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Pediatric Nephrology

, Volume 29, Issue 9, pp 1553–1560 | Cite as

Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

  • Yutaka Harita
  • Kiyonobu Ishizuka
  • Atsushi Tanego
  • Noriko Sugawara
  • Hiroko Chikamoto
  • Yuko Akioka
  • Haruko Tsurumi
  • Kenichiro Miura
  • Yoshimitsu Gotoh
  • Makoto Tsujita
  • Takayuki Yamamoto
  • Keiji Horike
  • Asami Takeda
  • Akira Oka
  • Takashi Igarashi
  • Motoshi Hattori
Original Article

Abstract

Background

Circulating factor(s) has been thought to be the underlying cause of focal segmental glomerulosclerosis (FSGS), and recent studies foster this idea by demonstrating increased soluble urokinase receptor (suPAR) levels in the serum of FSGS patients.

Methods

To explore the possible contribution of suPAR in FSGS pathogenesis, we analyzed serum suPAR levels in 17 patients with FSGS and compared them with those in patients with steroid-sensitive nephrotic syndrome, chronic glomerulonephritis, or non-glomerular kidney diseases.

Results

Serum suPAR levels in patients with FSGS were higher than those in patients with steroid-sensitive nephrotic syndrome or chronic glomerulonephritis, but not higher than those in patients with non-glomerular kidney diseases. suPAR levels negatively correlate with estimated glomerular filtration rate and were decreased after renal transplantation in patients with FSGS as well as in those with non-glomerular kidney diseases. Furthermore, 6 FSGS patients with post-transplant recurrence demonstrated that suPAR levels were not high during the recurrence.

Conclusions

Based on our results, elevated suPAR levels in FSGS patients were attributed mainly to decreased glomerular filtration. These data warrant further analysis for involvement of possible circulating factor(s) in FSGS pathogenesis.

Keywords

Soluble urokinase receptor Focal segmental glomerulosclerosis Post-transplant recurrence 

Notes

Acknowledgements

This work was supported, in part, by a Grant-in-Aid for Scientific Research (B) (22390204 to YH, SH and TI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Disclosure

The authors declare that they have no competing interests.

References

  1. 1.
    D'Agati VD, Kaskel FJ, Falk RJ (2011) Focal segmental glomerulosclerosis. N Engl J Med 365:2398–2411PubMedCrossRefGoogle Scholar
  2. 2.
    Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354:1387–1401PubMedCrossRefGoogle Scholar
  3. 3.
    Choy BY, Chan TM, Lai KN (2006) Recurrent glomerulonephritis after kidney transplantation. Am J Transplant 6:2535–2542PubMedCrossRefGoogle Scholar
  4. 4.
    Vinai M, Waber P, Seikaly MG (2010) Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review. Pediatr Transplant 14:314–325PubMedCrossRefGoogle Scholar
  5. 5.
    Gallon L, Leventhal J, Skaro A, Kanwar Y, Alvarado A (2012) Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med 366:1648–1649PubMedCrossRefGoogle Scholar
  6. 6.
    Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17:952–960PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, McMahan JL, Radeva M, Heil KM, Trautmann A, Anarat A, Emre S, Ghiggeri GM, Ozaltin F, Haffner D, Gipson DS, Kaskel F, Fischer DC, Schaefer F, Reiser J (2012) Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 23:2051–2059PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Roldan AL, Cubellis MV, Masucci MT, Behrendt N, Lund LR, Dano K, Appella E, Blasi F (1990) Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 9:467–474PubMedCentralPubMedGoogle Scholar
  9. 9.
    Sidenius N, Sier CF, Blasi F (2000) Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett 475:52–56PubMedCrossRefGoogle Scholar
  10. 10.
    Thuno M, Macho B, Eugen-Olsen J (2009) suPAR: the molecular crystal ball. Dis Markers 27:157–172PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Maas RJ, Wetzels JF, Deegens JK (2013) Serum-soluble urokinase receptor concentration in primary FSGS. Kidney Int 81:1043–1044CrossRefGoogle Scholar
  12. 12.
    Bock ME, Price HE, Gallon L, Langman CB (2013) Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: a single-center report. Clin J Am Soc Nephrol 8:1304–1311PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Franco Palacios CR, Lieske JC, Wadei HM, Rule AD, Fervenza FC, Voskoboev N, Garovic VD, Zand L, Stegall MD, Cosio FG, Amer H (2013) Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates. Transplantation 96:394–399PubMedCrossRefGoogle Scholar
  14. 14.
    Furue T, Hattori M, Tsukaguchi H, Kitamura A, Oomori T, Ogino D, Nakakura H, Ashida A, Miura K, Hisano M, Takahashi K, Chikamoto H, Akioka Y, Sakano T (2008) Clinical features and mutational survey of NPHS2 (podocin) in Japanese children with focal segmental glomerulosclerosis who underwent renal transplantation. Pediatr Transplant 12:341–346PubMedCrossRefGoogle Scholar
  15. 15.
    Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Am 34:571–590Google Scholar
  16. 16.
    Nagai T, Uemura O, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, Honda M (2013) Creatinine-based equations to estimate glomerular filtration rate in Japanese children aged between 2 and 11 years old with chronic kidney disease. Clin Exp Nephrol 17:877–881PubMedCrossRefGoogle Scholar
  17. 17.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992PubMedCrossRefGoogle Scholar
  18. 18.
    Pawlak K, Buraczewska-Buczko A, Mysliwiec M, Pawlak D (2010) Hyperfibrinolysis, uPA/suPAR system, kynurenines, and the prevalence of cardiovascular disease in patients with chronic renal failure on conservative treatment. Am J Med Sci 339:5–9PubMedCrossRefGoogle Scholar
  19. 19.
    Pawlak K, Ulazka B, Mysliwiec M, Pawlak D (2012) Vascular endothelial growth factor and uPA/suPAR system in early and advanced chronic kidney disease patients: a new link between angiogenesis and hyperfibrinolysis? Transl Res 160:346–354PubMedCrossRefGoogle Scholar
  20. 20.
    Huang J, Liu G, Zhang YM, Cui Z, Wang F, Liu XJ, Chu R, Chen Y, Zhao MH (2013) Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis. Kidney Int 84:366–372PubMedCrossRefGoogle Scholar
  21. 21.
    Behrendt N, Ronne E, Ploug M, Petri T, Lober D, Nielsen LS, Schleuning WD, Blasi F, Appella E, Dano K (1990) The human receptor for urokinase plasminogen activator. NH2-terminal amino acid sequence and glycosylation variants. J Biol Chem 265:6453–6460PubMedGoogle Scholar
  22. 22.
    Reiser J (2013) Circulating permeability factor suPAR: from concept to discovery to clinic. Trans Am Clin Climatol Assoc 124:133–138PubMedCentralPubMedGoogle Scholar
  23. 23.
    Sever S, Trachtman H, Wei C, Reiser J (2013) Is there clinical value in measuring suPAR levels in FSGS? Clin J Am Soc Nephrol 8:1273–1275PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Alachkar N, Wei C, Arend LJ, Jackson AM, Racusen LC, Fornoni A, Burke G, Rabb H, Kakkad K, Reiser J, Estrella MM (2013) Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy. Transplantation 96:649–656PubMedCrossRefGoogle Scholar
  25. 25.
    Wada T, Nangaku M, Maruyama S, Imai E, Shoji K, Kato S, Endo T, Muso E, Kamata K, Yokoyama H, Fujimoto K, Obata Y, Nishino T, Kato H, Uchida S, Sasatomi Y, Saito T, Matsuo S (2014) A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease. Kidney Int 85:641–648PubMedCrossRefGoogle Scholar
  26. 26.
    Sinha A, Bajpai J, Saini S, Bhatia D, Gupta A, Puraswani M, Dinda AK, Agarwal SK, Sopory S, Pandey RM, Hari P, Bagga A (2014) Serum-soluble urokinase receptor levels do not distinguish focal segmental glomerulosclerosis from other causes of nephrotic syndrome in children. Kidney Int 85:649–658PubMedCrossRefGoogle Scholar
  27. 27.
    Meijers B, Maas RJ, Sprangers B, Claes K, Poesen R, Bammens B, Naesens M, Deegens JK, Dietrich R, Storr M, Wetzels JF, Evenepoel P, Kuypers D (2014) The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis. Kidney Int 85:636–640PubMedCrossRefGoogle Scholar
  28. 28.
    Maruyama K, Iijima K, Ikeda M, Kitamura A, Tsukaguchi H, Yoshiya K, Hoshii S, Wada N, Uemura O, Satomura K, Honda M, Yoshikawa N (2003) NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. Pediatr Nephrol 18:412–416PubMedGoogle Scholar

Copyright information

© IPNA 2014

Authors and Affiliations

  • Yutaka Harita
    • 1
  • Kiyonobu Ishizuka
    • 2
  • Atsushi Tanego
    • 3
  • Noriko Sugawara
    • 2
  • Hiroko Chikamoto
    • 2
  • Yuko Akioka
    • 2
  • Haruko Tsurumi
    • 1
  • Kenichiro Miura
    • 1
  • Yoshimitsu Gotoh
    • 4
  • Makoto Tsujita
    • 5
  • Takayuki Yamamoto
    • 5
  • Keiji Horike
    • 5
  • Asami Takeda
    • 5
  • Akira Oka
    • 1
  • Takashi Igarashi
    • 1
  • Motoshi Hattori
    • 2
  1. 1.Department of Pediatrics, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Department of Pediatric NephrologyTokyo Women’s Medical UniversityTokyoJapan
  3. 3.Division of Biochemistry, School of Pharmaceutical SciencesKitasato UniversityTokyoJapan
  4. 4.Department of Pediatric NephrologyJapanese Red Cross Nagoya Daini HospitalNagoyaJapan
  5. 5.Kidney Disease CenterJapanese Red Cross Nagoya Daini HospitalNagoyaJapan

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