Electrolyte Excretion Rates Research Articles

POS-390 ELECTROLYTE PROFILES OF LUPUS NEPHRITIS PATIENTS TREATED WITH THE NOVEL CALCINEURIN INHIBITOR VOCLOSPORIN

Electrolyte imbalances, which can be modulated within the kidney, have been previously reported with calcineurin inhibitor (CNI) utilization in solid organ transplant.1,2Dietary supplementation of electrolytes may correct serum electrolyte imbalances; therefore, it can be useful to evaluate urinary excretion over time to detect changes in electrolytes due to diet or to confirm clinical findings in serum. Voclosporin is a novel CNI approved in the US for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Data from the pivotal Phase 3 AURORA 1 study showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids results in higher complete renal response rates at one year (40.8% vs 22.5%; OR 2.65; p<0.0001) in patients with lupus nephritis. AURORA 1 was a double-blind, randomized controlled trial designed to evaluate oral voclosporin (23.7 mg twice daily) compared to placebo in patients with active lupus nephritis, with all patients receiving MMF (target dose 1 g twice daily) and low-dose oral steroids (rapidly tapered to 2.5 mg daily at week 16). Serum electrolyte imbalances including hypomagnesemia are common adverse events associated with CNIs. In contrast to these reports, mean serum electrolyte concentrations of patients treated with voclosporin were within normal ranges in AURORA 1. As serum electrolytes concentrations can be impacted by dietary supplementation, we evaluated urinary excretion rates to assess if inadvertent dietary supplementation during the study had impacted the findings in serum. Twenty-four-hour urine samples from 60 patients in each treatment arm were selected including patients that responded to treatment at one year with at least 50% reduction in urine protein creatinine ratio (UPCR) from baseline (treatment responders), those who had not (non-responders), and patients who had at least 30% reduction from baseline in estimated glomerular filtration rate (eGFR) during the study. Mean change from baseline to one year in magnesium, potassium and sodium are presented as 24-hour urinary electrolyte excretion rates. Mean changes from baseline in urinary electrolyte excretion were small for magnesium (≤13.4 mg/24 hours) and potassium (≤6.4 mmol/24 hours) with no significant differences between treatment arms for any of the subgroups. Sodium excretion decreased from baseline in all subgroups (≤30.5 mmol/24 hours) except for responders in the control arm (increase of 14.0 mmol/24 hours) at one year (Table 1). Patients with lupus nephritis in AURORA 1 treated with voclosporin in combination with MMF and low-dose steroids achieved significantly higher complete renal response rates compared to patients treated with only MMF and low-dose steroids. At the doses studied, changes from baseline in urinary electrolyte excretion of magnesium, potassium, and sodium were not clinically meaningful in either treatment arm regardless of response to treatment. These results confirmed dietary supplementation did not impact the findings in serum concentrations. Together with the reported normal electrolyte concentrations in serum, this study confirms voclosporin has no meaningful impact on mean concentrations of electrolytes. This analysis further supports the safety and efficacy of voclosporin for the treatment of patients with lupus nephritis.

Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy

Abstract Objectives The aim of the present study is to evaluate the diagnostic powers of fractional magnesium, sodium and potassium as markers of renal tubular damage in normotensive type 2 diabetes mellitus (T2DM) patients with respect to microalbuminuria and estimated glomerular filtration rate (eGFR). Materials and methods Forty healthy volunteers and 91 normotensive T2DM patients were included in the study. Patient group was divided into two according to albuminuria level; 49 were normoalbuminuric and 42 were microalbuminuric. In addition to albumin in urine, urine and serum Na, K, Mg and creatinine values were measured to calculate fractional electrolyte excretion rates. Results In normoalbuminuric and microalbuminuric groups, fractional excretion of magnesium (FEMg) values were found to be significantly higher than the control group (p &lt; 0.05). There was a moderate correlation between FEMg and albümin to cratinin ratio (ACR) (Spearman r = 0.3215, p &lt; 0.05). In the ROC analysis for eGFR and FEMg based on microalbuminuria, the areas under the curve were 0.625 and 0.732, respectively (diagnostic sensitivity 59.52% and 66.67%; specificity 70.79% and 77.53%, p &lt; 0.05). Conclusion For renal tubular damage predicted by microalbuminuria, FEMg could be accepted as a candidate biochemical marker with diagnostic and prognostic value.

Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes.

Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomerular filtration rate. or electrolyte excretion rates between the Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex-treated fetuses was significantly lower (12.9 ± 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 ± 1.0 nl/min). This resetting of TGF sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TGF sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TGF response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.

Oleanolic acid modulates the renin-angiotensin system and cardiac natriuretic hormone concomitantly with volume and pressure balance in rats

Oleanolic acid is known to possess beneficial effects on the regulation of the cardiovascular homeostasis. However, the exact nature of the role of oleanolic acid on the regulation of body fluid balance and blood pressure homeostasis and its mechanisms involved are not well defined. Experiments were performed to identify the effects of oleanolic acid on the renin-angiotensin system and cardiac natriuretic hormone (ANP) system, and also renal function and blood pressure in normotensive and renovascular hypertensive rats. The change in the plasma levels of hormones and the expressions of renin, angiotensin II receptors, ANP, natriuretic peptide receptor-C, M2 muscarinic receptor and GIRK4 were determined in the kidney, heart and aorta. Oleanolic acid was administered orally for 1 or 3 weeks. Here, we found that oleanolic acid suppressed plasma levels of renin activity and aldosterone and intrarenal levels of renin and angiotensin II type 1 receptor expression and increased angiotensin II type 2 receptor in normotensive and hypertensive rats. Also, oleanolic acid increased plasma levels of ANP. Further, oleanolic acid suppressed angiotensin II type 1 receptor and natriuretic peptide receptor-C expression and increased angiotensin II type 2 receptor and ANP expression in the heart and aorta. Along with these changes, oleanolic acid accentuated urinary volume, electrolyte excretion and glomerular filtration rate in normotensive rats and suppressed arterial blood pressure in hypertensive rats. These findings suggest that beneficial effects of oleanolic acid on the cardiorenal system are closely associated with its roles on the renin-angiotensin system and cardiac natriuretic hormone system.

Real-time urinary electrolyte monitoring after furosemide administration in surgical ICU patients with normal renal function.

BackgroundAlthough the loop-diuretic furosemide is widely employed in critically ill patients with known long-term effects on plasma electrolytes, accurate data describing its acute effects on renal electrolyte handling and the generation of plasma electrolyte alterations are lacking. We hypothesized that the long-term effects of furosemide on plasma electrolytes and acid–base depend on its immediate effects on electrolyte excretion rate and patient clinical baseline characteristics. By monitoring urinary electrolytes quasi-continuously, we aimed to verify this hypothesis in a cohort of surgical ICU patients with normal renal function.MethodsWe retrospectively enrolled 39 consecutive patients admitted to a postoperative ICU after major surgery, and receiving single low-dose intravenous administration of furosemide. Urinary output, pH, sodium [Na+], potassium [K+], chloride [Cl−] and ammonium [NH4+] concentrations were measured every 10 min for three to 8 h. Urinary anion gap (AG), electrolyte excretion rate, fractional excretion (Fe) and time constant of urinary [Na+] variation (τNa+) were calculated.ResultsTen minutes after furosemide administration (12 ± 5 mg), urinary [Na+] and [Cl−], and their excretion rates, increased to similar levels (P < 0.001). After the first hour, urinary [Cl−] decreased less rapidly than [Na+], leading to a reduction in urinary AG and pH and an increment in urinary [NH4+] (P < 0.001). Median urinary [Cl−] over the first 3-h period was higher than baseline urinary and plasmatic [Cl−] (P < 0.001). During the first 2 h, difference between FeCl− and FeNa+ increased (P < 0.05). Baseline higher values of central venous pressure and FeNa+ were associated with greater increases in FeNa+ after furosemide (P = 0.03 and P = 0.007), whereas higher values of mean arterial and central venous pressures were associated with a longer τNa+ (P < 0.05). In patients receiving multiple administrations (n = 11), arterial pH, base excess and strong ion difference increased, due to a decrease in plasmatic [Cl−].ConclusionsLow-dose furosemide administration immediately modifies urinary electrolyte excretion rates, likely in relation to the ongoing proximal tubular activity, unveiled by its inhibitory action on Henle’s loop. Such effects, when cumulative, found the bases for the long-term alterations observed. Real-time urinary electrolyte monitoring may help in tailoring patient diuretic and hemodynamic therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-016-0168-y) contains supplementary material, which is available to authorized users.

Temporally Relationship between Renal Local Clock System and Circadian Rhythm of the Water Electrolyte Excretion

To investigate the relationship of the circadian rhythm of the urine volume and urine electrolytes excretion rate and the daily expression pattern of the clock genes and clock-controlled genes with the water electrolyte transportation circadian pattern in rat kidneys. Male adult SD rats were exposed to in a light:dark (12:12) cycles. We collected two period urine from zeitgeber time (ZT)00:00-ZT12:00 (light time,rest period) and ZT12:00-24:00 (dark time,activity period) and then compared the urinary excretion rates of volume, sodium, potassium, and chloride at light time with those at dark time. Rats were sacrificed every 4 hours throughout a 24-hour day-night cycle. Circadian clock gene CLOCK, BMAL1,Per1,Per2,Cry1,Cry2 and kidney specific clock-controlled gene NHE3,αENaC、NCC,Ptges,V1aR,V2R expression were profiled by real-time quantitative polymerase chain reaction. Data were analysed by a partial Fourier analysis and a stepwise regression technique. Urine volume and urine potassium excretion rate displayed high level at dark time and low at light time in SD rats (P<0.05),and urine sodium and chloride excretion rate also showed the trend(P>0.05).Clock gene CLOCK,BMAL1,Per1,Per2,Cry1,Cry2(P<0.05)and kidney specific clock-controlled gene NHE3, αENaC, NCC, Ptges, V1aR, V2R (P<0.05)mRNA expression showed circadian pattern,and the peak times of the genes were in the dark time. Urine volume and urine electrolyte excretion rate which displayed circadian pattern were temporally coupled with the rhythm of expression of clock and clock-controlled genes associated with water electrolyte transportation in rats kidney.

Changes in Renal Function and Oxidative Status Associated with the Hypotensive Effects of Oleanolic Acid and Related Synthetic Derivatives in Experimental Animals.

PurposeThe triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present study we to compared the effects of the triterpene on mean arterial blood pressure (MAP) and kidney function following acute administration in normotensive animals with those of its related oleanane synthetic derivatives (brominated oleanolic acid, Br-OA and oleanolic acid methyl ester, Me-OA). We also used experimental models of hypertension to further explore the effects of sub-chronic oral OA treatment and evaluated influences on oxidative status.MethodsOA was extracted from dried flower buds of Syzygium aromaticum using a previously validated protocol in our laboratory. Me-OA and Br-OA were synthesized according to a method described. Rats were supplemented with lithium chloride (12 mmol L-1) prior to experimentation in order to raise plasma lithium to allow measurements of lithium clearance and fractional excretion (FELi) as indices of proximal tubular Na+ handling. Anaesthetized animals were continuously infused via the right jugular with 0.077M NaCl. MAP was measured via a cannula inserted in the carotid artery, and urine was collected through a cannula inserted in the bladder. After a 3.5 h equilibration, MAP, urine flow, electrolyte excretion rates were determined for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods. OA, Me-OA and Br-OA were added to the infusate during the treatment period. We evaluated sub-chronic effects on MAP and kidney function in normotensive Wistar rats and in two animal models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DSS) rats, during 9-week administration of OA (p.o.). Tissue oxidative status was examined in these animals at the end of the study. Increasing evidence suggests that and renal function disturbances and oxidative stress play major roles in the pathogenesis of hypertension.ResultsAcute infusion OA and oleanane derivatives displayed qualitatively similar effects in decreasing MAP and increasing urinary Na+ outputs. The drugs increased the FENa and FELi without influencing GFR indicating that at least part of the overall natriuretic effect involved proximal tubular Na+ reabsorption. Sub-chronic OA administration (p.o.) also elicited hypotensive responses in Wistar, DSS and SHR rats. The MAP lowering effect was more marked in hypertensive animals and were positively correlated with increased urinary Na+ excretion. Compared with respective control rats, OA treatment reduced malondialdehyde (MDA, a marker of lipid peroxidation) and increased activities of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues.ConclusionsOA and oleanane derivatives have similar effects on MAP, kidney function and oxidative stress. The amelioration of oxidative stress and blood pressure lowering effects by OA are more marked in hypertensive animals and correlated with an increased urinary Na+ output.Novelty of the WorkThe results of this study are novel in that they show 1) a correlation between blood pressure reduction and increased urinary Na+ excretion by OA, 2) a more marked MAP reduction in hypertensive animals and 3) a drug-induced decrease in proximal tubule Na+ reabsorption. The results may also be clinically relevant because OA is effective via oral administration.

Sodium and potassium intake in Hungarian children and adolescents: Comparison of two cross sectional studies

The purpose of the study was to assess the sodium and potassium intake among Hungarian children and adolescents. The study was undertaken to estimate daily sodium and potassium intake by measuring 24-h urinary electrolyte excretion rate in 200 Hungarian children (age 1–18 years). Daily sodium and potassium intake positively correlated with age, body mass index, and systolic blood pressure. As a result of the parallel trend and time course of urinary sodium and potassium excretion the sodium to potassium ratio, the important risk factor for essential hypertension remained practically unchanged with age. We did not find a significant difference in this ratio between hypertensive and normotensive, or obese and non-obese children. Sodium and potassium intake expressed per kilogram body weight decreased steadily with age, but there was no significant difference between boys and girls. When adjustment was made for age and body mass index, using multivariate regression analysis, the systolic blood pressure proved to be independent of urinary sodium excretion and daily potassium intake. Compared with Dietary Reference Intake values, the present study demonstrates that, on average, Hungarian children and adolescents have a diet rich in sodium, and poor in potassium, although during the last 20 years a favourable trend can be detected.

Water and electrolyte imbalance in patients with metabolic syndrome

Considering the high incidence of renal impairment in metabolic syndrome (MS), an analysis of electrolyte metabolism was performed in 112 patients preoperatively and 53 patients postoperatively. Aldosterone level, adrenocorticotropic hormone level, neutrophil gelatinase-associated lipocalin level, cortisol level, β 2 -microglobulin level, serum vasopressin level, urinary microalbumin level measurements were taken as a combined patient assessment procedure. MS patients were found to demonstrate a decrease in circadian amounts of urea, potassium, sodium and chlorides excretion. An increase in vasopressin production and an enhancement of microalbumin excretion were detected. The specified disturbances developed as «a vicious circle»: fluid retention resulted in heperfiltration, with renal dysfunction leading to a deteriorated hydro-electrolyte imbalance. An improvement of circadian electrolyte excretion rates, as well as a decline in vasopressin and cortisol levels, occurred due to a reduction of abdominal fat volume.

Effects of Supplemental Recombinant Bovine Somatotropin (rbST) and Cooling with Misters and Fans on Renal Function in Relation to Regulation of Body Fluids in Different Stages of Lactation in Crossbred Holstein Cattle

The aim of this study was to investigate the effect of supplemental recombinant bovine somatotropin (rbST) and cooling with misters and fans on renal function in relation to regulation of body fluids in different stages of lactation in crossbred Holstein cattle. Ten, 87.5% crossbred Holstein cattle were divided into two groups of 5 animals each, housing in a normal shaded barn (NS) and in a shaded barn with a mister-fans cooling system (MF). The experiment in each group was divided into 3 phases, early- (Day 75 postpartum), mid- (Day 135 postpartum), and late stage of lactation (Day 195 postpartum). The pre-treatment study was conducted on the starting day of each stage of lactation and the treatment study was performed after the end of the pre-treatment, during which the animal was injected with 500 mg of rbST (POSILAC) every 14 days for three times. During the study, ambient temperature at the hottest period daily in the MF barn was significantly lower, while relative humidity was higher than that of the NS barn. The temperature humidity index (THI) in both barns ranged from 79-85 throughout the periods of study. Cows in the MF barn showed a lower rectal temperature and respiration rate as compared with cows in the NS barn. The effect of rbST administration increased both rectal temperature and respiration rates of cows housed in either the NS or MF barn. Milk yield significantly increased in cows treated with rbST in all stages of lactation. Increases in mammary blood flow, accompanied by increases of total body water (TBW), extracellular fluid (ECF), blood volume (BV) and plasma volume (PV), were observed in both groups of cows receiving rbST in all stages of lactation. No alterations of renal blood flow and glomerular filtration rate were observed in cows receiving rbST, but decreases in urinary excretion and fractional excretion of sodium, potassium and chloride ions appeared to correlate with reduction in the rate of urine flow and osmolar clearance during rbST administration. These results suggest that the effect of rbST supplementation to cows housed either in NS or MF barns on body fluid volume expansion is attributable to changes in the rate of electrolyte excretion by the kidney. The increased availability of renal tubular reabsorption of sodium, potassium and chloride ions during rbST treatment was a major factor in retaining body water through its colligative properties in exerting formation of an osmotic force mechanism.

Circadian Blood Pressure Classification Scheme and the Health of Patients with Chronic Kidney Disease

Background: In health, a sinusoidal rhythm is observed in systolic blood pressure (BP) that peaks (acrophase) during the waking hours (in-phase), but in those with chronic kidney disease (CKD) the acrophase is often observed during sleeping hours (out-of-phase). Yet in others the amplitude of the variation may be so blunted that acrophase may not be definable (phase-less). Circadian rhythms in systolic BP are often described by the dichotomous dipper classification but may not be adequate to fully characterize derangements in cyclical variation in BP. Methods: To compare classification of circadian BP variation by phase-based classification to dipper-status we examined the cross-sectional relationship of these classification patterns to several markers of health such as health-related quality of life (Kidney Disease Quality of Life Survey, KDQOL) and physical activity (actigraphy over 2 weeks). We also assessed the relationship of circadian BP variation with circadian variation in urine electrolyte and albumin excretion rates. Results: Among 103 veterans with CKD (97% men, age 69, diabetes mellitus 30%, eGFR 38.8 ml/min/1.73 m2) no differences were seen between dippers and non-dippers (n = 77, 75%) in eGFR, urinary Na and Cl excretion rates, or KDQOL. However, non-dippers had lower levels of physical activity and greater albuminuria compared to dippers. The same patients were classified to be in-phase (n = 36, 35%), phase-less (n = 19, 18%) or out-of-phase (n = 48, 47%). Patients in-phase had a higher eGFR and somewhat surprisingly also had the highest Na and Cl excretion rates compared to others. Those with out-of-phase systolic BP had the lowest physical composite score on KDQOL, the lowest level of physical activity, and the greatest amount of albuminuria. Conclusions: Among patients with CKD, circadian BP profile described by either dipper-based or phase-based classification is related to the level of physical activity and the severity of kidney damage. The circadian BP profile is related to overall health and nutritional intake only when using the phase-based classification. The value of these classification schemes to profile circadian BP will require longitudinal studies.

Effects of Persea americana Mill (Lauraceae) (avocado) ethanolic leaf extract (PAE) on blood glucose and kidney function in streptozotocin (STZ)-induced diabetic rats and on kidney cell lines of the proximal (LLC-PK1) and distal tubules (MDBK)

Extracts of Persea americana Mill (Lauraceae) ("Avocado") have been traditionally used to treat hypertension and diabetes mellitus. Accordingly, we studied the hypoglycaemic and renal function effects of P. americana leaf ethanolic extracts (PAE) in STZ-induced diabetic rats. Oral glucose tolerance responses to various doses of PAE were monitored in fasted rats following a glucose load. Rats treated with deionized water or standard hypoglycaemic drugs acted as untreated and treated positive controls, respectively. Acute renal effects of PAE were investigated in anesthetized rats challenged with 0.077 M NaCl after a 3.5-h equilibration for 4 h comprising 1 h control, 1.5 h treatment and 1.5 h recovery periods. PAE was added to the infusate during the treatment period. Hepatic glycogen concentration was measured after 6 weeks of daily treatment with PAE. PAE induced dose-dependent hypoglycaemic responses in STZ-induced diabetic rats while subchronic PAE treatment additionally increased hepatic glycogen concentrations. Acute PAE infusion decreased urine flow and electrolyte excretion rates, whilst subchronic treatment reduced plasma creatinine and urea concentrations. These results indicate not only the basis of the ethnomedicinal use of P. americana leaf extract in diabetes management, but also of need for further studies to identify and evaluate the safety of PAE's bioactive compounds.

Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure

Gitelmańs syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1,000,000, in Sweden, suggesting that approximately 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.

Urotensin II and renal function in the rat

Urotensin II (UII) is a potent vasoactive hormone in mammals. However, despite its well-known effects on epithelial sodium transport in fish, little is known about its actions on the mammalian kidney. The aim of this study was to determine the effects of UII on renal function in the rat. Using standard clearance methods, the effects of rUII and the rat UII receptor (UT) antagonist, urantide, were studied. UII was measured in plasma and urine by radioimmunoassay. UII and UT were localized in the kidney by immunohistochemistry and mRNA expression quantified. Rat urinary [UII] was 1,650-fold higher than that in plasma. Immunoreactive-UII was localized to the proximal tubules, outer and inner medullary collecting ducts (IMCD); UT receptor was identified in glomerular arterioles, thin ascending limbs, and IMCD. UII and UT mRNA expression was greater in the medulla; expression was higher still in spontaneously hypertensive rats (SHRs) associated with raised plasma (UII). Injection of rUII induced reductions in glomerular filtration rate (GFR), urine flow, and sodium excretion. Urantide infusion resulted in increases in these variables. Endogenous UII appears to contribute to the regulation of GFR and renal sodium and water handling in the rat. While hemodynamic changes predominate, we cannot rule out the possibility of a direct tubular action of UII. Increased expression of UII and UT in the SHR suggests that UII plays a role in the pathophysiology of cardiovascular disease.

Effect of dietary protein on electrolyte excretion in the mouse

Consuming either high or low protein content significantly affects kidney function. Ingesting a low protein (LP) diet impairs the kidney's ability to concentrate the urine and induces water diuresis whereas a high protein (HP) diet increases GFR, enhances the concentrating mechanism, and on the long-term, enlarges the kidney. Physicians prescribe LP diets for patients with chronic renal disease. HP diets have proven useful for treating obesity. Given the principle role of the kidney to control electrolyte homeostasis, the effect of dietary protein on electrolyte excretion requires investigation. Our purpose was to determine the effects of HP and LP diets on Na, K, and Ca excretion. Three groups of mice (n=4 each group) were placed in metabolic cages for 20 days and consumed 40%, 20%, or 6% casein (HP, normal-NP, LP, respectively) and water ad libitum. The protocol contained three periods. Mice consumed NP diet for the first five days. Two groups then consumed either HP or LP diet for the next ten days and returned to the NP diet for the final five days. Daily measurements included body weight, food and water intake, urine volume and osmolality, urine Na, K, and Ca levels. Data below show the average excretion (mEq/day) during the 10-day experimental period. No differences existed in the control period, i.e., the first five days. We conclude that LP diet increases Na, K, and Ca excretion whereas HP diet increases Ca excretion. LP diet induced water diuresis which likely caused high electrolyte excretion rates. HP diet produced osmotic diuresis and likely stimulated Na and K transport, but not Ca.

Icatibant has no impact on renal function in healthy subjects

The role of bradykinin (BK) in renal regulations is still controversial. To elucidate whether Icatibant, a potent BK antagonist on B2 receptors, can interfere with renal function under normal conditions, we performed sinistrin and para-aminohippurate (PAH) clearances, plasma levels and excretion rate of electrolytes, albumin, urate, endogenous lithium, as well as plasma renin, aldosterone and endothelin in 14 healthy males under Icatibant infusion. Part I (2 panels of 4 subjects) compared single 4h infusions (0.005 to 0.8 mg/kg) in ascending, double-blind, placebo-controlled design. Part II tested renal function on the 3rd day of a 72h Icatibant or placebo infusion, in a 2-way crossover, double blind design. No changes in glomerular filtration rate (sinistrin), renal blood flow (PAH), or in proximal renal tubular function (lithium and urate clearances) were detected. Sodium, potassium and chloride excretions, micro-albuminuria, urinary volume, and hematocrit remained unchanged. Vital signs (supine and orthostatic blood pressure, heart rate), body weight, and hormone concentrations were also unaltered. The safety and tolerability of Icatibant was excellent. This study had enough power to detect physiologically significant effects but not even trends for changes in renal function could be suspected. In conclusion, these results strongly advocate against a physiological role of BK in the regulation of renal function under normal conditions. Clinical Pharmacology & Therapeutics (2004) 75, P57–P57; doi: 10.1016/j.clpt.2003.11.215

Considerations for the evaluation of renal function in genetically engineered mice.

Transgenic and gene-targeting techniques have opened a new era of physiologic investigation: the field of functional genomics. The nearly exclusive use of the mouse in this discipline has necessitated the development and adaptation of sophisticated techniques for evaluating murine physiology at the cellular, tissue, organ and whole animal levels. Although many of the methodologies for exploring cardiorenal function have been successfully adapted from their use in the rat, there are important limitations and considerations that must be recognized when applying them in the mouse. Investigators have been successful in measuring a wide variety of functional variables at the whole kidney and even single nephron levels. Reviewed here are recent advances in the measurement of blood pressure, renal blood flow, whole kidney electrolyte excretion and clearance rates, single-nephron glomerular filtration rate and transport, and tubuloglomerular feedback.

Furosemide Compounds Enhance Urinary Excretion of Active Kallikrein Independently of Their Effects on Urinary Electrolyte Excretion

The chemical and diuretic effects of furosemide on the excretion and activation of urinary prokallikrein were investigated in rats by treatment with furosemide compounds with a range of diuretic activity or amiloride hydrochloride or the vehicle. Diuresis occurred with furosemide and benzyl furosemide, but not with isofurosemide, amiloride hydrochloride, or the vehicle. The urinary excretion rate of active kallikrein was significantly elevated above controls throughout the 72 h of treatment with all of the drugs tested, regardless of the level of diuresis or the rate of urinary electrolyte excretion. In contrast, the urinary excretion rate of total kallikrein (prokallikrein + active kallikrein) was unchanged in all groups. These data indicate that furosemide derivatives increase the activation, but not the excretion, of urinary prokallikrein and that these effects are unrelated to the chemical structure or diuretic activity of the compounds or to overall changes in urinary electrolyte excretion rates.

The effect of infusion of hypertonic saline on glomerular filtration rate and arginine vasotocin, prolactin and aldosterone in the domestic chicken.

Domestic fowl were infused for 60 min with isotonic saline followed by 90 min with hypertonic saline. Plasma electrolyte concentrations, osmolality and haematocrit were measured. Urine electrolyte excretion rates, osmolar output and urine flow rates were also monitored. From these results fractional excretions of electrolytes were calculated. The renal function markers inulin and rho-amino hippuric acid were infused to enable the measurement of glomerular filtration rate and plasma clearance of rho-amino hippuric acid, respectively. Plasma samples were also taken to assay for the hormones prolactin, aldosterone and arginine vasotocin. Plasma electrolytes and osmolality, fractional excretion of electrolytes and osmolar output all increased, while haematocrit decreased, throughout the experiment. However, no significant change was found in urine flow rate and little change was seen in glomerular filtration rate. The clearance of rho-amino hippuric acid, which provides an indication of renal plasma flow, increased during hypertonic saline infusion. Plasma concentrations of aldosterone and prolactin decreased during the experiment and plasma concentrations of arginine vasotocin increased. Infusion of hypertonic saline had no consistent effect on glomerular filtration rate, which may be due to conflicting influences of expansion of the extracellular fluid volume and increased plasma osmolality.

Role of Neutrophils and Macrophages in Experimental Nephrosis of the Rat

The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxlline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p <. 01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/ cytotoxic T-cells (0×8+), in kidneys of rats given either treatment compared with PAN control rats. In summary, both pentoxflline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role ofpentoxlline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.