Urinary mitochondrial DNA may be useful in diagnosing early diabetic nephropathy

Xue,Li; Yang,Xue; Song,Yuanyuan; Wang,Can; Zhou,Junjie; Liang,Hongyan

doi:10.3892/etm.2023.12270

Urinary mitochondrial DNA may be useful in diagnosing early diabetic nephropathy

Authors:
- Li Xue
- Xue Yang
- Yuanyuan Song
- Can Wang
- Junjie Zhou
- Hongyan Liang
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Affiliations: Department of Clinical Laboratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: October 24, 2023 https://doi.org/10.3892/etm.2023.12270
Article Number: 570
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to determine whether urinary mitochondrial (mt)DNA could be combined as a non‑invasive biomarker with other clinical findings of kidney injury to help diagnose early diabetic nephropathy (DN). A total of 165 patients with type 2 diabetes mellitus (T2DM) were enrolled in the present study and the mtDNA levels in urine were measured using quantitative PCR. The diagnostic value of urinary mtDNA levels in patients with T2DM was compared using estimated glomerular filtration rate (eGFR) or albumin‑to‑creatinine ratio staging. Spearman correlation analysis was used to analyze the correlation between urinary mtDNA and other clinical findings. Correlation factors for early DN were assessed using univariate logistic regression analysis. Urinary leukocyte and glucose levels do not interfere with urinary mtDNA levels. In patients with T2DM, the level of urinary mtDNA increases in the early stages of kidney injury and further increases with the severity of kidney injury. Urinary mtDNA levels in patients with eGFR 60‑90 ml/min/1.73 m² were higher than that in patients with eGFR >90 ml/min/1.73 m². The levels of urinary mt89DNA and mt349DNA were negatively correlated with the eGFR level (ρ=‑0.437; P<0.001; ρ=‑0.390; P<0.001) and positively correlated with the level of cystatin C (ρ=0.177; P=0.025; ρ=0.144; P=0.070). Urinary mtDNA is positively correlated with early DN occurrence [odds ratio (OR), 1.330; 95% confidence interval (CI), 1.175‑1.507; P<0.001; OR, 1.328; 95% CI, 1.156‑1.525; P<0.001]. In conclusion, urinary mtDNA combined with other clinical indicators of kidney injury may help the diagnosis of early DN.

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1	Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY and Yang CW: Chronic kidney disease: Global dimension and perspectives. Lancet. 382:260–272. 2013.PubMed/NCBI View Article : Google Scholar
2	Yang C, Wang H, Zhao X, Matsushita K, Coresh J, Zhang L and Zhao MH: CKD in China: Evolving spectrum and public health implications. Am J Kidney Dis. 76:258–264. 2020.PubMed/NCBI View Article : Google Scholar
3	Zhang L, Long J, Jiang W, Shi Y, He X, Zhou Z, Li Y, Yeung RO, Wang J, Matsushita K, et al: Trends in chronic kidney disease in China. N Engl J Med. 375:905–906. 2016.PubMed/NCBI View Article : Google Scholar
4	World Health Organization. The top 10 causes of death. WHO. 2020-12-09.
5	Morton RL and Shah KK: Kidney health in the context of economic development. Nat Rev Nephrol. 17:5–6. 2021.PubMed/NCBI View Article : Google Scholar
6	Luyckx VA, Cherney DZI and Bello AK: Preventing CKD in developed countries. Kidney Int Rep. 5:263–277. 2020.PubMed/NCBI View Article : Google Scholar
7	Fu H, Liu S, Bastacky SI, Wang X, Tian XJ and Zhou D: Diabetic kidney diseases revisited: A new perspective for a new era. Mol Metab. 30:250–263. 2019.PubMed/NCBI View Article : Google Scholar
8	Wei PZ and Szeto CC: Mitochondrial dysfunction in diabetic kidney disease. Clin Chim Acta. 496:108–116. 2019.PubMed/NCBI View Article : Google Scholar
9	Bhargava P and Schnellmann RG: Mitochondrial energetics in the kidney. Nat Rev Nephrol. 13:629–646. 2017.PubMed/NCBI View Article : Google Scholar
10	Schiffer TA and Friederich-Persson M: Mitochondrial reactive oxygen species and kidney hypoxia in the development of diabetic nephropathy. Front Physiol. 8(211)2017.PubMed/NCBI View Article : Google Scholar
11	Miranda-Diaz AG, Pazarin-Villasenor L, Yanowsky-Escatell FG and Andrade-Sierra J: Oxidative stress in diabetic nephropathy with early chronic kidney disease. J Diabetes Res. 2016(7047238)2016.PubMed/NCBI View Article : Google Scholar
12	Tang Z, Zeng F and Zhang XZ: Human genetics of diabetic nephropathy. Ren Fail. 37:363–371. 2015.PubMed/NCBI View Article : Google Scholar
13	Che R, Yuan Y, Huang S and Zhang A: Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol. 306:F367–F378. 2014.PubMed/NCBI View Article : Google Scholar
14	Galvan DL, Green NH and Danesh FR: The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 92:1051–1057. 2017.PubMed/NCBI View Article : Google Scholar
15	Zhang M, Zhang Y, Wu M, Li Z and Li X, Liu Z, Hu W, Liu H and Li X: Importance of urinary mitochondrial DNA in diagnosis and prognosis of kidney diseases. Mitochondrion. 61:174–178. 2021.PubMed/NCBI View Article : Google Scholar
16	Wei PZ, Kwan BC, Chow KM, Cheng PM, Luk CC, Li PK and Szeto CC: Urinary mitochondrial DNA level is an indicator of intra-renal mitochondrial depletion and renal scarring in diabetic nephropathy. Nephrol Dial Transplant. 33:784–788. 2018.PubMed/NCBI View Article : Google Scholar
17	Wei Z, Kwan BC, Chow KM, Cheng PM, Luk CC, Lai KB, Li PK and Szeto CC: Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases. BMC Nephrol. 19(367)2018.PubMed/NCBI View Article : Google Scholar
18	Padilla-Martinez F, Wojciechowska G, Szczerbinski L and Kretowski A: Circulating nucleic acid-based biomarkers of type 2 diabetes. Int J Mol Sci. 23(295)2021.PubMed/NCBI View Article : Google Scholar
19	Alberti KG and Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Med. 15:539–553. 1998.PubMed/NCBI View Article : Google Scholar
20	Zhang WZ, Rice MC, Hoffman KL, Oromendia C, Barjaktarevic IZ, Wells JM, Hastie AT, Labaki WW, Cooper CB, Comellas AP, et al: Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort. JCI insight. 5(e133984)2020.PubMed/NCBI View Article : Google Scholar
21	Żyłka A, Gala-Błądzińska A, Rybak K, Dumnicka P, Drożdż R and Kuśnierz-Cabala B: Role of new biomarkers for the diagnosis of nephropathy associated with diabetes type 2. Folia Med Cracov. 55:21–33. 2015.PubMed/NCBI
22	Kim K, Lee J, Park J, Lee E, Moon J, Lee S, Lee JS, Kim JH and Kim HS: Identification of novel biomarker for early detection of diabetic nephropathy. Biomedicines. 9(457)2021.PubMed/NCBI View Article : Google Scholar
23	Satirapoj B: Tubulointerstitial biomarkers for diabetic nephropathy. J Diabetes Res. 2018(2852398)2018.PubMed/NCBI View Article : Google Scholar
24	Fiseha T: Urinary biomarkers for early diabetic nephropathy in type 2 diabetic patients. Biomark Res. 3(16)2015.PubMed/NCBI View Article : Google Scholar
25	Yu SM and Bonventre JV: Acute kidney injury and progression of diabetic kidney disease. Adv Chronic Kidney Dis. 25:166–180. 2018.PubMed/NCBI View Article : Google Scholar
26	Higgins GC and Coughlan MT: Mitochondrial dysfunction and mitophagy: The beginning and end to diabetic nephropathy? Br J Pharmacol. 171:1917–1942. 2014.PubMed/NCBI View Article : Google Scholar
27	Said SM and Nasr SH: Silent diabetic nephropathy. Kidney Int. 90:24–26. 2016.PubMed/NCBI View Article : Google Scholar
28	Lee S and Choi ME: Urinary biomarkers for early diabetic nephropathy: Beyond albuminuria. Pediatr Nephrol. 30:1063–1075. 2014.PubMed/NCBI View Article : Google Scholar
29	Czajka A, Ajaz S, Gnudi L, Parsade CK, Jones P, Reid F and Malik AN: Altered mitochondrial function, mitochondrial DNA and reduced metabolic flexibility in patients with diabetic nephropathy. EBioMedicine. 2:499–512. 2015.PubMed/NCBI View Article : Google Scholar
30	Zhang WZ, Rice MC, Hoffman KL, Oromendia C, Barjaktarevic IZ, Wells JM, Hastie AT, Labaki WW, Cooper CB, Comellas AP, et al: Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort. JCI Insight. 5(e133984)2020.PubMed/NCBI View Article : Google Scholar
31	Lu T and Li J: Clinical applications of urinary cell-free DNA in cancer: Current insights and promising future. Am J Cancer Res. 7:2318–2332. 2017.PubMed/NCBI
32	Gluhovschi C, Gluhovschi G, Petrica L, Timar R, Velciov S, Ionita I, Kaycsa A and Timar B: Urinary biomarkers in the assessment of early diabetic nephropathy. J Diabetes Res. 2016(4626125)2016.PubMed/NCBI View Article : Google Scholar
33	Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, et al: Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 485:251–255. 2012.PubMed/NCBI View Article : Google Scholar
34	Chang HW, Tsui KH, Shen LC, Huang HW, Wang SN and Chang PL: Urinary cell-free DNA as a potential tumor marker for bladder cancer. Int J Biol Markers. 22:287–294. 2007.PubMed/NCBI View Article : Google Scholar
35	Chang CC, Chiu PF, Wu CL, Kuo CL, Huang CS, Liu CS and Huang CH: Urinary cell-free mitochondrial and nuclear deoxyribonucleic acid correlates with the prognosis of chronic kidney diseases. BMC Nephrol. 20(391)2019.PubMed/NCBI View Article : Google Scholar
36	Eirin A, Herrmann SM, Saad A, Abumoawad A, Tang H, Lerman A, Textor SC and Lerman LO: Urinary mitochondrial DNA copy number identifies renal mitochondrial injury in renovascular hypertensive patients undergoing renal revascularization: A pilot study. Acta Physiol (Oxf). 226(e13267)2019.PubMed/NCBI View Article : Google Scholar
37	Kustanovich A, Schwartz R, Peretz T and Grinshpun A: Life and death of circulating cell-free DNA. Cancer Biol Ther. 20:1057–1067. 2019.PubMed/NCBI View Article : Google Scholar
38	Cao H, Wu J, Luo J, Chen X, Yang J and Fang L: Urinary mitochondrial DNA: A potential early biomarker of diabetic nephropathy. Diabetes Metab Res Rev. 35(e3131)2019.PubMed/NCBI View Article : Google Scholar
39	Lin Y, Chang Y, Yang S, Wu K and Chu T: Update of pathophysiology and management of diabetic kidney disease. J Formos Med Assoc. 117:662–675. 2018.PubMed/NCBI View Article : Google Scholar
40	Ceriello A, Ihnat MA and Thorpe JE: Clinical review 2: The ‘metabolic memory’: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab. 94:410–415. 2009.PubMed/NCBI View Article : Google Scholar