Introduction

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

There may be no other body of chemistry tests in any branch of medical practice that is potentially as useful and so often indicated, yet infrequently utilized, as the 24-hour urine test for nephrolithiasis prophylaxis. In a large series of almost 29,000 high-risk stone formers, only 7.4% of patients underwent 24-hour urine testing within six months of their kidney stone. Nephrolithiasis patients were three times more likely to do 24-hour urine testing if they were treated by a nephrologist or urologist compared to a primary care physician. Repeat testing within six months of the initial 24-hour urine test, which is highly recommended to verify treatment efficacy and compliance, was only 16%.[4]

There are multiple reasons for this. Like all 24-hour urine collection tests, doing the collection itself is often considered tedious by patients as it drastically limits their activities on the day of the specimen collection. 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 often buried amid paragraphs of obligatory boilerplate, making it almost impossible to identify the most critical results. 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 what "optimal" levels of these chemistries would be because providing such information is not readily available or legally required.[8]

Once the critical data is available, analysis and treatment selection still need to be done. Evaluation and interpretation of the laboratory results are often erroneously perceived as overly complex and complicated. There are many different ways the various chemistry reference laboratories hide the data or otherwise make it confusing. Even for experienced experts, finding and clarifying critical data can be challenging.[8]

The purpose of this review is to simplify the analysis and evaluation of 24-hour urine collections and treatment selection, so local practitioners will be more comfortable using and interpreting this important test for their nephrolithiasis patients.

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 to be dietary. As socioeconomic status improves, people tend to "upgrade" their eating by converting to a more Western-style diet high in salt and meat. Men have a higher overall kidney stone risk due to their larger average body size and increased average daily food ingestion that results in larger amounts 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 not only identify chemical risk factors in the vast majority of patients but can significantly improve the urinary chemistry as well as reduce overall kidney stone related events.[3]

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

Who Should Be Tested?

All patients who have had at least one documented instance of a kidney stone should be informed about 24-hour urine prophylactic testing. The testing is specifically recommended for all pediatric nephrolithiasis patients and adult stone formers who have significant renal failure or high anesthetic/surgical risk factors. The 24-hour urine test is also recommended in urolithiasis patients with a history of multiple stones and repeated urolithiasis surgeries, renal transplants, ureteral reimplantations or solitary kidneys, chronic diarrhea (irritable bowel syndrome, short bowel syndrome, or post gastrointestinal [GI] bypass surgery), and all cystine stone formers.

Those who receive the most benefit from 24-hour urine testing are the most strongly motivated to follow a long-term course of preventive therapy even if they do not necessarily feel better with treatment. These patients should be encouraged to understand that there is no guarantee that preventative measures, even if followed precisely, will prevent all future stones. Patients should be warned that producing another stone while on prophylactic therapy does not mean the preventive treatment plan is not working, only that it is not perfect. 

The single most critical component of a successful preventive treatment plan is the patient's motivation, discipline, and the likelihood of long-term compliance. Any stone patient who is strongly motivated to follow a long-term course of preventive treatment and understands its limitations and sacrifices and the need for long-term compliance should not be denied 24-hour urine testing for kidney stone prophylactic therapy. The challenge for physicians is to identify that individual patients' treatable risk factors and provide effective dietary advice, medications, and supplements that will reduce that person's future stone risk while making minimal changes to their preferred diet and lifestyle.[4]

Specimen Requirements and Procedure

A 24-hour urine collection test needs to be done for 24 hours. While this seems obvious, some patients misinterpret the instructions, so it is worth taking the time to make sure they collect, store and process the specimen correctly. It is customary to discard the first voided specimen in the morning, then collect all other specimens, including the first voided specimen, the following morning. It is important to stress to patients the correct collection technique and procedures to avoid inadequate, under-collected specimens and over-collection. Many patients find it most convenient to do the collection on a Sunday so it can be mailed or delivered to the laboratory early on Monday morning.[9]

It is advisable to use a reference laboratory that routinely performs many 24-hour urine chemistry tests as quality control measures tend to be better, turnover time is reduced, and incomplete results are less likely. Using a single reference laboratory for all of the 24-hour urinary chemistries is recommended as it avoids incomplete test reports and reduces the lead time from specimen submission to receipt of the complete results.

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 955 mg to 2,936 mg in men and 601 mg to 1,689 mg in women. This can also be written as 13 to 29 mg/kg of body weight per 24 hours in men and 9 to 26 mg/kg of body weight per 24 hours in women. Insufficient total creatinine for a 24-hour urine test should raise the question of a possible inadequate collection.[9]

Several studies have suggested that two 24-hour urine tests provide substantially more reliable results than a single collection.[9] Up to 45% of patients will ultimately show substantial differences between the two 24-hour urine samples. However, the difficulty in obtaining these would include extra cost and a much greater degree of patient compliance.[9]

To paraphrase Dr. Fredric Coe, widely regarded as the world's leading expert in medical stone disease, a properly collected and performed 24-hour urine test is the cornerstone 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 will be erroneous, ultimately harming patients. No degree of medical expertise or experience can overcome the problems created by an improperly collected, poorly stored, incomplete, or otherwise badly performed 24-hour urine chemistry profile.

Diagnostic Tests

If the patient or patient's family has a history of cystine stones or if the stone's chemical composition is unknown, then 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 will convert urinary cystine to cysteine, which then binds to the nitroprusside turning the sample an intense purple color. This simple, qualitative test for urinary cystine will typically be positive at 75 mg cystine per gram creatinine. If positive, a quantitative cystine level should be checked.

While not technically part of the 24-hour urine test, other chemistry tests are extremely helpful. For example, it is beneficial to have the stone's chemical composition, if possible. Recommended serum chemistries include potassium, creatinine, phosphate, calcium, and uric acid. High or high-normal serum calcium levels and hypercalciuria on 24-hour urine testing suggest possible hyperparathyroidism for which specific testing (intact parathyroid hormone levels) should be performed. Elevated serum uric acid levels would suggest hyperuricemia and/or hyperuricosuria. Low serum phosphate might indicate renal phosphate leak, which causes a vitamin D-dependent form of hypercalciuria that only responds to oral phosphate supplementation.

24-Hour Urine Testing

An optimal 24-hour urine test should include calcium, citrate, magnesium, oxalate, phosphate, sodium, sulfate, uric acid, and volume values. The most significant of these will be discussed individually. There are separate review articles on each that should be checked for additional details and information beyond what is presented here.

Hypercalciuria (Calcium)[10]

Dietary calcium is necessary for human nutrition, affecting bone health and muscle activity. Serum calcium levels are carefully controlled, but in calcium nephrolithiasis, clinicians often find increased urinary calcium levels (hypercalciuria), which directly contribute to the formation of calcium stones.

High urinary calcium is frequently found in many patients with calcium kidney stones. Reducing dietary calcium seems an obvious treatment option if the ingested calcium is excessive, but most people have reasonable, moderate dietary calcium (dairy) intake. 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.

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

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

Thiazide medications are the next step if the dietary calcium intake is not unreasonable and serum chemistry indicates normal calcium levels. This class of drugs was originally used as a diuretic but has been found to be very useful in reducing urinary calcium excretion. Thiazides are now recommended, by both the EAU and the AUA guidelines, for patients with hypercalciuria and recurrent calcium nephrolithiasis.[11][12] They will not work if salt (sodium) is not controlled, so patients on thiazides are asked to limit their salt intake. Reducing daily sodium intake by 100 mEq can lower urinary calcium excretion by 50 mg a day. Thiazide use in hypercalciuric calcium stone formers can reduce median annual stone production from 2.94 to 0.05 (P<0.001).[13]

Thiazides can cause hypokalemia, increase uric acid levels and lower urinary citrate, but their beneficial effect overshadows these effects in substantially lowering urinary calcium. Potassium citrate should be added as needed if hyperuricosuria, hypokalemia, or hypocitraturia develops. Thiazides contain a sulfa molecule, so they must be initiated and used cautiously in patients with severe sulfa allergies.

Hydrochlorothiazide, chlorthalidone and indapamide are the most commonly prescribed thiazide medications. Of these, chlorthalidone and indapamide are generally preferred for use in stone disease due to their longer half-life and once-a-day dosing schedule. A repeat 24-hour urine test should be performed during treatment to check the effectiveness of the thiazide therapy and to monitor for hyperuricosuria or hypocitraturia, usually about three 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.[10] 

Hypercalciuria can cause bone calcium loss, resulting in osteopenia or osteoporosis, which is reversible using thiazides.[13][14]

Vitamin D deficiency will be found in many nephrolithiasis patients.[15] Treating these patients with vitamin D and calcium supplementation is somewhat controversial. Changes in hypercalciuria can be identified by performing repeat 24-hour urine studies at periodic intervals. Vitamin D supplementation and hypercalciuria treatment can be modified accordingly to optimize both chemistries.[16][17]

Oral phosphate supplements should be utilized if dietary calcium moderation with low urinary sodium and appropriately dosed thiazide therapy are inadequate to control hypercalciuria. These are generally some combination of sodium phosphate and potassium phosphate. Such phosphate supplements will lower calcium absorption by the GI tract directly, through intestinal calcium-binding, and indirectly, primarily through their effect on vitamin D.

In renal phosphate leak hypercalciuria, there is an obligatory excessive urinary loss of phosphate. This lowers the serum phosphate level, which stimulates vitamin D activation (conversion of 25 [OH] vitamin D to 1,25 [OH]2 vitamin D) by the kidneys. This higher vitamin D level will increase the GI absorption of phosphate to correct the hypophosphatemia and increase calcium absorption. Absorbed calcium is eventually excreted in the urine, causing hypercalciuria. Thiazides are ineffective because the underlying etiology is a vitamin D-dependent disorder. Treatment involves using an oral phosphate supplement to correct the hypophosphatemia without the need for increased renal vitamin D activation, which would otherwise result in unwanted hypercalciuria.[10] Proper treatment of renal phosphate leak hypercalciuria with oral phosphate supplementation can substantially reduce renal stone production and improve quality of life scores in this small group of affected patients.[18]

Bisphosphonates and rank ligand inhibitors will 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, there are only limited studies on their use in hypercalciuric patients. No long-term data is available, and they are not currently recommended or approved for that indication. Patient selection and appropriate monitoring would be critical as some obligatory hypercalciuric patients may not respond, possibly resulting in net calcium loss, hypocalcemia, worsening osteoporosis, and other metabolic problems.[10]

Hypercalciuria Summary

Excessive urinary calcium is a strong promoter of calcium urolithiasis. Strict limits on dietary calcium should be avoided as they often cause more harm than good through reduced intestinal oxalate-binding and resulting in hyperoxaluria, where calcium stone production increases. Moderate dietary calcium intake is recommended. Serum calcium should be checked, and further investigation for hyperparathyroidism is warranted if hypercalcemia is found. Medications such as thiazides can help the body retain calcium by reducing hypercalciuria, but sodium intake needs to be limited, or this beneficial hypocalciuric effect of thiazide treatment is lost. Thiazide therapy can cause an increase in uric acid levels and reduce urinary citrate, so many of these patients will also benefit from supplemental potassium citrate. Oral phosphate therapy should be used if these initial measures do not effectively control their hypercalciuria.

Urinary calcium excretion can be successfully managed by using one or more of these therapies in most patients with calcium kidney stones.

• "Normal" 24-hour urinary calcium excretion is less than 250 mg.
• "Optimal" would be less than 200 mg or less than 100 mg/L urine.

Hypocitraturia (Citrate)[19]

Citrate is the body’s natural urinary antacid and corresponds to serum bicarbonate, converted to citrate in the kidney. Serum bicarbonate is the body's primary chemical acid/base buffer.

Citrate is a wonderful urinary chemical. It not only neutralizes excess uric acid that helps dissolve uric acid stones and crystals, but it also helps prevent microscopic calcium oxalate crystals from sticking together and forming stones. Lemon juice is rich in natural citrate, so 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. However, every bit helps.

Citrate is found in almost all citrus fruits, but most patients with significantly reduced urinary citrate levels will require a specific, concentrated citrate supplement such as potassium citrate. This is available as both tablets and a liquid. The tablets tend to be quite large, like vitamin pills, which can be hard to swallow for some patients. The tablets will sometimes be seen in the stool, making some patients think they are not working. This 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 GI upset and stabilize urinary citrate levels. Patients need to be informed that it is not unusual to occasionally see a potassium citrate tablet in the stool.[20]

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 1,000 mL of urine. So if the urinary volume is high, extra citrate will be needed to maintain an optimal concentration level. Typical dosages of potassium citrate would be ten to twenty mEq 3 or 4 times a day.[20] Serum potassium levels should be checked periodically, especially when the potassium citrate dosage increases or the patient has renal failure. As a general guide, 30 mEq of potassium citrate will increase the daily urinary citrate level by about 200 mg. (Potassium citrate package insert)

If the potassium citrate dosage required is relatively low, the potassium citrate supplement should be taken at bedtime to mimic the "alkaline tide" that normally occurs overnight. A common nocturnal dosage would be two of the ten 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 extremely acidic urine and require substantial potassium citrate supplementation to optimize their urinary pH levels. Urine pH can be measured using pH paper available in most pharmacies or FDA-approved urinary dipsticks.[20]

Patients receiving subcutaneous human parathyroid hormone therapy for hypoparathyroidism have developed 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.[21]

Hypocitraturia is frequently found in various nephropathies. It is associated with the degree of renal impairment but not with serum bicarbonate level. This 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.[22]

Potassium citrate tablets act as urinary antacids and will increase both urinary alkalinity (pH) and citrate levels.[20] Limiting factors for potassium citrate supplementation include tolerability (some patients may notice some GI upset problems after taking potassium citrate supplements), difficulty swallowing the large tablets, and elevated serum potassium. The goal of therapy will vary according to the specific situation. For calcium oxalate stone formers, reaching and maintaining an optimal urinary citrate level of 300 mg/L of urine is the goal. 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. Optimal urinary pH levels in most calcium stone formers are usually around 6.5. One approach is to ask patients to take as much potassium citrate as they can reasonably tolerate as long as their urinary pH does not exceed 7 or serum potassium levels exceed normal limits.[20]

Alternative Treatments for Hypocitraturia Other than Potassium Citrate

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 has or is likely to develop hyperkalemia on standard potassium citrate supplements.  Disadvantages include a significant sodium load, frequent dosing requirements, and the need to take the medication as a liquid. 

Various citrate supplements (both prescription and non-prescription) are commercially available and relatively inexpensive. Some have substantially less potassium than standard potassium citrate prescription products, which is useful 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, post-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, but sodium bicarbonate carries a significant sodium load, increases urinary calcium, and is relatively short-acting.

Acetazolamide, a carbonic anhydrase inhibitor, is a diuretic that is indicated for treating high-altitude sickness and glaucoma. But it can also be used to raise urinary pH by reducing renal bicarbonate reabsorption as an alternative to or in addition to taking additional potassium citrate or sodium bicarbonate supplements. Acetazolamide effectively raises urinary pH, but it causes metabolic acidosis and predisposes patients to urinary calcium phosphate crystal formation and kidney stone production. Acetazolamide will significantly lower urinary citrate excretion, so it should not be used purely for hypocitraturia. The hypocitraturia it produces 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 would be 125 mg to 250 mg twice a day.[23]

Topiramate is another carbonic anhydrase inhibitor used to treat migraines and prevent seizures. It tends to cause metabolic acidosis, which reduces urinary citrate excretion. This effect disappears if the medication is stopped.[24] Its impact on urinary citrate can be minimized in patients who are unable to stop topiramate by the use of potassium citrate supplements.[24][25] While 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 are high in citrate but are also relatively high in oxalate. (Not recommended in patients with hyperoxaluria): Asparagus, barley, beans, brown rice, broccoli, green leafy vegetables, green beans, lettuce (romaine), collard greens, oats, quinoa, oatmeal, lentils, peanuts, wheat, and whole grains.

Hypocitraturia Summary

Citrate is the body’s natural urinary antacid that helps prevent both calcium and uric acid stone formation. If the urinary antacid or citrate level is low, patients should be asked to drink lemonade made from real lemon juice and take some extra potassium citrate tablets or liquid supplements. Some pure uric acid stones can be dissolved by adjusting the urinary antacid or citrate levels. Regularly checking the urinary pH may be necessary to maintain optimal potassium citrate dosing as well as urinary pH and citrate levels.

• "Normal" 24-hour urinary citrate is about 320 mg.
• "Optimal" 24-hour urinary citrate for calcium stone formers is about 320 mg per 1,000 ml urine, typically totaling about 640 mg or more and assuming an optimal 2,000 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 (Oxalate)

Oxalate is an organic chemical made 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, so they produce oxalate in various places, such as in their leaves, fruits, nuts, and seeds that they shed. As the dissolved calcium passes through these areas, it becomes tightly bound by the oxalate.  Eventually, that part of the plant is discarded, and the oxalate is removed along with its tightly bound calcium.

Humans make tea from the leaves and call many other plant products “food.” In this way, people ingest a fair amount of oxalate every day. This amount varies according to which varieties of vegetables and plants people eat, how much they ingest, and the original groundwater calcium content of the field 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 in the urine, oxalate tightly binds to any available calcium and starts to make calcium oxalate crystals and stones. Oxalate is 15 to 20 times stronger than calcium as a chemical promoter of nephrolithiasis, and the majority of calcium stones in humans are largely composed of calcium oxalate.

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

"Normal" urinary excretion is up to about 40 mg of oxalate daily, but the goal is to get this level down to less than 25 mg per day or less than 15 mg/L of urine in calcium oxalate stone formers.

Foods with particularly high oxalate levels include green leafy vegetables like spinach, collard greens and chard, beets, chocolate, nuts, rhubarb, and strong teas. Physicians primarily rely on dietary measures to reduce oxalate intake by avoiding higher oxalate foods and substituting lower oxalate choices.[26] While no specific medication will correct 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.[27] 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 <70 mg/day.

If such dietary measures prove inadequate, calcium supplements can be added. Calcium citrate is preferred as it dissolves better than other calcium supplement compounds. Taking it with a glass of milk is recommended. Calcium citrate without added vitamin D is suggested because it is desirable to avoid early intestinal calcium absorption, facilitating oxalate binding in the lower GI 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.[28][29]

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 will contain about 750 mg. Collard greens and rhubarb are similar high-oxalate foods that physicians may recommend the patient eliminate or severely limit in many hyperoxaluric nephrolithiasis patients.[30]

Vitamin B-6 is used to assist the liver in dealing with oxalate and hyperoxaluria. It is often recommended since it has other health uses and is quite inexpensive. It will sometimes reduce 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, usually lunch and dinner. Clinicians should provide patients with a complete listing of the oxalate content of foods. This is 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 very low calcium diets, which will 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. It 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 are post-bariatric surgery patients.[31]

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

Oxalobacter is a natural bacterial inhabitant of the intestinal tract, a facultative anaerobe, and can digest oxalate. Its oxalate-digesting enzyme may someday be available as a pill, capsule, or powder for therapeutic use in patients with hyperoxaluria.[32][33]

There is continuing research on using enzymes to help digest oxalate in the GI tract. Currently, at least three separate several oxalate-digesting decarboxylase enzymes are being studied. Significant reductions in urinary oxalate have been found in small studies.[31][34] A recent study of one oxalate decarboxylase showed significant benefits in reducing urinary oxalate by an average of 29%. This oxalate-digesting enzyme treatment was given to patients three times a day and showed an excellent safety profile.[35] However, the study was relatively small, involving only 33 individuals, the results showed a highly variable degree of urinary oxalate reduction, and most of the patients involved had relatively mild hyperoxaluria. Still, this is a promising start. Since there are no currently available specific therapeutic medications for patients with hyperoxaluria, it is hoped this product and others like it will soon become available.[35]

Stiripentol is an FDA-approved anti-seizure medication specifically designed for children over two years of age with Dravet syndrome. It inhibits lactic dehydrogenase (LDH) isoenzyme 5, which converts glyoxalate to oxalate. In animal models and a few children taking the medication, significant reductions (up to 66%) in oxalate excretion were observed.[36]

Enteric Hyperoxaluria

Patients with irritable bowel syndrome (IBS), previous bariatric (Roux-en-Y) surgery, or any chronic diarrhea problem, are at increased risk of kidney stone formation due to high urinary oxalate levels from enteric hyperoxaluria. This is a particularly severe form of hyperoxaluria, often at levels of double or even triple the normal daily maximum urinary oxalate excretion level. The condition is caused by fat malabsorption and is associated with many types of chronic intestinal disorders, particularly after bariatric surgery (Roux-en-Y). Fat malabsorption increases intestinal calcium binding by free fatty acids. This drastically reduces the free calcium available for oxalate binding in the lower GI 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, which contributes to reduced urinary volumes and a loss of bicarbonate (which is why these patients often complain of rectal burning). It also explains the severe hypocitraturia that typically accompanies this condition.[37]

Treatment of enteric hyperoxaluria includes increased fluid intake to offset the decreased urinary volume, calcium citrate supplements to increase intestinal oxalate-binding, potassium citrate (liquid versions if possible) for the bicarbonate loss and resulting hypocitraturia, reduction in dietary fats and oxalate, and the use of cholestyramine or similar bile acid sequestrants. A substantial amount of calcium citrate and potassium citrate supplementation may be needed to effectively correct the metabolic disturbances in these patients.

Recently, it has been suggested that enteric hyperoxaluria may also involve increased oxalate production from the liver and/or intestine. This hypothesis would help explain the lack of response to treatment in some enteric hyperoxaluric patients but will require more research to verify. 

SYNB8802 is an engineered bacterial therapeutic being studied for its ability to lower urinary oxalate in individuals with enteric hyperoxaluria. This has so far been successful when studied in mice and primates, where SYNB8802 was able to consume excess intestinal oxalate resulting in significantly reduced urinary oxalate levels in these animal models.[38]

Primary Hyperoxaluria

Primary hyperoxaluria is a very rare (1-3 patients per 1 million population in the USA and Europe) but severe form of hyperoxaluria. There are less than 10,000 known cases in the US, but estimates are that 80% of affected individuals are undiagnosed.[39] Primary hyperoxaluria is an autosomal recessive disorder that causes severe and sustained elevated oxalate levels in the serum and urine. This 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 B-6, dialysis, liver transplantation, and combined liver-kidney transplants.

The FDA approved Lumasiran for primary hyperoxaluria type 1 in November 2020. Lumasiran is a small interfering RNA that blocks glycolate oxidase, which normally converts glycolate to glyoxalate. This 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 six months of therapy.[40][41] Patients with elevated urinary oxalate (>70 mg/24 hours) and confirmed genetic testing for primary hyperoxaluria type 1 (alanine glyoxylate aminotransferase mutations) are potential candidates.[42]

Nedosiran is an investigational agent for primary hyperoxaluria. It works similarly to lumasiran but targets hepatic lactate dehydrogenase. This is significant because it could potentially affect all three types of primary hyperoxaluria. Early studies show a mean oxalate reduction average of 55%.[43][44][45] 

Lanthanum carbonate has been used as an intestinal oxalate binder with significant oxalate-reducing efficacy in limited animal studies and isolated human case reports.[46] Human studies have included two case reports of an anuric patient with primary hyperoxaluria type 1 on dialysis and a primary hyperoxaluria patient with normal renal function and severe hyperoxaluria of 109 mg/day. Both patients demonstrated significant oxalate reduction benefits from the lanthanum carbonate. Hyperoxalemia was normalized in the anuric patient, and the other individual saw a reduction in urinary oxalate of 55%![47] Lanthanum carbonate does not interfere with citrate therapy or affect urinary calcium excretion and is 99% excreted in the bile, so it can be used in patients with renal failure.[48] Its usual dosage is 250 mg three times a day. It is normally used to treat hyperphosphatemia in patients with end-stage renal failure on dialysis.[40][46][47]

Hyperoxaluria Summary

Oxalate is a naturally occurring chemical found in most plants and vegetables, especially spinach, kale, collard greens, and nuts. Its only known chemical function is to bind tightly to calcium. Unfortunately, in humans, this happens in the urinary tract, where calcium oxalate crystals can aggregate and create calcium oxalate stones. Oxalate is considered the single strongest kidney-stone-promoting urinary chemical. There is no specific medication for high urinary oxalate, so treatment relies mostly on reducing dietary oxalate intake. Selective use of calcium citrate supplements timed to coincide with the patient's high oxalate meals can be very helpful in limiting intestinal oxalate absorption and urinary oxalate levels. Vitamin B-6, iron supplements, oxalate-digesting enzymes, and cholestyramine can also be used and optimize all other urinary chemistries.

• "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.

Sodium (Salt)

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

Many people use too much salt and have difficulty reducing their salt intake. The human body only needs about 500 mg of sodium per day to live, yet Americans typically consume an average of 3,436 mg daily.

A single teaspoon of table salt has about 2,300 mg of sodium. The optimal salt intake should be no more than 1,500 mg daily, but even a modest limit of 2,300 mg daily would be helpful. This is not very much, considering that a typical hot dog has about 600 mg of sodium, not counting the condiments.

People get enough sodium for general health by eating fresh foods with little or no salt. A simple solution to high urinary sodium levels is to reduce dietary salt intake, but this can be hard because it is added to almost every packaged and prepared food and most recipes.

Electrolyte and "sports drinks" are generally discouraged due to their relatively high sodium content. 

Tips to Reduce Salt (Sodium) Intake

Beware of Hidden Salt

Canned food can be up to 10 times higher in salt than fresh or frozen food. Even “low sodium” on the label may only mean less salt was added. Look for cans with a “no salt added” label and then read the sodium levels listed to ensure. Canned vegetables and commercial tomato and vegetable juices have surprisingly high sodium levels due to added salt. Almost every canned food will have salt added, and usually quite a lot, so patients should read the labels carefully and compare.

When comparing sodium levels, be aware that food manufacturers will often list sodium content "per serving," and there are often multiple "servings" in the food product.

Salt is used in baking bread to keep the yeast from overworking. Cheese is naturally salty with one-half cup of cottage cheese and a single 1-ounce slice of American cheese, each containing 400 mg of sodium.

Any preserved meat, such as cold cuts, will be high in salt as it is used not only for taste but as a preservative.

Eating Out

Restaurant food, especially fast food, including pizza, is high in salt and sodium content. At the restaurant, recommend that patients ask their waiters to request that the chef omit salt in cooking and have any sauce on the side so patients can choose to use less.

Often, pepper or lemon juice can be a tasty substitute for salt in most dishes and recipes.

Restaurant soups are notoriously high in salt, and there is no way to take the salt out, so patients looking 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 will usually be very high in salt, so limit the use of ketchup, mustard, soy sauce, pickles, barbecue sauce, steak sauce, Worcestershire sauce, and prepared salad dressings. Substituting oil and vinegar for prepared or house salad dressing is also suggested.

Other Tips

• Select low-salt 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. If following a cooking recipe, remember that salt can always be added later if necessary. Have patients start by cutting all added cooking salt in half for a few weeks. After a few weeks, their taste buds will get used to the reduced salt, and it can often be reduced by another 50% easily. Herbs, spices, vinegar, pepper, and similar products can be reasonable salt substitutes.
• 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, ask patients to rinse them and drain them several times to eliminate as much salt as possible.
• Remind patients that sea salt has the same amount of sodium as regular table salt.
• “Low-sodium” only means that the product has between 25% to 50% less salt than the original. This helps, but the total sodium content may still be quite high.

Sodium Summary

Salt or sodium can increase fluid retention and bloating, interfere with calcium metabolism and block the effect of urinary calcium-lowering medications like thiazides. It can be difficult to avoid eating salt because it is included in many food products. Have patients follow the tips and suggestions above to optimize their salt intake and minimize urinary sodium levels.

• "Normal" 24-hour urinary sodium is less than 200 mg.
• "Optimal" 24-hour urinary sodium is less than 150 mg.

Hyperuricosuria (Uric Acid)

Uric acid is a waste product that is normally produced by the liver. Abnormally high uric acid levels in the blood can cause uric acid crystals to form in the joints, producing intense pain and inflammation, known as gout. This is usually due to a liver problem and is frequently treated with allopurinol, colchicine, indomethacin, probenecid, or febuxostat.

High uric acid levels in the urine can produce both uric acid and calcium oxalate stones depending on the specific urinary chemistry and pH. High meat (purine) intake will tend to increase the amount of uric acid the body produces. For these reasons, all dietary meats will tend to increase uric acid levels, including beef, pork, veal, seafood, fish, organ meats, poultry, and chicken. Most people tend to eat far more meat than they need. Fish and chicken are healthier than beef and pork for other reasons like cholesterol, but they are equivalent regarding uric acid production. A complete listing of uric acid food content in various foods can be found in the uric acid patient education guide section.

Elevated urinary uric acid levels will tend to produce uric acid crystals in the urine. These small crystals can act like seeds and allow calcium stones to form around them, similar to seeding a cloud. In this way, high uric acid levels in the urine can promote the formation of calcium stones.

Most pure uric acid stones are caused by too much total acid or insufficient antacid. PH measures antacid levels in urine and other fluids. Low antacid levels with a urine pH of 5 or less are typical of many uric acid stone formers. Normal urine pH is between 5 and 7. The optimal urinary pH in uric acid stone formers is usually around 6.5, so clinicians will typically ask patients to take enough supplemental urinary antacid (potassium citrate) tablets or liquid to maintain their urinary pH at 6.5 without going over 7.0. Potassium citrate supplements increase urinary pH and antacid (citrate) levels.

Pure uric acid stones can be dissolved with adequate antacid (potassium citrate) supplementation, which cannot be done with calcium stones. The patient must take sufficient potassium citrate to maintain an average urinary pH of around 6.5 to 7.  Many patients with uric acid stones have extremely acidic urine and require substantial antacid (potassium citrate) supplementation to optimize their urinary pH. PH paper, available in many pharmacies, can measure urine pH. Urinary dipsticks designed for home urine pH measurements are available online.

Allopurinol is frequently used when diet alone is inadequate and the blood or urinary uric acid levels are elevated because it normalizes these values by working directly on the liver. Elevated serum uric acid levels may also need to be treated, especially in patients with gout. Optimal blood uric acid levels are around 6 mg/dl, and the optimal 24-hour urine uric acid excretion is 600 mg or less. Allopurinol is generally used if this cannot be done with diet alone. Vitamin B-6 is sometimes added to the allopurinol as well. Febuxostat is a newer drug similar to allopurinol in lowering uric acid production.[49][50][51]

Colchicine and indomethacin are strong, anti-inflammatory drugs that do not directly affect serum or urinary uric acid levels and may cause significant side effects. Their use 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

Low Uric Acid Foods: 0 to 50 mg per 100 gm.

All fruits, vegetables including string beans, olives, and peas except those listed below, bread, cakes, pasta, and most breakfast cereals, dairy products including milk, cream, yogurt, ice cream, cheese and eggs, butter, cooking oils, salad dressings and mayonnaise, nuts except for peanuts, peanut butter and cashews, preserves and jams, and beverages including tea, coffee, and soft drinks.

Moderate Uric Acid Foods: 50 to 150 mg per 100 gm.

All poultry such as chicken, duck, and turkey except red meats including beef, veal, lamb, pork, bacon, and sausages, fish except the seafood listed below, shellfish and shrimp including oysters, mussels, clams and prawns, wholegrain bread, cereals, and pasta including brown rice and oatmeal, beans and lentils, including tofu, miso, and chickpeas, peanuts, peanut butter and cashews, green leafy vegetables such as cauliflower, broccoli, brussels sprouts, spinach, asparagus, avocado and mushrooms.

High Uric Acid Foods: 150 to 1,000 mg per 100 gm.

Wild or farmed game include pheasant, quail, rabbit, venison, organ meats such as liver, kidneys, heart, sweetbreads, foie gras, chopped liver, meat and yeast extracts such as Bovril, oxo, marmite, vegemite, fish egg products such as caviar, seafood such as scallops, herring, mackerel, trout, crayfish and lobster, small fish eaten whole or processed like anchovies, sardines, sprats, and anchovy paste.

Hyperuricosuria Summary

Uric acid is a waste product of meat protein (purine) metabolism. It can cause hyperuricemia and gout, promote calcium stone formation, and produce uric acid stones. Optimal treatment of uric acid stones may involve dietary limitations of meat, fish, beef, and poultry, along with medications like allopurinol to reduce liver production of uric acid and potassium citrate supplements, which act as natural urinary antacids that dissolve uric acid crystals and help prevent calcium stone production. Monitoring of urinary citrate levels by periodically checking the urinary pH and/or 24-hour urinary citrate levels is recommended for optimal benefit. 

• "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.

Low Urinary Volume

A high urinary volume is essential for the prevention of kidney stones. The average 24-hour urinary volume in normal individuals is about 1,300 ml per day or roughly 3 pints. Patients with kidney stones are asked to drink sufficient water to produce at least 2,000 mL or 2 liters of urine a day or more, which is slightly over a half-gallon or 4 pints. A low urinary volume will significantly increase the concentration of calcium, salt, and other minerals predisposing the patient to new kidney stone formation. The easiest way to correct this is to increase oral fluid intake, which is often difficult for many patients.

Clinicians should suggest that at least one-half of all new oral fluid intake should be water. Patients should avoid using electrolyte sports drinks and similar products to increase urinary output as they contain too much salt (sodium). Cranberry juice is not recommended in excess due to its moderately high oxalate content. If a patient likes cranberry juice, a glass or two is not a problem, but increasing it beyond moderate levels is not recommended. A good substitute for water is lemonade made with real lemon juice because lemon juice is high in citrate, a natural stone-preventing agent. The majority of any extra fluid ingested will increase the patient's urinary volume because all of the necessary, obligatory bodily requirements for fluids are already satisfied.

The patient's urine should appear no darker than a very pale yellow as a general rule. 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 and then adding up the totals for a 24-hour period. This makes it easy to compare to the optimal recommended levels. Specific gravity can measure urinary concentration. Optimal urinary specific gravity readings should consistently be 1.005 or less.[52]

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.

Modifying or associating various daily activities with a "penalty" that requires a small extra glass of water is another way of increasing fluid intake relatively painlessly. The plan consists of a series of “penalties” based on common everyday activities that will prompt and remind the patient to take an extra drink of water. This may be difficult initially, but it will become automatic once the patient becomes accustomed to the extra fluid. Depending on the patient's tolerance and metabolism, their system will gradually adjust to the increased fluid, and they will become thirsty if they fail to keep their fluid intake up. This usually takes about a month or 2 of regular increased fluid intake.

Each extra glass of water can be as little as just 4 ounces. The smaller glass of water is less intimidating and easier to drink, particularly when patients may not feel thirsty. Asking patients to drink an extra 8 or 12-ounce glass of water may sometimes be too intimidating, so substituting smaller glasses has been recommended. Drinking small 4-ounce glasses of water can quickly add up to a substantial increase in urinary output.[52]

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

Here are some tips and "penalties" that can help patients achieve and maintain a better urinary volume to help dilute all the urinary minerals and stone-producing chemicals they produce. Patients can implement as many of the following "penalties" as necessary to generate the daily target urinary output, which for most patients is at least 2,000 ml per day, and the "optimal" is 2,500 ml.

"Penalty" List

• Bathroom Penalty: An extra 4-ounce glass of water with every visit to the bathroom, regardless of the reason.
• Chair Penalty: Have a bottle of water and a 4-ounce glass next to their favorite chairs at home. Instruct the patient to drink one 4-ounce glass before getting up from the chair.
• Cheating Penalty: If they eat or drink a restricted item beyond the allowable limit, one extra glass of water.
• Kitchen Penalty: One glass of water whenever they walk into their kitchen.
• Leaving Home Penalty. One extra glass of water prior to leaving home and another when they return.
• Meal Penalty: One extra glass with each meal except when they eat out, where they will need two extra glasses.
• Medication Penalty: One extra glass of water when taking medications. This is in addition to whatever patients are instructed to take normally with their medications.
• Nighttime Bathroom Use Penalty: One glass of water whenever they get out of bed to go to the bathroom at night.
• Snack Penalty: One extra glass of water if they have a snack between meals or bedtime.
• Summertime Penalty: Double all other penalties during the summer or when outside temperatures exceed 85 degrees.
• Time Penalty: One glass of water if the patient has managed to avoid all other “penalties” for 2 hours during the daytime.
• Water Fountain Penalty: They must drink at least 5 swallows whenever they pass a water fountain.
• Work Penalty: One glass of water whenever they leave their main desk or workplace. Patients should always have water and a 4-ounce glass available on their desks, in their cars, or within easy reach.

If the above suggestions fail to adequately increase the urinary output, a diuretic medication can be used as a last resort. This will force a mandatory increase in urinary volume but can cause mineral and salt imbalance in the blood and a number of other complications. Failure to increase oral fluid intake while taking a diuretic can easily lead to dehydration.

It is rarely necessary to resort to all of these measures to increase the urinary output to optimal levels, but it is work, and it can be challenging for patients to do in the beginning. Eventually, the patient's system will adjust to the extra fluid, and they will start to get thirsty if they miss some of the extra fluid intake. Just advise them to stick with it long enough; the extra fluid intake will slowly become their new normal routine. No other treatment for the stone disease will be 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.

Check the patient's progress by having them measure their urinary volume monthly and suggest they add as many “penalties” as necessary to achieve their optimal total urinary volume target. This will significantly reduce the risk of forming new kidney stones.

A new vasopressin receptor antagonist (tolvaptan) has significantly increased urinary volumes in kidney stone formers.[53] Tolvaptan works to increase urinary output by enhancing free water excretion by the kidneys. A pilot study has been done to evaluate its safety and tolerability in human subjects.[54] It was tested in 4 young cystinuria patients. The patients all noted significantly increased urinary volumes. No liver problems or electrolyte abnormalities were seen, but all noted dramatically increased thirst.[54] A vasopressin antagonist can potentially reduce kidney most stone risk factors in patients who tend to be dehydrated but cannot adequately increase their oral fluid intake and urinary volumes.[55][56]

Low Urinary Volume Summary

Increasing urinary volume by drinking more water is helpful for all kidney stone formers regardless of any other factors. The amount of additional water to drink is best determined by measuring the urinary output and adjusting it as needed to generate a 24-hour urine volume of 2,000 to 2,500 mL. This can best be achieved by using the tips and suggestions mentioned earlier. In theory, there is no upper limit to the amount of urinary volume from the point of view of stone prevention. Still, realistically the inconvenience of the increased urinary frequency higher volumes produces makes it impractical. "Normal" and "Optimal" 24 Hour Urinary Volumes are 2,000 to 2,500 mL, respectively.

Clinical Significance

Why Do 24-Hour Urine Testing?

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. It can find and identify kidney stone chemical risk factors that are amenable to dietary or medical therapy and may have other medical or health-related benefits. It avoids preventable complications, pain, and surgeries. Future stone production can be reduced by 90% or more. It can identify underlying medical problems not easily diagnosed by any other means, such as hypercalciuria, renal tubular acidosis, renal phosphate leak, cystinuria, hyperoxaluria, and hypocitraturia. 24-hour urine testing is recommended by the American Urological Association (AUA Guidelines) and other professional organizations, even for first-time stone formers. Such testing can be kidney-saving or life-saving in some patients. There are also potential medical/legal implications. Finally, the testing, interpretation, and treatment selection can be greatly simplified, making it easy to perform and interpret in any medical practice by using the previously presented guidelines.

What to Do After Testing

After the patient has been on therapy for at least several months, performing another 24-hour urine test is advisable. The purpose is to ensure the treatment effectively controls the problem it is intended to correct and that the patient is compliant with therapy. This also allows for dosage adjustments and/or a change in therapy. Sometimes, a new problem will become evident. Most of the time, final adjustments are made, and a yearly 24-hour urine collection is recommended for maintenance. This visit can be combined with an annual KUB and/or the renal US to check for any newly formed stones. The yearly 24-hour urine recheck allows for reminding and reinforcing patient instructions, review of previously recommended therapies, and the annual renewal of any medications with possible dosage adjustments.  In complicated cases, repeating the 24-hour urine testing and treatment modifications every three months is recommended until optimal results are achieved, then usually yearly.  

When it Isn't 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 as there is currently no specific drug for this particular problem. In these cases, optimize as many chemistries as possible and try to achieve the best result possible for the rest.  24-hour urinary fluid volume is usually the first place to start with optimization. Maintaining good patient compliance is necessary, so a positive attitude is helpful when discussing results with patients. 

How to Increase Long-Term Patient Compliance With Therapy

There is no magic formula to ensure patient compliance with treatment. Start at the very beginning by informing patients that 24-hour urine testing will only be effective if they are committed to long-term compliance with treatment recommendations. If they miss a treatment, cheat on their recommended diet or fail therapy in some other way, they will not notice any immediate painful penalty. A bad diabetic who forgets to take their morning insulin will likely be in the Emergency Department for treatment of hyperglycemia that afternoon. They would be unlikely to forget their insulin treatment again. There is no immediate or obvious penalty for cheating or forgetting their therapy in kidney stone prophylaxis. But six months or a year later, they may develop a kidney stone they could have avoided. Inform prospective patients that it's human nature to take advantage of the lack of any immediate harm or penalty to "cheat" on their treatment. For many, this progresses to the point where they no longer follow prophylactic recommendations. Informing patients of this fact early in treatment seems to help long-term compliance, but this remains a common problem without a good solution.

Repeating the 24-hour urine test yearly also helps remind patients of the importance of their treatment and its effectiveness and assists the clinician in fine-tuning 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, moderate any excessive dietary calcium. Do not overly restrict calcium intake to avoid a reactive increase in oxaluria and possible osteoporosis. If the dietary calcium intake is reasonable and hypercalciuria persists, add indapamide 2.5 to 5 mg daily, chlorthalidone 25 to 50 mg per day, or a similar thiazide.  If the urinary sodium is elevated, the salt intake will have to be restricted, or the thiazide therapy will not effectively lower urinary calcium. If thiazides are unsuccessful, try oral phosphate therapy, as the patient may have a Vitamin D-dependent hypercalciuria.

Hyperoxaluria: Dietary measures are the primary treatment for hyperoxaluria. Add vitamin B-6 as it helps some patients with their liver metabolism of oxalate. If these steps are inadequate, a calcium citrate supplement can be added to the evening meal to help increase intestinal oxalate binding since most oxalate is ingested at that time. If the patient has chronic diarrhea, a history of bariatric surgery, or colitis, they may be prone to enteric hyperoxaluria, which requires calcium citrate and potassium citrate to control the oxaluria. Cholestyramine can help reduce bile acid effects, especially when other measures are insufficient. A probiotic can be added as it may help intestinal digestion of dietary oxalate by optimizing the gut bacteria.

Hypocitraturia: Lemonade made with real lemon juice will help a little, but most patients will need concentrated potassium citrate supplements, either tablets or liquid. The liquid version is preferred in patients with IBS or post-bariatric surgery. The optimal 24-hour urinary citrate is 300 mg/L or about 600 mg daily. Increase citrate supplementation 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. Consider adding sodium bicarbonate or a similar urinary antacid product as necessary for patients who cannot take more potassium citrate but have not yet reached their "target" levels of urinary citrate or pH.

Low Urinary Volume: Patients will need to increase their fluid intake. Use the “low urinary volume” guide listed earlier. It is possible to use a mild diuretic to help, but this can lead to further dehydration if patients still fail to increase their fluid intake.

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.

High Uric Acid: Ask patients to reduce their dietary purine (meat, fish, beef, poultry, pork, seafood) intake. Consider using allopurinol for elevated serum or urinary uric acid levels. If starting allopurinol, start at 100 mg and then gradually increase it. Use whatever dosage is needed to obtain optimal uric acid levels. For most patients, this is likely to be around 300 mg of allopurinol daily, but it can vary. Add vitamin B-6 if the patient is being started on allopurinol, as it prevents possible neuropathy, an uncommon but reported side effect. If the patient is making 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: It may not be possible for every patient to obtain an "optimal" level in all major 24-hour urine test chemistries, and some problems may prove stubbornly resistant to treatment. In such cases, try to "optimize" as many other chemistries as possible. Patients need to accept that treatment significantly reduces their kidney stone risk but does not entirely eliminate it. Increasing fluid intake is universally recommended, as this will always be correct. Pentosan polysulfate has been used in difficult or resistant nephrolithiasis cases to help reduce stone formation. The medication coats urinary crystals with a mucopolysaccharide layer that helps prevent their aggregation, reducing stone production and growth.

Enhancing Healthcare Team Outcomes

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. It can find and identify kidney stone chemical risk factors that are amenable to dietary or medical therapy and may have other medical or health-related benefits. It avoids preventable complications, pain, and surgeries. Future stone production can be reduced by 90% or more. It can identify underlying medical problems not easily diagnosed by any other means, such as hypercalciuria, renal tubular acidosis, renal phosphate leak, cystinuria, hyperoxaluria, and hypocitraturia. Such testing can be kidney-saving or life-saving in some patients with potential medical/legal implications. Finally, testing, interpretation, and treatment selection can be greatly simplified, making it easy to perform and interpret in any medical practice by using the previously presented guidelines. Clinicians and nurses should work together with laboratory technicians to obtain quality specimens and accurate results.