Cyclosporin reduces renal prostanoid excretion in type 1 diabetic patients.
Prostacyclin and thromboxane A2 are important regulators of kidney blood flow. To examine whether changes in their metabolism could be involved in the nephrotoxicity of cyclosporin, we determined urinary excretion of 6-keto PGF1a and dinor-6-keto PGF1a (prostacyclin metabolites) and dinor-TxB2 (thromboxane metabolite) in five newly diagnosed type 1 diabetic patients during and after stopping cyclosporin therapy. In the resting state, cyclosporin had no effect on prostanoid excretion. In response to exercise, urinary excretion of 6-keto PGF1a was reduced by 50% (P less than 0.02), dinor-6-keto PGF1a by 15% (P less than 0.05) and dinor-TxB2 by 45% (P less than 0.02), while albumin excretion increased 4.5-fold (P less than 0.05) during cyclosporin therapy. Simultaneously, there was a rise in serum creatinine concentration, and renal biopsy specimens obtained from three patients showed periglomerular and interstitial fibrosis and tubular atrophy. After the discontinuation of cyclosporin therapy, serum creatinine concentrations returned to normal, histological changes improved and there was an associated rise in urinary prostanoid excretion. These data suggest that a reduction in renal prostanoid synthesis by cyclosporin may diminish renal blood flow and function, and lead to histological changes in the kidney.
Koivisto
V A
VA
Second Department of Medicine, Helsinki University Hospital, Finland.
Leirisalo-Repo
M
M
Pelkonen
R
R
Turunen
U
U
Rapola
J
J
Viinikka
L
L
Ylikorkala
O
O
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use* / Q000633:toxicity; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D015444:Exercise; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007773:Lactates / Q000097:blood; D008297:Male; D011453:Prostaglandins / Q000652:urine*; D013928:Thromboxane A2 / Q000652:urine
D015121:6-Ketoprostaglandin F1 alpha; D001786:Blood Glucose; D016572:Cyclosporine; D006442:Glycated Hemoglobin; D007328:Insulin; D007773:Lactates; D011453:Prostaglandins; D013928:Thromboxane A2