Dietary sodium restriction reduces blood pressure in patients with treatment resistant hypertension.

PURPOSE: Patients with treatment resistant hypertension (TRH) are at particular risk of cardiovascular disease. Life style modification, including sodium restriction, is an important part of the treatment of these patients. We aimed to analyse if self-performed dietary sodium restriction could be implemented in patients with TRH and to evaluate the effect of this intervention on blood pressure (BP). Moreover, we aimed to examine if mechanisms involving nitric oxide, body water content and BNP, renal function and handling of sodium were involved in the effect on nocturnal and 24-h BP. Also, measurement of erythrocyte sodium sensitivity was included as a possible predictor for the effect of sodium restriction on BP levels. PATIENTS AND METHODS: TRH patients were included for this interventional four week study: two weeks on usual diet and two weeks on self-performed sodium restricted diet with supplementary handed out sodium-free bread. At the end of each period, 24-h BP and 24-h urine collections (sodium, potassium, ENaC) were performed, blood samples (BNP, NOx, salt blood test) were drawn, and bio impedance measurements were made. RESULTS: Fifteen patients, 11 males, with a mean age of 59 years were included. After sodium restriction, urinary sodium excretion decreased from 186 (70) to 91 [51] mmol/24-h, and all but one reduced sodium excretion. Nocturnal and 24-h systolic BP were significantly reduced (- 8 and - 10 mmHg, respectively, p < 0.05). NOx increased, BNP and extracellular water content decreased, all significantly. Change in NOx correlated to the change in 24-h systolic BP. BP response after sodium restriction was not related to sodium sensitivity examined by salt blood test. CONCLUSION: Self-performed dietary sodium restriction was feasible in a population of patients with TRH, and BP was significantly reduced. Increased NOx synthesis may be involved in the BP lowering effect of sodium restriction. TRIAL REGISTRATION: The study was registered in Clinical trials with ID: NCT06022133.

Bone Turnover, Mineralization, and Volume Estimated by 18F-Sodium Fluoride PET/CT and Biomarkers in Chronic Kidney Disease: Mineral and Bone Disorder Compared with Bone Biopsy.

INTRODUCTION: Invasive bone biopsy to assess bone metabolism in patients with chronic kidney disease-mineral and bone disorder may be replaced by the noninvasive 18F-NaF PET/CT and biomarkers of bone metabolism. We aimed to compare parameters of bone turnover, mineralization, and volume assessed by bone biopsies with results derived from 18F-NaF PET/CT and biomarkers (bone-specific alkaline phosphatase, osteocalcin, fibroblast growth factor 23, and osteoprotegerin). METHODS: A cross-sectional study included 17 dialysis patients, and results from 18F-NaF PET/CT scans and the biomarkers were directly compared with the results of histomorphometric analyses of tetracycline double-labeled trans-iliac bone biopsies. RESULTS: Bone biopsies showed 40% high, 20% normal, and 40% low bone turnover. No biopsies had generalized abnormal mineralization, and the bone volume/total tissue volume was low in 80% and high in 7%. The pelvic skeletal plasma clearance (Ki) from 18F-NaF PET/CT correlated with bone turnover parameters obtained by bone biopsy (activation frequency: r = 0.82, p < 0.01; bone formation rate/bone surface: r = 0.81, p < 0.01), and Ki defined low turnover with high sensitivity (83%) and specificity (100%). CT-derived radiodensity correlated with bone volume, r = 0.82, p < 0.01. Of the biomarkers, only osteocalcin showed a correlation with turnover assessed by histomorphometry. CONCLUSION: In conclusion, 18F-NaF PET/CT may be applicable for noninvasive assessment of bone turnover and volume in CKD-MBD.

Prednisolone treatment in acute interstitial nephritis (PRAISE) - protocol for the randomized controlled trial.

BACKGROUND: Acute interstitial nephritis (AIN) is an important and common cause of acute renal failure. There are no generally accepted guidelines for the treatment of AIN, due to the lack of prospective randomized trials. Since AIN is characterized by an enhanced immune response, immunosuppressive treatment could potentially improve prognosis by attenuating inflammation and subsequent fibrosis. Despite the limited evidence of effects of steroids and potential adverse effects, prednisolone is frequently used in the treatment of AIN and there is a strong need for clinical trials on the effects of immunosuppression, including steroids, in the treatment of AIN. We aimed to evaluate the effectiveness of prednisolone treatment in AIN, and hypothesized a positive effect of prednisolone treatment on renal function in AIN. METHODS: The study is a randomized, controlled, prospective, open label multicenter study, including incident adult patients with biopsy proven AIN. Patients will be randomized 1:1 to one of 2 treatment regimens: A. No prednisolone treatment (control group) and B. B) Oral prednisolone treatment staring with 60 mg daily tapered over 8 weeks. One hundred ten patients (55 in each group) are planned to be included and followed for 1 year. Primary outcome is renal function estimated by eGFR 3 months after inclusion. Secondary outcomes are renal function after 12 months and need for renal replacement therapy and quality of life after 3 and 12 months. In addition, with-in prednisolone group analysis are performed to estimate the importance of treatment delay. Exploratory analyses include analysis of biomarkers in urine and plasma and the evaluation of these biomarkers in relation to renal prognosis and re-evaluation of renal biopsies to identify possible renal prognostic factors. DISCUSSION: Strengths and possible limitations in the design are evaluated. The study will provide important information on the effects of prednisolone treatment in AIN and as well as prognostic information relevant for future use of biomarkers and histology. Ultimately, this would lead to improved and evidence based clinical guidelines for the treatment of AIN. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04376216 (Retrospectively registered on May 6, 2020).

Hemodynamic, renal and hormonal effects of lung protective ventilation during robot-assisted radical prostatectomy, analysis of secondary outcomes from a randomized controlled trial.

BACKGROUND: Lung protective ventilation with low tidal volume (TV) and increased positive end-expiratory pressure (PEEP) can have unfavorable effects on the cardiovascular system. We aimed to investigate whether lung protective ventilation has adverse impact on hemodynamic, renal and hormonal variables. METHODS: In this randomized, single-blinded, placebo-controlled study, 24 patients scheduled for robot-assisted radical prostatectomy were included. Patients were equally randomized to receive either ventilation with a TV of 6 ml/IBW and PEEP of 10 cm H2O (LTV-h.PEEP) or ventilation with a TV of 10 ml/IBW and PEEP of 4 cm H2O (HTV-l.PEEP). Before, during and after surgery, hemodynamic variables were measured, and blood and urine samples were collected. Blood samples were analyzed for plasma concentrations of electrolytes and vasoactive hormones. Urine samples were analyzed for excretions of electrolytes and markers of nephrotoxicity. RESULTS: Comparable variables were found among the two groups, except for significantly higher postoperative levels of plasma brain natriuretic peptide (p = 0.033), albumin excretion (p = 0.012) and excretion of epithelial sodium channel (p = 0.045) in the LTV-h.PEEP ventilation group compared to the HTV-l.PEEP ventilation group. In the combined cohort, we found a significant decrease in creatinine clearance (112.0 [83.4;126.7] ml/min at baseline vs. 45.1 [25.4;84.3] ml/min during surgery) and a significant increase in plasma concentrations of renin, angiotensin II, and aldosterone. CONCLUSION: Lung protective ventilation was associated with minor adverse hemodynamic and renal effects postoperatively. All patients showed a substantial but transient reduction in renal function accompanied by activation of the renin-angiotensin-aldosterone system. TRIAL REGISTRATION: ClinicalTrials, NCT02551341 . Registered 13 September 2015.

Transjugular intrahepatic portosystemic shunt: impact on systemic hemodynamics and renal and cardiac function in patients with cirrhosis.

Transjugular intrahepatic portosystemic shunt (TIPS) alleviates portal hypertension and possibly increases central blood volume (CBV). Moreover, renal function often improves; however, its effects on cardiac function are unclear. The aims of our study were to examine the effects of TIPS on hemodynamics and renal and cardiac function in patients with cirrhosis. In 25 cirrhotic patients, we analyzed systemic, cardiac, and splanchnic hemodynamics by catheterization of the liver veins and right heart chambers before and 1 wk after TIPS. Additionally, we measured renal and cardiac markers and performed advanced echocardiography before, 1 wk after, and 4 mo after TIPS. CBV increased significantly after TIPS (+4.6%, P < 0.05). Cardiac output (CO) increased (+15.3%, P < 0.005) due to an increase in stroke volume (SV) (+11.1%, P < 0.005), whereas heart rate (HR) was initially unchanged. Cardiopulmonary pressures increased after TIPS, whereas copeptin, a marker of vasopressin, decreased (-18%, P < 0.005) and proatrial natriuretic peptide increased (+52%, P < 0.0005) 1 wk after TIPS and returned to baseline 4 mo after TIPS. Plasma neutrophil gelatinase-associated lipocalin, renin, aldosterone, and serum creatinine decreased after TIPS (-36%, P < 0.005; -65%, P < 0.05; -90%, P < 0.005; and -13%, P < 0.005, respectively). Echocardiography revealed subtle changes in cardiac function after TIPS, although these were within the normal range. TIPS increases CBV by increasing CO and SV, whereas HR is initially unaltered. These results indicate an inability to increase the heart rate in response to a hemodynamic challenge that only partially increases CBV after TIPS. These changes, however, are sufficient for improving renal function. NEW & NOTEWORTHY For the first time, we have combined advanced techniques to study the integrated effects of transjugular intrahepatic portosystemic shunt (TIPS) in cirrhosis. We showed that TIPS increases central blood volume (CBV) through improved cardiac inotropy. Advanced echocardiography demonstrated that myocardial function was unaffected by the dramatic increase in preload after TIPS. Finally, renal function improved due to the increase in CBV. Recognition of these physiological changes significantly contributes to our clinical understanding of TIPS.

The effect of sodium nitrite infusion on renal function, brachial and central blood pressure during enzyme inhibition by allopurinol, enalapril or acetazolamide in healthy subjects: a randomized, double-blinded, placebo-controlled, crossover study.

BACKGROUND: Sodium nitrite (NaNO2) causes vasodilation, presumably by enzymatic conversion to nitric oxide (NO). Several enzymes with nitrite reducing capabilities have been discovered in vitro, but their relative importance in vivo has not been investigated. We aimed to examine the effects of NaNO2 on blood pressure, fractional sodium excretion (FENa), free water clearance (CH2O) and GFR, after pre-inhibition of xanthine oxidase, carbonic anhydrase, and angiotensin-converting enzyme. The latter as an approach to upregulate endothelial NO synthase activity. METHODS: In a double-blinded, placebo-controlled, crossover study, 16 healthy subjects were treated, in a randomized order, with placebo, allopurinol 150 mg twice daily (TD), enalapril 5 mg TD, or acetazolamide 250 mg TD. After 4 days of treatment and standardized diet, the subjects were examined at our lab. During intravenous infusion of 240 µg NaNO2/kg/hour for 2 h, we measured changes in brachial and central blood pressure (BP), plasma cyclic guanosine monophosphate (P-cGMP), plasma and urine osmolality, GFR by 51Cr-EDTA clearance, FENa and urinary excretion rate of cGMP (U-cGMP) and nitrite and nitrate (U-NOx). Subjects were supine and orally water-loaded throughout the examination day. RESULTS: Irrespective of pretreatment, we observed an increase in FENa, heart rate, U-NOx, and a decrease in CH2O and brachial systolic BP during NaNO2 infusion. P-cGMP and U-cGMP did not change during infusion. We observed a consistent trend towards a reduction in central systolic BP, which was only significant after allopurinol. CONCLUSION: This study showed a robust BP lowering, natriuretic and anti-aquaretic effect of intravenous NaNO2 regardless of preceding enzyme inhibition. None of the three enzyme inhibitors used convincingly modified the pharmacological effects of NaNO2. The steady cGMP indicates little or no conversion of nitrite to NO. Thus the effect of NaNO2 may not be mediated by NO generation. TRIAL REGISTRATION: EU Clinical Trials Register, 2013-003404-39 . Registered December 3 2013.

Effect of nebivolol on renal nitric oxide availability and tubular function in patients with essential hypertension.

AIMS: Nebivolol is a selective ß1 -receptor antagonist with vasodilating properties. In patients with essential hypertension, we tested the hypothesis that nebivolol increases systemic and renal nitric oxide (NO) availability using L-N(G) -monomethyl arginine (L-NMMA) as an inhibitor of NO production. METHODS: In a randomized, placebo-controlled, crossover study, patients with essential hypertension were treated with nebivolol for five days, along with a standardized diet and fluid intake. We examined the acute effects of systemic NO synthase inhibition with L-NMMA on brachial blood pressure (bBP), pulse wave velocity (PWV) and central blood pressure (cBP) estimated by applanation tonometry, glomerular filtration rate (GFR), fractional excretion of sodium (FENa ), urinary excretion of both aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ ), and plasma concentrations of nitrate/nitrite (p-NOx ) and vasoactive hormones after five days' treatment with placebo and nebivolol. RESULTS: Nebivolol significantly reduced PWV, bBP, cBP and plasma renin, angiotensin II and aldosterone concentrations. The renal parameters, p-NOx and plasma arginine vasopressin concentration were not changed by nebivolol. There was no difference between nebivolol and placebo in the response to L-NMMA, with LMMA inducing a similar increase in PWV, bBP and cBP and a similar decrease in GFR, uAQP2 and u-ENaCγ and FENa [mean change -0.62% (95% confidence interval {CI} -0.40 to -0.84) during placebo vs. -0.57% (95% CI -0.46 to -0.68; P = 0.564) during nebivolol treatment]. Vasoactive hormones were changed to a similar extend by L-NMMA during administration of nebivolol and placebo. CONCLUSIONS: Nebivolol did not change p-NOx , and inhibition of NO synthesis induced the same response in blood pressure, GFR, renal tubular function and vasoactive hormones during nebivolol and placebo. Thus, the data did not support the hypothesis that nebivolol changes vascular and renal NO availability in patients with essential hypertension.

Renal effects of NO-inhibition in patients with cirrhosis vs. healthy controls: a randomized placebo-controlled crossover study.

BACKGROUND: Nitric oxide (NO) is an important regulator of renal hemodynamics and sodium excretion. Systemic and splanchnic NO-synthesis is increased in liver cirrhosis contributing to the characteristic hyperdynamic circulation. The significance of renal NO in human cirrhosis is not clear. AIMS: In order to clarify the role of NO in the regulation of renal hemodynamics and sodium excretion in human cirrhosis, we studied the effects of N(G)-monomethyl-L-arginine (L-NMMA) - a nonselective NO-inhibitor - on blood pressure (MAP), heart rate (HR), GFR, RPF, UNa × V, FENa, FELi and plasma levels of renin, angII, aldo, ANP, BNP and cGMP in 13 patients with cirrhosis (Child gr.A: 8; Child gr.B+C: 5) and 13 healthy controls. METHODS: The study was randomized and placebo-controlled. Renal hemodynamics were assessed by measuring renal clearance of (51) Cr-EDTA and (125) I-Hippuran for GFR and RPF, respectively. RESULTS: L-NMMA induced a similar, significant increase in MAP in both groups and a more pronounced relative decrease in HR in the CIR group (P = 0.0209, anova). L-NMMA did not change GFR in any group, but RPF decreased significantly in both groups, but most pronouncedly in CIR (P = 0.0478, anova). FENa decreased significantly in both groups after l-NMMA, but the response was again most pronounced in the CIR group (P = 0.0270, anova). All parameters remained stable after placebo. No significant differences were observed between the effects of L-NMMA in Child gr.A vs. Child gr. B+C patients. CONCLUSION: The data supports the hypothesis that renal NO is enhanced in human cirrhosis.

Effect of atorvastatin on renal NO availability and tubular function in patients with stage II-III chronic kidney disease and type 2 diabetes.

BACKGROUND: Statins have beneficial effects on cardiovascular morbidity and mortality independently of reduction of plasma cholesterol. PURPOSE AND METHODS: In patients with type 2 diabetes and nephropathy, chronic kidney disease stage II-III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-NMMA as an inhibitor of NO production. We performed a randomized, placebo-controlled, crossover study, using atorvastatin/placebo treatment for five days with a standardized diet and fluid intake. We measured brachial BP (bBP), central BP (cBP), GFR, urinary output (OU), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of albumin (UAER and UACR), AQP2 (u-AQP2) and ENaC (u-ENaCγ) and plasma concentrations of vasoactive hormones: renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide. RESULTS: During atorvastatin and placebo treatment, L-NMMA infusion, changed the effect variables significantly, but to the same extent, i.e. an increase in bBP and cBP, and a decrease in GFR, OU, CH2O, FENa, u-AQP2 and u-ENaCγ. In addition, renin and angiotensin II was reduced, aldosterone increased, and vasopressin, endothelin-1 and brain natriuretic hormone unchanged. CONCLUSION: During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, atorvastatin did not change nitric oxide availability in type 2 diabetics with nephropathy.

Abnormal urinary excretion of NKCC2 and AQP2 in response to hypertonic saline in chronic kidney disease: an intervention study in patients with chronic kidney disease and healthy controls.

BACKGROUND: Renal handling of sodium and water is abnormal in chronic kidney disease (CKD). The aim of this study was to test the hypothesis that abnormal activity of the aquaporin-2 water channels (AQP2), the sodium-potassium-2chloride transporter (NKCC2) and/or the epithelial sodium channels (ENaC) contribute to this phenomenon. METHODS: 23 patients with CKD and 24 healthy controls at baseline and after 3% saline infusion were compared. The following measurements were performed: urinary concentrations of AQP2 (u-AQP2), NKCC2 (u-NKCC2), ENaC (u-ENaCγ), glomerular filtration rate (GFR) estimated by 51Cr-EDTA clearance, free water clearance (CH2O), urinary output (UO), fractional excretion of sodium (FENa), plasma concentrations of AVP, renin (PRC), Angiotensin II (ANG II), Aldosterone (Aldo) and body fluid volumes. RESULTS: At baseline, GFR was 34 ml/min in CKD patients and 89 ml/ml in controls. There were no significant differences in u-AQP2, u-NKCC2 or u-ENaCγ, but FENa, p-Aldo and p-AVP were higher in CKD patients than controls. In response to hypertonic saline, patients with CKD had an attenuated decrease in CH2O and UO. A greater increase in U-AQP2 was observed in CKD patients compared to controls. Furthermore, u-NKCC2 increased in CKD patients, whereas u-NKCC2 decreased in controls. Body fluid volumes did not significantly differ. CONCLUSIONS: In response to hypertonic saline, u-NKCC2 increased, suggesting an increased sodium reabsorption via NKCC2 in patients with CKD. U-AQP2 increased more in CKD patients, despite an attenuated decrease in CH2O. Thus, though high levels of p-AVP and p-Aldo, the kidneys can only partly compensate and counteract acute volume expansion due to a defective tubular response. TRIAL REGISTRATION: Clinical trial no: NCT01623661. Date of trial registration: 18.06.2012.

Cardiovascular effects of cholecalciferol treatment in dialysis patients--a randomized controlled trial.

BACKGROUND: Patients on chronic dialysis are at increased risk of vitamin D deficiency. In observational studies plasma 25-hydroxyvitamin D (p-25(OH) D) levels are inversely correlated with plasma BNP and adverse cardiovascular outcomes. Whether a causal relation exists has yet to be established. The aim of this study was to test the hypothesis that cholecalciferol supplementation improves cardiac function and reduces blood pressure (BP) and pulse wave velocity (PWV) in patients on chronic dialysis. METHODS: In a randomized, placebo-controlled, double-blind study, we investigated the effect of 75 µg (3000 IU) cholecalciferol daily for 6 months, in patients on chronic dialysis. We performed two-dimensional echocardiography, with doppler and tissue-doppler imaging, 24-h ambulatory BP (24-h BP), PWV, augmentation index (AIx), central BP (cBP) and brain natriuretic peptide (BNP) measurements at baseline and after 6 months. RESULTS: Sixty-four patients were allocated to the study. Fifty dialysis patients with a mean age of 68 years (range: 46-88) and baseline p-25(OH) D of 28 (20;53) nmol/l completed the trial. Cholecalciferol increased left ventricular (LV) volume, but had no impact on other parameters regarding LV structure or left atrial structure. LV systolic function, LV diastolic function, PWV, cBP, AIx and BNP were not changed in placebo or cholecalciferol group at follow-up. 24-h BP decreased significantly in placebo group and tended to decrease in cholecalciferol group without any difference between treatments. CONCLUSION: Six months of cholecalciferol treatment in patients on chronic dialysis did not improve 24-h BP, arterial stiffness or cardiac function. TRIAL REGISTRATION: NCT01312714, Registration Date: March 9, 2011.

Screening for hypertension in adults - the use of tonometric blood pressure monitoring.

OBJECTIVES: Arterial hypertension increases the risk of developing cardiovascular disease. Reliable screening tools for diagnosing hypertension are important to ensure correct risk stratification of subjects. In this study, we aimed to analyse if a wrist-worn device using a tonometric technique for measuring of 24-hour blood pressure could be used to diagnose hypertension and non-dipping. A conventional device using oscillometric measurements was used as golden standard. Secondary aim was to compare the degree of discomfort related to monitoring with the two devices. METHODS: In 89 subjects with a history of normal blood pressure and naive to ambulatory BP monitoring (ABPM), 24-hour ABPM was measured simultaneously with A&D TM2430 (oscillometric technique) and BPro (tonometric technique). RESULTS: When comparing measurements from the two devices, we found that the tonometric device misclassified 46% of hypertensive subjects and 69% of non-dippers. The tonometric device measured significantly lower systolic 24-hour and daytime blood pressure. The subjects reported less discomfort related to the tonometric than the oscillometric device. CONCLUSION: Despite less discomfort related to usage of the tonometric device for 24-hour blood pressure monitoring compared to an oscillometric device, misclassification of hypertension and non-dipping makes the tonometric device inappropriate as a screening instrument.

Effect of paricalcitol on renin and albuminuria in non-diabetic stage III-IV chronic kidney disease: a randomized placebo-controlled trial.

BACKGROUND: Vitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship. METHODS: In a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 µg/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance. RESULTS: Paricalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA. CONCLUSIONS: In this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01136564.

Effect of volume expansion with hypertonic- and isotonic saline and isotonic glucose on sodium and water transport in the principal cells in the kidney.

BACKGROUND: The renal distal nephron plays an important role in the maintenance of sodium balance, extra cellular volume and blood pressure. The degree of water transport, via aquaporin2 water channels (AQP2), and sodium transport, via epithelial sodium channels (ENaC) in renal collecting duct principal cells are reflected by the level of urinary excretion of AQP2 (u-AQP2) and the γ-fraction of ENaC (u-ENaCγ). The effects of an acute intravenous volume load with isotonic saline, hypertonic saline and glucose on u-AQP2, u-ENaCγ and underlying mechanisms have never been studied in a randomized, placebo-controlled trial in healthy humans. METHODS: We studied the effects of 0.9% saline (23 ml/kg), 3% saline (7 ml/kg) and 5% glucose (23 ml/kg) on u-AQP2 and u-ENaCγ, fractional sodium excretion (FENa), free water clearance (CH2O), and plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (ANG II) and aldosterone (Aldo) in a randomized, crossover study of 23 healthy subjects, who consumed a standardized diet, regarding calories, sodium and fluid for 4 days before each examination day. RESULTS: After isotonic saline infusion, u-AQP2 increased (27%). CH2O and u-ENaCγ were unchanged, whereas FENa increased (123%). After hypertonic saline infusion, there was an increase in u-AQP2 (25%), u-ENaCγ (19%) and FENa (96%), whereas CH2O decreased (-153%). After isotonic glucose infusion, there was a decrease in u-AQP2 (-16%), ENaCγ (-10%) and FENa (-44%) whereas CH2O increased (164%). AVP remained unchanged after isotonic saline and glucose, but increased after hypertonic saline (139%). PRC, AngII and p-Aldo decreased after isotonic and hypertonic saline infusion, but not after glucose infusion. CONCLUSIONS: Volume expansion with 3% and 0.9% saline increased u-AQP2, while isotonic glucose decreased u-AQP2. Infusion of hypertonic saline increased u-ENaCγ, whereas u-ENaCγ was not significantly changed after isotonic saline and tended to decrease after glucose. Thus, the transport of water and sodium is changed both via the aquaporin 2 water channels and the epithelial sodium channels during all three types of volume expansion to regulate and maintain water- and sodium homeostasis in the body. TRIAL REGISTRATION: Clinical Trial no: NCT01414088.

Technetium-99m-MAG3 and technetium-99m-DTPA: Renal clearance measured by the constant infusion technique - Old news?

BACKGROUND: Accurate, precise and straightforward methods for measuring glomerular filtration rate (GFR) and/or renal plasma flow (RPF) are still in demand today. The time-consuming constant infusion technique (CIT) is the gold standard and preferred for research, whereas the simple, but less precise, single injection technique (SIT) is used in clinical settings. This study investigated the use of 99m Tc-DTPA and 99m Tc-MAG3 by CIT as a measure of renal function. We developed and evaluated a model to balance the primer dose and infusion rate in an attempt to obtain plasma steady state as quickly as possible. METHODS: 14 healthy subjects received 99m Tc-DTPA and 6 hypertensive patients received 99m Tc-MAG3 in a standardized protocol. All participants had an eGFR above 60 ml/min and none had fluid retention. An intravenous primer injection of the relevant tracer was followed by a sustained infusion over 4.5 h with the same radiopharmaceutical. Blood and urine samples were collected at fixed intervals. RESULTS: 99m Tc-DTPA clearance reached steady state after 210 min (plasma clearance 78 ± 18 ml/min, urine clearance 110 ± 28 ml/min), whereas 99m Tc-MAG3  clearance achieved steady state after 150 min (plasma clearance 212 ± 56 ml/min, urine clearance 233 ± 59 ml/min). CONCLUSION: Constant infusion technique with fixed primer and infusion rate using 99m Tc-MAG3 is feasible for research purposes. The longer time for reaching plasma steady state using 99m Tc-DTPA makes CIT with this tracer less optimal. If the primer/sustained balance can be optimized, for example using a priori SIT information, 99m Tc-DTPA as tracer for CIT may also be feasible.

Protein-enriched diet increases water absorption via the aquaporin-2 water channels in healthy humans.

BACKGROUND: According to animal experiments, a protein-enriched diet increased renal absorption of sodium and water. We wanted to test the hypothesis that a protein-enriched diet would increase the expression of the aquaporin-2 water channels and the epithelial sodium channels in the distal part of the nephron using biomarkers for the activity of the two channels. METHODS: We performed a randomized, placebo controlled crossover study in 13 healthy humans to examine the effect of a protein-enriched diet on renal handling of water and sodium during baseline condition and during hypertonic saline infusion. We measured the effect of the protein-enriched diet on urinary excretions of aquaporin-2 (u-AQP2), the beta-fraction of the epithelial sodium channels (u-ENaC(beta)), free water clearance (C(H2O)), fractional excretion of sodium and vasoactive hormones. RESULTS: During baseline conditions, u-AQP2 increased, and C(H2O) decreased during the protein-enriched diet, whereas u-ENaC(beta) was unchanged, although the urinary sodium excretion increased. During hypertonic saline infusion, the response in the effect variables did not deviate between protein-enriched and normal diet. Plasma concentrations of angiotensin II and aldosterone increased as well as pulse rate. Vasopressin in plasma was unchanged, and prostaglandin E(2) fell during the protein-enriched diet. CONCLUSIONS: The protein-enriched diet increased water absorption via an increased transport via the aquaporin-2 water channels. The increased u-AQP2 might be due to a reduced prostaglandin level. The increase in renal sodium excretion seems to be mediated in another part of the nephron than the epithelial sodium channels.

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels.

BACKGROUND: Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels. METHODS: The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide. RESULTS: Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher. CONCLUSION: During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system TRIAL REGISTRATION: Clinical Trials Identifier: NCT00281762.

Eprosartan modulates the reflex activation of the sympathetic nervous system in sodium restricted healthy humans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: A sympatho-inhibitory effect of ACE-inhibitors and AT(1) receptor antagonists has been widely demonstrated in animal models, but in humans this effect tends only to be present during chronic treatment in conditions with pre-existing high levels of sympathetic activity. Sodium restriction increases renal sympathetic nerve activity and the activity of the renin-angiotensin system and may be a favourable condition to demonstrate sympatho-inhibition as a short-term effect of the AT(1) receptor antagonist eprosartan in healthy humans. WHAT THIS STUDY ADDS: Results from our study indicate that during sodium restriction eprosartan has a small inhibitory effect on nonbaroreflex mediated activation of the sympathetic nervous system. During arterial baroreflex mediated activation of the sympathetic nervous system this effect is, however, completely overruled by an increased sensitivity of the arterial baroreflex. AIMS To test the hypothesis that eprosartan inhibits both nonbaroreflex and arterial baroreflex mediated activation of the sympathetic nervous system, assessed by renal tubular function, systemic haemodynamics and vasoactive hormones, in sodium restricted healthy humans. METHODS: The effect of eprosartan on urinary sodium, lithium and water excretion, heart rate (HR), blood pressure and vasoactive hormones was measured before, during and after a cold pressor test (CPT) and sodium nitroprusside (SNP) infusion in a randomized, placebo controlled, double-blind, crossover study in 17 healthy subjects. Glomerular filtration rate and renal tubular function were determined by a continuous infusion clearance technique and vasoactive hormones by radioimmunoassays. RESULTS: Eprosartan attenuated the impact of the CPT on HR (mean difference from placebo (95% confidence interval) (3.9 (0.7, 7.0) min(-1)) and mean arterial pressure (MAP) (4.7 (0.3, 9.2) mmHg), but no effect of eprosartan was observed on the impact of the CPT on renal tubular function. During a SNP induced reduction in MAP of 10 mmHg eprosartan decreased fractional excretions of sodium (0.46 (0.14, 0.76)%) and lithium (5.1 (2.5, 7.6)%) and tended to increase HR (4.1 (-0.26, 8.4) min(-1)) and plasma concentrations of norepinephrine (33.8 (-5.8, 72.1) pg ml(-1)). CONCLUSIONS; These findings suggest that during mild sodium restriction eprosartan has a small inhibitory effect on nonbaroreflex mediated activation of the sympathetic nervous system. During arterial baroreflex mediated activation of the sympathetic nervous system this effect is, however, completely overruled by an increased sensitivity of the arterial baroreflex.

Nocturnal blood pressure decrease in patients with chronic kidney disease and in healthy controls - significance of obstructive sleep apnea and renal function.

BACKGROUND: Chronic kidney disease (CKD) is often associated with a blunted nocturnal BP decrease and OSA. However, it is not fully clear whether a relationship exists between reduction in renal function and obstructive sleep apnea (OSA) on the one hand and relative nocturnal BP decrease in CKD patients on the other. The aim of this study was to investigate the association between nocturnal BP decrease and renal function, the degree of OSA, vasoactive hormones, and renal sodium handling in CKD3-4 patients and healthy age-matched controls. METHODS: We performed brachial and central 24-hour ambulatory BP measurement and CRM in 70 CKD3-4 patients and 56 controls. In plasma, we measured renin, AngII, aldosterone, and vasopressin. In urine, 24-hour excretion of sodium, protein fractions from the epithelial sodium channel (u-ENaCγ), and the AQP2 water channels (u-AQP2) were measured. RESULTS: CKD patients had lower relative nocturnal BP decrease than controls: brachial (10% vs 17%, P=0.001) and central (6% vs 10%, P=0.001). Moderate-to-severe OSA was more frequent in patients (15 vs 1%, P<0.0001). Neither the presence of OSA nor eGFR were predictors of either brachial or central nocturnal BP decrease. CKD3-4 nondippers were more obese, had higher HbA1c level, and more often a history of acute myocardial infarction than CKD3-4 dippers (P<0.05). CONCLUSION: CKD3-4 patients had lower brachial and central nocturnal BP decrease than healthy controls. OSA and eGFR were not associated with nondipping in CKD patients or healthy controls. Nondipping in CKD3-4 was associated with obesity, diabetes, and cardiovascular disease. CLINICALTRIALSGOV ID: NCT01951196.

Effects of sodium nitrite on renal function and blood pressure in hypertensive vs. healthy study participants: a randomized, placebo-controlled, crossover study.

OBJECTIVE: Nitric oxide is a key player in regulating vascular tone. Impaired endothelial nitric oxide synthesis plays an important role in hypertension. Replenishing of nitric oxide by sodium nitrite (NaNO2) has not been investigated in patients with essential hypertension (EHT). We aimed to determine the effects of NaNO2 on blood pressure (BP) and renal sodium and water regulation in patients with EHT compared with healthy control study participants (CON). METHODS: In a placebo-controlled, crossover study, we infused 240 µg NaNO2/kg/h or isotonic saline for 2 h in 14 EHT and 14 CON. During infusion, we measured changes in brachial and central BP, free water clearance, fractional sodium excretion, and urinary excretion rate of γ-subunit of the epithelial sodium channel (U-ENaCγ), and aquaporin-2 (U-AQP2). RESULTS: Placebo-adjusted brachial SBP decreased 18 mmHg (P < 0.001) during NaNO2 infusion in EHT and 12 mmHg (P < 0.001) in CON (Pbetween = 0.024). Brachial DBP and central SBP decreased equally in both groups during NaNO2. In EHT, we found a decrease in U-ENaCγ during NaNO2 infusion. In both groups, we observed a decrease in fractional sodium excretion, free water clearance, and U-AQP2 during NaNO2 infusion. CONCLUSION: This study demonstrated an augmented BP-lowering effect of NaNO2 in patients with EHT. We observed an antinatriuretic and antidiuretic effect of NaNO2 in both groups, and a decrease in U-ENaCγ, solely in EHT. In both groups, we detected a nonvasopressin mediated decrease in U-AQP2, which is most likely compensatory to the decline in diuresis.