Establishing the molecular pathways involved in chronic allograft nephropathy for testing new noninvasive diagnostic markers

Transplantation. 2007 Feb 27;83(4):448-57. doi: 10.1097/


Background: Chronic allograft nephropathy (CAN) is a cause of graft loss. The multistage processes that result in CAN are poorly understood. Noninvasive assays for detecting allograft dysfunction and predicting long-term outcomes are a priority in transplantation (Tx).

Methods: Renal tissue from kidney transplant patients (KTP) with CAN (n=11) and normal kidneys (NK; n=7) were studied using microarrays. Markers resulting from the microarray analysis (transforming growth factor [TGF]-beta, epidermal growth factor receptor [EGFR], angiotensinogen [AGT]) were tested in urine (Ur) and peripheral blood (PB) samples from the CAN patients (collected at the biopsy time) using reverse-transcriptase real-time polymerase chain reaction. Ur and PB samples from long-term KTP with stable renal function (SRF; n=20) were used as control.

Results: Assuming unequal variances between CAN and NK, using a false discovery rate of 0.005, and running 1,000 of all possible permutations, 728 probe sets were differentially expressed. Genes related to fibrosis and extracellular matrix deposition (i.e., TGF-beta, laminin, gamma 2, metalloproteinases-9, and collagen type IX alpha 3) were up-regulated. Genes related to immunoglobulins, B cells, T-cell receptor, nuclear factor of activated T cells, and cytokine and chemokines receptors were also upregulated. EGFR and growth factor receptor activity (FGFR)2 were downregulated in CAN samples. AGT, EGFR, and TGF-beta levels were statistical different in urine but not in blood samples of CAN patients when compared to KTP with SRF (P<0.001, P=0.04, and P<0.001, respectively).

Conclusions: Genes related to fibrosis, extracellular matrix deposition, and immune response were found up-regulated in CAN. Markers resulting from the microarray analysis were differentially expressed in Ur samples of the CAN patients and in concordance with the microarray profiles.

MeSH terms

  • Adult
  • Angiotensinogen / genetics
  • Biomarkers
  • Chronic Disease
  • ErbB Receptors / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Graft Rejection / blood
  • Graft Rejection / diagnosis*
  • Graft Rejection / genetics*
  • Graft Rejection / urine
  • Humans
  • Kidney Diseases / blood
  • Kidney Diseases / diagnosis*
  • Kidney Diseases / genetics*
  • Kidney Diseases / urine
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • RNA, Messenger / genetics
  • Signal Transduction*
  • Transforming Growth Factor beta / genetics
  • Transplantation, Homologous


  • Biomarkers
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Angiotensinogen
  • ErbB Receptors