Renal impairment occurs in neonates receiving indomethacin for treatment of patent ductus arteriosus. Inhibition of cyclooxygenase within the neonatal kidney results in decreased prostaglandin synthesis and consequent reduction in renal perfusion. Indomethacin has been reported to cause short-term reduction in glomerular filtration that resolves after cessation of the drug. There is little information on the long-term effects of postnatal exposure to indomethacin. The aim of this study was to determine the incidence of renal impairment in infants treated with indomethacin in a single center, to determine whether there is evidence of renal impairment on day 30 or at discharge, and to identify risk factors for renal impairment. In a retrospective study, infants of less than 30 weeks completed gestation who received indomethacin to close the ductus arteriosus were matched with infants of the same gestation, birth weight, and severity of illness. Serum creatinine and glomerular filtration rates (GFR) were obtained prior to commencing indomethacin and on days 2, 7, and 30 following indomethacin administration. Acute renal failure was defined as an increase in creatinine of greater than 25%. Of those infants who were less than 30 weeks completed gestation, 24% had acute renal failure following indomethacin administration. There was a significant elevation in serum creatinine on day 2 and day 7 ( P<0.0001, P=0.002) and a decrease in GFR on day 2 and day 7 ( P<0.0001, P=0.01) following administration of indomethacin. Renal function had normalized by day 30 or discharge. The incidence of acute renal failure in neonates treated with indomethacin is clinically significant. Renal function returns to normal by day 30. Linear regression found no statistical significance for gestational age, day of indomethacin dosing, Clinical Risk Index for Babies (CRIB) score, and presence of an umbilical artery catheter to confound the effect of indomethacin on renal function.

These results demonstrate that CCR5 is involved in both the activation and recruitment of macrophages to rejecting islet xenografts but other pathways are involved.

Instant blood mediated inflammatory reaction (IBMIR)occurs when islets are exposed to blood and manifests clinically as portal vein thrombosis and graft failure. The aim of this study was to determine the impact of recombinant human activated protein C (rhAPC) and platelet inhibition on IBMIR in order to develop a better targeted treatment for this condition. Five thousand human islet cell equivalents (IEQ) were mixed in a PVC loop system with 7 mL of ABO compatible human blood and incubated with rhAPC, either alone or in combination with tirofiban. Admixing human islets and blood caused rapid clot formation, consumption of platelets, leukocytes, fibrinogen, coagulation factors and raised D-dimers. Islets were encased in a fibrin and platelet clot heavily infiltrated with neutrophils. Tirofiban monotherapy was ineffective, whereas rhAPC monotherapy prevented IBMIR in a dose-dependent manner, preserving islet integrity while maintaining platelet and leukocyte counts, fibrinogen and coagulation factor levels, and reducing D-dimer formation. The combination of tirofiban and low-dose rhAPC inhibited IBMIR synergistically with an efficacy equal to high dose rhAPC. Tirofiban and rhAPC worked synergistically to preserve islets, suggesting that co-inhibition of the platelet and coagulation pathways' contribution to thrombin generation is required for the optimal anti-IBMIR effect.