The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy, страница 2

Obstetric hazards Traumatic delivery Severe bleeding (placental ablation/twin-twin

blood transfusion)

Central nervous system damage/intraventricular hemorrhage Severe cyanotic heart disease

Septicemia/multiorgan failure Hypothermia

Iatrogenic                                                                  

Mechanical ventilation Renal artery and/or vein catheterization Drug therapy

ACE inhibition                        

Prostaglandin inhibitors

Tolazoline

D-Tubocurarine/pancuronium

Nephrotoxic agents

(aminoglycosides, amphotericin, radiocontrast)

attention to the major pathophysiological conditions that stress the neonatal kidney. A review of the current thera peutic approaches and a brief discussion of targets for future prevention and treatment of renal cell injury con clude this paper.                                  .. .

Vasoregulatory mechanisms of the neonatal kidney

Fetal renal function is characterized by a low glomerular filtration rate (GFR), the result of low mean arterial blood pressure (MAP) with very low renal blood flow (RBF) and high renal vascular resistance (RVR), as well as reduced glomerular filtration area. During gestation, nephrogenesis proceeds until the 35th week of gestation and GFR increases slowly pari passu [5]. After birth, GFR rises very rapidly because of an increase in MAP and glomerular hydraulic pressure, as well as a sharp fall in RVR, with redistribution if intrarenal blood flow from the juxtamedullary to the superficial cortical nephrons [6]. There is also an increase in the glomerular filtration surface. The GFR of the newborn is, however, still very low, both in absolute terms as well as corrected for adult body surface area (1.73 m²). This is a unique situation confined to the newborn and explains the vulnerability of renal (glomerular) function in early extrauterine life. In order to minimize this vulnerability and to assure that the low precarious effective filtration pressure is maintained under most pathophysiological circumstances, a delicate

balance of intrarenal vasoconstrictive and vasodilator forces is essential [7].

Vasoconstriction

One of the mechanisms for maintaining adequate GFR in face of a low neonatal MAP is postglomerular, efferent arteriolar vasoconstriction, which is mainly dependent on angiotensin II (All). The renin-angiotensin-aldoster-one system (RAAS) is very active during the perinatal period. In the human newborn and in developing animals, plasma renin activity, renal renin gene and renal АИ receptor expression are higher than in adults [8, 9]. At a very young age the pulmonary and intrarenal availability of angiotensin converting enzyme (ACE) is a rate-limiting factor for All production. This results in a higher sensitivity of neonates to the administration of inhibitors of ACE compared with adults [8].

The second potent vasoconstrictor peptide is endothe-lin (ET). In the first days of life ET is elevated (high urinary excretion), both in term and preterm neonates [10]. In newborn rat kidney membranes, the number of ET receptors is higher than in the membranes of the adult rat kidney, with comparable binding affinity [111. Surprisingly, higher doses of ET are needed in newborns than in adults to achieve the same renal vasoconstrictor effect [12]. The renal vasculature of fetal lambs was even reported to react with vasodilatation to low doses of ET [13]. This is probably due to release of nitric oxide (NO) which blunts the vasoconstrictor effects of ET, and may even cause vasodilatation in the newborn kidney [13, 14].

The sympathetic innervation of the newborn kidney transmits vasoconstrictor stimuli, which may affect the renal circulation during the transition from fetal to extra-uterine life [15, 16]. The sympathetic nervous system also has an important secondary role by stimulating the release of renin.