Depletion of clusterin in renal diseases causing nephrotic syndrome.
BACKGROUND
Clusterin is a lipoprotein that has anti-complement effects in membranous nephropathy (MN). In focal segmental glomerulosclerosis (FSGS), it inhibits permeability plasma factor activity and could influence proteinuria. Moreover, with aging, knockout mice for clusterin develop a progressive glomerulopathy with sclerosis.


METHODS
Since little is known about clusterin metabolism in humans, we determined clusterin levels and composition in the sera and urine of 23 patients with MN, 25 with FSGS and 23 with steroid-responsive nephrotic syndrome (NS). Renal localization was evaluated by immunofluorescence and morphometry.


RESULTS
Serum clusterin was markedly reduced in active MN, in FSGS and in children with NS compared to controls; after stable remission of proteinuria, nearly normal levels were restored. Among various biochemical variables, serum clusterin was inversely correlated with hypercholesterolemia. Urinary clusterin, representing a 0.01 fraction of serum, was higher in the urine from normal subjects and FSGS patients in remission with proteinuric MN, FSGS and idiopathic NS; clusterin was inversely correlated with proteinuria. In all cases, urinary and serum clusterin was composed of the same 80 kD isoforms. Finally, a decrease in focal segmental or global clusterin staining was found in FSGS glomeruli, especially in areas of sclerosis. Instead, in MN an overall increment of staining was observed that ranged from mild/focal to very intense/diffuse.


CONCLUSIONS
The overall pool of clusterin is reduced in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature. Depletion of clusterin should negatively affect the clinical outcome in nephrotic patients and efforts should be aimed at normalizing clusterin overall pool.
Ghiggeri
Gian Marco
GM
Laboratory on Pathophysiology of Uremia and Unit of Nephrology, Istituto Giannina Gaslini, Genova, Italy. labnefro@ospedale-gaslini.ge.it
Bruschi
Maurizio
M
Candiano
Giovanni
G
Rastaldi
Maria Pia
MP
Scolari
Francesco
F
Passerini
Patrizia
P
Musante
Luca
L
Pertica
Nicoletta
N
Caridi
Gianluca
G
Ferrario
Franco
F
Perfumo
Francesco
F
Ponticelli
Claudio
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D051152:Clusterin; D015331:Cohort Studies; D005260:Female; D005455:Fluorescent Antibody Technique; D015433:Glomerulonephritis, Membranous / Q000097:blood / Q000150:complications / Q000652:urine; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000150:complications / Q000652:urine; D006023:Glycoproteins / Q000097:blood* / Q000652:urine; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000097:blood* / Q000652:urine; D009404:Nephrotic Syndrome / Q000097:blood* / Q000209:etiology* / Q000652:urine
C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones