Vasoactive forms of nonsteroidal antiinflammatory agents such as indomethacin, aspirin and ibuprofen can induce renal hypoperfusion in neonates, especially preterm neonates, resulting in usually reversible, oliguric ARF (79). These drugs abolish the vasodilatory effects of prostaglandins, which maintain an effective GFR. Nonsteroidal antiinflammatory agents, when used during pregnancy for preventing toxemia and preterm birth or for treating polyhydramnios, easily pass the placenta. Postnatally these agents may be infused for closing a PDA or given orally for specific tubular disorders (see section on tubular dysfunction). Indomethacin has traditionally been the choice, but recently, ibuprofen has been advocated for its less severe renal toxicity (596). A systematic review (600) has shown that administration of ibuprofen reduced the risk of oliguria (urine output <1 ml/ kg/hour) (relative risk 0.22, 95% confidence interval 0.09, 0.51) but increased the risk for oxygen requirement at 28 days, as compared to indomethacin.

Indomethacin is excreted into the urine through the organic secretory pathway of the proximal tubule, which explains higher levels in more immature patients (601). Indomethacin administration was found to transiently decrease RBF in premature infants with symptomatic PDA (440). Some patients develop transient renal dysfunction, associated with a fall of PRA from the high levels that are attributed to renal hypoperfusion before closure of the PDA, and a transient rise in the plasma level of AVP (602). During prolonged administration of indomethacin, i.e., up to 1 week, hormonal levels normalize, and renal function tends to improve (602,603). Indomethacin causes NAG enzymuria and increases the proximal tubular reabsorption of solutes (e.g., Na+), the corticomedullary gradient, and the hydroosmotic effect of ADH. The latter two changes result in an increased ratio of urine to plasma osmolality and decreased free water clearance, leading to water retention and dilutional hyponatremia (604,605,606). Indomethacin administration may also cause oliguric ARF and decreased renal K+ excretion, resulting in hyperkalemia. The latter may result from hyporeninemic hypoaldosteronism, decreased Na+ delivery to the distal tubule, or ARF. Maternal administration of indomethacin may induce nephron dysgenesis (see Acute Renal Failure) (551,552), oligohydramnios, and neonatal renal failure (604). However, perinatal indomethacin does not seem to affect long-term renal growth, structure or function in children born at less than 33 weeks of gestation (607).

Indomethacin is contraindicated if Pcr is elevated, i.e., Pcr greater than 1.8 mg/dL and in the presence of oligoanuria or hyperkalemia. The incidence of nephrotoxicity is increased by the combination of indomethacin with other nephrotoxins. One randomized trial showed that decrease in renal blood flow velocity and in urine output is observed with bolus indomethacin administration but not with continuous infusion (608). Two systematic reviews of randomized clinical trials found no evidence to support the use of dopamine (609) or furosemide (610) to prevent renal dysfunction in indomethacin treated preterm neonates.

During a course of indomethacin, Pcr, serum electrolyte concentrations, and urine output should be monitored. The interval of drug administration should be adjusted according to Pcr or GFR, and fluid intake should be adjusted according to urine output. If oligoanuria develops, a challenge dose of furosemide should be given; fluid restriction should be initiated if oligoanuria persists.