Renal function and natriuresis-guided diuretic therapy - a pre-specified analysis from the PUSH-AHF trial.

AIM: In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. METHODS AND RESULTS: The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. CONCLUSIONS: Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.

Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial.

Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l-1. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .

Anterior Myocardial Infarction Complicated by Apical Thrombus and Purulent Pericarditis.

We describe a man with cardiac tamponade after anterior myocardial infarction (MI) with a mass on echocardiography, complicated by a S. Milleri purulent pericarditis. This case is an example of how 2 cardiac conditions can interfere with the diagnosis and management of each individual disorder, resulting in an extremely complex disease course. (Level of Difficulty: Beginner.).

Conservative initial postoperative anticoagulation strategy after HeartMate 3 left ventricular assist device implantation.

INTRODUCTION: Although anticoagulation therapy is mandated after implantation of a left ventricular assist device (LVAD), postoperative bleedings and reoperations occur relatively frequently and are associated with worse outcomes. We evaluated the use of a conservative postoperative anticoagulation protocol in patients implanted with a HeartMate 3 (HM3) LVAD. METHODS: In a single-centre retrospective analysis of postoperative outcomes after HM3 LVAD implantation, a standard (old) anticoagulation protocol (i.e. early, full-dose anticoagulation with low-molecular weight heparin and overlapping vitamin K antagonist) was compared with a new conservative anticoagulation protocol (i.e. slow initiation of vitamin K antagonists without overlapping heparin). Main outcomes were changes in international normalised ratio (INR), lactate dehydrogenase (LDH), bleeding and/or tamponade events requiring reoperation, length of stay and adverse events. RESULTS: In total, 73 patients (48 in old vs 25 in new protocol group) were evaluated. Mean age was 56 years (standard deviation 13) and most patients (78%) were males. Changes in INR and LDH in the first 14 days were similar in both groups (p = 0.50 and p = 0.997 for interaction, respectively). Number of bleeding/tamponade events requiring reoperation was lower in the new than in the old protocol group (4% vs 33%, p = 0.005). Postoperative 30-day mortality was similar, and we observed no thromboembolic events. Median (25th-75th percentiles) total length of postoperative hospital stay (27 (25-41) vs 21 (19-27) days, p < 0.001) and length of intensive care unit stay (5 (2-9) vs 2 (2-5) days, p = 0.022) were significantly shorter in the new protocol group. CONCLUSION: These retrospective data suggest that conservative slow initiation of anticoagulation therapy after HM3 LVAD implantation is associated with less bleeding/tamponade events requiring reoperation, a similar safety profile and a shorter duration of stay than the currently advised standard anticoagulation protocol.

Transcatheter edge-to-edge repair of tricuspid regurgitation in the Netherlands: state of the art and future perspectives.

Despite the high prevalence and adverse clinical outcomes of severe tricuspid regurgitation (TR), conventional treatment options, surgical or pharmacological, are limited. Surgery is associated with a high peri-operative risk and medical treatment has not clearly resulted in clinical improvements. Therefore, there is a high unmet need to reduce morbidity and mortality in patients with severe TR. During recent years, several transcatheter solutions have been studied. This review focuses on the transcatheter edge-to-edge repair of TR (TTVR) with respect to patient selection, the procedure, pre- and peri-procedural echocardiographic assessments and clinical outcomes. Furthermore, we highlight the current status of TTVR in the Netherlands and provide data from our initial experience at the University Medical Centre Groningen.

Natriuresis-guided therapy in acute heart failure: rationale and design of the Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) trial.

AIMS: Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have shown that measuring natriuresis early after hospital admission could reliably identify patients with a poor diuretic response during hospitalization who might require enhanced diuretic treatment. This study will test the hypothesis that natriuresis-guided therapy in patients with acute HF improves natriuresis and clinical outcomes. METHODS: The Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) is a pragmatic, single-centre, randomized, controlled, open-label study, aiming to recruit 310 acute HF patients requiring treatment with intravenous loop diuretics. Patients will be randomized to natriuresis-guided therapy or standard of care. Natriuresis will be determined at set time points after initiation of intravenous loop diuretics, and treatment will be adjusted based on the urinary sodium levels in the natriuresis-guided group using a pre-specified stepwise approach of increasing doses of loop diuretics and the initiation of combination diuretic therapy. The co-primary endpoint is 24-h urinary sodium excretion after start of loop diuretic therapy and a combined endpoint of all-cause mortality or first HF rehospitalization at 6 months. Secondary endpoints include 48- and 72-h sodium excretion, length of hospital stay, and percentage change in N-terminal pro brain natriuretic peptide at 48 and 72 h. CONCLUSION: The PUSH-AHF study will investigate whether natriuresis-guided therapy, using a pre-specified stepwise diuretic treatment approach, improves natriuresis and clinical outcomes in patients with acute HF.

Plasma sodium, extracellular fluid volume, and blood pressure in healthy men.

In the general population we recently reported a consistent association between plasma sodium and volume markers, suggesting that individuals with higher plasma sodium have higher extracellular fluid volume (ECFV). To test this hypothesis, we analyzed the association between plasma sodium and directly measured ECFV (iothalamate distribution volume) in healthy men. Second, we studied whether plasma sodium is associated with blood pressure. We analyzed data from 70 men (age 24 ± 7 years) at the end of two 7-day periods on a low-sodium diet (LS, 50 mmol Na/24 h) and a high-sodium diet (HS, 200 mmol Na/24 h), respectively. The association of plasma sodium with blood pressure was assessed in the combined data of the different sodium intakes by linear mixed effects models. A positive univariable association between plasma sodium and ECFV was found during HS (ß = 0.24, p = 0.042) and LS (ß = 0.23, p = 0.058), respectively. Individual values of plasma sodium on LS and HS diet were strongly correlated (ß = 0.68, p < 0.001), as were values for ECFV (ß = 0.54, p < 0.001). In the combined data set plasma sodium level was significantly associated with ECFV (B [SE] = 0.10 [0.04], p = 0.02), and systolic blood pressure (SBP, B [SE] = 0.73 [0.26], p = 0.006), independent of ECFV. In conclusion, plasma sodium concentration is positively associated with ECFV on both LS and HS intake. Our data confirm and extend prior data on individual regulation of plasma sodium and suggest that this is associated with individuality of the regulation of ECFV. Finally, plasma sodium level is associated with SBP, independent of ECFV and diet.

Clinical importance of urinary sodium excretion in acute heart failure.

AIMS: Urinary sodium assessment has recently been proposed as a target for loop diuretic therapy in acute heart failure (AHF). We aimed to investigate the time course, clinical correlates and prognostic importance of urinary sodium excretion in AHF. METHODS AND RESULTS: In a prospective cohort of 175 consecutive patients with an admission for AHF we evaluated urinary sodium excretion 6 h after initiation of loop diuretic therapy. Clinical outcome was all-cause mortality or heart failure rehospitalization. Mean age was 71 ± 14 years, and 44% were female. Median urinary sodium excretion was 130 (67-229) mmol at 6 h, 347 (211-526) mmol at 24 h, and decreased from day 2 to day 4. Lower urinary sodium excretion was independently associated with male gender, younger age, renal dysfunction and pre-admission loop diuretic use. There was a strong association between urinary sodium excretion at 6 h and 24 h urine volume (beta = 0.702, P < 0.001). Urinary sodium excretion after 6 h was a strong predictor of all-cause mortality after a median follow-up of 257 days (hazard ratio 3.81, 95% confidence interval 1.92-7.57; P < 0.001 for the lowest vs. the highest tertile of urinary sodium excretion) independent of established risk factors and urinary volume. Urinary sodium excretion was not associated with heart failure rehospitalization. CONCLUSION: In a modern, unselected, contemporary AHF population, low urinary sodium excretion during the first 6 h after initiation of loop diuretic therapy is associated with lower urine output in the first day and independently associated with all-cause mortality.

Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial.

BACKGROUND: Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. METHODS: In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. FINDINGS: Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. INTERPRETATION: We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. FUNDING: None.

Hemopexin activity is associated with angiotensin II responsiveness in humans.

BACKGROUND: Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro. Whether hemopexin is involved in the responsiveness to ang II in vivo is unknown. Therefore, we tested whether variations in endogenous hemopexin activity are associated with the responsiveness of blood pressure to ang II in healthy volunteers. METHOD: Healthy men (n = 33, age 26 ±â€Š9) were studied in balance on low sodium (50 mmol Na per 24 h) and high sodium (200 mmol Na per 24 h) diet, respectively. After baseline measurements of blood pressure, ang II was infused at 0.3, 1 and 3 ng/kg per min for 1 h per dose. Hemopexin activity was measured at baseline in EDTA-plasma samples by an amidolytic assay with a chromogenic substrate suitable for hemopexin activity evaluation. RESULTS: During high sodium the hemopexin activity was lower; 1.6 × 10 (0.6 × 10 - 4.7 × 10) versus 2.8 × 10 (1.1 × 10 - 5.1 × 10) arbitrary units (P < 0.01) and the pressor response to 3 ng ang II/kg per minute larger than during low sodium (17.6 ±â€Š6.5 versus 14.6 ±â€Š6.9 mmHg, P < 0.01). Hemopexin activity negatively correlated with the pressor response to ang II during either type of sodium intake (high sodium: r = 0.42, P < 0.05; low sodium: r = 0.35, P < 0.05). CONCLUSION: These in-vivo data obtained in healthy individuals support recent in-vitro data showing that active hemopexin downregulates the availability of the AT1-R. Therefore, activated hemopexin might be considered as a factor mediating ang II effects upon blood pressure by modulating AT1-R availability.

Performance of MDRD study and CKD-EPI equations for long-term follow-up of nondiabetic patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) typically extends over decades. Longitudinal monitoring of kidney function in CKD is thus of great importance. Here, we retrospectively evaluate use of the Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations to monitor long-term course of kidney function and to identify individuals with progressive kidney function loss. METHODS: Patients were selected from our outpatient clinic for having four glomerular filtration rate measurements (mGFR, (125)I-iothalamate) and at least ≥ 4 years of follow-up. Renal function slopes were obtained by within-individual linear regression. RESULTS: Sixty-five nondiabetic CKD patients (40 male, mean baseline age 44 ± 12 years) with a median (range) of 9 (4-16) mGFR measurements and a median follow-up of 11 (4-33) years were included. Both equations significantly underestimated mGFR/(BSA) at baseline and at the end of follow-up. mGFR slope was significantly underestimated by the MDRD study but not by CKD-EPI equation (slopes -1.41 ± 2.06, -1.07 ± 1.72 and -1.39 ± 1.77 mL/min/1.73 m(2)/year, respectively). Sensitivity and specificity to identify progressive kidney function loss (mGFR/(BSA) slope > 1.5 mL/min/1.73 m(2)/ year, n = 23) were 78 and 88% for the MDRD study and 91 and 80% for CKD-EPI equation. In the subgroup of progressors, both MDRD study and CKD-EPI equation underestimated the rate of mGFR loss (P < 0.05) CONCLUSIONS: Long-term course of mGFR is reasonably well estimated by CKD-EPI and slightly underestimated by MDRD study equation. Patients with progressive kidney function loss may, however, not be reliably identified, so caution is warranted when using these equations in clinical practice.

Higher body mass index is associated with higher fractional creatinine excretion in healthy subjects.

BACKGROUND: Accurate glomerular filtration rate (GFR) measurement in normal to high range is important for epidemiological studies and workup for kidney donation. Creatinine-based equations perform poorly in this GFR range. Creatinine clearance (CrCl) provides a substitute, provided urine is collected accurately and tubular creatinine handling can be accounted for. The latter is poorly characterized in the normal GFR range. METHODS: Therefore, we studied performance of CrCl, fractional creatinine excretion (FE(creat)) and its determinants in 226 potential kidney donors (47% males, mean 53 ± 10 years). GFR was assessed as (125)I-iothalamate clearance, simultaneously with 2-h CrCl and 24-h CrCl. RESULTS: Mean GFR was 101 ± 18, 2-h CrCl 110 ± 20 and 24-h CrCl 106 ± 29 mL/min/1.73 m(2). Mean bias of 24 h CrCl was 7.4 [inter-quartile range -6.7 to 20.0] mL/min/1.73 m(2), precision (R(2)) 0.39 and 30% accuracy 82%. Mean FE(creat) was 110 ± 11%. FE(creat) correlated with body mass index (BMI) (r = 0.34, P < 0.001). Consequently, bias of 24-h CrCl increased from 2.7 (inter-quartile range -6.5 to 16.7) to 8.6 (inter-quartile range -5.8 to 20.5) and 12.6 (inter-quartile range 7.0 to 25.4) mL/min in subjects with BMI <25, 25-30 and >30 kg/m(2), respectively (P < 0.05). On multivariate analysis, BMI and gender were predictors of FE(creat). CONCLUSIONS: CrCl systematically overestimates GFR in healthy subjects. The overestimation significantly correlates with BMI, with higher FE(creat) in subjects with higher BMI. The impact of BMI on tubular creatinine secretion can be accounted for, when using CrCl for GFR assessment in the normal to high range, by the following formula: GFR = 24-h CrCl - (22.75 + 0.76 × BMI - 0.29 × mean arterial pressure (-6.11 if female).

Lower HDL-C and apolipoprotein A-I are related to higher glomerular filtration rate in subjects without kidney disease.

Animal experiments show that the kidney contributes to apolipoprotein (apo)A-I catabolism. We tested relationships of HDL cholesterol (HDL-C) and apo-I with kidney function in subjects without severe chronic kidney disease. Included was a random sample of the general population (part of the PREVEND cohort). Kidney function [estimated glomerular filtration rate (e-GFR) by two well-established equations and creatinine clearance], HDL-C, triglycerides, apoA-I and insulin resistance (HOMAir) were measured in 2,484 fasting subjects (e-GFR>or=45 ml/min/1.73 m2) without macroalbuminuria, cardiovascular disease, diabetes, or the use of anti-hypertensives and/or lipid-lowering agents. HDL-C (r=-0.056 to -0.102, P<0.01 to <0.001) and apo A-I (r=-0.096 to -0.126, P<0.001) were correlated inversely with both GFR estimates and creatinine clearance in univariate analyses. Multiple linear regression analyses also demonstrated inverse relationships of HDL-C and apoA-I with all measures of kidney function even after adjustment for age, sex, waist circumference, HOMAir, triglycerides, and urinary albumin excretion (P=0.053 to 0.004). In conclusion, HDL-C and apoA-I are inversely related to e-GFR and creatinine clearance in subjects without severely compromised kidney function, which fits the concept that the kidney contributes to apoA-I regulation in humans. High glomerular filtration rate may be an independent determinant of a pro-atherogenic lipoprotein profile.

High plasma hemopexin activity is an independent risk factor for late graft failure in renal transplant recipients.

Chronic low-grade inflammation is involved in late renal transplant dysfunction. Recent studies suggest a role for hemopexin, an acute phase protein, in kidney damage. We investigated whether hemopexin activity (Hx) predicts graft failure in renal transplant recipients (RTRs). In 557 RTRs with functioning grafts for >or=1 year, Hx was measured in citrate-plasma. RTRs were divided according to Hx into two groups; A: sextile 1-5 (464 RTRs, 83%) and B: sextile 6 (92 RTRs, 17%). Hx [median (IQR) 11.1 (3.3-19.1) arbitrary units] was measured at 6.0 (2.6-11.5) years post-transplant. RTRs with high Hx (group B) had significantly higher urinary protein excretion (UP) and diastolic blood pressure than group A, despite significantly more prevalent use of renin-angiotensin-aldosterone system inhibitors. After follow-up [4.6 (3.8-5.2) years], incidence of graft failure in group A was 25 (5%) and in group B 14 (15%,P = 0.0009) After adjustment for high-sensitivity C-reactive protein (hsCRP), UP and other potential confounders, Hx remained an independent predictor of graft failure [HR = 2.5 (95% CI 1.2-5.3), P = 0.01]. In conclusion, elevated Hx predicts late graft failure in RTRs, independent of hsCRP and UP. This suggests that Hx measurement, next to measurement of creatinine clearance and UP, could be of value for the identification of RTRs at risk for graft failure.

Benefits of dietary sodium restriction in the management of chronic kidney disease.

PURPOSE OF REVIEW: To evaluate the role of restricting dietary sodium intake in chronic kidney disease (CKD) and its complications. RECENT FINDINGS: A consistent line of evidence shows that high dietary sodium intake is a determinant of therapy resistance to blockade of the renin-angiotensin-aldosterone system (RAAS). Addition of sodium restriction to RAAS blockade or to RAAS blockade combined with a diuretic permits a further reduction in urinary protein excretion of approximately 30%, which could be expected to reduce long-term renal risk by 25%. SUMMARY: High sodium intake increases blood pressure and proteinuria, induces glomerular hyperfiltration and blunts the response to RAAS blockade. Although recommended in international guidelines, sodium restriction is not a spearhead in treating renal patients. Sodium status is only rarely mentioned in recent large intervention studies in CKD. Sodium intake in CKD is similar to that in the general population. Reduction of sodium intake to the target of 50-85 mmol/24 h in patients with CKD reduces blood pressure and proteinuria, the latter by approximately 30%, and should be actively pursued to improve outcome in CKD.

Rise in extracellular fluid volume during high sodium depends on BMI in healthy men.

A high sodium (HS) intake is associated to increased cardiovascular and renal risk, especially in overweight subjects. We hypothesized that abnormal sodium and fluid handling is involved, independent of hypertension or insulin resistance. Therefore, we studied the relation between BMI and sodium-induced changes in extracellular fluid volume (ECFV; distribution volume of (125)I-iothalamate) in 78 healthy men, not selected for BMI. A total of 78 subjects with a median BMI of 22.5 (range: 19.2-33.9 kg/m(2)) were studied after 1 week on a low sodium (LS) diet (50 mmol Na(+)/d) and after 1 week on HS (200 mmol Na(+)/d). The change from LS to HS resulted in an increase in ECFV of 1.2 +/- 1.8 l. Individual changes in ECFV were correlated to BMI (r = 0.361, P < 0.01). Furthermore, in response to HS, a higher BMI was associated to a higher rise in filtered load of sodium (FL(Na(+)) = [Na(+)] x GFR, r = 0.281, P < 0.05). Thus, a shift to HS leads to a larger rise in ECFV in healthy subjects with higher BMI, associated with an elevated FL(Na(+)) during HS. Although no hypertension occurred in these healthy subjects, our data provide a potential explanation for the interaction of sodium intake and BMI on cardiovascular and renal risk. Exaggerated fluid retention may be an early pathogenic factor in the cardiorenal complications of overweight.