síndrome cardiorrenal tipo 2renal dysfunction. cardiorenal syndrome type 2 (crs2) is a term used to...
TRANSCRIPT
2017/2018
Cláudio André Melo Rodrigues
Síndrome Cardiorrenal Tipo 2 /
Cardiorenal Syndrome Type 2
março, 2018
2
Mestrado Integrado em Medicina
Área: Medicina
Tipologia: Monografia
Trabalho efetuado sob a Orientação de:
Doutor Manuel Joaquim Lopes Vaz da Silva
Trabalho organizado de acordo com as normas da revista :
Revista Portuguesa de Cardiologia
Cláudio André Melo Rodrigues
Síndrome Cardiorrenal Tipo 2 /
Cardiorenal Syndrome Type 2
março, 2018
3
4
1
Title: Cardiorenal Syndrome Type 2
Título: Síndrome Cardiorrenal Tipo 2
Nome: Cláudio André Melo Rodrigues
Orientador: Doutor Manuel Joaquim Lopes Vaz da Silva
Faculdade de Medicina da Universidade do Porto
Al. Prof. Hernâni Monteiro, 4200-319 Porto
Contacto: [email protected] / [email protected]
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Index
Abstract ………………………………………………………………………………………. 3 Resumo ……………………………………………………………………………………….. 4 List of abbreviations…………………………………………………………………………... 6 Introduction …………………………………………………………………………………... 8 Methods ……………………………………………………………………………………... 14 Chronic Heart Failure ………………………………………………………………….…….. 15 Chronic Kidney Disease……………………………………………………………………... 18 Definition, Diagnosis and Biomarkers ………………………………………………………. 20 Pathophysiology of Cardiorenal Syndrome Type 2 …………………………………...……... 27
1. Hemodynamic Factors ………………………………………………………...… 28
2. Neurohormonal Activation, Oxidative Stress and Inflammation ……...………… 29
3. Anemia ………………………………………………………………................... 35
4. Impact of Pharmacotherapy for the Management of Heart Failure …………..….. 36 Treatment Considerations in Cardiorenal Syndrome Type 2 …………………....................... 38 Conclusion …………………………………………………………………………………... 45 References …………………………………………………………………………...……… 46
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Abstract
Cardiac and kidney disease are becoming progressively more prevalent in the population
and may occur simultaneously. One of the most recognisable comorbidities in heart failure is
renal dysfunction.
Cardiorenal Syndrome Type 2 (CRS2) is a term used to designate clinical conditions in
which chronic abnormalities in cardiac function through a chronological and causal relationship
leads to chronic kidney disease. This syndrome has recently become the subject of increasing
discussion related to its diagnosis, pathogenesis and treatment since it is associated with a
significant morbidity and mortality.
Data from clinical and experimental studies reveal that CRS2 is a condition
characterized by a gradual deterioration of glomerular filtration rate, mild to moderate
proteinuria and expression of high levels of renal injury biomarkers. Renal disease progression
in the setting of CRS2 is elicited by triggers as maladaptive chronic neurohormonal stimulation,
chronic increases in renal venous pressure as well as chronic oxidative and inflammatory state
which leads and perpetuates structural renal injury, involving tubulointerstitial fibrosis and
glomerulosclerosis.
Much remains to be clarified about CRS2. There are still significant questions
concerning its pathophysiology and the existing therapy is actually a fragmented one, and
therefore there is a need for interventional trials in this setting, regarding new criteria to
optimize the management and improve outcomes in these patients.
The aim of this review is address the current knowledge about CRS2, including its
definition, pathophysiology, diagnosis and treatment strategies.
Keywords: Cardiorenal syndrome type 2, Chronic heart failure, Chronic kidney disease, Heart-
Kidney Interaction, Renal Injury, Inflammation, Oxidative Stress, Neurohormonal Activation
4
Resumo
As doenças cardíaca e renal têm-se tornado cada vez mais prevalentes na população,
sendo que podem ocorrer simultaneamente. Uma das comorbilidades mais reconhecidas na
insuficiência cardíaca é a disfunção renal.
A Síndrome Cardiorrenal Tipo 2 (CRS2) é um termo usado para designar a condição
em que as anomalias crónicas da função cardíaca, numa relação causal e cronológica, conduzem
ao desenvolvimento de doença renal crónica. Esta síndrome tem sido recentemente alvo de um
crescente debate em relação ao seu diagnóstico, patogénese e tratamento, uma vez que está
associada com morbilidade e mortalidade significativas.
Dados de estudos clínicos e experimentais revelam que a CRS2 é uma condição
caracterizada por uma deterioração gradual da taxa de filtração glomerular, proteinúria ligeira
a moderada e expressão de níveis elevados de biomarcadores de lesão renal. A progressão da
doença renal no contexto da CRS2 é despoletada por desencadeadores como a estimulação
neurohormonal crónica e mal adaptativa, aumentos crónicos na pressão venosa renal assim
como um estado oxidativo e inflamatório crónico que conduz e perpetua a lesão renal estrutural,
envolvendo fibrose tubulo-intesticial e glomerulosclerose.
Muito permanece por ser esclarecer na CRS2. Há ainda muitas questões relevantes
acerca da sua patofiosiologia, e a terapêutica atual é na verdade uma terapêutica fragmentada
e, por isso, é necessário conduzir mais estudos intervencionais no sentido de se criar critérios
que otimizem a abordagem e melhorem os outcomes nestes pacientes.
O objetivo desta revisão é abordar o conhecimento atual sobre a CRS2, incluindo a sua
definição, patofisiologia, diagnóstico e estratégias de tratamento.
5
Palavras-Chave: Síndrome Cardiorrenal tipo 2, Insuficiência Cardíaca Crónica, Doença Renal
Crónica, Interação Coração-Rim, Lesão Renal, Inflamação, Stress Oxidativo, Ativação
Neurohormonal
6
List of abbreviations
ACEI Angiotensin converting enzyme inhibitor
ACR Albumin-to-creatinine ratio
ACS Acute coronary syndrome
ADH Antidiuretic hormone
AER Albumin excretion rate
AIM Antioxidant inflammation modulator
AKI Acute kidney injury
ANGII Angiotensin II
ARBs Angiotensin II receptor antagonist
BNP Brain-Type Natriuretic Peptide
CAD Coronary artery disease
CHF Chronic heart failure
CKD Chronic kidney disease
CO Cardiac output
CRS Cardiorenal syndrome
CRS2 Cardiorenal syndrome type 2
cTns Cardiac troponins
CRT Cardiac resynchronization therapy
CysC Cystatin C
EF Ejection fraction
eGFR Estimated glomerular filtration rate
EPO Erythropoietin
ESA Erythropoiesis stimulating agents
ESRD End-stage renal disease
7
FGF-23 Fibroblast growth factor 23
GFR Glomerular filtration rate
GPCR G protein–coupled receptor
HF Heart failure
HFpEF Heart failure with preserved ejection fraction
HFrEF Heart failure with reduced ejection fraction
KIM-1 Kidney injury molecule-1
LAE Left atrial enlargement
LV Left ventricle
LVAD Left ventricular assist devices
LVEF Left ventricular ejection fraction
LVH Left ventricular hypertrophy
MI Myocardial infarction
NADPH oxidase Nicotinamide adenine dinucleotide phosphate-oxidase
NF-κB Nuclear factor kappa B
NAG N-acetyl-beta-D-glucosaminidase
NT-proBNP NT-pro-brain natriuretic peptide
NSAIDs Non-steroidal anti-inflammatory drugs
PD Peritoneal dialysis
RAAS Renin-angiotensin-aldosterone system
ROS Reactive oxigen species
sCr Serum creatinine
SNS Sympathetic nervous system
SVR Systemic vascular resistance
TGF-b Transforming growth factor beta
8
Introduction
The organ systems are closely linked. In the normal state, this connection helps maintain
optimal homeostasis and the functioning of the human body. The interaction between heart and
kidney is a striking example. Both organs are regulators of vital functions, such as blood
pressure, vascular tone, circulatory volume homeostasis, peripheral perfusion, diuresis,
natriuresis, and tissue oxygenation and the two organs have endothelial functions as well as a
role in cellular and humoral signaling.1
It is well known that many hospitalized patients simultaneously exhibit varying degrees
of cardiac and renal dysfunction.2 The interaction is bidirectional so that the leading disease of
the heart or kidney frequently involves injury or dysfunction in the other organ.3 Founded on
this cross-talk, the term cardiorenal syndrome has arisen. The most widely used classification
is that established by the Consensus Conference by the Acute Dialysis Quality Group, which
divides the CRS fundamentally into two core groups, the cardiorenal and renocardiac
syndromes, according to the origin of the disease (cardiac or renal); both CRS are then divided
into acute or chronic according to the onset of the disease.4 This classification was not proposed
to be unchangeable, as many patients may transit between different CRS subtypes (Table 1).5
Recently some authors such as Hatamizadeh et al. and Naranjo et al. have proposed
propose a new classification of cardiorenal syndromes (Table 2), not only focusing in the timing
and causality of the syndrome but also taking into account clinical manifestations and current
therapies and new treatment strategies,5,6 with Obi et al. additionally highlighting the related
potential damages.7
9
Table 1. Cardiorenal syndrome (CRS) subtypes.
Cardiorenal Subtype Description Examples/Etiology
CRS Type 1 (acute CRS)
Rapid worsening of cardiac function leading to acute kidney
injury
Acute MI with cardiogenic shock, acute decompensation of chronic heart failure, acute
valvular insufficiency
CRS Type 2 (chronic CRS)
Chronic abnormalities in cardiac function leading to chronic
kidney disease
CHF with chronic inflammation, long-term RAAS and SNS activation, chronic hypoperfusion
CRS Type 3 (acute renocardiac syndrome)
Acute worsening of renal function leading to cardiac
dysfunction (HF, arrhythmia, and so forth)
Acute kidney injury with uremia causing impaired contractility, hyperkalemia causing arrhythmias,
volume overload causing pulmonary edema
CRS Type 4 (chronic renocardiac
syndrome)
Chronic worsening of renal function leading to worsening
cardiac function
CKD leading to LVH, coronary disease and calcification, diastolic dysfunction, and so forth
CRS Type 5 Acute or chronic systemic
disease leading to both cardiac and renal dysfunction
Diabetes mellitus, amyloidosis, sepsis, vasculitis, sarcoidosis, systemic lupus erythematosus
CHF: chronic heart failure; CKD: chronic kidney disease; HF: heart failure; LVH: left ventricular hypertrophy;
MI: myocardial infarction; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system.
Adapted from Ronco et al. (2008),3 Cole et al. (2012)8 and De Vecchis et al. (2014).9
10
Table 2. The new CRS classification proposed by Hatamizadeh et al.
CRS category and definition Current strategies Potential strategies Potential harms
Hemodynamic Hemodynamic compromise
is the major clinical manifestation
Diuretics Ultrafiltration Vasodilators
Inotropic agents Natriuretic peptides
ACE inhibitors Digitalis
Dopamine Mechanical
circulatory assist devices
Heart and/or kidney transplantation
Vasopressin V2-receptor antagonists
ARBs Peritoneal dialysis Exercise training
Calcium sensitizers Endothelin-receptor antagonists
Luso-inotropic agents (e.g. istaroxime)
Cardiac myosin activators
Dual/triple RAAS blockade, antiarrhythmic
drugs (except for amiodarone and
dofetilide), calcium-channel blockers (except
for amlodipine), NSAIDs, thiazolidinediones, long-
term inotropic agents
Uremic Uremic manifestations are the most prominent clinical
appearances
Conventional peritoneal dialysis and hemodialysis
therapies
Toxin removal by super-high-flux hemofiltration and/or novel
absorbents High-protein diet
Vascular Cardiovascular and/or
renovascular manifestations are the most prominent
clinical findings
Statins Atherosclerosis risk factor modification Antiplatelet agents
Anticoagulants
ACE inhibitors ARBs
Endothelin-receptor antagonists Aldosterone-receptor antagonists
Nitric oxide Correction of pump failure and
anemia (by increasing shear stress and improving endothelial function)
Exercise training
Smoking
Neurohumoral Electrolyte disorders, acid–
base disorders or dysautonomia is the most
prominent finding
ACE inhibitors β-blockers
Aldosterone-receptor antagonists
ARBs FGF23-receptor blockers
Adenosine A1-receptor antagonists Direct renin inhibitors
Exercise training Kidney sympathectomy
Long-term inotropic agents, ACE inhibitors or
ARBs, aldosterone receptor blockers
Anemia and/or iron metabolism
Dysregulation of iron metabolism and anemia
Iron ESAs
Folic acid Cyanocobalamin Red blood cell
transfusion (in certain circumstances)
Nutritional support Vitamin C Carnitine
Anti-hepcidin therapy
ACE inhibitors or ARBs, aldosterone receptor
blockers
Mineral metabolism Dysregulation of calcium and phosphorus and their
regulators including vitamin D and FGF23 are the most
prominent clinical manifestations
Vitamin D agents Phosphorus binders
Calcimimetics Diet modification
FGF23-receptor blockers FGF23 antibodies
Calcium, warfarin, overdosed active vitamin
D
11
It should be noted that the category of any patient is dependent on the current clinical evaluation and may vary
over time. Attention must first be paid to the patient's most relevant clinical manifestation.
ACE: angiotensin-converting enzyme; AIM: antioxidant inflammation modulator; ARB: angiotensin-receptor
blocker; CRS: cardiorenal syndrome; ESA: erythropoiesis-stimulating agent; FGF23: fibroblast growth factor 23;
NSAIDs: non-steroidal anti- inflammatory drugs; RAAS: renin-angiotensin-aldosterone system.
Adapted from Naranjo et al. (2017),5 Hatamizadeh et al. (2013),6 e Obi et al. (2016).7
The prevalence of heart failure (HF) and chronic kidney disease (CKD) in Europe is
solidly increasing, much at the expense of the growing incidence of acute and chronic
cardiovascular disease, such as acute decompensated HF, arterial hypertension and cardiac
valve disease.10 However, this scenario seems to occur in other regions of the world, with data
from the United States that indicate a prevalence of symptomatic congestive HF estimated at
2% in those over 45 years of age with a lifetime risk of CHF estimated at 20%. CHF is the
prominent cause of admission in persons over 65 years, accounting for more than 1 million
hospitalizations yearly.5 In the context of CRS2, the impact of worsening heart failure is once
again clear through higher rates of death and re-hospitalization compared to those without
CRS211 (Figure 1A).
Renal failure is frequent among patients with chronic HF, in both reduced (HFrEF) and
preserved ejection fraction (HFpEF) as well as symptomatic and asymptomatic patients,5 with
a variable prevalence ranging from 20% to 57% worldwide,12 but according to K/DOQI clinical
Malnutrition–inflammation–cachexia
Malnutrition, cachexia and inflammatory state is the most prominent clinical
manifestation
Nutritional support Appetite stimulators
Exercise training
ACE inhibitors ARBs AIM
β-blockers Ghrelin
Growth hormone Anti-inflammatory and/or anti-
oxidative agents Volume overload correction (to
improve gut wall edema and nutrient absorption)
Muscle enhancers (e.g. anti-myostatin agents)
12
practice guidelines for chronic kidney disease, nearly 63% of patients with HF meet the
classification of stage 3–5 CKD with an estimated glomerular filtration rate < 60 ml/min/1.73
m2.13 Renal dysfunction takes a significant responsibility in the progression of cardiovascular
disease and performs as an independent risk factor for morbidity and mortality in patients with
heart failure5 (Figure 1B) and is correlated with elevated risk of readmission.12
It was shown even slight reductions in eGFR notably increase mortality risk.14
Figure 1 Kaplan-Meier curves.
A): Cardiac event-free survival analysis in patients with and without cardiorenal syndrome type 2. Patients with
CRS2 had higher rates of cardiac death and re-hospitalization due to worsening heart failure than those without
CRS2.
Taken and adapted from Salim et al. (2017)11 with permission.
B) Calculated GFR (using the simplified modification of diet in renal disease (MDRD) prediction equation (186
´ sCr-1.154 (mg/dL) ´ Age-0.203 (years) ´ 0.742 if female, ´ 1,212 if black) and relationship to prognosis in patients
with chronic heart failure. Patients with worse renal function at baseline had a poorer prognosis.
Taken and adapted from de Silva et al. (2006)12 with permission.
A) B)
13
The aim of the present work is to review the current knowledge about chronic cardio-
renal syndrome, also known as CRS type 2. First, key concepts in this syndrome such as
"chronic heart failure" and "chronic kidney disease" will be described. Then, the definition,
diagnosis, biomarkers and pathophysiology will be addressed. Finally, the current options for
the treatment of CRS2 will be outlined.
14
Methods
A literature search using PubMed’s data base was performed. Articles up to March 2018,
with no inferior date limitation, written in English or Portuguese were selected for inclusion.
The most recent articles were selected whenever possible. The search was conducted based on
MeSH terms using the following combinations: [cardiorenal syndrome type 2 AND (chronic
heart failure OR chronic heart disease) AND chronic renal disease]. A preliminary assessment
of eligibility was made through titles and abstracts. Potentially applicable articles were retrieved
and reviewed independently for final decision on inclusion. Unavailable and irrelevant articles
were excluded. Additional relevant articles found in the reference lists were also included.
15
Chronic Heart Failure
Chronic Heart Failure (CHF) is a condition in which the heart is incapable to perform
its major pump function effectively (ie, failing to provide sufficient blood flow to meet the
requirements of the various organs and apparatus of the organism or providing it at elevated
intracardiac pressures).9 It is a clinical syndrome in which patients have signs or symptoms of
HF for some time and objective evidence of an anomalous heart structure or function at rest,
generally confirmed by echocardiographic parameters quantification.15 In CHF there is
overexpression of biologically active substances, with cardiac myocytes contributing to that
production, and whose effects may prove to be harmful both by autocrine action and by
paracrine activity, particularly at the renal level (Table 3).16
Table 3. Biologically active substances overexpressed in CHF.
Vasodilator Significance Vasoconstrictor Significance
Adrenomedullin + Angiotensin II ++
Bradykinin + Aldosterone ++
Catecholamines- central effects ++ Arginine vasopressin ++
Dopamine ++ Catecholamines- peripheral effects ++
Natriuretic peptides ++ Endothelin ++
Nitric oxide ++ Thromboxane +
Vasodilator prostaglandins ++
+ = minor effect; ++ = major effect
Adapted from Preeti et al. (2016)16
16
HF is recognized as one of the 21st century epidemics and a public health problem,
affecting 1 to 2% of the adult population in industrialized countries,17 with its prevalence
growing in patients over 70 years of age (³10%).18 Hospitalization for HF is the flagrant cause
of admission in Western countries and accounts for a large percentage of the financial impact
of HF,17 estimated in $37.2 billion spent each year on HF in the United States.19 In hospital,
mortality is between 4-7% and within 12 weeks of discharge Mortality is around 13% in
European cohorts, and 5-year mortality reaching 60%.16 The leading cause of CHF, excluding
renal impairment, includes ischemic heart disease, diabetes mellitus, the metabolic syndrome
a Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics;
bBNP > 35 pg/ml and/or NT-proBNP > 125 pg/mL.
BNP: B-type natriuretic peptide; HF: heart failure; HFmrEF: heart failure with mid-range ejection fraction;
HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; LAE:
Table 4. Definition of HF with preserved, mid-range and reduced ejection fraction.
Type of HF HFrEF HFmrEF HFpEF
Cri
teri
a
1 Symptoms
and/or Signsa Symptoms and/or Signsa Symptoms and/or Signsa
2 LVEF <40% LVEF 40-49% LVEF ³50%
3 ---
1. Elevated levels of natriuretic
peptidesb;
2. At least one additional criterion:
a. relevant structural heart
disease (LVH and/or LAE),
b. diastolic dysfunction.
1. Elevated levels of natriuretic
peptidesb;
2. At least one additional criterion:
a. relevant structural heart
disease (LVH and/or
LAE),
b. diastolic dysfunction.
17
left atrial enlargement; LVEF: left ventricular ejection fraction; LVH: left ventricular hypertrophy; NT-proBNP:
N-terminal pro-B type natriuretic peptide.
Adapted from Ponikowski et al. (2016).20
Patients with CHF have an increasingly longer life expectancy and are dying less
frequently of primary arrhythmias, so that CRS is expected to become more frequent.21
The signs and symptoms of HF and its definition (HT with preserved, mid-range and
reduced ejection fraction) are presented in Tables 4 and 5.
Table 5. Symptoms and signs of heart failure.
Typical Symptoms
Breathlessness
Orthopnea
Paroxysmal nocturnal dyspnea
Reduced exercise tolerance
Fatigue, tiredness, increased time to recover after
exercise
Ankle swelling
More specific signs
Elevated jugular venous pressure
Hepatojugular reflux
Third heart sound (gallop rhythm)
Laterally displaced apical impulse
Adapted from Ponikowski et al. (2016).20
18
Chronic kidney disease
CKD is defined as the occurrence of anomalies of kidney function or structure or
decreased glomerular filtration rate (GFR<60 mL/min/1.73 m2) for at least three months.22
Kidney injury is defined as pathological alterations or markers of damage, including
abnormalities in blood or urine analyses or imaging techniques (Table 6)23 and overall CKD is
characterized by the gradual destruction of normal renal parenchyma due to a relentless process
of scarring.24 CKD can be categorizes according to GFR and albuminuria categories (Table
7).22
CKD: chronic kidney disease; GFR: glomerular filtration rate
Adapted from KDIGO 2012.22
The global prevalence of CKD is 8-16% and is growing worldwide,25 and latest
epidemiological studies have showed CKD is a substantial risk for cardiovascular events
independent of traditional risk factors, such as diabetes mellitus hypertension and
dyslipidemia.26 In this regard, cardiovascular disease, which has reached rates 10- to 20-fold
superior in patients with CKD versus age-matched non-CKD population, may justify more than
Table 6. Definition of chronic kidney disease.
Criteria for CKD (either of the following for more three months)
Markers of kidney
damage (one or more)
Albuminuria
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders Abnormalities detected
by histology
Structural abnormalities detected by imaging
History of kidney transplantation
Decreased GFR GFR < 60 ml/min/1.73 m2 (GFR categories G3a–G5)
19
50% of all deaths in this circumstance.5 The majority of CKD patients might never reach the
circumstance of needing renal replacement therapy to support life, since they are more
susceptible to die prematurely because of faster cardiovascular disease evolution.24 However,
those with ESRD treated with dialysis are more prone to death by primary cardiac arrhythmias
whilst in the general population coronary heart disease is the main cardiovascular cause of
death.27 Hence, CKD remains a critical health problem associated with high healthcare costs
and most important, high morbidity and mortality.25
In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill the criteria for CKD.
ACR: albumin-to-creatinine ratio; AER: albumin excretion rate; CKD: chronic kidney disease; ESRD: end-stage
renal disease; GFR: glomerular filtration rate.
Adapted from KDIGO 2012.22
Table 7. Glomerular filtration rate albuminuria categories in chronic kidney disease.
GFR category Terms GFR (ml/min/1.73m2)
G1 Normal or high ³90
G2 Mildly decreased 60-89
G3a Mildly to moderately decreased 45-59
G3b Moderately to severely decreased 30-44
G4 Severely decreased 15-29
G5 Kidney failure, including ESRD <15
Albuminuria category Terms AER (mg/24h) ACR (mg/g)
A1 Normal to mildy increased <30 <30
A2 Moderately increased 30-300 30-300
A3 Severely increased >300 >300
20
Definition, Diagnosis and Biomarkers
CRS2 is described by chronic anomalies in cardiac function that predispose to or cause
progressive renal injury and / or dysfunction, a condition frequently observed in clinical
practice.9,28 The definition of chronic cardiac impairment includes many different heart
conditions (as constrictive pericarditis, congenital cyanotic heart disease and atrial fibrillation)
but chronic HF remains the main cause, and henceforth is the principal focus on this review.29
CRS2 is the most common CRS and has been reported in 63% of patients admitted with
congestive HF.30
Observational animal and human studies have shown evidence that CHF leads to
variable levels of albuminuria / proteinuria, gradual reduction in GFR and expression of renal
injury biomarkers (Figure 2). Although several mechanisms have been suggested,
neurohormonal activation, hemodynamic factors as renal hypoperfusion and venous
congestion, inflammation and oxidative stress appear to be the principal ones.4,31
Figure 2 Cardiorenal Syndrome Type 2 and Renal Injury Biomarkers.
Adapted from Preeti et al. (2016).16
Serum creatinine
CRS2 Tubular injury/
insterstitial fibrosis
Cardio-Renal Syndrome Type 1LCOS and Congestion
Acute Kidney Injury
Acute Heart
Disease
• Upon initial recognition, AKI induced by primary cardiac dysfunctionimplies inadequate renal perfusion until proven otherwise. This shouldprompt clinicians to consider the diagnosis of a low cardiac output state(LCOS) and/or marked increase in venous pressure leading to kidneycongestion.• It is important to remember that central venous pressure translated to therenal veins is a product of right heart function, blood volume, and venouscapacitance which is largely regulated by neuro-hormonal systems.• Specific regulatory and counter-regulatory mechanisms are activated withvariable effects depending on the duration and the intensity of the insult.
Biomarkers
Decreased GFR
Glomerular injury
Galectin-3, NGAL,
KIM-1,
L-FABP, IL-18,
Cystatin C
Urinary albumin-
creatinie ratio
21
In addition to the more specific mechanisms, it is postulated that multiple episodes of
acute cardiac or renal decompensation may contribute to the progression of HF or CKD,28 as
suggested by data showing that prior hospitalizations for HF are predictors of mortality after
adjusting for other HF risk factors. Recurrence of admissions for HF is independently related
with the development of CKD (eGFR <60mL/min).4
The diagnosis, prevention and treatment of this syndrome are generally fragmented on
pathologies, focused on a single organ rather than a multidisciplinary approach. In 2010, for the
first time the “Acute Dialysis Quality Initiative Consensus Group” presented the CRS
definition, classification, and recommendations for the its diagnosis, prevention and
management, with emphasis on the recommendation of a close collaboration between
cardiologists and nephrologists to optimize the outcome of these patients.32 Given the
complexity of CRS, there is no severity scale so far, and therefore it is recommended to use the
specific classifications for HF (NYHA) and CKD (KDIGO/KDOQI).32
It is essential to note that the simple co-occurrence of cardiovascular disease and CKD
is not enough to establish a true diagnosis of CRS2. In the precise context of stable CHF, two
prerequisites are required to establish the diagnosis of CRS2: (1) CHF and chronic renal failure
coexist in the patient; (2) CHF is causally underlying the occurrence or progression of chronic
renal failure (Figure 3). This latter aspect should be sustained by temporal connection (ie, the
presumed or documented onset of chronic congestive HF temporally precede the occurrence or
progression of chronic renal failure) and by pathophysiological plausibility (ie, the expression
and grade of renal disease is reasonable justifiable by underlying heart disease) albeit available
studies are often inconclusive in determining which of the two processes is primary versus
secondary.9,28
22
Figure 3 Definition of Cardiorenal Syndrome Type 2.
Adapted from Cruz et al. (2013)28 and KDIGO 2012.22
The findings revealing renal dysfunction in the context of CRS2 include increased
serum creatinine (sCr) or, in individuals with lower muscle mass, a value of sCr in the near-
normal range, since it is associated with low eGFR values (<60mL/min/1.73m2), calculated
through the Modified Diet in Renal Diseases study or Cockcroft-Gault equations. Further
laboratory findings may be useful, such as the coexistence of albuminuria or anemia, or both.
The evaluation of renal dysfunction in HF clinical studies has been quite restricted to
conventional biomarkers such as creatinine (or its derivative, eGFR), and urinary protein
excretion. In CHF, both compromised renal function (denoted by elevated creatinine or
decreased eGFR) and augmented urinary excretion of albumin are powerful and independent
predictors of prognosis. Both are associated with elevated risk of death, cardiovascular death
and hospitalization in patients with diminished or preserved LVFE. In CKD, the level of eGFR
23
and albuminuria has been shown to have a prognostic value in relation to long-term renal
outcomes. However, this did not occur in the setting of CHF.10,28
Traditionally, eGFR stands as gold standard for the evaluation of renal function.
However, its use in the context of acutely decompensated HF or CHF is difficult, since formulas
that estimate eGFR are only validated when sCr is in a steady-state. SCr also presents important
limitations. The sCr reflects only the eGFR and not directly the tubular lesion, and the tubular
lesion can better predict and characterize acute kidney injury (AKI) and the progression of
chronic renal damage. In addition, sCr shows a relatively late elevation during an episode of
AKI, often when there is little to be done to prevent or counterbalance renal damage. In addition,
sCr levels are influenced by age, ethnicity and muscle mass, which in hospitalized patients with
HF, especially women and elderly individuals with low muscle mass, may lead to a lesser
recognition of renal failure,9 since eGFR could already have considerably decreased when sCr
levels surmount reference levels.15 Kervella et al. showed recently that the use of cystatin C for
GFR estimation in CRS2 may diagnoses with more accuracy reduced kidney function in
patients with CHF, since these patients often have muscle wasting leading to a misclassification
of CKD stages with the use of creatinine for eGFR.33,34
Ultrasound imaging plays an relevant role in the diagnosis and management of CRS.35
Renal ultrasound may show the reduction of cortical thickness, corticomedullary ratio and
hyperechogenicity of the parenchyma. The echocardiogram, in turn, may show high volumes
or atrial areas such as volume overload, normal or reduced ejection fraction (EF), right
chambers dilation and increased pulmonary artery pressure, pericardial effusion, and valvular
disease (calcific disease).4,10
If dysfunction in one organ can quickly lead to distant and harmful effects in the other,
it seems natural that early acknowledgment provides the best chance for opportune intervention
to ease or avoid the cycle of cardiac and renal co-dysfunction.1 There are indeed indications
24
that these patients may have ongoing kidney damage with constitutive release of biomarkers of
renal injury as for example, KIM-1, NAG and Cystatin C, uncoupled from loss of renal
function.36 In this regard, new renal biomarkers such as NGAL and those mentioned above
(Table 8) were studied in patients with CHF and in many but not all studies, levels of these
biomarkers were increased even if at modest levels in CHF compared to control subjects.28
Tubular damage evaluated by urinary markers such as NAG, NGAL, and KIM-1 is frequently
present among patients with chronic HF and highly associated with mortality.37 Unfortunately,
most are investigational instruments being evaluated for clinical usefulness.38
Table. 8 Cardiac and renal biomarkers of cardiorenal syndrome.
Cardiac biomarkers
Natriuretic
peptides
- The ability of BNP to predict the outcome of patients with CKD has been investigated in
different studies, and in many of them there has been a positive association between high levels
of BNP and mortality (total and cardiovascular) and progression of renal disease (HR of 1.38
95% CI 1.09 –1.76), and a even stronger association for NT-proBNP (HR of 2.28 CI 1.76 –
2.95).1,38,39 Moreover, there is evidence that increased levels of NT-proBNP are predictive of
subsequent death in pre-dialysis CKD patients (HR 9.6, P < 0.007).1,40
- Although valuable in the diagnosis of CHF, BNP and NT-proBNP are partially excreted by
the kidneys thus decreasing its specificity as a marker of CHF.18
Cardiac
troponins
- These markers can identify subclinical myocardial injury.41
- Current studies enrolled relatively small groups of patients and excluded patients with severe
CKD, so the troponin clinical significance in patients with HF and severe CKD is not fully
elucidated, but there are data to suggest that elevated levels of cTns may predict death among
ESRD patients without symptoms of ACS.31
- The troponin elevation may be justified by glomerular filtration reduction.41,42
Galectin-3
- This b-galactoside-binding lectin plays an relevant regulatory role in cardiac fibrosis and
remodeling.38,43
- It also has been implicated in the development of fibrosis in the liver, and together with TGF-
b, these are the mediators prominently involved in kidney fibrosis. 38,43
- Galectin-3 concentrations may be associated with severity of left ventricular impairment and
renal dysfunction.38
25
Tabela 8. Continued.
Renal biomarkers
Cystatin C
- An early marker of impaired glomerular filtration instead of tubular lesion.42,44 - Serum levels of Cystatin C may represent a more accurate test of renal function than sCr levels.9 - An independent predictor of death, cardiac transplantation and hospitalization for HF (HR 2.27, 95% CI 1.12-4.63).28,45 It was also correlated with the levels of NT-pro-BNP and measures of LV dysfunction.28,46
KIM-1 - Kidney
injury molecule 1
- Quantified in the urine after an ischemic or nephrotoxic insult to the proximal tubular cells,9 and so it is a early marker of proximal tubular damage and useful in early detection of acute kidney injury, especially in CHF.17 - Urine levels are elevated in symptomatic HF versus controls,28 and in CHF they were the best predictors of worsening renal function.37 - CHF patients show higher levels even with normal kidney function.34
NAG- N-acetyl-beta-
D-glucosaminidase
- A sensitive marker of acute renal impairment or renal dysfunction worsening.17 - Increases significantly in congestive HF, with an important prognostic role independent from the glomerular filtration rate.28,42,47 - This protein is also raised in HF patients with preserved renal function.34
Neutrophil-associated
lipocalin gelatinase
(NGAL)
- Involved in immune modulation, inflammation and neoplastic transformation.38 It is expressed at reduced levels in various human tissues including kidney, lung, stomach and colon.9 - NGAL expression is prominently increased in epithelial cells that have suffered injury - for example, in the renal tubular epithelium after any type of insult or stress, in the myocardium in failure, in myocarditis and also in atherosclerotic plaques.9,28 - The increase in serum NGAL levels occurs prior to sCr, and still correlates with the degree of renal tubular injury.9 - Serum and urine NGAL may be sensitive early markers of renal dysfunction in patients with CHF and normal sCr but reduced eGFR.41 - In some clinical studies, NGAL blood and urine levels in general also correlated with clinical and biochemical markers of HF severity,28 and recently a study demonstrates that plasma NGAL predicts mortality in patients with HF, both in patients with and without CKD.48 - Serum NGAL is not substantially correlated with EF or NYHA functional class or with other biomarkers like urinary KIM-1 and NAG.34
Albuminuria
- Micro- and macro-albuminuria are present in 20–30% and 5–10%, respectively, of the patients with HF.44 - Albuminuria, evaluated as the albumin-to-creatinine ratio in urine, is an recognized criterion for the diagnosis of CKD.44 - Correlations between reduced renal blood flow and albuminuria, elevated NT-proBNP levels and physical exam findings of volume overload have been proven, suggesting potential participation of arterial underfilling and venous congestion in the mechanism of albuminuria in HF.34 - It has been associated with an augmented risk of death that persists significant after adjustment for renal function or diabetes.44
26
Blood Urea Nitrogen
to Creatinine Ratio
(BUN/Cr)
- BUN/Cr has been broadly used clinically to differentiate intrinsic kidney disease from pre-renal renal dysfunction, so that it offers supplementary diagnostic and prognostic value in CRS.34 - Renal clearance of urea is determined by the quantity filtered and the degree of tubular reabsorption. Decreased GFR resulting from any etiology can lead to reduced urea filtration. On the other hand, the tubular reabsorption of urea is mainly influenced by neurohormonal activation with increases in angiotensin II and vasopressin leading to higher urea concentration in the proximal tubule and increased urea transporters in the collecting duct respectively, thereby boosting absorption.34,49 - In HF, with increased neurohormonal activation, the BUN is elevated disproportionately to serum creatinine on the contrary of intrinsic kidney disease, where filtration may be decreased, but tubular reabsorption of urea is preserved producing a lower BUN/Cr.34
ACS: acute coronary syndrome; BNP: Brain-Type Natriuretic Peptide; CAD: coronary artery disease; CHF:
chronic heart failure; CKD: chronic kidney disease; CRS: cardiorenal syndrome; cTns: cardiac troponins; EF:
ejection fraction; ESRD: end-stage renal disease; eGFR: estimated glomerular filtration rate; HR: hazard ratio;
LV: left ventricular; NT-proBNP: NT-pro-brain natriuretic peptide; sCr: serum creatinine, TGF-b: transforming
growth factor beta.
27
Pathophysiology of Cardiorenal Syndrome Type 2
In CRS2, the pathogenic mechanisms by which cardiac dysfunction triggers renal
dysfunction de novo or provoke the harmful progression of a pre-existing CKD is not so clear.
Indeed, in this case, worsening of renal function occurs in patients who are unaffected by
clinical signs and symptoms of hemodynamic imbalance (CRS2 patients do not have acute
decompensated HF by definition). Potential mechanisms involved, namely hemodynamic
factors, neurohormonal activation, oxidative stress, inflammation and anemia, which will be
detailed below, but overall it is supposed the underlying mechanisms of HF, co-morbidities
and/or their treatment affect renal function with subsequent development of renal failure (Figure
4).
Figure 4 Pathophysiology of chronic cardiorenal syndrome (type 2).
CO: cardiac output; RAAS: renin-angiotensin-aldosterone system
Adapted from Cruz et al. (2013)28 and KDIGO 2012.22
Cardio-Renal Syndrome Type 1LCOS and Congestion
Acute Kidney Injury
Acute Heart
Disease
• Upon initial recognition, AKI induced by primary cardiac dysfunctionimplies inadequate renal perfusion until proven otherwise. This shouldprompt clinicians to consider the diagnosis of a low cardiac output state(LCOS) and/or marked increase in venous pressure leading to kidneycongestion.• It is important to remember that central venous pressure translated to therenal veins is a product of right heart function, blood volume, and venouscapacitance which is largely regulated by neuro-hormonal systems.• Specific regulatory and counter-regulatory mechanisms are activated withvariable effects depending on the duration and the intensity of the insult.
• Inflammatory pathways • Arterial underfilling • Decreased CO and effective
circulating volume • Chronic neurohormonal activation
(RAAS and sympathetic tone) • Chronic venous congestion • Systemic inflammation
• Chronic renal hypoperfusion
• Tubular fibrosis • Tubular atrophy • Glomerulosclerosis
Chronic worsening of renal function
Chronic cardiac
dysfunction
Type 2 CRS
28
1) Hemodynamic Factors
Decreased glomerular filtration rate may be the result of reduced cardiac output in
HFrEF, but in HFpEF, in addition to decreased cardiac output as a result of increased filling
pressures, elevation of venous pressure is a relevant alternate cause of worsening renal function
in these patients.50-53 Thus, chronic HF is more likely to be illustrated by a long-standing renal
venous congestion and reduced renal perfusion, often predisposed by macro and microvascular
disease in the context of the same risk factors linked to cardiovascular disease.9,54
Although a large fraction of patients with a low eGFR have a more severe NYHA
functional class, the association between LVEF and eGFR has not been consistently proven.
Hence, patients with HFpEF appear to have an eGFR similar to patients with HFrEF.3,55-57 But
not all patients with HF and decreased renal function have hypotension or reduction in cardiac
output, and many patients with hypotension do not have reduced renal function, and even
increasing cardiac output does not necessarily improve renal outcomes.58
The prospective ESCAPE study did not demonstrate an association between cardiac
index and baseline renal function. The only relationship found was with increased pressure in
the right atrium, suggesting that renal congestion may be an important factor of renal
dysfunction that should be considered.59,60
Signs and symptoms of congestion, including increased jugular venous pressure, ascites,
peripheral edema, and orthopnea are often found and associated with decreased renal function
in patients with CHF.61,62 The most plausible explanation for the impact of venous congestion
on renal function is that increased renal venous pressure (renal perfusion pressure is calculated
by subtracting central venous pressure at mean arterial pressure) decreases the arterio-venous
pressure gradient in the kidney, and reduces the already compromised renal blood flow, causing
a decline in eGFR. As the kidneys have a tight renal capsule, an increase in venous pressure
may likely to increase renal interstitial pressure, which affects the entire capillary bed and
29
tubules, and possibly inducing local hypoxia,63 but since intratubular pressure is one of the
driving forces of glomerular filtration, any increase in intratubular pressure may oppose
glomerular filtration and decrease eGFR.64
Right ventricular dilation and dysfunction may also adversely affect renal function
through elevated venous pressure as well as compromising left ventricular filling, and
consequently, the forward output.5,58
Redirecting of blood from the medullary areas of the kidney in states of compromising
renal blood flow may cause hypoxic lesion of the highly metabolic renal tubular cells. The
hypoxic tubular lesion initiates a progressive loss of nephrons and gradual renal failure.
Microalbuminuria in HF patients may reflect early tubular damage that compromises the
absorption of albumin filtered by the damaged tubular cells.15 Furthermore, the reduction in
renal perfusion, coupled with atherosclerotic changes underlying possible comorbidities such
as diabetes mellitus and hypertension, may rapidly aggravate any pre-existing renal dysfunction
in this particular population.61
2) Neurohormonal Activation, Oxidative stress and Inflammation
In HF, reduction of left ventricular systolic or diastolic function results in decreased
cardiac output, ejection volume, arterial bed underfilling, elevated atrial pressure and venous
congestion.5 The decrease in the effective intravascular blood volume verified in chronic HF is
sensed at the level of the high-pressure baroreceptors, which are found in the left ventricle,
carotid sinus and aortic arch.60,64,65 This results in an activation of the SNS, with increased heart
rate and peripheral and renal vascular resistance. Increased renal adrenergic tone stimulates
RAAS. The activation of the SNS also stimulates the supra-optic and paraventricular nuclei of
30
the hypothalamus, resulting in the non-osmotic release of ADH66 and in this point it is known
that higher plasma ADH concentration is associated with higher cardiovascular mortality at 1
year.67
The SNS is activated to maintain the decreased cardiac output in chronic HF,31 therefore
increasing the activation of the RAAS, but at the expense of producing reactive oxygen species
(ROS) and the activation of the immune system. Chronic stimulation of the SNS has a growth
promoting effect at the level of the intrarenal blood vessel wall, which has recently been
identified as being mediated, at least in part, by the production of ROS.31 Moreover, it has long
been known that the kidneys of patients with HF release considerable amounts of renin into the
circulation68 due to increased activity of the SNS in addition to decreased renal artery pressure,
increased renal venous pressure, and decreased delivery of sodium to the distal nephron.69 SNS
activation indirectly leads to congestion because it causes arterial and venous tachycardia and
vasoconstriction which rises afterload and decreases preload, leading to a reduction in LV
function and eventually to LV remodeling.65
The RAAS is also activated in CHF, as previously mentioned, and ANGII has multiple
adverse effects on the cardiovascular system in HF patients, through a significant effect on
peripheral and renal vascular resistance, and also having a contribution on the stimulation of
the SNS, promoting the release of noradrenaline at pre-synaptic level. ANGII is an important
mediator of myocardial hypertrophy and remodeling, and high plasma concentrations of this
neurohormone further contribute to the deposition of extracellular matrix and fibrosis in the
kidney.8 ANGII has an important vasoconstrictive effect on the afferent and efferent arterioles
(particularly in the efferent44 whereas noradrenaline acts primarily on the aferente arteriole15)
and a contractor effect of mesangial cells, resulting in a decrease in the glomerular filtration
area, and consequently an increase in the retention of water and sodium.66 ANGII plays a role
in the regulation of the number and integrity of podocytes and may promote their detachment
31
and shedding as intraglomerular pressure increases due to its preponderant effect on efferent
arterioles.70 In addition to its (de)regulation of extracellular volume and vasoconstriction, one
of the most deleterious effects of angiotensin on CRS2 results from the activation of NADPH
oxidase in endothelial cells, renal tubules and cardiomyocytes, with consequent formation of
free radicals.31,57,71,72 As it potentiates modifications in the cellular redox state, ANGII is
implicated in vascular inflammation through the nuclear factor kappa B (NF-kB), which
induces the production of adhesion and chemotactic molecules.72,73 Hence, ANGII has been
shown to play an important role in the synthesis of proinflammatory cytokines in the kidney,
regulation of cell proliferation, fibrosis and apoptosis as well as vascular and myocardial
hypertrophy and endothelial dysfunction.49,66 Besides participating in the same activation
processes mediated by ANGII, high levels of serum aldosterone stimulate overexpression of
TGF-b and fibronectin production, leading to renal fibrosis and glomerulosclerosis.4,56
Endothelin represents one of the most potent vasoconstrictors and its increase in HF contributes
to vasoconstriction, particularly in the renal circulation,65 and also for renal inflammation and
fibrosis.56
In experimental studies in HF, a reduction in glomerular plasma flow was observed
along with eGFR (efferent arteriolar constriction); if these changes persist, focal and segmental
glomerulosclerosis can ensue, often associated to local renal increase in SNS activity and RAAS
activation.4,74
Recently, Kamal et al. (2017)75 have investigated the role of chronic stimulation of G
protein-coupled receptors (GPCRs), including adrenergic and endothelin receptors, and their
work suggest that GPCR-Gbg inhibition can be a future promising therapeutic approach on
preventing the heart and kidney damage in the setting of CRS2.
Natriuretic peptides are increased in HF and promote natriuresis, vasodilation, and
inhibition of the SNS and the RAAS, effects that even being beneficial are not effective in HF
32
patients. There is evidence to suggest that there is resistance to the effects of natriuretic peptides
as CHF worsens.76 There are several explanations for this phenomenon: down-regulation of
renal natriuretic peptide receptors; secretion of inactive precursor peptides; increased
endopeptidase activity, which restricts the delivery of natriuretic peptides to the distal nephron
level; increase of sodium reabsorption at the proximal level, decreasing its concentration in the
distal nephron, the local of activity of natriuretic peptides.66
Nitric oxide (NO) is produced from L-arginine under the coordination of the enzyme
nitric oxide synthase and has great importance in renal control of extracellular volume and
blood pressure since it induces vasodilation, natriuresis and desensitisation of tubuloglomerular
feedback.5,31 Superoxide has an contrary influence on extracellular volume control conditioning
an increase in blood pressure, and it can inactivate NO, and consequently generating
peroxynitrite and decreasing NO activity.77 In CRS2, it has been proposed that the impairment
of the L-arginine-nitric oxide pathway secondary to anomalous neurohormonal activation, the
physiological balance between NO and ROS is altered, with increased levels of ROS resulting
in low bioavailability of NO,31,60,69,77 which might have a significant responsibility in the
progression of CRS2 (Figure 5). Endothelial cells release NO in response to laminar shear
stress. Accordingly, a plausible mechanism of endothelial dysfunction in HF may be the lower
shear stress secondary to pump failure in HF. Shear stress also depends on blood viscosity and
consequently it is reduced when there is a decrease in hemoglobin concentration.5
33
Figure 5 L-arginine - NO pathway and its influence on Cardiorenal Syndrome Type 2.
L-arginine is the substrate for NO synthesis. Transmembrane transport of L-arginine in endothelial cells is mainly
intermediated through CAT-1, located in the plasma membrane of endothelial cells. CAT-1 also seems to be the
major L-arginine transporter expressed in the kidney and it is mostly concentrated in the inner medullary collecting
duct. According to published evidence, renal NO bioavailability is dependent on L-arginine transport and its
bioavailability is essential for regulation of normal renal vascular and tubular function. Chronic activation of the
SNS and the RAAS present in CHF and CKD may be responsible for chronic elevations in oxidative stress which
can impair L-arginine transport. Furthermore, additional factors for the low availability of NO are reduced eNOS
expression and uncoupling and elevated levels of inhibitors, such as ADMA, which along with marked breakdown
of NO due to high ROS levels create a vicious cycle of damage affecting concurrently the heart and kidney. L-
Intracellular
L-Arginine
pools
Endothelial Cell
CHF CKD
Chronic activation of the RAAS Chronic activation of the SNS
Endothelial dysfunction
Oxidative stress
CAT-1 eNOS
L-Arg
L-Arg NO
ADMA Inhibits eNOS
Extracellular space
Reduces L-Arg transport and uncouples eNOS
Buffers the activation of
the RAAS
34
arginine transport is a conceivable novel therapeutic target in CRS2 once enhancing L-arginine transport can
mitigate the activation of the RAAS and decrease oxidative stress.
ADMA: asymmetric dimethylarginine; CAT-1: cationic amino acid transporter-1; eNOS: Endothelial nitric oxide
synthase; L-Arg: L-arginine; NO: nitric oxide; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic
nervous system.
Adapted from Rajapakse et al. (2016).71
Oxidative stress is a major enhancer of inflammation, with increased synthesis of
proinflammatory cytokines namely IL-1, IL-6 and TNF-alpha, with the latter being also
increased by the elevated venous congestion and cardiac myocytes under the stress of
mechanical stretch or ischemia.28,64,73,78 The venous stasis and arteriolar vasoconstriction can
result in intestinal ischemia due to altered intestinal permeability79 and release of endotoxins
from gut bacteria, activating the immune system.80 The chronic inflammation ensued might
cause progressive toxic injury and renal cell apoptosis, which causes permanent kidney damage
and loss of kidney function. This inflammatory mechanism in the setting of high venous
pressure is described as a prime path of kidney function impairment specially in patients with
chronic cardiac dysfunction and preserved left ventricular systolic function.74,81
Following the initial insult, the impaired kidney undertakes a series of events, such as
fibroblast activation, in an effort to repair and recover from the injury. Accumulated renal
collagen is cross-linked and resilient to breakdown, which inevitably ends in loss of function
when normal tissue is supplanted with scar tissue. Consequently, renal fibrosis leads to renal
changes as glomerulosclerosis, tubulointerstitial fibrosis and tubular atrophy.
Glomerulosclerosis result in the obstruction of the capillary loops and eventually lead to loss of
glomerular function.78
35
3) Anemia
Anemia, CHF and CKD interrelate in a vicious circle to cause or aggravate each other.78
Overall, most studies in this matter estimate that the prevalence of anemia in the HF population
is greater than 20%82 and is associated with increased morbidity and mortality (Figure 6).71,82
Figure 6 Estimates of hazard ratio (with 95% CI) for all-cause mortality associated with a decrease in hemoglobin
of 1g/dL. Decreased hemoglobin in patients with CHF has been recurrently shown to be independently associated
with increased risk of hospitalization and all-cause mortality. Various studies have shown that a 1g/dL decline in
hemoglobin was independently associated with appreciably augmented mortality risk.
Taken and adapted from Tang and Katz (2006).83
Multiple etiologies have been proposed, considering that it is not only the result of
associated CKD, with increasing attention being given to the hostile effects of inflammatory
markers on erythropoiesis and iron metabolism.44 Hepcidin, which production increases with
inflammation, may contribute to the anemia observed in HF, due to the activation of
inflammatory pathways in this condition.5 However, the cause that may bring more insight to
the pathophysiology is resistance to erythropoietin. Indeed, patients with congestive heart
failure typically have elevated EPO plasma levels but are disproportionately low for the degree
of anemia compared to patients with ESRD who are functionally anephric and with absolute
of severe anemia on blood viscosity, oxygen tension in themicrovasculature, and nitric oxide availability.44,45 Lesserdegrees of anemia may contribute to neurohormonal activa-tion and disease progression in patients with CHF.46 Inpatients with !-thalassemia syndromes, heart failure is acommon complication that is likely mediated by the hemo-dynamic and neurohormonal effects of severe chronic anemiaand iron overload secondary to chronic transfusion require-ments.47 Aggressive iron chelation therapy greatly reducesbut does not eliminate the risk of heart failure in thesepatients.
Hemoglobin content in blood is an important determinantof oxygen delivery to skeletal muscle during exercise. Pa-tients with CHF lack normal physiological reserve to com-pensate for decreased hemoglobin and may manifest de-creased aerobic capacity in response to mild degrees ofanemia.48 Several investigators have reported associationbetween reduced hemoglobin and greater functional impair-ment as defined by New York Heart Association classifica-tion.3,15,49 Kalra and colleagues50 reported a linear relationbetween reduced hemoglobin values and peak oxygen con-sumption in anemic patients with CHF with hemoglobin!13.0 g/dL.
Cardiac mass increased by 25% in a rat model of chronicanemia.51 An inverse relation between hemoglobin value orhematocrit value and left ventricular hypertrophy has alsodescribed in clinical studies of patients with dialysis-dependent and predialysis chronic kidney disease.52 In asubgroup of patients with CHF enrolled in the RandomizedEtanercept North American Strategy to Study Antagonism ofCytokines (RENAISSANCE) trial with available cardiacMRI data, a 1-g/dL increase in hemoglobin was associatedwith a 4.1-g/m2 decrease in left ventricular mass over 24weeks.49 This observation was independent of study drugtreatment and does not provide evidence of a causal relationbetween changes in hemoglobin levels and changes in leftventricular mass. In two randomized trials of patients withchronic kidney disease, increased hemoglobin in response toerythropoietic agents was not associated with reduction in leftventricular hypertrophy.53,54
Anemia and Clinical OutcomesReduced hemoglobin in patients with CHF has been repeatedlyshown to be independently associated with increased risk ofhospitalization and all-cause mortality.2–6,8,9,11–13,15,19,42,49 Thesefindings in a diverse array of CHF populations are remarkablyconcordant and generally suggest a linear association betweenreduced hemoglobin and increased mortality risk. In studies thatanalyzed hemoglobin as a continuous variable, a 1-g/dL de-crease in hemoglobin was independently associated with signif-icantly increased mortality risk (Figure 2). The potential mech-anisms linking anemia to increased mortality risk in CHF havenot been characterized but may be related to changes in ventric-ular loading conditions and cardiac structure, altered neurohor-monal activation, or reduced free radical scavenging capacity. Itis also possible that anemia is a marker of more severeunderlying myocardial disease.
Treatment ApproachesThe clinical utility of blood transfusion in anemic cardiovas-cular disease populations is controversial. According to theguidelines from the American College of Physicians and theAmerican Society of Anesthesiology, the “transfusion thresh-old” for patients without known risk factors for cardiacdisease is a hemoglobin level in the range of 6 to 8 g/dL.55 In78 974 elderly patients hospitalized with acute myocardialinfarction, blood transfusion was associated with a signifi-cantly lower 30-day mortality rate among patients with ahematocrit "30% on admission.56 In 838 critically ill patients(26% with cardiovascular disease), maintaining hemoglobinat 10 to 12 g/dL did not provide additional benefits on 30-daymortality compared with maintaining hemoglobin at 7 to 9g/dL.57 Blood transfusion may be associated with otheradverse effects including immunosuppression with increasedrisk of infection, sensitization to HLA antigens, and ironoverload.58,59 Given this profile of risks and benefits, trans-fusion may be considered as an acute treatment for severeanemia on an individualized basis but does not appear to bea viable therapeutic strategy for the long-term management ofchronic anemia in CHF.
Although erythropoietin levels are modestly elevated inpatients with CHF, the increase is less than that observed inother anemic populations.27,38,60 Accordingly, anemia in CHFmay be responsive to exogenous erythropoietin supplemen-tation. The primary mechanism by which erythropoietinstimulates red blood cell production is inhibition of apoptosisof bone marrow erythrocyte progenitors.23 The erythropoietinreceptor is a member of the cytokine class I receptorsuperfamily.61 Ligand binding of erythropoietin to the ho-modimeric erythropoietin receptor activates antiapoptotic sig-nal transduction pathways.23,62 Bone marrow erythroid pro-genitor cells escape from apoptosis and proliferate to result in
Figure 2. Estimates of hazard ratio (with 95% CI) for all-causemortality associated with a decrease in hemoglobin of 1 g/dL.Estimates are derived from Cox proportional hazards modelswith adjustment for potential confounding variables. For studieswith first author Al-Ahmad, Kosiborod and Mozaffarian, esti-mates of hazard ratio were derived from published data assum-ing a 1 g/dL decrease in hemoglobin is equivalent to a 3%decrease in hematocrit. The analysis by Mozaffarian includedsubjects with hematocrit "37.5%. Anand and colleagues didnot report confidence intervals for their estimate of risk. Mag-gione and colleagues reported estimates of risk from 2 studypopulations enrolled in the IN-CHF registry and the Val-HeFTclinical trial.
2456 Circulation May 23, 2006
at University of Illinois at Chicago Library on February 7, 2015http://circ.ahajournals.org/Downloaded from
of severe anemia on blood viscosity, oxygen tension in themicrovasculature, and nitric oxide availability.44,45 Lesserdegrees of anemia may contribute to neurohormonal activa-tion and disease progression in patients with CHF.46 Inpatients with !-thalassemia syndromes, heart failure is acommon complication that is likely mediated by the hemo-dynamic and neurohormonal effects of severe chronic anemiaand iron overload secondary to chronic transfusion require-ments.47 Aggressive iron chelation therapy greatly reducesbut does not eliminate the risk of heart failure in thesepatients.
Hemoglobin content in blood is an important determinantof oxygen delivery to skeletal muscle during exercise. Pa-tients with CHF lack normal physiological reserve to com-pensate for decreased hemoglobin and may manifest de-creased aerobic capacity in response to mild degrees ofanemia.48 Several investigators have reported associationbetween reduced hemoglobin and greater functional impair-ment as defined by New York Heart Association classifica-tion.3,15,49 Kalra and colleagues50 reported a linear relationbetween reduced hemoglobin values and peak oxygen con-sumption in anemic patients with CHF with hemoglobin!13.0 g/dL.
Cardiac mass increased by 25% in a rat model of chronicanemia.51 An inverse relation between hemoglobin value orhematocrit value and left ventricular hypertrophy has alsodescribed in clinical studies of patients with dialysis-dependent and predialysis chronic kidney disease.52 In asubgroup of patients with CHF enrolled in the RandomizedEtanercept North American Strategy to Study Antagonism ofCytokines (RENAISSANCE) trial with available cardiacMRI data, a 1-g/dL increase in hemoglobin was associatedwith a 4.1-g/m2 decrease in left ventricular mass over 24weeks.49 This observation was independent of study drugtreatment and does not provide evidence of a causal relationbetween changes in hemoglobin levels and changes in leftventricular mass. In two randomized trials of patients withchronic kidney disease, increased hemoglobin in response toerythropoietic agents was not associated with reduction in leftventricular hypertrophy.53,54
Anemia and Clinical OutcomesReduced hemoglobin in patients with CHF has been repeatedlyshown to be independently associated with increased risk ofhospitalization and all-cause mortality.2–6,8,9,11–13,15,19,42,49 Thesefindings in a diverse array of CHF populations are remarkablyconcordant and generally suggest a linear association betweenreduced hemoglobin and increased mortality risk. In studies thatanalyzed hemoglobin as a continuous variable, a 1-g/dL de-crease in hemoglobin was independently associated with signif-icantly increased mortality risk (Figure 2). The potential mech-anisms linking anemia to increased mortality risk in CHF havenot been characterized but may be related to changes in ventric-ular loading conditions and cardiac structure, altered neurohor-monal activation, or reduced free radical scavenging capacity. Itis also possible that anemia is a marker of more severeunderlying myocardial disease.
Treatment ApproachesThe clinical utility of blood transfusion in anemic cardiovas-cular disease populations is controversial. According to theguidelines from the American College of Physicians and theAmerican Society of Anesthesiology, the “transfusion thresh-old” for patients without known risk factors for cardiacdisease is a hemoglobin level in the range of 6 to 8 g/dL.55 In78 974 elderly patients hospitalized with acute myocardialinfarction, blood transfusion was associated with a signifi-cantly lower 30-day mortality rate among patients with ahematocrit "30% on admission.56 In 838 critically ill patients(26% with cardiovascular disease), maintaining hemoglobinat 10 to 12 g/dL did not provide additional benefits on 30-daymortality compared with maintaining hemoglobin at 7 to 9g/dL.57 Blood transfusion may be associated with otheradverse effects including immunosuppression with increasedrisk of infection, sensitization to HLA antigens, and ironoverload.58,59 Given this profile of risks and benefits, trans-fusion may be considered as an acute treatment for severeanemia on an individualized basis but does not appear to bea viable therapeutic strategy for the long-term management ofchronic anemia in CHF.
Although erythropoietin levels are modestly elevated inpatients with CHF, the increase is less than that observed inother anemic populations.27,38,60 Accordingly, anemia in CHFmay be responsive to exogenous erythropoietin supplemen-tation. The primary mechanism by which erythropoietinstimulates red blood cell production is inhibition of apoptosisof bone marrow erythrocyte progenitors.23 The erythropoietinreceptor is a member of the cytokine class I receptorsuperfamily.61 Ligand binding of erythropoietin to the ho-modimeric erythropoietin receptor activates antiapoptotic sig-nal transduction pathways.23,62 Bone marrow erythroid pro-genitor cells escape from apoptosis and proliferate to result in
Figure 2. Estimates of hazard ratio (with 95% CI) for all-causemortality associated with a decrease in hemoglobin of 1 g/dL.Estimates are derived from Cox proportional hazards modelswith adjustment for potential confounding variables. For studieswith first author Al-Ahmad, Kosiborod and Mozaffarian, esti-mates of hazard ratio were derived from published data assum-ing a 1 g/dL decrease in hemoglobin is equivalent to a 3%decrease in hematocrit. The analysis by Mozaffarian includedsubjects with hematocrit "37.5%. Anand and colleagues didnot report confidence intervals for their estimate of risk. Mag-gione and colleagues reported estimates of risk from 2 studypopulations enrolled in the IN-CHF registry and the Val-HeFTclinical trial.
2456 Circulation May 23, 2006
at University of Illinois at Chicago Library on February 7, 2015http://circ.ahajournals.org/Downloaded from
36
deficiency of EPO.82 The loss of sensitivity to EPO is thought to be mediated by chronic
inflammation.44,82 Hemodilution due to excessive venous congestion and gastrointestinal tract
edema that causes malabsorption and/or malnutrition are other possible etiologies of anemia.56
Anemia may affect oxygen supply to the tubular cells producing chronic ischemia,
activation of renal interstitial fibroblasts and, ultimately, nephron loss and kidney damage.56 On
the other hand, as previously explained, anemia may be a cooperative factor for endothelial
dysfunction through reduction of shear stress, and contribute to worsening of cardiac and renal
function.5
4) Impact of Pharmacotherapy for the Management of Heart Failure
Pharmacological management of HF may have potential negative consequences on renal
function.67 Hypovolemia associated with diuretics, the early introduction of RAAS blockade
and iatrogenic hypotension have long been considered contributing factors to the genesis and
aggravation of CRS2.9
Patients with CHF often require higher dosages of loop diuretics to achieve comparable
sodium excretion given the attenuation of maximal response.9 This is the so-called "resistance
to diuretics", which eventually leads to harmful therapeutic approaches, due to excessive dose
increases of diuretics, which induce several detrimental phenomena such as exaggerated
stimulation of the tubule-glomerular feedback mechanism and activation of RAAS, a
subsequent reactive vasoconstriction of renal afferent arterioles and eGFR decrease, and
ultimately the elevation of sCr.9,57,84 This relatively weak response to loop diuretics is further
aggravated in the case of prolonged therapy with oral diuretics (ie, months to years), as it causes
hypertrophy of the distal tubular cells, which increases the reuptake of sodium, counteracting
37
the effect of diuretics.9,61 The cause of diuretic resistance is thought to be multifactorial:
inadequate dosing of diuretic, increased sodium intake, lower intestinal absorption of drugs,
decreased tubular secretion of diuretics, renal hypoperfusion, and the use of non-steroidal anti-
inflammatory drugs (NSAIDs).61 Resistance to diuretics can be plausibly suspected when urine
output is relatively weak (e.g. <1000mL per day), despite the maximum tolerated oral dose of
a loop diuretic (e.g. 250mg furosemide per day), along with the presence of signs and symptoms
of refractory hydrosaline retention.9,57,80
Another aspect to consider is the use of the combination of e.v. loop diuretics with
RAAS inhibitors (i.e., ACEIs and / or ARBs) in patients with chronic HF. The use of high doses
of e.v. loop diuretics in patients with chronic HF whose signs and symptoms are adequately
controlled should be promptly discouraged due to potential side effects (hypokalemia,
hypotension, neurohormonal activation and renal impairment).84 Renal dysfunction induced by
loop diuretics may be aggravated by the therapeutic implementation of an ACEI or ARB in full
dose, since ANGII blockade compromises the constricting tone of the glomerular efferent
arterioles in association with the excessive decline in the effective intravascular volume caused
by the diuretic e.v., with reduction of the eGFR, and an acute increase in the level of sCr.85
Thus, the resulting pharmacological actions are sufficient to trigger tubular dysfunction and
activation of the tubule-glomerular feedback, resulting in sustained decrease of intra-glomerular
pressure. Thereby, although the combination therapy of loop diuretics with high dose RAAS
blockers is capable of improving congestion in chronic HF, it may also be responsible for
decreasing renal flow and lowering the glomerular filtration fraction with deleterious effect on
the eGFR.9
In this way, iatrogenic influences can respond to renal damage as well as congestive
nephropathy itself. However, it should be noted that ACEIs, by altering intra-renal
hemodynamics and reducing the fraction of filtration, represent a nephroprotective mechanism
38
in the case of diabetic nephropathy, hypertension, chronic inflammatory diseases of the
glomeruli or in any nephropathy with albuminuria, but the reduction of the glomerular filtration
fraction related to ACEIs loses any meaning of renal protection in the circumstance of a reduced
renal flow due to the pathological decrease in the kidney perfusion gradient (ie, chronic
congestive nephropathy typical of chronic HF). Analogously, any drug-induced reduction in
filtration fraction is certainly detrimental in patients with chronic HF with marked decrease in
effective intravascular volume after excessive treatment for hemodynamic congestion, as it can
be seen in those who become relatively hypovolemic after high dose diuretic treatment.9
Treatment Considerations in Cardiorenal Syndrome Type 2
Unfortunately, there is little evidence of clinical trials in HF regarding the therapy of
patients with HF and significant renal dysfunction, since in these studies the predominantly
recruited population had relatively preserved renal function. As a result, the management of
CRS2 is largely empirical and fragmented.21 Accurate HF treatment is essential to reduce or
eliminate the causes that led to the appearance/progression of renal dysfunction.
Common principles in the management of these patients include regular measurement
of body weight, noninvasive hemodynamic monitoring, fluid restriction (1-1.5L/day), dosage
adjustment or even avoidance of nephrotoxic drugs71 and the treatment of hypertension,
dyslipidemia and diabetes.86 In CHF renal blood flow and the glomerular filtration rate are
already lowered and, therefore, NSAIDs can increase the risk of worsening CHF and CKD.87
During initiation of any new therapy, patients with renal impairment should have a frequent
assessment of electrolytes, urea and creatinine.71 Regarding diet, patients with renal disease
should make moderate restrictions on protein, potassium, phosphorus and magnesium, but
39
avoiding malnutrion.86 Pharmacological treatment and other strategies used in the management
of or under investigation in CRS type 2 are listed on table 9.
Table 9. Pharmacological agents and other strategies used in the management of or under investigation for the treatment of patients with chronic cardiorenal syndrome (CRS type 2).
Drug classes Intended action and effects Side effects and problems
ACE inhibitors and ARBs
- Reduce morbidity. - Prevent cardiac remodeling. - There is evidence that ACEIs may have renoprotective effects even in the context of impaired renal function.61 - The beneficial hemodynamic effects of ACEIs and ARBs in the renal circulation together with their anti-inflammatory, antifibrotic effects and antiproteinuric, reduce the rate of progression of renal disease.15 - ARBs as a second choice only in patients intolerant to ACEI.
- Monitor kidney function and electrolytes, worsening kidney function. - Hypotension, hyperkalemia.67 - Many of the large studies on ACEIs excluded the population of interest - patients with chronic HF and impaired renal function.88 - High increases in creatinine or decompensated renal function during treatment should raise suspicion of renal perfusion compromise, and also taking into account the possibilities of renal artery stenosis, a low circulating volume or an intercurrent disease.15 - According to the guidelines of the European Society of Cardiology for HF, it is reasonable to accept a 50% increase in serum creatinine or absolute levels of 3mg/dL, while an increase of 3-3.5mg / dL requires a 50% dose reduction.55 - ACEIs are eliminated primarily by the kidneys, so lower doses should be used initially. ARBs are mainly metabolised in the liver and initial dose adjustment is not always mandatory.15
Beta-blockers
- Reduce morbidity. - Control of hypertension and arrhythmias, anti-ischemic effect, prevent remodeling, favorable renal effects (carvedilol).67 - The beneficial effects of carvedilol and nebivolol were analogous in patients with HF with CKD and in patients with HF with normal renal function, without being associated with weight gain, diabetes mellitus and atherogenic dyslipidemia.16 - However, carvedilol was associated with a transient increase in sCr in
- Hypotension, bradyarrhythmias. - Deterioration in heart failure symptoms (transient). - Asthma. - Although definitive assumptions cannot be made for patients with HF and severe renal dysfunction, the b-blockers are likely to improve the outcome of these patients.15
40
CKD patients4,71 and nevibolol did not alter eGFR.89 - Bisoprolol, a b1-adrenergic antagonist, showed benefits in CKD stage III compared to the placebo group, with no increase in sCr levels. - Metoprolol had a better effect in patients with eGFR <45ml/min/1.73m2. 15
Mineralocorticoid Receptor Antagonists
- MRAs reduce mortality in patients with advanced HF and in post-infarction patients with adequate renal function.55 - MRAs have a renal and cardiac protective potential since aldosterone promotes inflammation and fibrosis in both organs.15 - There is convincing evidence that treatment with MRAs in HF with moderate renal dysfunction is beneficial.15
- MRAs have been contraindicated in patients with moderate to severe renal impairment because they can cause life-threatening hyperkalemia and worsening of renal impairment, specially in patients treated with ACEIs, ARBs, and decreased eGFR.15
Diuretics
- The mainstay of treatment for CRS2.90 - Control of diuresis and extracellular fluid volume.67 - Symptoms relief, namely orthopnea, paroxysmal nocturnal dyspnea and peripheral edema.55
- Volume depletion, hypotension, worsening renal failure, hyperuricemia, potassium imbalance, activation or potentiation of neurohormonal responses.61 - Diuretic resistance.67 - To limit the neurohormonal upregulation associated with the isolated use of diuretic, it has been suggested the use of hypertonic saline,63 with faster relief of congestion, shorter hospitalization time, and reduced release of BNP and troponins.58 - In order to overcome "diuretic resistance", the clinician should change the diuretic regimen in the following ways: (1) joining thiazide diuretics with loop diuretics (to block increased distal sodium reabsorption); (2) preferentially adopting an endovenous administration for loop diuretics; (3) using continuous infusions of diuretics to avoid the occurrence of post-diuretic salt retention; and (4) considering the use of aldosterone receptor antagonists to relieve congestion and reduce the dose of diuretic.9
Hydralazine and nitrates
- Vasodilators can rapidly reduce systemic vascular resistance, ventricular filling pressures, and CVP. This, in turn, decreases
- Headache, dizziness, hypotension, tolerance.67,91
41
workload, improves cardiac output and ejection volume, and, more importantly, reduces myocardial oxygen consumption.71 - May improve survival and symptoms when ACEIs and ARBs cannot be given.18
Inotropes
- Use if very low CO, when vasodilator agents can not be administered because of low systemic vascular resistance or low systemic pressure.71 - Increase of RBF, decrease of SVR.67 - Bridge to cardiac transplantation.67
- Increase in myocardial injury, arrhythmias.92 - Hypotension and coronary hypoperfusion.67 - Increased mortality and adverse cardiac events in both acute and chronic HF.57
Endothelin antagonists
- Blockade of endothelin-1 mediated vasoconstriction.
-No changes in mortality. -Currently licensed only for pulmonary hypertension.
Adenosine A1-receptor antagonists
- Blockade of adenosine mediated glomerular vasoconstriction. - May improve symptoms and prevent deterioration in renal function.
-Rolofylline had no effects on long-term outcomes.
Erythropoiesis stimulating agents and
EPO
- ESA may improve exercise capacity in patients with anaemia.67,91 - Clinical studies in this field have pointed out that administration of EPO in patients with CHF, CKD and anemia could improve cardiac function, reduce left ventricular size and BNP levels.2,93 - Activation of EPO receptors in the heart could be one of the protective pathways against inflammation, apoptosis and fibrosis in this organ.3,88
- Possible increase in blood pressure and thrombogenicity with ESA.67,91 - No well-defined impact on mortality and morbidity in CHF.71
Vasopressin antagonists
- Correction of hyponatremia, wich is a marker of poor prognosis in HF and decrease of congestion and dyspnea.67,94 - In the USA, it is approved for patients with hypervolemic or euvolemic hyponatraemia.9 - In contrast, in Europe, it is only approved for the treatment of adult patients with hyponatremia secondary to SIADH.9
- No benefit on mortality and morbidity.67 - Thirst.67
Parenteral iron - Improves exercise capacity and quality of life in iron deficient patients.88,91
-Toxicity.67 -No clear impact on mortality and morbidity.
42
Allopurinol - Treat hyperuricaemia that holds an adverse prognosis in CHF.
- Haematologic and cutaneous toxicity. - Precipitation of gout.
Warfarin/antiplatelets
- Warfarin is more effective than aspirin in preventing thromboembolism and in heart failure patients in AF with reduced LVEF.
- Risk of bleeding. - Potential risk of vascular calcification.
Other drugs
- Ivabradine and digoxin are recommended in patients with HF with reduced EF.15 - The sacubitril-valsartan combination was studied more recently, and was superior to enalapril in reducing the risk of death and hospitalization in patients with HF. 36,60,63 As it inhibits neprisylin, it is expected to protect and improve renal function.15
- None of these have been studied in patients with severe renal impairment, and consequently precaution should be taken in their use in patients with renal impairment.15
Other strategies Intended action and effects Side effects and problems
Renal replacement therapy
-Renal replacement therapy improves renal responsiveness and cardiac hemodynamics, but is usually used as a palliative option in the end stages of cardiorenal syndrome and does not provide a long-term solution.92,95 - Ultrafiltration does not cause any macula densa-mediated neurohormonal activation, unlike diuretics, since the removal of fluids is obtained through a circuit that does not involve the urinary tract or renal chemoreceptor apparatus of the macula densa.9,57 - Presently, ultrafiltration is reserved for patients with chronic volume overload resistant to therapy.9 - Peritoneal dialysis is associated with a 48% lower risk of cardiac death during the first two years of treatment versus hemodialysis.86 Recent publications suggest a positive impact of starting PD in patients with CRS2 on the hospitalization rate, functional status and quality of life.96,97
- Ultrafiltration almost always requires anti-coagulation.9 - Although baseline CKD is not contraindicated to ultrafiltration per se, it may potentiate the risk of unfavorable renal outcomes as a result of rapid fluid withdrawal in the UF. Indeed, in the presence of frank renal failure, it is usually advisable to avoid UF and alternatively use other renal replacement techniques, such as continuous haemofiltration or high-volume haemofiltration. However, UF is a valuable therapeutic tool in cases of decompensated HF with non-advanced renal dysfunction, especially if there is failure or resistance to diuretics (Figure 7).9
43
ACEIs: angiotensin converting enzyme inhibitors; ARBs: angiotensin II receptor antagonist; CO: cardiac output;
CRT: cardiac resynchronization therapy; EPO: erythropoietin; ESA: Erythropoiesis stimulating agents; LVAD:
left ventricular assist devices; PD: peritoneal dialysis; SVR: systemic vascular resistance.
Adapted from Davenport et al. (2010).91
Figure 7
Premuzic et al. (2017) have conducted the first study to analyze the impact of different CRRT modalities (CVVH
vs. SCUF) on survival of patients with HF and who developed cardiorenal syndrome. In this figure, is illustrated
the outcome for 2-year survival in all patients subdivided by CVVH or SCUF treatment at the end of follow-up.
Implantation devices
- CRT or LVAD may improve hypoperfusion in patients with HF.4 - CRT is advocated for patients who remain symptomatic (NYHA III–IV) despite optimal pharmacological treatment with poor LVEF and QRS prolongation (CRT was effective in reducing mortality and increased EF in NYHA III-IV patients with EF£ 35% and QRS ³ 120 ms).55 - In patients with NYHA I/II, EF<30% and a broad QRS, CRT improves HF without reducing the mortality rate.55 -Implantable cardiac defibrillators are recommended not only for survivors of cardiac arrest or persistent ventricular arrhythmias but also for symptomatic CHF patients with impaired LVEF.15,91
linear regression) of 1.57 [1.31, 1.89]. Differences insurvival between the three main causes of heart fail-ure treated with CVVH and SCUF are demonstratedin Table 3. There were only differences in bettersurvival with CVVH compared to SCUF treatmentin patients with cardiomyopathy (P = 0.016).
The patients were followed for 24 months, 54CVVH and 23 SCUF patients survived. Meansurvival time was longer in the CVVH group thanin the SCUF group (440.3 (95% CI 377.9, 502.6) vs.221.3 (95% CI 140.9, 301.6) days, log-rankP < 0.001) (Fig. 2).
Demographic, laboratory and clinical characteris-tics of the two groups of patients with cardiomyo-pathy treated with CVVH and SCUF aredemonstrated in Table 4. There were no differencesin age, gender and percentage of arterial hyperten-sion and diabetes between CVVH and SCUFgroups. Patients treated with CVVH had longerCRRT treatments and smaller rates of UF thanSCUF patients (P < 0.001) (Table 2). The initializa-tion of treatments was at significantly higher valuesof serum creatinine in CVVH patients, while thesepatients had higher hourly urine output (P < 0.01).SCUF patients had higher values of CVP as a signof volume overload at the start and at the end oftreatments. Mean survival time was longer in theCVVH group with cardiomyopathy than in theSCUF group (557.1 (95% CI 477.3, 636.8) vs. 134.5(95% CI 41.9, 227.1) days, log-rank P < 0.001)(Fig. 3).
We did not find significant differences in survivaltime in patients with coronary and valvular heartdisease (P > 0.05), as well as in survival time inpatients treated with different CRRT modalitiesand divided into subgroups by hourly urine output(P > 0.05). When we compared patients withcardiomyopathy and hourly urine output<10 mL/h, mean survival time was significantlylonger in patients treated with CVVH (557.3 (95%CI 477.3, 636.8) vs. 134.5 (95% CI 41.9, 227.1) days,log-rank P < 0.001) (Fig. 4). In patients with hourly
urine output >10 mL/h, we did not find a significantdifference.
DISCUSSION
Heart failure with worsening renal function andthe development of cardiorenal syndrome is associ-ated with increased risk of short and long-termmorbidity (6). The most important independentprognostic variables by some reports are signs of con-gestion, renal dysfunction and increased serum creat-inine levels (19,20). The UNLOAD (Ultrafiltrationversus Intravenous Diuretics for Patients Hospitalizedfor Acute Decompensated Congestive Heart Failure)trial (5) showed that SCUF is a treatment option forpatients with HF with reduced rate of readmissionto hospital but with an increase in serum creatininelevels after treatment. The SCUF as a treatment op-tion for patients with acute HF and preserved ejectionfraction was reported by Jefferies et al. (21). Thereare no present data comparing different CRRTmodalities for treatment of HF with associated renalfailure.
In this study we found that the group of patientstreated with CVVH survived significantly longer atthe end of the follow-up period than patients treatedwith SCUF (Fig. 1). Although patients treated withCVVH had longer CRRT treatments and smallerUF rates than SCUF patients, treatments were initi-ated at significantly higher values of serum creatinineand BUN in CVVH patients with no difference inhourly urine output between the two groups ofpatients. Patients treated with SCUF had an increase
FIG. 2. Outcome for 2-year survival in all patients subdivided bycontinuous veno-venous hemofiltration (CVVH) or slow continu-ous ultrafiltration (SCUF) treatment at the end of follow-up.[Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3. Differences in survival between three maincauses of heart failure treated with continuous veno-venoushemofiltration (CVVH) and slow continuous ultrafiltration
(SCUF)
Survived patients (N)
CVVH SCUF P
Coronary heart disease 21 7 0.089Cardiomyopathy 22 11 0.016Valvular heart disease 11 5 0.782
Descriptive characteristics were compared using χ2 test.
CVVH Improves Survival in Congestive Heart Failure 283
© 2017 International Society for Apheresis,Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy Ther Apher Dial, Vol. 21, No. 3, 2017
44
Slow continuous ultrafiltration continues to be the option of choice in patients with HF and preserved renal
function, but in those who developed cardiorenal syndrome SCUF is inferior to CVVH.
CRRT: continuous renal replacement therapy; CVVH: continuous veno-venous hemofiltration; SCUF: slow
continuous ultrafiltration.
Taken and adapted with permission from Premuzic et al. (2017).
45
Conclusion
The temporal linkage between heart disease and renal disease is an epidemiological and
pathophysiological facet of the CRS2 definition itself,28 since the HF temporally anticipates the
occurrence or progression of CKD and the expression and degree of kidney disease is plausibly
justified by the subjacent heart condition.28
Several intricate mechanisms have been suggested in CRS2. In the basis of this
syndrome is mainly chronic activation of RAAS and SNS secondary to arterial underfilling and
venous congestion.74 The long-lasting hypoperfusion sometimes related to chronic HF is also
associated with hypoxemia, which can inflict oxidative stress to the kidney, impairing NO
activity on the vascular endothelium and promoting a chronic inflammatory state.56,99 The
activation of inflammatory pathways may be the trigger to glomerulosclerosis, tubular fibrosis
and atrophy.67
While some progress has been made in the cardiorenal syndrome understanding, it is
necessary to implement new biomarkers that would allow early diagnosis before the appearance
of kidney irreversible changes, in order to slowdown the cardiorenal complications progression
in CHF patients with adverse impact on length and quality of life.34,100 In addition, there are
still no criteria for the assessment of severity and evolution in CRS2.
In the future, a better comprehension of the hemodynamic imbalances and fundamental
mechanistic pathways of CRS type 2 will aid in guiding the development of novel therapeutic
approaches and enable for more accurate categorization and selection of patient subpopulations
in which directed therapies will have the highest benefit.9
46
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2:14-9.
Acknowledgements
I am indebted to my mentor, Manuel Vaz da Silva MD, PhD, for all his valuable
critics, encouraging words, patience and commitment. I owe him my deepest gratitude
for helping me writing this manuscript.
ANEXOS - Normas da Revista Portuguesa de Cardiologia
A Revista Portuguesa de Cardiologia, órgão oficial da Sociedade Portuguesa de Cardiologia, é uma publicação científica internacional destinada ao estudo das doenças cardiovasculares.
Publica artigos em português na sua edição em papel e em portu-guês e inglês na sua edição online, sobre todas as áreas da Medicina Cardiovascular. Se os artigos são publicados apenas em inglês, esta versão surgirá simultaneamente em papel e online. Inclui regularmen-te artigos originais sobre investigação clínica ou básica, revisões te-máticas, casos clínicos, imagens em cardiologia, comentários editoriais e cartas ao editor. Para consultar as edições online deverá aceder através do link www.revportcardiol.org.
Todos os artigos são avaliados antes de serem aceites para publi-cação por peritos designados pelos Editores (peer review). A sub-missão de um artigo à Revista Portuguesa de Cardiologia implica que este nunca tenha sido publicado e que não esteja a ser avaliado para publicação noutra revista.
Os trabalhos submetidos para publicação são propriedade da Re-vista Portuguesa de Cardiologia e a sua reprodução total ou parcial deverá ser convenientemente autorizada. Todos os autores deverão enviar a Declaração de Originalidade, conferindo esses direitos à RPC, na altura em que os artigos são aceites para publicação.
Envio de manuscritosOs manuscritos para a Revista Portuguesa de Cardiologia são en-viados através do link http://www.ees.elsevier.com/repc. Para enviar um manuscrito, é apenas necessário aceder ao referido link e seguir todas as instruções que surgem. Esta revista faz parte do nosso Serviço de Transferência de Artigos. Isto significa que se o Editor considerar que o seu artigo é mais adequado para outra revista parceira, então poderemos perguntar se quer consi-derar a transferência para uma dessas revistas. Se concordar, o seu ar-tigo será transferido automaticamente em seu nome sem necessidade de reformatar o mesmo. De notar que o seu artigo será enviado no-vamente para revisão por parte da outra revista. Para mais informação: https://www.elsevier.com/authors/article-transfer-service
Responsabilidades ÉticasOs autores dos artigos aceitam a responsabilidade definida pelo Comité Internacional dos Editores das Revistas Médicas (consultar www.icmje.org).
Os trabalhos submetidos para publicação na Revista Portuguesa de Cardiologia devem respeitar as recomendações internacionais sobre investigação clínica (Declaração de Helsínquia da Associação Médica Mundial, revista recentemente) e com animais de laboratório (So-ciedade Americana de Fisiologia). Os estudos aleatorizados deverão seguir as normas CONSORT.
Informação sobre autorizaçõesA publicação de fotografias ou de dados dos doentes não devem identificar os mesmos. Em todos os casos, os autores devem apre-sentar o consentimento escrito por parte do doente que autorize a sua publicação, reprodução e divulgação em papel e na Revista Portu-guesa de Cardiologia. Do mesmo modo os autores são responsáveis por obter as respectivas autorizações para reproduzir na Revista Portuguesa de Cardiologia todo o material (texto, tabelas ou figuras) previamente publicado. Estas autorizações devem ser solicitadas ao autor e à editora que publicou o referido material.
Conflito de interessesCada um dos autores deverá indicar no seu artigo se existe ou não qualquer tipo de Conflito de Interesses.
Declaração de originalidadeO autor deverá enviar uma declaração de originalidade. Ver anexo IProtecção de dadosOs dados de carácter pessoal que se solicitam vão ser tratados num ficheiro automatizado da Sociedade Portuguesa de Cardiologia (SPC) com a finalidade de gerir a publicação do seu artigo na Revista Portugue-sa de Cardiologia (RPC). Salvo indique o contrário ao enviar o artigo, fica expressamente autorizado que os dados referentes ao seu nome, ape-lidos, local de trabalho e correio electrónico sejam publicados na RPC, bem como no portal da SPC (www.spc.pt) e no portal online www.revportcardiol.org, com o intuito de dar a conhecer a autoria do artigo e de possibilitar que os leitores possam comunicar com os autores.
INSTRUÇÕES AOS AUTORESTodos os manuscritos deverão ser apresentados de acordo com as normas de publicação. Pressupõe-se que o primeiro autor é o repon-sável pelo cumprimento das normas e que os restantes autores conhe-cem, participam e estão de acordo com o conteúdo do manucrito.
NOTA IMPORTANTE! Para que se possa iniciar o processo de avaliação, o documento com o corpo do artigo deverá incluir todos os elementos que fazem parte do artigo: Títulos em português e em inglês; autores; proveniência; palavras-chave e keywords; Resumos em português e em inglês; Corpo do artigo, incluindo as tabelas; bibliogra-fia; legendas das figuras e das tabelas.
1. Artigos OriginaisApresentação do documento:• Com espaço duplo, margens de 2,5 cm e páginas numeradas.• Não deverão exceder 5.000 palavras, contadas desde a primeira à última página, excluindo as tabelas.• Consta de dois documentos: primeira página e manuscrito• O manuscrito deve seguir sempre a mesma ordem: a) resumo estru-turado em português e palavras-chave; b) resumo estruturado em inglês e palavras-chave; c) quadro de abreviaturas em português e em inglês; d) texto; e) bibliografia; f) legendas das figuras; g) tabelas (opcional) e h) figuras (opcional)-
Primeira páginaTítulo completo (menos de 150 caracteres) em português e em inglês.
Nome e apelido dos autores pela ordem seguinte: nome próprio, seguido do apelido (pode conter dois nomes)
Proveniência (Serviço, Instituição, cidade, país) e financiamento caso haja.Endereço completo do autor a quem deve ser dirigida a corres-
pondência, fax e endereço electrónico.Faz-se referência ao número total de palavras do manuscrito (ex-
cluindo as tabelas).
Resumo estruturadoO resumo, com um máximo de 250 palavras, está dividido em qua-tro partes: a) Introdução e objectivos; b) Métodos; c) Resultados e d) Conclusões.
Normas de publicação da Revista Portuguesa de Cardiologia
Deverá ser elucidativo e não inclui referências bibliográficas nem abreviaturas (excepto as referentes a unidades de medida).
Inclui no final três a dez palavras-chave em português e em inglês. Deverão ser preferencialmente seleccionadas a partir da lista publica-da na Revista Portuguesa de Cardiologia, oriundas do Medical Subject Headings (MeSH) da National Libray of Medicine, disponível em: www.nlm.nihgov/mesh/meshhome.html.
O resumo e as palavras-chave em inglês devem ser apresentados da mesma forma.
TextoDeverá conter as seguintes partes devidamente assinaladas: a) In-trodução; b) Métodos; c) Resultados; d) Discussão e e) Conclusões. Poderá utilizar subdivisões adequadamente para organizar cada uma das secções.
As abreviaturas das unidades de medida são as recomendadas pela RPC (ver Anexo II).
Os agradecimentos situam-se no final do texto.
BibliografiaAs referências bibliográficas deverão ser citadas por ordem numérica no formato ‘superscript’, de acordo com a ordem de entrada no texto.
As referências bibliográficas não incluem comunicações pessoais, manuscritos ou qualquer dado não publicado. Todavia podem estar incluídos, entre parêntesis, ao longo do texto.
São citados abstracts com menos de dois anos de publicação, identificando-os com [abstract] colocado depois do título.
As revistas médicas são referenciadas com as abreviaturas utiliza-das pelo Index Medicus: List of Journals Indexed, tal como se publi-cam no número de Janeiro de cada ano. Disponível em: http://www.ncbi.nlm.nih.gov/entrez/citmatch_help.html#JournalLists.
O estilo e a pontuação das referências deverão seguir o modelo Vancouver 3.
Revista médica: Lista de todos os autores. Se o número de autores for superior a três, incluem-se os três primeiros, seguidos da abreviatu-ra latina et al. Exemplo:
17. Sousa PJ, Gonçalves PA, Marques H et al. Radiação na AngioTC cardíaca; preditores de maior dose utilizada e sua redução ao lon-go do tempo. Rev Port cardiol, 2010; 29:1655-65Capítulo em livro: Autores, título do capítulo, editores, título do
livro, cidade, editora e páginas. Exemplo: 23. Nabel EG, Nabel GJ. Gene therapy for cardiovascular disease. En: Haber E, editor. Molecular cardiovascular medicine. New York: Scientific American 1995. P79-96.Livro: Cite as páginas específicas. Exemplo: 30. Cohn PF. Silent myocardial ischemia and infarction. 3rd ed. New York: Mansel Dekker; 1993. P. 33.Material electrónico: Artigo de revista em formato electrónico.
Exemplo: Abood S. Quality improvement initiative in nursing homes: the ANA acts it an advisory role. Am J Nurs. [serie na internet.] 2002 Jun citado 12 Ago 2002:102(6): [aprox. 3] p. Disponível em: http://www.nursingworld.org/AJN/2002/june/Wawatch.htm. A Bibliografia será enviada como texto regular, nunca como nota de rodapé. Não se aceitam códigos específicos dos programas de gestão bibliográfica.
1. FigurasAs figuras correspondentes a gráficos e desenhos são enviadas no formato TIFF ou JPEG de preferência, com uma resolução nunca inferior a 300 dpi e utilizando o negro para linhas e texto. São alvo de numeração árabe de acordo com a ordem de entrada no texto.
• A grafia, símbolos, letras, etc, deverão ser enviados num tamanho que, ao ser reduzido, os mantenha claramente legíveis. Os detalhes especiais deverão ser assinalados com setas contrastantes com a figura.• As legendas das figuras devem ser incluídas numa folha aparte. No final devem ser identificadas as abreviaturas empregues por ordem alfabética.• As figuras não podem incluir dados que dêem a conhecer a pro-veniência do trabalho ou a identidade do paciente. As fotografias das pessoas devem ser feitas de maneira que estas não sejam identifica-das ou incluir-se-á o consentimento por parte da pessoa fotografada.
TabelasSão identificadas com numeração árabe de acordo com a ordem de entrada no texto.
Cada tabela será escrita a espaço duplo numa folha aparte.• Incluem um título na parte superior e na parte inferior são refe-ridas as abreviaturas por ordem alfabética.• O seu conteúdo é auto-explicativo e os dados que incluem não figuram no texto nem nas figuras.
2. Artigos de RevisãoNº máximo de palavras do artigo sem contar com o resumo e qua-dros- 5.000Nº máximo de palavras do Resumo - 250Nº máximo de Figuras - 10Nº máximo de quadros - 10Nº máximo de ref. bibliográficas - 100
3. Cartas ao EditorDevem ser enviadas sob esta rubrica e referem-se a artigos publica-dos na Revista. Serão somente consideradas as cartas recebidas no prazo de oito semanas após a publicação do artigo em questão.• Com espaço duplo, com margens de 2,5 cm.• O título (em português e em inglês), os autores (máximo quatro), proveniência, endereço e figuras devem ser especificados de acordo com as normas anteriormente referidas para os artigos originais.• Não podem exceder as 800 palavras.• Podem incluir um número máximo de duas figuras. As tabelas estão excluídas.
4. Casos ClínicosDevem ser enviados sob esta rubrica.• A espaço duplo com margens de 2,5 cm.• O título (em português e em inglês) não deve exceder 10 palavras
Os autores (máximo oito) proveniência, endereço e figuras serão especificados de acordo com as normas anteriormente referidas para os artigos originais.
O texto explicativo não pode exceder 3.000 palavras e contem in-formação de maior relevância. Todos os símbolos que possam constar nas imagens serão adequadamente explicados no texto.
Contêm um número máximo de 4 figuras e pode ser enviado mate-rial suplementar, como por exemplo vídeoclips.
5. Imagens em Cardiologia• A espaço duplo com margens de 2,5 cm.• O título (em português e em inglês) não deve exceder oito palavras• Os autores (máximo seis), proveniência, endereço e figuras serão especificados de acordo com as normas anteriormente referidas pa-ra os artigos originais.• O texto explicativo não pode exceder as 250 palavras e contem informação de maior relevância, sem referências bibliográficas. To-dos os símbolos que possam constar nas imagens serão adequada-mente explicados no texto.• Contêm um número máximo de quatro figuras.
Normas de publicação da revista portuguesa de cardiologia
ANEXO IISímbolos, abreviaturas de medidas ou estatística
6. Material adicional na WEBA Revista Portuguesa de Cardiologia aceita o envio de material electrónico adicional para apoiar e melhorar a apresentação da sua investigação científica. Contudo, unicamente se considerará para publicação o material electrónico adicional directamente relaciona-do com o conteúdo do artigo e a sua aceitação final dependerá do critério do Editor. O material adicional aceite não será traduzido e publicar-se-á electronicamente no formato da sua recepção.
Para assegurar que o material tenha o formato apropriado reco-mendamos o seguinte:
Formato Extensão Detalhes
Texto Word .doc ou docx Tamanho máximo 300 Kb
Imagem TIFF .tif Tamanho máximo 10MB
Audio MP3 .mp3 Tamanho máximo 10MB
Vídeo WMV .wmv Tamanho máximo 30MB
Os autores deverão submeter o material no formato electró-nico através do EES como arquivo multimédia juntamente com o artigo e conceber um título conciso e descritivo para cada arquivo.
Do mesmo modo, este tipo de material deverá cumprir também todos os requisitos e responsabilidades éticas gerais descritas nes-sas normas.
O Corpo Redactorial reserva-se o direito de recusar o material electrónico que não julgue apropriado.
ANEXO I
DECLARAÇÃO
Declaro que autorizo a publicação do manuscrito:
Ref.ª ........................................................................................
Título ...........................................................................................
.........................................................................................................
........................................................................................................
do qual sou autor ou c/autor.
Declaro ainda que presente manuscrito é original, não foi objecto de qualquer outro tipo de publicação e cedo a inteira propriedade à Revista Portuguesa de Cardiologia, ficando a sua reprodução, no todo ou em parte, dependente de prévia autorização dos editores.
Nome dos autores:
.........................................................................................................
.........................................................................................................
Assinaturas:
Normas de publicação da revista portuguesa de cardiologia
Designação
AmpereAnoCentímetro quadradoContagens por minutoContagens por segundoCurieElectrocardiogramaEquivalenteGrau CelsiusGramaHemoglobinaHertzHoraJouleLitroMetroMinutoMolarMoleNormal (concentração)OhmOsmolPesoPressão parcial de CO2
Pressão parcial de O2
QuilogramaSegundoSemanaSistema nervoso centralUnidade InternacionalVoltMilivoltVolumeWatts
Estatística:
Coeficiente de correlaçãoDesvio padrão (standard)Erro padrão (standard) da médiaGraus de liberdadeMédiaNão significativaNúmero de observaçõesProbabilidadeTeste «t» de Student
Português
Aanocm2
cpmcpsCiECGEq°CgHbHzhJL ou LmminMmolNΩosmolpesopCO2
pO2
kgsSemSNCUIVmVVolW
rDPEPMglχNSnpteste t
Inglês
Ayrcm2
cpmcpsCiECGEq°CgHbHzhJI ou LmminMmolNΩosmolWTpCO2
pO2
kgsecWkCNSIUVmVVolW
rSDSEMdfχNSnpt test