title: Sirolimus and proteinuria in renal transplant patients: evidence for a dose-dependent effect on slit diaphragm-associated proteins.
abstract: BACKGROUND
  The mechanisms underlying the development of proteinuria in renal-transplant recipients converted from calcineurin inhibitors to sirolimus are still unknown.
  
  
  METHODS
  This is a single-center cohort study. One hundred ten kidney transplant recipients converted from calcineurin inhibitors to sirolimus in the period from September 2000 to December 2005 were included in the study. All patients underwent a graft biopsy before conversion (T0) and a second protocol biopsy 2 years thereafter (T2), according to our standard clinical protocol. On the basis of the changes observed in proteinuria between T0 and T2 (median 70%), the patients were divided into two groups: group I (<70%) and group II (>70%). The authors blinded the sirolimus blood trough levels. We investigated in vivo the effects of sirolimus on nephrin, podocin, CD2ap, and actin protein expression. Slit diaphragm (SD)-associated protein expressions were evaluated in T0 and T2 biopsies. The same analysis was performed in cultured human podocytes treated with different doses of sirolimus (5, 10, 20, and 50 ng/mL).
  
  
  RESULTS
  The SD protein expression in group II T2 biopsies was significantly reduced compared with the T0 biopsies and with T2 group I biopsies. In addition, sirolimus blood trough levels directly and significantly correlated with the SD protein expression at T2 graft biopsies. Group II patients presented significantly higher sirolimus blood levels than group I. In vitro study confirmed that sirolimus effect on podocytes was dose dependent.
  
  
  CONCLUSIONS
  Our data suggest that sirolimus-induced proteinuria may be a dose-dependent effect of the drug on key podocyte structures.
authors.affiliation: Section of Nephrology, Department of Biomedical Sciences, University of Foggia, Italy. g.stallone@unifg.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stallone
authors.forename: Barbara
authors.initials: B
authors.lastname: Infante
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.forename: Maddalena
authors.initials: M
authors.lastname: Gigante
authors.forename: Eustacchio
authors.initials: E
authors.lastname: Montemurno
authors.forename: Antonia
authors.initials: A
authors.lastname: Loverre
authors.forename: Michele
authors.initials: M
authors.lastname: Rossini
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Schena
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D002460:Cell Line; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D015260:Neprilysin / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000209:etiology* / Q000503:physiopathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D013997:Time Factors; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D025721:WT1 Proteins; C113267:nephrin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D015260:Neprilysin; D020123:Sirolimus