Probabilistic (Bayesian) Modeling of Gene Expression in Transplant Glomerulopathy

Abstract

Transplant glomerulopathy (TG) is associated with rapid decline in glomerular filtration rate and poor outcome. We used low-density arrays with a novel probabilistic analysis to characterize relationships between gene transcripts and the development of TG in allograft recipients. Retrospective review identified TG in 10.8% of 963 core biopsies from 166 patients; patients with stable function were studied for comparison. The biopsies were analyzed for expression of 87 genes related to immune function and fibrosis by using real-time PCR , and a Bayesian model was generated and validated to predict histopathology based on gene expression. A total of 57 individual genes were increased in TG compared with stable function biopsies (P < 0. Long-term kidney allograft function continues to improve only modestly, despite dramatic improvements in acute rejection rates and short term patient and graft survivals. Despite its limitations, measurement of serum creatinine remains the primary monitoring modality following kidney transplantation. Significant changes in serum creatinine, and/or the development of proteinuria, result in a series of maneuvers to define the many potential etiologies of acute and chronic allograft dysfunction. Allograft biopsy is the "gold-standard" of these maneuvers, although morphological analysis may not easily distinguish these etiologies. Furthermore, the analysis may be limited in regards to prognostic importance and functional outcome. Thus, identification of biomarkers of allograft failure and the development of tools for their interpretation is of critical interest, both in providing disease detection in a more sensitive and specific fashion, and in allowing sufficient lead time for intervention. Additionally, such markers may allow for risk assessment and medical-regimen tailoring that is personalized to provide optimum outcomes.Transplant glomerulopathy (TG) is a disease of the kidney allograft initiated by endothelial injury. Morphologically, there is widening of the subendothelial space with accumulation of debris, mesangial interpositioning, and matrix deposition in the glomerular capillary wall, as well as capillary wall double-contouring in the absence of immune complex Supported in part by the US Navy Bureau of Medicine and Surgery and by the intramural research program of the National Institute of Diabetes Digestive and Kidney Diseases Z01-DK062008 (R.B.M.).The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. This work was prepared as part of our official duties. Title 17 U.S.C. §105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties.The author contributions are as follows: conception and design: E.A.E., ...

The Clinical and Genomic Significance of Donor-Specific Antibody–Positive/C4d-Negative and Donor-Specific Antibody–Negative/C4d-Negative Transplant Glomerulopathy

“…Homs et al reported increased expression of IFN-g, T-bet (a marker for Th1 CD4 T cells), and granzyme B (a CD8 marker) in TGP biopsy specimens, suggesting an active T cell-mediated inflammatory and cytotoxic process in the pathogenesis of TGP (11). Several other studies have also recognized that an increased cellular immune response involving T cells and monocytes is associated with the development of TGP (12)(13)(14). In our study group, half of the patients with DSA2/C4d2 TGP with g + ptc score of 0 or g + ptc + i score #1 had no significant inflammatory cells, but we did not have adequate biopsy samples for microarray gene expression analysis.…”

“…Elster et al investigated the intragraft gene expression of TGP biopsy specimens using 87 genes related to immune function and fibrosis (13). Fifty-seven genes were increased in 20 TGP biopsy specimens compared with stable kidney allografts, including ICAM-1, IL-10, CCL3, and CD86.…”

“…TGP is reported to be associated with donor-specific antibody (DSA), especially class II DSA (5,8), but histologic evidence of TGP may be seen without C4d and DSA (9). Increased chemokine (CXCL9 and CXCL10) and chemokine receptor (CXCR3) expression by glomerular leukocytes, which is associated with effector T cell activation (10) and other T cell-mediated inflammatory or cytotoxic processes (11)(12)(13)(14), have been demonstrated in TGP biopsy specimens. Nonimmune mechanisms may also be associated with TGP, as suggested by a recent report of hepatitis C virus infection (36%) and thrombotic microangiopathy (32%) in 25 patients with TGP (15).…”

Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor‐specific antibody

“…There are extensive animal and initial human data that T‐cell recognition of processed alloantigen via the indirect pathway is a key factor initiating and maintaining the progression of chronic allograft rejection . Increased intragraft effector T‐cell activation and other T cell‐mediated inflammatory or cytotoxic processes have been demonstrated in TG biopsies . We previously reported that DSA−/C4d− TG biopsies show increased expression of cytotoxic T cell‐associated transcripts but not gene transcripts seen in ABMR .…”

Matrix metalloproteinases in kidney homeostasis and diseases

“…Chronic rejection remains the major limitation of renal transplantation, and circumstantial evidence may indicate a role for MMPs. Numerous studies have collectively identified increases in MMP-2, MMP-7, MMP-8, and MMP-9, as well as TIMP-1 and -2 in cases of allograft rejection (16,27,68,80,104,105,145). Interestingly, polymorphisms in MMP-2 and -9 have been associated with increased allograft survival (116), and the immunosuppressive drug rapamycin inhibits MMP-9 expression while increasing TIMP-1 (94).…”