Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN.
BACKGROUND
There is little direct evidence that fibroblasts are involved in the progression of the renal interstitial fibrosis in human glomerulonephritis. With the availability of a new specific marker for fibroblasts, we determined the presence of fibroblasts in kidneys with IgA nephropathy (IgAN) and correlated their numbers with various clinical parameters. In particular, we also prospectively asked if the number of fibroblasts in the renal interstitium correlates with prognosis.


METHODS
Cells positive for fibroblast-specific protein 1 (FSP1) were localized in renal biopsy specimens using immunohistochemistry with anti-FSP1 antibody. Clinical features were analyzed by one-way analysis of variance (ANOVA) with the Bonferroni correction. To assess the prognostic impact of the number of FSP1+ fibroblasts on renal survival in 142 patients with normal serum creatinine, the relationship between covariates to renal survival were evaluated univariately using the log-rank test and multivariately using Cox proportional hazards.


RESULTS
Fibroblasts identified by their expression of FSP1 accumulate in areas showing severe interstitial fibrosis. Some tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) in fibrotic areas also express FSP1. Numbers of FSP1+ fibroblasts directly correlate with serum creatinine (r = 0.74, P < 0.0001) and inversely correlate with estimated creatinine clearance (r = -0.54, P < 0.0001), and by multivariate analysis, the clinical factors influencing renal survival are urinary protein excretion [> or = 1.0 g/day, relative risk (RR) = 4.20, P= 0.032], hypertension (RR 5.85, P = 0.0027), and > or = 20 FSP1+ fibroblasts per high power field (HPF) (RR 7.39, P = 0.0015). Staining for FSP1+ fibroblasts is largely nonoverlapping with alpha-smooth muscle actin+ (alpha-SMA) cells in the interstitium.


CONCLUSIONS
The target protein FSP1 identifies human fibroblasts and tubular epithelium undergoing EMT, and distinguishes them from the diaspora of alpha-SMA+ vascular smooth muscle cells. FSP1+ fibroblasts are critically related to the progression of IgAN; consequently, staining FSP1 in renal biopsy specimens provides a valuable histologic index of progression.
Nishitani
Yoshiharu
Y
First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Iwano
Masayuki
M
Yamaguchi
Yukinari
Y
Harada
Koji
K
Nakatani
Kimihiko
K
Akai
Yasuhiro
Y
Nishino
Toshihiko
T
Shiiki
Hideo
H
Kanauchi
Masao
M
Saito
Yoshihiko
Y
Neilson
Eric G
EG
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D000071999:S100 Calcium-Binding Protein A4
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D000071999:S100 Calcium-Binding Protein A4; C077591:S100A4 protein, human; D003404:Creatinine