Subclinical renal injury induced by transient cyclosporine exposure is associated with salt-sensitive hypertension.
Cyclosporine use is highly associated with the development of salt-sensitive hypertension. We hypothesized that subtle renal injury induced by cyclosporine could lead to salt sensitivity. Cyclosporine nephropathy was induced by treatment for 4 weeks with cyclosporine (15 mg/kg/day) on a low sodium (0.05%) diet, followed by stopping cyclosporine and placement on a high sodium (4%) diet for 4 additional weeks. Control groups included a group treated with cyclosporine (15 mg/kg/day) on a normal salt diet in which nephropathy does not develop, and a vehicle-treated group. A fourth group received half-dose of cyclosporine (8 mg/kg/day) on a low sodium diet, which results in mild nephropathy. Biopsies were obtained at the end of the cyclosporine administration (4 week) and at sacrifice (8 week), and blood pressure and renal function were measured. Rats treated with cyclosporine for 4 weeks on a low sodium diet developed classic features of tubulointerstitial disease and arteriolopathy; these changes were absent in the cyclosporine/normal salt group and in the vehicle group. At 4 weeks, all groups were switched to a high salt diet; only the rats with nephropathy developed hypertension. The degree of hypertension correlated closely with the degree of tubulointerstitial injury (r=0.85) and with the severity of the arteriolopathy (r=0.9) (p<0.0.1). Importantly, renal function (creatinine clearance) was normal in all groups at 8 weeks, documenting that the hypertension could not be attributed to cyclosporine-mediated alterations in glomerular filtration rate (GFR). One mechanism by which cyclosporine induces hypertension is the induction of subtle renal microvascular and tubulointerstitial disease. This mechanism is not dependent on GFR and may persist even after the cyclosporine is discontinued.
Andoh
T F
TF
Solid Organ Transplant Service, Legacy Good Samaritan Hospital, Portland, OR 97232, USA. tandoh@lhs.org
Johnson
R J
RJ
Lam
T
T
Bennett
W M
WM
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D004039:Diet, Sodium-Restricted; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000633:toxicity*
D007166:Immunosuppressive Agents; D012965:Sodium Chloride; D016572:Cyclosporine