Atrial natriuretic peptide suppresses compensatory renal growth in rats.

Atrial natriuretic peptide (ANP) inhibits the growth of a variety of cell types in vitro including mesangial cells. The effects of ANP on the growth of the kidney in vivo were evaluated. A 2-h infusion of 0.2 microgram/250 g body wt per minute of ANP suppressed the subsequent uptake of [3H]thymidine into the renal DNA of uninephrectomized but not intact rats. This treatment also depressed the ratio of RNA/DNA in kidneys undergoing compensatory growth. Correlative physiologic studies revealed enhanced GFR in rats with two kidneys infused with ANP, but no increase in the GFR of uninephrectomized rats. It was concluded that ANP may oppose the growth factor(s) mediating compensatory renal growth.

Dietary fish oil interferes with renal arachidonic acid metabolism in rats: correlations with renal physiology.

Dietary fish oil has been reported to have both beneficial and deleterious effects in animal models of renal disease, which may be related to alterations in renal eicosanoid metabolism. The influence of dietary fish oil on glomerular and renal tubular responses that are linked to arachidonic acid metabolism was examined. Dietary fish oil had antidiuretic and antinatriuretic effects, which correlated with reduced renal cortical endogenous prostaglandin E2 (PGE2). Fish oil altered the renal balance of dienoic prostacyclin (PGI2) to thromboxane (TXA2) in favor of vasodilation, which may explain the observed exaggerated compensatory increases in glomerular function in response to uninephrectomy. Intact rats fed fish oil for 6 months developed proteinuria and impaired glomerular filtration rates (GFR). These deleterious effects were associated with evidence of increased renal lipid peroxidation. These results suggest that dietary fish oil modifies glomerular and renal tubular function in rats, and worsens age-associated proteinuria and declines in GFR. These effects may reflect the impact of dietary fish oil on renal fatty acid composition and arachidonic acid metabolism.

The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat.

We were able to confirm previous studies demonstrating that administration of thyroxine is capable of ameliorating the severity of acute nephrotoxic renal failure in the rat. Nephrotoxic acute renal failure was induced by the subcutaneous injection of potassium dichromate (6.25 mg/kg) into Sprague-Dawley rats. Twenty-four hours after this injection, rats received an intraperitoneal injection of either thyroxine (80 micrograms/kg body wt) or normal saline. Forty-eight hours after the potassium dichromate injection, renal clearance studies were performed. Inulin clearance was significantly higher in the thyroxine-treated than in the saline-treated acute renal failure rats: 1.12 +/- 0.13 (SEM) mL/g versus 0.75 +/- 0.07 mL/min/g kidney wt (P = 0.025). Thyroxine treatment also effected an increase of p-aminohippuric acid extraction from 0.23 +/- 0.03 to 0.33 +/- 0.02 (P = 0.011) and a decrease in the fractional excretion of sodium from 0.38 +/- 0.21 to 0.11 +/- 0.03% (P = 0.037 by Mann-Whitney U test). In order to investigate one potential mechanism of the beneficial effect of thyroxine we studied renal tubular regeneration in this model of acute renal failure. Renal cortical uptake of labeled thymidine into DNA was significantly increased 48 h after the injection of potassium dichromate, and thyroxine administration further enhanced this repair process: 53.9 +/- 3.6 versus 81.4 +/- 5.3 dpm/200 pg of DNA (P = 0.0033).

Effects of dietary fish oil on renal growth and function in uninephrectomized rats.

The basic mechanisms of renal growth remain poorly understood. The work hypertrophy theory holds that after an acute reduction in renal mass, the growth of the kidney occurs as a consequence of increased renal function. Pharmacological inhibition of renal prostaglandin synthesis impairs the acute adaptive increases in both renal function and mass following partial nephrectomy. The present study examines the effects of four weeks of dietary fish oil on renal growth, function and arachidonic acid metabolites in intact and uninephrectomized male Sprague-Dawley rats. Dietary fish oil interferes with dienoic prostaglandin and thromboxane production in favor of synthesis of trienoic analogues. Control animals were pair-fed an identical diet with the exception that the fat was replaced by beef tallow. Renal cortical concentrations of arachidonic acid metabolites were reduced in animals fed fish oil, and urinary excretion of prostaglandin E2 was impaired. Fish oil feeding resulted in increased kidney weight without concomitant increases in renal function in intact animals. Glomerular filtration rate and renal plasma flow were greater in uninephrectomized rats fed fish oil compared to uninephrectomized controls pair-fed beef tallow. Augmentation of the compensatory increases in renal function observed with fish oil feeding was not associated with any additional renal hypertrophy. These data indicate that dietary fish oil has a profound impact on renal growth and function, which may be the consequence of altered renal and/or extrarenal arachidonic acid metabolism. Furthermore, the direction of the alterations in renal mass oppose that of renal function, providing clear and unique evidence against the work hypertrophy theory of renal growth.

Nitrendipine protects against aminoglycoside nephrotoxicity in the rat.

Aminoglycoside nephrotoxicity is a common clinical problem among hospitalized patients despite close attention to pharmacokinetics and dosing schedules. The present study was designed to evaluate the potential protective effect of nitrendipine, a calcium channel blocker, on the natural history of gentamicin renal injury in the rat. Gentamicin was administered intramuscularly in a dose of 40 mg/kg/day for 12 days to adult Fischer rats. Nitrendipine was given by gavage on a b.i.d. schedule in a dose of 30 mg/kg/day or 10 mg/kg/day. Gentamicin alone caused a significant decrease in glomerular filtration rate (GFR) and renal plasma flow (RPF). Concurrent administration of nitrendipine did not influence RPF, but promoted a significant increase in GFR. Nitrendipine also prevented the increase in urinary excretion of N-acetyl-glucosaminidase and beta-glucosidase, enzymatic markers of renal tubular injury in the gentamicin-treated animals. Gentamicin-induced pathologic injury was significantly ameliorated by nitrendipine. Renal cortical gentamicin content was diminished, but not significantly, by nitrendipine. The exact mechanism of action of nitrendipine in aminoglycoside-induced renal injury remains unknown. These observations suggest a potential pharmacologic approach to preventing a common problem with substantial morbidity.

Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis.

Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from less than 1 to 11 ml/min. Cefamandole was given as a 1-g intravenous dose infused over 30 min. Cefamandole concentrations were determined in serum, urine, and dialysis fluid by a high-performance liquid chromatographic method. The following average parameter values were obtained (range): half-life, 6.1 h (4.6 to 9.7); systemic clearance, 21.9 ml/min (8.4 to 35.5); renal clearance, 11.5 ml/min (0.03 to 22.3); dialysis clearance, 0.92 ml/min (0.7 to 1.3); nonrenal clearance, 12.2 ml/min (2.9 to 27.0); volume of distribution, 0.18 liter/kg (0.09 to 0.25); steady-state volume of distribution, 0.17 liter/kg (0.09 to 0.24). Approximately 5% of the dose was dialyzed (range, 2.8 to 8.3), indicating that there is no need to supplement a dosing regimen of cefamandole due to loss by dialysis. There was a positive correlation between creatinine clearance and the terminal elimination rate constant of cefamandole (r2 = 0.41) and cefamandole renal clearance (r2 = 0.83).

Inhibition of compensatory renal growth by indomethacin.

Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E2 and 6-keto prostaglandin F1 alpha concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p less than 0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentrations (p less than 0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.

Dietary calcium deprivation and secondary hyperparathyroidism in patients treated with chronic dialysis.

In 33 patients with end-stage renal disease undergoing chronic dialysis, serum parathyroid hormone (PTH) levels were correlated with serum concentrations and dietary intakes of calcium and phosphate. The average dietary calcium intake (549 +/- 54 mg/24 h) was lower than the recommended dietary allowance. There was a weak correlation between serum PTH and serum calcium concentrations (r = 0.39, p less than 0.03). There was also a significant negative exponential relationship between dietary calcium intake and serum PTH (y = 162e-0.0016x, r = 0.61, p less than 0.002). Likewise, when divided into low calcium (less than 500, 304 +/- 27 mg/24 h) and modest calcium (greater than 500, 809 +/- 56 mg/24 h) intake groups, in the low calcium-intake group, serum PTH (128 +/- 20 pg/ml) was more than 2-fold greater than that in the modest calcium-intake group (53 +/- 8 pg/ml, p less than 0.003). These results suggest that low dietary calcium intake may contribute to the occurrence of secondary hyperparathyroidism in patients with chronic renal failure undergoing chronic dialysis.

The effects of diltiazem and captopril on glycerol-induced acute renal failure in the rat. Functional, pathologic, and microangiographic studies.

To evaluate the effects of pharmacologic vasodilatation on glycerol-induced acute renal failure, we studied untreated animals and those given Captopril and Diltiazem at periods ranging from 30 minutes to four weeks after the onset of acute renal failure. At each time frame, comparative coded assessments of renal function, histology, and microangiography were performed. Diltiazem, a calcium channel blocker, significantly reduced the severity of the renal failure, decreased the extent of tubular cell necrosis, and was associated with a more rapid histologic and functional recovery. Captopril, an angiotensin converting enzyme inhibitor, did not influence renal function or pathology throughout the four-week observation period. Microangiography revealed marked differences among the experimental groups. Most notably, there was better visualization of the microvasculature in Diltiazem-treated kidneys at one and two weeks. However, at four weeks, all groups showed similar, severe microangiographic abnormalities. Diltiazem offers significant protection against glycerol-induced acute renal failure in rats. Its mechanism of action in this context remains unknown. Renal function and pathology do not correlate well with microangiographic perfusion patterns in this model of acute renal failure.

The protective effect of nitrendipine on gentamicin acute renal failure in rats.

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.

Effects of aldosterone, methylprednisolone and triiodothyronine on the response to water loading in the conscious hypothyroid rat with diabetes insipidus.

The role of the antidiuretic hormone-independent mechanisms underlying the impairment of water excretion in hypothyroidism remains controversial. We examined the excretion of an oral water load (50 ml/kg b.w.) over a 3-hour period before and after the administration of aldosterone, methylprednisolone, both aldosterone and methylprednisolone, and triiodothyronine in 12 hypothyroid and 7 age-matched control Wistar rats of the homozygous Brattleboro strain (DI). Conscious animals were studied to circumvent the adverse influence of anesthetics and to facilitate the re-examination of the same animals. At baseline, the hypothyroid DI rats exhibited a marked impairment in their response to water administration. In comparison to control DI rats they had a lower urine volume, CH2O, CH2O/V and creatinine clearance, and higher urine osmolality (p less than 0.005-less than 0.001). Because of the possibility of decreased delivery of filtrate due to dehydration in the DI animals, a separate group of DI rats received saline in place of the water load. Despite improvement in urine flow with saline, CH2O generation remained decreased in the hypothyroid DI rats. Methylprednisolone increased both urine volume (p less than 0.001) and CH2O (p less than 0.001) in the hypothyroid group, but CH2O formation remained below the values obtained in the control animals. While aldosterone and methylprednisolone alone and in combination improved utilization of distally-delivered filtrate for the formation of CH2O (p less than 0.02-0.005), neither hormone, either alone or in combination, fully corrected the dilution defect. In contrast, the administration of triiodothyronine fully normalized all the observed abnormalities in the hypothyroid rats, suggesting that thyroid hormone deficiency is directly responsible for the abnormal water-excretion in experimental hypothyroidism.

Cimetidine disposition in patients undergoing continuous ambulatory peritoneal dialysis.

Cimetidine disposition was determined in six patients undergoing continuous ambulatory peritoneal dialysis to ascertain the need for modification of conventional dosing regimens. Blood, dialysis fluid, and urine were collected for 48 hours after administration of a single intravenous dose of cimetidine. The following values were obtained: elimination half-life, 4.3 hours; systemic or total body clearance, 191 +/- 55 ml/min; and dialysis clearance, 4.2 +/- 3.1 ml/min. Approximately 2% of a cimetidine dose is removed by dialysis, indicating that there is no need to adjust the conventional renal failure dosing regimen in patients undergoing continuous ambulatory peritoneal dialysis.

Digoxin-quinidine interaction in patients with chronic renal failure.

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

Mechanisms of hemodynamic actions of furosemide: differentiation of vascular and renal effects on blood pressure in functionally anephric hypertensive patients.

To differentiate diuretic and direct cardiocirculatory properties of furosemide for elucidation of the vasodepressor mechanisms of action of the agent in the acute treatment of hypertension, the peripheral vascular effects of intravenous furosemide (3 mg/kg) on supine blood pressure (BP) and forearm hemodynamics in 11 functionally anephric hypertensive patients (creatinine clearance less than 2 ml/min) were studied. BP was recorded by sphygmomanometer and forearm hemodynamics were measured by strain gauge plethysmography. While diastolic BP decreased only 2.7 mm Hg at 30 minutes, forearm blood flow increased 55% (p less than 0.01) mediated by decreased peripheral vascular resistance of 30% (p less than 0.01) at 15 minutes which dissipated by 30 minutes. Systolic BP, indices of venous capacity, weight, hematocrit, serum electrolytes, and plasma renin activity were unchanged. No diuresis occurred. It is concluded that the early hypotensive effect of furosemide depends upon diuresis.

Renal acidification in the hypothyroid rat. Evaluation by urinary CO2 tension.

We have previously demonstrated an abnormal renal response to chronic acid loading in the hypothyroid rat. The present study was designed to characterize further this defect by examining the renal response to bicarbonate loading. Hypothyroidism was induced by the intraperitoneal injection of Na131I and animals were studied 10 or more weeks thereafter under anesthesia and compared with their age-matched littermates. Insulin clearance of hypothyroid animals was lower and fractional urine flow and sodium excretion rates were higher than in the control rats. At the time of maximal urinary bicarbonate levels, the urine PCO2 exceeded blood values (U - B PCO2) by 41 plus or minus 2 (mean plus or minus SE) mmHg (1 mmHg equals 133.22 Pa) in the controls and 25 plus or minus mmHg in the hypothyroid rats (p less than 0.001). Although maximal urinary bicarbonate concentrations achieved during bicarbonate loading were lower in the hypothyroid animals. U - B PCO2 was consistently less in controls when compared at similar urine bicarbonate concentrations. Thus, the difference in U - B PCO2 was not explained by lower urinary bicarbonate concentrations in the hypothyroid animals. Maximal U - B PCO2 during neutral phosphate loading was significantly less in the hypothyroid rats (38 plus or minus 2 mmHg) than in the controls (68 plus or minus 5 mmHg), p less than 0.001, arguing against a gradient defect of distal hydrogen ion handling. These data indicate that hypothyroid rats exhibit an impairment of distal hydrogen ion secretion.

Effect of prostaglandin inhibitors on renal function in the hypothyroid rat.

The mechanisms of the abnormal renal tubular handling of sodium and water in hypothyroidism are still unexplained. Since prostaglandins (PG) have been shown to diminish the tubular reabsorption of both sodium and water, this study was undertaken to examine the possibility that the tubular abnormalities observed in hypothyroidism are prostaglandin mediated. Renal clearance studies were performed in rats before and after administration of two prostaglandin synthetase inhibitors. There was no significant difference in the PG-inhibitor induced absolute and percentage decrease of sodium and fluid excretion between the normal and hypothyroid rats during mild volume expansion. This indicates that prostaglandins are not responsible for the increased fractional sodium and water excretion in hypothyroid animals.

Impaired renal bicarbonate reabsorption in the hypothyroid rat.

We previously demonstrated a decrease of sodium reabsorption in the proximal superficial nephron of the hypothyroid rat. The present clearance studies were designed to examine the renal handling of bicarbonate in hypothyroid rats. Hypothyroidism was induced by the intraperitoneal injection of Na131I and the animals were studied 10 or more wk thereafter under anesthesia and compared to their age-matched litter-mates. As is characteristic of hypothyroid animals, insulin clearance was lower and fractional urine flow and sodium excretion rates were higher than in the control rats. At the peak of the bicarbonate diuresis and at similar blood pH, PCO2, and bicarbonate levels, fractional renal bicarbonate excretion was significantly higher in the hypothyroid animals: 22 +/- 2 vs. 15 +/- 1%, P less than 0.02. This perturbation of bicarbonate reabsorption of the hypothyroid rats was independent of the influence of extracellular fluid volume expansion and appears closely related to the impaired sodium reabsorptive capacity characteristic of experimental hypothyroidism.

Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.

A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4-wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5-, 25-, 50-, or 75-mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50- and 75-mg groups but not significantly in the 25-mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smaller initial diuretic doses may provide equal efficacy with fewer side effects for many patients.