Pediatric Nephrology

, Volume 32, Issue 12, pp 2263–2271 | Cite as

Systematic assessment of urinary hydroxy-oxo-glutarate for diagnosis and follow-up of primary hyperoxaluria type III

  • Ada Ventzke
  • Markus Feldkötter
  • Andrew Wei
  • Jutta Becker
  • Bodo B. Beck
  • Bernd Hoppe
Original Article



There are currently three distinct autosomal recessive inherited types of primary hyperoxaluria (PH: PHI, PHII, and PHIII), all characterized by the endogenous overproduction of oxalate. The PH type is difficult to differentiate by clinical features alone. In addition to universal general characteristics to all hyperoxaluria subtypes, specific urinary metabolites can be detected: glycolate in PHI, L-glyceric acid in PHII, and hydroxy-oxo-glutarate (HOG) in PHIII. PHIII is considered to be the most benign form and is characterized by severe recurrent urolithiasis in early life, followed by clinical remission in many, but not all patients. We examined urinary HOG (UHOG) excretion as a diagnostic marker and its correlation to progression of the clinical course of PHIII.


UHOG was analyzed by combined ion chromatography/mass spectrometry (IC/MS) in urine samples from 30 PHIII and 68 PHI/II patients and 79 non-PH hyperoxaluria patients.


Mean UHOG excretion was significantly higher in patients with PHIII than in those with PHI/II and in non-PH patients(51.6 vs. 6.61 vs. 8.36 μmol/1.73 m2/24 h, respectively; p<0.01).


Significantly elevated UHOG excretion was exclusively seen in PHIII patients and showed a 100 % consensus with the results of hydroxy-oxo-glutarate aldolase (HOGA1) mutational analysis in newly diagnosed patients. However, UHOG excretion did not correlate with clinical course on follow-up and could not be used to discriminate between active stone formers and patients with a clinically uneventful follow-up.


Primary hyperoxaluria Primary hyperoxaluria type III Diagnosis Follow-up Hydroxy-oxo-glutarate 



We thank Przemyslaw Sikora (Lublin, Poland), Katarzyna Jobs (Warzaw, Poland), Marcin Zaniew, Lars Pape (Hannover, Germany), Burkhard Tönshoff (Heidelberg, Germany), Martin Bald (Stuttgart, Germany), Martin Pohl (Freiburg, Germany), Bärbel Lange-Sperandio (Munich, Germany), and Markus J. Kemper (Hamburg, Germany) for providing us with patient information and urine samples. We also thank B. Bär and D. Armborst (Germany) and F. Blanco (Spain) for extensive laboratory support. The work was partially supported by a grant from the German-Israeli Foundation (GIF) to (Bodo B. Beck & Bernd Hoppe)

Compliance with ethical standards

This study was approved by the local ethics committee and all material was obtained after written informed consent.

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Hoppe B, Beck BB, Milliner DS (2009) The primary hyperoxalurias. Kidney Int 75:1264–1271CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Archer HE, Dormer AE, Scowen EF, Watts RW (1957) Primary hyperoxaluria. Lancet 273:320–322CrossRefPubMedGoogle Scholar
  3. 3.
    Hoppe B (2012) An update on primary hyperoxaluria. Nat Rev Nephrol 8:467–475CrossRefPubMedGoogle Scholar
  4. 4.
    Milliner DS, Harris PC, Lieske JC (2015) Primary hyperoxaluria type 3. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K (eds) Gene reviews, University of Washington, SeattleGoogle Scholar
  5. 5.
    Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369:649–658CrossRefPubMedGoogle Scholar
  6. 6.
    Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE, Frishberg Y, Milliner DS (2011) Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 6:2289–2295CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen R, Rinat C, Monico CG, Feinstein S, Ben-Shalom E, Magen D, Weissman I, Charon C, Frishberg Y (2010) Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet 87:392–399CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Beck BB, Baasner A, Buescher A, Habbig S, Reintjes N, Kemper MJ, Sikora P, Mache C, Pohl M, Stahl M, Toenshoff B, Pape L, Fehrenbach H, Jacob DE, Grohe B, Wolf MT, Nürnberg G, Yigit G, Salido EC, Hoppe B (2013) Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 21:162–172CrossRefPubMedGoogle Scholar
  9. 9.
    Belostotsky R, Pitt JJ, Frishberg Y (2012) Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism. J Mol Med (Berl) 90:1497–1504CrossRefGoogle Scholar
  10. 10.
    Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC (2015) Rare kidney stone consortium phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 26:2559–2570CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kemper MJ, Conrad S, Muller-Wiefel DE (1997) Primary hyperoxaluria type 2. Eur J Pediatr 156:509–512CrossRefPubMedGoogle Scholar
  12. 12.
    Danpure CJ, Jennings PR, Watts RW (1987) Enzymological diagnosis of primary hyperoxaluria type 1 by measurement of hepatic alanine: glyoxylate aminotransferase activity. Lancet 1:289–291CrossRefPubMedGoogle Scholar
  13. 13.
    Milliner DS, Wilson DM, Smith LH (2001) Phenotypic expression of primary hyperoxaluria: comparative features of types I and II. Kidney Int 59:31–36CrossRefPubMedGoogle Scholar
  14. 14.
    Jacob DE, Grohe B, Geßner M, Beck BB, Hoppe B (2013) Kidney stones in primary hyperoxaluria: new lessons learnt. PLoS One 8:e70617CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Pitt JJ, Willis F, Tzanakos N, Belostotsky R, Frishberg Y (2015) 4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3. JIMD Rep 15:1–6PubMedGoogle Scholar
  16. 16.
    Riedel TJ, Knight J, Murray MS, Milliner DS, Holmes RP, Lowther WT (2012) 4-Hydroxy-2-oxoglutarate aldolase inactivity in primary hyperoxaluria type 3 and glyoxylate reductase inhibition. Biochim Biophys Acta 1822:1544–1552CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Toussaint C (1998) Pyridoxine-responsive PH1: treatment. J Nephrol 11[Suppl 1]:49–50PubMedGoogle Scholar
  18. 18.
    Milliner DS, Eickholt JT, Bergstralh EJ, Wilson DM, Smith LH (1994) Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med 331:1553–1558CrossRefPubMedGoogle Scholar
  19. 19.
    Leumann E, Hoppe B, Neuhaus T (1993) Management of primary hyperoxaluria: efficacy of oral citrate administration. Pediatr Nephrol 7:207–211CrossRefPubMedGoogle Scholar
  20. 20.
    Hamm LL (1990) Renal handling of citrate. Kidney Int 38:728–735CrossRefPubMedGoogle Scholar
  21. 21.
    Allard L, Cochat P, Leclerc AL, Cachat F, Fichtner C, De Souza VC, Garcia CD, Camoin-Schweitzer MC, Macher MA, Acquaviva-Bourdain C, Bacchetta J (2015) Renal function can be impaired in children with primary hyperoxaluria type 3. Pediatr Nephrol 30:1807–1813CrossRefPubMedGoogle Scholar
  22. 22.
    Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, Meek AM, Cogal AG, Lieske JC, Milliner DS (2016) Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol 11(1):119–126Google Scholar
  23. 23.
    Knight J, Jiang J, Assimos DG, Holmes RP (2006) Hydroxyproline ingestion and urinary oxalate and glycolate excretion. Kidney Int 70(11):1929–1934Google Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.Division of Pediatric Nephrology, Department of PediatricsUniversity of BonnBonnGermany
  2. 2.Northwestern UniversityChicagoUSA
  3. 3.Institute of Human GeneticsUniversity of CologneCologneGermany

Personalised recommendations