Hyperoxaluria

Hyperoxaluria is the term used to describe elevated oxalate levels in the urine. In general, oxaluria is considered normal if it does not exceed 40 mg per day. Otherwise, it is considered a pathology - hyperoxaluria.

Oxalates are produced in the body and ingested with food. Elevated levels are associated with a high risk of urinary stone formation. The pathological condition can escalate up to the development of oxalosis, in which there is massive oxalate deposition in the tissues.

Epidemiology

Statistics show that primary oxaluria affects at least 1 person for every 58,000 of the world's population.

The most common form of the disease is type 1. It accounts for about 80% of cases, while types 2 and 3 account for only 10% of cases each.

In general, crystalluria is a variation of urinary syndrome, when the examination of urine reveals the increased presence of salt crystals. Pediatricians note that such a condition is detected in almost every third baby. The specific weight of this violation among pediatric renal diseases is more than 60%. The most common is considered oxalate and calcium-oxalate crystalluria (75-80%). Prolonged hyperoxaluria entails changes in renal function or structural changes in various nephrotic compartments.

There are differentiated such stages of the pathological process:

• preclinical stage (salt diathesis);
• clinical stage (dysmetabolic nephropathy);
• urolithiasis.

According to epidemiologic statistics, calcium oxalate nephropathy is detected in 14% of cases of pediatric pathologies of the urinary system. At the same time, intermittent hyperoxaluria detected in childhood or adolescence often causes aggravation of tubulointerstitial disorders in adults, increased frequency of combined variations of the urinary syndrome, manifested by intense proteinuria, hematuria, symptoms of membranolysis of renal tubule epithelium, impaired function and structure of the urinary system.

Primary hyperoxaluria type 1 is usually detected late (in more than 30% of cases - at the stage of development of terminal renal failure). Every fourth patient with primary hypoxaluria type 2 develops terminal chronic renal failure, but with pathology type 3 cases of such a complication are quite rare.

Causes of the hyperoxaluria

Oxalate is an organic salt that is produced in the liver during metabolic processes, or ingested with food and excreted with urinary fluid, as it does not carry any proven benefit to the body.

The amount of salt components that are produced in the body and ingested with food varies from person to person. Many reasons are known to cause an increase in the level of oxalates. And the first reason is regular consumption of food with high presence of such salts.

The other most likely factor is excessive oxalate absorption in the intestine. This is possible if the mechanism of glycolate metabolism, by which oxalates are formed, is accelerated due to loss of enzymes that catalyze other mechanisms. However, in many cases, hyperoxaluria occurs for no apparent reason. In such a situation, the condition is said to be idiopathic.

In the process of binding to calcium, calcium oxalate is formed, which significantly increases the risks of stone formation in the kidneys and urinary tract. An overabundance can also accumulate in the circulatory system and tissues throughout the body. Such a condition is called oxalosis.

Primary hyperoxaluria is typified by the influence of inherited genetic defects on metabolism due to enzyme deficiencies. As a result, alternative mechanisms are engaged, which entails an increase in oxalate levels. Several types of primary pathology are known:

• Type 1 occurs against the background of alanine-glyoxylataminotransferase deficiency and is the most common;
• Type 2 develops due to a deficiency of D-glycerol dehydrogenase;
• Type 3 is not due to an obvious enzyme deficiency, but the body produces excessive amounts of oxalate.

Intestinal hyperoxaluria is the result of malabsorption. The disorder is associated with absorption problems in the small intestine. This condition develops:

• for chronic diarrhea;
• for inflammatory bowel disease;
• for pancreatic pathologies;
• with pathologies of the biliary system;
• after surgical resection of the small bowel;
• after bariatric surgery (for weight loss).

Risk factors

Specialists identify a number of factors that create favorable conditions for the occurrence of intestinal hyperoxaluria:

• diarrhea-induced decreased diuresis;
• decreased excretion of magnesium ions by the kidneys due to impaired intraintestinal absorption;
• A state of metabolic acidosis associated with intestinal loss of bicarbonates.

Intestinal dysbacteriosis plays a significant pathogenetic role, resulting in a decrease in the number of bacterial colonies (oxalobacterium formigenes) that break down up to half of exogenous oxalate. The deficiency of these bacteria makes oxalate available for absorption, which leads to an increase in their content in the blood and urinary fluid.

It also plays a role in decreased urinary excretion of citrates (inhibitors of oxalate crystallization), _B6 deficiency (inhibitor of oxalate formation).

Among the risk factors for secondary hyperoxaluria is genetic predisposition (accounts for up to 70% of pediatric hyperoxaluria cases). The problem causes a violation of oxalate metabolism, or a tendency to cytomembrane instability. Of no small importance are the processes of membrane destabilization: increased intensity of lipid peroxidation, activation of endogenous phospholipases, increased oxidative metabolism of granulocytes. As acidic phospholipids of cell membranes are destroyed, oxalate "germs" are formed. Oxalates may form locally in the kidneys. Provoking factors are prolonged intake of sulfonamides, environmental problems, poor nutrition, emotional, mental and physical overload.

The existence of a relationship between the development of hyperoxaluria and undifferentiated forms of connective tissue dysplasia has been proved, since many amino acids (in particular, glycine, serine) are components of collagen.

Pathogenesis

According to medical knowledge, the oxalic acid content in the body is maintained by both external sources (consumed foods and vitamin C) and internal processes (metabolism of the amino acids glycine and serine). It is normal for oxalate from food to bind with calcium in the intestine and to be excreted in the feces as insoluble calcium oxalate. A standard type of diet usually includes up to 1 g of oxalate, with only 3-4% of it being absorbed in the intestine.

Most of the oxalates that are excreted in the urine are formed during metabolic processes from amino acids such as glycine, serine, and oxyproline. Ascorbic acid is also partially involved. Physiologically, 10% of oxalates in urine are formed from ascorbic acid and 40% from glycine. Excessive amounts of oxalates are eliminated from the body mainly by the kidneys. If there is an excessive concentration of oxalates in the urine, they precipitate in the form of crystals. In healthy people, urine is a kind of salt solution in dynamic equilibrium due to inhibitory agents that provide dissolution or dispersal of its components. A decrease in inhibitory activity increases the risk of hyperoxaluria.

Oxalic acid metabolism is also supported by magnesium, which directly affects its excretion, increases the solubility of calcium phosphate, and prevents oxalate crystallization.

Two pathways are known for the etiopathogenesis of hyperoxaluria:

• Primary hyperoxaluria is hereditary and involves three genetically determined types of metabolic disorders: increased oxalate excretion, recurrent calcium-oxalate urolithiasis and/or nephrocalcinosis, and increasing inhibition of glomerular filtration with the formation of chronic renal function deficit.
• Secondary hyperoxaluria (sometimes called "spontaneous"), in turn, can be transient or permanent. It develops as a result of monotonous improper diet, viral infections, intercurrent pathologies. Alimentary hyperoxaluria is most often caused by excessive consumption of food rich in oxalic and ascorbic acids.

Intestinal hyperoxaluria develops as a result of increased absorption of oxalate, which is characteristic of chronic intestinal inflammatory processes and food allergies. In addition, increased absorption can be observed in any disorder of fatty intestinal absorption: this includes cystic fibrosis, pancreatic insufficiency, short bowel syndrome.

Most of the fatty acids are absorbed in the proximal intestinal compartments. When absorption is impaired, a significant proportion of calcium is lost due to a related relationship. This results in a deficiency of free calcium required for oxalate binding, leading to a dramatic increase in oxalate resorption and excretion with the urine.

Genetic hyperoxaluria is a rare form of autosomal recessive pathology in which there is a disorder of hepatic glyoxylate metabolism, resulting in excessive oxalate production. Of the three known variants of the disease, primary hyperoxaluria type 1 is considered the most common and severe disorder based on deficiency of the hepatic (adhermin-dependent) peroxisomal enzyme alanine-glyoxylate oxalate aminotransferase. All types of primary hypoxaluria are characterized by increased urinary excretion of oxalates, which causes the development of recurrent urolithiasis and/or increasing nephrocalcinosis, and then, against the background of inhibition of glomerular filtration, oxalate deposition in tissues occurs and systemic oxalosis develops.

Symptoms of the hyperoxaluria

Hyperoxaluria can manifest itself in different ways, depending on the area of oxalate accumulation. Most often it is a matter of stone formation in the kidneys, with sand and small stones often not causing any symptomatology and secretly excreted during urination. Larger stones regularly cause pain on the side of the lesion. Many patients complain of a burning sensation when urinating, sometimes blood is detected in the urine. As the salts accumulate, a state of nephrocalcinosis is formed.

Salt accumulation in bone tissue on the background of hyperoxaluria determines the tendency to fractures and prevents skeletal growth in childhood.

Capillary blood circulation deteriorates, causing occasional numbness in the hands and feet. In severe cases, ulcers form on the skin.

Nervous system function is impaired, and peripheral nephropathy may develop. There is often intermittent muscle weakness, coordination disorders, paralysis.

Intestinal hyperoxaluria is manifested by diarrhea resistant to the use of conventional medications. Such diarrhea can cause dehydration, which only exacerbates the risks of kidney stone formation.

Other likely symptoms include: anemia, abnormal heart rhythm, and heart failure.

Hyperoxaluria in children

The first signs of hyperoxaluria in childhood can be detected as early as 1 year of life, although most often the disorder is recorded in the years of intensive development - that is, about 7-8 years, and in adolescence. In many cases, hyperoxaluria is detected accidentally - for example, during diagnostic measures for viral infections, intercurrent pathologies. Sometimes close people of the child suspect something wrong when they notice a decrease in daily diuresis, salt precipitation, the appearance of recurrent abdominal pain.

Common symptoms include irritation of the external genitalia, burning sensation during urination, and other dysuria. Frequent genitourinary infections may occur.

Visually, the urine is saturated and visible sediment may be detected. Suspicious sign indicating possible hyperoxaluria: hyperstenuria against the background of absence of glucosuria. After some time, there is a small microhematuria, proteinuria, leukocyturia, which indicates kidney damage (dysmetabolic nephropathy develops).

Complications and consequences

The most dangerous complication of hyperoxaluria is chronic renal failure. Progression of the disorder in most cases leads to death.

Against the background of hyperoxaluria in early childhood may impair physical development, slow skeletal growth. Often such children are diagnosed with dyslexia, arthritis, myocarditis.

Generalized oxalosis is complicated by hyperparathyroidism, which is accompanied by excessive bone fragility, joint distortions.

In the development of urolithiasis due to hyperoxaluria, these adverse effects may occur:

• chronic inflammation (pyelonephritis or cystitis), with possible chronicization of the process;
• paranephritis, apostematous pyelonephritis, carbuncles and renal abscesses, necrosis of renal papillae and, as a result, sepsis;
• pyonephrosis (terminal stage of purulent-destructive pyelonephritis).

With chronic concomitant hematuria, anemia often develops.

Diagnostics of the hyperoxaluria

Diagnostic measures are based on clinical manifestations and laboratory tests, which include, first of all, determination of daily excretion of oxalates in terms of urinary creatinine.

Laboratory tests are the main way to diagnose hyperoxaluria. Microscopic examination of the urine sediment reveals oxalates, which are color-neutral crystals that are envelope-shaped. However, the detection of oxalates is not a sufficient basis for a definitive diagnosis.

Biochemistry of daily urine (salt transport) helps to find out whether it is hyperoxaluria and hypercalciuria. The norm of oxalate indicator is less than 0.57 mg/kilogram per day, and calcium - less than 4 mg/kilogram per day.

The calcium/creatinine and oxalate/creatinine ratios are also indicative in diagnostic terms.

If hyperoxaluria is suspected in childhood, a study of the anticrystal-forming property of urine in relation to calcium oxalate, which is usually reduced in pathology, is prescribed. Peroxide testing helps to determine the degree of activity of the process of oxidation of cytomembrane lipids.

Then ultrasound diagnostics is appointed: echopositive inclusions in the pelvis and calyxes may be detected.

Instrumental diagnostics, in addition to ultrasound, can be represented by radiography, computed tomography. Additionally and on indications, the composition of urinary concretions is assessed, genetic testing is performed (mainly in suspected primary hyperoxaluria).

Differential diagnosis

When making a diagnosis of hyperoxaluria, it is necessary to establish the primary or secondary pathology, to find out the probability of the influence of certain external factors.

Normally, many salts enter the body by absorption in the intestine. Therefore, secondary hyperoxaluria is often found against the background of a predominantly oxalate diet, impaired fat absorption in the intestine, as well as in patients who follow a diet with low calcium intake and increased use of ascorbic acid. With inflammation of intestinal tissues, undergone surgery for resection of the small intestine or stomach, increased absorption of organic salts and, accordingly, increased excretion with urine is noted. Secondary hyperoxaluria is sometimes detected in premature infants with birth weight deficiency, as well as in patients fed parenterally. In addition, intoxication with ethylene glycol, which is a precursor of oxalate, is sometimes a causative factor.

Primary hyperoxaluria requires exclusion in the development of pediatric urolithiasis, or in patients with recurrent nephrocalcinosis (or with a predisposition to hereditary nephrocalcinosis).

For differential diagnosis between primary hyperoxaluria of the first and second types in international practice, glycolate and oxalate indices in plasma, glycolate and L-glyceric acid excretion are investigated.

Treatment of the hyperoxaluria

In primary hyperoxaluria, treatment is aimed at preventing salt deposition in tissues and organs, reducing oxalate production and presence in the urine. An important role is played by early diagnostic and timely therapeutic measures, which allows to preserve renal function. Conservative methods are resorted to immediately after the appearance of suspected hyperoxaluria:

• Increasing the volume of fluid intake to 2-3 liters per day with an even distribution throughout the day, which reduces the concentration of salts in the urine and reduce the likelihood of oxalate deposits in the tubules (in babies may be used nasogastric tube or percutaneous gastrostomy).
• Administration of medications based on potassium citrate to inhibit the crystallization of calcium oxalate and improve the alkaline values of urine (0.1-0.15 k per kilogram per day). Urinary pH should be maintained in the range of 6.2-6.8 (potassium salt is replaced with sodium citrate if renal insufficiency is diagnosed). To improve the solubility of calcium oxalate, neutral phosphate (orthophosphate at 30-40 mg per kilogram of weight per day with a maximum dosage of 60 mg per kilogram per day) or/and magnesium oxide at 500 mg/m² per day are additionally administered orally. Treatment with orthophosphate is discontinued when renal filtration capacity deteriorates to prevent phosphate accumulation and worsening of secondary hyperparathyroidism.
• Limit the presence of oxalate-containing foods in the diet (sorrel, spinach, chocolate, etc.). The presence of calcium in the diet is not limited. The intake of large amounts of ascorbic acid and vitamin D is excluded.
• Adequate doses of vitamin _B6 (effective in about 20% of cases), with an initial dosage of 5 mg per kilogram per day, increasing to 20 mg per kilogram per day. The response to pyridoxine is determined after 12 weeks of treatment: a positive result is said if the daily urinary oxalate excretion is reduced by at least 30%. If the administration of pyridoxine was ineffective, the drug is canceled. And with a positive result, the vitamin drug is prescribed for life, or until radical changes in the body (for example, until liver transplantation). Important: treatment is carried out under the supervision of a doctor, since regular high doses of vitamin _B6 can lead to the development of sensory neuropathy.

To date, there is insufficient proven data on the success of probiotic use with Oxalobacterium formigenes, which prevents oxalate absorption in the intestine. Although the results of such treatment are recognized by experts as encouraging.

Other potentially promising drugs:

• Dequalinium chloride (able to restore adequate peroxisomal transport of AGT and inhibit mis-targeted transport into mitochondria;
• RNA interference (indirectly lowers oxalate production);
• Styripentol (an anticonvulsant drug that helps reduce hepatic oxalate synthesis).

Special urological treatment is indicated for patients with urolithiasis. In case of obstruction of the urinary system, nephrostomy, urethroscopy, ureteral stenting may be used. It is undesirable to perform open surgery for stone removal, as it increases the risk of acute renal failure, as well as shock-wave extracorporeal lithitripsy (due to the high risk of damage to the organ affected by nephrocalcinosis and microlithiasis).

When indicated, in complicated cases, patients undergo dialysis, renal transplantation in the form of combined kidney and liver transplantation, isolated kidney or liver transplantation.

What vitamin is recommended for hyperoxaluria?

It is recommended to additionally consume vitamins A and E, which have the ability to membrane stabilization - that is, they improve the functional state of renal cell membranes. In addition, these vitamins are antioxidants that prevent the negative effects of free radicals on organs and tissues.

In addition to pharmacy preparations, vitamin A is present in cod liver, egg yolks, pork and beef liver, milk and cream, carrots and pumpkin, sea buckthorn berries, butter.

Vitamin E can be found in many vegetable oils, including sunflower oil, corn oil, soybean oil, and nuts and seeds.

It is desirable to have vitamin _B6 in the diet, which is found in nuts, sea fish, beef liver, millet, egg yolks, wheat germ, garlic. Vitamin _B6 normalizes diuresis, improves metabolic processes, participates in the metabolism of magnesium.

Magnesium is an equally important component that is recommended for patients with oxalaturia. Under normal metabolic processes, magnesium is able to bind almost half of urinary oxalates, thus creating competition with calcium. People who have magnesium in their diet form less calcium oxalates and more magnesium oxalates. Pine nuts and pistachios, almonds and peanuts, cashews, walnuts and hazelnuts, as well as dried fruits, buckwheat and oatmeal, seaweed and mustard, wheat, and sunflower seeds should be included in the menu.

But the amount of ascorbic acid should be reduced, as vitamin C in oxalaturia promotes the formation of stones. Ascorbic acid is present in kiwi, sauerkraut, currants, citrus fruits, rose hips, sweet peppers.

Diet for hyperoxaluria

In hyperoxaluria exclude foods containing natural oxalates - in particular, oxalic acid, which is found in fairly large quantities in cocoa and chocolate, rhubarb and dill, leaves of sorrel, celery and spinach, as well as in citrus, parsley, portulaca, rich broths and jellies. Minimize the use of carrots, beets, Brussels sprouts, asparagus, and chicory.

Pumpkin and eggplant, potatoes, peas and corn, cereals, white cabbage and broccoli, raspberries and blackberries, cucumbers and tomatoes, bell peppers, bread, milk and meat can be included in the menu. Mushrooms, melons, apples and apricots are also allowed.

It is important to reduce the intake of salt and salty foods, as sodium accelerates the excretion of calcium through the kidneys.

Do not forget about the need to drink enough water - at least 30 ml per 1 kg of body weight (in the absence of contraindications). It is especially recommended to drink both simple pure water and fresh pumpkin, zucchini, cucumber, watermelon juice, or lime tea. It is allowed to drink mineral water "Truskavetskaya", Borjomi", "Essentuki -4", "Essentuki - 7", and other low-mineralized waters with magnesium.

Prevention

Preventive measures are based on the normalization of metabolic processes, maintaining a healthy composition of urine and blood.

It is imperative to control your diet. It should be balanced, complete, with a minimum of salt and sugar, fast food and convenience foods, with a large proportion of plant foods.

In order to avoid congestion in the urinary system, it is necessary to consume enough fluids, optimally at least 2 liters for an adult. We are talking only about clean drinking water: tea, coffee and first courses are not taken into account. At the same time, doctors warn: you can not drink saturated mineral waters on a permanent basis, which is associated with a large percentage of salt composition.

An integral part of a healthy lifestyle and the prevention of hyperoxaluria is the abandonment of bad habits and adequate rest, including night sleep.

The diet should include cereals, legumes, dairy products, vegetables and fruits, as well as other foods that help to alkalize the urine.

A sedentary lifestyle is strongly discouraged. Hypodynamia slows down the urinary fluid outflow, contributing to the appearance of deposits in the urinary system.

Medication prophylaxis and drug intake in general should be monitored and adjusted by a physician. Self-medication is dangerous and often leads to the development of complications.

Forecast

Refusal of medical help, failure to comply with medical recommendations is associated with an unfavorable prognosis for the patient. Every second patient with primary hyperoxaluria, starting from adolescence, shows signs of renal failure. By about thirty years of age, chronic renal failure is found in almost 80% of patients with hyperoxaluria.

Improve the prognosis:

• early detection of the disease;
• adherence to a strict diet and drinking regimen;
• Compliance with all medical appointments, dispensary monitoring.

Hyperoxaluria is an indication for regular urine analysis, Zimnitsky test, as well as systematic renal ultrasound with subsequent consultation with a nephrologist.