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Aims: Early evaluation of the natriuretic response is recommended to guide diuretic therapy in acute decompensated heart failure (ADHF). However, its implementation in daily practice is hampered by implementation barriers and increased time constraints. The Readily Available Urinary Sodium Analysis in Patients with Acute Decompensated Heart Failure (EASY-HF) study assessed the feasibility, efficacy and safety of a nurse-led urinary sodium-based diuretic titration protocol with the use of a point-of-care urinary sodium sensor., Methods and Results: The EASY-HF study was a single-centre, randomized, open-label study comparing diuretic management at the treating physician's discretion as standard of care (SOC) with a nurse-led natriuresis-guided protocol in patients with ADHF. The LAQUAtwin Sodium Meter (HORIBA) was used as point-of-care sensor to measure urine sodium concentration. The primary endpoint was natriuresis after 48 h. Secondary endpoints included safety profile and user-friendliness of both the protocol and the point-of-care sensor. Sixty patients were randomized towards SOC (n = 30) versus protocolized care (n = 30). The mean age was 80 ± 8 years, 25% were women and median N-terminal pro-B-type natriuretic peptide was 4667 (2667-7709) ng/L. Natriuresis after 48 h was significantly higher in the protocolized versus SOC group (820 ± 279 vs. 657 ± 273 mmol; p = 0.027). Pre-defined safety endpoints were similar among both groups. The sensor-based protocol was evaluated as easy to use by the nursing staff, and preferred over urinary collections., Conclusion: A nurse-led diuretic titration protocol via a point-of-care urinary sodium sensor was feasible, safe and resulted in an increased natriuresis in ADHF compared to SOC., (© 2024 European Society of Cardiology.)

Aims: The clinical significance of the measurement of urine sodium concentration (UNa + ) in response to loop diuretic administration in patients with acute heart failure (AHF) is still unsettled. We studied the association of serial measurements of spot UNa + during the first 48 h of AHF treatment with the indices of decongestion, renal function, and prognosis., Methods and Results: We enrolled 111 AHF patients, all of whom received intravenous furosemide on admission. The mean spot UNa + significantly increased in the 6 h sample (P < 0.05 vs. baseline) and returned to baseline values in the 24 and 48 h samples. Based on the increase or decrease/no change of UNa + in the 6 and 48 h samples vs. baseline, patients were divided into two groups at each time point, respectively. Patients did not differ in baseline clinical and laboratory characteristics. Patients with a decrease/no change of UNa + in the 6 and 48 h samples had a lower weight loss during hospitalization. Patients with a decrease/no change of UNa + in the 48 h sample had a poorer diuretic response and a significant increase in the urinary levels of the tubular biomarkers: kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Low UNa + and decrease/no change in UNa + in the 6 and 48 h samples were independent predictors of higher risk of all-cause mortality during 1-year follow-up (all P < 0.05)., Conclusion: In AHF, low spot UNa+ and lack to increase UNa + in response to intravenous diuretics are associated with poor diuretic response, markers of tubular injury and high risk of 1-year mortality., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF., Methods and Results: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR., Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Aims: Recent studies indicate the need to redefine worsening renal function (WRF) in acute heart failure (AHF), linking a rise in creatinine with clinical status to identify patients who develop 'true WRF'. We evaluated the usefulness of serial assessment of urinary levels of neutrophil gelatinase-associated lipocalin (uNGAL), kidney injury molecule-1 (uKIM-1), and cystatin C (uCysC) for prediction of 'true WRF'., Methods and Results: In 132 patients with AHF, uNGAL, uKIM-1, and uCysC were measured using a highly sensitive immunoassay based on a single-molecule counting technology (Singulex, Alameda, CA, USA) at baseline, day 2, and day 3. Patients who developed WRF (a ≥0.3 mg/dL increase in serum creatinine or a >25% decrease in the estimated glomerular filtration rate from the baseline value) were differentiated into those 'true WRF' (presence of deterioration/no improvement in clinical status during hospitalization) vs. 'pseudo-WRF' (uneventful clinical course). 'True WRF' occurred in 13 (10%), 'pseudo-WRF' in 15 (11%), whereas the remaining 104 (79%) patients did not develop WRF. Patients with 'true WRF' were more often females, had higher levels of NT-proBNP, creatinine, and urea on admission, higher urine albumin to creatinine ratio at day 2, higher uNGAL at baseline, day 2, and day 3, and higher KIM-1 at day 2 (vs. pseudo-WRF vs. without WRF, all P < 0.05). Patients with pseudo-WRF did not differ from those without WRF. In the multivariable model, elevated uNGAL at all time points and uKIM-1 at day 2 remained independent predictors of 'true WRF'., Conclusion: Elevated levels of uNGAL and uKIM-1 may predict development of 'true WRF' in AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Aims: Urine proteome analysis (UPA) has already provided accurate discriminatory patterns of urinary peptides for renal disease, coronary artery disease, and asymptomatic LV diastolic dysfunction. UPA has now been used to characterize a discriminatory peptide biomarker pattern and establish a diagnostic classifier for heart failure patients with reduced ejection fraction (HFrEF) in the presence of chronic kidney disease (CKD)., Methods and Results: We analysed the urine proteome profiles obtained by capillary electrophoresis online coupled to micro-TOF (time of flight) mass spectrometry of 126 individuals, 59 HFrEF patients and 67 controls matched for age, sex, and renal function. In total, 107 significant discriminatory peptides were identified and used to establish a support vector machine-based classifier that was successfully applied to a test set of 25 HFrEF patients and 33 controls, achieving 84% sensitivity and 91% specificity. The majority of sequenced peptides were fragments of collagen type I and III., Conclusion: UPA was able to identify a set of HFrEF-specific urinary peptide biomarkers on a background of CKD that were successfully utilized to establish a syndrome's classifier., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: Interventional trials provide evidence for a beneficial effect of reduced dietary sodium intake on blood pressure. The association of sodium intake with heart failure which is a long-term complication of hypertension has not been examined., Methods and Results: Hazard ratios [HRs, 95% confidence interval (CI)] of heart failure comparing quintiles of estimated 24 h urinary sodium excretion (USE) were calculated in apparently healthy men (9017) and women (10,840) aged 39–79 participating in the EPIC study in Norfolk. During a mean follow-up of 12.9 years, 1210 incident cases of heart failure occurred. Compared with the reference category (128 mmol/day≤USE≤148 mmol/day), the top quintile (USE≥191 mmol/day) was associated with a significantly increased hazard of heart failure (1.32, 1.07–1.62) in multivariable analysis adjusting for age, sex, body mass index, diabetes, cholesterol, social class, educational level, smoking, physical activity, and alcohol consumption, with a marked attenuation (1.21, 0.98–1.49) when further adjusting for blood pressure. The bottom quintile (USE≤127 mmol/day) was also associated with an increased hazard of heart failure (1.29, 1.04–1.60) in multivariable analysis without relevant attenuation by blood pressure adjustment (1.26, 1.02–1.56), but with substantial attenuation when adjusting for interim ischaemic heart disease and baseline C-reactive protein levels and exclusion of events during the first 2 years (1.18, 0.96–1.47)., Conclusion: We demonstrate a U-shaped association between USE and heart failure risk in an apparently healthy middle-aged population. The risk associated with the high range of USE was attenuated after adjustment for blood pressure, whereas the risk associated with the low range of USE was attenuated after adjustment for pre-existing disease processes., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Aims: There is growing recognition of the clinical importance of cardiorenal syndrome-the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk., Methods and Results: This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01-3.29; P < 0.05). Participants with a combination of low GFR (<60 mL/min/1.72 m(2)) and high KIM-1/creatinine (>128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 (P < 0.001)., Conclusion: Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.

Aims: Reliable detectors of worsening renal function (WRF) in Emergency Department (ED) patients with acute heart failure (AHF) are limited. We hypothesized that initial urinary neutrophil gelatinase-associated lipocalcin (NGAL) levels, and changes in urinary NGAL levels after initial ED AHF therapy, would be associated with WRF and adverse events., Methods and Results: Urinary NGAL upon ED presentation and 12-24 h after ED treatment was measured in a cohort of ED patients with AHF. NGAL was corrected for urinary creatinine (uCr). WRF was defined as RIFLE stages 1, 2, or 3, or a creatinine increase of ≥0.3 mg/dL. Patients were prospectively followed for 5- and 30-day adverse cardiovascular events. The 399 patients had a median age of 63 years, 50% were Caucasian, and 62% were male. Those with WRF at 72-96 h were more likely to have a higher initial NGAL value (71 vs. 32 ng NGAL/mg uCr) (P = 0.005), and a higher NGAL level at 12-24 h after ED therapy (107 vs. 25ng NGAL/mg uCr, P < 0.001). In a multivariable model, NGAL at 12-24 h remained a significant predictor of WRF (P = 0.012). Of all variables available 12-24 h after initial therapy, the only significant predictor of 30-day events was an elevated urinary NGAL level (P = 0.02)., Conclusions: Urinary NGAL levels determined 12-24 h after ED therapy are significantly associated with both WRF at 72-96 h and 30-day adverse events. This suggests that early management strategies may have an impact on subsequent WRF and outcomes. If confirmed, NGAL may have a role for guiding therapeutic decisions.

Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by multiple co-morbidities, including chronic kidney disease that is one of the prognostic risks for these patients. This study was performed to evaluate the value of determination of albuminuria using a urine dipstick test (UDT), combined with estimated glomerular filtration rate (eGFR), for predicition of mortality in HFpEF., Methods and Results: We enrolled 2465 consecutive patients with overt HF with EF ≥50% in our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) study (NCT00418041). We defined trace or more UDT as positive. We divided the patients into the following four groups based on eGFR and UDT; group 1 (G1) (eGFR ≥60, negative UDT), G2 (eGFR ≥60, positive UDT), G3 (eGFR <60, negative UDT), and G4 (eGFR <60, positive UDT). In total, 29.5% of the HFpEF patients had a positive UDT. HFpEF patients with a positive UDT were characterized by higher brain natriuretic peptide levels and frequent histories of hypertension or diabetes. During a mean follow-up of 2.5 years, HFpEF patients with a positive UDT showed higher mortality in each stratum of eGFR levels. A multivariable adjusted Cox model showed that when compared with G1 (reference), the hazard ratio of all-cause death for G2, G3, and G4 was 2.44 (95% confidence interval 1.47-4.05, P=0.001), 1.43 (0.92-2.23, P=0.12), and 2.71 (1.72-4.27, P<0.001), respectively. Furthermore, the prognostic value of a positive UDT was robust for both cardiovascular and non-cardiovascular deaths., Conclusions: These results indicate that measurement of albuminuria in addition to eGFR is useful for appropriate risk stratification in HFpEF patients.

Aims: Patients with chronic heart failure are often characterized by impaired renal function, also referred to as cardiorenal syndrome (CRS). The aim of this study was to assess whether novel markers of kidney injury are elevated in chronic heart failure and CRS., Methods and Results: The new renal biomarkers kidney injury molecule-1 (KIM-1), N-acetyl-ß-d-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) were assessed from urine samples of 173 individuals. Patients with chronic heart failure (n= 150) were characterized by decreased ejection fraction (32 ± 9% vs. controls 62 ± 4%, P < 0.001) and increased plasma N-terminal pro-brain natriuretic peptide (median 1460 pg/mL, interquartile range (IQR) 630-3000 pg/mL vs. controls 56, IQR 25-64l pg/mL, P < 0.001). Urinary analysis showed that KIM-1 was significantly elevated in heart failure patients compared with healthy controls (1100, IQR 620-1920 vs. 550, IQR 320-740 ng/g urinary creatinine, P < 0.001). Further, KIM-1 increased significantly with decreasing left ventricular function (r = -0.37, P < 0.001) and severity of New York Heart Association (NYHA)-class (r = 0.5, P < 0.001). N-acetyl-ß-d-glucosaminidase showed a weaker response but correlated significantly with left ventricular dysfunction (r = -0.18, P= 0.015) and more severe clinical condition (r = 0.22, P= 0.04). In contrast, NGAL showed no significant correlation. Kidney injury molecule-1 and NAG were also predictors of all-cause mortality and the composite of all-cause mortality and rehospitalization for heart failure (all P < 0.05)., Conclusions: Kidney injury molecule-1 and NAG are elevated in symptomatic heart failure. This finding may be present in patients with apparently normal kidney function and indicates tubular injury in chronic heart failure. Kidney injury molecule-1 and NAG are potential markers of CRS with additional prognostic value.

Aims: To examine the relationships between baseline characteristics and urinary albumin excretion in the extensively phenotyped patients in the ALiskiren Observation of heart Failure Treatment (ALOFT) study., Methods and Results: Urinary albumin creatinine ratio (UACR) was available in 190 of 302 (63%) patients randomized in ALOFT. Of these, 107 (56%) had normal albumin excretion, 63 (33%) microalbuminuria, and 20 (11%) macroalbuminuria. Compared with patients with normoalbuminuria, those with microalbuminuria had a greater prevalence of diabetes (48 vs. 26%, P = 0.005) and a lower estimated glomerular filtration rate (eGFR) (60.7 vs. 68.3 mL/min/1.73 m(2), P = 0.01). Patients with macroalbuminuria had additional differences from those with a normal UACR, including younger age (63 vs. 69 years, P = 0.02), higher glycated haemoglobin (HbA1c; 7.9 vs. 6.2%, P < 0.001), and different echocardiographic findings. Of the non-diabetic patients, 28% had microalbuminuria and 7% had macroalbuminuria. Independent predictors of UACR in these patients included N-terminal pro B-type natriuretic peptide (NT-proBNP), HbA1c, and left ventricular diastolic dimension. Increased UACR was not associated with markers of inflammation or of renin angiotensin aldosterone system activation and was not reduced by aliskiren., Conclusions: Increased UACR is common in patients with heart failure, including non-diabetics. Urinary albumin creatinine ratio is independently associated with HbA1c and NT-proBNP, even in non-diabetic patients.

Aims: Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) is a strong biochemical marker of heart failure and left ventricular dysfunction (LVD). Due to renal arterio-venous clearance of NT-proBNP and the correlation of plasma concentrations with renal function, we hypothesized that NT-proBNP may have potential as a urinary marker. The objective of this study was to assess urinary concentrations of NT-proBNP and to identify the predictive value of urinary NT-proBNP for detecting LVD and heart failure., Methods and Results: N-terminal pro-brain natriuretic peptide (Elecsys proBNP((R)), Roche) was assessed simultaneously in fresh spot urine and plasma from 191 individuals. In patients with heart failure (n = 149), urinary and plasma NT-proBNP concentrations were positively correlated (r = 0.79, P < 0.001), but urinary NT-proBNP was significantly lower than plasma NT-proBNP (42 +/- 25 vs. 1389 +/- 325 pg/mL, P < 0.001). Upon receiver operating curve analysis, urinary NT-proBNP detected LV dysfunction (ejection fraction <40%) with a sensitivity of 91% and a specificity of 98% at a cutpoint of 22 pg/mL [area under the curves (AUC) 0.98]. At the same cutpoint, symptomatic heart failure (NYHA-class > 2) was detected with a sensitivity of 97% and specificity of 98% (AUC 0.99) and clinical signs of fluid retention were detected with a sensitivity and specificity of 98% each (AUC 0.99)., Conclusion: N-terminal pro-brain natriuretic peptide concentrations were markedly lower in the urine than in the plasma. However, urinary NT-proBNP levels increased stepwise with the severity of heart failure and LVD, and therefore yielded satisfactory predictive values for the detection of significant LVD and symptomatic heart failure. Measurement of urinary NT-proBNP is a novel, promising, and simple method for the biochemical detection of heart failure.

Background: Proinflammatory cytokines are important mediators in heart failure (HF). Recently, urinary levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been determined., Aims: The purpose of this study was to measure the urinary levels of TNF-alpha and IL-6 receptors, sTNF-RI, sTNF-RII, sIL-6R, and the relationship with plasma levels and NYHA classes in HF., Methods: Plasma and urine were collected from 114 HF patients and sTNF-RI, sTNF-RII and sIL-6R (ng/ml) were analyzed., Results: For the whole population, plasma levels of sTNF-RI were 2.1+/-0.1, of sTNF-RII were 5.0+/-0.3 and of sIL-6R were 49.8+/-2.5. Urinary levels were: sTNF-RI, 2.8+/-0.5, r=0.5, p<0.001; sTNF-RII, 12.6+/-2.1, r=0.4, p<0.001; and sIL-6R, 4.2+/-0.4, NS. In NYHA III subjects, we found sTNF-RI, r=0.6, p<0.01, sTNF-RII, r=0.5, p<0.05, and sILR-6, r=0.5, p<0.05. Both plasma TNF receptors and urinary levels of sTNF-RII were higher in patients in a more severe NYHA class (p<0.05)., Conclusions: Urine is a good environment to study sTNF-RI and sTNF-RII, and this fact has diagnostic and prognostic implications. Plasma and urinary levels of TNF receptors showed a fair correlation, which was increased in higher NYHA classes. Plasma and urinary levels of sIL6R showed a good correlation in NYHA III. The TNF receptor levels in urine increased in patients with more severe HF.

Aims: Proinflammatory cytokines are important mediators for the development of heart failure and increased plasma levels of these cytokines have been reported in patients with this condition. The purpose of the study was to investigate whether urine, a non-invasively obtained biological sample, was an appropriate medium in which to measure the concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in patients in the advanced stages of the disease., Methods and Results: Thirty consecutive patients who had severe congestive heart failure (NYHA classes III and IV) and 30 matched healthy control subjects were enrolled. Plasma and the first urine of the day were collected and TNF-alpha and IL-6 were quantitatively analyzed by enzyme-linked immunosorbent assays. For every subject there were no differences in the amount of cytokine determined in plasma and urine. Both urine and plasma levels of IL-6 and TNF-alpha were greater in heart failure patients than in controls., Conclusion: Our results show that plasmatic and urinary levels of proinflammatory cytokines did not differ significantly. Thus, urine may be a good milieu in which to study these cytokines and may have diagnostic, prognostic and therapeutic implications.

We investigated the relationship between plasma renin activity (PRA) and serum ([sNa(+)]) and urinary ([uNa(+)]) sodium concentrations in 124 congestive heart failure (CHF) patients (II-IV NYHA class) and 20 healthy subjects. According to PRA (> or <3 ng ml(-1) h(-1)) and [sNa(+)] (> or <135 mEq l(-1)), patients were classified as Group A (normal PRA and normal [sNa(+)], n=39), Group B (increased PRA and normal [sNa(+)], n=62) and Group C (low [sNa(+)], n=23). Measurements were performed at rest and, in 26 cases, after extracorporeal ultrafiltration (UF). At rest, [sNa(+)] and [uNa(+)], and their difference ([sNa(+)]-[uNa(+)]), were linearly correlated with PRA, but the values did not allow differentiation of control subjects from patients or differentiation of patients with from those without renin-angiotensin system (RAS) activation. Conversely, the [sNa(+)]/[uNa(+)] ratio showed the best correlation with PRA (r=0.79, P<0.0001). UF-induced PRA changes were linearly correlated with [sNa(+)]/[uNa(+)] ratio changes (r=0.67, P=0.002), but not with those of [sNa(+)], [uNa(+)] and [sNa(+)]-[uNa(+)]. In CHF, the [sNa(+)]/[uNa(+)] ratio best correlates with PRA and reflects the basal activity as well as the rapid changes (as those induced by UF) of the RAS. Therefore, it can be considered a strong and easily available marker of PRA., (Copyright 2002 European Society of Cardiology)