Functional and structural characteristics of experimental FK 506 nephrotoxicity.
1. FK 506 (Tacrolimus, Prograf) is a novel immunosuppressant which is effective in solid organ transplantation and autoimmune diseases. The lack of a suitable animal model has hindered the study of the nephrotoxicity of the drug which has emerged as a common adverse effect in clinical trials. We report both acute and chronic nephrotoxicity with tacrolimus (FK) in which renal structure and function are worsened by sodium depletion. 2. Pair fed male Sprague-Dawley rats were given FK (3 or 6 mg/kg, p.o.) or vehicle for 7, 21 and 42 days on low salt or normal diet. The FK whole blood trough levels achieved (3-10 ng/mL) were similar to those observed in FK treated transplant patients. 3. In salt depleted animals treated for 7 days, FK (6 mg/kg) decreased renal blood flow and glomerular filtration rate (1.8 +/- 0.1 and 0.2 +/- 0.1 mL/min per 100 g vs 2.9 +/- 0.2 and 1.1 +/- 0.1 mL/min per 100 g in the vehicle group, P < 0.01). 4. After 21 days of treatment of FK on low salt diet but not normal salt, FK induced focal collapse and vacuolization in proximal tubules and discrete or confluent zones of tubulointerstitial oedema and mononuclear cell infiltration. 5. After 42 days in salt depleted rats, there was significant tubulointerstitial scarring that was associated with an increased plasma renin activity (PRA) (64 +/- 10 vs 30 +/- 4 ng AI/mL per h in the vehicle group, P < 0.05). Animals given normal salt diets did not develop significant histological lesions even up to 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland 97201, USA.
T F
TF
Andoh
E A
EA
Burdmann
J
J
Lindsley
D C
DC
Houghton
W M
WM
Bennett
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000097:blood / Q000633:toxicity*; D007444:Inulin; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007677:Kidney Function Tests; D008275:Magnesium Deficiency / Q000097:blood / Q000139:chemically induced; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000502:physiology; D016559:Tacrolimus / Q000097:blood / Q000633:toxicity*; D014563:Urodynamics / Q000187:drug effects
D007166:Immunosuppressive Agents; D007444:Inulin; D012964:Sodium; D003404:Creatinine; D012083:Renin; D016559:Tacrolimus