Molecular assessment of renal allografts has already been suggested in antibody-mediated rejection (ABMR), but little is known about the gene transcript patterns in particular renal compartments. We used laser capture microdissection coupled with quantitative RT-PCR to distinguish the transcript patterns in the glomeruli and tubulointerstitium of kidney allografts in sensitized retransplant recipients at high risk of ABMR. The expressions of 13 genes were quantified in biopsies with acute active ABMR, chronic active ABMR, acute tubular necrosis (ATN), and normal findings. The transcripts were either compartment specific (TGFB1 in the glomeruli and HAVCR1 and IGHG1 in the tubulointerstitium), ABMR specific (GNLY), or follow-up specific (CXCL10 and CX3CR1). The transcriptional profiles of early acute ABMR shared similarities with ATN. The transcripts of CXCL10 and TGFB1 increased in the glomeruli in both acute ABMR and chronic active ABMR. Chronic active ABMR was associated with the upregulation of most genes (SH2D1B, CX3CR1, IGHG1, MS4A1, C5, CD46, and TGFB1) in the tubulointerstitium. In this study, we show distinct gene expression patterns in specific renal compartments reflecting cellular infiltration observed by conventional histology. In comparison with active ABMR, chronic active ABMR is associated with increased transcripts of tubulointerstitial origin.

• Keywords
• antibody-mediated rejection, gene expression, kidney transplantation, laser capture microdissection, renal compartments,
• MeSH
• Biopsy MeSH
• Chronic Disease MeSH
• Adult MeSH
• Kidney Glomerulus immunology   metabolism   pathology   MeSH
• HLA Antigens immunology   MeSH
• Isoantibodies immunology   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Laser Capture Microdissection MeSH
• Kidney immunology   metabolism   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Graft Rejection genetics   immunology   metabolism   pathology   MeSH
• Aged MeSH
• Gene Expression Profiling MeSH
• Case-Control Studies MeSH
• Transcriptome * MeSH
• Kidney Transplantation adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• HLA Antigens MeSH
• Isoantibodies MeSH

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

• MeSH
• Acyclovir analogs & derivatives   therapeutic use   MeSH
• Antiviral Agents therapeutic use   MeSH
• Atrophy MeSH
• Biopsy MeSH
• Cytomegalovirus Infections mortality   prevention & control   MeSH
• Cytomegalovirus isolation & purification   MeSH
• Adult MeSH
• Fibrosis MeSH
• Ganciclovir analogs & derivatives   therapeutic use   MeSH
• Kaplan-Meier Estimate MeSH
• Kidney pathology   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Follow-Up Studies MeSH
• Graft Survival MeSH
• Kidney Transplantation * mortality   MeSH
• Valacyclovir MeSH
• Valganciclovir MeSH
• Valine analogs & derivatives   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Acyclovir MeSH
• Antiviral Agents MeSH
• Ganciclovir MeSH
• Valacyclovir MeSH
• Valganciclovir MeSH
• Valine MeSH

Earlier detection of antibody-mediated rejection of kidney allografts may improve graft outcomes. Profiling of gene expression holds promise for the diagnosis and prognosis of antibody-mediated rejection. Here, we identified 730 patients who received kidney transplants during 2002-2005, including 21 patients (2.9%) who experienced early acute antibody-mediated rejection. We also identified a matched group of 43 patients with early acute T cell-mediated rejection to serve as controls. Compared with patients with T cell-mediated rejection, those with antibody-mediated rejection had significantly higher intrarenal mRNA expression of the cytoprotective heme oxygenase-1 but had lower expression of the regulatory T cell marker forkhead box P3 (FoxP3), the B cell marker CD20, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES). T cell infiltration was similar in both groups of patients. Compared with grafts that had a favorable course, those that failed as a result of antibody-mediated rejection had expression profiles suggesting a lack of regulation (less FoxP3, TGF-beta1, RANTES, and CD20). Grafts that failed as a result of T cell-mediated rejection only revealed lower expression of CD20 mRNA. In summary, these data suggest that severe antibody-mediated rejection and T cell-mediated rejection result in graft loss by distinct mechanisms. Molecular phenotypes of early acute rejection might help to identify grafts with poor prognosis, allowing earlier application of additional therapies.

• MeSH
• Antigens, CD20 genetics   metabolism   MeSH
• Chemokine CCL5 genetics   metabolism   MeSH
• Adult MeSH
• Phenotype * MeSH
• Forkhead Transcription Factors genetics   metabolism   MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Predictive Value of Tests MeSH
• Prognosis MeSH
• Antibodies immunology   MeSH
• Graft Rejection genetics   immunology   MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Gene Expression Profiling * MeSH
• Case-Control Studies MeSH
• T-Lymphocytes immunology   MeSH
• Transforming Growth Factor beta1 genetics   metabolism   MeSH
• Kidney Transplantation immunology   physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, CD20 MeSH
• Chemokine CCL5 MeSH
• Forkhead Transcription Factors MeSH
• FOXP3 protein, human MeSH Browser
• Antibodies MeSH
• Transforming Growth Factor beta1 MeSH