Introduction

Roughly half of all symptomatic renal calculi are potentially preventable with proper diagnosis and treatment for underlying chemical stone-promoting risk factors.[1][2][3] There is little question that our current medical evaluation and prophylactic therapy for recurrent nephrolithiasis is underutilized and generally inadequate.[4] In 2012, the annual direct and indirect costs of nephrolithiasis were estimated at over $10 billion.[5] This figure is predicted to exceed $15 billion by 2030 due to general population growth and the increasing prevalence of risk factors, such as diabetes, metabolic syndrome, and obesity, for kidney stones.[6] In addition, quality of life scores are dramatically lowered in patients with nephrolithiasis, even in those with asymptomatic stones.[7] 

Second only to actual kidney stone analysis, the 24-hour urine test is the most useful diagnostic test for nephrolithiasis prophylaxis. In a comprehensive study involving nearly 29,000 individuals at high risk for nephrolithiasis, only 7.4% of patients underwent 24-hour urine testing within 6 months of their kidney stone. Nephrolithiasis patients were 3 times more likely to undergo 24-hour urine testing if a nephrologist or urologist treated them compared to a primary care physician. Repeat testing within 6 months of the initial 24-hour urine test, which is highly recommended to verify treatment efficacy and compliance, was only 16%.[4] Multiple reasons underlie testing underuse. Similar to all 24-hour urine collection tests, it drastically limits activities on the day of the specimen collection; therefore, this can be tedious. Portions of the urinary chemistry are sometimes sent to different reference laboratories, often leading to unacceptable delays and incomplete results that cannot be easily interpreted. The most critical results are usually buried amid paragraphs of obligatory boilerplate, making it almost impossible to identify. Even worse, results are often presented as 24-hour totals that are either high or low or normal or abnormal without regard for concentration, pH, or the optimal levels of these chemistries.[8]

After the critical data are available, analysis and treatment selection must still be conducted. Evaluating and interpreting the laboratory results are often erroneously perceived as overly complicated. Even experienced experts may find it challenging to locate and clarify critical data.[8] This review aims to streamline the analysis and evaluation of a 24-hour urine collection and treatment selection, thereby empowering practitioners to feel more confident in using and interpreting this important test for patients with nephrolithiasis.

Etiology and Epidemiology

The overall incidence of nephrolithiasis is increasing. According to the National Health and Nutrition Examination Survey, about 6.3% of men and 4.1% of women were affected by urolithiasis in 1994. By 2012, this had increased to 10.6% of men and 7.1% of women. The reason for this is likely dietary. As socioeconomic status improves, individuals tend to upgrade their eating by converting to a more Western-style diet high in salt and meat. Men have a higher risk for kidney stones due to their larger average body size and increased average daily food ingestion, leading to higher levels of urinary chemicals. Obesity and diabetes are also independent risk factors for stone disease.[4]

Specific customized medical management with appropriate dietary modifications based on properly performed and interpreted 24-hour urinary chemistry profiles in nephrolithiasis patients can identify chemical risk factors, improve urinary chemistries, and reduce overall kidney stone–related events.[3]

When tested, the most common significant urinary chemical abnormalities contributing to kidney stone formation include hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, high urinary sodium, and low urinary volume.[4]

Who Should Undergo Testing?

All patients with a documented instance of a kidney stone should be informed about 24-hour urine prophylactic testing. Highly motivated patients should be offered testing and prophylactic treatment.

Testing is specifically recommended for all pediatric nephrolithiasis patients and adult stone formers with significant renal failure or high anesthetic/surgical risk factors. A 24-hour urine test is also recommended for urolithiasis patients with a history of multiple stones; repeated urolithiasis surgeries; renal transplant; ureteral reimplantation; solitary kidney; chronic diarrhea, including irritable bowel syndrome, short bowel syndrome, or post-gastrointestinal bypass surgery; and all cystine stone formers.

Individuals who receive the most benefit from 24-hour urine testing are those strongly motivated to follow a long-term course of preventive therapy. Patients should be warned that producing another stone while on prophylactic therapy does not necessarily indicate that the preventive treatment plan is ineffective. Instead, it indicates that the risk of stone formation is decreased compared to not receiving treatment. 

The single most critical component of a successful preventive treatment plan is the patient's motivation, discipline, and the likelihood of long-term compliance. The challenge for physicians is identifying individual patient risk factors and providing effective advice on medications, supplements, diet, and lifestyle.[4]

24-hour urine testing is particularly recommended in the following situations:

• Abnormal urinary tract anatomy
• Chronic diarrheal states
• Family history of kidney stones
• First stone before 21 years
• High risk for anesthesia or surgery
• Morbid obesity
• Nephrocalcinosis
• Previous surgery for kidney stones
• Renal failure
• Recurrent or multiple urinary tract infections
• Recurrent or multiple stones
• Reimplanted ureters
• Ureteropelvic junction obstruction
• Solitary kidney
• Stone composition of cystine, calcium phosphate, or uric acid [9][10]

Specimen Requirements and Procedure

A 24-hour urine collection test must be conducted for exactly that designated time frame. Although this seems obvious, it is worth reviewing the collection and storage of the sample. The collection process starts with emptying the bladder and then collecting all other urine specimens for the next 24 hours. The last specimen should be a complete void of the bladder exactly 24 hours after the start of collection. Emphasizing the correct collection technique and procedures is crucial to avoid under-collection or over-collection. Patients should be made aware that they must choose a day on which they can collect all urine specimens for 24 hours. Refrigerating the sample and promptly delivering it to the laboratory for processing can improve accuracy.[11][12]

Using a reference laboratory that routinely performs many 24-hour urine chemistry tests is advisable, as quality control measures tend to be better, turnover time is reduced, and incomplete results are less likely. Using a reliable reference laboratory with complete test reports and fast processing is recommended.

One way to estimate the reliability of the collection is to measure the 24-hour total creatinine in the specimen. Normal 24-hour urine total creatinine excretion is about 20 to 25 mg/kg in men and 15 to 20 mg/kg in women (per 24 hours), although expected excretion also varies based on factors such as diet, age, and muscle and body mass index.[13][14] Insufficient total creatinine for a 24-hour urine test should raise the question of a possibly inadequate collection.[15]

Several studies have suggested that two 24-hour urine tests provide substantially more reliable results compared to a single collection.[11] Up to 45% of patients show substantial differences between the two 24-hour urine samples. However, this includes additional costs and a greater degree of patient compliance.[11]

Properly collected and performed 24-hour urine tests and kidney stone analyses are the cornerstones of preventive therapy. If the test results are incomplete or unreliable due to improper collection, poor handling, or substandard laboratory testing procedures, the resulting analysis and treatment recommendations are erroneous, ultimately harming patients.

Diagnostic Tests

Serum and Urine Laboratories

If the patient or patient's family has a history of cystine nephrolithiasis, a urinary screening test for cystine (the sodium nitroprusside test) should be performed. In this test, sodium cyanide is added to the urine test sample. Cyanide converts urinary cystine to cysteine. The cysteine then binds to the nitroprusside, resulting in an intense purple color of the sample. This simple, qualitative test for urinary cystine typically yields a positive result at 75 mg cystine per gram creatinine. If positive, a quantitative cystine level should be determined. See StatPearls' companion resource, "Cystinuria," for more information.

Other chemistry tests, including serum potassium, creatinine, phosphate, calcium, vitamin D, oxalate, and uric acid, are extremely helpful. High or high-normal serum calcium levels and hypercalciuria observed in 24-hour urine testing suggest possible hyperparathyroidism for which specific testing (intact parathyroid hormone levels or parathyroid hormone–related peptide) should be performed. Elevated serum uric acid levels suggest hyperuricemia or hyperuricosuria. Low serum phosphate levels might indicate renal phosphate leak, which causes a vitamin D–dependent form of hypercalciuria that only responds to oral phosphate supplementation. Elevated vitamin D could suggest sarcoidosis.

24-Hour Urine Testing

An optimal 24-hour urine test should include calcium, citrate, oxalate, phosphate, sodium, sulfate, uric acid, creatinine, urea, and volume values. The most significant of these is discussed individually. Separate review activities on each should be conducted for additional details and information.

Hypercalciuria (Elevated Urine Calcium)

Dietary calcium: Dietary calcium is necessary for human nutrition and vital to bone health and muscle activity. Serum calcium levels are well-regulated, but hypercalciuria often contributes to calcium nephrolithiasis. Hypercalciuria is frequently found in many patients with calcium kidney stones. Reducing dietary calcium seems an obvious treatment option in cases where calcium intake is excessive, but most people consume moderate amounts of calcium in their diet. See StatPearls' companion resource, "Milk-Alkali Syndrome," for more information. There are also special situations and disorders, such as hyperparathyroidism, during pregnancy and in patients with osteoporosis, where it can become difficult or impossible to optimize urinary calcium levels through diet without potentially causing harm elsewhere.[16]

An overly restrictive diet of dietary calcium can increase calcium nephrolithiasis due to a lack of intestinal calcium binding to other chemicals, especially oxalate. This scenario causes an increase in oxalate absorption, which offsets the reduced urinary calcium, resulting in increased nephrolithiasis.

Typical, high-calcium foods include all dairy products such as milk, cheese, ice cream, and yogurt. Other high-calcium foods include sardines, mackerel, flax seeds, spinach and other green leafy vegetables, molasses, beans, broccoli, almonds, and grains. 

Thiazide medications: Thiazide medications are the next step if the dietary calcium intake is not unreasonable and serum chemistry indicates normal calcium levels. Thiazides are now recommended by the European Association of Urology (EAU) and the American Urological Association (AUA) guidelines for patients with hypercalciuria and recurrent calcium nephrolithiasis.[17][18] However, it is crucial to control sodium for thiazides to be effective; therefore, patients on thiazides are advised to limit their salt intake. Reducing daily sodium intake by 100 mEq can lower urinary calcium excretion by 50 mg daily. Thiazide use in hypercalciuric calcium stone formers can reduce median annual stone production from 2.94 to 0.05 (P < .001).[19]

Thiazides can cause adverse effects such as hypokalemia, increased uric acid levels, and reduced urinary citrate. However, their beneficial effects in substantially lowering urinary calcium overshadow these adverse effects. If hyperuricosuria, hypokalemia, or hypocitraturia develops, potassium citrate should be added as needed. Thiazides contain a sulfa molecule; therefore, they must be initiated and used cautiously in patients with sulfa allergies.

Hydrochlorothiazide, chlorthalidone and indapamide are the most commonly prescribed thiazide medications. Of these, chlorthalidone and indapamide are generally preferred for stone disease due to their longer half-life and once-daily dosing schedule. A repeat 24-hour urine test should be performed during treatment to determine the effectiveness of the thiazide therapy and to monitor for hyperuricosuria or hypocitraturia, typically about 3 months after starting the treatment. If the urinary calcium levels remain elevated, an adjustment in the treatment can be made, such as increasing the thiazide dosage, choosing an alternative therapy such as phosphates, or gaining better control of dietary sodium and calcium intake.[16] Hypercalciuria can also cause bone calcium loss, resulting in osteopenia or osteoporosis, which is reversible using thiazides.[19][20]

Vitamin D: Vitamin D deficiency is found in many nephrolithiasis patients.[21] Treating nephrolithiasis patients with vitamin D supplementation is somewhat controversial, and 24-hour urine studies assessing hypercalciuria should be followed if treatment is initiated. Vitamin D supplementation and hypercalciuria treatment can be modified accordingly to optimize both chemistries.[22][23] See StatPearls' companion resource, "Vitamin D Deficiency," for more information.

Oral phosphate supplementation: Oral phosphate supplementation with sodium phosphate or potassium phosphate should be utilized if dietary calcium moderation with low urinary sodium and appropriately dosed thiazide therapy are inadequate to control hypercalciuria. Such phosphate supplements lower calcium absorption by the gastrointestinal tract directly, through intestinal calcium-binding, and indirectly, primarily by decreasing the levels of 1,25-vitamin D.

In renal phosphate leak hypercalciuria, there is an obligatory excessive loss of urinary phosphate. This condition lowers the serum phosphate level, stimulating vitamin D activation (conversion of 25-vitamin D to 1,25-vitamin D) by the kidneys. This higher vitamin D level increases the gastrointestinal absorption of phosphate and calcium absorption. Absorbed calcium is eventually excreted in the urine, causing hypercalciuria.

Thiazides are ineffective in treating renal phosphate leak hypercalciuria because the underlying etiology is a vitamin D–dependent disorder.[16] Proper treatment of this condition with oral phosphate supplementation can substantially reduce renal stone production and improve quality of life scores in this small group of affected patients.[24]

Bisphosphonates and RANK ligand inhibitors: Bisphosphonates and rank ligand inhibitors both increase calcium deposition in bone, and there is some limited evidence that they can reduce hypercalciuria. Theoretically, their use seems reasonable in patients with resistant hypercalciuria, especially if associated with osteopenia or osteoporosis. However, limited research has been conducted on their use in hypercalciuric patients; therefore, they are not currently recommended or approved for this indication. Patient selection and appropriate monitoring are critical as some obligatory hypercalciuric patients may not respond, possibly resulting in net calcium loss, hypocalcemia, worsening osteoporosis, and other metabolic problems.[16] See StatPearls' companion resource, "Hypercalciuria," for more information.

Optimal levels

• Normal 24-hour urinary calcium excretion is less than 250 mg.

• Optimal is less than 200 mg or less than 100 mg/L urine.

Hypocitraturia (Low Urinary Citrate)

Citrate, the body's natural urinary alkalinizing agent, corresponds to serum bicarbonate, which is converted to citrate in the kidney. Serum bicarbonate is the body's primary chemical acid/base buffer.[25]

Citrate, a natural inhibitor of stone formation, not only neutralizes excess uric acid that helps dissolve uric acid stones and crystals but also helps prevent microscopic calcium oxalate crystals from aggregating and forming stones. Lemon juice is rich in natural citrate; therefore, lemonade made from real lemon juice is often suggested as an alternative to water as the primarily recommended beverage for all kidney stone formers. Unfortunately, it takes enormous amounts of lemonade to significantly affect serious hypocitraturia. 

Citrate is found in almost all citrus fruits, but most patients with significantly reduced urinary citrate levels require a specific, concentrated citrate supplement such as potassium citrate. This supplement is available in both tablet and liquid forms. The tablets tend to be quite large, which can be hard for some patients to swallow. Occasionally, patients may notice the tablets in their stool, leading them to believe that the supplement is ineffective. This occurrence is normal as the tablet carrier is typically made of wax and is designed to pass harmlessly through the intestinal tract to allow for slow absorption of the citrate, which also helps minimize gastrointestinal upset and stabilize urinary citrate levels. Patients should be reassured that occasionally, tablets may be noticed in the stool.[26]

The amount of citrate required to optimize the urinary chemistry depends partly on the type of kidney stone produced. For calcium oxalate stones, the optimal citrate level is about 320 mg per 1000 mL of urine. Typical dosages of potassium citrate are 10 to 20 mEq taken 3 or 4 times a day.[26] Serum potassium levels should be determined periodically, especially when the potassium citrate dosage increases or the patient has renal failure. As a general guide, 30 mEq of potassium citrate increases the daily urinary citrate level by about 200 mg.

If the required potassium citrate dosage is relatively low, the supplement should be taken at bedtime to mimic the alkaline tide that normally occurs overnight. A common nocturnal dosage is two of the 10 mEq potassium citrate tablets taken shortly before bedtime.

Pure uric acid calculi, but not calcium stones, can be dissolved with adequate potassium citrate supplementation and urinary alkalinization. Here, the key is to use sufficient potassium citrate to maintain an average urinary pH of around 6.5 to 7. Many patients with uric acid stones have highly acidic urine and require substantial potassium citrate supplementation to optimize their urinary pH levels. Urine pH can be measured using pH paper or urinary dipsticks available in most pharmacies.[26]

Patients receiving subcutaneous human parathyroid hormone therapy for hypoparathyroidism can develop hypocitraturia. These patients, especially those with a history of nephrolithiasis or nephrocalcinosis, should be monitored for hypocitraturia and treated with appropriate potassium citrate supplements as necessary.[27]

Hypocitraturia is frequently observed in various nephropathies and is associated with the severity of renal impairment but not with serum bicarbonate levels. This finding suggests that it could serve as a marker of renal function and possibly as a prognostic factor, but this possibility has not yet been studied.[28]

Potassium citrate tablets act as urinary antacids, increasing urinary alkalinity (pH) and citrate levels.[26] Limiting factors for potassium citrate supplementation include tolerability (some patients may notice gastrointestinal upset after taking potassium citrate supplements), difficulty swallowing the large tablets, and elevated serum potassium. The goal of therapy varies according to the specific situation.

For calcium oxalate stone formers, the goal is to reach and maintain an optimal urinary citrate level of 300 mg/L of urine. Optimal urinary pH levels in most calcium stone formers are typically around 6.5.

For uric acid stone formers, the goal is to achieve an optimal urinary pH of 6.5 to 7 to maximize uric acid solubility regardless of the actual citrate excretion level. In cystinuria, the goal is set higher at a pH of 7.5.

Alternative Treatments for Hypocitraturia

A combination of sodium citrate and potassium citrate, in either dissolvable crystals or liquid form, is often used when additional urinary alkalinization is needed, but the patient may develop hyperkalemia on standard potassium citrate supplements. Disadvantages include a significant sodium load, frequent dosing requirements, and the need to consume the medication as a liquid.

Various citrate supplements, both prescription and non-prescription, are commercially available and relatively inexpensive. Some have substantially less potassium compared to standard potassium citrate prescription products, which is helpful in patients with renal failure or hyperkalemia. A combination of potassium citrate, magnesium citrate, and sodium bicarbonate is preferred. Some are virtually tasteless, and several are available as liquids, which are particularly useful in patients with chronic diarrhea, irritable bowel syndrome, colitis, Roux-en-Y gastric bypass surgery, and in patients who fail to improve their hypocitraturia on standard potassium citrate tablet supplementation. However, the degree of urinary alkalinization varies, and no standardization exists. 

Sodium bicarbonate can boost citrate excretion if serum potassium levels preclude additional potassium supplementation. However, it carries a significant sodium load, increases urinary calcium, and is relatively short-acting.

Acetazolamide, a carbonic anhydrase inhibitor, is a diuretic indicated for treating high-altitude sickness and glaucoma. However, it can also raise urinary pH by reducing renal bicarbonate reabsorption as an alternative to or in addition to taking additional potassium citrate or sodium bicarbonate supplements. Although acetazolamide effectively raises urinary pH, it can lead to metabolic acidosis and predispose some patients to the formation of urinary calcium phosphate crystals and the production of kidney stones.

Acetazolamide significantly lowers urinary citrate excretion; therefore, it should not be used in the setting of hypocitraturia. The resulting hypocitraturia is relatively unresponsive to potassium citrate supplementation. Due to all these limitations, acetazolamide is rarely utilized clinically for stone disease, except for rare cases of cystinuria where the pH benefits are deemed sufficient to justify its use. A typical dosage is 125 to 250 mg twice a day.[29]

Topiramate is another carbonic anhydrase inhibitor used to treat migraines and prevent seizures. This drug tends to cause metabolic acidosis, which reduces urinary citrate excretion.[30] The impact of the drug on urinary citrate can be minimized in patients who are unable to stop topiramate by the use of potassium citrate supplements.[30][31] Although similar to acetazolamide, its overall effect on urinary chemistry is milder, and the hypocitraturia it produces can be more easily mitigated with potassium citrate supplementation.

High-citrate foods include lemon juice; lemonade made with real lemon juice; citrus fruits; juices; oranges; bananas; dried apricots; melons; peas; potatoes, especially with the skin; tomatoes; cod; flounder; salmon; sardines; tuna; chicken; and yogurt.

The following foods are high in citrate but are also relatively high in oxalate; therefore, they are not recommended in patients with hyperoxaluria: Asparagus, beans, brown rice, broccoli, green leafy vegetables, green beans, Romaine lettuce, collard greens, oats, lentils, peanuts, and whole grains. See StatPearls' companion resource, "Hypocitraturia," for further information. 

Optimal levels

• Normal 24-hour urinary citrate is about 320 mg.

• Optimal 24-hour urinary citrate for calcium stone formers is about 320 mg per 1000 mL urine, typically totaling about 640 mg or more and assuming 2000 mL of urine production daily.

• Optimal 24-hour urinary pH for uric acid stone formers is 6.5 for maintenance and 7 for stone dissolution.

Hyperoxaluria (Elevated Urinary Oxalate)

Oxalate is an organic chemical produced by plants to help eliminate unwanted calcium absorbed by their roots from the local groundwater. Plants do not use calcium metabolically, as they have no bones or muscles; therefore, they produce oxalate in their leaves, fruits, nuts, and seeds, which are subsequently shed. As the dissolved calcium passes through these areas, it becomes tightly bound by the oxalate. Eventually, these parts of the plant are discarded, and the oxalate is removed along with its tightly bound calcium.

Humans make tea from the leaves and call many other plant-based products as food. In this way, people ingest a fair amount of oxalate, with the levels varying based on the types of plants consumed, the quantities ingested, and the original groundwater calcium content where the plant was grown.

Dietary oxalate constitutes about 50% or more of the total oxalate excreted in the urine. The rest comes from endogenous hepatic production. Oxalate has no beneficial role in human nutrition and passes through the system until it is excreted in the urine. The problem is that once it reaches the urine, oxalate tightly binds to any available calcium, leading to the formation of calcium oxalate crystals and stones. Oxalate is 15 to 20 times stronger compared to calcium as a chemical promoter of nephrolithiasis, and most calcium stones in humans are largely composed of calcium oxalate.

Oxalate is primarily absorbed in the colon and the distal ileum and is found in 5% to 24% of all patients with gastrointestinal malabsorption disorders. The incidence is increasing due to the increase in contributory bowel diseases and bariatric surgeries in the general population.

Enteric hyperoxaluria: Patients with irritable bowel syndrome, previous gastrointestinal surgery such as Roux-en-Y gastric bypass surgery, or any chronic diarrhea situation are at increased risk of kidney stone formation due to high urinary oxalate levels from enteric hyperoxaluria. This form of hyperoxaluria is particularly severe, often leading to oxalate excretion levels double or even triple the normal daily amount. The condition is caused by fat malabsorption and is associated with many types of chronic intestinal disorders, particularly after bariatric surgery.[32][33][34][35]

Fat malabsorption increases intestinal calcium binding by free fatty acids, thereby significantly reducing the free calcium available for oxalate binding in the lower gastrointestinal tract and large bowel. At the same time, high levels of bile salts and fatty acids increase colonic permeability and oxalate absorption by up to 300 times, further compounding the problem. Chronic diarrhea causes additional fluid loss, leading to reduced urinary volumes and a loss of bicarbonate, which often manifests as rectal burning. Furthermore, this condition typically results in severe hypocitraturia.[36]

Primary hyperoxaluria: Primary hyperoxaluria is a rare but severe form of hyperoxaluria, affecting 1 to 3 patients per 1 million population in the USA and Europe.[37] Primary hyperoxaluria is an autosomal recessive disorder that causes severe and sustained elevated oxalate levels in the serum and urine. This condition results in severe, repeated, and potentially dangerous calcium oxalate kidney stone disease that does not respond well to standard oxalate-lowering therapies. Traditional therapy includes standard hyperoxaluria treatments, high-dose vitamin B6, dialysis, liver transplantation, and combined liver-kidney transplants. Primary hyperoxaluria generally requires medication.

Hyperoxaluria Treatment 

Foods with particularly high oxalate levels include green leafy vegetables such as spinach, collard greens, and chard; beets; chocolate; nuts; rhubarb; and strong teas. For enteric hyperoxaluria, dietary measures to reduce oxalate intake can be effective.[38] Although no specific medication corrects high urinary oxalate, increased dietary calcium and calcium citrate supplements are used to increase intestinal oxalate binding, thereby reducing oxalate absorption. Dietary calcium is more effective and generally preferred over supplements.[39] From a practical point of view, lowering the ingestion of high oxalate foods and increasing dietary calcium, particularly with lunch and dinner, is often adequate in controlling hyperoxaluria of less than 70 mg/day. The only food specifically prohibited in many hyperoxaluric nephrolithiasis patients is spinach. A single bite of cooked spinach can have more than 75 mg of oxalate, and a standard portion of a half cup contains about 750 mg. Collard greens and rhubarb, which are similar to high-oxalate foods, may also be recommended for elimination in patients with hyperoxaluric nephrolithiasis.[40]

If such dietary measures prove inadequate, calcium supplements can be added. Calcium citrate is preferred as it dissolves better compared to other calcium supplements. Calcium citrate without added vitamin D is suggested because it is desirable to avoid early intestinal calcium absorption, facilitating oxalate binding in the lower gastrointestinal tract. Calcium citrate with magnesium citrate is acceptable as the added magnesium helps offset the tendency of calcium supplementation to cause constipation. Increased dietary calcium ingestion is also highly recommended, especially if it can be ingested simultaneously with higher oxalate foods. Alternative oxalate-binding agents, such as iron, can be substituted if calcium cannot be used but are less effective.[41][42]

Vitamin B-6 is used to assist the liver in dealing with oxalate and hyperoxaluria. Vitamin B-6 is often recommended due to its various health benefits and cost-effectiveness. In some cases, it reduces oxalate levels substantially, but large doses are sometimes required.

In most cases, the most effective treatment for high urinary oxalate levels is controlling the oral intake of higher oxalate foods and adding dietary calcium to each higher oxalate meal, typically lunch and dinner. Clinicians should provide patients with a complete listing of the oxalate content of foods, available online or through the VP Foundation. Other dietary measures include lowering salt intake, limiting ingested meat protein, taking extra vitamin B-6, and avoiding low calcium diets, which decrease intestinal oxalate binding, thereby increasing absorption and ultimately raising urinary oxalate levels.

Cholestyramine is a bile acid–binding resin that is primarily used for cholesterol control. This drug removes bile acids from the body, which can help reduce urinary oxalate that is not responsive to other therapies. For this reason, it is often recommended in hyperoxaluric patients who have undergone bariatric surgery.[43]

Using a probiotic (healthy gut bacteria) product is more controversial. Probiotics provide the intestinal tract with beneficial gut bacteria that may help some people handle oxalate better; however, limited information exists on their efficacy in reducing urinary oxalate excretion.

Oxalobacter formigenes are natural bacterial inhabitants of the intestinal tract, facultative anaerobes, and can digest oxalate. The oxalate-digesting enzyme of Oxalobacter formigenes may someday be available as a pill, capsule, or powder for therapeutic use in patients with hyperoxaluria.[44][45]

Lumasiran is a small interfering RNA that blocks glycolate oxidase, which normally converts glycolate to glyoxalate. This drug is metabolically upstream from the defective hepatic alanine glyoxalate aminotransferase that is abnormally converting glyoxalate to oxalate. By reducing the glyoxalate precursor, the medication effectively lowers hepatic oxalate production in affected individuals. Clinical studies have shown over 50% reduction in urinary oxalate in primary hyperoxaluria type 1 patients treated with lumasiran, and 84% had normal or near-normal urinary oxalate levels after 6 months of therapy.[46][47] Patients with elevated urinary oxalate (>70 mg/24 hours) and confirmed genetic testing for primary hyperoxaluria type 1, particularly those with alanine glyoxylate aminotransferase mutations, are potential candidates.[48]

Nedosiran, an investigational agent for primary hyperoxaluria, works similarly to lumasiran but targets hepatic lactate dehydrogenase. This drug is significant because it could potentially affect all three types of primary hyperoxaluria. Early studies show a mean oxalate reduction average of 55%.[49][50][51] 

Stiripentol is a Food and Drug Administration (FDA)-approved anti-seizure medication specifically designed for children aged 2 with Dravet syndrome. This drug inhibits lactic dehydrogenase isoenzyme 5, which converts glyoxalate to oxalate.[52] See StatPearls' companion resource, "Hyperoxaluria," for more information.

Optimal levels

• Normal urinary oxalate levels are less than 40 mg daily.

• Optimal daily levels of urinary oxalate are less than 25 mg daily or less than 15 mg/L of urine.

Hypernatriuria (Elevated Urinary Sodium)

High dietary salt or sodium levels cause increased fluid retention, add a preload fluid burden on the heart, and increase urinary calcium excretion. All of these effects are harmful, especially for nephrolithiasis patients with hypercalciuria. Unless the salt intake level is controlled, the hypocalciuric effect of thiazide therapy for hypercalciuria in calcium stone formers is partially or completely nullified.

The human body only needs about 500 mg of sodium daily to live, yet Americans typically consume an average of 3436 mg daily. A single teaspoon of table salt has about 2300 mg of sodium. The optimal salt intake should be no more than 1500 mg daily, but even a modest limit of 2300 mg daily can improve risk factors. As a frame of reference, a typical fast-food cheeseburger has about 800 mg of sodium.

A simple solution to high urinary sodium levels is to reduce dietary salt intake. However, this can be difficult because it is added to almost every packaged and prepared food and most recipes. Electrolytes and sports drinks are generally discouraged due to their relatively high sodium content. 

Tips to reduce salt intake

Beware of hidden salt: Canned food can contain up to 10 times more salt compared to fresh or frozen food. Even low sodium on the label may only mean less salt was added. Cans should be looked out for labels that say no added salt, and then the listed sodium levels should be read. Canned vegetables and commercial tomato and vegetable juices have surprisingly high sodium levels. When comparing sodium levels, it should be noted that sodium content is often listed per serving by food manufacturers, and there are often multiple servings in the food product.

Salt is used in baking bread to prevent the yeast from overworking. Cheese is also naturally salty, with a half cup of cottage cheese or a single 1-ounce slice of American cheese containing 400 mg of sodium. Preserved meats, such as cold cuts, are high in salt, as it is used not only for taste but also as a preservative.

Eating out: Restaurant food, especially fast food such as pizza, is high in salt and sodium content. When dining out, patients are advised to request their waiters to ask the chef to omit salt during cooking and serve any sauce on the side, allowing patients to choose less usage.

Restaurant soups are notoriously high in salt, and there is no way to take the salt out. Therefore, patients seeking to reduce salt intake should avoid these. Homemade soup, where a patient can completely control the salt content, is a better option. Sauces, gravies, and condiments typically contain high levels of salt; therefore, patients are advised to limit the use of ketchup, mustard, soy sauce, pickles, barbecue sauce, steak sauce, Worcestershire sauce, and prepared salad dressings. 

Other tips:

• Select low-sodium or no-added-salt varieties whenever possible.

• Remove the salt shaker from the dining table at home.

• Use little or no salt in food preparation or cooking at home.

• Be very cautious about using salt substitutes that contain potassium chloride. Since these can raise serum potassium levels, physicians recommend that patients avoid them or use very little.

• If canned vegetables must be used, patients are advised to rinse them and drain them several times to eliminate as much salt as possible.

• Patients must be reminded that sea salt has the same amount of sodium as regular table salt.

• Low-sodium only means that the product has between 25% and 50% less salt compared to the original. The total sodium content may still be high.

Optimal levels

• Normal 24-hour urinary sodium is less than 200 mg.

• Optimal 24-hour urinary sodium is less than 150 mg.

Hyperuricosuria (Elevated Urinary Uric Acid)

Uric acid is a waste product that is normally produced by the liver. Abnormally high levels of uric acid in the blood can lead to the formation of uric acid crystals in the joints, resulting in severe pain and inflammation, known as gout. This condition is typically due to a liver problem and is frequently treated with allopurinol, colchicine, indomethacin, probenecid, or febuxostat.

High levels of uric acid in the urine can produce both uric acid and calcium oxalate stones depending on the specific urinary chemistry and pH. High meat (purine) intake increases the amount of uric acid the body produces. For these reasons, all dietary meats, including beef, pork, veal, seafood, fish, organ meats, poultry, and chicken, increase uric acid levels. Most people tend to eat far more meat compared to what they need. Fish and chicken are healthier compared to beef and pork for reasons such as cholesterol, although they are equivalent regarding uric acid production. For a complete list of uric acid content in various foods, refer to the uric acid patient education guide section.

Elevated urinary uric acid levels tend to produce uric acid crystals in the urine. These small crystals can act like seeds, allowing calcium stones to form around them. Thus, high levels of uric acid in the urine can promote the formation of calcium stones.

Most pure uric acid stones are caused by excessive urinary acid or insufficient bicarbonate. An acidic urine pH of 5 or less is often found in many uric acid stone formers. Normal urine pH is between 5 and 7. The optimal urinary pH in uric acid stone formers is typically around 6.5; therefore, clinicians typically advise patients to take enough citrate supplements to maintain their urinary pH between 6.5 and 7.0.

Pure uric acid stones, but not calcium-based stones, can be dissolved with adequate citrate supplementation. Many patients with uric acid stones have highly acidic urine and require substantial antacid supplementation, such as potassium citrate, to optimize their urinary pH. Urine pH paper and dipsticks are available in many pharmacies or online.

Allopurinol is frequently used for high serum uric acid when diet alone is inadequate, by inhibiting xanthine oxidase in the liver. Optimal serum uric acid levels are around 6 mg/dL, and the optimal 24-hour urine uric acid excretion is 600 mg or less. Vitamin B-6 is sometimes added to the allopurinol as well. Febuxostat is a newer drug that functions similarly to allopurinol in lowering uric acid production.[53][54][55]

Colchicine and indomethacin are strong, anti-inflammatory drugs that do not directly affect serum or urinary uric acid levels and may cause significant adverse effects. The use of these drugs is limited to the management of acute gout attacks. Chronic or continued use for gout is not recommended, as other agents are better suited for prophylaxis.

Patients with uric acid stones should not take probenecid because it increases uricosuria and uric acid stone production.

Uric acid content of foods: Most studies show that plant-based vegetables and foods high in uric acid, such as soy, tofu, lentils, and chickpeas, do not increase the risk of hyperuricemia. Dietary factors that increase this risk are red meat, seafood, organ meats, alcohol, and fructose.[56][57] 

Optimal levels

• Normal serum uric acid is 7.5 to 8.5 mg/dL.

• Optimal serum uric acid is less than 6 mg/dL.

• Normal 24-hour urine uric acid is 750 mg.

• Optimal 24-hour urine uric acid is less than 600 mg.

Hypovolemia (Low Urinary Volume)

A high urinary volume is essential for preventing kidney stones. The average 24-hour urinary volume in normal individuals is about 1300 mL per day. Patients with kidney stones are asked to drink sufficient water to produce at least 2000 mL of urine a day. A low urinary volume significantly increases the concentrations of calcium, salt, and other minerals, predisposing patients to kidney stone formation. The easiest way to correct this is to increase oral fluid intake.

The majority of fluid intake should be water. Patients should avoid using electrolyte sports drinks and similar products to increase urinary output as they contain excessive amounts of sodium. Cranberry juice is not recommended due to its moderately high oxalate and sugar content. A good substitute for water is lemonade made with real lemon juice, as lemon juice is high in citrate, a natural stone-preventing agent. 

As a general rule, the patient's urine should appear no darker than a very pale yellow. To help keep track of the 24-hour urinary volume, it is recommended that once a month, the patient should record their 24-hour urine output by measuring it in a urinal or collection hat. Urinary concentration can be measured using specific gravity; optimal urinary specific gravity readings should consistently be 1.005 or less.[58]

Other suggestions include the following:

• Substitute high-fluid content desserts, such as frozen ices, sherbet, melons, grapes, and fruit, in place of pastries, cookies, and cakes.

• Maintain the humidity level between 40% and 45% in the home and workplace to minimize insensible fluid loss through the skin and normal respiration.

• Limit salt and sodium intake, as excessive salt intake can increase fluid retention and make the urine more concentrated.

• Drinking small amounts of water, such as 4 oz, frequently may help improve fluid intake and be less intimidating than drinking larger amounts. Drinking small glasses of water can quickly add up to a substantial increase in urinary output.[58]

• Depending on the patient's tolerance and metabolism, their system gradually adjusts to the increased fluid, and they become thirsty if they fail to keep their fluid intake up. This adjustment typically takes about 1 or 2 months of regular increased fluid intake.

• No matter how much fluid the patient claims to be drinking, if their urinary volume is less than optimal, they are not drinking enough.

• Diuretic medications can be used as a last resort to force a mandatory increase in urinary volume but can cause mineral and salt imbalance in the blood and several other complications. Failure to increase oral fluid intake while taking a diuretic can easily lead to dehydration.

Resorting to all of these measures to increase the urinary output to optimal levels is rarely necessary, but patients may find it challenging in the beginning. No other treatment for the stone disease is as effective as successfully adjusting the patient's urinary volume to optimal levels, and no other treatment is likely to be effective unless the urinary volume is adequate and sustained.

A new vasopressin receptor antagonist, tolvaptan, has significantly increased urinary volumes in kidney stone formers.[59] Tolvaptan works to increase urinary output by enhancing free water excretion by the kidneys. A pilot study has evaluated its safety and tolerability in human subjects,[60] particularly in 4 young cystinuria patients. The patients all noted significantly increased urinary volumes. No liver problems or electrolyte abnormalities were observed, but all noted dramatically increased thirst.[60] A vasopressin antagonist can potentially reduce kidney stone risk factors in dehydrated patients but cannot adequately increase their oral fluid intake and urinary volumes.[61][62]

Optimal levels

• Normal volume is 2000 mL over 24 hours.

• Optimal urinary volume is 2500 mL over 24 hours.

Clinical Significance

What to do After Testing

After the patient has been in therapy for at least several months, another 24-hour urine test is advisable. The test aims to ensure that the treatment effectively controls the intended problem and that the patient is compliant with therapy. In addition, it allows for dosage adjustments or a change in therapy. Subsequently, an annual 24-hour urine collection is recommended for maintenance. 

The annual 24-hour urine recheck provides an opportunity to reinforce patient instructions, review previously recommended therapies, and renew any medications with possible dosage adjustments. In complicated cases, repeating the 24-hour urine testing and treatment modifications every 3 months is recommended until optimal results are achieved, typically yearly.

When it is not Possible to Optimize the 24-hour Urinary Chemistry

Optimizing every 24-hour urine chemistry in some patients is not always possible. Hyperoxaluria is particularly difficult. In these cases, as many chemistries as possible should be optimized. Increasing 24-hour urinary fluid volume is typically the first and easiest risk factor to mitigate.

How to Increase Long-Term Patient Compliance With Therapy

There is no magic formula to ensure patient compliance with treatment. Patients should be informed that 24-hour urine testing is only effective if they are committed to long-term compliance with treatment recommendations. Skipping treatments, deviating from recommended diets, or failing therapy in some other way may not result in immediate consequences but could lead to avoidable kidney 6 months or a year later. Informing patients that they should follow recommendations despite occasional slips and about the importance of long-term prevention seems to help long-term compliance, but this remains a common problem without a good solution.

Repeating the 24-hour urine test annually reminds patients about the importance of their treatment and its effectiveness and allows the clinician to fine-tune the patient's therapy.

Summary of Treatments for Abnormal 24-Hour Urine Tests

Hypercalciuria

If the serum calcium is normal and hyperparathyroidism is ruled out, excessive dietary calcium should be reduced. Calcium intake should not be overly restricted to avoid a reactive increase in oxaluria and possible osteoporosis. If the dietary calcium intake is reasonable and hypercalciuria persists, indapamide 2.5 to 5 mg daily, chlorthalidone 25 to 50 mg per day, or a similar thiazide can be added. If the urinary sodium is elevated, the salt intake must be restricted, or the thiazide therapy does not effectively lower urinary calcium. If thiazides are unsuccessful, vitamin D–dependent hypercalciuria should be considered.

Oral phosphate supplementation with sodium phosphate or potassium phosphate should be utilized if dietary calcium moderation with low urinary sodium and appropriately dosed thiazide therapy are inadequate to control hypercalciuria. Such phosphate supplements directly lower calcium absorption by the gastrointestinal tract through intestinal calcium-binding and indirectly, primarily by decreasing 1,25-vitamin D.

Bisphosphonates and RANK ligand inhibitors can be used in certain situations of refractory hypercalcemia and osteopenia or osteoporosis.[16]

Hyperoxaluria

Enteric hyperoxaluria: Dietary measures are the primary treatment for hyperoxaluria. Increased fluid intake can help offset fluid depletion associated with hyperoxaluria from gastrointestinal surgery or gastrointestinal disorders, which can cause fluid depletion and loss of bicarbonate; these can be treated with increased fluid intake and oral citrate supplements. Calcium citrate can also help bind intestinal oxalate, making it unavailable for urinary excretion. A substantial amount of calcium citrate and potassium citrate supplementation may be needed to correct the metabolic disturbances in these patients effectively. Cholestyramine can help reduce bile acid effects, especially when other measures are insufficient. A probiotic can be added to support intestinal digestion of dietary oxalate by optimizing the gut bacteria. Adding vitamin B6 helps some patients with the liver metabolism of oxalate.

Recently, it has been suggested that enteric hyperoxaluria may also involve increased oxalate production from the liver or intestine. This hypothesis helps explain the lack of response to treatment in some enteric hyperoxaluric patients, but further research is needed to confirm its validity. 

Primary hyperoxaluria: This rare genetic condition typically requires medication to treat. Lumasiran, nedosiran, and stiripentol help decrease endogenous oxalate production in the liver.

Hypocitraturia

Lemonade made with real lemon juice helps a little, but most patients need concentrated potassium citrate supplements, either tablets or liquid. The liquid version is preferred in patients with irritable bowel syndrome or post-bariatric surgery. Citrate supplementation should increased as much as possible until the patient reaches tolerance, serum potassium reaches the normal upper limit, optimal citrate levels are achieved, or the urine pH reaches 7. The addition of sodium bicarbonate or a similar urinary antacid product should be considered necessary for patients who cannot take more potassium citrate but have not yet reached their target urinary citrate levels or pH.

Low Urinary Volume: Patients must increase their fluid intake to achieve an optimal urine output of at least 2500 mL. Water intake should be recommended until this goal is achieved. A mild diuretic can help, but if patients still fail to increase their fluid intake, this can lead to further dehydration.

High Urinary Sodium: Reducing dietary salt is the most effective treatment for this problem. Control of urinary sodium is necessary to allow the hypocalciuric effect of thiazides to be realized.

Hyperuricosuria

Patients should be asked to reduce their dietary purine intake. Allopurinol may be considered for elevated serum or urinary uric acid levels. If allopurinol is initiated, it should be started at 100 mg and then gradually increased as needed to achieve optimal uric acid levels. For most patients, this is likely to be around 300 mg of allopurinol daily, but it can vary. Vitamin B6 should be added if the patient is being started on allopurinol, as it prevents possible neuropathy, an uncommon but reported adverse effect. For patients forming uric acid stones, the preferred therapy is to use potassium citrate to optimize urinary pH to around 6.5 or more, but allopurinol can be used selectively if either serum or urinary uric acid levels are elevated. Febuxostat can be an option for patients who are intolerant or allergic to allopurinol.

General advice: Not every patient may achieve an optimal level in all major 24-hour urine test chemistries, and some problems may prove stubbornly resistant to treatment. In such cases, as many chemistries must be optimized as possible. Patients must accept that treatment significantly reduces their kidney stone risk but does not entirely eliminate it. Increasing fluid intake is universally recommended, as this is always helpful. Pentosan polysulfate has been used in complex or resistant nephrolithiasis cases to help reduce stone formation. The medication coats urinary crystals with a mucopolysaccharide layer that helps prevent aggregation, reducing stone production and growth.

Enhancing Healthcare Team Outcomes

Despite the availability of evidence-based guidelines for managing nephrolithiasis, the incidence of new cases and recurrent stones has continued to rise steadily over the years. All interprofessional healthcare team members, including physicians, advanced practice practitioners, nursing staff, and pharmacists, should be familiar with the presentation of nephrolithiasis.

There is no question that 24-hour urine for nephrolithiasis prevention analysis is considered the standard of care by many national experts and professional organizations. This method helps avoid preventable complications, pain, and surgeries and can reduce stone production by 90% or more. In addition, it can identify underlying medical conditions that are difficult to diagnose through other means, such as hypercalciuria, renal tubular acidosis, renal phosphate leak, cystinuria, hyperoxaluria, and hypocitraturia. This type of testing can be life-saving kidney-saving or can preserve kidney function in some patients.

Finally, testing, interpretation, and treatment selection can be greatly simplified, making it easy to perform and interpret in any medical practice using the previously presented guidelines. Clinicians and nurses should work with laboratory technicians to obtain quality specimens and accurate results.