Increase In Urinary Sodium Excretion Research Articles

Abstract P641: Angiotensin Receptor Blocker Improves Pressure Natriuresis in Select African-Americans

Objective: Hypertension in ~30-60% of African-Americans (AAs) is resistant to single or combination therapy, indicating the necessity for novel screening strategies in this population. Our research supports a strategy that identifies a subset of AAs (approximately 1 in 3) who increase their retained sodium load during mental stress (MS) with an accompanying volume-mediated increase in blood pressure (BP) that remains elevated until the volume expansion diminishes. We hypothesize is due to activation of the renin-angiotensin system (RAS). Design and Method: We conducted a double blind placebo controlled crossover trial comparing the effects of irbesartan to placebo on sodium handling and consequent BP during MS. Subjects included 213 AA adults, of which 168 (78%) completed the study. After 7 days of vehicle (placebo or irbesartan) subjects underwent a 3 hr protocol comprised of 1 hr rest, 1 hr competitive video games, and 1 hr recovery. Blood and urine were obtained after each hour and BP every 15 mins. A 1 week washout ensued before subjects crossed over to repeat with the alternate vehicle. Subjects were divided into those who exhibited expected increases in urinary sodium excretion (U Na V) (Excreters) or reduced U Na V (Retainers) during MS as defined by previous data. Statistical analysis was performed using crossover methods with a pooled analysis that assumes equal variances and the Satterthwaite test of treatment difference (Stest) that assumes unequal variances. Results: Both statistical tests revealed that U Na V increased significantly for retainers (n=55) on irbesartan (p<0.002 and p<0.015, mean ± SD (pooled =7.15 ± 6.78, Stest =7.15)) normalizing the sodium response to MS. Irbesartan also enhanced U Na V during MS in excreters (n=113) with significant differences (p<0.001 and p<0.001, mean ± SD (pooled = 4.18 ± 9.03, Stest =4.18)). Overall SBP response was significantly reduced with treatment (p< 0.001 and p< 0.001, mean ± SD (pooled = -5.08 ± 3.19, Stest = -5.08)). Conclusion: Agents that block the RAS are not usually considered effective in AAs. However, our results suggest identification and treatment of AAs who increase their retained sodium load during MS with these agents will reduce the percentage of AAs with hypertension resistant to standard therapy.

LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone.

LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.

Increase in urinary sodium excretion in spinal cord injury patients in the emergency department.

Spinal cord injury (SCI) is a pathological condition known to produce hyponatremia. The aim of this study was to elucidate the dynamics of urinary sodium excretion in patients with spinal cord injury. SCI patients undergoing intensive care management were enrolled in this study. These patients were divided into two groups: those with Frankel Grade A spinal cord injury manifesting complete, severe motor disorders (FA group) and those with incomplete spinal cord injury (non-FA group). The occurrence of episode of hyponatremia (serum sodium <135 mmol/L), hypotension, and bradycardia during the first 14 hospital days was counted and fractional excretion of sodium (FENa) was calculated on the 1st, 7th, and 14th hospital days. Thirty-four patients (FA group, n = 9; non-FA group, n = 25) were included. Eight patients (88.9 %) in the FA group and three patients (12 %) in the non-FA group experienced at least one episode of hyponatremia during the first 14 hospital days. In the FA group, the FENa was significantly increased on the 7th and 14th hospital days compared to the 1st hospital day. FENa on the 14th hospital day was a significant independent predictor of hyponatremic episodes. Hypotension and bradycardia as the symptoms of sympathetic blockade differed significantly as independent predictors of increased FENa on the 14th hospital day. Urinary sodium excretion calculated by FENa increased in patients with severe spinal cord injury. Sympathetic blockade due to SCI may increase urine sodium excretion and lead to hyponatremia.

Effect of dipeptidyl peptidase-4 inhibition on circadian blood pressure during the development of salt-dependent hypertension in rats.

A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg(-1) twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.

Abstract 533: Effect of Dipeptidyl Peptidase-4 Inhibition on Blood Pressure and Its Dipping Pattern in Dahl Salt-Sensitive Rats

Several studies have indicated that treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors decreases blood pressure. We aimed to examine the effects of vildagliptin, a specific DPP-4 inhibitor, on blood pressure and its dipping pattern in Dahl salt-sensitive (DSS) rats. Male DSS rats were treated with a high salt (8% NaCl) diet and vehicle (0.5% carboxymethylcellulose) or vildagliptin (3 or 10 mg/kg, twice daily, p.o.) for 7 days (n = 7 per group). Mean arterial pressure (MAP) was measured by telemetry. High salt diet for 7 days significantly increased MAP with an extreme dipping pattern of blood pressure in DSS rats. Vildagliptin dose-dependently inhibited DPP-4 enzymatic activity and increased plasma GLP-1 levels. Furthermore, vildagliptin dose-dependently attenuated the development of salt-induced hypertension. Interestingly, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern. In anesthetized high salt-diet DSS rats, acute intra-cerebroventricular infusion of vildagliptin (50, 500 or 2500 μg in 10 μl solution) did not alter MAP or heart rate (n = 4). These data suggest that treatment with the DPP-4 inhibitor, vildagliptin, attenuates the extreme dipping pattern of blood pressure and development of salt sensitive hypertension by increasing urinary sodium excretion. These effects of vildagliptin may not be mediated through the central nervous system.

AT₂ receptor activation induces natriuresis and lowers blood pressure.

Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist. To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice. In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension. AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension.

Angiotensin type 2 receptor stimulation increases renal function in female, but not male, spontaneously hypertensive rats.

Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R stimulation to modulate renal function in hypertension, we examined the influence of the AT2R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT2R stimulation significantly increased renal blood flow in female hypertensive rats (PTreatment<0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT2R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT2R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT2R expression in female than in male hypertensive rats. Taken together, acute AT2R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT2R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT2R as a therapeutic target for cardiovascular disease, particularly in women.

Radiofrequency renal nerve ablation decreases blood pressure in SHR accompanied by increased urinary sodium excretion (857.4)

We have shown that radiofrequency catheter ablation of the renal arteries (RF‐RDN) decreases blood pressure (BP) in spontaneously hypertensive rats (SHR). Here, we studied the effects of RF‐RDN on changes in water and sodium excretion and urinary angiotensinogen levels in SHR with established hypertension. Methods Nineteen‐week old male SHR were instrumented with telemetry probes for measurement of BP. After 1‐week, control BP was measured. The next day SHR randomly received either bilateral Sham‐RDN (n=5) or RF‐RDN (n=6) of the renal arteries (Biosense Webster Stockert 70 generator and RF‐probe). BP (Systolic, SBP; Diastolic, DBP) was then measured for 2 weeks. Rats were then placed in metabolic cages for collection of urine and measurement of 24‐hr water and sodium balance. Results BP was significantly decreased in RF‐RDN SHR (2 weeks; ΔSBP, ‐12±5; ΔDBP, ‐9±4 mmHg) as compared to sham SHR (2 weeks; ΔSBP, ‐2±2; ΔDBP, 2±2 mmHg). RF‐RDN SHR increased urinary sodium excretion (RF‐RDN, 0.33±0.02; Sham, 0.25±0.03 mEq/day) and food intake (RF‐RDN 21±1; Sham 17±1 g/day). However, there were no significant differences between groups in 24‐hr daily water (RF‐RDN, 21±1; Sham, 19±2 ml) or sodium balance (RF‐RDN, 0.59±0.04; Sham, 0.48±0.06 mEq), or urinary angiotensinogen, protein and creatinine excretion rates. At the end of week 2, kidney norepinephrine levels in RF‐RDN rats (left, 0±0; right, 10±10 ng/g kidney) were markedly decreased compared with levels from sham SHR (left, 130±10; right, 110±10 ng/g kidney). Conclusions These data demonstrate that in hypertensive SHR, bilateral RF‐RDN produces an increase in urinary sodium excretion, which may potentially contribute to the concurrent decrease in BP.Grant Funding Source: Biosense Webster IIS‐175 to DRK &amp; FS; P30 GM103337 to LGN; P20 GM103514 to DRK

Urinary sodium excretion has positive correlation with activation of urinary renin angiotensin system and reactive oxygen species in hypertensive chronic kidney disease.

It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.

The renin–aldosterone axis in kidney transplant recipients and its association with allograft function and structure

The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with GFR change, interstitial expansion and end-stage renal disease (ESRD) we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria or interstitial expansion. Losartan use, [HR 0.48 (95% CI 0.21–1.0), insignificant], and Caucasian donor, [HR 0.18 (95% CI 0.07–0.4), significant] were associated with less doubling of serum creatinine, death or ESRD. Hypertension, less than 3 HLA-matches, the combination of tacrolimus-rapamycin and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD, [HR 1.01 (95% CI 1.00–1.02)]. Thus, systemic RAAS is not overly activated in kidney transplant recipients but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.

Reactive oxygen species mediate dopamine-induced signaling in renal proximal tubule cells

Intrarenally-produced dopamine (DA) induces a large increase in urinary sodium excretion mainly due to the inhibition of tubular sodium reabsorption. We aimed to study the participation of reactive oxygen species (ROS) in DA signaling pathway in proximal tubule cells. Our results show that DA increased ROS production in OK cells and indicate the mitochondria as the main source of ROS. DA also increased ERK1/2, superoxide dismutase (SOD) and transcription factor κB (NF-κB) activity. These findings suggest that DA generates mitochondria-derived ROS that activate ERK1/2 and subsequently NF-κB and SOD activity at concentrations that exert a physiological regulation of renal function.

Long‐Term Renal Denervation Normalizes Disrupted Blood Pressure Circadian Rhythm and Ameliorates Cardiovascular Injury in a Rat Model of Metabolic Syndrome

BackgroundAlthough renal denervation significantly reduces blood pressure in patients with resistant hypertension, the role of the renal nerve in hypertension with metabolic syndrome is unknown. We investigated the impact of long‐term renal denervation on SHR/NDmcr‐cp(+/+) (SHRcp) rats, a useful rat model of metabolic syndrome, to determine the role of the renal nerve in hypertension with metabolic syndrome.Methods and ResultsSHRcp rats were divided into (1) a renal denervation (RD) group and (2) a sham operation group (control) to examine the effects of long‐term RD on blood pressure circadian rhythm, renal sodium retention‐related molecules, the renin‐angiotensin‐aldosterone system, metabolic disorders, and organ injury. RD in SHRcp rats not only significantly reduced blood pressure but also normalized blood pressure circadian rhythm from the nondipper to the dipper type, and this improvement was associated with an increase in urinary sodium excretion and the suppression of renal Na+‐Cl− cotransporter upregulation. RD significantly reduced plasma renin activity. RD significantly prevented cardiovascular remodeling and impairment of vascular endothelial function and attenuated cardiovascular oxidative stress. However, RD failed to ameliorate obesity, metabolic disorders, and renal injury and failed to reduce systemic sympathetic activity in SHRcp rats.ConclusionsBy including the upregulation of the Na+‐Cl− cotransporter, the renal sympathetic nerve is involved in the disruption of blood pressure circadian rhythm as well as hypertension in metabolic syndrome. Thus, RD seems to be a useful therapeutic strategy for hypertension with metabolic syndrome.

GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure

Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R-dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r(-/-) or Nppa(-/-) mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R-dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r(-/-) mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa(-/-) mice. These findings define a gut-heart GLP-1R-dependent and ANP-dependent axis that regulates blood pressure.

Early Inhibition of Natriuresis Suppresses Symptomatic Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage

Background: Hyponatremia is a common complication occurring in one third of patients after subarachnoid hemorrhage (SAH). One mechanism that likely mediates the development of hyponatremia in SAH is cerebral salt wasting syndrome (CSWS), which induces natriuresis and reduces total blood volume, resulting in a risk of symptomatic vasospasm (SVS). The mineral corticoid fludrocortisone acetate enhances sodium reabsorption in the renal distal tubules and may help prevent post-SAH hyponatremia. However, management with fludrocortisone acetate is ineffective if hyponatremia is advanced, because CSWS and subsequent SVS develop rapidly. Therefore, an additional earlier marker is required to predict the development of hyponatremia for the initiation of immediate treatment in select patients. However, no conclusive evidence exists showing that hyponatremia influences the risk of SVS, and no standard treatment protocol exists for treating hyponatremia in patients with SAH. This study was undertaken to evaluate whether selective early treatment of hyponatremia prevents SVS in patients with increased urinary sodium excretion in the early phase following SAH. Methods: A total of 103 patients with aneurysmal SAH were managed for a postoperative electrolyte disorder after aneurysmal clipping or coil embolization. Between 2004 and 2007 (period 1), 54 patients started treatment to correct the electrolyte disorder after hyponatremia had occurred. Between 2007 and 2011 (period 2), 49 patients were prospectively subjected to sodium replacement treatment according to their daily sodium balance, and inhibition of natriuresis with fludrocortisone acetate was initiated just after an increase in urinary sodium excretion >300 mEq/day. The occurrence of hyponatremia, SVS, and outcomes were compared between the two periods. Results: Hyponatremia was observed in 14 patients (26%) in period 1 and 7 patients (14%) in period 2. The incidence of fludrocortisone acetate administration was significantly higher, and initiation of electrolyte correction was significantly earlier, in period 2 patients. We observed a significant difference in the frequency of SVS, which occurred in 10 patients (18.5%) in period 1 and 3 patients (6.1%) in period 2. Both urinary sodium excretion and urine volume at day 7 were significantly different between the two periods. However, no significant difference was observed in overall outcome between the two periods. Conclusions: Early inhibition of natriuresis with fludrocortisone acetate before the occurrence of hyponatremia prevented SVS after aneurysmal SAH. Increased urinary sodium excretion in the early phase of SAH is a good indicator for the initiation of electrolyte correction with fludrocortisone acetate.

Intrarenal angiotensin III is the predominant agonist for proximal tubule angiotensin type 2 receptors.

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.

Effect of Vitamin D Repletion on Urinary Calcium Excretion among Kidney Stone Formers

Despite the important role of vitamin D in maintaining bone health, many clinicians are reluctant to treat vitamin D deficiency in kidney stone formers because of the theoretical risk of increasing urinary calcium excretion. This study examined the effect of vitamin D repletion on urinary calcium excretion among stone formers. Participants (n=29) were recruited from urology clinics affiliated with New York Presbyterian Hospital. Enrollment criteria included a history of nephrolithiasis, urinary calcium excretion between 150 and 400 mg/d, and a serum 25-hydroxyvitamin D level <30 ng/ml. Participants were given oral ergocalciferol (50,000 IU/wk) for 8 weeks. Serum and 24-hour urine tests were repeated after 8 weeks. Levels of 25-hydroxyvitamin D increased significantly after vitamin D repletion (17±6 and 35±10 ng/ml, P<0.001), but mean 24-hour urinary calcium excretion did not change (257±54 and 255±88 mg/d at baseline and follow-up, respectively, P=0.91). However, 11 participants had an increase in urinary calcium excretion ≥20 mg/d; these participants also had an increase in urine sodium excretion, likely reflecting dietary variability. No participant experienced adverse effects from vitamin D, including hypercalcemia. Among stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not seem to increase mean urinary calcium excretion, although a subset of individuals may have an increase. These data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but 24-hour urinary calcium excretion should be monitored after repletion.

Dietary sodium loading in normotensive healthy volunteers does not increase arterial vascular reactivity or blood pressure

Studies of dietary sodium on vascular function and blood pressure in normotensive volunteers have shown conflicting results. There are very limited data available on the effect of chronic sodium loading from a low-sodium diet to a high-sodium diet on vascular function and blood pressure in normotensive volunteers. To assess the effect of modifying dietary sodium intake on arterial function and surrogate markers of arterial remodelling in normal healthy volunteers. Twenty-three normotensive volunteers met the inclusion criteria. After a 2 week run-in with a low-sodium diet (60 mmol/day), the participants maintained their low-sodium diets and were randomly assigned to receive sequentially one of three interventions for 4 weeks, with a 2 week washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B) and tomato juice containing 140 mmol Na (C). The outcomes measured were changes in pulse wave velocity (PWV), systolic blood pressure and diastolic blood pressure. There was no difference in PWV between interventions (B-A 0.00 m/s, 95% CI: -0.30, 0.31 m/s; C-A 0.01 m/s, 95% CI: -0.38, 0.40 m/s). There was also no change in pulse wave analysis, systolic or diastolic blood pressure between interventions. There was an appropriate increase in urinary sodium excretion in the added sodium interventions. Dietary salt loading did not produce significant increases in PWV and blood pressure in normotensive subjects with systolic blood pressure <130 mmHg. The lack of an observed effect supports Guyton's pressure-natriuresis hypothesis with appropriate renal excretion of the excess sodium load.

Effects of insulin detemir and NPH insulin on renal handling of sodium, fluid retention and weight in type 2 diabetic patients

In type 2 diabetic patients, insulin detemir (B29Lys(ε-tetradecanoyl),desB30 human insulin) induces less weight gain than NPH insulin. Due to the proposed reduction of tubular action by insulin detemir, type 2 diabetic patients should have increased urinary sodium excretion, thereby reducing extracellular volume and body weight when changed from NPH insulin to insulin detemir. In a randomised, open-labelled, two-way crossover study of 24 patients with type 2 diabetes, patients were first treated with NPH insulin or insulin detemir for 8 weeks. Thereafter, they were changed to the other insulin for 8 weeks. In a third 1 week period, they were changed back to the first insulin. At the end of 8 weeks, body weight was reduced by 0.8 ± 0.2 kg (mean ± SEM) on insulin detemir compared with NPH insulin (p < 0.01). After insulin detemir treatment, we also observed a significant reduction of lean body mass (0.8 ± 0.2 kg, p < 0.05) and a non-significant reduction of extracellular volume (0.8 ± 0.5 l/1.73 m², p = 0.14). The weight loss occurred after as early as 1 week (0.8 ± 0.2 kg, p < 0.001), with a simultaneous and transient increase of urinary sodium excretion (p = 0.07). Insulin detemir induces significant and sustained weight loss, which is first observed at 1 week after changing from NPH insulin. The initial weight loss seems to be related to changes in fluid volume and may reflect changed insulin action in the kidneys.

Quantitating nocturia: a study into the recording of solute and water excretion to determine causation

Nocturia is common but the clinical assessment of its severity and cause rarely involves any biochemical analysis. Investigating the cause of nocturia needs to be informed by the overall 24 h fluid and solute excretion patterns. The aim of this study was to establish a practical method of monitoring the renal excretion of water and solutes over a complete 24 h cycle. The excretion patterns of sodium, volume and osmoles were assessed in 89 healthy control subjects over a 24 h period by sampling each voiding from the 24 h collection and then using the total urine creatinine as the denominator. A group of 21 patients under investigation for sleep-disordered breathing (SDB: a group of disorders known to increase the risk of nocturia) were also studied to determine comparative excretion patterns. Reference excretion patterns of sodium, volume and osmoles were described. Patients under investigation for SDB had overall a significant (P < 0.001) increase in urine sodium excretion at night (nocturnal natriuresis) matched by an increased osmotic excretion and accompanied by a significantly increased nocturnal urine volume (P < 0.001). Breaking down a 24 h urine collection into voided aliquots provides practical information on the pattern of water and solute excretion. Such patterns may assist in identifying the underlying mechanism of significant nocturia in individual patients presenting with this symptom, and could be used as a method of monitoring treatment.

Pharmacokinetic and pharmacodynamic interaction between furosemide and the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen

Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renal-clearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.7-86.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steady-state, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ng•h/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticals®, Inc. (1. Brater, Am J Medicine, 1986; 2. Müller, Eur J Clin Pharmacol, 1995; 3. Flector Patch PI, 2009). Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renal-clearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.7-86.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steady-state, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ng•h/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticals®, Inc. (1. Brater, Am J Medicine, 1986; 2. Müller, Eur J Clin Pharmacol, 1995; 3. Flector Patch PI, 2009).