Review
Why Is Your Patient Still Short of Breath? Understanding the
Complex Pathophysiology of Dyspnea in Chronic Kidney
Disease
Fabio Rosario Salerno,* Grace Parraga,*† and Christopher William McIntyre*
*Department of Medicine and Medical Biophysics, Schulich School of Medicine and Dentistry, The University
of Western Ontario, London, Canada, and †Robarts Research Institute, The University of Western Ontario,
London, Canada
ABSTRACT
Dyspnea is one of the most common symptoms associ-
ated with CKD. It has a profound influence on the
quality of life of CKD patients, and its underlying
causes are often associated with a negative prognosis.
However, its pathophysiology is poorly understood.
While hemodialysis may address fluid overload, it often
does not significantly improve breathlessness, suggesting
multiple and co-existing alternative issues exist. The aim
of this article is to discuss the main pathophysiologic
mechanisms and the most important putative etiologies
underlying dyspnea in CKD patients. Congestive heart
failure, unrecognized chronic lung disease, pulmonary
hypertension, lung fibrosis, air microembolism, dialyzer
Dyspnea is one of the most common symptoms
reported by patients with chronic kidney disease
(CKD). Observational studies have found that its
prevalence in conservatively managed patients with
end-stage renal disease (ESRD) may be as high as
60% (1). The prevalence of this symptom only par-
tially improves after the start of renal replacement
therapy (2). Symptoms associated with CKD have a
serious impact on patients’ quality of life. Despite
being ubiquitous, dyspnea has not been addressed
systematically and understanding its underlying
etiology is often a difficult clinical challenge.
Many patients continue to experience significant
dyspnea despite having being dialyzed to apparent
euvolemia.
Respiratory disorders may be due to complica-
tions related to CKD, HD treatment, or other unre-
lated etiologies (Table 1). Many of the potential
Address correspondence to: Professor Chris McIntyre,
Lilibeth Caberto Kidney Clinical Research Unit Room
ELL-101, London Health Sciences Centre, Victoria Hospital,
800 Commissioners Rd E London, Ontario, N6A5W9
Canada, Tel.: 1-519-685-8500, e-mail: cmcint48@uwo.ca.
Seminars in Dialysis—2016
DOI: 10.1111/sdi.12548
© 2016 Wiley Periodicals, Inc.
1
bio-incompatibility, anemia, sodium, and fluid overload
are potential frequent causes of breathing disorders in
this population. However, the relative contributions in
any one given patient are poorly understood. Systemic
inflammation is a common theme and contributes to the
development of endothelial dysfunction, lung fibrosis,
anemia, malnutrition, and muscle wasting. The introduc-
tion of novel multimodal imaging techniques, including
pulmonary functional magnetic resonance imaging with
inhaled contrast agents, could provide new insights into
the pathophysiology of dyspnea in CKD patients and
ultimately contribute to improving our clinical manage-
ment of this symptom.
pathomechanisms are not routinely considered in
general clinical care. The aim of this review is to
outline the main pathophysiological mechanisms
underlying dyspnea in CKD patients, focusing
especially on the ESRD and HD population, and
to examine the potential of novel imaging tech-
niques for improving our understanding of this
symptom.
Pulmonary Congestion
Both autopsy and clinical studies have found that
pulmonary congestion is a common feature in
ESRD patients in renal replacement therapy (3,4).
Regardless of its etiology, pulmonary congestion
causes dyspnea by inducing restrictive ventilation
due to reduced pulmonary compliance and pul-
monary diffusing capacity, resulting from thickening
of the alveolar-endothelial interface by interstitial
edema.
According to Starling’s equation, three main fac-
tors may contribute to the development of pul-
monary congestion. The first factor is an increase in
pulmonary capillary hydrostatic pressure, usually
the consequence of fluid overload and/or congestive
2 Salerno et al.
TABLE 1. Summary of CKD and HD-associated respiratory disorders.

Disorder Clinical Evaluation Diagnostic Tests

Anemia Fatigue, exertional dyspnea, muscle weakness, weight loss, melena, CBC, absolute reticulocyte count, ferritin,
tachycardia, pale skin and mucosae, conjunctival pallor, angular transferrin saturation, vitamin B12, folate,
cheilitis, koilonychia fecal occult blood test
COPD Tobacco use, cough, increased sputum production, symptom relief Pulmonary function tests, chest radiography
with bronchodilators, wheezing, rhonchi, decreased breath
sounds, paradoxic pulse, barrel chest
Metastatic lung Subtle onset dyspnea, dry cough, long-standing PTH, calcium, phosphate, chest radiography,
calcification hyperparathyroidism, brown tumor, failed renal transplantation, chest CT
poor calcium-phosphate metabolism control, poor compliance to
diet and phosphate binder medications, clubbing
Protein energy- Weight loss, muscle wasting, muscle weakness, peripheral edema Serum albumin, pulmonary function tests,
wasting bioimpedance analysis
syndrome
Pulmonary Exertional dyspnea, orthopnea, weight gain, high interdialytic Chest radiography, chest ultrasound, ECG,
congestion weight gains, short dialysis time, frequent intradialytic echocardiography, pulmonary function tests,
hypotension, poor adherence to HD treatments, poor compliance bioimpedance analysis
to fluid and salt restriction, poor nutritional status, inspiratory
crackles, peripheral edema, jugular vein distention, wheezing,
hypertension
Pulmonary Subtle onset exertional dyspnea, dry cough, use of cellulose-based Pulmonary function tests, high-resolution chest
fibrosis dialyzers, high HD blood flow rate (>550 ml/min), vascular CT
access dysfunction (arterial line pressure <210 mmHg), hypoxia,
persistent inspiratory crackles, clubbing
Pulmonary Fatigue, exertional dyspnea, chest pain, congestive heart failure, Echocardiography, pulmonary scintigraphy,
hypertension tachycardia, lower extremity edema, jugular vein distention, right heart catheterization
hepatomegaly, hepatojugular reflux
CBC, complete blood count; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CT, computed tomogra-
phy; ECG, electrocardiogram; HD, hemodialysis; PTH, parathyroid hormone.

heart failure. In CKD patients, it is not easy to dis- Pulmonary Hypertension

tinguish congestive heart failure, due to intrinsic
impairment of myocardial function, from circula-
tory congestion resulting from fluid overload. In
this setting, the diagnostic label of “uremic car-
diomyopathy” is often applied to describe the com-
plex cardiac involvement in CKD patients. This
construct includes left ventricular hypertrophy, left
ventricular systolic and diastolic dysfunction,
myocardial fibrosis, coronary microvascular disease,
and cardiovascular calcification (5). All these
aspects contribute to the development of congestive
heart failure, which is highly prevalent in this popu-
lation (6). This is further emphasized in the study
by Shlipak et al. (7), suggesting that symptoms
attributable to subclinical congestive heart failure
are very common in CKD patients and that conges-
tive heart failure is probably markedly underesti-
mated in clinical practice.
The second factor to consider is the reduction in
pulmonary capillary oncotic pressure related to
hypoalbuminemia. Hypoalbuminemia is the conse-
quence of malnutrition and systemic inflammation
in CKD and is strongly related to mortality (8).
Third, pulmonary congestion can result from
increased permeability of the alveolar-capillary
membrane, a potential consequence of the increased
concentration of inflammatory mediators and ure-
mic toxins characteristic of CKD patients. This
hypothesis was suggested by Wallin et al. (9), who
have observed that pulmonary congestion in HD
patients was partially independent from interdialytic
weight gain and prescribed ultrafiltration rate.
According to the WHO classification, pulmonary
hypertension in CKD has been classified (rather
unsatisfactorily) as being caused by “unclear multi-
factorial mechanisms” (10). Its prevalence in ESRD
patients varies between 10% and 70%, related to
the patients’ age and dialysis vintage (11). Cur-
rently, the precise importance of pulmonary hyper-
tension in determining dyspnea in ESRD/HD
patients is unknown. The PEPPER study found the
prevalence of unexplained dyspnea to be as high as
75% in these patients either in conservative care or
in HD treatment (12). All patients in this study
underwent a single right heart catheterization (in
patients in conservative care), or before and after
HD (in those receiving HD). Sixty-five percent of
the patients had postcapillary pulmonary hyperten-
sion, while 13% had precapillary pulmonary hyper-
tension. Half the cases of precapillary pulmonary
hypertension had no evidence of underlying respira-
tory disorders and were attributed to HD. More-
over, the authors suggested that a relevant
precapillary component is present in most HD
patients with postcapillary pulmonary hypertension,
due to the high transpulmonary pressure gradient
they observed.
These findings suggest that ESRD and HD them-
selves may be important contributors to precapillary
pulmonary hypertension, potentially due to pul-
monary vascular injury and endothelial dysfunction.
Indeed, HD-associated recurrent air microembolism
may lead to pulmonary vascular damage and
 UNDERSTANDING DYSPNEA IN CKD PATIENTS
remodeling, as detailed further on this review.
Increased levels of vasoconstrictors such as endothe-
lin-1 and angiotensin II are commonly found in
CKD patients (13). Chronic hypoxia, which is a
major pulmonary vasoconstrictor, is also a likely to
play a role in precapillary pulmonary hypertension,
due to the high prevalence of sleep apnea and
COPD in the CKD population (14,15). However,
postcapillary pulmonary hypertension remains by
far the most common form of pulmonary hyperten-
sion in ESRD patients. It is usually related to fluid
overload and left ventricular dysfunction (12).
The role of the arteriovenous fistula in the devel-
opment of pulmonary hypertension in ESRD
patients is less clear. The creation of an arteriove-
nous fistula reduces systemic vascular resistance,
increases venous return to the heart, and increases
cardiac output, thus enhancing blood flow in the
pulmonary circulation. While a study by Havlucu
et al. (16) found a significant correlation between
arteriovenous fistula blood flow and systolic pul-
monary artery pressure, recent clinical trials have
failed to confirm this finding (17–19). Moreover,
studies by Unal et al. have found no significant dif-
ference in the prevalence of pulmonary hypertension
in ESRD patients before and after arteriovenous
fistula creation, both in the short (19) and long
terms (18).
Lung Fibrosis
Autopsy-based studies of deceased HD patients
described interstitial fibrosis as the most common
chronic lung pathologic finding (3,20). Several other
studies also highlighted the presence of indirect
signs of interstitial fibrosis in HD patients, such as
isolated pulmonary diffusion abnormalities and
restrictive ventilatory defects (21,22). Interestingly,
these changes were associated with dialysis vintage,
suggesting that the development of pulmonary
fibrosis may be the result of prolonged exposure to
recurrent pulmonary insults, in a manner analo-
gous to the accumulation of recurrent cardiac
insults (23).
Dialyzer membrane bio-incompatibility is one of
the most important factors already identified as
being responsible for the development of interstitial
fibrosis. The contact between plasma and the dia-
lyzer leads to the activation of the complement cas-
cade and promotes pulmonary leukostasis. The
activated neutrophils in the lung interstitium then
release inflammatory mediators into the pulmonary
microcirculation, promoting local inflammation,
bronchoconstriction, and vasoconstriction (23).
This process is held responsible for the development
of hypoxemia, regional ventilation-perfusion mis-
match, and pulmonary hypertension during HD.
The recurrent inflammatory response also leads to
chronic selective damage to the pulmonary alveolar-
capillary membrane, with collagen deposition and
3
diffuse interstitial lung fibrosis (21). These effects
are well documented and prominent with cellulosic
membranes but whether similar (and likely less sev-
ere) blood—membrane interactions occur with
newer more biocompatible dialyzers has not been
explored sufficiently.
Chronic pulmonary congestion itself may also be
associated with lung fibrosis. In patients with
congestive heart failure, pulmonary “brown indura-
tion,” i.e., the accumulation of alveolar macro-
phages loaded with hemosiderin due to pulmonary
capillary hypertension, was associated with alveolar
septal fibrosis (24). Areas of lung fibrosis were also
reported in CKD patients with severe forms of
metastatic pulmonary calcifications. In these cases,
the calcium deposits trigger a desmoplastic reaction
resulting in interstitial fibrosis, which is the likely
responsible for the development of progressive res-
piratory failure (25).
Air Microembolism
Air microembolism is a clinically relevant side
effect of extracorporeal therapies and may be a sig-
nificant cause of pulmonary morbidity in chronic
HD patients. Several studies have reported that air
microbubbles forming in the extracorporeal HD cir-
cuit may pass the venous safety system against air
infusion without triggering an alarm (26,27). A
computational study has suggested that most bub-
bles of 200 lm in diameter and almost all the bub-
bles of <50 lm in diameter pass through the air
trap and enter the patients’ venous circulation (26).
These microbubbles end up entrapped in the pul-
monary vessels, where they obstruct the pulmonary
capillaries, activating platelet aggregation, the coag-
ulation cascade, and the complement system, pro-
moting endothelial damage, atherosclerosis, and
pulmonary vascular remodeling (28). Additionally,
microbubbles are usually coated with fibrin and
other denatured proteins, slowing significantly their
clearance from the circulation and increasing further
the body exposure to their effects (29).
Chronic, recurrent microbubble-induced lung
injury may partially explain the anatomic and func-
tional pulmonary alterations reported in HD
patients, especially pulmonary fibrosis and pul-
monary hypertension, and their relationship with
HD vintage (28). Several different factors promot-
ing the formation of microbubbles have been identi-
fied. Turbulent flow may lead to microbubble
formation at different levels, especially at the arteri-
ovenous vascular access (28) and in the air trap
itself (26). This observation was further reinforced
by the association of microbubble formation with
higher blood flows (>550 ml/minute) and negative
pressures in the arterial lines (<210 mmHg) (27).
Insufficient rinsing of the HD lines is also associ-
ated with microbubble formation, due to remaining
air in the tubes and the dialyzer (28).
4 Salerno et al.
Unrecognized Intercurrent Lung Disease in
CKD Patients
Little is known about lung involvement in
patients with CKD. A common concern is that the
presence of lung disease is often overlooked in
ESRD patients due to the heavy burden of other
comorbidities and the common attribution of dysp-
nea to CKD-related complications, such as pul-
monary congestion. Chronic obstructive pulmonary
disease (COPD) is frequently associated with CKD
(30). In a US survey of 769,984 HD patients, the
prevalence of diagnosed COPD at the start of HD
was calculated as 7.5% and found to be associated
with a higher mortality and lower kidney transplan-
tation rates (31).
A Danish study by Plesner et al. (15) found a 46%
prevalence of COPD in a cohort of 255 patients with
ESRD on HD; only 20% of these patients actually
had a confirmed diagnosis before the study, leaving
an astounding 80% of COPD cases undiagnosed.
This high prevalence may be partially explained by
COPD and CKD having tobacco smoking as a
shared common risk factor. Chronic hypoxia is also
linked to CKD progression: reduced oxygen delivery
in the kidneys is associated with renal tubular cell
apoptosis and with the differentiation of epithelial
and mesenchymal cells into fibroblasts, directly lead-
ing to tubulointerstitial fibrosis and a further reduc-
tion in oxygen diffusion (29).
Finally, metastatic lung calcification is a meta-
bolic lung disease characterized by the deposition of
crystalline or amorphous Whitlockite calcifications
in the pulmonary parenchyma. It has been recog-
nized as an apparently benign, long-term complica-
tion of secondary hyperparathyroidism in patients
with CKD (25). Autopsy studies have found a
prevalence of metastatic pulmonary calcification in
60–75% of chronic HD patients (32). This condition
is usually asymptomatic and rarely specifically com-
mented on, as chest radiographic findings are scarce
and often nonspecific (33). However, several cases
of respiratory failure have been reported and associ-
ated with severe lung involvement and interstitial
lung fibrosis (34).
Anemia
Anemia is a common complication of CKD, which
should always be considered in the differential diag-
nosis of dyspnea (35). Regardless of its etiology, ane-
mia causes a reduction in blood oxygen content
which leads to increased extraction of oxygen from
the blood by peripheral tissues, and consequently to
a decrease in the venous partial pressure of oxygen.
At reduced venous partial oxygen venous pressure,
preexisting pulmonary venous-arterial shunts open,
also reducing arterial partial oxygen pressure. The
low arterial partial oxygen pressure is sensed by
the carotid chemoreceptors, which send a signal to
the brain stem, where it is integrated, resulting in the
sensation of shortness of breath (36).
In general, there is no specific hemoglobin level at
which patients start to experience symptoms. A
study on otherwise healthy patients showed that
oxygen delivery to tissues may be maintained, at
rest, with hemoglobin levels as low as 5 g/dl, as
long as the intravascular volume is preserved (37).
Symptoms appear with higher hemoglobin levels
when tissue oxygen demand increases (typically
under exertion) or when the heart is unable to
increase cardiac output (e.g., in congestive heart
failure) (37). No specific data are available on the
association between anemia in the CKD population
and dyspnea. However, the high prevalence of con-
gestive heart failure in the CKD population is likely
to reduce these patients’ tolerance to low hemoglo-
bin levels (6).
Systemic Inflammation
The relationship between dyspnea and inflamma-
tion in the CKD population is complex and multi-
faceted. Uremia itself is associated with a chronic
state of systemic inflammation due to an increase in
circulatory inflammatory mediators, responsible for
oxidative stress, endothelial dysfunction, and
atherosclerosis (38). Additionally, inflammation, the
severity of which increases as renal function decli-
nes, also contributes to malnutrition (39). It also
plays a role in the pathogenesis of anemia in CKD
patients by promoting hepcidin synthesis by the
liver which decreases both gastrointestinal dietary
iron absorption and the mobilization of stored iron
from the reticuloendothelial system (40).
The association of inflammation, malnutrition,
hypercatabolic status, and uremic toxins in CKD
patients—the so-called protein energy-wasting syn-
drome (41)—contributes to muscle wasting and
reduced respiratory muscle strength. Nascimento
et al. (8) found that ESRD patients with increased
levels of high sensitivity C-reactive protein at
the initiation of renal replacement therapy had
lower muscle mass and, notably, restrictive ventila-
tory defects. Systemic inflammation plays also a
major role in the pathogenesis and morbidity
of COPD, by promoting airway remodeling and
muscle wasting (42).
Sodium Overload and Airway Responsiveness
The importance of sodium overload in dyspnea,
independent of fluid overload, has not been consid-
ered in mainstream clinical literature. The recent
discovery by Titze et al. (43) of “osmotically inac-
tive sodium deposition” in the interstitial space of
the skin has radically challenged the traditional
two-compartment model for sodium and water bal-
ance; it implies that humans can accumulate sodium
 UNDERSTANDING DYSPNEA IN CKD PATIENTS
without water retention. This discovery, in addition
to the observations that hypertension in dialysis
patients is seen without apparent fluid overload and
that achieving a normal blood pressure is possible
by “fine tuning” sodium balance through an accu-
rate prescription of a hypotonic sodium dialysate
concentration (44,45), leads to the important con-
clusion that sodium excess may be “metabolically
active,” altering the function of vascular smooth
muscle cells, leading to hypertension and other
adverse consequences.
We hypothesize that water-free sodium overload
may contribute to the development of bron-
chospasm and airway hyperresponsiveness in ESRD
patients and thus to dyspnea. Sodium balance in
dialysis patients is achieved essentially by regulating
dietary salt intake and sodium removal during dia-
lytic treatments. Salt intake during the interdialytic
period depends on patients’ behavior and is the
major determinant of thirst, extracellular volume,
and interdialytic weight gain, ultimately leading to
symptomatic fluid overload (46). Sodium removal
during standard HD treatments occurs both by con-
vection and by diffusion. Barriers exist to limit the
amount of sodium that can be removed by dialy-
sate. The Gibbs–Donnan effect, with anionic repul-
sion of positively charged ions by proteins coating
the dialysis membrane, results in a 3–5% reduction
in sodium depuration. This is compounded by other
factors that reduce the amount of sodium available
for removal from plasma water, such as ingested
sodium being associated with other ions and plasma
proteins (45). Mechanical ultrafiltrate will always
contain a lower sodium concentration than the
plasma it was derived from.
Convection is the main source of sodium removal
(ffi75%) and determined by ultrafiltration rate/vol-
ume. Diffusion is required to ensure full removal of
the ingested sodium load. This is dependent on the
sodium gradient between the patient’s plasma water
sodium concentration and the sodium concentration
delivered in dialysate (45). Both convection and dif-
fusion are influenced by treatment time (47). How-
ever, the introduction in clinical practice of
standard thrice weekly, 4-hour (or shorter) HD
treatments has led to routine use of higher dialysate
sodium concentrations to prevent hemodynamic
instability related to the high ultrafiltration rates
necessary to achieve dry weight. This mitigates
against the degree of diffusive clearance of sodium
required to fully remove the amount of sodium
ingested in the interdialytic period. In long term,
this potentially results in substantial accumulation
of sodium in most patients.
A number of provocative studies suggest that
excess sodium may also affect airway function. Bur-
ney first suggested that the prevalence of asthma
was related to Western lifestyles, including the
excessive consumption of salt. The author found a
strong correlation between per capita salt purchase
in England and Wales and asthma mortality in
adult males and children (48). In a subsequent
5
observational study in asthmatic patients, 24-hour
urinary sodium excretion was associated with
increased bronchial reactivity after a histamine chal-
lenge test (49). In a randomized, controlled trial by
the same author, greater bronchial reactivity was
observed in male asthmatics randomized to sodium
chloride supplements (50).
These findings may be explained by two main
pathophysiological hypotheses, relating sodium and
bronchial smooth muscle cell activity. According to
Blaustein’s hypothesis for sodium and hypertension, a
high-salt diet increases the concentrations of circulat-
ing inhibitors of the Na+/K+ ATPase with digitalis-
like activity, which enhance vascular smooth muscle
cells responsiveness (51). Indeed, the inhibition of
Na+/K+ ATPase in smooth muscle cells causes the
increase in intracellular sodium concentration, invert-
ing the activity of the Na+/Ca2+ exchanger and
increasing intracellular calcium concentration with
subsequent enhanced contractility. Ouabain, a Na+/
K+ ATPase inhibitor, also has the property of con-
tracting human airway smooth muscle cells (52) and
increases the release of histamine by leukocytes (53),
enhancing airway responsiveness.
The other hypothesis relates to the beta-adrenergic
theory of asthma, postulating that asthma is caused
by a disturbed function of beta2-adrenergic response.
This view is supported by the original finding
that sodium load reduces circulating catecholamine
concentrations (54). A so-called high-salt diet causes
the down-regulation of beta2-adrenoceptors in lym-
phocytes and a concomitant up-regulation of alpha2-
adrenoceptors in platelets (55). If these findings are
applicable to airway smooth muscle cells, a high
sodium diet would also reduce beta2-adrenoceptor-
mediated bronchodilatation.
Expanding Our Understanding of Dyspnea in
CKD Patients
The high prevalence of dyspnea and its heavy
burden on both the quality of life and prognosis in
dialysis patients is driving the need for new studies
using novel approaches to achieve a deeper, system-
atic understanding of respiratory function in these
patients and identify additional therapeutic oppor-
tunities to improve their care. Chest ultrasound has
emerged as a practical tool for evaluation of respi-
ratory disease in patients presenting in both outpa-
tient and critical care settings. This technique
exhibits higher sensitivity and specificity than tradi-
tional chest radiography in detecting a wide range
of lung disorders (56), encouraging its employment
in many clinical settings.
Chest ultrasound has been recently applied in the
chronic HD population to detect the presence of
extravascular lung water, in order to guide fluid
removal by ultrafiltration (57,58). These studies
found a significant decrease in the number of
detected lung B-lines (sonographic vertical artifacts
associated with increased lung parenchymal density)
6 Salerno et al.
(59), after HD-driven fluid removal by ultrafiltra-
tion, suggesting that B-lines are related to the
degree of lung congestion and may be used as a sign
of effective reduction in extravascular lung water.
Subsequent studies also found a direct relationship
between the number of detected lung B-lines before
HD treatment and mortality (4,60), further reinforc-
ing the hypothesis that chest ultrasound could be
used to guide the amount of fluid removal to
improve the prognosis of HD patients.
While these studies show the potential for chest
ultrasound, there may be some possible pitfalls to be
aware of when applying this technique on chronically
short-of-breath HD patients. Indeed, the detection of
multiple lung B-lines may be associated with other
respiratory disorders. For example, many parenchy-
mal lung diseases can produce an increase in lung
density, either by reducing lung air content or by
increasing its solid content (either in tissue, water, or
both), favoring the production of B-lines (56). In this
case, the differential diagnosis of pulmonary conges-
tion should take into account, for example, intersti-
tial lung diseases and pulmonary fibrosis.
The introduction of novel imaging techniques
such as lung magnetic resonance imaging and quan-
titative CT has made it possible to obtain structural,
functional, and dynamic imaging of the lung, with a
greater sensitivity to abnormalities than scintigraphy
or traditional respiratory function tests such as
spirometry (61). In particular, by employing hyper-
polarized 129Xe lung magnetic resonance imaging, it
is now possible to acquire static and dynamic regio-
nal ventilation, ventilation/perfusion, and gas diffu-
sive transport biomarkers in a minimally invasive
way without radiation exposure (61).
We believe that it is possible to make use of these
state-of-the-art medical imaging techniques to
acquire both morphologic and functional pulmonary
data in ESRD patients who report unexplained dysp-
nea. In order to improve our understanding of this
symptom, patients should be studied in three differ-
ent situations. First, an objective, comprehensive
assessment of respiratory function in resting condi-
tions is necessary to explore the correlation between
imaging findings and the reported severity of dysp-
nea. Second, as several studies have evidenced that
dyspnea in HD patients is a major cause of their limi-
tations in physical performance (62,63), the relation-
ship between respiratory disorders in ESRD and
physical exercise has to be investigated. Third, it will
be necessary to observe the effect of different specific
conditions on pulmonary function to confirm the
validity of the pathophysiologic hypotheses pre-
sented above. In particular, few studies exist on the
effects of the newer biocompatible dialyzers on lung
function. Moreover, the effect of dialysate cooling in
the prevention of intradialytic hypoxemia is interest-
ing and should be further investigated (64). By using
appropriate imaging-based surrogates, we will be
also able to further investigate the consequences of
fluid overload on lung volumes and regional ventila-
tion and evaluate the effects of ultrafiltration during
dialysis. Finally, we aim to observe the effects of
beta2-adrenergic agonists, calcium channel inhibi-
tors, and sodium removal mediated by HD on air-
way function.
Approaching the CKD Patient with Chronic
Dyspnea
A diagnostic algorithm for chronic dyspnea
in CKD patients is represented in Fig. 1. As no
data are available supporting an evidence-based

Initial clinical
assessment
Diagnosis established

Is volume overload
present?
Yes No
Yes Diuretic treatment /
No diagnosis
Probe dry weight
established

Does dyspnea
persist?
Second level tests
Yes
No
Is volume overload Diagnosis established
Diagnosis established
present?
No

Cardio-respiratory No diagnosis
referral established

Fig. 1. Diagnostic algorithm for chronic dyspnea in the CKD-HD patient. The initial clinical assessment consists of a basic volume
assessment, electrocardiogram, chest radiography and laboratory tests. Second-level tests include bioimpedance analysis, echocardiogra-
phy, chest ultrasound, pulmonary function tests, chest CT, pulmonary scintigraphy and positron-emission tomography scan, as clinically
indicated. A cardio-respiratory referral is indicated in case of an inconclusive diagnosis or if further investigations are necessary (right
heart catheterization, bronchoscopy and lung biopsy).
 UNDERSTANDING DYSPNEA IN CKD PATIENTS
approach to dyspnea in the CKD patient, our
approach is based on clinical experience and patho-
physiological principles, addressing what we believe
are the most common respiratory complications.
The initial assessment should be mainly aimed at
ruling out the most apparent causes of dyspnea,
namely pulmonary congestion due to volume over-
load, congestive heart failure, anemia and malnutri-
tion. We do not advise assessing natriuretic peptide
levels for the diagnosis of congestive heart failure,
as they are significantly affected by CKD stage (65).
If either no cause of dyspnea is identified or the
symptom persists after treating volume overload, a
reassessment with second-level tests should be per-
formed. Treating dyspnea by volume removal
should be avoided without evidences of volume
overload, especially in the chronic HD patient, due
to the risk of intradialytic hypotension and tissue
hypoperfusion (66).
At this stage, we suggest a more detailed volume
status assessment with bioimpedance analysis,
echocardiography, and/or chest ultrasound, based
on the center expertise and availability, to rule out
subtle cases of volume overload. Echocardiography
should also serve to detect signs of myocardial dys-
function and as a screening test for pulmonary
hypertension.
Pulmonary function tests should be used to diag-
nose airflow obstruction and lung volume restric-
tion; second-level imaging should be performed in
case of suspect interstitial lung disease, metastatic
pulmonary calcifications, malignancy, and pul-
monary thromboembolism.
A respirology or cardiology referral is advised
in order to proceed with further investigations
(e.g., bronchoscopy, lung biopsy and right heart
catheterization).
Conclusion
Dyspnea in CKD is multifactorial in origin. Its
pathophysiology is potentially broad and certainly
poorly understood. The introduction of novel imag-
ing techniques allows us to improve our understand-
ing of the pathophysiology and etiology of dyspnea
in CKD patients. This is essential and should be an
urgent research priority for its optimal management
to improve both the prognosis and quality of life of
our patients.
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