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 syndrome and iron supplementation-more benefits than risks: a narrative review.

Intravenous iron administration has emerged as a crucial intervention for managing patients with cardiorenal syndrome (CRS) and iron deficiency, with or without the presence of anemia. Multiple studies have demonstrated the benefits of intravenous iron supplementation in improving anemia, symptoms, and functional capacity in patients with HF and iron deficiency. Furthermore, iron supplementation has been associated with a reduction in hospitalizations for HF exacerbation and the improvement of patients' quality of life and clinical outcomes. In addition to its effects on HF management, emerging evidence suggests a potential positive impact on kidney function in patients with CRS. Studies have shown an increase in estimated glomerular filtration rate and improvements in renal function markers in patients receiving intravenous iron therapy, highlighting the potential of this intervention in patients with CRS. This paper reviews the existing literature on the impact of intravenous iron therapy in these patient populations and explores its effects on various clinical outcomes. Future research endeavors are eagerly awaited to further improve our understanding of its clinical implications and optimize patient outcomes.

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.

Prognostic Impact of the UMIPIC Program in the Follow Up in Patients with Heart Failure and Cardiorenal Syndrome.

BACKGROUND: Individuals suffering from heart failure (HF) and cardiorenal syndrome (CRS) represent a special group of patients considering their age, multiple health issues, and treatment challenges. These factors make them more susceptible to frequent hospital stays and a higher mortality rate. UMIPIC is a multidisciplinary care model program for patients with heart failure follow up provided by internists and nurses who are experts in this entity. Our study delved into the effectiveness of this specialized care program (UMIPIC) in mitigating these risks for HF and CRS patients. METHODS: We analyzed the medical records of 3255 patients diagnosed with HF and CRS types 2 and 4, sourced from the RICA registry. These patients were divided into two distinct groups: those enrolled in the UMIPIC program (1205 patients) and those under standard care (2050 patients). Using propensity score matching, we ensured that both groups were comparable. The study focused on tracking hospital admissions and mortality rates for one year after an HF-related hospital stay. RESULTS: Patients in the UMIPIC group experienced fewer hospital readmissions due to HF compared to their counterparts (20% vs. 32%; Hazard Ratio [HR] = 0.48; 95% Confidence Interval [95% CI]: 0.40-0.57; p < 0.001). They also showed a lower mortality rate (24% vs. 36%; HR = 0.64; 95% CI: 0.54-0.75; p < 0.001). Furthermore, the UMIPIC group had fewer total hospital admissions (36% vs. 47%; HR = 0.58; 95% CI: 0.51-0.66; p < 0.001). CONCLUSIONS: The UMIPIC program, centered on holistic and ongoing care, effectively reduces both hospital admissions and mortality rates for HF and CRS patients after a one-year follow-up period.

Diuretic dose is a strong prognostic factor in ambulatory patients awaiting heart transplantation.

AIMS: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT). METHODS AND RESULTS: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05). CONCLUSIONS: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients.

[Connotation of Shenqi Pills based on severe cases in cardiovascular care unit and modern pathophysiological mechanism and application of Shenqi Pills for heart failure, renal failure, cardiorenal syndrome, and diuretic resistance in critical care medicine].

Shenqi Pills, first recorded in Essentials from the Golden Cabinet(Jin Kui Yao Lue) from ZHANG Zhong-jing in Han dynasty, have the effect of warming and tonifying the kidney Qi and are mainly used for the treatment of insufficiency of kidney Qi and kidney Yang. According to modern medicine, kidney Qi involves heart function, kidney function, immune function, and so on. The clinical indications of Shenqi Pills include kidney deficiency, abnormal fluid, and abnormal urination, and the last one is classified into little urine, much urine, and dysuria. In clinical settings, Shenqi Pills can be applied for the treatment of heart failure, renal failure, cardiorenal syndrome, and diuretic resistance, as well as endocrine, urological, orthopedic, and other chronic degenerative diseases. Shenqi Pills are ideal prescriptions for the weak constitution and emergency treatment. It is of great value and significance to carry out in-depth research on the connotation of the classic articles by integrating TCM and western medicine based on "pathogenesis combined with pathology and drug properties combined with pharmacology".

Cardiorenal syndrome and diabetes: an evil pairing.

Cardiorenal syndrome (CRS) is a pathology where the heart and kidney are involved, and the deterioration of one of them leads to the malfunction of the other. Diabetes mellitus (DM) carries a higher risk of HF and a worse prognosis. Furthermore, almost half of people with DM will have chronic kidney disease (CKD), which means that DM is the main cause of kidney failure. The triad of cardiorenal syndrome and diabetes is known to be associated with increased risk of hospitalization and mortality. Cardiorenal units, with a multidisciplinary team (cardiologist, nephrologist, nursing), multiple tools for diagnosis, as well as new treatments that help to better control cardio-renal-metabolic patients, offer holistic management of patients with CRS. In recent years, the appearance of drugs such as sodium-glucose cotransporter type 2 inhibitors, have shown cardiovascular benefits, initially in patients with type 2 DM and later in CKD and heart failure with and without DM2, offering a new therapeutic opportunity, especially for cardiorenal patients. In addition, glucagon-like peptide-1 receptor agonists have shown CV benefits in patients with DM and CV disease in addition to a reduced risk of CKD progression.

Connotation of Shenqi Pills based on severe cases in cardiovascular care unit and modern pathophysiological mechanism and application of Shenqi Pills for heart failure, renal failure, cardiorenal syndrome, and diuretic resistance in critical care medicine / 中国中药杂志

Shenqi Pills, first recorded in Essentials from the Golden Cabinet(Jin Kui Yao Lue) from ZHANG Zhong-jing in Han dynasty, have the effect of warming and tonifying the kidney Qi and are mainly used for the treatment of insufficiency of kidney Qi and kidney Yang. According to modern medicine, kidney Qi involves heart function, kidney function, immune function, and so on. The clinical indications of Shenqi Pills include kidney deficiency, abnormal fluid, and abnormal urination, and the last one is classified into little urine, much urine, and dysuria. In clinical settings, Shenqi Pills can be applied for the treatment of heart failure, renal failure, cardiorenal syndrome, and diuretic resistance, as well as endocrine, urological, orthopedic, and other chronic degenerative diseases. Shenqi Pills are ideal prescriptions for the weak constitution and emergency treatment. It is of great value and significance to carry out in-depth research on the connotation of the classic articles by integrating TCM and western medicine based on "pathogenesis combined with pathology and drug properties combined with pharmacology".

A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin.

BACKGROUND: Cardiovascular diseases are the major cause of mortality in patients with advanced chronic kidney diseases. The predominant abnormality observed among this population is cardiac dysfunction secondary to myocardial remodelings, such as hypertrophy and fibrosis, emphasizing the need to develop potent therapies that maintain cardiac function in patients with end-stage renal disease. AIMS: To identify potential compounds and their targets as treatments for cardiorenal syndrome type 4 (CRS) using molecular phenotyping and in vivo/in vitro experiments. METHODS: Gene expression was assessed using bioinformatics and verified in animal experiments using 5/6 nephrectomized mice (NPM). Based on this information, a molecular phenotyping strategy was pursued to screen potential compounds. Picrosirius red staining, wheat germ agglutinin staining, Echocardiography, immunofluorescence staining, and real-time quantitative PCR (qPCR) were utilized to evaluate the effects of compounds on CRS in vivo. Furthermore, qPCR, immunofluorescence staining and flow cytometry were applied to assess the effects of these compounds on macrophages/cardiac fibroblasts/cardiomyocytes. RNA-Seq analysis was performed to locate the targets of the selected compounds. Western blotting was performed to validate the targets and mechanisms. The reversibility of these effects was tested by overexpressing Osteopontin (OPN). RESULTS: OPN expression increased more remarkably in individuals with uremia-induced cardiac dysfunction than in other cardiomyopathies. Lobetyolin (LBT) was identified in the compound screen, and it improved cardiac dysfunction and suppressed remodeling in NPM mice. Additionally, OPN modulated the effect of LBT on cardiac dysfunction in vivo and in vitro. Further experiments revealed that LBT suppressed OPN expression via the phosphorylation of c-Jun N-terminal protein kinase (JNK) signaling pathway. CONCLUSIONS: LBT improved CRS by inhibiting OPN expression through the JNK pathway. This study is the first to describe a cardioprotective effect of LBT and provides new insights into CRS drug discovery.

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700-800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS. While the interplay between both organs is clearly of importance in CRS, the involvement of UTs in pro-arrhythmic remodeling is only poorly investigated, especially regarding the mechanistic background. Currently, the clinical approach against potential arrhythmic events is mainly restricted to symptom treatment, stressing the need for fundamental research on UT in relation to electrophysiology. This review addresses the existing knowledge of UTs and cardiac electrophysiology, and the experimental research gap between fundamental research and clinical research of the CRS. Clinically, mainly absorbents like ibuprofen and AST-120 are studied, which show limited safe and efficient usability. Experimental research shows disturbances in cardiac electrical activation and conduction after inducing CKD or exposure to UTs, but are scarcely present or focus solely on already well-investigated UTs. Based on UTs data derived from CKD patient cohort studies, a clinically relevant overview of physiological and pathological UTs concentrations is created. Using this, future experimental research is stimulated to involve electrophysiologically translatable animals, such as rabbits, or in vitro engineered heart tissues.

Zhen-Wu decoction and lactiflorin, an ingredient predicted by in silico modelling, alleviate uremia induced cardiac endothelial injury via Nrf2 activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiorenal syndrome type 4 (CRS type 4), with high rates of morbidity and mortality, has become a social and economic problem worldwide over the last few decades. Zhen-Wu decoction, a traditional medicine used in East Asia, has been widely used in the treatment of cardiovascular disease and kidney disease, and has shown potential therapeutic effects for the clinical treatment of CRS type 4. However, the underlying mechanism has not been extensively explored. AIM OF THE STUDY: The purpose of this study was to investigate the effect and underlying mechanism of Zhen-Wu decoction on uremic cardiomyopathy, offering a potential target for clinical treatment of CRS type 4. MATERIALS AND METHODS: Five/six nephrectomized mice were utilized for experiments in vivo. The cardioprotective effects of Zhen-Wu decoction were evaluated by echocardiography and tissue staining. RNA-Seq data were used to investigate the potential pharmacological mechanism. The prediction of targets and active components was based on our previous strategy. Subsequently, the protective effect of the selected compound was verified in experiments in vitro. RESULTS: Zhen-Wu decoction alleviated cardiac dysfunction and endothelial injury in 5/6 nephrectomized mice, and the mechanism may involve the inflammatory process and oxidative stress. The activation of the Nrf2 signaling pathway was predicted to be a potential target of Zhen-Wu decoction in protecting endothelial cells. Through our machine learning strategy, we found that lactiflorin as an ingredient in Zhen-Wu decoction, alleviates IS-induced endothelial cell injury by blocking Keap1 and activating Nrf2. CONCLUSIONS: The present study demonstrated that Zhen-Wu decoction and lactiflorin could protect endothelial cells against oxidative stress in mice after nephrectomy by activating the Nrf2 signaling pathway.

Impact of Homoarginine on Myocardial Function and Remodeling in a Rat Model of Chronic Renal Failure.

PURPOSE: Low plasma concentrations of the amino acid homoarginine (HA) have been shown to correlate with adverse cardiovascular outcome, particularly in patients with chronic kidney disease. The present study sought to investigate the effect of HA treatment on cardiac remodeling in rats undergoing artificially induced renal insufficiency by 5/6 nephrectomy (5/6 Nx). METHODS: A total of 33 male Wistar rats were randomly divided into sham and 5/6 Nx groups, receiving either placebo treatment or 400 mg·kg-1·day-1 HA over a 4-week period. RESULTS: 5/6 Nx per se resulted in adverse myocardial remodeling with aggravated cardiac function and associated cardiac overload as the most obvious alteration (-23% ejection fraction, P < 0.0001), as well as increased myocardial fibrosis (+80%, P = 0.0005) compared to placebo treated sham animals. HA treatment of 5/6 Nx rats has led to an improvement of ejection fraction (+24%, P = 0.0003) and fractional shortening (+21%, P = 0.0126), as well as a decrease of collagen deposition (-32%, P = 0.0041), left ventricular weight (-14%, P = 0.0468), and myocyte cross-sectional area (-12%, P < 0.0001). These changes were accompanied by a downregulation of atrial natriuretic factor (-65% P < 0.0001) and collagen type V alpha 1 chain (-44%, P = 0.0006). Sham animals revealed no significant changes in cardiac function, myocardial fibrosis, or any of the aforementioned molecular changes after drug treatment. CONCLUSION: Dietary HA supplementation appears to have the potential of preventing cardiac remodeling and improving heart function in the setting of chronic kidney disease. Our findings shed new light on HA as a possible new therapeutic agent for patients at high cardiovascular risk.

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.

Glucocorticoids Reverse Diluted Hyponatremia Through Inhibiting Arginine Vasopressin Pathway in Heart Failure Rats.

Background Arginine vasopressin dependent antidiuresis plays a key role in water-sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result in hyponatremia, all of which can be reversed by glucocorticoid supplement. Methods and Results Heart failure was induced by coronary artery ligation for 8 weeks. A total of 32 rats were randomly assigned to 4 groups (n=8/group): sham surgery group, congestive heart failure group, dexamethasone group, and dexamethasone in combination with glucocorticoid receptor antagonist RU486 group. An acute water loading test was administered 6 hours after drug administration. Left ventricular function was measured by a pressure-volume catheter. Protein expressions were determined by immunohistochemistry and immunoblotting. The pressure-volume loop analysis showed that dexamethasone improves cardiac function in rats with heart failure. Western blotting confirmed that dexamethasone remarkably reduces the expressions of V2R, aquaporin 2, and aquaporin 3 in the renal-collecting ducts. As a result of V2R downregulation, the expressions of glucocorticoid regulated kinase 1, apical epithelial sodium channels, and the furosemide-sensitive Na-K-2Cl cotransporter were also downregulated. These favorable effects induced by dexamethasone were mostly abolished by the glucocorticoid receptor inhibitor RU486, indicating that the aforementioned effects are glucocorticoid receptor mediated. Conclusions Glucocorticoids can reverse diluted hyponatremia via inhibiting the vasopressin receptor pathway in rats with heart failure.

Benefits of peritoneal ultrafiltration in HFpEF and HFrEF patients.

BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P <  0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P <  0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P <  0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.

[Vascular dysfunction in Cardiorenal Syndrome type 4].

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Time Course of the Effects of Buxin Yishen Decoction in Promoting Heart Function and Inhibiting the Progression of Renal Fibrosis in Myocardial Infarction Caused Type 2 Cardiorenal Syndrome Rats.

This study aimed to investigate the therapeutic effect of traditional Chinese medicine-Buxin Yishen decoction (BXYS) on type 2 cardiorenal syndrome (CRS) caused by myocardial infarction and explore the possible mechanism BXYS works. A chronic heart failure (CHF) rat model induced by left anterior descending coronary artery ligation was used and five groups were created that included a sham group, a CHF model group, a fosinopril group, a BXYS (0.4 g/kg) group and a BXYS (0.8 g/kg) group. Heart function, renal hemodynamics, neuroendocrine factors, serum, and urine concentration of soluble form connective tissue growth factor (sCTGF), expression of CTGF mRNA, CTGF, α-smooth muscle actin (α-SMA), and low-density lipoprotein receptor-related protein (LRP) in renal tissues were evaluated after 28 days and 60 days of drug administration. Histological analysis of kidney tissues was also performed. In vitro experiments were designed to verify the results of in vivo experiments by detecting factors including CTGF, α-SMA, in NRK-52E cells. Rats with CHF showed obvious pathophysiological changes including: altered renal hemodynamic parameters; dysregulated heart function; changes to serum concentrations of angiotensin II (AngII), cyclic guanosine monophosphate (cGMP), serum creatinine (Scr), blood urea nitrogen (BUN), C-reactive protein (CRP), brain natriuretic peptide (BNP); high serum and urine sCTGF concentration; high CTGF mRNA, CTGF, α-SMA and LRP expression in renal tissues; increased extracellular matrix (ECM) deposition and fibrosis in renal tissues. Treatment of BXYS was correlated with a restoration of heart function and improvement of renal hemodynamics, lower serum and urine sCTGF, lower CTGF mRNA, CTGF, α-SMA and LRP expression in renal tissues and lower ECM deposition. In addition, in vitro experiments showed that treatment with BXYS reduced the α-SMA and LRP concentration in NRK-52E cells, which were similar in vivo experiments. In conclusion, the current study provided evidences that BXYS played a role in improving heart function and delaying the progress of renal fibrosis. Meanwhile, the CTGF-LRP pathway might be one of the therapeutic targets for myocardial infarction caused type 2 CRS which showed a positive change after BXYS treatment and is worthy of further exploration.

Alpha-Tocopherol during lactation and after weaning alters the programming effect of prenatal high salt intake on cardiac and renal functions of adult male offspring.

Maternal salt overload programs cardiovascular and renal alterations in the offspring. However, beneficial and harmful effects of high dose vitamin E supplementation have been described in humans and animals. We investigated the hypothesis as to whether cardiac and renal alterations can be programmed by gestational salt overload, and can become further modified during lactation and after weaning. Male Wistar rats were used, being the offspring of mothers that drank either tap water or 0.3 mol/L NaCl for 20 days before and during pregnancy. α-Tocopherol (0.35 g/kg) was administered to mothers daily during lactation or to their offspring for 3 weeks post-weaning. Systolic blood pressure (tcSBP) was measured in juvenile rats aged 210 days. The response of mean arterial pressure (MAP) and heart rate (HR) to intravenous infusion of angiotensin II (Ang II) was also examined. Left ventricle plasma membrane (PMCA) and sarcoplasmic reticulum Ca2+ -ATPase (SERCA) activities, and certain parameters of renal function, were measured. Maternal saline programmed for increased body mass and kidney mass/body mass ratio, increased tcSBP, increased mean arterial pressure and heart rate with anomalous response to infused Ang II. In the heart, saline increased PMCA and α-Tocopherol per se increased PMCA/SERCA. In the kidney, the most remarkable result was the silent saline programming of CrCl , which was sensitized for a sharp decrease after α-Tocopherol. In conclusion, the combination of maternal saline overload and high α-Tocopherol immediately after birth leads to simultaneous cardiovascular and renal alterations in the young offspring, like those encountered in type V cardiorenal syndrome.

Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance.

AIMS: To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF). METHODS AND RESULTS: This prospective, two-centre study included 34 AHF patients on loop diuretics with volume overload. All had a serum sodium concentration < 135 mmol/L and/or serum urea/creatinine ratio > 50 and/or an admission serum creatinine increase of > 0.3 mg/dL compared to baseline. Patients were randomised towards acetazolamide 250-500 mg daily plus bumetanide 1-2 mg bid vs. high-dose loop diuretics (bumetanide bid with daily dose twice the oral maintenance dose). The primary endpoint was natriuresis after 24 h. Natriuresis after 24 h was similar in the combinational treatment vs. loop diuretic only arm (264 ± 126 vs. 234 ± 133 mmol; P = 0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84 ± 46 vs. 52 ± 42 mmol/mg bumetanide; P = 0.048). More patients in the combinational treatment arm had an increase in serum creatinine levels > 0.3 mg/dL (P = 0.046). N-terminal pro-B-type natriuretic peptide reduction and peak neurohumoral activation within 72 h were comparable among treatment arms. There was a non-significant trend towards lower all-cause mortality or heart failure readmissions in the group receiving acetazolamide with low-dose loop diuretics vs. high-dose loop diuretic monotherapy (P = 0.098). CONCLUSION: Addition of acetazolamide increases the natriuretic response to loop diuretics compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT01973335.