The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes.
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 >or=135 ml/min per 1.73 m(2)), and 12 subjects exhibited normofiltration (GFR <135 ml/min per 1.73 m(2)).


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 m(2)) but increased GFR in the normofiltration group (118 +/- 5 to 138 +/- 5 ml/min per 1.73 m(2)). 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.
Cherney
David Z I
DZ
Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Canada.
Miller
Judith A
JA
Scholey
James W
JW
Bradley
Timothy J
TJ
Slorach
Cameron
C
Curtis
Jaqueline R
JR
Dekker
Maria G
MG
Nasrallah
Rania
R
Hébert
Richard L
RL
Sochett
Etienne B
EB
D000293:Adolescent; D000328:Adult; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000473:pathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib