Vavrincova-Yaghi Diana, Seelen Marc A, Kema Ido P, Deelman Leo E, van der Heuvel Marius C, Breukelman Henk, Van den Eynde Benoit J, Henning Rob H, van Goor Harry, Sandovici Maria
1 Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands. 2 Graduate School for Drug Exploration (GUIDE), University of Groningen, University Medical Center Groningen, the Netherlands. 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia. 4 Department of Internal Medicine, University of Groningen, University Medical Center Groningen, the Netherlands. 5 Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 6 Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, the Netherlands. 7 Ludwig Institute for Cancer Research, Brussels, Belgium. 8 de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 9 Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Transplantation. 2015 Aug;99(8):e97-104. doi: 10.1097/TP.0000000000000603.
Chronic transplant dysfunction (CTD) is the leading cause of long-term loss of the renal allograft. So far, no single test is available to reliably predict the risk for CTD. Monitoring of tryptophan (trp) metabolism through indoleamine 2.3-dioxygenase (IDO) has been previously proposed to predict acute rejection of human kidney transplants. Here, we investigate the potential of IDO/trp degradation along the kynurenine (kyn) pathway to predict the long-term outcome of human kidney transplantation.
During the 2-year follow-up blood, urine, and kidney biopsies were collected from 48 renal transplant patients. Concentrations of kyn and trp in serum and urine were measured at 2 weeks, 6 months, and 2 years after transplantation. Kynurenine to tryptophan ratio was calculated as an estimate of trp degradation. To evaluate the histological changes and IDO expression, respectively, periodic acid schiff staining and immunohistochemistry for IDO were performed on biopsies taken at 6 months and 2 years.
Two years after transplantation, kyn/trp was increased in urine and decreased in serum as compared to 2-week values. In 2-year biopsies, IDO expression was mainly found in infiltrating inflammatory cells and in the glomeruli. The urine level of trp 2 weeks after transplantation predicted the serum creatinine 6 months and the estimated creatinine clearance 2 years after transplantation. Additionally, serum level of kyn 6 months after transplantation predicted the serum creatinine 2 years after transplantation.
Early serum and urine levels of trp and kyn may offer a novel route for early detection of patients at risk for developing CTD.
慢性移植肾功能障碍（CTD）是肾移植长期失功的主要原因。到目前为止，尚无单一检测方法可可靠预测CTD风险。此前有人提出通过吲哚胺2,3-双加氧酶（IDO）监测色氨酸（trp）代谢来预测人肾移植的急性排斥反应。在此，我们研究沿犬尿氨酸（kyn）途径的IDO/trp降解预测人肾移植长期预后的潜力。
在2年随访期间，收集了48例肾移植患者的血液、尿液和肾活检组织。在移植后2周、6个月和2年时测量血清和尿液中kyn和trp的浓度。计算犬尿氨酸与色氨酸比值作为trp降解的估计值。为分别评估组织学变化和IDO表达，对6个月和2年时获取的活检组织进行高碘酸希夫染色和IDO免疫组化。
移植后2年，与移植后2周的值相比，尿液中kyn/trp升高，血清中降低。在2年时的活检组织中，IDO表达主要见于浸润性炎症细胞和肾小球。移植后2周时尿液中trp水平可预测移植后6个月时的血清肌酐及2年时的估计肌酐清除率。此外，移植后6个月时血清中kyn水平可预测移植后2年时的血清肌酐。
trp和kyn的早期血清及尿液水平可能为早期发现有发生CTD风险的患者提供一条新途径。
