title: Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery.
abstract: BACKGROUND
  Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery.
  
  
  METHODS
  Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network.
  
  
  RESULTS
  Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress.
  
  
  CONCLUSIONS
  These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function.
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: Hátylas
authors.initials: H
authors.lastname: Azevedo
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Paulo Guilherme
authors.initials: PG
authors.lastname: Renesto
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.|Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Albert Einstein, São Paulo, Brazil.
authors.forename: Rogério
authors.initials: R
authors.lastname: Chinen
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Erika
authors.initials: E
authors.lastname: Naka
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.|Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Albert Einstein, São Paulo, Brazil.
authors.forename: Ana Cristina Carvalho
authors.initials: AC
authors.lastname: de Matos
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Marcos Antônio
authors.initials: MA
authors.lastname: Cenedeze
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Moreira-Filho
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, Universidade de São Paulo (USP), São Paulo, Brazil. niels@icb.usp.br.|Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. niels@icb.usp.br.
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Câmara
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. alvaro.pfilho@einstein.br.|Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Albert Einstein, São Paulo, Brazil. alvaro.pfilho@einstein.br.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
mesh_terms: D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage; D005198:Fanconi Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000652:urine; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011897:Random Allocation; D054840:Retinol-Binding Proteins, Cellular / Q000652:urine; D013256:Steroids / Q000008:administration & dosage; D059467:Transcriptome / Q000235:genetics*
chemical_list: D054840:Retinol-Binding Proteins, Cellular; D013256:Steroids; D016572:Cyclosporine; D001379:Azathioprine