Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

Shunsaku Nakagawa,Motoko Yanagita,Atsushi Fukatsu,Yoshinobu Igarashi,Noriyuki Iehara,Takeshi Matsubara,Kazuo Matsubara,Moto Kajiwara,Satohiro Masuda,Haruka Shinke,Kumiko Nishihara,Hiroshi Yamada,Hitomi Miyata,Eri Tomita,Hideharu Abe

doi:10.1371/journal.pone.0136994

Abstract

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.

Highlights

Physiological changes in the course of chronic kidney disease (CKD) produce a complex series of outcomes, including loss of kidney function, leading to end-stage renal failure
The differences between the gene expression profiles of these 48 biopsies and that of a control kidney RNA sample were assessed by microarray analysis
We conducted a microarray analysis of renal biopsies from individuals with CKD to explore their gene expression patterns in relation to relevant histopathological information. This resulted in the identification of gene expression differences that associated with progression of tubulointerstitial fibrosis and tubular cell damage, and these results were validated in a rodent model of CKD

Summary

Introduction

Physiological changes in the course of chronic kidney disease (CKD) produce a complex series of outcomes, including loss of kidney function, leading to end-stage renal failure. In CKD, the irreversible and progressive loss of nephrons results in glomerular sclerosis, tubular atrophy, tubulointerstitial fibrosis, and eventually further reductions in nephron numbers Pathological changes such as tubular cell atrophy and interstitial fibrosis are commonly seen in progressive renal disease, irrespective of the initial etiology; these are cardinal features of CKD [1, 2]. Naesens et al used microarrays to profile renal allografts and identified a molecular signature associated with tubular atrophy and interstitial fibrosis following kidney transplantation [10]. These findings suggested that transcriptional profiling of renal biopsy specimens from CKD patients could assist with diagnosis or therapeutic intervention in this condition. They provided information that may contribute to the identification of useful CKD biomarkers in urine and other body fluids

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