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).

The Nx_5/6 experimental model involves two separate surgical procedures to reduce renal mass, usually performed one week apart. In general, first, a total nephrectomy of one kidney is carried out and second, the poles of the contralateral kidney are excised. Pole excision varies depending on the species and the specific model used. In mice, direct ligation or excision of the renal poles is currently performed, whereas in rats, ligation of the lateral renal arteries is often used (47,51).

The Nx_5/6 model is used to induce CKD in rodents and is employed to investigate cardiac damage secondary to kidney injury. The surgical excision of one kidney and partial infarction of the other greatly lowers functional nephron mass and reduces eGFR. It is a useful tool for studying the pathophysiology of CRS since it closely mirrors progressive renal failure and associated CV complications observed in human CKD. Reduction in nephron mass results in compensatory hyperfiltration, thereby promoting glomerular hypertension, proteinuria and further renal damage (52). This series of events includes glomerulosclerosis, tubulointerstitial fibrosis and progressive renal failure.

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 Nx_5/6 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).

The Nx_5/6 model promotes structural and functional cardiac alterations, as evidenced by increased levels of markers such as atrial natriuretic peptide (ANP) and BNP, which begin to rise ~5 weeks after surgery and remain persistently elevated in both cardiac and plasma over extended periods (58,59,62,67,68). Similar to the kidney, the heart shows early immune cell infiltration, including T cells and monocytes, as early as day 5 following injury (112). Along with fibrotic markers such as fibronectin, collagens I, III, IV and V, TGF-β, and α-smooth muscle actin (α-SMA) (53-55,69-74), pro-inflammatory cytokine expression highly increases (53,60,69,73). This is followed by an increase in apoptotic cells 4 weeks after surgery (58,66,74-76,79). This model also exhibits endothelial damage beyond the heart and kidneys, as demonstrated by increased expression of vascular adhesion molecules and elevated levels of vasoconstrictors such as endothelin-1 and norepinephrine (69,81,82,113). These molecular, structural and vascular alterations aggravate the course of CRS by promoting increased arterial stiffness and impaired vasomodulation, thereby limiting renal adaptation to haemodynamic fluctuations.

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 Nx_5/6 (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, Nx_5/6 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 Nx_5/6 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.

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 Nx_5/6, 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.

As aforementioned, the Nx_5/6 model is one of the most widely used experimental systems to study CKD and its CV complications, making it particularly relevant to the study of CRS4/3. The model reliably reproduces cardiac complications commonly seen in advanced CKD. From a translational perspective, this model provides a clinically relevant platform to investigate mechanisms and test interventions targeting the CV sequelae of CKD.

The cardiotoxic effect of uraemia has been evaluated through this model, in the cardiac pathology of rats with Nx_5/6 (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, Nx_5/6 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.

The nephron loss induced by Nx_5/6 leads to chronic hypertension due to the alteration of sodium and water excretion, which impairs cardiac contractility and diastolic strain, while increasing cardiac mass. The reduction in cardiac contractility is largely attributed to LVH and diastolic dysfunction, characterized by increased myocardial cell diameter and volume, along with a decreased capillary density, as observed in experimental models of renal failure.

The Nx_5/6 model has also contributed to an understanding of the systemic pathways increasingly recognized in clinical settings, such as the gut-kidney-heart axis. Alterations in gut microbiota and microbial metabolites in Nx_5/6 animals have been associated with cardiorenal dysfunction, suggesting potential therapeutic targets with emerging clinical interest (225). Despite the aforementioned strengths, the clinical translatability of the Nx_5/6 model is limited by several factors. It does not fully replicate the comorbid landscape of human CKD, notably lacking common features such as diabetes, obesity and atherosclerosis, which often exacerbate CV risk. Moreover, differences in CV responses across rodent strains introduce variability and may complicate the extrapolation to diverse human populations (90).

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.