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

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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.

Electronic supplementary material

The online version of this article (10.1186/s12882-019-1549-x) contains supplementary material, which is available to authorized users.

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Most cited references 35

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Mitochondrial DNA That Escapes from Autophagy Causes Inflammation and Heart Failure

Takafumi Oka, Shungo Hikoso, Osamu Yamaguchi … (2012)

Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure 1 . However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA 2,3,4 . Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes 5 . Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA 6 , or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

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Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

Josef Coresh, Tanvir Turin, Kunihiro Matsushita … (2014)

The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event. To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

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Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.

Dana Rapoport, H. Lee, Kiyoshi Mori … (2005)

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

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Author and article information

Contributors

Chia-Chu Chang: chiachuchang0312@gmail.com

Ping-Fang Chiu: 68505@cch.org.tw

Chia-Lin Wu: 143843@cch.org.tw

Cheng-Ling Kuo: 97026@cch.org.tw

Ching-Shan Huang: 149390@cch.org.tw

Chin-San Liu: liu48111@gmail.com

Ching-Hui Huang: 28071@cch.org.tw

Journal

Journal ID (nlm-ta): BMC Nephrol

Journal ID (iso-abbrev): BMC Nephrol

Title: BMC Nephrology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2369

Publication date (Electronic): 28 October 2019

Publication date PMC-release: 28 October 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 391

Affiliations

[1 ]ISNI 0000 0004 0572 8068, GRID grid.415517.3, Department of Internal Medicine, , Kuang Tien General Hospital, ; Taichung, Taiwan

[2 ]ISNI 0000 0004 1770 3722, GRID grid.411432.1, Department of Nutrition, , Hungkuang University, ; Taichung, Taiwan

[3 ]ISNI 0000 0004 0532 2041, GRID grid.411641.7, School of Medicine, , Chung Shan Medical University, ; Taichung, Taiwan

[4 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Nephrology Division, Department of Internal Medicine, , Changhua Christian Hospital, ; Changhua, Taiwan

[5 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Vascular & Genomic Research Center, , Changhua Christian Hospital, ; Changhua, Taiwan

[6 ]ISNI 0000 0004 0532 1428, GRID grid.265231.1, Center of General Education Tunghai University, ; Taichung, Taiwan

[7 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Internal Medicine Research Center, , Changhua Christian Hospital, ; Changhua, Taiwan

[8 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Department of Neurology, , Changhua Christian Hospital, ; Changhua, Taiwan

[9 ]ISNI 0000 0004 0572 7372, GRID grid.413814.b, Department of Cardiology, , Changhua Christian Hospital, ; Changhua, Taiwan

[10 ]ISNI 0000 0000 9193 1222, GRID grid.412038.c, Institute of Statistics and Information Science, , National Changhua University of Education, ; Changhua, Taiwan

[11 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, School of Medicine, College of Medicine, , Kaohsiung Medical University, ; Kaohsiung, Taiwan

[12 ]ISNI 0000 0004 0639 2615, GRID grid.440368.d, Department of Beauty Science and Graduate Institute of Beauty Science Technology, , Chienkuo Technology University, ; Changhua, Taiwan

Article

Publisher ID: 1549

DOI: 10.1186/s12882-019-1549-x

PMC ID: 6816217

PubMed ID: 31660901

SO-VID: 66e17f61-e1e2-401f-802e-23e7131a2679

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 February 2019

Date accepted : 4 September 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100007632, Changhua Christian Hospital;

Award ID: 104-CCH-ICO-002 and 103-CCH-IRP-009

Award Recipient : Chia-Chu Chang

Custom metadata

ScienceOpen disciplines: Nephrology

Keywords: cell-free mitochondrial deoxyribonucleic acid,cf-mtdna,cell-free nuclear deoxyribonucleic acid,cf-ndna,neutrophil gelatinase-associated lipocalin,ngal,chronic kidney disease

Data availability:

ScienceOpen disciplines: Nephrology

Keywords: cell-free mitochondrial deoxyribonucleic acid, cf-mtdna, cell-free nuclear deoxyribonucleic acid, cf-ndna, neutrophil gelatinase-associated lipocalin, ngal, chronic kidney disease

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

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Abstract

Introduction

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Nephrology

Most cited references 35

Mitochondrial DNA That Escapes from Autophagy Causes Inflammation and Heart Failure

Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.

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