Hyperoxaluria

Synonym: Oxalosis, oxaluria

See also our Renal Stones record.

Hyperoxaluria is defined by the presence of excess amounts of oxalic acid (oxalate) in the urine. This is more precisely defined as urinary excretion of >40–45 mg/day of oxalate; or >30mg per 24 hours per gram of excreted creatinine.

It is a relatively common finding in those who suffer from calcium oxalate renal tract stones, with 20–30% of such patients having some degree of excessive urinary oxalate excretion.

Oxalate is produced by plants (found particularly in leaves, fruit and nuts), ingested in the diet and absorbed from the gut, mainly the colon. More is absorbed in the summer months, perhaps related to seasonal changes in diet. The concentration in particular plants is unpredictable as it is greatly affected by growing conditions. It is important in for example mitochondrial metabolism in fungi and bacteria, but appears to be a metabolic by-product of no particular physiological importance in humans (a bit like uric acid). It has great affinity for calcium and calcium oxalate is relatively insoluble in urine. Urinary oxalate is the most potent cause of kidney stone formation being something like ten times more potent than excess urinary calcium. High concentrations lead to formation of calcium oxalate-apatite crystals and ultimately to nephrolithiasis.¹

• Primary hyperoxaluria:
  • Type I – due to recessive mutation in gene encoding hepatic alanine-glyoxylate aminotransferase (AGXT). Leads to glycolic aciduria and hyperoxaluria. Autosomal recessive inheritance and the most common of the primary hyperoxalurias..
  • Type II – due to mutation in gene encoding hepatic glyoxylate reductase/hydroxypyruvate reductase (GRHPR). Leads to l-glyceric aciduria and hyperoxaluria.
  • Type III – no identified enzyme deficiency. 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 diarrhoea.
  • 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, chronic pancreatic and biliary tract disease causing fat malabsorption (including cystic fibrosis).
• Idiopathic (mild) hyperoxaluria:
  • It is by far the commonest 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.

Overall hyperoxaluria appears to be more of a problem in developed countries. This probably relates to diet. In Japan increased animal protein and fat intake has been linked to a rise in calcium oxalate nephrolithiasis.¹

Incidence

Primary hyperoxaluria type I incidence roughly 1 in 120,000 live births.

Prevalence

• Primary hyperoxaluria type I - approx. 10.5/million population.
• Urolithiasis is undoubtedly common in the UK, although exact figures are hard to come by. Oxalate stones are the commonest kind of urinary tract stone.
• Hypercalcuria is more common as a metabolic problem, but the potency of oxalate in forming stones makes calcium oxalate the most common type of kidney stone.
• Kidney stones are 3 times more common in men than women.
• Enteric hyperoxaluria is thought to account for about 5% of cases of hyperoxaluria.
• Idiopathic hyperoxaluria is by far the commonest type.

• Idiopathic hyperoxaluria (including dietary causes):
  • This accounts for most mild hyperoxaluria.
  • Diet is thought now to have more of a role.¹
  • It is usually asymptomatic until complications of nephrolithiasis ensue.
  • It usually presents in middle age and more typically in men.
• 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.²
  • Death from renal failure occurs before age 20 years if untreated.
  • 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). This is caused by extensive crystallisation of calcium oxalate in the walls of small arteries.
  • There is also a progressive peripheral neuropathy caused by calcium oxalate deposition within axons and walls of vasa nervorum. These features usually appear in patients in terminal renal failure treated with dialysis or unsuccessful renal transplantation.
  • A small group of adult patients present having followed a benign course (survival up to age 60).
  • The normal clinical course is of recurrent stones leading inevitably to renal failure.
  • This diagnosis should be considered in any child with urinary stones or nephrocalcinosis or in adults with recurrent calcium oxalate stones where no alternative explanation is found, especially if there is a long history.

• Collect 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 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:
  • Intravenous pyelogram (IVP)
  • Ultrasound
  • CT 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 consumption¹
• A record of fluid intake may help to detect those patients who may benefit by drinking more.

• Primary hyperoxaluria:
  • Definitive cure is by early liver and kidney transplantation.^3,4,5
  • Pyridoxine can be used and should be continued if urinary oxalate monitoring shows a beneficial response. High doses may be needed (500–1500 mg daily). Danger of pyridoxine-induced neuropathy.
  • Orthophosphate therapy can be given in the absence of renal failure.
  • Magnesium hydroxide/oxide chelate with oxalate in the intestinal tract and can reduce absorption.
  • Urinary volumes should be maintained at 3–4 l/day.
  • Glycosaminoglycans such as pentosan polysulphate are also used with some success.
  • Oxalobacter formigenes are bacteria which degrade oxalate. Ingestion may be a treatment for primary hyperoxaluria.^4,6
  • 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.⁷
  • Ultimately it is hoped that gene therapy may help in this condition.
• Enteric hyperoxaluria:
  • Patient should eat low-fat, reduced meat and low oxalate diet.
  • Calcium citrate supplementation is the most effective treatment.
  • Potassium citrate can be given to increase urinary pH and citrate levels which reduce stone formation.
  • Cholestyramine 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 and tea and excessive meat intake which increase oxalate absorption. See Internet section below for more detail of low oxalate diet.
  • 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 litres per square metre per day).⁸
  • Administration of oxalate-degrading bacteria such as Oxalobacter formigenes which break down oxalate in the intestine may prove a useful therapeutic avenue. They appear to be deficient in some patients with hyperoxaluria, but achieving reliable gut colonisation has been difficult.^9,8

Good in secondary hyperoxalurias. Untreated or unresponsive cases of primary hyperoxaluria have a poor outlook with chronic renal failure and severe nephrocalcinosis inevitable.

Recurrent urolithiasis occurs in all forms of hyperoxaluria. Renal failure is a frequent outcome of primary hyperoxaluria. Established urolithiasis is best treated surgically using nephroscopic lithotomy, endoscopic lithotripsy using ultrasonic, electrohydraulic or laser techniques or extracorporeal shock wave lithotripsy. Stenting and nephrostomy formation may be required to clear stones or debris.