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The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

¹ Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Canada
² Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Canada
³ Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Canada
⁴ Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Canada

Address correspondence and reprint requests to Judith A. Miller, MD, FRCP(C), MSc, MHSc, Toronto General Hospital, 585 University Ave., 8N-846, Toronto, Ontario, Canada M5G 2N2. E-mail: judith.miller{at}utoronto.ca

Key Words: AER, albumin excretion rate • Ang II, angiotensin II • COX2, cyclooxygenase-2 • ELISA, enzyme-linked immunosorbent assay • ERPF, effective renal plasma flow • GFR, glomerular filtration rate • Hct, hematocrit • MAP, mean arterial pressure • PAH, paraaminohippurate • PGD, 9,11β-dihydroxy-15-oxo-2,3,18,19-tetranor-prost-5-ene-1,20-dioic acid • PGE, prostaglandin E • PGI, 2,3-dinor-6-keto-PGF₁ • RAS, renin angiotensin system • RBF, renal blood flow • RVR, renal vascular resistance • TXB2, 11-dehydro-TxB₂

OBJECTIVE—Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).

RESEARCH DESIGN AND METHODS—Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR 135 ml/min per 1.73 m²), and 12 subjects exhibited normofiltration (GFR <135 ml/min per 1.73 m²).

RESULTS—Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 ± 5 to 139 ± 5 ml/min per 1.73 m²) but increased GFR in the normofiltration group (118 ± 5 to 138 ± 5 ml/min per 1.73 m²). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.

CONCLUSIONS—In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states.

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