Non-cardiac comorbidities in heart failure: an update on diagnostic and management strategies.

Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication and coordination among healthcare providers is crucial to providing the best possible care for these patients. Poorly controlled hypertension contributes to left ventricular remodeling and diastolic dysfunction, emphasizing the importance of optimal blood pressure control while avoiding adverse effects. Among HF patients with diabetes, SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing HF-related morbidity and mortality. Chronic kidney disease exacerbates HF and vice versa, forming the vicious cardiorenal syndrome, so disease-modifying therapies should be maintained in HF patients with comorbid CKD, even with transient changes in kidney function. Anemia in HF patients may be multifactorial, and there is growing evidence for the benefit of intravenous iron supplementation in HF patients with iron deficiency with or without anemia. Obesity, although a risk factor for HF, paradoxically offers a better prognosis once HF is established, though developing treatment strategies may improve symptoms and cardiac performance. In HF patients with stroke and atrial fibrillation, anticoagulation therapy is recommended. Among HF patients with sleep-disordered breathing, continuous positive airway pressure may improve sleep quality. Chronic obstructive pulmonary disease often coexists with HF, and many patients can tolerate cardioselective beta-blockers. Cancer patients with comorbid HF require careful consideration of cardiotoxicity risks associated with cancer therapies. Depression is underdiagnosed in HF patients and significantly impacts prognosis. Cognitive impairment is prevalent in HF patients and impacts their self-care and overall quality of life.

Risk factors and early prediction of cardiorenal syndrome type 3 among acute kidney injury patients: a cohort study.

BACKGROUND: Type 3 cardiorenal syndrome (CRS type 3) triggers acute cardiac injury from acute kidney injury (AKI), raising mortality in AKI patients. We aimed to identify risk factors for CRS type 3 and develop a predictive nomogram. METHODS: In this retrospective study, 805 AKI patients admitted at the Department of Nephrology, Second Hospital of Shanxi Medical University from 1 January 2017, to 31 December 2021, were categorized into a study cohort (406 patients from 2017.1.1-2021.6.30, with 63 CRS type 3 cases) and a validation cohort (126 patients from 1 July 2021 to 31 Dec 2021, with 22 CRS type 3 cases). Risk factors for CRS type 3, identified by logistic regression, informed the construction of a predictive nomogram. Its performance and accuracy were evaluated by the area under the curve (AUC), calibration curve and decision curve analysis, with further validation through a validation cohort. RESULTS: The nomogram included 6 risk factors: age (OR = 1.03; 95%CI = 1.009-1.052; p = 0.006), cardiovascular disease (CVD) history (OR = 2.802; 95%CI = 1.193-6.582; p = 0.018), mean artery pressure (MAP) (OR = 1.033; 95%CI = 1.012-1.054; p = 0.002), hemoglobin (OR = 0.973; 95%CI = 0.96--0.987; p < 0.001), homocysteine (OR = 1.05; 95%CI = 1.03-1.069; p < 0.001), AKI stage [(stage 1: reference), (stage 2: OR = 5.427; 95%CI = 1.781-16.534; p = 0.003), (stage 3: OR = 5.554; 95%CI = 2.234-13.805; p < 0.001)]. The nomogram exhibited excellent predictive performance with an AUC of 0.907 in the study cohort and 0.892 in the validation cohort. Calibration and decision curve analyses upheld its accuracy and clinical utility. CONCLUSIONS: We developed a nomogram predicting CRS type 3 in AKI patients, incorporating 6 risk factors: age, CVD history, MAP, hemoglobin, homocysteine, and AKI stage, enhancing early risk identification and patient management.

Hepato-Cardio-Renal Syndrome.

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).

Rat Models of Cardiorenal Syndrome and Methods for Functional Assessment.

Cardiorenal syndrome (CRS) is a clinical disorder involving combined heart and kidney dysfunction, which leads to poor clinical outcomes. To understand the complex pathophysiology and mechanisms that lie behind this disease setting, and design/evaluate appropriate treatment strategies, suitable animal models are required. Described here are the protocols for establishing surgically induced animal models of CRS including important methods to determine clinically relevant measures of cardiac and renal function, commonly used to assess the degree of organ dysfunction in the model and treatment efficacy when evaluating novel therapeutic strategies.

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

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

Practical Requirements for the Development of an Advanced Cardiorenal Unit.

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

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

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

[Clinical practice guideline for the diagnosis and treatment of cardiorenal syndrome (2023 Edition)].

The guideline was co-authored by a working group composed of multidisciplinary experts in nephrology, cardiology, critical care medicine, and evidence-based medicine. It focused on eight clinical issues concerning prediction, diagnosis and assessment of cardiorenal syndrome, prevention, treatment of drugs and their selection, mechanical circulatory support and blood purification therapy, heart and/or kidney transplantation, treatment of major complications, multidisciplinary combination therapy, and special diagnosis and treatment in children and pregnant women, mainly based on evidence-based evidence of cardiorenal syndrome, heart failure and chronic kidney disease. Meanwhile, the domestic and foreign clinical guidelines in related fields were referenced to put forward recommendations. The present guideline aims to guide and standardize the clinical practice of diagnosis, prevention, treatment and management of cardiorenal syndrome, promote the development of clinical trials, and improve the level of prevention, treatment and scientific research.

The Value of Soluble ST2 in Predicting Cardiorenal Syndrome Type 1 in Acute Myocardial Infarction Patients.

OBJECTIVE: To investigate the predictive value of soluble growth stimulation expressed gene 2 (sST2) for the development of Cardiorenal syndrome type 1 (CRS1) in patients with acute myocardial infarction during hospitalization. METHODS: A retrospective study included 202 patients with acute myocardial infarction, divided into the CRS1 group (n = 61) and the Non-CRS1 group (n = 141) by the CRS1 occurrence. A logistic regression analysis was applied to find independent predictors of the CRS1 occurrence during hospitalization. Receiver operating characteristic (ROC) curves were applied to analyze the predictive values of sST2, N-terminal pro-B type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR). RESULT: The multivariate logistic regression analysis revealed that sST2, NT-proBNP, eGFR, Multivessel coronary artery disease, and diuretic use were independent predictors of the CRS1 occurrence during hospitalization. Application of ROC curve analysis displayed that sST2 had the largest area under the curve (AUC) value of 0.874, sensitivity of 0.770, and specificity of 0.894; sST2, eGFR, and NT-proBNP as combined predictors had an AUC value of 0.908, sensitivity of 0.820, and specificity of 0.908. The ROC curves of sST2 and the combined predictive indices were compared using MedCalc software (version 19.6.3), and no statistically significant difference was found between the two (p = 0.142). The cutoff values of the three indicators were determined by the maximum Youden index. When sST2 ≥61.8 ng/mL, eGFR ≤80.6 mL/min/1.73 m2 and NT-proBNP ≥1525 pg/mL were classified as abnormal range, it was found that more number of abnormal indicators may be more advantageous of risk stratification in CRS1. CONCLUSIONS: sST2 can be used as a novel predictor of the CRS1 occurrence in patients with acute myocardial infarction during hospitalization. sST2, eGFR, and NT-proBNP combined may have better predictive value.

CARDIORENAL SYNDROME AND COVID-19.

The purpose of this paper is to analyses the cases with cardiorenal syndrome, and the ratio of cardiovascular disease and COVID-19. Prospective methods were used to conduct this research, including the period (January 2020-December 2021). Cases of patients treated at the Nephrology Clinic at the University Clinical Center of Kosovo (UCCK) have been studied. The categorical variables were analyzed with the X² test and the Fisher exact test. The study included 120 patients with acute renal disease treated at the Nephrology Clinic at the University Clinical Center of Kosovo (UCCK), of which 46 (38.3%) female and 74 (61.6%) male. Of the 120 patients included in the study 4 were 18-34 years old, 8 were 35-49 years old, 30 were 50-64 years old, and 78 were > 65 years old. There is a strong link between cardiorenal syndrome and age. Regarding cardiorenal syndrome and its association with other diseases in this prospective study were found these concomitant diseases such as: diabetes mellitus type 2, secondary anemia, hypothyroidism, hyperparathyroidism, pneumonia, sepsis, ascites, mesenteric tumor, hyperkalemia, and Covid-19 Infection. There is a strong link between cardiorenal syndrome and COVID-19 Infection. In recent decades various studies have been done against the definition of cardiorenal syndrome, the understanding of pathophysiology, the use of new biomarkers that represent a new dimension in the diagnostic algorithm, and the difficulties in treating this syndrome.

Diagnostic value and utility of commonly used biomarkers of cardiac and renal function in cardiorenal syndromes: a narrative review.

Cardiorenal syndrome (CRS), first defined in 2004 as a consequence of the interactions between the kidneys and other circulatory departments leading to acute heart failure, has since been recognized as a complex clinical entity that is hard to define, diagnose and classify. The framework for the classification of CRS according to pathophysiologic background was laid out in 2008, dividing CRS into five distinct phenotypes. However, determining the timing of individual organ injuries and making a diagnosis of either renal or cardiac failure remains an elusive task. In clinical practice, the diagnosis and phenotyping of CRS is mostly based on using laboratory biomarkers in order to directly or indirectly estimate the degree of end-organ functional decline. Therefore, a well-educated clinician should be aware of the effects that the reduction of renal and cardiac function has on the diagnostic and predictive value and properties of the most commonly used biomarkers (e.g. troponins, N-terminal pro-brain natriuretic peptide, serum creatinine etc). They should also be acquainted, on a basic level, with emerging biomarkers that are specific to either the degree of glomerular integrity (cystatin C) or tubular injury (neutrophil gelatinase-associated lipocalin). This narrative review aims to provide a scoping overview of the different roles that biomarkers play in both the diagnosis of CRS and the prognosis of the disease in patients who have been diagnosed with it, along with highlighting the most important pitfalls in their interpretation in the context of impaired renal and/or cardiac function.

The Bidirectional Association of Chronic Kidney Disease, Type 2 Diabetes, Atherosclerotic Cardiovascular Disease, and Heart Failure: The Cardio-Renal-Metabolic Syndrome.

Background: The cardiometabolic syndrome focuses on the association between type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD), whereas the cardiorenal syndrome focuses on the association between chronic kidney disease (CKD) and heart failure (HF). Consideration of these two syndromes as a single entity has not been well described. Methods: We used the electronic medical records of Kaiser Permanente Northwest to identify 387,985 members aged 18+ years with a serum creatinine measured from 2005 to 2017. If the estimated glomerular filtration rate was <60 mL/min per 1.73 m2, we required a second confirmatory measurement 3-12 months later. Patients were followed through 2019. We calculated the age- and gender-adjusted incidence and progression of CKD per 1000 person-years using generalized estimating equations. We used Cox proportional hazard models to assess the time-dependent effect of each condition on incidence of the other conditions. Results: CKD incidence rates were highest in patients with T2DM, ASCVD, and HF (27.0 per 1000 person-years [95% confidence interval (CI) 24.8-29.4] vs. 5.9 [5.8-6.0] in patients with none of these conditions). Similar results were obtained for CKD progression (309.0, 283.9-336.4 for all three conditions vs. 147.9, 143.3-152.4 for no condition). In time-dependent models, all three conditions were independently associated with CKD incidence, being highest for HF (hazard ratio 2.14, 95% CI 2.07-2.21). All relationships between CKD, T2DM, ASCVD, and HF were significant and bidirectional. Conclusions: The presence of CKD, T2DM, HF, and ASCVD each conveys risk on the others. A cardiometabolic renal syndrome comprising these conditions may be an important disease entity that requires a comprehensive treatment approach.

Updates in Cardiorenal Syndrome.

Cardiorenal syndrome is a term that refers to a collection of disorders involving both the heart and kidneys, encompassing multi-directional pathways between the 2 organs mediated through low arterial perfusion, venous congestion, and neurohormonal activation. The pathophysiology is complex and includes hemodynamic and neurohormonal changes, but inconsistent findings from recent studies suggest this is very heterogenous disorder. Management for ADHF remains focused on decongestion and neurohormonal blockade to overcome the intense sodium and fluid avidity of the CRS.

Contemporary laboratory assessment of acute cardiorenal syndrome for early diagnosis: A call for action.

Acute cardiorenal syndrome (CRS), categorized as CRS type 1 and 3, is defined by the interplay of acute kidney injury or dysfunction and acute cardiac disease. For optimized diagnosis and management of CRS, strategies targeting multi-organ dysfunction must be adopted. Early diagnosis of acute CRS is important to enable timely initiation of appropriate treatment to prevent serious morbidity and mortality; however, traditional biomarkers are suboptimal. Over the past 2 decades, numerous biomarkers have been investigated for a better and more rapid diagnosis of CRS. Yet, the uptake of these contemporary biomarkers has been slow, possibly owing to the use of imperfect gold-standard reference tests. We believe that there is now scope for use of contemporary laboratory test panels to improve the diagnosis of acute CRS. In this review, we briefly discuss a proposed set of biomarkers for the diagnosis of type 1 and type 3 CRS.

New Insight in Cardiorenal Syndrome: From Biomarkers to Therapy.

Cardiorenal syndrome consists in the coexistence of acute or chronic dysfunction of heart and kidneys resulting in a cascade of feedback mechanisms and causing damage to both organs associated with high morbidity and mortality. In the last few years, different biomarkers have been investigated with the aim to achieve an early and accurate diagnosis of cardiorenal syndrome, to provide a prognostic role and to guide the development of targeted pharmacological and non-pharmacological therapies. In such a context, sodium-glucose cotransporter 2 (SGLT2) inhibitors, recommended as the first-line choice in the management of heart failure, might represent a promising strategy in the management of cardiorenal syndrome due to their efficacy in reducing both cardiac and renal outcomes. In this review, we will discuss the current knowledge on the pathophysiology of cardiorenal syndrome in adults, as well as the utility of biomarkers in cardiac and kidney dysfunction and potential insights into novel therapeutics.

CircRNA-mediated pathology: a new preliminary insight into the mechanism of type II cardio-renal syndrome.

AIM: The aim of this research was to investigate the expression of peripheral blood circular RNA (circRNA) in patients with type II cardio-renal syndrome, uncover the potential function and possible mechanisms mediated by circRNAs, and ultimately provide gene target support for the treatment of type II cardio-renal syndrome. METHODS: CircRNAs in the peripheral blood from five healthy individuals and 20 type II cardio-renal syndrome patients were collected for micro-array analysis. Another cohort study consisting of 12 normal cases and 15 type II cardiorenal syndrome patients was conducted to verify the chosen circRNA by quantitative real-time polymerase chain reaction. RESULTS: A total of 2 884 circRNAs were found to be differentially expressed in the group of patients with type II cardio-renal syndrome. Of these, 1 989 were upregulated and 895 were downregulated. One circRNA was then selected as a candidate biomarker and further validated in the second cohort. CONCLUSIONS: Differentially expressed mRNAs between patients with type II cardio-renal syndrome and healthy controls were enriched in two pathways, including haematopoietic cell lineage and cell adhesion molecules. CircRNA-mediated pathology is indispensable and plays an important role in the progress of type II cardio-renal syndrome. More importantly, hsa_cir_0001763 may be an important character in circRNA-mediated pathology.

Prognostic Significance of Risk Factors and Biomarkers in Patients Hospitalized for Cardiorenal Syndromes: A Pilot Study.

BACKGROUND: Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, are an entity characterized by high morbidity and mortality. OBJECTIVE: To evaluate the prognostic role of risk factors and biomarkers in patients hospitalized for CRS. METHODS: In this observational cohort study, 100 consecutive patients hospitalized for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers were measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. RESULTS: Patients were classified into two groups; Group 1 (N= 52): discharged being dialysis-independent, Group 2 (N=48): death/dialysis dependence at discharge. No significant differences were detected in baseline characteristics between the two groups. Group 2 patients used renin-angiotensin-aldosterone system blockers (RAASb) less often and more frequently presented with oliguria/anuria. Group 2 patients had significantly lower hemoglobin, serum albumin, and 25-hydroxy-vitamin D (25(OH)D). At the same time, serum phosphate, potassium, and parathyroid hormone (PTH) were significantly higher in Group 2 patients. In a multivariate regression analysis, lack of prior RAASb and lower 25(OH)D levels were independently associated with an increased risk of death or dialysis dependence at discharge. 25(OH)D/PTH ratio was the most accurate predictor of the composite endpoint (Sensitivity: 79.4%, Specificity: 70.4%). CONCLUSION: Lack of prior RAASb use, high PTH, low 25(OH)D levels, and low 25(OH) D/PTH ratio are associated with a poor prognosis in patients hospitalized for CRS.

Recent Developments in the Evaluation and Management of Cardiorenal Syndrome: A Comprehensive Review.

Cardiorenal syndrome (CRS) is an increasingly recognized diagnostic entity associated with high morbidity and mortality among acutely ill heart failure (HF) patients with acute and/ or chronic kidney diseases (CKD). While traditionally viewed as a state of decline in glomerular filtration rate (GFR) due to decreased renal perfusion, mainly due to therapeutic interventions to relieve congestive in HF, recent insights into the underlying pathophysiologic mechanisms of CRS led to a broader definition and further classification of CRS into 5 distinct types. In this comprehensive review, we discuss the classification of CRS, highlighting the underlying common pathogenetic pathways of heart failure and kidney injury, including increased congestion, neurohormonal dysregulation, oxidative stress as well as inflammation, and cytokine storm that are particularly evident in COVID-19 patients with multiorgan failure and also in those with other disorders including sepsis, systemic lupus erythematosus and amyloidosis. In this review we also present the recent advances in the diagnostic strategies of CRS including cardiac and renal biomarkers as well as advanced cardiac and renal imaging techniques that are available to aid in the diagnosis as well as in the prognostication of this disorder. Finally, we discuss the various therapeutic options available to-date, including fluid optimization, hemofiltration, renal replacement therapy as well as the role of SGLT2 inhibitors in light of recent data from RCTs. It is important to note that, CRS population are either excluded or underrepresented, at best, in major RCTs and therefore, therapeutic recommendations are largely extrapolated from HF and CKD clinical trials.