Top

BMC Nephrology

Published in:

Open Access 01-12-2019 | Chronic Kidney Disease | Research article

Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases

Authors: Chia-Chu Chang, Ping-Fang Chiu, Chia-Lin Wu, Cheng-Ling Kuo, Ching-Shan Huang, Chin-San Liu, Ching-Hui Huang

Published in: BMC Nephrology | Issue 1/2019

Abstract

Introduction

Cell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients.

Methods

One hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA.

Results

Patients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months.

Conclusions

Urinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.

Available only for authorised users

Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res. 2017;179:24–37. https://doi.org/10.1016/j.trsl.2016.04.007.CrossRefPubMed

Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2005;67:2089–100. https://doi.org/10.1111/j.1523-1755.2005.00365.x.CrossRefPubMed

Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet. 2005;365:331–40. https://doi.org/10.1016/S0140-6736(05)17789-7.CrossRefPubMed

Bello AK, Nwankwo E, El Nahas AM. Prevention of chronic kidney disease: a global challenge. Kidney Int Suppl. 2005;98:S11–7. https://doi.org/10.1111/j.1523-1755.2005.09802.x.CrossRef

Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382:339–52. https://doi.org/10.1016/S0140-6736(13)60595-4.CrossRefPubMed

Che R, Yuan Y, Huang S, Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Phys Renal Phys. 2013;306:F367–78. https://doi.org/10.1152/ajprenal.00571.2013.CrossRef

Yuan Y, Chen Y, Zhang P, Huang S, Zhu C, Ding G, et al. Mitochondrial dysfunction accounts for aldosterone-induced epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells. Free Radic Biol Med. 2012;53:30–43. https://doi.org/10.1016/j.freeradbiomed.2012.03.015.CrossRefPubMed

Zhang A, Jia Z, Guo X, Yang T. Aldosterone induces epithelial mesenchymal transition via ROS of mitochondrial origin. Am J Physiol Ren Physiol. 2007;293:F723–31. https://doi.org/10.1152/ajprenal.00480.2006.CrossRef

Emma F, Montini G, Parikh SM, Salviati L. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol. 2016;12:267–80. https://doi.org/10.1038/nrneph.2015.214.CrossRefPubMedPubMedCentral

10.

Zhu C, Huang S, Yuan Y, Ding G, Chen R, Liu B, et al. Mitochondrial dysfunction mediates aldosterone-induced podocyte damage. A therapeutic target of PPAR gamma. Am J Pathol. 2011;178:2020–31. https://doi.org/10.1016/j.ajpath.2011.01.029.CrossRefPubMedPubMedCentral

11.

He L, Wei Q, Liu J, Yi M, Liu Y, Liu H, et al. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int. 2017;92:1071–83. https://doi.org/10.1016/j.kint.2017.06.030.CrossRefPubMedPubMedCentral

12.

Kawakami T, Gomez IG, Ren S, Hudkins K, Roach A, Alpers CE, et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J Am Soc Nephrol. 2015;26:1040–52. https://doi.org/10.1681/ASN.2013111202.CrossRefPubMed

13.

Gong W, Mao S, Yu J, Song J, Jia Z, Huang S, et al. NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy. Am J Phys Renal Phys. 2016;310:F1081–8. https://doi.org/10.1152/ajprenal.00534.2015.CrossRef

14.

Hallan S, Sharma K. The role of mitochondria in diabetic kidney disease. Curr Diab Rep. 2016;16:61. https://doi.org/10.1007/s11892-016-0748-0.CrossRefPubMed

15.

Higgins GC, Coughlan MT. Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br J Pharmacol. 2014;171:1917–42. https://doi.org/10.1111/bph.12503.CrossRefPubMedPubMedCentral

16.

Mandel P, Metais P. Les acides du plasma sanguin chez l’homme. C R Acad Sci Paris. 1948;142:241–3 PMID:18875018.

17.

Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. https://doi.org/10.1038/nature08780.CrossRefPubMedPubMedCentral

18.

Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 2012;485:251–U142. https://doi.org/10.1038/nature10992.CrossRefPubMedPubMedCentral

19.

Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013;10:e1001577. https://doi.org/10.1371/journal.pmed.1001577.CrossRefPubMedPubMedCentral

20.

Tin A, Grams ME, Ashar FN, Lane JA, Rosenberg AZ, Grove ML, et al. Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the atherosclerosis risk in communities study. J Am Soc Nephrol. 2016;27:2467–73. https://doi.org/10.1681/ASN.2015060661.CrossRefPubMedPubMedCentral

21.

Cao H, Ye H, Sun Z, Shen X, Song Z, Wu X, et al. Circulatory mitochondrial DNA is a pro-inflammatory agent in maintenance hemodialysis patients. PLoS One. 2014;9:e113179. https://doi.org/10.1371/journal.pone.0113179.CrossRefPubMedPubMedCentral

22.

Lo Y.M., Rainer T.H., Chan L.Y., Hjelm N.M., Cocks R.A.. (2000) Plasma DNA as a prognostic marker in trauma patients. Clin Chem 46, 319–323. PMID: 10702517.

23.

Rainer TH, Lam NYL. Circulating nucleic acids and critical illness. Ann N Y Acad Sci. 2006;1075:271–7. https://doi.org/10.1196/annals.1368.035.CrossRefPubMed

24.

Antonatos D, Patsilinakos S, Spanodimos S, Korkonikitas P, Tsigas D. Cell-free DNA levels as a prognostic marker in acute myocardial infarction. Ann N Y Acad Sci. 2006;1075:278–81. https://doi.org/10.1196/annals.1368.037.CrossRefPubMed

25.

Rhodes A, Wort SJ, Thomas H, Collinson P, Bennett ED. Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Crit Care. 2006;10:R60. https://doi.org/10.1186/cc4894.CrossRefPubMedPubMedCentral

26.

Saukkonen K, Lakkisto P, Varpula M, Varpula T, Voipio-Pulkki LM, Pettilä V, et al. Association of cell-free plasma DNA with hospital mortality and organ dysfunction in intensive care unit patients. Intensive Care Med. 2007;33:1624–7. https://doi.org/10.1007/s00134-007-0686-z.CrossRefPubMed

27.

Hurtado-Roca Y, Ledesma M, Gonzalez-Lazaro M, Moreno-Loshuertos R, Fernandez-Silva P, Enriquez JA, et al. Adjusting MtDNA quantification in whole blood for peripheral blood platelet and leukocyte counts. PLoS One. 2016;11:e0163770. https://doi.org/10.1371/journal.pone.0163770.CrossRefPubMedPubMedCentral

28.

Urata M, Koga-Wada Y, Kayamori Y, Kang D. Platelet contamination causes large variation as well as overestimation of mitochondrial DNA content of peripheral blood mononuclear cells. Ann Clin Biochem. 2008;45:513–4. https://doi.org/10.1258/acb.2008.008008.CrossRefPubMed

29.

Lee JE, Park H, Ju YS, Kwak M, Kim JI, Oh HY, et al. Higher mitochondrial DNA copy number is associated with lower prevalence of microalbuminuria. Exp Mol Med. 2009;41:253–8. https://doi.org/10.3858/emm.2009.41.4.028.CrossRefPubMedPubMedCentral

30.

Lu T, Li J. (2017) Clinical applications of urinary cell-free DNA in cancer: current insights and promising future. Am J Cancer Res 7, 2318–2332. PubMed PMID: 29218253; PubMed Central PMCID: PMC5714758.

31.

Ho PWL, Pang WF, Luk CCW, Ng JKC, Chow KM, Kwan BCH, et al. Urinary mitochondrial DNA level as a biomarker of acute kidney injury. Kidney Dis. 2017;3:78–83. https://doi.org/10.1159/000475883.CrossRef

32.

Whitaker RM, Stallons LJ, Kneff JE, Alge JL, Harmon JL, Rahn JJ, et al. Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury. Kidney Int. 2015;88:1336–44. https://doi.org/10.1038/ki.2015.240.CrossRefPubMedPubMedCentral

33.

Botezatu I, Serdyuk O, Potapova G, Shelepov V, Alechina R, Molyaka Y, et al. (2000) Genetic analysis of DNA excreted in urine: a new approach for detecting specific genomic DNA sequences from cells dying in an organism. Clin Chem 46, 1078–1084. PMID: 10926886.

34.

Lichtenstein AV, Melkonyan HS, Tomei LD, Umansky SR. Circulating nucleic acids and apoptosis. Ann N Y Acad Sci. 2001;945:239–49. https://doi.org/10.1111/j.1749-6632.2001.tb03892.x.CrossRefPubMed

35.

Levey, A.S., Coresh, J., Balk, E., Kausz, A.T., Levin, A., Steffes, M.W., et al. (2003) National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 139, 137–147. PMID: 12859163.CrossRefPubMed

36.

Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311:2518–31. https://doi.org/10.1001/jama.2014.6634.CrossRefPubMedPubMedCentral

37.

Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, et al. (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 62, 768–775. PubMed PMID: 9529358; PubMed Central PMCID: PMC1377040.CrossRefPubMed

38.

García Moreira V, Prieto García B, de la Cera Martínez T, Alvarez Menéndez FV. Elevated transrenal DNA (cell-free urine DNA) in patients with urinary tract infection compared to healthy controls. Clin Biochem. 2009;42:729–31. https://doi.org/10.1016/j.clinbiochem.2008.12.021.CrossRefPubMed

39.

Wei PZ, Kwan BCH, Chow KM, Cheng PMS, Luk CCW, Li PKT, et al. Urinary mitochondrial DNA level is an indicator of intra-renal mitochondrial depletion and renal scarring in diabetic nephropathy. Nephrol Dial Transplant. 2018;33:784–8. https://doi.org/10.1093/ndt/gfx339.CrossRefPubMed

40.

Green DR, Llambi F. Cell death signaling. Cold Spring Harb Perspect Biol. 2015;7:a006080. https://doi.org/10.1101/cshperspect.a006080.CrossRefPubMedPubMedCentral

41.

Tower J. Programmed cell death in aging. Ageing Res Rev. 2015;23:90–100. https://doi.org/10.1016/j.arr.2015.04.002.CrossRefPubMedPubMedCentral

42.

Madeo F, Zimmermann A, Kroemer G, Kroemer G. Essential role for autophagy in life span extension. J Clin Invest. 2015;125:85–93. https://doi.org/10.1172/JCI73946.CrossRefPubMedPubMedCentral

43.

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222. https://doi.org/10.1080/15548627.2015.1100356.CrossRefPubMedPubMedCentral

44.

Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93. https://doi.org/10.1016/j.molcel.2010.09.023.CrossRefPubMedPubMedCentral

45.

Jin J, Ku YH, Kim Y, Kim Y, Kim K, Lee JY, et al. Differential proteome profiling using iTRAQ in microalbuminuric and normoalbuminuric type 2 diabetic patients. Exp Diabetes Res. 2012;2012:168602. https://doi.org/10.1155/2012/168602.CrossRefPubMedPubMedCentral

46.

Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, et al. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol. 2007;18:913–22. https://doi.org/10.1681/ASN.2006070767.CrossRefPubMed

47.

Guo Z, Liu X, Li M, Shao C, Tao J, Sun W, et al. Differential urinary glycoproteome analysis of type 2 diabetic nephropathy using 2D-LC-MS/MS and iTRAQ quantification. J Transl Med. 2015;13:371. https://doi.org/10.1186/s12967-015-0712-9.CrossRefPubMedPubMedCentral

48.

Chien HY, Chen CY, Chiu YH, Lin YC, Li WC. Differential microRNA profiles predict diabetic nephropathy progression in Taiwan. Int J Med Sci. 2016;13:457–65. https://doi.org/10.7150/ijms.15548.CrossRefPubMedPubMedCentral

49.

Harder JL, Hodgin JB, Kretzler M. Integrative biology of diabetic kidney disease. Kidney Dis (Basel). 2015;1:194–203. https://doi.org/10.1159/000439196.CrossRef

50.

Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008;148:810–9. 18519927.CrossRefPubMedPubMedCentral

51.

Paragas N, Qiu A, Zhang Q, Samstein B, Deng SX, Schmidt-Ott KM, et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med. 2011;17:216–22. https://doi.org/10.1038/nm.2290.CrossRefPubMedPubMedCentral

52.

Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:337–44. https://doi.org/10.2215/CJN.03530708.CrossRefPubMedPubMedCentral

53.

Malyszko J, Malyszko JS, Bachorzewska-Gajewska H, Poniatowski B, Dobrzycki S, Mysliwiec M. Neutrophil gelatinase associated lipocalin is a new and sensitive marker of kidney function in chronic kidney disease patients and renal allograft recipients. Transplant Proc. 2009;41:158–61. https://doi.org/10.1016/j.transproceed.2008.10.088.CrossRefPubMed

54.

Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, et al. Chronic renal insufficiency cohort (CRIC) study investigators: urine neutrophil gelatinase–associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney Int. 2013;83:909–14. https://doi.org/10.1038/ki.2012.458.CrossRefPubMedPubMedCentral

55.

Mishra, J., Qing, M., Prada, A., Zahedi, K., Yang, Y., Barasch, J., et al. (2003) Identification of NGAL as a novel early urinary marker for ischemic renal injury. J Am Soc Nephrol 14, 2534–2543. PMID: 14514731.

56.

Mori K, Lee HT, Rapoport D, Drexler I, Foster K, Yang J, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 2005;115:610–21. https://doi.org/10.1172/JCI23056.CrossRefPubMedPubMedCentral

Title: Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases
Authors: Chia-Chu Chang
Ping-Fang Chiu
Chia-Lin Wu
Cheng-Ling Kuo
Ching-Shan Huang
Chin-San Liu
Ching-Hui Huang
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Chronic Kidney Disease
Published in: BMC Nephrology / Issue 1/2019
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-019-1549-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Evaluating the effect of garlic extract on serum inflammatory markers of peritoneal dialysis patients: a randomized double-blind clinical trial study

Comparison between three different equations for the estimation of glomerular filtration rate in predicting mortality after coronary artery bypass

Use of the KDQOL-36™ for assessment of health-related quality of life among dialysis patients in the United States

Pirfenidone prevents acute kidney injury in the rat

Factors associated with adverse outcomes from cardiovascular events in the kidney transplant population: an analysis of national discharge data, hospital characteristics, and process measures

Normality data of eGFR and validity of commonly used screening tests for CKD in an area with endemic CKD of unknown etiology; need for age and sex based precise cutoff values

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage