In previous years, the relationship between kidney
failure and heart disease has gained more attention and is now a
major focus of research in the scientific community (1-4).
Extensive research supports the idea of a bidirectional
relationship, demonstrating that renal failure might affect the
progression and development of cardiac diseases, and vice versa
(3,5). This pathophysiological concept is
known as cardiorenal syndrome (CRS) and consists of five distinct
subtypes based on the organ of origin (heart or kidney) and the
rate of progression (acute or chronic). Type 1 CRS is characterized
by an acute decline in cardiac function, causing acute renal
damage; type 2 leads to chronic cardiac abnormalities, resulting in
chronic renal damage; type 3 leads to acute renal damage causing
acute cardiac dysfunction; type 4 leads to chronic renal damage,
resulting in chronic cardiac dysfunction; and finally type 5
involves systemic diseases causing simultaneous cardiac and renal
damage (Table I) (1,3,5).
The present narrative review aims to provide an
overview of the principal experimental models used to investigate
CRS. Relevant publications were identified through structured
searches of the PubMed/MEDLINE (https://pubmed.ncbi.nlm.nih.gov), Web of Science
(https://www.webofscience.com) and Scopus
(https://www.scopus.com) databases. The search
strategy targeted experimental studies describing renal injury
models associated with cardiac dysfunction, as well as the
pathophysiological mechanisms underlying kidney/heart interactions.
Keywords and their combinations included 'cardiorenal syndrome',
'renal injury', 'acute kidney injury', 'chronic kidney disease',
'renal ischemia-reperfusion', '5/6 nephrectomy', 'unilateral
ureteral obstruction', 'cisplatin nephrotoxicity', 'adenine-induced
CKD', 'experimental models', 'cardiac remodelling' and
'kidney-heart axis'.
The search primarily covered studies published
between 1990 and 2025, although earlier landmark publications
describing the development of classical experimental models were
also considered when relevant. Studies were prioritized if they, i)
described well-characterized experimental models of renal injury,
ii) reported cardiac structural or functional consequences of
kidney dysfunction or iii) provided mechanistic insights into
renal/cardiac interactions, including inflammatory, metabolic and
neurohormonal pathways. Both surgical and chemical models of kidney
injury were considered. Additional references were identified
through manual screening of reference lists from key reviews and
primary articles.
Given the narrative nature of this review, the aim
was not to perform an exhaustive systematic synthesis but rather to
highlight representative, mechanistically informative studies that
have contributed to the current understanding of experimental CRS
types 3 and 4 models and their translational relevance to human
disease.
CRS3 is triggered by acute renal damage, resulting
in an acute cardiac dysfunction. A central pathophysiological
driver is neurohormonal activation. Indeed, AKI from haemodynamic
or organic causes leads to impaired renal perfusion, interstitial
oedema, tubular obstruction, hypoxia or endothelial dysfunction,
and induces an activation of the renin-angiotensin-aldosterone
system (RAAS) and the sympathetic nervous system (SNS), leading to
pre-renal vasoconstriction, sodium and fluid retention. An increase
in peripheral and systemic vascular resistance elevates cardiac
afterload and workload, thereby predisposing the heart to failure
(24,25). At the same time, oxidative stress
and inflammation carry out a pivotal role, as AKI stimulates the
release of reactive oxygen species (ROS) and pro-inflammatory
cytokines, thereby directly promoting damage to endothelial and
myofibrillar cells and further increasing vascular permeability
(26).
Electrolyte and acid-base imbalances are also
involved in CRS3 pathophysiology. When AKI is associated with
tubular renal dysfunction, potassium excretion and acid-base
buffering homeostasis are dysregulated, causing dyskalemia and
metabolic acidosis, both influencing cardiac contractility and
electrical conduction, increasing the risk of arrhythmias and
sudden cardiac arrest (26,27). As the kidneys carry out a central
role in regulating fluid homeostasis, AKI can result in venous
congestion, increased cardiac preload and subsequent cardiac
dysfunction. These alterations contribute to the development of
pulmonary oedema, all of which can substantially compromise cardiac
output (28). Emerging studies
have also highlighted the contribution of mitochondrial dysfunction
in CRS3, demonstrating that ischemic kidney injury promotes toxin
accumulation, which impairs mitochondrial activity in
cardiomyocytes, reducing energy production and increasing
susceptibility to apoptosis (29-31). Accordingly, during AKI, excretion
of uremic toxins such as indoxyl sulphate and p-cresyl sulphate is
associated with direct cardiotoxic effects, worsening myocardial
structure and function (32).
CRS4 is a chronic process where CKD gradually
worsens CV disease and increases mortality (33). Similar to CRS3, neurohormonal
activation is essential since constant RAAS and SNS stimulation
causes systemic hypertension, left ventricular hypertrophy (LVH)
and myocardial fibrosis. Chronic renal injury leads to impaired
tubulo-glomerular function, resulting in elevated plasma urea
levels and accumulation of uremic toxins, particularly in advanced
stages of CKD. This contributes to the development of uremic
cardiomyopathy, a condition characterized by left ventricular
impairment, diastolic abnormalities and pericardial effusion.
Prolonged exposure to uremic toxins promotes myocardial fibrosis
and microvascular damage, which are hallmarks of CRS4 (34-36).
Further aggravating CV health, CKD disrupts calcium
and phosphate metabolism through altered parathyroid hormone, and
vitamin D regulation. This imbalance promotes vascular
calcification, arterial stiffness and endothelial dysfunction,
enhancing the risk of developing ischemic heart disease (37). Another main process in CRS4 is
chronic inflammation, which contributes substantially to CV
complications. Indeed, this chronic inflammation promotes
endothelial dysfunction, accelerates the progression of
atherosclerosis and triggers adverse myocardial remodelling
(38,39). These processes collectively
impair vascular integrity and cardiac function, increasing the risk
of ischemic events, arrhythmias and HF (40,41).
Since CRS represents a primarily pathophysiological
syndrome, its clinical diagnosis is complicated by the convergence
and interaction of multiple overlapping signs and symptoms. Thus,
comprehensive diagnostics are necessary to determine both the
nature and severity of cardiorenal involvement and to guide patient
management. Clinical examination should integrate signs of cardiac
and renal dysfunction, including manifestations of volume overload
(for example, peripheral edema, pulmonary crackles, jugular venous
distention) alongside careful monitoring of urine output.
Laboratory investigations typically include the measurement of
renal function, such as serum creatinine and eGFR, as well as
cardiac biomarkers, including troponins and natriuretic peptides [B
natriuretic peptide (BNP) or NT-proBNP], which reflect myocardial
injury and wall stress. Additional parameters, including
urinalysis, serum electrolyte and a complete blood count, provide
insight into systemic homeostasis.
Importantly, aligning preclinical readouts with
clinical staging frameworks requires not only the selection of
analogous parameters but also their consistent and standardized
reporting. To reduce study heterogeneity and enhance comparability
with human CRS definitions, the present review recommended that
preclinical investigations include a defined core outcome set
covering both organ systems. For renal injury, these outcomes
should include: i) Functional markers [serum creatinine, blood urea
nitrogen (BUN), urine output], ii) structural damage assessments
[such as kidney injury molecule-1 (KIM-1) for tubular injury] and
iii) validated injury biomarkers [such as neutrophil
gelatinase-associated lipocalin (NGAL) or tissue inhibitor of
metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding
protein-7 (IGFBP7)] where available. For cardiac dysfunction, the
core dataset should include: i) Functional parameters (ejection
fraction, fractional shortening), ii) structural remodelling
indices (hypertrophy and/or fibrosis) and iii) circulating cardiac
biomarkers (for example, BNP or NT-proBNP) when technically
feasible. Explicit reporting of these parameters would facilitate
alignment with clinical CRS staging, enable cross-study comparisons
and strengthen translational interpretability of experimental
findings.
Finally, given the bidirectional and progressive
nature of cardiac and renal dysfunction in CRS types 3 and 4, early
identification and intervention depend on integrated, longitudinal
assessment across these parameters. A standardized and clinically
anchored evaluation framework in preclinical models is essential to
improving mechanistic insight and advancing therapeutic
development.
Both surgical and chemical models are widely used to
study kidney diseases associated with cardiac injury. Surgical
approaches, such as nephrectomy, ureteral obstruction or ischaemia,
allow precise control over the location and extent of renal damage,
facilitating the investigation of pathophysiological mechanisms and
therapeutic interventions (42,43). By contrast, chemical models using
nephrotoxic agents such as cisplatin provide a less invasive,
cost-effective and scalable alternative to induce renal injury.
While each method has its advantages and limitations, their
combined use offers complementary insights into the cross-talk
between kidneys and the heart and supports the development of
targeted therapeutic strategies.
For >5 decades, surgical models of kidney damage
have been created to mimic the pathophysiology of several renal
disease causes (44-46). Among these models, 5/6
nephrectomy (Nx5/6) was considered to closely mimic the
pathophysiology of CKD (47), as
the reduction in renal mass triggers a progressive decline in
kidney function. Another widely used experimental model is
unilateral ureteral obstruction (UUO), which replicates key
characteristics of obstructive nephropathy, a condition affecting
10% of patients with CKD (48).
Finally, the renal ischaemia-reperfusion (rIR) model, which covers
situations highlighting a short-term kidney damage followed by a
later restoration of renal function, is frequently used to
investigate AKI (49,50).
Multiple studies using this model have reported
varying degrees of cardiac damage, occurring as early as 5 days up
to 32 weeks after surgery. The CV phenotype following
Nx5/6 includes hypertension, LVH and cardiac fibrosis.
Additional characteristics, such as reduction of ejection fraction
and fractional shortening, have been reported. However, according
to the literature, variations in these parameters may be influenced
by multiple factors, including the duration of the model, species,
strain and housing conditions [Table II (53-111)]. Aside from the
well-characterized renal damage, including immune cell infiltration
(53-55,63), elevated levels of
pro-inflammatory cytokines and chemokines (IL-6, TNF-α, IL-1β and
monocyte chemoattractant protein-1) (56,60,64), and increased interstitial and
glomerular fibrosis (53,61,63,65),
this model also exhibits a notable increase in apoptosis markers
within renal and cardiac tissue (57,60,66).
Systemic complications following haemodynamic and
inflammatory alterations may promote an elevated oxidative stress
in both renal and cardiac tissues over time (54,69,71,76-78,80), following heightened protein
(79) and lipid oxidation
(76,80). This seems to be partly due to a
decrease in erythropoietin production after Nx5/6
(60,89), decreasing both haemoglobin and
haematocrit levels (60,66,76,83), thus maintaining an oxidative
condition. In addition, haemodynamic alteration is maintained due
to SNS activity modulation (84-86) and activation of the RAAS
(62,68,80,84,87,88,90,114). Experimental therapies targeting
antioxidant delivery and pharmacological RAAS blockade have been
reported, showing varying levels of renal and cardiac protection
(115,116). Moreover, Nx5/6
exhibited metabolic disturbances, including raised ionic and lipid
metabolite blood levels (68,69,71,91-94), despite increased diuresis in
affected animals (61,93). These findings highlighted the
possibility of dietary approaches to help slow the disease
progression. To resume, the Nx5/6 model is a
well-established method for inducing CKD and studying its systemic
effects, particularly CRS. By substantially reducing nephron mass,
it mimics key features of human CKD, including inflammation,
fibrosis, oxidative stress and CV complications such as hypertrophy
and fibrosis.
The UUO model involves surgical obstruction of one
ureter, either partially or completely. This is a well-established
model that causes gradual renal damage marked by tubulointerstitial
inflammation and later fibrosis. Ureteral occlusion increases
intratubular pressure, initiating nephron damage. This mechanical
stress, along with exposure to harmful substances, induces tubular
cell damage, triggering aberrant cellular activation, dysregulated
cell cycle progression or cell death (117). Notably, this model allows
researchers to investigate tissue damage without renal dysfunction
(defined by a decrease in eGFR or an increased serum creatinine);
thus, cardiac complications such as LVH and cardiac fibrosis still
manifest [Table III (98,112,118-136)].
The UUO model is characterized by the local
production of cytokines, chemokines and adhesion molecules, thus
promoting the recruitment of immune cells. Several studies have
shown that neutrophil and macrophage infiltration occurs ≤3 days
following ureteral obstruction (137-139), whereas CD4+ and
CD8+ lymphocyte infiltration was more pronounced after 7
days (140-142). All these elements aggravate
tubule cell damage by intensifying inflammation.
UUO causes extensive functional and structural
alterations in the kidney, including tubular atrophy, interstitial
fibrosis and glomerular sclerosis beyond inflammation. Activation
of the TGF-β/Smad signalling pathway, upregulation of pro-fibrotic
mediators such as connective tissue growth factor and plasminogen
activator inhibitor-1 (143,144), drives these pathological
changes. This promotes in particular myofibroblast activation,
expressing α-SMA and further, the progression of interstitial
fibrosis characterized by an increase in activated fibroblasts and
the accumulation of extracellular matrix components (118,122,123).
Beyond its renal effects, UUO also exerts a
considerable influence on the CV system, contributing to cardiac
remodelling and dysfunction through systemic inflammation,
oxidative stress and altered haemodynamics. Indeed, even before the
onset of overt kidney failure, early signs of cardiac hypertrophy
and fibrosis suggest that renal injury can directly contribute to
cardiac remodelling. Increased oxidative stress, upregulation of
the TGF-β/Smad signalling pathway and elevated inflammatory
cytokine expression are associated with the fibrotic modifications
in the heart (119,123,124). In addition to myocardial
fibrosis, UUO may promote endothelial dysfunction, increased
arterial stiffness, poor vasodilation and elevated cardiac damage
markers such as BNP and ANP (119,145,146), therefore aggravating CRS. The
extent of these CV alterations varies depending on the rodent
strain and experimental conditions.
Further aggravating the renal injury, the RAAS is
upregulated as it drives pre-renal vasoconstriction, sodium
retention and inflammation (122,147). Experimental studies using the
UUO model have shown that inhibition of the RAAS by
angiotensin-converting enzyme (ACE) inhibitors or aldosterone
antagonists may reduce cardiac fibrosis, hypertrophy and vascular
dysfunction (119,122,124,125). These results highlight the
therapeutic potential of RAAS blockade in treating CKD-associated
CV disease.
In conclusion, along with notable CV effects
including cardiac hypertrophy and fibrosis, the UUO model
appropriately shows the progression of renal injury marked by
tubulointerstitial inflammation and later fibrosis. It is a useful
instrument for investigating cardiorenal interactions and possible
therapies since it highlights the essential roles of inflammation,
TGF-β/Smad signalling and RAAS activation in driving both renal and
cardiac pathology.
rIR injury represents a key model for studying AKI
and transition to CKD. This model could also contribute to the
knowledge of CRS, a condition in which AKI promotes cardiac
dysfunction and structural damage. Reperfusion, after renal
ischemia induced by a transient renal pedicle clamping, which
causes a brief period of reduced blood flow, results in extensive
cellular injury due to the abrupt restoration of oxygen and
nutrients. Moreover, this process leads to oxidative stress,
inflammation and tissue damage. The rIR model can be applied in
different ways, depending on the type of ischemia (unilateral or
bilateral), the duration of ischemia or the need to increase the
renal severity of the model through unilateral nephrectomy,
promoting transient renal dysfunction, regardless of the
reperfusion time (Table III).
The pathophysiology of rIR may lead to mitochondrial dysfunction,
enhanced ROS generation and activation of pro-inflammatory pathways
(148).
Systemic release of plasma pro-inflammatory
cytokines (TNF-α, IFN-γ, IL-1β, IL-6 and IL-10) is one of the major
effects of rIR (126-128). These cytokines stimulate NF-κB
and JAK/STAT pathways, contributing to cardiac inflammation and
fibrosis (128,149,150). Endothelial dysfunction, which
is characterized by impaired vasodilation and increased vascular
permeability (151), also
results from the inflammatory response, thus contributing to renal
and cardiac dysfunction. Oxidative stress is also observed after
rIR. ROS accumulation results in lipid peroxidation, protein
oxidation and mitochondrial damage, and can impair cardiac
contractility and induce apoptosis in cardiomyocytes (127,129,152). Additionally, oxidative stress
could induce the activation of RAAS (153), promoting hypertension, cardiac
hypertrophy and myocardial fibrosis.
rIR can also alter cardiac function, inducing
cardiomyocyte calcium handling by cardiomyocytes. Perturbation of
intracellular calcium homeostasis results in the inability of the
cell to regulate excitation-contraction coupling, predisposing to
arrhythmias and decreasing cardiac output (128,154). Furthermore, the renal
dysfunction leads to the accumulation of uremic toxins such as
p-cresyl sulphate and indoxyl sulphate which also contribute to
cardiomyocyte injury, increased oxidative stress and myocardial
fibrosis (155,156).
Neurohormonal activation secondary to rIR is
characterized by elevated SNS activity and impairment in the RAAS
(157,158). The resulting alterations cause
a dysregulation of the vasoreactivity, and the heart afterload
promotes left ventricle hypertrophy (159). Fluid retention from chronic
volume overload adds to the worsening of cardiac remodelling and
the risk for HF.
Pharmacologic interventions that reduce
inflammation, oxidative stress and neurohumoral activation have
been shown to attenuate heart injury in experimental models of rIR.
Indeed, antioxidant, anti-inflammatory and RAAS-inhibiting drugs
(including ACE inhibitors or angiotensin receptor blockers) can
decrease myocardial fibrosis and enhance cardiac function after rIR
(127,130,160-162). For instance, pharmacological
inhibition of the lectin Galectin-3 prevented cardiac injury
following AKI, by reducing renal damage and inflammation, thereby
limiting cytokine release, cardiac macrophage infiltration and
fibrosis, ultimately restoring cardiac function (126).
Hence, rIR injury may emerge as a major element of
CRS, connecting AKI with secondary cardiac dysfunction through
systemic inflammation, oxidative stress, calcium mishandling,
neurohumoral activation and uremic toxicity. Elucidating these
mechanisms is key to the development of therapeutic approaches
targeted at blocking the advancement of CRS3 and improving patient
outcomes.
Among the various chemical nephrotoxic agents used
in experimental nephrology, cisplatin and adenine stand out as the
most widely used compounds upon which to model AKI and CKD,
respectively. These nephrotoxins induce reproducible renal injury
through well-defined mechanisms; cisplatin causes acute tubular
necrosis and inflammation, while adenine leads to
tubulointerstitial fibrosis and progressive CKD. Both models have
been useful in elucidating the systemic consequences of kidney
dysfunction on the heart, enabling the investigation of
haemodynamic alterations, oxidative stress, fibrosis and
inflammatory pathways that contribute to cardiac remodelling in
cardiorenal syndromes [Table IV
(98,163-187)].
Cisplatin is a widely used chemotherapeutic agent
whose major dose-limiting side effect is acute nephrotoxicity,
primarily targeting the proximal tubules. In rodent models,
systemic administration induces a marked decline of renal function,
proximal tubular necrosis (188), inflammation (189) and oxidative stress (190), closely reproducing the clinical
profile of nephrotoxic AKI observed in patients with cancer
(163,191-193). The severity of injury depends
on the dose, strain and treatment duration, and in prolonged
regimens, may progress to persistent injury with interstitial
fibrosis.
Although this model is primarily used to study
drug-induced nephrotoxicity, multiple studies have shown that
cisplatin induced AKI. In rodent models, cisplatin-induced AKI is
typically induced using doses ranging from 3 to 10 mg/kg, mostly
administered intraperitoneally, either as a single injection or as
repeated weekly injections over 1-3 weeks, depending on the desired
severity of renal injury. These regimens produce dose-dependent
tubular injury, inflammation and oxidative stress (Table IV). In C57BL/6 mice, weekly
regimens of 6 mg/kg for 3 weeks may reduce ejection fraction and
stroke volume, induce LVH, impair diastolic relaxation and promote
myocardial fibrosis (163).
These changes are accompanied by cardiomyocyte apoptosis,
activation of inflammatory pathways and dysregulation of PI3K/Akt
signalling (164,165). Other studies have identified
endoplasmic reticulum stress and mitochondrial ultrastructural
damage as central drivers of contractile impairment (166) as well as gut microbiota
dysbiosis which exacerbates systemic inflammation (163). Antioxidant and
anti-inflammatory interventions have demonstrated both renal and
cardiac protection. Taurine (165), salvianolic acid B (167), maltol (164), probiotics
(Lactobacillus) (163)
and polyphenol-rich plant extracts (168) may reduce oxidative stress,
attenuate myocardial fibrosis and preserve left ventricular
function.
Taken together, the cisplatin-induced AKI model
provides a reproducible and clinically relevant platform for
studying kidney and heart interactions in CRS3, particularly during
the acute phase. However, its application to the study of chronic
cardiac remodelling and dysfunction is more limited, as the
majority of protocols focus on short-term outcomes and CV injury is
typically secondary to renal and systemic toxicity. Extended or
repeated dosing regimens may help to model the AKI to CKD
transition and to characterize mechanisms of sustained cardiac
injury.
Adenine-induced CKD is a well-established,
non-surgical rodent model extensively used to study CRS4, in which
chronic renal injury contributes to progressive CV disease. This
model is typically generated through dietary administration of
adenine at concentrations ranging from 0.15 to 0.75%, incorporated
into rodent chow. Protocol duration generally varies from 2 to 20
weeks, depending on the severity of renal injury required.
Alternative protocols include gavage or intraperitoneal
administration, although dietary exposure remains the most widely
used approach (Table IV). The
adenine is metabolized in the liver to 2,8-dihydroxyadenine, a
poorly soluble metabolite that precipitates in renal tubules. This
crystal deposition induces tubular obstruction, inflammation and
progressive tubulointerstitial fibrosis, ultimately leading to a
sustained decline in renal function (194). This model faithfully reproduces
several hallmarks of human CKD, including elevated serum creatinine
and BUN, azotaemia, proteinuria, altered urine output, mineral
metabolism disorders, systemic inflammation and interstitial
fibrosis (171,187).
Importantly, multiple studies have demonstrated
that adenine-induced CKD is associated with consistent CV
alterations characteristic of CRS4 (172,173). For instance, prolonged
administration of adenine (0.15% for 20 weeks) has been shown to
impair systolic function (reduced ejection fraction) and induce
myocardial fibrosis with extracellular matrix accumulation
(174). Early metabolic
remodelling has also been described, with fibroblast growth factor
23 (FGF23)-FGFR4 signalling driving mitochondrial dysfunction and
concentric LVH in C57BL/6 mice (175). Other studies report diastolic
dysfunction with preserved systolic performance, mimicking the HF
with the preserved ejection fraction (HFpEF) phenotype frequently
observed in patients with CKD (176). Additional haemodynamic changes
include hypertension, altered circadian blood pressure rhythms and
non-dipping profiles contributing to CV burden (177-179,187).
Additionally, sex-specific differences have been
documented. For instance, in Wistar rats, both sexes developed
myocardial fibrosis under adenine feeding, but males exhibited more
severe renal impairment, concentric hypertrophy and alterations in
ERK1/2 and oestrogen receptor signalling pathways (178). Furthermore, adenine-induced
uraemia increases myocardial susceptibility to secondary insults;
ischaemia-reperfusion injury severity is exacerbated in uremic
rats, particularly under air pollution exposure, underscoring
heightened mitochondrial vulnerability and oxidative stress
(186).
Collectively, these findings establish the adenine
model as a robust and mechanistically informative platform for
studying CRS4. It recapitulates key features of renal injury,
systemic inflammation, myocardial fibrosis, cardiac hypertrophy and
haemodynamic alterations relevant to human disease. Nevertheless,
certain limitations must be considered, including dose-dependent
weight loss, variability in disease severity based on dietary
concentration and duration and limited progression to
glomerulosclerosis (194).
Despite this, adenine-induced CKD remains a cornerstone
experimental model for dissecting the mechanisms linking chronic
renal dysfunction to adverse CV remodelling.
Overall, both surgical and chemical models provide
complementary and well-established platforms for studying renal
disease-induced cardiac dysfunction in CRS (Table V). Surgical approaches such as
Nx5/6, UUO and rIR enable controlled investigation of
CKD and AKI-driven mechanisms, including inflammation, fibrosis,
oxidative stress and neurohumoral activation, all of which
contribute to cardiac remodeling and dysfunction. In parallel,
chemical models such as cisplatin and adenine offer reproducible
and scalable alternatives that recapitulate acute and chronic renal
injury and their systemic cardiovascular consequences. While each
model captures specific aspects of CRS pathophysiology, none fully
reflects the complexity of human disease. Therefore, their combined
and context-dependent use remains essential for elucidating
kidney-heart crosstalk and advancing translational therapeutic
strategies.
Animal models are indispensable for investigating
the complex pathophysiology of CRS, offering controlled and
reproducible environments that are difficult to achieve in human
studies enabling detailed exploration of disease mechanisms and
therapeutic interventions (195,196). A major advantage of these
models lies in the ability to tightly regulate genetic, dietary and
environmental variables, thereby enhancing experimental
reproducibility and facilitating the validation of mechanistic
hypotheses and the preclinical testing of novel therapies (195-198). In addition, animal models allow
investigation of organ crosstalk and the progression of dysfunction
in one organ following injury to the other, processes that are
difficult to isolate in clinical settings (197-199). The relatively rapid progression
of the disease in these models, occurring over weeks or months
rather than the years seen in humans, facilitates efficient study
of disease onset, trajectory and treatment response (196,200,201). Consequently, a range of CRS
phenotypes, including those driven by CKD, HF or metabolic
syndrome, can be simulated to support the development of targeted
interventions (196,201,202).
However, translating findings from experimental
models to clinical CRS remains challenging. In clinical practice,
the interpretation of renal and cardiac biomarkers in CRS is often
complicated by several confounding factors. Baseline CKD may alter
serum creatinine and natriuretic peptides levels (203,204), while fluid overload,
haemodynamic instability or diuretic therapy can affect urine
output and circulating biomarkers (1,205,206). Similarly, medications such as
vasopressors, renin-angiotensin system inhibitors or nephrotoxic
drugs may modify both renal and cardiac function (207-209). These factors should be
considered when interpreting preclinical findings, particularly in
CRS types 3 and 4, where establishing the temporal relationship
between renal and cardiac dysfunction may be difficult.
Despite their strengths, current animal models have
several limitations. Species-specific physiological differences,
particularly in cardiovascular and renal systems, may limit the
extrapolation to humans (195,199,210). Moreover, the majority of models
focus on isolated organ injury or acute pathological processes and
therefore fail to capture the chronic, multifactorial and
progressive nature of human CRS (197,198,211). In particular, the frequent
absence of common comorbidities such as diabetes, hypertension,
atherosclerosis and ageing represents a major gap as these factors
substantially shape disease trajectory and patient outcomes
(196,200). To improve clinical fidelity,
experimental models can be refined by combining classical renal
injury models with established cardiometabolic conditions. For
example, renal ischaemia-reperfusion or adenine-induced CKD may be
studied using a diabetic background (for example,
streptozotocin-induced diabetes or db/db mice), hypertensive models
(for example, angiotensin II infusion or spontaneously hypertensive
rats) or atherosclerosis-prone strains such as
ApoE−/− mice. The incorporation of aged
animals or dietary interventions, including high-fat or
high-phosphate diets, can further approximate the metabolic and
vascular environment typical observed in human CRS. Importantly,
incorporating comorbidities enhances clinical fidelity but
complicates interpretation, as they alter renal baselines,
biomarkers and cardiac remodelling. Combined models improve
translational relevance but increase complexity, so model choice
should align with mechanistic vs. translational study goals.
Ethical and regulatory constraints, particularly large animal
studies, must also be considered (198,210) (Fig. 1) and the clinical relevance of
selected preclinical models are discussed [Table VI (51,212-220)].
The cardiotoxic effect of uraemia has been
evaluated through this model, in the cardiac pathology of rats with
Nx5/6 (without acute myocardial infarction), where
capillary/myocardial cell mismatch and interstitial fibrosis were
found. Similarly, autopsy studies have shown that the number of
capillaries per myocardial cell decreases, and fibrosis increases
in uremic patients (221,222). Accumulation of uremic toxins
not only affects myocardial remodelling but is also associated with
an increase in the incidence of ischemic heart disease. Indeed,
Nx5/6 induced uremic rats have lower myocardial cell
volume density, a substantially larger ratio of infarct area and
reduced intrinsic tolerance of myocardium to ischemic injury
(223,224). These findings suggest that
uremic cardiomyopathy may increase susceptibility to ischemic
injury, supporting clinical observations that patients with
advanced CKD have a higher risk of cardiovascular events. They also
advocate for the immediate use of currently available
anti-remodelling strategies, such as β-blockers, ACE inhibitors or
angiotensin II type 1 (AT1) receptor blockers, in
patients with CKD after an acute myocardial infarction.
From a translational standpoint, UUO has been
highly involved in transcriptomic profiling studies, revealing both
coding and non-coding RNA signatures that may serve as biomarkers
or therapeutic targets for renal fibrosis and potentially CRS
(226). Furthermore, due to its
consistency and rapid progression, the model is well-suited for
early-phase drug screening and mechanistic validation of
nephroprotective compounds.
The UUO model is a key experimental tool for
studying obstructive nephropathy, hydronephrosis and renal
interstitial fibrosis. It induces rapid urine obstruction by
ligating one ureter, resulting in hydronephrosis and renal oedema.
Clinically, hydronephrosis is characterized by loss of renal
medullary tissue, most often as a consequence of obstructive
nephropathy. In humans, the leading causes include congenital
anomalies, urolithiasis, malignancy or fibrotic inflammatory
processes. Both paediatric and adult case reports have shown an
association between hydronephrosis and elevated blood pressure,
where the surgical relief of the obstruction often alleviates the
hypertension (227,228). In a study using Sprague Dawley
rats with spontaneous hydronephrosis, impaired cardiac autonomic
regulation, including elevated resting heart rate, reduced heart
rate variability and blunted baroreflex sensitivity, has been
reported. These changes occurred independently of peripheral RAAS
activation and were attributed to enhanced angiotensin II activity
in the nucleus tractus solitarius, a key point in clinical CRS
(229).
However, the UUO model does not fully capture the
chronic, recurrent and multifactorial characteristics of human CKD
and obstructive uropathy. Most importantly, UUO induces profound
structural changes with relatively modest or absent long-term
functional decline in the contralateral kidney, which limits its
utility in modelling the progressive renal impairment
characteristic of CRS (230).
Despite these constraints, emerging evidence suggests that
prolonged UUO can lead to systemic consequences, including cardiac
fibrosis, inflammation and lymphangiogenesis, indicating its
partial utility in modelling the renal-to-cardiac axis central to
CRS 3/4 (214,231). Species-specific signalling must
be considered when using animal models. Although
endothelial-to-mesenchymal transition may play a role in fibrosis
in UUO mice, its contribution seems limited in human kidneys
(232,233).
rIR injury models are widely employed in
preclinical research to simulate AKI, delayed graft function and
early post-transplant complications. These models are also highly
relevant for studying CRS, particularly type 3, in which acute
renal insults lead to secondary cardiac dysfunction, and type 4,
where persistent renal injury contributes to progressive CV
remodelling. rIR models replicate key pathophysiological events
observed in human AKI and kidney transplantation. From a
translational perspective, these models recapitulate key features
of human ischemic injury and post-transplant pathology, including
the transition from acute to chronic injury characterized by
interstitial fibrosis, tubular atrophy and persistent inflammation.
In clinical settings involving rIR, such as kidney transplantation,
partial nephrectomy, renal artery angioplasty, cardiopulmonary
bypass, aortic bypass surgery or other medical conditions, these
procedures remain among the most frequent causes of acute renal
failure.
Molecular and transcriptomic signatures from these
models show substantial overlap with human kidney transplant
biopsies, supporting their utility in preclinical evaluation of
targeted therapies and identification of prognostic biomarkers
(234). Some biomarkers
validated by animal experiments have also been applied to predict
human AKI, including neutrophil NGAL, liver-type fatty acid-binding
protein (L-FABP), KIM-1, tissue inhibitor of metalloproteinase-2
(TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7).
Serum IL-6 and IL-8 have been confirmed as early indicators of AKI
in patients undergoing cardiac bypass surgery (235-237). Importantly, these models have
also revealed the systemic impact of renal ischemia on distant
organs, including the heart. Experimental data show that cytokine
release following rIR can contribute to myocardial inflammation and
dysfunction, offering mechanistic insight into the renal-to-cardiac
axis that defines CRS (238-240). As such, these models are
clinically relevant for investigating the early inflammation and
haemodynamic drivers of cardiac injury following AKI.
The rIR rodent model shares similarities with
certain aspects of AKI in humans, such as kidney tissue damage,
tubular epithelial cell proliferation, inflammatory response and
fibrosis. In both rats and mice, ischemic injury leads to the
proliferation of proximal renal tubular cells (241). Similar evidence of post-injury
recovery response has also been observed in human biopsy samples
after ischaemic or renal injury, as well as in cases of delayed
transplant function (242).
However, the regenerative capacity of human kidneys
is limited, resulting in a slower and incomplete recovery process
after AKI compared with that of mice (242,243). Therefore, the progression and
severity of diseases in rodent rIR models may not be the same as in
human AKI. Renal tubular injury is evident in human kidneys, but
necrosis after ischemia appears patchy, while in rodent models, it
is more pronounced as cell death. Furthermore, these models lack
key human-specific modifiers such as alloimmune responses, chronic
immunosuppression and patient-level comorbidities (for example,
diabetes or CV disease), which influence both renal and cardiac
outcomes in clinical settings (216).
Cisplatin is a widely used chemotherapeutic agent
with well-documented nephrotoxicity and emerging evidence of CV
complications in humans. In preclinical research, cisplatin-induced
AKI serves as a clinically relevant model for investigating the
kidney-heart axis in patients with cancer, particularly within the
framework of CRS3, where AKI precipitates or exacerbates cardiac
dysfunction. Cisplatin-induced AKI may contribute to systemic
endothelial dysfunction, electrolyte disturbances and a
pro-thrombotic state, factors known to impact CV homeostasis. When
compounded by high phosphate diets, aging or Klotho deficiency,
these models exhibit uremic vasculopathy and cardiac remodelling,
reinforcing their utility for studying CRS (244,245). Importantly, combination models
that integrate cisplatin exposure with dietary or genetic risk
factors (for example, high phosphate, aged mice, Klotho deficiency)
allow the simulation of AKI-to-CKD progression and concurrent CV
injury, thereby extending the model's relevance to CRS 3/4
(244,245). The mechanistic pathways
activated in cisplatin-induced injury may not fully represent those
in metabolic or haemodynamic CKD. Additionally, preclinical models
often lack confounding factors common in patients with cancer, such
as polypharmacy, pre-existing CV disease and heterogeneous tumour
biology. The clinical relevance of these models is underscored by
known risk factors for cisplatin nephrotoxicity, including
pre-existing CKD, CV disease and NSAID use (246). Standard preventive strategies,
such as intravenous hydration, magnesium supplementation and
mannitol-induced diuresis, are mirrored in preclinical designs.
Novel therapeutic approaches, including antioxidant compounds,
mitochondrial protectants and natural products, are currently under
investigation in these models (247-249).
Adenine-induced CKD models in rodents induce
tubulointerstitial injury, renal insufficiency and a spectrum of
metabolic disturbances that closely mimic the human CKD phenotype.
Animals consistently develop elevated plasma urea and creatinine,
anaemia, hyperphosphatemia, hypocalcemia and altered levels of
FGF23, all of which are hallmarks of advanced CKD and drivers of CV
disease in patients (176,196,250). Cardiac alterations observed in
adenine-induced CKD include LVH, increased end-diastolic pressure
and diastolic dysfunction with preserved systolic function. This
mirrors the clinical presentation of HFpEF, a common cardiac
manifestation in patients with CKD (176,251). Furthermore, this model induces
substantial cardiac oxidative stress, inflammation and DNA damage,
with upregulation of Nrf2 and pro-inflammatory cytokines (250,252), but also endothelial
dysfunction, characterized by impaired nitric oxide (NO)-dependent
vasodilation in the aorta, and a prothrombotic state with elevated
platelet counts, both of which reinforce the model's relevance for
studying vascular contributions to CRS and CV risk in CKD and mimic
the closely reproduce the complex CV alterations observed in human
(250,253). Although the abrupt onset and
severity of renal dysfunction in experimental models may differ
from the more gradual and heterogeneous progression seen in
clinical settings, this discrepancy may limit the generalizability
of therapeutic outcomes.
CRS3 and CRS4 highlight the complex bidirectional
interactions between renal and cardiac dysfunction through shared
mechanisms including inflammation, oxidative stress and
neurohormonal activation. Experimental models such as
Nx5/6, UUO, rIR, cisplatin and adenine-induced injury
reproduce key aspects of these syndromes and have substantially
improved the mechanistic understanding of kidney-heart
interactions. However, important limitations remain, including
species-specific differences, the frequent absence of common
comorbidities, and the limited ability to reproduce the progressive
and multifactorial nature of human CRS. Addressing these
limitations, future research should prioritize the development of
models incorporating cardiometabolic comorbidities, improved
standardization of experimental readouts aligned with clinical CRS
definitions and integrative multiorgan models that better capture
the chronic and bidirectional progression of cardiorenal
dysfunction. Such approaches may help bridge the gap between
experimental discovery and clinical translation.
Not applicable.
SMF, SH, JRO, JJB, and LB prepared the manuscript.
CAA, LB, and CEC critically reviewed and edited the manuscript. All
the authors contributed to the article, and all authors read and
approved the final manuscript. Data authentication not
applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This work was supported by the French National Research Agency
(grant no. ANR-22-CE14-0024) and the National Agency of Research
and Development (ANID) Fondecyt Regular (grant no. 1231909) and the
ECOS ANID (grant no. 20210024/C21S03).
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