PROTEIN ENERGY WASTING IN DIALYSIS PATIENTS
Fluid Overload and Inflammation—A Vicious Cycle
Joselyn Reyes-Bahamonde, Jochen G. Raimann, Stephan Thijssen, Nathan W. Levin,
and Peter Kotanko
Renal Research Institute, New York, New York
Inflammation in CKD
Inflammation is prevalent in the majority of patients
with chronic kidney disease (CKD). This is indicated by
higher levels of inflammatory markers such as C-reactive
protein (CRP), serum amyloid A, and cytokines such as
interleukin-6 (IL-6) and tumor necrosis factor alpha
(TNF-a) (1). Increased levels of inflammatory markers
can be observed at any CKD stage for reasons not yet
fully understood. A relationship between elevated
inflammatory biomarkers and a progressive reduction
of residual renal function has been reported (1–3).
Evidence also exists suggesting a link between inflam-
mation and protein energy malnutrition. Proinflamma-
tory cytokines may suppress appetite, promote muscle
wasting, and hypoalbuminemia, and may be involved in
atherogenesis (4). Strong evidence links the symptom
complex of malnutrition, inflammation, and athero-
sclerosis (MIA syndrome) with mortality in CKD 5D
patients (5,6). In this context, inflammation is of impor-
tance in a chain of interconnected events (Fig. 1). What
follows is an outline of the interconnection between the
depicted events; we will put forward a hypothesis linking
fluid overload (FO) to inflammation and vice versa.
Endothelial Damage
Inflammation plays a central role in the development
of endothelial dysfunction, atherosclerosis, and vascular
calcification. Inflammation leads to secretion of acute
phase proteins and cytokines, complement activation,
and immune cell recruitment (7,8). Inflammation, speci-
fically high levels of TNF-a, may be a promoting factor
in the development of left ventricular hypertrophy
(LVH) (9). While TNF-a is expressed by inflammatory
cells within the myocardium (10,11), dilated cardio-
myopathy has been observed in transgenic mice with
cardiac-specific overexpression of TNF-a (9). Proinflam-
matory cytokines trigger the proliferation of smooth
muscle cells and vascular remodeling by activating pro-
liferative signaling pathways in the cell (11,12). Further-
more, activation of cardiomyocyte-specific IkB kinase
(IKK ⁄ NF-kB) by TNF-a has been implicated in the
development of cardiac hypertrophy (11). TNF-a
activation has also been associated with endothelial
Address correspondence to: Peter Kotanko, M.D., Renal
Research Institute, 207 East 94th street; Suite 303, New
York, NY 10128, Tel.: +1 646 672 4042, Fax: +1 646 672 4174,
or e-mail: peter.kotanko@rriny.com.
Seminars in Dialysis—Vol 26, No 1 (January–February) 2013
pp. 16–39
DOI: 10.1111/sdi.12024
ª 2012 Wiley Periodicals, Inc.
31
damage and the initiation of a chain of inflammatory
events, which compromise the integrity of the vascular
wall (12).
Endothelial dysfunction, clinically reflected by an
increased pulse wave velocity (PWV), is present in
almost 50% of predialysis CKD 4 and 5 patients (12).
PWV associates with an increased risk of cardiovascular
(CV) events and all-cause mortality in patients with
reduced kidney function (12,13). A PWV increase of
1 m ⁄ second was associated with a relative risk of death
of 1.14 (95% CI: 1.05–1.24) (14).
Cardiovascular Disease
A majority of CKD 5D patients suffer from cardio-
vascular disease (CVD), which is the main cause of mor-
tality in this population (15,16). Evidence indicates a
positive relationship between increased PWV, arterial
stiffness, and left ventricular mass (13,20). Certainly, an
expanded extracellular fluid volume (ECV) and hyper-
tension and, possibly, the accumulation of uremic toxins
are causative factors of LVH (17). LVH develops early
in CKD and further progresses with declining kidney
function (18). A left atrial diameter larger than 4.7 cm,
an increased left ventricular mass index, and a left ventri-
cular ejection fraction below 55% are independently
associated with adverse CV outcomes in CKD patients
(19). LVH is considered a predictor of heart failure in
CKD patients (20,21).
Diastolic Dysfunction
Myocardial changes may lead to progressive
impairment of cardiac contractility, stiffening of the
myocardial wall and subsequently, to the development
of systolic and diastolic dysfunction (22). The hallmark
of diastolic dysfunction is abnormal ventricular
stiffening with elevated filling pressures. Diastolic dys-
function is associated with poor cardiac outcomes (22)
and may result in progressive CVD and eventually con-
gestive heart failure (CHF). In hemodialysis (HD)
patients, diastolic dysfunction is highly prevalent; it may
compromise hemodynamic stability during HD and
thereby increasing the risk of intradialytic hypotension.
HD Intolerance
Diastolic dysfunction impairs the ability to cope with
the hemodynamic challenges caused by ultrafiltration
and rapid depletion of the intravascular volume during
dialysis. Intradialytic hypotension and associated
32 Reyes-Bahamonde et al.

Fig. 1. Vicious cycle of inflammation and fluid overload. Antidiuretic Hormone (ADH), hemodialysis (HD), neurohormonal activation
(NHA), renin-angiotensin-aldosterone-system (RAAS), sodium (Na+) sympathetic nervous system (SNS), ultrafiltration (UF).

symptoms are more likely in patients with decreased Low Ultrafiltration Rate ⁄ Short Treatment
cardiac output (23,24). Hypoperfusion during HD Time ⁄ Na Profiling
affects vital organs, including the brain (25) and the
Intradialytic complications have been associated with
gastrointestinal system (26). In the central nervous
poor outcomes, including mortality (30). As outlined
system an increased frequency of leukoaraiosis has been
earlier, rapid removal of excess fluid is likely to result in
noted, possibly related to intradialytic hypoperfusion
intradialytic events. The most efficient way to prevent
during hypotensive episodes (25). Hypoperfusion of the
this is a prolongation of HD time or more frequent treat-
gut is discussed below.
ments. Logistic, organizational, and budgetary reasons
often do not allow this in clinical practice. The inability
Cardiac Stunning to determine objectively an optimal post HD target
weight, also referred to as ‘‘dry weight’’ within current
Cardiac hypoperfusion during hypotensive episodes
technical possibilities is a further complication. Recent
results in myocardial dysfunction, in particular
developments in bioimpedance techniques to establish a
motion hypokinesis (27,28). Recurrent episodes of
state of normal fluid status, may help solve this problem
intradialytic myocardial ischemia may eventually lead
(31).
to chronic and irreversible myocardial injury, in parti-
Several techniques have been proposed to minimize
cular, myocardial fibrosis (29) Burton et al. studied
the occurrence of symptoms and prevent HD intoler-
HD patients with dialysis-related myocardial stun-
ance. A popular, commonly used technique is sodium
ning; at reevaluation 12 months later, one-third had
profiling, although its adverse effects when not per-
developed fixed systolic dysfunction of the previously
formed appropriately are well known (increased inter-
stunned myocardial segments; reduced ejection frac-
dialytic weight gain [IDWG] and blood pressure).
tion and decreased blood pressure were also observed
Reduction of the commonly positive sodium balance by
(29).
 PROTEIN ENERGY WASTING IN DIALYSIS PATIENTS
dietary and intradialytic means lowers IDWG and con-
sequently ultrafiltration rate (32).
On the other hand, high dialysate sodium concen-
trations have been used to reduce intradialytic hypo-
tension and hypoperfusion symptoms such as
cramping and nausea. However, dialysate-sodium-
concentrations resulting in positive dialysate to serum
sodium gradients and leading to sodium flux into the
patient, have been shown to cause an expansion of
extracellular volume. In consequence this may lead to
FO and hypertension (32,33). Ultrafiltration profiling
has not yet been studied in sufficiently powered ran-
domized trials, but evidence suggests potential posi-
tive effects on HD intolerance (34). Increased length
or frequency of HD, such as in short daily and noc-
turnal HD may be of value to prevent FO (35).
Extracellular Volume Expansion
As noted above, ECV expansion and high sodium
intake, is highly prevalent in HD patients and is asso-
ciated with increased mortality (36,37). Increased
intradialytic sodium flux into the patient increases
IDWG due to compensatory water intake to restore
the serum sodium concentration to a stable sodium
‘‘set point’’ (37,38) and resulting in increased blood
pressure.
The harmful effects of sodium are not limited to FO.
Sodium may also be considered a uremic toxin due to
the fact that salt intake has been related to arterial stiff-
ness, LVH, and fibrosis independently of blood pressure
(39,40). Salt intake has been identified to stimulate the
expression of transforming growth factor-b, a pro-fibro-
tic protein, in the kidney, aortic, and endothelial cells. In
addition, sodium excess may also increase oxidative
stress activity (40,41).
The presence of FO and high IDWG leads to an
increased ultrafiltration rate (unless treatment time is
prolonged) to achieve post HD target weight. High
UFR can produce hypoperfusion in different organs
including the intestines (42), where the intestinal barrier
built by epithelial cells (enterocytes) is broken down
allowing an invasion of bacteria and endotoxins into the
blood stream (26).
Barrier Breakdown in the Gut and Bacterial
Translocation
The intestinal mucosa plays an essential role in the
absorption of nutrients, but also is an important barrier
between intestinal flora and the blood. The main compo-
nents of the intestinal barrier are mucus, a continuous
layer of enterocytes interconnected with tight junctions,
and an immune barrier formed by secreted immunoglo-
bulin A and immune cells (43). The gut is the natural
habitat for a variety of microorganisms, which are sepa-
rated from the body through the physical and immuno-
logical barriers in the gut. Furthermore, uremic patients
with CKD show variations of flora colonization—espe-
cially aerobic and anaerobic bacteria in the duodenum
and jejunum, areas that are normally not colonized (44).
33
In animal models, bowel wall edema and ischemia
have been reported as sequelae of FO (45). As men-
tioned before, high Na intake is ultimately linked to
intense UFR, which favors hemodynamic instability.
The subsequent intradialytic hypotension and hypoper-
fusion of the gastrointestinal system may cause mesen-
teric ischemia; this increases gut permeability (46),
breaks down protective barriers, and allows overgrowth
of species with potential pathogenicity (47) as well as
translocation of microorganisms or endotoxins. When
endotoxins reach the blood stream they form a complex
with endotoxin-binding protein, which activates mono-
cytes and macrophages, increases TNF-a and other
cytokines resulting in a state of chronic inflammation.
Several studies have reported this relationship
between FO and inflammation; a correlation between
plasma endotoxin levels and signs of FO has been noted
(48). Inflammation is accompanied by hypoalbumine-
mia (49), and thus a reduction in oncotic pressure, which
also may contribute to bowel wall edema and increased
gut permeability (50,51).
The importance of FO as a promoter of endotoxine-
mia is underlined by a study in 40 patients with different
degree of CHF and 14 healthy subjects. In this study,
endotoxin levels were highest in CHF patients with per-
ipheral edema compared with stable CHF patients and
healthy controls (52). After diuretic therapy, endotoxin
levels decreased from 0.96 to 0.45 EU ⁄ ml in 8 of 10
patients (43). While bowel edema cannot be measured
directly in clinical practice, it may be related to the pre-
sence of peripheral edema. A landmark study in CKD
patients showed that endotoxin levels were increased in
all stages of CKD. Levels were higher in advanced stages
of renal disease but, remarkably, dialysis patients had
levels almost six times higher than nondialysis patients
(46).
Neurohumoral Activation
During HD, the neurohumoral system is activated to
maintain adequate organ perfusion (53). This response
reduces hemodynamic instability and hypoperfusion
during fluid removal (54). Autonomic dysfunction may
also contribute to intradialytic instability (53,55) and
reduce physical performance (56). Angiotensin II
stimulates IL-6 and nuclear factor kappa-light-chain-
enhancer of activated B cells (NFjB) which results in
endothelial damage (8). Aldosterone in combination
with increased salt intake promotes inflammation and
oxidative stress (57,58).
Several studies have also shown elevated basal anti-
diuretic hormone (ADH) levels in HD patients (59). It is
unknown if the higher levels are caused by the plasma
volume reduction during HD, the repeated changes in
osmolality, the occurrence of hypotensive episodes, or
related to autonomic dysfunction (60). Recently, copep-
tin, the 39 amino acids C-terminal part of pro-ADH, has
been proposed as a surrogate marker for the unstable
ADH. A rise of copeptin levels preceded the increase in
troponin T in patients with myocardial infarction. In
patients with CHF copeptin is a promising marker of
34 Reyes-Bahamonde et al.
all-cause mortality and worsening of HF. A relationship
between copeptin and renal function has been noted
although it is not clear if high copeptin levels are a conse-
quence of declining renal function or if it plays some cau-
sative role in its decline (61). Copeptin has also been
related to cardiovascular events in HD patients (61).
Treatment of FO and Its Effects on CVD and
Inflammation
Given the poor prognosis of fluid-overloaded HD
patients (36) there is an urgent need to develop technolo-
gies and treatment strategies to achieve a normal fluid
status (‘‘dry weight’’) post dialysis. While reduction of
dietary salt intake is an elusive goal in many patients, a
reduction in intradialytic salt loading (lowering dialysate
sodium levels; judicious use of saline for priming, rin-
sing, and treatment of intradialytic morbid events) is
operationally feasible (62). To date, there is no general
agreement on means to objectively determine ‘‘dry
weight’’; however, bioimpedance is a promising technol-
ogy to assess FO (31).
While operationally challenging, increased treatment
time and more frequent HD may be needed in some
patients to actually achieve the then determined ‘‘dry
weight.’’ The recently reported primary results of the pro-
spective randomized Frequent Hemodialysis Network
Daily Trial indicate beneficial effects of more frequent
dialysis on left ventricular mass and several secondary
outcomes in patients receiving more frequent short daily
hemodialysis (60,63). More frequent short daily HD
improved blood pressure and reduced the number of pre-
scribed antihypertensive drugs (63). Reduction of FO
improves CV outcomes by the potential regression of
LVH and improvement of blood pressure (15).
The control of fluid status also improved the systemic
inflammatory response (64). In fact, several studies have
shown a reduction in inflammatory markers while redu-
cing FO. Sato et al. studied eight patients with advanced
CHF reflected by dyspnea, pulmonary edema, radio-
graphic findings, and depressed LV ejection fraction.
After intensive treatment, a significant decrease in CRP
and IL-6 levels in parallel with CHF improvement was
noted (65).
In conclusion, CVD is a key factor contributing to
HD intolerance and is likely linked to inflammation.
CVD promotes intradialytic hypotension which may
impair the integrity of the intestinal barrier allowing
translocation of bacterial endotoxins, which in turn trig-
gers inflammatory responses. Based on this reasoning
we hypothesize that reduction of FO translates into
diminution of inflammation. While this hypothesis needs
formal and rigorous testing in HD patients, it is sup-
ported by current observational evidence.
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