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Endocan as a potential diagnostic or prognostic biomarker for chronic kidney disease Hyun Gyu Lee1,4, Hoon Young Choi2,4 and Jong-Sup Bae3 Developing specific markers for early detection of adverse events such as kidney failure, cardiovascular events, and all-cause mortality in chronic kidney disease (CKD) patients remains a major challenge. Cardiovascular events are the main cause of morbidity and mortality in CKD patients. Recent research supposes endocan as a biomarker for evaluating cardiovascular events, inflammatory diseases, and cancers. Yilmaz et al. propose serum endocan levels as a novel prediction marker of all-cause mortality and cardiovascular events in CKD patients. Kidney International (2014) 86, 1079–1081. doi:10.1038/ki.2014.292

Patients with chronic kidney disease (CKD) face a high risk of adverse outcomes such as kidney failure, cardiovascular events, and all-cause mortality.1 Accurate and generalizable risk prediction models for these adverse events in CKD patients are urgently needed.2 Recently, the kidney failure risk equation for prediction of kidney failure in CKD patients was developed;3 however, there are no prediction models evaluating the risk of cardiovascular events.4 Yilmaz et al.5 (this issue) applied serum endocan levels to a novel prediction model of all-cause mortality and cardiovascular events in CKD patients. They report that endocan levels increased in the presence of deteriorating glomerular 1 Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea and 3College of Pharmacy, Cell and Matrix Research Institute, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea Correspondence: Jong-Sup Bae, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Republic of Korea. E-mail: [email protected] 4

These authors contributed equally to this work.

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filtration rate, showing an inverse correlation with serum endocan levels, and its value influenced all-cause mortality and cardiovascular events in the CKD patients independently of traditional and nontraditional risk factors. Moreover, plasma endocan was significantly associated with markers of inflammation (high-sensitivity C-reactive protein) and vascular abnormalities (flow-mediated vasodilation and carotid intima–media thickness). The authors investigated whether endocan was associated with an increased risk of death and cardiovascular events independent of traditional (hypertension, diabetes mellitus, cigarette smoking, and dyslipidemia) and nontraditional risk factors (inflammation, vascular calcification, and oxidative stress) using three adjusted models for survival and time-to-event analysis of cardiovascular outcomes. Cox proportional hazards models were adjusted initially only with endocan, and subsequently for several groups of covariates. In model 1, they adjusted for traditional cardiovascular risk factors: age, sex, smoking status, diabetes, systolic blood pressure, high-density lipoprotein, and total cholesterol. In model 2, they adjusted for renal-specific cardio-

vascular risk factors: estimated glomerular filtration rates, proteinuria, and high-sensitivity C-reactive protein. In model 3, they adjusted for all the variables used in the previous two models. Remarkably, in all three models, endocan was found to be independently associated with all-cause mortality and cardiovascular events. In the final model adjusting for both traditional and renal-specific cardiovascular risk factors, the authors unveiled that endocan was a strong predictor for mortality and cardiovascular events in CKD patients. Moreover, endocan was recognized as an improvement to the model prediction capability for cardiovascular events in CKD patients in this study. Although the results suggest that serum endocan levels provide new insights into the relationship among inflammation, vasculature, and longterm glycemic control in CKD patients, an association between endocan and hemoglobin A1c (HbA1c), a marker of glycemic control in diabetes, has not been shown in the present study. In this regard, the authors state that HbA1c values would not have added much discrimination on outcomes, given the small number of patients with diabetes and advanced CKD enrolled in the study. However, because glycemic control status plays an important role in cardiovascular risk in CKD patients with diabetes, and HbA1c has increased the ability to predict cardiovascular events mainly in diabetes, further studies should be performed with more patients with both diabetes and CKD. Serum endocan levels, solely or in combination with other biomarkers, have been verified as a biomarker for various diseases, including some kinds of cancers (originating from the brain, lung, liver, kidney, bladder, and so on), systemic inflammations, and cardiovascular diseases.6 Endocan is only physiologically expressed and secreted as a soluble form in vascular endothelial cells of the lung and kidney.7,8 Endocan expression in endothelial cells is upregulated in response to proangiogenic factors such as vascular endothelial growth factor (VEGF) and 1079

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proinflammatory cytokines, such as tumor necrosis factor-a, interleukin1b, and lipopolysaccharide, but downregulated by interferon-g, which would result in regression of inflammatory responses.6,9,10 The potential of endocan as a biomarker for various diseases may be due to the tight and specific regulation of its expression. ESM-1 promoter activity was observed only in cells of endothelial origin,11 which may be due to the existence of endothelial-specific transcription factors that have not yet been identified. It is also expressed in tumor endothelium in vivo by regulation of tumor-derived factors, one of which was later verified as a VEGF. VEGF-induced endocan expression is dependent on the balance of positive PKC/NFKB and negative PI3K/ AKT/FKHRL1 signaling pathways (Figure 1).12 Moreover, endocan was not induced during early embryogenesis in spite of abundant expression of VEGF,12 which suggests the existence of another regulatory mechanism. Recently, it was reported that hypoxia-inducible factor-1a (HIF-1a) could regulate endocan in colon cancer.13 Our unpublished data showed that there are some CpG islands and putative HIF-1a response elements in the ESM-1 promoter. During cancer progression, unknown epigenetic mechanisms may induce demethylation of CpG islands, allowing HIF-1a access to HIF-1a response elements to induce endocan in cancer cells (Figure 1). Further studies are required to verify this hypothesis. In the study by Yilmaz et al.,5 there are some limitations. They have performed just a single measurement of serum endocan. A single point measurement of serum endocan is a little relevant, but serial multiple measurements could give more information on prognostic outcome of CKD. For instance, Li and Wang et al. performed multiple point measurements of serum endocan level during evaluation of acute rejection after renal transplantation.14 Multiple measurement of serum endocan level could discriminate acute rejection from renal 1080

VEGF-A

Endocan

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Exon I Exon II Exon III ESM-1

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Figure 1 | The regulation mechanism of endocan expression. VEGF-induced endocan expression is regulated by PKC/NFKB (positive) and PI3K/AKT/FKHRL1 (negative) signaling pathways. The balance of two signaling pathways influences ESM-1 promoter activities. (Hypothesis) The ESM-1 promoter is methylated in most tissues. During cancer progression or systemic inflammation, demethylation of CpG islands in the ESM-1 promoter allows HIF-1a to bind the HIF-1a response element (HRE).

allograft dysfunction. They additionally showed that endocan expression was located mainly in glomeruli, which may give a clue to the origin of serum endocan in CKD patients. Another instance is a report on serum endocan levels in septic patients.10,15 The severity of sepsis showed positive correlation with initial serum endocan levels. Moreover, it was significantly increased in non-survivors. However, the lack of multiple follow-up data on serum endocan levels prohibits the evaluation of sepsis treatment outcome, which requires multiple measurements. Another limitation is that Yilmaz et al.5 did not rule out accompanying cancers or other inflammatory diseases, which could be sources of serum endocan. Serum endocan is detected as a few hundred picograms in 1 ml of serum under normal physiologic conditions.10,16,17 Serum endocan solely could not inform regarding the location or kinds of diseases, but its detection over the

normal range may give a clue to search for some diseases, such as systemic inflammatory diseases, cardiovascular diseases, and various cancers. Finally, it is unclear whether the increased serum endocan level in CKD patients was the result of an increased secretion or a decreased renal clearance. The clearance mechanism of endocan has not yet been identified. As renal function declines, serum endocan level increases, which may be due to increased production or decreased clearance. The former might be due to kidney inflammation, which is preferable. In this report, serum endocan levels of patients in the third quartile (6.6 ng/ml) or fourth quartile (13.3 ng/ml) in the CKD classification based on estimated glomerular filtration rate were significantly higher than those of patients in the first (1.2 ng/ml) and second quartiles (2.8 ng/ml). This pattern was the same for high-sensitivity C-reactive protein, which was induced considerably by kidney inflammation.18 Kidney International (2014) 86

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However, the reason why serum endocan levels were significantly higher in CKD than in any other disease conditions must be evaluated. The possibility that the increased serum endocan levels in CKD patients resulted from decreased clearance could be evaluated simply by urine endocan level. Serial follow-up of serum endocan levels in CKD patients could also be informative in this regard. In conclusion, Yilmaz et al. have reported an endocan as a novel prediction marker of all-cause mortality and cardiovascular events in CKD patients. More detailed study of molecular mechanisms in endocan expression and degradation in CKD may increase the value of serum endocan levels.

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by cytokines. J Biol Chem 1996; 271: 20458–20464. Bechard D, Meignin V, Scherpereel A et al. Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodies. J Vasc Res 2000; 37: 417–425. Lee W, Ku SK, Kim SW et al. Endocan elicits severe vascular inflammatory responses in vitro and in vivo. J Cell Physiol 2014; 229: 620–630. Scherpereel A, Depontieu F, Grigoriu B et al. Endocan, a new endothelial marker in human sepsis. Crit Care Med 2006; 34: 532–537. Tsai JC, Zhang J, Minami T et al. Cloning and characterization of the human lung endothelial-cell-specific molecule-1 promoter. J Vasc Res 2002; 39: 148–159. Abid MR, Yi X, Yano K et al. Vascular endocan is preferentially expressed in tumor endothelium. Microvasc Res 2006; 72: 136–145. Kim JH, Park MY, Kim CN et al. Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1alpha in human colon carcinoma: impact of ESM-1 on prognosis and its correlation with

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clinicopathological features. Oncol Rep 2012; 28: 1701–1708. Li S, Wang L, Wang C et al. Detection on dynamic changes of endothelial cell specific molecule-1 in acute rejection after renal transplantation. Urology 2012; 80: 738.e1–738.e8. Filep JG. Endocan or endothelial cellspecific molecule-1: a novel prognostic marker of sepsis? Crit Care Med 2006; 34: 574–575. Balta S, Mikhailidis DP, Demirkol S et al. Endocan—a novel inflammatory indicator in newly diagnosed patients with hypertension: a pilot study. Angiology (advance online publication, 8 January 2014; doi:10.1177/ 0003319713513492). Ozaki K, Toshikuni N, George J et al. Serum endocan as a novel prognostic biomarker in patients with hepatocellular carcinoma. J Cancer 2014; 5: 221–230. Stuveling EM, Hillege HL, Bakker SJ et al. C-reactive protein is associated with renal function abnormalities in a nondiabetic population. Kidney Int 2003; 63: 654–661.

DISCLOSURE

All the authors declared no competing interests. ACKNOWLEDGMENTS

see clinical investigation on page 1253

The authors thank Dong-Su Jang (medical illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, Korea) for his help with the illustrations. This study was supported by the National Research Foundation of Korea funded by the Korean government (Ministry of Science, ICT and Future Planning) (grant NRF-2012R1A4A1028835).

Pathology vs. molecular genetics: (re)defining the spectrum of Alport syndrome

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Kidney International (2014) 86

Jeffrey H. Miner1

Kidney International (2014) 86, 1081–1083. doi:10.1038/ki.2014.326 KEYWORDS: Alport syndrome; FSGS; genetics; glomerular disease

Alport syndrome is one of the bestcharacterized genetic diseases that affect the kidney, in terms of its presentation, 1 Renal Division, Washington University School of Medicine, St Louis, Missouri, USA Correspondence: Jeffrey H. Miner, Renal Division 8126, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA. E-mail: [email protected]

pathological features, and molecular genetics. The syndrome includes hematuria that usually begins in childhood, with eventual progression to proteinuria and end-stage renal disease. Ultrastructural analysis reveals a thickened, split glomerular basement membrane (GBM) with a basket weavelike appearance that is considered 1081

Endocan as a potential diagnostic or prognostic biomarker for chronic kidney disease.

Developing specific markers for early detection of adverse events such as kidney failure, cardiovascular events, and all-cause mortality in chronic ki...
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