Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An update on primary hyperoxaluria



The autosomal recessive inherited primary hyperoxalurias types I, II and III are caused by defects in glyoxylate metabolism that lead to the endogenous overproduction of oxalate. Type III primary hyperoxaluria was first described in 2010 and further types are likely to exist. In all forms, urinary excretion of oxalate is strongly elevated (>1 mmol/1.73 m2 body surface area per day; normal <0.5 mmol/1.73 m2 body surface area per day), which results in recurrent urolithiasis and/or progressive nephrocalcinosis. All entities can induce kidney damage, which is followed by reduced oxalate elimination and consequent systemic deposition of calcium oxalate crystals. Systemic oxalosis should be prevented, but diagnosis is all too often missed or delayed until end-stage renal disease (ESRD) occurs; this outcome occurs in >30% of patients with primary hyperoxaluria type I. The fact that such a large proportion of patients have such poor outcomes is particularly unfortunate as ESRD can be delayed or even prevented by early intervention. Treatment options for primary hyperoxaluria include alkaline citrate, orthophosphate, or magnesium. In addition, pyridoxine treatment can be used to normalize or reduce oxalate excretion in about 30% of patients with primary hyperoxaluria type I. Time on dialysis should be short to avoid overt systemic oxalosis. Transplantation methods depend on the type of primary hyperoxaluria and on the particular patient, but combined liver and kidney transplantation is the method of choice in patients with primary hyperoxaluria type I and isolated kidney transplantation is the preferred method in those with primary hyperoxaluria type II. To the best of our knowledge, progression to ESRD has not yet been reported in any patient with primary hyperoxaluria type III.

Key Points

  • The primary hyperoxalurias are rare genetic diseases caused by deficiencies in glyoxylate metabolism

  • The main first symptoms of primary hyperoxaluria are recurrent urolithiasis and/or progressive nephrocalcinosis, or early end-stage renal disease in the case of infantile oxalosis

  • Every child with a first kidney stone and all adults who have recurrent calcium oxalate kidney stones should be screened for primary hyperoxaluria

  • Primary hyperoxaluria type I in particular is a devastating disease that all too often leads to early end-stage renal disease

  • If the diagnosis of primary hyperoxaluria is made early, disease progression can be slowed

  • The transplantation procedure of choice is isolated kidney transplantation in patients with type II primary hyperoxaluria, and usually combined liver–kidney transplantation in type I disease

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Imaging studies in patients with primary hyperoxaluria.
Figure 2: Calcium oxalate depositions and severe systemic oxalosis.
Figure 3: Differences in calcium oxalate stones from different patient groups.


  1. 1

    Van Woerden, C. S., Groothoff, J. W., Wanders, R. J., Davin, J. C. & Wijburg, F. A. Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol. Dial. Transplant. 18, 273–279 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Hoppe, B. & Langman, C. A United States survey on diagnosis, treatment and outcome of primary hyperoxaluria. Pediatr. Nephrol. 18, 986–991 (2003).

    Article  Google Scholar 

  3. 3

    Cochat, P. et al. Primary hyperoxaluria type 1: still challenging! Pediatr. Nephrol. 21, 1075–1081 (2006).

    Article  Google Scholar 

  4. 4

    Kopp, N. & Leumann, E. Changing pattern of primary hyperoxaluria in Switzerland. Nephrol. Dial. Transplant. 10, 2224–2227 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Hoppe, B., Beck, B. B. & Milliner, D. S. The primary hyperoxalurias. Kidney Int. 75, 1264–1271 (2009).

    CAS  Article  Google Scholar 

  6. 6

    Leumann, E. & Hoppe, B. The primary hyperoxalurias. J. Am. Soc. Nephrol. 12, 1986–1993 (2001).

    CAS  PubMed  Google Scholar 

  7. 7

    Hoppe, B., Latta, K., von Schnakenburg, C. & Kemper, M. J. Primary hyperoxaluria—the German experience. Am. J. Nephrol. 25, 276–281 (2005).

    Article  Google Scholar 

  8. 8

    Latta, K. & Brodehl, J. Primary hyperoxaluria type I. Eur. J. Pediatr. 149, 518–522 (1990).

    CAS  Article  Google Scholar 

  9. 9

    Akhan, O. et al. Systemic oxalosis: pathognomonic renal and specific extrarenal findings on US and CT. Pediatr. Radiol. 25, 15–16 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Hoppe, B. et al. Plasma calcium-oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure. Kidney Int. 56, 268–274 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Herrmann, G., Krieg, T., Weber, M., Sidhu, H. & Hoppe, B. Unusual painful sclerotic like plaques on the legs of a patient with late diagnosis of primary hyperoxaluria type I. Br. J. Dermatol. 151, 1104–1107 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Milliner, D. S. The primary hyperoxalurias: an algorithm for diagnosis. Am. J. Nephrol. 25, 154–160 (2005).

    Article  Google Scholar 

  13. 13

    Lieske, J. C. et al. International Registry for primary hyperoxaluria. Am. J. Nephrol. 25, 290–296 (2005).

    Article  Google Scholar 

  14. 14

    van Woerden, C. et al. The collaborative European cohort of primary hyperoxalurias: clinical and genetic characterization with prediction of outcome [abstract]. Pediatr. Nephrol. 25, 1911 (2010).

    Google Scholar 

  15. 15

    Danpure, C. J. Molecular aetiology of primary hyperoxaluria type 1. Nephron Exp. Nephrol. 98, e39–e44 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Danpure, C. J., Lumb, M. J., Birdsey, G. M. & Zhang, X. Alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting in human hereditary kidney stone disease. Biochim. Biophys. Acta 1647, 70–75 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Hoppe, B., Dittlich, K., Fehrenbach, H., Plum, G. & Beck, B. B. Reduction of plasma oxalate levels by oral application of Oxalobacter formigenes in 2 patients with infantile oxalosis. Am. J. Kidney Dis. 58, 453–455 (2011).

    Article  Google Scholar 

  18. 18

    Hoppe, B. et al. A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type I: lack of relationship between genotype, enzymic phenotype and disease severity. Am. J. Kidney Dis. 29, 36–44 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Hoppe, B. Evidence of true genotype-phenotype correlation in primary hyperoxaluria type 1. Kidney Int. 77, 383–385 (2010).

    Article  Google Scholar 

  20. 20

    Harambat, J. et al. Genotype–phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int. 77, 443–449 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Lorenzo, V. et al. Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: single-center experience. Kidney Int. 70, 1115–1119 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Coulter-Mackie, M. B. & Rumsby, G. Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis. Mol. Genet. Metab. 83, 38–46 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Takayama, T., Nagata, M., Ichiyama, A. & Ozono, S. Primary hyperoxaluria type 1 in Japan. Am. J. Nephrol. 25, 297–302 (2005).

    Article  Google Scholar 

  24. 24

    Cregeen, D. P., Williams, E. L., Hulton, S. & Rumsby, G. Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. Hum. Mutat. 22, 497–506 (2003).

    Article  Google Scholar 

  25. 25

    Kemper, M. J., Conrad, S. & Müller-Wiefel, D. E. Primary hyperoxaluria type 2. Eur. J. Pediatr. 156, 509–512 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Milliner, D. S., Wilson, D. M. & Smith, L. H. Phenotypic expression of primary hyperoxaluria: comparative features of types I and II. Kidney Int. 59, 31–36 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Rumsby, G., Sharma, A., Cregeen, D. P. & Solomon, L. R. Primary hyperoxaluria type 2 without L-glycericaciduria: is the disease under-diagnosed? Nephrol. Dial. Transplant. 16, 1697–1699 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Belostotsky, R. et al. Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am. J. Hum. Gen. 87, 392–399 (2010).

    CAS  Article  Google Scholar 

  29. 29

    Monico, C. G. et al. Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin. J. Am. Soc. Nephrol. 6, 2289–2295 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Williams, E. L. et al. The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrol. Dial. Transplant.

  31. 31

    Riedel, T. J. et al. Structural and biochemical studies of human 4-hydroxy-2-oxoglutarate aldolase: implications for hydroxyproline metabolism in primary hyperoxaluria. PLoS ONE 6, e26021 (2011).

    CAS  Article  Google Scholar 

  32. 32

    Habbig, S., Beck, B. B. & Hoppe, B. Nephrocalcinosis and urolithiasis in children. Kidney Int. 80, 1278–1291 (2011).

    Article  Google Scholar 

  33. 33

    Daudon, M. et al. Examination of whewellite kidney stones by scanning electron microscopy and powder neutron diffraction techniques. J. Appl. Cryst. 42, 109–115 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Daudon, M., Jungers, P. & Bazin, D. Peculiar morphology of stones in primary hyperoxaluria. N. Engl. J. Med. 359, 100–102 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Hoppe, B. & Leumann, E. In Physician's Guide to the Treatment and Follow-up of Metabolic Diseases (eds Blau, N., Hoffmann, G., Leonard, J. & Clarke, J.) 279–285 (Springer Verlag, Heidelberg, 2005).

    Google Scholar 

  36. 36

    Leumann, E. P., Dietl, A. & Matasovic, A. Urinary oxalate and glycolate excretion in healthy infants and children. Pediatr. Nephrol. 4, 493–497 (1990).

    CAS  Article  Google Scholar 

  37. 37

    Hoppe, B., Leumann, E. & Milliner, D. In Comprehensive Pediatric Nephrology (eds Geary, D. & Schäfer, F.) 499–525 (Elsevier/WB Saunders, New York, 2008).

    Google Scholar 

  38. 38

    Marangella, M., Petrarulo, M., Vitale, C., Cosseddu, D. & Linari, F. Plasma and urine glycolate assays for differentiating the hyperoxaluria syndromes. J. Urol. 148, 986–989 (1992).

    CAS  Article  Google Scholar 

  39. 39

    Marangella, M. et al. Plasma profiles and dialysis kinetics of oxalate in patients receiving hemodialysis. Nephron 60, 64–70 (1992).

    Article  Google Scholar 

  40. 40

    Williams, E. & Rumsby, G. Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin. Chem. 53, 1216–1221 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Rumsby, G., Williams, E. & Coulter-Mackie, M. Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int. 66, 959–963 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Monico, C. G. et al. Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J. Am. Soc. Nephrol. 18, 1905–1914 (2007).

    CAS  Article  Google Scholar 

  43. 43

    Williams, E. L. et al. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum. Mutat. 30, 910–917 (2009).

    CAS  Article  Google Scholar 

  44. 44

    van Woerden, C. S. et al. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int. 66, 746–752 (2004).

    CAS  Article  Google Scholar 

  45. 45

    Pirulli, D., Marangella, M. & Amoroso, A. Primary hyperoxaluria: genotype-phenotype correlation. J. Nephrol. 16, 297–309 (2003).

    CAS  PubMed  Google Scholar 

  46. 46

    Monico, C. G., Rossetti, S., Olson, J. B. & Milliner, D. S. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int. 67, 1704–1709 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Sikora, P. et al. [13C2] oxalate absorption in children with idiopathic calcium oxalate urolithiasis or primary hyperoxaluria. Kidney Int. 73, 1181–1186 (2008).

    CAS  Article  Google Scholar 

  48. 48

    Hatch, M., Freel, R. W. & Vaziri, N. D. Regulatory aspects of oxalate secretion in enteric oxalate elimination. J. Am. Soc. Nephrol. 10 (Suppl. 14), S324–S328 (1999).

    CAS  PubMed  Google Scholar 

  49. 49

    Hatch, M. & Freel, R. W. Intestinal transport of an obdurate anion: oxalate. Urol. Res. 33, 1–16 (2005).

    CAS  Article  Google Scholar 

  50. 50

    Hatch, M. et al. Oxalobacter sp. reduces urinary oxalate excretion promoting enteric oxalate excretion. Kidney Int. 69, 691–698 (2006).

    CAS  Article  Google Scholar 

  51. 51

    Allison, M. J., Dawson, K. A., Mayberry, W. R. & Foss, J. G. Oxalobacter formigenes gen. nov., sp. nov.: oxalate-degrading anaerobes that inhabit the gastrointestinal tract. Arch. Microbiol. 141, 1–7 (1985).

    CAS  Article  Google Scholar 

  52. 52

    Hoppe, B. et al. Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type I. Kidney Int. 70, 1305–1311 (2006).

    CAS  Article  Google Scholar 

  53. 53

    Grujic, D. et al. Hyperoxaluria is reduced and nephrocalcinosis prevented with an oxalate-degrading enzyme in mice with hyperoxaluria. Am. J. Nephrol. 29, 86–93 (2009).

    CAS  Article  Google Scholar 

  54. 54

    Hatch, M., Gjymishka, A., Salido, E. C., Allison, M. J. & Freel, R. W. Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G461–G469 (2011).

    CAS  Article  Google Scholar 

  55. 55

    Hoppe, B. et al. Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria. Nephrol. Dial. Transplant. 26, 3609–3615 (2011).

    Article  Google Scholar 

  56. 56

    Robijn, S., Hoppe, B., Vervaet, B. A., D'Haese, P. C. & Verhulst, A. Hyperoxaluria: a gut-kidney axis? Kidney Int. 80, 1146–1158 (2011).

    CAS  Article  Google Scholar 

  57. 57

    Leumann, E., Hoppe, B. & Neuhaus, T. Management of primary hyperoxaluria: efficacy of oral citrate administration. Pediatr. Nephrol. 7, 207–211 (1993).

    CAS  Article  Google Scholar 

  58. 58

    Milliner, D. S., Eickholt, J. T., Bergstralh, E. J., Wilson, D. M. & Smith, L. H. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N. Engl. J. Med. 331, 1553–1558 (1994).

    CAS  Article  Google Scholar 

  59. 59

    Hamm, L. L. Renal handling of citrate. Kidney Int. 38, 728–735 (1990).

    CAS  Article  Google Scholar 

  60. 60

    Monico, C. G., Olson, J. B. & Milliner, D. S. Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria. Am. J. Nephrol. 25, 183–188 (2005).

    CAS  Article  Google Scholar 

  61. 61

    Harambat, J. et al. Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin. J. Am. Soc. Nephrol. 7, 458–465 (2012).

    Article  Google Scholar 

  62. 62

    Illies, F., Bonzel, K. E., Wingen, A. M., Latta, K. & Hoyer, P. F. Clearance and removal of oxalate in children on intensified dialysis for primary hyperoxaluria type 1. Kidney Int. 70, 1642–1648 (2006).

    CAS  Article  Google Scholar 

  63. 63

    Hoppe, B. et al. Oxalate elimination via hemodialysis or peritoneal dialysis in children with chronic renal failure. Pediatr. Nephrol. 10, 488–492 (1996).

    CAS  Article  Google Scholar 

  64. 64

    Bunchman, T. E. & Swartz, R. D. Oxalate removal in type I hyperoxaluria or acquired oxalosis using HD and equilibration PD. Perit. Dial. Int. 14, 81–84 (1994).

    CAS  PubMed  Google Scholar 

  65. 65

    Bergstralh, E. J. et al. Transplantation outcomes in primary hyperoxaluria. Am. J. Transplant. 10, 2493–2501 (2010).

    CAS  Article  Google Scholar 

  66. 66

    Brinkert, F. et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation 87, 1415–1421 (2009).

    Article  Google Scholar 

  67. 67

    Jamieson, N. V. & European PHI Transplantation Study Group. A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984–2004. Am. J. Nephrol. 25, 282–289 (2005).

    Article  Google Scholar 

  68. 68

    Nolkemper, D. et al. Long-term results of pre-emptive liver transplantation in primary hyperoxaluria type 1. Pediatr. Transplant. 3, 177–181 (2000).

    Article  Google Scholar 

  69. 69

    Saborio, P. & Scheinman, J. I. Transplantation for primary hyperoxaluria in the United States. Kidney Int. 56, 1094–1100 (1999).

    CAS  Article  Google Scholar 

  70. 70

    Monico, C. G. & Milliner, D. S. Combined liver-kidney and kidney-alone transplantation in primary hyperoxaluria. Liver Transpl. 7, 954–963 (2001).

    CAS  Article  Google Scholar 

  71. 71

    Decramer, S. et al. Urine in clinical proteomics. Mol. Cell Proteomics 7, 1850–1862 (2008).

    CAS  Article  Google Scholar 

  72. 72

    Canales, B. K. et al. Proteome of human calcium kidney stones. Urology 76, 1017.e.13–e20 (2010).

    Article  Google Scholar 

  73. 73

    Wu, Z., Asokan, A. & Samulski, R. J. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther. 14, 316–327 (2006).

    CAS  Article  Google Scholar 

  74. 74

    Salido, E. et al. Phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer. Mol. Ther. 19, 870–875 (2011).

    CAS  Article  Google Scholar 

  75. 75

    Tanriover, B., Mejia, A., Foster, S. V. & Mubarak, A. Primary hyperoxaluria involving the liver and hepatic artery: images of an aggressive disease. Kidney Int. 77, 651 (2010).

    Article  Google Scholar 

  76. 76

    Beck, B. B. et al. Liver cell transplantation in severe infantile oxalosis—a potential bridging procedure to orthotopic liver transplantation? Nephrol. Dial. Transplant.

  77. 77

    Danpure, C. J. Primary hyperoxaluria: from gene defects to designer drugs. Nephrol. Dial. Transplant. 20, 1525–1529 (2005).

    Article  Google Scholar 

  78. 78

    Pey, A. L., Salido, E. & Sanchez-Ruiz, J. M. Role of low native state kinetic stability and interaction of partially unfolded states with molecular chaperones in the mitochondrial protein mistargeting associated with primary hyperoxaluria. Amino Acids 41, 1233–1245 (2011).

    CAS  Article  Google Scholar 

  79. 79

    Hopper, E. D., Pittman, A. M., Fitzgerald, M. C. & Tucker, C. L. In vivo and in vitro examination of stability of primary hyperoxaluria-associated human alanine:glyoxylate aminotransferase. J. Biol. Chem. 283, 30493–30502 (2008).

    CAS  Article  Google Scholar 

Download references

Author information



Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hoppe, B. An update on primary hyperoxaluria. Nat Rev Nephrol 8, 467–475 (2012).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing