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Diagnosis and management of primary hyperoxaluria type 1
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Read time: 10 mins
Last updated:6th Apr 2021
Published:6th Apr 2021

Treatment objectives

Clinical suspicion combined with a full patient history and urine testing can point to an early diagnosis of primary hyperoxaluria type 1 (PH1), with genetic testing used to confirm1,2.

If the disease is caught in the early stages of development, the objectives of treatment should be to keep oxalate levels down, limit oxalate deposition and slow progressive decline in kidney function4,5.

Traditional management strategies

A number of traditional non-surgical management strategies are used in PH1; however, each has its limitations4,5.

  • Hyperhydration
  • Alkali citrates
  • Pyridoxine
  • Dialysis
  • Dual liver and kidney transplantation

Hyperhydration

Hyperhydration is a conservative management option for PH1 aimed at improving the dilution of urinary calcium oxalate2. Patients are required to drink large volumes of water, at least 3 L per m2 of body surface area (BSA) per day1,2,4. As an example, a 4-year-old child with a BSA of 0.68 m2 would require at least 2 L per day1.

Considerations

Hydration must be continual, at regular intervals through the day and night, and children may require a tube to facilitate this2,4,6. This can place a high burden on children and families, including affecting their psychological well-being7.

Patients may experience frequent interruptions to their daily activities caused by the need to use the toilet6. Furthermore, quality of life – including socialising, school and spending time with friends – is affected by the need to be constantly hydrating, which can lead to poor compliance6,7.

Alkali citrates

Alkali citrates may be used to decrease crystallisation of calcium oxalate4,5. These include potassium, sodium and magnesium, with choice dependent on the stage of renal function4,5,8,9. Alkali citrates work by forming complexes with urinary calcium, decreasing the amount of calcium oxalate available to deposit2.

Considerations

There is evidence to suggest that some patients may experience gastrointestinal issues with alkali citrates9. This, plus the number of tablets and their size, may contribute to reduced adherence in some patients10.

Pyridoxine

Pyridoxine (vitamin B6) improves targeting of alanine:glyoxylate aminotransferase (AGT) to hepatic peroxisomes, which increases the expression of AGT and improves catalytic activity2,5. Due to its effectiveness at reducing urinary oxalate in patients who respond, studies suggest it should be trialled in all patients diagnosed with PH14,5.

Considerations

Few patients are responsive to pyridoxine5,11. In fact, only 30–50% of patients are considered to be pyridoxine responders, defined as having a >30% decrease in urinary oxalate levels after 3 months of treatment4,5,11. Patients with specific mutations (Gly170Arg or Phe152Ile) are more likely to respond to treatment, though these mutations are only present in around 30–40% of patients4,5,12. Only ~5% of patients receiving pyridoxine achieve normalisation of urinary oxalate13.

Intensive dialysis

Dialysis is only recommended when hyperhydration and other management methods are unable to cope with increasing plasma oxalate levels4. The objective of dialysis is to maintain a plasma oxalate level <30–45 µmol/L 1. Traditional dialysis isn’t enough to cope with the volume of oxalate production and, as such, patients require intensive haemodialysis1,5. Those requiring intensive dialysis may need haemodialysis 4–7 times per week, in some cases up to 15 hours/day2,5,7. Peritoneal dialysis may be used at home, though this is suboptimal4,5.

Considerations

Even intensive dialysis only removes a proportion of total body oxalate, so it can only be considered a bridge to transplantation4,5. Furthermore, the intensity required places a significant burden on quality of life (Figure 1)14.

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Figure 1. The burden of dialysis on children and their carers (adapted from Lawrence & Wattenberg 20207).

Dual liver and kidney transplantation

Dual liver and kidney transplantation is a curative option for PH1 and is recommended pre-emptively in patients with CKD stage 3b to prevent progression to systemic oxalosis2,4. Kidney transplantation alone does not address the overproduction of oxalate, and should not be performed in isolation2,4.

Considerations

Liver transplantation is associated with high morbidity and mortality, and patient survival is worse for transplant recipients with PH1 than for those with other conditions1,15,16. Particularly in children, the dual liver and kidney procedure itself is complex17. Following transplantation, the risk of malignancy is 2–4 times higher in patients receiving a liver transplant than in the general population18, and patients also require lifelong immunosuppression2. Due to slow resolubilisation of systemic calcium oxalate, levels of urinary oxalate can remain elevated after transplantation and may take over 5 years to clear completely4,5.

Refer to the ERA-EDTA European Renal Best Practice Guidelines on the Management and Evaluation of the Kidney Donor and Recipient (era-edta.org/en/erbp/guidance/transplantation/transplantation/) for further guidance on kidney transplantation.

Knowledge check

New therapeutic targets in PH1

New therapeutic options for PH1 have been developed that target and prevent liver oxalate production, without the need for transplantation3.

Oxalate degraders

Oxalate degraders utilise oral formulations of a specific bacteria – Oxalobacter formigenes – that naturally degrade oxalate, promoting the movement of oxalate via gut transporter from plasma to the intestine (Figure 2)19,20.

Only a small percentage of total oxalate comes from diet21; however, a Phase 2 single-arm study of eight patients on dialysis demonstrated ~40% reductions in plasma oxalate after 2 years of treatment22. A Phase 3 study is currently ongoing23.

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Figure 2. Overview of the possible gut–kidney axis in nephrolithiasis (adapted from Ticinesi et al. 201924).

Ribonucleic acid interference (RNAi)

RNAi has the potential to enable selective silencing of any gene by targeting messenger ribonucleic acid (mRNA) for degradation (Figure 3)25. This prevents the expression of specific proteins, which may have an effect in certain diseases25.

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Figure 3. Mechanism of action of RNAi (adapted from Wilson & Doudna 201325 and Niemietz et al. 201526). 

In patients with PH1, the enzyme AGT is absent or deficient, leading to an accumulation of glyoxylate due to lack of conversion to glycine and – as a result – overproduction of oxalate1. Potential targets for RNAi in PH1 are other key enzymes in the oxalate metabolic pathway; suppressing production of enzymes such as GO or LDH could lead to a reduction in oxalate production (Figure 4)27,28.

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Figure 4. Potential targets of RNAi therapies (adapted from Cochat & Rumsby 20131 and Fargue et al. 201829). AGT, alanine:glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase/hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase.

Gene therapy

Gene therapy is a process that involves replacing the defective AGT enzyme in the bulk of the liver21. While some success has been achieved in animal studies using adeno-associated viral vectors, further studies, including human testing, are required to investigate optimal delivery systems and find a way to overcome the production of antibodies to the replaced enzyme and the need for immunosuppression21.

Knowledge check

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Date of preparation: March 2021 │ OXL-CEMEA-00011

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