Primary Hyperoxaluria Type III - A Recent Update

Introduction

Hyperoxaluria occurs when excess oxalate (a naturally occurring compound found in food) is present in urine. Hyperoxaluria can be inherited or acquired (secondary hyperoxaluria) by consuming hyperoxaluria-rich food (spinach, soy products, almonds, potatoes). Primary hyperoxaluria is caused by the liver's ineffective enzyme production, leading to excess oxalate accumulation. Kidneys are responsible for the filtration of oxalate. The oxalate combines with calcium in the kidneys to form kidney stones and crystals. There are three types of primary hyperoxaluria based on the type of genes affected. Kidney failure due to hyperoxaluria causes oxalate accumulation in the eyes, bones, skin, muscles, blood vessels, and heart, causing a condition known as oxalosis.

What Is Primary Hyperoxaluria Type III?

Type III is caused by recurrent deposition of calcium oxalate stones in the kidney seen in childhood or adolescence, causing reduced kidney function. The condition is inherited in an autosomal recessive pattern due to a mutation in the HOGA1 (hydroxy- oxo- glutarate- aldolase 1) gene. As a result, there is a disruption in glyoxylate metabolism. The oxalate formation tends to occur before five years. The stone formation reduces in adulthood. Some adults may have multiple stone formations and severe renal complications.

Type III hyperoxaluria has the lowest incidence among all types of hyperoxaluria. The incidence of type III is more common in Ashkenazi Jewish descent. The patients may not develop clinical symptoms and can go undiagnosed. Hence, the true incidence is not determined.

What Are the Clinical Manifestations of Primary Hyperoxaluria Type III?

Type III hyperoxaluria presents with symptoms of

• Hematuria (blood in urine).

• Frequent urination and pain while urinating.

• Pain in the back, the area below the ribs that does not reduce.

• Renal inflammation.

• Chills or fever.

• Interstitial fibrosis (inflammation and scarring of lungs).

• Urolithiasis (kidney stones).

• Urinary tract infection.

• Hyperoxaluria (excess oxalate in urine) and hypercalciuria (excess calcium in the urine) are seen.

However, the symptoms are not severe compared to type I and II hyperoxaluria. The symptoms vary between individuals and can be mild to severe.

How to Diagnose Primary Hyperoxaluria Type III?

• The presence of multiple kidney stones (calcium oxalate) can help in diagnosis. Renal ultrasound is used for diagnosis.

• The formation of kidney stones since childhood.

• 24-hour urine oxalate and supersaturation study.

• Urine oxalates greater than 0.7 millimoles per liter/1.73 m2/24 (millimoles per meter square) hours in patients with preserved kidney function.

• Nephrocalcinosis (accumulation of generalized stones in the kidney) can be suggestive of the condition.

• Increased plasma oxalate concentration in patients with reduced kidney function.

• Biallelic pathogenic variants in HOGA1.

• Kidney function assessment shows reduced functioning and examination for serum creatinine.

• Prenatal genetic testing if family history is positive for type III hyperoxaluria.

• 4- hydroxy - 2- oxoglutarate and Urinary glycolate urine metabolites are elevated in Type III.

What Assessments Should Be Done Before Management?

• Imaging studies of the kidney to determine the number and location of stones.

• Plasma oxalate concentration is measured.

• 24-hour assessment of oxalate, pH (potential of hydrogen), calcium, citrate, and urine volume to guide the treatment course.

• Kidney function assessment with serum creatinine and eGFR (estimated glomerular filtration rate).

What Is the Treatment of Primary Hyperoxaluria Type III?

Treatment is done to lower calcium oxalate levels and prevent calcium oxalate crystals in the kidney.

Medical Approach

• The prescription dose of vitamin B6 (pyridoxine) is consumed to reduce oxalate levels. Thiazide diuretics may also be effective.

• Increased fluid intake to 2.5 to 3 L of water to reduce calcium oxalate saturation in urine.

• Administration of calcium oxalate crystallization inhibitors like potassium, sodium citrate, orthophosphate, or magnesium to prevent calcium oxalate formation.

• Although chronic kidney disease is rare, a reduced glomerular function of less than 40 ml/min/1.73 m2 (milliliters per minute per square meter) may result in increased plasma oxalate and systemic oxalosis. If plasma oxalate increases to 35-50 mol/L (moles per liter), dialysis or transplantation may be necessary.

Patients without major complications are assessed for kidney pain, frequency of urination, assessment of high fluid intake, and regular medication intake.

Surgical Approach

If kidney stone formation is seen, the stone can be excreted through urine. However, shockwave lithotripsy, ureteroscopy, or percutaneous nephrolithotomy are used if the stones do not resolve.

1. Shockwave Lithotripsy: Shockwaves from the outer body are targeted on kidney stones, causing stones' fragmentation. Larger stones cannot be treated in this method. The technique works well with stones less than 2 cm.

2. Ureteroscopy: Ureteroscopy is a procedure done to determine a kidney stone's location. A small telescope called a ureteroscope is passed through the urethra and bladder to locate the stone. The procedure is done under anesthesia. First, a small stone is removed completely from the bladder with the help of a basket device. However, larger stones that cannot pass through the ureter are fragmented with the help of a laser to enable their removal with basket devices.

3. Percutaneous Nephrolithotomy: The procedure involves the formation of the pathway from the skin on the back of the kidney. Then, surgeons use a special instrument to pass through the tube to remove the stone. Larger stones are removed in this technique, which may be useful when other procedures fail to remove renal stones.

Severe hyperoxaluria causes dysfunction of the kidney. Kidney dialysis or organ transplantation is useful in managing severely damaged kidneys.

1. Kidney Dialysis - Kidney dialysis is done as a bridge to organ transplantation. However, the patient must only be subjected to dialysis for a short time as it may increase the chance of developing sepsis and cardiovascular conditions.

2. Kidney Transplant - A kidney transplant is the last resort in treating renal disease. However, in most cases, patients may require a liver transplant to resolve the condition, as primary hyperoxaluria is an inborn error due to inadequate enzyme secretion by the liver.

What Are the Complications of Primary Hyperoxaluria Type III?

Chronic kidney disease may develop due to frequent kidney stone formation. End-stage renal disease can develop in rare cases causing kidney failure and even death.

Signs of an End-Stage Kidney Failure:

• Decreased or absent urine output.

• Feeling ill and tired.

• Loss of appetite, nausea, and vomiting.

• Swelling of hands and feet.

What Is the Differential Diagnosis of Primary Hyperoxaluria Type III?

Nephrocalcinosis of prematurity is a condition that occurs in infants born before 28 weeks gestation and presents with nephrocalcinosis (generalized calcium deposition on kidneys) and nephrolithiasis (renal stones). Since both conditions occur in infancy, an adequate diagnosis must be made to differentiate the disease.

How to Prevent Primary Hyperoxaluria Type III?

• Relieving urinary tract obstruction by stent placement or stone removal.

• Urinary tract infections are treated promptly.

• Avoiding excess dietary oxalate intake.

• Frequent fluid intake and excretion of urine after the stone removal procedure.

Following these steps enables effective management of the condition and can prevent disease progression.

Conclusion

Primary hyperoxaluria does not have any cure. Type III hyperoxaluria is less severe than type I and II. Systemic oxalosis is not seen in type III. However, early diagnosis and treatment with the prevention of renal stones enable good patient outcomes. If the condition is left untreated, it can lead to end-stage renal disease.