Oxalate (Urine)

Diagnostic Use

Primary hyperoxalurias (PH):

In hyperoxalurias, excessive oxalate in the urine combines with calcium to form poorly soluble calcium oxalate which can cause recurrent nephrocalcinosis, nephrolithiasis and, if persistent, end stage renal failure (ESRF).

When oxalate excretion exceeds renal oxalate clearance, e.g. when GFR is <30ml/min/1.73m2, plasma oxalate concentration starts to rise. Super-saturation of plasma oxalate leads to systemic oxalosis, affecting organs like heart, retina, bone (including bone marrow) and peripheral nerves. Although these conditions are rare, they account for about 1-2% of children under 15 years who require renal replacement therapy in Europe and North America.   In countries with high frequency of parental consanguinity, the percentage is higher.

The clinical phenotype of PH varies widely even within families, from failure to thrive, ESRF and death in infancy/childhood to nephrocalcinosis/recurrent nephrolithiasis with normal or reduced renal function in childhood/adulthood to asymptomatic finding in adulthood through family screening.

There are 3 types of PH, all autosomal recessive disorders causing enzyme defects at the glyoxylate pathway:

• Type 1 is the most severe form of the disease. It affects hepatic peroxisomal alanine glyoxylate aminotransferase (AGT) which converts glyoxylate to glycine, which is soluble.   It accounts for about 80% of cases.   When unable to form glycine, the retained glyoxylate is either reduced to glycolate or oxidised to oxalate. Unlike glycolate, which is also water soluble, oxalate precipitates as calcium oxalate which can cause a spectrum of renal stone diseases.   Increased urine glycolate in the presence of hyperoxaluria is suggestive, but not diagnostic, of type 1 PH. It is not a very sensitive marker as about 1/3 of patients have no hyperglycolic aciduria, and not very specific as raised urine glycolic acid can come from dietary sources.
• Type 2 affects cytosolic enzyme, Glyoxylate reductase/Hydroxypyruvate reductase (GRHPR), which reduces glyoxylate to glycolate. The retained glyoxylate is metabolised instead to oxalate and L-glyceric acid. It accounts for about 10% of cases; Increased urine L-glycerate in the presence of hyperoxaluria is suggestive of type 2 PH.
• Type 3 affects the hepatic mitochondrial enzyme, 4-Hydroxy-2-oxoglutarate aldolase (HOGA). The molecular mechanism causing hyperoxaluria is unclear. Type 3 accounts for about 10% of PH cases but is likely more frequent than type 2. Similar to type 1, hyperoxaluria and mild hyperglycolic aciduria can be found. However unlike type 1, some type 3 patients also have hypercalciuria.

The mutations can be confirmed by genetic testing. However, sendaway genetic mutation testing is only available to specialised urologists/nephrologists.

Secondary hyperoxalurias (SH):

SH can arise from high oxalate low calcium diet (dietary or ‘enteric’ hyperoxalurias). Normally less than 10% of oxalate from dietary sources is absorbed but in some gastrointestinal diseases like coeliac disease, short gut syndrome, inflammatory bowel diseases or chronic pancreatic insufficiency, there is hyper-absorption of dietary oxalate (enteric hyperoxalurias). Gastric bypass surgery can also increase oxalate absorption (more so from Roux-en-Y gastric bypass than banding).

Patients with enteric hyperoxaluria usually have clinical evidence of fat malabsorption as the unabsorbed free fatty acids bind dietary calcium, rendering dietary oxalate more easily absorbed. Unabsorbed bile acids and fatty acids can also induce colonic mucosal injury, further increasing enteric absorption of oxalate. The urine oxalate level in SH can vary widely between days, depending on the dietary oxalate content.

Excessive vitamin C intake and ethylene glycol poisoning can also induce hyperoxaluria.   At least two measurements are recommended to assess excretion in patients with recurrent renal stones under dietary modification.

Dietary oxalate: A reduced oxalate intake may not be effective in reducing urinary oxalate excretion. Those with normal urine oxalate levels do not benefit from oxalate restriction. Oxalate foods provide other benefits for reducing risk of kidney stones such as bicarbonate precursors, fibre and phytate.

Nutrition interventions to address hyperoxaluria:

1. Ensure adequate calcium intake to optimise binding of oxalate in the gastrointestinal tract. Recommend calcium ?containing foods and beverages at meals.
2. May need to reduce intake of the highest oxalate foods if consuming excessive amounts. Highest oxalate foods include; Spinach, rhubarb, beetroot (both the root and the greens), nuts and nut butters, chocolate and cocoa, wheat bran (in high amounts), soybeans and foods made from soy.

Interpretation

Urine and plasma Oxalate tests

There is no definitive cut point for hypeoxaluria to separate PH from SH.   Excretion in dietary hyperoxuluria is usually less than 560 umol oxalate per day. Although >700 umol/day/1.73m ² is considered suspicious of PH, occasionally patients with enteric hyperoxalurias can have urine oxalate exceeding 1000 umol/day/1.73m ² . On the other hand, while most mildly raised urine oxalate results are due to SH, PH patients can occasionally have oxalate excretion within the 450-700 umol/day/1.73m ² range.   Hence, there should still be a strong suspicion for PH if there is history of recurrent calcium oxalate stones, presentation at young age, or family history of PH.

The test of choice in patients with recurrent stones is urine oxalate, unless eGFR is <30 ml/min/1.73 m ² .   On the other hand, urinary oxalate excretion can be normal and diagnostically misleading in PH patients with GFR <30 ml/min/1.73 m ² due to reduced urinary excretion.   Plasma oxalate level is usually normal or only mildly raised in hyperoxalurias (even primary causes) unless there is considerable decline in glomerular filtration rate.   Note that ESRF from any cause (not just from primary hyperoxalurias) can also raise plasma oxalate due to inadequate excretion. There is no clear cut point for plasma oxalate to distinguish PH related or PH unrelated renal insufficiency. However, some laboratories consider plasma oxalate >20umol/L warrants further investigation and >50umol/L as suggestive of PH.

In children, the oxalate to creatinine ratio can be determined on random urine specimens. As the ratio falls rapidly, especially in the first 2 years, its interpretation requires age-specific ranges. Premature infants have higher oxalate to creatinine ratio than term infants, especially if they are receiving total parenteral nutrition with amino acids. Not uncommonly serial spot urine oxalate/creatinine ratios can give conflicting results due to fluctuations in both dietary intake of oxalate and degree of urine concentration at the time.   Therefore, if one or more spot urine results (out of 3) has level(s) above the age specific upper reference limit, hyperoxaluria should be confirmed by a 24-h urine collection with result correction to body surface area (see Reference Intervals section).

The primary hyperoxalurias: a practical approach to diagnosis and treatment. Int J Surg 2016; 36:649-654

Reference Intervals

1. 24 hour urine:

Unit: umol/day

Adults (>=16 yrs):       0 – 450 umol/day/1.73m ²

Children (<16 yrs):     0 – 500 umol/day/1.73m ²

24 hour urine oxalate excretion is reported in “umol/day” while the unit for reference limit is in “umol/day/1.73m  ² “.  The two units are generally comparable in adults of average body size.  However, for children or for adult at the more extreme ends of body weight, suggest correcting the result for body surface area.  Multiply the result (in umol/L) by the ratio of 1.73 over their calculated body surface area before it is interpreted against the reference limit (in umol/day/1.73m  ² ).

Body surface area can be derived from online calculators e.g. at https://www.pediatriconcall.com/calculators/body-surface-area-du-bois-method      e.g.(DuBois and DuBois formula for adult; Haycock or Gehan-George formula for children).

24 hour urine oxalate >= 700 umol/day/1.73m  ² in the setting of kidney stones should prompt investigation of primary or secondary causes of hyperoxaluria.

2. Random urine:

Unit: umol/mmol creatinine

Testing oxalate on spot urine is reserved for children <15 yrs.  Those who are >= 15 yrs old should always aim for a 24 hour urine collect.

For children <15 yrs: suggest collect 3 random spot urine samples on different days to allow for variation between samples.  If any of the 3 results is above the age specific reference limit, collect a carefully done 24 hour urine for oxalate testing.  Consult Paediatric Nephrology team if abnormal.