New roles for renin in heart failure and cardio-renal interaction

In ons lichaam werken hart en nieren intensief samen. Zodra een van beide beschadigd raakt, zien we vaak ook schade ontstaan aan de ander. Een belangrijk hormoon in de communicatie tussen beiden is renine, dat een rol speelt bij bloeddrukregulatie. Of renine zelf schadelijk is, was echter onduidelijk. Om hier meer inzicht in te krijgen hebben we allereest renine gemeten bij ca 6000 gezonde mensen. Hierbij bleek dat mensen een hoog renine een verhoogde kans hadden om hart- en vaatziekten te ontwikkelen, onafhankelijk van de bloeddruk. Het effect van renine op nierfunctieachteruitgang was echter minder eenduidig. Daarnaast hebben we de nierfunctie en hormonen in patiënten met hartfalen gemeten. Hierbij bleek dat in tegenstelling tot gezonde mensen, de nierfunctie sterk afhankelijk was van de bloeddoorstroming. Verder bleken veel patiënten met hartfalen een vitamine D tekort te hebben. Door dit aan te vullen met tabletten daalden de renine spiegels. In een volgende studie bij patiënten met zowel hartfalen als een verminderde nierfunctie, bleek het rechtstreeks blokkeren van het renine hormoon met een medicijn echter niet te lijden tot een verbetering van de nierdoorbloeding, maar wel een daling van de filtratiesnelheid van de nier. Concluderend, lijkt renine een belangrijke rol te spelen bij het ontwikkelen van hart- en nierziekten, maar lijkt het zowel positieve als negatieve effecten te hebben en is het blokkeren van renine niet altijd goed. Mogelijk kunnen we in de toekomst gerichter ingrijpen op verschillende hormoonsystemen, waarbij we ook de positieve effecten kunnen gebruiken

New roles for renin in heart failure and cardio-renal interaction

In ons lichaam werken hart en nieren intensief samen. Zodra een van beide beschadigd raakt, zien we vaak ook schade ontstaan aan de ander. Een belangrijk hormoon in de communicatie tussen beiden is renine, dat een rol speelt bij bloeddrukregulatie. Of renine zelf schadelijk is, was echter onduidelijk. Om hier meer inzicht in te krijgen hebben we allereest renine gemeten bij ca 6000 gezonde mensen. Hierbij bleek dat mensen een hoog renine een verhoogde kans hadden om hart- en vaatziekten te ontwikkelen, onafhankelijk van de bloeddruk. Het effect van renine op nierfunctieachteruitgang was echter minder eenduidig. Daarnaast hebben we de nierfunctie en hormonen in patiënten met hartfalen gemeten. Hierbij bleek dat in tegenstelling tot gezonde mensen, de nierfunctie sterk afhankelijk was van de bloeddoorstroming. Verder bleken veel patiënten met hartfalen een vitamine D tekort te hebben. Door dit aan te vullen met tabletten daalden de renine spiegels. In een volgende studie bij patiënten met zowel hartfalen als een verminderde nierfunctie, bleek het rechtstreeks blokkeren van het renine hormoon met een medicijn echter niet te lijden tot een verbetering van de nierdoorbloeding, maar wel een daling van de filtratiesnelheid van de nier. Concluderend, lijkt renine een belangrijke rol te spelen bij het ontwikkelen van hart- en nierziekten, maar lijkt het zowel positieve als negatieve effecten te hebben en is het blokkeren van renine niet altijd goed. Mogelijk kunnen we in de toekomst gerichter ingrijpen op verschillende hormoonsystemen, waarbij we ook de positieve effecten kunnen gebruiken

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

AbstractBackgroundThe 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.MethodsSerum 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.ResultsHE4 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).ConclusionsHE4 levels are increased in CHF, correlate with HF severity and kidney function, and predict HF outcome

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 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

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

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo 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). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/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, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn 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 concentration

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo 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). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/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, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn 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