Renal function tests: what do they mean? A review of renal anatomy, biochemistry, and physiology.
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Renal physiology, biochemistry, and anatomy are reviewed. For the most part, those aspects of these disciplines will be discussed which relate directly to the question of the evaluation of nephrotoxicity. In addition, emphasis is placed on those procedures and techniques which are useful in the evaluation of nephrotoxicity. A detailed discussion of histological and anatomical considerations is not given, since this is probably the least useful criterion for evaluation of renal damage. This information is intended as background for the remainder of the symposium which will be directed toward an understanding of specific nephrotoxicity phenomena. (+info)
Effect of fasting on temporal variation in the nephrotoxicity of amphotericin B in rats.
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Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of N-acetyl-beta-D-glucosaminidase and beta-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (P < 0.05) in fasting rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also significantly higher (P < 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (P < 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (P < 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats. (+info)
Mechanism for the posture-specific plasma volume increase after a single intense exercise protocol.
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To test the hypothesis that exercise-induced hypervolemia is a posture-dependent process, we measured plasma volume, plasma albumin content, and renal function in seven healthy subjects for 22 h after single upright (Up) or supine (Sup) intense (85% peak oxygen consumption rate) exercise. This posture was maintained for 5 h after exercise. Plasma volume decreased during exercise but returned to control levels by 5 h of recovery in both postures. By 22 h of recovery, plasma volume increased 2.4 +/- 0.8 ml/kg in Up but decreased 2.1 +/- 0.8 ml/kg in Sup. The plasma volume expansion in Up was accompanied by an increase in plasma albumin content (0.11 +/- 0.04 g/kg; P < 0.05). Plasma albumin content was unchanged in Sup. Urine volume and sodium clearance were lower in Up than Sup (P < 0.05) by 5 h of recovery. These data suggest that increased plasma albumin content contributes to the acute phase of exercise-induced hypervolemia. More importantly, the mechanism by which exercise influences the distribution of albumin between extra- and intravascular stores after exercise is altered by posture and is unknown. We speculate that factors associated with postural changes (e.g., central venous pressure) modify the increase in plasma albumin content and the plasma volume expansion after exercise. (+info)
P2 purinoceptor saturation by adenosine triphosphate impairs renal autoregulation in dogs.
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Recent studies have suggested a role for P2 purinoceptors on vascular smooth muscle cells in the mechanism of renal autoregulation. Experiments were performed in anesthetized dogs (n = 9) to examine renal blood flow (RBF) autoregulatory efficiency before and after saturation of P2 purinoceptors with acute intra-arterial administration of ATP (1 mg/kg per min). Dogs were pretreated with the nitric oxide synthase inhibitor nitro-L-arginine (NLA) (50 microg/kg per min), to avoid endothelial P2 receptor-mediated effects on nitric oxide release caused by the intra-arterial ATP infusions. NLA treatment decreased RBF (5.3+/-0.3 to 3.6+/-0.2 ml/min per g) and sodium excretion (3.6+/-0.4 to 0.9+/-0.2 ml/min per g) without producing significant changes in GFR (0.92+/-0.04 to 0.90+/-0.06 ml/min per g) or RBF autoregulatory efficiency. ATP administration to NLA-treated dogs resulted in further decreases in RBF (2.8+/-0.2 ml/min per g), GFR (0.58+/-0.05 ml/min per g), and sodium excretion (0.6+/-0.2 micromol/min per g). In addition, there was marked impairment of RBF autoregulatory efficiency during ATP infusion. The slopes of the arterial pressure-blood flow relationships at renal arterial pressures of >75 mmHg were significantly altered, from 0.003+/-0.001 to 0.2+/-0.002 ml/min per g per mmHg. Discontinuation of ATP infusion restored RBF autoregulatory efficiency. Norepinephrine (5 microg/kg per min) administration in these NLA-treated dogs decreased RBF (2.5+/-0.3 ml/min per g; n = 4) to a similar extent, compared with ATP, but did not impair RBF autoregulation. These results support the hypothesis that P2 purinoceptors may be involved in mediating autoregulatory adjustments in renal vascular resistance. (+info)
Role of xanthine oxidase in passive Heymann nephritis in rats.
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Passive Heymann nephritis (PHN) in rats is a model of human membranous nephropathy characterized by formation of subepithelial immune deposits in the glomerular capillary wall and complement activation. Oxygen radicals have been implicated in the subsequent glomerular damage which leads to proteinuria. This study examines the involvement of xanthine oxidase in this process. Xanthine oxidase activity was increased nearly twofold in glomeruli isolated 1 and 12 d after induction of PHN, and this was associated with increased glomerular superoxide anion generation. Analysis of glomerular samples by Northern and Western blotting revealed no quantitative changes in xanthine oxidoreductase expression in PHN, suggesting conversion of xanthine dehydrogenase to the oxidase form as the cause of increased activity. Treatment of rats with tungsten, an inhibitor of xanthine oxidase, before induction of PHN resulted in a marked decrease in glomerular xanthine oxidase activity and superoxide anion generation, and decreased proteinuria by 80% (day 12: 423+/-245 mg/d in PHN versus 78+/-53 mg/d in tungsten-treated PHN animals, P < 0.01). These findings point to a pivotal role of xanthine oxidase in the pathophysiology of PHN and could be of importance in the therapy of human membranous nephropathy. (+info)
Renal function in high-output heart failure in rats: role of endogenous natriuretic peptides.
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The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2+/-1.1 microl/min versus 27.5+/-3.1 microl/min with vehicle, P < 0.001) and in HS-142-1-treated shunted rats (8.1+/-1.3 microl/min versus 19.9+/-2.3 microl/min with vehicle, P < 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6+/-0.3 ml/min versus 2.1+/-0.4 ml/min with vehicle, P < 0.05) and after an acute volume load (1.2+/-0.4 ml/min versus 2.6+/-0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure. (+info)
Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease.
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Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD. (+info)
Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.
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One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency (F: per week), duration (T: min per treatment), and blood/dialysate flow rates (QB/QD: ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and beta2-microglobulin (beta2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, QB = 350, QD = 600; B (daily/short-time): F = 7, T = 100, QB = 350, QD = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, QB = 300, QD = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates (G) for U, Cr, and beta2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and beta2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and beta2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; beta2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (beta2M). The following conclusions can be made: (1) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. (2) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and beta2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes. (+info)