Atrial natriuretic factor after heart operations in children. Relation to hemodynamic and renal parameters.

The purpose of this study was to measure changes in serum atrial natriuretic factor concentrations immediately after heart operations in children under baseline conditions and in response to continuous infusion of dopamine (2.5 and 5.0 micrograms/kg/min). During control periods, levels of atrial natriuretic factor were elevated at 190 +/- 24 and 199 +/- 36 pg/ml. The cardiac index was 2.6 L/min/m2 and the renal plasma flow was decreased to 269 +/- 41 ml/min/1.73 m2, indicating a state of renal vasoconstriction (mean renal fraction of cardiac index of 10.0% +/- 1.0%). The mean sodium fractional reabsorption was 99.0% +/- 0.2%. During dopamine infusion, atrial natriuretic factor concentrations increased to 259 +/- 57 pg/ml and to 280 +/- 56 pg/ml, with dopamine 2.5 and 5.0 micrograms/kg/min, respectively (p = not significant), whereas left atrial pressure decreased from 11.7 +/- 0.9 mm Hg during the control period to 10.1 +/- 0.9 and to 9.9 +/- 1.0 mm Hg (p less than 0.05). No correlation was found between changes in left atrial pressure and atrial natriuretic factor levels. Dopamine at 5 micrograms/kg/min increased the cardiac index to 3.0 +/- 0.2 L/min/m2 (p less than 0.001) and the renal plasma flow to 406 +/- 61 ml/min 1.73 m2 (p less than 0.001), alleviating the renal vasoconstriction. The mean urinary sodium excretion increased to 0.33 +/- 0.08 mmol/kg/hr (p less than 0.01). The atrial natriuretic factor plasma concentrations were not related to the urinary sodium excretion, renal plasma flow, or glomerular filtration rate during the control period or during dopamine treatment. These data indicate that after heart operations in children, low urinary sodium excretion occurs despite high circulating atrial natriuretic factor levels. Atrial natriuretic factor concentrations were related neither to left atrial pressures nor to the renal changes induced by dopamine.     

Evidence that atrial natriuretic factor is the humoral factor by which volume loading or mannitol infusion produces an improved renal function after acute ischemia. An experimental study in dogs

This experimental study in dogs was designed to investigate whether maximal loading produces atrial natriuretic factor (ANF) release and whether this physiological peptide is involved in the improvement of the early renal function recovery after acute ischemia. The experimental protocol included a renal artery occlusion for 45 min in uninephrectomized dogs and the measurement of various parameters of renal function over 2-hr period after declamping. There were 3 experimental groups. In the control group (I) (n = 10), the dogs received, after ischemia, an isotonic saline solution infusion at a rate of 0.2 ml/kg/min. In group II, (n = 10) the animals underwent acute volemic expansion (1 ml/kg/min) with whole blood (hematocrit approximately equal to 25%) during the ischemic period, and after declamping, an isotonic saline infusion (NaCl 0.9%) infusion at the same rate as in the control group. In group III, (n = 8) the dogs only received NaCl 0.9% (0.2 ml/kg/min) before ischemia and alpha human ANF (3.6 ng/kg/min) dissolved in saline after ischemia and during the 2 hr of the renal recovery period. Volemic expansion induced a highly significant increase of the cardiac filling pressures concomitant with a prompt but transient 5-6-fold increase in ANF levels (357 +/- 92 pg/ml versus 60 +/- 4.1 pg/ml in controls at the time of declamping [P less than 0.05]). With these higher plasma ANF levels in overloaded animals, we observed, 2 hr after declamping, considerably improved renal function recovery in terms of glomerular filtration rate--37.5% +/- 8.7 versus 11.8 +/- 3.9%; urinary sodium excretion rate--53.89 mu eq/min versus 5.36 +/- 1.2 mu eq/min (P less than 0.01); total Na reabsorption rate--1.2 +/- 0.23 meq/min versus 0.28 +/- 0.09 meq/min (P less than 0.01) (group II vs. controls, respectively). A 1-28 alpha ANF infusion after the ischemic insult allowed a comparable but more significant improved recovery of renal function--indeed, 2 hr after declamping, the GFR reached 73.7 +/- 14% of the preoperative GFR values. The urinary sodium excretion rate was 15-fold higher than in controls, and the total and fractional sodium reabsorption rates followed a similar increase. These beneficial effects of ANF were obtained with low doses of synthetic ANF (3.6 ng/kg/min) inducing plasma levels slightly higher (120 pg/ml) than in controls and comparable to the levels reached in the overloading group. In addition, maximal loading or ANF infusion produces an inhibition of the aldosterone rise occurring after the ischemic insult.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cyclosporine administration on renal hemodynamics in conscious rats

The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

A renal function study in 30 patients on long-term lithium therapy.

30 patients on long-term lithium therapy have been studied. The results are presented of the urinary concentrating ability after water deprivation and the intranasal administration of vasopressin, of the simultaneous determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), of the minimal urine pH after an oral dose of ammonium chloride, and of the urinary beta-2-microglobulin excretion. Mean urine concentration (+/- SEM) after 22 hr water deprivation (= Uosm) amounted to 854 +/- 22 mOsm/kg H2O, mean GFR was 101 +/- 4 ml/min, mean ERPF 360 +/- 18 ml/min, and mean minimal urine pH 4.95 +/- 0.06. In 8 out of 30 patients there was polyuria. In these 8 patients the values were 778 +/- 51 mOsm/kg H2O, 113 +/- 6 ml/min, 415 +/- 33 ml/min and 4.99 +/- 0.08, respectively. Serum levels of beta-2-microglobulin and lysozyme and the urinary excretion of beta-2-microglobulin were normal in all patients. No correlation was established between Uosm and the serum lithium concentration during the test (0.8 +/- 0.05 mmoles/l) nor between Uosm and the average serum lithium level during treatment (0.79 +/- 0.03). GFR was only correlated with age. It was found that administration of indomethacin during the concentration test increased Uosm in these patients. The results suggest that, given proper dosage and surveillance, long-term treatment with lithium is not likely to cause disturbances in renal function.     

Prednisolone can increase glomerular permeability to proteins in nephrotic syndrome

In patients with a nephrotic syndrome administration of prednisolone causes an increase of proteinuria. To elucidate the mechanism of this effect we have studied the acute proteinuric effect of prednisolone, 125 to 150 mg intravenously, in nine patients (7 M, 2F) with a nephrotic syndrome. Mean age (+/- SD) of the patients was 53 +/- 6 years, mean endogenous creatinine clearance 104 +/- 30 ml/min, and mean proteinuria 7.7 +/- 3.0 g/24 hr. After administration of prednisolone, urinary total protein excretion rose in all patients from a mean (+/- SEM) of 4.89 +/- 0.59 mg/min before to 9.09 +/- 0.99 mg/min at five hours after administration (P less than 0.01). Glomerular filtration rate (inulin clearance), effective renal plasma flow (PAH clearance), and filtration fraction did not change significantly. The increases of urinary excretion of albumin (median %: +92%), IgG (median %: +88%), and transferrin (median %: +76%) were comparable and correlated significantly. Urinary excretion of beta 2-microglobulin did not change significantly however. We conclude that intravenous administration of prednisolone to patients with a nephrotic syndrome causes an increase in urinary protein excretion rate which cannot be explained by changes in renal hemodynamics or tubular protein reabsorption, and which therefore must be the result of a change in glomerular permselectivity characteristics.     

Cyclosporine's effect on functional reserve in the renal allograft

Thirteen renal allograft recipients (6 patients on cyclosporine/7 patients on azathioprine) participated in a short-term oral protein-loading study to determine the effect of cyclosporine on an allograft's functional reserve. The baseline glomerular filtration rate of the two groups were similar (52 +/- 18 ml/min/1.73 m2 for the azathioprine/conventional therapy (CT) group and 47 +/- 12 ml/min/1.73 m2 for the cyclosporine (CsA) group), as were the baseline effective renal plasma flows (218 +/- 78 ml/min/1.73 m2 and 222 +/- 75 ml/min/1.73 m2, respectively). At 3 hr following the protein load there was an increase in GFR to 66 +/- 28 ml/min/1.73 m2 in the CT group. The GFR (39 +/- 8 ml/min/1.73 m2) of the CsA group at this time was unchanged. The responses in ERPF were similar. No significant difference was found between the two groups baseline RAA profiles (4.7 +/- 3.3 ng/ml/hr (CT) and 4.7 +/- 1.7 ng/ml/hr [CsA]), or those at the third hour (8.1 +/- 8.3 ng/ml/hr (CT) and 3.5 +/- 1.9 ng/ml/hr [CsA]). The data in this study indicate that CsA alters the renal allograft's response to a protein meal. This difference may be related to an altered vasodilatory response. This altered vascular reactivity may be mediated through renin activation and/or other hemodynamic regulators such as prostaglandins.     

Reduction of glomerular hyperfiltration by dopamine D(2)-like receptor blockade in experimental diabetes mellitus.

BACKGROUND: Dopamine D(2)-like receptors are involved in the physiological response of renal haemodynamics to amino-acid infusion. The present study was performed to investigate whether domperidone, a D(2)-like receptor antagonist, modulates the pathological hyperfiltration in experimental diabetes mellitus. METHODS: Renal function was studied in anaesthetized rats 2 weeks after induction of moderate diabetes mellitus by streptozotocin, and in non-diabetic controls. Rats in both groups continuously received domperidone or vehicle via drinking water. Following infusion of Ringer's saline for measurement of baseline values, an i.v. amino-acid load was applied to investigate the renal functional reserve. RESULTS: In vehicle-treated diabetic rats baseline glomerular filtration rate and renal plasma flow were significantly higher compared with controls (1.10+/- 0.04 vs. 0.83+/-0.02 (P<0.004) and 4.83+/-0.26 vs 3.32+/-0.24 ml/min/100 g body weight (bw) (P<0.001) respectively). Domperidone completely normalized glomerular filtration rate and renal plasma flow in diabetic rats to values observed in vehicle-treated controls (0.81+/-0.07 (P=0.740) and 3.35+/- 0.30 ml/min/100 g bw (P=0.889) respectively). In the clearance experiments, arterial blood pressure, urinary flow rate and sodium excretion did not significantly differ when comparing the four groups. However, in conscious rats, urinary flow rate and sodium excretion were significantly higher in diabetic rats compared with non-diabetic controls. In both non-diabetic groups, amino-acid infusion induced a significant glomerular hyperfiltration that was completely absent in diabetic rats, and restored by domperidone treatment. In conscious vehicle-treated diabetic rats urinary albumin excretion was enhanced (449.0+/-47.7 vs. 185.7+/- 18.1 microg/24 h in non-diabetic rats (P<0.001)) and significantly lowered in diabetic rats by domperidone treatment (109.8+/-15.4 microg/24 h (P<0.001)). CONCLUSION: The data suggest that dopaminergic mechanisms are involved in the changes in renal haemodynamics during early experimental diabetes mellitus in rats.     

Effects of ciclosporin on plasma renin activity, catecholamines and prostaglandins in patients with idiopathic uveitis

Animals and humans undergoing treatment with ciclosporin (CS) show a reversible increase in renal vascular resistance and a decrease in glomerular filtration rate. The causes of these abnormalities have not yet been established. We evaluated the effects of a 1-week treatment with CS on creatinine clearance, renal arachidonic acid metabolites, plasma renin activity (PRA), plasma aldosterone levels, urinary excretion and plasma levels of catecholamines in 7 patients with idiopathic uveitis. We show that CS treatment induces a significant (p less than 0.05) decrease in creatinine clearance (from 132 +/- 0.5 to 108 +/- 8 ml/min); urinary 6-keto-PGF1 excretion (from 17.8 +/- 4.9 to 10.9 +/- 3.3 ng/mmol creatinine), urinary thromboxane B2 excretion (from 7.0 +/- 1.0 to 3.6 +/- 0.9 ng/mmol creatinine), upright PRA (from 4.2 +/- 0.9 to 2.3 +/- 0.8) and supine PRA (from 2.0 +/- 0.5 to 1.1 +/- 0.3). We found no change in plasma aldosterone levels and plasma levels and urinary excretion of catecholamines. We suggest that the reversible renal vasoconstriction observed in patients treated with CS may be induced by inhibition of renal prostacyclin synthesis. In this setting inhibition of PRA and angiotensin II formation may impair autoregulation of effective filtration pressure and therefore glomerular filtration rate.     

Protein-induced glomerular hyperfiltration: role of hormonal factors

High protein diets acutely elevate the glomerular filtration rate. To characterize this response we administered 1 g of protein/kg body weight as a beef steak meal to nine, healthy male subjects and measured glomerular filtration rate (inulin clearance), renal plasma flow (p-amino hippurate clearance), plasma renin activity, aldosterone and plasma and urinary catecholamines. The subjects ingested the meal on three separate days and were pretreated with either placebo, 50 mg indomethacin (to inhibit renal prostaglandin synthesis), or 10 mg enalapril (to inhibit angiotensin II synthesis). Following placebo treatment protein feeding significantly increased the glomerular filtration rate, from a pre-meal level of 101 +/- 7 ml/min/1.73 m2 to a post-meal level of 130 +/- 6 ml/min/1.73 m2, P less than 0.005. A parallel rise in renal plasma flow and a fall in renal vascular resistance were noted. Indomethacin pretreatment attenuated the increase in glomerular filtration rate following the protein meal, 105 +/- 6 ml/min/1.73 m2 pre-meal level to 118 +/- 4 ml/min/1.73 m2 post-meal, P greater than 0.1. Enalapril pretreatment had no significant effect on protein-induced glomerular hyperfiltration. Protein feeding following placebo increased plasma aldosterone concentration while the concentrations were unchanged in the studies where enalapril or indomethacin was administered. Protein feeding following placebo or indomethacin did not alter plasma renin activity while plasma renin activity rose following enalapril administration. Urinary norepinephrine excretion rose while plasma norepinephrine concentration was unchanged in all three study groups. A decrease in urinary dopamine excretion was also noted four hours after the protein meal was ingested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of thromboxane synthase inhibition with CGS 13080 in human cyclosporine nephrotoxicity.

Cyclosporine is a potent immunosuppressive agent, however, its use is limited by nephrotoxicity. Increased production of the potent vasoconstrictor thromboxane A2 contributes to cyclosporine nephrotoxicity in animal models, but the role of thromboxane in human cyclosporine nephrotoxicity has not been established. We therefore studied cyclosporine-treated renal allograft recipients who had evidence of toxicity manifested by decreased renal function. We measured GFR and PAH clearance (CPAH) before, during, and one week after a 48-hour intravenous infusion of the thromboxane synthase inhibitor CGS 13080. At baseline, the urinary excretion of TXB2 and 2,3-dinor-TXB2 was elevated in the study patients compared to healthy subjects. CGS 13080 infusion caused selective and nearly complete inhibition of thromboxane metabolite excretion in all patients. Mean CPAH improved 33% from 223 +/- 45 to 298 +/- 59 ml/min/m2 (P = 0.055) during infusion, while mean GFR improved 9% from 50.1 +/- 3.9 at baseline to 54.6 +/- 4.5 ml/min/1.73 m2 (P = 0.111). The effect on GFR occurred primarily in those patients taking calcium channel blockers. The mean increase in GFR in these 5 patients was 10.0 +/- 2.8 versus -1.0 +/- 2.8 ml/min/m2 in the remainder. We conclude that thromboxane synthase inhibitors may be useful in attenuating the nephrotoxic effects of cyclosporine following renal transplantation.     

Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency

Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decreases in GFR (K: from 36 +/- 3 to 20 +/- 4 ml/min, P = 0.001; I: from 37 +/- 6 to 30 +/- 7 ml/min, P = 0.032; in RPF (K: from 194 +/- 21 to 146 +/- 21 ml/min, P = 0.002; I: from 222 +/- 33 to 147 +/- 18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 +/- 0.25 to 0.08 +/- 0.02 ng/min, P = 0.05; I: from 0.34 +/- 0.06 to 0.18 +/- 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/CIn) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for atrial natriuretic peptide in endothelin-induced natriuresis.

Systemic administration of low-dose endothelin increases urinary sodium excretion rate despite mild to moderate reductions in renal plasma flow and glomerular filtration rates. The role of atrial natriuretic peptide in endothelin-induced natriuresis was investigated. Administration of 2.50 pmol/min of endothelin to euvolemic rats resulted in increases in plasma atrial natriuretic peptide levels from 127 +/- 18 to 169 +/- 23 pg/mL. However, a lower dose of endothelin (0.63 pmol/min) or saline did not increase plasma levels of atrial natriuretic peptide. Mean arterial pressure was unchanged at the lower dose of endothelin and increased only slightly in rats receiving 2.5 pmol/min. To assess functional significance, renal responses to endothelin (2.5 pmol/min) in the absence and presence of a specific anti-rat atrial natriuretic peptide antibody were compared. Equivalent reductions in renal blood flow were observed. Urinary sodium excretion rates increased significantly in non-ANP-antibody-treated rats by 33 +/- 7 and 82 +/- 20% at 10 and 30 min, respectively. Atrial natriuretic peptide antibody blunted markedly endothelin-induced natriuresis: urinary sodium excretion rates changed insignificantly by 18 +/- 10 and 30 +/- 14%, respectively. Thus, endothelin infusion results in increases in plasma atrial natriuretic peptide levels, which may contribute to endothelin-induced natriuresis, providing evidence for potentially significant interactions between these peptide hormones in the regulation of sodium balance and renal vascular tone.     

Influence of a low sodium diet on the renal response to amino acid infusions in humans

In experimental animals, a high protein diet has been shown to accelerate end-stage renal disease by inducing glomerular hyperperfusion. In this study, we found that intravenous administration of amino acid, used as one component of parenteral nutrition, to normal volunteers resulted in a significant increase in renal blood flow (from 517 +/- 29 to 754 +/- 60 ml/min) and glomerular filtration rate (from 106 +/- 6 to 165 +/- 12 ml/min) without altering systemic blood pressure, renal excretion of electrolytes, plasma renin activity, or plasma aldosterone concentration, and excretory rates of prostaglandins E2 were increased (from 665 +/- 61 to 1,034 +/- 153 pg/min). These amino acid-induced renal hemodynamic effects were abolished when the volunteers received a low sodium diet (20 mEq/day) for three days before the amino acid infusions. However, the hemodynamic effects were restored when the subjects receiving low sodium diets were pretreated with captopril. Under these conditions, amino acid infusions increased renal blood flow (from 388 +/- 11 to 597 +/- 27 ml/min) and glomerular filtration rate (from 80 +/- 4 to 118 +/- 9 ml/min). Reduction of prostaglandin synthesis with indomethacin in volunteers receiving a normal sodium intake was also capable of significantly decreasing the amino acid effects on renal hemodynamics. The results indicate that the renal hemodynamic effects of amino acid infusion are strongly influenced by angiotensin II and prostaglandin formation.     

Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects

BACKGROUND: The side effects of cyclosporine, nephrotoxicity and hypertension, contribute to long-term renal graft failure and cardiovascular morbidity in graft recipients. It is not clear whether tacrolimus is as nephrotoxic and hypertensive as cyclosporine. Data on this subject are not consistent because of differences in dosage and duration of treatment and the presence of comorbidity in the studied patients. A comparison of both drugs with respect to renal hemodynamics and blood pressure has not been performed yet in healthy subjects. METHODS: We studied blood pressure, glomerular filtration rate, and effective renal plasma flow in eight healthy subjects at baseline and after 2 weeks administration of cyclosporine and tacrolimus, in randomized order. Trough levels of either drug were within the currently recommended therapeutical range of 100-200 ng/ml for cyclosporine and 5-15 ng/ml for tacrolimus. RESULTS: Tacrolimus did not influence renal hemodynamic parameters, in contrast to cyclosporine. During cyclosporine, glomerular filtration rate decreased from 98+/-9 ml/min/1.732 to 85+/-10 ml/min/1.732 (P<0.05), and ERPF decreased from 597+/-108 ml/min/1.732 to 438+/-84 ml/min/1.732 (P<0.01). Mean arterial blood pressure increased from 93+/-8 mmHg to 108+/-10 mmHg (P<0.05) during cyclosporine and remained unchanged during tacrolimus. CONCLUSIONS: We conclude that tacrolimus given during 2 weeks in the currently advised dosage has no unfavorable effects on renal hemodynamics and blood pressure in healthy individuals. The use of tacrolimus in organ transplant recipients may in the long-term lead to better renal function and less cardiovascular morbidity than the use of cyclosporine.     

Dissociation of glomerular filtration and renal blood flow in HgCl2-induced acute renal failure

This study evaluates the role of early renal vasoconstriction in the pathogenesis of mercuric chloride (HgCl2)-induced acute renal failure (ARF) in the dog. Within 3 hr after mercury, glomerular filtration rate (GFR), from 45 +/- 4 25 +/- 2 ml/min, and renal blood flow (RBF), from 268 +/- 22 to 161 +/- 19 ml/min, decreased simultaneously. A rise in diuresis and urinary solute excretion occurred. Morphological and functional studies excluded a major role for tubular leakage or obstruction. An attempt was made to prevent the early renal vasoconstriction, by the administration of Haemaccel, a plasma volume expander, alone or in combination with phentolamine. In both settings the fall in RBF after mercury was prevented. Haemaccel volume expansion alone provoked a significant rise in GFR before HgCl2, but the GFR fell by 29% 3 hr after HgCl2. The Haemaccel/phentolamine combination had no influence on pre-mercury GFR values. In this group, a decrease of GFR by 44% was noted 3 hr after mercury. In conclusion, changes in GFR and renal hemodynamics can be dissociated in the early phase of nephrotoxic ARF. The fall in GFR can be attributed either to a decrease in glomerular ultrafiltration capacity and/or changes in glomerular afferent and efferent resistances, leading to a decrease in glomerular hydrostatic pressure.     

Effect of furosemide on the obstructed kidney

The effect of furosemide on the obstructed kidney was studied in dogs. In control kidneys (n = 4) the renal blood flow (RBF) was increased transiently after intravenous infusion of 20 mg of furosemide; from 12.9 +/- 1.2 to 14.8 +/- 1.4 ml/min/kg.B.W. No change in the renal pelvic pressure was observed. Urine flow increased from 0.47 +/- 0.12 to 4.98 +/- 1.15 ml/min at 20 minutes after furosemide administration. Increases in the fractional fluid excretion rate (V/GFR), the fractional sodium excretion rate (FENa) and the fractional potassium excretion rate (FEK) were observed and the maximum values were obtained at 20 minutes after furosemide administration. In two-week unilateral incompletely obstructed kidneys (incomplete UUO; n = 5), RBF was lower than that of the control kidney, whereas a tendency of transient increase was also noticed after furosemide administration; from 8.4 +/- 1.9 to 10.5 +/- 2.3 ml/min/kg.B.W. The renal pelvic pressure increased immediately and transiently after furosemide infusion. Increase in the urine flow was significant, but the value was lower than that of control, and the maximum value was marked at 20 minutes after furosemide administration. V/GFR, FENa and FEK were also increased in incomplete UUO, but the peak values were lower than those of control. In two-week unilateral completely obstructed kidneys (complete UUO; n = 5), RBF was markedly decreased (3.14 +/- 0.38 ml/min/kg.B.W.), and no significant increase was noticed after furosemide administration. The renal pelvic pressure was gradually and continuously increased after furosemide infusion. The fractional excretion rate of pelvic urine components was variable. In particular, V/GFR was significantly increased 60 minutes after furosemide administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of demeclocycline on renal function and urinary prostaglandin E2 and kallikrein in hyponatremic cirrhotics

8 cirrhotics with hyponatremia were given demeclocycline (DMC) 900 mg/day to investigate its effect on renal function, plasma renin activity, aldosterone and urinary excretion of prostaglandin E2 and kallikrein. In 7 patients DMC induced an increase of free water clearance (from -0.36 +/- 0.06 to 0.13 +/- 0.06 ml/min) and serum sodium concentration (from 125.4 +/- 0.09 to 131.1 +/- 1.0 mEq/l, mmol/l). In 5 of these patients DMC also induced a marked reduction of glomerular filtration rate (from 72.2 +/- 6.2 to 31,2 +/- 4.7 ml/min) and renal plasma flow (from 468 +/- 98 to 195 +/- 55 ml/min) which could not be explained on the basis of hypovolemia. In each case this renal impairment was not associated with changes in urinary concentration of beta 2-microglobulin, urinary casts excretion, fresh urine sediment or urine protein content and disappeared after discontinuation of the drug. DMC induced a marked increase in the urinary excretion of prostaglandin E2 (from 0.82 +/- 0.27 to 6.16 +/- 1.91 ng/min) in 6 out of the 7 patients who responded to DMC and a marked reduction in urinary kallikrein (from 16.1 +/- 4.4 to 4.2 +/- 1.6 pkat/min) in the 5 patients who developed renal insufficiency. The serum DMC concentration was greater than 5 micrograms/ml in all patients who responded to DMC, greater than 8 micrograms/ml in all cases who developed renal insufficiency and of 3 micrograms/ml in the case not responding to DMC. (ABSTRACT TRUNCATED AT 250 WORDS)     

The long-term effects of a new converting enzyme inhibitor, delapril hydrochloride, on renal function, renin-angiotensin-aldosterone system and kallikrein-kinin prostaglandin system in hypertensive patients

The effects of a new angiotensin converting enzyme inhibitor, delapril hydrochloride, (delapril) on renal function, and the renin-angiotensin-aldosterone and kallikrein-kinin prostaglandin systems were studied in 10 hypertensive patients. After 4 to 12 months (7.6 +/- 0.9 [SE]) of treatment with 15-60 mg/day (36 +/- 6.8) of delapril (b.i.d.), mean arterial pressure was decreased from 126 +/- 3.0 to 110 +/- 4.4 mmHg (p less than 0.01). Although renal blood flow (RBF), assessed by PAH clearance and hematocrit, was increased from 437 +/- 51 to 490 +/- 49 ml/min (p less than 0.05) and renal vascular resistance was decreased (p less than 0.05), glomerular filtration rate, measured by endogenous creatinine clearance, did not change significantly. Thus, filtration fraction was reduced (p less than 0.01). Plasma renin activity was increased from 1.5 +/- 0.3 to 4.4 +/- 1.1 ng/ml/hr (p less than 0.01). Plasma aldosterone concentration tended to decrease (p less than 0.1), and urinary aldosterone excretion showed on significant change. Although urinary kallikrein and prostaglandin E2 excretions were increased (p less than 0.05), urinary thromboxane B2 excretions was reduced (p less than 0.05). In addition, the changes in RBF were significantly correlated with those in urinary PGE2 excretion (r = 0.63, p less than 0.05). These results suggest that the antihypertensive effect of delapril is multifactorial and that the improvement of RBF seen during delapril administration in the present study may be partly due to the suppression of the renin-angiotensin-aldosterone system and the activation of kallikrein-kinin-prostaglandin system.     

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.