Osmolar Clearance Research Articles

Effects of supplemental recombinant bovine somatotropin and mist-fan cooling on the renal tubular handling of sodium in different stages of lactation in crossbred Holstein cattle

The effect of supplementary administration of recombinant bovine somatotrophin (rbST) on the renal tubular handling of sodium in crossbred 87.5% Holstein cattle housed in normal shade (NS) or mist-fan cooled (MF) barns was evaluated. The cows were injected with 500mg rbST at three different stages of lactation. The MF barn housed cows showed a slightly decreased ambient temperature and temperature humidity index, but an increased relative humidity. Rectal temperature and respiration rates were significantly lower in cooled cows. The rbST treated cows, housed in NS or MF barns, showed markedly increased milk yields, total body water, extracellular fluid and plasma volume levels, along with a reduced rate of urine flow and urinary excretion of sodium, potassium and chloride ions and osmolar clearance, in all three stages of lactation. Renal tubular sodium and water reabsorption were increased after rbST administration without any alteration in the renal hemodynamics. Lithium clearance data suggested that the site of response is in the proximal nephron segment, which may be mediated via increases in the plasma levels of aldosterone and IGF-1, but not vasopressin, during rbST administration.

Renal function and endocrine responses to arm exercise in euhydrated individuals with spinal cord injury

This study investigated the renal and endocrine responses to arm exercise in persons with spinal cord injury (SCI) under euhydration conditions (ad libitum drinking of water) and determined the physiological effects of exercise on renal function in these subjects. Eleven SCI (spinal lesions between T6 and L1, American Spinal Injury Association impairment scale A) and 14 able-bodied (AB) persons first rested for 1h in a sitting position, before undergoing 2-h arm-crank ergometer exercise at 60% of maximum oxygen consumption followed by a 2-h recovery period. On another day, all subjects participated in a time control study (5h of rest condition in sitting position). Urine and blood samples were collected hourly. There were no differences in mean blood pressure between the two groups. SCI patients showed attenuated increase in plasma adrenaline and increase in plasma aldosterone compared with AB controls, but similar changes in human atrial natriuretic polypeptide, plasma renin activity and plasma antidiuretic hormone following the exercise. Creatinine clearance, osmolal clearance, free water clearance and fractional excretion of Na(+) did not change during exercise in any of the subjects. These findings suggested that activated aldosterone and attenuated adrenaline responses during exercise in SCI could be due to adaptation to disordered sympathetic nervous system triggered to maintain renal function. The results showed no exercise-related adverse effects on renal function in hydrated subjects with SCI.

Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease

Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

The Significance of a Serum Creatinine in Defining Renal Function in Seriously Injured and Septic Patients

Most current analyses of multiple organ failure after injury use the serum creatinine (SCr) as a surrogate for defining renal insufficiency (RI) or renal failure (RF). This study correlates SCr with glomerular filtration rate, renal perfusion, and renal excretion in injured and septic patients. The 289 injured patients were in shock for an average of 32 minutes and received an average of 13.9 transfusions by the end of the operation. The 34 septic patients were in shock for an average of 23 minutes and received 8.4 crystalloid during operation. The renal studies included (SCr), inulin clearance (CIn), and creatinine clearance (CCr), renal plasma flow (CPAH), renal blood flow, and the clearance of sodium (CNa++), osmolar clearance (COsm), and urine output. All clearance studies followed the classic methodologies described by Homer Smith, including weight-guided leading dose, steady-state serum levels, and urine collections made exactly 15 minutes after serum collections. The average SCr in 289 trauma and septic patients was 1.23 mg/dL and 1.3 mg/dL, respectively. The average CCr was 106 mL/min and 103 mL/min, whereas the average CIn was 96 mL/min and 95 mL/min, respectively. The CIn correlated (p<0.0005) with CCr in all patients, whereas the CIn was lower than CCr due to the tubular excretion of creatinine. For the group of patients with RI (CIn between 10 and 30 mL/min) and nonoliguric RF (CIn<10 mL/min), the average CCr was 3.1. Other values in this subgroup included an average CCr 23.6 mL/min, CIn 14.6 mL/min, CPAH 69.9 mL/min, renal blood flow 138 mL/min, CNa 0.7 mL/min, COsm 1.5 mL/min, and urine output 1.4 mL/min. Although nephrectomy in 15 of 36 patients with renal injury or death in 21 patients was associated with a higher SCr, the relationship between SCr and renal function studies remained the same as with survivors and patients without renal injury. The best SCr value for defining RI was 2.4 mg/dL and for RF was 3.1 mg/dL. Based on these findings, one can recommend that when SCr data are extracted from large trauma registries, the definition of RI should be inferred when the SCr exceeds 2.4 mg/dL, and RF should be diagnosed when the SCr exceeds 3.1 mg/dL.

Clinical study on desmopressin acetate therapy in patients with adipsic hypernatremia: Five cases report

Objective Adipsic hypernatremia is very rare in clinical practice and only a few cases have been reported so far. Since the pathogenesis of adipsic hypernatremia is unclear, therapeutic method is very limited and uncertain. We previously found the existence of partial central diabetes insipidus in the patient with adipsic hypernatremia according to a series of clinical studies. In this clinical study, we observed the response of vasopressin in the treatment of adipsic hypernatremia as a routinely used agent in treating central diabetes insipidus.Methods Five patients with chronic sustained hypernatremia and hypodipsia were diagnosed as adipsic hypernatremia according to the criteria by Halter. After testing plasma electrolytes, urinary osmolality, plasma osmolality, and free water clearance (CH2O);with evaluating thirsty grade and anterior pituitary function, patients were forced to drink water 2 000-2 500 ml each day combined with prednisone and/or levethyroxin supplementation therapy if hypopituitarsm was revealed. One week later, since the hypernatremia was unrelieved, desmopressin acetate (0.05-0.2 mg/d)was administered to those 5 patients. About 5-7 days later, plasma electrolytes, urinary and plasma osmolality, and free water clearance ( CH2O ) were reevaluated. Osmolality was detected by the method of freezing point depression and thirst grade by the method of visual analogue scales. Results The plasma sodium was 160-190 mmol/L and plasma osmolality was 330-370 mmoL/L without thirsty perception during the hospitalization. Four of the five patients were revealed to be suffering from hypopituitarism, but the hypernatremia could not be corrected by intentional water intake combined with prednisone treatment. After administering vasopressin 0.05-0.2 mg/d to these patients, that hypernatremia was relieved, and hyperosmolality and hypodypsia were improved effectively. During this period of time, no side effects were detected in these patients. Conclusion We testified the existence of central partial diabetes insipidus in the patients with adipsic hypernatremia. Desmopressin acetate in the treatment of adipsic hypernatremia is proved to be effective, simple, and safe. Key words: Adipsic hypernatremia; Central diabetes insipidus; Therapy; Vasopressin

Relationship between the amount of fluid ingestion and renal concentrating ability during heavy exercise in the heat

This study examined whether the prevention of body mass loss during exercise in the heat by fluid ingestion would attenuate the decline in renal concentrating ability. Seven untrained subjects performed 105 min of intermittent exercise (15 min of exercise alternating with 3 min of rest) on a cycle ergometer at 70% VO2max(32°C and 60% RH). Subjects were tested under four conditions: (1) no fluid ingestion (NF), (2) ad libitum fluid ingestion (AF), (3) fluid ingestion equal to 1% of body mass (1% FL), (4) fluid ingestion equal to 2% of body mass (2% FL). Fluid was ingested immediately before exercise and at 15, 33, 51, 69 and 87 min of exercise in AF, 1% FL and 2% FL. Urine and blood samples were taken before and after exercise. During NF, AF, 1% FL and 2% FL, body mass loss was 2.2±0.1%, 1.1±0.2%, 1.1±0.1%, 0.1±0.1%, respectively. Total sweat loss was approximately 2% of body mass in all trials. Urine flow rate during exercise was 0.3±0.0, 0.4±0.1, 0.4±0.1, 0.5±0.1 ml/min during NF, AF, 1% FL and 2% FL, respectively, and was lower (p&lt;0.05) than the pre-exercise level in NF and AF. Urine to serum osmolality ratio in 2% FL was higher (p&lt;0.05) during exercise than the pre-exercise level. Creatinine clearance decreased (p&lt;0.05) in all trials, and was higher (p&lt;0.05) in 2% FL than in NF. Osmolar clearance was lower (p&lt;0.05) during exercise than the pre-exercise level in NF, AF and 1% FL, and was higher (p&lt;0.05) in 2% FL than in NF. Free water clearance increased (p&lt;0.05) during exercise than the pre-exercise level in NF, AF and 1% FL, and was lower (p&lt;0.05) in 2% FL than in NF. During exercise, 2% FL resulted in a concentrated urine production. Fluid ingestion in amounts equal to body mass loss at approximately 2% reduction in body mass is capable of attenuating the decline in renal concentrating ability during heavy exercise in the heat.

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.

Long-Term EGF Treatment Partially Prevents Reduction of Renal Blood Flow in Response to Neonatally Induced Partial Unilateral Ureteral Obstruction

Background/Aims: To investigate the effects of long-term epidermal growth factor (EGF) treatment on kidney growth, renal blood flow (RBF), AQP2 expression and urine output in newborn rats with partial unilateral ureteral obstruction (PUUO). Methods: PUUO (n = 29) and sham-operated control (CON) (n = 26) was created in 2-day-old rats. Fifteen PUUO and 14 CON rats were treated with EGF beginning from the second day after operation to 8 weeks of age. Total kidney volume (TKV) and RBF were measured by MRI at weeks 4 and 8, respectively. Urine volume and osmolality, plasma osmolality, and free water clearance were measured. Renal AQP2 expression was determined using semiquantitative immunoblotting. Results: PUUO induced a severe hydronephrosis and RBF reduction in the obstructed kidney which was attenuated in EGF-treated rats. Body weight, urine output and free water clearance increased, osmolality and the osmolar clearance decreased significantly in EGF-treated rats, despite unchanged AQP2 levels. Conclusions: Long-term EGF treatment attenuated the obstruction- induced RBF reduction. Body weight, urine output increased, and urine osmolality decreased in both control and PUUO rats treated with EGF. Solute-free water clearance increased in PUUO rats which seem to be independent of AQP2 expression.

Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease

Background. Antagonists of relevant Gs protein-coupled and agonists of relevant Gi protein-coupled receptors lower renal cAMP and inhibit growth of renal cysts in animal models of human ARPKD (PCK rat) and/or ADPKD (Pkd2−/WS25 mouse). A calcium-sensing receptor (CaR) is expressed in various tubular segments and couples to Gq, thereby activating phospholipase Cγ, InsP3 generation and calcium mobilization from intracellular stores, and Gi proteins. By both mechanisms, CaR activation could lower intracellular cAMP and inhibit renal cyst growth.Methods. PCK rat and Pkd2−/WS25 mouse littermates were fed rodent chow without or with R-568, a type 2 calcimimetic, at a concentration of 0.05% or 0.1% between 3 and 10 or 16 weeks of age. Histomorphometric analysis was performed with Meta-Morph software. Western analysis and immunohistochemical staining were performed using antibodies for aquaporin-2, urea transporter UT-A1 and CaR. Northern blot hybridization was used to quantify the expression of vasopressin V2 receptor and aquaporin 2 mRNAs. Cyclic AMP was measured using an enzyme immunoassay kit.Results. R-568 had no effect on kidney weight, cyst volume, plasma BUN concentration or severity of the polycystic liver disease. A significant reduction in renal interstitial fibrosis was detected in PCK rats, but not in Pkd2−/WS25 mice. R-568 administration, as anticipated, resulted in hypocalcemia and hyperphosphatemia, and significant increases in urine output, osmolar clearance, and urinary excretions of sodium, potassium and calcium.Conclusions. CaR activation had no detectable effect on cystogenesis in models of autosomal recessive or dominant polycystic kidney disease. The lack of protective effect could be due to the absence of CaR in the outer medullary and cortical collecting ducts, the reduction in extracellular calcium and the unaffected levels of renal cAMP and renal expression of cAMP-dependent genes. A possible beneficial effect on interstitial fibrosis deserves further study at more advanced stages of the disease.

Renal effects of aspirin are clearly dose‐dependent and are of clinical importance from a dose of 160 mg

High doses of aspirin counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. It is not known how low-dose aspirin, with concomitant ACE-inhibitor treatment, affects renal function. To study renal effects of different doses of aspirin in elderly healthy volunteers who had an activated renin-angiotensin system. Sixteen subjects each received two different doses of aspirin (0 and160 mg or 80 and 320 mg) after pre-treatment with bendroflumethiazide and enalapril, in a randomised double-blind, cross-over fashion. Least square means of the observations 30 to 180 min after dosing, showed that urine flow, GFR, excretion rates of sodium, osmolality clearance and free water clearance were significantly decreased in a dose-dependent manner. Urine flow, sodium excretion rate and free water clearance were significantly lower with 320 mg aspirin vs. 0 mg and 80 mg, and GFR was significantly lower with 320 mg vs. 80 mg. Urine flow, sodium excretion rate, free water and osmolality clearance was significantly lower with aspirin 160 mg vs. 0 mg. The dose-dependent renal effects of aspirin are of clinical importance from a dose of 160 mg. The adverse influence of aspirin doses higher than 80 mg should be taken into consideration in patients with heart failure.

Pharmacologic Vasopressin Levels May Protect Renal Function in a Porcine (Sus Scrofa) Model of Vasodilatory Septic Shock

Acute renal failure commonly occurs with severe sepsis and is associated with high mortality. Pharmacologic administration of vasopressin (VP) increases urine output in septic shock. To elucidate the mechanism by which pharmacologic VP induces diuresis, VP was administered at a low dose of 10 and a high dose of 100 ng/kg/min to piglets with endotoxin‐induced septic shock. VP‐100 produced a 4‐fold increase in urine flow (0.05 ± 0.02 vs. 0.23 ± 0.04 ml/kg/min), creatinine clearance, and filtration fraction compared to VP‐10 while the mean arterial pressure (MAP), delta MAP, and renal blood flow were similar between the groups. High dose VP demonstrated increased osmolar clearance (0.07 ± 0.05 vs. 0.21 ± 0.13 ml/kg/min), Na excretion, and fractional excretion (FE) of sodium (2.04 ± 0.83 vs. 4.51 ± 0.57) despite an increase in aldosterone and no change in renin levels. There was no change in the FE of urea or potassium between groups. The production of dilute urine was evidenced by increased free water clearance (−0.02 ± 0.01 to 0.03 ± 0.02 ml/kg/min), decreased urine osmolality (415 ± 21 vs. 282 ± 22 mOsm/kg H2O), and decreased urine protein (5.3 ± 0.87 vs. 1.9 ± 0.54 mg/ml) observed in the high but not low dose of VP. Thus at high dose VP, the increase in the filtration fraction and the FENa which lead to an increased excretion of dilute urine suggest a tubular osmotic mechanism that may be renal protective in septic shock.

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (C(Na)), lithium clearance (C(Li)), osmolal clearance (C(Osm)), and urine sodium concentration (U(Na)) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 +/- 19 versus 92 +/- 25 mL/min, P < 0.005) and in the R group (31 +/- 19 versus 41 +/- 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in C(Na) (0.89 +/- 0.21 versus 1.52 +/- 1.45 mL/min, P < 0.05), C(Li) (17.3 +/- 8.9 versus 21.5 +/- 11.6 mL/min, P < 0.05), and C(Osm) (2.10 +/- 0.81 versus 3.06 +/- 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in C(Na) (0.11 +/- 0.18 versus 0.35 +/- 0.40 mL/min, P < 0.05) and C(Li) (5.5 +/- 4.2 versus 9.5 +/- 8.55 mL/min, P < 0.05). U(Na) increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients.

Treatments with losartan or enalapril are equally sensitive to deterioration in renal function from cyclooxygenase inhibition

The beneficial effects of angiotensin converting enzyme (ACE)-inhibitors are in part mediated through the inhibition of the degradation of the vasodilator bradykinin. The bradykinin effect is counteracted by cyclooxygenase-inhibitors. Angiotensin receptor blockers (ARBs) do not affect bradykinin. To test the hypothesis that renal counteraction from a cyclooxygenase-inhibitor, diclofenac, is different in subjects treated with an ACE-inhibitor, enalapril compared with an ARB, losartan. Twelve elderly, healthy, slightly over-hydrated subjects received diclofenac orally after pre-treatment with a diuretic, bendroflumethiazide, and enalapril or bendroflumethiazide and losartan, in a double-blind cross-over fashion, with a wash-out period of at least 1 week. Diclofenac reduced GFR significantly from 81(64-98) ml/min at first observations after dose for enalapril to 29(16-42) and from 76(64-88) after losartan to 35(24-46). There was no significant difference between enalapril and losartan in GFR. Diclofenac induced decreases in urine flow, excretion rates and clearances of sodium, osmolality clearance and free water clearance, irrespective of treatment with enalapril or losartan. However, serum potassium and handling of potassium were significantly lower after losartan-treatment. The negative renal effects of diclofenac administration in subjects with activation of the renin-angiotensin system and enalapril treatment are the same in subjects with activation of the renin-angiotensin system and losartan treatment.

Indomethacin decreases furosemide-induced natriuresis and diuresis on the neonatal kidney

Indomethacin is used to pharmacologically occlude patent ductus arteriosus in preterm infants. It induces renal untoward effects and furosemide is administered simultaneously to counteract them. The effect of furosemide is blunted by indomethacin. We analyzed comparatively the interactions of furosemide and indomethacin at the organic anion transport system in adult and newborn individuals. Adult and 5-day-old Wistar rats were allocated into three groups: (1) indomethacin (10 mg/kg, ip); (2) furosemide (2 mg/kg, ip); and (3) indomethacin/furosemide, at the same doses. Urinary flow, glomerular filtration rate (GFR), sodium and potassium fractional excretions, and free-water and osmolal clearances were estimated. Para-aminohippuric acid (PAH) uptake was measured in renal cortical slices to study the organic anion's secretory pathway. In adult and newborn rats, furosemide-induced increments in urinary fluxes and excretions of sodium and potassium were blunted by indomethacin administered simultaneously. PAH uptake was decreased to a further extent by indomethacin than by furosemide, suggesting that inhibition of the diuretic effect might be related to competition in the secretion of furosemide. Inhibitory interaction between indomethacin and furosemide was achieved at approximately 10-fold lower concentrations in the newborn than in the adult rats, suggesting that tubular secretion in the neonate is more sensitive to the action of these drugs than in the adult individual.

Alpha-tocopherol protects against the renal damage caused by potassium dichromate

Exposure to hexavalent chromium (Cr 6+) causes mutagenic, carcinogenic, and toxic effects, some of which have been associated with its oxidative capacity. In the kidney, Cr 6+ has been claimed to provoke necrosis of the proximal tubular cells. Our aim was to assess the functional involvement of the different segments that form the nephron in a model of acute renal failure caused by potassium dichromate and the participation of oxidative damage in this process. We also studied the possible protective effect of α-tocopherol (α-TOC) against renal damage. Wistar female rats 200 g body weight (bw) received potassium dichromate (15 mg/kg, sc, single dose). Lipid peroxidation and renal function were evaluated on days 0, 1, 2, 3, 7, 10, and 14. A second group received α-TOC (125 mg/kg, by gavage) 5 days before and during dichromate exposure (same dose as for the first group), and was monitored at 0, 2, and 7 days of exposure. Creatinine clearance, glucose and sodium fractional excretions, p-aminohippurate uptake, free-water and osmolal clearances were also measured. Thiobarbituric acid-reactive substances were quantified in renal cortex. The results revealed altered proximal tubule function, decreased glomerular filtration, and distal segment dysfunction, accompanied by oxidative damage 48 h after exposure to dichromate. In the α-TOC-treated group proximal reabsorptive and secretory functions were preserved, suggesting that oxidative damage is a participating mechanism in dichromate toxicity on these functions. In contrast α-TOC did not prevent glomerular or distal dysfunction, indicating selectivity of the protection afforded by this compound on the toxicity of dichromate, at the several components of the nephron.

Reduced water and sodium intakes associated with high levels of natriuretic factor following common bile duct ligation in the rabbit

Renal failure complicating obstructive jaundice (OJ) is probably linked to reduction of the extracellular water compartment. To elucidate the mechanism by which OJ leads to isotonic water depletion we studied a group of rabbits with OJ after common bile duct ligation (n = 17) and another group of sham operated rabbits (n = 14) for 10 days. Water intake and balance for two study periods (1-4 and 7-10 days after operation) were calculated. Renal function, sodium balance and plasma atrial natriuretic factor were determined on the fourth and tenth days after operation. Water intake and balance were lower in the OJ group both in the first study period (230 versus 519 ml/days 1-4, P less than 0.001; and -2.4 versus 219 ml/days 1-4, P less than 0.0001 respectively) and in the second study period (260 versus 865 ml/days 7-10, P less than 0.0001; and 11 versus 379 ml/days 7-10, P less than 0.0001 respectively). Sodium intake was negligible in the OJ group both on day four (0.73 versus 7.15 mM/24 h, P less than 0.0001) and on day 10 (0.78 versus 15.78 mM/24 h, P less than 0.0001). As a result plasma osmolality did not change. Day 10 urine osmolality and osmolar clearance were reduced in the OJ group (653 versus 1103 mOsm/kg, P less than 0.0001 and 0.09 versus 0.25 ml/min, P less than 0.0001 respectively) together with a decreased creatinine clearance (3 versus 11 ml/min, P less than 0.0001). Atrial natriuretic factor was increased in jaundiced rabbits (day 4, 22.7 versus 7.5 fmol/ml, P less than 0.0001; and day 10, 26.5 versus 11.2 fmol/ml, P less than 0.02). These findings suggest that OJ leads to an isotonic volume depletion resulting from abnormalities of the extracellular volume regulating mechanisms. These appear to be secondary to an inappropriate elevation of the atrial natriuretic factor plasma concentration.

Cyclooxygenase inhibition causes marked impairment of renal function in elderly subjects treated with diuretics and ACE‐inhibitors

Treatment with angiotensin-converting enzyme (ACE)-inhibitors is known to cause an initial reduction in glomerular filtration rate (GFR) in patients with congestive heart failure. The long-term beneficial effects of ACE-inhibitors in these patients can be counteracted by cyclooxygenase-inhibitors. To quantify the negative renal effects of the cyclooxygenase-inhibitor diclofenac in elderly healthy subjects and to assess how treatment with an ACE-inhibitor, after activation of the renin-angiotensin system, influences these renal effects. Fourteen elderly, healthy subjects received oral diclofenac and placebo in a double-blind cross-over fashion. The study was divided in two parts; in part one, subjects received no pre-treatment and in part two, the subjects were given pre-treatment with bendroflumethiazide and enalapril in order to activate the renin-angiotensin system. Diclofenac induced significant (p<0.05) decreases in GFR, urine flow, excretion rates of sodium and potassium, electrolyte clearance, osmolality clearance and free water clearance both with and without renin-angiotensin system activation. Least square means (95% CI) of all observations during the first 6 h after dosing showed that diclofenac caused a reduction in GFR from 71 (64-78) to 59 (52-66) ml/min. After pre-treatment, diclofenac further reduced GFR from 60 (52-67) to 48 (40-55) ml/min. After diclofenac administration, urine flow fell from 7.4 (6.4-8.3) to 5.1 (4.2-6.1) ml/min, after pre-treatment, diclofenac gave a further reduction from 4.1 (3.1-5.1) to 2.2 (1.3-3.2) ml/min. More than half of the reductions were caused by the pre-treatment. Renal function in elderly, healthy subjects is impaired after acute intake of diclofenac. This impairment is observed both with and without activation of the renin-angiotensin system and ACE-inhibitor treatment but is more pronounced after pre-treatment.

Urinary nitrite excretion and urinary variables in patients with primary nocturnal frequency of micturition: effects of indomethacin suppositories

Urinary nitrite excretion was measured in patients with primary nocturnal frequency of micturition (PNFM) and in normal individuals. Effects of indomethacin suppository on urine volume and other urinary variables were evaluated. The study comprised seven patients with PNFM and seven healthy control (age range 30-45 years). Nitrite was assayed in spot morning urine samples; urine volume, urine osmolality and electrolytes, serum osmolality and electrolytes and functional bladder capacity (FBC) were assayed. Both groups were then given 100 mg of indomethacin suppository daily for a maximum of 10 days and urinary variables were re-evaluated during day 10. Results showed that urinary nitrite excretion of patients with PNFM was greater than that of the normal subjects (230+/-62 umol/l vs. 42+/-30 umol/l, P<0.05). The mean (SD) 24 h urine volume and osmolality, the night urine volume and osmolality, serum osmolality, FBC, creatinine clearance, fractional excretion of sodium (FENa), fractional excretion of potassium (FEK), and urinary excretion of glucose and potassium were lower in patients with PNFM as compared with normal individuals, although not statistically significantly so, except for FBC that was significantly lower in the patients. Urinary excretion of sodium, calcium, chloride, phosphorus, magnesium, day-night urinary volume ratio, spot morning osmolality, nocturnal index, and nocturnal polyuria index were higher in patients with PNFM. Indomethacin decreased the 24 h urinary volume by 21%, creatinine clearance by 12%, osmolar clearance by 14% and urinary protein excretion by 38% in the patients. These variables decreased by 26, 45, 17 and 12% respectively in the healthy subjects, whereas 24 h urinary protein excretion increased mildly by 9%. Indomethacin increased day-night urinary volume ratio by 73% in the healthy subjects. It might be concluded that urinary nitrite excretion, urinary excretion of sodium, chloride, phosphorus, calcium, and magnesium increased and FBC decreased in patients with PNFM; Indomethacin decreased urinary volume, FENa, FEK, osmolar clearance, and free water clearance in the healthy subjects and the patients. These might explain the mechanism of action of indomethacin to reduce frequency of voiding. The possible interaction of prostaglandin and NO in the pathogenesis of PNFM is discussed.

Programmed syndrome of hypernatremic hypertension in ovine twin lambs

An increased risk of adult hypertension, obesity, and coronary heart disease occurs in low birth weight or intrauterine growth-restricted newborn infants as a result of fetal programming. Human twins represent a natural model of low birth weight and intrauterine growth restriction because they are significantly smaller at birth than singleton infants because of both earlier delivery and reduced intrauterine growth. Increased blood pressure has been reported in several epidemiologic studies of human twin offspring, although this has not been confirmed in an animal model. Because the sheep pregnancy consists of singleton and twin litters, we sought to determine the impact of ovine twin gestation and twin nursing on the cardiovascular and renal function of the offspring. Newborn lambs (n = 12) were studied at 21 +/- 2 day of life. Both singleton (n = 6) and twin lambs (n = 6) were born to ewes provided ad libitum water and food throughout gestation. After the delivery, ewes were provided ad libitum water and food, and newborn lambs were allowed ad libitum nursing with the maternal ewe. At 15 +/- 2 days of age, the lambs were prepared with vascular and renal catheters and studied at 21 +/- 2 days. After a 2-hour basal period, lambs received an intravenous infusion of hypotonic (0.075 mol/L) NaCl (0.15 ml/kg/hr) for an additional 2 hours. Newborn arterial blood pressure, heart rate, and urine flow were monitored continuously, and arterial blood samples were obtained before, during, and after the infusion. At birth, twin lambs weighed 30% less than singleton lambs (3.5 +/- 0.1 kg vs 5.0 +/- 0.2 kg; P < .05), although 50% less at 21 days (5.2 +/- 0.6 vs 10.8 +/- 1.2 kg). There were marked differences in basal arterial blood values between twin and singleton lambs at 21 days, with twins having significantly increased plasma sodium and systolic, diastolic, and mean arterial pressures and reduced glomerular filtration rates, urine osmolality, osmolar excretion, and osmolar clearance (per kg body weight) compared with singleton lambs. In response to hypotonic saline solution infusion, the plasma composition and blood pressure differences between twin and singleton lambs persisted. These results indicate that ovine twin gestation and nursing markedly reduced body weight at 21 days of age, with evidence of plasma hypernatremia, hypertension, and reduced glomerular filtration rates, which persisted throughout hypotonic saline solution infusion. Consistent with epidemiologic studies of humans, these results demonstrate that gestational/newborn nutrient stress may program hypertension in offspring.

Oxygen Therapy Improves Renal Function in Patients with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) may cause edema independently of cardiac function. This study assessed the effects of oxygen therapy in renal hemodynamics and excretion of sodium and water in COPD patients. Twelve COPD patients without cor pulmonale (PaO2≤ 60 mmHg), aged 66 ± 9 years, were studied before and after 72 h of O2 therapy. Oxygen increased PaO2 from 56 ± 4 to 85 ± 22 mmHg (p< 0.0001), whereas PaCO2 did not change significantly. Oxygen induced significant increments in glomerular filtration rate (90 ± 21 to 111 ± 36 mL/min/1.73 m2, p = 0.03), sodium filtered load (10 ± 3 to 12 ± 5 mEq/min, p = 0.004), sodium excreted load (79 ± 67 to 194 ± 106 mEq/day, p = 0.0006), fractional excretion of sodium (0.51 ± 0.49 to 1.30 ± 1.32%, p = 0.015) diuresis (1048 ± 548 to 1893 ± 440 mL/day, p = 0.002), osmolar clearance (1.43 ± 0.7 to 2.08 ± 0.6 mOsm/min, p = 0.008) and decreased hematocrit (48 ± 4 to 44 ± 3%, p = 0.0038). Renal plasma flow and filtration fraction did not change after oxygen. In summary, use of oxygen caused increases of 36% in GFR, 35% in filtered load of sodium, 118% in diuresis, 258% in excreted load of sodium, and 178% in fractional excretion of sodium. These data suggest that oxygen-induced natriuresis and diuresis were likely more dependent of changes in the tubular manipulation of sodium than in glomerular hemodynamics. These changes occurred with a mild increase in PCO2, showing that oxygen therapy caused renal improvement independently of amelioration of hypercapnia.