Cyclosporine nephrotoxicity: blood volume, sodium conservation, and renal hemodynamics.
Glomerular filtration rate (GFR) and renal blood flow (RBF) are depressed by chronic cyclosporine treatment. We examined the hypothesis that depletion of extracellular or intravascular fluid volume contributes to the renal vasoconstriction of early cyclosporine nephrotoxicity (CCN). Control and CCN rats were given 10 mg/kg cyclosporine A or vehicle intramuscularly daily for 7 days. The effects of extracellular volume expansion, both acute (AVE, 10% body wt saline) and chronic (CVE, 10% body wt/day saline ip, 10 days including cyclosporine A treatment period), on renal hemodynamics were measured. In CCN, AVE completely normalized GFR and RBF, whereas CVE partially prevented the development of CCN. Renal autoregulatory ability was depressed in CCN but was largely restored by AVE. Intravascular volumes were measured with Evans blue and 51Cr-labeled red cells. Plasma and red cell volumes were reduced by 24% in CCN, indicating circulatory hypovolemia. Acute repletion of the deficit in blood volume by acute administration of an isoncotic solution (1.8 ml/100 g body wt of 5% albumin in isotonic saline) restored GFR and RBF to levels similar to those in control rats. Extracellular fluid volume, estimated as inulin space, was similar in both CCN and control groups. A metabolic study (7 day) showed stool Na loss in CCN to be twice that in controls but both groups remained in sodium balance. We conclude that the renal vasoconstriction produced in the rat by short-term cyclosporine treatment is, at least in part, prerenal in origin and related to the development of circulatory hypovolemia.
Devarajan
P
P
Department of Pediatrics, School of Medicine, State University of New York, Stony Brook 11794.
Kaskel
F J
FJ
Arbeit
L A
LA
Moore
L C
LC
D000818:Animals; D001810:Blood Volume; D003524:Cyclosporins / Q000633:toxicity*; D005919:Glomerular Filtration Rate; D006439:Hemodynamics / Q000187:drug effects; D006706:Homeostasis; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow; D012964:Sodium / Q000378:metabolism*
D003524:Cyclosporins; D012964:Sodium