Skip to main content
SpringerLink
Log in

Hyperfiltration and uricosuria in adolescents with type 1 diabetes

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

Abstract

Background

Urine uric acid (UUA) has been implicated in the pathogenesis of diabetic nephropathy via its effect on tubular cells. We hypothesized that the UUA level would be higher in adolescents with type 1 diabetes (T1D) than in those without T1D. We also hypothesized that UUA and fractional uric acid excretion (FeUA) would be higher in adolescents with T1D and hyperfiltration [estimated glomerular filtration rate (eGFR) ≥141 mL/min/1.73 m2] than in those without hyperfiltration.

Methods

The UUA concentration was determined and FeUA calculated in adolescents with (n = 239) and without T1D (n = 75). The eGFR was calculated using the Zappitelli equation based on serum creatinine and cystatin C concentrations.

Results

Compared to the non-diabetic adolescents enrolled in the study, those with T1D had a higher eGFR (mean ± standard deviation: 120 ± 22 vs. 112 ± 16 mL/min/1.73 m2; p = 0.0006), lower urine pH (6.2 ± 0.8 vs. 6.5 ± 1.0; p = 0.01), and higher UUA (37.7 ± 18.6 vs. 32.8 ± 18.1 mg/dL; p  = 0.049) and FeUA (median [interquartile range]: 6.2 [4.3–8.7] vs. 5.2 [3.6–7.0] %; p = 0.02). Among adolescents with T1D, those with hyperfiltration had higher median FeUA (8.6 [5.2–9.9] vs. 6.0 [4.2–8.3] %; p = 0.02) than those without hyperfiltration.

Conclusions

The adolescents with T1D enrolled in the study had higher eGFR, higher UUA and more acidic urine than the non-diabetic controls, which may have increased their risk of UUA crystallization. Adolescents with T1D and hyperfiltration had higher FeUA than those without hyperfiltration. These hypothesis-generating observations may suggest a potential pathophysiologic association between uricosuria and hyperfiltration.

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
Fig. 2

Similar content being viewed by others

References

  1. Maahs DM, Rewers M (2006) Editorial: Mortality and renal disease in type 1 diabetes mellitus—progress made, more to be done. J Clin Endocrinol Metab 91:3757–3759

    Article  PubMed  Google Scholar 

  2. Orchard TJ, Secrest AM, Miller RG, Costacou T (2010) In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 53:2312–2319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bjornstad P, Cherney D, Maahs DM (2014) Early diabetic nephropathy in type 1 diabetes: new insights. Curr Opin Endocrinol Diabetes Obes 21:279–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bjornstad P, Cherney DZ, Snell-Bergeon JK, Pyle L, Rewers M, Johnson RJ, Maahs DM (2015) Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes. Nephrol Dial Transplant 30:1706–1711

    Article  PubMed  Google Scholar 

  5. Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116:288–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Premaratne E, Verma S, Ekinci EI, Theverkalam G, Jerums G, MacIsaac RJ (2014) The impact of hyperfiltration on the diabetic kidney. Diabetes Metab 41:5–17

    Article  PubMed  Google Scholar 

  7. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG (2009) Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 52:691–697

    Article  CAS  PubMed  Google Scholar 

  8. Bjornstad P, Maahs DM, Rivard CJ, Pyle L, Rewers M, Johnson RJ, Snell-Bergeon JK (2014) Serum uric acid predicts vascular complications in adults with type 1 diabetes: the coronary artery calcification in type 1 diabetes study. Acta Diabetol 51:783–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gilbert RE, Cooper ME (1999) The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int 56:1627–1637

    Article  CAS  PubMed  Google Scholar 

  10. Ginevri F, Piccotti E, Alinovi R, DeToni T, Biagini C, Chiggeri GM, Gusmano R (1993) Reversible tubular proteinuria precedes microalbuminuria and correlates with the metabolic status in diabetic children. Pediatr Nephrol 7:23–26

    Article  CAS  PubMed  Google Scholar 

  11. Ryu ES, Kim MJ, Shin HS, Jang YH, Choi HS, Jo I, Johnson RJ, Kang DH (2013) Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am J Physiol Renal Physiol 304:F471–480

    Article  CAS  PubMed  Google Scholar 

  12. Lytvyn Y, Škrtić M, Yang GK, Yip PM, Perkins BA, Cherney DZ (2015) Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol 308:F77–83

    Article  CAS  PubMed  Google Scholar 

  13. Bjornstad P, Pyle L, Nguyen N, Snell-Bergeon JK, Bishop FK, Wadwa RP, Maahs DM (2015) Achieving international society for pediatric and adolescent diabetes and american diabetes association clinical guidelines offers cardiorenal protection for youth with type 1 diabetes. Pediatr Diabetes 16:22–30

    Article  CAS  PubMed  Google Scholar 

  14. Specht BJ, Wadwa RP, Snell-Bergeon JK, Nadeau KJ, Bishop FK, Maahs DM (2013) Estimated insulin sensitivity and cardiovascular disease risk factors in adolescents with and without type 1 diabetes. J Pediatr 162:297–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maahs DM, Prentice N, McFann K, Snell-Bergeon JK, Jalal D, Bishop FK, Aragon B, Wadwa RP (2011) Age and sex influence cystatin C in adolescents with and without type 1 diabetes. Diabetes Care 34:2360–2362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bacchetta J, Cochat P, Rognant N, Ranchin B, Hadj-Aissa A, Dubourg L (2011) Which creatinine and cystatin C equations can be reliably used in children? Clin J Am Soc Nephrol 6:552–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fadrowski JJ, Neu AM, Schwartz GJ, Furth SL (2011) Pediatric GFR estimating equations applied to adolescents in the general population. Clin J Am Soc Nephrol 6:1427–1435

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chiarelli F, Cipollone F, Romano F, Tumini S, Costantini F, di Ricco L, Pomilio M, Pierdomenico SD, Marini M, Cuccurullo F, Mezzetti A (2000) Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration. Diabetes 49:1258–1263

    Article  CAS  PubMed  Google Scholar 

  20. Hostetter TH, Rennke HG, Brenner BM (1982) Compensatory renal hemodynamic injury: a final common pathway of residual nephron destruction. Am J Kidney Dis 1:310–314

    Article  CAS  PubMed  Google Scholar 

  21. Hostetter TH, Rennke HG, Brenner BM (1982) The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72:375–380

    Article  CAS  PubMed  Google Scholar 

  22. Roncal-Jimenez C, Garcia-Trabanino R, Barregard L, Lanaspa MA, Wesseling C, Harra T, Aragόn A, Grases F, Jarquin ER, González MA, Weiss I, Glaser J, Sánchez-Lozada LG, Johnson RJ (2015) Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on mesoamerican nephropathy. Am J Kidney Dis. doi:10.1053/j.ajkd.2015.08.021

    PubMed  Google Scholar 

  23. Cook JD, Strauss KA, Caplan YH, Lodico CP, Bush DM (2007) Urine pH: the effects of time and temperature after collection. J Anal Toxicol 31:486–496

    Article  CAS  PubMed  Google Scholar 

  24. Drummond K, Mauer M (2002) The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 51:1580–1587

    Article  CAS  PubMed  Google Scholar 

  25. Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, Maahs DM, Snell-Bergeon JK, Johnson RJ, Nakagawa T (2015) Fructose and uric acid in diabetic nephropathy. Diabetologia 58:1993–2002

    Article  CAS  PubMed  Google Scholar 

  26. Lanaspa MA, Ishimoto T, Cicerchi C, Tamura Y, Roncal-Jimenez CA, Chen W, Tanabe K, Andres-Hernando A, Orlicky DJ, Finol E, Inaba S, Li N, Rivard CJ, Kosugi T, Sanchez-Lozada LG, Petrash JM, Sautin YY, Ejaz AA, Kitagawa W, Garcia GE, Bonthron DT, Asipu A, Diggle CP, Rodriguez-Iturbe B, Nakagawa T, Johnson RJ (2014) Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 25:2526–2538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim SM, Choi YW, Seok HY, Jeong KH, Lee SH, Lee TW, Ihm CG, Lim SJ, Moon JY (2012) Reducing serum uric acid attenuates TGF-beta1-induced profibrogenic progression in type 2 diabetic nephropathy. Nephron Exp Nephrol 121:e109–21

    Article  CAS  PubMed  Google Scholar 

  28. Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A, PERL Consortium (2013) Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep 13:550–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Verzola D, Ratto E, Villaggio B, Parodi EL, Pontremoli R, Garibotto G, Viazzi F (2014) Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLoS One 9:e115210

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schepers MS, van Ballegooijen ES, Bangma CH, Verkoelen CF (2005) Crystals cause acute necrotic cell death in renal proximal tubule cells, but not in collecting tubule cells. Kidney Int 68:1543–1553

    Article  PubMed  Google Scholar 

  31. Kim YG, Huang XR, Suga S, Mazzali M, Tang D, Metz C, Bucala R, Kivlighn S, Johnson RJ, Lan HY (2000) Involvement of macrophage migration inhibitory factor (MIF) in experimental uric acid nephropathy. Mol Med 6:837–848

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241

    Article  CAS  PubMed  Google Scholar 

  33. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (2004) Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 15:164–173

    Article  PubMed  Google Scholar 

  34. Zhou Y, Fang L, Jiang L, Wen P, Cao H, He W, Dai C, Yang J (2012) Uric acid induces renal inflammation via activating tubular NF-kappaB signaling pathway. PLoS One 7:e39738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Han HJ, Lim MJ, Lee YJ, Lee JH, Yang IS, Taub M (2007) Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-kappaβ. Am J Physiol Renal Physiol 292:F373–381

    Article  CAS  PubMed  Google Scholar 

  36. Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L, Henderson GN, Johnson RJ, Sautin YY (2009) Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol 20:545–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bouvet Y, Bouissou F, Coulais Y, Séronie-Vivien S, Tafani M, Decramer S, Chatelut E (2006) GFR is better estimated by considering both serum cystatin C and creatinine levels. Pediatr Nephrol 21:1299–306

    Article  PubMed  Google Scholar 

  38. Sharma AP, Yasin A, Garg AX, Filler G (2011) Diagnostic accuracy of cystatin C-based eGFR equations at different GFR levels in children. Clin J Am Soc Nephrol 6:1599–1608

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Support for this study was provided by NIDDK grants (T32DK06387, DK075360), JDRF (11-2007-694), and CTSI UL-1 RR025780. The study was performed at the Barbara Davis Center for Childhood Diabetes, Aurora, CO. Dr. Maahs was supported by a grant from NIDDK (DK075360), Dr. Snell-Bergeon by an American Diabetes Association Junior Faculty Award (7-13-CD-10), and Dr. Wadwa by an early career award from the Juvenile Diabetes Research Foundation (11-2007-694).

Author contributions

PB researched, wrote, contributed to discussion, and reviewed/edited the manuscript; LP researched, performed the statistical analyses, contributed to the discussion, reviewed/edited the manuscript; CR researched, contributed to the discussion, reviewed/edited the manuscript; MGL researched, contributed to the discussion, reviewed/edited the manuscript; JKSB researched, contributed to the discussion, reviewed/edited the manuscript; RJJ researched, contributed to the discussion, reviewed/edited the manuscript; RPW researched, contributed to discussion, and reviewed/edited the manuscript; DMM researched, contributed to discussion, and reviewed/edited the manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    Petter Bjornstad, Laura Pyle, Janet K. Snell-Bergeon, R. Paul Wadwa & David M. Maahs

  2. Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA

    Petter Bjornstad, Franziska K. Bishop, Janet K. Snell-Bergeon, Richard J. Johnson, R. Paul Wadwa & David M. Maahs

  3. Department of Medicine, Division of Nephrology, University of Colorado School of Medicine, Aurora, CO, USA

    Carlos Roncal, Tamara Milagres, Miguel Angel Lanaspa, Richard J. Johnson & David M. Maahs

Authors
  1. Petter Bjornstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Roncal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tamara Milagres
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Pyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miguel Angel Lanaspa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Franziska K. Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Janet K. Snell-Bergeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard J. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Paul Wadwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David M. Maahs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petter Bjornstad.

Ethics declarations

The study was approved by the Colorado Multiple Institution Review Board, and informed consent and assent (for subjects <18 years) were obtained from all subjects.

Conflict of interest disclosure

Drs. Bjornstad, Roncal, Pyle Lanaspa, Snell-Bergeon, Wadwa, and Maahs and Ms. Harra and Bishop have no conflict of interest to disclose. Dr Johnson holds a patent related to lowering uric acid in the treatment of diabetic nephropathy and has shares with XORT therapeutics.

Duality of interest

Drs. Bjornstad, Pyle and Maahs are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bjornstad, P., Roncal, C., Milagres, T. et al. Hyperfiltration and uricosuria in adolescents with type 1 diabetes. Pediatr Nephrol 31, 787–793 (2016). https://doi.org/10.1007/s00467-015-3299-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-015-3299-8

Keywords

Search

Navigation