Related Experiment Videos
Cyclosporin reduces renal prostanoid excretion in type 1 diabetic patients
V A Koivisto1, M Leirisalo-Repo, R Pelkonen
1Second Department of Medicine, Helsinki University Hospital, Finland.
Abstract:
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.
Insights
Cyclosporin therapy reduced kidney blood flow and function by decreasing prostacyclin and thromboxane A2 (prostanoid) synthesis, leading to kidney damage in type 1 diabetic patients. Stopping the drug reversed these effects.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Prostacyclin and thromboxane A2 are key regulators of renal blood flow.
- Cyclosporin is known to cause nephrotoxicity, but the underlying mechanisms are not fully understood.
- Altered prostanoid metabolism may contribute to cyclosporin-induced kidney dysfunction.
Purpose of the Study:
- To investigate the role of prostacyclin and thromboxane A2 metabolism in cyclosporin nephrotoxicity.
- To assess the impact of cyclosporin therapy on urinary prostanoid excretion in type 1 diabetic patients.
Main Methods:
- Urinary excretion of prostacyclin metabolites (6-keto PGF1a, dinor-6-keto PGF1a) and thromboxane metabolite (dinor-TxB2) was measured.
- Measurements were taken in five type 1 diabetic patients during and after cyclosporin therapy, including during exercise.
- Renal function was assessed by serum creatinine levels and albumin excretion; renal histology was evaluated via biopsy.
Main Results:
- Cyclosporin therapy significantly reduced urinary excretion of 6-keto PGF1a, dinor-6-keto PGF1a, and dinor-TxB2 during exercise.
- Albumin excretion increased, and serum creatinine levels rose during cyclosporin treatment.
- Renal biopsy revealed fibrosis and tubular atrophy, which improved after cyclosporin discontinuation, coinciding with increased prostanoid excretion.
Conclusions:
- Cyclosporin reduces renal prostanoid synthesis, potentially impairing renal blood flow and function.
- This reduction in prostanoid synthesis may be a key mechanism underlying cyclosporin-induced nephrotoxicity.
- Reversal of histological damage and improved renal function after stopping cyclosporin correlates with restored prostanoid excretion.