Response of insulin-like growth factor I and renal hemodynamics to a high- and low-protein diet in the rat

An increase in plasma insulin-like growth factor I (IGF-I) levels by growth hormone injection or IGF-I infusion can raise renal plasma flow and glomerular filtration rate. However, it is not known whether a more physiological stimulus for IGF-I will also increase IGF-I in the kidney and whether the increase in renal or serum IGF-I is correlated with the increase in renal plasma flow and glomerular filtration rate. Male rats were pair fed either a high-protein (36% protein, N = 9) or a low-protein but isocaloric diet (9% protein, N = 9) for 10 to 14 days. Renal plasma flow and glomerular filtration rate were then estimated by clearance measurements, and IGF-I was measured in extracted serum, liver, renal cortical tissue, and glomeruli. Body weight gain and combined kidney weight were higher in high-protein rats as compared with low-protein animals (0.86 +/- 0.02 SEM versus 0.77 +/- 0.02 g/100 g body wt; P less than 0.05), but liver weights were not different. Serum, liver, and glomerular IGF-I levels were also higher in the high-protein rats as compared with the low-protein animals (serum, 1.12 +/- 0.03 versus 0.80 +/- 0.06 U/mL, P less than 0.05; liver, 183 +/- 17 versus 117 +/- 16 mU/g wet wt, P less than 0.05; glomeruli, 7.43 +/- 0.73 versus 4.81 +/- 0.59 mU/mg of protein, P less than 0.05). In contrast, the renal cortical IGF-I levels were not different in high-protein versus low-protein rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide: a potential mediator of amino acid-induced renal hyperemia and hyperfiltration

The role of nitric oxide in the modulation of systemic and renal hemodynamics was examined by using N omega-monomethyl-L-arginine (L-NMMA, 110 micrograms/kg/min), a competitive inhibitor of the conversion of L-arginine to nitric oxide. L-NMMA or saline vehicle (9.6 microL/min) was infused intravenously into anesthetized euvolemic Munich-Wistar rats. After 30 min, L-NMMA resulted in a uniform increase in mean arterial blood pressure (111 +/- 1 to 128 +/- 2 mmHg; P less than 0.05) and a modest reduction in renal plasma flow rate (4.4 +/- 0.2 to 4.2 +/- 0.1 mL/min; P less than 0.05), without change in glomerular filtration rate (1.16 +/- 0.03 to 1.15 +/- 0.03 mL/min); vehicle had no effect on these renal parameters. These rats were then subdivided to receive an intravenous infusion (37 microL/min) of either 10% glycine, 11.4% mixed amino acids, or equiosmolar dextrose. L-NMMA pretreatment markedly attenuated glycine-induced hyperfiltration (10 +/- 6 versus 33 +/- 5%, L-NMMA versus vehicle; P less than 0.05) and obliterated the renal hyperemic response (-7 +/- 6 versus 16 +/- 4%, L-NMMA versus vehicle; P less than 0.05). L-NMMA also caused modest blunting of the mixed amino acid-induced hyperfiltration (18 +/- 4 versus 30 +/- 4%, L-NMMA versus vehicle; P = 0.056) but failed to curtail the renal hyperemia (16 +/- 6 versus 20 +/- 4%). Dextrose had no effect on glomerular filtration rate or renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of aging on glomerular hemodynamics in the rat.

Glomerular hemodynamics were measured in male Sprague-Dawley rats, aged 4 to 5 months (young) or 20 to 22 months (old). Body weight (BW) and left kidney weights (KW) were higher in old rats than young (BW: 507 +/- 12 g v 342 +/- 11 g, P less than 0.001; KW: 2.0 +/- 0.1 g v 1.3 +/- 0.1 g, P less than 0.001). Arterial blood pressure (AP) was slightly higher in old rats, but within the normotensive range (106 +/- 4 mm Hg v 94 +/- 4 mm Hg, P less than 0.05). Glomerular filtration rate (GFR; factored for KW) was lower in old versus young rats (0.67 +/- 0.05 mL/min/gKW v 1.00 +/- 0.08 mL/min/gKW, P less than 0.02). The cortical surface of the kidney in old (but not young) rats showed marked heterogeneity and single-nephron (SN)GFR was measured only in filtering nephrons and was higher and more variable in old versus young rats. Glomerular blood pressure (PGC) was unchanged in old compared with young rats (53 +/- 4 mm Hg v 55 +/- 2 mm Hg). There was a significantly greater level of glomerular sclerosis (in outer cortical glomeruli) in old versus young rats, and glomerular volume was substantially greater in old rats. This study suggests that age-related glomerulopathy is not primarily mediated by glomerular capillary hypertension.     

Effect of cyclosporin A on renal function and kidney growth in the uninephrectomized rat

This study was designed to characterize the effect of cyclosporin A (CsA) on renal function and compensatory kidney growth in a rat model of uninephrectomy (Ux). The infusion of CsA (12.5 mg/k body wt) after acute Ux resulted in a fall in glomerular filtration rate (GFR) and renal plasma flow (RPF) and a marked increase in renal vascular resistance (RVR). Three weeks following Ux, GFR was also reduced in CsA treated animals as compared to pair-fed controls (0.39 +/- 0.03 vs. 0.67 +/- 0.06 ml/min/100 g, P less than 0.001), but RPF was not (1.97 +/- 0.14 vs 2.19 +/- 0.34 ml/min/100 g). The reduction in GFR seen in rats treated with CsA was fully reversible two weeks after discontinuation of the drug. Three weeks after Ux, kidney weight in CsA-treated animals increased to the level of pair-fed controls (1.50 +/- 0.05 vs. 1.57 +/- 0.06 g) but renal cortical RNA (39.4 +/- 4.3 vs. 49.3 +/- 1.3 micrograms/ml, P less than 0.05), DNA (26.4 +/- 1.7 vs. 34.7 +/- 2.1 micrograms/ml, P less than 0.01), and protein content (6.4 +/- 0.3 vs. 7.8 +/- 0.2 mg/dl, P less than 0.001) were all markedly reduced. Unilateral renal denervation in CsA-treated rats resulted in an increase in GFR and RPF as compared to that of pair-fed sham-denervated animals also treated with CsA (0.57 +/- 0.06 vs. 0.39 +/- 0.03 ml/min/100 g, P less than 0.025 and 2.14 +/- 0.14 vs. 1.63 +/- 0.20 ml/min/100 g, P less than 0.025, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity

The mechanism of cyclosporine A (CyA) nephrotoxicity is unclear. In order to evaluate renal microcirculation seven euvolemic Munich-Wistar (MW) rats were studied after acute CyA treatment (50 mg/kg, i.v.). Both total glomerular filtration rate (GFR, 0.96 +/- 0.04 vs. 0.47 +/- 0.07 ml/min) and single nephron GFR (27.90 +/- 3.39 vs. 14.02 +/- 3.49 nl/min) declined significantly (P less than 0.001). It was observed an increase in afferent (RA, increases 188%) and efferent (RE, increases 360%) arteriolar resistances that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.001). Mean glomerular capillary hydraulic pressure (PGC) increased from 45 +/- 1 to 55 +/- 4 mm Hg (P less than 0.05) and the glomerular ultrafiltration coefficient (Kf) decreased by 70% (0.096 +/- 0.030 to 0.031 +/- 0.010 nl/sec X mm Hg, P less than 0.05). Additionally, in order to study hormonal participation in this nephrotoxicity, other three groups of MW rats were previously treated with captopril (2 mg/kg, i.v.), verapamil (20 micrograms/kg/min, i.v.) or indomethacin (2 mg/kg, i.v.). Both captopril and verapamil minimized the renal effects of CyA, with a decline of approximately 25% instead of approximately 50% on GFR and RPF. Moreover, two groups of Brattleboro rats were studied. Acute CyA administration in homozygote Brattleboro rats produced a decline of only approximately 22% and approximately 31%, respectively, in GFR and renal plasma flow (RPF), when compared with MW rats (P less than 0.05). Similar results were observed in heterozygote Brattleboro rats when compared with MW rats, disclosing differences due to a different strain of rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function

Dose-related cyclosporine-induced renal dysfunction is the most frequent adverse effect noted with this exciting immunosuppressive drug. To investigate pathogenetic factors involved, we studied renal tubular function and afferent arteriolar morphology during severe experimental cyclosporine-induced reduction in glomerular filtration rate. Pair-fed male rats were given cyclosporine 50 mg/kg or olive oil vehicle alone by gavage for periods of 3-14 days. Glomerular filtration rate declined progressively, reaching a nadir of 0.18 +/- .05 ml/min/100 g vs. .86 +/- .03 ml/min/100 g in controls at 14 days (P less than 0.001). Despite the severe reduction in glomerular filtration rate there was no difference in fractional sodium excretion, fractional lithium excretion, enzymuria, or in vitro renal cortical slice uptake of tetraethylammonium in cyclosporine and vehicle-treated animals. Light microscopy showed vacuolar changes without evidence of tubular necrosis at 7 and 14 days in cyclosporine-treated rats. Progressive decline in the diameter of the afferent arteriole was noted by scanning electron microscopy. By day 14 the lumenal diameter of afferent arterioles from cyclosporine-treated animals was 8.9 +/- 0.4 micron vs. 13.5 +/- 0.4 micron in controls (P less than 0.05). We conclude that afferent arteriolar vasoconstriction rather than direct tubular injury is a major pathogenetic factor in experimental cyclosporine nephrotoxicity.     

Effect of platelet-activating factor antagonist on cyclosporine nephrotoxicity. Glomerular hemodynamics evaluation

In order to evaluate the effect of platelet-activating factor (PAF) antagonist BN 52021 (5 mg/kg i.v.) on cyclosporine (50 mg/kg i.v.) nephrotoxicity, euvolemic Munich-Wistar rats were submitted to micropuncture studies. BN 52021 alone did not change the total (1.08 +/- 0.07 vs. 1.04 +/- 0.06 ml/min) or single nephron (SN) (29.1 +/- 50 vs. 31.3 +/- 4.0 nl/min) and glomerular filtration rate. The CsA administration caused a decline on GFR (0.47 +/- 0.07 vs. 0.96 +/- 0.04 ml/min, P less than 0.05) and on SNGFR (14.0 +/- 3.5 vs. 27.9 +/- 3.4 ml/min, P less than 0.05). An increase in afferent (RA) and efferent (RE) arteriolar resistances, 180% and 360%, respectively, that caused a decrease on glomerular plasma flow rate (QA) from 100.99 +/- 17.09 to 44.37 +/- 13.37 nl/min (P less than 0.05) was observed. Moreover, the glomerular ultrafiltration coefficient (Kf) declined by 70% (0.096 +/- 0.003 to 0.031 +/- 0.10 ml/sec mmHg, P less than 0.05). The previous BN 52021 administration on rats treated with CsA blunted its effects on superficial nephrons. The SNGFR (22.3 +/- 3.0 vs. 28.0 +/- 25 nl/min), QA (72.2 +/- 5.9 vs. 91.7 +/- 12.1 nl/min) and KF (0.038 +/- 0.009 vs. 0.048 +/- 0.005 nl/s mmHg) remained unaltered. By contrast, the total renal function was not prevented by BN 52021 treatment: GFR 0.45 +/- 0.12 vs. 0.94 +/- 0.05 ml/min (P less than 0.05). Thus, this study suggests that PAF may participate in CsA nephrotoxicity. Furthermore, the protective effect of BN 52021 on superficial nephrons may indicate that BN 52021 is a drug that can minimize the impairment of renal function induced by CsA.     

Renal cortical mitochondrial integrity in experimental cyclosporine nephrotoxicity

The function of renal cortical mitochondria isolated from rats with cyclosporine nephrotoxicity was studied. Renal cortical mitochondria were isolated from 5 male Fischer rats after 14 days of daily intraperitoneal administration of CsA, 25 mg/kg body wt. Compared with the mitochondrial function of 5 pair-fed control rats receiving vehicle alone, state 3 respiration (ADP-dependent) using several substrates was mildly depressed only with pyruvate-malate supported respiration (27 +/- 3 vs. 36 +/- 2 nmol O2/min/mg protein; P less than 0.05). The Ca2+ accumulation rate was slightly reduced (354 +/- 14 vs. 416 +/- 18 nmol/min/mg protein; P less than 0.025) while the cytochrome enzyme concentrations were not different from controls. Respiratory control ratios were not affected (CsA group: 9.5 +/- 2.8, control group: 8.9 +/- 2.3; glutamate-malate as substrates). These minor alterations in mitochondrial function occurred in the presence of severe depression in the glomerular filtration rate and renal morphologic changes commonly seen with CsA administration. Moreover, there was no increase in enzymuria. These results indicate that CsA has minor effects on the respiratory function of renal cortical mitochondria. The severe depression in the glomerular filtration rate is out of proportion to these minor alterations in mitochondrial function. These findings argue against a prominent role for a direct toxic action of CsA on tubular cells in the pathogenesis of acute cyclosporine-induced renal dysfunction.     

Glomerular hemodynamics in cyclosporine nephrotoxicity following uninephrectomy

Experiments were performed to determine the cause of the reduced glomerular filtration rate (GFR) in cyclosporine nephrotoxicity during compensatory renal growth. Sprague-Dawley rats were uninephrectomized and given daily injections of cyclosporine (30 mg/kg, i.m.) or vehicle (olive oil), and studied 7 or 14 days later. In cyclosporine treated rats GFR was lower seven days (1.34 +/- 0.10 vs. 1.68 +/- 0.07 ml/min) and 14 days (1.19 +/- 0.08 vs. 1.58 +/- 0.04, P less than 0.025) following uninephrectomy. Arterial blood pressure, cardiac output and renal blood flow (RBF) were not different in cyclosporine and control rats. Kidney mass increased to the same extent in cyclosporine and control rats. Micropuncture of the glomerular microcirculation in similarly prepared Munich-Wistar rats demonstrated low whole kidney GFR (1.10 +/- 0.07 vs. 1.55 +/- 0.13 ml/min, P less than 0.01), and single nephron GFR (31.07 +/- 2.27 vs. 42.36 +/- 2.47 nl/min, P less than 0.005) in cyclosporine treated rats as compared to controls. Single nephron plasma flow, afferent and efferent arteriolar resistance, the transglomerular hydrostatic pressure gradient, and arterial blood pressure were the same in both groups. The glomerular capillary ultrafiltration coefficient (Kf) was lower in cyclosporine treated rats compared to controls [0.039 +/- 0.002 vs. 0.075 +/- 0.013 nl/(sec.mm Hg), P less than 0.025]. We conclude that in this model of cyclosporine nephrotoxicity the low GFR is caused solely by a reduction in Kf, and that cyclosporine can reduce GFR without causing renal vasoconstriction.     

Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity.

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for Et(A) receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 +/- 0.25 and 1.73 +/- 0.38 ml/min and GFR decreasing by some 20% to 0.61 +/- 0.05 and 0.67 +/- 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 +/- 0.29 and 1.92 +/- 0.34 ml/min and GFR 0.60 +/- 0.09 and 0.70 +/- 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 +/- 0.28 ml/min versus 2.96 +/- 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 +/- 0.16 ml/min versus 1.12 +/- 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 +/- 0.34 ml/min to 2.39 +/- 0.19 and GFR from 1.04 +/- 0.10 ml/min to 0.85 +/- 0.07 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

BACKGROUND: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. METHODS: Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats. RESULTS: CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality. CONCLUSIONS: MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.     

Reduced glomerular thromboxane receptor sites and vasoconstrictor responses in diabetic rats.

Glomerular thromboxane production and urinary thromboxane excretion are increased in early diabetes, but in spite of this renal blood flow and glomerular filtration rate are significantly higher than in control animals. To study the possibility of a defect in thromboxane actions in the kidney, we have measured glomerular thromboxane receptors and the renal hemodynamic response to the administration of a stable thromboxane analog in diabetic rats. Glomerular thromboxane receptors were studied in hyperglycemic diabetic rats 7 to 10 days after injection of streptozotocin (65 mg/kg, i.v.) and in normal controls. Scatchard analysis of equilibrium binding using the thromboxane antagonist, [3H]-SQ29548, demonstrated one class of high affinity thromboxane receptor sites in control (Kd = 19.9 +/- 2.6 nM, N = 16) and diabetic rats (Kd = 19.8 +/- 2.1 nM, N = 8, P = NS). The number of thromboxane receptors was reduced by 44% in diabetic rats (control, 374 +/- 20 vs. diabetic, 210 +/- 21 fmol/mg, P less than 0.01). Thromboxane binding in diabetic rats was not restored to normal levels by thromboxane synthetase inhibition with OKY046. Diabetic rats had higher renal blood flow (diabetic, 7.03 +/- 0.18 vs. control, 6.33 +/- 0.13 ml/min, P less than 0.05) and glomerular filtration rate (2.42 +/- 0.10 vs. 1.96 +/- 0.07 ml/min, P less than 0.05). Infusion of the stable thromboxane agonist, U46619 (0.1 micrograms/kg/min), reduced renal blood flow and glomerular filtration rate in all animals, but the constrictor responses were blunted by 50% in hyperglycemic diabetic rats compared with normal controls or euglycemic diabetic rats (P less than 0.05). Control of blood glucose with insulin normalized the number of glomerular thromboxane receptor sites, reversed hyperfiltration and restored glomerular responses to thromboxane agonist. The abnormalities of glomerular thromboxane receptors are similar to changes in angiotensin II receptors, and suggest a generalized defect in vasoconstrictor receptors in the diabetic kidney.     

Co-participation of thromboxane A2 and leukotriene C4 and D4 in mediating cyclosporine-induced acute renal failure.

The relative role of thromboxane (TxA2) and sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) in the acute renal failure induced by cyclosporine was studied in the rats. Bolus i.v. administration of 20 mg/kg of CsA but not vehicle to adult male Sprague-Dawley rats resulted in a significant fall in glomerular filtration rate from 0.85 +/- 0.10 and renal plasma flow (RPF) 2.45 +/- 0.14 ml/min/100 g body wt to values at 20 min of 0.47 +/- 0.03 and 1.01 +/- 0.12 ml/min/100 g body wt (P less than 0.01), respectively, without a fall in mean arterial pressure. This hemodynamic effect was maintained for the following 40-min period. Pretreatment of rats with the TxA2 receptor antagonist GR32191 (3 mg/kg i.v.) allowed a partial but significant preservation of GFR (0.60 +/- 0.05 ml/min/100 g body wt) and RPF (1.55 +/- 0.12 ml/min/100 g body wt). In addition, the antagonism of endogenously produced LTC4 and LTD4 with the putative receptor antagonist L-649,923 (1 mg/kg i.v.) partially prevented the fall in GFR (0.65 +/- 0.07 ml/min/100 g body wt) and RPF (1.80 +/- 0.18 ml/min/100 g body wt) at 20 min after CsA injection. The combined administration of GR32191 and L-649,923 completely abolished the CsA-induced decline in GFR (0.80 +/- 0.09 ml/min/100 g body wt) and RPF (2.40 +/- 0.12 ml/min/100 g body wt). These findings suggest that TxA2 and LTC4/LTD4 participate in mediating renal function deterioration induced by acute CsA administration in the rat.     

Effect of chronic theophylline administration on amphotericin B nephrotoxicity in rats

The effect of chronic theophylline administration on amphotericin B nephrotoxicity was investigated in rats. A 7-day treatment of amphotericin B (5 mg/kg/day i.p.) significantly reduced the glomerular filtration rate (GFR) measured as inuline clearance and creatinine clearance (0.74 +/- 0.29 and 0.16 +/- 0.04 ml/min, respectively) in comparison to vehicle-treated rats (2.04 +/- 0.23 and 1.29 +/- 0.19 ml/min, respectively). The reduced GFR led to evaluations in serum creatinine and BUN concentrations (0.94 +/- 0.09 and 78 +/- 11 mg/dl) in comparison to their own values before treatment (0.45 +/- 0.11 and 19 +/- 3 mg/dl). In addition amphotericin B induced an increase in sodium and a decrease in potassium excretion, the fractional sodium excretion was elevated 50-fold. The methylxanthine, theophylline, had a beneficial effect on the outcome of amphotericin-B-induced renal failure. The inuline clearance was 1.17 +/- 0.04 ml/min, the creatinine clearance 0.43 +/- 0.03 ml/min, the serum creatinine concentration 0.76 +/- 0.05 mg/dl and the BUN concentration 40 +/- 6 mg/dl. Theophylline had no effect on total sodium excretion and potassium excretion. The fractional sodium excretion, however, improved significantly. Theophylline as well as sodium deoxycholate, the detergent of amphotericin B, given alone had no effect on renal hemodynamics measured after 7 days.     

The acute effect of passive Heymann nephritis on renal blood flow and glomerular filtration rate in rats

The acute renal hemodynamic changes during induction of passive Heymann nephritis (PHN) may be of importance for the understanding of the pathogenesis of this model. We studied the renal blood flow (RBF) and glomerular filtration rate (GFR) during and after infusion of anti-FxlA into the left renal artery of rats for 10 min. 3 control groups were given 0.9% NaCl, 1 and 2 mg of normal rabbit IgG, respectively. The experimental groups were given 1 and 2 mg IgG fraction of anti-FxlA. Compared to controls, both RBF and GFR were substantially reduced during the first 20-30 min after infusion and remained unaltered for the rest of the observation period. After 20-30 min, RBF in the 1-mg group was 4.8 +/- 0.77 ml/min/g kidney weight versus control, 6.4 +/- 1.23 (NS), and in the 2-mg group, 3.5 +/- 0.65 ml/min/g versus control, 6.4 +/- 1.07 (p less than 0.05). Similarly, in the 1-mg group, GFR was 0.40 +/- 0.08 ml/min/g versus control, 0.76 +/- 0.11 (p less than 0.05), and in the 2-mg group, 0.14 +/- 0.05 versus control, 0.77 +/- 0.12 (p less than 0.0001). The reductions were greater in the 2-mg than in the 1-mg infused experimental groups, but this difference did not reach statistical significance. Immunofluorescence showed typical granular fluorescence of rabbit IgG along the glomerular basement membrane, and electron microscopy showed subepithelial immune deposits. This indicates that in the initial phase of PHN, corresponding with the formation of immune complexes, a pronounced fall in RBF and GFR occurs.     

Chronic cyclosporine-induced nephrotoxiciy in heart transplant patients: long-term benefits of treatment with mycophenolate mofetil and low-dose cyclosporine

BACKGROUND: Cyclosporine-induced nephropathy is a major limitation in heart transplant patients. Cyclosporine dose reduction may lead to substantial early improvement in renal function. Our aim was to study the long-term benefits of therapy with low doses of cyclosporine plus mycophenolate mofetil in heart transplant patients with drug-induced nephrotoxicity. METHODS: Twenty-five adult heart transplant patients with cyclosporine-related nephrotoxicity (mean posttransplant = 41.7 +/- 25.7 months) were included in the retrospective analysis (22 men, mean age = 58.8 +/- 7.9 years.). Patients were switched from azathioprine to mycophenolate mofetil (1 to 3 g/d), followed by a stepwise reduction in cyclosporine dosage (trough cyclosporine level maintained around 100 ng/mL). Renal function was determined by serial measurements of serum creatinine and glomerular filtration rate at 3-month intervals. RESULTS: With a mean follow-up of 30 +/- 13 months, the baseline creatinine of 2.37 +/- 0.5 mg/dL decreased to 1.59 +/- 0.40 mg/dL (P < .0001). The baseline glomerular filtration rate of 36.77 +/- 10.10 mL/min improved to 54.98 +/- 13.80 mL/min (P < .0001). The cyclosporine level was the unique independent variable associated with renal functional improvement (partial R(2) = 0.4). Within the first 3 months, renal function displayed a rapid improvement after conversion to mycophenolate mofetil (P < .001), reaching a plateau, without further significant improvement over the course of time. CONCLUSIONS: Cyclosporine-induced nephrotoxicity is not a progressive, irreversible disease. Reduction in cyclosporine exposure by addition of mycophenolate mofetil is useful to achieve long-term renal functional improvement, thereby avoiding chronic renal failure. A unique, significant factor associated with this improvement was the reduction in cyclosporine level.     

The protective mechanism of thyroidectomy in a rat model of chronic renal failure

Selective thyroidectomy (Tx) has been shown to attenuate proteinuria and disease progression in models of chronic renal failure (CRF). In this investigation, four groups of Munich-Wistar rats were studied to determine if glomerular dynamics or another renal metabolic consequence of Tx was responsible for the protective effect as measured by 24-hour protein excretion (UPROT). The groups were TxT4, thyroxine-replaced Tx rats with five-sixths nephrectomy; Tx, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy; TxI, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy that were given continuous intraperitoneal isoproterenol to restore systemic and renal hemodynamics; and TxT4(C), two-kidney Tx rats receiving replacement thyroxine that served as normal controls. Five-sixths nephrectomy was carried out 2 weeks after Tx, and experiments were carried out 1 week later. Serum T4 was profoundly reduced and there was failure to gain weight in Tx and TxI rats, despite similar protein intakes in all groups. Cardiac output was reduced in Tx, but was similar in TxI to levels in TxT4 rats. Whole-kidney glomerular filtration rate was lower in Tx, at 0.145 +/- 0.052 mL/min (P less than 0.05), but similar in TxI (0.305 +/- 0.147 mL/min) to that in TxT4 rats (0.317 +/- 0.135 mL/min). Twenty-four-hour urinary protein, which was 129 +/- 57 mg in TxT4, was reduced in Tx to 9 +/- 3 mg (P less than 0.01) but restored in TxI to 89 +/- 30 mg, a level similar to that in TxT4.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for leukotrienes in cyclosporine nephrotoxicity

BACKGROUND: Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. METHODS: The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA-treated animals for six days. RESULTS: CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 +/- 0.6 vs. 4.1 +/- 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE4 (1431 +/- 207 vs. 953 +/- 125 pg/24 h, P < 0.05) and N-acetyl-LTE4 (4411 +/- 848 vs. 463 +/- 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 +/- 1.1 vs. 1.7 +/- 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 +/- 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. CONCLUSIONS: These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity.     

Prevention of acute cyclosporine nephrotoxicity by atrial natriuretic factor after ischemia in the rat

The present experimental study investigates whether the atrial natriuretic factor (ANF) is able to prevent the nephrotoxic effects of cyclosporine infused after 30 min of warm renal ischemia in the rat. At 2 hr after the end of ischemia, the glomerular filtration rate was improved by an ANF infusion: 390 +/- 19 microliters/min/100 g versus 298.3 +/- 31 microliters/min/100 g in ANF and saline-infused rats, respectively (P less than 0.05). Intravenous CsA infusion at a dose of 2.5 mg/kg/day produced a more pronounced fall in GFR when compared with the control: 205.4 +/- 19.7 microliters/min/100 g versus 298.3 +/- 31 microliters/min/100 g in CsA and saline, respectively (P less than 0.05). In contrast, a synthetic rat atriopeptin III (0.5 microgram/kg/min) infusion after ischemia given together with CsA prevented its deleterious effects upon GFR: 316 +/- 22 microliters/min/100 g versus 205.4 +/- 19 microliters/min/100 g in ANF/CsA versus CsA alone (P less than 0.001). Moreover, the natriuretic ANF effects remained unaffected by high plasma CsA peak levels: indeed, other parameters of renal function--urinary flow, urinary sodium concentration and excretion rates, and urinary sodium reabsorption and fractional excretion rates, were significantly increased in ANF alone or CsA/ANF groups. These preliminary results suggest that ANF may be useful in renal transplantation or in the management of patients given large doses of CsA (liver or heart transplant) since, despite nephrotoxic CsA levels (greater than 1500 ng/ml), ANF provides an improved GFR and tubular function after ischemia.     

Effect of indomethacin on glomerular permselectivity and hemodynamics in nephrotoxic serum nephritis

The present study was undertaken to determine the effects of prostaglandin synthesis inhibition on glomerular hemodynamics in nephrotoxic serum nephritis and to elucidate the mechanisms by which prostaglandin synthesis inhibition reduces proteinuria in nephritic rats. Dextran sieving studies were performed before and after intravenous administration of indomethacin to control rats and to nephritic rats with heavy proteinuria. Indomethacin did not significantly alter mean arterial pressure, glomerular filtration rate or proteinuria in control rats nor were significant changes in dextran sieving observed. By contrast, in nephritic rats indomethacin significantly reduced glomerular filtration rate (2.58 +/- 0.50 vs. 1.39 +/- 0.27 ml/min, P less than 0.001), proteinuria (0.198 +/- 0.079 vs. 0.048 +/- 0.019 mg/min, P less than 0.05) and filtration rate-corrected proteinuria (0.059 +/- 0.033 vs. 0.031 +/- 0.013 mg/ml GFR, P less than 0.05). The fractional clearance of neutral dextrans with molecular radii exceeding 42 A were elevated above control values in nephritic rats (P less than 0.05). After administration of indomethacin, the fractional clearance of neutral dextrans uniformly declined toward control values and remained elevated only for molecular radii exceeding 54 A. Assessment of glomerular hemodynamics in nephritic rats before and after indomethacin showed significant declines in single nephron filtration rate (31.5 +/- 3.0 vs. 21.2 +/- 2.5 nl/min, P less than 0.02), glomerular plasma flow rate (99.5 +/- 6.7 vs. 68.5 +/- 7.8 nl/min, P less than 0.05) and glomerular ultrafiltration coefficient (0.0430 +/- 0.0033 vs. 0.0339 +/- 0.0032 nl.sec-1.mm Hg-1, p less than 0.05). Indomethacin did not significantly change these parameters in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)