Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function.

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.

Body Mass Index and Clinical and Health Status Outcomes in Chronic Coronary Disease and Advanced Kidney Disease in the ISCHEMIA-CKD Trial.

OBJECTIVE: This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy. METHODS: Baseline BMI was analyzed as both a continuous and categorical variable (< 25, ≥ 25 to < 30, ≥ 30 kg/m2). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale. RESULTS: Body mass index ≥ 30 kg/m2 vs < 25 kg/m2 demonstrated increased risk for MI (hazard ratio [HR] [95% confidence interval] = 1.81 [1.12-2.92]) and for D/MI (HR 1.45 [1.06-1.96]) with a HR for MI of 1.22 (1.05-1.40) per 5 kg/m2 increase in BMI in unadjusted analysis. In multivariate analyses, a BMI ≥ 30 kg/m2 was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P < .05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome. CONCLUSIONS: In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted.

Sodium-glucose cotransporter 2 inhibitors and cardiorenal outcomes in kidney transplantation.

PURPOSE OF REVIEW: This review aims to explore the current evidence regarding cardiovascular and kidney outcomes in patients who undergo treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) post kidney transplantation. RECENT FINDINGS: Summary findings from individual studies included in this review showed largely favorable results in the kidney transplant recipients (KTRs) being treated with SGLT2i.These outcomes included parameters such as allograft function, glycemic control, proteinuria, blood pressure, weight loss and safety profile, among others. Almost all the studies reported an initial 'dip' in eGFR, followed by recovery, after the initiation of SGLT2i treatment. None of the studies reported significant interaction of SGLT2i with immunosuppressive medications. The most common adverse effects noted in these studies were infection-related including UTI and genital mycosis. None of the studies reported acute graft rejection attributable to SGLT2i therapy. SUMMARY: SGLT2i can play a significant role in improving health outcomes in KTRs. However, clinical trials with larger representation of KTRs longer follow-up period are needed to draw more substantial conclusions.

Impact of arteriovenous fistula on flow states in the evaluation of aortic stenosis among ESKD patients on dialysis.

INTRODUCTION: An arteriovenous fistula (AVF) in patients with end-stage kidney disease (ESKD) can influence flow states. We sought to evaluate if assessment of aortic stenosis (AS) by transthoracic echocardiographic (TTE) differs in the presence of AVF compared to other dialysis accesses in patients on dialysis. METHODS: We identified consecutive ESKD patients on dialysis and concomitant AS from a single center between January 2000 and March 2021. We analyzed TTE parameters of AS severity (velocities, gradients, aortic valve area [AVA]) and hemodynamics (cardiac output [CO], valvuloarterial impedance [Zva]) and compared AS parameters in patients with AVF versus other dialysis access. RESULTS: The cohort included 94 patients with co-prevalent ESKD and AS; mean age 66 years, 71% male; 43% Black, 24% severe AS. Dialysis access: 53% AVF, 47% others. In the overall cohort, no significant differences were noted between AVF versus non-AVF in AVA/CO/Zva, but with notable subgroup differences. In mild AS, CO was significantly higher in AVF versus non-AVF (6.3 vs. 5.2 L/min; p = .04). In severe AS, Zva was higher in the AVF versus non-AVF (4.6 vs. 3.6 mm Hg/mL/m2 ). With increasing AS severity in the AVF group, CO decreased, coupled with increase in Zva, likely counterbalancing the net hemodynamic impact of the AVF. CONCLUSION: Among ESKD patients with AS, TTE parameters of flow states and AS severity differed in those with AVF versus other dialysis accesses and varied with progression in severity of AS. Future longitudinal assessment of hemodynamic parameters in a larger cohort of co-prevalent ESRD and AS would be valuable.

Cardiovascular Disease in Diabetes and Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common occurrence in patients with diabetes mellitus (DM), occurring in approximately 40% of cases. DM is also an important risk factor for cardiovascular disease (CVD), but CKD is an important mediator of this risk. Multiple CVD outcomes trials have revealed a greater risk for CVD events in patients with diabetes with CKD versus those without. Thus, reducing the risk of CKD in diabetes should result in improved CVD outcomes. To date, of blood pressure (BP) control, glycemic control, and inhibition of the renin-angiotensin system (RASI), glycemic control appears to have the best evidence for preventing CKD development. In established CKD, especially with albuminuria, RASI slows the progression of CKD. More recently, sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1RA) have revolutionized the care of patients with diabetes with and without CKD. SGLT2i and GLP1RA have proven to reduce mortality, heart failure (HF) hospitalizations, and worsening CKD in patients with diabetes with and without existing CKD. The future of limiting CVD in diabetes and CKD is promising, and more evidence is forthcoming regarding combinations of evidence-based therapies to further minimize CVD events.

Plasma metabolomics profiles in Black and White participants of the Adventist Health Study-2 cohort.

BACKGROUND: Black Americans suffer disparities in risk for cardiometabolic and other chronic diseases. Findings from the Adventist Health Study-2 (AHS-2) cohort have shown associations of plant-based dietary patterns and healthy lifestyle factors with prevention of such diseases. Hence, it is likely that racial differences in metabolic profiles correlating with disparities in chronic diseases are explained largely by diet and lifestyle, besides social determinants of health. METHODS: Untargeted plasma metabolomics screening was performed on plasma samples from 350 participants of the AHS-2, including 171 Black and 179 White participants, using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a global platform of 892 metabolites. Differences in metabolites or biochemical subclasses by race were analyzed using linear regression, considering various models adjusted for known confounders, dietary and/or other lifestyle behaviors, social vulnerability, and psychosocial stress. The Storey permutation approach was used to adjust for false discovery at FDR < 0.05. RESULTS: Linear regression revealed differential abundance of over 40% of individual metabolites or biochemical subclasses when comparing Black with White participants after adjustment for false discovery (FDR < 0.05), with the vast majority showing lower abundance in Blacks. Associations were not appreciably altered with adjustment for dietary patterns and socioeconomic or psychosocial stress. Metabolite subclasses showing consistently lower abundance in Black participants included various lipids, such as lysophospholipids, phosphatidylethanolamines, monoacylglycerols, diacylglycerols, and long-chain monounsaturated fatty acids, among other subclasses or lipid categories. Among all biochemical subclasses, creatine metabolism exclusively showed higher abundance in Black participants, although among metabolites within this subclass, only creatine showed differential abundance after adjustment for glomerular filtration rate. Notable metabolites in higher abundance in Black participants included methyl and propyl paraben sulfates, piperine metabolites, and a considerable proportion of acetylated amino acids, including many previously found associated with glomerular filtration rate. CONCLUSIONS: Differences in metabolic profiles were evident when comparing Black and White participants of the AHS-2 cohort. These differences are likely attributed in part to dietary behaviors not adequately explained by dietary pattern covariates, besides other environmental or genetic factors. Alterations in these metabolites and associated subclasses may have implications for the prevention of chronic diseases in Black Americans.

Proportional troponin changes and risk for outcomes with intervention strategies in non-ST-elevation acute coronary syndrome across kidney function.

AIMS: This analysis evaluates whether proportional serial cardiac troponin (cTn) change predicts benefit from an early versus delayed invasive, or conservative treatment strategies across kidney function in non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: Patients diagnosed with NSTE-ACS in the Veterans Health Administration between 1999 and 2022 were categorized into terciles (<20%, 20 to ≤80%, >80%) of proportional change in serial cTn. Primary outcome included mortality or rehospitalization for myocardial infarction at 6 and 12 months, in survivors of index admission. Adjusted hazard ratio (HR) with 95% confidence Intervals (95% confidence interval [CI]) were calculated for the primary outcome for an early invasive (≤24 h of the index admission), delayed invasive (>24 h of index admission to 90-days postdischarge), or a conservative management. RESULTS: Chronic kidney disease (CKD) was more prevalent (45.3%) in the lowest versus 42.2% and 43% in middle and highest terciles, respectively (p < 0.001). Primary outcome is more likely for conservative versus early invasive strategy at 6 (HR: 1.44, 95% CI: 1.37-1.50) and 12 months (HR: 1.44, 95% CI: 1.39-1.50). A >80% proportional change demonstrated HR (95% CI): 0.90 (0.83-0.97) and 0.93 (0.88-1.00; p = 0.041) for primary outcome at 6 and 12 months, respectively, when an early versus delayed invasive strategy was used, across CKD stages. CONCLUSIONS: Overall, the invasive strategy was safe and associated with improved outcomes across kidney function in NSTE-ACS. Additionally, >80% proportional change in serial troponin in NSTE-ACS is associated with benefit from an early versus a delayed invasive strategy regardless of kidney function. These findings deserve confirmation in randomized controlled trials.

A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association.

A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.

Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.

Outcomes of Severe Acute Kidney Injury in Pediatric Trauma Patients; The Trauma Quality Improvement Program Database Study.

INTRODUCTION: Acute kidney injury (AKI) has been associated with higher mortality and morbidity in trauma victims. There is a paucity of information regarding the outcomes of severe AKI (sAKI) in pediatric trauma patients. Therefore, the trauma quality improvement program database (TQIP) was used to assess that hypothesis sAKI will be associated with higher mortality among pediatric trauma patients. METHODS: The TQIP database was accessed for the study. Patients aged <18 years old admitted to the hospital after sustaining injury were included in the study. Demographics, injury severity score (ISS) and Glasgow coma scale (GCS) score, other body regions injuries, and available comorbidities were included in the study. Propensity score matching analysis was performed to compare the two groups, sAKI vs. no sAKI on patients' characteristics and outcomes. All p values are two-sided. A p-value <0.05 is considered statistically significant. RESULTS: Out of 139,832 patients who qualified for the study, 106 (0.1%) patients suffered from sAKI. Pair-matched analysis showed no significant difference between the groups, sAKI, and no sAKI, regarding the in-hospital mortality (14.3% vs. 12.4%, P = 0.838). There was a prolonged hospital length of stay in the sAKI group when compared to the no sAKI group, (27 days [21-33] vs. 10 [9-14], P < 0.001). There was a higher incidence of deep vein thrombosis (DVT) (12.4% vs. 2.9%, P = 0.024) in the sAKI group as well. CONCLUSION: The sAKI patients stayed in the hospital approximately three times longer and had a 4-fold increase in the occurrence of DVT. No significant difference was found between the groups in in-hospital mortality. TYPE OF STUDY: Retrospective cohort study.

Incidence of Chronic Kidney Disease Following Acute Coronavirus Disease 2019 Based on South Carolina Statewide Data.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was associated with severe acute illness including multiple organ failure. Acute kidney injury (AKI) was a common finding, often requiring dialysis support. OBJECTIVE: Define the incidence of new clinically identified chronic kidney disease (CKD) among patients with COVID-19 and no pre-existing kidney disease. DESIGN PARTICIPANTS: The South Carolina (SC) Department of Health and Environmental Control (DHEC) COVID-19 mandatory reporting registry of SC residents testing for COVID-19 between March 2020 and October 2021 was included. DESIGN MAIN MEASURES: The primary outcome was a new incidence of a CKD diagnosis (N18.x) in those without a pre-existing diagnosis of CKD during the follow-up period of March 2020 to January 14, 2022. Patients were stratified by severity of illness (hospitalized or not, intensive care unit needed or not). The new incidence of CKD diagnosis was examined using logistic regression and cox proportional hazards analyses. KEY RESULTS: Among patients with COVID-19 (N = 683,958) without a pre-existing CKD diagnosis, 8322 (1.2 %) were found to have a new diagnosis of CKD. The strongest predictors for subsequent CKD diagnosis were age ≥ 60 years hazard ratio (HR) 31.5 (95% confidence interval [95%CI] 25.5-38.8), and intervening (between COVID-19 and CKD diagnoses) AKI diagnosis HR 20.7 (95%CI 19.7-21.7). The presence of AKI was associated with an HR of 23.6, 95% CI 22.3-25.0, among those not hospitalized, and HR of 6.2, 95% CI 5.7-6.8 among those hospitalized, for subsequent CKD. COVID-19 was not significantly associated with subsequent CKD after accounting for the severity of illness and comorbidities. CONCLUSION: Among SC residents, COVID-19 was not associated with CKD independent from indicators of the severity of illness, especially AKI diagnosis. Kidney-specific follow-up testing may be reserved for those high-risk for CKD development. Further prospective registries should examine the long-term kidney consequences to confirm these findings.

Minor injury turns into major problem in severe acute kidney injury: a propensity matched analysis.

Objective: Severe acute kidney injury (sAKI) has been associated with a higher mortality in trauma patients, and severity of trauma often correlates with risk of sAKI. Whether minor to moderate trauma is associated with sAKI is less clear. The purpose of the study was to examine the outcomes of minor to moderate trauma patients who developed sAKI. Methods: The National Trauma Database participant use files of 2017 and 2018 were accessed for the study. All patients aged 18 years old and above who sustained an Injury Severity Score (ISS) of <16 and who were brought to a level I or level II trauma center were included in the study. sAKI was defined as an abrupt decrease in kidney function either three times increase in serum creatinine (SCr) level from the baseline or increase in SCr to ≥4.0 mg/dL (≥353.6 µmol/L), initiation of renal replacement therapy, or anuria for ≥12 hours. Propensity matching analysis was performed between the groups who developed sAKI and without sAKI. Outcome of interest was in-hospital mortality. Results: A total of 655 872 patients fulfilled the inclusion criteria with complete information, of which 1896 patients were found to have sAKI. There were significant differences between the two groups on baseline characteristics. The propensity score matching eliminated all the differences and created 1896 pairs of patients. The median hospital length of stay was longer in patients with sAKI when compared with patients who did not develop sAKI (14 (13 to 15) vs. 5 (5 to 5), days p<0.001). The overall in-hospital mortality was 20.6% in patients with sAKI compared with 2.1% without sAKI (p<0.001). Conclusion: The occurrence of sAKI in minor to moderate trauma patients was less than 0.5%. There was a three times longer hospital stay in patients with sAKI and 10-fold increase in mortality when compared with patients who did not develop sAKI. Level of evidence: IV. Study type: Observational cohort study.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). OBJECTIVES: This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. METHODS: Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. RESULTS: A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. CONCLUSIONS: In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360).

A Clinical Perspective on Arsenic Exposure and Development of Atherosclerotic Cardiovascular Disease.

Cardiovascular risk has traditionally been defined by modifiable and non-modifiable risk factors, such as tobacco use, hyperlipidemia, and family history. However, chemicals and pollutants may also play a role in cardiovascular disease (CVD) risk. Arsenic is a naturally occurring element that is widely distributed in the Earth's crust. Inorganic arsenic (iAs) has been implicated in the pathogenesis of atherosclerosis, with chronic high-dose exposure to iAs (> 100 µg/L) being linked to CVD; however, whether low-to-moderate dose exposures of iAs (< 100 µg/L) are associated with the development of CVD is unclear. Due to limitations of the existing literature, it is difficult to define a threshold for iAs toxicity. Studies demonstrate that the effect of iAs on CVD is far more complex with influences from several factors, including diet, genetics, metabolism, and traditional risk factors such as hypertension and smoking. In this article, we review the existing data of low-to-moderate dose iAs exposure and its effect on CVD, along with highlighting the potential mechanisms of action.

Angiotensin Receptor Neprilysin Inhibitor Use and Blood Pressure Lowering in Patients With Heart Failure With Reduced Ejection Fraction Across the Spectrum of Kidney Function: An Analysis of the Veterans Administrative Health System.

BACKGROUND: A substantial proportion of patients with heart failure and kidney disease have poorly controlled blood pressures. This study aimed to evaluate patterns of blood pressure after initiation of an angiotensin receptor neprilysin inhibitor (ARNI) or an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) across the spectrum of kidney function. METHODS: Between 2016 and 2020, we evaluated 26,091 patients admitted to a Veterans Affairs hospital for an acute heart failure exacerbation with reduced ejection fraction. We assessed patterns of systolic and diastolic blood pressure among those started on ARNI or ACEI/ARB over 6 months, overall and across estimated glomerular filtration rate (eGFR). To account for differential treatment factors, we applied 1:1 propensity score matching using 15 known baseline covariates. RESULTS: There were 13,781 individuals treated with an ACEI or ARB and 2589 individuals treated with an ARNI prescription. After propensity score matching, 839 patients were matched in each of the ARNI and ACEI/ARB groups. Mean baseline estimated glomerular filtration rate (eGFR) was 63.8 (standard deviation 21.6), and 10% had stage 4 or 5 chronic kidney disease. Patients in the ARNI group experienced greater systolic blood pressure reduction at month 3 (-5.2 mmHg vs -2.2 mmHg, ARNI vs ACEI/ARB; P < 0.001), and month 6 (-4.7 mmHg vs -1.85 mmHg, ARNI vs ACEI/ARB; P < 0.001). These differences in systolic blood pressure by 6 months did not vary by eGFR above and below 60 mL/min/1.73m2 or continuously across a wide range of eGFR (Pinteraction > 0.10 for both). CONCLUSION: The use of ARNI was associated with significant reduction in blood pressure as compared to the ACEI/ARB group overall and across the eGFR spectrum, including in advanced chronic kidney disease.