This site is intended for healthcare professionals
Diagnosis and management of primary hyperoxaluria type 1
Declaration of sponsorship Alnylam Pharmaceuticals

PH1 overview

Declaration of sponsorship Alnylam Pharmaceuticals
Read time: 30 mins
Last updated:6th Apr 2021
Published:6th Apr 2021

Primary hyperoxaluria type 1 (PH1) is a life-limiting disease of oxalate overproduction, in which patients can present with a wide spectrum of clinical manifestations, from kidney stones to end-stage kidney disease (ESKD) to oxalate deposition in the eyes, heart and skin1,2. Early intervention is imperative and this resource will detail the pathophysiology of PH1, offer typical patient presentations and give a review of current management options.

Oxalate is formed in the liver in response to excess glyoxylate, which is generated by glycolate oxidase (GO) through the oxidation of glycolate, a product of intermediary metabolism derived largely from endogenous collagen1,3,5.

In healthy humans, most glyoxylate is converted to glycine by the vitamin B6-dependent peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT)5. Any excess glyoxylate is converted to oxalate and transported to the kidneys, which excrete oxalate in the urine1. In patients with PH1, the AGT is absent or deficient, leading to an accumulation of glyoxylate due to lack of conversion to glycine and – as a result – overproduction of oxalate (Figure 1)3,5.

A10087 - Alnylam - Medthority-01.png

Figure 1. Oxalate production (adapted from Cochat & Rumsby 20131 and Fargue et al. 20185). AGT, alanine:glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase/hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase.

Oxalate overproduction causes renal damage

Oxalate combines with calcium within the kidney tubules and urine to form the insoluble and toxic substance calcium oxalate1,2. Crystallisation of calcium oxalate in the urinary tract can result in recurrent urolithiasis and nephrocalcinosis, as well as direct damage to the renal tubular cells (Figure 2)1.

A10087 - Alnylam - Medthority-18.png

Figure 2. Calcium oxalate crystals on renal biopsy (image sourced from Cossey et al. 20206). 

Exposure to oxalate promotes a toxic response in renal cells, altering the properties of membrane surfaces and cellular lipids, disrupting mitochondrial function and generating changes in gene expression7. In addition, attempts by renal tubular cells to digest oxalate crystals through phagocytosis in lysosomes can lead to necrosis, which promotes inflammation and fibrosis (Figure 3)8.

A10087 - Alnylam - Medthority 8.1-14.png

Figure 3. Molecular mechanisms of crystal-induced inflammation (adapted from Mulay et al. 20178). Cat-B, cathepsin B; DAMP, damage-associated molecular pattern; IL-1β, interleukin 1β; MLKL, mixed lineage kinase domain-like; NF-κB, nuclear factor κB; NLRP3, nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3; RIPK, receptor-interacting serine/threonine-protein kinase; ROS, reactive oxygen species; TNF, tumour necrosis factor; TNFR, tumour necrosis factor receptor.

As renal function declines, oxalate production outstrips renal oxalate clearance and deposits form throughout vital organs around the body, including bone, heart, eyes and skin – a devastating condition called systemic oxalosis1,4. These conditions can be long-lasting, irreversible and even life-threatening1,4.

Conservative management approaches such as hyperhydration and intensive dialysis are used to clear oxalate, slowing progression to systemic oxalosis1,2. Liver transplantation, which replaces the faulty gene associated with oxalate overproduction, is a potentially curative option for PH11. Dual liver–kidney transplant is recommended, although significant risks are associated with transplantation1,2.

The importance of measuring oxalate

Measuring urinary oxalate (UOx) can aid in the diagnosis and monitoring progression of PH1 (see PH1 diagnosis section for more information on the role of urinary oxalate in diagnosis)1,9. Studies have demonstrated that patients with higher levels of UOx are the most likely to progress to ESKD and are more likely to have nephrocalcinosis10–13.

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

The overproduction of oxalate by the liver, due to a faulty AGT gene, causes progressive damage to the kidneys, renal failure and – in severe cases – widespread deposits in vital organs around the body1. The median age of onset is 5.5 years, with PH1 accounting for 1–2% of paediatric ESKD1. However, while clinical presentations can be seen in infancy, including nephrocalcinosis and failure to thrive, PH1 can occur at almost any age, from birth to later decades of life1.

Chronic kidney disease (CKD) has a profound effect on quality of life19. Impaired physical functioning and general health and sleep disturbances are common among patients with CKD, in addition to frequent comorbidities and associations with cardiovascular disease19.

In PH1, a number of additional factors may have a significant impact on quality of life for patients and families, including1,20:

  • burdensome management techniques
  • recurrent urolithiasis
  • fear of disease outcomes

Burdensome management techniques

Management techniques are designed to reduce urinary oxalate in order to slow oxalate depositions and decline in kidney function, as well as delay time to dialysis and transplantation2,21. To cope with the overproduction of oxalate, burdensome methods are required, including hyperhydration and high-intensity dialysis, which both have a significant impact on quality of life20,22.

With hyperhydration, patients are required to drink large volumes of fluid – at least 3 L per m2 of body surface area (BSA) per day. As an example, a 4-year-old child with a BSA of 0.68 m2 would require at least 2 L of water per day1. Hydration must be continual, at regular intervals through the day and night, placing a high burden on patients and caregivers9,20,21,23.

Asking children to drink through the night is problematic and, as such, they may require a tube to facilitate hyperhydration9,21,23. Patients experience frequent interruptions to their daily activities20. Furthermore, quality of life – including socialising, school, work and spending time with friends – is affected by the need to be constantly hydrating20. This can lead to poor compliance (Figure 4)23.

A10087 - Alnylam - Medthority-12.png

Figure 4. Limitations of hyperhydration as a management option for PH1 (adapted from Lawrence & Wattenberg 202020, Cochat et al. 201221 and Medina & Roman 202024).

As renal function declines and the kidneys are less able to clear oxalate from the body, dialysis may be required1. However, a standard dialysis regimen for patients with CKD of 3 days a week is not enough to effectively keep up with oxalate clearance12. As such, patients with PH1 require intensive dialysis, including haemodialysis and sometimes peritoneal dialysis at home and night-time dialysis9,12,21. In some cases, this can be up to 15 hours a day, 4–7 times a week2,9,20. As dialysis is only a bridge to transplantation, some patients may require long-term treatment while awaiting a suitable organ2,21. This can have a profound effect on quality of life20.

Recurrent urolithiasis

Recurrent kidney stones are a common experience in patients with PH1 and often the first indication of the disease1. Recurrences can be frequent, unpredictable and may continue throughout a patient's life20. Even one kidney stone can take months to pass if it’s over 5 mm and 50% of those will require surgical intervention25. Stone removal procedures can be physically and emotionally traumatic for patients and families and may lead to acute episodes of renal decline (Figure 5)20,25. More than 50% of patients considered kidney stones and associated procedures to have a negative effect on their quality of life20.

A10087 - Alnylam - Medthority 8-13 (1).png

Figure 5. The impact of kidney stones and associated procedures (adapted from Lawrence 202020).

Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

References

  1. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013;369:649–58.
  2. Milliner DS, Harris PC, Cogal AG, Lieske JC (2017). Primary Hyperoxaluria Type 1. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1283/ (accessed November 2020).
  3. Cochat P. Primary hyperoxaluria type 1. Kidney Int. 1999;55(6):2533–47.
  4. Beck BB, Hoppe B. Is there a genotype–phenotype correlation in primary hyperoxaluria type 1? Kidney Int. 2006;70:984–6.
  5. Fargue S, Milliner DS, Knight J, Olson JB, Lowther WT, Holmes RP. Hydroxyproline metabolism and oxalate synthesis in primary hyperoxaluria. J Am Soc Nephrol. 2018;29(6):1615–23.
  6. Cossey LN, Dvanajscak Z, Larsen CP. A diagnostician's field guide to crystalline nephropathies. Semin Diagn Pathol. 2020;37(3):135–42.
  7. Jonassen JA, Kohjimoto Y, Scheid CR, Schmidt M. Oxalate toxicity in renal cells. Urol Res. 2005;33:329–39.
  8. Mulay SR, Anders HJ. Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol. 2017;13:226–40.
  9. Sas DJ, Harris PC, Milliner DS. Recent advances in the identification and management of inherited hyperoxalurias. Urolithiasis. 2019;47:79–89.
  10. Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, et al. Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol. 2016;11(1):119–26.
  11. Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, et al. Phenotype–genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol. 2015;26(10):2559–70.
  12. Tang X, Voskoboev NV, Wannarka SL, Olson JB, Milliner DS, Lieske JC. Oxalate quantification in hemodialysate to assess dialysis adequacy for primary hyperoxaluria. Am J Nephrol. 2014;39(5):376–82.
  13. Soliman NA, Nabhan MM, Abdelrahman SM, Abdelaziz H, Helmy R, Ghanim K, et al. Clinical spectrum of primary hyperoxaluria type 1: experience of a tertiary center. Nephrol Ther. 2017;13(3):176–82.
  14. Perinpam M, Enders FT, Mara KC, Vaughan LE, Mehta RA, Voskoboev N, et al. Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease. Clin Biochem. 2017;50(18):1014–19.
  15. Toussaint C, De Pauw L, Vienne A, Gevenois PA, Quintin J, Gelin M, et al. Radiological and histological improvement of oxalate osteopathy after combined liver-kidney transplantation in primary hyperoxaluria type 1. Am J Kidney Dis. 1993;21(1):54–63.
  16. Bastani B, Mistry BM, Nahass GT, Joh J, Dundoo G, Solomon H. Oxalate kinetics and reversal of the complications after orthotopic liver transplantation in a patient with primary hyperoxalosis type 1 awaiting renal transplantation. Am J Nephrol. 1999;19:64–9.
  17. Watts RW, Morgan SH, Danpure CJ, Purkiss P, Calne RY, Rolles K, et al. Combined hepatic and renal transplantation in primary hyperoxaluria type I: clinical report of nine cases. Am J Med. 1991;90(2):179–88.
  18. Milliner DS, McGregor TL, Thompson A, Dehmel B, Knight J, Rosskamp R, et al. End points for clinical trials in primary hyperoxaluria. Clin J Am Soc Nephrol. 2020;15(7):1056–65.
  19. Mujais SK, Story K, Brouillette J, Takano T, Soroka S, Franek C, et al. Health-related quality of life in CKD patients: correlates and evolution over time. Clin J Am Soc Nephrol. 2009;4(8):1293–301.
  20. Lawrence JE, Wattenberg DJ. Primary hyperoxaluria: the patient and caregiver perspective. Clin J Am Soc Nephrol. 2020;15(7):909–11.
  21. Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, et al. Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant. 2012;27(5):1729–36.
  22. Bayoumi M, Al Harbi A, Al Suwaida A, Al Ghonaim M, Al Wakeel J, Mishkiry A. Predictors of quality of life in hemodialysis patients. Saudi J Kidney Dis Transpl. 2013;24(2):254–9.
  23. Cochat P, Groothoff J. Primary hyperoxaluria type 1: practical and ethical issues. Pediatr Nephrol. 2013;28:2273–81.
  24. Medina PG, Roman LE. Importance of assessing compliance with conservative treatment of primary hyperoxaluria type 1: a case report of a patient with I244T/c.969-3C>G mutation. Perm J. 2020;24:19.136.
  25. Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008;35(2):369–91.
Register for free access to this exclusive healthcare learning resource


Why sign up with Medthority?

Develop your knowledge with our disease and condition focused Learning Zones

Access content from credible sources, including expert-led commentary, videos, podcasts, and webinars as well as clinical trials, treatment information and guidelines 

Personalised dashboard providing updates and recommendations for content within your areas of interest

Welcome:

Developed by EPG Health for Medthority.com, with all content provided by Alnylam Pharmaceuticals. Learning Zone sponsored and funded by Alnylam Pharmaceuticals. Please note that this material is intended for healthcare professionals only. 

Date of preparation: February 2021 │ OXL-CEMEA-00012

© Copyright 2021