Subido por amsnefro1978

Heart failure in chronic kidney disease

Nephrol Dial Transplant (2020) 1–8
doi: 10.1093/ndt/gfaa284
Heart failure in chronic kidney disease: the emerging role
of myocardial fibrosis
Department of Nephrology, University of Navarra Clinic, Pamplona, Spain, 2Program of Cardiovascular Diseases, CIMA Universidad de
Navarra, Pamplona, Spain, 3Institute of Medical Research of Navarra, IDISNA, Pamplona, Spain, 4Center of Network Biomedical Research in
Cardiovascular Diseases (CIBERCV), Carlos III Institute of Health, Madrid, Spain and 5Department of Cardiology and Cardiac Surgery,
University of Navarra Clinic, Pamplona, Spain
Correspondence to: Javier Dı́ez; E-mail: [email protected]
Heart failure (HF) is one of the main causes of morbidity and
mortality in patients with chronic kidney disease (CKD).
Decreased glomerular filtration rate is associated with diffuse
deposition of fibrotic tissue in the myocardial interstitium [i.e.
myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in
the turnover of fibrillary collagen that lead to the excessive
synthesis and deposition of collagen fibres. The accumulation
of stiff fibrotic tissue alters the mechanical properties of the
myocardium, thus contributing to the development of HF.
Accumulating evidence suggests that several mechanisms are
operative along the different stages of CKD that may converge
to alter fibroblasts and collagen turnover in the heart.
Therefore, focusing on MIF might enable the identification of
fibrosis-related biomarkers and targets that could potentially
lead to a new strategy for the prevention and treatment of HF in
patients with CKD. This article summarizes current knowledge
on the mechanisms and detrimental consequences of MIF in
CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical–pathological variability of
MIF and track its clinical evolution in CKD patients. Finally,
the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in
CKD patients, especially those with HF, will be also discussed.
Patients with the dual burden of CKD and HF experience
unacceptably high rates of symptom load, hospitalization and
mortality [2], thus representing a growing health, economic
and societal problem as the ageing population leads to higher
numbers of affected individuals. In this regard, remarkable
interest has been placed recently on processes through which
the diseased kidney facilitates HF. Beyond macroscopic left ventricular (LV) hypertrophy, the microscopic lesions constitutive
of the structural remodelling of the myocardium that impairs
cardiac function [e.g. cardiomyocyte hypertrophy, myocardial
interstitial fibrosis (MIF) and coronary microvascular disease]
are frequent findings in endomyocardial biopsies (EMBs) and
necropsy studies in patients with CKD [3], namely in those
with kidney failure [4]. In particular, recent scientific work has
identified causal connections between CKD and MIF [5].
Furthermore, it has been proposed that MIF may play a key
role in the pathophysiology of HF in CKD patients [6].
Therefore, focusing on MIF might enable development of new
strategies for the prevention and treatment of HF in CKD. This
article summarizes available knowledge on the mechanisms
and detrimental consequences of MIF in CKD, discusses the validity and usefulness of non-invasive biomarkers to detect MIF
in CKD patients with HF and analyses the currently existing
and potential future therapeutic tools aimed at reversing MIF in
these patients.
Keywords: biomarkers, chronic kidney disease, fibrosis, heart
Cardiac disease in patients with chronic kidney disease (CKD)
is more frequent and more severe compared with the non-CKD
population [1]. Either ischaemic or non-ischaemic in origin,
cardiac diseases present in CKD patients evolve to chronic congestive heart failure (HF) (i.e. type 4 cardiorenal syndrome) [2].
MIF is characterized by the diffuse deposition of an excess of
collagen fibres within the myocardial interstitium that expands
the interstitial space. The extent of MIF is quantified as the percentage of total myocardial tissue occupied by collagen fibres,
denoted as collagen volume fraction (CVF) and determined in
myocardial samples by collagen-specific stain. Microscopically,
three patterns of fibrous deposits can be distinguished in
MIF (Figure 1) [7]: microscars, thick sheaths located in the
C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Gregorio Romero-González1, Arantxa González2,3,4, Bego~
na López2,3,4, Susana Ravassa
Javier Dı́ez1,2,3,4,5
Perivascular fibrosis
Peri- and intercardiomyocyte bands
FIGURE 1: Endomyocardial biopsy of a patient with CKD Stage 3a
and HF. Sections were stained with picrosirius red and collagen
deposits were identified in red as perivascular, microscars and periand intercardiomyocytic bands (magnification 400). With permission from Lopez B et al. Kidney Int 2008; 74(Suppl 111): S19-S23.
perivascular space around intramural coronary arteries and
arterioles and bands surrounding the cardiac muscle bundles
and individual cardiomyocytes. Recent evidence suggests that
beyond the quantity of collagen fibres, its structural quality (i.e.
the degree of cross-linking among its constitutive fibrils) is relevant in MIF present in the failing human heart [8].
Although the expansion of the myocardial interstitium in
CKD was described in the middle of the past century [9, 10],
the presence of MIF in patients with CKD and patients submitted to kidney replacement therapy (KRT) was for the first time
demonstrated and characterized in detail in post-mortem studies performed at the end of the century [11, 12]. Later clinical
and population-based post-mortem studies have shown that
patients with CKD have significantly more interstitial fibrotic
tissue (as assessed by CVF) in the heart compared with subjects
without CKD, that the stage of CKD directly correlates with the
extent of MIF, thus being the more severe fibrosis found in
patients with kidney failure and patients on KRT, and that
CKD is associated with MIF independent of other potential
confounding variables [13, 14]. MIF can become an extensive
injury in the failing heart of CKD patients, as demonstrated in a
study with EMB performed in patients on haemodialysis with
HF showing that CVF represented >20%, with the three patterns of fibrotic deposits previously mentioned coexisting in the
biopsy samples from most patients [15].
From a general point of view, the pathogenesis of MIF is characterized by the activation of resident cardiac fibroblasts, the differentiation of fibroblasts to myofibroblasts and the transition
of other cardiac cell types to myofibroblasts [16]. Both activated
fibroblasts and myofibroblasts produce a pro-fibrotic secretome
G. Romero-González et al.
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Microscopic scar
that in turn leads to alterations in the extracellular turnover of
fibrillary collagen types I and III with synthesis predominating
over degradation, thus resulting in the excessive deposition of
collagen fibres within the interstitium [7, 8, 16] (Figure 2).
In particular, the combination of excessive synthesis of mature
collagen type I molecules by procollagen proteinases and
excessive cross-linking of collagen-type fibrils plus reduced or
unchanged collagen type I fibre degradation by matrix
metalloproteinase-1 are the key alteration of collagen type I
turnover involved in MIF (Figure 2). Biomechanical stress–
induced alarmins, cytokines and chemokines participate in the
activation of cardiac fibroblasts and the generation of myofibroblasts through the stimulation of a number of pro-fibrotic
signalling pathways, among which the transforming growth
factor (TGF)-b-regulated pathway stands out [16].
It is known that advanced stages of CKD are characterized
by stimulation of fibrogenesis in several organs and tissues, including the heart and the aortic and large arteries vessel wall,
leading to LV dysfunction and arterial stiffness, respectively
[17, 18]. Clinical data obtained in patients with CKD Stages 2
and 3 suggest that the two processes occur in parallel, thus lending support to the possibility of the interaction of their responsible mechanisms. [19].
As regards the heart, it has been demonstrated in surgical
and non-surgical experimental models of short- and long-term
kidney function impairment in animals that the development
of MIF is characterized by stimulation of pro-fibrotic genes and
signalling pathways linked to TGF-b and by the predominant
deposition of collagen type I fibres [20–22]. Of note, in these
models, MIF is associated with LV diastolic and systolic dysfunction [20–22]. Thus it has been proposed that in CKD, several groups of pro-fibrotic factors can induce biomechanical
stress of cardiac cells and thus trigger MIF [5, 17] (Table 1).
These hypothetical factors include haemodynamic factors (e.g.
pressure overload due to coexisting hypertension and volume
overload related to the progressive decline of diuresis) and nonhaemodynamic factors associated with the progressive loss of
kidney function fe.g. neuro-hormonal activation, including
activation of the renin–angiotensin–aldosterone system
[RAAS]; chronic inflammation [mediated by activation of the
nucleotide-binding oligomerization domain (NOD), leucinerich repeat (LRR) and pyrin domain-containing protein 3
(NLRP3) inflammasome], oxidative stress, endothelial dysfunction, anaemia and mineral metabolism disorders leading to excess parathyroid hormone and/or vitamin D deficiencyg. In
contrast, as a result of decreasing glomerular filtration rate
(GFR), increased synthesis of pro-fibrotic substances by various
organs occurs, which may also promote MIF [e.g. cystatin C,
fibroblast growth factor-23, advanced glycation end-products,
nitric oxide inhibitors, trimethylamine N-oxide (TMAO) and
endogenous cardiotonic steroids]. Finally, several uraemic retention solutes (e.g. indoxyl sulphate, p-cresol sulphate, b2
microglobulin) are pro-fibrotic factors that can also be involved
in MIF in kidney failure. Of interest, some of these factors may
share CKD-specific pro-fibrotic mediators. For instance, recent
findings suggest that microRNA-29b can play an important
role in the mechanism of MIF related to vitamin D deficiency
Procollagen type I precursor secreted to the
extracellular space by activated fibroblasts
Collagen type I
Mature collagen type I molecule
Termino-terminal self-assembly of collagen
type I molecules = collagen type I microfibril
Mature collagen
type I molecule
Latero-lateral self-assembly of collagen
type I microfibrils = collagen type I fibril
Cysteine proteases
Lysyl oxidases
Cross-linking of collagen type I fibrils = collagen type I fibre
Intramolecular and intermolecular covalent
bonds, cross-links, between lysine residues
in the molecules of two collagen type I fibrils
First step degradation
of collagen type I fibres
Big N-terminal collagen type I telopeptide
MMP-9 and MMP-10
Second step degradation
of collagen type I fibres
Degradation of
collagen type I fibres
FIGURE 2: Schematic representation of the extracellular steps involved in the synthesis and degradation of collagen type I fibres. In MIF, the
excessive deposition of collagen type I fibres is the result of the predominance of their synthesis over their degradation (see text). All the
enzymes intervening in this process are tightly regulated by stimulatory (e.g. procollagen C-proteinase enhancer) and inhibitory factors (e.g.
tissue inhibitors of MMPs). PINP: N-terminal pro-peptide of procollagen type I; PICP: C-terminal pro-peptide of procollagen type I; CITP: Cterminal telo-peptide of collagen type I.
[23] and excess endogenous cardiotonic steroids in experimental CKD [24, 25].
MIF is involved in LV dysfunction as well as in arrhythmias
and alterations of myocardial perfusion in patients with HF
(Figure 3), thus contributing to poor outcomes in this population [7]. Indeed, as demonstrated in clinical–pathological studies, MIF is associated with LV dysfunction, both diastolic
(i.e. increased myocardial stiffness hampers passive inflow and
causes a backward flow that further impairs early filling) and
systolic (i.e. altered alignment of collagen fibres relative to cardiomyocytes impairs transmission of force generated by cardiomyocytes to the ventricular chamber, detrimentally affecting
contractility), in HF patients with either preserved or reduced
ejection fraction (HFpEF and HFrEF, respectively) [26, 27].
In addition, MIF is independently associated with outcomes
(i.e. all-cause and cardiovascular mortality and hospitalization
for HF) in HF patients [28, 29]. As the presence of CKD is associated with both more severe LV stiffness and dysfunction [30]
and worst prognosis [31] in HF patients, the possibility exists
that MIF may play a significant role in the progression and outcomes of HF in CKD patients [6]. In support of this possibility,
it has been reported that in patients on haemodialysis with
severe dilated cardiomyopathy and HF, the extent of MIF was a
strong and independent predictor of cardiac death [15].
There is abundant evidence on MIF being an important
pathophysiological contributor to ventricular arrhythmias as
well as to atrial fibrillation (AF) [7]. CKD patients, especially
those undergoing dialysis treatment, are more prone to develop arrhythmias, particularly ventricular arrhythmias and
AF [1], and half of cardiovascular deaths in CKD, especially
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Synthesis of
collagen type I fibres
Table 1. Pro-fibrotic factors present in CKD and potentially involved in
the development of MIF
Uraemic retention
Arterial hypertension
Volume overload
Angiotensin II and aldosterone
Interleukins 1b, 18 and 6
Superoxide anion
Serum uric acid
Serum phosphate
Parathyroid hormone excess
Vitamin D deficiency
Cystatin C
Fibroblast growth factor-23
Advanced glycation end-products
Endogenous cardiotonic steroids
Nitric oxide inhibitors
Trimethylamine N-oxide
Indoxyl sulphate
p-Cresol sulphate
b2 microglobulin
Adapted from Hulshoff et al. [5], González et al. [7], Mutsaers et al. [17] and Dı́ez et al.
in the population with kidney failure, are related to cardiac
arrhythmia and sudden cardiac death [1]. Therefore the possibility exists that MIF may be the structural substrate invoed
in the genesis of ventricular and atrial arrhythmias in CKD
patients. In support of this possibility are experimental studies showing that the development of MIF that accompanies
decreasing GFR is associated with the appearance of ventricular arrhythmias [32] and AF [33]. In the clinic, it was recently reported that patients with CKD Stages 1–3 with
elevated serum indoxyl sulphate levels showed a higher AF
recurrence rate after successful catheter ablation, with serum
indoxyl sulphate being a significant predictor of AF recurrence [34]. Of note, a positive correlation between CVF and
circulating levels of indoxyl sulphate has been found in
subtotal-nephrectomized rats with MIF [35].
In HF patients, MIF, i.e. perivascular fibrosis, is associated
with the severity of coronary microvascular disease and is inversely correlated with coronary flow reserve [36], thus facilitating myocardial ischaemia. Additionally, perivascular deposition
of fibrotic tissue increases oxygen diffusion distance, leading to
the impairment of oxygen supply to the cardiomyocytes [37].
Coronary microvascular disease (i.e. endothelial dysfunction of
intramyocardial arteries, remodelling of the wall of arterioles
and reduced capillarization) is common in CKD patients, particularly in those with kidney failure in dialysis treatment, and
has been invoed also in reduced coronary flow reserve, which in
turn is associated with cardiovascular mortality in this population [38]. It has been proposed that in patients with kidney failure, MIF, particularly perivascular fibrosis, may contribute to
coronary microvascular disease through extrinsic compression
of intramyocardial vessels [39].
Although direct microscopic examination of myocardial tissue
obtained by EMB is the most accurate procedure to assess MIF,
it remains an underutilized tool due to the paucity of human tissue samples, which is caused by the perceived risk associated
with EMB, namely in CKD patients. An additional limitation to
obtaining tissue samples is sampling error due to the patchy distribution of fibrotic deposits, restricting the diagnostic accuracy.
Alternatively, MIF can be assessed non-invasively in HF
patients by imaging and/or circulating biomarkers. Although
cardiac magnetic resonance (CMR) techniques are widely used
for imaging of cardiac fibrosis, measuring myocardial extracellular volume fraction (ECV) using gadolinium as a contrast
agent, the severe consequences of gadolinium administration in
CKD patients (i.e. nephrogenic systemic fibrosis) has driven
new gadolinium-free CMR methodologies, allowing the characterization of MIF in these patients using the native T1 as a readout [40]. Indeed, recent studies using these approaches have
identified alterations in native T1 attributable to MIF in nonHF patients with CKD Stages 1–4 [41], patients with kidney
failure [42] and patients on haemodialysis [43]. However, a recent study showed that MIF quantification by ECV but not by
native T1 was an independent risk factor for HF, providing
incremental prognostic value and risk stratification for cardiac
events in haemodialysis patients [44]. Therefore, additional
studies are required to ascertain the more accurate and safe
procedure to diagnose MIF in CKD patients using CMR. In this
regard, using macrocyclic gadolinium-based contrast agents
(e.g. gadoterate meglumine and gadobutrol) appears to be safe
even in patients receiving haemodialysis, with no significant reduction in image quality [45].
Speckle tracking echocardiography (STE) assesses myocardial deformation at both the segmental and global levels, thus
allowing myocardial tissue characterization [46]. In this regard,
the extent of MIF has been linked to the degree of reduction in
myocardial global longitudinal strain (GLS) in patients with HF
[46]. While a reduced myocardial GLS has been reported in all
stages of CKD and in patients on KRT [47], no data are yet
available on this parameter in these populations when presenting with HF. Molecular imaging methods (e.g. single-photon
emission computed tomography and positron emission tomography) alone or in combination with CMR hold great potential
in efficiently identifying and quantifying collagen as a hallmark
of MIF [48]. However, there are still no data on their employment to assess MIF in CKD patients.
Some circulating biomarkers related to the extracellular metabolism of collagen type I and associated with MIF have been
characterized in clinical–pathological studies performed in HF
patients [49]. For instance, serum levels of the carboxy-terminal
propeptide of procollagen type I (PICP), released during the
synthesis of mature collagen type I molecules from their procollagen type I precursors by procollagen proteinases, directly correlate with the amount of collagen type I deposition in the
myocardium of HF patients. On the other hand, the serum
carboxy-terminal telopeptide of collagen type I (generated during the degradation of collagen type I fibres) to matrix
metalloproteinase-1 ratio (CITP:MMP-1) inversely correlates
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Endocrine and metabolic
Main representative factors
Altered electrical
activity of
alignment of
Compression of
small arteries
and arterioles
O2 diffusion
Reduced V
and re-entry
and ectopic
of generated
flow reserve
O2 availability
and hypoxia
Ventricular and
atrial arrhythmias
FIGURE 3: Pathophysiological pathways involved in the major clinical complications of MIF that negatively influence the cardiovascular
outcomes and prognosis of patients with CKD (V, membrane potential; O2, oxygen).
with myocardial collagen type I cross-linking in HF patients.
Recently it was reported that in patients with HF, a combination of high serum PICP and low serum CITP:MMP-1 ratio
identifies a subgroup of patients with a high risk of HF hospitalization or death from cardiovascular causes [50], suggesting
that these patients may present a high clinical risk pattern for
MIF (i.e. malignant MIF). Of interest, the prevalence of this biomarker combination in HFpEF is higher in patients with CKD
Stages 1–4 than in patients without CKD [51] (Figure 4). In addition, there is an effect modification of CKD on the association
of this biomarker combination with LV diastolic dysfunction in
HFpEF patients [51]. There is a necessity to investigate the usefulness of the biomarker combination in patients with kidney
failure, as CITP is filtered by the kidney and may accumulate in
blood when the GFR is <30 mL/min/1.73 m2.
There is currently no fully effective anti-fibrotic therapy.
However, there is clinical and experimental evidence that MIF
can be reversed with treatment. From this perspective, a
strategy based on three therapeutic approaches can be proposed
to reverse MIF in patients in different stages of CKD and
patients submitted to KRT (Figure 5).
First, treatment of HF patients with drugs interfering with
the RAAS [particularly the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, the angiotensin receptor blocker
(ARB) losartan and the mineralocorticoid receptor antagonist
(MRA) spironolactone] has been shown to reduce CVF in EMB
[7, 49]. Of note, as the use of steroidal MRA is limited in
patients with advanced stages of CKD because of a high sideeffect burden (overall hyperkalaemia), the use of non-steroidal
MRA may be considered. Indeed, Phase 2 randomized clinical
trials have demonstrated that the non-steroidal MRA finerenone has a superior safety profile to spironolactone and eplerenone in patients with CKD Stage 5 and exhibits potent in vitro
and in vivo experimental anti-fibrotic effects [52]. On the other
hand, it has been shown that the loop diuretic torasemide
reduces MIF (both CVF and the degree of collagen crosslinking) in the myocardium of HF patients with CKD Stages
1–3 [53]. The anti-fibrotic effect was associated with the reduction of LV stiffness and the amelioration of HF clinical and
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hormonal parameters, as well as the circulating level of PICP in
torasemide-treated patients [53]. As the effects on MIF were
not observed in furosemide-treated patients, the possibility
exists that torasemide exerts diuretic-independent anti-fibrotic
actions [i.e. inhibition of the enzymes procollagen C-proteinase
that synthesizes mature collagen type I molecules from their
precursors and lysyl oxidases that mediate the cross-linking between collagen type I fibrils to form collagen type I fibres
(Figure 2)] [53]. In this regard, it can be hypothesized that
P < 0.001
Patients with biomarker combination
of high clinical risk MIF (%)
HF +
HF +
FIGURE 4: Frequency distribution of the combination of bio-
markers of high clinical risk of MIF (see text) in patients without
and with Stages 1–4 (CKD and CKDþ groups, respectively), classified in subgroups according to the absence or presence of HF with
preserved ejection fraction (HF and HFþ, respectively). Adapted
with permission from Eiros et al. [51].
stage 1
stage 2
stage 3
Type of evidence
Direct clinical
stage 4
stage 5
Readout parameters
Histopathological parameters
and collagen-related
circulating biomarkers
Steroidal MRA
Direct clinical
Successful kidney
CMR- and STEderived biomarkers
Indirect clinical
Non-steroidal MRA
Ferric citrate
Vitamin D receptor activators
Hydroxylase inhibitors
NLRP3 inflammasome inhibitors
Anti-TMAO agents
Anti-indoxylsulfate measures
FIGURE 5: Proposed approach to treat MIF in HF patients along the different Kidney Disease: Improving Global Outcomes stages of CKD
and during KRT. The proposal is based on both clinical and experimental studies in which different types of readout parameters were used to
assess the effects of treatment on MIF.
G. Romero-González et al.
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patients with HFpEF and CKD Stages 1–4 presenting with the
biomarker combination of high serum PICP (thus reflecting
high collagen type I synthesis) and a low serum CITP:MMP-1
ratio (thus reflecting high collagen type I cross-linking) may be
a subsidiary of a tailored treatment with torasemide on top of
other HF medications. Additional studies are required to evaluate this possibility, as well as studies aimed at ascertaining the
cardiac anti-fibrotic usefulness of torasemide in patients with
kidney failure and patients on dialysis.
As CMR-derived parameters assessing MIF (e.g. ECV and
native T1) worsen with haemodialysis vintage [54], it can be
suggested that targeting interdialysis volume and pressure
overload in haemodialysis patients may be one of the ways to
act on MIF in these patients, as blood pressure and volume control have substantial impacts on cardiac complications, especially HF [55]. Additionally, avoiding intradialysis
haemodynamic instability that causes myocardial ischaemia
and injury may also prevent the reparative response leading to
MIF [56]. In this framework, one of the potential benefits of individualized cardioprotective dialysis may be the reversal of
MIF. Finally, although scarce, there is evidence that successful
kidney transplantation is associated with mid- and long-term
improvement in the CMR parameters ECV and native T1 [57]
and in the STE parameter GLS [58], which may be associated
with the regression of MIF. Clearly, more studies are required
to delineate the role of recovery of renal function and/or immunosuppressive treatment in kidney transplantation on MIF.
Second, in the setting of CKD there is experimental evidence
that some pharmacological agents aimed at treating the complications of the loss of kidney function (i.e. anaemia and disturbances of mineral metabolism) may also be useful for treating
MIF, as their use in animal models of CKD is associated with
reductions in CVF among other histomolecular parameters associated with fibrosis. For instance, ferric citrate [59], vitamin D
receptor activators [23] and prolyl hydroxylase inhibitors [60]
The development of HF in patients with CKD represents a huge
and urgent unmet medical need and, as such, a better understanding of the link between both conditions is mandatory. The
notion is emerging that the progressive deterioration of cardiac
function in CKD can be related in part to the fact that the progressive loss of renal function stimulates several mechanisms
that facilitate MIF. In this conceptual framework, limited data
and a large potential for impact make it necessary to develop
optimal strategies for the diagnosis of MIF in CKD patients, as
well as strategies aimed at individualized prevention and management in these patients, namely in those with kidney failure
and those on KRT. This means that the time has come for
nephrologists, cardiologists and other specialists with a background in the implementation of HF medicine to work together, as patients with CKD and HF are cardiorenal patients
with systemic involvement and challenging requirements that
must be faced from a multidisciplinary clinical vision and
This project was funded by the Spanish Ministry of Science,
Innovation and Universities [Instituto de Salud Carlos III:
CIBERCV CB16/11/00483, the ERA-CVD Joint Transnational
Call 2016 LYMIT-DIS (AC16/00020) and LIPCAR-HF
(AC16/00016), the European Commission H2020 Programme
(CRUCIAL project 848109) and the Dirección General de
Industria, Energı́a e Innovación, Gobierno de Navarra, Spain
(MINERVA project 0011-1411-2018-000053)].
None declared.
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attenuate MIF and improve cardiac function in different models
of kidney failure in rodents. Third, the manifold fibrogenic
mediators and pathways that are activated in CKD offer a multitude of potential targets for novel anti-fibrotic interventions
useful in this condition. Some experimental examples may
illustrate this approach. Suppression of NLRP3 inflammasome
activation with the polyphenolic compound theracurmin ameliorates MIF and LV diastolic dysfunction in rats with kidney
failure secondary to subtotal nephrectomy [61]. Reduction of
plasma levels of TMAO with the guanylate cyclase C agonist
linaclotide is associated with a reduction of MIF in mice with
adenine-induced kidney failure [62]. A decrease of serum indoxyl sulphate levels using the oral charcoal adsorbent AST120 was associated with a reduction of MIF and improvement
of LV diastolic dysfunction in subtotal-nephrectomized rats
[35]. Clearly these promising preclinical studies need to be
transferred to the clinic and therapeutic approaches that survive
Phase 1 and 2 clinical trials must be identified.
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