Effect of selective inhibition of thromboxane synthesis on renal function in diabetic nephropathy

P. S. Kontessis, S. L. Jones, S. E. Barrow, P. D. Stratton, P. Alessandrini, S. De Cosmo, J. M. Ritter, G. C. Viberti

Research output: Contribution to journalArticlepeer-review

Abstract

Studies of nondiabetic renal disease suggest that thromboxane may be an important mediator of abnormal renal function. The role of thromboxane in diabetic nephropathy is not fully understood. We measured in a double-blind, randomized, placebocontrolled crossover study the effect of a thromboxane synthase inhibitor (FCE 22178, 400 mg two or three times per day) on urinary excretion of thromboxane B2 and 6-ke-to-prostaglandin F, glomerular filtration rate (measured as clearance of polyfructosan), effective renal plasma flow (clearance of paraaminohippuric acid), fractional clearances of albumin and immunoglobin G and the reabsorption rate of β2-microglobulin in 15 patients with type 1 (insulin-dependent) diabetic nephropathy. In seven additional patients, the effect of the thromboxane synthase inhibitor given as 400 mg twice per day was compared with that of the thromboxane synthase inhibitor given as 400 mg three times per day. FCE 22178 administration caused a significant inhibition in the excretion of urinary thromboxane B2 and 2,3-dinor-thromboxane B2 compared with placebo (12.3 ± 2.1 vs 24.6 ± 5.1 ng/gm creatinine, p = 0.006, and 78.5 ± 20.3 vs 335.5 ± 84.1 ng/gm creatinine, p = 0.004, respectively) without any compensatory increase of 6-keto- prostaglandin F or 2,3-dinor-6-keto-prostaglandin F that reflect prostacyclin I2 biosynthesis. Glomerular filtration rate, effective renal plasma flow, renal vascular resistance, and filtration fraction were not significantly different after placebo or thromboxane synthase inhibitor treatment. Fractional clearance of albumin and fractional clearance of immunoglobin G fell significantly after the treatment with FCE 22178 compared with placebo (placebo vs active: fractional clearance of albumin, 4.78 ± 1.18 × 10-4vs 3.38 ± 0.98 × 10-4 p = 0.008, fractional clearance of immunoglobin G 5.15 ± 1.29 × 10-4 vs 4.13 ± 1.10 × 10-7, p = 0.025) but the reabsorption rate of β2-microglobulin remained unchanged. Mean arterial blood pressure, serum fructosamine, and serum lipids were similar after placebo or thromboxane synthase inhibitor treatment. Administration of the thromboxane synthase inhibitor three times per day resulted in a lower fractional clearance of albumin than when given twice per day (2.62 ± 0.93 × 10-4 vs 3.53 ± 1.0 × 10-4, p = 0.04) without any significant changes in renal haemodynamics. In the short term, FCE 22178 significantly lowers renal thromboxane A2 biosynthesis and reduces urinary protein excretion without untoward effects on renal hemodynamics, blood pressure, and carbohydrate and lipid metabolism in patients with insulin-dependent diabetes mellitus and moderate renal failure. The long-term implication of this effect remains to be elucidated.

Original languageEnglish
Pages (from-to)415-423
Number of pages9
JournalThe Journal of Laboratory and Clinical Medicine
Volume121
Issue number3
Publication statusPublished - 1993

ASJC Scopus subject areas

  • Medicine(all)
  • Pathology and Forensic Medicine

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