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Background: This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS)., Methods and Results: An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1-5 (all p<0.0001)., Conclusion: Combined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Heart failure and chronic kidney disease are common and clinically important conditions that regularly coexist. Electrophysiologic changes of advanced heart failure often result in abnormal conduction, causing dyssynchronous contraction, and development of ventricular arrhythmias, which can lead to sudden cardiac arrest. In the last 2 decades, implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been developed to address these complications. However, when the coexisting chronic kidney disease is advanced, the associated pathophysiologic cardiovascular changes can alter the efficacy and safety of those interventions and complicate the management. This review explores the impact of comorbid advanced heart failure and advanced chronic kidney disease on the efficacy and safety of implantable cardioverter-defibrillator and cardiac resynchronization therapy, the currently available evidence, and potential future directions., Competing Interests: Funding Support and Author Disclosures Dr Cleland has received research grants from Bristol Myers Squibb, CSL-Vifor, and Pharmacosmos; and has received honoraria for advisory boards and speaking from Biopeutics, Boehringer Ingelheim, Bristol Myers Squibb, CSL-Vifor, and Pharmacosmos. Dr Abraham has received personal fees from Medtronic and Abbott. Dr Lip is a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, no fees are received personally; is a National Institute for Health and Care Research (NIHR) Senior Investigator and coprincipal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 899871. Dr Hatamizadeh has served as advisory board member for Horizon Therapeutics; and receives research support from Sarfez Pharmaceutical Company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

This study tested the hypothesis that empagliflozin (EMPA) therapy effectively protected renal and heart functions via downregulating reactive oxygen species (ROS) and activating AMPK signaling in cardiorenal syndrome (CRS) (induced by doxorubicin-5/6 nephrectomy) rats. In vitro result showed that underwent p-Cresol treatment, the H9C2/NRK-52E cell viabilities, were significantly suppressed, whereas cellular levels of ROS and early/late apoptosis of these cells were significantly increased that were significantly reversed by EMPA treatment (all p < 0.001). The protein levels of the cell-stress/oxidative signaling (p-PI3K/p-Akt/p-mTOR/NOXs/p-DRP1) were significantly activated, whereas the mitochondrial biogenesis signaling (p-AMPK/SIRT-1/TFAM/PGC-1α) was significantly repressed in these two cell lines treated by p-Cresol and all of these were significantly reversed by EMPA treatment (all p < 0.001). Male-adult-SD rats were categorized into groups 1 [sham-operated control (SC)]/2 [SC + high protein diet (H PD ) since day 1 after CKD induction]/3 (CRS + H PD )/4 (CRS + H PD +EMPA/20 mg/kg/day) and heart/kidney were harvested by day 60. By day 63, the renal function parameters (creatinine/BUN/proteinuria)/renal artery restrictive index/cellular levels of ROS/inflammation were significantly increased in group 3 than in groups 1/2, whereas heart function exhibited an opposite pattern of ROS among the groups, and all of these parameters were significantly reversed by EMPA treatment (all p < 0.0001). The protein levels of inflammation/ oxidative-stress/cell-stress signalings were highest in group 2, lowest in group 1 and significantly lower in group 4 than in group 2, whereas the AMPK-mitochondrial biogenesis displayed an opposite manner of oxidative-stress among the groups (all p < 0.0001). EMPA treatment effectively protected the heart/kidney against CRS damage via suppressing ROS signaling and upregulating AMPK-mediated mitochondrial biogenesis., (© 2024. The Author(s).)

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Cardiorenal syndrome (CRS) refers to concomitant dysfunction of both the heart and kidneys. The pathology in CRS is bidirectional. Many individuals with kidney disease will develop cardiovascular complications. Conversely, rates of acute kidney injury and chronic kidney disease are high in cardiac patients. While our understanding of CRS has greatly increased over the past 15 years, most research has occurred in adult populations. Improving cardiorenal outcomes in children and adolescents requires increased collaboration and research that spans organ systems. The purpose of this review is to discuss key features of CRS and help bring to light future opportunities for pediatric-specific research., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Despite a large amount of research on synchronous and mutually induced kidney and heart damage, the basis of the disease is still not fully clarified. Healthy mitochondria are essential for normal kidney and heart function. Mitochondrial dysfunction occurs when the clearance or process of generation and fragmentation of mitochondria is disturbed. The kidney is the second organ after the heart in terms of the number of mitochondria. Kidney tubules are rich in mitochondria due to the high energy requirements for absorption of large amounts of ultrafiltrate and dissolved substances. The place of action of oxidative stress is the influence on the balance in the production and breakdown of the mitochondrial reactive oxygen species. A more precise determination of the place and role of key factors that play a role in the onset of the disease is necessary for understanding the nature of the onset of the disease and the creation of therapy in the future. This underscores the urgent need for further research. The narrative review integrates results found in previously performed studies that have evaluated oxidative stress participation in cardiorenal syndrome type 3.

Background: Cardiorenal syndrome (CRS) is a complex condition characterized by the interplay of immune imbalance and inflammation. The C-reactive protein-Albumin-lymphocyte (CALLY) CALLY index serves as a new immune-nutritional scoring system, but its predictive value for CRS remains to be established., Methods: In this study, we analyzed data from 27,978 participants in National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. The CALLY index was calculated as the ratio of albumin to lymphocyte, divided by C-reactive protein (CRP) multiplied by 10 4 . CRS was defined by the coexistence of cardiovascular disease and chronic kidney disease (eGFR <60 mL/min/1.73 m 2 ). Multivariate weighted logistic regression models were employed to determine the odds ratio and 95 % confidence interval for the association between the CALLY index and CRS. Receiver operating characteristic (ROC) curves and restricted cubic spline (RCS) curves were used to assess the predictive efficacy and nonlinear relationship, respectively., Results: The prevalence of CRS in the study population was 1.22 %. Our findings revealed a significant inverse relationship between the CALLY index and CRS risk, with lower CALLY index values being associated with a higher likelihood of CRS (OR = 0.95, 95 % CI = 0.94-0.96, P < 0.001). Participants in higher quartiles of the CALLY index showed a progressively reduced risk of CRS (P for trend <0.001). Moreover, the CALLY index demonstrated superior predictive performance compared to other inflammatory indicators, such as systemic immune-inflammation index (SII), neutrophil/high-density lipoprotein ratio (NHR), lymphocyte/high-density lipoprotein ratio (LHR), monocyte/high-density lipoprotein ratio (MHR), and platelet/high-density lipoprotein ratio (PHR) (AUC = 0.672, 95 % CI = 0.643-0.701)., Conclusions: This study underscores the significant negative correlation between the CALLY index and the risk of cardiorenal syndrome. The CALLY index emerges as a robust and independent predictor of CRS, outperforming traditional inflammatory markers. This finding highlights the potential utility of the CALLY index as a clinical tool for identifying individuals at risk for CRS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The impact of peritoneal filling on hepato-splanchnic perfusion during peritoneal dialysis has not been fully elucidated yet., Methods: Measurements were done in 20 prevalent peritoneal dialysis patients during a peritoneal equilibration test (PET) with 2L of standard dialysate. Data were obtained in the drained state at baseline ( T 0 ), after instillation ( T 1 ), and after 2 h of dwell time ( T 2 ). Intra-abdominal pressure (IAP) was measured by Durand's approach. The hepatic clearance index (KI) of indocyanine-green (ICG) was determined as an indirect measure of hepato-splanchnic blood flow. Cardiac index (CI), heart rate (HR), and total peripheral resistance index (TPRI) were derived from continuous arterial pulse analysis. Fluid volume overload (VO) was evaluated by multifrequency bioimpedance analysis. Ejection fraction (EF) was obtained from echocardiographic examination., Results: IAP was 5.8 ± 3.5 mmHg at baseline ( T 0 ), rose to 9.4 ± 2.8 mmHg after instillation of dialysate ( T 1 ), and further to 9.7 ± 2.8 mmHg after 2 h of dwell time ( p  < 0.001). KI slightly declined from 0.60 ± 0.22 L/min/m 2 at T 0 to 0.53 ± 0.15 L/min/m 2 at T 1 ( p  = 0.075), and returned to 0.59 ± 0.22 L/min/m 2 at T 2 ( p  = 0.052). CI, HR, and TPRI did not change significantly. In five patients with an EF < 40% KI was significantly lower at T 1 (0.42 ± 0.12 L/min/m 2 ; p  = 0.039), and further decreased at T 2 (0.40 ± 0.04 L/min/m 2 ; p  = 0.016) compared to patients with normal EF ( T 1 : 0.58 ± 0.15 L/min/m 2 and T 2 : 0.67 ± 0.22 L/min/m 2 )., Conclusions: Overall, hepatic clearance of ICG as a marker of hepato-splanchnic blood flow is not affected by the filling of the peritoneal cavity.

Cardiorenal syndrome refers to the interrelated dysfunction of the heart or kidney resulting in a cascade of feedback mechanisms, hemodynamic, neurohormonal, and immunological and/or biochemical feedback pathways causing damage in the other organ. Cardiorenal syndrome is categorized into five clinical subtypes depending on the perceived primary precipitant of organ injury and is associated with high morbidity and mortality. Therefore, the development of tools for the earliest identification of cardiorenal syndrome in hospitalized patients is of extremely high significance to ameliorate the prognosis and outcome of these patients. There is increasing interest in identifying molecules serving as biomarkers, reflecting hemodynamic changes, heart and kidney damage and/or dysfunction and oxidative stress-induced cell damage or changes in the extracellular matrix of both the heart and kidneys. Biomarkers provide important insights into the pathophysiology of cardiorenal syndrome and are invaluable tools to predict the decrease in renal function during cardiac dysfunction and vice versa. Based on the pathophysiological mechanisms of cardiorenal syndrome, we reviewed and evaluated the available literature on serum and urinary biomarkers as predictors of kidney and/or heart injury. In addition, heart- and kidney-specific biomarkers were also evaluated based on their reference to kidney and cardiac (dys)function respectively, and whether they would provide any prediction and prognostication of cardiorenal syndrome. In this article, we discuss the current knowledge on the pathophysiology of different types of cardiorenal syndrome, examine the clinical utility of candidate biomarkers in the early diagnosis of cardiorenal syndrome, and guide treatment by evaluating the respective roles of the involved pathophysiological pathways., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Cardiorenal syndrome (CRS) is defined as a broad spectrum of conditions encompassing both the heart and kidneys in which acute or chronic heart disorder may induce acute or chronic tubular injury in the kidneys and vice versa. Early diagnosis allows timely intervention and attenuates disease progression. Two well-established biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and brain (B-type) natriuretic peptide (BNP), are reflective of impaired cardiac and kidney function associated with poor prognosis in various cardiac disorders, including heart failure and coronary artery disease. Given the ongoing contribution of CRS to the high morbidity and mortality post-MI, early risk stratification and preventive measures are highly significant. In this review, we examine Surface Plasmon Resonance (SPR) optical biosensors for detection of these biomarkers and discuss potential implications of this highly sensitive and specific technology in CRS detection, treatment and outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Continuous ultrafiltration consists a decongestion method for patients with refractory decompensated heart failure with diuretic resistance as it enables the energetic withdrawal of isotonic fluid under controlled rate according to the patient's vital signs, offering decongestion without exceeding plasma refill rate., Case Summary: A 62-year-old male with history of Holt-Oram syndrome with Eisenmenger physiology presented with worsening dyspnoea. Patient initial clinical and laboratory examination, renal vein ultrasound, and echocardiogram were consistent with significant congestion. A combined strategy of intravenous furosemide with early initiation of continuous ultrafiltration at an adjustable rate for 4 days was finally selected. Patient remained haemodynamically stable during the total treatment time and exhibited significant clinical and laboratory improvement. Consecutive renal vein ultrasounds and echocardiograms demonstrated a continuous and steady recession of congestion. During the 4 days of ultrafiltration, total fluid loss was estimated at 42 L. Patient remained asymptomatic without signs of worsened congestion at 1, 3, and 5 months follow-up., Discussion: Our case depicts that continuous ultrafiltration without exceeding plasma refill rate allows an impaired right ventricle to maintain significant preload. This suggests that it might be considered for patients in whom a session of short classic ultrafiltration might have detrimental results regarding cardiac output., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In rats with unilateral nephrectomy and cardiac dysfunction, renal function deteriorates at an accelerated rate, as evidenced by increased proteinuria. Whether myocardial infarct-induced heart failure (HF) exacerbates renal injury in hypertensive rats with mild renal injury has not been reported. Rats underwent either coronary ligation or sham surgery. Thirty spontaneously hypertensive rats (SHRs) aged 8 weeks were randomly divided into two groups. Group 1 was the sham group, in which the rats underwent thoracotomy without ligation of the coronary artery. Group 2 underwent coronary artery ligation. The rats in group 2 underwent coronary artery ligation on week 0. The experiment lasted 12 weeks. Urine was collected in metabolic cages over a 24-h period. Urine was collected from the rats 2 days before the end of the experiment, and the ratio of urinary protein to urinary creatinine was measured in the clinical laboratory. All rats were examined by echocardiogram one day before the end of the experiment. On the last day of the experiment, blood was collected and sent to the laboratory for analysis. Hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining were performed on heart and kidney sections. The ejection fraction in group 2 was lower than that in group 1 (P < 0.001). The urinary albumin to creatinine ratio in group 2 was greater than that in group 1 (P < 0.001). The urea and creatinine levels in group 1 were significantly lower than those in group 2 (P < 0.01). The levels of brain natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were greater in the second group than in the first group (P < 0.05). The interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels in group 2 were significantly greater than those in group 1 (P < 0.001). The malondialdehyde (MDA) levels in Group 2 were greater than those in Group 1 (P < 0.01). The glutathione peroxidase (GSH-Px) levels in Group 2 were lower than those in Group 1 (P < 0.05). The level of angiotensin II (AT-II) in group 1 was lower than that in group 2 (P < 0.001). Cardiac dysfunction secondary to myocardial infarction could induce cardiorenal interactions in SHRs. It could be interpreted by the activation of oxidative stress, changes in inflammation and alteration of renin-angiotensin-aldosterone system., (© 2024. The Author(s).)

Chronic kidney disease (CKD) can lead to cardiac dysfunction in a condition known as cardiorenal syndrome (CRS). It is postulated that the accumulation of uremic toxins in the bloodstream, as a consequence of declining kidney function, may contribute to these adverse cardiac effects. While CRS in adults has been extensively studied, there is a significant knowledge gap with pediatric patients. Uremic toxin levels in children remain inadequately characterized and quantified compared to adults. This review aims to systematically evaluate the association between uremic toxin concentrations and cardiac changes in pediatric CRS and to examine the impact of different dialysis modalities, specifically hemodialysis and peritoneal dialysis, on uremic toxin clearance and cardiovascular parameters. To address this, we conducted a systematic literature search of PubMed, following PRISMA guidelines. We used the terms "uremic toxins" and "cardiorenal syndrome" with variations in syntax to search for studies discussing the relationship between uremic toxin levels in CKD, the subsequent impact on cardiac parameters, and the emergence of cardiac dysfunction. Full-text articles written in English, conducted on humans aged from birth to 18 years, and published until December 2021 were included. A comprehensive literature search yielded six studies, and their risk of bias was assessed using JBI Critical Appraisal Checklists. Our systematic review is registered on PROSPERO, number CRD42023460072. This synthesis intends to provide an understanding of the role of uremic toxins in pediatric CRS. The findings reveal that pediatric patients with end-stage CKD on dialysis exhibit elevated uremic toxin levels, which are significantly associated with cardiovascular disease parameters. Additionally, the severity of CKD correlated with higher uremic toxin levels. No conclusive evidence was found to support the superiority of either hemodialysis or peritoneal dialysis in terms of uremic toxin clearance or cardiovascular outcomes. More pediatric-specific standardized and longitudinal studies are needed to develop targeted treatments and improve clinical outcomes and the quality of life for affected children.

Congestive nephropathy is an underappreciated manifestation of cardiorenal syndrome and is characterized by a potentially reversible kidney dysfunction caused by a reduced renal venous outflow secondary to right-sided heart failure or intra-abdominal hypertension. To date, the histological diagnostic criteria for congestive nephropathy have not been defined. We herein report a case of acute renal dysfunction following cardiac allograft failure and present a review of the relevant literature to elucidate the current understanding of the disease. Our case demonstrated that congestion-driven nephropathy may be histopathologically characterized by markedly dilated veins and peritubular capillaries, focally accentuated low-grade acute tubular damage, small areas of interstitial fibrosis, and tubular atrophy on a background of normal glomeruli and predominantly normal tubular cell differentiation., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Fractional excretion of urea nitrogen (FEUN), used to differentiate the cause of acute kidney injury, has emerged as a useful fluid index in patients with heart failure (HF). We hypothesized that FEUN could be useful in identifying worsening renal function (WRF) associated with poor outcomes in patients with acute HF (AHF)., Methods and Results: Overall, 1103 patients with AHF (median age, 78 years; male proportion, 60%) were categorized into six groups according to the presence of WRF and FEUN values (low, ≤32.1%; medium, >32.1% and ≤38.0%; and high, >38.0%) at discharge. WRF was defined as an increase of ≥0.3 mg/dL in the serum creatinine level from admission to discharge. FEUN was calculated by the following formula: (urinary urea × serum creatinine) × 100/(serum urea × urinary creatinine). The cut-off values for low, medium, and high FEUN were based on a previous study. The primary outcome of this study was HF readmission after hospital discharge. During the 1 year follow-up, 170 HF readmissions occurred. Kaplan-Meier analysis revealed significantly higher HF readmission rates in patients with WRF than in those without WRF (log-rank test, P < 0.001). Additionally, among patients with WRF, HF readmission rates were lowest in those with medium FEUN values, followed by those with low FEUN values and those with high FEUN values. On multivariable analysis, the presence of WRF with low or high FEUN values was independently associated with increased HF readmission, as compared with the absence of WRF with medium FEUN values. Notably, no association was noted between WRF with medium FEUN values and HF readmission., Conclusions: The prognostic impact of WRF was significantly mediated by the FEUN values and was associated with worse outcomes only when the FEUN values were either low or high. Our study suggests that FEUN can identify prognostically relevant WRF in patients with AHF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: This study investigated whether the oral vasopressin V 2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet-cold pattern), from the viewpoint of cardiorenal syndrome., Methods: Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria-Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups., Results: Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet-cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417)., Conclusion: There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The term "Cardiorenal Syndrome" (CRS) refers to the complex interplay between heart and kidney dysfunction. First described by Robert Bright in 1836, CRS was brought to its modern view by Ronco et al. in 2008, who defined it as one organ's primary dysfunction leading to secondary dysfunction in the other, a view that led to the distinction of five different types depending on the organ of primary dysfunction and the temporal pattern (acute vs. chronic). Their pathophysiology is intricate, involving various hemodynamic, neurohormonal, and inflammatory processes that result in damage to both organs. While traditional biomarkers have been utilized for diagnosing and prognosticating CRS, they are inadequate for the early detection of acute renal damage. Hence, there is a pressing need to discover new biomarkers to enhance clinical outcomes and treatment approaches.

Goodpasture's syndrome (GPS) is a rare small vessel vasculitis characterized by circulating antibodies directed against the glomerular and alveolar basement membrane leading to renal and pulmonary manifestations. Here, we discuss a unique case of a 30-year-old Caucasian male smoker initially presenting with hemoptysis and anemia who was found to have biopsy-proven GPS with elevated anti-glomerular basement membrane (anti-GBM) antibodies. Unfortunately, the patient failed four months of standard treatment for GPS leading to end-stage renal disease (ESRD), while uniquely developing cardiorenal syndrome (CRS) with non-ischemic cardiomyopathy resulting in systolic and diastolic heart failure (HF). Despite aggressive medical management and hemodialysis, the patient's cardiac function continued to decline and the decision was made to insert an automatic implantable cardioverter defibrillator (AICD). To our knowledge, this is the first reported case of an anti-GBM-positive GPS patient who developed dilated cardiomyopathy. The importance of this report is to illustrate the rarity of developing CRS with non-ischemic cardiomyopathy and congestive heart failure from GPS and highlight the difficulty of determining management changes beyond guideline-directed medical therapy (GDMT) in GPS to slow the progression of worsening cardiac function., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Chinniah et al.)

Background: Heart failure with preserved ejection fraction (HFpEF) often coexists with chronic kidney disease (CKD). Exercise intolerance is a major determinant of quality of life and morbidity in both scenarios. We aimed to evaluate the associations between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) with maximal aerobic capacity (peak VO 2 ) in ambulatory HFpEF and whether these associations were influenced by kidney function., Methods: This single-centre study prospectively enrolled 133 patients with HFpEF who performed maximal cardiopulmonary exercise testing. Patients were stratified across estimated glomerular filtration rate (eGFR) categories (<60 ml/min/1.73 m 2 versus ≥60 ml/min/1.73 m 2 )., Results: The mean age of the sample was 73.2 ± 10.5 years and 56.4% were female. The median of peak VO 2 was 11.0 ml/kg/min (interquartile range 9.0-13.0). A total of 67 (50.4%) patients had an eGFR <60 ml/min/1.73 m 2 . Those patients had higher levels of NT-proBNP and lower peak VO 2 , without differences in CA125. In the whole sample, NT-proBNP and CA125 were inversely correlated with peak VO 2 ( r  = -0.43, P  < .001 and r  = -0.22, P  = .010, respectively). After multivariate analysis, we found a differential association between NT-proBNP and peak VO 2 across eGFR strata ( P for interaction = .045). In patients with an eGFR ≥60 ml/min/1.73 m 2 , higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60 ml/min/1.73 m 2 , NT-proBNP was not significantly associated with peak VO 2 [β = 0.02 (95% confidence interval -0.19-0.23), P  = .834]. Higher CA125 was linear and significantly associated with worse functional capacity without evidence of heterogeneity across eGFR strata ( P for interaction = .620)., Conclusions: In patients with stable HFpEF, NT-proBNP was not associated with maximal functional capacity when CKD was present. CA125 emerged as a useful biomarker for estimating effort intolerance in HFpEF irrespective of the presence of CKD., Competing Interests: J.N. is a member of the CKJ editorial board. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: Diabetes Mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia and/or insulin resistance. If left uncontrolled, it can lead to a combination of cardiac and renal alterations known as cardiorenal syndrome. Additionally, oxidative stress and inflammation contribute to tissue damage, thereby reducing the life expectancy of individuals with diabetes., Aim: The aim of this study was to identify early molecular markers associated with cardiorenal syndrome, oxidative stress, and inflammation, and to investigate their correlation with the duration of exposure to DM., Methods: An experimental DM model was employed using Wistar rats. The rats were divided into four groups: diabetic rats at 7 days (DM7), diabetic rats at 30 days (DM30), control sham at 7 days (CS7), and control sham at 30 days (CS30). Blood and brain tissue from the brainstem region were collected at 7 and 30 days after confirming DM induction. Gene expression analysis of Bnp, Anp, Cat, Gpx, Sod, Tnf-α, and Il-6 was performed., Results: The analysis revealed lower expression values of Cat in the brainstem tissue of the DM7 group compared to the NDS7 group. Moreover, diabetic animals exhibited statistically lower levels of Tnf-α in their peripheral blood compared to the control animals., Conclusion: This study concluded that DM alters the oxidative balance in the brainstem after 7 days of DM induction, resulting in lower Cat expression levels. Although some genes did not show statistical differences after 30 days of DM induction, other genes exhibited no expression values, indicating possible gene silencing. The study identified an imbalance in the studied pathways and concluded that the organism undergoes a compensatory state in response to the initial metabolic alterations caused by DM., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes., Methods and Results: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity., Conclusions: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A recent American Heart Association Scientific Statement and Presidential Advisory recognized a new syndrome, the cardiovascular-kidney-metabolic syndrome. This expands our understanding of what has been called cardiorenal syndrome by incorporating the pathophysiological interrelatedness of metabolic risk factors into the previous concept of cardiorenal syndrome. Importantly, perturbation of cardiac or renal physiology combines to produce significant detrimental outcomes. The cardiorenal syndrome is a significant part of the cardiovascular-kidney-metabolic syndrome and contributes to health care cost, disability, and mortality. It is a vexing malady that has generated considerable interest. To understand the syndrome evaluation of its teleological origins is important. In life's beginning, eukaryotes acquired exocytosis for excretion, formed tubular secretory systems for clearance, and a mesenchymal nucleic acid vasoform for nutritional distribution. Those structures progressed to cardiovascular and renal systems of evolving organisms, whose migration to rivers and land imposed complex, coordinated, homeostatic roles to maintain intravascular stability. Tissue mineralization of vertebrate endoskeleton added renal calcium balance regulation, which in kidney failure results in cardiovascular calcification. Insight into cardiorenal disease can be traced to ancient Egyptian and Chinese medicine, through the Scientific Revolution, and into current insights regarding human physiology and pathophysiology. The post-World War II epidemic of cardiovascular mortality generated considerable information on cardiovascular disease, which being higher in patients with kidney disease, drew increasing health concerns. The cardiorenal syndrome was formally introduced in this setting with a focus on ultrafiltration to manage volume overload. An evolutionary review of insight into cardiorenal syndrome will help us better understand the new cardiovascular-kidney-metabolic syndrome., Competing Interests: Disclosures None.

Acute kidney injury (AKI) can cause distal cardiac dysfunction; however, the underlying mechanism is unknown. Oxidative stress is proved prominent in AKI-induced cardiac dysfunction, and a possible bridge role of oxidative-stress products in cardio-renal interaction has been reported. Therefore, this study aimed to investigate the critical role of circulating reactive oxygen species (ROS) in mediating cardiac dysfunction after bilateral renal ischemia-reperfusion injury (IRI). We observed the diastolic dysfunction in the mice following renal IRI, accompanied by reduced ATP levels, oxidative stress, and branched-chain amino acids (BCAA) accumulation in the heart. Notably, ROS levels showed a sequential increase in the kidneys, circulation, and heart. Treatment with tempol, an ROS scavenger, significantly restored cardiac diastolic function in the renal IRI mice, corroborating the bridge role of circulating ROS. Accumulating evidence has identified oxidative stress as upstream of Mst1/Hippo in cardiac injury, which could regulate the expression of downstream genes related to mitochondrial quality control, leading to lower ATP, higher ROS and metabolic disorder. To verify this, we examined the activation of the Mst1/Hippo pathway in the heart of renal IRI mice, which was alleviated by tempol treatment as well. In vitro, analysis revealed that Mst1-knockdown cardiomyocytes could be activated by hydrogen peroxide (H 2 O 2 ). Analysis of Mst1-overexpression cardiomyocytes confirmed the critical role of the Mst1/Hippo pathway in oxidative stress and BCAA dysmetabolism. Therefore, our results indicated that circulating ROS following renal IRI activates the Mst1/Hippo pathway of myocardium, leading to cardiac oxidative stress and diastolic dysfunction. This finding provides new insights for the clinical exploration of improved treatment options for cardiorenal syndrome., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background/Objectives : Cardiorenal syndrome (CRS) is a disorder of the heart and kidneys, with one type of organ dysfunction affecting the other. The pathophysiology is complex, and its actual description has been questioned. We used clustering analysis to identify clinically relevant phenogroups among patients with CRS. Methods : Data for patients admitted from 1 January 2012 to 31 December 2012 were collected from the French national medico-administrative database. Patients with a diagnosis of heart failure and chronic kidney disease and at least 5 years of follow-up were included. Results : In total, 13,665 patients were included and four clusters were identified. Cluster 1 could be described as the vascular-diabetes cluster. It comprised 1930 patients (14.1%), among which 60% had diabetes, 94% had coronary artery disease (CAD), and 80% had peripheral artery disease (PAD). Cluster 2 could be described as the vascular cluster. It comprised 2487 patients (18.2%), among which 33% had diabetes, 85% had CAD, and 78% had PAD. Cluster 3 could be described as the metabolic cluster. It comprised 2163 patients (15.8%), among which 87% had diabetes, 67% dyslipidemia, and 62% obesity. Cluster 4 comprised 7085 patients (51.8%) and could be described as the low-vascular cluster. The vascular cluster was the only one associated with a higher risk of cardiovascular death (HR: 1.48 [1.32-1.66]). The metabolic cluster was associated with a higher risk of kidney replacement therapy (HR: 1.33 [1.17-1.51]). Conclusions : Our study supports a new classification of CRS based on the vascular aspect of pathophysiology differentiating microvascular or macrovascular lesions. These results could have an impact on patients' medical treatment.

In recent decades, there has been considerable effort in investigating the clinical utility of renal Doppler measurements in both cardiovascular and renal disorders. In particular, a measure of renal arterial resistance, the renal resistive index (RRI), has been demonstrated to predict chronic kidney disease progression and acute kidney injury in different clinical settings. Furthermore, it is linked to a poorer prognosis in individuals suffering from chronic heart failure. Examining the renal venous flow through pulsed Doppler can offer additional insights into renal congestion and cardiovascular outcomes for these patients. This review seeks to summarize the existing data concerning the clinical significance of arterial and venous renal Doppler measurements across various cardiovascular and renal disease contexts.

Background: With the development of pathophysiology, cardiorenal syndrome (CRS), a complex and severe disease, has received increasing attention. Monocyte to high-density lipoprotein-cholesterol ratio (MHR) and body mass index (BMI) are independent risk factors for cardiovascular diseases, but their association with CRS remains unexplored. This study aims to explore the independent and joint effects of MHR and BMI on CRS., Methods: We included 42,178 NHANES participants. The determination of CRS referred to the simultaneous presence of cardiovascular disease (identified through self-report) and chronic kidney disease (eGFR < 60 mL/min per 1.73 m²). We employed multivariate weighted logistic regression to evaluate the odds ratio (OR) and 95% confidence interval (CI) for the independent and joint associations of MHR and BMI with CRS. We also conducted restricted cubic spines to explore nonlinear associations., Results: The prevalence of CRS was 3.45% among all participants. An increase in both MHR and BMI is associated with a higher risk of CRS (MHR: OR = 1.799, 95% CI = 1.520-2.129, P < 0.001, P-trend < 0.001; BMI: OR = 1.037, 95% CI = 1.023-1.051, P < 0.001). Individuals who simultaneously fall into the highest quartile of MHR and have a BMI of 30 or more face the highest risk of CRS compared to those in the lowest MHR quartile with a BMI of less than 25 (OR = 3.45, 95% CI = 2.40-4.98, P < 0.001). However, there is no interactive association between MHR and BMI with CRS., Conclusions: Higher MHR and BMI are associated with higher odds of CRS. MHR and BMI can serve as tools for early prevention and intervention of CRS, respectively., (© 2024. The Author(s).)

Background: Traditionally, low cardiac output has been considered the primary hemodynamic driver of renal function and injury. Adult data suggest that central venous pressure (CVP) is a more important factor., Objectives: The authors hypothesized that in children with cardiovascular disease, higher CVP predicts lower estimated glomerular filtration rate (eGFR) and worsening renal function (WRF)., Methods: We performed a single-center cohort study of patients aged 3 months to 21 years with biventricular circulation undergoing cardiac catheterization. Pearson's correlation and linear and Cox regression analyses were performed to determine associations with eGFR at the time of catheterization and WFR within 180 days after catheterization., Results: 312 patients had median age 7.9 years (IQR: 2.3 to 14.5 years), median eGFR 97 mL/min/1.73 m 2 (IQR: 81-118 mL/min/1.73 m 2 ), median CVP 7 mm Hg (IQR: 5-9 mm Hg), and median cardiac index 3.7 mL/min/m 2 (IQR: 2.9-4.6 mL/min/m 2 ). Nearly half (48%) were transplant recipients. In multivariable analysis, CVP was independently associated with eGFR (β = -2.65; 95% CI: -4.02, -1.28; P  < 0.001), as was being a transplant recipient (β = -10.20; 95% CI: -17.74, -2.65; P  = 0.008), while cardiac index was not. Fifty-one patients (16%) developed WRF. In a proportional hazards model adjusting for cardiac index, only higher CVP (HR: 1.10; 95% CI: 1.04-1.17; P  = 0.002) and greater contrast volume by weight (HR: 1.05; 95% CI: 1.01-1.10; P  = 0.021) predicted WRF. CVP ≥7 mm Hg likewise predicted WRF (HR: 2.57; 95% CI: 1.29-5.12; P  = 0.007)., Conclusions: Among children with a spectrum of cardiovascular disease, higher CVP is associated with lower eGFR and development of WRF, independent of cardiac index., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Acute kidney injury represents a significant threat in cardiac surgery regarding complications and costs. Novel preventive approaches are needed, as the therapeutic modalities are still limited. As experimental studies have demonstrated, glutamine, a conditionally essential amino acid, might have a protective role in this setting. Moreover, the levels of glutamine after the cardiopulmonary bypass are significantly lower. In clinical practice, various trials have investigated the effects of glutamine supplementation on cardiac surgery with encouraging results. However, these studies are heterogeneous regarding the selection criteria, timing, dose, outcomes studied, and way of glutamine administration. This narrative review aims to present the potential role of glutamine in cardiac surgery-associated acute kidney injury prevention, starting from the experimental studies and guidelines to the clinical practice and future directions.

Aims: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance., Methods and Results: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved., Conclusions: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS., Clinical Trial Registration: RED DESERT (NCT04116034), SAHARA (NCT04882358)., (© 2024 European Society of Cardiology.)

Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of tubular damage, and its elevation has been described in human and canine cardiorenal syndrome. The aim was to evaluate the association between echocardiographic indexes and urine NGAL (uNGAL) and uNGAL normalized to urine creatinine (uNGALC) in dogs with MMVD. This is a multicentric prospective cross-sectional study. A total of 77 dogs with MMVD at different ACVIM stages were included. All dogs underwent echocardiography, serum chemistry, and urinalysis. Echocardiographic data analyzed were shortening fraction (SF), left ventricular diastolic (LVIDDn) and systolic (LVIDSn) diameters normalized for body weight, left atrium to aortic root ratio (LA/Ao), maximal (LAV Max ) and minimal (LAV Min ) left atrial volumes, LA stroke volume (LASV), early diastolic mitral peak velocity (E Vmax ), E Vmax to tissue Doppler E' wave (E/E'), aortic (VTI Ao ) and mitralic (VTI Mit ) velocity time integrals and their ratio (VTI Mit /VTI Ao ), and tricuspid regurgitation velocity (TR Vmax ). In the univariate analysis LASV, TR Vmax , LAV Max , LVIDDn, and VTI Mit /VTI Ao were independent predictors of increased uNGAL and uNGALC; however, only LASV [(OR: 1.96, 95% CI: 1.16 to 3.31) P = 0.01 for NGAL, and (OR: 2.79, 95% CI: 1.50 to 5.17) P < 0.001 for NGALC] and TR Vmax [(OR: 1.73, 95% CI: 1.20-2.51) P = 0.002 for NGAL, and (OR: 1.50, 95% CI: 10.07-2.10) P = 0.015 for NGALC] remained statistically significant in the multivariable analysis. Based on our results, LASV and TR Vmax are associated with increased uNGAL and uNGALC. These parameters might detect dogs with MMVD at higher risk of developing kidney damage., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Although guideline-directed medical therapy is well established, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF with consequent higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as cornerstones to reduce residual risk of both cardiovascular mortality and readmission for heart failure. The following review will debate about emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the new therapeutic strategies in cardiorenal patients., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

Background: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs)., Methods: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury., Results: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury., Conclusions: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

Background: Inflammation is essential in cardiorenal syndrome, however there is still a lack of evidence proving the interaction between cardiac injury, renal dysfunction and the inflammatory response. This study aimed to illustrate the association between renal dysfunction and cardiac injury with a specific focus on the role of inflammation., Methods: A single-center, retrospective study included patients with heart failure admitted to the cardiovascular department from September 2019 to April 2022. Patients received cardiovascular magnetic resonance (CMR) imaging (T1 mapping and late gadolinium enhancement (LGE)). Demographic, creatinine and native T1 were analyzed using pearson correlation, linear regression and adjusted for confounders. Interaction and subgroup analysis were performed., Results: Finally, 50 validated heart failure (HF) patients (age 58.5 ± 14.8 years; 78.0% men) were included. Cardiac global native T1 for the high estimated glomeruar filtration rate (eGFR) group was 1117.0 ± 56.6 ms, and for the low eGFR group was 1096.5 ± 61.8 ms. Univariate analysis identified global native T1 ( β = 0.16, 95% confidence interval (CI): 0.04-0.28, p = 0.014) and C-reactive protein (CRP) ( β = 0.30, 95% CI: 0.15-0.45, p < 0.001) as determinants of creatinine. Multivariable linear regression analysis identified global native T1 ( β = 0.12, 95% CI: 0.01-0.123, p = 0.040) as a determinant of creatinine while age and diabetes were adjusted. Significant interactions between CRP and global native T1 in relation to creatinine level ( p for interaction = 0.005) were identified., Conclusions: Kidney dysfunction was associated with cardiac injury and inflammation, respectively. The interaction between myocardial injury and kidney dysfunction is contingent on the severity of the inflammatory response. Further studies were needed to identify the mechanisms of the inflammatory response in cardiorenal syndrome., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Renal circulation evaluation is essential in understanding the cardiorenal relationship in heart failure (HF), and there is a growing interest in imaging techniques that visualize renal circulation. This study aimed to assess the effectiveness of superb microvascular imaging (SMI) in evaluating renal circulation in HF patients., Method: The study included 71 HF patients undergoing cardiac catheterization. Prior to catheterization, renal ultrasound examinations were performed. A control group of 18 subjects without HF was also included. SMI was used to measure the vascular index (VI), which was calculated as the percentage of blood flow signal area in the region of interest. The intrarenal perfusion index (IRPI) was determined as a fluctuation index of VI, reflecting variations in the number of blood cells moving through renal tissue during the cardiac cycle., Results: Using the upper 95% confidence interval of IRPI (0.6) from the control group, HF patients were classified into two groups. Patients with IRPI > 0.6 showed a more congestive profile. Right atrial pressure and biphasic or monophasic Doppler intrarenal flow pattern were independent determinants of IRPI > 0.6. In addition, IRPI remained a significant predictor of estimated glomerular filtration rate (eGFR)., Conclusion: The parameter IRPI as variations in SMI signal during the cardiac cycle may be a useful evaluation method for renal perfusion impairment in HF., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

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 m 2 ( 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.

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., (© 2024. The Author(s).)

Cardiovascular disease (CVD) is highly prevalent in patients suffering from chronic kidney disease (CKD). The risk of patients with CKD developing CVD is manifested already in the early stages of CKD development. The impact of declined kidney function on increased cardiovascular risk and the underlying mechanisms are complex and multifactorial. This review discusses the impact of (a) traditional cardiovascular risk factors such as smoking, dyslipidemia, diabetes, and hypertension as well as (b) CKD-specific pathophysiological and molecular mechanisms associated with an increased cardiovascular risk. The latter include uremic toxins, post-translational modifications and uremic lipids, innate immune cell activation and inflammation, oxidative stress, endothelial cell dysfunction, increased coagulation and altered platelet responses, vascular calcification, renin-angiotensin-aldosterone-system (RAAS) and sympathetic activation, as well as anemia. Unraveling the complex interplay of different risk factors, especially in the context of patient subcohorts, will help to find new therapeutic approaches in order to reduce the increased cardiovascular risk in this vulnerable patient cohort., (© 2024. The Author(s).)

Heart failure with preserved ejection fraction (HFpEF) comprises approximately one-half of all diagnoses of heart failure. There is significant overlap of this clinical syndrome with chronic kidney disease (CKD), with many shared comorbid conditions. The presence of CKD in patients with HFpEF is one of the most powerful risk factors for adverse clinical outcomes, including death and heart failure hospitalization. The pathophysiology linking HFpEF and CKD remains unclear, but it is postulated to consist of numerous bidirectional pathways, including endothelial dysfunction, inflammation, obesity, insulin resistance, and impaired sodium handling. The diagnosis of HFpEF requires certain criteria to be satisfied, including signs and symptoms consistent with volume overload caused by structural or functional cardiac abnormalities and evidence of increased cardiac filling pressures. There are numerous overlapping metabolic clinical syndromes in patients with HFpEF and CKD that can serve as targets for intervention. With an increasing number of therapies available for HFpEF and CKD as well as for obesity and diabetes, improved recognition and diagnosis are paramount for appropriate management and improved clinical outcomes in patients with both HFpEF and CKD., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hepatorenal syndrome has conventionally been regarded as a multisystem syndrome in which pathophysiologic pathways that link cirrhosis with impairment in kidney function are followed by dysfunction of several organs such as the heart. The advances in cardiac studies have helped diagnose more subtle cardiac abnormalities that would have otherwise remained unnoticed in a significant subset of patients with advanced liver disease and cirrhosis. Accumulating data suggests that in many instances, the cardiac dysfunction precedes and predicts development of kidney disease in such patients. These observations point to the heart as a key player in hepatorenal syndrome and challenge the notion that the cardiac abnormalities are either the consequence of aberrancies in hepatorenal interactions or have only minor effects. As such, the disturbances traditionally bundled within hepatorenal syndrome may indeed represent a hepatic form of cardiorenal syndrome whereby the liver affects the kidney in part through cardiorenal pathways (that is, hepato-cardio-renal syndrome)., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Chronic Cardiovascular and Kidney Disorder (CCKD) represents a growing challenge in healthcare, characterized by the complex interplay between heart and kidney diseases. This manuscript delves into the "butterfly effect" in CCKD, a phenomenon in which acute injuries in one organ lead to progressive dysfunction in the other. Through extensive review, we explore the pathophysiology underlying this effect, emphasizing the roles of acute kidney injury (AKI) and heart failure (HF) in exacerbating each other. We highlight emerging therapies, such as renin-angiotensin-aldosterone system (RAAS) inhibitors, SGLT2 inhibitors, and GLP1 agonists, that show promise in mitigating the progression of CCKD. Additionally, we discuss novel therapeutic targets, including Galectin-3 inhibition and IL33/ST2 pathway modulation, and their potential in altering the course of CCKD. Our comprehensive analysis underscores the importance of recognizing and treating the intertwined nature of cardiac and renal dysfunctions, paving the way for more effective management strategies for this multifaceted syndrome., Competing Interests: The authors declare no conflicts of interest.

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., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)