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Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones
N D Sturrock1, C C Lang, P H Baylis
1Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, Scotland.
Abstract:
We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone.
Insights
Cyclosporine rapidly increases blood pressure and reduces urine output within four days. Early effects suggest hypertension is not sodium-dependent, with altered water handling and potential distal nephron effects.
Area of Science:
- Nephrology
- Pharmacology
- Physiology
Background:
- Cyclosporine is a vital immunosuppressant with known nephrotoxicity and hypertensive side effects.
- Understanding early cyclosporine effects is crucial for mitigating adverse renal outcomes.
Purpose of the Study:
- To investigate the sequential physiological effects of cyclosporine initiation over the first four days.
- To elucidate the primary and secondary mechanisms in cyclosporine-induced nephrotoxicity and hypertension.
Main Methods:
- Sequential monitoring of systemic blood pressure, urine volume, plasma renin activity, and renal sodium excretion.
- Assessment of glomerular filtration rate and effective renal plasma flow.
- Evaluation of cyclosporine's antidiuretic effects with and without vasopressin infusion.
Main Results:
- Acute increase in systemic blood pressure and decreased urine volume by day 1.
- Suppression of plasma renin activity by day 2.
- Natriuresis observed by day 4, with augmented antidiuretic effects and unchanged renal hemodynamics.
- Hypertension was not sodium-dependent; antidiuresis suggested a distal nephron effect.
Conclusions:
- Early cyclosporine administration triggers hypertension independent of sodium balance.
- Altered renal water handling, potentially at the distal nephron, contributes to cyclosporine's effects.
- These findings inform strategies to manage cyclosporine-associated nephrotoxicity and hypertension.