Abstract
The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.
Highlights
Kidney transplantation is the best available treatment for patients with end-stage kidney disease [1,2]
Since it is known that cyclosporine A (CsA) nephrotoxicity includes pathological increased production and decreased degradation of extracellular matrix proteins, including collagen, and TGF-β up-regulation [20,21,22], we explored a potential differential role of PRO-C6 as a biomarker of fibrosis among patients under different immunosuppressive regimens
This study shows, in a homogeneous well-characterized cohort of kidney transplant recipients (KTRs) who were participants of the maintenance immunosuppression early after kidney transplantation (MECANO) clinical trial, that 6-month post-transplant plasma concentration of PRO-C6 associates with graft biopsy-proven fibrotic and inflammatory changes, both cross-sectionally (IF/TA score) and longitudinally (IF/TA score and ti-score)
Summary
Kidney transplantation is the best available treatment for patients with end-stage kidney disease [1,2]. An important threat to long-term graft survival is progressive loss of kidney allograft function related to progressive fibrosis [4]. Early identification of fibrosis appearance remains a challenge [5]. Biopsy samples are the gold standard for the detection of established kidney fibrosis, but this has the evident drawback as a follow-up measurement of requiring an invasive procedure, which generates discomfort for the patients and can be complicated by bleeding. Great interest exists in finding non-invasive biomarkers that can detect fibrosis formation, ideally at early stages [4]
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