title: Cyclosporine and rapamycin act in a synergistic and dose-dependent manner in a model of immunosuppressant-induced kidney damage.
abstract: The combination of cyclosporine (CSA) and rapamycin (RAPA) is a potent and commonly used approach to immunosuppression following solid-organ transplantation. By applying varying doses of CSA and RAPA to the rat salt-depleted model, we aimed to find a dose combination that favored antiproliferation/antifibrosis rather than toxicity. Male Sprague-Dawley rats (350 to 500 g) were salt-depleted for 7 days prior to commencing CSA and RAPA treatment. Serum creatinine and urinary protein/creatinine ratios were measured. Fibrosis was estimated with Sirius red staining of extracellular collagen. mRNA expression of TGF-beta, MMP-2, MMP-9, TIMP-1, and collagen III was assessed with reverse transcriptase PCR. A rise in serum creatinine at 7 and 28 days was observed for CSA 15 mg/kg/d (P = .002) but not CSA 7.5 mg (P = .06) or RAPA 1 mg (P = .69) compared to controls. Twenty-four-hour urinary protein excretion was unchanged compared to controls for all drug doses and combinations. Of the dose combinations, CSA 7.5 mg/d + RAPA 0.5 mg/d produced the lowest serum creatinine for all time points, and inhibited profibrotic TIMP-1 (P = .017), while increasing antifibrotic MMP-2 (P = .009) mRNA expression, compared to CSA treatment alone. Expression of TGF-beta and collagen III was unaltered between groups. CSA treatment produced molecular and biochemical changes indicating renal damage. Addition of RAPA can attenuate this damage, but only with a dose reduction of both agents. The most favorable results were for the dose combination CSA 7.5 mg/kg/d plus RAPA 0.5 mg/kg/d.
authors.affiliation: Transplantation Surgery Group, University of Leicester, Leicester, UK. nicholasbrook@fastmail.fm
authors.forename: N R
authors.initials: NR
authors.lastname: Brook
authors.forename: J R
authors.initials: JR
authors.lastname: Waller
authors.forename: G R
authors.initials: GR
authors.lastname: Bicknell
authors.forename: M L
authors.initials: ML
authors.lastname: Nicholson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003404:Creatinine / Q000097:blood*; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D004039:Diet, Sodium-Restricted; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus