Continuing Education Activity

Renal calculi are the products of abnormal crystallization of sediments in the urine. Although the acute interventions for all types of stones are similar, the diagnosis and management of the underlying conditions will vary and may indicate a metabolic or genetic disorder. Calcium oxalate stones are the most common type of renal calculi and result from an imbalance between the urinary levels of calcium and oxalate or a lack of urinary stone inhibitors. This activity outlines the evaluation and management of hyperoxaluria and highlights the interprofessional team's role in improving care for patients with this condition.

Objectives:

• Identify the predisposing factors for developing calcium oxalate renal calculi.
• Describe the etiology of primary and secondary hyperoxalurias.
• Review the different parameters of treatment for patients with hyperoxaluria.
• Explain the importance of improving care coordination among the interprofessional team to improve outcomes for patients affected by renal calculi and hyperoxaluria.

Introduction

Renal calculi are the products of crystallization of specific stone-forming components seen in about 10% of people, and 80% of these are calcium stones.[1] The most common stone, calcium oxalate, is formed primarily due to an imbalance between calcium and oxalate levels in the body and/or a lack of adequate crystallization inhibitors. The causes of excess urinary oxalate or hyperoxaluria can be classified, based on the etiology and severity of the clinical presentation, into primary and secondary hyperoxaluria. Though they both present with kidney stones, they differ in the extent and rapidity of onset of local and systemic complications.[2][3]

The acute management of renal calculi has been well studied and standardized.[4][5] It is also necessary to understand when to evaluate a patient further for an underlying cause of the calculi. This will improve the patient's quality of life and prevent or delay recurrences and other unpleasant complications of hyperoxaluria. In general, clinicians should offer 24-hour urine testing and preventive therapy to every nephrolithiasis patient, but they usually recommend it only to those who are strongly motivated to follow a long-term course of preventive treatments.

Among urinary chemicals, oxalate is the single strongest promotor of renal calculi. Kidney stone risk increases 2.5 to 3.5 times when the urinary oxalate level increases from 20 mg a day to 40 mg. Even relatively small changes in urinary oxalate can have a very significant impact on kidney stone production.[6] Unfortunately, we currently lack a good, specific, simple treatment for such an important contributor to recurrent nephrolithiasis. It is therefore important for clinicians who care for these patients to become familiar with the available treatments for hyperoxaluria and the goals of therapy.  

Etiology

Hyperoxaluria can be broadly divided into primary (rare) and secondary (common) based on etiology.

Primary hyperoxaluria is caused by an inherent genetic defect or absence of a specific enzymatic activity, ultimately leading to greatly increased oxalate levels in the body. The incidence of primary hyperoxaluria is slightly less than 3 to 1,000,000 population or about 1,000 persons in the US, making it extremely rare. Symptoms typically appear in childhood with a median age of presentation of only 4 to 5 years old. It often leads to multiple recurrent calcium oxalate nephrolithiasis, nephrocalcinosis, and progressive renal damage, which may become end-stage requiring dialysis. Of the three types of primary hyperoxaluria, type 1 is by far the most common, being responsible for 80 percent of the reported cases.

• Primary Hyperoxaluria Type 1: Glyoxalate is produced as an intermediate molecule in the metabolism of hydroxyproline, glycolate, and glycine. Glyoxalate is generally detoxified in the peroxisome of the hepatocytes by the enzyme alanine:glyoxylate-aminotransferase (AGT), which converts glyoxalate to glycine. In the event of a deficiency or absence of this enzyme, glyoxalate accumulates in the cytosol, where it is converted to oxalate by lactate dehydrogenase. A deficiency of this B6-dependent enzyme (AGT) has been linked to the AGXT gene mutation on chromosome 2.[3][7][8][9]
• Primary Hyperoxaluria Type 2: On chromosome 10, a specific gene codes for the enzyme glyoxalate hydroxypyruvate reductase (GRHPR). This enzyme converts glyoxalate to glycolate. A deficiency of this enzyme will lead to a buildup of glyoxalate, which is eventually converted by LDH to oxalate.[3][9]
• Primary Hyperoxaluria Type 3: This is the least common type. It is caused by a deficiency of mitochondrial enzyme 4-hydroxy 2-oxoglutarate aldolase coded by the gene HOGA1 on chromosome 9. Lack of this enzyme limits conversion of 4-hydroxy 2-oxoglutarate into glyoxalate. This will divert more of the oxoglutarate towards the oxalate pathway.[3][10]

Secondary hyperoxaluria mainly pertains to excess exogenous oxalate gained either through diet or due to intestinal pathologies. The overwhelming majority of hyperoxaluric patients will have the secondary type of the disorder. The following are some of the causes of secondary hyperoxaluria:

Diet

• Dietary sources include foods rich in oxalates such as spinach, rhubarb, collard greens, nuts, beets, and tea, among others. High dietary oxalate has been thought to play a relatively small (10-20%) contributory role in hyperoxaluria.[11] However, there is evidence that dietary oxalate may be responsible for up to 50% or more of total urinary oxalate excretion, making it an important and significant risk factor.[11][12][13] 
• The 24-hour urinary oxalate increases 1.7 mg for every 100 mg of dietary oxalate ingested.[14] This can be significant as it has been shown that changes in 24-hour urinary oxalate excretion as small as 4 mg can increase the risk of nephrolithiasis by 60% to as much as 100%![6]
• Increased vitamin C is a risk factor for hyperoxaluria, as vitamin C is a potential precursor to oxalate. Amounts exceeding 1,000 mg a day of vitamin C are considered a potential risk factor. 
• Cranberry juice and concentrates are not recommended in calcium oxalate stone formers or patients with hyperoxaluria due to their relatively high oxalate content.[15]
• Dietary calcium combines with oxalate in the intestine, which protects against excessive oxalate absorption and hyperoxaluria. Therefore, decreased calcium in the diet becomes a risk factor for hyperoxaluria.[16][17]

Enteric Hyperoxaluria

• Enteric hyperoxaluria: Free intestinal calcium will tightly bond to free oxalate creating an insoluble molecule of calcium oxalate. This lowers free intestinal oxalate levels and prevents excessive oxalate absorption, which would otherwise eventually be excreted by the kidney. However, intestinal pathologies leading to fat malabsorption, such as Roux-N-Y intestinal bypass surgery, cause a buildup of unabsorbed fatty acids and bile salts in the intestinal lumen that bond to the ingested dietary calcium, which results in inadequate intestinal oxalate binding and subsequent increased oxalate absorption. As the malabsorption continues further in the intestinal lumen, the colon's permeability to oxalate increases, aggravating the problem. The soluble oxalate, which could not combine with calcium, diffuses passively into the blood and is eventually filtered by the kidneys resulting in very severe hyperoxaluria. In addition to this, vitamin B6 deficiency often ensues in these conditions, further increasing endogenous oxalate production.[3][18] 
• While usually associated with Roux-N-Y intestinal bypass surgery, enteric hyperoxaluria can be found in any condition that results in chronic diarrhea such as chronic biliary disease, various pancreatic disorders, short bowel syndrome, fat malabsorption, and irritable bowel syndrome.

Other Causes

• Pancreatic insufficiency in patients with chronic pancreatitis develops saponification due to the binding of calcium and unabsorbed fatty acids, leaving an excess of unbound intestinal oxalate to be absorbed, then filtered by the kidneys and excreted in the urine.[19][20]
• Oxalobacter formigenes: This gram-negative, facultative anaerobic, oxalate-degrading bacteria normally colonizes the colon by age 3. Antibiotic use, inflammatory bowel disease, or dietary changes may lead to disruption of the Oxalobacter colonies with subsequent increased intestinal oxalate absorption.[3][18] Patients who have lost their natural Oxalobacter colonization have been found to have a 40% increase in their average urinary oxalate levels compared to calcium oxalate stone formers with normal intestinal Oxalobacter.[21][22] Unfortunately, it is extremely difficult to restore natural intestinal Oxalobacter colonies once they are lost. (Oxalobacter) is relatively resistant to sulfa and penicillin antibiotics but very sensitive to tetracyclines, macrolides, and fluoroquinolones.) Female stone forming patients with recurrent urinary tract infections have significantly higher average urinary oxalate levels than similar female patients who do not have a history of multiple infections. This is most likely due to the loss of intestinal Oxalobacter from the multiple courses of antibiotics used to treat the frequent urinary infections.[23] A similar process appears to happen in patients with cystic fibrosis who also tend to use antibiotics frequently. In a study of cystic fibrosis patients who had viable intestinal Oxalobacter colonies, their urinary oxalate levels were normal, while over 50% of similar cystic fibrosis patients who had lost their Oxalobacter were found to be hyperoxaluric.[24]

Epidemiology

In 2012 a survey suggested that in the United States, approximately 1 out of 11 people suffered from renal stones, which are considerably higher than the numbers recorded in a previous study done 13 years ago. The same survey revealed that men had been affected more than women (10.6% men and 7.1% of women), but the percentage of women with stone has been increasing in recent decades.[25]

Calcium stones comprise about 80% of all kidney stone diseases, with calcium oxalate being the far more predominant one (approximately 75%).[26][27] The risk of recurrence with calcium stone is about 60% in 10 years without the appropriate preventive measures.[26]

The estimated overall incidence of secondary hyperoxaluria appears to be increasing over time. Typical rates of hyperoxaluria are from 25% to 45% of all recurrent calcium stone formers.[28] Rates are higher in men compared to women. They are also higher in non-American populations compared to the US. Asian countries typically have higher rates of hyperoxaluria than Western countries.[28] The reasons for this are somewhat unclear but are likely due to cultural, genetic, and dietary issues. This significantly increased incidence of hyperoxaluria is also thought to be a major contributing factor to the observed rise in global nephrolithiasis rates. Further studies are needed to confirm this finding.[28]

There does appear to be a protective effect from female sex hormones on oxalate excretion, while testosterone has a detrimental effect.[29][30][31][32] The exact reason for this is unclear and will require more study to elucidate.

Greater bodyweight does appear to increase urinary oxalate, but there are conflicting data as to whether this is relatively proportionate or if men actually excrete more oxalate and uric acid than women of similar size.[33][34] However, obesity is associated with higher urinary oxalate levels in both men and women.  Among stone formers, obese patients have been found to have oxalate levels about 33% higher than non-obese stone-forming patients.[33]

Whites have higher rates of nephrolithiasis and hyperoxaluria than Blacks. Urinary oxalate excretion has been found to be higher in Whites after a controlled, high oxalate meal than in Blacks. The reason for this is unclear but is thought to be due to genetic factors, with Whites having a higher rate of intestinal oxalate absorption than Blacks.[35][36] There does not appear to be an age-related factor with regards to oxalate absorption.[37][38] 

Primary hyperoxaluria (PH) is quite rare, and while usually diagnosed in the pediatric age group, it is often diagnosed very late into the course of the disease, usually only after the development of nephrocalcinosis or end-stage renal disease (ESRD). Primary hyperoxaluria type 1 is the most common form of primary hyperoxaluria. The prevalence of the disease ranges from 1 to 3 per one million population in the US, with an approximate incidence rate of approximately 1 in 100,000 live births per year in Europe. Higher rates are reported from inbred populations. Primary hyperoxaluria is responsible for <1% of the pediatric ESRD population in registries from the USA, UK, and Japan.[39]

Pathophysiology

Oxalate is an organic acid produced by plants. It is primarily found in the leaves, fruits, nuts, and bark, typically in portions of the plant that can be shed. Its only function is the binding of circulating calcium originally absorbed by the plant through the root system. Therefore, a plant's oxalate load will depend not only on the type of plant but also on the calcium content of the groundwater in the field in which it is grown. This accounts for a large variation in oxalate levels even from the same plant variety.  Unfortunately, oxalate is typically found in portions of plants that humans often consume, particularly in green leafy vegetables like spinach. Animal food sources eaten by humans have virtually no oxalate content. Oxalate was first discovered in sheep who became sick and even died when eating in certain fields, which were later determined to have vegetation with very high oxalate levels, which the sheep were eating. 

In humans, oxalate has no known beneficial or nutritional effect. It is absorbed primarily in the colon, passed through the liver, and is excreted in the proximal renal tubule. Some oxalate may be generated by glycolate metabolism in the liver or converted from excess vitamin C. In the urine, oxalate forms a strong bond with calcium forming crystals and eventually stones depending on the concentration and the presence or absence of various promotors and inhibitors of stone formation such as citrate. Urinary oxalate is the single, strongest promotor of kidney stones known. It is typically 15 to 20 times stronger than urinary calcium in promoting the formation of calcium oxalate kidney stones. The solubility of oxalate at body temperature at a pH of 7 is only about 5 mg/L, so urine is usually supersaturated with oxalate in most people. It does not form stones in everyone due to the activity of urinary stone inhibitors like citrate. Oxalate forms a soluble complex with sodium and potassium; it is only when combined with calcium that it forms insoluble crystals of calcium oxalate. Calcium oxalate tends to form at relatively low urinary pH (<7.2), while calcium phosphate will form when the urine is more alkaline (>7.2).

From the point of view of crystallization science, stone formation results from a combination of abnormal factors that influence the chemistry, supersaturation, and rate-controlling processes involved in the formation of crystals of the various kidney stone-forming minerals. The principal thermodynamic driving force is the degree of supersaturation of the fluid in which this process occurs. The laws of crystallization hold for both intracellular and extracellular crystal formation. The following steps lead to the formation of calcium oxalate stones:[40]

1. Nucleation: This is the first step leading to crystallization and can occur either homogeneously or heterogeneously. Homogeneous crystal nucleation requires a greater degree of calcium oxalate supersaturation compared to heterogeneous nucleation. By contrast, heterogeneous nucleation requires lesser amounts of precipitating salts due to the presence of proteins and other organic polymers that provide chemically active surfaces that facilitate the nucleation process. Heterogeneous nucleation is the more common mechanism of human calcium oxalate crystal formation in humans.

2. Supersaturation: A relative supersaturation level is a measurement of the potential for a crystal to form in the urine. It varies with each solute and balances the chemical crystal promotors and inhibitors. The level at which nucleation occurs is referred to as the formation product of the mineral concerned. This provides a range of supersaturation values where facilitating de novo crystal nucleation is possible.

3. Crystal growth and agglomeration: Once a crystal is established, the surrounding urine facilitates the growth of this crystal. These growing crystals stagnate at sites where the urinary flow is relatively sluggish, either due to narrowing of the tubule as in the proximal tubule, when it meets the loop of Henle, at the papillary base where renal tubules bend, or at the slit-like openings of the collecting duct that structurally favor plugging. When these come in contact with the surrounding epithelial cells, they grow into macromolecules. These travel along the length of the tubules whilst continuously accumulating crystals on the way.

4. Rate of crystal growth: This is determined by the relative supersaturation level as well as accompanying components that promote crystallization like magnesium, citrate, pyrophosphate, matrix substance A, various uncharacterized urinary proteins, glycoproteins, glycosaminoglycans and the polymerized form of Tamm–Horsfall protein, amongst others.

Histopathology

Gross appearance: The gross appearance is unique to each type of stone. An oxalate stone reveals a nodular surface of the stone on gross examination. Calcium oxalate monohydrate is usually dark brown and extremely hard.  Calcium oxalate dihydrate is lighter in color, much more fragile, and may show facets. On dissection, most calcium oxalate stones reveal concentric laminations and radial striations.

Microscopy: Examining the individual crystals reveals thin and plate-like structures that generally acquire a "pyramidal" or "dumb-bell" shape through twinning, as seen in urinary sediments.[40]

History and Physical

The clinical presentation of both primary and secondary hyperoxaluria can be seen in several age groups and are preferably reviewed as renal and systemic manifestations. Secondary hyperoxaluria patients have a lower propensity for systemic manifestations.

Renal: The renal manifestations can be seen mainly due to the increased urinary oxalate excretion and its combination with calcium, leading to calcium oxalate nephrolithiasis. A typical patient will present to the emergency department with symptoms of renal colic, including severe, acute abdominal, or flank pain radiating to the groin, often associated with nausea and vomiting. Urinary difficulties and hematuria commonly accompany this presentation. Unlike those with an acute abdomen, kidney stone patients are constantly moving, trying to find a more comfortable position, helping to make the initial diagnosis relatively easy. 

The crystallization and deposition of calcium oxalate within the renal parenchymal tissues is known as nephrocalcinosis. Together, these two processes of nephrocalcinosis and calcium oxalate stone formation will cause inflammation and progressive renal injury that eventually can lead to a decline in renal function and ultimately possible end-stage renal disease (ESRD).[7] A glomerular filtration rate (GFR) below 30 – 50 mL/min per 1.73 m2 will exacerbate this condition by further decreasing urinary oxalate excretion while increasing its buildup in the plasma leading to possible calcium oxalate deposition within secondary tissues and organs. This threshold level is known as the supersaturation point of calcium oxalate. When this level is exceeded, tissue crystallization and calcium oxalate crystal deposition will begin.[39] Calcium oxalate crystal formation within tissues can be highly inflammatory, painful and very irritating. 

Primary hyperoxaluria type 2 is milder than type 1, mainly due to lower urinary oxalate excretion, whereas recurrent renal stones are characteristic of primary hyperoxaluria type 3.

Systemic: The secondary deposition of calcium oxalate, more commonly associated with primary hyperoxaluria or severe enteric hyperoxaluria, gives rise to various systemic manifestations. Based on the organ affected, these include:[39][41][42] 

• Heart: Conduction defects, heart blocks, and cardiomyopathy.
• Hematology: Anemia due to oxalate deposition in the bone marrow that is unresponsive to erythropoietin-stimulating agents (ESA).
• Nervous system: Peripheral neuropathy, retinopathy, and cerebral infarcts.
• Skeletal: Bone pain, pathological fractures, the involvement of the joints like synovitis and chondrocalcinosis.
• Vaginal: Vaginal pain and dyspareunia from submucosal calcium oxalate crystal deposits.
• Vascular: Non-healing ulcers and gangrene due to ischemia of blood vessels. There have also been reports of refractory hypotension.

Evaluation

A patient presenting with acute renal colic symptoms should be investigated with a urinalysis and a non-contrast CT scan of the abdomen and pelvis.  A KUB and renal ultrasound can be an alternative, but the non-contrast CT scan is the gold standard for evaluating flank pain, especially if associated with any hematuria. A KUB is recommended immediately after the CT scan if any significant stones are found to aid in tracking the progress of the stone and to determine its radio-opacity. Calcium oxalate stones are likely to be visible on the KUB if they are large enough, usually 2 to 3 mm or larger.  The evaluation of any underlying hyperoxaluria will be considered separately.

A chemical analysis of all urinary calculi should be done whenever possible, and their composition should be studied for determining the possible etiology. Calcium oxalate monohydrate (whewellite) and calcium oxalate dihydrate (weddellite) assume dumbbell and pyramid crystalline forms in the urine, respectively. This may sometimes be of some help in determining the underlying cause as pure calcium oxalate monohydrate is typically seen in primary hyperoxaluria, whereas both pure and mixed calcium oxalate stones (monohydrate and dihydrate) are seen in secondary hyperoxaluria.[3][7][39]

Any patient suspected of hyperoxaluria should be tested for urinary oxalate excretion by collecting a 24-hour urine sample. This should preferably not be done in the hospital but rather by the patient at home while on their regular diet and usual activities. The testing is best done at a lab that does large numbers of urinary chemistries. It is typically done in combination with other urinary chemistries as part of the evaluation of kidney stone formers for nephrolithiasis prevention and prophylactic treatment.  The other chemistries tested are typically urinary volume, pH, calcium, citrate, creatinine, magnesium, phosphate, uric acid, sodium, and serum calcium and uric acid.[43]

For most practical purposes, a normal 24-hour urinary oxalate level in adults would be 40 mg or less with an "optimal" level of 25 mg or less. Urinary oxalate concentration should be 20 mg oxalate/1000 ml urine or less.[44]

A urine oxalate to creatinine ratio is also widely utilized, although the age-specific normal limits should be used for comparison.[3][39][45]

Mild or moderate hyperoxaluria (usually from 40 to 60 mg a day) is generally considered dietary. 

Correcting the 24-hour urine oxalate level for the patient's body surface area is somewhat controversial. The corrected value is not typically given on the 24-hour urine laboratory reports, just the usual normal reference range. If using the body surface area, the urine oxalate excretion is <0.45 mmol/1.73 m^2 per 24 hours. Urinary oxalate excretion of more than 1.0 mmol/1.73 m^2 per 24 hours is typically seen in primary hyperoxaluria or enteric hyperoxaluria. Some experts argue that the surface area correction is relatively meaningless as the crystals and stones will form based solely on the relative supersaturation level, which is not dependent on body surface area measurements. 

Repeat 24-hour urine testing is recommended about every 3 months until optimal levels are obtained and at least yearly thereafter. 

The diagnosis of primary hyperoxaluria is rare and unusual. More often than not, it becomes apparent only after the development of end-stage renal failure (ESRD) and dialysis.[3][10] Patients with primary hyperoxaluria will have a 24-hour urinary oxalate level of >75 mg, and many will exceed 100 mg or more a day. A few circumstances which could be clues for investigating for this condition are:

• An episode of renal calculi in a child, especially if younger than 5 years.
• Recurring episodes of calcium oxalate renal calculi in adults.
• Hyperoxaluria of greater than 100 mg/24 hours, although these high levels can also present in enteric hyperoxaluria. In enteric hyperoxaluria, calcium excretion is usually <100 mg/day, the patient often has chronic diarrhea, and there is usually severe hypocitraturia. Patients who have undergone gastric bypass surgery, such as a Roux-en-Y procedure, are far more likely to have enteric hyperoxaluria rather than primary hyperoxaluria as the cause of their calcium oxalate stone disease.
• Any patient diagnosed with calcium oxalate nephrocalcinosis, which is the deposition of calcium oxalate within the renal tissue. If this nephrocalcinosis is accompanied by a decrease in glomerular filtration rate (GFR), it is even more suggestive of primary hyperoxaluria. (However, nephrocalcinosis may also be caused by calcium phosphate deposition from renal tubular acidosis, which is the more common presentation.)
• A patient diagnosed with renal failure but without a clear underlying cause for it or a history of renal calculi.
• If the renal stones sampled from the patient are indicative of primary hyperoxaluria type 1, which are calcium oxalate monohydrate (whewellite) calculi.[46]

To differentiate between type 1 and 2 biochemically, glycolate and glycerate levels are useful, if elevated. Raised urinary glycolate level is seen in primary hyperoxaluria type 1 and glycerate in type 2.[3][7][39] For type 3, an increased urinary level of 4-hydroxyoxoglutarate (HOG) and dihydroxyglutarate (DHG) are suggestive of the diagnosis.[10]

An associated renal injury is common in cases of primary hyperoxaluria, which might lead to a decrease in GFR, which would, in turn, lead to a decrease in oxalate excretion. Initial urinary oxalate measurements can sometimes be misleading, and hence a plasma oxalate concentration would be needed in these situations. A normal plasma oxalate level is between 1 to 5 μmol/L.[3][39]

Confirmatory tests include direct genetic testing or measuring the AGT enzyme activity following a liver biopsy. Non-invasive definitive diagnosis of primary hyperoxaluria is provided by testing for AGXT, GRHPR, and HOGA1 genes.[3]

Genetic testing for primary hyperoxaluria is recommended by the American Urological Association Guidelines if urinary oxalate is >75 mg/day (or >0.85 mmol/24h/1.73 m).[47] It should also be considered in children with significant hyperoxaluria, recurrent oxalate nephrolithiasis, or nephrocalcinosis.

Genetic Screening for Nephrolithiasis and Primary Hyperoxaluria

In the US, a totally free genetic screening panel for nephrolithiasis, (particularly primary hyperoxaluria type 1), is currently available from Invitae at no cost to patients, physicians, or insurers. It is also available in selected countries outside the United States. The screening panel is recommended for all patients, both adults and children, with a family history of primary hyperoxaluria or a 24-hour urinary oxalate level >75 mg (or >0.85 mmol/24h/1.73 m). Children with a history of nephrocalcinosis, hyperoxaluria, or nephrolithiasis may also qualify. The screening is done from a DNA source such as a saliva specimen, buccal swab, or a blood sample. For more information, call 1-800-436-3037 in the US or 1-415-930-4018 worldwide. (email: www.invitae.com/contact, www.clientservices@invitae.com, or globalsupport@invitae.com)

In the US, free telephone-based genetic counseling is currently available for primary hyperoxaluria patients through InformedDNA at 888-475-3128. 

Treatment / Management

Management of a patient with hyperoxaluria includes conservative, medical, and surgical measures along with the treatment of their nephrolithiasis. Isolated renal stone treatment could be conservative using fluids and alpha-blockers or surgical if the stone or stones are large, fail to pass, or the problem becomes complicated by infection. Here we focus on the prevention and treatment of patients with an established diagnosis of hyperoxaluria.

Fluid Intake: A greater fluid intake will increase the volume of urine and reduce the supersaturation of calcium oxalate. It is preferable to concentrate on measuring and focusing on urinary volume rather than on any particular oral intake goal. It is recommended that the oral intake should be sufficient to generate at least 2,000 ml of urine a day.[1][42][44][48] We usually recommend that patients measure their 24-hour urinary volume at home once a month until it is consistently more than 2 liters a day.[48]

Urinary Citrate and Alkalinization: Potassium citrate is used to provide adequate urinary citrate levels and keep the urine pH at a favorable 6.2 to 6.8.  (Sodium citrate can be used in cases of renal failure.) Adequate urinary citrate levels (optimally at 250 to 300 mg/liter or 500 to 600 mg daily total) help prevent the aggregation of calcium oxalate crystals into stones. Potassium citrate supplements are often given along with thiazide diuretics which decrease citrate levels along with treating hypercalciuria.[3][39][49][50] The use of oral orthophosphates together with pyridoxine (vitamin B-6) has also been proven to help reduce the formation of calcium oxalate stones.[51]

Dietary Measures: Dietary modifications in secondary hyperoxaluria have been useful and are easily applied. Although randomized controlled trials have proven that restricting dietary calcium is detrimental, the beneficial effect of calcium supplementation in protecting against oxalate stones is less clear.[1][42] A reasonable calcium diet should be used with calcium citrate supplementation during the higher oxalate-containing meals. (Iron can be substituted for calcium as a binding agent for oxalate, but calcium is more effective.) Any excessive intake of vitamin C should be limited.[42][52] Consumption of oxalate-rich foods like tea, dark-leafy vegetables, spinach, kale, rhubarb, nuts, cranberries, beets, and chocolates should be limited.[1][16] 

Pyridoxine (Vitamin B-6) should be supplemented as it can help patients reduce their hyperoxaluria, some significantly.[53] Up to 500 mg, in divided doses, has been recommended and found to be successful for some individuals. About 50% of patients with secondary hyperoxaluria will respond to pyridoxine which is cheap, non-toxic, and reasonably effective.[53] Women seem to respond to pyridoxine therapy better than men; the reason for this is unclear.[53]

A general low-fat, low-oxalate diet is recommended.

Other Therapies

Orthophosphates, particularly in combination with pyridoxine, have been successfully used to treat primary and secondary hyperoxaluria.[51] The phosphate supplement increases urinary pyrophosphate which binds urinary calcium, while the pyridoxine helps reduce hyperoxaluria. Orthophosphates should not be used in patients with significant renal failure. 

Magnesium supplements (usually magnesium oxide or magnesium hydroxide) will reduce oxalate absorption by binding with oxalate in the intestinal tract but may promote diarrhea when used alone.[51] As with phosphate, it works best when used together with pyridoxine and can be used with orthophosphates. The selection of which supplement to use (orthophosphates, magnesium, or both) should be based on urinary chemistry levels of phosphate and magnesium and renal function. Magnesium supplementation alone may promote diarrhea. Neither orthophosphate nor magnesium supplementation will affect endogenous oxalate production.

Cholestyramine is primarily used to manage bile acid malabsorption. This increases intestinal oxalate binding, thereby reducing its absorption. Cholestyramine will also bind intestinal oxalate directly and help reduce diarrhea, making it particularly useful in enteric hyperoxaluria.[54] However, it can also cause constipation.  In large doses, it releases chloride, which can potentially cause hyperchloremic acidosis. Cholestyramine will interfere with the absorption of many other medications and vitamins, especially thiazide diuretics, vitamin A, folic acid, and vitamin D.

Pentosan polysulfate (Elmiron), a synthetic glycosaminoglycan, can reduce calcium oxalate nephrolithiasis primarily through the inhibition of crystal aggregation. It also appears to help lower intestinal oxalate transport and reduce urinary oxalate excretion.[55][56][57][58][59]

Oxalobacter formigenes, although involved in the pathogenesis of hyperoxaluria when deficient, confers only limited benefit when given as an oral supplement, but research is ongoing to help restore it effectively to the GI tract in hyperoxaluric patients.[45][60] Several controlled trials of oral Oxalobacter therapy were able to re-establish intestinal colonies in primary hyperoxaluria patients, but they all failed to demonstrate any significant reduction in plasma or urinary oxalate compared to placebo.[60][61][62] So far, there are no reported controlled studies of oral Oxalobacter therapy for enteric or secondary hyperoxaluria.

Summary of Treatments for Secondary Hyperoxaluria

• Low fat, low oxalate diet. Avoid excessive meat intake, spinach, cranberries, kale, rhubarb, and collard greens, as these have the highest oxalate content.
• Limit excess Vitamin C and Vitamin D.
• Pyridoxine (Vitamin B-6) supplementation.
• Normal/high calcium diet to increase intestinal oxalate binding.
• Calcium citrate supplements (or iron as an alternative) with higher oxalate meals (usually lunch and dinner). May use Calcium/Magnesium Citrate if calcium alone is too constipating. (The optimal calcium:magnesium ratio is 2:1.)
• Potassium citrate supplementation to optimize urinary pH and 24-hour urine citrate levels. Liquid preparations are preferred in patients with bowel problems or chronic diarrhea. Low potassium, liquid citrate supplements are commercially available.
• Urinary volume optimization: 2,000 ml per day minimum is recommended, but some patients may need over 2,500 ml, 3,000 ml, or more of urine production daily to control their urinary oxalate concentrations. This may mean waking up in the middle of the night to drink more water.
• Cholestyramine will help with bile malabsorption, increase intestinal oxalate binding and reduce diarrhea.
• Pentosan polysulfate (Elmiron) can help lower urinary oxalate excretion, but its main benefit is reducing calcium oxalate crystal aggregation. 
• Anti-diarrheal therapy should be used if there is chronic diarrhea.
• Orthophosphate and/or magnesium supplementation. Do not use orthophosphates in patients with significant renal failure. 
• Recheck 24-hour urine testing every 3 months until optimal results are obtained, then yearly. 
• In cases of severe hyperoxaluria and all children with hyperoxaluria, consider screening for primary and/or enteric hyperoxaluria as appropriate.  
• Optimize all other urinary chemical components (calcium, citrate, uric acid, volume) that may promote stone formation.

Enteric hyperoxaluria patients are also advised to consume a low-fat diet along with calcium and citrate supplements together with a restriction of oxalate-rich foods.[18] Calcium citrate supplements are the primary medical treatment for enteric hyperoxaluria and can be very helpful when taken with high oxalate meals.[63] For this purpose, calcium citrate with or without magnesium is recommended. Magnesium helps avoid constipation which is sometimes associated with calcium supplements. Extra vitamin D should also be avoided as it is desirable for the extra calcium to remain longer in the intestinal tract. Iron can be used as an alternative or supplemental oxalate binding agent, but it is not as effective as calcium.  Aluminum may also be used for oxalate binding, but the risk of aluminum toxicity limits its use.

Higher dietary salt causes increased urinary sodium levels that exacerbate hypercalciuria and cause an increased propensity to form calcium oxalate stones. Limiting the amount of sodium intake has proven to help prevent recurrences of renal stones.[1][64] Excess meat protein in the diet also increases urinary calcium and uric acid excretion; and, therefore, should be somewhat limited in patients with a history of renal calcium stones.[1][65][66] Potassium citrate supplements will help correct hypocitraturia. Liquid supplements are preferred due to the short transit times. Cholestyramine helps control bile acid malabsorption, improves intestinal oxalate binding directly and indirectly; and reduces diarrhea, which frequently accompanies enteric hyperoxaluria.[54] Finally, all other kidney stone chemical factors should be optimized as much as possible.[65] As a last resort, the GI bypass surgery can be reversed.  

Treatments for Primary Hyperoxaluria

Dietary measures do not play a major role in primary hyperoxaluria as the excess oxalate in this condition is endogenous. Early, aggressive treatment is necessary to prevent loss of renal function so utilization of all of the above measures is reasonable, including high dose pyridoxine, orthophosphate and/or magnesium supplementation, increased urinary volume, pentosan polysulfate (Elmiron), Lumasiran, and intensive dialysis. Liver-kidney transplants are a last-resort therapy when all other measures are insufficient. 

Lumasiran and Nedosiran: In November 2020, the FDA approved the use of lumasiran for type 1 primary hyperoxaluria. It is the first available, effective therapy for primary hyperoxaluria short of combined liver/kidney transplantation. Lumasiran arose from a new type of therapy called small interfering RNA (siRNA) that targets specific enzymes. In this case, the targeted enzyme is the mRNA for the hepatic hydroxamic oxidase 1 gene, which encodes glycolate oxidase. Blocking glycolate oxidase, which is chemically upstream from AGT where the genetic defect that causes primary hyperoxaluria is located, effectively lowers oxalate production in these individuals. Studies in both adults and children have shown dramatic results with an average 65% reduction in oxalate production and 52% of patients returning to normal oxalate levels which were maintained for at least 6 months.[67][68][69] However, it does nothing for other types of primary or secondary hyperoxaluria. The medication is administered by a subcutaneous injection every 3 months after an initial induction phase of 4 monthly injections. It is approved for both adults and children in the US and the European Union.

Like lumasiran, nedosiran is also an RNA interference therapy but it's designed to target hepatic lactate dehydrogenase (LDH) which converts glyoxalate to oxalate. Experimentally, it has demonstrated dramatically lower plasma and urinary oxalate levels in type 1 primary hyperoxaluria.  While not yet FDA approved, a compassionate use exception was made in the case of a 17-year-old primary hyperoxaluria type 1 patient (originally diagnosed at age 5) who was already on aggressive, daily dialysis awaiting a combined liver-kidney transplant. The nedosiran treatment was well tolerated and effective in decreasing her serum oxalate level by about 75% despite significantly decreasing her dialysis treatments from daily to the standard three times a week. This result has been sustained for 6 months. This success may allow the patient to avoid a liver transplant although she will still need a new kidney. Nedosiran appears to be the first effective, oxalate-lowering therapy for primary hyperoxaluria type 1 patients who have ESRD.[70][71][70] 

Pyridoxine Supplementation: The role of the defective AGT enzyme was previously described in the pathophysiology of primary hyperoxaluria type 1. This enzyme requires pyridoxal phosphate as a cofactor. Patients with a deficiency of this enzyme could be supplemented with 5-20 mg/kg pyridoxine to boost the AGT enzyme activity. This results in a dose of 150 to 500 mg of pyridoxine daily. Some patients can achieve normal urinary oxalate levels with pyridoxine therapy alone.[53] Pyridoxine enhances the conversion of glyoxylate to glycine, leaving less glyoxalate to be metabolized to oxalate.[72] The specific genotype of the patient's enzyme defect will determine their responsiveness to pyridoxine, and a positive response has been seen in only 30% of primary hyperoxaluria patients. Type 2 and type 3 primary hyperoxaluria patients will not benefit from this therapy as their defective enzymes do not include pyridoxine as a cofactor.[7][39][53][73] 

Dialysis: The role of dialysis is controversial. Serum oxalate levels of 30 to 45 μmol/L lead to tissue deposition, and the aim of dialysis is to keep the oxalate level below that to prevent supersaturation. In patients with ESRD due to primary hyperoxaluria, dialysis cannot remove oxalate as quickly as it accumulates in the blood. In these cases, a special intensive dialysis regimen has to be put into place, which has more sessions per week as compared to the standard dialysis therapy, along with combining both hemodialysis and peritoneal dialysis to achieve maximum oxalate clearance.[3][7] This typically results in 6 to 8 hours of dialysis daily, substantially more than is needed for end-stage renal failure alone. Due to these drawbacks, dialysis has limited indications. Patients waiting for a liver or renal transplant, post-transplant patients with suboptimal hepatic or renal function, or elderly patients who are unfit for surgery are a few of the circumstances where intensive dialysis for severe hyperoxaluria might be considered.[39][74] Nedosiran, as mentioned above, is a new experimental treatment that has already demonstrated significant effectiveness in severely hyperoxaluric patients with ESRD on dialysis.[70]  

Transplant: The procedures to choose from are 1) an isolated liver transplant, 2) an isolated renal transplant or 3) a combined liver-renal transplant. The final decision is made after due consideration of various factors. Patients with ESRD or a GFR approaching end-stage levels may require renal transplants. A liver transplant is the only curative measure in patients with type 1 primary hyperoxaluria as the problem is dysfunction/defect at the level of the hepatic AGT enzyme. In patients that show a positive response to pyridoxine by increasing AGT activity, an isolated renal transplant may be considered.[75] However, the results of isolated renal transplants have been dismal due to lower allograft survival rates in patients with primary hyperoxaluria compared to other ESRD patients. Children and young adults may be considered for a sequential liver-renal transplant.[3] In general, a transplant is considered when the glomerular filtration rate (GFR) drops to 25 mL/min or less. Overall 5-year survival after a combined liver-kidney transplant for type 1 primary hyperoxaluria is 80%.[76]

Primary hyperoxaluria type 2 manifests due to the defective enzyme glyoxalate/hydroxypyruvate reductase (GRHPR), which can be found in tissues other than the liver; therefore, an isolated renal transplant has been recommended for these patients.[77]

Primary hyperoxaluria type 3 patients are not usually referred for renal transplantation as the chances of them developing ESRD are extremely low.[3][45]

There is minimal data on renal transplantation in patients with secondary hyperoxaluria.[3]

Experimental Treatments

Future therapies for controlling hyperoxaluria being investigated include the following:[61][78][79][80][81][82][83][84]

• Probiotic supplementation
• Vitamin E and other anti-oxidant supplementation
• L-cysteine has shown activity in animal models in lowering urinary oxalate and calcium levels. No data yet on any therapeutic effect in humans.
• Recombinant gene therapy to replace defective hepatic enzymes
• Stiripentol, a drug approved by the FDA in 2018 for use in epilepsy and Dravet syndrome, has demonstrated the ability to reduce hepatic oxalate synthesis at the cellular level in vitro. It inhibits the lactate dehydrogenase-5 isoenzyme which converts hepatic glyoxylate to oxalate. Stiripentol has been shown to be effective in reducing urinary oxalate but so far only in rats.
• Lyophilized Oxalobacter formigenes
• Reintroduction of intestinal Oxalobacter formigenes. "Oxabact" is a freeze-dried preparation of Oxalobacter formigenes which is undergoing testing for hyperoxaluria.
• Oxalate digesting enzyme preparations (Oxazyme, Nephure, Reloxaliase). Reloxaliase is specifically being evaluated for patients with enteric hyperoxaluria.
• Intestinal oxalate transport (SLC) blockers (SLC26A3 is the major transporter in transcellular oxalate absorption, and S1C26A6 is thought to be involved in transcellular intestinal secretion)
• Hepatocyte cell transplantation
• Organic marine hydrocolloid (reduced urinary oxalate by 20% in one limited study in patients with severe enteric hyperoxaluria)
• RNA interference therapy (similar to Lumasiran) utilizing lipid nanoparticles and N-acetyl galactosamine delivery systems
• RNA interference therapy targeting hepatic LDH (would make the treatment more useful for other types of hyperoxaluria; similar to Nedosiran.)
• RNA interference therapy targeting non-hepatic enzymes or intestinal oxalate transport mechanisms.
• Use of gene-editing technology (Crispr) to correct specific enzyme pathways for primary hyperoxaluria. This offers the potential for a single, curative treatment.

Experimental Plant-Based Therapies: In early animal studies, banana stem juice appeared promising as a possible therapy for hyperoxaluria.[85] Lupeol is chemically a pentacyclic triterpene which is extracted from the bark of the Varuna tree (Crataeva nurvala). It has been shown to significantly reduce urinary oxalate in animals and also minimize renal tubular damage.[86] An oxalate-digesting enzyme has been extracted from beet stems and found to be effective in animals.[87] In fact, a surprising number of various plant-based extracts have shown activity in reducing urinary oxalate levels in animals including Bombax eiba, Hibiscus sabdariffa, Aierva lanaa, Bryophyllum pinnatum, Costus igneius, and Ipomoea eriocarpa, among others. Unfortunately, none of these plant-based remedies has been tested in hyperoxaluric humans to date.

Differential Diagnosis

The differential diagnosis should include conditions that lead to nephrolithiasis, specifically calcium oxalate stones, and excess deposition in tissues leading to nephrocalcinosis. 

• Enteric hyperoxaluria
• Idiopathic calcium oxalate stone disease. This condition presents as a milder form of primary hyperoxaluria along with mild hypercalciuria.
• Medullary Sponge Kidney
• Nephrocalcinosis of prematurity[7]
• Primary hyperoxaluria type 1 
• Primary hyperoxaluria type 2
• Primary hyperoxaluria type 3 
• Renal tubular acidosis
• Secondary hyperoxaluria

Prognosis

The prognosis of hyperoxaluria depends on the type of hyperoxaluria, time of diagnosis, and early initiation of treatment, amongst other things.

Most patients with secondary hyperoxaluria can be controlled by dietary measures combined with increased urinary volume, optimization of all other urinary stone chemistries, and various supplements/treatments as outlined earlier. 

Studies suggest that most enteric hyperoxaluria patients have a better prognosis if medical interventions are initiated early, coupled with dietary measures that are strictly followed. The patient is maintained on a low oxalate diet continuously while being treated for their underlying condition. Calcium citrate and potassium citrate are the primary medical treatments, with liquid therapies being preferred. Optimization of all other urinary stone chemistries is also recommended. Cholestyramine is reasonable to help control both hyperoxaluria and chronic diarrhea, often associated with enteric hyperoxaluria. Reasonable control of stone production is usually possible with aggressive treatment. However, if ESRD does occur in these patients, careful monitoring of peri-transplantation and post-transplantation oxalate, along with maintaining an adequate urine output, should be done.[88]

Primary Hyperoxaluria Type 1 reportedly has the worst prognosis, with a very high possibility of the patient developing nephrocalcinosis or ESRD.[3] In infants, about 50% will develop ESRD, and the mortality rate is over 50% in this age group.[89] Chronic renal failure is found in about half of all pediatric primary hyperoxaluria patients by age 15 and 80% by 30 years of age. The availability of intensive dialysis and medical treatment can slow down the progression of the disease.[76] However, if the blood oxalate level cannot be kept in check, an organ transplant (combined liver and renal) is the only available cure.[90] Nedosiran therapy, which is still investigational, or lumasiran, which is FDA-approved, should be considered in these patients.

Complications

The complications of calcium oxalate stones in the urinary tract include:

• Urosepsis
• Hydronephrosis
• Anuria 
• Formation of abscesses
• Urine extravasation
• Post-renal obstruction and the gradual decline of kidney function[40]

The development of nephrocalcinosis, further leading to ESRD, is the most dangerous complication. Along with the kidneys, the involvement of the other organ systems is also seen as a complication of the long-term buildup of oxalate in the serum.

Deterrence and Patient Education

Patient education in individuals with a tendency for oxalate precipitation is of utmost importance to reduce episodes of stone formation. Preventing dehydration by consuming adequate water and restricting oxalate-rich food in the diet are two of the easiest ways to prevent recurrent stone formation. A decreased vitamin C in the diet is advisable. Sodium and protein content in the diet should be decreased along with oxalate.[1][16] Additionally, patients with secondary hyperoxaluria or an underlying etiology for steatorrhea are kept on a low-fat diet to prevent the entrapment of calcium ions in this luminal fat and subsequent increase in oxalate absorption.[91]

In patients with primary hyperoxaluria, the inheritance occurs in an autosomal recessive pattern and therefore genetic counseling is important.[7]

Pearls and Other Issues

• Take advantage of the free genetic screening services for primary hyperoxaluria and nephrolithiasis that are currently available for patients with significant hyperoxaluria.
• Consider genetic testing for children with recurrent oxalate stones and for adults with daily urinary oxalate excretion of 75 mg or more.
• Hyperoxaluria is often a difficult problem to treat. Initial therapy with calcium citrate supplementation, lower dietary oxalate, and pyridoxine may not be successful.
• In cases where hyperoxaluria treatment has failed to normalize urinary oxalate levels, optimize all of the other treatable urinary chemistries (calcium, citrate, pH, uric acid, and volume) as much as possible. 

Enhancing Healthcare Team Outcomes

Patients suffering from renal calculi due to hyperoxaluria should receive counsel regarding all the different preventive measures to which they should adhere to avoid recurrent stone formation. The diagnosis and counseling are the responsibility of both the physician and the nurse practitioner. The dietician is responsible for carefully crafting their diet whilst keeping in mind their dietary restrictions on oxalate-rich food, along with an increase in fluid intake. Patients with recurrent episodes and children with early-onset nephrolithiasis are examples of patient groups that would understandably require a high level of motivation to follow the fairly strict recommended preventive measures. If followed diligently, they can significantly decrease the recurrence rate of calcium oxalate stones in nephrolithiasis patients. This requires a combined effort of patients, physicians, nursing staff, and dieticians.[92] 

A good nephrolithiasis preventive program should be combined with a regular evaluation for systemic symptoms along with kidney and liver function monitoring. For aggressive curative interventions like liver-kidney transplants, a transplant surgeon should be consulted. The role of oral citrate to reduce urinary calcium oxalate saturation and precipitation has been studied, and long-term administration to patients with hyperoxaluria has been advised to further reduce the recurrence of calcium oxalate stones.[49] For more information on citrate and nephrolithiasis prophylaxis, please review our companion StatPearls reference article "Hypocitraturia and Renal Calculi" by Leslie S and Bashir K at PMID: 33232062.[93] 

Collaboration, communication, and shared decision-making are key elements for a good outcome. This requires an interprofessional healthcare team consisting of clinicians, specialists, mid-level practitioners, nursing staff, pharmacists, and various tech staff (radiology, lab, etc.) The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluation of all joint activities. [Level 2] This will result in optimal patient outcomes. [Level 5]