Abstract
BackgroundProximal 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.MethodsThirty-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.ResultsOnly 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.ConclusionThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-015-0059-6) contains supplementary material, which is available to authorized users.
Highlights
Proximal tubular dysfunction (PTD) is characterized by proteinuria, aminoaciduria, and glucosuria
The biopsies of three patients from group 1 showed no evidence of interstitial fibrosis and tubular atrophy (IF/TA), while nine, three, and zero biopsies showed mild, moderate, and severe IF/TA, respectively
For group 2, the biopsies of two patients at enrollment showed no evidence of IF/TA, while nine, five, and two biopsies showed mild, moderate, and severe IF/TA, Table 1 Baseline clinical and laboratory characteristics of the renal transplant patients enrolled in this study (n = 33)
Summary
Proximal tubular dysfunction (PTD) is characterized by proteinuria, aminoaciduria, and glucosuria It is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins [1, 2]. Increased urinary levels of the LMWP urinary retinol-binding protein (uRBP) have been associated with tubular injury and fibrosis after renal transplantation [8, 9]. 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
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