Skip to main content

Advertisement

Log in

1H NMR-based metabolomic study of metabolic profiling for the urine of kidney stone patients

  • Original Paper
  • Published:
Urolithiasis Aims and scope Submit manuscript

Abstract

Kidney stone is a chronic metabolic disease that caused by many factors, especially by the metabolic disturbances of urine compositions, but the metabolic profiling of the urine from kidney stone patients remains poorly explored. In the present study, 1H NMR spectroscopy and multivariate pattern recognition analytical techniques were combined to explore the metabolic profiling of the urine from kidney stone patients. A total of 216 urine samples obtained from kidney stone patients (n = 110) and healthy controls (n = 106) were investigated. The results indicated that principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) models were capable of distinguishing kidney stone patients from healthy controls. In addition, a total of 15 metabolites was obviously different in concentration between the two groups. Furthermore, four metabolic pathways, including glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, phenylalanine metabolism and citrate cycle (TCA cycle), were closely associated with kidney stone. Together, our results established a preliminary metabolic profiling of the urine from kidney stone patients via using 1H NMR-based analytical techniques for the first time and provided a novel method for recognizing and observing the kidney stone disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Romero V, Akpinar H, Assimos DG (2010) Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol 12:e86–e96

    PubMed  PubMed Central  Google Scholar 

  2. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC (2003) Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int 63:1817–1823

    PubMed  Google Scholar 

  3. Goldfarb DS (2009) In the clinic Nephrolithiasis. Ann Intern Med 151:ITC2.2–ITC2.16

    Google Scholar 

  4. Skolarikos A, Straub M, Knoll T, Sarica K, Seitz C, Petřík A, Türk C (2015) Metabolic evaluation and recurrence prevention for urinary stone patients: EAU guidelines. Eur Urol 67:750–763

    PubMed  Google Scholar 

  5. Duan X, Kong Z, Mai X, Lan Y, Liu Y, Yang Z, Zhao Z, Deng T, Zeng T, Cai C, Li S, Zhong W, Wu W, Zeng G (2018) Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney. Redox Biol 16:414–425

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Boonla C, Tosukhowong P, Spittau B, Schlosser A, Pimratana C, Krieglstein K (2014) Inflammatory and fibrotic proteins proteomically identified as key protein constituents in urine and stone matrix of patients with kidney calculi. Clin Chim Acta 429:81–89

    CAS  PubMed  Google Scholar 

  7. Kovacevic L, Lu H, Goldfarb DS, Lakshmanan Y, Caruso JA (2015) Urine proteomic analysis in cystinuric children with renal stones. J Pediatr Urol 11:217.e1–217.e6

    Google Scholar 

  8. Okumura N, Tsujihata M, Momohara C, Yoshioka I, Suto K, Nonomura N, Okuyama A, Takao T (2013) Diversity in protein profiles of individual calcium oxalate kidney stones. PLoS One 8:e68624

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Faerk J, Peitersen B, Petersen S, Michaelsen KF (2002) Bone mineralisation in premature infants cannot be predicted from serum alkaline phosphatase or serum phosphate. Arch Dis Child Fetal Neonatal Ed 87:F133–F136

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang M, Yang X, Ren L, Li S, He X, Wu X, Liu T, Lin L, Li Y, Sun C (2014) Biomarkers identified by urinary metabonomics for noninvasive diagnosis of nutritional rickets. J Proteome Res 13:4131–4142

    CAS  PubMed  Google Scholar 

  11. Ouyang X, Dai Y, Wen JL, Wang LX (2013) 1H NMR-based metabolomic study of metabolic profiling for systemic lupus erythematosus. Lupus 20:1411–1420

    Google Scholar 

  12. Maher AD, Crockford D, Toft H, Malmodin D, Faber JH, McCarthy MI, Barrett A, Allen M, Walker M, Holmes E, Lindon JC, Nicholson JK (2008) Optimization of human plasma 1H NMR spectroscopic data processing for high-throughput metabolic phenotyping studies and detection of insulin resistance related to type 2 diabetes. Anal Chem 80:7354–7362

    CAS  PubMed  Google Scholar 

  13. Sinclair AJ, Viant MR, Ball AK, Burdon MA, Walker EA, Stewart PM, Rauz S, Young SP (2010) NMR based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases–a diagnostic tool? NMR Biomed 23:123–132

    CAS  PubMed  Google Scholar 

  14. Kang SM, Park JC, Shin MJ, Lee H, Oh J, Ryu DH, Hwang GS, Chung JH (2011) 1H nuclear magnetic resonance based metabolic urinary profiling of patients with ischemic heart failure. Clin Biochem 44:293–299

    PubMed  Google Scholar 

  15. Chan AW, Mercier P, Schiller D, Bailey R, Robbins S, Eurich DT, Sawyer MB, Broadhurst D (2016) 1H-NMR urinary metabolomic profiling for diagnosis of gastric cancer. Br J Cancer 14:59–62

    Google Scholar 

  16. Lamego I, Duarte IF, Marques MP, Gil AM (2014) Metabolic markers of MG-63 osteosarcoma cell line response to doxorubicin and methotrexate treatment: comparison to cisplatin. J Proteome Res 13:6033–6045

    CAS  PubMed  Google Scholar 

  17. Eisner R, Stretch C, Eastman T, Xia J, Hau D, Damaraju S, Greiner R, Wishart DS, Baracos V (2011) Learning to predict cancer-associated skeletal muscle wasting from H-NMR profiles of urinary metabolomics. Metabolomics 7:25–34

    CAS  Google Scholar 

  18. Slupsky CM, Rankin KN, Wagner J, Fu H, Chang D, Weljie AM, Saude EJ, Lix B, Adamko DJ, Shah S, Greiner R, Sykes BD, Marrie TJ (2007) Investigations of the effects of gender, diurnal variation, and age in human urinary metabolomic profiles. Anal Chem 79:6995–7004

    CAS  PubMed  Google Scholar 

  19. Davis VW, Schiller DE, Eurich D, Bathe OF, Sawyer MB (2013) Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature. Ann Surg Oncol 20(Suppl 3):S415–S423

    PubMed  Google Scholar 

  20. Ji J, Zhang L, Zhang H, Sun C, Sun J, Jiang H, Abdalhai MH, Zhang Y, Sun X (2016) 1H NMR-based urine metabolomics for the evaluation of kidney injury in Wistar rats by 3-MCPD. Toxicol Res (Camb) 5(2):689–696

    CAS  Google Scholar 

  21. Dona AC, Kyriakides M, Scott F, Shephard EA, Varshavi D, Veselkov K, Everett JR (2016) A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments. Comput Struct Biotechnol J 14:135–153

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Weljie AM, Newton J, Mercier P, Carlson E, Slupsky CM (2006) Targeted profiling: quantitative analysis of 1H NMR metabolomics data. Anal Chem 78:4430–4442

    CAS  PubMed  Google Scholar 

  23. Stacklies W, Redestig H, Scholz M, Walther D, Selbig J (2007) pcaMethods—a bioconductor package providing PCA methods for incomplete data. Bioinformatics 23:1164–1167

    CAS  PubMed  Google Scholar 

  24. Mevik BH, Wehrens R (2007) The plsPackage: principal component and partial least squares regression in R. J Stat Softw 18:1–24

    Google Scholar 

  25. Zhou A, Ni J, Xu Z, Wang Y, Lu S, Sha W, Karakousis PC, Yao YF (2013) Application of 1H-NMR spectroscopy-based metabolomics to sera of tuberculosis patients. J Proteome Res 12(10):4642–4649

    CAS  PubMed  Google Scholar 

  26. Zhang JD, Wiemann S (2009) KEGGgraph: a graph approach to KEGG PATHWAY in R and bioconductor. Bioinformatics 25:1470–1471

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ennis JL, Asplin JR (2016) The role of the 24-h urine collection in the management of nephrolithiasis. Int J Surg 36(Pt D):633–637

    PubMed  Google Scholar 

  28. Khan SR, Pearle MS, Robertson WG, Gambaro G, Canales BK, Doizi S, Traxer O, Tiselius HG (2016) Kidney stones. Nat Rev Dis Primers 2:16008

    PubMed  PubMed Central  Google Scholar 

  29. Morgan MSC, Pearle MS (2016) Medical management of renal stones. BMJ 352:i52

    PubMed  Google Scholar 

  30. Bihl G, Meyers A (2001) Recurrent renal stone disease-advances in pathogenesis and clinical management. Lancet 358(9282):651–656

    CAS  PubMed  Google Scholar 

  31. Niu QY, Li ZY, Du GH, Qin XM (2016) 1H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model. J Pharm Biomed Anal 118:338–348

    CAS  PubMed  Google Scholar 

  32. Jiang J, Knight J, Easter LH, Neiberg R, Holmes RP, Assimos DG (2011) Impact of dietary calcium and oxalate, and Oxalobacter formigenes colonization on urinary oxalate excretion. J Urol 186:135–139

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaufman DW, Kelly JP, Curhan GC, Anderson TE, Dretler SP, Preminger GM, Cave DR (2008) Oxalobacter formigenes may reduce the risk of calcium oxalate kidney stones. J Am Soc Nephrol 19:1197–1203

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Siener R, Bangen U, Sidhu H, Hönow R, von Unruh G, Hesse A (2013) The role of Oxalobacter formigenes colonization in calcium oxalate stone disease. Kidney Int 83:1144–1149

    CAS  PubMed  Google Scholar 

  35. Manfredini R, De Giorgi A, Storari A, Fabbian F (2016) Pears and renal stones: possible weapon for prevention? A comprehensive narrative review. Eur Rev Med Pharmacol 20:414–425

    CAS  Google Scholar 

  36. Mills EL, Kelly B, O’Neill LAJ (2017) Mitochondria are the powerhouses of immunity. Nat Immunol 18(5):488–498

    CAS  PubMed  Google Scholar 

  37. Cao Y, Sagi S, Häcker A, Steidler A, Alken P, Knoll T (2006) Impact of hypoxia and hypercapnia on calcium oxalate toxicity in renal epithelial and interstitial cells. Urol Res 34:271–276

    CAS  PubMed  Google Scholar 

  38. Sun YJ, Wang HP, Liang YJ, Yang L, Li W, Wu YJ (2012) An NMR-based metabonomic investigation of the subacute effects of melamine in rats. J Proteome Res 11:2544–2550

    CAS  PubMed  Google Scholar 

  39. Won EY, Yoon MK, Kim SW, Jung Y, Bae HW, Lee D, Park SG, Lee CH, Hwang GS, Chi SW (2013) Gender-specific metabolomic profiling of obesity in leptin-deficient ob/ob mice by 1H NMR spectroscopy. PLoS One 8:e75998

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nicholson JK, Connelly J, Lindon JC, Holmes E (2002) Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Discov 1:153–161

    CAS  PubMed  Google Scholar 

  41. Meimaridou E, Lobos E, Hothersall JS (2006) Renal oxidative vulnerability due to changes in mitochondrial-glutathione and energy homeostasis in a rat model of calcium oxalate urolithiasis. Am J Physiol Renal Physiol 291:F731–F740

    CAS  PubMed  Google Scholar 

  42. Atanassova SS, Panchev P, Ivanova M (2010) Plasma levels and urinary excretion of amino acids by subjects with renal calculi. Amino Acids 38:1277–1282

    CAS  PubMed  Google Scholar 

  43. Zinsser HH, Stem F, Marshall S, Karp F, Seneca E, Gursel E (1971) Urinary organic acids found in B6 deficient rats and calcium oxalate calculus patients. Br J Urol 43:523–535

    CAS  PubMed  Google Scholar 

  44. Heijkenskjold F, Molierberg H (1956) The presence of amino acids in urinary calculi. Scand J Clin Lab Invest 8:230–233

    CAS  PubMed  Google Scholar 

  45. Khan SR (2012) Is oxidative stress, a link between nephrolithiasis and obesity, hypertension, diabetes, chronic kidney disease, metabolic syndrome? Urol Res 40:95–112

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Khan SR (2013) Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. J Urol 189:803–811

    CAS  PubMed  Google Scholar 

  47. Muteliefu G, Enomoto A, Jiang P, Takahashi M, Niwa T (2009) Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol Dial Transplan 24:2051–2058

    CAS  Google Scholar 

  48. Okada A, Nomura S, Higashibata Y, Hirose M, Gao B, Yoshimura M, Itoh Y, Yasui T, Tozawa K, Kohri K (2007) Successful formation of calcium oxalate crystal deposition in mouse kidney by intraabdominal glyoxylate injection. Urol Res 35:89–99

    CAS  PubMed  Google Scholar 

  49. Guo C, Cenac TA, Li Y, McMartin KE (2007) Calcium oxalate, and not other metabolites, is responsible for the renal toxicity of ethylene glycol. Toxicol Lett 173:8–16

    CAS  PubMed  Google Scholar 

  50. Poldelski V, Johnson A, Wright S, Rosa VD, Zager RA (2001) Ethylene glycolmediated tubular injury: identification of critical metabolites and injury pathways. Am J Kidney Dis 38:339–348

    CAS  PubMed  Google Scholar 

  51. Thamilselvan V, Menon M, Thamilselvan S (2014) Oxalate at physiological urine concentrations induces oxidative injury in renal epithelial cells: effect of α-tocopherol and ascorbic acid. BJU Int 114:140–150

    CAS  PubMed  Google Scholar 

  52. Lange JN, Wood KD, Knight J, Assimos DG, Holmes RP (2012) Glyoxal formation and its role in endogenous oxalate synthesis. Adv Urol. https://doi.org/10.1155/2012/819202

    Article  PubMed  PubMed Central  Google Scholar 

  53. Aggarwal KP, Tandon S, Naik PK, Singh SK, Tandon C (2013) Peeping into human renal calcium oxalate stone matrix: characterization of novel proteins involved in the intricate mechanism of urolithiasis. PLoS One 8:e69916

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kelsey R (2016) Stones: gut microbiome is unique in kidney stone disease. Nat Rev Urol 13(7):368

    CAS  PubMed  Google Scholar 

  55. Stern JM, Moazami S, Qiu Y, Kurland I, Chen Z, Agalliu I, Burk R, Davies KP (2016) Evidence for a distinct gut microbiome in kidney stone formers compared to non-stone formers. Urolithiasis 44(5):399–407

    PubMed  Google Scholar 

  56. Ticinesi A, Milani C, Guerra A, Allegri F, Lauretani F, Nouvenne A, Mancabelli L, Lugli GA, Turroni F, Duranti S, Mangifesta M, Viappiani A, Ferrario C, Dodi R, Dall’Asta M, Del Rio D, Ventura M, Meschi T (2018) Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. Gut  67(12):2097–2106

    CAS  PubMed  Google Scholar 

  57. Niu QY, Li ZY, Du GH, Qin XM (2016) 1H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model. J Pharm Biomed Anal 118:338–348

    CAS  PubMed  Google Scholar 

Download references

Funding

This study was financed by Grants from the Guangzhou Science Technology and Innovation Commission (No. 201704020193, No. 201607010162 and No. 201604020001), the National Natural Science Foundation of China (No. 81670643, No. 81601273 and No. 81870483), the Collaborative Innovation Project of Guangzhou Education Bureau (No. 1201620011) and the Science and Technology Planning Project of Guangdong Province (No. 2017B030314108).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Guohua Zeng.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All procedures performed in the present study involving human participants were in accordance with the ethical standards of the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 294 kb)

Supplementary material 2 (DOCX 81 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Duan, X., Zhang, T., Ou, L. et al. 1H NMR-based metabolomic study of metabolic profiling for the urine of kidney stone patients. Urolithiasis 48, 27–35 (2020). https://doi.org/10.1007/s00240-019-01132-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-019-01132-2

Keywords

Navigation