Hyperoxaluria
DISEASE DEFINITION
The term hyperoxaluria describes a condition in which too much oxalic acid is excreted in the urine (more than 40 mg per 24 hours in adults). This can lead to the formation of kidney stones, kidney calcification (“nephrocalcinosis”) and, in severe cases, to kidney failure (ESKD) and damage to other organs due to oxalic acid accumulation (“systemic oxalosis”).
There are two types of hyperoxaluria, depending on the underlying cause:
Primary hyperoxaluria: A term that refers to a group of rare congenital diseases in which the body itself produces too much oxalic acid, resulting in high levels of oxalic acid in the urine.
Secondary hyperoxaluria: This form of hyperoxaluria is caused by increased intestinal absorption of oxalic acid from food, usually because of an intestinal disorder with impaired fat absorption, or because of an extremely high oxalic acid intake.
WHAT IS THE CAUSE?
Primary hyperoxaluria (PH) is caused by a genetic abnormality (mutation) that affects metabolism in such a way that too much oxalic acid is produced in the body:
PH1, >90% PH, most severe form: Mutations in the AGXT gene, which is responsible for the conversion of glyoxylate to glycine in the liver. When this process is impaired, glyoxylate is converted into oxalic acid. Nearly 70% of patients eventually develop kidney failure
PH2, 5-10%: Mutations in the GRHPR gene. Less severe course; approximately 20% develop kidney failure
PH3, 5-10%: Mutations in the HOGA1 gene. Probably the least severe form
Secondary (enteric) hyperoxaluria is the most common form of hyperoxaluria. It is mainly seen in intestinal diseases that lead to a reduced fat absorption, such as inflammatory bowel diseases—Crohn's disease, ulcerative colitis—or after stomach reduction surgery. Excessive consumption of oxalic acid-rich foods or very high doses of vitamin C can also cause secondary hyperoxaluria.
SYMPTOMS
Symptoms caused by hyperoxaluria initially arise from the precipitation of calcium oxalate crystals in the kidney, which can lead to kidney stones or kidney calcification (nephrocalcinosis), and in severe cases to kidney damage and loss of kidney function, ultimately resulting in kidney failure (ESKD). In the latter case, oxalic acid can no longer leave the body and accumulates in various other organs (bones, heart, eyes, blood vessels, nerve fibers – systemic oxalosis). This may lead to following symptoms:
Recurrent kidney stone attacks, usually colic pain (often the first manifestation)
Kidney calcification (nephrocalcinosis): often found by chance via ultrasound
Hematuria (blood in the urine)
Flank or abdominal pain
Dysuria (painful urination)
Signs of urinary tract infection, frequent urge to urinate
Signs of kidney failure (may be the first manifestation!)
Signs of systemic oxalosis: bone pain, bone fractures, visual disturbances, heart failure (only in cases of kidney failure)
DIAGNOSIS
- Urine test: increased amount of oxalic acid in 24-hour urine collection = diagnostic
- Genetic test: cornerstone of diagnosis when Primary Hyperoxaluria is suspected
- Blood test: elevated plasma oxalic acid (only in case of poor kidney function)
- Stone analysis: type of calcium oxalate crystal is typical for type of hyperoxaluria
- Imaging: ultrasound of the kidneys or CT scan to detect stones or kidney calcification.
TREATMENT
Most treatment measures focus on preventing kidney stones or kidney calcification:
| Hyperhydration | Drinking large amounts of water significantly reduces the risk of calcium oxalate precipitation in the kidneys and thus the formation of stones | ||
| Crystallization inhibitors | Potassium citrate keeps calcium oxalate in solution, and high citrate excretion thus reduces stone formation | ||
| Pyridoxine (vitamin B6) | Approximately 30% of European PH1 patients have reduced AGT function, which can be remedied with vitamin B6, sometimes normalizing oxalic acid excretion completely | ||
| Dietary measures | Restriction of oxalic acid-rich foods is mainly effective in secondary hyperoxaluria | ||
| Treatment of underlying disease | In enteral hyperoxaluria | ||
| Intensive dialysis | In case of kidney failure | ||
| Transplantation |
| ||
| iRNA therapy | Lumasiran (Oxlumo®) and Nedosiran (Rivfloza®). Both effectively reduce oxalic acid production in PH1 patients; lumasiran has been approved by the FDA and EMA, nedosiran only by the FDA. Both are administered via injections under the skin (subcutaneously) |
► There are currently no causal treatments for PH.
PROGNOSIS
Early diagnosis and treatment have been shown to have a positive impact on prognosis, especially in PH1 patients, in terms of preventing kidney failure and immediately life-threatening systemic oxalosis.
Most severe form; more than 70% of patients eventually develop kidney failure (ESKD), sometimes as early as infancy; this occurs earlier in life on average in B6-insensitive PH1 patients than in B6-sensitive patients, but these patients can also present with kidney failure. Timely diagnosis is essential to prevent kidney failure with treatment.
Milder form; approximately 20% develop kidney failure, almost always at a later age.
Most benign form, almost exclusively kidney stones, very few cases of severe kidney damage described.
Usually treatable with dietary measures, extra fluid intake, and citrate. Kidney failure is rare but does occur.