The acute pressure natriuresis response is suppressed by selective ETA receptor blockade

Hypertension is a major risk factor for cardiovascular disease. In a significant minority of people, it develops when salt intake is increased (salt-sensitivity). It is not clear whether this represents impaired vascular function or disruption to the relationship between blood pressure (BP) and renal salt-handling (pressure natriuresis, PN). Endothelin-1 (ET-1) regulates BP via ETA and ETB receptor subtypes. Blockade of ETA receptors reduces BP, but promotes sodium retention by an unknown mechanism. ETB blockade increases both BP and sodium retention. We hypothesised that ETA blockade promotes sodium and water retention by suppressing PN. We also investigated whether suppression of PN might reflect off-target ETB blockade. Acute PN was induced by sequential arterial ligation in male Sprague Dawley rats. Intravenous atrasentan (ETA antagonist, 5mg/kg) halved the normal increase in medullary perfusion and reduced sodium and water excretion by >60%. This was not due to off-target ETB blockade because intravenous A-192621 (ETB antagonist, 10mg/kg) increased natriuresis by 50% without modifying medullary perfusion. In a separate experiment in salt-loaded rats monitored by radiotelemetry, oral atrasentan reduced systolic and diastolic BP by ~10mmHg, but additional oral A-192621 reversed these effects. Endogenous ETA stimulation has natriuretic effects mediated by renal vascular dilation while endogenous ETB stimulation in the kidney has antinatriuretic effects via renal tubular mechanisms. Pharmacological manipulation of vascular function with ET antagonists modifies the BP set-point, but even highly selective ETA antagonists attenuate PN, which may be associated with salt and water retention.

Proteolytic activation of the epithelial sodium channel (ENaC) by factor VII activating protease (FSAP) and its relevance for sodium retention in nephrotic mice

Proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases is thought to contribute to renal sodium retention in nephrotic syndrome. However, the identity of the responsible proteases remains elusive. This study evaluated factor VII activating protease (FSAP) as a candidate in this context. We analyzed FSAP in the urine of patients with nephrotic syndrome and nephrotic mice and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in FSAP-deficient mice (Habp2−/−) with experimental nephrotic syndrome induced by doxorubicin. In urine samples from nephrotic humans, high concentrations of FSAP were detected both as zymogen and in its active state. Recombinant serine protease domain of FSAP stimulated ENaC-mediated whole-cell currents in a time- and concentration-dependent manner. Mutating the putative prostasin cleavage site in γ-ENaC (γRKRK178AAAA) prevented channel stimulation by the serine protease domain of FSAP. In a mouse model for nephrotic syndrome, active FSAP was present in nephrotic urine of Habp2+/+ but not of Habp2−/− mice. However, Habp2−/− mice were not protected from sodium retention compared to nephrotic Habp2+/+ mice. Western blot analysis revealed that in nephrotic Habp2−/− mice, proteolytic cleavage of α- and γ-ENaC was similar to that in nephrotic Habp2+/+ animals. In conclusion, active FSAP is excreted in the urine of nephrotic patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site of γ-ENaC. However, endogenous FSAP is not essential for sodium retention in nephrotic mice.

Role of Fluid and Sodium Retention in Experimental Ventilator-Induced Lung Injury

Background: Ventilator-induced lung injury (VILI) via respiratory mechanics is deeply interwoven with hemodynamic, kidney and fluid/electrolyte changes. We aimed to assess the role of positive fluid balance in the framework of ventilation-induced lung injury.Methods:Post-hoc analysis of seventy-eight pigs invasively ventilated for 48 h with mechanical power ranging from 18 to 137 J/min and divided into two groups: high vs. low pleural pressure (10.0 ± 2.8 vs. 4.4 ± 1.5 cmH2O; p < 0.01). Respiratory mechanics, hemodynamics, fluid, sodium and osmotic balances, were assessed at 0, 6, 12, 24, 48 h. Sodium distribution between intracellular, extracellular and non-osmotic sodium storage compartments was estimated assuming osmotic equilibrium. Lung weight, wet-to-dry ratios of lung, kidney, liver, bowel and muscle were measured at the end of the experiment.Results: High pleural pressure group had significant higher cardiac output (2.96 ± 0.92 vs. 3.41 ± 1.68 L/min; p < 0.01), use of norepinephrine/epinephrine (1.76 ± 3.31 vs. 5.79 ± 9.69 mcg/kg; p < 0.01) and total fluid infusions (3.06 ± 2.32 vs. 4.04 ± 3.04 L; p < 0.01). This hemodynamic status was associated with significantly increased sodium and fluid retention (at 48 h, respectively, 601.3 ± 334.7 vs. 1073.2 ± 525.9 mmol, p < 0.01; and 2.99 ± 2.54 vs. 6.66 ± 3.87 L, p < 0.01). Ten percent of the infused sodium was stored in an osmotically inactive compartment. Increasing fluid and sodium retention was positively associated with lung-weight (R2 = 0.43, p < 0.01; R2 = 0.48, p < 0.01) and with wet-to-dry ratio of the lungs (R2 = 0.14, p < 0.01; R2 = 0.18, p < 0.01) and kidneys (R2 = 0.11, p = 0.02; R2 = 0.12, p = 0.01).Conclusion: Increased mechanical power and pleural pressures dictated an increase in hemodynamic support resulting in proportionally increased sodium and fluid retention and pulmonary edema.

Experimental nephrotic syndrome leads to proteolytic activation of the epithelial sodium channel (ENaC) in the mouse kidney

Proteolytic activation of the renal epithelial sodium channel ENaC involves cleavage events in its α- and γ-subunits and is thought to mediate sodium retention in nephrotic syndrome (NS). However, detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α- and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the N-terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed sodium retention and increased expression of fragments of α- and γ-ENaC cleaved at both the proximal and more prominently at the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented sodium retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α- and γ-ENaC was similarly found in healthy mice treated with a low salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and more prominently distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.

Pathogenesis and Treatment of Refractory Oedema in Nephrotic Syndrome

Oedema is a hallmark feature of nephrotic syndrome (NS) and can cause significant patient morbidity. The pathogenesis of oedema formation is complex and results from abnormalities in sodium retention, inter-play of neurohormonal factors, and changes in capillary filtration barrier. Salt retention is often primary (‘overfill’ theory) because of increased sodium-potassium adenosine triphosphatase activity in the collecting duct cells, increased direct epithelial sodium channel activation (ENaC) by urinary proteases (independent of aldosterone), and an overall increased effective arterial blood volume. However, a subset of patients with NS, especially children, demonstrate decreased effective arterial blood volume (‘underfill’ theory) and secondary sodium retention as the primary mechanism of oedema formation. Increased capillary permeability and vascular inflammation contributes as well. Loop diuretics with or without salt-poor albumin are the mainstay of therapy in adults, although no large clinical trials exist to guide diuretic choice or dosage. Combination diuretic therapy is recommended to achieve multi-site nephron blockade and overcome diuretic resistance, which is a frequent challenge. Use of direct ENaC inhibitors (amiloride) in combination with loop diuretics may be especially beneficial given the primary role of ENaC in sodium retention. Aquaretics such as vasopressin receptor antagonists may have a role in treatment as well. Well-designed clinical trials are essential to guide therapy of refractory oedema in NS. In this review, the authors discuss the pathogenesis of oedema formation in patients with NS and propose a treatment algorithm for management of resistant oedema based on the limited available evidence.

Short-Term RCT of Increased Dietary Potassium from Potato or Potassium Gluconate: Effect on Blood Pressure, Microcirculation, and Potassium and Sodium Retention in Pre-Hypertensive-to-Hypertensive Adults

Increased potassium intake has been linked to improvements in cardiovascular and other health outcomes. We assessed increasing potassium intake through food or supplements as part of a controlled diet on blood pressure (BP), microcirculation (endothelial function), and potassium and sodium retention in thirty pre-hypertensive-to-hypertensive men and women. Participants were randomly assigned to a sequence of four 17 day dietary potassium treatments: a basal diet (control) of 60 mmol/d and three phases of 85 mmol/d added as potatoes, French fries, or a potassium gluconate supplement. Blood pressure was measured by manual auscultation, cutaneous microvascular and endothelial function by thermal hyperemia, utilizing laser Doppler flowmetry, and mineral retention by metabolic balance. There were no significant differences among treatments for end-of-treatment BP, change in BP over time, or endothelial function using a mixed-model ANOVA. However, there was a greater change in systolic blood pressure (SBP) over time by feeding baked/boiled potatoes compared with control (−6.0 mmHg vs. −2.6 mmHg; p = 0.011) using contrast analysis. Potassium retention was highest with supplements. Individuals with a higher cardiometabolic risk may benefit by increasing potassium intake. This trial was registered at ClinicalTrials.gov as NCT02697708.

MO717EFFECT ON BLOOD PRESSURE OF UNCOMPENSATED 130 MM SODIUM DIALYSATE IN CAPD PATIENT WITH RESISTANT HYPERTENSION

Background and Aims In peritoneal dialysis (PD) blood pressure (BP) control is largely unsatisfied mainly due to sodium retention. Currently, sodium removal in PD patients depends substantially on ultrafiltration. Lowering sodium in PD solution might improve sodium removal by diffusion, though the real benefit of low PD solution remains still undetermined. Method In this case report, we used a novel uncompensated glucose-based PD solution (DextroCore LS, Iperboreal Pharma, Italy) containing 130 mM sodium to treat resistant hypertension in 78-year-old female treated by CAPD (3 dwells glucose 1.5% a day, Na 132). Results At baseline, Ambulatory BP monitoring (ABPM) showed 24h-BP (152/81 mmHg), diurnal BP (151/83 mmHg) and nocturnal BP (153/75 mmHg), with inversion of circadian rhythm in systolic BP (systolic night/day ratio: 1.02), despite the use of three anti-hypertensive (doxazosin 4mg, amlodipine 10 mg, telmisartan 80 mg) and diuretic (furosemide 250 mg) at adequate doses. She had no signs of hypervolemia. We switched from standard PD (132 mM/L) to low sodium PD solution using 1.5% glucose bags with sodium concentration of 130 mM. CAPD schedule was confirmed. Second ABPM after six months reported a reduction 24h BP (131/73 mmHg), diurnal (134/75 mmHg) and nocturnal BP (122/67 mmHg), with restoring of circadian BP rhythm. No change in body weight, UF and residual diuresis was found. Diet and therapy prescriptions were unmodified. No side effects were reported. Conclusion Six-months PD treatment with uncompensated glucose-based PD solution containing 130 mM sodium in all daily dwells has allowed to reduce systolic BP (-16 mmHg) in a CAPD patient affected by resistant hypertension, with no change in ultrafiltration and residual diuresis.

078 Chronic sleep and circadian disruption differentially affects blood pressure, renal sodium retention, and aldosterone secretion

Introduction Chronic sleep restriction (CSR) and recurrent circadian disruption (RCD; e.g., rotating shiftwork) can increase an individual’s risk of cardiovascular and kidney disease. However, no study has assessed whether CSR and RCD together increase blood pressure (BP) and alter renal function (RF). We tested the hypotheses that the combination of CSR and RCD would increase blood pressure, renal sodium retention, and aldosterone secretion in individuals living for 3 weeks on an imposed non-24-h sleep-wake (SW) schedule (induces RCD) and controlled diet with or without CSR. Methods Seventeen (9M) healthy participants (aged 26.1±4.5y [mean±SD]) were scheduled to twenty-four 20-h Forced Desynchrony days and were randomized to either Control (1:2 sleep:wake, 6.67h sleep:13.33h wake; n=8) or CSR (1:3.3 sleep:wake, 4.67h sleep: 5.33h wake; n=9) SW conditions during a 32-day inpatient protocol. BP was measured following ~80–90 min in constant seated posture after scheduled waketime. All urine voids were collected, combined and sampled in 3-6h blocks throughout the study. Samples were assayed for sodium, potassium and aldosterone and analyzed as both excretion rates and total secretion (both per 20h). Data were assigned circadian phase using fitted core body temperature and analyzed using mixed-effects models with circadian phase, aligned/misaligned sleep, or time awake (with associated scheduled activity, sleep/wake, and feeding behaviors) and their interactions as fixed effects. Results There was a significant interaction between aligned/misaligned sleep and condition for resting BP (p=0.02), such that systolic BP was ~6% higher following circadian-misaligned sleep in CSR compared to Control (p=0.04). Renal sodium and potassium followed a robust circadian pattern (p<0.0001), with limited influence of time awake. In contrast, the timing of aldosterone excretion was affected by time awake (p<0.05). Total daily renal sodium secretion decreased from beginning to end of the protocol (p=0.03), with no change in sodium consumption and aldosterone secretion (p=0.95). Conclusion Under conditions similar to rotating shiftwork, systolic BP increased and sodium, potassium, and aldosterone were differentially influenced by circadian phase and scheduled behaviors. Additionally, renal sodium secretion decreased despite minimal changes in aldosterone secretion, suggesting increased renal aldosterone sensitivity. These findings may provide insight into mechanisms contributing to poor cardiovascular and renal health observed in shiftwork. Support (if any):