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Published in: BMC Nephrology 1/2018

Open Access 01-12-2018 | Research article

The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study

Authors: Hyo Jin Kim, Eunjeong Kang, Yun Kyu Oh, Yeong Hoon Kim, Seung Hyeok Han, Tae Hyun Yoo, Dong-Wan Chae, Joongyub Lee, Curie Ahn, Kook-Hwan Oh

Published in: BMC Nephrology | Issue 1/2018

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Abstract

Background

Klotho, a protein linked to aging, has emerged as a pivotal player in mineral bone metabolism and might explain the relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD). The present study aimed to investigate the association between serum klotho and cardiac parameters from a large-scale Korean CKD cohort.

Methods

We analyzed 2101 participants from KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort who had been measured for serum klotho levels. Left ventricular hypertrophy evaluated by left ventricular mass index (LVMI) and arterial stiffness measured by brachial-to-ankle pulse wave velocity (baPWV) were explored as cardiovascular parameters.

Results

Patients were 53.6 ± 12.2 years old and 61.1% were male. The mean estimated glomerular filtration rate (eGFR) was 53.0 ± 30.7 mL/min/1.73m2. The median serum klotho level was 536 (interquartile range [IQR]: 420–667) pg/mL. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001, P for linear trend < 0.001). Ascending quartiles of klotho were significantly associated with decreased LMVI (P < 0.001, P for linear trend< 0.001). A multivariable linear regression model showed serum klotho had a significant inverse association with LVMI (β − 0.04; 95% CI [confidence interval] -0.004, − 0.00007; P = 0.041). However, there was no significant association between serum klotho and baPWV after adjustment (β 0.003; 95% CI -0.04, 0.05; P = 0.876).

Trial registration

This trial was registered on ClinicalTrials.gov on 28 June 2012 (NCT01630486).

Conclusions

Serum klotho was an independent biomarker of LVMI, but not arterial stiffness.
Literature
1.
go back to reference Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112–9.CrossRefPubMed Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112–9.CrossRefPubMed
2.
go back to reference Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.CrossRefPubMed Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.CrossRefPubMed
3.
go back to reference Taddei S, Nami R, Bruno RM, Quatrini I, Nuti R. Hypertension, left ventricular hypertrophy and chronic kidney disease. Heart Fail Rev. 2011;16:615–20.CrossRefPubMed Taddei S, Nami R, Bruno RM, Quatrini I, Nuti R. Hypertension, left ventricular hypertrophy and chronic kidney disease. Heart Fail Rev. 2011;16:615–20.CrossRefPubMed
4.
go back to reference Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol. 2001;12:1079–84.PubMed Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol. 2001;12:1079–84.PubMed
5.
go back to reference Gross ML, Hypertrophy RE. Fibrosis in the cardiomyopathy of uremia--beyond coronary heart disease. Semin Dial. 2008;21:308–18.CrossRefPubMed Gross ML, Hypertrophy RE. Fibrosis in the cardiomyopathy of uremia--beyond coronary heart disease. Semin Dial. 2008;21:308–18.CrossRefPubMed
6.
go back to reference Glassock RJ, Pecoits-Filho R, Barberato SH. Left ventricular mass in chronic kidney disease and ESRD. Clin J Am Soc Nephrol. 2009;4(Suppl 1):S79–91.CrossRefPubMed Glassock RJ, Pecoits-Filho R, Barberato SH. Left ventricular mass in chronic kidney disease and ESRD. Clin J Am Soc Nephrol. 2009;4(Suppl 1):S79–91.CrossRefPubMed
8.
go back to reference Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, et al. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens. 2010;28:163–9.CrossRefPubMed Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, et al. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens. 2010;28:163–9.CrossRefPubMed
9.
go back to reference Townsend RR. Arterial stiffness and chronic kidney disease: lessons from the chronic renal insufficiency cohort study. Curr Opin Nephrol Hypertens. 2015;24:47–53.CrossRefPubMedPubMedCentral Townsend RR. Arterial stiffness and chronic kidney disease: lessons from the chronic renal insufficiency cohort study. Curr Opin Nephrol Hypertens. 2015;24:47–53.CrossRefPubMedPubMedCentral
10.
go back to reference Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.CrossRefPubMed Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.CrossRefPubMed
12.
go back to reference Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol. 2015;26:1150–60.CrossRefPubMed Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol. 2015;26:1150–60.CrossRefPubMed
13.
go back to reference Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124–36.CrossRefPubMedPubMedCentral Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124–36.CrossRefPubMedPubMedCentral
14.
go back to reference Chen K, Zhou X, Sun Z. Haplodeficiency of klotho gene causes arterial stiffening via upregulation of Scleraxis expression and induction of autophagy. Hypertension. 2015;66:1006–13.CrossRefPubMedPubMedCentral Chen K, Zhou X, Sun Z. Haplodeficiency of klotho gene causes arterial stiffening via upregulation of Scleraxis expression and induction of autophagy. Hypertension. 2015;66:1006–13.CrossRefPubMedPubMedCentral
15.
16.
go back to reference Yang K, Wang C, Nie L, Zhao X, Gu J, Guan X, et al. Klotho protects against Indoxyl Sulphate-induced myocardial hypertrophy. J Am Soc Nephrol. 2015;26:2434–46.CrossRefPubMedPubMedCentral Yang K, Wang C, Nie L, Zhao X, Gu J, Guan X, et al. Klotho protects against Indoxyl Sulphate-induced myocardial hypertrophy. J Am Soc Nephrol. 2015;26:2434–46.CrossRefPubMedPubMedCentral
17.
go back to reference Buiten MS, de Bie MK, Bouma-de Krijger A, van Dam B, Dekker FW, Jukema JW, et al. Soluble klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol. 2014;15:197.CrossRefPubMedPubMedCentral Buiten MS, de Bie MK, Bouma-de Krijger A, van Dam B, Dekker FW, Jukema JW, et al. Soluble klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol. 2014;15:197.CrossRefPubMedPubMedCentral
18.
go back to reference Oh KH, Park SK, Park HC, Chin HJ, Chae DW, Choi KH, et al. KNOW-CKD (KoreaN cohort study for outcome in patients with chronic kidney disease): design and methods. BMC Nephrol. 2014;15:80.CrossRefPubMedPubMedCentral Oh KH, Park SK, Park HC, Chin HJ, Chae DW, Choi KH, et al. KNOW-CKD (KoreaN cohort study for outcome in patients with chronic kidney disease): design and methods. BMC Nephrol. 2014;15:80.CrossRefPubMedPubMedCentral
19.
go back to reference Siekmann L. Determination of creatinine in human serum by isotope dilution-mass spectrometry. Definitive methods in clinical chemistry, IV. J Clin Chem Clin Biochem. 1985;23:137–44.PubMed Siekmann L. Determination of creatinine in human serum by isotope dilution-mass spectrometry. Definitive methods in clinical chemistry, IV. J Clin Chem Clin Biochem. 1985;23:137–44.PubMed
20.
go back to reference Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRefPubMedPubMedCentral Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRefPubMedPubMedCentral
21.
go back to reference Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. Establishment of sandwich ELISA for soluble alpha-klotho measurement: age-dependent change of soluble alpha-klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010;398:513–8.CrossRefPubMedPubMedCentral Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. Establishment of sandwich ELISA for soluble alpha-klotho measurement: age-dependent change of soluble alpha-klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010;398:513–8.CrossRefPubMedPubMedCentral
22.
go back to reference de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol. 1992;20:1251–60.CrossRefPubMed de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol. 1992;20:1251–60.CrossRefPubMed
23.
go back to reference Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–63.CrossRefPubMed Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–63.CrossRefPubMed
24.
go back to reference de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995;25:1056–62.CrossRefPubMed de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995;25:1056–62.CrossRefPubMed
25.
go back to reference Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016. 2016;69:1167. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016. 2016;69:1167.
26.
go back to reference Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the heart failure and echocardiography associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–50.CrossRefPubMed Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the heart failure and echocardiography associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–50.CrossRefPubMed
27.
go back to reference Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O’Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation. 1983;68:50–8.CrossRefPubMed Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O’Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation. 1983;68:50–8.CrossRefPubMed
28.
go back to reference Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PW. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis. 1997;132:245–50.CrossRefPubMed Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PW. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis. 1997;132:245–50.CrossRefPubMed
29.
go back to reference Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–32.CrossRefPubMed Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–32.CrossRefPubMed
30.
go back to reference Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, et al. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2009;53:345–52.CrossRefPubMedPubMedCentral Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, et al. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2009;53:345–52.CrossRefPubMedPubMedCentral
31.
go back to reference Menon V, Gul A, Sarnak MJ. Cardiovascular risk factors in chronic kidney disease. Kidney Int. 2005;68:1413–8.CrossRefPubMed Menon V, Gul A, Sarnak MJ. Cardiovascular risk factors in chronic kidney disease. Kidney Int. 2005;68:1413–8.CrossRefPubMed
32.
go back to reference Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347–54.CrossRefPubMed Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347–54.CrossRefPubMed
33.
go back to reference Astor BC, Arnett DK, Brown A, Coresh J. Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the atherosclerosis risk in communities (ARIC) study. Am J Kidney Dis. 2004;43:836–45.CrossRefPubMed Astor BC, Arnett DK, Brown A, Coresh J. Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the atherosclerosis risk in communities (ARIC) study. Am J Kidney Dis. 2004;43:836–45.CrossRefPubMed
34.
go back to reference Edwards NC, Hirth A, Ferro CJ, Townend JN, Steeds RP. Subclinical abnormalities of left ventricular myocardial deformation in early-stage chronic kidney disease: the precursor of uremic cardiomyopathy? J Am Soc Echocardiogr. 2008;21:1293–8.CrossRefPubMed Edwards NC, Hirth A, Ferro CJ, Townend JN, Steeds RP. Subclinical abnormalities of left ventricular myocardial deformation in early-stage chronic kidney disease: the precursor of uremic cardiomyopathy? J Am Soc Echocardiogr. 2008;21:1293–8.CrossRefPubMed
35.
go back to reference Devereux RB, Roman MJ, Liu JE, Welty TK, Lee ET, Rodeheffer R, et al. Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the strong heart study. Am J Cardiol. 2000;86:1090–6.CrossRefPubMed Devereux RB, Roman MJ, Liu JE, Welty TK, Lee ET, Rodeheffer R, et al. Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the strong heart study. Am J Cardiol. 2000;86:1090–6.CrossRefPubMed
36.
go back to reference Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL. Cardioprotection by klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun. 2012;3:1238.CrossRefPubMedPubMedCentral Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL. Cardioprotection by klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun. 2012;3:1238.CrossRefPubMedPubMedCentral
37.
go back to reference Tanaka S, Fujita S, Kizawa S, Morita H, Ishizaka N. Association between FGF23, alpha-klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLoS One. 2016;11:e0156860.CrossRefPubMedPubMedCentral Tanaka S, Fujita S, Kizawa S, Morita H, Ishizaka N. Association between FGF23, alpha-klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLoS One. 2016;11:e0156860.CrossRefPubMedPubMedCentral
38.
go back to reference Seiler S, Rogacev KS, Roth HJ, Shafein P, Emrich I, Neuhaus S, et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol. 2014;9:1049–58.CrossRefPubMedPubMedCentral Seiler S, Rogacev KS, Roth HJ, Shafein P, Emrich I, Neuhaus S, et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol. 2014;9:1049–58.CrossRefPubMedPubMedCentral
40.
go back to reference Saito Y, Nakamura T, Ohyama Y, Suzuki T, Iida A, Shiraki-Iida T, et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem Biophys Res Commun. 2000;276:767–72.CrossRefPubMed Saito Y, Nakamura T, Ohyama Y, Suzuki T, Iida A, Shiraki-Iida T, et al. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem Biophys Res Commun. 2000;276:767–72.CrossRefPubMed
41.
go back to reference Kusaba T, Okigaki M, Matui A, Murakami M, Ishikawa K, Kimura T, et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci U S A. 2010;107:19308–13.CrossRefPubMedPubMedCentral Kusaba T, Okigaki M, Matui A, Murakami M, Ishikawa K, Kimura T, et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci U S A. 2010;107:19308–13.CrossRefPubMedPubMedCentral
42.
go back to reference Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, et al. A decreased level of serum soluble klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One. 2013;8:e56695.CrossRefPubMedPubMedCentral Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Ogawa A, et al. A decreased level of serum soluble klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One. 2013;8:e56695.CrossRefPubMedPubMedCentral
43.
go back to reference Inci A, Sari F, Olmaz R, Coban M, Dolu S, Sarikaya M, et al. Soluble klotho levels in diabetic nephropathy: relationship with arterial stiffness. Eur Rev Med Pharmacol Sci. 2016;20:3230–7.PubMed Inci A, Sari F, Olmaz R, Coban M, Dolu S, Sarikaya M, et al. Soluble klotho levels in diabetic nephropathy: relationship with arterial stiffness. Eur Rev Med Pharmacol Sci. 2016;20:3230–7.PubMed
44.
go back to reference Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab. 2010;95:E352–7.CrossRefPubMedPubMedCentral Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab. 2010;95:E352–7.CrossRefPubMedPubMedCentral
45.
go back to reference Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012;97:3357–65.CrossRefPubMed Smith ER, Cai MM, McMahon LP, Holt SG. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012;97:3357–65.CrossRefPubMed
Metadata
Title
The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study
Authors
Hyo Jin Kim
Eunjeong Kang
Yun Kyu Oh
Yeong Hoon Kim
Seung Hyeok Han
Tae Hyun Yoo
Dong-Wan Chae
Joongyub Lee
Curie Ahn
Kook-Hwan Oh
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2018
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-018-0851-3

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