Introduction
Background
Hyperoxaluria, defined as excessive urinary oxalate, is a common abnormal finding in patients with calcium oxalate kidney stones. Some degree of excessive urinary oxalate is found in 20-30% of all patients with recurrent calcium oxalate stones.
Oxalate is an organic salt with the chemical formula of C2 04. At physiological pH levels, oxalate forms a soluble salt with sodium and potassium; however, when combined with calcium, it produces an insoluble product termed calcium oxalate, which is the most common chemical compound found in kidney stones. If not for oxalate's high affinity for calcium and the low solubility of calcium oxalate, oxalate and oxalate metabolism would be of little interest. Urinary oxalate is the single strongest chemical promotor of kidney stone formation. Ounce for ounce, it is roughly 15-20 times more potent than excess urinary calcium.
Oxalate is normally produced in plants, primarily in their leaves, nuts, fruit, and bark. The amount of oxalate manufactured depends not only on the particular variety of plant but also on the soil and water conditions in which it grows. In general, plants that are grown in fields with a high concentration of ground water calcium have higher concentrations of oxalate. This is one reason why precisely calculating dietary oxalate is difficult. Oxalate content within the same plant species can vary widely. For example, potatoes contain oxalate levels of 5.5-30 mg per 100 g, broccoli has levels of 0.3-13 mg per 100 g, and wheat bran has levels of 58-524 mg per 100 g.
Plants use oxalate as a calcium sink. Any excess calcium absorbed by the plant from ground water is extracted from the plant's tissue fluid by the oxalate in the leaves, fruits, nuts, or bark. Eventually, the plant sheds these structures. When humans eat these plant products, they also ingest a variable quantity of oxalate. Food products from animal sources have virtually no oxalate content.
Oxalate is involved in various metabolic and homeostatic mechanisms in fungi and bacteria and may play an important role in various aspects of animal metabolism, including mitochondrial activity regulation, thyroid function, gluconeogenesis, and glycolysis. However, in humans, oxalate seems to have no substantially beneficial role and acts as a metabolic end-product, much like uric acid. Interestingly, oxalate was first discovered in animals when sheep became ill after eating vegetation later found to have high oxalate content.
Daily oxalate intake is usually 80-120 mg/d; it can range from 44-350 mg/d in individuals who eat a typical Western diet. The solubility of oxalate at body temperature is only approximately 5 mg/L at a pH of 7.0.
The normal upper level of urinary oxalate excretion is 40 mg (440 µmol) in 24 hours. Men have a slightly higher normal value (43 mg/d in men vs 32 mg/d in women), but this is primarily due to larger body habitus and larger average meal size rather than any real intrinsic metabolic difference. Stone formation risk probably depends more on absolute total oxalate excretion and concentration than on arbitrary normal values.
An alternative definition of hyperoxaluria that corrects for size differences is 30 mg of urinary oxalate per 24 hours per gram of excreted creatinine. Still, the relative concentration of oxalate is probably more significant than either of these definitions acknowledges.
Among persons with stones, urinary oxalate levels tend to be significantly higher in summer than in winter. This may be due to the increased consumption of seasonal foods naturally high in oxalate. In addition, the average mean urinary oxalate excretion in persons with calcium stones tends to be higher than in individuals without calcium stones.
Pathophysiology
High levels of oxalate in the system can produce various health problems. However, the focus of this article is the primary disorder of kidney stone formation.
Oxalate is absorbed primarily from the colon, but it can be absorbed directly from anywhere in the intestinal tract. In addition, oxalate is created from endogenous sources in the liver as part of glycolate metabolism. In the kidney, oxalate is secreted in the proximal tubule via 2 separate carriers involving sodium and chloride exchange. Hyperoxaluria is defined as a urinary oxalate excretion that exceeds 40 mg/day. The 4 main types of hyperoxaluria include (1) primary hyperoxaluria (types I and II), (2) enteric hyperoxaluria, (3) dietary hyperoxaluria, and (4) idiopathic or mild hyperoxaluria.
Primary Hyperoxaluria
This is a very rare but serious disorder caused by a congenital defect; it results in very high levels (>200 mg/d) of endogenous oxalate production. Without treatment, the prognosis for these patients is poor. Renal failure develops in 50% of patients with primary hyperoxaluria by age 15 years and in 80% by age 30 years. Normal dialysis for uremia cannot remove enough serum oxalate to protect the kidneys and other organs from widespread calcium oxalate deposition (ie, oxalosis) and calcium oxalate stone production.
Type I hyperoxaluria
Type I hyperoxaluria is the more common variety. It occurs in 1 per 120,000 live births and is transmitted as an autosomal recessive trait. It is caused by a deficiency of the peroxisomal liver-specific alanine:glyoxylate aminotransferase gene (ie, AGT). Pyridoxine (vitamin B-6) is a cofactor in this chemical pathway, which normally converts glyoxylic acid (C2 H2 O3) to glycine. When the pathway is blocked because of a deficiency or absence of this enzyme, the result is high levels of glycolic and oxalic acid, which readily convert to oxalate; this is then excreted in the urine. This leads to nephrocalcinosis and the eventual development of end-stage renal failure, usually in childhood.
The median age for presentation of initial symptoms related to hyperoxaluria is 5 years. Oxalate deposition can occur in other organs (eg, bones, joints, eyes, heart). In particular, bone tends to be the major repository of excess oxalate in persons with primary hyperoxaluria. Bone oxalate levels are negligible in healthy individuals. Oxalate deposition in the skeleton tends to increase bone resorption and to decrease osteoblast activity.
Because symptoms occur relatively late and are associated with serious complications, all pediatric patients who have stones should be screened for hyperoxaluria. Discovering this condition in siblings may allow earlier testing, detection, diagnosis, and preemptive therapy.
Treatment of type I hyperoxaluria involves a combination of medical and surgical therapies with combined kidney and liver transplantation. However, the survival rates and organ survival rates in patients who undergo treatment for type I hyperoxaluria are inferior to such rates in general transplant patients. In selected patients, early liver transplantation prior to the development of overt renal failure may preserve the native kidneys, thus avoiding renal transplantation. In general, transplantation is considered when the glomerular filtration rate (GFR) falls to below 25 mL/min/1.73 m2. Renal transplantation alone is insufficient because the liver defect causing the hyperoxaluria is not corrected.
New and future treatment modalities under investigation include probiotic supplementation, chaperones and hepatocyte cell transplantation, and recombinant gene therapy to replace the enzyme.
Type II hyperoxaluria
Type II hyperoxaluria is much less common than type I hyperoxaluria and is due to a deficiency of D-glyceric dehydrogenase. This deficiency promotes the conversion of glyoxylate to oxalate. The two types of primary hyperoxaluria result in approximately the same degree of hyperoxaluria. However, end-stage renal disease is slightly less common in patients with type II primary hyperoxaluria. Pyridoxine is generally not effective in patients with type II primary hyperoxaluria.
Enteric Hyperoxaluria
Enteric hyperoxaluria accounts for approximately 5% of all cases of hyperoxaluria. It is due to a gastrointestinal problem usually associated with chronic diarrhea. Malabsorption from any cause, such as colitis or jejunoileal bypass surgery, can result in enteric hyperoxaluria.
The chronic diarrhea results in smaller levels of intestinal calcium for oxalate binding. Without the calcium necessary to adequately bind oxalate in the intestinal tract, additional oxalate is absorbed and then excreted in the urinary tract. Exposure of the colonic mucosa to excess bile salts increases its oxalate permeability. Enteric hyperoxaluria is characterized by severe hyperoxaluria (usually >80 mg/d), low urinary volumes, hypocalciuria, and hypocitraturia.
Enteric hyperoxaluria should be considered in any patient with calcium oxalate stone disease and any type of chronic diarrhea. Other conditions associated with enteric hyperoxaluria include fat malabsorption, steatorrhea, inflammatory bowel disease, pancreatic insufficiency, biliary cirrhosis, and short-bowel syndrome.
Hyperoxaluria has been reported to be the most common urinary metabolic abnormality in patients with stones who have undergone bariatric surgery. The recent proliferation of bariatric surgery cases may result in an increased prevalence of enteric hyperoxaluria in the future.
Dietary Hyperoxaluria
A high intake of oxalate-rich foods (eg, chocolate, nuts, spinach) and a diet rich in animal protein can result in hyperoxaluria. Low dietary calcium intake can also result in hyperoxaluria via decreased intestinal binding of oxalate and the resulting increased absorption. Ascorbic acid can be converted in oxalate, resulting in increased urinary oxalate levels.
Oxalobacter formigenes is an intestinal bacterium that can degrade oxalate. Some studies have shown a correlation between decreased activity of this bacterium in the intestine and hyperoxaluria and stone formation.1,2
Idiopathic or Mild Hyperoxaluria
This is by far the most common variety of hyperoxaluria observed in patients with calcium oxalate stones. It may be due to a simple dietary excess of high-oxalate food sources or to increased endogenous oxalate production. Urinary oxalate excretion is usually 40-60 mg/d. While originally thought to be caused mainly by endogenous oxalate production, recent evidence suggests that up to 50% or more of urinary oxalate is related to diet.
In 1986, Baggio et al found an enhanced, altered red blood cell membrane oxalate transport mechanism in approximately 80% of patients with idiopathic kidney stones that was not present in the siblings of these patients, who did not have stones.3 The variable response among patients to a controlled oxalate diet also suggests that a genetic component may play a role in the development of hyperoxaluria by modifying intestinal oxalate absorption.
The problem with oxalate is its strong chemical affinity for calcium and the relatively low solubility of the resulting salt. Most people have a relative supersaturation of calcium oxalate in their urine, which is kept from precipitating by various factors, including dilutional volume and specific inhibitors such as citrate. Optimizing these other risk factors has a beneficial effect on reducing calcium oxalate stone production.
Frequency
United States
Approximately 30 million Americans have kidney stone disease, and 1.2 million new cases are encountered each year. The most common type of kidney stone is calcium oxalate. Although hypercalciuria may be the more common metabolic problem, excess urinary oxalate is a much stronger promotor of urinary stone formation than excess urinary calcium.
International
Hyperoxaluria seems to be a greater problem in countries that are more highly developed. In Japan, an increasing incidence of calcium oxalate stone disease seems to have accompanied gradual changes in dietary trends. As animal protein and fat intake increases among the Japanese population, oxalate absorption, oxaluria, and calcium oxalate stone disease also increase. Increased dietary fat allows for an increase in calcium complexation, with fatty acids causing a mild form of enteric hyperoxaluria. Primary hyperoxaluria is more common among Muslims.
Mortality/Morbidity
As with all forms of stone disease, the consequences are related to stone formation and subsequent damage to the urinary tract. These may include pain, renal obstruction, urosepsis, renal insufficiency, renal failure, and even death.
Primary hyperoxaluria in particular is associated with the most serious health consequences. Approximately half of patients diagnosed with this disorder develop end-stage renal disease, and the mortality rate, particularly in infants, is high (>50%).
Race
Kidney stones are more common in whites than in blacks. This is well-established and is thought to be primarily due to the difference in average socioeconomic status and dietary influences.
An intriguing study from South Africa by Lewandowski et al found that urinary oxalate excretion after a controlled oral oxalate load was much higher in whites than in blacks.4 This was thought to be due to increased intestinal oxalate transport in the white study group.
A similar study by Rodgers and Lewandowski found that a low-calcium diet caused a statistically significant increase in urinary oxalate only in blacks.5 The cause for these racial differences has not been determined, but genetic factors are thought to be involved.
Sex
Kidney stones are 3 times more common in men as in women, but the reason for this difference is not always clear. Different reference ranges of several urinary metabolites (eg, uric acid, calcium, oxalate) illustrate the difficulties in determining the actual cause of stones in different populations. Whether the different values are (1) the result of differences in metabolism related to the effects of sex hormones or (2) incidental to the known differences in dietary intake and body weight is unknown.
Powell et al reviewed the issue of obesity associated with kidney stone formation based on a large national database.6 In general, women who were obese and had stones tended to be at somewhat higher risk than women who were not obese who had stones. However, little, if any, difference was observed in men. In both men and women, mean urinary oxalate levels were approximately one third higher in those who were obese and had stones than in those who were not obese and had stones. However, when urinary volume and concentration were considered, the mean average urinary oxalate concentration among men who were obese and had stones was only slightly increased; the same was not true among women who were obese and had stones.
Estrogen seems to play a slightly protective role in women by increasing relative citrate excretion. Some recent evidence suggests that, for oxalate, the differences are due purely to body weight.6 When this is considered and corrected with the definition of 30 mg of urinary oxalate per 24 hours per gram of excreted creatinine, the results of one study showed essentially no unexplained differences. However, a review by Gary Curhan of Harvard based on several very large series found that men have substantially higher mean urinary oxalate and uric acid levels than women in similar weight categories. This suggests that men have higher average urinary oxalate levels than women, even when weight differences are corrected.
Women have a higher response rate to pyridoxine therapy for mild and moderate hyperoxaluria disorders than men do. The reason for this discrepancy is unclear.
The mean urinary glycosaminoglycans concentration is lower in men with stones than in women with stones; this may play a role in the difference in the stone formation rate between the sexes.
Kidney stones are equally prevalent among males and females in childhood and in the postmenopausal age group, suggesting that female sex hormones may play a somewhat protective role. An interesting study in rats by Iguchi et al seems to confirm this.7 Four groups of rats were tested. Two groups underwent oophorectomy, while a third underwent a sham surgery. One of the 2 oophorectomized rat groups received supplemental estrogen and progesterone. Except for the control group, all groups were given ethylene glycol and vitamin D supplementation to induce calcium oxalate kidney stone formation.
The findings indicated that the urinary oxalate excretion rate was significantly higher in the oophorectomized group than in the groups that retained their ovaries or received supplemental female sex hormones. The renal calcium content, crystal deposition, and osteopontin levels were also higher in the oophorectomized group. The investigators concluded that female sex hormones may protect against calcium oxalate stone formation, with oxalate excretion being a key factor.
A similar study by Fan et al found the same protective benefit from estrogen.8 Neutered rats given estrogen supplementation had lower levels of urinary and plasma oxalate and did not develop calcium oxalate crystals, even when given ethylene glycol to induce hyperoxaluria. In comparison, 88% of the rats given testosterone produced significant calcium oxalate crystals and had higher serum and urine oxalate levels, which suggests that testosterone plays a significant role in the development of calcium oxalate stones and hyperoxaluria in men. Another animal study, also by Fan et al, described significantly decreased urinary oxalate levels in both castrated rats and those treated with high-dose finasteride (Proscar), suggesting that dihydrotestosterone may be responsible for some of the differences noted in oxalate excretion between men and women.9
Clearly, more research would be helpful in determining the true role of sex hormones in hyperoxaluria and calcium oxalate stone disease.
Age
No significant differences in mean urinary oxalate excretion levels or concentration between geriatric and younger cohorts of individuals with calcium oxalate stones have been found.
Clinical
History
- Occasionally, oxalate poisoning is reported.
- Symptoms of oxalate poisoning include local irritation and systemic effects. Patients experience burning of the mouth, pharynx, and esophagus; swallowing difficulties; diarrhea; bradycardia; cardiac arrhythmia; heart failure; and renal failure. In rare cases, convulsions and unconsciousness can develop.
- Severe poisoning has been caused by ingestion of the common household plant Dieffenbachia, with symptoms of severe corrosive burns of the mouth, oropharynx, esophagus, and stomach.
- Treatment for acute oxalate poisoning includes gastric lavage with a calcium solution such as 0.15% calcium hydroxide solution. Brisk diuresis is stimulated with rapid hydration to avoid calcium oxalate crystallization in the kidney. Sodium bicarbonate and sodium hydroxide should not be used because sodium oxalate is readily absorbed, increasing the systemic oxalosis effects.
Causes
- Mild, idiopathic, or dietary hyperoxaluria
- Most patients with relatively mild urinary hyperoxaluria (approximately 40-60 mg/d) have this type of hyperoxaluria. Previously, dietary oxalate was thought to play a relatively minor role in hyperoxaluria and to account for only 10-20% of the total urinary oxalate produced. Recent evidence suggests that dietary oxalate plays a much more important role and may be responsible for 50% of the total urinary oxalate.10,11,12 In one study, dietary sources were found to be directly responsible for 80% of the total excreted oxalate.
- Many patients, perhaps as many as 80%, have an abnormal or altered cellular membrane oxalate transport mechanism, which causes abnormally high absorption of dietary oxalate.
- Others may have a deficiency of intestinal O formigenes. These normal intestinal facultative anaerobic bacteria naturally digest oxalate. When the bacteria are lost through prolonged antibiotic use or other reasons, increased intestinal oxalate absorption is likely. Oxalobacter is relatively resistant to penicillin and sulfa but sensitive to macrolides, fluoroquinolones, and tetracyclines. Patients with calcium oxalate stones who have lost their natural intestinal Oxalobacter are found to have 40% higher average urinary oxalate levels than patients with calcium oxalate stones who have normal intestinal Oxalobacter colonies. Oxalobacter usually colonizes the intestinal tract at approximately age 3 years. Once lost, recolonizing Oxalobacter in the intestinal tract is very difficult.
- Bioavailability of ingested oxalate, dietary calcium and magnesium levels, intestinal transit time, use of sodium cellulose phosphate (which removes calcium and magnesium from the intestine), and lack of intestinal oxalate binders can all affect oxalate absorption. Ethylene glycol ingestion and methoxyflurane exposure can also cause hyperoxaluria through a hepatic metabolic pathway. The rest are thought to be caused by metabolic or hepatic activity.
- Enteric hyperoxaluria
- Fat malabsorption caused by various disorders can lead to severe hyperoxaluria due to increased intestinal oxalate absorption. These disorders include intestinal bacterial overgrowth syndromes, fat malabsorption, chronic biliary or pancreatic disease, various intestinal bypass surgical procedures, inflammatory bowel disease, or any medical condition that causes chronic diarrhea.
- The basic mechanism is competition for the available ingested calcium, the leading intestinal oxalate-binding agent. Most of the bile acids produced during digestion are reabsorbed in the proximal intestinal tract. When this fails to occur, calcium and magnesium bind to these bile acids through saponification. This leaves very little free calcium available for absorption or binding with oxalate in the lower intestinal tract, resulting in high levels of oxalate absorption and hypocalciuria. Increased intestinal membrane oxalate transport and absorption may also occur through direct exposure of the intestinal lining to excess bile salts and fatty acids.
- In enteric hyperoxaluria, intestinal calcium from the diet is predominantly bound to the fatty acids instead of oxalate. This leaves the intestinal oxalate free and unbound, which leads to increased oxalate absorption in the colon and subsequent urinary oxalate excess.
- This condition is characterized by very high urinary oxalate levels (usually >80 mg/d) and hypocalciuria, with urinary calcium excretion usually less than 100 mg/d. Generally, a chronic diarrheal state is present, leading to hypocitraturia and relative dehydration in addition to the hyperoxaluria. The unabsorbed bile salts and fatty acids may damage or injure the colonic mucosa, further increasing oxalate absorption.
- Oxalate absorption by the colon has been shown to increase up to 300-fold following small-bowel bypass surgery; therefore, these individuals must be screened for enteric hyperoxaluria. In some severe cases, the bypass may need to be reversed to control the hyperoxaluria.
- Primary hyperoxaluria (genetic)
- This rare form of hyperoxaluria is due exclusively to a genetic defect that causes a loss of specific enzymatic activity. With the normal metabolic pathway blocked, the alternative pathway that leads to oxalate production as an end-product of glycolate metabolism becomes extremely active, resulting in extremely high oxalate production.
- In primary hyperoxaluria type I, the missing enzyme is alanine-glyoxylate aminotransferase (ie, the AGT gene) and is normally found only in the hepatic peroxisomes. This enzyme is necessary to detoxify glyoxylate. When alanine-glyoxylate aminotransferase is lacking, oxalate production soars.
- In primary hyperoxaluria type II, the missing enzyme is D-glyceric dehydrogenase, which can be detected in leukocyte preparations.
- A liver biopsy can be helpful in determining which type of enzyme defect is present. Urinary oxalate excretion is typically more than 100 mg/d in both types of primary hyperoxaluria.
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Keywords
hyperoxaluria, enteric hyperoxaluria, high urinary oxalate, excessive urinary oxalate, kidney stones, renal stones, nephrolithiasis, oxalosis, oxaluria, primary hyperoxaluria, urinary calculi, oxalic acid, calcium oxalate, nephrocalcinosis, extrarenal oxalosis, progressive renal failure, uremia, alanine-glyoxylate aminotransferase, AGT, AGXT gene, end-stage renal failure, hypocalciuria, hypocitraturia, primary hyperoxaluria, Oxalobacter, Oxalobacter formigenes, O formigenes, cholestyramine, kidney stone formation, dietary hyperoxaluria, idiopathic hyperoxaluria, mild hyperoxaluria, type I hyperoxaluria, type II hyperoxaluria
