The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy, страница 9

receive loop diuretics [94]. A randomized controlled trial of early FM therapy in premature infants with RDS did not, however, show a change in GFR or an improvement of the overall prognosis [95]. We recently demonstrated this clearly with the loop diuretic torasemide in oliguric hypoxemic newborn rabbits [96, 97]. FM increases the incidence of PDA by stimulation of PG synthesis [98, 99], and has therefore been proposed as a treatment for newborns with renal dysfunction due to inhibition of PG synthesis. FM prevents the renal side-effects of indomethacin, with no apparent change in the efficacy of indomethacin in the closure of PDA [100]. Prolonged FM treatment may result in hypovolemia and electrolyte abnormalities (hy-pokalemia) [94]. In preterm neonates, particularly in those with a gestational age of less than 31 weeks', the half-life of FM is prolonged, frequently exceeding 24 h [101]. The current generally recommended dosing interval of 12 h for FM (1 mg/kg) is therefore inappropriate; it should be increased to 24 h in infants of less than 31 weeks' gestational age. Low-dose FM (1 mg/kg per dose) is often ineffective, but a good therapeutic response can be achieved with high doses (2-4 mg/kg per dose), although this carries the risk of toxic blood levels due to the low clearance rate of the drug [101, 102].

The routine use of mannitol as an osmotic diuretic is definitely not recommended in newborns. It is well known from studies in adult patients that mannitol can cause and/or exacerbate renal failure [103]. This is also true for neonates, particularly those who already have impaired renal function. In low birth weight infants hypertonic mannitol increases the risk of intraventricular (cerebral) hemorrhage; its use should therefore be avoided [104].

Renal replacement therapy

Prolonged ARF may be associated with a variety of complications, such as electrolyte disturbances, fluid overload, hypertension, or severe uremic symptoms, unresponsive to conservative management. In these patients, temporary dialysis treatment should be considered. A discussion of the various practical aspects of the dialysis modalities (peritoneal dialysis or continuous arterio-venous hemofiltration) is beyond the scope of the present review [105, 106].

Targets for future prevention and therapy of ARF

Background

We have not discussed the renal parenchymal damage that may result from VMNP with prolonged renal ischemia. In order to present future targets for prevention and therapy of this form of ARF we must, however, pay some attention to the resulting intrinsic renal damage and the accompanying physiological perturbations.

The renal morphological changes in prerenal ARF are relatively mild. In this form of VMNP, there is apparently enough postglomerular blood flow to prevent extensive damage to the renal tissues, despite the low GFR. The damage that does occur is characterized by edema, cell swelling, dilatation and collapse of tubular structures, infiltration with neutrophils, tubular cell necrosis, apoptosis of tubular cells, dissolution of the cytoskeleton of tubular cells, and blockage of the tubular lumina with necrotic cell debris [33, 107]. The tubular lesions can be rather sparse, with patchy necrosis along the entire neph-ron and signs of regeneration of cells. In newborn infants with severe prerenal ARF, larger necrotic, cortical and medullary tubular lesions can also be seen [108]. This finding forms the basis for the descriptive term acute tubular necrosis. In many instances the tubular cells are severely injured, whereas the tubular basement membrane is relatively spared. Rupture of the tubular basement membrane can, however, occur. Regeneration of the necrotic areas is the rule [109].

Depletion of cellular adenosine triphosphate (ATP) stores and high intracellular calcium