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 so 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%.
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 the day of the specimen collection. Portions of the urinary chemistry are sometimes sent to different reference laboratories which often leads to unacceptable delays and incomplete results that cannot be easily interpreted. The most critical results are often buried amid paragraphs of obligatory boilerplate, again 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.
Once the critical data is available, analysis and treatment selection still needs to be done. Evaluation and interpretation of the laboratory results is 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 the critical data can be challenging.
The purpose of this review is to simplify the analysis and evaluation of 24-hour urine collections as well as treatment selection, so local practitioners will be more comfortable using and interpreting this important test for their nephrolithiasis patients.
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.
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.
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 as well as for adult stone formers who have a 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, or solitary kidneys, chronic diarrhea (irritable bowel syndrome (IBS), short bowel syndrome or post gastrointestinal [GI] bypass surgery), and all cystine stone formers.
Those who receive the most benefit from 24-hour urine test are those who 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 preventive measures, even if followed precisely, will prevent 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. It is therefore suggested that any stone patient who is strongly motivated to follow a long-term course of preventive treatment and understands its limitations and sacrifices, as well as 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 patient's treatable risk factors and provide effective dietary advice, medications, and supplements that will reduce his future stone risk while making minimal changes in his preferred diet and lifestyle.
A 24-hour urine collection test needs to be done for 24 hours. It is customary to discard the first voided specimen in the morning, then collect all other specimens up to and 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 as well as over-collection. For most patients, we recommend having them do the collection on a Sunday so it can be mailed or delivered to the laboratory early on Monday morning.
It is advisable to use a reference laboratory that routinely performs many 24-hour urine chemistry tests as their quality control measures tend to be better, turnover time is reduced, and incomplete results are less likely. We also recommend using a single reference laboratory for all of the 24-hour urinary testings whenever possible. This avoids incomplete test results and reduces the lead time from specimen submission to receipt of the 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 excretion of creatinine is 955 mg to 2936 mg in men, 601 mg to 1689 mg in women. This can also be written as 13 to 29 mg/kg of body weight per 24 hours in men, 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.
Several studies have suggested that two 24-hour urine tests provide substantially more reliable results than just a single collection. 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.
To paraphrase Dr. Fred Coe, a 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 not reliable due to improper collection, irregular handling, or substandard laboratory test 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 a poorly performed 24-hour urine collection chemistry profile.
If the patient or patient's family has a history of cystine stones or if the chemical composition of the stone is not known, 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 levels of 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 always best to have the stone chemical composition, if possible. Recommended serum chemistries include potassium, creatinine, phosphate, calcium, and uric acid. High or high-normal serum calcium levels, along with hypercalciuria on 24-hour urine testing would 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 suggest renal phosphate leak which causes a vitamin D dependent form of hypercalciuria which only responds to oral phosphate supplementation.
24-Hour Urine Testing
An optimal 24-hour urine test should include values for calcium, citrate, magnesium, oxalate, phosphate, sodium, sulfate, uric acid, and volume. The most significant of these will be discussed individually, and there are separate review articles on each of them which should be checked for additional details and information beyond what is presented here.
Calcium is necessary in human nutrition for bone health and muscle activity. Serum calcium levels are carefully controlled, but in calcium nephrolithiasis, clinicians often find increased urinary calcium levels (hypercalciuria), and this directly contributes to the formation of calcium stones.
High urinary calcium is a frequent finding 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.
A diet that is too restrictive 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.
If the dietary calcium intake is not unreasonable and serum chemistry indicates normal calcium levels, the next step is to add a thiazide-type medication. This class of drug was originally designed as a diuretic but has been found to be useful in reducing urinary calcium excretion. It will not work if salt (sodium) is not controlled, so patients on thiazides are asked to limit their salt intake. Thiazides can also increase uric acid levels and lower urinary citrate, but their beneficial effect overshadows these effects in substantially lowering urinary calcium. Thiazides contain a sulfa molecule, so they need to be started and used cautiously in patients with severe sulfa allergies. Currently, the preferred "thiazide" medication is indapamide (Lozol) which some physicians prefer because it is a once a day drug even though it is not technically a thiazide. A repeat 24-hour urine test should be performed during treatment to check the effectiveness of the thiazide therapy, usually 2 to 3 months after starting the medication. If the urinary calcium levels remain elevated, an adjustment in the treatment can be made to increase the thiazides dosage or better control sodium intake.
If dietary calcium moderation with low urinary sodium and appropriately dosed thiazide therapy are inadequate to control the hypercalciuria, an oral phosphate medication should be utilized. This will lower calcium absorption by the GI tract both directly and indirectly, primarily through its effect on vitamin D. In renal phosphate leak hypercalciuria, there is an obligatory excessive urinary loss of phosphate. This lowers serum phosphate levels which stimulate 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 GI absorption of phosphate to correct the hypophosphatemia, but will also increase calcium absorption as well. The additional absorbed calcium is eventually excreted in the urine causing the hypercalciuria. Thiazides do not work here 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 the increased renal vitamin D activation which would otherwise result in the unwanted hypercalciuria.
Bisphosphonates and rank ligand inhibitors will both increase calcium deposition in bone, and there is some limited evidence that they can reduce hypercalciuria. Their use theoretically 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 are 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.
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 hyperoxaluria where calcium stone production increases. Moderate dietary calcium intake is recommended. Medications such as thiazides can help the body retain calcium reducing hypercalciuria, but sodium intake needs to be limited, or this beneficial hypocalciuric effect is lost. Thiazide therapy can cause an increase in uric acid levels and reduce urinary citrate so many of these patients may benefit from supplemental potassium citrate as well. If these initial measures are not effective, then oral phosphate therapy should be used. Urinary calcium excretion can be successfully managed in the vast majority of patients with kidney stones by using one or more of these therapies.
Citrate is the body’s natural urinary antacid and corresponds to serum bicarbonate which is 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 an enormous amount of lemonade to affect serious hypocitraturia significantly. 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 which makes 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.
The amount of citrate required to optimize the urinary chemistry depends in part on the type of kidney stone that is being produced. For calcium oxalate stones, the optimal citrate level is about 300 mg per 1000 mL of urine. So if the urinary volume is high, extra citrate will be needed to maintain an optimal urinary citrate concentration level. Typical dosages of potassium citrate would be ten mEq 3 or 4 times a day.
If the dosage required is relatively low, it is recommended that this extra potassium citrate supplement be taken at bedtime to mimic the "alkaline tide" that normally occurs overnight. A common nocturnal only dosage would be two of the ten mEq potassium citrate tablets.
Pure uric acid stones, but not calcium stones, can be dissolved with adequate potassium citrate supplementation. 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 by using pH paper available in most pharmacies or by special FDA-approved urinary dipsticks.
Limiting factors for potassium citrate supplementation include tolerability (some patients may notice some GI upset problems after taking potassium citrate supplements), difficulty in 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 stones, 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, so physicians will typically ask patients to take as much potassium citrate as they can reasonably tolerate as long as their urinary pH does not exceed 7. Potassium citrate tablets act as urinary antacids and will increase both urinary alkalinity (pH) and citrate levels.
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.
Sodium bicarbonate can be used to boost citrate excretion if serum potassium levels preclude additional potassium supplementation, but sodium bicarbonate carries a significant sodium load 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 or in addition to taking additional potassium citrate or sodium bicarbonate supplements. A typical dosage would be 125 mg to 250 mg twice a day.
High-citrate foods: 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.
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 just by adjusting the urinary antacid or citrate levels. Checking the urinary pH regularly may be needed to maintain optimal potassium citrate dosing as well as urinary pH and citrate levels.
Oxalate is an organic chemical made by plants to help them 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 tend to make tea from the leaves and call many of the other shed that plants 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 of them they ingest, and the original groundwater calcium content of the field where the plant was grown.
Dietary oxalate constitutes about 50% 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.
"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 the oxalate intake by avoiding higher oxalate foods and substituting lower oxalate choices. While there is no specific medication that will correct high urinary oxalate, dietary calcium citrate supplements are used to increase intestinal oxalate-binding thereby reducing oxalate absorption. Calcium citrate is preferred as it dissolves better than most calcium supplements. Taking it with a glass of milk is recommended. Calcium citrate without added vitamin D is suggested because it is desireable to avoid early intestinal calcium absorption which facilitates oxalate binding in the lower GI tract. Dietary calcium sources are also recommended if they can be ingested at the same time as the higher oxalate foods. If calcium cannot be used, then alternative oxalate-binding agents such as iron can be substituted.
The only food that is specifically prohibited in many hyperoxaluric nephrolithiasis patients is spinach. This is because a single bite of cooked spinach can have more than 75 mg of oxalate and a standard portion of a half cup will have about 750 mg. Kale and collard greens are similar high-oxalate foods that physicians recommend be eliminated or severely limited in hyperoxaluric nephrolithiasis patients.
In the majority of cases, the most effective treatment for high urinary oxalate levels is controlling the oral intake of higher oxalate foods. Clinicians can provide a complete listing of the oxalate content of foods is available.
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.
Cholestyramine is a bile, acid-binding, resin that is primarily used for cholesterol control. It works by removing bile acids from the body which can help reduce urinary oxalate not responsive to other therapies. For this reason, it is often recommended in hyperoxaluric patients who are post-bariatric surgery patients.
The use of a probiotic (healthy gut bacteria) product such as VSL-3 is a bit more controversial. Probiotics provide the intestinal tract with healthy 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.
There is continuing research on using enzymes from Oxalobacter formigenes to help digest oxalate in the GI tract. Oxalobacter is a natural bacterial inhabitant of the intestinal tract and can digest oxalate. Its oxalate digesting enzyme may someday be available as a pill or capsule.
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, and the incidence is increasing due to the increase in contributory bowel diseases and bariatric surgeries in the general population.
Patients with irritable bowel syndrome (IBS), previous bariatric (Roux-en-Y) surgery or any type of 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). The 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 which further compounds the problem. Chronic diarrhea causes additional fluid loss, and this loss 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.
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 if possible) for the bicarbonate loss and hypocitraturia, reduction in dietary fats and oxalate, and the use of cholestyramine or similar bile acid sequestrants.
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 crystals of calcium oxalate 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 we rely 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, and cholestyramine can also be used.
High levels of dietary salt or sodium will cause increased fluid retention and bloat, place 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 a difficult time 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 3436 mg daily.
A single teaspoon of table salt has about 2300 mg of sodium. Optimal salt intake should be no more than 1500 mg a day, but even a modest limitation to 2300 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 where little or no salt has been added. 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 recipe.
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 that less salt was added. Look for cans with a “no salt added” label and then read the actual sodium levels listed to make sure. Canned vegetables and tomato and “V-8” juices have surprisingly high sodium levels due to added salt. In general, almost every canned food will have salt added and usually quite a lot, so people should 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.
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.
Very 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 these, and 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, and prepared salad dressings. Substituting oil and vinegar for prepared or house salad dressing.
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 so many food products. Have patients follow the tips and suggestions listed above to optimize their salt intake and minimize urinary sodium levels.
Hyperuricosuria (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 cause uric acid crystals to form in the joints producing intense pain and inflammation, which is known as gout. This is usually due to a liver problem and frequently treated with allopurinol, colchicine, indomethacin, probenecid or febuxostat (Uloric).
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 will tend to increase the amount of uric acid the body produces. For this 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 when it comes to uric acid production, they are equivalent. 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 uric acid or not enough 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. 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 is something that cannot be done with calcium stones. The key is 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. There is also a urinary dipstick designed for home urine pH measurements that is available online.
Elevated serum uric acid levels may also need to be treated, especially in patients with hyperuricemia or gout. Allopurinol is frequently used in situations where 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. Optimal blood uric acid levels are around 6, and the optimal 24-hour urine uric acid excretion is 600 mg or less. If this cannot be done with diet alone, then allopurinol is used. Vitamin B-6 is sometimes added to the allopurinol as well. Febuxostat (Uloric) is a newer drug that is very similar to allopurinol.
Colchicine and indomethacin are strong, anti-inflammatory drugs which do not directly affect uric acid levels and may cause side effects. Their use is limited to management of acute gout attacks.
Patients with uric acid stones should not be taking probenecid because it increases uricosuria and increases 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 1000 mg per 100 gm
Wild or farmed game such as pheasant, quail, rabbit and venison, organ meats such as liver, kidneys, heart, sweetbreads, foie gras and chopped liver, meat and yeast extracts such as Bovril, oxo, marmite and 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
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.
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 1300 ml per day or roughly 3 pints. Patients with kidney stones are asked to drink sufficient water to produce at least about 2000 mL or 2 L 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 the oral fluid intake, but this is often difficult for many patients to accomplish.
Clinicians suggest that at least one-half of all new oral fluid intake should be water. Patients should avoid using “Gatorade” 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 happens to like cranberry juice, a glass or 2 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 go directly toward increasing the patient's urinary volume because all of the necessary, obligatory bodily requirements for fluids are already satisfied.
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 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.
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 in the home and workplace between 40% and 45% to minimize insensible fluid loss through the skin and from just normal respiration.
Limit salt and sodium intake. 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 at first, but once the patient becomes accustomed to the extra fluid, it will become automatic. 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.
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 that for most patients is at least 2000 ml per day.
If all of the above suggestions fail to increase the urinary output sufficiently adequately, 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 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 hard 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 intakes. Just advise them to stick with it long enough, and 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 for them to achieve their optimal total urinary volume target. This will greatly reduce their risk of forming new kidney stones.
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 2000 to 2500 mL. This can best be achieved by using the tips and suggestions mentioned earlier.
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 which 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 who also have 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 just by using the guidelines previous presented.
What to Do After Testing
After the patient has been on therapy for at least several months, it is advisable to perform another 24-hour urine test. The purpose is to make sure the treatment is effectively controlling the problem it was 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 yearly visit can optionally be combined with a yearly KUB and/or the renal US to check for any newly formed stones. The yearly 24-hour urine recheck allows for reminding and reinforcement of patient instructions, review of previously recommended therapies as well as the annual renewal of any medications with possible dosage adjustments. In complicated cases, we generally recommend repeating the 24-hour urine testing and treatment modifications every three months until optimal results are achieved; then usually yearly.
When it Isn't Possible to Optimize the 24-Hour Urinary Chemistry
It is not always possible to optimize every 24-hour urine chemistry in some patients. 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 do the best you can 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 when discussing results with patients is helpful.
Summary of Treatments for Abnormal 24-Hour Urine Tests
Hypercalciuria: If the serum calcium is normal and hyperparathyroidism is ruled out, start with moderation of any excessive dietary calcium. Do not be overly restrictive of calcium intake to avoid a reactive increase in oxaluria and possible osteoporosis. If the dietary calcium intake is reasonable and hypercalciuria persists, add indapamide (Lozol) 2.5 to 5 mg daily or a similar thiazide. If urinary sodium is elevated, the salt intake will have to be restricted, or the thiazide therapy will not be effective in lowering 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 not adequate, 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 be used to help reduce bile acid effects; especially when other measures are insufficient. A probiotic such as VSL 3 can be added as it may help with 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. 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 and/or acetazolamide 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: Reduction in 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 first 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 which is 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. In patients who are intolerant or allergic to allopurinol, Uloric (febuxostat) can be used.
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 of the other chemistries as possible. It is important for patients to accept that treatment significantly reduces their kidney stone risk, but does not eliminate it. Increasing fluid intake can always be recommended as this will always be correct. Pentosan polysulfate (Elmiron) 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.
If still totally lost and confused, do not be afraid or hesitant to contact a local medical stone disease expert in nephrology or urology in your area or the nearest university medical center.
Questions, comments, suggestions and reprint requests for this review article should be directed to the Corresponding Author: Stephen W. Leslie, MD FACS, Creighton University Comprehensive Kidney Stone Center, CHI-Bergan Mercy Clinic, 7710 Mercy Road, Suite 1000, Omaha NE 68124. 402-717-2500. Stephenleslie@creighton.edu