• Mythri Shankar, MD

Primary hyperoxaluria & the future

By

Mythri Shankar @nephromythri

Assistant Professor

Department of Nephrology

Institute of Nephrourology, Bengaluru, India


Primary hyperoxaluria (PH) are rare autosomal recessive inborn errors of metabolism which cause increased production of oxalate where oxalate deposits as calcium oxalate in various organ systems. Increased urinary excretion of oxalate can damage the kidneys by causing nephrocalcinosis and leads to end stage kidney disease.


Genetics:

PH is caused by autosomal recessive mutations of three genes involved in the glyoxylate metabolism.


PH type 1: The most common type and accounts for 70% to 80% of PH. It is caused by a mutation in the alanine:glyoxylate aminotransferase (AGT), a hepatic peroxisomal enzyme. It is the most severe form of PH and rapidly progresses to end stage kidney disease by early adulthood.


PH type 2: The next most common type of PH accounting for 10% of all PH cases. It is due to a mutation of hepatic cytosolic enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). It has wide tissue distribution unlike AGT and can lead to recurrent oxalate stones.


PH type 3: This is the mildest form and accounts for 5 to 10% of all PH cases. It is due to a mutation in the HOGA1 gene, which is a liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme.


Surprisingly, 5% to 10% of PH have no detectable genetic mutations.



Correlation between genotype and phenotype: Type 1 PH is severe and progresses to end stage kidney disease (ESKD) by early adulthood. Type 2 PH is less severe, typically presenting with kidney stones with a high risk of progression to ESKD. However, the progression to ESKD is slow. Type 3 PH is the mildest form and which does not usually cause progression to ESKD. Among family members with the same mutation, the severity may vary. Some may present only with kidney stones while others may progress to ESKD.


Among the genetic variants of PH type 1, AGXT p.Gly170Arg is the most common and treatment with pyridoxine reduces oxalate excretion.


Oxalate deposition in the kidneys:

Excess production of oxalate is excreted by the kidneys. Increased urinary excretion of oxalate causes supersaturation of urine with oxalate which leads to aggregation of crystals, kidney stones and eventual development of nephrocalcinosis. Nephrocalcinosis itself causes kidney inflammation and fibrosis, which if persistent, leads to ESKD.


Oxalate deposition in other organs:

When the eGFR falls below 30 ml/min/1.73m2, plasma oxalate levels increase beyond kidney excretion capacity resulting in extrarenal oxalate deposition, which includes skin, bone, myocardium, vessel walls, central nervous system and retina


Diagnosis:

1.Clinically suspect PH in the following case scenarios:

  • Recurrent calcium stone formers , especially those with oxalate crystals in urine

  • “Whewellite” - Calcium oxalate monohydrate kidney stones

  • Nephrocalcinosis

2. Metabolic evaluation:

  • Increased urinary oxalate excretion ( >90 mg/1.73m2/day)

  • In infants and children, a spot oxalate:creatinine ratio is preferred as 24-hr urine collection is difficult

  • Plasma oxalate and glycolate levels are used in patients with decreased kidney function

3. Differentiating the types of PH

  • PH 1 - Increased urinary excretion of oxalate and glycolate

  • PH 2 - Elevated L-glyceric acid levels

  • PH 3 - Increased urinary excretion of hydroxy-oxo-glutarate


4. Gene testing

Definitive diagnosis is by molecular diagnostic methods. Testing by whole gene sequencing, next generation sequencing or targeted mutation analysis is confirmatory.


5. Prenatal analysis is by genetic testing of the chorionic villi or amniotic cells in patients with family history of PH and a known mutation.


6. If genetic analysis is not available, liver biopsy is done to confirm the diagnosis by analysis of enzymes and proteins.


Treatment:

Early diagnosis and treatment of PH1 is necessary in order to prevent progression to ESKD, and is the mainstay of management. Treatment of ESKD due to PH can be accomplished by dual kidney and liver transplant. Liver transplantation restores the missing enzyme and offers a definitive cure. Undiagnosed disease prior to kidney transplant leads to failure of the transplanted kidney as well as due to calcium oxalate deposits.


With the evolution of the newer RNA interference (RNAi) drugs as treatment modalities, liver transplants may be unneccesary in the future. These RNAi drugs significantly reduce the oxalate levels and prevent progression of kidney injury.


Medical management:

  1. Fluid therapy: fluid intake to maintain a urine output of more than 3 litres per day. Gastric tubes may be necessary for infants.

  2. Administration of oral neutral phosphate, citric acid and magnesium oxide: urinary citrate, phosphate and magnesium binds with oxalate and inhibits the precipitation of calcium oxalate.

  3. Avoid foods rich in oxalate such as chocolate, tea, spinach and rhubarb.

  4. Oxalobacter formigenes - It is an obligate anaerobic colonic bacteria which increases endogenous oxalate excretion. However, the evidence for its use is limited.

  5. Pyridoxal phosphate (PP) - PH 1 with p.Gly170Arg or p.Phe152lle mutations respond to pyridoxal phosphate as oxalate lowering therapy. PP promotes the conversion of glyoxylate to glycine rather than oxalate.

  6. RNAi therapy:

  7. Lumisaran (RNAi agent) targets glycolate oxidase, depletes the substrate for oxalate synthesis, thereby reducing the production of oxalate. In the year 2020, the US Food and drug administration (FDA) has approved this drug for PH type 1 based on clinical studies which showed a 50% decrease in urinary oxalate levels. Phase 3 trial at 12 months showed sustained and continued efficacy with an acceptable safety profile.

  8. Nedosiran : Second generation RNAi which targets hepatic lactate dehydrogenase A (LDH A) may be safe in treating all types of PH.



VA by Divya Bajpai @divyaa24



VA by Edger Lerma @edgarvlermamd


Transplantation:

ESKD due to PH1 - Various transplant options are available such as isolated liver transplant, isolated kidney transplant, sequential liver and kidney transplant, combined liver and kidney transplant. Until robust evidence is available, combined liver and kidney transplant is recommended for ESKD patients due to PH1.


ESKD due to PH2- There is insufficient data to support optimal modality of transplant.


Summary:

PH is a rare autosomal recessive enzymatic defect in glyoxalate metabolism leading to increased production of calcium oxalate which deposits in various organs especially the kidneys. This leads to ESKD in some patients. PH type 1 due to AGXT mutations is the most common (70% to 80%), PH type 2 (10% of PH cases) is due to GRHPR mutations and PH type 3 (5% of PH cases) is due to HOGA1 mutations. Nephrocalcinosis and recurrent kidney stones are the most common clinical presentations. Diagnosis is by clinical suspicion, increased urinary oxalate levels and it is confirmed by genetic analysis. Medical interventions to reduce calcium oxalate deposition include high fluid intake, neutral phosphate, pyridoxine and recently RNAi agents - Lumasiran and Nedosiran. Although multiple transplant options are available (liver transplant, kidney transplant, simultaneous liver and kidney transplant), it is still not clear which one is optimal.



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