High sirolimus levels may induce focal segmental glomerulosclerosis de novo.
Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.
Letavernier
Emmanuel
E
Service de Transplantation Adulte Hôpital Necker, 149 rue de Sèvres 75743 Paris, France.
Bruneval
Patrick
P
Mandet
Chantal
C
Duong Van Huyen
Jean-Paul
JP
Péraldi
Marie-Noëlle
MN
Helal
Imed
I
Noël
Laure-Hélène
LH
Legendre
Christophe
C
D000328:Adult; D001706:Biopsy; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000139:chemically induced*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects*
D007166:Immunosuppressive Agents; D020123:Sirolimus