Hyperoxaluria

1 What is Hyperoxaluria?

The usual definition of hyperoxaluria is urinary oxalate excretion that exceeds 40 mg/day.

An alternative definition of hyperoxaluria that corrects for size differences is 30 mg of urinary oxalate per 24 hours per gram of excreted creatinine.

CLASSIFICATION:
Primary hyperoxaluria represents a group of genetic disorders resulting in endogenous overproduction of oxalate. Secondary hyperoxaluria results from gastrointestinal disorders associated with fat malabsorption and increased absorption of dietary oxalate.

Primary hyperoxaluria:

  • Type I - due to recessive mutation in gene encoding hepatic alanine-glyoxylate aminotransferase (AGXT). It leads to glycolic aciduria and hyperoxaluria. There is autosomal recessive inheritance and it is the most common of the primary hyperoxalurias.
  • Type II - due to mutation in gene encoding hepatic glyoxylate reductase/hydroxypyruvate reductase (GRHPR). It leads to L-glyceric aciduria and hyperoxaluria.
  • Type III - this has no identified enzyme deficiency. It may be due to inborn error of oxalate absorption/excretion or abnormality of peroxisome biogenesis.

Enteric hyperoxaluria:

  • Accounts for about 5% of cases of hyperoxaluria.
  • Excess exposure to bile salts of bowel mucosa increases oxalate absorption.
  • It is caused by a variety of intestinal disorders that tend to cause chronic diarrhea.
  • Loss of intestinal calcium leads to increased oxalate absorption and subsequent urinary excretion.
  • Related conditions include jejuno-ileal bypass, small intestine resection, blind loops, Crohn's disease, and chronic pancreatic and biliary tract disease causing fat malabsorption (including cystic fibrosis).

Idiopathic (mild) hyperoxaluria:

  • It is by far the most common type of hyperoxaluria.
  • It may be due to excessive oxalate intake in diet or increased endogenous production.
  • It is likely to be more problematic in those with low urinary volumes.
  • Provoked hyperoxaluria: excessive vitamin C intake, oxalate or ethylene glycol poisoning, inhalational anaesthetic reactions, urinary tract glycine irrigation, aspergillus infection, pyridoxine deficiency.

2 Symptoms

The first symptoms of oxalosis are usually blood in the urine, the painful passage of kidney stones, or urinary tract obstruction.

Symptoms of oxalosis include:

  • Blood in Urine
  • Kidney Stones
  • Nausea
  • Vomiting
  • Abdominal Pain
  • Tetany
  • Protein in Urine
  • Urinary Tract Obstruction
  • Kidney Fibrosis
  • Haematuria

In advanced stages, the accumulation of oxalate crystals in the bones and joints will lead to bone disease. It may also cause anemia and skin ulcers.

Primary hyperoxaluria:

  • It may present in the first months of life with seizures, advanced renal failure and few, if any, calculi but dense nephrocalcinosis.
  • Patients normally present in childhood with recurrent urolithiasis.
  • Death from renal failure usually occurs before age 20 years if untreated but a minority of patients may have a more benign course.
  • The latter stages of disease are associated with dense calcium oxalate nephrocalcinosis and development of ischaemic lesions in the extremities (especially in the pads of the fingers and toes).
  • There is also a progressive peripheral neuropathy.
  • The normal clinical course is of recurrent stones leading inevitably to renal failure.
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3 Causes

The causes of hyperoxaluria may vary depending on its type:

  • Dietary hyperoxaluria: Eating a diet of high oxalate content foods can cause high levels of oxalate in the urine and can increase your risk of hyperoxaluria or kidney stones. Generally, if diet changes are made, the urine oxalate will then decrease. Ask your doctor or dietitian for a list of high-oxalate foods.
  • Enteric hyperoxaluria: Several intestinal diseases, including Crohn’s disease and short bowel syndrome as a result of surgical procedures like Bariatric surgery may increase the absorption of oxalate from foods, which can then increase the amount of oxalate excreted in the urine. Avoiding, foods high in oxalate in particularly important.
  • Primary hyperoxaluria (PH): It is a rare, inherited (genetic) disorder of liver metabolism that often results in life-threatening damage to the kidneys. In this type, the liver doesn’t create enough of a certain protein (enzyme) that prevents overproduction of oxalate, or the enzyme doesn’t work properly. Unlike dietary or enteric hyperoxaluria, the amount of oxalate in the urine is not greatly affected by changes in dietary oxalate.

4 Making a Diagnosis

The following factors contribute to a diagnosis of hyperoxaluria:

  • 24-hour urine sample to assess daily urinary oxalate excretion (and 24-hour urinary creatinine excretion/clearance to ensure collection is adequate). Consider also measuring:
    • Other products that lead to stone formation, such as calcium, urate, sodium and phosphate.
    • Inhibitors of stone formation (for example, potassium citrate and magnesium).
  • 24-hour urinary volume and pH (to assess contribution of dehydration and pH to stone formation).
  • Check U&E to assess renal function.
  • If primary hyperoxaluria is possible, perform percutaneous needle liver biopsy for AGXT or GRHPR activity assay.
  • Imaging studies: There are no specific tests for hyperoxaluria. However, studies may be useful to detect and assess; for example, any urolithiasis and/or hydronephrosis, including intravenous pyelogram (IVP), ultrasound and CT/MRI scanning.
  • A dietary questionnaire may help to detect:
    • Those with excessive oxalate consumption (for example, spinach, rhubarb, cranberry, nuts).
    • Excessive vitamin C consumption (controversial).
    • High meat protein consumption.
  • A record of fluid intake may help to detect those patients who may benefit by drinking more.

5 Treatment

Treatment of hyperoxaluria vary depending on its type.

Primary hyperoxaluria:

  • Definitive cure is by early liver and kidney transplantation.
  • Pyridoxine can be used and should be continued if urinary oxalate monitoring shows a beneficial response.
  • Magnesium hydroxide/oxide chelate with oxalate in the intestinal tract can reduce absorption.
  • Urinary volumes should be maintained at 3-4 L/day.
  • Glycosaminoglycans such as pentosan polysulfate are also used with some success.
  • Oxalobacter formigenes is a bacterium which degrades oxalate. Ingestion may be a treatment for primary hyperoxaluria.
  • Intensive dialysis is needed when there is renal failure (more than is required for simple uraemia).
  • All patients who do not respond to pyridoxine eventually require liver transplantation ± renal transplant.
  • Ultimately, it is hoped that gene therapy may help in this condition.

Enteric hyperoxaluria:

  • Patients should eat low-fat meat and have a diet low in oxalate.
  • Calcium citrate supplementation is the most effective treatment.
  • Potassium citrate can be given to increase urinary pH and citrate levels which reduce stone formation.
  • Colestyramine and organic marine hydrocolloid may also be used to reduce oxalate absorption.
  • Organic marine colloid may be helpful in binding oxalate in the gut and reducing urinary excretion.
  • Treatment of underlying enteric causes may be helpful.

Idiopathic hyperoxaluria:

  • Dietary oxalate restriction and maintenance of high urinary flow. Avoid foods such as spinach, rhubarb, nuts, beetroot, chocolate, wheat bran, tea and excessive meat intake which increase oxalate absorption.
  • Pyridoxine may be trialled and continued in those who show reductions in urinary oxalate restriction.
  • Phosphate and magnesium supplementation may be used.
  • Avoid excessive vitamin C intake.
  • Increase fluid intake (more than 1.5 L per square metre per day).
  • Administration of an oxalate-degrading bacterium such as O. formigenes, which breaks down oxalate in the intestine, may prove a useful therapeutic avenue. These bacteria appear to be deficient in some patients with hyperoxaluria, but achieving reliable gut colonisation has been difficult.

6 Risks and Complications

The various complications of hyperoxaluria include:

  • Gangrene
  • Osteoporosis
  • Heart block
  • Renal failure
  • Nephrolithiasis
  • Nephrocalcinosis
  • Hyperoxaluria
  • Pathological fracture
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