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)     

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.     

Effects of chronic cyclosporine administration on renal blood flow and intrarenal blood flow distribution

Cyclosporine-induced decreases in renal blood flow (RBF) and glomerular function are well documented. Glomerular filtration and tubular function may be affected by changes in both total renal blood flow and cortical blood flow distribution (CBFD). The effect of CsA on RBF, CBFD, glomerular filtration rate, and tubular function was studied in conscious ewes receiving a mean CsA dose of 30 mg/kg/day for 28 days with mean CsA trough levels of 344 +/- 45 ng/ml. RBF and CBFD were determined by the injection of 15 microns radioactive microspheres before and after one month of treatment with CsA or its vehicle, olive oil. RBF decreased by 24% from 7.65 +/- 0.87 to 5.79 +/- 0.42 ml/min/g of kidney in CsA-treated ewes (P = 0.014), while no decrease was noted in the control group (7.92 +/- 1.10 vs. 7.62 +/- 0.71). Intracortical blood flow decreased in proportion to the fall in total renal blood flow--thus CsA treatment did not change the cortical distribution of flow. There was a 25% decrease in GFR, as determined by inulin clearance, in the CsA-treated group (80 +/- 6 vs. 62 +/- 3 ml/min; P = 0.027) while there was a nonsignificant increase in control animals (62 +/- 11 vs. 92 +/- 7 ml/min). There was no evidence of tubular dysfunction in either group. There were also no changes in urinary excretion rates of prostaglandins PGE2, 6-keto-PGF1 alpha or thromboxane B2, nor were there changes in plasma renin activity. CsA induced decreases in RBF occur red without redistribution of cortical blood flow, indicating that altered cortical distribution of blood flow is not responsible for the changes in GFR or tubular function that have been reported. The changes in renal blood flow and glomerular filtration rate are independent of changes in renal prostaglandin production, and are likely not associated with altered plasma renin activity.     

Effects of uninephrectomy and high protein feeding in cyclosporine nephropathy

Using a recently described rodent model of chronic cyclosporine nephropathy (CCN), the effects of uninephrectomy (UNx) and high protein feeding on the development of CCN were studied. After 28 days of i.p. cyclosporine (Cs; 25 mg/kg/day) in UNx and sham nephrectomized (SNx) rats, the single kidney GFR was higher in UNx animals (0.55 +/- 0.09 vs. 0.29 +/- 0.05 ml/min, P less than 0.04) as was RPF (3.05 +/- 0.46 vs. 1.45 +/- 0.37 ml/min, P less than 0.04). Morphometric evaluation of the chronic tubulointerstitial lesion (TI) demonstrated lower scores and relative protection in the UNx group (16.48 +/- 3.52 vs. 64.76 +/- 18.30, P less than 0.01). In separate groups of rats undergoing UNx or SNx and subsequent treatment with Cs, dry kidney weights confirmed that compensatory renal hypertrophy was present in UNx animals. The modulating effect of dietary protein on the lesion of CCN was studied in UNx rats fed a 5% or 60% protein diet during the period of Cs treatment. At the end of the study period animals fed the high protein diet demonstrated a higher RPF (3.19 +/- 0.58 vs. 1.58 +/- 0.29 ml/min, P less than 0.04), higher GFR (0.55 +/- 0.07 vs. 0.35 +/- 0.04 ml/min, P less than 0.05) and lower TI score (64.45 +/- 17.35 vs. 130.32 +/- 23.48, P less than 0.04) when compared with animals consuming a low protein diet. We conclude that the relative renal vasodilation induced by partial ablation of renal mass and high protein feeding affords some protection against the development of CCN.     

Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes.

Since renal hemodynamic disturbances are important in renal injury and are exacerbated by elevated plasma amino acid concentrations in insulin-dependent diabetes, we measured glomerular filtration rate (GFR) and renal plasma flow (RPF) after an overnight fast and during amino acid infusion in 12 patients with NIDDM and nine normal subjects. In the diabetic patients (plasma glucose 12.4 +/- 0.6 mmol/liter), the fasting GFR (113 +/- 6 vs. 98 +/- 7 ml/min.1.73 m2 in normal subjects, P = 0.056) and RPF (635 +/- 37 vs. 540 +/- 20 ml/min.1.73 m2 in normal subjects, P less than 0.05) were increased. After amino acid infusion, the increase in GFR (159 +/- 7 vs. 121 +/- 6 ml/min.1.73 m2 in normal subjects, P less than 0.05) and RPF (970 +/- 51 vs. 700 +/- 18 ml/min.1.73 m2 in normal subjects, P less than 0.05) were augmented. Insulin infusion for 36 hours did not change these responses. After three weeks of insulin therapy (plasma glucose 5.9 +/- 0.2 mmol/liter), the amino acid-stimulated GFR (143 +/- 5 ml/min.1.73 m2) and RPF (836 +/- 30 ml/min.1.73 m2) declined (P less than 0.05), while the fasting values remained unchanged. The right kidney volume was measured by ultrasonography and found to decrease after three weeks of insulin therapy from 188 +/- 12 to 165 +/- 9 ml/1.73 m2 (P less than 0.05). However, both values were greater than that in the normal subjects, 124 +/- 13 ml/1.73 m2 (P less than 0.01). Glomerular hyperfiltration and hyperperfusion became augmented during hyperaminoacidemia in our NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the effect of experimental cyclosporine toxicity on male reproduction and renal function. Reversal by concomitant human chorionic gonadotropin administration

Administration of cyclosporine to rats has been shown to impair testicular function, resulting in a decrease in sperm counts and fertility. In order to determine whether or not the deleterious effects of CsA could be reversed by hormonal therapy, mature male Sprague Dawley rats were treated with CsA (40 mg/kg/day, s.c.) alone or in combination with human chorionic gonadotropin (hCG) (5 micrograms/day/r; s.c.) for 14 days. Cyclosporine administration decreased the body weight (290 +/- 5.30 vs. 339 +/- 8.7 g; P less than 0.05) and reproductive organ weights (testis 1.49 +/- 0.42 vs. 1.60 +/- 0.03 g; epididymis 0.41 +/- 0.02 vs. 0.49 +/- 0.002 g; seminal vesicle 0.61 +/- 0.09 vs. 1.60 +/- 0.05 g; prostate 0.28 +/- 0.04 vs. 0.60 +/- 0.06 g; P less than 0.05) testicular sperm counts (5.80 +/- 0.42 vs. 8.49 +/- 0.48 x 10(7)/100 mg tissue; P less than 0.05) and epididymal sperm counts, (28.2 +/- 0.95 vs. 51 51.62 +/- 2.17 x 10(7)/100 mg tissue; P less than 0.05) and fertility (25% vs. 100%). Serum levels of LH were elevated (101.98 +/- 21.48 vs. 25.6 +/- 5.18 ng/ml; P less than 0.05) and testosterone was decreased (0.48 +/- 0.07 vs. 2.06 +/- 0.56 ng/ml; P less than 0.05). The administration of hCG to the CsA-treated rats restored the reproductive organ weights (testis 1.56 +/- 0.043 g; seminal vesicle 1.04 +/- 0.05 g; prostate 0.70 +/- 0.06 g) and sperm counts (testicular 7.88 +/- 1.0 x 10(7)/100 mg tissue; epididymal 59.86 +/- 4.16 x 10(7)/100 mg tissue; P less than 0.05) Serum levels of testosterone (18.63 +/- 4.45 ng/ml) and LH (431.65 +/- 31.41 ng/ml) were significantly elevated, as compared with control and CsA-treated groups (P less than 0.05). All the rats in the gonadotropin-treated group were fertile, as compared with 25% in the CsA-treated group. CsA reduced the kidney weight (1.17 +/- 0.02 vs. 1.27 +/- 0.03 g; P less than 0.05) and increased the levels of serum creatinine (0.97 +/- 0.07 vs. 0.59 +/- 0.03 mg/dl; P less than 0.05): these changes were ameliorated by the administration of hCG (kidney weight 1.35 +/- 0.03 g; creatinine 0.76 +/- 0.09 mg/dl).     

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.     

Effects of the calcium antagonist felodipine on renal haemodynamics, tubular sodium handling, and blood pressure in cyclosporin-treated dermatological patients

BACKGROUND: Deterioration of renal function and rise in blood pressure are clinically important side-effects of cyclosporin (CsA) treatment. Calcium antagonists may have a renoprotective effect against CsA nephrotoxicity. PURPOSE: To investigate the effect of the dihydropyridine calcium-channel blocker felodipine on renal haemodynamics, tubular sodium handling, and blood pressure in CsA- treated patients with no primary renal disease, 18 patients with various CsA-treated dermatological diseases were allocated to receive either felodipine 5 mg (extended release tablets) once daily for 4 weeks followed by placebo for 4 weeks, or vice versa, in a prospective, randomized, double-blind study. The patients were investigated before treatment and at the end of each treatment period. RESULTS: After felodipine, both glomerular filtration rate (GFR) and renal plasma flow (RPF) were significantly higher compared to placebo (89.4 +/- 17.5 (mean +/- SD) vs 79.0 +/- 15.9 ml/min and 412.0 +/- 107.6 vs 326.1 +/- 78.0 ml/min respectively, P < 0.001 for both), and filtration fraction (FF) was lower (0.22 +/- 0.03 vs 0.25 +/- 0.03, P < 0.001). Both systolic and diastolic blood pressure were lower after felodipine compared to placebo (116 +/- 11/71 +/- 7 vs 133 +/- 18/83 +/- 10 mmHg, P < 0.001 for both). Furthermore, proximal output of sodium, i.e. fractional excretion of lithium, was higher after felodipine (26.9 +/- 7.3% vs 20.4 +/- 5.5%, P < 0.001) as well as total sodium excretion (0.33 +/- 0.19 vs 0.19 +/- 0.08 mmol/min, P < 0.001). CONCLUSIONS: It is concluded, that felodipine 5 mg once daily for 4 weeks increased GFR, RPF, and sodium excretion in cyclosporin-treated dermatological patients with no primary renal disease. Furthermore, felodipine lowers blood pressure in these patients. The effects of felodipine may be due to an antagonizing effect against CsA-induced 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.     

The impairment of true glomerular filtration rate in long-term cyclosporine-treated pediatric allograft recipients

We performed indium-111-DTPA plasma clearance studies in 61 pediatric kidney and liver recipients treated with cyclosporine to compare true glomerular filtration rate with calculated GFR (cGFR). The mean true GFR of 61.9 +/- 36.6 ml/min/1.73 m2 indicated renal impairment. The mean cGFR of 85.2 +/- 22.4 ml/min/1.73 m2 was significantly higher (P less than 0.001), and overestimated GFR by 38%. cGFR alone did not accurately reflect the degree of renal dysfunction. A group of 48 pediatric orthotopic liver transplant recipients was studied in more detail: 73% of these patients had a true GFR less than 70 ml/min/1.73 m2, while 85% had a true GFR below 90 ml/min/1.73 m2, the lower limit for normal GFR in children. The mean true GFR for patients treated more than 24 months with CsA was lower (P = 0.02) than patients treated with CsA for 12 to 24 months. OLT patients with normal true GFR (greater than 90 ml/min/1.73 m2) had significantly lower plasma CsA levels, and 50% of patients with a true GFR less than or equal to 50 ml/min/1.73 m2 had hypertension. There was no effect on true GFR of age, liver function, azathioprine use, or peritransplant treatment with other nephrotoxic drugs. We conclude that true GFR is significantly impaired in long-term CsA-treated allograft pediatric recipients. Calculations of GFR underestimate the degree of renal dysfunction. As patients treated greater than 24 months had the lowest true GFRs, the fall in GFR may be progressive.     

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.     

Renal kallikrein responses to dietary protein: a possible mediator of hyperfiltration

We studied GFR, RPF and renal kallikrein in rats fed 9%, 25%, or 50% protein (casein) diets for 8 to 13 days. CFR and RPF increased progressively with increasing dietary protein. Renal excretion of active kallikrein (microgram/day) was 128 +/- 9, 174 +/- 11 and 228 +/- 14 in 9%, 25%, and 50% protein-fed rats, respectively (P less than 0.02 or less between groups). Prokallikrein excretion in these groups was 23 +/- 7, 77 +/- 11 and 118 +/- 15 micrograms/day, respectively (P less than 0.005 or less between groups). The in vivo renal kallikrein synthesis rate, relative to total protein synthesis, was reduced in 9% protein-fed rats (2.74 +/- 0.24) compared to rats fed 25% (3.93 +/- 0.34, P less than 0.02) or 50% protein (4.41 +/- 0.30, P less than 0.001). These changes in synthesis and excretion rates were not accompanied by changes in renal tissue levels of active or prokallikrein. In all groups, GFR and RPF correlated directly with the renal excretion of active kallikrein, prokallikrein or total kallikrein (r = 0.41 to 0.66, P less than 0.01). Treatment of 50% protein-fed rats with aprotinin, a kallikrein inhibitor, markedly lowered renal and urinary kallikrein-like esterase activity. Left kidney GFR and RPF were significantly reduced in aprotinin-treated rats compared to vehicle-treated rats (1.54 +/- 0.15 and 4.86 +/- 0.38 ml/min vs. 1.89 +/- 0.10 and 5.93 +/- 0.22 ml/min, GFR and RPF, respectively, P less than 0.05 or less).(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated dietary protein intake impairs the renal hemodynamic response to hyperaminoacidemia in patients with primary glomerular diseases

We have evaluated the renal hemodynamic response to a mixed amino acid infusion in 7 control subjects and in 8 patients with primary glomerulonephritis (GN). In order to evaluate the role of dietary protein intake in this response, GN patients were maintained for 3 weeks on two separate dietary regimens providing 130 +/- 5 g of protein/day (study 1) and 60 +/- 3 g of protein/day (study 2), respectively. Normal subjects were studied while consuming a free diet. In GN patients, following the reduction in dietary protein intake basal RPF and GFR decreased from 589 +/- 109 to 422 +/- 81 ml/1.73 m2/min (p less than 0.01, vs. study 1) and from 75 +/- 7 to 70 +/- 8 ml/1.73 m2/min (p = NS). Filtration fraction rose from 0.14 +/- 0.02 to 0.19 +/- 0.03 (p less than 0.05). In study 1, during amino acid infusion GFR and RPF did not change significantly from baseline (75 +/- 7 vs. 66 +/- 8 ml/1.73 m2/min at 180 min and 589 +/- 109 vs. 567 +/- 102 ml/1.73 m2/min, respectively). These results are at variance with data obtained in normal controls in whom both GFR and RPF rose significantly following hyperaminoacidemia. In contrast, when dietary protein intake was reduced, a normal renal hemodynamic response to amino acid infusion was restored (GFR went from 70 +/- 8 to 90 +/- 18 ml/1.73 m2/min and RPF from 422 +/- 81 to 517 +/- 90 ml/1.73 m2/min, both p less than 0.05 vs. basal), both absolute and percentage increases were similar to what was observed in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by constant inulin and PAH infusion during euglycemia and intravenous dextrose-induced moderate hyperglycemia in seven insulin-dependent diabetics with persistently elevated GFR, seven diabetics with normal GFR, and in six normal control subjects. In euglycemia, RPF was higher and calculated renal vascular resistance (RVR) lower in the hyperfiltering than the normofiltering group (P less than 0.05 for both variables), but filtration fraction (FF) was similar in all groups. During hyperglycemia, mean GFR rose significantly from 157 +/- 20 to 174 +/- 30 ml/min/1.73 m2 (11.9%; P less than 0.05) in the hyperfiltering group only. There was no statistically significant change in mean GFR in the normofiltering diabetic (116 +/- 6 vs. 114 +/- 13 ml/min/1.73 m2) and the normal control groups (117 +/- 15 vs. 113 +/- 14 ml/min/1.73 m2). RPF and FF rose by 5.8% and 9.2%, respectively, in the hyperfiltering group only, with no change in the normofiltering or normal control groups. No change in RVR was found in any group. Total tubular sodium reabsorption was higher during euglycemia in the hyperfiltering diabetics (P less than 0.01), and rose significantly during hyperglycemia (P less than 0.05) in this group only. Overnight euglycemia did not remove the increased glomerular filtration and flow of hyperfiltering diabetics. Hyperglycemia further accentuated hyperfiltration by elevating renal plasma flow and filtration fraction.     

Renal response to a protein meal in children with single kidneys

The renal response of healthy adults to an oral protein load results in a significant increase of renal plasma flow (RPF) and glomerular filtration rate (GFR) 100 to 150 min after the meal. The renal response to protein loading of single kidney adults is unclear and it has not been evaluated yet in children. Therefore, we studied 8 children 10.2 +/- 1.1 years old, 6.7 +/- 1.41 years after nephrectomy (SK) and 4 healthy children (C). RPF was estimated by para-amino-hippurate clearance (Cpah) and GFR by inulin clearance (Cin) before and after an oral protein load of 1.5 g protein/kg body wt and expressed in ml/min/1.73 m2 BSA. Mean baseline Cin were similar in SK and in C (90 +/- 8 vs 103 +/- 12) while baseline Cpah was lower in SK (339 +/- 19 vs 481 +/- 36, p less than 0.005). After the meal GFR and RPF increased significantly in C (155 +/- 18 and 783 +/- 68, p less than 0.005 and p less than 0.05 vs baseline values, respectively) whereas no significant GFR and RPF changes were seen in SK (81 +/- 9 and 350 +/- 42, respectively). However, the 3 SK children with lower protein intake showed a mild vasodilating response. We conclude that in single kidney children hyperfiltration occurs at baseline conditions and the renal response to acute protein loading is partially or completely blunted, being modulated by protein intake.     

Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers.

BACKGROUND: A single oral dose of cyclosporin-A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA-nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA-nephrotoxicity reduces renal fibrosis and maintains renal function. METHODS: In the present study, the effect on renal haemodynamics of a single dose of the new oral formulation of CsA (neoral) was assessed before and after 6 weeks of vitamin E (800 IU/day, 2-fold increase in serum vitamin E). GFR (inulin clearance) and RPF (para-amino hippuric acid clearance) were measured before and after a single dose of 5 mg/kg of neoral in 12 healthy subjects under standardised conditions. RESULTS: Although the mean area under the curve of the CsA levels was 21% lower after the vitamin E period, the peak CsA level at 120 min after neoral was similar both before and after vitamin E administration. At 120 min after neoral, a transient reduction in RPF and GFR was noted both before and after vitamin E administration. The nadir of the reductions in RPF (-81 +/-27 ml/min) and GFR (-14 +/- 6 ml/min) at 120 min compared with baseline tended to be lower before than after the treatment with vitamin E (-51 +/- 33 ml/min of RPF and -12 +/- 8, ml/min of GFR, respectively). Plasma and urine levels of F2-isoprostanes (free radical-catalysed vasoconstrictive prostanoids (F2-iso) at 120 min after the administration of neoral were not different from the pre-neoral levels. CONCLUSION: The findings demonstrate that a single oral dose of neoral causes transient, yet significant, reductions in RPF and GFR, and suggest that F2-iso might not be involved in the CsA-induced acute renal vasoconstriction. The tendency for a lower reduction in RPF and GFR following CsA during the vitamin E period in healthy humans warrants additional studies in transplant patients.     

Beneficial effects of the urinary trypsin inhibitor urinastatin on renal insults induced by gentamicin and mercuric chloride (HgCl2) poisoning.

The authors investigated the protective effects of the urinary trypsin inhibitor urinastatin on acute renal failure induced in rats by gentamicin (240 mg/kg body weight i.p. for 3 days) and by mercuric chloride (3 mg/kg s.c.). In rats injected with gentamicin, glomerular filtration rate (GFR), renal plasma flow (RPF), and percent fractional sodium excretion (%FENa) were 151 +/- 51 microliters/min/100 g body weight, 0.69 +/- 0.31 ml/min/100 g and 0.73 +/- 0.32, respectively, whereas in rats given 100,000 U of urinastatin the renal function was significantly ameliorated (GFR 318 +/- 43 microliters/min/100 g RPF 1.41 +/- 0.35 ml/min/100 g), although the %FENa (0.46 +/- 0.26) was not significantly improved. A 50,000-unit dose of urinastatin prevented the deterioration of renal function to some extent following administration of gentamicin: GFR 219 +/- 66 microliters/min/100 g and RPF 0.93 +/- 0.43 ml/min/100 g. In the study using mercuric chloride, treatment with 75,000 U of urinastatin protected the kidney from HgCl2 poisoning, yielding values of 294 +/- 93 microliters/min/100 g (GFR), 1.03 +/- 0.41 ml/min/100 g (RPF), and 1.44 +/- 0.72 microliters/min/100 g (%FENa) as compared with respective values of 169 +/- 48 microliters/min/100 g, 0.7 +/- 0.18 ml/min/100 g, and 2.22 +/- 1.35 in the untreated rats. Renal histology revealed mild to moderate tubular epithelial changes in untreated rats, but preservation of an almost normal tubular structure in urinastatin-treated rats in both studies.     

Renal kallikrein and hemodynamic abnormalities of diabetic kidney.

The relationship between renal hemodynamic abnormalities and renal kallikrein activity was studied in streptozocin-induced diabetic rats. Diabetic rats were either not treated with insulin and had plasma glucose levels greater than 400 mg/dl (severely hyperglycemic diabetic [SD]) or were treated with 1.5-1.75 U/day protamine zinc insulin and had glucose levels of 200-300 mg/dl (moderately hyperglycemic diabetic [MD]). In SD rats, kidney tissue level and excretion of active kallikrein were reduced after 3 wk compared with age-matched nondiabetic control rats (tissue, 11.7 +/- 1.9 vs. 20.5 +/- 1.8 ng/mg protein, P less than 0.005; urine, 126 +/- 12 vs. 179 +/- 10 micrograms/24 h, P less than 0.005). Despite increased kidney size, renal plasma flow (RPF) was reduced in SD rats (5.38 +/- 0.23 vs. 6.37 +/- 0.20 ml/min, P less than 0.05). Glomerular filtration rate (GFR) was not significantly lower (2.77 +/- 0.60 vs. 3.02 +/- 0.56 ml/min). In MD rats, kidney tissue level and excretion of active kallikrein were increased after 5 wk compared with age-matched nondiabetic control rats (tissue, 28.4 +/- 1.3 vs. 23.3 +/- 1.7 ng/mg protein, P less than 0.05; urine, 289 +/- 16 vs. 196 +/- 13 micrograms/24 h, P less than 0.001). In MD rats, GFR and RPF were increased (3.80 +/- 0.11 and 8.04 +/- 0.17 ml/min, respectively) compared with control rats (3.22 +/- 0.05 and 7.28 +/- 0.09 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Doses of endothelin have natriuretic effects in conscious rats with cirrhosis and ascites

MAP, RPF, GFR, V and UNaV were measured in nine conscious control and in 11 conscious cirrhotic rats with ascites before and following two bolus injections (100 and 600 pmol/kg body wt) of endothelin (ET). PRA and plasma concentration of aldosterone and ANP were measured in basal conditions and following the high dose ET. ET induced similar increase in MAP and decrease in RPF and GFR in control and cirrhotic rats. High-dose ET produced a significant reduction in UNaV in control rats (from 2.22 +/- 0.46 to 1.14 +/- 0.28 microEq/min, P less than 0.01). By contrast, it induced marked natriuresis in cirrhotic rats (from 0.76 +/- 0.18 to 2.31 +/- 0.70 microEq/min, P less than 0.05). ET significantly increased aldosterone (control rats: 59.3 +/- 2.2 vs. 85.4 +/- 7.4 ng/dl, P less than 0.025; cirrhotic rats: 115.0 +/- 15.8 vs. 163.9 +/- 30.8, ng/dl, P less than 0.05) and ANP (control rats: 20.1 +/- 3.4 vs. 42.7 +/- 7.7, fmol/ml, P less than 0.025; cirrhotic rats: 107.5 +/- 17.3 vs. 214.2 +/- 41.1, fmol/ml, P less than 0.025) and significantly suppressed PRA (control rats: 2.5 +/- 0.5 vs. 0.2 +/- 0.04, ng/ml.hr, P less than 0.025; cirrhotic rats: 16.6 +/- 2.9 vs. 5.0 +/- 1.1, ng/ml.hr, P less than 0.01) in both groups of animals. These results indicate that ET has marked natriuretic properties in cirrhosis with ascites due to inhibition of tubular sodium reabsorption.     

The renal hemodynamic response following a meat meal in children with chronic renal failure and in healthy controls

The renal hemodynamic response to a meat meal (2 g/kg BW) was studied in 11 healthy children and in 10 children with a mean plasma creatinine concentration of 2.6 +/- 0.1 mg/dl due to chronic renal failure (CRF) of various etiologies. In the healthy status, after a meat meal, the glomerular filtration rate (GFR) increased significantly from a baseline value of 119.0 +/- 5.0 to a peak of 159 +/- 5.8 ml/min x 1.73 m2; in CRF baseline GFR averaged 49 +/- 4.0 and at peak 76.6 +/- 7.2 ml/min x 1.73 m2 (p less than 0.005). The peak GFR response was reached earlier in healthy subjects than in CRF (p less than 0.05) and did not correlate with age or with baseline GFR. Renal plasma flow (RPF) in healthy controls increased from 532 +/- 32 at baseline to 646 +/- 42.9 ml/min x 1.73 m2 after the meal (p less than 0.005). Also in CRF after a meat meal there was a significant increase in RPF from 278 +/- 51 to 65 +/- 66 ml/min x 1.73 m2 (p less than 0.005). The filtration fraction was not affected. The percent increase over baseline values of GFR and RPF at the peak was significantly higher in diseased children. Renal reserve averaged 28.1 +/- 5.3 ml/min in diseased children and 39.7 +/- 5.2 ml/min (p less than 0.01). The data indicate that (1) a meat meal is a suitable method to recruit renal reserve in normal children and in children with chronic renal failure, and (2) the renal reserve is normal in chronic renal failure.