This study was designed to evaluate the effect of indomethacin (ID) on renal perfusion in 13 neonates with symptomatic patent ductus arteriosus (PDA). Serial blood flow velocity in the left renal artery was measured just before and at 10, 30, 45, 60, 75 and 90 min after ID administration. Serum creatinine (Cr), sodium (Na), and osmolarity were measured just before, at 12 and 24 h, and at 3 days after ID administration. Timed urine also was collected for measurement of amount, fractional excretion of Na (FENa), and creatinine clearance (CCr). ID decreased end-diastolic flow velocity of renal artery and increased Pourcelot’s index, starting at 10 min and lasting for 75 min (p < 0.05). Serum Cr significantly increased at 12 h, and hourly urine output and CCr decreased for 24 h. Serum Na and osmolarity decreased for a period of at least 3 days (p < 0.05). FENa decreased at 12–24 h (p < 0.05). We conclude that ID treatment can induce significant renal dysfunction due to diminution of renal perfusion in human neonates.
The renin-angiotensin system plays an important role in renal growth and development. Exposure of the neonate to angiotensin converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. It has been demonstrated that ACE inhibition in the developing kidney reduces the renal expression of growth factors, which may account for renal growth impairment. This study was designed to investigate the relationship between renal growth impairment and the expression of transforming growth factor-beta1 (TGF-beta1), TGF-beta receptor I [TbetaRI, activin-like kinase (ALK)-1 and ALK-5], and TGF-beta receptor II (TbetaRII). Newborn rat pups were treated with enalapril (30 mg/kg per day) or vehicle for 7 days, and kidneys were removed for Western blotting of TGF-beta1, ALK-1, ALK-5, and TbetaRII, and for RT-PCR of ALK-5 and TbetaRII. TGF-beta1, ALK-1, ALK-5, and TbetaRII were also detected by immunohistochemistry. Enalapril treatment resulted in an increased mortality (30.4%) by day 7, and reduced body weight and kidney weight ( P<0.05 versus vehicle). Enalapril decreased renal TGF-beta1, ALK-1, and ALK-5 protein expression ( P<0.05). Also, enalapril decreased ALK-5 mRNA expression ( P<0.05). TbetaRII expression was not changed by enalapril treatment. These results indicate that ACE inhibition in the developing kidney decreases TGF-beta1, ALK-1, and ALK-5 expression, which may account for renal growth impairment. TbetaRII may not be modulated by ACE inhibition in the developing kidney.
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