Étude clinique et expérimentale

The role of prostaglandins (PG), renin-angiotensin system (RAS) and calcium (Ca) in the control of renal hemodynamics and glomerular filtration rate (GFR) in chronic hypercalcemia (serum Ca 12.8 mg%) was studied. Renal blood flow (RBF, 6.39 ml/min per gram kidney weight [gkw]) and GFR (0.52 ml/min per gkw) were significantly decreased in hypercalcemic rats when compared with normocalcemic rats (7.15, P < 0.001 and 0.74, P < 0.05, respectively). These changes in RBF and GFR occurred independent of any significant alterations in systemic hemodynamics, blood and plasma volume. Inhibition of the renal PG with indomethacin resulted in marked decrements in both RBF (6.39-4.12 ml/min per gkw, P < 0.01) and GFR (0.52-0.19 ml/min per gkw, P < 0.01) in hypercalcemic rats, whereas there was no significant alterations in normocalcemic rats. Inhibition of the RAS with captopril resulted in marked increments in both RBF (6.39-7.35 ml/min per gkw, P < 0.05) and GFR (0.52-0.74 ml/min per gkw, P < 0.05) in hypercalcemic rats. In fact, there was no significant difference from the RBF and GFR of similarly treated normocalcemic rats. Similar results were also obtained with the competitive angiotensin II (AII) antagonist (sarcosyl(1)-isoleucyl(5)-glycyl(8)) AII. Since both the renal PG and the RAS are involved in the control of RBF and GFR in hypercalcemia, the role of each is best revealed in the absence of the other. Hence, comparison of the RBF and GFR in the PG-inhibited hypercalcemic rats in the presence of AII (4.12 and 0.19 ml/min per gkw, respectively) and absence of AII (5.99 and 0.53 ml/min per gkw, P < 0.01 for both) reveals the vasoconstrictive role for AII in hypercalcemia. On the other hand, comparison of the RBF and GFR in the AII-inhibited hypercalcemic rats in the presence of PG (7.35 and 0.74 ml/min per gkw, respectively) and absence of PG (5.99 and 0.53 ml/min per gkw, P < 0.01 and P < 0.05, respectively) reveals the vasodilatory role for PG in hypercalcemia. Finally, comparison of the RBF and GFR in both PG- and AII-inhibited hypercalcemic rats (5.99 and 0.53 ml/min per gkw, respectively) with similarly treated normocalcemic rats (7.30 and 0.94 ml/min per gkw, P < 0.001 and P < 0.005, respectively) reveals the vasoconstrictive role for Ca in chronic hypercalcemia. Our study therefore demonstrates that in chronic hypercalcemia the RBF and GFR are controlled by an active interplay of the vasoconstrictive effect of AII, the vasodilatory effect of renal PG, and the direct vasoconstrictive effect of Ca, independent of either AII or PG. The sum total of these forces produces a modest but significant decrease in RBF and GFR.

Renal actions of the selective angiotensin AT 2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat

This study aimed to evaluate the urinary excretion of sodium and potassium, and to estimate the main food sources of sodium in Maputo dwellers. A cross-sectional evaluation of a sample of 100 hospital workers was conducted between October 2012 and May 2013. Sodium and potassium urinary excretion was assessed in a 24-h urine sample; creatinine excretion was used to exclude unlikely urine values. Food intake in the same period of urine collection was assessed using a 24-h dietary recall. The Food Processor Plus® was used to estimate sodium intake corresponding to naturally occurring sodium and sodium added to processed foods (non-discretionary sodium). Salt added during culinary preparations (discretionary sodium) was computed as the difference between urinary sodium excretion and non-discretionary sodium. The mean (standard deviation) urinary sodium excretion was 4220 (1830) mg/day, and 92% of the participants were above the World Health Organization (WHO) recommendations. Discretionary sodium contributed 60.1% of total dietary sodium intake, followed by sodium from processed foods (29.0%) and naturally occurring sodium (10.9%). The mean (standard deviation) urinary potassium excretion was 1909 (778) mg/day, and 96% of the participants were below the WHO potassium intake recommendation. The mean (standard deviation) sodium to potassium molar ratio was 4.2 (2.4). Interventions to decrease sodium and increase potassium intake are needed in Mozambique.

Background:The low accuracy of equations predicting 24-h urinary sodium excretion using a single spot urine sample contributed to the misclassification of individual sodium intake levels. The application of single spot urine sample is limited by a lack of representativity of urinary sodium excretion, possibly due to the circadian rhythm in urinary excretion. This study aimed to explore the circadian rhythm, characteristics, and parameters in a healthy young adult Chinese population as a theoretical foundation for developing new approaches.Methods:Eighty-five participants (mean age 32.4 years) completed the 24-h urine collection by successively collecting each of the single-voided specimens within 24 h. The concentrations of the urinary sodium, potassium, and creatinine for each voided specimen were measured. Cosinor analysis was applied to explore the circadian rhythm of the urinary sodium, potassium, and creatinine excretion. The excretion per hour was computed for analyzing the change over time with repeated-measures analysis of variance and a cubic spline model.Results:The metabolism of urinary sodium, potassium, and creatinine showed different patterns of circadian rhythm, although the urinary sodium excretion showed non-significant parameters in the cosinor model. A significant circadian rhythm of urinary creatinine excretion was observed, while the circadian rhythm of sodium was less significant than that of potassium. The circadian rhythm of urinary sodium and creatinine excretion showed synchronization to some extent, which had a nocturnal peak and fell to the lowest around noon to afternoon. In contrast, the peak of potassium was observed in the morning and dropped to the lowest point in the evening. The hourly urinary excretion followed a similar circadian rhythm.Conclusion:It is necessary to consider the circadian rhythm of urinary sodium, potassium, and creatinine excretion in adults while exploring the estimation model for 24-h urinary sodium excretion using spot urine.

The effects of intravenous infusion of ornithine-vasopressin (OVP) and desamino-D-arginine-vasopressin (dDAVP) were studied in normal and hydrated Merino sheep. In normal sheep, OVP resulted in a diuresis, increased urinary sodium and potassium excretion, and a fall in the plasma potassium concentration. Renal plasma flow remained constant but glomerular filtration rate and filtration fraction rose markedly. dDAVP in normal sheep was antidiuretic, but its only significant effect was a small decrease in plasma osmolality. In the hydrated sheep OVP was antidiuretic and resulted in increased urinary excretion of sodium and potassium, and a fall in the plasma potassium level. Renal plasma flow fell, but glomerular filtration and filtration fraction tended to rise. dDAVP in the hydrated sheep was also antidiuretic but urinary sodium and potassium excretion was reduced. Renal plasma flow and glomerular filtration fell, with a small decrease in filtration fraction. These results suggest that the diuretic effect in normal sheep and the electrolyte-excreting effects in both normal and hydrated sheep of OVP are related to the increase in glomerular filtration, which in turn is dependent on the vasopressor activity of the hormone. The increase in glomerular filtration caused by OVP is due to an increase in the filtration fraction of an unchanged renal plasma flow, which could be brought about by an increase in renal efferent arteriolar tone. The effects of hydration of the sheep were the conventional increased urine flow, decreased urine osmolality and decreased solute-free water reabsorption. Sodium and potassium excretion rose slightly and plasma osmolality fell. Renal plasma flow and glomerular filtration both increased with little change in filtration fraction. These effects could be brought about by suppression of endogenous vasopressin and a decrease in both afferent and efferent renal arteriolar tone.

The contribution of peripheral arterial chemoreceptors to cardiovascular and renal responses to acute hypocapnic hypoxia is currently not well understood. We compared the effects of normobaric hypoxia on mean arterial blood pressure (MABP), heart rate, glomerular filtration rate (GFR), renal blood flow (RBF), and renal volume and electrolyte excretion in conscious unilaterally nephrectomized carotid body-denervated (n = 10) and sham-operated (n = 10) control rats. Thirty minutes of normobaric hypoxia (12.5% O2) resulted in significant reductions in arterial PO2 and PCO2 as well as decreases in MABP, GFR, RBF, and renal sodium, potassium, and water excretion. These effects occurred more rapidly and/or were significantly more pronounced in carotid body-denervated than in sham-operated rats. These data indicate that moderate acute hypocapnic hypoxia has profound effects on systemic and renal hemodynamics as well as on renal excretory function in conscious rats. We conclude that stimulation of the peripheral arterial chemoreceptors can partially offset the hypoxia-induced decreases in MABP, RBF, GFR, urine flow, and urinary sodium and potassium excretion, thereby helping to maintain cardiovascular as well as fluid and electrolyte homeostasis.

Renal actions of the angiotensin AT 2 receptor ligands CGP 42112 and PD 123319 after blockade of the renin-angiotensin system

Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined. We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors. Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR. This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25(OH)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.

Renal effects of low-dose aminophylline and enprofylline in newborn rabbits

The aim of the study was to investigate the effects of percutaneous nephrolithotomy (PCN) and extracorporeal shock wave lithotripsy (ESWL) on renal function and urinary prostaglandin excretion. Twenty/ESWL patients and 20 PCN patients were studied pre-, 24 h and two weeks after treatment. Twenty-four hours after treatment PCN resulted in a fall in serum potassium, sodium and calcium. There was a small rise in urinary prostaglandin excretion. All results had returned to normal by two weeks. ESWL caused a rise in serum creatinine with a fall in calculated glomerular filtration rate (GFR). This was coupled with a fall in urinary excretion of sodium, potassium, and calcium. There was a rise in urinary prostaglandin excretion. Serum calcium and LDH levels also rose. All results had returned to normal by two weeks except urinary calcium excretion, and serum albumin had now fallen. ESWL had more effect on renal function in the acute phase of treatment than PCN.

Currently, more than half of the drugs in clinical use are chiral compounds. In many instances the enantiomers of chiral drugs demonstrate pronounced differences in biological activity, toxicology, pharmacokinetics, and metabolism. Administration of racemic U‐50,488, a highly selective chiral κ‐opioid receptor agonist, produces a marked sodium and potassium sparing diuresis (i.e. aquaresis), dysphoria, and analgesia in conscious rats. Though U‐50,488 enantiomers have been the subject of various behavioral and analgesic studies, there is a distinct lack of data pertaining to isomers and kappa induced aquaresis. Therefore, the aim of the present study was to pharmacologically characterize the renal excretory effects produced by the isolated (−)‐(1S,2S)‐U‐50,488 versus (+)‐(1R,2R)‐U50,488 enantiomers. Methods Male Sprague‐Dawley rats with an indwelling intracerebroventricular (ICV) cannula were surgically implanted with an arterial, venous, and bladder catheter and continuously infused intravenously (i.v.) with iso‐saline. After stabilization, mean arterial pressure (MAP), heart rate (HR), and urine flow rate (V) were measured in conscious rats for 20‐min before (control) and 90‐min after (experimental) ICV bolus injection (1 ug) of (−)‐(1S,2S)‐U‐50,488, (+)‐(1R,2R)‐U50,488, racemic (+/−)‐U‐50,488, or vehicle (n=6/group). Urine samples were analyzed for urinary sodium excretion (UNaV) and urinary potassium excretion (UKV). Results ICV injection of racemic U‐50,488 (1 ug) produced a significant diuretic (control (C), 56±6, 30‐min, 152±7 ul/min), antinatriuretic (C, 8.7±2.2, 30 min, 3.7±2 ueq/min), and antikaluretic (C, 1.1±0.5; 0.4±0.4 ueq/min) response. At the same dose, both the (−)‐(1S,2S)‐U‐50,488 and (+)‐(1R,2R)‐U50,488 isomers produced a significant sodium and potassium sparing diuresis without changing MAP or HR. At 1 ug, (−)‐(1S,2S)‐U‐50,488 significantly increased peak urine flow rate (C, 58±6 ul/min; 20 min 196±29 ul/min) and decreased urinary sodium (C, 8.9±2.3 μeq/min; 30 min 3.9±0.8 μeq/min) and potassium (C, 0.8±0.2 μeq/min, 30 min, 0.2±0.1 μeq/min) excretion. In contrast, 1 ug of (+)‐(1R,2R)‐U50,488 increased urine flow rate to a lessor magnitude (C, 57±6 ul/min; 10 min 119±26 ul/min) while decreasing urinary sodium excretion (C, 8.0±0.7 μeq/min, 30 min 4.3±1.5 μeq/min) but not urinary potassium excretion. ICV pretreatment (1ug, 10 min) with the kappa antagonist nor‐BNI abolished the kappa‐mediated diuresis by both enantiomers and racemic U‐50,488.ConclusionsThese results indicate (−)‐(1S,2S)‐U‐50,488 is the predominant isomer responsible for producing the centrally mediated aquaresis observed with racemic U‐50,488. Blockade of the aquaresis by ICV nor‐BNI indicates that both enantiomers mediate their renal excretory effects through activation of central kappa receptors. Further renal excretory studies are needed to fully elucidate the pharmacological variances between these two compounds and determine whether a selective entaniomer of U‐50,488 may be used therapeutically as a water diuretic.Support or Funding InformationNIH P30GM106392 (DRK)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The glomerular hemodynamic response to streptozotocin (STZ)-induced experimental diabetes differs depending on metabolic control and rat strain used. The present study characterize the glomerular filtration rate (GFR) and other renal parameters, weekly up to eight weeks of diabetes in STZ-diabetic Wistar Furth rats. The STZ-treated rats became diabetic within 24 h after treatment and retained a blood glucose concentration of 20-25 mmol/l throughout the experimental period. The GFR was transiently increased during the first 3-5 weeks after induction of diabetes, but thereafter did not differ from control animals. The renal weight increased by ~50% during the first week after induction of diabetes, thereafter no further increase in weight occurred. The urinary flow rate and urinary osmolar excretion were ~10 times higher in diabetic animals when compared to non-diabetic animals. Although they remained markedly higher than in non-diabetic animals, both the urinary flow rate and the urinary osmolar excretion peaked after 3 weeks of diabetes and thereafter tended to decrease. The urinary sodium and potassium excretions did not differ between non-diabetic and diabetic animals. We conclude that the transient increase in the GFR seen in the human disease, occurs in Wistar Furth rats, which is in contrast to a majority of other rat strains, where the GFR is persistently increased.

ABSTRACTBackgroundPotassium intake has been shown to be inversely associated with blood pressure and premature mortality. Previous studies have suggested that the association between potassium intake and blood pressure is modified by obesity, but whether obesity similarly influences the association between potassium intake and mortality is unclear.ObjectivesWe investigated whether potassium intake, reflected by 24-h urinary excretion, is associated with all-cause mortality, and explored potential effect modification by obesity.MethodsWe performed a prospective cohort study in community-dwelling individuals. The association between urinary potassium excretion and all-cause mortality was investigated by using multivariable Cox regression. We performed multiplicative interaction analysis and subgroup analyses according to BMI and waist circumference.ResultsIn 8533 individuals (50% male), the mean age was 50 ± 13 y, mean urinary potassium excretion was 71 ± 21 mmol/24 h, median BMI (in kg/m2) was 25.6 (IQR: 23.1, 28.4) and mean waist circumference was 89 ± 13 cm. During median follow-up of 18.4 (IQR: 13.5, 18.8) y, 1663 participants died. Low urinary potassium excretion (first compared with third sex-specific quintile) was associated with an increased mortality risk (fully adjusted HR: 1.38; 95% CI: 1.18, 1.61), P < 0.001, irrespective of body dimensions (HR range for all body dimensions: 1.36–1.70, all P < 0.05). High urinary potassium excretion (fifth compared with third quintile) was associated with increased mortality risk in participants with obesity (BMI ≥30; HR: 1.52; CI: 1.00, 2.30), but not in participants without obesity (BMI: <25; HR: 0.89; 95% CI: 0.62, 1.26; P-interaction = 0.001).ConclusionsLow potassium intake was associated with increased mortality risk in community-dwelling individuals. In individuals with obesity, high potassium intake was also associated with increased mortality risk.

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.

The influence of 1.0 Hz renal nerve stimulation (RNS) on the renal excretion of sodium and bicarbonate was determined in anesthetized dogs before and during inhibition of renal bicarbonate reabsorption. RNS decreased both urinary sodium and bicarbonate excretion without changing arterial pressure, renal blood flow, or glomerular filtration rate. Pharmacological blockade of bicarbonate reabsorption with acetazolamide prevented RNS-induced decreases in bicarbonate excretion and reduced the antinatriuretic response. Physiological blockade of tubular bicarbonate reabsorption with intrarenal sodium bicarbonate infusion (1 M) abolished both the antinatriuretic response to RNS and the decrease in bicarbonate excretion. This physiological blockade of neurogenic antinatriuresis resulted from alkalinization of the urine and/or peritubular blood rather than an increase in filtered sodium load, because during intrarenal infusion of 1 M sodium chloride RNS concomitantly decreased sodium and urinary bicarbonate excretion. Since antinatriuretic responses and the decrease in bicarbonate excretion response to RNS were significantly decreased by blockade of bicarbonate reabsorption (with acetazolamide and intrarenal sodium bicarbonate infusion), antinatriuresis during RNS is partly mediated by a mechanism dependent on intact bicarbonate reabsorption. The data suggest that renal nerve activity may participate in the normal regulation of acid-base balance via changes in bicarbonate excretion.