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MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

ABSTRACT: BACKGROUND:A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS:Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3?cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS:The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS:miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

SUBMITTER: Trevisani F

PROVIDER: S-EPMC5129818 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

Trevisani Francesco F Ghidini Michele M Larcher Alessandro A Lampis Andrea A Lote Hazel H Manunta Paolo P Alibrandi Maria Teresa Sciarrone MT Zagato Laura L Citterio Lorena L Dell'Antonio Giacomo G Carenzi Cristina C Capasso Giovambattista G Rugge Massimo M Rigotti Paolo P Bertini Roberto R Cascione Luciano L Briganti Alberto A Salonia Andrea A Benigni Fabio F Braconi Chiara C Fassan Matteo M Hahne Jens Claus JC Montorsi Francesco F Valeri Nicola N

British journal of cancer 20161101 11

<h4>Background</h4>A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes.<h4>Methods</h4>Primary objective of our study was to define miRs whose dereg ...[more]

PMID: 27802451

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Project description:BackgroundSeveral predictive factors for chronic kidney disease (CKD) following radical nephrectomy (RN) or partial nephrectomy (PN) have been identified. However, early postoperative laboratory values were infrequently considered as potential predictors. Therefore, this study aimed to develop predictive models for CKD 1 year after RN or PN using early postoperative laboratory values, including serum creatinine (SCr) levels, in addition to preoperative and intraoperative factors. Moreover, the optimal SCr sampling time point for the best prediction of CKD was determined.MethodsData were retrospectively collected from patients with renal cell cancer who underwent laparoscopic or robotic RN (n = 557) or PN (n = 999). Preoperative, intraoperative, and postoperative factors, including laboratory values, were incorporated during model development. We developed 8 final models using information collected at different time points (preoperative, postoperative day [POD] 0 to 5, and postoperative 1 month). Lastly, we combined all possible subsets of the developed models to generate 120 meta-models. Furthermore, we built a web application to facilitate the implementation of the model.ResultsThe magnitude of postoperative elevation of SCr and history of CKD were the most important predictors for CKD at 1 year, followed by RN (compared to PN) and older age. Among the final models, the model using features of POD 4 showed the best performance for correctly predicting the stages of CKD at 1 year compared to other models (accuracy: 79% of POD 4 model versus 75% of POD 0 model, 76% of POD 1 model, 77% of POD 2 model, 78% of POD 3 model, 76% of POD 5 model, and 73% in postoperative 1 month model). Therefore, POD 4 may be the optimal sampling time point for postoperative SCr. A web application is hosted at https://dongy.shinyapps.io/aki_ckd .ConclusionsOur predictive model, which incorporated postoperative laboratory values, especially SCr levels, in addition to preoperative and intraoperative factors, effectively predicted the occurrence of CKD 1 year after RN or PN and may be helpful for comprehensive management planning.

Project description:BackgroundPartial nephrectomy and radical nephrectomy are the relevant surgical therapy options for localised renal cell carcinoma. However, debate regarding the effects of these surgical approaches continues and it is important to identify and summarise high-quality studies to make surgical treatment recommendations.ObjectivesTo assess the effects of partial nephrectomy compared with radical nephrectomy for clinically localised renal cell carcinoma.Search methodsWe searched CENTRAL, MEDLINE, PubMed, Embase, Web of Science, BIOSIS, LILACS, Scopus, two trial registries and abstracts from three major conferences to 24 February 2017, together with reference lists; and contacted selected experts in the field.Selection criteriaWe included a randomised controlled trial comparing partial and radical nephrectomy for participants with small renal masses.Data collection and analysisOne review author screened all of the titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Next, two review authors independently assessed full-text reports, identified relevant studies, evaluated the eligibility of the studies for inclusion, assessed trial quality and extracted data. The update of the literature search was performed by two independent review authors. We used Review Manager 5 for data synthesis and data analyses.Main resultsWe identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years.Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000.Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life.Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses.Authors' conclusionsPartial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.

Project description:Histone deacetylase 3 (HDAC3) plays a pivotal role in the repression of cartilage-specific gene expression in human chondrocytes. The aim of this study was to determine whether microRNA-193b-3p (miR-193b-3p) regulates the expression of HDAC3 during chondrogenesis and chondrocyte metabolism. Methods: miR-193b-3p expression was assessed in a human mesenchymal stem cell (hMSC) model of chondrogenesis, in interleukin-1? (IL-1?)-treated primary human chondrocytes (PHCs), and in non-degraded and degraded cartilage. hMSCs and PHCs were transfected with miR-193b-3p or its antisense inhibitor. A direct interaction between miR-193b-3p and its putative binding site in the 3'-untranslated region (3'-UTR) of HDAC3 mRNA was confirmed by performing luciferase reporter assays. Chondrocytes were transfected with miR-193b-3p before performing a chromatin immunoprecipitation assay with an anti-acetylated histone H3 antibody. To investigate miR-193b-3p-transfected PHCs in vivo, they were seeded in tricalcium phosphate-collagen-hyaluronate (TCP-COL-HA) scaffolds, which were then implanted in nude mice. In addition, plasma exosomal miR-193b-3p in samples from normal controls and patients with osteoarthritis (OA) were measured. Results: miR-193b-3p expression was elevated in chondrogenic and hypertrophic hMSCs, while expression was significantly reduced in degraded cartilage compared to non-degraded cartilage. In addition, miR-193b-3p suppressed the activity of reporter constructs containing the 3'-UTR of HDAC3, inhibited HDAC3 expression, and promoted histone H3 acetylation in the COL2A1, AGGRECAN, COMP, and SOX9 promoters. Treatment with the HDAC inhibitor trichostatin A (TSA) increased cartilage-specific gene expression and enhanced hMSCs chondrogenesis. TSA also increased AGGRECAN expression and decreased MMP13 expression in IL-1?-treated PHCs. Further, 8 weeks after implanting PHC-seeded TCP-COL-HA scaffolds subcutaneously in nude mice, we found that miR-193b overexpression strongly enhanced in vivo cartilage formation compared to that found under control conditions. We also found that patients with OA had lower plasma exosomal miR-193b levels than control subjects. Conclusions: These findings indicate that miR-193b-3p directly targets HDAC3, promotes H3 acetylation, and regulates hMSC chondrogenesis and metabolism in PHCs.

Project description:ObjectiveTo identify the association between renal tumor complexity and pathologic renal sinus invasion (RSI) and evaluate the usefulness of computed tomography tumor features for predicting RSI in patients with renal cell carcinoma (RCC).Materials and methodsThis retrospective study included 276 consecutive patients who underwent radical nephrectomy for RCC with a size of ≤ 7 cm between January 2014 and October 2017. Tumor complexity and anatomical renal sinus involvement were evaluated using two standardized scoring systems: the radius (R), exophytic or endophytic (E), nearness to collecting system or sinus (N), anterior or posterior (A), and location relative to polar lines (RENAL) nephrometry and preoperative aspects and dimensions used for anatomical classification (PADUA) system. CT-based tumor features, including shape, enhancement pattern, margin at the interface of the renal sinus (smooth vs. non-smooth), and finger-like projection of the mass, were also assessed by two independent radiologists. Univariable and multivariable logistic regression analyses were performed to identify significant predictors of RSI. The positive predictive value, negative predictive value (NPV), accuracy of anatomical renal sinus involvement, and tumor features were evaluated.ResultsEighty-one of 276 patients (29.3%) demonstrated RSI. Among highly complex tumors (RENAL or PADUA score ≥ 10), the frequencies of RSI were 42.4% (39/92) and 38.0% (71/187) using RENAL and PADUA scores, respectively. Multivariable analysis showed that a non-smooth margin and the presence of a finger-like projection were significant predictors of RSI. Anatomical renal sinus involvement showed high NPVs (91.7% and 95.2%) but low accuracy (40.2% and 43.1%) for RSI, whereas the presence of a non-smooth margin or finger-like projection demonstrated comparably high NPVs (90.0% and 91.3% for both readers) and improved accuracy (67.0% and 73.9%, respectively).ConclusionA non-smooth margin or the presence of a finger-like projection can be used as a preoperative CT-based tumor feature for predicting RSI in patients with RCC.

Dataset Information

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

Publications

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

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