Abnormal prostanoid metabolism in lupus nephritis and the effects of a thromboxane A2 synthetase inhibitor, DP-1904

Abstract

Abnormalities of prostanoid metabolism, which may affect renal function, were studied in lupus nephritis. The subjects were 31 patients with lupus nephritis, ten with non-renal SLE, and four with renal, non-SLE collagen disease. Urinary levels of various prostanoids, thromboxane B₂(TXB₂), 11-dehydro-TXB₂, 6-keto-PGF1α,2,3-dinor-6-keto-PGF1α and PGE₂, and plasma level of 11-dehydro-TXB₂were determined. The effects of four days' dosing of a selective thromboxane A₂(TXA₂) synthetase inhibitor, DP-1904 (DP), on pros tanoid metabolism, were also studied.Urinary excretion of TXB₂, which reflects the renal production of TXA₂, was signifi cantly increased in the patients with lupus nephritis as compared with non-renal SLE (p < 0.05). The urinary TXB₂/6-keto-PGF1α ratio was also increased in lupus nephritis as compared with non-renal SLE or healthy controls (p < 0.01), indicating a prostanoid imbal ance, which may lead to impaired renal function and subsequent pathology. The urinary TXB₂/6-keto-PGF_1αratio in these lupus nephritis patients showed negative correlations with Ccr and positive correlations with anti-DNA antibody titer (p < 0.001).DP was administered orally (400 mg/day, given in two divided doses) for four days to eight lupus nephritis patients. The urinary excretion of TXB₂and urinary TXB₂/6-keto- PGF1α ratio were decreased after one to two days of treatment in all patients. An increase in creatinine clearance used as a measure of renal function was observed in four of eight patients. Furthermore, no side effects were elicited during the four days of treatment.The conclusions reached were that the abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function through hemodynamic mediation, and that the deviated metabolism was reversible and, at least partially, corrected by a TXA₂syn thetase inhibitor.