Loss of nephrin expression in glomeruli of kidney-transplanted patients under m-TOR inhibitor therapy.
The development of proteinuria has been observed in kidney-transplanted patients on m-TOR inhibitor (m-TORi) treatment. Recent studies suggest that m-TORi(s) may alter the behavior and integrity of glomerular podocytes. We analyzed renal biopsies from kidney-transplanted patients and evaluated the expression of nephrin, a critical component of the glomerular slit-diaphragm. In a group of patients on 'de novo' m-TORi-treatment, the expression of nephrin within glomeruli was significantly reduced in all cases compared to pretransplant donor biopsies. Biopsies from control transplant patients not treated with m-TORi(s) failed to present a loss of nephrin. In a group of patients subsequently converted to m-TORi-treatment, a protocol biopsy performed before introduction of m-TORi was also available. The expression of nephrin in the pre-m-TORi biopsies was similar to that observed in the pretransplant donor biopsies but was significantly reduced after introduction of m-TORi(s). Proteinuria increased after the m-TORi inititiation in this group. However, in some cases proteinuria remained normal despite reduction of nephrin. In vitro, sirolimus downregulated nephrin expression by human podocytes. Our results suggest that m-TORi(s) may affect nephrin expression in kidney-transplanted patients, consistently with the observation in vitro on cultured podocytes.
Biancone
L
L
Division of Nephrology Dialysis and Transplantation, Department of Internal Medicine, San Giovanni Battista Hospital and University of Torino, Italy. luigi.biancone@unito.it
Bussolati
B
B
Mazzucco
G
G
Barreca
A
A
Gallo
E
E
Rossetti
M
M
Messina
M
M
Nuschak
B
B
Fop
F
F
Medica
D
D
Cantaluppi
V
V
Camussi
G
G
Segoloni
G P
GP
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D050199:Podocytes / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D008565:Membrane Proteins; C113267:nephrin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus