PH1 overview

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 collagen^1,3,5.

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.

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 oxalate^1,2. 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.

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.

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 oxalosis^1,4. These conditions can be long-lasting, irreversible and even life-threatening^1,4.

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, including^1,20:

• 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 transplantation^2,21. 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 life^20,22.

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 caregivers^9,20,21,23.

References

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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.
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8. Mulay SR, Anders HJ. Crystal nephropathies: mechanisms of crystal-induced kidney injury. Nat Rev Nephrol. 2017;13:226–40.
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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.
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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.
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