Practical Approaches to the Management of Cardiorenal Disease beyond Congestion.

BACKGROUND: The coexistence of heart and kidney diseases, also called cardiorenal syndrome, is very common, leads to increased morbidity and mortality, and poses diagnostic and therapeutic difficulties. There is a risk-treatment paradox, such that patients with the highest risk are treated with lesser disease-modifying medical therapies. SUMMARY: In this document, different scientific societies propose a practical approach to address and optimize cardiorenal therapies and related comorbidities systematically in chronic cardiorenal disease beyond congestion. Cardiorenal programs have emerged as novel models that may assist in delivering coordinated and holistic management for these patients. KEY MESSAGES: (1) Cardiorenal disease is a ubiquitous entity in clinical practice and is associated with numerous barriers that limit medical treatment. (2) The present article focuses on the practical approaches to managing chronic cardiorenal disease beyond congestion to overcome some of these barriers and improve the treatment of this high-risk population.

Novel Perspectives in Chronic Kidney Disease-Specific Cardiovascular Disease.

Chronic kidney disease (CKD) affects > 10% of the global adult population and significantly increases the risk of cardiovascular disease (CVD), which remains the leading cause of death in this population. The development and progression of CVD-compared to the general population-is premature and accelerated, manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. CKD and CV disease combine to cause multimorbid cardiorenal syndrome (CRS) due to contributions from shared risk factors, including systolic hypertension, diabetes mellitus, obesity, and dyslipidemia. Additional neurohormonal activation, innate immunity, and inflammation contribute to progressive cardiac and renal deterioration, reflecting the strong bidirectional interaction between these organ systems. A shared molecular pathophysiology-including inflammation, oxidative stress, senescence, and hemodynamic fluctuations characterise all types of CRS. This review highlights the evolving paradigm and recent advances in our understanding of the molecular biology of CRS, outlining the potential for disease-specific therapies and biomarker disease detection.

Bioinformatics analysis of the microRNA genes associated with type 2 cardiorenal syndrome.

BACKGROUND: MicroRNAs (miRNAs) are important regulatory factors in the normal developmental stages of the heart and kidney. However, it is currently unclear how miRNA is expressed in type 2 cardiorenal syndrome (CRS). This study aimed to detect the differential expression of miRNAs and to clarify the main enrichment pathways of differentially expressed miRNA target genes in type 2 CRS. METHODS: Five cases of healthy control (Group 1), eight of chronic heart failure (CHF, Group 2) and seven of type 2 CRS (Group 3) were enrolled, respectively. Total RNA was extracted from the peripheral blood of each group. To predict the miRNA target genes and biological signalling pathways closely related to type 2 CRS, the Agilent miRNA microarray platform was used for miRNA profiling and bioinformatics analysis of the isolated total RNA samples. RESULTS: After the microarray analysis was done to screen for differentially expressed circulating miRNAs among the three different groups of samples, the target genes and bioinformatic pathways of the differential miRNAs were predicted. A total of 38 differential miRNAs (15 up- and 23 down-regulated) were found in Group 3 compared with Group 1, and a total of 42 differential miRNAs (11 up- and 31 down-regulated) were found in Group 3 compared to Group 2. According to the Gene Ontology (GO) function and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, the top 10 lists of molecular functions, cellular composition and biological processes, and the top 30 signalling pathways of predicted gene targets of the differentially expressed miRNAs were discriminated among the three groups. CONCLUSION: Between the patients with CHF and type 2 CRS, miRNAs were differentially expressed. Prediction of target genes of differentially expressed miRNAs and the use of GO function and KEGG pathway analysis may reveal the molecular mechanisms of CRS. Circulating miRNAs may contribute to the diagnosis of CRS, and further and larger studies are needed to enhance the robustness of our findings.

Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.

[Cardiorenal syndrome in geriatric patients]. / Kardiorenales Syndrom bei geriatrischen Patienten.

The unfavorable mutual influence of the kidney and heart functions in acute or chronic kidney and/or heart failure has defined the cardiorenal syndrome (CRS) since a consensus conference in 2004. The pathophysiological considerations and the subsequent treatment approaches determine the classification into five types. The syndrome has a high prevalence in geriatric patients. The interactions of medications on one or the other organ system require an interaction of treatment modalities in order to improve the prognosis and prevent acute deterioration. Exact knowledge of the respective indications, differential treatment approaches and specifics in dealing with CRS can improve the current undertreatment due to concerns about side effects.

Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome.

Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial injury may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote cardiac mitochondrial quality control, we assessed whether these proteins were dysregulated during CRS-3-related cardiac depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of CRS-3. DUSP1 transgenic (DUSP1Tg) mice were protected from CRS-3-induced myocardial damage, as evidenced by their improved heart function and myocardial structure. CRS-3 induced the inflammatory response, oxidative stress and mitochondrial dysfunction in wild-type hearts, but not in DUSP1Tg hearts. DUSP1 overexpression normalized cardiac mitochondrial quality control during CRS-3 by suppressing mitochondrial fission, restoring mitochondrial fusion, re-activating mitophagy and augmenting mitochondrial biogenesis. We found that DUSP1 sustained cardiac mitochondrial quality control by binding directly to PHB2 and maintaining PHB2 phosphorylation, while CRS-3 disrupted this physiological interaction. Transgenic knock-in mice carrying the Phb2S91D variant were less susceptible to cardiac depression upon CRS-3, due to a reduced inflammatory response, suppressed oxidative stress and improved mitochondrial quality control in their heart tissues. Thus, CRS-3-induced myocardial dysfunction can be attributed to reduced DUSP1 expression and disrupted DUSP1/PHB2 binding, leading to defective cardiac mitochondrial quality control.

Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.

Renal sympathetic denervation improves pressure-natriuresis relationship in cardiorenal syndrome: insight from studies with Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula.

The aim was to evaluate the effects of renal denervation (RDN) on autoregulation of renal hemodynamics and the pressure-natriuresis relationship in Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF)-induced heart failure (HF). RDN was performed one week after creation of ACF or sham-operation. Animals were prepared for evaluation of autoregulatory capacity of renal blood flow (RBF) and glomerular filtration rate (GFR), and of the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. Their basal values of blood pressure and renal function were significantly lower than with innervated sham-operated TGR (p < 0.05 in all cases): mean arterial pressure (MAP) (115 ± 2 vs. 160 ± 3 mmHg), RBF (6.91 ± 0.33 vs. 10.87 ± 0.38 ml.min-1.g-1), urine flow (UF) (11.3 ± 1.79 vs. 43.17 ± 3.24 µl.min-1.g-1) and absolute sodium excretion (UNaV) (1.08 ± 0.27 vs, 6.38 ± 0.76 µmol.min-1.g-1). After denervation ACF TGR showed improved autoregulation of RBF: at lowest RAP level (80 mmHg) the value was higher than in innervated ACF TGR (6.92 ± 0.26 vs. 4.54 ± 0.22 ml.min-1.g-1, p < 0.05). Also, the pressure-natriuresis relationship was markedly improved after RDN: at the RAP of 80 mmHg UF equaled 4.31 ± 0.99 vs. 0.26 ± 0.09 µl.min-1.g-1 recorded in innervated ACF TGR, UNaV was 0.31 ± 0.05 vs. 0.04 ± 0.01 µmol min-1.g-1 (p < 0.05 in all cases). In conclusion, in our model of hypertensive rat with ACF-induced HF, RDN improved autoregulatory capacity of RBF and the pressure-natriuresis relationship when measured at the stage of HF decompensation.

Practical Requirements for the Development of an Advanced Cardiorenal Unit.

BACKGROUND: Heart failure is frequently associated with kidney disease, and patients with kidney disease are at increased risk of heart failure. The co-occurrence of both entities not only significantly increases morbidity and mortality but also complicates therapy. SUMMARY: Cardiorenal syndrome often requires a broad, comprehensive, and multidisciplinary approach. As a result, a need has arisen to create specialized cardiorenal units that allow for rigorous and personalized management of this condition. Moreover, in some cases, cardiorenal syndrome is more complex, owing to an acute and critical situation that requires the concept of the cardiorenal unit to be extended toward advanced diagnostic and therapeutic positions, thus confirming the need for an advanced cardiorenal unit. The creation of these units constitutes a real challenge, necessitating a specific multilevel action plan, covering governance and management, type of patient, personnel requirements, service portfolio, care process, information systems, and other resources. Specific lines of action must be proposed for each of the relevant points in order to facilitate development of these units, together with continuous evaluation of unit activity through specific indicators, and to detect areas for improvement. KEY MESSAGES: This study addresses the conditions and organizational characteristics that enable the creation, development, and continuous improvement of advanced cardiorenal units.

Cell-Specific Targeting of the Endothelium in the Cardiorenal Syndrome.

BACKGROUND: The vascular endothelium serves as a semi-selective permeable barrier as a conduit for transport of fluid, solutes, and various cell populations between the vessel lumen and tissues. The endothelium thus has a dynamic role in the regulation of coagulation, immune system, lipid and electrolyte transport, as well as neurohumoral influences on vascular tone and end-organ injury to tissues such as the heart and kidney. SUMMARY: Within this framework, pharmacologic strategies for heart and kidney diseases including blood pressure, glycemic control, and lipid reduction provide significant risk reduction, yet certain populations are at risk for substantial residual risk for disease progression and treatment resistance and often have unwanted off-target effects leaving the need for adjunct, alternative targeted therapies. Recent advances in techniques in sequencing and spatial transcriptomics have paved the way for the development of new therapies for targeting heart and kidney disease that include various gene, cell, and nano-based therapies. Cell-specific endothelium-specific targeting of viral vectors will enable their use for the treatment of heart and kidney diseases with gene therapy that can avoid unwanted off-target effects, improve treatment resistance, and reduce residual risk for disease progression. KEY MESSAGES: The vascular endothelium is an important therapeutic target for chronic kidney and cardiovascular diseases. Developing endothelial-specific gene therapies can benefit patients who develop resistance to current treatments.

MAPK/NF-κB signaling mediates atrazine-induced cardiorenal syndrome and antagonism of lycopene.

Atrazine (ATZ) is the most prevalent herbicide that has been widely used in agriculture to control broadleaf weeds and improve crop yield and quality. The heavy use of ATZ has caused serious environmental pollution and toxicity to human health. Lycopene (LYC), is a carotenoid that exhibits numerous health benefits, such as prevention of cardiovascular diseases and nephropathy. However, it remains unclear that whether ATZ causes cardiorenal injury or even cardiorenal syndrome (CRS) and the beneficial role of LYC on it. To test this hypothesis, mice were treated with LYC and/or ATZ for 21 days by oral gavage. This study demonstrated that ATZ exposure caused cardiorenal morphological alterations, and several inflammatory cell infiltrations mediated by activating NF-κB signaling pathways. Interestingly, dysregulation of MAPK signaling pathways and MAPK phosphorylation caused by ATZ have been implicated in cardiorenal diseases. ATZ exposure up-regulated cardiac and renal injury associated biomarkers levels that suggested the occurrence of CRS. However, these all changes were reverted, and the phenomenon of CAR was disappeared by LYC co-treatment. Based on our findings, we postulated a novel mechanism to elucidate pesticide-induced CRS and indicated that LYC can be a preventive and therapeutic agent for treating CRS by targeting MAPK/NF-κB signaling pathways.

Emodin alleviates CRS4-induced mitochondrial damage via activation of the PGC1α signaling.

Cardiorenal syndrome type 4 (CRS4), a progressive deterioration of cardiac function secondary to chronic kidney disease (CKD), is a leading cause of death in patients with CKD. In this study, we aimed to investigate the cardioprotective effect of emodin on CRS4. C57BL/6 mice with 5/6 nephrectomy and HL-1 cells stimulated with 5% CKD mouse serum were used for in vivo and in vitro experiments. To assess the cardioprotective potential of emodin, we employed a comprehensive array of methodologies, including echocardiography, tissue staining, immunofluorescence staining, biochemical detection, flow cytometry, real-time quantitative PCR, and western blot analysis. Our results showed that emodin exerted protective effects on the function and structure of the residual kidney. Emodin also reduced pathologic changes in the cardiac morphology and function of these mice. These effects may have been related to emodin-mediated suppression of reactive oxygen species production, reduction of mitochondrial oxidative damage, and increase of oxidative metabolism via restoration of PGC1α expression and that of its target genes. In contrast, inhibition of PGC1α expression significantly reversed emodin-mediated cardioprotection in vivo. In conclusion, emodin protects the heart from 5/6 nephrectomy-induced mitochondrial damage via activation of the PGC1α signaling. The findings obtained in our study can be used to develop effective therapeutic strategies for patients with CRS4.

Cardiorenal Interactions in Acute Heart Failure: Renal Proximal Tubules in the Spotlight.

BACKGROUND: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics. SUMMARY: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms. KEY MESSAGE: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF.

Clinical Significance of Apela in Acute Cardiorenal Insuffiency of Chronic Heart Failure.

INTRODUCTION: Apela has a wide range of biological effects on the cardiovascular system, but the changes and significance of endogenous Apela in patients with chronic heart failure (CHF) and acute deterioration of cardiac and renal function are unclear. METHODS: A total of 69 patients with stable CHF combined with well-preserved renal function were enrolled and followed for 12 months. The effects of Apela on human renal glomerular endothelial cells (hRGEC), human glomerular mesangial cells (hMC), and human renal tubular epithelial cells (HK-2) were observed. RESULTS: Serum Apela concentration was positively correlated with NYHA class (r = 0.711) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration (r = 0.303) but negatively correlated with left ventricular ejection fraction (LVEF) (r = -0.374) and 6-min walk distance (r = -0.860) in patients with stable CHF. Twenty-one patients experiencing deterioration of renal and cardiac function were diagnosed with cardiorenal syndrome (CRS) during the follow-up period. In addition, the serum Apela, as well as the difference in Apela between stable and worsening phases (ΔApela), was correlated with the estimated glomerular filtration rate (eGFR) and ΔeGFR in patients with CRS. Apela significantly inhibited the upregulated expression of MCP-1 and TNF-α induced by angiotensin II (AngII) in hRGEC, hMC, and HK-2 cells. Apela inhibited the adhesion of THP-1 cells to hRGEC and promoted the tubular formation of hRGEC. Moreover, Apela enhanced the expression of MMP-9 in hMC but inhibited the upregulated expression of α-SMA and vimentin in HK-2 cells by AngII. CONCLUSION: This study suggests that the level of Apela can be used to diagnose heart failure and assess the severity of cardiac dysfunction in patients with stable CHF, and its dynamic changes can be used to evaluate the damage to renal function in patients with CRS. Apela plays multiple protective effects on renal cells, highlighting its clinical application prospect in the prevention and treatment of CRS.

Nitric Oxide Plays a Dual Role in Cardiorenal Syndrome in Vitro Model.

BACKGROUND/AIMS: Nitric oxide (NO) plays a dual role, acting as both an oxidant and a reducer, with various effects depending on its concentration and environment. Acute kidney injury's (AKI) pathogenesis observed in cardiorenal syndrome 3 (CRS 3) involves inflammatory responses and the production of reactive oxygen and nitrogen species. However, the role of NO on the development of CRS 3 is still not completely understood. The study aimed to mimic CRS 3 in vitro and investigate NO signaling and inflammatory molecules. METHODS: Thus, HEK293 cells were submitted to normoxia (NX) or hypoxia (HX) protocols for 16 h followed by 3 h of reoxygenation, treated or not with L-NAME. Conditionate medium by HEK293 was transferred to H9c2 for 24 h. Cellular viability was evaluated by MTT assay, real time PCR was used to analyze gene expression and NO content were evaluated in the intra and extracellular medium by amperimetry. RESULTS: Carbonic anhydrase 9 (CA9) expression increased 2.9-fold after hypoxia. Hypoxia reduced 18 % cell viability in HEK293 that was restored by L-NAME treatment. The sum of nitrite (NO2-) and S-nitrosothiol (S-NO) fractions in HEK293 cells showed a substantial decrease on NO intracellular content (38 %). Both IL-6 and IL-10 decreased in all groups compared to NX cells. Besides TNF-α and Bax/Bcl2 ratio increased in hypoxia (approximately 120-fold and 600-fold, respectively) and L-NAME restored this effect. Regarding H9c2 cells, the S-NO fractions showed a substantial decrease in extracellular content after HX (17%) that was not restored by L-NAME. IL-1ß decreases in cardiac cells treated with conditioned medium from HX/L-NAME. CONCLUSION: In conclusion this study highlights the complex interplay of NO and inflammatory factors in hypoxia-induced renal and cardiac cell responses, with potential implications for cardiorenal syndrome.

Prevalence, clinical correlates and outcomes of cardiorenal anemia syndrome among patients with heart failure attending tertiary referral hospital in Dodoma, Tanzania: A protocol of a prospective observational study.

BACKGROUND: Cardiorenal anemia syndrome (CRAS) is a common complication among patients with heart failure and is associated with poor clinical outcomes. However, there is a paucity of published data concerning CRAS, despite of significant increase in heart failure patients attending medical services in developing countries. This study aims to assess the prevalence, clinical correlates, and outcomes of CRAS among patients with heart failure attending the Benjamin Mkapa Hospital in Dodoma, Tanzania. METHODOLOGY: A prospective observational study is ongoing at the Benjamin Mkapa Hospital in Dodoma, Tanzania. Currently, 92 patients have been recruited into this study and process is not yet completed. The socio-demographic data, clinical correlates, and prevalence of CRAS will be determined at baseline meanwhile, the outcomes of CRAS will be determined during a follow-up period of six months from the date of enrollment. CRAS is the primary outcome of the study. Data will be categorized into CRAS and non-CRAS during statistical analysis. Mean and standard deviation will be used for normally distributed continuous variables while median and interquartile range will be used for skewed data. Frequencies and percentages will summarize categorical variables. Clinical correlates and outcomes of CRAS will be analyzed and compared by using univariate and multivariate logistic regression and Cox proportional hazards models. A two-tailed p-value of less than 0.05 will indicate statistical significance.

Effect on Kidney Function Recovery Guiding Decongestion with VExUS in Patients with Cardiorenal Syndrome 1: A Randomized Control Trial.

INTRODUCTION: In cardiorenal syndrome type 1 (CRS1), vascular congestion is central to the pathophysiology of heart failure and thus a key target for management. The venous evaluation by ultrasound (VExUS) system could guide decongestion effectively and thereby improve outcomes. METHODS: In this randomized clinical trial, patients with CRS1 (i.e., increase in creatinine ≥0.3 mg/dL) were randomized to guide decongestion with VExUS compared to usual clinical evaluation. The primary endpoint was to assess kidney function recovery (KFR), and the key secondary endpoint was decongestion evaluated by physical examination and changes in brain natriuretic peptide (BNP) and CA-125. Exploratory endpoints included days of hospitalization and mortality. RESULTS: From March 2022 to February 2023, a total of 140 patients were randomized 1:1 (70 in the VExUS and 70 in the control group). KFR was not statistically different between groups. However, VExUS improved more than twice the odds to achieve decongestion (odds ratio [OR]: 2.6, 95% CI: 1.9-3.0, p = 0.01) and the odds to reach a decrease of BNP >30% (OR: 2.4, 95% CI: 1.3-4.1, p = 0.01). The survival at 90 days, recongestion, and CA-125 were similar between groups. CONCLUSION: In patients with CRS1, we observed that VExUS-guided decongestion did not improve the probability of KFR but improved the odds to achieve decongestion.

Gualou xiebai decoction ameliorates cardiorenal syndrome type II by regulation of PI3K/AKT/NF-κB signalling pathway.

BACKGROUND: Cardiorenal syndromes type II (CRS2) is a multi-organ ailment that manifests as a combination of cardiac and renal dysfunction, resulting in chronic kidney disease due to chronic cardiac insufficiency. It affects at least 26 million people worldwide, and its prevalence is increasing. Gualou Xiebai Decoction (GXD), a traditional Chinese medicine (TCM) with a rich history of application in the management of coronary artery disease, has been explored for its potential therapeutic benefits in CRS2. Nevertheless, the mechanism by which GXD alleviates CRS2 remains obscure, necessitating further investigation. PURPOSE: The aim of this study was to assess the effects of the ethanolic extract of GXD on CRS2 and to elucidate the underlying mechanism in a rat model of myocardial infarction, offering a potential target for clinical treatment for CRS2. STUDY DESIGN AND METHODS: A rat model of CRS2 was induced by surgical myocardial infarction and treated with GXD for 10 weeks. Cardiac function was assessed using echocardiography, while serum and urine biochemistry were analyzed to evaluate potential cardiac and renal damage. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations. In addition, network pharmacology analysis and molecular docking were utilized to predict the primary active compounds, potential therapeutic targets, and interventional pathways through which GXD could potentially exert its effects on CRS2. Subsequently, these predictions were confirmed in vivo and vitro through various analyses. RESULTS: The current investigation employed echocardiography to exhibit the apparent cardiac remodeling following the induction of myocardial infarction. Damage to the heart and kidneys of CRS2 rats was effectively ameliorated by administration of GXD. The outcomes derived from the analyses of HE and Masson staining indicated that the pathological damage to the heart and kidney tissues of rats in the GXD groups was considerably alleviated. Using network pharmacology analysis, AKT1, IL-6, and TNF-α were identified as plausible therapeutic targets for the treatment of CRS with GXD. Subsequent functional and pathway enrichment analysis of the underlying targets disclosed that the PI3K/AKT/NF-κB signaling pathway may be involved in the mechanism of GXD in the treatment of CRS2. Immunohistochemical, western blot, RT-PCR and immunofluorescence staining were employed to demonstrate that GXD can regulate the PI3K/AKT/NF-κB signaling pathway in the CRS2 rat model. Ultimately, administration of the PI3K/AKT agonist 740Y-P counteracted the effect of diosmetin, which was one of the potential active components of GXD analysed by compound-target-disease network, on p-PI3K and p-AKT in vitro. CONCLUSIONS: The findings of this study suggest that GXD improves cardiac and renal function in CRS2 rats and that the underlying mechanism involves inhibition of the PI3K/AKT/NF-κB pathway.