Skip to main content
SpringerLink
Log in

The role of urinary TIMP1 and MMP9 levels in predicting vesicoureteral reflux in neonates with antenatal hydronephrosis

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Antenatal hydronephrosis (AH) is commonly found on evaluation of pregnant women and 20–30 % of neonates have vesicoureteral reflux (VUR). In order to diagnose VUR, we required invasive testing and exposure of the neonate to radiation. The concentrations of a matrix metalloproteinase, MMP9, and its inhibitor TIMP1, were analyzed in hydronephrotic newborns with VUR and were compared to those without reflux.

Methods

The neonates with a history of prenatal hydronephrosis were enrolled in two groups based on imaging study results, the neonates with VUR and without VUR. Neonates with a normal prenatal history and postnatal ultrasound were placed in a third group. We measured the random urinary levels of MMP9, TIMP1, and creatinine, their cut-off values and the MMP9/Cr and MMP9/TIMP1/Cr ratio was calculated, and an ROC curve was drawn.

Results

Sixty-nine neonates were enrolled in three groups; 27 patients (20 male, seven female) with AH and VUR were in group 1, 23 neonates (19 male, four female) without VUR were placed in group 2, and 19 (15 male, four female) acted as controls in group 3. The differences between the three groups and the normal and total hydronephrotic groups were statistically significant for MMP9, the MMP9/Cr, MMP9/TIMP1, and MMP9/TIMP1/Cr ratios. The urinary TIMP1 and TIMP1/Cr ratios were not significantly different between the groups. A cut-off value of MMP9 was measured as 358.5 ng/ml (sensitivity [sens] 74 %, specificity [spec] 78 %) and was used to compare groups 1 and 2. For groups 2 and 3, this cut-off was 181.00 pg/ml (sens 91 %, spec 89 %). The cut-off values measured for the MMP9/TIMP1 ratio were 30.32 (sens 70 %, spec 61 %) and 9.85 (sens 96 %, spec 89 %) to compare groups 1 and 2, and 2 and 3, respectively. We found no valuable cut-offs for the TIMP1 and TIMP1/Cr values. There was no difference between neonates with mild, moderate, and severe VUR according to urinary biomarker concentrations.

Conclusions

Evaluation of urinary levels of MMP9, or the MMP9/Cr, MMP9/TIMP1, or MMP9/TIMP1/Cr ratios may help us to differentiate the newborns with hydronephrosis and VUR from those without reflux.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Caiulo VA, Caiulo S, Gargasole C, Chiriacò G, Latini G, Cataldi L, Mele G (2012) Ultrasound mass screening for congenital anomalies of the kidney and urinary tract. Pediatr Nephrol 27:949–953

    Article  PubMed  Google Scholar 

  2. Mohammadjafari H, Alam A, Kosarian M, Mousavi S-A, Kosarian S (2009) Vesicoureteral reflux in neonates with hydronephrosis; Role of imaging tools. Iran J Pediatr 19:347–353

    Google Scholar 

  3. Klein J, Gonzalez J, Miravete M, Caubet C, Chaaya R, Decramer S, Bandin F, Bascands JL, Buffin-Meyer B, Schanstra JP (2011) Congenital ureteropelvic junction obstruction: human disease and animal models. Int J Exp Pathol 92:168–192

    Article  PubMed Central  PubMed  Google Scholar 

  4. Yamaçake KG, Nguyen HT (2013) Current management of antenatal hydronephrosis. Pediatr Nephrol 28:237–243

    Article  PubMed  Google Scholar 

  5. Wadie GM, Moriarty KP (2012) The impact of vesicoureteral reflux treatment on the incidence of urinary tract infection. Pediatr Nephrol 27:529–538

    Article  PubMed  Google Scholar 

  6. Mure P-Y, Mouriquand P (2008) Upper urinary tract dilatation: prenatal diagnosis, management and outcome. Semin Fetal Neonatal Med 13:152–163

    Article  PubMed  Google Scholar 

  7. Taranta-Janusz K, Wasilewska A, Dębek W, Waszkiewicz-Stojda M (2012) Urinary cytokine profiles in unilateral congenital hydronephrosis. Pediatr Nephrol 27:2107–2113

    Article  PubMed Central  PubMed  Google Scholar 

  8. Vasconcelos MA, Bouzada MCF, Silveira KD, Moura LR, Santos FF, Oliveira JM, Carvalho FF, Teixeira MM, e Silva ACS, Oliveira EA (2011) Urinary levels of TGF β-1 and of cytokines in patients with prenatally detected nephrouropathies. Pediatr Nephrol 26:739–747

    Article  PubMed  Google Scholar 

  9. Chevalier RL (2004) Biomarkers of congenital obstructive nephropathy: past, present and future. J Urol 172:852–857

    Article  PubMed  Google Scholar 

  10. Li Z, Zhao Z, Liu X, Su Z, Shang X, Wen J (2012) Prediction of the outcome of antenatal hydronephrosis: significance of urinary EGF. Pediatr Nephrol 27:2251–2259

    Article  PubMed  Google Scholar 

  11. Martin J, Eynstone L, Davies M, Steadman R (2001) Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix. J Am Soc Neprol 12:88–96

    CAS  Google Scholar 

  12. Legallicier B, Trugman G, Murphy G, Lelongt B, Ronco P (2001) Expression of the type IV collagenase system during mouse kidney development and tubule segmentation. J Am Soc Nehrol 12:2358–2369

    CAS  Google Scholar 

  13. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573

    Article  PubMed  CAS  Google Scholar 

  14. Ahmed A, Haylor J, El Nahas A, Johnson T (2007) Localization of matrix metalloproteinases and their inhibitors in experimental progressive kidney scarring. Kidney Int 71:755–763

    Article  PubMed  CAS  Google Scholar 

  15. Cai G, Zhang X, Hong Q, Shao F, Shang X, Fu B, Feng Z, Lin H, Wang J, Shi S (2008) Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation. Nephrol Dial Transplant 23:1861–1875

    Article  PubMed  CAS  Google Scholar 

  16. Kim H, Oda T, Lopez-Guisa J, Wing D, Edwards DR, Soloway PD, Eddy AA (2001) TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 12:736–748

    PubMed  CAS  Google Scholar 

  17. Ahmed AKH (2009) Matrix metalloproteinases and their inhibitors in kidney scarring: culprits or innocents. J Health Sci 55:473–483

    Article  CAS  Google Scholar 

  18. Ronco P, Chatziantoniou C (2008) Matrix metalloproteinases and matrix receptors in progression and reversal of kidney disease: therapeutic perspectives. Kidney Int 74:873–878

    Article  PubMed  CAS  Google Scholar 

  19. Lelongt B, Legallicier B, Piedagnel R, Ronco PM (2001) Do matrix metalloproteinases MMP-2 and MMP-9 (gelatinases) play a role in renal development, physiology and glomerular diseases? Curr Opin Nephrol Hypertens 10:7–12

    Article  PubMed  CAS  Google Scholar 

  20. Lenz O, Elliot SJ, Stetler-Stevenson WG (2000) Matrix metalloproteinases in renal development and disease. J Am Soc Nephro 11:574–581

    CAS  Google Scholar 

  21. Yilmaz A, Bilge I, Kiyak A, Gedikbasi A, Sucu A, Aksu B, Emre S, Sirin A (2012) Matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in vesicoureteral reflux. Pediatr Nephrol 27:435–441

    Article  PubMed  Google Scholar 

  22. Dias CS, Bouzada MCF, Pereira AK, Barros PS, Chaves ACL, Amaro AP, Oliveira EA (2009) Predictive factors for vesicoureteral reflux and prenatally diagnosed renal pelvic dilatation. J Urol 182:2440–2445

    Article  PubMed  Google Scholar 

  23. Grazioli S, Parvex P, Merlini L, Combescure C, Girardin E (2010) Antenatal and postnatal ultrasound in the evaluation of the risk of vesicoureteral reflux. Pediatr Nephrol 25:1687–1692

    Article  PubMed  Google Scholar 

  24. Müller G, Zeisberg M, Strutz F (2000) The importance of tubulointerstitial damage in progressive renal disease. Nephrol Dial Transplant 15:76–77

    Article  PubMed  Google Scholar 

  25. Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217

    Article  PubMed  CAS  Google Scholar 

  26. Parks WC, Wilson CL, López-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629

    Article  PubMed  CAS  Google Scholar 

  27. Sasaguri Y, Tanimoto A (2002) Extracellular matrix and matrix metalloproteinases in atherosclerosis. Connect Tissue 34:327–336

    CAS  Google Scholar 

  28. Lelongt B, Bengatta S, Ronco P (2005) Role of matrix metalloproteinase-9 (MMP-9) in kidney development and injury. Kidney Int 68:1963–1964

    Article  Google Scholar 

  29. Han W, Waikar S, Johnson A, Betensky R, Dent C, Devarajan P, Bonventre J (2007) Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 73:863–869

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Cui XG, An RH, Wang LM, Zhu YH, Mei CL (2006) Expression of matrix metalloproteinases-1/tissue inhibitor of metalloprotein-1 in kidney of patients with autosomal dominant polycystic kidney disease. Acad J Second Mil Med Univ 27:1174–1177

    CAS  Google Scholar 

  31. Woernle M, Roeder M, Sauter M, Ribeiro A (2009) Role of matrix metalloproteinases in viral-associated glomerulonephritis. Nephrol Dial Transplant 24:1113–1121

    Article  CAS  Google Scholar 

  32. Endo T, Nakabayashi K, Sekiuchi M, Kuroda T, Soejima A, Yamada A (2006) Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohistochemical staining. Clin Exp Biol 10:253–261

    CAS  Google Scholar 

  33. Bellayr I, Mu X, Li Y (2009) Biochemical insights into the role of matrix metalloproteinases in regeneration: challenges and recent developments. Futur Med Chem 1:1095–1111

    Article  CAS  Google Scholar 

  34. Catania JM, Chen G, Parrish AR (2007) Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol-Renal Physiol 292:F905–F911

    Article  PubMed  CAS  Google Scholar 

  35. Du X, Shimizu A, Masuda Y, Kuwahara N, Arai T, Kataoka M, Uchiyama M, Kaneko T, Akimoto T, Iino Y (2012) Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy. Lab Invest 92:1149–1160

    Article  PubMed  CAS  Google Scholar 

  36. Nicksa GA, Yu DC, Curatolo AS, McNeish BL, Barnewolt CE, Valim C, Buchmiller TL, Moses MA, Fauza DO (2010) Prenatal urinary matrix metalloproteinase profiling as a potential diagnostic tool in fetal obstructive uropathy. J Pediatr Surg 45:70–73

    Article  PubMed  Google Scholar 

  37. Chromek M, Tullus K, Hertting O, Jaremko G, Khalil A, Li Y-H, Brauner A (2003) Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in acute pyelonephritis and renal scarring. Pediatr Res 53:698–705

    Article  PubMed  CAS  Google Scholar 

  38. Hatipoglu S, Sevketoglu E, Gedikbasi A, Yilmaz A, Kiyak A, Mulazimoglu M, Aydogan G, Ozpacaci T (2011) Urinary MMP-9/NGAL complex in children with acute cystitis. Pediatr Nephrol 26:1263–1268

    Article  PubMed  Google Scholar 

  39. Tenderenda E, Zoch-Zwierz W, Wasilewska A, Porowski T, Taranta-Janusz K, Kołodziejczyk Z, Michaluk-Skutnik J (2009) Matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 in the urine of children with pyelonephritis]. Pol Merkur Lekarski 27:10

    PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare no conflicts of interest with respect to the authorship and/or publication of this study.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Cellular and Molecular Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Hamid Mohammadjafari

  2. Department of Immunology, Cellular and Molecular Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Alireza Rafiei

  3. Department of Radiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Mohammad Abedi & Abdolrasul Aalaee

  4. Mazandaran University of Medical Sciences, Sari, Iran

    Ehsan Abedi

Authors
  1. Hamid Mohammadjafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alireza Rafiei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Abedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abdolrasul Aalaee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ehsan Abedi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hamid Mohammadjafari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mohammadjafari, H., Rafiei, A., Abedi, M. et al. The role of urinary TIMP1 and MMP9 levels in predicting vesicoureteral reflux in neonates with antenatal hydronephrosis. Pediatr Nephrol 29, 871–878 (2014). https://doi.org/10.1007/s00467-013-2693-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-013-2693-3

Keywords

Search

Navigation