Review

Clinical management of the uraemic syndrome in chronic

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

www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4 1

 Review
Lorraine, Nancy, France
(Prof P Rossignol); Association Panel 1: Consequences of the uraemic syndrome
Lorraine pour le Traitement de
l’Insuffisance Rénale, Cardiovascular
Vandoeuvre lès Nancy, France Hypertension, fluid overload, cardiac decompensation,
(Prof P Rossignol); Department vascular damage and stiffness, cardiovascular events,
of Nephrology, Transplantation
and Internal Medicine, Medical
pericarditis
University of Silesia, Katowice,
Haematological
Poland (Prof A Wiecek MD); and
INSERM U970, Hôpital Anaemia, erythrocyte fragility, immune dysfunction
Européen Georges Pompidou, (susceptibility to infections, low response to vaccination),
Paris (Prof G M London MD) inflammation, hypercoagulability, bleeding tendency
Correspondence to:
Prof Raymond Vanholder, Endocrine
Nephrology Section, University Hyperparathyroidism, insulin resistance, impotence,
Hospital, De Pintelaan infertility, thyroid dysfunction, hyperaldosteronism, growth
185, B9000 Ghent, Belgium
raymond.vanholder@ugent.be
disturbance, adipokine dysbalance, klotho deficiency and
FGF-23 excess, active vitamin D deficiency
See Online for appendix
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
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
2 www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
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,
 Review

GFR* Definition Therapeutic approaches Pathophysiological changes Mortality

Stage 1 >90 Normal kidney function, but Observation, blood pressure and Klotho deficiency Increased overall and
urine abnormalities (eg, cardiovascular risk factor control, cardiovascular
haematuria or prevention of cardiovascular disease mortality +
albuminuria†), proven
structural kidney damage,
or genetic trait
Stage 2 60–89 Mildly reduced kidney Observation, blood pressure and Klotho deficiency, elevated FGF-23 Increased overall and
function associated with cardiovascular risk factor control, cardiovascular
other findings (as in stage 1) prevention of cardiovascular disease mortality +
Stage 3A 45–59; Moderately reduced kidney Observation, blood pressure and Klotho deficiency, elevated FGF-23 Increased overall and
Stage 3B 30–44 function cardiovascular risk factor control, and PTH, malnutrition, hypertension, cardiovascular
prevention of cardiovascular disease, left ventricular hypertrophy, anaemia mortality ++
treatment of anaemia and metabolic bone
disease, prevention of chronic kidney
disease progression
Stage 4 15–29 Severely reduced kidney Planning for renal replacement therapy, Klotho deficiency, elevated FGF-23 Increased overall and
function blood pressure and cardiovascular risk and PTH, malnutrition, hypertension, cardiovascular
factor control, prevention of cardiovascular left ventricular hypertrophy, anaemia, mortality +++
disease, treatment of anaemia and hypertriglyceridaemia,
metabolic bone disease, prevention of hyperphosphataemia, metabolic
chronic kidney disease progression acidosis, hyperkalaemia
Stage 5 <15 Very severe kidney failure or Renal replacement therapy or conservative Klotho deficiency, elevated FGF-23 Increased overall and
end-stage kidney disease approach, blood pressure and and PTH, malnutrition, hypertension, cardiovascular
cardiovascular risk factor control, left ventricular hypertrophy, anaemia, mortality ++++
prevention of cardiovascular disease, hypertriglyceridaemia,
treatment of anaemia and metabolic bone hyperphosphataemia, metabolic
disease acidosis, hyperkalaemia, need for
renal replacement therapy

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

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

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 Review

osteochondrogenic phenotype (Runx2, osterix, Sox9).24

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

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ROS Uraemic retention Infectious agents Vasoactive agents Mitochondrial Dialysis-related Dyslipidaemia
products Infection, Angiotensin II, dysfunction factors OxLDL
AGEs, ADMA, IS, pCS, endotoxin (LPS), noradrenaline, Bioincompatibility,
TMAO, phosphate bacterial DNA, endothelin I, dialysis fluid impurities
peptidoglycan aldosterone

↑NF-κB

Cytokines and chemokines

Proinflammatory (eg, interleukin 6, MCP-1),
profibrotic (eg, TGF-β)

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.

A B C D

E F G

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).

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

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 Review

microbleeds; figure 3E–G) and cognitive disorders

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

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 Review

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

On dialysis, additional catabolism takes place in Overweight risk ++ + + ++ +++

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
*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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 Review
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
8 www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
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

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,
www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
Review
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,
9
 Review
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
10 www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
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

Search strategy and selection criteria
We searched PubMed, Embase, Web of Science, and the
Cochrane Library for articles published in English up to Dec 1,
2015. Search terms related to the main topics of this Review
were used—eg, “metabolic bone disease” or “inflammation”
and “chronic kidney disease”, “chronic renal failure” or “chronic
kidney disease” and “physiopathology”, “treatment”, “therapy”,
“outcomes”, “morbidity”, or “mortality”. Randomised
controlled trials or large observational studies on hard
outcomes were retained by preference. Reference lists of the
resulting articles were searched for other relevant papers.
Review articles are cited to provide readers with more details
and more references than space permits in this narrative
review, and were selected for their comprehensiveness and
compactness.
(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
www.thelancet.com/diabetes-endocrinology Published online March 2, 2016 http://dx.doi.org/10.1016/S2213-8587(16)00033-4
Review
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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