Molecular Pathways Involved in Loss of Kidney Graft Function with Tubular Atrophy and Interstitial Fibrosis

Abstract

Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF) causes most kidney allograft losses. We aimed to identify the molecular pathways involved in IF/TA progression. Kidney biopsies from normal kidneys (n = 24), normal allografts (n = 6), and allografts with IF/TA (n = 17) were analyzed using high-density oligonucleotide microarray. Probe set level tests of hypotheses tests were conducted to identify genes with a significant trend in gene expression across the three groups using Jonckheere-Terpstra test for trend. Interaction networks and functional analysis were used. An unsupervised hierarchical clustering analysis showed that all the IF/TA samples were associated with high correlation. Gene ontology classified the differentially expressed genes as related to immune response, inflammation, and matrix deposition. Chemokines (CX), CX receptor (for example, CCL5 and CXCR4), interleukin, and interleukin receptor (for example, IL-8 and IL10RA) genes were overexpressed in IF/TA samples compared with normal allografts and normal kidneys. Genes involved in apoptosis (for example, CASP4 and CASP5) were importantly overexpressed in IF/TA. Genes related to angiogenesis (for example, ANGPTL3, ANGPT2, and VEGF) were downregulated in IF/TA. Genes related to matrix production-deposition were upregulated in IF/TA. A distinctive gene expression pattern was observed in IF/TA samples compared with normal allografts and normal kidneys. We were able to establish a trend in gene expression for genes involved in different pathways among the studied groups. The top-scored networks were related to immune response, inflammation, and cellto-cell interaction, showing the importance of chronic inflammation in progressive graft deterioration.

Histogenomics: Association of Gene Expression Patterns With Histological Parameters in Kidney Biopsies

“…In a recent study, Maluf et al (13) identified genes and molecular pathways associated with ta and if and the loss of kidney graft function. Genes associated with damaged tissue were mainly involved in inflammatory processes like the chemokine ligand 5 (CCL5), the chemokine receptor 4 (CXCR4), interleukin 8 (IL8), and the interleukin 10 receptor alpha (IL10RA), or the proapoptotic caspase genes 4 and 5 (CASP4 and CASP5).…”

Impaired Kidney Allograft: How Long Can It Function? A Single-Center Study of the Transplantation Population

“…Our study of long-term outcome in kidney transplant patients with impaired function (eGFR < 40 mL/min/1.73 m 2 after 6 months) has shown that death-censored graft survival was predominantly dependent on the immune insult, that is, the severity of early rejection episodes and occurrence of late rejection episodes. For a decade the progressive renal allograft dysfunction resulting from cumulative histologic damage to the allograft was believed to be the major cause of late renal allograft loss after recipient death with a functioning graft [4,5]. Results of this study have shown that the principle determinant leading to graft failure in patients with inferior graft function seems to be severe immune response superimposed on kidney procured from advanced-age donors and suffering from DGF or surgical complications.…”

Defining nephrotic syndrome from an integrative genomics perspective

“…Maluf et al [89] observed a distinctive gene expression pattern in kidney allografts with tubular atrophy and interstitial fibrosis versus normal tissue. These genes were related to immune response, inflammation and matrix deposition.…”