A. Arrajab et al., DELETERIOUS EFFECT OF CYCLOSPORINES ON THE ISCHEMIC KIDNEY IN THE RATAND THE PROTECTION BY THE CALCIUM-ANTAGONIST VERAPAMIL, Journal of the American Society of Nephrology, 5(1), 1994, pp. 93-101
Cyclosporine A (CsA) nephrotoxicity has been suggested to be aggravate
d in the presence of ischemia, as occurs after renal transplantation.
Cyclosporine G (CsG) may be less nephrotoxic than CsA. This study eval
uated in the rat (1) the effect of CsA and CsG on blood flow and the f
unction of the kidney subjected to 60 min of warm ischemia and (2) the
protective effect of the calcium antagonist verapamil (VP). After lef
t nephrectomy, ischemia was induced in the right kidney by the clampin
g of the kidney pedicle for 60 min, which resulted in a significant in
crease in serum creatinine (SCr) to 2.30 +/- 0.25 mg/dL by Day 1 with
25% mortality by Day 7. The administration of CsA or CsG (20 mg/kg iv
daily for 7 days) after 60 min of renal ischemia significantly increas
ed SCr and mortality compared with ischemia alone. In another set of e
xperiments, 60 min of warm ischemia was applied to the right kidney an
d RBF was measured in both kidneys with a laser Doppler flowmeter. Blo
od flow in the ischemic kidney returned to the preischemic level by 15
min after the removal of the vascular clamp in the control animals. I
n contrast, in animals treated with CsA, a significant decrease in RBF
was seen in both kidneys; however, blood flow in the ischemic kidney
was significantly lower than that in the nonischemic kidney. CsG also
decreased RBF in both kidneys, although in the left (nonischemic) kidn
ey, RBF remained significantly higher with CsG than with CsA. VP treat
ment (0.35 mg/kg iv daily for 7 days) to animals subjected to 60 min o
f renal ischemia and CsA administration prevented the decrease in RBF
and the increase in SCr and mortality. It is concluded that the ischem
ic kidney is more susceptible to CsA nephrotoxicity than the nonischem
ic kidney. Although CsG is less detrimental to the nonischemic kidney,
it has a nephrotoxic effect on the ischemic kidney similar to that of
CsA. Finally, the calcium antagonist VP prevents CsA-induced renal dy
sfunction in the ischemic kidney, most likely as a result of its renal
hemodynamic effect.