can be attributed to poor outcomes of
their malnourished counterparts,42
partly related to the
negative effects of inflammation. Unfortunately, focused
and conclusive studies on lifestyle in chronic kidney
disease are scarce.
Diet
A key factor of the dietary management of the uraemic
syndrome is to supply enough nutrition, but not too
much, because the body needs fuel, but cannot handle
well enough the end products of cellular metabolism.
This notion is particularly true of proteins because they
cannot be stored to adjust for intake fluctuations.
Accumulation of uraemic retention products and
metabolic poisoning in chronic kidney disease can be
ameliorated by reduced protein intake, which, rather
than being left to spontaneous evolution, should be
prescribed as a well balanced, carefully controlled, low-
protein diet. Thus, patients with stages 3–5 chronic
kidney disease who are not yet on dialysis should be
educated to pursue an equilibrium between sufficient
energy intake (at least 30 kcal/kg per day) and reduced
protein intake (0·6 to 0·8 g/kg per day, 50% of which
should be high value proteins of animal origin containing
essential aminoacids (table 2).43
This approach reportedly
reduces serum urea by 30%, and improves insulin
resistance, phosphate and parathyroid metabolism,
blood pressure, and anaemia.43
Reduction of phosphorus
intake allows better control of mineral bone disease and
reduces the need for oral phosphate binders. Sodium
intake should be targeted to a maximum of 6 g sodium
chloride per day and, if possible, lower (table 2), except in
the case of salt-losing nephropathy, in which intake can
be higher. Specialised dietitians should regularly be
involved in the implementation of advice to correctly
educate the patient. At least three encounters per year
have been suggested for the first year of care.44
This only
seems practical from chronic kidney disease stage 4
onwards. 24 h urine collections allow the monitoring of
daily protein intake (via urea measurements) and sodium
intake and should be done twice yearly to control and
implement the diet. If intentional weight loss is planned,
the benefit should be balanced against the risk of protein
wasting, particularly in the late stages of chronic kidney
disease.
On dialysis, additional catabolism takes place in
response to chronic inflammation, surgical interventions,
recurrent sepsis, and nutrient losses during the dialysis
procedure. Whereas caloric intake can be maintained
above 30 kcal/kg per day, protein intake should be
increased to more than 1·0 g/kg per day of protein in
patients on haemodialysis and 1·2 g/kg per day in
peritoneal dialysis (table 2).45
In stable patients, protein intake can be calculated as
protein catabolic rate from pre-dialysis and post-dialysis
urea measurements. Fluid intake is an indicator of
nutritional status. In patients with anuria, interdialytic
weight gain was positively associated with protein catabolic
rate.46
Reduced weight gain, or a low serum urea or
creatinine pre-dialysis are negative signs and should prompt
rapid dietary intervention.47
Nevertheless, fluid intake that is
too high and interdialytic weight gain increase intradialytic
ultrafiltration rate, which should be avoided because of its
association with mortality in patients on dialysis.48
Dietary phosphate intake should be controlled without
causing a reduction in protein intake, because a reduction
in protein intake is associated with worse survival.49
Foods
and beverages rich in phosphate, such as preserves,
processed meat, frozen foods, dairy products, and soft
drinks should be discouraged. Potassium intake that is too
high should also be avoided (table 2). For more detailed
dietary advice see appendix.
Pharmacological treatment
Chronic kidney disease is a challenging disease with
few treatment options to prevent progression. In
clinical practice, measurements of albumin-to-
creatinine ratio and eGFR allow risk classification for
chronic kidney disease progression and cardiovascular
mortality. Additional biomarkers might be helpful in
refining these strategies, but their use needs further
validation.
Chronic
kidney
disease
stages 3–5,
not on
dialysis
Receiving
haemodialysis
Receiving
peritoneal
dialysis
Had
transplant
<3 months
ago
Had
transplant
≥3 months
ago
Diet Low protein Standard
protein
Standard
protein
High protein Low protein
Target protein intake
(g/kg per day)
0·6–0·8
(or less with
keto-
analogues)
1·0–1·2 1·2 1·4 0·6–0·8
Target energy intake
(kcal/kg per day)
30–35 30–35 30–35 30–35 30–35
Salt intake (mg per
day)*
<6000 <5000 <5000 <6000 <6000
Potassium intake
(mg per day)
2500 2500 2500 Free Free†
Phosphorus intake
(mg per day)
<800 <1000 <1000 Free <800
Wasting risk ++ +++ +++ +++ +
Overweight risk ++ + + ++ +++
*Except in case of salt-losing nephropathy. †Except in case of hyperkalaemia (>5·5 mmol/L). Risk of being overweight
indicated as mild (+), moderate (++), and severe (+++).
Table 2: Integrated optimum nutrition of patients with chronic kidney disease

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The mainstays of non-specific prevention of chronic
kidney disease progression, irrespective of cause, include
blood pressure control and proteinuria-directed strategies
to preserve residual kidney function, with special emphasis
on angiotensin-converting enzyme (ACE) inhibitors or
angiotensin-receptor blockers.50
In diabetic nephropathy,
strategies that focus on strict glycaemic control slow down
progression.51
Although hyperlipidaemia could play a role
in progression, there is no consensus regarding statin
treatment for nephroprotection.52,53
In a randomised controlled trial54
of bicarbonate
supplementation with a target serum bicarbonate
concentration greater than 23 mmol/L, progression of
chronic kidney disease was slowed and nutritional status
improved. In another randomised controlled trial,55
reduction of uric acid by allopurinol treatment was
nephroprotective. In a trial56
in patients with diabetic
nephropathy, pentoxifylline reduced the rate of decline in
eGFR and proteinuria. The findings of these three
studies should, however, be confirmed in larger
controlled trials.
Uraemia is a strong, independent risk factor for
cardiovascular disease, therefore, patients with chronic
kidney disease need close cardiovascular follow-up as
part of their management strategy to prevent chronic
kidney disease progression.
Approaches targeting inflammation (eg, anti-
inflammatory drugs or statins) did not provide health
benefits for patients with chronic kidney disease. In the
AURORA trial,57
rosuvastatin lowered serum C-reactive
protein concentrations by 27%, but failed to reduce
mortality or the risk of cardiovascular events. Resistance
to interventions targeting inflammation could depend
on the severity of inflammation in end-stage kidney
disease (in the AURORA trial,57
median C-reactive
protein in the treatment group remained four times
above upper normal concentrations), and on its
multifactorial origin. Interference of proinflammatory
and oxidative mechanisms—by the reduction of NF-κB
activation and activation of nuclear factor-erythroid-2-
related factor 2—seemed an attractive option to reduce
the enhanced risk of all-cause and cardiovascular death
in advanced chronic kidney disease. However, a trial58
testing a NF-κB blocker (bardoxolone) in patients with
chronic kidney disease and type 2 diabetes was
prematurely terminated because of excessive risk of
cardiovascular events in the bardoxolone group.
In pre-dialysis chronic kidney disease, the well
established cardiovascular benefit of antihypertensive
treatment has led to specific guidelines recommending
target blood pressures of 140/90 mm Hg or less in
chronic kidney disease (130/80 mm Hg or less in the
presence of proteinuria).59
The relation between pre-
dialysis or post-dialysis blood pressure and mortality in
patients on dialysis is inverse or U-shaped, which is a
classical example of reverse causality. However, dialysis-
related blood pressure values hardly reflect true blood
pressure burden in patients on haemodialysis.60
Out-of-
dialysis systolic blood pressure, in fact, predicts a linear
increase in the risk of death from 110 mm Hg or higher,61
as in the general population.
Antihypertensive treatment reduces the incidence of
death and cardiovascular events at all risk levels and in
absolute terms most of all in patients with a higher
baseline risk.62
In the SPRINT trial,63
patients with
hypertension randomised to target systolic blood
pressures of less than 120 mm Hg had fewer
cardiovascular events than in those targeted to less than
140 mm Hg, in general and in the subgroup with chronic
kidney disease. In patients with end-stage kidney disease,
including patients with heart failure, the use of
antihypertensive drugs reduces mortality,64
but treatment
should be titrated to tolerable levels—ie, to minimise the
risk of hypotension by autonomic dysfunction or arterial
stiffness,65
which enhance the risk for ischaemic events.
Optimisation of volume control at constant ultrafiltration
rate (eg, by more frequent or extended dialysis), and
judicious use of antihypertensive drugs accounting for
comorbidities and pharmacokinetic profile66
could reduce
cardiovascular risk in patients on dialysis. In a single
centre-based observational study,67
extended haemo-
dialysis (24 h per week) in an older population resulted in
good blood pressure control without antihypertensive
drugs.
Controlling hyperglycaemia in patients with renal
failure and diabetes is difficult because of the higher risk
of hypoglycaemia as compared with the diabetic
population without chronic kidney disease.68
Target
HbA1c levels should account for additional risk factors,
with the aim to achieve strict control in those with low
risk, but more leniency in those with comorbidities and
high risk for hypoglycaemia.69
Patients with diabetes,
chronic kidney disease, and heart failure, ischaemic
heart disease, or hypertension, can be treated with renin–
angiotensin system blockers at a maximally tolerated
dose. However, combinations of ACE inhibitors and
angiotensin II receptor blockers should be used carefully
in patients with chronic kidney disease not yet on
dialysis69
to avoid hyperkalaemia, kidney impairment,
and hypotensive symptoms,50
although in a meta-
analysis,70
a positive effect on kidney function
preservation was suggested with this combination in
people with diabetes.
Empagliflozin, a sodium-glucose co-transporter
inhibitor, significantly reduced a composite of cardio-
vascular events and death in patients with diabetes type 2
and eGFR more than 30 mL/min per 1·73 m² at high
cardiovascular risk (26% with chronic kidney disease
stage 3).71
Because of malnutrition and inflammation, hyper-
cholesterolaemia often regresses as chronic kidney
disease advances. Identification of dyslipidaemia (high
total or LDL cholesterol, low HDL cholesterol, high
triglycerides) in patients with end-stage kidney disease is

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deemed useful by existing Kidney Disease Improving
Global Outcomes (KDIGO) guidelines to assess overall
cardiovascular risk,72
but follow-up of lipid concentrations
is not recommended because of the absence of evidence
that this approach improves clinical outcomes.
Findings from the SHARP trial73
and subsequent
meta-analysis53
showed the usefulness of an absolute
reduction of LDL cholesterol in patients with chronic
kidney disease to decrease the associated cardiovascular
risk. Cholesterol-lowering therapy is especially
recommended by KDIGO in all patients with chronic
kidney disease at stage 3–5, who are more than 50 years
of age and not on dialysis.72
However, the benefit of
statins was less prominent in end-stage kidney
disease,57,74
which discouraged their use in end-stage
kidney disease, irrespective of inflammation or
malnutrition. In patients already treated, however, this
therapy can be continued.69
Results from a large end-stage kidney disease cohort in
the USA showed no survival benefit of lowering
phosphate concentrations with calcium carbonate or
acetate.75
Findings from another observational study76
showed a reduction in death risk in patients who were
given any type of phosphate binder. Results from a meta-
analysis77
of seven trials in haemodialysis patients and
one in moderate chronic kidney disease showed lower
mortality in patients given the non-calcium-based
phosphate binder sevelamer. However, this apparent
benefit (heterogeneity I²=89%) is potentially skewed by a
study in patients on haemodialysis in which sevelamer
reduced the death risk by 91%, hence, the issue remains
unresolved. Serum phosphate concentrations between
0·68 and 1·93 mmol/L do not associate with an excessive
death risk in dialysis patients.78
The decision to treat hyperphosphataemia should take
into account serum calcium, PTH, and serum vitamin D
concentrations from the early stages of chronic kidney
disease-associated mineral bone disorder.78
Secondary
hyperparathyroidism has been implicated in the
cardiovascular risk of chronic kidney disease. However,
improvement of mortality and cardiovascular outcome
was inconclusive in a large trial79
of calcium receptor
agonist cinacalcet in secondary hyperparathyroidism, and
this finding was confirmed by meta-analysis.80
Many patients with chronic kidney disease have low
serum concentrations of 25-hydroxyvitamin D or
calcitriol, but a randomised, placebo-controlled trial
testing their supplementation on hard endpoints is not
yet available. However, these supplements might help
control hyperparathyroidism. The effect of modulation of
uraemic retention product concentrations on metabolic
bone disease and cardiovascular outcomes needs to be
investigated because several of these retention products
are associated with both complications.81
Malnutrition should be diagnosed using the
International Society for Renal Nutrition and Metabolism
protein energy wasting criteria,82
which include clinical,
laboratory, and body composition measurements.
Wasting scores can predict survival and should be used
more frequently to help identify patients at risk of death
from wasting. An increase in nutrient intake is the key
intervention and has been shown to be effective even in
the context of chronic inflammation. One or two units of
oral supplements taken separately from regular meals to
avoid further reductions in spontaneous intake should be
used as a primary measure. The FINE study,83
which
compared oral nutritional supplements with or without
parenteral nutrition in dialysis patients with protein
energy wasting, was negative for its primary endpoints
(eg, mortality). Oral supplements were well tolerated and
increase total nutrient intake, serum albumin, and
serum prealbumin.83
Results of a multivariate analysis
showed that mortality was reduced if serum prealbumin
increased above 30 mg/L in the first 3 months of
supplementation.83
Therefore, in ambulatory patients, if
nutritional status does not improve within 4 weeks,
enteral feeding should be considered. For hospital
inpatients, intensive nutrition through a nasogastric tube
or percutaneous gastrostomy can be considered if oral
energy intake is less than 20 kcal/kg per day for more
than 10 days.
Few randomised controlled trials have been done that
investigate the effect of the restoration of intestinal
symbiosis in chronic kidney disease by giving patients
prebiotics (selectively fermentable ingredients),
probiotics (live biotherapeutics), or synbiotics (com-
bination of prebiotics and probiotics) to reduce
circulating concentrations of uraemic retention products,
inflammation, oxidative stress, and progression of
chronic kidney disease. Specific prebiotics decrease
serum indoxyl sulfate and urea nitrogen.84,85
Results from
a study86
in patients receiving peritoneal dialysis showed
a significant reduction in concentrations of pro-
inflammatory cytokines, an increase in concentrations of
anti-inflammatory cytokines, and better preservation of
residual kidney function in the group receiving
probiotics. Synbiotic therapy reduces the concentration
of p-cresol.87
In several of the above trials, however, the
intervention was coupled to a low-protein diet, which
could itself decrease uremic toxin concentration and
progression of kidney failure. The actual effect of
restoring intestinal symbiosis on the intestinal
microbiota profile or on hard outcomes was not assessed
in any of the above trials.
Reduction of indoxyl sulfate by intestinal sorbents, such
as AST-120, stopped progression of chronic kidney
disease in small Japanese randomised trials.88,89
This
benefit was not confirmed in a large European–American
randomised controlled trial.90
Interventions improving
symbiosis need further study before their efficacy can be
accepted.
The conventional approaches for iron repletion in
chronic kidney disease are oral ferrous salts or intravenous
colloidal compounds. High concentrations of hepcidin,

10. 10 www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
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however, make intestinal iron uptake ineffective.
Additionally, oral iron intake further contributes to the
pill burden of patients with chronic kidney disease and
causes severe gastrointestinal side-effects. Therefore,
intravenous iron has gained popularity in the past 5 years.
However, experimental and observational data suggest
unwanted immunological, cardiovascular, and renal
effects of such treatment,91,92
which might differ between
classic preparations and new, more stable formulations.91
Long-term prospective studies are, however, unavailable.
The introduction of recombinant human erythropoietin
was one of the major steps forward in the treatment of
renal anaemia. Both short-acting and long-acting
erythropoiesis stimulating agents are in use at present.
According to the existing guidelines, the decision of
whether and when to start treatment with an
erythropoiesis stimulating agent should be individualised
and take into account related risks and anaemic
symptoms.34
The target values for erythropoiesis
stimulating agent therapy are 10·0–12·0 g/dL.34
These
drugs should be used with care in patients at high risk of
stroke or with active or past malignancy.34
Blood transfusions might be considered, especially in
patients with haemoglobin concentration of less than
7·0 g/dL, who are resistant to erythropoiesis-stimulating
agents, or at potential risk of complications with
erythropoiesis stimulating agent therapy.93
However, the
risk of developing panel reactive antibodies should be
taken into account in transplant candidates.
Few data are available on the effect of treatment for
chronic kidney disease on risk of stroke and other
neurological disorders in patients with this disease,
particularly in those with end-stage kidney disease.
Patients with chronic kidney disease have been under-
represented in the cardiovascular trials that prove net
benefit of commonly used preventive treatments (eg,
antihypertensive drugs, low-dose aspirin, carotid revascu-
larisation, and thromboprophylaxis for atrial fibrillation),
and safety and efficacy of many of these treatments in
chronic kidney disease remains uncertain. Conflicting
results have been reported on the effect of statins in
patients with chronic kidney disease. In a Cochrane
review,53
the authors concluded that statins did not
necessarily have effects on stroke in patients with chronic
kidney disease who did not need dialysis, by contrast
with another meta-analysis94
in which statins were
associated with a decrease in cardiovascular disease in
chronic kidney disease, including stroke. Correcting
anaemia might not prevent stroke and could even
increase its risk in chronic kidney disease.95
Moreover,
the effect of anaemia treatment on cognitive disorders
remains a matter of debate.
Oxidative stress, inflammation, or uraemic retention
products could contribute to neurological disorders in
patients with chronic kidney disease. Thus, treatments
modulating these factors might improve neurological
outcomes. To the best of our knowledge, no direct
interventional trials have targeted these abnormalities.
However, improvement of intra-dialytic haemodynamic
stability by cooling dialysate has been shown to protect
against brain injury.65
Renal replacement therapy
Replacement of kidney function requires trans-
plantation or dialysis, and haemodialysis and peritoneal
dialysis are the main dialysis modalities (for more on
different dialysis strategies see appendix). Haemodialysis
is usually done three times weekly, whereas peritoneal
dialysis clears retention products with lower efficiency
but does so continuously. The high efficiency solute
removal provided by a single haemodialysis session over
4 h should be extrapolated to the full interdialytic interval
of 48–72 h, by comparison with kidney removal capacity.
Thus, renal replacement therapy through dialysis allows
the anuric patient to have a kidney-equivalent filtration
rate of only 5–10 mL/min for small molecules that are
the size of urea or creatinine, which results in higher
uraemic solute concentrations than is normal. In
general, dialysis removes retention products of higher
molecular weight or those bound to protein less
efficiently than the normal kidney. Oral phosphate
binders are frequently needed to maintain serum
phosphate concentrations that are close to normal. The
standard dialysis clearance of small proteins such as
cytokines, FGF-23, and β2-microglobulin is negligible,
as compared with normal kidneys. Clearance of
β2-microglobulin (11·8 kDa), deemed representative of
middle-sized molecules, was estimated at 3–19 mL/min
for a conventional haemodialysis session (ie,
0·17–1·0 mL/min when averaged over 72 h), as compared
with 65 mL/min in a normally functioning kidney.96
Conventional haemodialysis relies on diffusion for
solute removal, whereas haemodiafiltration also
depends on convective transport. This additional
mechanism enhances the removal of middle-sized
molecules, such as β2-microglobulin and FGF-23, but
has little effect on many protein-bound retention
products.97,98
However, β2-microglobulin clearance per
single haemodiafiltration session is still far from
normal kidney removal rates when averaged over
48–72 h (3·6 mL/min higher than conventional
haemodialysis).99
Despite this poor efficiency, findings
from a randomised controlled trial100
published in 2013,
suggested that haemodiafiltration could improve hard
outcomes versus standard dialysis, but a meta-analysis
of all studies showed improvement only for cardio-
vascular mortality, but not overall mortality.
Additionally, the reliability of potential benefits found
in this meta-analysis was deemed debatable because
the studies included in the analysis had several
methodological limitations.101
Dialyser design changes might further improve removal
of middle molecules.102
However, for each additional
20 mg of β2-microglobulin removed in a single session

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(less than 10% increase), 1·24 g of albumin were lost (40%
increase).102
Researchers who aim to increase protein-
bound solute removal are exploring how to increase the
release of uraemic retention products from their protein-
bound states,103
for example by including adsorbents, but
length of dialysis using these technologies is a limiting
factor.97
Extension of haemodialysis time, in daily or
extended regimens, either at home or in centre, can
improve weekly solute clearance.97,98
Transplanted kidneys develop hypertrophy and mean
eGFR is 60–70 mL/min per 1·73 m² 1 year after
transplantation.104
However, in a cross-sectional study of
graft recipients 5 years after their transplantation, more
than 70% of patients had measured GFR of less than
60 mL/min per 1·73 m², and thus, had limited removal
capacity.105
Serum β2-microglobulin concentrations of
3·0 mg/L or more were observed in 58% of kidney
transplant recipients at discharge.106
Kidney graft
handling of certain uraemic retention products might be
abnormal. For example, phosphate leakage is frequent
early after transplantation, especially in patients with
severe hyperparathyroidism.105
Over time, kidney grafts
lose function—the half-life of a cadaveric kidney graft is
9 years and 12 years for a living-donor graft.
Conclusion
Patients with chronic kidney disease have complex
pathophysiology for which the underlying mechanisms
intertwine (appendix). Inflammation and disturbed
bone homoeostasis in particular lead to complications
and high and accelerated mortality. Management
(appendix) cannot always be based on high-level
evidence, because of difficulties in the recruitment of
patients with sufficiently homogeneous background of
primary disease, metabolic features, and response to the
uraemic syndrome. Specific therapeutic recom-
mendations are, therefore, based on an amalgam of
high-level and lower-level evidence and uraemia-related
pathophysiological reasoning. Therapeutic approaches
cannot always be extrapolated from the general
population, because beneficial interventions in the
general population often have a different effect in
populations with chronic kidney disease. Treatment of
one aspect of the uraemic syndrome might exacerbate
other deleterious elements. In future studies, a more
holistic therapeutic approach to cope with the high
mortality of this disease could be more useful rather
than the pursuit of one single factor as is usual practice
in randomised controlled trials. Therapeutic approaches
should focus on additional outcomes beyond mortality,
especially standardised quality of life. Consultation with
patients to understand what is important to them might
be useful for the definition of patient-related outcomes.
Contributors
All authors wrote the first draft of one or more sections of the Review,
and all contributed to the editing of subsequent versions.
RV coordinated the initiative, merged the texts, and did general editing.
Declaration of interests
RV has received travel grants and honoraria from Nipro, Bayer, and
Fresenius Medical Care, and has acted as a consultant for Fresenius
Medical Care and Debiotech. DF has acted as a consultant for Fresenius
Kabi. GHH has received study grants from Pharmacosmos and
Fresenius Medical Care. ZAM has received speaker’s honoraria and
research grants from Amgen, Genzyme, Fresenius Medical Care, and
Shire. AO has received speaker’s honoraria and research grants from
Amgen, Genzyme, Fresenius Medical Care, Servier, and Shire. PR has
received honoraria from Baxter-Gambro, Fresenius, and Relypsa. AW has
received speaker’s and consulting honoraria from Amgen, Fresenius
Medical Care, Astellas, Roche, GlaxoSmithKline, Pharmacosmos, and
Teva. GG, MK, FM, CZ, and GML declare no competing interests.
Acknowledgments
The European Renal and Cardiovascular Medicine (EURECA-m)
working group is one of the working groups of the European Renal
Association—European Dialysis and Transplant Association
(ERA-EDTA) and is composed of members whose careers have been
devoted to unravelling the pathophysiology of cardiovascular disease in
chronic kidney disease and to defining accurate therapeutic approaches
to address this problem.
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