Glomerular Hemodynamic Effects of Cyclosporine

Abstract

We evaluated the effects of acute and chronic Cyclosporine (CsA) administration on renal microcirculation, as well as the role of hormonal systems in this nephrotoxicity. Studies were performed in euvolemic Munich-Wistar rats by using a micropuncture technique. Acute CsA infusion caused a decline in single nephron (SN) glomerular filtration rate (GFR) due to a decrease in glomerular plasma flow (QA) and a decrease in the glomerular ultrafiltration coefficient (Kf), despite an increase in transcapillary hydraulic pressure difference (ΔP). Both captopril and verapamil partially prevented the decrease in whole kidney function altered by acute CsA infusion. Conversely, indomethacin did not modify these parameters, suggesting that the renin-angiotensin system and calcium play a role in CsA nephrotoxicity, while the prostaglandin system participated in this event by a direct blocking of CsA. The platelet activating factor (PAF) antagonist, (BN 52 021), blunted CsA effects on superficial nephron function. Since dazmegrel, a thromboxane synthetase inhibitor, did not change the SNGFR already altered by CsA, the beneficial effects of BN 52 021 would appear to be related to a direct blocking of PAF actions. Acute CsA nephrotoxicity was not fully demonstrated in Brattleboro rats, who present a hereditary absence of antidiuretic hormone (ADH), thus suggesting that the absence of ADH can be a protective factor in CsA nephrotoxicity. Short-term chronic infusion of CsA provoked a decline in SNGFR due to a decrease in QA and ΔP, while Kf remained unaltered. Glomerular hemodynamic patterns in acute and chronic CsA administration were different, suggesting that distinct pathophysiological mechanisms were involved and that distinct pathophysiological approaches would be required to improve knowledge of CsA nephrotoxicity.