Anne Prévot

In utero exposure to immunosuppressive drugs.

The number of pregnant women receiving immunosuppressants for anti-rejection therapy or autoimmune diseases is increasing. All immunosuppressive drugs cross the placenta, raising questions about the long-term outcome of the children exposed in utero. There is no higher risk of congenital anomalies. However, an increased incidence of prematurity, intrauterine growth retardation (IUGR) and generally low birth weight has been reported, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporine, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes.

Nimesulide, a Cyclooxygenase-2 Preferential Inhibitor, Impairs Renal Function in the Newborn Rabbit

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 μg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 μg · kg−1 · min−1 infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (−5, −23, and −44%), GFR (−12, −23, and −47%), and renal blood flow (−23, −23, and −48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT1) receptors, using losartan, a specific AT1-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (−11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT1-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT2 receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (−15%), probably by inhibiting systemic AT1 receptors. GFR significantly decreased (−25%), whereas renal blood flow remained stable. The decrease in filtration fraction (−21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, −28%), with decreased GFR and renal blood flow (−57% and −51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.

Renal effects of adenosine A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine in hypoxemic newborn rabbits.

The key role of intrarenal adenosine in mediating the hypoxemic acute renal insufficiency in newborn rabbits has been well demonstrated using the nonspecific adenosine antagonist theophylline. The present study was designed to define the role of adenosine A1 receptors during systemic hypoxemia by using the specific A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Renal function parameters were assessed in 31 anesthetized and mechanically ventilated newborn rabbits. In normoxia, DPCPX infusion induced a significant increase in diuresis (+44%) and GFR (+19%), despite a significant decrease in renal blood flow (RBF) (−22%) and an increase in renal vascular resistance (RVR) (+37%). In hypoxemic conditions, diuresis (−19%), GFR (−26%), and RBF (−35%) were decreased, whereas RVR increased (+33%). DPCPX administration hindered the hypoxemia-induced decrease in GFR and diuresis. However, RBF was still significantly decreased (−27%), whereas RVR increased (+22%). In all groups, the filtration fraction increased significantly. The overall results support the hypothesis that, in physiologic conditions, intrarenal adenosine plays a key role in regulating glomerular filtration in the neonatal period through preferential A1-mediated afferent vasoconstriction. During a hypoxemic stress, the A1-specific antagonist DPCPX only partially prevented the hypoxemia-induced changes, as illustrated by the elevated RVR and drop in RBF. These findings imply that the contribution of intrarenal adenosine to the acute adverse effects of hypoxemia might not be solely mediated via the A1 receptor.

Endothelin, angiotensin II and adenosine in acute cyclosporine A nephrotoxicity.

Abstract We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. In the present study, we evaluated the role of endothelin (ET), angiotensin II (AII) and adenosine in this experimental model. All animals received CsA (25 mg/kg/day) for 5 days. Renal function parameters were first measured in a 30-min period, showing renal insufficiency in all animals. Then, rabbits were administered bosentan (10 mg/kg; antagonist of ETA/B receptors), perindopril (20 µg/kg; angiotensin-converting enzyme inhibitor), or theophylline (1 mg/kg; adenosine receptor blocker at micromolar concentrations). After a 40-min equilibration period, renal function was assessed again for 30 min. Bosentan, perindopril and theophylline significantly reduced renal vascular resistance (–28±5%, –39±7% and –8±3%, respectively), and improved renal blood flow (+38±15%, +66±16% and +20±5%), glomerular filtration rate (+33±9%, +52±13% and +50±8%) and diuresis (+48±9%, +76±19% and +73±14%). Filtration fraction was unchanged with bosentan, decreased with perindopril (–10±9%) and increased with theophylline (+24±5%). The overall results suggest that ET, AII and adenosine are involved in the acute renal failure induced by CsA. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with ET- and adenosine-mediated afferent arteriolar constriction as well as ET- and AII-mediated efferent arteriolar constriction.

Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity

Abstract We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. As exogenous adenosine infusion mimics the haemodynamic changes that characterize acute renal failure (ARF), we wanted to know whether adenosine was a mediator in this model and whether an adenosine receptor blocker could prevent the CsA-induced ARF. Group 1 were untreated controls. Group 2 received CsA (25 mg/kg per day) for 5 days. Renal function parameters were measured, showing ARF in all animals compared to controls. Theophylline (1 mg/kg i.v. bolus) was then administered and renal function was reassessed. Theophylline significantly reduced renal vascular resistance (–8%) and increased renal blood flow (RBF) (+20%), glomerular filtration rate (GFR) (+50%), filtration fraction (+24%) and diuresis (+73%), suggesting that adenosine was involved in the CsA-induced ARF. In group 3, theophylline (30 mg/kg per day) was given concomitantly with CsA for 5 days. GFR was normalized, but theophylline did not hinder the drop in RBF seen with CsA alone in group 2. Microscopy observation of the kidneys showed that chronic theophylline administration aggravated the morphological changes induced by CsA alone. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with an adenosine-mediated afferent arteriolar constriction which cannot be prevented by concomitant theophylline administration.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.