Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506

Takeshi F. Andoh, Emmanuel A. Burdmann, Nora Fransechini, Donald Houghton, William M. Bennett

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunophilin, also inhibits calcineurin. We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.), RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood flow and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drugs is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand may be related to inhibition of calcineurin.

Original languageEnglish (US)
Pages (from-to)1110-1117
Number of pages8
JournalKidney International
Volume50
Issue number4
StatePublished - 1996
Externally publishedYes

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Calcineurin
Tacrolimus
Sirolimus
Cyclosporine
Kidney
Immunosuppressive Agents
Glomerular Filtration Rate
Pharmaceutical Preparations
Immunophilins
Nephrocalcinosis
Sodium-Restricted Diet
Renal Circulation
Wounds and Injuries
Vasoconstriction
Magnesium
Nitric Oxide
Theoretical Models

ASJC Scopus subject areas

  • Nephrology

Cite this

Andoh, T. F., Burdmann, E. A., Fransechini, N., Houghton, D., & Bennett, W. M. (1996). Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney International, 50(4), 1110-1117.

Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. / Andoh, Takeshi F.; Burdmann, Emmanuel A.; Fransechini, Nora; Houghton, Donald; Bennett, William M.

In: Kidney International, Vol. 50, No. 4, 1996, p. 1110-1117.

Research output: Contribution to journalArticle

Andoh, TF, Burdmann, EA, Fransechini, N, Houghton, D & Bennett, WM 1996, 'Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506', Kidney International, vol. 50, no. 4, pp. 1110-1117.
Andoh TF, Burdmann EA, Fransechini N, Houghton D, Bennett WM. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney International. 1996;50(4):1110-1117.
Andoh, Takeshi F. ; Burdmann, Emmanuel A. ; Fransechini, Nora ; Houghton, Donald ; Bennett, William M. / Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. In: Kidney International. 1996 ; Vol. 50, No. 4. pp. 1110-1117.
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