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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO.

22, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2015.04.024

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Cardio-Pulmonary-Renal Interactions
A Multidisciplinary Approach

Faeq Husain-Syed, MD,*y Peter A. McCullough, MD, MPH,zx Horst-Walter Birk, MD,y Matthias Renker, MD,k
Alessandra Brocca, MSC,* Werner Seeger, MD,y Claudio Ronco, MD*

ABSTRACT

Over the past decade, science has greatly advanced our understanding of interdependent feedback mechanisms
involving the heart, lung, and kidney. Organ injury is the consequence of maladaptive neurohormonal activation,
oxidative stress, abnormal immune cell signaling, and a host of other mechanisms that precipitate adverse
functional and structural changes. The presentation of interorgan crosstalk may include an acute, chronic, or acute
on chronic timeframe. We review the current, state-of-the-art understanding of cardio-pulmonary-renal interac-
tions and their related pathophysiology, perpetuating nature, and cycles of increased susceptibility and reciprocal
progression. To this end, we present a multidisciplinary approach to frame the diverse spectrum of published
observations on the topic. Assessment of organ functional reserve and use of biomarkers are valuable clinical
strategies to screen and detect disease, assist in diagnosis, assess prognosis, and predict recovery or progression
to chronic disease. (J Am Coll Cardiol 2015;65:2433–48) © 2015 by the American College of Cardiology
Foundation.

T he concept of organ crosstalk refers to the


complex biological communication
feedback between different organs, medi-
ated via mechanical, soluble, and cellular mecha-
and
cardiovascular disease outcomes in these forms of
CRS. Finally, CRS type 5 describes a systemic insult
to both the heart and the kidneys, such as sepsis,
where both organs are injured simultaneously in
nisms. Although crosstalk is essential to maintain persons with previously normal heart and kidney
body homeostasis, pathological states in 1 or more function at baseline. Pulmonary-renal syndromes
organs can lead to functional and structural represent heterogeneous clinical entities, described
dysfunction in other organs. The classification of by a combination of diffuse alveolar hemorrhage
cardiorenal syndromes has been expanded into 5 on the basis of pulmonary capillaritis in conjunction
subtypes. Types 1 and 2 involve acute and chronic with glomerulonephritis as well as acute respiratory
cardiovascular disease scenarios leading to acute distress syndrome (ARDS) associated with AKI in the
kidney injury (AKI) or accelerated chronic kidney absence of hematuria. Hepatorenal syndrome can
disease (CKD). Types 3 and 4 describe AKI and involve the development of functional cardiopulmo-
CKD, respectively, leading primarily to heart fai- nary changes and AKI in patients with advanced
lure (HF), although it is possible that acute coro- liver failure (acute or chronic) and is beyond the
nary syndromes, stroke, and arrhythmias could be scope of this review.

From the *International Renal Research Institute of Vicenza, San Bortolo Hospital, Vicenza, Italy; yDepartment of Internal
Medicine II, University Clinic Giessen and Marburg Lung Center, Member of the German Center for Lung Research—Campus
Giessen, Giessen, Germany; zBaylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton
Heart and Vascular Hospital, Dallas, Texas; xThe Heart Hospital, Plano, Texas; and the kDepartment of Internal Medicine I,
Division of Cardiology and Angiology, University Clinic Giessen and Marburg—Campus Giessen, Giessen, Germany. Dr. Ronco has
received honoraria from GE, Fresenius Medical Care, Baxter, Asahi, Otsuka, Astute, and Toray. All other authors have reported
that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

Manuscript received March 24, 2015; revised manuscript received April 18, 2015, accepted April 20, 2015.
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

ABBREVIATIONS CARDIO-PULMONARY-RENAL can be seen as a result of increased pulmonary


AND ACRONYMS INTERACTIONS: NEED FOR capillary permeability, elevated intravascular hydro-
DEFINITION OF A SYNDROME? static pressure, low colloid osmotic pressure, and
AKI = acute kidney injury
insufficient lymphatic drainage (1). Changes to the
ARDS = acute respiratory
With growing knowledge of interdependent alveolar-capillary barrier can induce an inflammatory
distress syndrome
feedback mechanisms involved in the heart, cascade and oxidative stress of the pulmonary
BNP = B-type natriuretic
peptide lung, and kidney crosstalk, the descriptive microcirculation, which results in cycles of alveolar
CKD = chronic kidney disease
classification of a syndrome can represent a wall injury predisposing and/or aggravating lung
framework for exploring epidemiology, injury (Figure 1B) (2). Invasive and noninvasive mea-
CPRI = cardio-pulmonary-renal
interactions pathophysiology, detection, and manage- surements include analysis of pulmonary edema
FGF = fibroblast growth factor ment. Because of the complicated courses of fluid, exhaled breath condensate (pH, arachidonic
GFR = glomerular filtration
hospitalization and the high mortality of acid derivatives), proinflammatory cytokines (inter-
rate patients with involvement of all 3 organs, leukin [IL]-1b, -2, -6, -8, -12, and -17; interferon
HF = heart failure an integrative approach is needed. The gamma; and tumor necrosis factor [TNF]-a ), anti-
LV = left ventricular sequence of organ involvement can vary inflammatory cytokines (IL-4, -5, -10, and -13 and
PH = pulmonary hypertension
depending on the acuity and nature of the TGF- b), and chemokines (IL-8, monocyte chemo-
underlying disorder. Many patients with attractant protein-1, and macrophage inflammatory
disorders of 1 organ (e.g., CKD) die of complications of protein-1b ), reactive oxygen and nitrogen species,
the other (e.g., HF) before the first organ’s failure and exhaled nitric oxide (3,4). The concept of sub-
reaches its fullest extent, or the dysfunction of every clinical lung injury (e.g., due to previous smoking)
organ may develop slowly until a “collapse” is takes into account that even asymptomatic events
reached and full-blown decompensation occurs. That can lead to increased future susceptibility to respi-
is, each dysfunctional organ has the ability to initiate ratory failure events, and new diagnostic techniques
and perpetuate mutual injury through hemodynamic, may provide early detection (5,6).
neurohormonal, and cell signaling feedback mecha- Circulating factors have been implicated in the
nisms, while multiple episodes of acute (on chronic) pathogenesis of pulmonary inflammation following
decompensation may lead to reciprocal end-organ renal and hepatic ischemia/reperfusion injury in an-
disease progression (Central Illustration). Given the imal models and humans (7-9). In ischemic AKI,
multitude of contributing factors and the time experimental studies demonstrate increased pulmo-
sequence of events in cardio-pulmonary-renal in- nary vascular permeability, cellular apoptosis, alve-
teractions (CPRI), it is challenging to identify the olar hemorrhage, and leukocyte trafficking due to the
underlying pathophysiological mechanisms and production and/or decreased clearance of mediators
develop a strategy for diagnostic and therapeutic of lung injury (2). Intraluminal neutrophils contribute
intervention. This review summarizes recent ad- through phagocytosis and release of mediators,
vances in our understanding of CPRI. including reactive oxygen species and proteases, and
activation of dendritic cells, augmenting the immune
LUNG IN ORGAN CROSSTALK: response. Pro-inflammatory cytokines produced by
THE PULMONOLOGIST’S VIEW renal tubular cells as well as white blood cells include
TNF- a and IL-1 b and -6. Conversely, there are coun-
Open to environmental influence, the lung is a highly terbalancing cell signaling peptides, including the
immunologic organ, representing a gateway to the anti-inflammatory IL-10, which has been shown to
environment. The lung has critical pathophysiolog- reduce lung injury in experimental models (2).
ical connections to the failing heart and kidney Delayed recovery of kidney function may impair res-
(Figure 1A). olution of lung inflammation post-AKI (10). The
LUNG INJURY, ABNORMAL CELL SIGNALING, AND altered mechanisms for water transport in pulmonary
OXIDATIVE STRESS. The lung conducts gas exchange edema are described in detail in the “Uremic Lung”
via 3 mechanisms: ventilation, diffusion, and perfu- section.
sion. Any imbalance can cause respiratory distur- MECHANICAL VENTILATION AND ARDS. Mechanical
bance, which can be compensated to a certain degree ventilation increases intrathoracic pressure and pro-
by hyperventilation, greater oxygen extraction from duces adverse hemodynamic effects that are oppo-
blood by the tissues, and increased cardiac output, site to normal spontaneous ventilation. Mechanical
depending on the organ’s functional reserve. In both ventilation compresses pulmonary vasculature, which
noncardiogenic and cardiogenic pulmonary edema, may result in increased right ventricular afterload and
fluid accumulation in the fissure and alveolar spaces diminished cardiac output, leading to hypotension
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JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

CENTRAL I LLU ST RAT ION Cardio-Pulmonary-Renal Interactions

Husain-Syed, F. et al. J Am Coll Cardiol. 2015; 65(22):2433–48.

Multiple dependent inflammatory pathways promote injury and elevate the risk for chronic disease of the heart, lung, and kidney, including increased
expression of soluble pro-inflammatory mediators, innate and adaptive immunity, physiological derangements, and cellular apoptosis. The figure illustrates
the cellular and molecular crosstalk and potential biomarkers in acute and chronic cardio-pulmonary-renal interactions. BNP ¼ B-type natriuretic peptide;
ENaC ¼ epithelial sodium channel; FGF ¼ fibroblast growth factor; GST ¼ glutathione S-transferase; hs-cTnT ¼ high-sensitivity cardiac troponin T; ICAM ¼
intercellular adhesion molecule; IGFBP ¼ insulin-like growth factor binding protein; IL ¼ interleukin; KIM ¼ kidney injury molecule; L-FABP ¼ L-type fatty
acid binding protein; NAG ¼ N-acetyl-b-D-glucosaminidase; NGAL ¼ neutrophil gelatinase-associated lipocalin; NKCC1 ¼ sodium-potassium chloride
cotransporter 1; TIMP ¼ tissue inhibitor of metalloproteinase; TGF ¼ transforming growth factor; TNF ¼ tumor necrosis factor.

and fluid-responsive shock; this scenario is commonly impaired venous return to the right heart, resulting
seen in the initial post-intubated period when venti- in CPRI.
lation is initiated. Similarly, decreased venous return The severest form of lung injury is ARDS. Its defi-
and/or diminished diaphragmatic and abdominal wall nition includes the onset of lung failure within 1 week
compliance can compromise renal blood flow (11). of the onset of illness, and it is characterized by
Importantly, increased intra-abdominal pressure may hypoxemia in the presence of bilateral infiltrates on
contribute to reduced ventilatory volumes, impaired the chest x-ray that cannot be explained by HF or
throughput of blood through the kidneys, and fluid overload. Whereas resolution of cardiogenic
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

F I G U R E 1 The Lung in Cardio-Pulmonary-Renal Interactions

A Chronic Acute Pulmonary embolism


Pneumonia
Obstructive/Restrictive lung disease
Emphysema
Acute Chronic

ARDS Cystic fibrosis


ventilation PH
Trauma
Toxic agents

Acute Chronic
Recovery/Non- Utilization RFR
Subclinical AKI Glomerular/ Sclerosis/Fibrosis
recovery
Interstitial
CKD AKI
ESRD Inflammation/Apoptosis Subclinical damage
Endothelial dysfunction inflammation/Apoptosis
Chronic Acute PEEP Endothelial dysfunction
Blood gas disturbance Chronic blood gas disturbance Acute Chronic
venous congestion Chronic venous congestion

Recovery/Non- Subclinical Ischemic insult Increased ischemic risk


recovery myocardial injury Arrhythmia LV hypertrophy
Chronic HF Acute HF Acute HF RV/LV dyfunction

B Activated neutrophils Cytotoxic Anti-inflammatory Pro-fibrotic Anti-fibrotic


ROS IL-10 TGF-β IL-33
Local dentritic cells Pro-inflammatory IL-1, IL-6, TNF-α
IL-1, IL-6, TNF-α Soluble ST2
Macrophages Galectin-3

Apoptosis, necrosis Fibrosis

Type II cell Inactivated


surfactant

Type I cell acute chronic Alveolar wall


thickening

Fibrin Hyaline membrane

Surfactant layer
klotho (-) Klotho (-)
Edema fluid ECM

Necrotic or apoptotic
Alveolar cells type I cell RAAS (-)

Fibroblast Myofibroblast

The primary involvement and acuity of organ failure leads to pathophysiological interactions and contributing factors in organ crosstalk. (A) The vicious circle of kidney
and heart injury, reserve capacity and chronic organ failure, and its clinical features. (B) The cellular pattern of lung injury, repair, and fibrosis. Klotho may be an
intermediate mediator that attenuates acute and chronic injury in all 3 organs. AKI ¼ acute kidney injury; ARDS ¼ acute respiratory distress syndrome; CKD ¼ chronic
kidney disease; ECM ¼ extracellular matrix; ESRD ¼ end stage renal disease; HF ¼ heart failure; IL ¼ interleukin; LV ¼ left ventricular; PEEP ¼ positive end-expiratory
pressure; PH ¼ pulmonary hypertension; RAAS ¼ renin-angiotensin-aldosterone system; RFR ¼ renal functional reserve; ROS ¼ reactive oxygen species; RV ¼ right
ventricular; TGF ¼ transforming growth factor; TNF ¼ tumor necrosis factor.

pulmonary edema can be rapid, the rate of edema units, and development of a high-permeability pul-
resolution in most patients with ARDS is markedly monary edema, all of which result in clinically-stiff,
impaired (1). The role of the alveolar-capillary barrier noncompliant, and heterogeneous lungs. Often
is very important in ARDS and governs both the requiring mechanical ventilation, it can itself in-
rapidity of onset and the delayed clearance of alve- duce and/or exacerbate lung injury contributing to
olar fluid. ARDS is a major cause of mortality associ- distant organ effects and deleterious outcomes
ated with appreciable morbidity, and AKI as an (2). Mechanistically speaking, pathophysiological
additional risk factor often develops as a component changes occur from the direct effect of high pressure
of a multiorgan system dysfunction. Even though on the lung: barotrauma, from the damage caused by
ARDS mortality is currently declining (25% to 40%), lung overdistension; volutrauma, from the shear
AKI combined with ARDS increases mortality to 50% stress of repetitive opening and closing of alveoli; and
to 80% and negatively affects clinical outcomes, ris- atelectotrauma, from the generation of cytokines
ing with AKI severity (12). ARDS is a breakdown of and an inflammatory cascade, resulting in bio-
normal lung architecture, loss of functioning lung trauma. Here, lung-protective ventilation strategies
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JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

not only improve mortality from ARDS, but also inflammation affecting distant organs (22). Poly-
lead to improved distant organ function, suggesting pharmacy is frequent in these cohorts, and impaired
the presence of iatrogenic trauma as a result of renal clearance of drugs could increase the risk of
high volume ventilation that can further trigger adverse reactions. Pulmonary congestion in chronic
hemodynamic, neurohormonal, and cell signaling HF can initiate lung structural remodeling by prolif-
pathophysiological mechanisms (including right ven- eration of fibroblasts with fibrosis and extracellular
tricular stress with progressive pulmonary hyper- matrix deposition, resulting in thickening of the
tension [PH]) (10,13). In addition, fluid overload and alveolar wall (Figure 1B) (23). Similar mechanisms are
venous congestion is an independent predictor of assumed in CKD, in addition to uremia-related
increased mortality in AKI that is thought to further dysfunction of the pulmonary microcirculation (24).
contribute to respiratory complications (14). Here, the Although the resultant reduction in vascular perme-
goal of optimal fluid management for recovery of both ability is initially protective against pulmonary
organs is an area of active study (10). Furthermore, edema and can be seen as a restorative mechanism,
the role of inhaled nitric oxide for alleviation of the process can cause a restrictive, poorly compliant
ARDS and altering renal function has to be defined, lung with impaired gas exchange, and reduced exer-
including its anti-inflammatory properties (15). Sev- cise capacity. The lung diffusion capacity for carbon
eral favorable effects are known, although trials monoxide is one of the most clinically-valuable tests
and meta-analyses have failed to demonstrate its to assess the alveolar-capillary membrane. In acute
beneficial use in ARDS (16). Inhaled nitric oxide cau- decompensated HF, it can be normal or elevated due
ses selective vasodilation of pulmonary vessels in to an increased alveolar capillary blood volume,
ventilated areas without affecting systemic blood whereas the previously-mentioned mechanisms can
pressure and cardiac output, improves ventilation- lead to its impairment in chronic HF (25). In CKD, a
perfusion mismatch, and is a valuable option to marked decrease in diffusion capacity for carbon
reduce PH in susceptible patients (17). In addition, monoxide correlates with the severity of renal
nitric oxide exerts positive effects in acute hyperoxic impairment after correcting the effects of renal ane-
lung injury models by diminishing inflammation and mia (26). The multifunctional protein Klotho regu-
by protecting both endothelium and alveolar epithe- lates phosphate/calcium metabolism and is identified
lium from oxidative injury (18). as an important molecule in the aging processes. Its
Outside of the setting of ARDS, there is convincing cytoprotective role is currently investigated in CKD
evidence that pro-inflammatory effects of mechanical and cardiac remodeling, and Klotho appears as 1 of
ventilation can be a source of AKI. In lung-injurious several unifying mechanisms in the CPRI. Animal
ventilator strategies, animal models demonstrate studies emphasize its antioxidative (27) and anti-
the production of a variety of inflammatory cytokines fibrotic (28) capacity by suppressing vascular endo-
(e.g., IL-8 and monocyte chemotactic protein-1), thelial growth factor and the pro-fibrotic TGF-b 1/
expression of nitric oxide synthase (shown to exert Smad 3 expression in pulmonary epithelia.
cytotoxic effects), induction of renal epithelial cell Chronic hypoxia and vascular remodeling is
apoptosis, and dysregulation of renal vascular assumed to be responsible for resultant secondary and
response (19). Injurious mechanical ventilation in- in some cases fixed pre-capillary PH, which is an in-
duces myocardial inflammation, including the dependent predictor of mortality (29). The transition
up-regulation of pro-inflammatory myocardial cy- from a primary vasoconstrictive to a vasoproliferative
clooxygenases and expression of IL-8, whereas process is the hallmark of fixed PH. This histopatho-
lung-protective strategies ameliorate myocardial logical pattern is defined by “hypertrophy of the
inflammation (20). medial layer of the vessel wall, hyperplasia of the
PULMONARY VASCULAR REMODELING AND FIBROSIS. intimal layer, proliferation of the adventitial layer,
Patients with chronic respiratory disease often have and/or plexiform lesions” (29). The natural course of
multiple comorbidities such as concomitant cardio- PH is generally progressive, with osteoblastic trans-
vascular disease, hypertension, and a decline in formation of vascular smooth muscle cells and depo-
renal function (21). The diseases’ natural course sition of hydroxyapatite crystals in the interstitium.
and severity, as well as quality of life, are diverse, As a result, pulmonary vascular stiffness markedly
depending on pathology in the respiratory system increases. In this scenario, a selective pulmonary
and on other organ dysfunction. Comorbidities are vasoactive therapy can potentially worsen a patient’s
frequently the reason for hospitalization and have condition by causing increased venous engorgement
led to a common view that chronic respiratory disor- and a shift of the interventricular septum, thus
ders contribute to both airway and systemic inducing left ventricular (LV) failure with pulmonary
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

edema (30). PH has been reported in >60% of patients Among those, HF is a pivotal and progressive condi-
with HF with reduced ejection fraction, >80% of pa- tion that leads to a cascade sequence of interorgan
tients with HF with preserved ejection fraction, and in crosstalk, including lung and kidney (Figure 2A). HF
78% of patients prior to mitral valve surgery (31). comprises different scenarios, depending on acuity
First established in 1998, the clinical classification and origin (38). Most frequently, acute decom-
of PH has become more granular over time, and in pensated HF develops in the presence of an under-
2013, chronic renal failure was added as a risk factor lying chronic HF, although in 15% to 30% of all causes
(29). The prevalence of PH and concomitant CKD it may present as new onset HF.
increases with declining renal function, and in current Distant organ damage is often proportional to
understanding, kidney function may itself have an duration of HF and represents a daily multidisci-
effect on pulmonary vascular remodeling in a predis- plinary challenge. Recently, a TNM–like method was
posed patient, analogous to connective tissue disease, proposed for HF staging, which includes the charac-
human immunodeficiency virus, or portal hyper- terization “H” for heart, “L” for lung, and “M” for
tension (32). Pathophysiological features include malfunction of other organs including the kidney
endothelial dysfunction, decreased bioavailability of (39). Most distant organ malfunctions (e.g., liver,
nitric oxide, increased levels of endothelin-1, fluid kidney, or bowel) are the result of right-sided HF and
overload, and shunting via arteriovenous fistulae (32). acute on chronic venous congestion (40). Addition-
BLOOD GAS DISTURBANCES. Maintenance of normal ally, AKI occurs in 25% to 33% of acute decom-
gas exchange is not achieved in patients with chronic pensated HF, which is an independent risk factor for
underlying pulmonary disease and in severely ill pa- prolonged hospitalization, need for renal replace-
tients; hypoxemia and/or hypercapnia develops with ment therapies, readmission, increased stroke risk,
relative degrees of renal acid/base compensation. and mortality (41). In 60% of cases of acutely
Reflecting alveolar ventilation in most cases, acute decompensated HF, AKI can be seen as an exacerba-
and chronic changes in carbon dioxide tension elicit tion of previously-diagnosed CKD, whereas in chronic
renal adaptive buffering mechanisms. In pulmonary HF, CKD has been reported as a comorbidity in 26% to
diseases, vasodilator properties of hypercapnia lead 63% (42).
to a decrease in systemic vascular resistance and CARDIAC INJURY, ABNORMAL CELL SIGNALING,

blood pressure with consequent neurohormonal AND OXIDATIVE STRESS. Analogous to the lung,

activation, retention of salt and water, and reduction cardiomyocytes show the ability to promote distant
in renal blood flow and glomerular filtration rate organ damage (e.g., AKI), following ischemic and
(GFR); cardiac output is not reduced, and renal blood mechanical injury via innate immune system res-
flow and GFR increase when hypercapnia improves ponse, neurohormonal signaling, and possibly, by
(21,33). Supported by recent findings, the relative release of metabolic products (e.g., catalytic iron)
contribution of blood gas disturbances may be crucial (41). IL-1 and TNF-a induce expression of ICAM-1, an
in CPRI and its prognosis. The targeted long-term use intercellular adhesion molecule promoting diape-
of noninvasive ventilation (biphasic positive airway desis of leukocytes into interstitium, thereby
pressure) for reduction of hypercapnia in stable depressing LV function by presumably inducing car-
chronic obstructive pulmonary disease patients diomyocyte hypoxia and apoptosis (Figure 2B) (43). In
significantly improves survival (34). Likewise, forms response to biomechanical strain, ST2 acts as a decoy
of assistance in ventilation for obstructive and central for IL-33 on its receptors in resident satellite cells and
sleep apnea effect improvements in renal blood flow cardiomyocytes. Additionally, in response to stimu-
and glomerular filtration (35). Short-term noninvasive lation by aldosterone and other factors, macrophages
ventilation reduces albuminuria, high-sensitivity C- secrete galectin-3, which is a powerful stimulus for
reactive protein levels, and urinary norepinephrine fibroblasts to proliferate and produce increased
excretion in HF patients (36). On the contrary, interstitial collagen. In concomitant AKI, renal
permissive hypercapnia in acute respiratory disorders tubular cells can further contribute to the circulating
may be beneficial in diminishing lung inflammation levels of inflammatory cytokines. The important role
and lung/kidney cell apoptosis (37). of these cells in the handling of inflammatory medi-
ators and resulting efflux into systemic circulation is
HEART IN ORGAN CROSSTALK: discussed in the section “Acute Kidney Injury,
THE CARDIOLOGIST’S VIEW Abnormal Cell Signaling, and Oxidative Stress” (44).
Oxidative stress has been implicated as the final
Cardiovascular diseases remain the major cause for common pathway of injury in various pathological
hospitalization, disability, and mortality worldwide. systems that are prevalent in cardiac, pulmonary, and
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JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

F I G U R E 2 The Heart in Cardio-Pulmonary-Renal Interactions

A Chronic Acute
Acute myocardial Myocarditis
Acute Chronic

infarction Ischemic heart disease


Arrhythmia Hypertensive heart
Hypertensive emergency disease
Cardiac surgery Cardiomyopathy
Pericardial tamponade
Toxic agents

Acute Chronic
Recovery/Non- Utilization RFR
recovery Subclinical AKI Glomerular/ Sclerosis/Fibrosis
CKD AKI Interstitial
ESRD Inflammation/Apoptosis Subclinical damage
Endothelial dysfunction inflammation/Apoptosis
Chronic Acute Sympathetic activation Endothelial dysfunction Acute Chronic
Low cardiac output Increased RVR/PVR
Venous congestion Chronic hypoperfusion
Chronic venous congestion

Recovery/Non- Subclinical lung Impaired gas exchange Impaired gas


recovery injury Pulmonary congestion exchange
Chronic lung failure Lung injury Low compliance Lung edema
Precapillary PH Postcapillary PH

B Activated neutrophils
Adhesive Pro-fibrotic Anti-fibrotic
ICAM-1 TGF-β IL-33
Local dentritic cells Cytotoxic IL-1, IL-6, TNF-α
ROS Soluble ST2
Macrophages Pro-inflammatory Galectin-3
IL-1, IL-6, IL-8, TNF-α

Apoptosis, necrosis Fibrosis

acute chronic

Cardiomyocytes Klotho (-)


Klotho (-) RAAS (-)
FGF23 (+) ECM

Fibroblast Myofibroblast

(A) The vicious circle of heart and lung injury, reserve capacity, and chronic organ failure, and its clinical features. (B) The cellular pattern of renal injury, repair, and
fibrosis. FGF23 may contribute to cardiac remodeling in concert with Klotho deficiency. FGF ¼ fibroblast growth factor; ICAM ¼ intercellular adhesion molecule;
IGFBP ¼ insulin-like growth factor binding protein; PVR ¼ pulmonary vascular resistance; RVR ¼ renal vascular resistance; other abbreviations as in Figure 1.

renal disorders (1,44). Accumulation of oxidative- stroke work due to the typically low resistance of the
damage products and failure to adapt to reactive ox- pulmonary vasculature (45). In PH, the stressed heart
ygen species stress may result in an immune system tries to balance pre-load and afterload to accommo-
activation and a proinflammatory and/or profibrotic date increased pulmonary vascular resistance.
milieu to generate functional and structural abnor- Resultant neurohormonal activation (endothelin,
malities, and consequently evoke cell death. arginine vasopressin) leads to water and salt reten-
RIGHT VENTRICULAR STRESS AND VENOUS CONGESTION. tion, worsening venous congestion, and further
Pulmonary vascular resistance is in constant inter- reduced cardiac output (46).
play with right ventricular function. In the normal In HF, renal failure has traditionally been thought
state, the right ventricle is a thin-walled, compliant, to be caused by renal hypoperfusion due to low-
low-pressure chamber that pumps the same stroke output failure. However, most hospitalizations for
volume as the left ventricle, but with z25% of the acute decompensated HF occur because of symptoms
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

of pulmonary and systemic venous congestion rather and pump failure. Accumulation of cardiac fibrosis
than poor perfusion (47). As 85% of the total blood may be the mechanism by which age contributes as
volume is located in the venous side of circulation, an a determinant of HF in the community (51).
expansion in total blood volume may occur without At a cellular level, angiotensin and aldosterone
changes in the arterial circulation (46). However, a are major stimuli for galectin-3 secretion with acti-
dysfunctional left ventricle is prone to afterload var- vation of oxidant stress signaling pathways that
iations, and therefore, increased systemic blood decrease levels of bioavailable nitric oxide, increase
pressure can cause pulmonary congestion, irre- inflammation and TGF- b, and promote fibroblast
spective of the intravascular volume. As reviewed proliferation, migration, extracellular matrix remod-
earlier, the pulmonary sequelae extend beyond sim- eling, and deposition of pro-collagen (52,53). Fibrosis
ply lung edema and congestive pneumonia. Hydro- in the myocardium, lung, and kidney strongly sug-
static effects can induce lung injury and barrier gests that neurohormonal translation to cell signals
dysfunction, initiating a cascade of local and systemic is part of the pathogenesis and progression of
organ injury, whereby pulmonary vascular remodel- disease. The mammalian fibroblast growth factor
ing results from chronic affection. Recurrent decom- (FGF) family plays a crucial role via distinct action
pensation can account for the vulnerability of HF mechanisms among cardiomyokines and represents
patients. Additionally, venous congestion may in- a promising novel endeavor. FGF2 and FGF23 pro-
crease gut endotoxin absorption contributing to the mote cardiac hypertrophy and fibrosis by activating
harmful environment, although activation of venous mitogen-activated protein kinases signaling and
endothelium itself is a stimulus for release of in- circulating ( a )-Klotho-independent calcineurin/nu-
flammatory mediators (48). As with the heart, the clear factor of activated T cells signaling, respec-
surrogate central venous pressure is 1 of the most tively. FGF2 significantly induces TGF- b1 that acts
important hemodynamic determinants for worsening downstream of angiotensin II and promotes cardiac
renal function and is independently associated with remodeling (54). The bone-derived hormone FGF23
higher mortality (47). On the basis of animal models, regulates phosphate in association with parathyroid
venous congestion is likely to decrease renal perfu- hormone and vitamin D in coordination with its
sion pressure through an increase in back pressure coreceptor Klotho, whereas CKD progression results
and formation of renal edema, although the renal in elevated serum levels of FGF23 (55). In con-
“intracapsular tamponade” may aggravate back trast, FGF16 and FGF21 seem to prevent cardiac
pressure (49). Venous congestion represents a part of remodeling (54). In vitro, Klotho inhibits TGF-b1–,
a cascade with stepwise development of fluid over- angiotensin II–, or high phosphate-induced fibrosis
load, deteriorating LV dysfunction, pulmonary (56) and confers resistance to oxidative stress and
congestion, secondary fixed pre-capillary PH, right endothelial dysfunction (57). In experimental mo-
ventricular overload and enlargement with tricuspid dels, intravenous delivery of a -Klotho can ameliorate
incompetence, and interference with LV filling. The cardiac hypertrophy, independent of FGF23 and
additional resultant central venous pressure rise is phosphate levels (55). However, the mechanism of
transmitted to the kidney and leads to a positive a-Klotho–independent FGF23 signaling in the heart
feedback loop evolving toward refractory congestive remains unclear (54). Whether modulation of this
HF. Those patients are at high risk and have a narrow complex system would improve cardiac outcome
window for fluid management of venous congestion; in such a high-risk population awaits further
extremes in either parameter can be associated with investigation.
worsened renal and right ventricular function. LV remodeling is associated with increased inter-
CARDIAC REMODELING AND FIBROSIS. HF repre- stitial matrix, decreased capillary density, accelerated
sents a heterogeneous group of syndromes leading apoptosis, chamber dilation, and dyssynchrony,
to structural (hypertrophy, fibrosis, and/or ventricu- leading to pump failure and sudden death (58).
lar dilation) and functional alterations (myocardial HF with preserved systolic function remains an
stiffness and incomplete relaxation of contractile elusive condition associated with concentric LV hy-
units) (50). Here, sequence of abnormal gene ex- pertrophy and impairment of diastolic LV function.
pression, cell signaling, and oxidative stress due to It accounts for more than one-half of hospitaliza-
uncontrolled hypertension, diabetes mellitus, and tions for HF and has no agreed-upon definitions for
other factors are a common link that is responsible detection or management (59). Activation of the renin-
for exuberant repair (fibrosis) pathways (Figure 2B) angiotensin-aldosterone system is 1 potential unifying
(41). The transformation predisposes the heart to element in diastolic HF and CPRI, and the poten-
become more vulnerable to re-entrant arrhythmias tial efficacy and antifibrotic role of mineralocorticoid
JACC VOL. 65, NO. 22, 2015 Husain-Syed et al. 2441
JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

receptor antagonists in cardiac, pulmonary, and mechanisms including epigenetic processes


renal disease merits further investigation in clinical (Figure 3B). In animal models, the kidney responds
trials (52). with an expression of IL-1 b, vascular cell adhesion
molecule-1, and TGF- b consistent with renal cell in-
KIDNEY IN ORGAN CROSSTALK: filtrates and, in advanced stages, perivascular, peri-
THE NEPHROLOGIST’S VIEW glomerular, and peritubular fibrosis with increased
markers of collagen formation (63). Here, innate and
The kidney is the window to neurohumoral and adaptive, cellular, and humoral immune systems
immunological diseases and plays a key role in contribute to AKI, which are presumably involved in
clearance, fluid, electrolyte, and acid-base homeo- repair process as well (62). However, a detailed dis-
stasis in mammalian physiology. AKI remains 1 of the cussion of immunomodulation is beyond the scope
most complex clinical challenges and is associated of this review. Recently, many efforts have been
with excess morbidity and mortality, especially in made to dissect the mechanisms of ischemic pre-
critically ill patients (44). Regardless of the cause, conditioning as a powerful intervention to protect
cardiac and/or pulmonary symptoms are the leading the heart, lung, and kidney from injury (64,65).
clinical manifestation (Figure 3A). Current definitions Endothelial cells, cardiomyocytes, and vascular
of AKI are commonly linked to creatinine rise and smooth muscle cells have all been shown to alter
urinary output, are insensitive to the severity of renal cellular processes as a result of repeated episodes of
injury, and can lead to delayed diagnosis and under- nonlethal hypoxia. Thus, these changes may some-
estimation of the degree of tubular damage. The day be mimicked by drugs or other interventions to
concept of subclinical AKI emphasizes that even pa- improve cell survival during ischemic episodes. AKI
tients who do not fulfill current consensus criteria for can clearly lead to CKD. The incidence of tubu-
AKI are still likely to have acute tubular damage that lointerstitial fibrosis has the best correlation with
may expose them to an increased susceptibility to CKD development (66). Interestingly, Klotho is
future injury and elevated risk for subsequent CKD mainly expressed in renal distal convoluted tubules
development (60), providing a significant impulse for (56). Thus, renal tubular cells and renal fibroblasts
the initiation of organ crosstalk with the heart and may be the primary cell types in the progressive
lung. The recent KDIGO clinical practice guideline development of CKD contributing to the progressive
proposed a new conceptual model, called acute kid- nature of cardiovascular and pulmonary diseases.
ney disease, to emphasize the need to follow patients
UREMIC LUNG. Chronic uremia affects the lungs and
who survived AKI episodes. Here, assessment of renal
results in the characteristic central butterfly appear-
functional reserve seems to be a promising tool to
ance that contrasts with the translucent periphery in
predict kidney recovery versus early function decline
anteroposterior x-rays of the lung. In 1951, Bass et al.
(61). Despite medical advances and the widespread
(67) reported its association with cardiac hypertrophy
availability of renal replacement therapy, the mor-
and LV failure in advanced kidney failure. Uremia
tality rate of severe AKI has not declined in recent
results in a decrease in diffusion capacity for carbon
decades, reaching 50%, and therapy is limited (62).
monoxide (26), small airway dysfunction (68), and
Early and increased renal replacement therapy does
impaired peak oxygen consumption (69). The uremic
not appear to improve outcome. Much of the mor-
milieu presumably contributes to the development of
tality risk is thought to be the consequence of com-
lung injury and dysfunction, which can be reversed
plex interactions between the actual insult, activation
by renal transplantation (9,70). With the introduction
of inflammation, and distant organ effects. To reduce
of dialysis, the classic presentation of uremic lung in
the systemic inflammatory response, especially in
the absence of volume overload has become less
combination with AKI, recent efforts are being made
common. Still, its pathophysiologic principles are
to use renal replacement therapy as a means to
operative in CPRI.
reduce cytokines.
At a cellular level, mechanisms for impaired reso-
AKI, ABNORMAL CELL SIGNALING, AND OXIDATIVE lution of pulmonary edema in acute lung injury (1),
STRESS. The renal tubular epithelium is funda- in cardiogenic pulmonary edema (71), and in re-
mental in the regulation of inflammatory processes sponse to AKI (9) have been identified demonstrating
and is immunologically active (44,62). During AKI, it reduced expression of epithelial sodium channel,
represents a major site of cell injury and death, sodium-potassium ATPase, and aquaporin 5. Epithe-
catalyzing circulating mediators in local and sys- lial sodium channel-inhibition (e.g., with amiloride)
temic inflammation/oxidative stress by different can alter alveolar fluid clearance, promoting reversed
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

F I G U R E 3 The Kidney in Cardio-Pulmonary-Renal Interactions

A Chronic Acute Acute Chronic

Glomerular/Interstitial Hypertensive nephropathy


disease Ischemic nephropathy
Acute tubular necrosis Chronic
Acute pyelonephritis glomerular/Interstitial
Acute urinary obstruction disease
Hypovolemia Chronic obstructive
nephropathy

Acute Chronic

Recovery/Non- Subclinical Subclinical Ischemic insult Increased ischemic risk


recovery myocardial injury Inflammation/Apoptosis inflammation/Apoptosis Arrhythmia LV hypertrophy
Chronic HF Acute HF Endothelial dysfunction Endothelial dysfunction Acute HF RV/LV dysfunction
Electrolyte/Acid base disorder Anemia Uremic cardiomyopathy
Uremic solute retention Bone mineral disorder
Sympathetic/RAAS activation Electrolyte/Acid base disorder
Chronic Acute Acute Chronic
Uremic solute retention
Sympathetic/RAAS activation

Recovery/Non- Subclinical lung Impaired gas exchange Impaired gas exchange


recovery injury Lung edema Pulmonary congestion
Chronic lung failure Lung injury PH PH
Uremic lung

B
Activated neutrophils Adhesive Pro-fibrotic Anti-fibrotic
VCAM-1 TGF-β IL-33
Local dentritic cells Cytotoxic IL-1, IL-6, TNF-α
ROS Soluble ST2
Macrophages Pro-inflammatory Galectin-3
IL-1, IL-6, TNF-α

Apoptosis, necrosis Fibrosis

acute chronic

Klotho (-) RAAS (-) Klotho (-) ECM


Renal tubular cells

Fibroblast Myofibroblast

(A) The vicious circle of heart and lung injury, reserve capacity, and chronic organ failure, and its clinical features. (B) The cellular pattern of renal injury, repair, and
fibrosis. Activation of RAAS may contribute to renal fibrosis by diminishing the cytoprotective effects of Klotho. HF ¼ heart failure; LV ¼ left ventricular; RV ¼ right
ventricular; VCAM ¼ vascular cell adhesion molecule; other abbreviations as in Figure 1.

transepithelial ion transport with active augmenta- vessels. Still, these mechanisms cannot account
tion of pulmonary edema. In animal model, inhibition for cardiovascular risk, as reflected in high rates of
of either the apical cystic fibrosis transmembrane sudden cardiac death, HF, sustained arrhythmias, and
conductance regulator or sodium-potassium-chloride myocardial infarction (72). Uremic cardiomyopathy
cotransporter 1 (e.g., with furosemide) can prevent defines the structural and electrophysiological remod-
active alveolar fluid secretion (71). eling of the heart, characterized by biventricular
UREMIC CARDIOMYOPATHY. CKD accelerates coro- hypertrophy, systolic and diastolic dysfunction, capil-
nary artery atherosclerosis by several mechanisms, lary rarefication, cardiac fibrosis, and an enhanced
notably hypertension, dyslipidemia, and abnormal susceptibility to further injury (73). Involvement of
calcium/phosphorus metabolism, associated with vas- the fibrotic pericardium is classically manifested
cular remodeling and development of noncompliant as acute on chronic uremic pericarditis with sterile
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JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

effusion, and is a less common complication since the ORGAN FUNCTIONAL RESERVE
introduction of dialysis. Contrarily, reversal of renal
dysfunction (e.g., after renal transplantation) can Given the multitude of contributing factors and
improve cardiac function (74). Uremic cardiomyopathy the time sequence of events in CPRI, it is chal-
may represent the advanced alteration of cardiac lenging to predict early functional and/or structural
remodeling described earlier and FGF23 excess/Klotho changes. The normal heart, lung, and kidney permit
deficiency might make a considerable contribution in a degree of physiological reserve that can maintain
CKD patients (56). normal organ function for any given insult. The
In type 3 cardiorenal syndrome, AKI can lead to functional reserve of an organ can be defined as the
cardiac dysfunction by fluid overload, electrolyte and difference between the minimum baseline function
acid-base shift, and renin-angiotensin-aldosterone and the maximum attainable function in response
system or central nervous system activation. Analo- to a physiological or pathological stimulus. Yet, the
gous to the lung, AKI induces endothelial cell mutual dependence of the organs is not defined.
activation, leukocyte trafficking, and myocardial in- In daily routine, assessment of cardiac and pulmo-
filtration (the role of ICAM-1 was reviewed earlier), nary functional reserve is a valuable parameter to
and pro-apoptotic cascades, resulting in myocardial define status, recovery, and prognosis toward the
damage and long-term dysfunction (44). Following organ’s response to an acute event or chronic
cardiac ischemia, ventricular fibrillation appears disease. Care and attention is needed in chronic
much more frequent in the setting of AKI (75). disorders, because these patients are more prone
Impaired cardiac function alters the interdependency to develop injury, decreasing the remaining func-
of the cardiopulmonary circuit. Pulmonary conges- tional mass. Thus, patients with “acute on chronic”
tion, in combination with AKI-induced compromise organ injury are at the highest risk. Genetic dispo-
of tubular epithelial ion pumps, may act syner- sition and environment influence the individual
gistically to further compromise cardiopulmonary course, while the organ functional reserve declines
function. with age as a consequence of physiological aging.
Frequent physical activity can develop and maintain
CKD AND FIBROSIS. The high prevalence and burden cardiopulmonary reserve best reflected by peak ox-
of CKD is well established and can represent the ygen consumption, but no factors have been iden-
origin and/or continuum of chronic cardiopulmo- tified that can lead to increased renal functional
nary disorders. The concept of subclinical AKI was reserve.
discussed, and early pathological changes can occur
without apparent clinical presentation due to the CARDIAC FUNCTIONAL RESERVE. Cardiac func-
high renal adaptability, but they still depict a slowly tional reserve is the ability of the myocardium to
progressing degenerative process that is both local augment its cardiac output and tissue delivery of
and systemic. Once the adaptive threshold is reached, oxygen during stress. The spectrum of myocardial
the progression to CKD is fast. It is generally accepted dysfunction may range from diastolic dysfunction in
that all primary causes of CKD share a common the early stage to overt systolic dysfunction. Both
pathogenic pathway of progressive renal injury due limit exercise tolerance before resulting in symptoms
to the destructive consequences of fibrosis. As fi- at rest, normally manifested by exertional dyspnea
brosis increases, the nephron that normally has a and impaired oxygen kinetic during exercise. LV
potent regenerative capacity loses this ability, leading diastolic reserve is the ability of the LV filling pres-
to apoptosis. Proteinuria is a surrogate marker of sures to remain normal during stress, whereas in
CKD progression and reflects endothelial dysfunc- systolic dysfunction, stress can reveal both LV and
tion. Even a modest increase in albuminuria is asso- right ventricular impaired contractile reserve (e.g., to
ciated with chronic pulmonary disorders (76), right unmask subclinical ischemia or PH) (79,80). However,
ventricular/LV remodeling, and adverse cardiovas- the presence and extent of coronary artery disease,
cular outcomes (77), although by the time proteinuria ischemic burden, old myocardial infarction, and
manifests, renal structural damage has already medication (e.g., diminished chronotropic reserve
occurred. Here, clinical and emerging biomarkers with beta-blockers) are all factors determining
(e.g., galectin-3) have been identified (78). Still, it is assessment (79). Probably the best measure of cardiac
important to underscore that most CKD patients will functional reserve is the peak oxygen consumption
never reach the point of needing renal replacement measured during maximal exercise and expressed as
therapy. They are more likely to die prematurely due ml/kg/min. This variable has been shown to be pre-
to accelerated cardiovascular diseases. dictive of survival in the general population and in
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Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

those with myocardial infarction, HF, and virtually all text, we review a select group of currently-
other chronic conditions. established and promising future biomarkers in CPRI.
PULMONARY FUNCTIONAL RESERVE. Pulmonary HIGH-SENSITIVITY CARDIAC TROPONIN. High-sensitivity
functional reserve is the ability of the lung to troponin I and T have been introduced as biomarkers
augment its respiratory minute volume during stress. of myocardial injury detectable at a much earlier
Its measurement is complex and includes several stage compared with prior troponin assays. In stable
variables for determination whether exercise capacity PH, chronic obstructive pulmonary disease, and CKD,
is reduced (mostly the case) or a reduced ventilatory elevated levels may indicate subclinical myocardial
capacity limits exercise. The breathing reserve, injury that subsequently contributes to HF (83,84).
expressed as the difference between the maximal Knowledge of its determinants in CPRI may guide
voluntary ventilation and the maximum exercise further research and help to stratify patients at early
ventilation, and respiratory frequency represent cardiovascular risk.
valuable criteria for maximal pulmonary exertion
B-TYPE NATRIURETIC PEPTIDE AND N-TERMINAL
(81). As with cardiac functional reserve, the peak ox-
PRO–B-TYPE NATRIURETIC PEPTIDE. B-type natri-
ygen consumption can be thought of as an objective
uretic peptide (BNP) and its inactive cleavage protein
surrogate of cardiorespiratory endurance and aerobic
N-terminal pro–B-type natriuretic peptide (NT-
fitness, because it reflects both pulmonary capabil-
proBNP) are markers of cardiac stretch from increased
ities for ventilation and gas exchange as well as car-
wall tension, and are established diagnostic, prog-
diac output and tissue perfusion (82).
nostic, and management tools for acutely decom-
RENAL FUNCTIONAL RESERVE. The concept of renal pensated HF, chronic HF, and acute coronary
functional reserve represents the capacity of intact syndromes (85). BNP is also prognostic for PH, prob-
nephron mass to increase GFR in response to stress ably due to increased right ventricular wall tension
and stands for the difference between peak “stress” and up-regulation of the pre-proBNP gene (86). Ele-
GFR induced by protein load (oral or intravenous) vations in BNP in the setting of acutely decom-
and the baseline GFR (61). In physiological (e.g., pensated HF and acute coronary syndromes is
pregnancy or solitary kidney) or pathological hy- associated with an increased risk of AKI (38,85).
perfiltration (e.g., diabetes mellitus or nephrotic Patients with CKD have higher levels of BNP than age-
syndrome), renal functional reserve allows for an in- and sex-matched patients with normal renal func-
crease in GFR by recruitment of dormant nephrons, tion, and this probably represents both increased
replacing the lost function and maintaining the whole cardiac production of BNP due to subclinical pressure
organ GFR. Renal functional reserve may represent a overload, volume overload, and cardiomyopathy as
future tool to exploit renal filtration capacity, even well as decreased renal clearance, more notably with
when subclinical damage is present and creatinine is NT-proBNP than BNP (38).
still normal, whereas a reduction of renal functional
SOLUBLE SUPPRESSOR OF TUMORIGENICITY 2. Sol-
reserve may represent the equivalent of renal frailty
uble suppressor of tumorigenicity 2 (ST2) is a circu-
or susceptibility to insults.
lating inhibitor of the IL-33 receptor and counteracts
BIOMARKERS the antifibrotic effects of IL-33 (87). Soluble ST2 has
received major attention as it may have an important
Inflammation is classically defined by 4 elements: role in the development of fibrosis and/or as a
immune cells (typically granulocytes), antibodies, biomarker of disease severity, although it lacks organ
cell signals (cytokines, interleukins, and so on), and specificity. Higher concentrations are associated with
complement. In the absence of infection, acute organ worse outcome in ARDS and PH (88,89). Soluble ST2
injury in the lungs, heart, and kidneys has very little has prognostic value in risk stratification for HF, and
involvement by granulocytes, antibodies, or comple- presumably CKD, and is not adversely influenced by
ment. Thus, inflammation, despite its popularity as a age and impaired renal function (90).
term, may not be optimal to describe the primary role GALECTIN-3. Galectin-3 is a b -galactoside–binding
of abnormal cell signaling in the pathogenesis of lectin with putative roles in immunomodulation,
CPRI. Novel biomarkers extend the spectrum to pre- transformation, and aldosterone-induced fibro-
vention, early diagnostic evaluation, treatment, and genesis. In the heart, galectin-3 is implicated in the
course of the disorder (Central Illustration). However, pathogenesis of fibrosis but is also increased with
the relative paucity of biomarkers that link a cardio- normal aging and renal impairment (53). Galectin-3
pulmonary-renal interaction should be emphasized levels have prognostic value in patients with HF, in-
as an area that needs further study. In the following dependent of etiology and HF typology, and provide
JACC VOL. 65, NO. 22, 2015 Husain-Syed et al. 2445
JUNE 9, 2015:2433–48 Cardio-Pulmonary-Renal Interactions

an additive value to natriuretic peptide measure- acid binding protein (L-FABP) into the urine. L-FABP
ments. Galectin-3 has been shown to promote TGF- b – is a housekeeping protein that moves rapidly out of
mediated activation of fibroblasts in the lung (91) and the cytosol through the apical membrane of tubular
kidney (78). Complementary prospective studies are epithelial cells and has been shown to be an early
needed to assess whether galectin-3 may be used to marker of AKI (95). It can be readily measured and is
predict which patient with cardiac, pulmonary, and a commercialized urine test for AKI. Its relation-
renal involvement may benefit from antifibrotic ships to other manifestations of CPRI have not been
agents. determined.
RENAL CELL CYCLE ARREST MARKERS. In the KIDNEY INJURY MOLECULE-1. Kidney injury molecule
setting of cellular injury, 1 of the earliest processes to (KIM)-1 is a transmembrane tubular protein solely
be affected is the cell cycle, which is down-regulated expressed in response to ischemic or nephrotoxic
to preserve cellular energetics and metabolic func- insults to proximal renal tubular cells, and has been
tions in the setting of hypoxia or other insults. Both proposed as an early marker of AKI as well as
the proximal and distal renal tubular cells release important in the transition from AKI to CKD (96).
tissue inhibitor of metalloproteinase (TIMP)-2 and KIM-1 is measurable in blood and urine and is
insulin-like growth factor binding protein (IGFBP)-7, predictive of AKI in patients undergoing coronary
which are measured in the urine and appear to angiography and in HF (95). Conversely, higher
predict a reduction in renal filtration function at $12 levels are associated with incident HF risk (97).
h after serious illness (92). The multiplication of the There are no data describing the use of KIM-1 in
2 concentrations yields a renal risk score, with a pulmonary disorders.
score >0.3 U having a high negative predictive value
USE OF BIOMARKERS IN COMBINATION. The Acute
and a score >1.2 a strong positive predictive value in
AKI. The relationship of these cell-cycle arrest Dialysis Quality Initiative panel has recommended

makers in the urine, which have been recently the use of both functional (creatinine, cystatin C)

become available as a commercialized, in-vitro filtration markers as well as renal tubular injury

diagnostic test, and other manifestations of CPRI markers (TIMP-2, IGFBP-7, NGAL, L-FABP, KIM-1,

have not been explored. IL-18, and so on) to both screen and detect AKI as
well as to aid in the prognosis for important out-
NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN. Neu-
comes, including the need for dialysis and mortality
trophil gelatinase associated lipocalin (NGAL) is
(98). This has been well supported by recent pub-
expressed in the distal tubules and collecting duct,
lished data in several settings including patients un-
seems to be 1 of the earliest renal markers of ischemic
dergoing cardiac surgery (99).
or nephrotoxic injury, and is detected in blood and
urine soon after AKI (93). Moreover, NGAL has been CONCLUSIONS
implicated in the induction of cardiomyocytes
apoptosis and is highly expressed in failing myocar- We have summarized current concepts in the patho-
dium (65). Plasma NGAL has been associated with genesis of CPRI including abnormalities, cardiopul-
adverse cardiovascular outcomes or death and is a monary and systemic hemodynamics, neurohormonal
strong predictor of all-cause mortality in acute activation, abnormal cell signaling, and tissue fi-
decompensated HF, suggesting that renal damage has brosis. A sustained injury to the alveolar-capillary
a role in determining the prognosis of HF patients. barrier can initiate lung structural and vascular
However, peak 24-h urinary NGAL seems to predict remodeling, leading to chronic lung disease and pul-
best the 30-day mortality and dialysis in intensive monary hypertension. Cardiac injury represents the
care patients, compared with plasma NGAL and cys- origin of cascading deleterious events that may lead
tatin C (93). In small studies, plasma and urinary to myocardial remodeling with fibrosis and heart
levels of NGAL do not correlate with PH (94). Yet, its failure. Acute kidney injury might occur as a result
role in acute decompensated right ventricular failure of abnormal immune cell signaling of the injured
is not defined. Plasma, but not urinary NGAL, in- tubular epithelial cells, whereas recurrent AKI leads
creases markedly with GFR reduction and can possibly to an elevated risk for subsequent CKD development.
generate a high number of false positive diagnoses Much is yet to be learned about the time sequence of
of AKI in stable CKD patients. Both plasma and organ injury and damage and what, if any, are the key
urine NGAL are commercially available assays for AKI. modifiable mediators in the propagation of organ
L-TYPE FATTY ACID BINDING PROTEIN. In the dysfunction. Multiple disciplines working together
setting of AKI, renal tubular cells release L-type fatty hold the hope of future interventions that can lead to
2446 Husain-Syed et al. JACC VOL. 65, NO. 22, 2015

Cardio-Pulmonary-Renal Interactions JUNE 9, 2015:2433–48

improved survival in the critically ill patient with


evidence of cardiac, pulmonary, and renal failure. REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Faeq Husain-Syed, Department of Nephrology, Dial-
ACKNOWLEDGMENTS The authors thank Drs. Fernando ysis and Renal Transplantation, International Renal
E. Núñez Gomez, Daniel Murillo Brambila, Aashish Research Institute of Vicenza, San Bortolo Hospital,
Sharma, Renhua Lu, and Carla Estremadoyro for their Via Rodolfi, 37, Vicenza 36100, Veneto, Italy. E-mail:
devoted help in the development of the manuscript. faeqhusain@yahoo.de.

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