Functional and structural characteristics of experimental FK 506 nephrotoxicity

T. F. Andoh, E. A. Burdmann, J. Lindsley, Donald Houghton, W. M. Bennett

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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. 6. Sodium depletion is critical for the development of FK induced progressive striped tubulointerstitial fibrosis associated with an increase in PRA. These data suggest a role for the renin-angiotensin system in the pathogenesis of functional and structural changes of chronic FK nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)646-654
Number of pages9
JournalClinical and Experimental Pharmacology and Physiology
Volume22
Issue number9
StatePublished - 1995

Fingerprint

Tacrolimus
Salts
Renin
Sodium
Diet
Sodium-Restricted Diet
Renal Circulation
Organ Transplantation
Immunosuppressive Agents
Renin-Angiotensin System
Glomerular Filtration Rate
Autoimmune Diseases
Cicatrix
Sprague Dawley Rats
Edema
Fibrosis
Animal Models
Clinical Trials
Transplants
Kidney

Keywords

  • GFR
  • Hypomagnesaemia
  • Renin-angiotensin system
  • Salt depletion
  • Tracolimus
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Physiology
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Functional and structural characteristics of experimental FK 506 nephrotoxicity. / Andoh, T. F.; Burdmann, E. A.; Lindsley, J.; Houghton, Donald; Bennett, W. M.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 22, No. 9, 1995, p. 646-654.

Research output: Contribution to journalArticle

Andoh, T. F. ; Burdmann, E. A. ; Lindsley, J. ; Houghton, Donald ; Bennett, W. M. / Functional and structural characteristics of experimental FK 506 nephrotoxicity. In: Clinical and Experimental Pharmacology and Physiology. 1995 ; Vol. 22, No. 9. pp. 646-654.
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