Biomarker for cardiorenal syndrome risk in patients with liver cirrhosis and type 2 diabetes in Saudi Arabia.

OBJECTIVES: To evaluate the correlation between different attributes, levels of biomarkers, and the probability of developing cardiorenal syndrome (CRS) in patients who have been diagnosed with type 2 diabetes mellitus (T2DM) and liver cirrhosis (LC). The hypothesis suggests that liver illness may be linked to renal impairment, cardiac dysfunction, and the development of cardiorenal syndrome METHODS: The current study retrospectively assessed the medical records of patients who had LC and T2DM diagnoses and were hospitalized at Al Madina Al Munwara hospitals in 2022 and 2023. RESULTS: This research investigated T2DM patients with physician-confirmed to have LC. Poor glycemic control is indicated by high blood glucose and glycated hemoglobin (HbA1c) readings in research participants. High blood pressure, atherogenic plasma indicator (AIP), and obesity plagued most of these individuals. High creatinine, moderate estimated Glomerular Filtration Rate (eGFR) decline, and a modest urinary albumin-to-creatinine (UACR) rise were the most prevalent variables in LC and T2DM patients. Cardiorenal syndrome risk factors, including elevated blood pressure, triglyceride levels, body mass index (BMI), and high-sensitivity C-reactive protein (hs-CRP) concentrations, were identified through logistic regression. It has been demonstrated that the prevalence of these risk factors increases with age; women may be at a greater risk for developing CRS. Specific biomarker evaluations classified 108 (22.6%) LC and T2DM patients at high risk for chronic kidney disease (CKD), 100 (20%) at risk for cardiovascular disease (CVD), and 91 (18.2%) at risk for CRS. CONCLUSION: The current assessment included 500 patients with T2DM and LC. The risk factors for CRS identified in this study included elevated cholesterol and triglyceride levels, high BMI, and elevated blood pressure, with age being a significant factor, particularly in female patients. Early identification of these characteristics in patients with LC and T2DM could aid in mitigating the progression of chronic illnesses and their associated complications.

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.

Demographic trends of cardiorenal and heart failure deaths in the United States, 2011-2020.

BACKGROUND: Heart failure (HF) and kidney disease frequently co-occur, increasing mortality risk. The cardiorenal syndrome results from damage to either the heart or kidney impacting the other organ. The epidemiology of cardiorenal syndrome among the general population is incompletely characterized and despite shared risk factors with HF, differences in mortality risk across key demographics have not been well described. Thus, the primary goal of this study was to analyze annual trends in cardiorenal-related mortality, evaluate if these trends differed by age, sex, and race or ethnicity, and describe these trends against a backdrop of HF mortality. METHODS AND FINDINGS: The Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research database was used to examine cardiorenal- and HF-related mortality in the US between 2011and 2020. International Classification of Diseases, 10 Revision codes were used to classify cardiorenal-related deaths (I13.x) and HF-related deaths (I11.0, I13.0, I13.2, and I50.x), among decedents aged 15 years or older. Decedents were further stratified by age group, sex, race, or ethnicity. Crude and age-adjusted mortality rates (AAMR) per 100,000 persons were calculated. A total of 97,135 cardiorenal-related deaths and 3,453,655 HF-related deaths occurred. Cardiorenal-related mortality (AAMR, 3.26; 95% CI: 3.23-3.28) was significantly lower than HF-related mortality (AAMR, 115.7; 95% CI: 115.6-115.8). The annual percent change (APC) was greater and increased over time for cardiorenal-related mortality (2011-2015: APC, 7.1%; 95% CI: 0.7-13.9%; 2015-2020: APC, 19.7%, 95% CI: 16.3-23.2%), whereas HF-related mortality also increased over that time period, but at a consistently lower rate (2011-2020: APC, 2.4%; 95% CI: 1.7-3.1%). Mortality was highest among older and male decedents for both causes. Cardiorenal-related deaths were more common in non-Hispanic or Latino Blacks compared to Whites, but similar rates were observed for HF-related mortality. A larger proportion of cardiorenal-related deaths, compared to HF-related deaths, listed cardiorenal syndrome as the underlying cause of death (67.0% vs. 1.2%). CONCLUSIONS: HF-related deaths substantially outnumber cardiorenal-related deaths; however, cardiorenal-related deaths are increasing at an alarming rate with the highest burden among non-Hispanic or Latino Blacks. Continued surveillance of cardiorenal-related mortality trends is critical and future studies that contain detailed biomarker and social determinants of health information are needed to identify mechanisms underlying differences in mortality trends.

Independent and joint associations of monocyte to high-density lipoprotein-cholesterol ratio and body mass index with cardiorenal syndrome: insights from NHANES 2003-2020.

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.

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

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

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.

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.

Sex differences in Cardiorenal Syndrome: Insights from CARDIOREN Registry.

PURPOSE OF THE WORK: Although sex-specific differences in heart failure (HF) or kidney disease (KD) have been analyzed separately, the predominant cardiorenal phenotype by sex has not been described. This study aims to explore the sex-related differences in cardiorenal syndrome (CRS) in a contemporary cohort of outpatients with HF. FINDINGS: An analysis of the Cardiorenal Spanish registry (CARDIOREN) was performed. CARDIOREN Registry is a prospective multicenter observational registry including 1107 chronic ambulatory HF patients (37% females) from 13 Spanish HF clinics. Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73 m2 was present in 59.1% of the overall HF population, being this prevalence higher in the female population (63.2% vs. 56.6%, p = 0.032, median age: 81 years old, IQR:74-86). Among those with kidney dysfunction, women displayed higher odds of showing HF with preserved ejection fraction (HFpEF) (odds ratio [OR] = 4.07; confidence interval [CI] 95%: 2.65-6.25, p < 0.001), prior valvular heart disease (OR = 1.76; CI 95%:1.13-2.75, p = 0.014), anemia (OR: 2.02; CI 95%:1.30-3.14, p = 0.002), more advanced kidney disease (OR for CKD stage 3: 1.81; CI 95%:1.04-3.13, p = 0.034; OR for CKD stage 4: 2.49, CI 95%:1.31-4.70, p = 0.004) and clinical features of congestion (OR:1.51; CI 95%: 1.02-2.25, p = 0.039). On the contrary, males with cardiorenal disease showed higher odds of presenting HF with reduced ejection fraction (HFrEF) (OR:3.13; CI 95%: 1.90-5.16, p < 0.005), ischemic cardiomyopathy (OR:2.17; CI 95%: 1.31-3.61, p = 0.003), hypertension (OR = 2.11; CI 95%:1.18-3.78, p = 0.009), atrial fibrillation (OR:1.71; CI 95%: 1.06-2.75, p = 0.025), and hyperkalemia (OR:2.43, CI 95%: 1.31-4.50, p = 0.005). In this contemporary registry of chronic ambulatory HF patients, we observed sex-related differences in patients with combined heart and kidney disease. The emerging cardiorenal phenotype characterized by advanced CKD, congestion, and HFpEF was predominantly observed in women, whereas HFrEF, ischemic etiology, hypertension, hyperkalemia, and atrial fibrillation were more frequently observed in men.

Type 2 diabetes and cardiorenal syndromes. A nationwide French hospital cohort study.

AIM: Type 2 diabetes mellitus (T2DM) is a risk factor for cardiac and renal complications; its effect on cardiorenal syndromes is unknown. METHODS: In a French nationwide cohort of 5,123,193 patients hospitalized in 2012 with ≥5 years of follow-up, we assessed the effect of T2DM on cardiorenal syndrome (CRS) (using cardiorenal, renocardiac, and simultaneous subtypes) incidence and outcomes using 1:1 propensity matching. RESULTS: Among 4,605,236 adults without cardiorenal syndrome, 380,581 (8.5%) with T2DM were matched to 380,581 adults without T2DM. During follow-up, CRS occurred in 104,788 patients: simultaneous n = 25,225 (24.0%); cardiorenal n = 51,745 (49.4%); renocardiac n = 27,818 (26.5%). T2DM doubled the risk of incident CRS (1.30% versus 0.65%/year; adjusted hazard ratio (HR) for any cardiorenal syndrome: 2.14 [95% confidence interval 2.10;2.19]; renocardiac: 2.43 [2.34;2.53]; cardiorenal: 2.09 [2.03;2.15]; simultaneous: 1.94 [1.86;2.03]. Among the 26,396 adults with CRS in 2012, 11,355 (43.0%) had T2DM and were younger than non-diabetic adults (77.4 ± 9.5 versus 82.3 ± 10.0); 8,314 patients with T2DM were matched to 8,314 patients without. T2DM increased risk of: end-stage kidney disease, adjusted HR 1.50 [1.39;1.62]; myocardial infarction 1.35 [1.19;1.53]; cardiovascular death 1.20 [1.13;1.27]; heart failure 1.17 [1.12;1.21]; and all-cause death 1.09 [1.06;1.13], but not ischemic stroke. CONCLUSION: Patients with T2DM represent almost half of patients with CRS and are younger than their non-diabetic counterparts. T2DM doubles the risk of CRS and increases the risk of death, cardiovascular outcome, and end-stage kidney disease but not ischemic stroke after CRS.

Frontier and Hotspot Evolution in Cardiorenal Syndrome: A Bibliometric Analysis From 2003 to 2022.

In the last 20 years, the cardiorenal syndrome (CRS) field has received growing attention. There have been innovations in cardiorenal interaction patterns, biological markers and management of CRS, and even significant changes in its concept and the paradigm of CRS pathophysiology, which considerably increases the difficulties in understanding and in-depth study of this field. However, few study summarized the development process of CRS and critical issues. This review focuses on topical evolutions and emerging trends in CRS pathophysiology, diagnostic pathways, and treatment strategies. A quantitative retrospective analysis, visual review, and evaluation of 1452 articles published in the domain of CRS from 2003 to 2022 was conducted using a bibliometric analysis based on the classic CiteSpace and VOSviewer software rather than a general review, aiming to provide reasonable ideas and directions for future research on CRS.

Clinical outcomes and 30-day readmissions for heart failure with reduced ejection fraction with cardiorenal syndrome: A National Cohort Study.

BACKGROUND: Literature regarding outcomes of cardiorenal syndrome (CRS) among heart failure with reduced ejection fraction (HFrEF) is limited. OBJECTIVE: To study the clinical outcomes and 30-day readmission rates of CRS patients with HFrEF. METHODS: Data from the Nationwide Readmissions Database (NRD) that constitutes 49.1% of the stratified sample of all hospitals in the United States (US), representing >95% of the national population, was analyzed for the CRS with HFrEF visits from 2018 to 2019. CRS was defined by the ICD-10 codes. RESULTS: Out of the 1,530,749 index CRS-related hospitalizations (mean age:64.37 ± 13.30 years; 38.6%females) 73,126 (6.0%) CKD I-II, 883,119 (72.6%) CKD III-IV, and 258,835 (21.3%) CKD V-and-more related encounters were recorded. Mortality was higher among CKD stage V-and-more in comparison to other subgroups(7.6%vs5.73%;p < 0.001). AKI with underlying CKD was more common among stage III-IV compared to other subgroups (55.9%vs43.7%;p < 0.001). Respiratory failure, the second major complication, was more common among stage V-and-more compared to other subgroups (32.5%vs30%;p < 0.001). The overall CRS-related 30-day readmission rate was 22.7%, with CKD V-and-more accounting for highest rates(29.89%), followed by CKD stage III-IV(20.05%) and CKD I-II(12.99%). The primary etiology for 30-day readmission was cardiovascular among all subgroups (54.2%, 54.6%, and 41.80%, which corresponds to CKD I-II, CKD III-IV and CKD V-and-more, respectively). CONCLUSION: CRS among HFrEF accounts for substantial healthcare burden with high 30-day readmission rates. Higher all-cause mortality and 30-day readmissions were associated with worse renal disease. This would suggest that more vigilance is needed by physicians for discharge planning among this patient population.

Cardiorenal Nexus: A Review With Focus on Combined Chronic Heart and Kidney Failure, and Insights From Recent Clinical Trials.

The cardiorenal nexus encompasses a bidirectional relationship between the heart and the kidneys. Chronic abnormalities in cardiac function can lead to progressive kidney disease, and chronic kidney disease can lead to progressively decreasing cardiac function and increasing risk of cardiovascular disease, including heart failure. About 15% of US adults have chronic kidney disease, 2% have heart failure, and 9% have cardiovascular disease. Prevalence rates of chronic kidney disease, cardiovascular disease, and associated morbidities such as type 2 diabetes are expected to increase with an aging population. Observational studies provide evidence for the cardiorenal nexus. Follow-up data from placebo arms of clinical trials in chronic kidney disease or cardiovascular disease show higher rates of renal and cardiovascular outcome events in patient subgroups with type 2 diabetes than in those without type 2 diabetes. The cardiorenal syndromes develop along an interlinked pathophysiological trajectory that requires a holistic, collaborative approach involving a multidisciplinary team. There is now a compendium of treatment options. Greater understanding of the underlying pathophysiology of the cardiorenal nexus will support optimization of the management of these interlinked disease states.

Long-term impact of cardiorenal syndromes on major outcomes based on their chronology: a comprehensive French nationwide cohort study.

BACKGROUND: Cardiorenal syndromes (CRSs) are reputed to result in worse prognosis than isolated heart failure (HF) and chronic kidney disease (CKD). Whether it is true for all major outcomes over the long-term regardless of CRS chronology (simultaneous, cardiorenal and renocardiac CRS) is unknown. METHODS: The 5-year adjusted risk of major outcomes was assessed in this nationwide retrospective cohort study in all 385 687 with either CKD or HF (out of 5 123 193 patients who were admitted in a French hospital in 2012). RESULTS: Overall, 84.0% patients had HF and 8.9% had CKD (they had similar age, sex ratio, diabetes and hypertension prevalence), while 7.1% had CRS (cardiorenal: 44.6%, renocardiac: 14.5%, simultaneous CRS: 40.8%).The incidence of major outcomes was 57.3%, 53.0%, 79.2% for death; 18.8%, 10.9%, 27.5% for cardiovascular death; 52.6%, 34.7%, 64.3% for HF; 6.2%, 5.5%, 5.6% for myocardial infarction (MI); 6.1%, 5.8%, 5.3% for ischaemic stroke; and 23.1%, 4.8%, 16.1% for end-stage kidney disease (ESKD) for isolated CKD, isolated HF and CRS, respectively.As compared with isolated CKD or HF, the risk of death, cardiovascular death and HF was markedly increased in CRS, the worse phenotype being cardiorenal CRS, while the increased risk of MI and ischaemic stroke associated with CRS subtypes was statistically but not clinically significant. As compared with isolated CKD, the risk of ESKD was similar for cardiorenal CRS only and marginally increased for renocardiac and simultaneous CRS. We could not find a synergy between HF and CKD on major clinical outcomes in the whole population (n = 5 123 193 patients). CONCLUSIONS: The additional impact of CRS versus isolated HF or CKD on long-term kidney and cardiovascular risk is highly heterogenous, depending of the event considered and CRS chronology. No synergy between HF and CKD could be demonstrated.

Arterial-renal Syndrome in Patients with ESRD, a New Disease Paradigm.

BACKGROUND: Patients with end-stage renal disease (ESRD) often present with an increased risk of cardiovascular disease. Conditions of compromised cardiovascular health such as atrial fibrillation (AFIB) and peripheral arterial disease (PAD) may alter biomarker levels in a way that reflects worsening ESRD. This study profiled biomarkers and laboratory parameters of endothelium dysfunction in patients with ESRD, categorized by additional AFIB and PAD conditions. METHODS: Citrated blood samples were collected from 95 patients with ESRD. Biomarker levels were measured from plasma samples using sandwich ELISAs, including tissue plasminogen activator (tPA), D-dimer, and nitrotyrosine. Lab parameters, including BUN, calcium, creatinine, parathyroid hormone, phosphate, alkaline phosphatase, ferritin, transferrin, and total iron capacity, and patient comorbidities were obtained from patient medical records. The comorbidities were determined through provider notes, and evidence of applicable testing. RESULTS: 14.89% of patients were found to have atrial fibrillation (n = 14), 30.85% of patients were found to have peripheral arterial disease (n = 29), and 6.38% of patients were found to have both peripheral arterial disease and atrial fibrillation (n = 6). When compared to patients with only ESRD, patients with ESRD and PAD showed elevated levels of D-Dimer (p = .0314) and nitrotyrosine (p = .0330). When compared to patients with only ESRD, patients with atrial fibrillation showed elevated levels of D-Dimer (p = .0372), nitrotyrosine (p = .0322), and tPA (p = .0198). CONCLUSION: When compared to patients with just ESRD, patients with concomitant PAD had elevated levels of Nitrotyrosine and D-dimer; while patients with concomitant Afib had elevated levels of nitrotyrosine, D-dimer, as well as tPA.

Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study.

BACKGROUND: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. METHODS AND RESULTS: This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. CONCLUSION: Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.

Risk factors and outcome variables of cardiorenal syndrome type 1 from the nephrologist's perspective.

BACKGROUND AND AIM: In cardiorenal syndrome (CRS) type 1, acute cardiac failure or acute decompensation of chronic heart failure causes acute kidney injury (AKI). Every individual AKI episode increases the risk for chronic kidney disease (CKD) in the long term. In this study, we aimed to evaluate epidemiological characteristics and outcome variables of CRS type 1 individuals from the nephrologist's perspective. METHODS: The study was performed in a retrospective, observational manner. All AKI patients treated at the Brandenburg Hospital of the Medical School of Brandenburg between January and December 2019 were screened for diagnostic criteria of CRS type 1. Endpoints were in-hospital death, need for dialysis, and renal recovery. RESULTS: During the screening, 198 out of 1189 (16.6%) AKI subjects were assigned to the diagnosis CRS type 1. The overall in-hospital mortality was 19.2%; 9.6% of the patients required dialysis due to AKI. Complete recovery of kidney function was observed in 86 individuals (43.4%); incomplete recovery occurred in 55 patients (27.8%). Mortality-predictive variables were AKIN stage 2, longer ICU treatment, and insulin-dependent diabetes. Regarding dialysis, AKIN stage 3 and higher potassium at the time of diagnosis were predictive. Subjects with longer in-hospital stay recovered more often from CRS type 1. CONCLUSIONS: The incidence of CRS type 1 is high (∼16% of all in-hospital AKI subjects) and the mortality is higher than the average mortality of AKI in general. At the same time, complete recovery of kidney function occurs less frequent. The kidney-related follow-up management of CRS type 1 needs to be significantly optimized to improve the long-term outcome of affected patients.

Additional burden of iron deficiency in heart failure patients beyond the cardio-renal anaemia syndrome: findings from the BIOSTAT-CHF study.

AIMS: Whereas the combination of anaemia and chronic kidney disease (CKD) has been extensively studied in patients with heart failure (HF), the contribution of iron deficiency (ID) to this dysfunctional interplay is unknown. We aimed to assess clinical associates and pathophysiological pathways related to ID in this multimorbid syndrome. METHODS AND RESULTS: We studied 2151 patients with HF from the BIOSTAT-CHF cohort. Patients were stratified based on ID (transferrin saturation <20%), anaemia (World Health Organization definition) and/or CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2 ). Patients were mainly men (73.3%), with a median age of 70.5 (interquartile range 61.4-78.1). ID was more prevalent than CKD and anaemia (63.3%, 47.2% and 35.6% respectively), with highest prevalence in those with concomitant CKD and anaemia (77.5% vs. 59.3%; p < 0.001). There was a considerable overlap in biomarkers and pathways between patients with isolated ID, anaemia or CKD, or in combination, with processes related to immunity, inflammation, cell survival and cancer amongst the common pathways. Key biomarkers shared between syndromes with ID included transferrin receptor, interleukin-6, fibroblast growth factor-23, and bone morphogenetic protein 6. Having ID, either alone or on top of anaemia and/or CKD, was associated with a lower overall summary Kansas City Cardiomyopathy Questionnaire score, an impaired 6-min walk test and increased incidence of hospitalizations and/or mortality in multivariable analyses (all p < 0.05). CONCLUSION: Iron deficiency, CKD and/or anaemia in patients with HF have great overlap in biomarker profiles, suggesting common pathways associated with these syndromes. ID either alone or on top of CKD and anaemia is associated with worse quality of life, exercise capacity and prognosis of patients with worsening HF.

Association between the risk of heart failure hospitalization and end-stage renal disease with digoxin usage in patients with cardiorenal syndrome: A population-based study.

Background: The management of the coexistence of heart disease and kidney disease is increasingly challenging for clinicians. Chronic kidney disease (CKD) is not only a prevalent comorbidity of patients with heart failure but has also been identified as a noteworthy risk factor for all-cause mortality and poor clinical outcomes. Digoxin is one of the commonest treatments for heart disease. There are few trials investigating the role of digoxin in patients with cardiorenal syndrome (CRS). This study aims to examine the association between digoxin usage and clinical outcomes in patients with CRS in a nationwide cohort. Method: We conducted a population-based study that included 705 digoxin users with CRS; each patient was age, sex, comorbidities, and medications matched with three non-users who were randomly selected from the CRS population. Cox proportional hazards regression analysis was conducted to estimate the effects of digoxin on the incidence of all-cause mortality, congestive heart failure (CHF) hospitalization, coronary artery disease (CAD) hospitalization, and end-stage renal disease (ESRD). Results: The all-cause mortality rate was significantly higher in digoxin users than in non-users (adjusted hazard ratio [aHR] = 1.26; 95% confidence interval [CI] = 1.09-1.46, p = 0.002). In a subgroup analysis, there was significantly high mortality in the 0.26-0.75 defined daily dose (DDD) subgroup of digoxin users (aHR = 1.49; 95% CI = 1.23-1.82, p<0.001). Thus, the p for trend was 0.013. With digoxin prescription, the CHF hospitalization was significantly higher [subdistribution HR (sHR) = 1.17; 95% CI = 1.05-1.30, p = 0.004], especially in the >0.75 DDD subgroup (sHR = 1.19; 95% CI = 1.01-1.41, p = 0.046; p for trend = 0.006). The digoxin usage lowered the coronary artery disease (CAD) hospitalization in the > 0.75 DDD subgroup (sHR = 0.79; 95% CI = 0.63-0.99, p = 0.048). In renal function progression, more patients with CRS entered ESRD with digoxin usage (sHR = 1.34; 95% CI = 1.16-1.54, p<0.001). There was a significantly greater incidence of ESRD in the < 0.26 DDD and 0.26-0.75 DDD subgroups of digoxin users (sHR = 1.32; 95% CI = 1.06-1.66, p = 0.015; sHR = 1.44; 95% CI = 1.18-1.75; p for trend<0.001). Conclusion: Digoxin should be prescribed with caution to patients with CRS.

Cardionephrology and cardiorenal disease in Italy: state of the art.

The interactions and feedback mechanisms involved in heart and renal failure are more complex than previously thought and are grouped under the term "cardio-renal axis". In the last decades, it has always been emphasized that renal dysfunction in patients with heart failure can be attributed exclusively to low renal plasma flow resulting from reduced cardiac output. In the last two decades cardiorenal syndrome has been established to set complex and close interactions between heart and kidney. Cardiologists and nephrologist should interact in their daily clinical practice to provide better patients' management. In this review, we will point out main features of cardiorenal axis and cardiorenal syndrome to shift into specific sets of management in Italy starting by Guyton's hypothesis till present days.