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McKinnon MB, Rini BI, Haake SM. Biomarker-informed care for patients with renal cell carcinoma. NATURE CANCER 2025:10.1038/s43018-025-00942-1. [PMID: 40240621 DOI: 10.1038/s43018-025-00942-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 03/06/2025] [Indexed: 04/18/2025]
Abstract
Kidney cancer is a commonly diagnosed cancer in adults, and clear cell renal cell carcinoma (ccRCC) is the most common histological subtype. Immune checkpoint inhibitors have revolutionized care for patients with ccRCC, either as adjuvant therapy or combined with other agents in advanced disease. However, biomarkers to predict therapeutic benefits are lacking. Here, we explore biomarkers that predict therapeutic response in other tumor types and discuss the reasons for their ineffectiveness in ccRCC. We also review emerging predictive and prognostic biomarkers to prioritize in ccRCC, including gene expression signatures.
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Affiliation(s)
- Mackenzie B McKinnon
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Brian I Rini
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Scott M Haake
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
- Department of Veterans Affairs, Nashville, TN, USA.
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2
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Puia D, Ivănuță M, Pricop C. Kidney Injury Molecule-1 as a Biomarker for Renal Cancer: Current Insights and Future Perspectives-A Narrative Review. Int J Mol Sci 2025; 26:3431. [PMID: 40244290 PMCID: PMC11989683 DOI: 10.3390/ijms26073431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 03/30/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025] Open
Abstract
Kidney injury molecule-1 (KIM-1) is a transmembrane protein that is significantly upregulated in renal cells following injury. It has considerable potential as a biomarker for diagnosing and monitoring renal cell carcinoma (RCC). This review examines KIM-1 expression across multiple biological sources-including tissue, blood, and urine-and highlights its strong association with RCC risk. Clinical studies have shown that KIM-1 levels decline within weeks after nephrectomy, underscoring its utility in assessing therapeutic response. Additionally, urinary KIM-1 levels correlate with histopathological outcomes following cisplatin treatment, supporting its role as a non-invasive marker for treatment effectiveness. Despite these promising findings, several challenges remain. These include variability in assay performance and the modulatory effects of the tumour microenvironment on KIM-1 expression. Overcoming these technical limitations is crucial for integrating KIM-1 into clinical workflows. Furthermore, its potential role in guiding combination therapies-such as tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and mTOR inhibitors-could enhance therapeutic precision while minimizing toxicity. Continued research is essential to validate these applications and facilitate the routine clinical use of KIM-1 in RCC management.
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Affiliation(s)
- Dragoș Puia
- “Grigore T Popa”, Faculty of Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.P.); (C.P.)
- Department of Urology, “Dr. C.I. Parhon” Clinical Hospital, 700503 Iasi, Romania
- Center for Morphological and Spectroscopic Analysis of Urinary Stones “Michel Daudon”, 700503 Iasi, Romania
| | - Marius Ivănuță
- “Grigore T Popa”, Faculty of Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.P.); (C.P.)
- Department of Urology, “Dr. C.I. Parhon” Clinical Hospital, 700503 Iasi, Romania
- Center for Morphological and Spectroscopic Analysis of Urinary Stones “Michel Daudon”, 700503 Iasi, Romania
| | - Cătălin Pricop
- “Grigore T Popa”, Faculty of Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.P.); (C.P.)
- Department of Urology, “Dr. C.I. Parhon” Clinical Hospital, 700503 Iasi, Romania
- Center for Morphological and Spectroscopic Analysis of Urinary Stones “Michel Daudon”, 700503 Iasi, Romania
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3
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He S, Liu D, Chen J, Zhang X, Liang J, Zhao J, Hu X, Liu Z, Zeng H, Sun G. Liquid-based kidney injury molecule-1 as a diagnostic and prognostic indicator in renal cell carcinoma: A systematic review and meta-analysis. Int Urol Nephrol 2025:10.1007/s11255-025-04447-9. [PMID: 40117075 DOI: 10.1007/s11255-025-04447-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/01/2025] [Indexed: 03/23/2025]
Abstract
PURPOSE Noninvasive biomarkers for renal cell carcinoma (RCC) are vital but scarce. Kidney injury molecule-1 (KIM-1) is a transmembranous glycoprotein that is sensitive and specific to kidney injury. KIM-1 is overexpressed in RCC, and its ectodomain can be detected in blood and urine. Here, we explored whether KIM-1 is a diagnostic or prognostic indicator in RCC. METHODS A comprehensive online literature search was performed in PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrails, and Database of major urological or oncological congress. We screened the literature and extracted the data according to the selection criteria. The quality of eligible studies was measured via the Quality Assessment of Diagnostic Accuracy Studies-2 tool and the Newcastle-Ottawa scale. The certainty of the evidence (CoE) was assessed by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) score. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the curve of the summary receiver operating characteristic curve (AUROC), and survival outcomes were subsequently estimated in Stata and MetaDisc. Subgroup analysis, meta-regression, and sensitivity analysis were performed to reveal the source of heterogeneity. RESULTS A total of eight studies were included for further analysis. The pooled sensitivity of KIM-1 for RCC diagnosis was 0.78 (95% CI: 0.69-0.85, I2 = 84.61%, p < 0.01), and the pooled specificity was 0.79 (95% CI: 0.65-0.89, I2 = 90.72%, p < 0.01). The AUROC was 0.85 (95% CI: 0.82-0.88). A moderate CoE was indicated by GRADE score. A higher KIM-1 level was associated with worse disease-free survival (HR = 1.76, 95% CI: 1.48-2.09, I2 = 0.00%, p < 0.001). Study continent, number of study center, and sample type are the potential contributors of heterogeneity. CONCLUSION Liquid-based KIM-1 is a promising noninvasive biomarker for early RCC detection, surveillance, and prognosis prediction. More validations in large cohorts are needed to confirm these findings.
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Affiliation(s)
- Sike He
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Dingbang Liu
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Junru Chen
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Xingming Zhang
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Jiayu Liang
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Jinge Zhao
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Xu Hu
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Zhenhua Liu
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China
| | - Hao Zeng
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China.
| | - Guangxi Sun
- Department of Urology, Institute of Urology, West China Hospital, Chengdu, China.
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4
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Hu Z, Chen S, Zhang E, Wei L, Wang J, Shang Q, Gao X, Huang Y. Novel inflammatory markers in intracerebral hemorrhage: Results from Olink proteomics analysis. FASEB J 2025; 39:e70341. [PMID: 39853806 PMCID: PMC11760662 DOI: 10.1096/fj.202402183rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/04/2025] [Accepted: 01/13/2025] [Indexed: 01/26/2025]
Abstract
Inflammation is a crucial factor in intracerebral hemorrhage (ICH) pathophysiology, but specific inflammatory biomarkers in ICH patients remain unclear. This study aimed to identify novel circulating inflammatory biomarkers for improved ICH prediction and diagnosis. We profiled expression levels of 92 cardiovascular disease related proteins in plasma from 26 matched ICH patients and controls using Olink technology. Differentially expressed proteins were validated using ELISA and RT-qPCR in a second matched cohort. Receiver operating characteristic (ROC) curves evaluated how well the diagnostic tests performed. The study identified 18 inflammatory-related proteins with significantly different expression levels between ICH patients and controls. These proteins participate in critical biological processes and pathways, such as the regulation of inflammatory mediator secretion, cell death, immune cell proliferation and differentiation, pathogen response, and PI3K-Akt and JAK-STAT pathways. Notably, we discovered for the first time that Kidney Injury Molecule-1 (KIM1) is significantly upregulated in the plasma of ICH patients, suggesting its potential as a predictive and diagnostic biomarker for ICH. Validation results from ELISA and RT-qPCR showed that Interleukin-6 (IL-6), Pentraxin 3 (PTX3), KIM1, and Galectin-9 (Gal-9) concentrations were markedly increased in the blood plasma and white matter of individuals with ICH. ROC analysis showed that the combined marker of IL-6, PTX3, KIM1 and Gal-9 had a high diagnostic efficacy (AUC = 0.941). This study identified a novel biomarker panel (IL-6, PTX3, KIM1, Gal-9) for ICH diagnosis. KIM1 upregulation in ICH patients is a novel finding, further investigation is needed into its expression and function in ICH.
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Affiliation(s)
- Ziliang Hu
- Cixi Biomedical Research InstituteWenzhou Medical UniversityNingboZhejiangChina
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
| | - Siqi Chen
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
| | - Enhao Zhang
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
| | - Liangzhe Wei
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
| | - Jieyi Wang
- Department of Clinical LaboratoryThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Qing Shang
- Department of NeurologyThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Xiang Gao
- Cixi Biomedical Research InstituteWenzhou Medical UniversityNingboZhejiangChina
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
| | - Yi Huang
- Department of Neurosurgery, Ningbo Key Laboratory of Nervous System and Brain FunctionThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang ProvinceNingboZhejiangChina
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Rajandram R, Suren Raj TL, Gobe GC, Kuppusamy S. Liquid biopsy for renal cell carcinoma. Clin Chim Acta 2025; 565:119964. [PMID: 39265757 DOI: 10.1016/j.cca.2024.119964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 09/07/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024]
Abstract
Liquid biopsies offer a less invasive alternative to tissue biopsies for diagnosis, prognosis, and determining therapeutic potential in renal cell carcinoma (RCC). Unfortunately, clinical studies using liquid biopsy biomarkers in RCC are limited. Accordingly, we examine RCC biomarkers, derived from urine, plasma, serum and feces of potential impact and clinical outcome in these patients. A PRISMA checklist was used to identify valuable liquid biopsy biomarkers for diagnosis (plasma cfDNA, serum- or urine-derived circulating RNAs, exosomes and proteins), prognosis (plasma cfDNA, plasma- or serum-derived RNAs, and proteins), and therapeutic response (plasma- and serum-derived proteins). Although other analytes have been identified, their application for routine clinical use remains unclear. In general, panels appear more effective than single biomarkers. Important considerations included proof of reproducibility. Unfortunately, many of the examined studies were insufficiently large and lacked multi-center rigor. Cost-effectiveness was also not available. Accordingly, it is clear that more standardized protocols need to be developed before liquid biopsies can be successfully integrated into clinical practice in RCC.
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Affiliation(s)
- Retnagowri Rajandram
- Division of Urology, Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
| | - Tulsi Laxmi Suren Raj
- Division of Urology, Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Glenda Carolyn Gobe
- Kidney Disease Research Collaborative, Translational Research Institute, and School of Biomedical Sciences, University of Queensland, Brisbane, Australia
| | - Shanggar Kuppusamy
- Division of Urology, Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
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Ibrahim H, Sharawy MH, Hamed MF, Abu-Elsaad N. Peficitinib halts acute kidney injury via JAK/STAT3 and growth factors immunomodulation. Eur J Pharmacol 2024; 984:177020. [PMID: 39349115 DOI: 10.1016/j.ejphar.2024.177020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 08/27/2024] [Accepted: 09/26/2024] [Indexed: 10/02/2024]
Abstract
Acute Kidney Injury (AKI) is characterized by a sudden loss of kidney function and its management continues to be a challenge. In this study the effect of peficitinib, a Janus kinase inhibitor (JAKi), was studied in an aim to stop the progression of AKI at an early point of injury. Adult male mice were injected with aristolochic acid (AA) a single dose (10 mg/kg, i.p) to induce AKI. Peficitinib was injected in one of the two tested doses (5 or 10 mg/kg, i.p) 1 h after AA injection and was continued daily for seven days. Histopathological evaluation showed that peficitinib alleviated necrosis and hyaline cast formation induced by aristolochic acid. It decreased serum creatinine and the kidney injury molecule-1 (KIM-1) elevated by AA. Peficitinib also mitigated AA induced oxidative stress through regulating total antioxidant capacity (TAC) and reduced glutathione (GSH) level in renal tissue. Additionally, renal sections isolated from groups that received peficitinib revealed a decrease in vascular endothelial growth factor receptor 1 interstitial expression and transforming growth factor-beta 1 (TGF-β1) renal level. Peficitinib received groups showed a decrease in the active phosphorylated form of signal transducers and activators of transcription (STAT3). Moreover, peficitinib decreased renal protein levels and gene expression of the pro-inflammatory cytokines; interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ). These findings suggest that peficitinib is helpful in halting AKI progression into chronic kidney disease through modulating JAK/STAT3 dependent inflammatory pathways and growth factors involved in normal glomerular function.
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Affiliation(s)
- Hassnaa Ibrahim
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 33516, Egypt; Pharmacist at Urology and Nephrology Center, Mansoura University, Mansoura, 33516, Egypt
| | - Maha H Sharawy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 33516, Egypt.
| | - Mohamed F Hamed
- Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 33516, Egypt
| | - Nashwa Abu-Elsaad
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 33516, Egypt
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Baryła M, Skrzycki M, Danielewicz R, Kosieradzki M, Struga M. Protein biomarkers in assessing kidney quality before transplantation‑current status and future perspectives (Review). Int J Mol Med 2024; 54:107. [PMID: 39370783 PMCID: PMC11448562 DOI: 10.3892/ijmm.2024.5431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/31/2024] [Indexed: 10/08/2024] Open
Abstract
To meet the demand for kidney transplants (KTx), organs are frequently retrieved not only from standard criteria donors (SCD; a donor who is aged <50 years and suffered brain death from any number of causes, such as traumatic injuries or a stroke) but also from expanded criteria donors (any donor aged >60 years or donors aged >50 years with two of the following: A history of high blood pressure, a creatinine serum level ≥1.5 mg/dl or death resulting from a stroke). This comes at the cost of a higher risk of primary non‑function (the permanent hyperkalemia, hyperuremia and fluid overload that result in the need for continuous dialysis after KTx), delayed graft function (the need for dialysis session at least once during the first week after KTx), earlier graft loss and urinary complications (vesico‑ureteral reflux, obstruction of the vesico‑ureteral anastomosis, urine leakage). At present, there are no commercially available diagnostic tools for assessing kidney quality prior to KTx. Currently available predictive models based on clinical data, such as the Kidney Donor Profile Index, are insufficient. One promising option is the application of perfusion solutions for protein biomarkers of kidney quality and predictors of short‑ and long‑term outcomes. However, to date, protein markers that can be detected with ELISA, western blotting and cytotoxic assays have not been identified to be a beneficial predictors of kidney quality. These include lactate dehydrogenases, glutathione S‑transferases, fatty acid binding proteins, extracellular histones, IL‑18, neutrophil gelatinase‑associated lipocalin, MMPs and kidney injury molecule‑1. However, novel methods, including liquid chromatography‑mass spectrometry (LC‑MS) and microarrays, allow the analysis of all renal proteins suspended/dissolved in the acellular preservation solution used for kidney storage before KTx (including hypothermic machine perfusion as one of kidney storage methods) e.g. Belzer University of Wisconsin. Recent proteomic studies utilizing LC‑MS have identified complement pathway elements (C3, C1QB, C4BPA, C1S, C1R and C1RL), desmoplakin, blood coagulation pathway elements and immunoglobulin heavy variable 2‑26 to be novel predictors of kidney quality before transplantation. This was because they were found to correlate with estimated glomerular filtration rate at 3 and 12 months after kidney transplantation. However, further proteomic studies focusing on distinct markers obtained from hypothermic and normothermic machine perfusion are needed to confirm their predictive value and to improve kidney storage methods. Therefore, the present literature review from PubMed, Scopus, Embase and Web of Science was performed with the aims of summarizing the current knowledge on the most frequently studied single protein biomarkers. In addition, novel analytical methods and insights into organ injury during preservation were documented, where future directions in assessing organ quality before kidney transplantation were also discussed.
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Affiliation(s)
- Maksymilian Baryła
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Michał Skrzycki
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Roman Danielewicz
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Maciej Kosieradzki
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
| | - Marta Struga
- Department of General and Transplant Surgery, Infant Jesus Hospital, Medical University of Warsaw, 02-006 Warsaw, Poland
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Xu W, Gaborieau V, Niman SM, Mukeria A, Liu X, Maremanda KP, Takakura A, Zaridze D, Freedman ML, Xie W, McDermott DF, Choueiri TK, Catalano PJ, Sabbisetti V, Bonventre J, Pierorazio PM, Singla N, Brennan P, Bhatt RS. Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association With Clinical Outcomes. J Clin Oncol 2024; 42:2691-2701. [PMID: 38701382 PMCID: PMC11539753 DOI: 10.1200/jco.23.00699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 11/17/2023] [Accepted: 02/20/2024] [Indexed: 05/05/2024] Open
Abstract
PURPOSE Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses. METHODS Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes. RESULTS In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC. CONCLUSION Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.
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Affiliation(s)
- Wenxin Xu
- Dana-Farber Cancer Institute, Boston, United States
| | | | | | - Anush Mukeria
- N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia
| | - Xiaowen Liu
- Beth Israel Deaconess Medical Center, Boston, United States
| | | | | | - David Zaridze
- N.N. Blokhin National Medical Research Centre of Oncology, Moscow, Russia
| | | | - Wanling Xie
- Dana-Farber Cancer Institute, Boston, United States
| | | | | | | | | | | | | | - Nirmish Singla
- Brady Urological Institute, Johns Hopkins University, United States
| | - Paul Brennan
- International Agency for Research on Cancer, Lyon, France
| | - Rupal S. Bhatt
- Beth Israel Deaconess Medical Center, Boston, United States
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Tutunea-Fatan E, Arumugarajah S, Suri RS, Edgar CR, Hon I, Dikeakos JD, Gunaratnam L. Sensing Dying Cells in Health and Disease: The Importance of Kidney Injury Molecule-1. J Am Soc Nephrol 2024; 35:795-808. [PMID: 38353655 PMCID: PMC11164124 DOI: 10.1681/asn.0000000000000334] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024] Open
Abstract
Kidney injury molecule-1 (KIM-1), also known as T-cell Ig and mucin domain-1 (TIM-1), is a widely recognized biomarker for AKI, but its biological function is less appreciated. KIM-1/TIM-1 belongs to the T-cell Ig and mucin domain family of conserved transmembrane proteins, which bear the characteristic six-cysteine Ig-like variable domain. The latter enables binding of KIM-1/TIM-1 to its natural ligand, phosphatidylserine, expressed on the surface of apoptotic cells and necrotic cells. KIM-1/TIM-1 is expressed in a variety of tissues and plays fundamental roles in regulating sterile inflammation and adaptive immune responses. In the kidney, KIM-1 is upregulated on injured renal proximal tubule cells, which transforms them into phagocytes for clearance of dying cells and helps to dampen sterile inflammation. TIM-1, expressed in T cells, B cells, and natural killer T cells, is essential for cell activation and immune regulatory functions in the host. Functional polymorphisms in the gene for KIM-1/TIM-1, HAVCR1 , have been associated with susceptibility to immunoinflammatory conditions and hepatitis A virus-induced liver failure, which is thought to be due to a differential ability of KIM-1/TIM-1 variants to bind phosphatidylserine. This review will summarize the role of KIM-1/TIM-1 in health and disease and its potential clinical applications as a biomarker and therapeutic target in humans.
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Affiliation(s)
- Elena Tutunea-Fatan
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
| | - Shabitha Arumugarajah
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Rita S. Suri
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Cassandra R. Edgar
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Ingrid Hon
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jimmy D. Dikeakos
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Lakshman Gunaratnam
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Zhang X, Huo Z, Jia X, Xiong Y, Li B, Zhang L, Li X, Li X, Fang Y, Dong X, Chen G. (+)-Catechin ameliorates diabetic nephropathy injury by inhibiting endoplasmic reticulum stress-related NLRP3-mediated inflammation. Food Funct 2024; 15:5450-5465. [PMID: 38687305 DOI: 10.1039/d3fo05400d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
Endoplasmic reticulum (ER) stress and chronic sterile inflammation are associated with the pathogenesis of diabetic nephropathy (DN). Catechins are natural polyphenolic compounds found in green tea that possess some health benefits. However, whether (+)-catechin can reduce tubular injury in DN by regulating ER stress and NLRP3-associated inflammation remains uncertain. This study examined the effects of (+)-catechin on streptozotocin (STZ)-induced diabetic mice and on palmitic acid (PA)-treated HK-2 cells. In vivo, a DN mouse model was generated by injecting STZ. The biochemical indicators of serum and urine, as well as renal histopathology and ultrastructure were analysed. To predict the mechanisms associated with (+)-catechin, network pharmacology and molecular docking were used. Finally, quantitative real-time PCR (qPCR), western blot analysis and immunofluorescence analysis were performed to measure the mRNA and protein expressions of specific targets in the renal tissue of DN mice and PA-treated HK-2 cells to validate the predicted results. (+)-Catechin significantly ameliorated renal function and pathological changes associated with tubular injury by inhibiting ER stress by downregulating of GRP78, PEAK, CHOP, ATF6 and XBP1. In addition, (+)-catechin inhibited renal inflammation by suppressing NLRP3 associated inflammation, which was characterized by the downregulation of NLRP3, ASC, AIM2, Caspase1, IL-1β and IL-18 in DN mice and PA-treated HK-2 cells. Collectively, these findings suggested that (+)-catechin exerted a renoprotective effect against DN by inhibiting ER stress and NLRP3-related inflammation to ameliorate tubular injury, suggesting the therapeutic potential of (+)-catechin.
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Affiliation(s)
- Xiwen Zhang
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Zhihao Huo
- Guangdong Clinical Research Academy of Chinese Medicine, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xiaotong Jia
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Yuanyuan Xiong
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Baohua Li
- Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liangyou Zhang
- Guangdong Clinical Research Academy of Chinese Medicine, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Xin Li
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, China
| | - Xianhong Li
- Guangdong Clinical Research Academy of Chinese Medicine, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yinrui Fang
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Xin Dong
- Guangdong Clinical Research Academy of Chinese Medicine, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Gangyi Chen
- Guangdong Clinical Research Academy of Chinese Medicine, Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
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11
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Repetto O, Vettori R, Steffan A, Cannizzaro R, De Re V. Circulating Proteins as Diagnostic Markers in Gastric Cancer. Int J Mol Sci 2023; 24:16931. [PMID: 38069253 PMCID: PMC10706891 DOI: 10.3390/ijms242316931] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Gastric cancer (GC) is a highly malignant disease affecting humans worldwide and has a poor prognosis. Most GC cases are detected at advanced stages due to the cancer lacking early detectable symptoms. Therefore, there is great interest in improving early diagnosis by implementing targeted prevention strategies. Markers are necessary for early detection and to guide clinicians to the best personalized treatment. The current semi-invasive endoscopic methods to detect GC are invasive, costly, and time-consuming. Recent advances in proteomics technologies have enabled the screening of many samples and the detection of novel biomarkers and disease-related signature signaling networks. These biomarkers include circulating proteins from different fluids (e.g., plasma, serum, urine, and saliva) and extracellular vesicles. We review relevant published studies on circulating protein biomarkers in GC and detail their application as potential biomarkers for GC diagnosis. Identifying highly sensitive and highly specific diagnostic markers for GC may improve patient survival rates and contribute to advancing precision/personalized medicine.
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Affiliation(s)
- Ombretta Repetto
- Facility of Bio-Proteomics, Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy
| | - Roberto Vettori
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (R.V.); (A.S.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (R.V.); (A.S.)
| | - Renato Cannizzaro
- Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy;
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Valli De Re
- Facility of Bio-Proteomics, Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy
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12
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Sganga S, Riondino S, Iannantuono GM, Rosenfeld R, Roselli M, Torino F. Antibody-Drug Conjugates for the Treatment of Renal Cancer: A Scoping Review on Current Evidence and Clinical Perspectives. J Pers Med 2023; 13:1339. [PMID: 37763107 PMCID: PMC10532725 DOI: 10.3390/jpm13091339] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are complex chemical structures composed of a monoclonal antibody, serving as a link to target cells, which is conjugated with a potent cytotoxic drug (i.e., payload) through a chemical linker. Inspired by Paul Ehrlich's concept of the ideal anticancer drug as a "magic bullet", ADCs are also highly specific anticancer agents, as they have been demonstrated to recognize, bind, and neutralize cancer cells, limiting injuries to normal cells. ADCs are among the newest pharmacologic breakthroughs in treating solid and hematologic malignancies. Indeed, in recent years, various ADCs have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of several cancers, resulting in a "practice-changing" approach. However, despite these successes, no ADC is approved for treating patients affected by renal cell carcinoma (RCC). In the present paper, we thoroughly reviewed the current literature and summarized preclinical studies and clinical trials that evaluated the activity and toxicity profile of ADCs in RCC patients. Moreover, we scrutinized the potential causes that, until now, hampered the therapeutical success of ADCs in those patients. Finally, we discussed novel strategies that would improve the development of ADCs and their efficacy in treating RCC patients.
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Affiliation(s)
| | | | | | | | | | - Francesco Torino
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (S.S.); (S.R.); (G.M.I.); (R.R.); (M.R.)
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13
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Joshi N, Bhat F, Bellad A, Sathe G, Jain A, Chavan S, Sirdeshmukh R, Pandey A. Urinary Proteomics for Discovery of Gastric Cancer Biomarkers to Enable Precision Clinical Oncology. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:361-371. [PMID: 37579183 PMCID: PMC10625469 DOI: 10.1089/omi.2023.0077] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
For precision in clinical oncology practice, detection of tumor-derived peptides and proteins in urine offers an attractive and noninvasive alternative for diagnostic or screening purposes. In this study, we report comparative quantitative proteomic profiling of urine samples from patients with gastric cancer and healthy controls using tandem mass tags-based multiplexed mass spectrometry approach. We identified 1504 proteins, of which 246 were differentially expressed in gastric cancer cases. Notably, ephrin A1 (EFNA1), pepsinogen A3 (PGA3), sortilin 1 (SORT1), and vitronectin (VTN) were among the upregulated proteins, which are known to play crucial roles in the progression of gastric cancer. We also found other overexpressed proteins, including shisa family member 5 (SHISA5), mucin like 1 (MUCL1), and leukocyte cell derived chemotaxin 2 (LECT2), which had not previously been linked to gastric cancer. Using a novel approach for targeted proteomics, SureQuant, we validated changes in abundance of a subset of proteins discovered in this study. We confirmed the overexpression of vitronectin and sortilin 1 in an independent set of urine samples. Altogether, this study provides molecular candidates for biomarker development in gastric cancer, and the findings also support the promise of urinary proteomics for noninvasive diagnostics and personalized/precision medicine in the oncology clinic.
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Affiliation(s)
- Neha Joshi
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Firdous Bhat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Anikha Bellad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Anu Jain
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sandip Chavan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ravi Sirdeshmukh
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Akhilesh Pandey
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
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14
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Catanese L, Siwy J, Mischak H, Wendt R, Beige J, Rupprecht H. Recent Advances in Urinary Peptide and Proteomic Biomarkers in Chronic Kidney Disease: A Systematic Review. Int J Mol Sci 2023; 24:ijms24119156. [PMID: 37298105 DOI: 10.3390/ijms24119156] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms "marker *" OR biomarker * AND "renal disease" OR "kidney disease" AND "proteome *" OR "peptid *" AND "urin *". English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 95445 Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany
| | | | - Ralph Wendt
- Department of Nephrology, St. Georg Hospital Leipzig, 04129 Leipzig, Germany
| | - Joachim Beige
- Department of Nephrology, St. Georg Hospital Leipzig, 04129 Leipzig, Germany
- Department of Internal Medicine II, Martin-Luther-University Halle/Wittenberg, 06108 Halle/Saale, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 04129 Leipzig, Germany
| | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 95445 Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
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15
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Nolazco JI, Soerensen SJC, Chung BI. Biomarkers for the Detection and Surveillance of Renal Cancer. Urol Clin North Am 2023; 50:191-204. [PMID: 36948666 DOI: 10.1016/j.ucl.2023.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Renal cell carcinoma (RCC) is a heterogeneous disease characterized by a broad spectrum of disorders in terms of genetics, molecular and clinical characteristics. There is an urgent need for noninvasive tools to stratify and select patients for treatment accurately. In this review, we analyze serum, urinary, and imaging biomarkers that have the potential to detect malignant tumors in patients with RCC. We discuss the characteristics of these numerous biomarkers and their ability to be used routinely in clinical practice. The development of biomarkers continues to evolve with promising prospects.
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Affiliation(s)
- José Ignacio Nolazco
- Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA; Servicio de Urología, Hospital Universitario Austral, Universidad Austral, Av Juan Domingo Perón 1500, B1629AHJ Pilar, Argentina.
| | - Simon John Christoph Soerensen
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, USA
| | - Benjamin I Chung
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
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16
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Kim HH, Moon OJ, Seol YH, Lee J. A simple urine test by 3D-plus-3D immunoassay guides precise in vitro cancer diagnosis. Bioeng Transl Med 2023; 8:e10489. [PMID: 37206218 PMCID: PMC10189436 DOI: 10.1002/btm2.10489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 01/19/2023] Open
Abstract
Although a variety of urinary cancer markers are available for in vitro diagnosis, inherent problems of urine environment-containing various inorganic/organic ions/molecules that vary in concentration over a 20-fold range or more and significantly attenuate antibody avidity for markers-render conventional immunoassays unsuitable, remaining unresolved and a major challenge. Here we developed a 3D-plus-3D (3p3) immunoassay method, based on a single-step urinary marker detection by 3D-antibody probes, which are free of steric hindrance and capable of omnidirectional capture of markers in a 3D solution. The 3p3 immunoassay showed an excellent performance in the diagnosis of prostate cancer (PCa) through detecting PCa-specific urinary engrailed-2 protein, demonstrating 100% sensitivity and 100% specificity with the urine specimens of PCa-related and other related disease patients and healthy individuals. This innovative approach holds a great potential in opening up a novel clinical route for precise in vitro cancer diagnosis and also pushing urine immunoassay closer to more widespread adoption.
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Affiliation(s)
- Hye Hyun Kim
- Department of Chemical and Biological Engineering, College of EngineeringKorea UniversitySeoulRepublic of Korea
| | - Ok Jeong Moon
- Department of Chemical and Biological Engineering, College of EngineeringKorea UniversitySeoulRepublic of Korea
| | - Yong Hwan Seol
- Department of Chemical and Biological Engineering, College of EngineeringKorea UniversitySeoulRepublic of Korea
| | - Jeewon Lee
- Department of Chemical and Biological Engineering, College of EngineeringKorea UniversitySeoulRepublic of Korea
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17
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Nozaki Y, Shiga T, Ashida C, Tomita D, Itami T, Kishimoto K, Kinoshita K, Matsumura I. U-KIM-1 as a predictor of treatment response in lupus nephritis. Lupus 2023; 32:54-62. [PMID: 36305170 DOI: 10.1177/09612033221135871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. METHODS U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. RESULTS In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12 months after treatment intensification. CONCLUSIONS These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.
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Affiliation(s)
- Yuji Nozaki
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Toshihiko Shiga
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Chisato Ashida
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Daisuke Tomita
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Tetsu Itami
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Kazuya Kishimoto
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Koji Kinoshita
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, 326473Kindai University School of Medicine, Osaka-Sayama, Japan
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18
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Epidemiology and Prevention of Renal Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14164059. [PMID: 36011051 PMCID: PMC9406474 DOI: 10.3390/cancers14164059] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
With 400,000 diagnosed and 180,000 deaths in 2020, renal cell carcinoma (RCC) accounts for 2.4% of all cancer diagnoses worldwide. The highest disease burden developed countries, primarily in Europe and North America. Incidence is projected to increase in the future as more countries shift to Western lifestyles. Risk factors for RCC include fixed factors such as gender, age, and hereditary diseases, as well as intervening factors such as smoking, obesity, hypertension, diabetes, diet and alcohol, and occupational exposure. Intervening factors in primary prevention, understanding of congenital risk factors and the establishment of early diagnostic tools are important for RCC. This review will discuss RCC epidemiology, risk factors, and biomarkers involved in reducing incidence and improving survival.
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19
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Feng D, Gao P, Henley N, Dubuissez M, Chen N, Laurin LP, Royal V, Pichette V, Gerarduzzi C. SMOC2 promotes an epithelial-mesenchymal transition and a pro-metastatic phenotype in epithelial cells of renal cell carcinoma origin. Cell Death Dis 2022; 13:639. [PMID: 35869056 PMCID: PMC9307531 DOI: 10.1038/s41419-022-05059-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 06/22/2022] [Accepted: 07/01/2022] [Indexed: 01/21/2023]
Abstract
Renal Cell Carcinoma (RCC) is the most common form of all renal cancer cases, and well-known for its highly aggressive metastatic behavior. SMOC2 is a recently described non-structural component of the extracellular matrix (ECM) that is highly expressed during tissue remodeling processes with emerging roles in cancers, yet its role in RCC remains elusive. Using gene expression profiles from patient samples, we identified SMOC2 as being significantly expressed in RCC tissue compared to normal renal tissue, which correlated with shorter RCC patient survival. Specifically, de novo protein synthesis of SMOC2 was shown to be much higher in the tubular epithelial cells of patients with biopsy-proven RCC. More importantly, we provide evidence of SMOC2 triggering kidney epithelial cells into an epithelial-to-mesenchymal transition (EMT), a phenotype known to promote metastasis. We found that SMOC2 induced mesenchymal-like morphology and activities in both RCC and non-RCC kidney epithelial cell lines. Mechanistically, treatment of RCC cell lines ACHN and 786-O with SMOC2 (recombinant and enforced expression) caused a significant increase in EMT-markers, -matrix production, -proliferation, and -migration, which were inhibited by targeting SMOC2 by siRNA. We further characterized SMOC2 activation of EMT to occur through the integrin β3, FAK and paxillin pathway. The proliferation and metastatic potential of SMOC2 overexpressing ACHN and 786-O cell lines were validated in vivo by their significantly higher tumor growth in kidneys and systemic dissemination into other organs when compared to their respective controls. In principle, understanding the impact that SMOC2 has on EMT may lead to more evidence-based treatments and biomarkers for RCC metastasis.
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Affiliation(s)
- Daniel Feng
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Peng Gao
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Nathalie Henley
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Marion Dubuissez
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Nan Chen
- Faculty of Science, University of British Columbia, Vancouver, British Columbia, Canada
| | - Louis-Philippe Laurin
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Virginie Royal
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
| | - Vincent Pichette
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Casimiro Gerarduzzi
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
- Centre de recherche de l'Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l'Université de Montréal, Montréal, Québec, Canada.
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
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20
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Ludwig L, Husnik R, Rätsep E, Beeler-Marfisi J, Stalker M, Wood GA, Woods JP. Unilateral primary carcinoma of the kidney with central nervous system invasion and vertebral lysis in a cat. JFMS Open Rep 2022; 8:20551169221141319. [PMID: 36601445 PMCID: PMC9806377 DOI: 10.1177/20551169221141319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Case summary A young adult female spayed domestic shorthair cat presented for acute hindlimb weakness and anorexia with a 1-month history of lethargy, hyporexia and weight loss. A mass was palpable in the caudolateral abdomen and the left hindlimb was diffusely edematous. Abdominal ultrasound showed hydronephrosis of the left kidney with suspected hydroureter and heterogeneous tissue in the dorsal abdomen. CT evaluation confirmed a mass extending from the left kidney through the lumbar musculature with hydronephrosis, aortic attenuation, caudal vena caval thrombosis and lysis of vertebrae 4 and 5. Fine-needle aspiration of the mass suggested squamous cell carcinoma. Owing to clinical deterioration, euthanasia was elected. At necropsy, the left kidney was firmly adhered to the lumbar region with tissue that obliterated the musculature and surrounded the aorta and vena cava. There was hydronephrosis of the left kidney. Histopathologic evaluation of the mass revealed islands of neoplastic epithelial cells separated by fibrous connective tissue and areas of gradual keratinization with rare squamous metaplasia. The histologic diagnosis was invasive carcinoma with desmoplasia and vascular invasion. Relevance and novel information Primary carcinomas of the kidney in cats are rare and this report documents a progression of disease not previously reported in cats. This is the second reported case of a primary carcinoma of renal origin with features of squamous cell carcinoma in a cat, and the first with lumbar and vascular invasion. This is also the first use of kidney injury molecule-1 to help investigate tumor differentiation in cats.
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Affiliation(s)
- Latasha Ludwig
- Department of Pathobiology, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Roman Husnik
- Department of Veterinary Clinical
Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN,
USA
- Department of Clinical Studies, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Emily Rätsep
- Department of Pathobiology, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
- Animal Health Laboratory, University of
Guelph, Kemptville, ON, Canada
| | - Janet Beeler-Marfisi
- Department of Pathobiology, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Margaret Stalker
- Animal Health Laboratory, University of
Guelph, Guelph, ON, Canada
| | - Geoffrey A Wood
- Department of Pathobiology, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
| | - J Paul Woods
- Department of Clinical Studies, Ontario
Veterinary College, University of Guelph, Guelph, ON, Canada
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21
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Telford EA, Sanders AJ, Owen S, Ruge F, Harrison GM, Jiang WG, Martin TA. Hepatitis A Virus Cellular Receptor 1 (HAVcr-1) Initiates Prostate Cancer Progression in Human Cells via Hepatocyte Growth Factor (HGF)-Induced Changes in Junctional Integrity. Biomolecules 2022; 12:biom12020338. [PMID: 35204839 PMCID: PMC8869406 DOI: 10.3390/biom12020338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/10/2022] [Accepted: 02/17/2022] [Indexed: 11/16/2022] Open
Abstract
Background: HAVcR-1 has been linked to cancer aetiology and may regulate junctional complexes, with its role in prostate cancer still unexplored. This study aims to investigate the expression of HAVcR-1 in prostate cancer samples and the exploration of the cellular/molecular impact of HAVcR-1. Methods: Levels of HAVcR-1 ectodomain in the serum of prostate cancer patients were compared to healthy controls, and assessed as the total protein and gene expression of HAVcR-1 and tissues sections. The manipulation of HAVcR-1 levels within prostate cancer cell lines determined changes in cell behaviour using in vitro cell models and barrier function assays. Protein/phosphoprotein levels were assessed using Western blotting. Results: Levels of HAVcR-1 ectodomain from serum were decreased in patients with prostate cancer. Ectodomain levels correlated with the Gleason score. Histologically, the total protein/gene expression of HAVcR-1 was overexpressed in prostate cancer. The overexpression of HAVcR-1 in prostate cancer cell lines resulted in key changes in cell behaviour and the phosphorylation of β-catenin with a concurrent decrease in membranous E-cadherin, increased nuclear β-catenin and increased cyclin D1 protein expression, which were associated with HGF-promoted changes in the barrier function. Conclusions: HAVcR-1 expression and ectodomain release coincides with the presence of prostate cancer; thus, indicating HAVcR-1 as a potential biomarker to aid in diagnostics, and implicating HAVcR-1 in the dysregulation of junctional complexes.
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22
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Schmidt IM, Srivastava A, Sabbisetti V, McMahon GM, He J, Chen J, Kusek JW, Taliercio J, Ricardo AC, Hsu CY, Kimmel PL, Liu KD, Mifflin TE, Nelson RG, Vasan RS, Xie D, Zhang X, Palsson R, Stillman IE, Rennke HG, Feldman HI, Bonventre JV, Waikar SS. Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies. Am J Kidney Dis 2022; 79:231-243.e1. [PMID: 34175376 PMCID: PMC8709877 DOI: 10.1053/j.ajkd.2021.05.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 05/03/2021] [Indexed: 01/27/2023]
Abstract
RATIONALE & OBJECTIVE Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN Prospective, observational cohort study. SETTING & PARTICIPANTS 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 levels in prospective analyses. OUTCOMES Baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH Multivariable-adjusted linear regression models tested associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 levels with future kidney failure and death. RESULTS In the BKBC Study, higher plasma KIM-1 levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, CKD in 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, CKD in 1,153 participants progressed to kidney failure and 1,356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure after multivariable adjustment (hazard ratios of 1.19 [95% CI, 1.03-1.38] and 1.10 [95% CI, 1.06-1.15] for BKBC and CRIC, respectively). There was no statistically significant association of plasma KIM-1 levels with death in either cohort. LIMITATIONS Generalizability and unmeasured confounding. CONCLUSIONS Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in 2 cohort studies of individuals with kidney diseases.
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Affiliation(s)
- Insa M Schmidt
- Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston Medical Center Boston, Massachusetts; Renal Division, Brigham & Women's Hospital, Harvard Medical School Boston, Massachusetts
| | - Anand Srivastava
- Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Venkata Sabbisetti
- Renal Division, Brigham & Women's Hospital, Harvard Medical School Boston, Massachusetts
| | - Gearoid M McMahon
- Renal Division, Brigham & Women's Hospital, Harvard Medical School Boston, Massachusetts
| | - Jiang He
- Department of Epidemiology and Medicine, Tulane University School of Public Health and Tropical Medicine, Tulane University School of Medicine, New Orleans, Louisana
| | - Jing Chen
- Department of Epidemiology and Medicine, Tulane University School of Public Health and Tropical Medicine, Tulane University School of Medicine, New Orleans, Louisana
| | - John W Kusek
- Department of Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jonathan Taliercio
- Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ana C Ricardo
- Division of Nephrology, Department of Medicine, University of Illinois, Chicago, Illinois
| | - Chi-Yuan Hsu
- Division of Nephrology, University of California San Francisco School of Medicine, San Francisco, California
| | - Paul L Kimmel
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Kathleen D Liu
- Division of Nephrology, University of California San Francisco School of Medicine, San Francisco, California
| | - Theodore E Mifflin
- Department of Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert G Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
| | - Ramachandran S Vasan
- Section of Preventive Medicine and Epidemiology, Boston University Boston, Massachusetts
| | - Dawei Xie
- Department of Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaoming Zhang
- Department of Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ragnar Palsson
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Isaac E Stillman
- Department of Pathology, Beth Israel Deaconess Medical Center Boston, Massachusetts
| | - Helmut G Rennke
- Pathology Department, Brigham & Women's Hospital, Boston, Massachusetts
| | - Harold I Feldman
- Department of Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joseph V Bonventre
- Renal Division, Brigham & Women's Hospital, Harvard Medical School Boston, Massachusetts
| | - Sushrut S Waikar
- Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston Medical Center Boston, Massachusetts; Renal Division, Brigham & Women's Hospital, Harvard Medical School Boston, Massachusetts.
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23
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The Role of Circulating Biomarkers in the Oncological Management of Metastatic Renal Cell Carcinoma: Where Do We Stand Now? Biomedicines 2021; 10:biomedicines10010090. [PMID: 35052770 PMCID: PMC8773056 DOI: 10.3390/biomedicines10010090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/25/2021] [Accepted: 12/29/2021] [Indexed: 01/08/2023] Open
Abstract
Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches.
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24
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Koniari I, Artopoulou E, Velissaris D, Ainslie M, Mplani V, Karavasili G, Kounis N, Tsigkas G. Biomarkers in the clinical management of patients with atrial fibrillation and heart failure. J Geriatr Cardiol 2021; 18:908-951. [PMID: 34908928 PMCID: PMC8648548 DOI: 10.11909/j.issn.1671-5411.2021.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Atrial fibrillation (AF) and heart failure (HF) are two cardiovascular diseases with an increasing prevalence worldwide. These conditions share common pathophysiologiesand frequently co-exit. In fact, the occurrence of either condition can 'cause' the development of the other, creating a new patient group that demands different management strategies to that if they occur in isolation. Regardless of the temproral association of the two conditions, their presence is linked with adverse cardiovascular outcomes, increased rate of hospitalizations, and increased economic burden on healthcare systems. The use of low-cost, easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF. Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information. These will then guide patient centred therapeutic management. The current biomarkers that offer potential for guiding therapy, focus on the physiological pathways of miRNA, myocardial stretch and injury, oxidative stress, inflammation, fibrosis, coagulation and renal impairment. Each of these has different utility in current clinincal practice.
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Affiliation(s)
- Ioanna Koniari
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Mark Ainslie
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
- Division of Cardiovascular Sciences, University of Manchester
| | - Virginia Mplani
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Georgia Karavasili
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, Patras, Greece
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25
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Białek Ł, Niemczyk M, Czerwińska K, Nowak M, Sadowska A, Borkowski T, Radziszewski P, Dobruch J, Kryst P, Poletajew S. Human kidney injury molecule-1 as a urine biomarker differentiating urothelial and renal cell carcinoma. Cent European J Urol 2021; 74:295-299. [PMID: 34729216 PMCID: PMC8552939 DOI: 10.5173/ceju.2021.0080.2.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/10/2021] [Accepted: 05/27/2021] [Indexed: 11/22/2022] Open
Abstract
Introduction Urine concentration of human kidney injury molecule-1 (KIM-1) is suggested to be increased in patients with renal cell carcinoma (RCC). However, it has never been tested in patients with urothelial tumors, while preoperative differentiation between RCC and upper tract urothelial carcinoma (UTUC) plays an essential role in therapeutic decisions. The aim of the study was to evaluate the role of urinary KIM-1 expression in preoperative differentiation between RCC and urothelial carcinoma (UC). Material and methods Sixty-four participants were enrolled in the study, including 30 patients with RCC and 27 with UC (16 with UTUC and 11 with bladder tumor). Preoperative urinary KIM-1 levels were measured using a commercially available ELISA kit and normalized to urinary creatinine levels. Results The median concentration of urinary KIM-1 normalized to urinary creatinine was lower in patients with RCC compared to UC (1.35 vs 1.86 ng/mg creatinine, p = 0.04). The comparison between RCC and UTUC shows even more significant difference (1.33 vs 2.23 ng/mg creatinine, p = 0.02). Urinary KIM-1 concentration did not correlate with tumor stage nor grade in any of the groups. ROC analysis to identify UC revealed AUC of 0.657 with sensitivity 33.3% and specificity 96.7% at the cut-off value of 3.226 ng/mg creatinine. Among patients with eGFR ≥60 mL/min/1.73 m², ROC analysis to detect UC achieved AUC of 0.727 with sensitivity 69.5% and specificity 70.2%. Conclusions Urine KIM-1 can potentially differentiate UC from RCC. However, a wide range of observed results and limited sensitivity and specificity requires caution in making clinical decisions before confirmatory studies.
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Affiliation(s)
- Łukasz Białek
- I Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Michał Niemczyk
- Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Czerwińska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Nowak
- Department of Urology, St. Lucas Hospital, Tarnów, Poland
| | - Anna Sadowska
- Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Borkowski
- Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Radziszewski
- Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland
| | - Jakub Dobruch
- I Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Piotr Kryst
- Second Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Sławomir Poletajew
- Second Department of Urology, Centre of Postgraduate Medical Education, Warsaw, Poland
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26
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Karmakova ТА, Sergeeva NS, Kanukoev КY, Alekseev BY, Kaprin АD. Kidney Injury Molecule 1 (KIM-1): a Multifunctional Glycoprotein and Biological Marker (Review). Sovrem Tekhnologii Med 2021; 13:64-78. [PMID: 34603757 PMCID: PMC8482821 DOI: 10.17691/stm2021.13.3.08] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
KIM-1 (kidney injury molecule 1) is a transmembrane glycoprotein also known as HAVcr-1 and TIM-1 belongs to the T-cell immunoglobulin and mucin domain family (TIM) of proteins. TIM glycoproteins are presented on the immune cells and participate in the regulation of immune reactions. KIM-1 differs from other members of its family in that it is expressed not only by immunocompetent cells but epithelial cells as well. Cellular and humoral effects mediated by KIM-1 are involved in a variety of physiological and pathophysiological processes. Current understanding of the mechanisms determining the participation of KIM-1 in viral invasion, the immune response regulation, adaptive reactions of the kidney epithelium to acute ischemic or toxic injury, in progression of chronic renal diseases, and kidney cancer development have been presented in this review. Data of clinical researches demonstrating the association of KIM-1 with viral diseases and immune disorders have also been analyzed. Potential application of KIM-1 as urinary or serological marker in renal and cardiovascular diseases has been considered.
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Affiliation(s)
- Т А Karmakova
- Leading Researcher, Department of Predicting the Effectiveness of Conservative Therapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia
| | - N S Sergeeva
- Professor, Head of the Department of Predicting the Effectiveness of Conservative Therapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia; Professor, Department of Biology; Pirogov Russian National Research Medical University, 1 Ostrovitianova St., Moscow, 117997, Russia
| | - К Yu Kanukoev
- Urologist, Department of Urology with Chemotherapy; P. Hertsen Moscow Oncology Research Institute - Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 3, 2 Botkinsky Proezd, Moscow, 125284, Russia
| | - B Ya Alekseev
- Professor, Deputy General Director for Science; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 4 Koroleva St., Obninsk, 249036, Russia
| | - А D Kaprin
- Professor, Academician of the Russian Academy of Sciences, General Director; National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 4 Koroleva St., Obninsk, 249036, Russia
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27
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Flitcroft JG, Verheyen J, Vemulkar T, Welbourne EN, Rossi SH, Welsh SJ, Cowburn RP, Stewart GD. Early detection of kidney cancer using urinary proteins: a truly non-invasive strategy. BJU Int 2021; 129:290-303. [PMID: 34570419 DOI: 10.1111/bju.15601] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES To review urinary protein biomarkers as potential non-invasive, easily obtainable, early diagnostic tools in renal cell carcinoma (RCC). METHODS A PubMed database search was performed up to the year 2020 to identify primary studies reporting potential urinary protein biomarkers for RCC. Separate searches were conducted to identify studies describing appropriate methods of developing cancer screening programmes and detection of cancer biomarkers. RESULTS Several urinary protein biomarkers are under validation for RCC diagnostics, e.g. aquaporin-1, perilipin-2, carbonic anhydrase-9, Raf-kinase inhibitory protein, nuclear matrix protein-22, 14-3-3 Protein β/α and neutrophil gelatinase-associated lipocalin. However, none has yet been validated or approved for clinical use due to low sensitivity or specificity, inconsistencies in appropriate study design, or lack of external validation. CONCLUSIONS Evaluation of biomarkers' feasibility, sample preparation and storage, biomarker validation, and the application of novel technologies may provide a solution that maximises the potential for a truly non-invasive biomarker in early RCC diagnostics.
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Affiliation(s)
- Jordan G Flitcroft
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Jeroen Verheyen
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Tarun Vemulkar
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Emma N Welbourne
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Sabrina H Rossi
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Sarah J Welsh
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Russell P Cowburn
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Grant D Stewart
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
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28
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Sergeeva NS, Kanukoev KY, Karmakova TA, Alentov II, Marshutina NV, Kaprin AD. On normalizing of urinary KIM-1 level to urine creatinine in patients with renal cell cancer. Klin Lab Diagn 2021; 66:517-524. [PMID: 34543529 DOI: 10.51620/0869-2084-2021-66-9-517-524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
KIM-1 (kidney injury molecule 1), a marker of acute kidney injury, is produced by epithelial cells of renal proximal tubules. Elevated KIM-1 levels in urine and plasma are associated with renal cell carcinoma (RCC). The aim of this study was to compare the significance of non-normalized uKIM-1 values and those normalized to urine creatinine, as urinary biomarkers in RCC. The uKIM-1, urine creatinine and their ratio (uKIM-1/Cre) were studied in 118 RCC patients and 58 apparently healthy subjects. The median of uKIM-1 in the healthy group was 0.71 ng/ml (1st and 3rd quartiles were 0.35 and 1.23, respectively) and in RCC patients it was 2.36 (1.43; 5.93) ng/ml. The medians of uKIM-1/Cre were 0.77 (0.49; 1.18) and 2.42 (1.41; 4.61) ng/mgCre, respectively. Stage I RCC is statistically significantly different from stages II-III and stage IV using uKIM-1/Cre values (p = 0.0056 and p = 0.0012, respectively); using uKIM-1 values significant differences occur only when comparing stages I and IV (p = 0.015). In both healthy individuals and RCC patients, uKIM-1/Cre levels were slightly lower in subgroups younger than 50 years than in subgroups older than 50 years, whereas a similar trend was observed for uKIM-1 only in patients. In healthy men and male patients, uKIM-1 levels were higher than in the corresponding groups of women (the differences were not statistically significant), but the use of uKIM-1/Cre values eliminated the gender differences. A high correlation was found between the concentrations of uKIM-1 and urine creatinine in three healthy subjects followed up for 3 weeks (Spearman's correlation coefficients were 0.758, 0.825 and 0.933, respectively). The data obtained are clear evidence of the need for normalization uKIM-1 to urine creatinine in RCC patients.
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Affiliation(s)
- N S Sergeeva
- P.A. Hertsen Moscow Oncology Research Institute - Branch of the Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation.,N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation
| | - K Yu Kanukoev
- P.A. Hertsen Moscow Oncology Research Institute - Branch of the Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation
| | - T A Karmakova
- P.A. Hertsen Moscow Oncology Research Institute - Branch of the Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation
| | - I I Alentov
- P.A. Hertsen Moscow Oncology Research Institute - Branch of the Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation
| | - N V Marshutina
- P.A. Hertsen Moscow Oncology Research Institute - Branch of the Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation
| | - A D Kaprin
- Federal State Budgetary Institution "National Medical Research Radiological Centre", Ministry of Health of the Russian Federation.,People's friendship university of Russia
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29
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Al-Bataineh MM, Kinlough CL, Mi Z, Jackson EK, Mutchler SM, Emlet DR, Kellum JA, Hughey RP. KIM-1-mediated anti-inflammatory activity is preserved by MUC1 induction in the proximal tubule during ischemia-reperfusion injury. Am J Physiol Renal Physiol 2021; 321:F135-F148. [PMID: 34151589 PMCID: PMC8424662 DOI: 10.1152/ajprenal.00127.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 11/22/2022] Open
Abstract
Cell-associated kidney injury molecule-1 (KIM-1) exerts an anti-inflammatory role following kidney injury by mediating efferocytosis and downregulating the NF-κB pathway. KIM-1 cleavage blunts its anti-inflammatory activities. We reported that mucin 1 (MUC1) is protective in a mouse model of ischemia-reperfusion injury (IRI). As both KIM-1 and MUC1 are induced in the proximal tubule (PT) during IRI and are a disintegrin and metalloprotease 17 (ADAM17) substrates, we tested the hypothesis that MUC1 protects KIM-1 activity. Muc1 knockout (KO) mice and wild-type (WT) littermates were subjected to IRI. KIM-1, MUC1, and ADAM17 levels (and signaling pathways) were assessed by immunoblot analysis. PT localization was assessed by confocal microscopy and an in situ proximity ligation assay. Findings were extended using human kidneys and urine as well as KIM-1-mediated efferocytosis assays in mouse PT cultures. In response to tubular injury in mouse and human kidneys, we observed induction and coexpression of KIM-1 and MUC1 in the PT. Compared with WT mice, Muc1 KO mice had higher urinary KIM-1 and lower kidney KIM-1. KIM-1 was apical in the PT of WT kidneys but predominately with luminal debris in Muc1 KO mice. Efferocytosis was reduced in Muc1 KO PT cultures compared with WT cultures, whereas inflammation was increased in Muc1 KO kidneys compared with WT kidneys. MUC1 was cleaved by ADAM17 in PT cultures and blocked KIM-1 shedding in Madin-Darby canine kidney cells. We conclude that KIM-1-mediated efferocytosis and thus anti-inflammatory activity during IRI is preserved in the injured kidney by MUC1 inhibition of KIM-1 shedding.NEW & NOTEWORTHY KIM-1 plays a key role in the recovery of the tubule epithelium during renal IRI by mediating efferocytosis and associated signaling that suppresses inflammation. Excessive cleavage of KIM-1 by ADAM17 provides a decoy receptor that aggravates efferocytosis and subsequent signaling. Our data from experiments in mice, patients, and cultured cells show that MUC1 is also induced during IRI and competes with KIM-1 for cleavage by ADAM17. Consequently, MUC1 protects KIM-1 anti-inflammatory activity in the damaged kidney.
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Affiliation(s)
- Mohammad M Al-Bataineh
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Carol L Kinlough
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Zaichuan Mi
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Edwin K Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Stephanie M Mutchler
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David R Emlet
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John A Kellum
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Rebecca P Hughey
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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30
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Sarami I, Shi J, Lin B, Liu H, Monroe R, Lin F. Evaluation of Human Kidney Injury Molecule 1 (hKIM-1) Expression in Tumors From Various Organs by Messenger RNA In Situ Hybridization. Am J Clin Pathol 2021; 156:288-299. [PMID: 33608720 DOI: 10.1093/ajcp/aqaa236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVES Human kidney injury molecule 1 (hKIM-1) is a sensitive and specific marker for detection of clear cell renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC), and ovarian clear cell carcinoma (OCCC). Its use was limited to a few surgical pathology laboratories because this specific antibody to hKIM-1 was not commercially available. We investigated the diagnostic utility of RNA in situ hybridization/RNAscope in the detection of hKIM-1 in tumors from various organs. METHODS RNAscope for hKIM-1 was performed on 1,252 cases on tissue microarray sections, including CRCC (n = 185), PRCC (n = 59), chromophobe renal cell carcinoma (n = 18), oncocytoma (n = 12), OCCC (n = 27), and metastatic CRCC (n = 46). RESULTS Fifty-nine (100%) of 59 PRCCs, 94 (95%) of 99 low-grade CRCCs, 83 (96%) of 86 high-grade CRCCs, and 24 (89%) of 27 OCCCs, and 44 (96%) of 46 metastatic CRCCs were positive for hKIM-1. In contrast, hKIM-1 expression was not seen in normal renal tubules or in most nonrenal tumors. Low-level expression could be seen in a small percentage of urothelial, hepatocellular, and colon carcinomas. CONCLUSIONS hKIM-1 is a sensitive and relatively specific marker (1) for diagnosing PRCC, CRCC, and OCCC when working on a tumor of unknown origin and (2) for differentiating CRCC from chromophobe renal cell carcinoma and oncocytoma.
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Affiliation(s)
| | | | | | - Haiyan Liu
- Geisinger Medical Center, Danville, PA, USA
| | | | - Fan Lin
- Geisinger Medical Center, Danville, PA, USA
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Lee JC, Yotis DM, Lee JY, Sarabusky MA, Shrum B, Champagne A, Ismail OZ, Tutunea-Fatan E, Leong HS, Gunaratnam L. Kidney injury molecule-1 inhibits metastasis of renal cell carcinoma. Sci Rep 2021; 11:11840. [PMID: 34088927 PMCID: PMC8178330 DOI: 10.1038/s41598-021-90919-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/19/2021] [Indexed: 11/15/2022] Open
Abstract
Metastasis is present in approximately 30% of patients diagnosed with renal cell carcinoma (RCC) and is associated with a 5-year survival rate of < 15%. Kidney injury molecule 1 (KIM-1), encoded by the HAVCR1 gene, is a proximal tubule cell-surface glycoprotein and a biomarker for early detection of RCC, but its pathophysiological significance in RCC remains unclear. We generated human and murine RCC cell lines either expressing or lacking KIM-1, respectively, and compared their growth and metastatic properties using validated methods. Surprisingly, KIM-1 expression had no effect on cell proliferation or subcutaneous tumour growth in immune deficient (Rag1−/−) Balb/c mice, but inhibited cell invasion and formation of lung metastasis in the same model. Further, we show that the inhibitory effect of KIM-1 on metastases was observed in both immune deficient and immune competent mice. Transcriptomic profiling identified the mRNA for the pro-metastatic GTPase, Rab27b, to be downregulated significantly in KIM-1 expressing human and murine RCC cells. Finally, analysis of The Cancer Genome Atlas (TCGA) data revealed that elevated HAVCR1 mRNA expression in the two most common types of RCC, clear cell and papillary RCC, tumours correlated with significantly improved overall patient survival. Our findings reveal a novel role for KIM-1 in inhibiting metastasis of RCC and suggests that tumour-associated KIM-1 expression may be a favourable prognostic factor.
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Affiliation(s)
- Jasper C Lee
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada
| | - Demitra M Yotis
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Ji Yun Lee
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada
| | - Marie A Sarabusky
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada
| | - Bradly Shrum
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada
| | - Audrey Champagne
- Centre de recherche du CHU de Québec-Université Laval, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Ola Z Ismail
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Elena Tutunea-Fatan
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada
| | - Hon S Leong
- Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Lakshman Gunaratnam
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. .,Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, ON, Canada. .,Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, Room A10-208, 339 Windermere Road, London, ON, N6A 5A5, Canada.
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Mori Y, Ajay AK, Chang JH, Mou S, Zhao H, Kishi S, Li J, Brooks CR, Xiao S, Woo HM, Sabbisetti VS, Palmer SC, Galichon P, Li L, Henderson JM, Kuchroo VK, Hawkins J, Ichimura T, Bonventre JV. KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease. Cell Metab 2021; 33:1042-1061.e7. [PMID: 33951465 PMCID: PMC8132466 DOI: 10.1016/j.cmet.2021.04.004] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 01/03/2021] [Accepted: 04/08/2021] [Indexed: 12/30/2022]
Abstract
Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD.
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Affiliation(s)
- Yutaro Mori
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Amrendra K Ajay
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jae-Hyung Chang
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Shan Mou
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Renal Division, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Huiping Zhao
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Nephrology, Peking University People's Hospital, Beijing 100044, China
| | - Seiji Kishi
- Department of Nephrology, Graduate School of Biomedical Science, Tokushima University, Tokushima 770-8503, Japan
| | - Jiahua Li
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Craig R Brooks
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Sheng Xiao
- Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Celsius Therapeutics, Cambridge, MA 02139, USA
| | - Heung-Myong Woo
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; School of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
| | - Venkata S Sabbisetti
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Suetonia C Palmer
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Pierre Galichon
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Li Li
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joel M Henderson
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Vijay K Kuchroo
- Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Julie Hawkins
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT 06877, USA
| | - Takaharu Ichimura
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Joseph V Bonventre
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Kot K, Łanocha-Arendarczyk N, Ptak M, Łanocha A, Kalisińska E, Kosik-Bogacka D. Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections. Int J Mol Sci 2021; 22:4209. [PMID: 33921746 PMCID: PMC8073708 DOI: 10.3390/ijms22084209] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/12/2021] [Accepted: 04/17/2021] [Indexed: 11/17/2022] Open
Abstract
Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients' morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.
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Affiliation(s)
- Karolina Kot
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (K.K.); (N.Ł.-A.); (E.K.)
| | - Natalia Łanocha-Arendarczyk
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (K.K.); (N.Ł.-A.); (E.K.)
| | - Michał Ptak
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Aleksandra Łanocha
- Department of Haematology and Transplantology, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Elżbieta Kalisińska
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (K.K.); (N.Ł.-A.); (E.K.)
| | - Danuta Kosik-Bogacka
- Independent Laboratory of Pharmaceutical Botany, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
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Singleton RK, Heath AK, Clasen JL, Scelo G, Johansson M, Calvez-Kelm FL, Weiderpass E, Liedberg F, Ljungberg B, Harbs J, Olsen A, Tjønneland A, Dahm CC, Kaaks R, Fortner RT, Panico S, Tagliabue G, Masala G, Tumino R, Ricceri F, Gram IT, Santiuste C, Bonet C, Rodriguez-Barranco M, Schulze MB, Bergmann MM, Travis RC, Tzoulaki I, Riboli E, Muller DC. Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study. Cancer Epidemiol Biomarkers Prev 2021; 30:507-512. [PMID: 33335022 DOI: 10.1158/1055-9965.epi-20-1438] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/11/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. METHODS Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. RESULTS The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. CONCLUSIONS Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. IMPACT Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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Affiliation(s)
- Rosie K Singleton
- School of Public Health, Imperial College London, London, United Kingdom
| | - Alicia K Heath
- School of Public Health, Imperial College London, London, United Kingdom
| | - Joanna L Clasen
- School of Public Health, Imperial College London, London, United Kingdom
| | | | | | | | | | - Fredrik Liedberg
- Institution of Translational Medicine, Lund University, Malmö, Sweden
| | - Börje Ljungberg
- Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umea, Sweden
| | - Justin Harbs
- Department of Radiation Sciences, Umeå University, Umea, Sweden
| | - Anja Olsen
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Public Health, University of Århus, Århus, Denmark
| | - Anne Tjønneland
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | | | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Salvatore Panico
- Department of Clinical and Surgical Medicine, Federico II University, Naples, Italy
| | - Giovanna Tagliabue
- Lombardy Cancer Registry Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Giovanna Masala
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy
| | - Rosario Tumino
- Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7), Ragusa, Italy
| | - Fulvio Ricceri
- Department of Clinical and Biological Sciences, University of Turin, Orbassano (TO), Italy
- Unit of Epidemiology Regional Health Service ASL TO3, Grugliasco (TO), Italy
| | - Inger T Gram
- Faculty of Health Sciences, Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Carmen Santiuste
- Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Spain
| | - Catalina Bonet
- Unit of Nutrition, Environment, and Cancer, Catalan Institute of Oncology, Barcelona, Spain
| | - Miguel Rodriguez-Barranco
- Escuela Andaluza de Salud Pública (EASP), Granada, Madrid, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Mattias B Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DifE), Potsdam, Germany
- Institute of Nutrition Science, University of Potsdam, Nuthetal, Germany
| | - Manuela M Bergmann
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke (DifE), Potsdam, Germany
| | - Ruth C Travis
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Ioanna Tzoulaki
- School of Public Health, Imperial College London, London, United Kingdom
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- University of Ioannina Medical School, Ioannina, Greece
| | - Elio Riboli
- School of Public Health, Imperial College London, London, United Kingdom
| | - David C Muller
- School of Public Health, Imperial College London, London, United Kingdom.
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Higenamine Improves Cardiac and Renal Fibrosis in Rats With Cardiorenal Syndrome via ASK1 Signaling Pathway. J Cardiovasc Pharmacol 2021; 75:535-544. [PMID: 32168151 DOI: 10.1097/fjc.0000000000000822] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The pathogenesis of cardiorenal syndrome (CRS) is very complex, and currently there is no effective treatment for CRS. Higenamine (HI) has been shown to improve cardiac function in rats with heart failure. However, the role of higenamine in CRS remains unknown. Here, in vitro, higenamine treatment markedly reduced neonatal rat cardiac fibroblast collagen synthesis and inhibited neonatal rat cardiac myocyte hypertrophy. In our study, a rat model of type 2 CRS was induced by left anterior descending coronary artery ligation combined with 5/6 subtotal nephrectomy (STNx). Higenamine treatment decreased serum creatinine (Scr), blood urea nitrogen, and brain natriuretic peptide levels and was capable of improving left ventricular remodeling and systolic function in CRS rats, accompanied with decreased expression of transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and collagen I (Col1A1). Moreover, higenamine significantly inhibited the protein expression of phosphorylated apoptosis signal-regulated kinase 1 (p-ASK1) and downstream mitogen-activated protein kinases (MAPK) (ERK, P38)/NF-κB in cardiorenal tissues of CRS rats and neonatal rat cardiac fibroblast/neonatal rat cardiac myocyte cells. Our study demonstrated that higenamine improved cardiorenal function in CRS rats and attenuated heart and kidney fibrosis possibly via targeting ASK1/MAPK (ERK, P38)/NF-κB signaling pathway. This finding extends our knowledge on the role of higenamine in cardiorenal fibrosis, providing a potential target to prevent the progression of CRS.
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Unal ET, Ozer EA, Kahramaner Z, Erdemir A, Cosar H, Sutcuoglu S. Value of urinary kidney injury molecule-1 levels in predicting acute kidney injury in very low birth weight preterm infants. J Int Med Res 2020; 48:300060520977442. [PMID: 33372811 PMCID: PMC7783886 DOI: 10.1177/0300060520977442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Objective This study aimed to evaluate the significance of urinary kidney injury
molecule-1 (uKIM-1) levels in predicting acute kidney injury (AKI) and
mortality in very low birth weight (VLBW) preterm infants. Methods This prospective, observational cohort study was conducted on 39 VLBW preterm
infants. Serum creatinine (SCr) and uKIM-1 levels were measured in the first
24 and 48 to 72 hours of life. The estimated glomerular filtration rate
(eGFR) was calculated. Levels of uKIM-1 were measured with an enzyme-linked
immunosorbent assay. Results Among 39 VLBW infants, 9 (23%) developed AKI. The mortality rate was 17.9%
(n = 7 neonates). There was no significant difference in SCr levels, uKIM-1
levels, or the eGFR obtained in the first 24 hours in the AKI group compared
with controls. However, significant differences were found in SCr and uKIM-1
levels, and the eGFR rate at 48 to 72 hours between the groups. Levels of
uKIM-1 were significantly higher in non-survivors than in survivors in the
first 24 and 48 to 72 hours of life. Conclusion The level of uKIM-1 can be used as a simple noninvasive diagnostic method for
predicting AKI and mortality, especially within 48 to 72 hours of life. Clinical trial registration: We do not have a clinical trial
registration ID. In Turkey, clinical trial registration is not required for
non-drug, noninvasive, clinical studies.
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Affiliation(s)
- Ebru Turkoglu Unal
- Department of Neonatology, Sisli Etfal Training and Research Hospital, Istanbul, Turkey
| | - Esra Arun Ozer
- Department of Pediatrics, Tinaztepe University Faculty of Medicine, Izmir, Turkey
| | - Zelal Kahramaner
- Department of Neonatology, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Aydin Erdemir
- Department of Neonatology, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Hese Cosar
- Department of Neonatology, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Sumer Sutcuoglu
- Department of Neonatology, Tepecik Training and Research Hospital, Izmir, Turkey
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Mapping and functional characterization of murine kidney injury molecule-1 proteolytic cleavage site. Mol Cell Biochem 2020; 476:1093-1108. [PMID: 33211259 DOI: 10.1007/s11010-020-03975-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 11/06/2020] [Indexed: 12/24/2022]
Abstract
Kidney injury molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain 1 (TIM-1), is a transmembrane glycoprotein expressed on proximal tubule epithelia during acute kidney injury (AKI). Extracellular domain of KIM-1 undergoes spontaneous and activated ectodomain shedding into urine and blood via metalloproteases. Soluble KIM-1 (blood and urinary) is a reliable clinical biomarker of proximal tubular injury, but the biological significance of shedding remains unknown. The aim of this study was to identify the specific shedding enzyme and the proteolytic cleavage site of murine KIM-1, followed by the characterization of its functional relevance. In this regard, isoleucine (I) I202 was identified as the potential cleavage site. Mutation of isoleucine I202 to glutamine (I202Q) or alanine (I202A) significantly reduced both constitutive and induced KIM-1 shedding and ultimately efferocytosis. It was also uncovered that ADAM10 is the major sheddase that mediates the proteolytic cleavage of murine KIM-1. In addition, ADAM10-induced KIM-1 shedding was required for efficient phagocytic clearance of apoptotic cells. Importantly, the findings that the addition of exogenous shed KIM-1 rescued the phagocytic impairment suggest that shed KIM-1 is capable of modulating efferocytosis of apoptotic bodies and could represent a potential functional role of the soluble ectodomain KIM-1 during AKI.
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Lakshminarayanan H, Rutishauser D, Schraml P, Moch H, Bolck HA. Liquid Biopsies in Renal Cell Carcinoma-Recent Advances and Promising New Technologies for the Early Detection of Metastatic Disease. Front Oncol 2020; 10:582843. [PMID: 33194717 PMCID: PMC7656014 DOI: 10.3389/fonc.2020.582843] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/29/2020] [Indexed: 12/21/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) displays a highly varying clinical progression, from slow growing localized tumors to very aggressive metastatic disease (mRCC). Almost a third of all patients with ccRCC show metastatic dissemination at presentation while another third develop metastasis during the course of the disease. Survival rates of mRCC patients remain low despite the development of novel targeted treatment regimens. Biomarkers indicating disease progression could help to define its aggressive potential and thus guide patient management. However, molecular markers that can reliably assess metastatic dissemination and disease recurrence in ccRCC have not been recommended for clinical practice to date. Liquid biopsies could provide an attractive and non-invasive method to determine the risk of recurrence or metastatic dissemination during follow-up and thus assist the search for surveillance biomarkers in ccRCC tumors. A wide spectrum of circulating molecules have already shown considerable potential for ccRCC diagnosis and prognostication. In this review, we outline state of the art of the key circulating analytes such as cfDNA, cfRNA, proteins, and exosomes that may serve as biomarkers for the longitudinal monitoring of ccRCC progression to metastasis. Moreover, we address some of the prevailing limitations in the past approaches and present promising adoptable technologies that could help to pursue the implementation of liquid biopsies as a prognostic tool for mRCC.
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Affiliation(s)
| | | | | | - Holger Moch
- Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Hella A. Bolck
- Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
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Griffin BR, You Z, Noureddine L, Gitomer B, Perrenoud L, Wang W, Chonchol M, Jalal D. KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results. Am J Nephrol 2020; 51:473-479. [PMID: 32541154 DOI: 10.1159/000508051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/22/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. METHODS Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. RESULTS Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. CONCLUSION Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.
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Affiliation(s)
- Benjamin R Griffin
- Division of Nephrology and Hypertension, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA,
- Center for Access and Delivery Research and Evaluation (CADRE), Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA,
| | - Zhiying You
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Lama Noureddine
- Division of Nephrology and Hypertension, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Berenice Gitomer
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Loni Perrenoud
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Wei Wang
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Diana Jalal
- Division of Nephrology and Hypertension, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
- Center for Access and Delivery Research and Evaluation (CADRE), Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, USA
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Safety and efficacy of CDX-014, an antibody-drug conjugate directed against T cell immunoglobulin mucin-1 in advanced renal cell carcinoma. Invest New Drugs 2020; 38:1807-1814. [PMID: 32472319 DOI: 10.1007/s10637-020-00945-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/06/2020] [Indexed: 01/08/2023]
Abstract
CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registration https://clinicaltrials.gov/ct2/show/NCT02837991 NCT02837991; July 20, 2016.
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Aragón CC, Tafúr RA, Suárez-Avellaneda A, Martínez MDT, Salas ADL, Tobón GJ. Urinary biomarkers in lupus nephritis. J Transl Autoimmun 2020; 3:100042. [PMID: 32743523 PMCID: PMC7388339 DOI: 10.1016/j.jtauto.2020.100042] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 01/07/2020] [Accepted: 02/06/2020] [Indexed: 02/08/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease that can affect any organ of the body. Multiple mechanisms may contribute to the pathophysiology of systemic lupus, including failure to remove apoptotic bodies, hyperactivity of self-reactive B and T lymphocytes, abnormal exposure to autoantigens, and increased levels of B-cell stimulatory cytokines. The involvement of the kidney, called lupus nephritis (LN), during the course of the disease affects between 30% and 60% of adult SLE patients, and up to 70% of children. LN is an immune-mediated glomerulonephritis that is a common and serious finding in patients with SLE. Nowadays, renal biopsy is considered the gold standard for classifying LN, besides its degree of activity or chronicity. Nevertheless, renal biopsy lacks the ability to predict which patients will respond to immunosuppressive therapy and is a costly and risky procedure that is not practical in the monitoring of LN because serial repetitions would be necessary. Consequently, many serum and urinary biomarkers have been studied in SLE patients for the complementary study of LN, existing conventional biomarkers like proteinuria, protein/creatinine ratio in spot urine, 24 h urine proteinuria, creatinine clearance, among others and non-conventional biomarkers, like Monocyte chemoattractant protein-1 (MCP-1), have been correlated with the histological findings of the different types of LN. In this article, we review the advances in lupus nephritis urinary biomarkers. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to follow response to therapy. In addition, some of these markers have been found to be involved in the pathogenesis of lupus nephritis.
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Affiliation(s)
- Cristian C. Aragón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - Raúl-Alejandro Tafúr
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Ana Suárez-Avellaneda
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
| | - MD. Tatiana Martínez
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Alejandra de las Salas
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
- Universidad Icesi, Medical School, Cali, Colombia
| | - Gabriel J. Tobón
- GIRAT: Grupo de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Fundación Valle Del Lili and Universidad Icesi, Cali, Colombia
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Tan X, Broses LJ, Zhou M, Day KC, Liu W, Li Z, Weizer AZ, Munson KA, Khaing Oo MK, Day ML, Fan X. Multiparameter urine analysis for quantitative bladder cancer surveillance of orthotopic xenografted mice. LAB ON A CHIP 2020; 20:634-646. [PMID: 31922156 DOI: 10.1039/c9lc01006h] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The human-derived orthotopic xenograft mouse model is an effective platform for performing in vivo bladder cancer studies to examine tumor development, metastasis, and therapeutic effects of drugs. To date, the surveillance of tumor progression in real time for orthotopic bladder xenografts is highly dependent on semi-quantitative in vivo imaging technologies such as bioluminescence. While these imaging technologies can estimate tumor progression, they are burdened with requirements such as anesthetics, specialized equipment, and genetic modification of the injected cell line. Thus, a convenient and non-invasive technology to quantitatively monitor the growth of bladder cancer in orthotopic xenografts is highly desired. In this work, using a microfluidic chemiluminescent ELISA platform, we have successfully developed a rapid, multiparameter urine-based and non-invasive biomolecular prognostic technology for orthotopic bladder cancer xenografts. This method consists of two steps. First, the concentrations of a panel of four urinary biomarkers are quantified from the urine of mice bearing orthotopic bladder xenografts. Second, machine learning and principal component analysis (PCA) algorithms are applied to analyze the urinary biomarkers, and subsequently, a score is assigned to indicate the tumor growth. With this methodology, we have quantitatively monitored the orthotopic growth of human bladder cancer that was inoculated with low, medium, and high cancer cell numbers. We also employed this method and performed a proof of principle experiment to examine the in vivo therapeutic efficacy of the EGFR inhibitor, dacomitinib.
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Affiliation(s)
- Xiaotian Tan
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Luke J Broses
- Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. and Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Menglian Zhou
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Kathleen C Day
- Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. and Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenyi Liu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Ziqi Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Alon Z Weizer
- Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. and Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katherine A Munson
- Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. and Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Mark L Day
- Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. and Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xudong Fan
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
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Keshavarz Shahbaz S, Pourrezagholi F, Nafar M, Ahmadpoor P, Barabadi M, Foroughi F, Hosseinzadeh M, Yekaninejad MS, Amirzargar A. Dynamic variation of kidney injury molecule-1 mRNA and protein expression in blood and urine of renal transplant recipients: a cohort study. Clin Exp Nephrol 2019; 23:1235-1249. [PMID: 31302846 DOI: 10.1007/s10157-019-01765-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/14/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Acute renal dysfunction still constitutes a highly significant obstacle to renal transplantation outcome. Kidney injury molecule-1 is highly upregulated in proximal tubular cells and shed into the urine and blood circulation following kidney injury. The aim of current cohort study was to evaluate the urine KIM-1 (uKIM-1) mRNA expression level and its protein concentration in blood and urine samples to determine whether sequential monitoring of KIM-1 in renal allograft recipients is a reliable biomarker for predicting the clinical status and outcome. METHODS Both uKIM-1 mRNA expression level and the level of serum and uKIM-1 protein concentration in the 52 renal transplant recipients were respectively quantified using real-time PCR and ELISA methods at 2, 90 and 180 days after transplantation. RESULT KIM-1 mRNA and protein expression level in the blood and urine samples of patients with graft dysfunction was significantly higher than patients with well-functioning graft on days 2, 90 and 180 after transplantation. Receiver-operating characteristic curve analysis of mRNA and protein expression levels showed that urinary and blood KIM-1 at months 3 and 6 could predict acute renal dysfunction at 6 months and 1 year after transplantation. CONCLUSION Sequential monitoring of uKIM-1 mRNA expression level and its protein concentration in the serum and urine samples of renal transplant patients suggests that KIM-1 could be a sensitive and specific biomarker for early diagnosis and prognosis of kidney allograft injury.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Building No. 7, Poursina Ave, Tehran, Iran
| | - Fatemeh Pourrezagholi
- Department of Nephrology, Chronic Kidney Disease Research Center, Shahid Labbafinejad Medical Center and Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohesn Nafar
- Department of Nephrology, Chronic Kidney Disease Research Center, Shahid Labbafinejad Medical Center and Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pedram Ahmadpoor
- Department of Nephrology, Chronic Kidney Disease Research Center, Shahid Labbafinejad Medical Center and Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehri Barabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Building No. 7, Poursina Ave, Tehran, Iran
| | - Farshad Foroughi
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Morteza Hosseinzadeh
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Building No. 7, Poursina Ave, Tehran, Iran.
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Review and Comparison of Cancer Biomarker Trends in Urine as a Basis for New Diagnostic Pathways. Cancers (Basel) 2019; 11:cancers11091244. [PMID: 31450698 PMCID: PMC6770126 DOI: 10.3390/cancers11091244] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/20/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the major causes of mortality worldwide and its already large burden is projected to increase significantly in the near future with a predicted 22 million new cancer cases and 13 million cancer-related deaths occurring annually by 2030. Unfortunately, current procedures for diagnosis are characterized by low diagnostic accuracies. Given the proved correlation between cancer presence and alterations of biological fluid composition, many researchers suggested their characterization to improve cancer detection at early stages. This paper reviews the information that can be found in the scientific literature, regarding the correlation of different cancer forms with the presence of specific metabolites in human urine, in a schematic and easily interpretable form, because of the huge amount of relevant literature. The originality of this paper relies on the attempt to point out the odor properties of such metabolites, and thus to highlight the correlation between urine odor alterations and cancer presence, which is proven by recent literature suggesting the analysis of urine odor for diagnostic purposes. This investigation aims to evaluate the possibility to compare the results of studies based on different approaches to be able in the future to identify those compounds responsible for urine odor alteration.
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Diagnostic role of kidney injury molecule-1 in renal cell carcinoma. Int Urol Nephrol 2019; 51:1893-1902. [DOI: 10.1007/s11255-019-02231-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 07/10/2019] [Indexed: 10/26/2022]
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Lorente D, Trilla E, Meseguer A, Arevalo J, Nemours S, Planas J, Placer J, Celma A, Salvador C, Regis L, Schwartzmann I, Morote J. The role of STAT3 protein as a prognostic factor in the clear cell renal carcinoma. Systematic review. Actas Urol Esp 2019; 43:118-123. [PMID: 30466966 DOI: 10.1016/j.acuro.2018.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/28/2018] [Accepted: 08/31/2018] [Indexed: 11/27/2022]
Abstract
CONTEXT AND OBJECTIVE There have been significant advances in the knowledge of renal carcinogenesis n the last years. Nowadays, renal tumors are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyse literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC). EVIDENCE ACQUISITION In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were"renal cell carcinoma"and"STAT3"or"STAT-3"and"prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analysed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria. EVIDENCE SYNTHESIS STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease. CONCLUSIONS STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness.
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Affiliation(s)
- D Lorente
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - E Trilla
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España.
| | - A Meseguer
- Unidad de Fisiopatología Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, España
| | - J Arevalo
- Unidad de Fisiopatología Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, España
| | - S Nemours
- Unidad de Fisiopatología Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, España
| | - J Planas
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - J Placer
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - A Celma
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - C Salvador
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - L Regis
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - I Schwartzmann
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
| | - J Morote
- Servicio de Urología, Hospital de la Vall d'Hebrón, Universidad Autónoma de Barcelona, Barcelona, España
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Song J, Yu J, Prayogo GW, Cao W, Wu Y, Jia Z, Zhang A. Understanding kidney injury molecule 1: a novel immune factor in kidney pathophysiology. Am J Transl Res 2019; 11:1219-1229. [PMID: 30972157 PMCID: PMC6456506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/02/2019] [Indexed: 06/09/2023]
Abstract
Kidney injury molecule 1 (KIM-1) is a type I membrane protein, comprising an extracellular portion and a cytoplasmic portion. It is also named as HAVCR1 (Hepatitis A virus cellular receptor 1) or TIM1 (T-cell immunoglobulin mucin receptor 1), and is expressed in the kidney, liver, and spleen. KIM-1 plays different roles via various molecular targets in immune diseases and kidney injury. KIM-1 is involved in HAV infections, autoimmunity, immune tolerance, and atopic diseases. The urinary KIM-1 level is closely related to its tissue level, and correspondingly related to kidney tissue damage. KIM-1 is not only an early biomarker of acute kidney injury (AKI), but also has a potential role in predicting the long-term renal outcome. In this review, we provide a summary of KIM-1's activities, focusing on the latest studies concerning the important roles of KIM-1 in the immune system and kidney diseases.
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Affiliation(s)
- Jiayu Song
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Jing Yu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Gabriella Wenda Prayogo
- Department of Endocrinology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
| | - Weidong Cao
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Yimei Wu
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
| | - Aihua Zhang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical UniversityNanjing 210008, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical UniversityNanjing 210029, China
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Liu L, Song Z, Zhao Y, Li C, Wei H, Ma J, Du Y. HAVCR1 expression might be a novel prognostic factor for gastric cancer. PLoS One 2018; 13:e0206423. [PMID: 30388143 PMCID: PMC6214515 DOI: 10.1371/journal.pone.0206423] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 10/13/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis A virus cellular receptor 1 (HAVCR1), which is also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a TIM gene family member. In this study, we aimed to characterize the expression profile of HAVCR1 in GC, its prognostic value and the potential epigenetic mechanism leading to its dysregulation. Bioinformatic analysis was performed by using genomic, clinicopathological and survival data in the human protein atlas (HPA) and the Cancer Genome Atlas (TCGA). Results showed that HAVCR1 was significantly upregulated at the mRNA and protein level in GC tissues compared to the adjacent normal tissues. In addition, HAVCR1 upregulation was an independent indicator of shorter OS (HR: 1.698, 95%CI: 1.221–2.361, p = 0.002), after adjustment of older age, differentiation status, pathological stages and the presence of residual tumor and was also an independent indicator of shorter RFS (HR: 2.577, 95%CI: 1.583–4.197, p<0.001), after adjustment of gender and histological grade. The methylation level of two CpG sites (cg11188031 and cg07320595) was negatively correlated with HAVCR1 expression. However, only high methylation level of cg07320595 was associated with significantly longer OS (p = 0.018) and RFS (p = 0.021). Based on these findings, we infer that HAVCR1 upregulation might serve as a valuable prognostic marker in terms of OS and RFS in GC patients. Cg07320595 might be a critical CpG site influencing HAVCR1 expression.
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Affiliation(s)
- Lingling Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Zhaoquan Song
- Clinical Laboratory, Linyi Luozhuang Central Hospital, Linyi, Shandong, China
| | - Yingchun Zhao
- The 1 Ward of the Department of Paediatrics, Zhangqiu People’s Hospital, Jinan, Shandong, China
| | - Chao Li
- Department of NMR, Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
- * E-mail:
| | - Hua Wei
- Department of Endoscopy, Huaihe Hospital, Henan University, Kaifeng, China
| | - Ji Ma
- Department of Endoscopy, Huaihe Hospital, Henan University, Kaifeng, China
| | - Yaowu Du
- Laboratory for Nanomedicine, School of Basic Medical Science, Henan University, Kaifeng, China
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Haque ME, Khan F, Chi L, Gurung S, Vadevoo SMP, Park RW, Kim DK, Kim SK, Lee B. A Phage Display-Identified Peptide Selectively Binds to Kidney Injury Molecule-1 (KIM-1) and Detects KIM-1-Overexpressing Tumors in vivo. Cancer Res Treat 2018; 51:861-875. [PMID: 30282451 PMCID: PMC6639206 DOI: 10.4143/crt.2018.214] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 09/26/2018] [Indexed: 01/05/2023] Open
Abstract
PURPOSE This study was carried out to identify a peptide that selectively binds to kidney injury molecule-1 (KIM-1) by screening a phage-displayed peptide library and to use the peptide for the detection of KIM-1overexpressing tumors in vivo. MATERIALS AND METHODS Biopanning of a phage-displayed peptide library was performed on KIM-1-coated plates. The binding of phage clones, peptides, and a peptide multimer to the KIM-1 protein and KIM-1-overexpressing and KIM-1-low expressing cells was examined by enzyme-linked immunosorbent assay, fluorometry, and flow cytometry. A biotin-peptide multimer was generated using NeutrAvidin. In vivo homing of the peptide to KIM-1-overexpressing and KIM1-low expressing tumors in mice was examined by whole-body fluorescence imaging. RESULTS A phage clone displaying the CNWMINKEC peptide showed higher binding affinity to KIM-1 and KIM-1-overexpressing 769-P renal tumor cells compared to other phage clones selected after biopanning. The CNWMINKEC peptide and a NeutrAvidin/biotin-CNWMINKEC multimer selectively bound to KIM-1 over albumin and to KIM-1-overexpressing 769-P cells and A549 lung tumor cells compared to KIM-1-low expressing HEK293 normal cells. Co-localization and competition assays using an anti-KIM-1 antibody demonstrated that the binding of the CNWMINKEC peptide to 769-P cells was specifically mediated by KIM-1. The CNWMINKEC peptide was not cytotoxic to cells and was stable for up to 24 hours in the presence of serum. Whole-body fluorescence imaging demonstrated selective homing of the CNWM-INKEC peptide to KIM-1-overexpressing A498 renal tumor compared to KIM1-low expressing HepG2 liver tumor in mice. CONCLUSION The CNWMINKEC peptide is a promising probe for in vivo imaging and detection of KIM-1‒overexpressing tumors.
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Affiliation(s)
- Md Enamul Haque
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea.,BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea.,CMRI, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Fatima Khan
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Lianhua Chi
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Smriti Gurung
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
| | | | - Rang-Woon Park
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Dong-Kyu Kim
- Laboratory Animal Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Sang Kyoon Kim
- Laboratory Animal Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Byungheon Lee
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea.,BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Korea.,CMRI, School of Medicine, Kyungpook National University, Daegu, Korea
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Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol 2018; 36:1341-1353. [PMID: 29610964 PMCID: PMC6105141 DOI: 10.1007/s00345-018-2286-7] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023] Open
Abstract
PURPOSE The widespread use of abdominal imaging has affected the epidemiology of renal cell carcinoma (RCC). Despite this, over 25% of individuals with RCC have evidence of metastases at presentation. Screening for RCC has the potential to downstage the disease. METHODS We performed a literature review on the epidemiology of RCC and evidence base regarding screening. Furthermore, contemporary RCC epidemiology data was obtained for the United Kingdom and trends in age-standardised rates of incidence and mortality were analysed by annual percentage change statistics and joinpoint regression. RESULTS The incidence of RCC in the UK increased by 3.1% annually from 1993 through 2014. Urinary dipstick is an inadequate screening tool due to low sensitivity and specificity. It is unlikely that CT would be recommended for population screening due to cost, radiation dose and increased potential for other incidental findings. Screening ultrasound has a sensitivity and specificity of 82-83% and 98-99%, respectively; however, accuracy is dependent on tumour size. No clinically validated urinary nor serum biomarkers have been identified. Major barriers to population screening include the relatively low prevalence of the disease, the potential for false positives and over-diagnosis of slow-growing RCCs. Individual patient risk-stratification based on a combination of risk factors may improve screening efficiency and minimise harms by identifying a group at high risk of RCC. CONCLUSION The incidence of RCC is increasing. The optimal screening modality and target population remain to be elucidated. An analysis of the benefits and harms of screening for patients and society is warranted.
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Affiliation(s)
- Sabrina H. Rossi
- Academic Urology Group, University of Cambridge, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Hills Road, Box 43, Cambridge, CB2 0QQ UK
| | - Tobias Klatte
- Department of Urology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ UK
| | - Juliet Usher-Smith
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB2 0SR UK
| | - Grant D. Stewart
- Academic Urology Group, University of Cambridge, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Hills Road, Box 43, Cambridge, CB2 0QQ UK
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