Dolores Mosig

ROLE OF BRADYKININ IN THE NEONATAL RENAL EFFECTS OF ANGIOTENSIN CONVERTING ENZYME INHIBITION

The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE): production of angiotensin II and degradation of bradykinin. The deleterious effect of converting enzyme inhibitors (CEI) on neonatal renal function have been ascribed to the elevated activity of the renin-angiotensin system. In order to clarify the role of bradykinin in the CEI-induced renal dysfunction of the newborn, the effect of perindoprilat was investigated in anesthetized newborn rabbits with intact or inhibited bradykinin B2 receptors. Inulin and PAH clearances were used as indices of GFR and renal plasma flow, respectively. Perindoprilat (20 microg/kg i.v.) caused marked systemic and renal vasodilation, reflected by a fall in blood pressure and renal vascular resistance. GFR decreased, while urine flow rate did not change. Prior inhibition of the B2 receptors by Hoe 140 (300 microg/kg s.c.) did not prevent any of the hemodynamic changes caused by perindoprilat, indicating that bradykinin accumulation does not contribute to the CEI-induced neonatal renal effects. A control group receiving only Hoe 140 revealed that BK maintains postglomerular vasodilation via B2 receptors in basal conditions. Thus, the absence of functional B2 receptors in the newborn was not responsible for the failure of Hoe 140 to prevent the perindoprilat-induced changes. Species- and/or age-related differences in the kinin-metabolism could explain these results, suggesting that in the newborn rabbit other kininases than ACE are mainly responsible for the degradation of bradykinin.

The Renal Hemodynamic Effects of Ibuprofen in the Newborn Rabbit

In early childhood, nonsteroidal anti-inflammatory drugs are mainly used to either prevent or treat premature labor of the mother and patent ductus arteriosus of the newborn infant. The most frequently used prostaglandin-synthesis inhibitor is indomethacin. Fetuses exposed to indomethacin in utero have been born with renal developmental defects, and in both the unborn child and the term and premature newborn this drug may compromise renal glomerular function. The latter has in the past also been observed when i.v. indomethacin or i.v. acetylsalicylic acid (aspirin) were administered to newborn rabbits. The present experiments were designed to evaluate whether ibuprofen has less renal side effects than indomethacin, as claimed. Three groups of anesthetized, ventilated, normoxemic neonatal rabbits were infused with increasing doses of ibuprofen (0.02, 0.2, 2.0 mg/kg body weight) and the following renal parameters were measured: urine volume, urinary sodium excretion, GFR, and renal plasma flow. Renal blood flow, filtration fraction, and the renal vascular resistance were calculated according to standard formulae. Intravenous ibuprofen caused a dose-dependent, significant reduction in urine volume, GFR, and renal blood flow with a fall in filtration fraction in the animals receiving the highest dose of ibuprofen (2 mg/kg body weight). There was a very steep rise in renal vascular resistance. Urinary sodium excretion decreased. These experiments in neonatal rabbits clearly show that acute i.v. doses of ibuprofen also have significant renal hemodynamic and functional side effects, not less than seen previously with indomethacin.

Comparison of the glomerular filtration rate in children by the new revised Schwartz formula and a new generalized formula.

The most widely used formula for estimating glomerular filtration rate (eGFR) in children is the Schwartz formula. It was revised in 2009 using iohexol clearances with measured GFR (mGFR) ranging between 15 and 75 ml/min × 1.73 m(2). Here we assessed the accuracy of the Schwartz formula using the inulin clearance (iGFR) method to evaluate its accuracy for children with less renal impairment comparing 551 iGFRs of 392 children with their Schwartz eGFRs. Serum creatinine was measured using the compensated Jaffe method. In order to find the best relationship between iGFR and eGFR, a linear quadratic regression model was fitted and a more accurate formula was derived. This quadratic formula was: 0.68 × (Height (cm)/serum creatinine (mg/dl))-0.0008 × (height (cm)/serum creatinine (mg/dl))(2)+0.48 × age (years)-(21.53 in males or 25.68 in females). This formula was validated using a split-half cross-validation technique and also externally validated with a new cohort of 127 children. Results show that the Schwartz formula is accurate until a height (Ht)/serum creatinine value of 251, corresponding to an iGFR of 103 ml/min × 1.73 m(2), but significantly unreliable for higher values. For an accuracy of 20 percent, the quadratic formula was significantly better than the Schwartz formula for all patients and for patients with a Ht/serum creatinine of 251 or greater. Thus, the new quadratic formula could replace the revised Schwartz formula, which is accurate for children with moderate renal failure but not for those with less renal impairment or hyperfiltration.

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.

New combined serum creatinine and cystatin C quadratic formula for GFR assessment in children.

BACKGROUND AND OBJECTIVES The estimated GFR (eGFR) is important in clinical practice. To find the best formula for eGFR, this study assessed the best model of correlation between sinistrin clearance (iGFR) and the solely or combined cystatin C (CysC)- and serum creatinine (SCreat)-derived models. It also evaluated the accuracy of the combined Schwartz formula across all GFR levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Two hundred thirty-eight iGFRs performed between January 2012 and April 2013 for 238 children were analyzed. Regression techniques were used to fit the different equations used for eGFR (i.e., logarithmic, inverse, linear, and quadratic). The performance of each model was evaluated using the Cohen κ correlation coefficient and the percentage reaching 30% accuracy was calculated. RESULTS The best model of correlation between iGFRs and CysC is linear; however, it presents a low κ coefficient (0.24) and is far below the Kidney Disease Outcomes Quality Initiative targets to be validated, with only 84% of eGFRs reaching accuracy of 30%. SCreat and iGFRs showed the best correlation in a fitted quadratic model with a κ coefficient of 0.53 and 93% accuracy. Adding CysC significantly (P<0.001) increased the κ coefficient to 0.56 and the quadratic model accuracy to 97%. Therefore, a combined SCreat and CysC quadratic formula was derived and internally validated using the cross-validation technique. This quadratic formula significantly outperformed the combined Schwartz formula, which was biased for an iGFR≥91 ml/min per 1.73 m(2). CONCLUSIONS This study allowed deriving a new combined SCreat and CysC quadratic formula that could replace the combined Schwartz formula, which is accurate only for children with moderate chronic kidney disease.

The renal hemodynamic effects of Aspirin in newborn and young adult rabbits

Abstract. A group of neonatal (n=10) and 12-week-old (n=12) anesthetized, ventilated New Zealand white rabbits received an acute i.v. dose (40 mg/kg body weight) of acetylsalicylic acid (ASA, Aspirin). In the neonatal animals, i.v. ASA caused within 20 min a significant (P<0.01) fall in renal blood flow and glomerular filtration rate (GFR), with an equally significant (P<0.01) increase in filtration fraction and renal vascular resistance. The latter indicates greatly augmented renal vasconstriction or more precisely reduction in intrarenal vasodilatation by inhibition of vasodilatory prostaglandin (PG) synthesis. Urine volume decreased. The 12-week-old young adult animals responded in a similar, but significantly attenuated fashion. These experiments demonstrate that inhibition of PG synthesis in neonatal animals causes very rapid, reversible vasoconstriction, with a reduction in GFR. In addition, this study confirms previous observations that the renal hemodynamic response to the inhibition of PG synthesis is far more pronounced in neonatal animals than in (young) adult rabbits.

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.

Combined Serum Creatinine and Cystatin C Schwartz Formula Predicts Kidney Function Better than the Combined CKD-EPI Formula in Children

Background: The combined serum creatinine (SCreat) and cystatin C (CysC) CKD-EPI formula constitutes a new advance for glomerular filtration rate (GFR) estimation in adults. Using inulin clearances (iGFRs), the revised SCreat and the combined Schwartz formulas, this study aims to evaluate the applicability of the combined CKD-EPI formula in children. Method: 201 iGFRs for 201 children were analyzed and divided by chronic kidney disease (CKD) stages (iGFRs ≥90 ml/min/1.73 m2, 90 > iGFRs > 60, and iGFRs ≤59), and by age groups (<10, 10-15, and >15 years). Medians with 95% confidence intervals of bias, precision, and accuracies within 30% of the iGFRs, for all three formulas, were compared using the Wilcoxon signed-rank test. Results: For the entire cohort and for all CKD and age groups, medians of bias for the CKD-EPI formula were significantly higher (p < 0.001) and precision was significantly lower than the solely SCreat and the combined SCreat and CysC Schwartz formulas. We also found that using the CKD-EPI formula, bias decreased and accuracy increased while the child age group increased, with a better formula performance above 15 years of age. However, the CKD-EPI formula accuracy is 58% compared to 93 and 92% for the SCreat and combined Schwartz formulas in this adolescent group. Conclusions: The performance of the combined CKD-EPI formula improves in adolescence compared with younger ages. Nevertheless, the CKD-EPI formula performs more poorly than the SCreat and the combined Schwartz formula in pediatric population.

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.

Microalbuminuria and hyperfiltration in subjects with nephro-urological disorders

BACKGROUND Microalbuminuria (MA) has been shown to be an early biomarker of renal damage. It is postulated that MA is the early result of hyperfiltration, which could evolve into glomerular sclerosis and renal failure if hyperfiltration is left untreated. We hypothesized that MA is a good indicator of hyperfiltration in children with kidney disorders, obviating the need to calculate the filtration fraction (FF). METHODS A total of 155 children or young adults were prospectively included [42 single kidney (SK), 61 vesico-ureteral reflux, 23 obstructive uropathies, 29 other kidney diseases]. We measured inulin, para-aminohippuric acid clearances, FF and MA. Prediction of hyperfiltration was explored by studying the association between the FF and other variables such as urinary albumin (Alb), urinary albumin-creatinine ratio (ACR) and creatinine clearance. RESULTS A significant but weak association between urinary Alb or ACR and FF was found in subjects with an SK (Spearman correlation coefficients 0.32 and 0.19, respectively). Multivariate analysis also showed that urinary Alb and ACR significantly predict FF only in subjects with an SK (r(2) = 0.17, P = 0.01 and r(2) = 0.13, P = 0.02, respectively). This holds true only in subjects with an SK and inulin clearance >90 mL/min/1.73 m(2) (r(2) = 0.41, P < 0.001). There was no association between creatinine clearance and FF. CONCLUSIONS MA is not associated with FF in our subjects with nephro-urological disorders, except in those with an SK, where the association is weak, indicating that MA is due to other mechanisms than high FF and cannot predict hyperfiltration in such groups.