What is primary hyperoxaluria type 1 (PH1)?
PH1 is a rare and progressive genetic disorder that causes oxalate overproduction by the liver. This causes progressive kidney damage which can lead to end-stage kidney disease.1
PH1 is one of 3 known PH (primary hyperoxaluria) subtypes1,2
There are 3 known subtypes of primary hyperoxaluria, but each can cause kidney stones and progressive kidney damage. PH1 is the most commonly diagnosed subtype of PH.1,2
The progression of PH12
- PH1 is a genetic condition that results in a liver enzyme deficiency causing dysregulation in glyoxylate metabolism. Hepatic LDH converts glyoxylate into oxalate—the final step in the overproduction of oxalate.
- Excessive oxalate is produced in the liver and combines with calcium to form CaOx crystals.
- CaOx crystals aggregate to form stones in kidneys and can also cause nephrocalcinosis.
- This can result in progressive kidney damage, end-stage kidney disease, and in some cases, life-threatening systemic oxalosis.
CaOx=calcium oxalate; LDH=lactate dehydrogenase.
The symptom presentation and disease course of PH1 is unpredictable and varies by patient. Early diagnosis and appropriate management are critical.3,4
Mechanism of disease
Normal glyoxylate metabolic pathway5
Dysregulated glyoxylate metabolic pathway in PH16
- PH1 is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene, resulting in deficiency of the AGT enzyme and buildup of glyoxylate.1,2,7
- In PH1, hepatic LDH catalyzes the final step in this pathway, converting abnormally high glyoxylate into excessive oxalate.2
GRHPR=glyoxylate reductase/hydroxypyruvate reductase; GO=glycolate oxidase.
Access a downloadable PH1 overview
Prefer to see PH1 details in a simple PDF? Download this 8-page overview of PH1, including MOD, prognosis data, SOC, and more—all in one place.
MOD=mechanism of disease; SOC=standard of care.
Signs and symptoms of PH1
Early diagnosis is crucial for appropriate management of PH1. It is important to understand and recognize key signs and symptoms, which can include3,7-9:
Family history
of kidney or bladder stones
Single kidney stone
in a child
Recurrent stones
in adults
Chronic kidney disease (CKD)
with no known etiology
Nephrocalcinosis
Systemic oxalosis
Severe infantile form:
failure to thrive, end-stage renal disease, severe retinal abnormalities
End-stage renal disease
(ESRD)
Elevated urinary oxalate (UOx) levels
Unmet needs in PH1
Most current standard-of-care approaches do not address the underlying cause of oxalate overproduction in PH1.2
PH1 progression is unpredictable; therefore, it should be treated early and monitored continuously.2,3 Current treatments include:
Hyperhydration can be intense, uncomfortable, and difficult to maintain.2,10
- adults/older adolescents: 4 liters water/day
- school-age children: 2-3 liters water/day
- infants/small children: 1-1.5 liters water/day
- gastronomy tube for infants or adults struggling with water intake
Pyridoxine (vitamin B6) supplementation is only effective in reducing UOx levels in a subset of PH1 patients.2
- One study showed two-thirds of patients with PH1 are completely unresponsive to pyridoxine.11
Stone removal surgeries can cause unintended consequences. They often are only a temporary solution to a chronic problem and do not address the underlying cause of oxalate overproduction.12,13
- Patients with PH overwhelmingly form stones composed of calcium oxalate, which can be resistant to fragmentation by extracorporeal shock wave lithotripsy (ESWL).10
Conventional dialysis often cannot remove enough oxalate to prevent PH1 disease progression, requiring increased treatment time and frequency.2
- Often serves as a temporary therapy; the goal is to keep plasma oxalate levels below plasma calcium oxalate supersaturation (30-45 μmol/L) to prevent systemic oxalosis in patients awaiting organ transplant.8,10,14
Dual liver-kidney transplant may eventually be required for patients with advanced CKD.2
- 23% to 36% of transplanted organs may fail within 5 years of transplant.15
- Kidney and liver transplant recipients require lifelong immunosuppression.16
References:
- Lai C, Pursell N, Gierut J, et al. Specific inhibition of hepatic lactate dehydrogenase reduces oxalate production in mouse models of primary hyperoxaluria. Mol Ther. 2018;26(8):1983-1995. doi:10.1016/ j.ymthe.2018.05.016
- Groothoff JW, Metry E, Deesker L, et al. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat Rev Nephrol. 2023;19(3):194-211. doi:10.1038/s41581-022-00661-1
- Fargue S, Harambat J, Gagnadoux MF, et al. Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1. Kidney Int. 2009;76(7):767-773. doi:10.1038/ki.2009.237
- Michael M, Harvey E, Milliner DS, et al. Diagnosis and management of primary hyperoxalurias: best practices. Pediatr Nephrol. 2024 Nov;39(11):3143-3155. doi:10.1007/s00467-024-06328-2
- Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013;369(7):649-58. doi:10.1056/NEJMra1301564
- Martin-Higueras C, Torres A, Salido E. Molecular therapy of primary hyperoxaluria. J Inherit Metab Dis. 2017;40(4):481-489. doi:10.1007/s10545-017-0045-3
- Soliman NA, Nabhan MM, Abdelrahman SM, et al. Clinical spectrum of primary hyperoxaluria type 1: experience of a tertiary center. Nephrol Ther. 2017;13(3):176-182. doi:10.1016/j.nephro.2016.08.002
- Cochat P, Hulton SA, Acquaviva C, et al. Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant. 2012;27(5):1729-1736. doi:10.1093/ndt/gfs078
- Milliner DS, Harris PC, Sas DJ, Cogal AG, Lieske JC. Primary hyperoxaluria type 1. 2002 Jun 19. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025.
- Sas DJ, Harris PC, Milliner DS. Recent advances in the identification and management of inherited hyperoxalurias. Urolithiasis. 2019;47(1):79-89. doi:10.1007/s00240-018-1093-3
- Mandrile G, van Woerden CS, Berchialla P, et al. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int. 2014;86(6):1197-1204. doi:10.1038/ki.2014.222
- Khan SR, Pearle MS, Robertson WG, et al. Kidney stones. Nat Rev Dis Primers. 2016;2:16008. doi:10.1038/nrdp.2016.8
- Carrasco A Jr, Granberg CF, Gettman MT, Milliner DS, Krambeck AE. Surgical management of stone disease in patients with primary hyperoxaluria. Urology. 2015;85(3):522-6. doi:10.1016/j.urology.2014.11.018
- Harambat J, van Stralen KJ, Espinosa L, Groothoff JW, et al; European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry. Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol. 2012;7(3):458-65. doi:10.2215/CJN.07430711
- Bergstralh EJ, Monico CG, Lieske JC, et al. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501. doi:10.1111/j.1600-6143.2010.03271.x
- Neuberger JM, Bechstein WO, Kuypers DRJ, et al. Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients: a guidance report and clinical checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) group. Transplantation. 2017;101(4S suppl 2):S1-S56. doi:10.1097/TP.0000000000001651