HE4 Serum Levels Are Associated with Heart Failure Severity in Patients With Chronic Heart Failure.

BACKGROUND: The novel biomarker human epididymis protein 4 (HE4) shows prognostic value in acute heart failure (HF) patients. We measured HE4 levels in patients with chronic heart failure (CHF) and correlated them to HF severity, kidney function, and HF biomarkers, and determined its predictive value. METHODS: Serum HE4 levels in patients (n = 101) with stable CHF with reduced left ventricular ejection fraction (LVEF <45%) from the Vitamin D CHF (VitD-CHF) study (NCT01092130) were compared with those in age- and sex-matched healthy control subjects (n = 58) from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. RESULTS: HE4 levels were higher in CHF compared with control subjects (69.2 pmol/L [interquartile range 55.6-93.8] vs 56.1 pmol/L [46.6-69.0]; P < .001) and were higher with increasing New York Heart Association functional class. Levels were associated with HF risk factors, including age, gender, diabetes, smoking and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). HE4 demonstrated strong associations with kidney function and HF fibrosis biomarkers. In a multivariable model, we identified creatinine, NT-proBNP, galectin-3, high-sensitive troponin T, and smoking as factors associated with HE4. Independently from these factors, HE4 levels predicted death and HF rehospitalization (5-year follow-up, hazard ratio 3.8; confidence interval 1.31-11.1; P = .014). CONCLUSIONS: HE4 levels are increased in CHF, correlate with HF severity and kidney function, and predict HF outcome.

Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction.

INTRODUCTION: Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF). METHODS AND RESULTS: We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with (125)I-iothalamate/(131)I-hippuran clearances with a mean follow-up of 34.6 ± 4.4 months. Fifteen percent were female, with age 58 ± 12 years and left ventricular ejection fraction (LVEF) 29 ± 10%. Baseline GFR was 81 ± 23 mL/min/1.73 m(2) and declined 0.6 ± 4.7 mL/min/1.73 m(2) per year. Baseline ERPF was 292 ± 83 mL/min/1.73 m(2) and declined 4.3 ± 19 mL/min/1.73 m(2) per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N-terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001). CONCLUSION: In this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion.

Effect of additive renin inhibition with aliskiren on renal blood flow in patients with Chronic Heart Failure and Renal Dysfunction (Additive Renin Inhibition with Aliskiren on renal blood flow and Neurohormonal Activation in patients with Chronic Heart Failure and Renal Dysfunction).

AIMS: We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals. METHODS AND RESULTS: Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007). CONCLUSIONS: Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction.

Vitamin D supplementation and testosterone concentrations in male human subjects.

OBJECTIVE: A possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DESIGN: To investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). METHODS: In study 1, 92 subjects were randomized to either vitamin D (2000 IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6 weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. RESULTS: Serum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36 nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 0.5 and 0 nmol/l in studies 1, 2 and 3, respectively). CONCLUSIONS: In this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations.

Renal handling of galectin-3 in the general population, chronic heart failure, and hemodialysis.

BACKGROUND: Galectin-3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin-3 levels. We aimed to describe galectin-3 renal handling in HF. METHODS AND RESULTS: In Sprague-Dawley rats, we infused galectin-3 and studied distribution and renal clearance. Furthermore, galectin-3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin-3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin-3. Plasma galectin-3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P<0.001), while urinary galectin-3 in HF patients was comparable (28.1 ng/mL versus 35.1 ng/mL, P=0.830). The calculated galectin-3 excretion rate was lower in HF patient (2.3 mL/min [1.5 to 3.4] versus 3.9 mL/min [2.3 to 6.4] in control subjects; P=0.005). This corresponded with a significantly lower fractional excretion of galectin-3 in HF patients (2.4% [1.7 to 3.7] versus 3.0% [1.9 to 5.5]; P=0.018). These differences, however, were no longer significant after correction for age, gender, diabetes, and smoking. HF patients who received diuretics (49%) showed significantly higher aldosterone and galectin-3 levels. Hemodialysis patients (n=105; mean age 63 years; 65% male), without urinary galectin-3 excretion, had strongly increased median plasma galectin-3 levels (70.6 ng/mL). CONCLUSIONS: In this small cross-sectional study, we report that urine levels of galectin-3 are not increased in HF patients, despite substantially increased plasma galectin-3 levels. The impaired renal handling of galectin-3 in patients with HF may explain the described relation between renal function and galectin-3 and may account for the elevated plasma galectin-3 in HF.

Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial).

BACKGROUND: Many chronic heart failure (CHF) patients have low vitamin D (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients. METHODS AND RESULTS: We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriuretic peptide natriuretic peptide and fibrosis markers. CONCLUSIONS: Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration.

Plasma renin and outcome in the community: data from PREVEND.

AIMS: The renin-angiotensin system plays a central role in patients with established cardiovascular (CV) disease, but the prognostic effect of plasma renin in the community is unclear. METHODS AND RESULTS: The relationship between plasma renin concentration and CV events was studied in 6228 subjects who were enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, and who were not using antihypertensive medication. Plasma renin concentration was measured using a direct automated immunochemiluminescent assay. The mean (± SD) age was 47(± 12) years, 49% were male; the mean follow-up was 10.5 years. The median (Q1-Q3) plasma renin was 17.6 (10.9-27.2) µIU/mL, and plasma aldosterone was 119 (93-153) ng/L. The primary outcome was a composite of fatal (n = 27) and non-fatal (n = 408) CV events. Adjusted for age and sex each doubling of plasma renin was associated with a hazard ratio (HR) for the primary outcome of 1.22 (95% CI: 1.04-1.43; P= 0.015). In a multivariable model, plasma renin showed a positive correlation with heart rate and male sex and a negative correlation with blood pressure, urinary sodium, glucose, and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) (adjusted R(2): 0.167, P< 0.001). After adjustment for covariates associated with plasma renin, the HR for reaching the primary outcome was 1.28 (95% CI: 1.09-1.49, P= 0.002). Plasma renin was associated with CV events regardless of blood pressure, but in subjects using antihypertensive medication this association was absent. CONCLUSION: Plasma renin concentration is associated with an increased risk for CV events in a community-based cohort not on antihypertensive medication.

New roles for renin and prorenin in heart failure and cardiorenal crosstalk.

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.

High cumulative incidence of cancer in patients with cardio-renal-anaemia syndrome.

AIMS: The combination of chronic kidney disease (CKD), chronic heart failure (HF), and anaemia, the so-called cardio-renal-anaemia syndrome (CRA) is associated with dysregulation of erythropoietin levels and inflammation. Both have been associated with the development of cancer. This study aimed to determine the cumulative incidence of cancer in patients with CRA, as compared with anaemic CKD and control patients. METHODS AND RESULTS: Patients aged <80 years who attended the nephrology or cardiology outpatient clinics between March 2006 and November 2007 were eligible for inclusion in this retrospective case-control study if haemoglobin <8.1 mmol/L (13 g/dL) and serum creatinine >80 mmol/L (0.90 mg/dL). Medical records dating back to 1996 were reviewed. The relationship between cancer and CRA, chronic HF, CKD, and anaemia was analysed using logistic regression analysis. Data from 1087 patients were reviewed. We identified 348 patients with both CKD and anaemia, of whom 132(38.3%) had CRA. The control group included 264 patients attending the hypertension outpatient clinic. Patients with CRA had a 19% cumulative incidence of cancer compared with 11% for patients with anaemia, CKD and no chronic HF, and 11% in the control group. The odds ratio (OR) for cancer was 1.8(95% CI 1.0-3.2) for the CRA group compared with the control group. Chronic HF was an independent risk factor for cancer after correction for age and gender (adjusted OR 2.0; 95% CI 1.2-3.3, P = 0.007). CONCLUSION: The cumulative incidence of cancer among patients with CRA is high compared with controls and to anaemic CKD patients without chronic HF. Chronic HF was an independent risk factor for cancer. These results stress the importance of clarifying the mechanisms involved in the development of cancer in CRA.