MOLECULAR MECHANISMS OF CHRONIC KIDNEY GRAFT INJURY

W. Park¹, M. Griffin², M.D. Stegall¹, F. Cosio^3
1Transplantation Surgery, Mayo Clinic, Rochester/MN/UNITED STATES OF AMERICA, ², Regenerative Medicine Institute, National University of Ireland, Galway/IRELAND, ³Nephrology, Mayo Clinic, Rochester/MN/UNITED STATES OF AMERICA

Body: Introduction. Despite excellent 5-yr graft survival, many living donor kidney transplants (LDKTx) with normal or mild interstitial fibrosis on 1-yr protocol biopsy show significant decrements in GFR between 1 and 5 yrs. This study assessed intragraft gene expression in 1-yr protocol biopsies that might identify patients destined for a decline in GFR. Methods. Inclusion criteria: 1) Adult LDKTx from 2000-07 with 1-yr protocol biopsy classified as either normal (i/cg=0, ci=0; n=181) or mild fibrosis (i/cg=0, ci=1-2; n=89); 2) tacrolimus-treated without DGF, AR or BK during the first year; and 3) 1-yr eGFR ≥40 ml/min (modified MDRD). To determine the stability of patient GFR, the mean eGFR was calculated for sequential 6 month intervals between 1 and 5 years post-transplant. From these means (≥5 /pt) a linear equation was created to determine if the patient had Stable GFR (slope ≥ -3 ml/min/yr) or Declining GFR (slope < -3.0 ml/min/yr). Gene expression profiles on 1-yr biopsies were assessed by whole transcriptome microarray. Results. 213/270 (79%) subjects were classified as Stable GFR (mean slope= 0.5 ± 2.2 ml/min/yr) and 57/270 (21%) as Declining GFR (mean slope= -6.5 ± 3.8). Importantly, the incidence of Declining GFR was similar in allografts whose 1-yr biopsy was normal (20%) or had mild fibrosis (24%). Mean eGFR follow-up was longer (1840 ± 378 vs 1650 ± 385 days, p<0.01) and death-censored graft survival was higher (100% vs 90%) for the Stable GFR group. Microarray analysis of 1-yr biopsies revealed differential expression of 652/14529 genes between Stable and Declining GFR patients. Declining GFR was associated with upregulation of multiple immune/inflammatory pathways and genes involved in Antigen Presentation (i.e. HLA-DRβ), Dendritic Cell Maturation (IRF8), T-helper Differentiation (IFNγR1) and Interferon Signaling (IRF1). Analysis of Pathobiology-Based Transcripts indicated increased expression of IFNγ-induced and CTL-associated transcripts. Kidney injury-associated transcripts were not differentially expressed. Conclusions. Increased expression of immune/inflammatory transcripts in relatively normal 1-yr protocol biopsies correlates with subsequent GFR decline in LDKTx. This might allow for the early identification of patients in whom therapeutic interventions are needed.

Disclosure: All authors have declared no conflicts of interest.