Background

Kidney stones, affecting 10% of people, are commonly made up of calcium stones, with calcium oxalate being the most frequent type. Calcium oxalate stones are formed due to an imbalance in oxalate and calcium levels and insufficient inhibitors to prevent crystallization. Hyperoxaluria, a condition characterized by excessive urinary oxalate, is a major risk factor for kidney stone formation.

The severity and clinical presentation of hyperoxaluria determine whether it is primary or secondary. Of all urinary chemicals, oxalate is the most potent promoter of renal calculi. Even small increases in urinary oxalate levels can significantly increase the risk of kidney stone formation, with the risk rising to 3.5 times when the level rises from 20 to 40 mg per day.

Epidemiology

In 2012, a survey revealed that the prevalence of kidney stones in the United States had increased significantly compared to a study conducted 13 years earlier. The survey indicated that almost 1 in 11 people were affected by kidney stones, with a higher incidence among men than women. However, recent studies have shown an increase in women with kidney stones. Calcium stones are the most common type of kidney stone, accounting for 80% of cases, with calcium oxalate being the predominant form, comprising 75% of cases. The recurrence rate of calcium stones is high, with a 60% risk of recurrence within ten years without appropriate preventive measures.

The incidence of secondary hyperoxaluria has also increased over time, particularly among recurrent calcium stone formers, affecting 25% to 45% of cases, with higher prevalence among men than women. Asian countries have higher rates of hyperoxaluria than Western countries, likely due to cultural, genetic, and dietary factors. This increase in hyperoxaluria is considered a significant contributing factor to the global rise in nephrolithiasis rates, although further research is necessary to confirm this finding. Bodyweight is a known factor that increases urinary oxalate levels.

However, conflicting data exist on whether this increase is proportional to body size or whether men excrete more oxalate and uric acid than women of similar size. Understanding the risk factors for kidney stones, such as hyperoxaluria and body weight, can help individuals take appropriate preventive measures to reduce their risk of developing this painful condition. Studies have shown that individuals of White ethnicity have higher rates of nephrolithiasis and hyperoxaluria than those of Black ethnicity.

White individuals eliminate more urinary oxalate than Black individuals after consuming a high oxalate meal. However, this discrepancy is not yet fully understood and is believed to be related to genetic factors. Age does not seem to play a role in oxalate absorption, so the ethnic difference in oxalate absorption is believed to be due to genetic factors and not influenced by age. More research is needed to understand the mechanisms behind these ethnic differences fully and to develop effective prevention and treatment strategies for nephrolithiasis and hyperoxaluria.

Anatomy

Pathophysiology

Oxalate is the organic acid plants produce, mainly in their leaves, fruits, nuts, and bark. It binds to calcium, which is then absorbed by the plant’s root system. Therefore, the amount of oxalate in plants can vary depending on the plant type and the calcium content of the groundwater where it grows. Unfortunately, oxalate is often found in parts of plants that humans eat, especially in green leafy vegetables like spinach. Animal food sources consumed by humans generally have very low oxalate content.

When humans consume oxalate, it has no known nutritional or beneficial effect. The body absorbs it primarily in the colon, passes through the liver, and is eventually excreted in the proximal renal tubule. Some oxalate may be produced by glycolate metabolism in the liver or converted from excess vitamin C. In the urine, oxalate forms a strong bond with calcium, leading to the formation of crystals and potentially kidney stones, depending on the concentration and presence of inhibitors and promotors of stone formation, such as citrate.

Urinary oxalate is the most potent promoter of kidney stones, being 15 to 20 times stronger than urinary calcium in promoting the formation of calcium oxalate stones. Although oxalate is generally poorly soluble in the human body, urine is usually supersaturated with oxalate in most people. However, the activity of urinary stone inhibitors like citrate can prevent stone formation. Oxalate forms a soluble complex with sodium and potassium but combines with calcium to form insoluble calcium oxalate crystals.

Calcium oxalate crystals tend to form in urine with a relatively low pH (less than 7.2), while calcium phosphate crystals will form when the urine is more alkaline (more than 7.2). Crystal formation occurs when a certain concentration of ions in a solution exceeds the solubility limit, resulting in the precipitation of solid crystals. Homogeneous nucleation occurs when supersaturation levels are extremely high, leading to spontaneous nucleus formation in the absence of any foreign particles.

However, in most cases, crystal formation occurs through heterogeneous nucleation, where foreign particles or surfaces act as nucleation sites for crystal growth. In the case of human calcium oxalate crystal formation, heterogeneous nucleation is the more common mechanism. This is due to the presence of proteins and other organic polymers in the urine, which provides surfaces for calcium oxalate crystal growth. These surfaces have a high degree of chemical activity and can catalyze the formation of crystals, even at lower supersaturation levels.

Etiology

Primary hyperoxaluria is a rare genetic disorder that results from an inherited defect or absence of a specific enzyme, leading to an abnormal accumulation of oxalate in the body. This condition usually manifests during childhood, with most cases diagnosed at around 4 to 5 years old. It is characterized by recurrent episodes of kidney stones made of calcium oxalate, nephrocalcinosis, and progressive kidney damage that may eventually require dialysis.

There are three types of primary hyperoxaluria, with type 1 being the most common, accounting for 80% of reported cases. Type 1 primary hyperoxaluria arises due to a genetic defect that affects the metabolism of hydroxyproline, glycolate, and glycine, accumulating glyoxalate as an intermediate molecule. Normally, glyoxalate is detoxified in the peroxisomes of liver cells by an enzyme called alanine: glyoxylate-aminotransferase (AGT), which converts it into glycine.

However, in the absence or deficiency of AGT, glyoxalate accumulates in the cytosol, which is converted to oxalate by lactate dehydrogenase. The AGT enzyme deficiency is associated with a mutation in the AGXT gene on chromosome 2, which impairs the proper functioning of the enzyme. In summary, primary hyperoxaluria is a rare genetic disorder that results from an inherited deficiency or absence of a specific enzyme. In type 1 primary hyperoxaluria, the AGT enzyme is deficient or absent, leading to the accumulation of glyoxalate and its subsequent conversion to oxalate, which causes kidney stones and progressive renal damage.

Primary Hyperoxaluria Type 3 is a rare form of the condition. It arises due to a deficiency of the mitochondrial enzyme 4-hydroxy 2-oxoglutarate aldolase encoded by the HOGA1 gene on chromosome 9. When this enzyme is deficient, converting 4-hydroxy 2-oxoglutarate into glyoxalate is restricted, leading to a higher proportion of oxoglutarate directed toward the oxalate pathway.

Dietary sources containing oxalates, such as rhubarb, spinach, collard greens, beets, nuts, and tea, have long been associated with hyperoxaluria. In this condition, there are high levels of oxalate in the urine. Although it was initially thought that dietary oxalate played only a minor role of about 20% in the development of hyperoxaluria, there is now compelling evidence to suggest that dietary oxalate can account for up to 50% or more of total urinary oxalate excretion, making it a significant risk factor.

Research has shown that for every 100 mg of dietary oxalate ingested, the 24-hour urinary oxalate increases by 1.7 mg. Therefore, individuals who consume foods high in oxalate should limit their intake to prevent excessive absorption and urinary excretion. Vitamin C, commonly found in citrus fruits and supplements, is a potential risk factor for hyperoxaluria. This is because vitamin C can be converted to oxalate in the body. Therefore, individuals consuming more than 1,000 mg of vitamin C daily should exercise caution and monitor their urinary oxalate levels.

Cranberry juice and concentrates, commonly used for urinary tract infections, are not recommended for individuals with hyperoxaluria or calcium oxalate stone formers due to their relatively high oxalate content. On the other hand, dietary calcium has been shown to bind with oxalate in the intestine, thereby preventing excessive oxalate absorption and hyperoxaluria. Therefore, reducing dietary calcium intake can increase the risk of hyperoxaluria.

Genetics

Prognostic Factors

Various factors, including the type of hyperoxaluria, the time of diagnosis, and the prompt initiation of treatment influence the prognosis for hyperoxaluria. In particular, secondary hyperoxaluria can often be managed through a combination of dietary measures and increased urinary volume, along with other treatments and supplements as necessary. Patients with enteric hyperoxaluria may have a more positive prognosis if medical interventions are implemented early and accompanied by strict adherence to a low-oxalate diet.

Patients with hyperoxaluria need to receive appropriate treatment as early as possible to prevent long-term complications. This typically involves implementing a low-oxalate diet and taking medications such as calcium citrate and potassium citrate to reduce oxalate levels in the urine. Liquid forms of these therapies may be preferred to ensure better absorption and efficacy.

In addition to these measures, optimizing other urinary stone chemistries can also be beneficial for managing hyperoxaluria. This may involve monitoring levels of magnesium, calcium, and other substances in the urine and taking additional supplements or medications as needed to promote healthy urinary function.

Clinical History

Clinical History

The formation and accumulation of calcium oxalate crystals in the renal parenchymal tissues characterize nephrocalcinosis. This process can lead to the development of calcium oxalate stones, which can cause inflammation and damage to the kidneys, ultimately leading to a decline in renal function and the potential development of end-stage renal disease. When calcium oxalate crystals form and deposit in the kidneys, they can form stones that can block the flow of urine and cause pain.

Additionally, these crystals in the renal parenchyma can cause inflammation and tissue damage over time, leading to the progressive decline of kidney function. If left untreated, this can eventually lead to the development of ESRD, a condition in which the kidneys can no longer function adequately, requiring dialysis or kidney transplantation to sustain life. It is important to diagnose and treat nephrocalcinosis and calcium oxalate stone formation early to prevent further kidney damage and the potential development of ESRD.

Calcium oxalate deposition, often associated with primary hyperoxaluria or severe enteric hyperoxaluria, can result in various systemic manifestations. This occurs when excess amounts of oxalate, a natural waste product, build up in the body and combine with calcium to form crystals deposited in various tissues and organs. One of the most common manifestations of this condition is in the heart, where the deposition of calcium oxalate can lead to heart blocks, conduction defects, and cardiomyopathy.

This can cause symptoms such as palpitations, shortness of breath, and chest pain; in severe cases, it can even result in heart failure. The nervous system can also be affected by calcium oxalate deposition, leading to peripheral neuropathy, retinopathy, and cerebral infarcts. Peripheral neuropathy is characterized by numbness, tingling, and pain in the extremities, while retinopathy can cause visual disturbances and even blindness.

Cerebral infarcts occur when a blockage in the blood vessels supplying the brain causes damage to the brain tissue, leading to symptoms such as paralysis, speech difficulties, and cognitive impairment. Other manifestations of calcium oxalate deposition include bone pain, pathological fractures, and joint involvement, such as synovitis and chondrocalcinosis.

Physical Examination

Physical Examination

Renal manifestations can arise due to the increased excretion of oxalate in urine. Combining oxalate with calcium leads to the formation of calcium oxalate nephrolithiasis, the most common type of kidney stone. The symptoms of renal colic caused by kidney stones are severe and acute, typically presenting as abdominal or flank pain that radiates to the groin. Patients also experience nausea, vomiting, urinary difficulties, and hematuria.

The presentation of kidney stone patients is distinct from those with an acute abdomen, as they are in constant motion, trying to find a comfortable position to relieve their pain. This movement can often aid in the initial diagnosis of kidney stones. Furthermore, it is essential to consider other medical conditions that may present with similar symptoms, such as appendicitis, urinary tract infections, or other gastrointestinal disorders.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential Diagnoses

• Enteric hyperoxaluria
• Medullary Sponge Kidney
• Renal tubular acidosis
• Secondary hyperoxaluria
• Nephrocalcinosis of prematurity
• Primary hyperoxaluria

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The management of patients with hyperoxaluria involves a range of measures, including conservative, medical, and surgical interventions. Treatment for nephrolithiasis, or kidney stones, may involve conservative measures such as increasing fluid intake and using alpha-blockers or surgical intervention for larger stones that fail to pass or become complicated by infection. One effective way to manage hyperoxaluria is by increasing fluid intake, which can increase urine volume and reduce the amount of calcium oxalate in the urine.

It is important to focus on measuring and monitoring urinary volume rather than setting specific oral intake goals. It is recommended that patients consume enough fluids to produce at least 2,000 ml of urine per day. Patients are advised to measure their 24-hour urinary volume at home once a month until they consistently produce more than 2 liters of urine per day.

By increasing fluid intake and monitoring urinary volume, patients with hyperoxaluria can effectively manage their condition and reduce the likelihood of developing kidney stones. Conservative measures such as increasing fluid intake and using alpha-blockers can be effective for treating isolated renal stones, while surgical intervention may be necessary for larger stones or those that become complicated by infection.

Dietary modifications have proven effective and easily applicable in managing secondary hyperoxaluria. Although randomized controlled trials have demonstrated that limiting dietary calcium is not helpful, the role of calcium supplementation in preventing oxalate stone formation is still uncertain. A balanced diet with calcium citrate supplements during meals that contain high levels of oxalate is recommended. While iron can also bind to oxalate, calcium is a more effective option. It is recommended to avoid excessive intake of vitamin C.

Additionally, it is important to limit the consumption of foods high in oxalate, such as dark leafy vegetables, spinach, tea, kale, nuts, rhubarb, beets, cranberries, and chocolates. In managing secondary hyperoxaluria, dietary modifications are effective and easy to implement. While restricting calcium in the diet is detrimental, the role of calcium supplementation in preventing oxalate stone formation is still unclear. Therefore, a well-balanced diet with calcium citrate supplements during high oxalate-containing meals is recommended.

Although iron can be used as a binding agent for oxalate, calcium is considered more effective. To avoid any adverse effects, limiting excessive vitamin C intake is also important. Magnesium supplements, such as magnesium oxide or hydroxide, can decrease oxalate absorption by binding with oxalate in the gut. However, when used alone, they may cause diarrhea. Pyridoxine can enhance the effectiveness of magnesium supplements, and orthophosphates can also be combined with magnesium, depending on urinary chemistry levels and renal function.

Supplementation with magnesium alone may induce diarrhea, while neither magnesium nor orthophosphate supplementation will affect endogenous oxalate production. Cholestyramine is mainly used to manage bile acid malabsorption, enhancing intestinal oxalate binding and reducing absorption. Cholestyramine can also directly bind with intestinal oxalate, thus decreasing diarrhea and proving particularly beneficial in enteric hyperoxaluria.

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