Gaetano Ruocco

Admission plasma neutrophil gelatinase associated lipocalin (NGAL) predicts worsening renal function during hospitalization and post discharge outcome in patients with acute heart failure.

Abstract Background: The role of neutrophil gelatinase-associated lipocalin (NGAL) has been described in chronic heart failure (HF), however less data are available in patients admitted for acute HF. Methods: We evaluated the role of NGAL in predicting in-hospital worsening renal function (WRF) and post-discharge follow-up during six months period in patients with acute HF. All patients were submitted to creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and B-type natriuretic peptide (BNP) measurement during hospitalization and before discharge. Results: Patients with chronic kidney dysfunction (CKD) demonstrated higher NGAL respect to subject with preserved renal function (241 ± 218 and 130 ± 80 ng/ml; P = 0.0001). In subgroup that developed WRF during hospitalization, NGAL levels were significantly increased respect to patients without WRF (272 ± 205 versus 136 ± 127 ng/ml; P = 0.0001). A cut off of 134 ng/ml has been related to WRF with good sensibility and specificity (92% and 71% AUC 0.83; P = 0.001). Multivariable Cox regression analysis showed that cut-off of 134 ng/ml was the only marker related to death (HR: 1.75; 95% CI: 1.24–2.45; P < 0.001). Follow-up analysis confirmed that NGAL > 130 ng/ml was associated with adverse events during a six-month period. Conclusion: Admission NGAL measurement appears a sensible tool for in-hospital WRF prediction as well as an early marker for adverse outcome during post discharge vulnerable phase.

Comparison of Neutrophil Gelatinase-Associated Lipocalin Versus B-Type Natriuretic Peptide and Cystatin C to Predict Early Acute Kidney Injury and Outcome in Patients With Acute Heart Failure

Neutrophil gelatinase-associated lipocalin (NGAL) has been described in chronic heart failure (HF) as marker of tubular damage and renal dysfunction; however, less data are available in patients with acute HF. Because of high rate of acute kidney injury (AKI) development, we aimed to investigate the role of NGAL in predicting early AKI development; second, we compared NGAL with respect to cystatin C, B-type natriuretic peptide (BNP), renal function, and blood urea nitrogen (BUN) for outcome prediction. We measured admission serum NGAL, cystatin C, and BNP in 231 patients affected to acute HF; all patients were submitted to daily creatinine, estimated glomerular filtration rate, and measurement to identify inhospital AKI defined by Risk, Injury, Failure, Loss, End-Stage Kidney Disease and Acute Kidney Injury Network criteria. We also measured admission and discharge estimated glomerular filtration rate, creatinine, and BUN to evaluate their prognostic role during a 6-month follow-up period; 78 patients developed AKI during hospitalization. In these subjects, NGAL levels were significantly increased respect to patients without AKI (295 ± 228 vs 129 ± 108 ng/ml, p <0.001). A cutoff of 134 ng/ml has been related to AKI with good sensibility and specificity (85% and 80%, respectively; area under the curve 0.81, p <0.001). BNP was also mildly increased (1,000 ± 906 vs 746 ± 580 pg/ml, p = 0.03) but not cystatin C. Patients with chronic kidney disease demonstrated higher NGAL levels compared with subjects with preserved renal function (258 ± 249 and 120 ± 77 ng/ml, p <0.001). The receiver-operating characteristic curve analysis demonstrated that increased NGAL values were associated with increased mortality (cutoff 170 ng/ml, sensibility 60%, specificity 82%, accuracy 71%, area under the curve 0.77, p <0.001). The same significant correlation was also found for BUN at discharge (cutoff 100 mg/dl, sensibility 65%, specificity 85%, accuracy 71%, area under the curve 0.77, p <0.001). Multivariable Cox regression analysis showed that cutoff 170 ng/ml was related with adverse outcome (hazard ratio 1.77, confidence interval 1.24 to 2.83, p = 0.01). In conclusion, NGAL measurement is a sensible tool to predict AKI during hospitalization. Elevated NGAL levels appear to be related to BUN increase and post-discharge outcome. This suggests a prognostic role of tubular damage beyond renal dysfunction.

The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions

Anemia is a common finding in congestive heart failure (CHF) and is associated with an increased mortality and morbidity. Several conditions can cause depression of erythroid progenitor cells: reduction of iron absorption and reuptake, decreased bone marrow activity, reduced endogenous erythropoietin production, and chronic inflammatory state. Anemia’s etiology in CHF is complex and partially understood; it involves several systems including impaired hemodynamic condition, reduced kidney and bone perfusion, increased inflammatory activity, and neurohormonal overdrive. The use of erythropoiesis stimulating agents (ESAs) such as erythropoietin and its derivatives is recently debated; the last interventional trial seems to demonstrate a neutral or negative effect in the active arm with darbepoetin treatment. The current data is opposite to many single blind studies and previous meta-analysis showing an improvement in quality of life, New York Heart Association class, and exercise tolerance using ESA therapy. These contrasting data raise several concerns regarding the target of hemoglobin levels needing intervention, the exact anemia classification and categorization, and the standardization of hematocrit cutoffs. Some cardiac and systemic conditions (ie, hypertension, atrial fibrillation, prothrombotic status) may predispose to adverse events, and ESA administration should be avoided. To prevent the negative effects, high-dosage and chronic administration should be avoided. Clarification of these items could probably identify patients that may benefit from additional iron or ESA treatment. In this review, we discuss the interventional trials made in anemic heart failure patients, the underlying mechanism of anemia in CHF, and the potential role of ESA in this setting.

Loop diuretics in acute heart failure: beyond the decongestive relief for the kidney

Current goals in the acute treatment of heart failure are focused on pulmonary and systemic decongestion with loop diuretics as the cornerstone of therapy. Despite rapid relief of symptoms in patients with acute decompensated heart failure, after intravenous use of loop diuretics, the use of these agents has been consistently associated with adverse events, including hypokalemia, azotemia, hypotension, and increased mortality. Two recent randomized trials have shown that continuous infusions of loop diuretics did not offer benefit but were associated with adverse events, including hyponatremia, prolonged hospital stay, and increased rate of readmissions. This is probably due to the limitations of congestion evaluation as well as to the deleterious effects linked to drug administration, particularly at higher dosage. The impaired renal function often associated with this treatment is not extensively explored and could deserve more specific studies. Several questions remain to be answered about the best diuretic modality administration, global clinical impact during acute and post-discharge period, and the role of renal function deterioration during treatment. Thus, if loop diuretics are a necessary part of the treatment for acute heart failure, then there must be an approach that allows personalization of therapy for optimal benefit and avoidance of adverse events.

Role of BNP and echo measurement for pulmonary hypertension recognition in patients with interstitial lung disease: An algorithm application model

BACKGROUND This study evaluated the role of echocardiography and BNP in patients with interstitial lung disease (ILD), to identify those with PH and RV dysfunction. The aims of this study were: 1-to evaluate the accuracy of an algorithm including BNP, DLCO and echocardiographic measurements to identify PH and RV dysfunction; 2- to evaluate BNP and Echo values concordance in relation to right catheterization measurement. METHODS We analyzed 113 patients with diagnosis of ILD. Echo examination included: Pulmonary systolic, diastolic and mean Arterial Pressure (PAPs, PAPd, PAP mean), End-Diastolic and End-Systolic right ventricle diameters, Inferior Caval Vein diameter, and Tricuspid Annular Plane Systolic Excursion (TAPSE). Patients revealing increased PAPs at echocardiography underwent to catheterization. RESULTS Patients with PAPs > 40 mm Hg (37 patients), PAPmean ≥ 25 mm Hg (23 patients) and PAPd ≥ 20 mm Hg showed BNP increased (157 ± 96 vs 16 ± 14 pg/ml p = 0.004; 201 ± 120 vs 28 ± 17 pg/mL; 124 ± 88 vs 23 ± 18 pg/ml p < 0.001) as patients with TAPSE ≤16 mm (25 patients) (145 ± 104 vs 26 ± 21 pg/ml p < 0.001). In catheterized patients (37 patients) BNP was increased in patients with invasive PAPs > 40 mm Hg (165 ± 112 vs 29 ± 14 pg/ml p < 0.02), as well as in patients with Wedge pressure > 14 mm Hg (199 + 153 vs 54 + 39 pg/mL; p = 0.01). ROC Curve analysis showed that elevated values of BNP, PAPs, PAP mean are able to assess PH. On the other hand, lower values of DLCO (<40%) and TAPSE (≤16 mm) detect PH. Logistic regression analysis of the previous parameters, confirmed their diagnostic role in PH detection. CONCLUSIONS In patients with ILD, an algorithm including BNP, DLCO and echocardiography could be useful for non invasive screening of PH. CLINICAL TRIAL REGISTRATION NAME AND NUMBER ARTEMIS-HP trial; ID number: NCT00879229.

Additional value of Galectin-3 to BNP in acute heart failure patients with preserved ejection fraction

BACKGROUND Almost half of patients with acute heart failure have preserved ejection fraction (HFpEF). HFpEF is a diagnostic challenge using traditional investigation tools; Galectin-3 (Gal-3) is an emerging biomarker useful in individuals at risk for HF. The aim of our study is to analyse the relation and prognostic value of Gal-3, BNP and renal dysfunction in patients with HFpEF compared to patients with reduced ejection fraction (HFrEF). METHODS We enrolled 98 patients with acute heart failure (AHF) and measured Gal-3, BNP, and estimated glomerular filtration rate (eGFR) within 12h of hospital admission. On the basis of echocardiographic findings we divided our sample into two groups: patients with HFrHF (ejection fraction<50%) or HFpEF (ejection fraction>50%). Patients were followed up at 6months. RESULTS No differences in Gal-3 levels were found in the two subgroups (HFrEF: 19.5±5.1ng/mL; HFpEF: 20.5±8.7, p=0.56). Gal-3 was inversely related to renal dysfunction (LogGal-3 vs eGFR: r=-0.30, p=0.01) but did not correlate with LogBNP levels (r=0.07, p=0.55). Gal-3 was associated with more advanced diastolic dysfunction in HFpEF (p=0.009). In addition LogGal-3 was related to diastolic LV stiffness (all patients: r=0.45, p<0.001; HFpEF: r=0.64, p<0.001). Cox regression analysis showed that LogGal-3>1.30 was related to poor outcome independently from renal dysfunction and other risk factors only in HFpEF (univariate HR 23.98 [3.03-89.45]; p<0.001). Adjusted for renal dysfunction (HR 16.32 [1.98-34.09]; p=0.009). CONCLUSIONS Gal-3 is not able to distinguish between HFrEF and HFpEF patients. However it is related to diastolic dysfunction severity and LV stiffness in HFpEF. Gal-3 demonstrates a prognostic role independently from renal dysfunction in subjects with HFpEF.

Different diuretic dose and response in acute decompensated heart failure: Clinical characteristics and prognostic significance

BACKGROUND The question regarding the correct balance between optimal loop diuretic dose administration and best modality is under debate as well as the exact relation existing between congestion and renal dysfunction. We sought to evaluate the effects of different diuretic modalities (low [LD] versus high dose [HD]) and dose administration on decongestion, Worsening renal function (WRF) and outcome. METHODS We retrospectively analyzed data of DIUR-HF study matching for LD vs HD (cut off 125mg/day), and diuretic efficiency (DE) (weight loss/40mg daily of furosemide). We also evaluated WRF rate (creatinine increase during hospitalization ≥0.3mg/dl or estimated glomerular filtration rate (eGFR) reduction ≥25%) together with decongestion. RESULTS HD patients (n.55) were older, more frequently affected by diabetes and chronic kidney disease (CKD) and demonstrated higher rate of inhospital WRF (65% vs 29% p=0.001) and 180-days adverse events (70% vs 23% p<0.001) respect to LD patients (n.41). Patients with low DE showed a higher 180days adverse events rate than higher DE patients (p=0.02). Univariate and multivariable analysis suggests a significant relationship between adverse events and low DE (patients with DE under median value) (U-HR=2.59 [1.44-4.64]; p=0.001. M-HR=3.16 [1.55-6.46]; p=0.002); continuous administration (HR=3.12 [1.65-5.91]; p<0.001) and WRF (HR=5.30 [2.79-10.09]; p<0.001) were also related with adverse events. CONCLUSIONS HD and poor DE are two conditions associated with adverse outcome. Both situations are the consequence of previous detrimental clinical status and they appear strictly related to WRF occurrence.

Chronic kidney disease and worsening renal function in acute heart failure: different phenotypes with similar prognostic impact?

Nearly a third of patients with acute heart failure experience concomitant renal dysfunction. This condition is often associated with increased costs of care, length of hospitalisation and high mortality. Although the clinical impact of chronic kidney disease (CKD) has been well established, the exact clinical significance of worsening renal function (WRF) during the acute and post-hospitalisation phases is not completely understood. Therefore, it is still unclear which of the common laboratory markers are able to identify WRF at an early stage. Recent studies comparing CKD with WRF showed contradictory results; this could depend on a different WRF definition, clinical characteristics, haemodynamic disorders and the presence of prior renal dysfunction in the population enrolled. The current definition of acute cardiorenal syndrome focuses on both the heart and kidney but it lacks precise laboratory marker cut-offs and a specific diagnostic approach. WRF and CKD could represent different pathophysiological mechanisms in the setting of acute heart failure; the traditional view includes reduced cardiac output with systemic and renal vasoconstriction. Nevertheless, it has become a mixed model that encompasses both forward and backward haemodynamic dysfunction. Increased central venous pressure, renal congestion with tubular obliteration, tubulo-glomerular feedback and increased abdominal pressure are all potential additional contributors. The impact of WRF on patients who experience preserved renal function and individuals affected with CKD is currently unknown. Therefore it is extremely important to understand the origins, the clinical significance and the prognostic impact of WRF on CKD.

The Role of Natriuretic Peptides for the Diagnosis of Left Ventricular Dysfunction

Natriuretic peptides (NPs) are entered in current guidelines for heart failure (HF) diagnosis and management because of their high specificity and sensibility in screening patients with acute dyspnea. Due to their availability and relatively low cost, they became the first step examinations in HF patients evaluation at hospital admission together with clinical and chest radiography examination. NPs are released following any cardiac haemodynamic stress due to volume or pressure overload and should be considered as a mirror of cardiac condition helping in recognizing patients with poor outcome. Moreover, the exact role of NPs in early HF stages, in isolated diastolic dysfunction, and in general population is questioned. Several promising reports described their potential role; however, the wide cut-off definition, inclusion criteria, and intrinsic measurement biases do not actually consent to their clinical application in these settings. A multimodality strategy including both NPs and imaging studies appears to be the best strategy to define the cardiac dysfunction etiology and its severity as well as to identify patients with higher risk. In this review, we describe the current and potential role of NPs in patients with asymptomatic cardiac insufficiency, evaluating the requirement to obtain a better standardization for imaging as for laboratory criteria.

Prevalence of Hyperuricemia in Patients With Acute Heart Failure With Either Reduced or Preserved Ejection Fraction

The relation between uric acid (UA) and heart failure has been described; however, there is little detail concerning acute heart failure (AHF) in patients with reduced versus preserved ejection fraction heart failure (HFrEF, HFpEF). We studied 324 consecutive AHF patients screened from interventional Diur-HF Trial (NCT01441245) from January 2011 to February 2016, and divided into HFrEF (EF <50%) and HFpEF (EF ≥50%). We defined hyperuricemia as serum UA ≥7.0 mg/dL in men and ≥6 mg/dL in women. Patients were followed up for 6 months after discharge. The primary outcome was heart failure hospitalization or death. Among 173 HFrEF and 151 HFpEF cases, hyperuricemia was found in 43% and 57%, respectively (p = 0.01). Hyperuricemia was also more frequent in women (74% vs 60%; p = 0.008), those with diabetes (39% vs 19%; p <0.001), hypertension (62% vs 43%; p = 0.001), and atrial fibrillation (48% vs 34%; p = 0.01). In patients with HFrEF, univariate analysis found that hyperuricemia (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.02 to 2.15; p = 0.04) and congestion score ≥3 (HR 2.83, 95% CI 1.52 to 5.28; p <0.001) were associated with the primary end point; after adjustment, only congestion score ≥3 (HR 2.08, 95% CI 1.06 to 4.10; p = 0.03) confirmed this trend. Conversely, in patients with HFpEF, hyperuricemia was the only significant predictor of the primary end point both in univariate (HR 2.25, 95% CI 1.44 to 3.50; p <0.001) and multivariate analyses (HR 2.38, 95% CI 1.32 to 4.28; p = 0.004). In conclusion, in AHF hyperuricemia is common in both in HFrEF and in HFpEF. In the HFpEF subgroup, hyperuricemia was the only independent predictor of heart failure hospitalization or death.