Transcriptomic responses associated with kidney injury and repair in acute decompensated heart failure

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure

Cardiorenal syndrome type I (CRS I) is defined as the development of acute kidney injury (AKI) following acute decompensated heart failure (ADHF). The clinical significance of endothelial markers in ADHF-associated AKI has yet to be clarified. This study therefore investigated the biological processes linking ADHF and AKI with the aim of determining whether the plasma markers of endothelial injury and activation are associated with AKI in patients with ADHF. The study prospectively recruited 125 consecutive patients admitted to a coronary critical unit due to ADHF. Patients with and without AKI were compared in terms of soluble thrombomodulin (sTM), angiopoietin (Ang)-1 and −2 plasma levels as well as baseline characteristics. Among the study population, 14 (11.2%) patients developed CRS within 7 days after admission. The hemoglobin levels (median [IQR]11.3[10.8–12.6] vs. 13.5 [12.2–15.0] g/dL, p = 0.003) and baseline eGFR (66.5[35.7–87.9] vs. 78.5 [64.9–107.5] mL/minute/1.73m2, p = 0.044) of patients with CRS were lower than those of patients without CRS. Patients with CRS also presented elevated plasma levels of BNP (1317.5 [222.6–3375.5] vs. 258.2 [63.2–925.8] pg/mL, p = 0.008), Ang-2 (3993.0 [1561.3–15722.7] vs. 1805.9 [1196.9–3302.3] pg/mL, p = 0.006), and sTM (6665.7 [4707.1–11947.3] vs. 4132.2 [3338.0–5531.8] ng/mL, p < 0.001), compared to patients without CRS. Multivariate logistic regression analysis based on forward stepwise method identified that log sTM was the only independent risk factor for AKI (OR, 13.83; 3.02–63.28, p = 0.001). Furthermore, higher sTM levels were associated with AKI in patients with ADHF. These findings suggest a novel approach to dealing with kidney injury in the context of ADHF, involving the use of baseline biomarker profiles to identify individuals at risk of developing AKI. KEY MESSAGES The clinical significance of endothelial markers in acute decompensated heart failure (ADHF)-associated acute kidney injury (AKI) has not previously been clarified. This study revealed that markers of endothelial injury (i.e. plasma soluble thrombomodulin (sTM) levels) were higher in ADHF patients with AKI than in those without AKI. Multivariate analysis identified sTM level > cutoff value of 4,855.2 pg/mL as an independent factor associated with the development of AKI. sTM could potentially be used as a biomarker to predict the development of AKI in patients with heart failure. These findings suggest a novel approach to dealing with kidney injury in the context of ADHF, involving the use of baseline biomarker profiles to identify individuals at risk of developing AKI.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

THE AIM: to evaluate the morphological picture and its relationship with markers of acute kidney injury and other prognostic parameters in patients with severe fatal acute decompensation of heart failure (ADHF).PATIENTS AND METHODS: material obtained from 62 patients 47–82 years old (mean age 72.8±2.1 years) with severe acute decompensation of chronic heart failure resulting in death. The red cell distribution width, erythrocyte sedimentation rate haemoglobin, creatinine, total bilirubin, C-reactive protein content in blood at admission and shortly before death were determined. Autopsy with subsequent detailed examination of renal tissue was performed in all cases.RESULTS: The average duration of hospitalization of deceased patients with ADHF was 6,9±1,1 days. The main cause of death in 25 patients (40,3%) was pulmonary oedema due to pulmonary embolism, or against the background of heart failure, its acute decompensation developed – 37 patients (59,7%). On autopsy acute tubular injury was found in 36 patients (58.1%), with its direct strong correlation with the red cell distribution width, creatinine level, C-reactive protein; medium strength correlation with erythrocytes, total bilirubin; weak strength correlation – with transaminases was revealed.CONCLUSION: In fatal ADHF, AKI occurred with high frequency and was characterized mainly by acute tubular epithelial injury of varying severity. Acute kidney injury in fatal ADHF was strongly associated with elevated levels of CRP, RDW, and creatinine, increased heart weight, and the presence of hydrothorax. There was a correlation of medium strength with decreased red blood cell count and increased total bilirubin levels, and a weak correlation with elevated transaminase concentrations. Acute kidney injury is one of the components of thanatogenesis associated with the combined effect of inflammatory factors.

Introduction: There has been little focus on hospitalized acute decompensated heart failure (ADHF) that develops after admission, which may occur because of comorbid conditions, over-administration of fluid or post-surgical complications. Aims: To compare patient characteristics, case fatality, and hospital length of stay (LOS) associated with ADHF that develops after hospital admission as compared to those with ADHF at admission. Methods: Hospitalizations with possible ADHF were sampled, based on HF ICD codes, among those aged &gt; 55 years from the four communities of the Atherosclerosis Risk in Communities Study (2005-2010). Medical records were abstracted with events classified by physician panel or computer classified. Case fatality was obtained through the National Death Index. We identified 4,503 (unweighted) events with definite/probable ADHF, after excluding those with unknown time of decompensation (n=81), hospital transfers (n=102), and race other than black or white (n=118). Demographic and clinical characteristics were compared by ADHF onset (at/after admission). Logistic regression was used to evaluate the association of ADHF onset with in-hospital mortality, and 28-days and one-year mortality, adjusted for demographics and comorbidity. Linear regression was used to evaluate the association of ADHF onset with log-transformed hospital LOS, adjusted for demographics. All analyses were weighted to account for the stratified sampling design. Results: Of 21,052 (weighted) ADHF events, 7.4% (n=1561) developed ADHF after admission. Patients with ADHF occurring after admission were older (mean: 79 vs. 75 years), and more likely white and female. Those with ADHF at admission were more likely to have a positive smoking history, COPD, and to be on dialysis. Presence of diabetes, hypertension and coronary artery disease were not significantly different between groups. In hospital mortality (16.5% vs. 6.3%; OR= 2.7, 95% CI=1.9-3.8) and 28-day mortality (23.9% vs. 10.1%; OR= 2.4, 95% CI=1.7-3.4) was higher among those who developed ADHF after admission. One-year case fatality was similar (39.4% vs. 33.6%; OR= 1.2, 95% CI=0.9-1.6). Unadjusted mean LOS was longer for those with ADHF occurring after admission (12.8 days, 95% CI=11.8-13.8) than those with ADHF at admission (7.2 days, 95% CI=6.8-7.6). The adjusted and geometric mean LOS was 1.3 days (95% CI=1.2-1.4) longer for those who developed ADHF after admission. Conclusion: Although patients with ADHF onset after admission were slightly older, differences in comorbidity do not indicate an easily identifiable subgroup for closer in-hospital monitoring. Development of ADHF after admission was associated with an alarmingly high early case fatality and longer hospital LOS compared to those with ADHF at hospital admission.

Cardiorenal Syndrome in Critical Care: The Acute Cardiorenal and Renocardiac Syndromes

Background and Aims Impaired renal function is a common finding in patients with cardiac diseases and confers an adverse prognosis in this population. To evaluate the incidence, phenotypes and prognostic value of cardiorenal interrelations in patients with acute decompensated heart failure (ADHF) and non-ST-elevation acute coronary syndrome (NSTE-ACS). Method we examined 278 patients with ADHF (85.3% had anamnesis of symptomatic HF with frequent hospitalizations, 20.1% had ejection fraction &amp;lt;35%) and 288 with NSTE-ACS (64.9% developed myocardial infarction (MI)). In ADHF group in comparison with NSTE-ACS the patients were younger (69.7±10.2 vs 72±12.1 years, p&amp;lt;0.01), there were more males (55.4 vs 36.5%, p&amp;lt;0.001), smokers and alcohol abusers (47.8 and 30.6% vs 8 and 5.6%, p&amp;lt;0.001). The comorbidities were more typical for ADHF group: atrial fibrillation 46 vs 24% (p&amp;lt;0.001), obesity 55.8 vs 30.9% (p&amp;lt;0.001), anemia 40.6 vs 25.3% (p&amp;lt;0.001), diabetes mellitus 33.1 vs 23.3% (p&amp;lt;0.01). Chronic kidney disease (CKD) and acute kidney injury (AKI) were diagnosed according to KDIGO 2012 Guidelines. AKI phenotypes were identified depending on time of development (community- or hospital-acquired), persistency (transient or persistent), history of CKD (AKI de novo or AKI on CKD). Results Incidence of CKD in patients with ADHF and NSTE-ACS was 45 and 46.5%, CKD was first diagnosed on admission in 57.6 and 64.2% of patients respectively. In 7.6% cases of ADHF and 14.2% of NSTE-ACS groups the duration of impaired kidney function was unknown. No associations of existing CKD and in-hospital mortality were detected. Incidence of AKI in ADHF and NSTE-ACS groups was 43.5 and 37.2%. The hospital-acquired AKI, AKI on CKD and persistent AKI were found in 52.9, 47.9 and 46.3% of ADHF patients, and in 57.9, 58.9 and 50.5% in NSTE-ACS group respectively. In-hospital mortality was higher in patients with AKI in ADHF and NSTE-ACS groups (12.4 vs 5%, p&amp;lt;0.01 and 17.8 vs 3.3%, p&amp;lt;0.001). Mortality in patients with ADHF and hospital-acquired persistent AKI de novo and community-acquired persistent AKI on CKD was 41 and 29%, and in community-acquired transient AKI on CKD in the NSTE-ACS group – 29%. Conclusion Different cardiorenal interrelations were revealed in 75.2% of patients with ADHF and in 61.8% with NSTE-ACS. In patients with acute cardiac diseases high in-hospital mortality is tightly associated with phenotypes of hospital-acquired persistent AKI de novo and community-acquired persistent AKI on CKD in ADHF, and in community-acquired transient AKI on CKD in the NSTE-ACS.

Calling for Targeted Trials in Cardiorenal Syndromes

Aim. To identify risk factors for acute decompensated heart failure (ADHF) in patients with type 2 diabetes (T2D).Material and methods. In the cardiology department, 129 patients with ADHF were registered within 8 months, 59 (45,7%) of them had T2D. The study included 117 ADHF patients who were divided into two groups depending on the presence of T2D: group 1 (n=49; 41,9%) — patients with T2D, group 2 (n=67; 55,9%) without T2D. The ADHF was verified by rapid progress of hypoperfusion and congestion, which required emergency hospitalization and inotropic and/or intravenous diuretic therapy. In the first 48 hours of hospitalization, echocardiography was performed, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and creatinine were determined; the glomerular filtration rate was estimated.Results. The incidence of T2D among patients with ADHF was 45,7%. There were following risk factors for ADHF in T2D patients: diabetic ketoacidosis (p=0,002), hypertensive crisis (p=0,017), history of acute coronary syndrome (p=0,048), atrial fibrillation (p=0,030), chronic kidney disease (p=0,003), pneumonia (p=0,035), progression of anemia (p=0,049), low prevalence of beta-blockers use (p=0,001), use of inappropriate antidiabetic drugs for HF patients (sulfonylureas, insulin). ADHF, assessed by NT-proBNP level, was significantly more severe in T2D patients (p=0,001) with pronounced congestion symptoms (p=0,001), which led to an increase in the need for diuretic therapy (p=0,002). Cardiac remodeling in T2D patients with ADHF is characterized mainly by the preserved left ventricular ejection fraction (LVEF), severe LV diastolic dysfunction (LVDD) and LV hypertrophy (LVH).Conclusion. The development of ADHF in T2D patients is associated with various risk factors and is characterized by severe congestion symptoms, high need for diuretic therapy, mainly preserved LVEF in combination with severe LVDD and LVH.

Aim. To determine the incidence, risk factors and course of acute decompensated heart failure (ADHF) in patients with prediabetes.Material and methods. Within 24 months, 426 patients hospitalized to cardiology department of a multidisciplinary hospital with ADHF were consecutively included in the study. In addition, 136 patients who met the inclusion criteria and did not have exclusion criteria were divided into 2 groups depending on prediabetes presence. The first group consisted of 51 (37,5%) patients with prediabetes, the second — 85 (62,5%) patients without this pathology. ADHF was verified based on a rapid increase in symptoms and signs of hypoperfusion. Prediabetes was defined according to World Health Organization criteria. The risk level for type 2 diabetes was determined using the FINDRISC online calculator. In the first 48 hours of hospitalization, echocardiography was performed. The serum concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cystatin C was determined using enzyme immunoassay.Results. The incidence of prediabetes among patients with ADHF was 37,5%. In 9,8%, prediabetes was verified prior to hospitalization. Patients with prediabetes and ADHF were younger and were more likely to have obesity with a body mass index (BMI) of more than 30 kg/m2, non-alcoholic fatty liver disease, and higher waist circumference. In patients with ADHF and prediabetes, congestion symptoms were more pronounced, their higher frequency was recorded, as well as the frequency of wet-warm phenotype. Spironolactone dose was higher during hospitalization in the group of patients with ADHF and prediabetes. In the same group, the duration of hospitalization was longer. Prevalence of ADHF with preserved and mildly reduced ejection fraction (EF), severity of LV diastolic dysfunction (DD), LV mass index in patients with BMI &gt;30 g/m2, left atrial volume index, pulmonary artery systolic pressure were significantly higher in the group of patients with ADHF and prediabetes. At a high risk of type 2 diabetes, the concentrations of NT-proBNP, triglyceride/glucose index, cystatin C, LV diastolic dysfunction severity were significantly higher, and the glomerular filtration rate was lower.Conclusion. The development of ADHF in patients with prediabetes is interrelated with multiple risk factors and comorbidities, characterized by more pronounced congestion, longer hospitalization, predominantly preserved and mildly reduced EF in combination with severe LVDD, LV hypertrophy, and activation of nonspecific inflammation.

Background: Acute Kidney Injury (AKI) is a common clinical syndrome in hospitalized patients, especially in intensive care units and is a strong risk factor for development of Chronic Kidney Disease (CKD). AKI is a common association in patients admitted for Acute Decompensated Heart Failure (ADHF). AKI is an independent predictor of mortality and poor long term outcome in patients presenting with ADHF. Presently available diagnostic tests in particular serum creatinine, are not helpful in early detection of AKI. Thus a diagnostic tool which can help in early detection of AKI, differentiate various types of AKI, grade the severity of AKI, and suggest appropriate management strategy in patients with ADHF, is need of the hour.Objectives: To analyze role of urine microscopy &amp; urinary biomarkers (N-Acetyl-beta-DGlucosaminidase, NAG; and Kidney injury molecule type 1, KIM-1) in early detection of AKI and its differentiation into pre-renal and ATN variety in patients admitted with a clinical diagnosis of ADHF. Materials and Methods: 40 patients of ADHF with AKI, along with 25 controls (ADHF without AKI) were studied from January 2019 to December 2019. Urine microscopy with sediment analysis and measurement of urinary biomarkers were done.Results: Urine microscopy helped in differentiation of pre-renal AKI from ATN. The role of urinary sediment examination in risk stratification of AKI did not show a significant correlation between presence of granular casts and three stages of AKI with a P value of 0.561. Levels of urinary KIM-1 and NAG were higher in ADHF with AKI cases as compared to controls with a significant P value of &lt;0&gt; Conclusions: Urine microscopy is a readily available &amp; inexpensive tool which can help in differential diagnosis of AKI into pre-renal AKI and ATN variety; so that correct therapy can be initiated in time but may not always help to risk stratify patients. The two urinary biomarkers analyzed (KIM-1 and NAG) are useful in early detection of AKI in ADHF patients, however their combination did not have any added advantage of early diagnosis.

DOPPLER ULTRASOUND ASSESSMENT OF INTRA-RENAL VENOUS FLOW IN PATIENTS WITH ACUTE DECOMPENSATE HEART FAILURE: A POTENTIAL ACUTE CARDIORENAL SYNDROME BIOMARKER

Introduction The incidence of heart failure has exponentially increased over the last few decades and acute decompensated diastolic heart failure is one of the leading causes of hospitalization and readmission. Cardiac amyloidosis is one of the rapidly progressing heart conditions. It occurs due to amorphous proteinaceous material called amyloid into the extracellular space of the heart. The infiltration of the heart from amyloid protein has a broad spectrum of presentation, including diastolic heart failure. Purpose Heart failure due to amyloidosis is characterized by diastolic dysfunction resulting from restrictive cardiomyopathy. The outcomes of hospitalized patient with acute decompensated diastolic heart failure in amyloidosis patients compared to those without amyloidosis is not well defined. Methods We conducted a retrospective cohort study by utilizing the National Inpatient sample database from 2017. Using International Classification of disease (ICD)-10 codes, patients with the diagnosis of acute and acute on chronic diastolic heart failure were enrolled in the study. They were further stratified based on the presence of amyloidosis. The primary outcome was to measure in-hospital mortality, while secondary outcomes included development of acute kidney injury (AKI), Acute respiratory failure (ARF), shock and arrhythmias. Results Out of the 915,694 patients with Acute Decompensated diastolic heart failure, about 2270 had amyloidosis as secondary diagnosis. 6.1% of ADHF and amyloidosis died in hospital, compared to 4.2% in those without amyloidosis (aOR=1.35 CI=0.89–2.05, p=0.197). On multivariate analysis, patients with Amyloidosis had increased odds of developing AKI (aOR=1.40 CI 1.13–1.72, p=0.001), Cardiogenic shock (aOR=2.67 CI 1.56–4.55, p&amp;lt;0.001) and arrhythmias (aOR=1.34, CI 1.10–1.64, p=0.004). The incidence of ARF was however lower in patients without amyloidosis compared to those with it (aOR=0.60, CI 0.47–0.75, p&amp;lt;0.001). Conclusion Amyloidosis is one of the underappreciated and underdiagnosed causes of heart failure. Our study shows an increased risk of complications in acute decompensated heart failure with the presence of amyloidosis. Thus, physicians must be aware of this clinical entity for early diagnosis as patients with advanced disease are likely to have poor prognoses. Funding Acknowledgement Type of funding sources: None.

Clinical practice guidelines for the provision of renal service in Hong Kong: General Nephrology.