Calculators, Algorithms, Drug Interaction CheckersTools
Back To Search Results

Hypocitraturia and Renal Calculi

Author: Stephen W. Leslie Editor: Khalid Bashir Updated: 8/1/2024 4:39:35 AM

Introduction

Citrate—a natural inhibitor of stone formation—binds to calcium in the urine, preventing it from forming crystals that can aggregate into stones. Insufficient citrate levels increase the risk of calcium stone formation, leading to the development of renal calculi. Hypocitraturia is characterized by low or insufficient citrate excretion in the urine and is one of the most common and treatable causes of kidney stones. This condition is a significant metabolic abnormality linked to the formation of renal calculi. Notably, it is estimated that half of all symptomatic kidney stones could be prevented with proper diagnosis and prophylactic treatment of underlying chemical nephrolithiasis risk factors.[1][2] Preventive medical evaluation and treatment of stone disease are underutilized, inconsistent, and generally inadequate.[3] Additionally, quality-of-life scores are significantly reduced in nephrolithiasis patients, even in those with asymptomatic stones.[4]

Direct and indirect costs for kidney stone treatment are estimated at over $10 billion annually and are predicted to exceed $15 billion by 2030. This increase is due to the rising incidence of stone disease from associated disorders such as diabetes and obesity, general population growth, and the effects of global warming.[5] Hypocitraturia was first reported by Boothby and Adams in 1934 and later confirmed by Kissin and Locks in 1941. Initially, this information was largely ignored or attributed to bacterial consumption of citrate until 1962, when Hodgkinson first suggested that hypocitraturia was a unique urinary chemical disorder in patients with nephrolithiasis.[6]

Hypocitraturia is officially defined as urinary citrate excretion of less than 320 mg per day. Many experts have questioned this definition, as it is based on statistical analyses of large numbers of 24-hour urine tests from the general population, rather than on factors such as saturation ratios, supersaturation, pH, crystallization points, stone chemical composition, or the minimal concentrations necessary to prevent urinary stones.[7][8] Currently, "optimal" levels of urinary chemistries, such as citrate, are not reported in standard laboratory reports. 

Hypocitraturia is estimated to be present in about 30% (ranging from 10% to 60%) of all kidney stone formers, although this varies according to the specific definition of hypocitraturia used and the type of stone.[9] Notably, it is the sole identifiable stone-promoting chemical abnormality in about 10% of all calcium stone-forming patients and is also a contributing factor associated with other metabolic problems in about half of these patients. Long-term optimization of potassium citrate supplementation can reduce calcium nephrolithiasis by 80%.[10] Optimized citrate supplementation has been shown to reduce recurrent nephrolithiasis in patients who adhere to the therapy.[11][12][13]

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

In normal individuals, urinary citrate excretion is directly related to the net gastrointestinal absorption of alkali.[14] Low urinary citrate is often associated with poor dietary choices, such as high meat and sodium intake combined with low fruit (especially citrus) consumption. Medications such as thiazides, angiotensin-converting enzyme (ACE) inhibitors, topiramate, and acetazolamide can all cause hypocitraturia. Additionally, low urinary citrate is found in conditions such as irritable bowel syndrome (IBS), colitis, short bowel syndrome, chronic diarrhea, and after Roux-en-Y gastric bypass surgery.

Urinary citrate levels are higher in females, and in conditions such as metabolic alkalosis, as well as due to estrogens, parathyroid hormone, growth hormone, and vitamin D. They are decreased by testosterone in males, starvation, and all types of acidosis, including dietary, metabolic, uremic, or diabetic.[15] The patient's ethnic background does not significantly affect urinary citrate excretion, but genetic factors play an important primary or contributing role in at least some nephrolithiasis patients.[16][17][18][19][20][21]

Specific causes of hypocitraturia include:

  • Acetazolamide therapy: This creates hyperchloremic acidosis by reducing bicarbonate reabsorption in the proximal renal tubule, similar to the mechanism in distal renal tubular acidosis.[22] 
  • ACE inhibitors: These increase adenosine triphosphate (ATP) citrate lyase activity.[23] 
  • Autosomal dominant polycystic kidney disease.[24] Please see StatPearls' companion resource, "Autosomal Dominant Polycystic Kidney Disease," for more information. 
  • Chronic diarrhea syndrome, colitis, and IBS: These conditions lead to alkali loss in the stool, which can also cause a burning rectal sensation in patients with chronic diarrhea due to a mild chemical alkali burn.[25][26][27] 
  • Chronic renal failure: A reduced glomerular filtration rate results in less filtered citrate. This effect is offset by increased fractional citrate excretion, so hypocitraturia is typically not apparent until renal failure is relatively advanced.[28] This presents a challenge in treatment, as excessive potassium citrate supplementation can lead to hyperkalemia in chronic renal failure patients.[29] Therefore, low potassium citrate supplements are preferred in these cases. 
  • Citrate gastrointestinal malabsorption: Some patients may demonstrate a reduced response to oral citrate supplementation due to a primary intestinal absorptive defect.[30][31] 
  • Dietary factors: These factors typically include high animal protein, high sodium, low citrus, and low alkali intake diet.[32] 
  • Distal renal tubular acidosis.[33][34][35] 
  • Ethacrynic acid.[32] 
  • Gastric bypass surgery: Particularly Roux-en-Y procedures.[25][36][37][38][39] 
  • Genetic factors.[18][19][20][21] 
  • Gout, hyperuricosuria, and gouty diathesis.[40] 
  • Glycogen storage disease, type 1.[41] 
  • High animal protein diet: This contributes to a high acid ash load because animal proteins are rich in sulfates and phosphates, which are excreted as acids. A low animal protein diet can increase urinary citrate by an average of 25%.[42][43] 
  • High sodium intake: A high sodium diet can decrease urinary citrate by 20% due to sodium-induced hypokalemia.[14][23][42][44][45] 
  • Horseshoe kidneys: More than 50% of nephrolithiasis patients with a horseshoe kidney will demonstrate hypocitraturia.[46] 
  • Hypokalemia: This results from increased intracellular acidosis.[47][48] 
  • Ketogenic diets.[32] 
  • Medullary sponge kidney.[49][50][51] Please see StatPearls' companion resource, "Medullary Sponge Kidney," for more information. 
  • Primary hyperaldosteronism: This results from chronic hypokalemia produced by this disorder.[52] 
  • Thiazide diuretics: This causes hypocitraturia through the hypokalemia associated with these medications.[53] 
  • Topiramate therapy: Due to the induced metabolic acidosis.[54][55][56][57] 
  • Starvation: This increases citrate absorption by directly stimulating cellular transporters and increasing acidosis.[58] 
  • Strenuous physical exercise: This causes hypocitraturia due to lactic acidosis.
  • Urinary tract infections: The infections result from direct bacterial breakdown of citrate. Up to 30% of calcium oxalate stone formers may have a history of Escherichia coli urinary tract infections.

Chronic Diarrheal States, Colitis, and Irritable Bowel Syndrome

The overall risk of nephrolithiasis is significantly increased by up to 38% in patients with chronic diarrheal states, colitis, and IBS compared to the general population.[59] Chronic diarrhea causes significant bicarbonate loss, leading to hypocitraturia. Inflammatory changes in the bowel wall, surgical resections, and intestinal malabsorption also contribute to citrate loss and hypocitraturia. Patients with ileostomies lose large amounts of alkaline fluids and are prone to dehydration, metabolic acidosis, and severe hypocitraturia, resulting in a high risk for urinary stone disease, particularly uric acid calculi.[59]

Among IBS patients, those with Crohn disease tend to have the highest incidence of hypocitraturia and nephrolithiasis, especially if they have also undergone intestinal surgical resections. Urolithiasis develops in up to 28% of Crohn patients who have had a resection of the terminal ileum.[60] In Crohn disease, urine pH is a significant risk factor for urolithiasis; patients with a urine pH of 6 or less are at an 8 times greater risk of developing urinary stones compared to those with a urinary pH of 6.5 or higher.[61] 

Enteric hyperoxaluria, resulting from intestinal calcium malabsorption and relative dehydration due to chronic diarrhea, also contributes to an increased risk of nephrolithiasis in this group.[27] Liquid citrate preparations are recommended over tablets for treatment in this population.

Distal Renal Tubular Acidosis 

Among the various metabolic acidotic conditions due to kidney disorders, only distal renal tubular acidosis (type 1 renal tubular acidosis) has been consistently associated with nephrolithiasis, typically leading to the formation of calcium phosphate stones.[62] Distal renal tubular acidosis can be either complete or incomplete, genetic (often seen in children), or acquired (usually in adults). The most common acquired etiologies include Sjögren syndrome and rheumatoid arthritis. 

Distal renal tubular acidosis is characterized by persistent urinary alkalinity, hypercalciuria, hypocitraturia, nephrocalcinosis, calcium phosphate nephrolithiasis, hypokalemia, and osteoporosis. The condition arises from a failure of hydrogen ion excretion in the distal renal tubule, leading to metabolic acidosis. This acidosis is partially buffered by calcium released from bone, contributing to osteoporosis. Additionally, increased intestinal calcium absorption and reduced renal calcium reabsorption result in hypercalciuria. The severity of hypercalciuria is roughly proportional to the degree of acidemia.[35][63][64]

Hypocitraturia in distal renal tubular acidosis results from increased citrate reabsorption in the proximal renal tubule due to metabolic acidosis, while the elevated urinary pH is directly related to the kidney's inability to excrete excess acid.[35][63][64] Hypokalemia in this condition is caused by renal potassium wasting.[65][66] Chronic alkaline urine, combined with hypercalciuria and hypocitraturia, leads to nephrocalcinosis and calcium phosphate stone formation. Appropriate potassium citrate therapy can correct metabolic acidosis, hypercalciuria, and hypokalemia, thereby reversing osteoporosis, halting nephrocalcinosis, and reducing calcium phosphate stone production.[67]

Gastric Bypass Surgery

Although Roux-en-Y gastric bypass surgery is no longer the most commonly performed bariatric procedure in the United States—having been surpassed by the gastric sleeve—it remains highly effective and constitutes a significant portion of all weight-loss surgeries.[39] Over 1 million Roux-en-Y surgeries were performed in the United States in the decade leading up to 2015.[68] The risk of kidney stones is increased after Roux-en-Y surgery, roughly 3 times higher compared to obese, age-matched controls, with 18.6% of Roux-en-Y patients developing stones within the first 2 postoperative years.[37] The risk is highest among those with a history of kidney stones before the surgery, approximately double that of patients without a prior history of nephrolithiasis.[37] 

Patients undergoing Roux-en-Y gastric bypass surgery typically experience a 40% reduction in urinary citrate, alongside a 50% or more increase in urinary oxalate and a 30% decrease in daily urinary volume. These changes significantly increase their risk of nephrolithiasis.[37][69] Urinary citrate levels generally decrease further over time after surgery. Liquid citrate preparations are preferred for treatment in these patients due to their rapid intestinal transit time, which reduces the absorption issues associated with tablets.[70]  

Topiramate Therapy

Topiramate, a carbonic anhydrase inhibitor such as acetazolamide, is increasingly used in epilepsy as an anticonvulsant and for migraines. It is also used off-label for weight loss and pain management.[55][71][72] Topiramate induces mild metabolic acidosis through a mechanism similar to distal renal tubular acidosis, leading to hypocitraturia, hypercalciuria, hypokalemia, urinary alkalinity, and an increased risk of kidney stones, particularly those composed primarily of calcium phosphate.[73] The degree of hypocitraturia induced by topiramate varies; generally, the starting dose reduces urinary citrate by about 40%, which can increase to 65% at higher dosages.[54][55] For patients with kidney stones taking topiramate and exhibiting hypocitraturia, potassium citrate therapy can help increase urinary citrate levels and reverse its other undesirable chemical effects.[55][71][72]

Epidemiology

The exact prevalence of hypocitraturia can vary widely depending on the precise definition used. However, incidence rates appear to be rising, especially among obese individuals and those using topiramate.[36] A significant difference in the rate of hypocitraturia among different racial groups, including Whites, Blacks, or Asians, does not appear despite the significantly higher reported rate of nephrolithiasis in Caucasians.[16] In addition, older patients with nephrolithiasis are more likely to have hypocitraturia compared to younger patients.[74] 

Although women generally have higher citrate levels than men, hypocitraturia is more common among female stone formers than their male counterparts. Among female stone formers, hypocitraturia is more prevalent in premenopausal women compared to postmenopausal women.[75][76][77] In premenopausal women, the highest urinary citrate levels correspond with their estrogen peak during the menstrual cycle.[78]

The incidence of kidney stones among women is on the rise. The reasons for this trend are not entirely clear but may be linked to increased participation of women in the workforce, which leads to changes in activity levels, diet, and stress similar to those experienced by men. Additionally, women tend to experience higher rates of obesity, engage in dieting more frequently, and undergo more bariatric surgeries than men—all of which contribute to an increased risk of kidney stones.[79] Women also are at higher risk for stones after being pregnant. For women aged 50 or younger, a single prior pregnancy increases their incidence of developing kidney stones by almost 100%, with additional pregnancies further increasing their overall nephrolithiasis risk.[80]

Pathophysiology

In the kidney, urinary citrate levels are predominantly determined by acid/base status and cellular metabolism in the proximal tubules of the renal cortex. Citrate absorption is regulated by the apical membrane cotransporter NaDC, while cellular metabolism involves ATP citrate lyase and mitochondrial enzymes in the proximal tubules. During chronic acidosis, citrate transport and cellular metabolism are enhanced, leading to hypocitraturia. Conversely, an alkaline load reduces these cellular activities, resulting in increased urinary citrate excretion.[81]

Renal cells contain large amounts of ATP citrate lyase, which converts intracellular citrate into acetyl coenzyme A.[82] The activity of ATP citrate lyase is increased by factors such as metabolic acidosis, potassium deficiency, insulin, glucose metabolites, and dietary influences such as high carbohydrate intake.[82] Notably, using a competitive inhibitor of ATP citrate lyase, such as 4S-hydroxycitrate, has been shown to quadruple urinary citrate levels in chronic metabolic acidosis.[82] 

Dietary citrate intake averages about 4 g daily and is efficiently absorbed from the intestine in both healthy individuals and hypocitraturic stone formers.[83][84] Serum citrate is filtered by the renal glomerulus and reabsorbed in the proximal tubule, with only approximately 25% (ranging from 10% to 35%) of filtered citrate ultimately excreted in the urine.[85][86][87] Hormones that affect bone health, including estrogens, vitamin D, and parathyroid hormone, generally increase urinary citrate excretion.[88][89]

Hypocitraturia affects stone disease in several ways, as follows: 

  • Urinary citrate forms a soluble complex with calcium, reducing the availability of ionic (free) calcium to form urinary crystals and stones. This effect is somewhat pH-dependent, becoming more pronounced as urinary pH increases.[90]
  • Urinary citrate directly inhibits the crystallization and aggregation of calcium crystals in the urine.[91] 
  • Urinary citrate raises pH, significantly increasing uric acid solubility as pH approaches 6.5 to 7. Uric acid stones generally do not form with a sustained urinary pH of 6.5 or higher.[92][93] 
  • Hypocitraturia reduces urinary osteopontin, an important component of the matrix of urinary calculi.[91] 
  • Hypocitraturia diminishes the inhibitory effect of urinary macromolecules, primarily Tamm-Horsfall protein, on nephrolithiasis.[94][95][96] 
  • Hypocitraturia increases urinary viscosity by decreasing calcium binding, leading to greater viscosity as free calcium interacts with urinary macromolecules such as Tamm-Horsfall protein.[97]

History and Physical

Specific physical findings or medical history are not typically associated with hypocitraturia. However, patients taking acetazolamide or topiramate, as well as those with a history of nephrocalcinosis or kidney stones—especially if composed of calcium phosphate—are at increased risk. Patients with a history of pure uric acid stones may have normal citrate levels but might still require additional urinary alkalinization. Please see StatPearls' companion resource, "Uric Acid Nephrolithiasis," for more information.

Additional risk factors to consider from the medical history include gastric bypass surgery (especially the Roux-en-Y type), IBS, chronic diarrhea, prior intestinal surgery, gout, and a personal or family history of nephrolithiasis, as well as previous kidney stone surgeries. Reviewing prior 24-hour urine tests for nephrolithiasis prophylaxis and chemical stone composition analyses of previous renal calculi can also be helpful.

Evaluation

By definition, the diagnosis of hypocitraturia requires a 24-hour urine test. Some clinicians recommend a second 24-hour urine test if the initial results are "normal." This helps avoid clinical confusion due to spurious, anecdotal, or incidental changes in diet, activities, fluid intake, or personal routine. Many stone clinics frequently order a second 24-hour urine test 3 months after starting initial therapy. This approach allows clinicians to identify any "spurious" readings and make final adjustments to the patient's therapy. Please see StatPearls' companion resource, "24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines," for more information. In addition, it can be reasonably assumed that calcium oxalate nephrolithiasis patients who are post-Roux-en-Y gastric bypass, have IBS with chronic diarrhea, or are taking acetazolamide, thiazides, or topiramate will all have some degree of hypocitraturia even without a formal 24-hour urine test. 

The optimal timing for 24-hour urine testing is somewhat controversial. The test should always be done on an outpatient basis, never in the hospital where diet and fluid intake are controlled. Patients should return to their regular diet and activities after hospitalization or surgery for optimal results. Many experts prefer to wait 30 days after the last kidney stone event or surgery before performing the 24-hour urine test. Although urine chemistry may not change significantly, patients who were eager for preventive testing immediately after surgery may reconsider their long-term commitment to follow therapy when discussing testing again after 30 days. 

The "official" definition of hypocitraturia as 320 mg citrate per 24 hours, used by many laboratories, has been questioned by numerous experts. This threshold was arbitrarily selected from statistical analyses and did not consider factors such as age, gender, body mass, or stone composition. This was not based on solute concentrations, pH, normal median totals, supersaturation ratios, or any determination of what "optimal" urinary citrate levels should be for stone formers.[7][8] Please see StatPearls' companion resource, "24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines," for more information.

While 24-hour urine chemistry totals are provided in these commercial tests, urinary concentrations are generally not. Laboratories are only required to provide "normal" ranges for urine chemistries, not "optimal" or "target" levels, making it difficult for many clinicians to determine which stone formers actually have hypocitraturia and would benefit from treatment. A group of patients may have normal or even high urinary citrate levels but still need supplemental alkalinization therapy. These patients demonstrate significant aciduria (low pH) despite above-average urinary citrate levels. Many will form uric acid stones due to persistent aciduria despite high urinary citrate levels. 

Many experts recommend using an alternate target for urinary citrate levels. The median daily average of urinary citrate in healthy, non-stone-forming adults is 640 mg. Given that the minimum recommended daily urinary output for nephrolithiasis patients is 2000 mL, a concentration of 320 mg/L of urine seems to be a reasonable "optimal" concentration. This suggests that many calcium stone-forming patients with marginal 24-hour urinary citrate totals between 320 and 640 mg would benefit from some degree of citrate supplementation therapy. 

Another consideration is urinary pH. Persistent, severely acidotic urine, especially in uric acid stone formers, should be aggressively treated with alkalinization (citrate) therapy sufficient to normalize aciduria regardless of total urinary citrate levels. In other words, aciduria should be treated in addition to low urinary citrate levels, particularly in uric acid nephrolithiasis and cystinuria patients. The goal is to optimize both urinary citrate levels and pH whenever possible.[98][99] 

The citrate-to-creatinine ratio or the calcium-to-citrate ratio may also help identify patients who would benefit from citrate supplementation therapy, but the gold standard remains 24-hour urine testing.[100][101][102][103][104] A ratio of less than 180 mg citrate per 1000 mg creatinine or more than 0.33 mg calcium per mg citrate in random urine testing has been suggested as indicating a higher stone risk and possible hypocitraturia. These ratios have primarily been used in children as obtaining a reliable 24-hour urine sample is far more difficult than in adults.[105][106]

Summary of Diagnostic Criteria for Hypocitraturia

  • The 24-hour urinary citrate concentration should be 320 mg/L or more. Treatment should be considered if the citrate concentration is less than 250 mg/L.
  • The "optimal" level should be 640 mg or more. Citrate supplemental therapy should generally be considered if the daily urinary citrate is less than 500 mg.
  • Citrate supplementation should be considered if mg citrate per gram of creatinine is less than 180 or mg calcium per mg citrate is more than 0.33. 
  • Urine pH:
    • For most stone formers, the optimal pH ranges from 6 to 6.5.
    • The optimal pH for uric acid stone formers is  6.5 for maintenance and prophylaxis and 7 for stone dissolution.
    • For patients with cystinuria, the optimal pH is 7.5.

Treatment / Management

Management Strategies for Low Urinary Citrate

When possible, treatment of low urinary citrate targets the underlying etiology, such as improving dietary intake and discontinuing carbonic anhydrase-inhibiting medications. When this is not feasible or the cause is idiopathic, treatment primarily involves oral urinary alkalinizing medications.

Dietary measures: Dietary measures alone can help raise urinary citrate levels, but very large amounts of citrate are usually required for any clinically significant improvement.[107][108] 

  •  Citrus fruits are generally high in citrate, with lemons having a particularly high concentration. When converted to lemonade, this can improve urinary citrate levels and overall urinary volume.[108][109][110]
    • (B2)
  • Orange juice contains 160 mEq/L of citrate and 50 mEq/L of potassium. However, it is relatively high in sugar, increases oxaluria, and does not reduce hypercalciuria as effectively as potassium citrate supplementation.[111]
    • (A1)
  • Coconut water has been shown to effectively increase urinary citrate. While not particularly high in citrate, it has a very high alkaline load with 50% fewer calories and 60% less sugar than grapefruit and orange juice.[112] In a study, drinking coconut water instead of tap water increased urinary citrate by 29%, although it required consuming 1.92 L daily.[112]
  • Calcium citrate has not been adequately evaluated as a urinary citrate booster, but it is recommended as a calcium supplement due to its superior solubility compared to other forms. Its overall effect on stone production is relatively neutral. Any worsening of hypercalciuria is offset by increased urinary citrate levels and the intestinal oxalate-binding effect of its free calcium.[113][114]

Potassium citrate supplementation: This is generally the treatment of choice for hypocitraturia, as dietary measures alone are often insufficient and require very large quantities to achieve significant improvements. Potassium citrate reduces the supersaturation ratio of calcium oxalate without significantly increasing the supersaturation of calcium phosphate.[115][116][117] Patients already on potassium supplements can be switched to potassium citrate, but serum potassium levels must be monitored, especially for those with renal failure, those on potassium-sparing diuretics, or those taking large amounts of potassium citrate (>100 mEq/d).

Potassium citrate tablets are readily available, well-tolerated, and relatively inexpensive, often providing predictable results. Additionally, potassium citrate addresses hypokalemia, a potential cause of hypocitraturia, and may also reduce urinary calcium excretion.[118] Potassium citrate therapy has been shown to reduce urinary calcium excretion by 30% in hypocitraturic calcium oxalate stone formers.[119] This effect is attributed to increased gastrointestinal calcium binding to citrate, leading to reduced calcium absorption, a decrease in bone turnover due to improved acid buffering from the alkali, and/or a direct hypocalciuric effect on the distal renal tubule.[119][120](A1)

Sodium citrate products and sodium bicarbonate have notable alkalinizing effects; however, excess sodium can exacerbate hyperuricosuria and worsen hypercalciuria.[121][122] (A1)

Citrate absorption is influenced by renal and gastrointestinal factors, including intestinal transit time, gastrointestinal bypass surgery, and other absorptive characteristics. Underlying metabolic and renal disorders, such as acidosis, medullary sponge kidney, and renal failure, can also affect absorption. While potassium citrate therapy remains beneficial, it should be used cautiously in patients with struvite (triple phosphate or infection) stones, which typically require alkaline urine to grow. 

Potassium citrate tablets come in 5, 10, and 15 mEq dosages and are often designed with a wax matrix for slow release. Patients should be informed that seeing whole tablets in their stool does not indicate the medication is ineffective.[35] Some patients may stop their potassium citrate therapy prematurely upon seeing whole tablets in their stool, mistakenly believing the medication is not being absorbed. This issue can be addressed by informing patients that the appearance of the tablet ghost carrier in the stool is normal and expected, as the medication is extracted during the intestinal passage.(B3)

Potassium citrate supplementation should be adjusted until optimal urinary citrate and pH levels are achieved. This can be challenging due to the need for significant patient compliance, including repeated 24-hour urine tests and frequent daily medication intake, with no immediate perceived benefits. Additionally, patient tolerance issues, such as gastrointestinal upset or difficulty swallowing large tablets, can further complicate adherence. Patient compliance is a significant issue, with 48% of patients discontinuing therapy in long-term studies due to cost and adverse effects.[123] Patients can monitor their urinary pH using readily available, inexpensive dipsticks. Initial multiple pH readings are recommended when adjusting citrate supplementation. Once stabilized at the target level, less frequent pH measurements are sufficient.(A1)

The amount of citrate needed can be estimated using the following formula: According to the potassium citrate package insert, 30 mEq of potassium citrate daily typically increases urinary citrate by approximately 200 mg per 24 hours.

Serum potassium levels should be monitored periodically, especially in patients with renal failure or a history of hyperkalemia. If patients develop hyperkalemia, additional potassium should not be administered. Sodium bicarbonate can increase urinary citrate without adding potassium and is relatively inexpensive; however, it carries a significant sodium load, which may lead to fluid retention and worsen hypercalciuria. Besides its sodium load, sodium citrate also has a minimal impact on calcium oxalate supersaturation compared to potassium citrate.[17] (B3)

Liquid potassium citrate preparations are preferred for patients with Roux-en-Y gastric bypass, short bowel syndrome, chronic diarrhea, IBS, or those who do not respond well to potassium citrate tablets.[124][125] These liquid citrate supplements are better and more quickly absorbed than tablets. They may also have higher citrate concentrations than tablets, but availability can be problematic, and their taste can make compliance challenging.[83][124][125] Some patients may develop gastrointestinal upset, abdominal discomfort, or diarrhea from potassium citrate supplementation. These adverse effects can be minimized by taking the potassium citrate with food or altering the form of the potassium citrate supplement.[120] (A1)

Citrate supplements with lower potassium content are available in various formulations, both prescription and over-the-counter (OTC), including potassium citrate, sodium citrate, magnesium citrate, citric acid, and sodium bicarbonate. One popular formulation, litholyte, comes as a 10 mEq citrate packet, which comes as a 10-mEq citrate packet. This contains 5 mEq of potassium citrate, 2.5 mEq of sodium bicarbonate, and 2.5 mEq of magnesium citrate, offering the equivalent citrate of a standard 10 mEq potassium citrate tablet but with half the potassium content. Litholyte provides advantages such as better absorption, fewer gastrointestinal issues, liquid formulation (so that no large or difficult tablets to swallow), fewer overall adverse effects, lower cost, and no taste (when consumed).[126] Citrate supplements are optimal for use in children due to their lack of taste, making them easy to add to routine beverages for pediatric hypocitraturic patients. They can be ordered online and do not require a prescription.

Non-prescription urinary alkalinizing agents have varying degrees of alkalinizing effects, and their efficacy, compared to standard prescription potassium citrate products, is not well established.[127] They are generally recommended when factors such as cost, formulation, reduced potassium content, or other patient-specific considerations make them preferable to standard potassium citrate therapy. A comprehensive review and comparison of these OTC alkalinizing products has been published, and a summary by Fredric Coe from the University of Chicago is available at: https://kidneystones.uchicago.edu/2021/06/02/moonstone-ksptabs-litholyte-kidney-cop/. 

In distal renal tubular acidosis, potassium citrate treatment effectively corrects metabolic acidosis, hypercalciuria, and hypokalemia. It also helps reverse osteoporosis, halt nephrocalcinosis, and reduce calcium phosphate stone formation. However, achieving these benefits often requires relatively large doses of potassium citrate.[67] 

Citrate inhibits struvite stone formation by chelating magnesium, complexing with calcium, and coating struvite crystal surfaces, even in an increased pH environment.[128][129][130][131] Potassium citrate therapy also prevents struvite stone recurrence after extracorporeal shockwave lithotripsy (ESWL) and improves the clearance rate of residual fragments of calcium oxalate and struvite stones.[132][133] About 20% of patients with hypocitraturia are resistant to citrate supplementation therapy. Thus, a follow-up 24-hour urine test is recommended for all patients on potassium citrate therapy, as this "resistant" group may need more aggressive treatment to achieve optimal urinary citrate and pH levels.[17][134][135](A1)

Cystine becomes progressively more soluble in urine as the pH increases, similar to uric acid stones. Cystine stone formers generally require a urinary pH of at least 7, with 7.5 being "optimal." Please see StatPearls' companion resource, "Cystinuria," for more information. Achieving this pH may necessitate very high doses of potassium citrate, up to 3 or 4 mg/kg/d, in divided doses.[136] Acetazolamide has been used to help maintain pH, particularly overnight, but it can cause adverse effects such as metabolic acidosis, bone demineralization, hypocitraturia, and an increased risk of calcium phosphate stones. Daily urinary volumes of 3 L or more are also recommended.[136]

Potassium magnesium citrate may be more effective than potassium citrate alone in increasing urinary citrate levels and pH and in preventing kidney stones.[137] In addition, it raises urinary pH and reduces uric acid and calcium oxalate saturation ratios more effectively than potassium citrate.[138][139][140][141] Additionally, potassium magnesium citrate increases urinary magnesium levels, which independently enhances urinary citrate and has a generally beneficial effect on nephrolithiasis that potassium citrate alone does not provide.[142] Magnesium forms complexes with urinary citrate, disrupting the NaCT citrate transport mechanism and increasing citrate excretion.[142] (A1)

For these reasons, potassium magnesium citrate is considered a superior urinary citrate supplement compared to potassium citrate.[82] However, it requires multiple doses throughout the day, has not been extensively studied, optimal dosing has not been established, and it is not widely available.(B3)

Suggested Recommended Therapy Targets for Hypocitraturic Stone Formers

  • Optimal urinary citrate levels: For most stone formers, optimal levels should be at least 640 mg per 24 hours or 320 mg/L. Higher urinary citrate levels are acceptable if urinary pH and serum potassium levels remain within safe ranges. Please see StatPearls' companion resource, "24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines," for more information.
  • Calcium stone formers: The optimal urine pH is between 6 and 6.5 for calcium stone formers.
  • Uric acid stone prophylaxis: Maintenance therapy for uric acid stone prophylaxis is generally considered optimal at a urinary pH of 6.5, regardless of the total citrate level.[92][93] 
  • Cystine stone formers: The optimal urinary pH for cystine stone formers is 7.5. Achieving this pH is ideal, but a pH of at least 7 is necessary to maintain reasonable solubility for 250 mg of cystine/L of urine, increasing to 500 mg/L at pH 7.5. Please see StatPearls' companion resource, "Cystinuria," for more information.
  • Urinary pH levels: Levels more than 7.2 are not generally recommended (except in cystinuria), as they can promote calcium phosphate precipitation.
    • (A1)

Differential Diagnosis

When evaluating a patient with hypocitraturia and renal calculi, it is important to consider a range of potential differential diagnoses that can contribute to or mimic low urinary citrate levels and kidney stone formation. These include:

  • Carbonic anhydrase inhibitors
  • Distal renal tubular acidosis
  • Hypercalciuria
  • Hyperoxaluria
  • Hyperuricosuria

Prognosis

Most patients with low urinary citrate can be managed with oral alkali therapy. If hyperkalemia, rapid intestinal transit time, or gastrointestinal discomfort limit potassium citrate use, alternative options such as lower potassium alkalinizing supplements or plain sodium bicarbonate can be considered. Liquid preparations can be used for patients who have difficulty absorbing tablets. Nephrolithiasis patients with IBS often experience improvement when their bowel issues are effectively managed. 

Randomized controlled trials on citrate therapy for hypocitraturic stone formers have generally shown significant reductions in new stone formation in treated subjects compared to controls.[139][143][144][145] Over two-thirds (69%) of untreated stone formers will continue to develop stones, compared to only 2% of patients receiving optimized prophylactic medical therapy.[146] 

Overall compliance with citrate supplementation is somewhat less than optimal, at 73.3% after 6 months. This is due to several factors, including the need for a dosage schedule of 3 to 4 times daily, the large size of the tablets, poor absorption necessitating increasing doses, hyperkalemia, and the appearance of "ghost" tablets in the stool, which some patients incorrectly interpret as being ineffective. Additionally, the lack of noticeable clinical benefit and the absence of immediate or obvious clinical effects or harm if therapy is briefly interrupted, either deliberately or accidentally, also contribute to poor compliance.

Clinicians should make every effort to reinforce the long-term benefits of continuing therapy, even if there is no obvious clinical improvement and no apparent harm if therapy is temporarily stopped.[147] Counseling patients before starting therapy and at each yearly 24-hour urine recheck is recommended. With proper treatment, hypocitraturia can be successfully managed, if not completely reversed, and patients can expect substantially fewer new renal calculi while adhering to adequate citrate therapy.

Complications

Some patients on potassium citrate therapy may develop hyperkalemia, which limits their dosage. Potassium citrate therapy can also cause adverse effects, including stomach upset, abdominal pain, and diarrhea. Additionally, calcium phosphate stones can form if urine pH consistently exceeds 7.2. Patients with chronic renal failure are at a higher risk of hyperkalemia and should be monitored carefully.

The citrate from liquid potassium citrate preparations is absorbed better and more quickly than from tablets. However, some liquid forms have significantly more gastrointestinal adverse effects, and many patients find the taste objectionable.[10] Some of the OTC citrate supplements mentioned earlier may be exceptions, as they claim to cause minimal stomach upset and are virtually tasteless.[148]

Deterrence and Patient Education

Effective deterrence and patient education are critical components in managing hypocitraturia and preventing renal calculi. Untreated renal calculi can lead to complications, resulting in morbidity and mortality. In addition, it is estimated that half of all symptomatic kidney stones could be prevented with proper diagnosis and prophylactic treatment of underlying chemical nephrolithiasis risk factors.  

The American Urological Association (AUA) now recommends that all nephrolithiasis patients be informed about 24-hour urine testing for prophylactic treatment to prevent future stones.[149] This will ultimately result in more kidney stone patients being tested and, consequently, more patients being identified as hypocitraturic. 

Educating patients about the importance of maintaining adequate hydration, adhering to dietary modifications, and understanding the role of citrate in inhibiting stone formation can significantly reduce recurrence rates. Patients should be informed about the benefits of potassium citrate supplementation and the need for regular follow-ups to monitor urinary citrate levels and overall kidney health. Additionally, emphasizing lifestyle changes, such as reducing sodium and animal protein intake, can further minimize the risk of stone formation. Empowering patients with knowledge and proactive strategies enhances compliance and long-term management success, ultimately improving their quality of life.

Pearls and Other Issues

Acetazolamide and topiramate are carbonic anhydrase inhibitors that produce alkaline urine, which may sometimes be useful in uric acid urolithiasis while decreasing citrate excretion.[150][151] Their use in stone disease is usually limited to situations such as uric acid lithiasis and cystine stone disease, where alternative methods of urinary alkalinization are inadequate. The hypocitraturic effect of topiramate can be partially negated with potassium citrate supplementation but generally not with acetazolamide.

For patients for whom a 24-hour urine determination is unavailable, it is recommended that 20 mEq potassium citrate (2 tablets of 10 mEq strength) be used empirically at bedtime or with dinner.

Nephrolithiasis patients taking acetazolamide or topiramate, having had Roux-en-Y gastric bypass, or being on thiazide therapy can be presumed to have some degree of hypocitraturia even if they decline 24-hour urine testing. After carefully discussing the pros and cons with these patients, consider starting them on potassium citrate therapy. 

Patients with uric acid stones are more likely to have severe aciduria than hyperuricosuria or hyperuricemia. A blood test for serum uric acid is recommended, as allopurinol can be justified based on hyperuricemia. Even without 24-hour urine testing, potassium citrate therapy can be reasonably offered to these patients based on their aciduria and stone composition. They can then be followed with serial urinary pH levels and their citrate therapy titrated accordingly.

Urinary citrate is a potent inhibitor of calcium phosphate crystal growth and stone formation, responsible for about 50% of the total chemical inhibitory effect on calcium phosphate precipitation in normal urine.[152]

Hypocitraturia: Summary and Clinical Tips

  • Potassium citrate is the mainstay of urinary alkalinization therapy and citrate supplementation. The total citrate excretion is not clinically significant for patients whose goal is optimizing the pH.
  • Dietary therapy with citrus food items, including lemonade, orange juice, and powdered lemonade, can be used even though they may not correct significant hypocitraturia without citrate supplementation. Despite its high citrate levels, grapefruit juice is not recommended as it inhibits cytochrome P450 enzymes and does not seem to reduce overall urinary risk factors for stone formation.[153]
  • Every 30 mEq of potassium citrate is expected to increase urinary citrate by 200 mg. Failure to achieve this increase indicates poor citrate absorption. In such cases, switching to liquid citrate therapy and/or sodium bicarbonate should be considered.
  • Optimal urinary citrate significantly reduces the formation of all common stone types (calcium oxalate, calcium phosphate, cystine, struvite, and uric acid). Clinicians do not need to know the stone's chemical composition to use citrate therapy.
  • Serum potassium should be monitored periodically, especially in patients with renal failure and those taking 60 mEq or more potassium citrate. If hyperkalemia develops, a low-potassium citrate alternative should be considered. 
  • Patients with nephrolithiasis taking acetazolamide, thiazides, or topiramate, or post-Roux-en-Y gastric bypass patients, can generally be assumed to have some level of hypocitraturia, even without formal 24-hour urine testing. Empiric citrate therapy can be considered, which can be monitored by urinary pH in patients unable or unwilling to undergo 24-hour urine testing. 
  • Patients should be warned that observing undissolved potassium citrate tablets in the stool is normal, and they should not be concerned or stop treatment. The wax matrix ghost carrier remains after the medication has been released.
  • Urinary alkalinization to a pH of 6.5 is the preferred treatment for uric acid stones. However, using allopurinol or similar agents is recommended and will be helpful in patients with elevated serum or urine uric acid levels. 
  • Potassium citrate can also be used in calcium phosphate stone formers if the urinary pH is maintained at less than 7.2. 
  • Generic potassium citrate is now reasonably affordable, and OTC citrate supplements are also available in pharmacies and online.

Suggested Optimal Range for Urinary Citrate and Guideline for Supplemental Citrate Therapy in Kidney Stone Formers

  • 24-Hour urine citrate should optimally be 640 mg or more. Treatment should be considered if the daily citrate total is below 500 mg.
  • 24-Hour urinary citrate concentration should be 320 mg/L or more. Supplemental therapy should be considered if the citrate concentration is below 250 mg/L. 
  • A dosage of 30 mEq of potassium citrate is estimated to increase daily urinary citrate by 200 mg roughly.
  • For most stone formers, the optimal urine pH is between 6 and 6.5. In uric acid stone formers, the optimal urinary pH for maintenance is 6.5, and for stone dissolution, it is 7.
  • For patients with cystinuria, the optimal urinary pH is 7.5, depending on cystine concentration.
  • pH levels above 7.2 are generally not recommended (except in cystinuria) as they may promote calcium phosphate precipitation.

Enhancing Healthcare Team Outcomes

Renal calculi are a common condition encountered by healthcare professionals in primary care centers worldwide. In an extensive clinical database of almost 50,000 nephrolithiasis patients, less than 1% showed no abnormal or suboptimal chemistries, with a significant portion having abnormal or suboptimal urinary citrate levels. Collaboration among interprofessional healthcare providers is crucial for the early diagnosis and active management of hypocitraturia in patients with kidney stone disease. As hypocitraturia is one of the most treatable urinary chemical abnormalities, effective management relies on a coordinated approach.

Testing 24-hour urines and treating abnormalities can significantly improve urinary chemistry risk factors and reduce the recurrence of nephrolithiasis.[10][11][12][13] According to current AUA guidelines, all patients with nephrolithiasis should be offered access to a 24-hour urine test for kidney stone prophylaxis, particularly for those with multiple stones or high surgical risk.[149]

All interprofessional healthcare team members should collaborate to communicate this information to nephrolithiasis patients. Optimal management of kidney stone disease requires a multidisciplinary team approach, including early diagnosis of acute renal colic, prompt urologic surgical intervention for clinically significant stones when appropriate, and ensuring that all nephrolithiasis patients are informed about the option to minimize future stone formation through 24-hour urine testing and prophylactic treatment for conditions such as hypocitraturia. This collaborative effort should involve urology, nephrology, primary care, and other members of the healthcare team.

References

[1]

Ferraro PM, Taylor EN, Gambaro G, Curhan GC. Dietary and Lifestyle Risk Factors Associated with Incident Kidney Stones in Men and Women. The Journal of urology. 2017 Oct:198(4):858-863. doi: 10.1016/j.juro.2017.03.124. Epub 2017 Mar 30     [PubMed PMID: 28365271]

[2]

Goldfarb DS, Fischer ME, Keich Y, Goldberg J. A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney international. 2005 Mar:67(3):1053-61     [PubMed PMID: 15698445]

[3]

Milose JC, Kaufman SR, Hollenbeck BK, Wolf JS Jr, Hollingsworth JM. Prevalence of 24-hour urine collection in high risk stone formers. The Journal of urology. 2014 Feb:191(2):376-80. doi: 10.1016/j.juro.2013.08.080. Epub 2013 Sep 7     [PubMed PMID: 24018242]

[4]

Penniston KL, Sninsky BC, Nakada SY. Preliminary Evidence of Decreased Disease-Specific Health-Related Quality of Life in Asymptomatic Stone Patients. Journal of endourology. 2016 May:30 Suppl 1():S42-5. doi: 10.1089/end.2016.0074. Epub 2016 Mar 9     [PubMed PMID: 26864746]

Level 2 (mid-level) evidence

[5]

Antonelli JA, Maalouf NM, Pearle MS, Lotan Y. Use of the National Health and Nutrition Examination Survey to calculate the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. European urology. 2014 Oct:66(4):724-9. doi: 10.1016/j.eururo.2014.06.036. Epub 2014 Jul 9     [PubMed PMID: 25015037]

Level 3 (low-level) evidence

[6]

HODGKINSON A. Citric acid excretion in normal adults and in patients with renal calculus. Clinical science. 1962 Oct:23():203-12     [PubMed PMID: 13963791]

[7]

Nicar MJ, Skurla C, Sakhaee K, Pak CY. Low urinary citrate excretion in nephrolithiasis. Urology. 1983 Jan:21(1):8-14     [PubMed PMID: 6823713]

[8]

Pak CY. Citrate and renal calculi: an update. Mineral and electrolyte metabolism. 1994:20(6):371-7     [PubMed PMID: 7783699]

[9]

Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol. The American journal of medicine. 1995 Jan:98(1):50-9     [PubMed PMID: 7825619]

[10]

Pak CY, Fuller C, Sakhaee K, Preminger GM, Britton F. Long-term treatment of calcium nephrolithiasis with potassium citrate. The Journal of urology. 1985 Jul:134(1):11-9     [PubMed PMID: 3892044]

[11]

Hollingsworth JM, Oerline MK, Hsi RS, Crivelli JJ, Krampe N, Asplin JR, Shahinian VB. Real-World Effectiveness of Preventive Pharmacological Therapy in Patients With Urolithiasis: A Retrospective Cohort Study. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2024 Jul:84(1):83-93.e1. doi: 10.1053/j.ajkd.2023.12.015. Epub 2024 Mar 1     [PubMed PMID: 38432593]

Level 2 (mid-level) evidence

[12]

Arivoli K, Valicevic AN, Oerline MK, Hsi RS, Patel SR, Hollingsworth JM, Shahinian VB. Preventive Pharmacological Therapy and Risk of Recurrent Urinary Stone Disease. Clinical journal of the American Society of Nephrology : CJASN. 2024 May 1:19(5):565-572. doi: 10.2215/CJN.0000000000000428. Epub 2024 Feb 12     [PubMed PMID: 38345854]

[13]

Abu-Ghanem Y, Kleinmann N, Erlich T, Winkler HZ, Zilberman DE. The Impact of Dietary Modifications and Medical Management on 24-Hour Urinary Metabolic Profiles and the Status of Renal Stone Disease in Recurrent Stone Formers. The Israel Medical Association journal : IMAJ. 2021 Jan:23(1):12-16     [PubMed PMID: 33443336]

[14]

Pak CY. Citrate and renal calculi: new insights and future directions. American journal of kidney diseases : the official journal of the National Kidney Foundation. 1991 Apr:17(4):420-5     [PubMed PMID: 2008910]

Level 3 (low-level) evidence

[15]

SHAH A, CONSTANT MA, BECKER B. Urinary excretion of citrate in humans following administration of acetazolamide (diamox). A.M.A. archives of ophthalmology. 1958 Apr:59(4):536-40     [PubMed PMID: 13519975]

[16]

Maloney ME, Springhart WP, Ekeruo WO, Young MD, Enemchukwu CU, Preminger GM. Ethnic background has minimal impact on the etiology of nephrolithiasis. The Journal of urology. 2005 Jun:173(6):2001-4     [PubMed PMID: 15879804]

Level 2 (mid-level) evidence

[17]

Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Frontiers in bioscience : a journal and virtual library. 2003 Sep 1:8():s1084-106     [PubMed PMID: 12957820]

Level 3 (low-level) evidence

[18]

Shah O, Assimos DG, Holmes RP. Genetic and dietary factors in urinary citrate excretion. Journal of endourology. 2005 Mar:19(2):177-82     [PubMed PMID: 15798414]

Level 2 (mid-level) evidence

[19]

Goodman HO, Brommage R, Assimos DG, Holmes RP. Genes in idiopathic calcium oxalate stone disease. World journal of urology. 1997:15(3):186-94     [PubMed PMID: 9228726]

[20]

Goodman HO, Holmes RP, Assimos DG. Genetic factors in calcium oxalate stone disease. The Journal of urology. 1995 Feb:153(2):301-7     [PubMed PMID: 7815569]

[21]

Okamoto N, Aruga S, Matsuzaki S, Takahashi S, Matsushita K, Kitamura T. Associations between renal sodium-citrate cotransporter (hNaDC-1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls. International journal of urology : official journal of the Japanese Urological Association. 2007 Apr:14(4):344-9     [PubMed PMID: 17470169]

Level 2 (mid-level) evidence

[22]

Goldfarb DS. A woman with recurrent calcium phosphate kidney stones. Clinical journal of the American Society of Nephrology : CJASN. 2012 Jul:7(7):1172-8. doi: 10.2215/CJN.00560112. Epub 2012 May 17     [PubMed PMID: 22595827]

Level 3 (low-level) evidence

[23]

Melnick JZ, Preisig PA, Haynes S, Pak CY, Sakhaee K, Alpern RJ. Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia. Kidney international. 1998 Nov:54(5):1670-4     [PubMed PMID: 9844143]

Level 3 (low-level) evidence

[24]

Chasan O, Mirioglu S, Artan AS, Gursu M, Kazancioglu R, Elcioglu OC. Assessment of metabolic risk factors for nephrolithiasis in patients with autosomal dominant polycystic kidney disease: a cross-sectional study. Clinical and experimental nephrology. 2023 Nov:27(11):912-918. doi: 10.1007/s10157-023-02378-2. Epub 2023 Jul 26     [PubMed PMID: 37493903]

Level 2 (mid-level) evidence

[25]

Gkentzis A, Kimuli M, Cartledge J, Traxer O, Biyani CS. Urolithiasis in inflammatory bowel disease and bariatric surgery. World journal of nephrology. 2016 Nov 6:5(6):538-546     [PubMed PMID: 27872836]

[26]

Worcester EM. Stones from bowel disease. Endocrinology and metabolism clinics of North America. 2002 Dec:31(4):979-99     [PubMed PMID: 12474641]

[27]

Bianchi L, Gaiani F, Bizzarri B, Minelli R, Cortegoso Valdivia P, Leandro G, Di Mario F, De' Angelis GL, Ruberto C. Renal lithiasis and inflammatory bowel diseases, an update on pediatric population. Acta bio-medica : Atenei Parmensis. 2018 Dec 17:89(9-S):76-80. doi: 10.23750/abm.v89i9-S.7908. Epub 2018 Dec 17     [PubMed PMID: 30561398]

[28]

Marangella M, Vitale C, Manganaro M, Cosseddu D, Martini C, Petrarulo M, Linari F. Renal handling of citrate in chronic renal insufficiency. Nephron. 1991:57(4):439-43     [PubMed PMID: 2046827]

[29]

Uribarri J. Chronic kidney disease and kidney stones. Current opinion in nephrology and hypertension. 2020 Mar:29(2):237-242. doi: 10.1097/MNH.0000000000000582. Epub     [PubMed PMID: 31972597]

Level 3 (low-level) evidence

[30]

Cowley DM, McWhinney BC, Brown JM, Chalmers AH. Chemical factors important to calcium nephrolithiasis: evidence for impaired hydroxycarboxylic acid absorption causing hyperoxaluria. Clinical chemistry. 1987 Feb:33(2 Pt 1):243-7     [PubMed PMID: 3802507]

[31]

Cowley DM, McWhinney BC, Brown JM, Chalmers AH. Effect of citrate on the urinary excretion of calcium and oxalate: relevance to calcium oxalate nephrolithiasis. Clinical chemistry. 1989 Jan:35(1):23-8     [PubMed PMID: 2910576]

[32]

Zuckerman JM, Assimos DG. Hypocitraturia: pathophysiology and medical management. Reviews in urology. 2009 Summer:11(3):134-44     [PubMed PMID: 19918339]

[33]

Watanabe T. Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead. Pediatric health, medicine and therapeutics. 2018:9():181-190. doi: 10.2147/PHMT.S174459. Epub 2018 Dec 12     [PubMed PMID: 30588151]

Level 3 (low-level) evidence

[34]

Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Alexander RT, Law L, Gil-Peña H, Greenbaum LA, Santos F. Hereditary Distal Renal Tubular Acidosis. GeneReviews(®). 1993:():     [PubMed PMID: 31600044]

[35]

Fuster DG, Moe OW. Incomplete Distal Renal Tubular Acidosis and Kidney Stones. Advances in chronic kidney disease. 2018 Jul:25(4):366-374. doi: 10.1053/j.ackd.2018.05.007. Epub     [PubMed PMID: 30139463]

Level 3 (low-level) evidence

[36]

Youssef RF, Martin JW, Sakhaee K, Poindexter J, Dianatnejad S, Scales CD, Preminger GM, Lipkin ME. Rising occurrence of hypocitraturia and hyperoxaluria associated with increasing prevalence of stone disease in calcium kidney stone formers. Scandinavian journal of urology. 2020 Oct:54(5):426-430. doi: 10.1080/21681805.2020.1794955. Epub 2020 Jul 27     [PubMed PMID: 32715836]

[37]

Canales BK, Hatch M. Kidney stone incidence and metabolic urinary changes after modern bariatric surgery: review of clinical studies, experimental models, and prevention strategies. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2014 Jul-Aug:10(4):734-42. doi: 10.1016/j.soard.2014.03.026. Epub 2014 Apr 15     [PubMed PMID: 24969092]

[38]

Bhatti UH, Duffy AJ, Roberts KE, Shariff AH. Nephrolithiasis after bariatric surgery: A review of pathophysiologic mechanisms and procedural risk. International journal of surgery (London, England). 2016 Dec:36(Pt D):618-623. doi: 10.1016/j.ijsu.2016.11.025. Epub 2016 Nov 12     [PubMed PMID: 27847289]

[39]

Espino-Grosso PM, Canales BK. Kidney Stones After Bariatric Surgery: Risk Assessment and Mitigation. Bariatric surgical practice and patient care. 2017 Mar 1:12(1):3-9. doi: 10.1089/bari.2016.0048. Epub     [PubMed PMID: 28465866]

[40]

Moe OW, Xu LHR. Hyperuricosuric calcium urolithiasis. Journal of nephrology. 2018 Apr:31(2):189-196. doi: 10.1007/s40620-018-0469-3. Epub 2018 Jan 24     [PubMed PMID: 29368300]

[41]

Weinstein DA, Somers MJ, Wolfsdorf JI. Decreased urinary citrate excretion in type 1a glycogen storage disease. The Journal of pediatrics. 2001 Mar:138(3):378-82     [PubMed PMID: 11241046]

[42]

Ferraro PM, Bargagli M, Trinchieri A, Gambaro G. Risk of Kidney Stones: Influence of Dietary Factors, Dietary Patterns, and Vegetarian-Vegan Diets. Nutrients. 2020 Mar 15:12(3):. doi: 10.3390/nu12030779. Epub 2020 Mar 15     [PubMed PMID: 32183500]

[43]

Breslau NA, Brinkley L, Hill KD, Pak CY. Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism. The Journal of clinical endocrinology and metabolism. 1988 Jan:66(1):140-6     [PubMed PMID: 2826524]

Level 3 (low-level) evidence

[44]

Sakhaee K, Harvey JA, Padalino PK, Whitson P, Pak CY. The potential role of salt abuse on the risk for kidney stone formation. The Journal of urology. 1993 Aug:150(2 Pt 1):310-2     [PubMed PMID: 8326549]

[45]

Adler S, Zett B, Anderson B, Fraley DS. Effect of volume expansion on renal citrate and ammonia metabolism in KCl-deficient rats. The Journal of clinical investigation. 1975 Aug:56(2):391-400     [PubMed PMID: 239022]

Level 3 (low-level) evidence

[46]

Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys. Journal of endourology. 2004 Mar:18(2):157-61     [PubMed PMID: 15072623]

Level 2 (mid-level) evidence

[47]

Vallés PG, Batlle D. Hypokalemic Distal Renal Tubular Acidosis. Advances in chronic kidney disease. 2018 Jul:25(4):303-320. doi: 10.1053/j.ackd.2018.05.003. Epub     [PubMed PMID: 30139458]

Level 3 (low-level) evidence

[48]

Adam WR, Koretsky AP, Weiner MW. 31P-NMR in vivo measurement of renal intracellular pH: effects of acidosis and K+ depletion in rats. The American journal of physiology. 1986 Nov:251(5 Pt 2):F904-10     [PubMed PMID: 3777186]

Level 3 (low-level) evidence

[49]

Cicerello E, Ciaccia M, Cova G, Mangano M. The impact of potassium citrate therapy in the natural course of Medullary Sponge Kidney with associated nephrolithiasis. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2019 Jul 2:91(2):. doi: 10.4081/aiua.2019.2.102. Epub 2019 Jul 2     [PubMed PMID: 31266277]

[50]

Imam TH, Patail H, Patail H. Medullary Sponge Kidney: Current Perspectives. International journal of nephrology and renovascular disease. 2019:12():213-218. doi: 10.2147/IJNRD.S169336. Epub 2019 Sep 26     [PubMed PMID: 31576161]

Level 3 (low-level) evidence

[51]

Fabris A, Lupo A, Bernich P, Abaterusso C, Marchionna N, Nouvenne A, Gambaro G. Long-term treatment with potassium citrate and renal stones in medullary sponge kidney. Clinical journal of the American Society of Nephrology : CJASN. 2010 Sep:5(9):1663-8. doi: 10.2215/CJN.00220110. Epub 2010 Jun 24     [PubMed PMID: 20576821]

Level 2 (mid-level) evidence

[52]

Shey J, Cameron MA, Sakhaee K, Moe OW. Recurrent calcium nephrolithiasis associated with primary aldosteronism. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2004 Jul:44(1):e7-12     [PubMed PMID: 15211456]

Level 3 (low-level) evidence

[53]

Pak CY, Peterson R, Sakhaee K, Fuller C, Preminger G, Reisch J. Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. The American journal of medicine. 1985 Sep:79(3):284-8     [PubMed PMID: 4036979]

[54]

Warner BW, LaGrange CA, Tucker T, Bensalem-Owen M, Pais VM Jr. Induction of progressive profound hypocitraturia with increasing doses of topiramate. Urology. 2008 Jul:72(1):29-32; discussion 32-3. doi: 10.1016/j.urology.2008.01.042. Epub 2008 Apr 24     [PubMed PMID: 18436283]

[55]

Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K. Biochemical and stone-risk profiles with topiramate treatment. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2006 Oct:48(4):555-63     [PubMed PMID: 16997051]

Level 2 (mid-level) evidence

[56]

Vega D, Maalouf NM, Sakhaee K. Increased propensity for calcium phosphate kidney stones with topiramate use. Expert opinion on drug safety. 2007 Sep:6(5):547-57     [PubMed PMID: 17877442]

Level 3 (low-level) evidence

[57]

Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. British journal of clinical pharmacology. 2009 Nov:68(5):655-61. doi: 10.1111/j.1365-2125.2009.03521.x. Epub     [PubMed PMID: 19916989]

[58]

Windus DW, Cohn DE, Heifets M. Effects of fasting on citrate transport by the brush-border membrane of rat kidney. The American journal of physiology. 1986 Oct:251(4 Pt 2):F678-82     [PubMed PMID: 3766743]

Level 3 (low-level) evidence

[59]

Cury DB, Moss AC, Schor N. Nephrolithiasis in patients with inflammatory bowel disease in the community. International journal of nephrology and renovascular disease. 2013:6():139-42. doi: 10.2147/IJNRD.S45466. Epub 2013 Jul 29     [PubMed PMID: 23935383]

[60]

Andersson H, Bosaeus I, Fasth S, Hellberg R, Hultén L. Cholelithiasis and urolithiasis in Crohn's disease. Scandinavian journal of gastroenterology. 1987 Mar:22(2):253-6     [PubMed PMID: 3576131]

[61]

Ishii G, Nakajima K, Tanaka N, Hara H, Kato M, Ishii N. Clinical evaluation of urolithiasis in Crohn's disease. International journal of urology : official journal of the Japanese Urological Association. 2009 May:16(5):477-80. doi: 10.1111/j.1442-2042.2009.02285.x. Epub 2009 Apr 1     [PubMed PMID: 19341366]

[62]

Rodríguez Soriano J. Renal tubular acidosis: the clinical entity. Journal of the American Society of Nephrology : JASN. 2002 Aug:13(8):2160-70     [PubMed PMID: 12138150]

[63]

Bleich HL, Moore MJ, Lemann J Jr, Adams ND, Gray RW. Urinary calcium excretion in human beings. The New England journal of medicine. 1979 Sep 6:301(10):535-41     [PubMed PMID: 37442]

Level 3 (low-level) evidence

[64]

Nijenhuis T, Renkema KY, Hoenderop JG, Bindels RJ. Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins. Journal of the American Society of Nephrology : JASN. 2006 Mar:17(3):617-26     [PubMed PMID: 16421227]

Level 3 (low-level) evidence

[65]

Sebastian A, McSherry E, Morris RC Jr. Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. The Journal of clinical investigation. 1971 Mar:50(3):667-78     [PubMed PMID: 5101785]

[66]

Stanton BA. Renal potassium transport: morphological and functional adaptations. The American journal of physiology. 1989 Nov:257(5 Pt 2):R989-97     [PubMed PMID: 2686470]

Level 3 (low-level) evidence

[67]

Preminger GM, Sakhaee K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. The Journal of urology. 1985 Jul:134(1):20-3     [PubMed PMID: 4009822]

[68]

Pope GD, Birkmeyer JD, Finlayson SR. National trends in utilization and in-hospital outcomes of bariatric surgery. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2002 Nov-Dec:6(6):855-60; discussion 861     [PubMed PMID: 12504224]

[69]

Duffey BG, Alanee S, Pedro RN, Hinck B, Kriedberg C, Ikramuddin S, Kellogg T, Stessman M, Moeding A, Monga M. Hyperoxaluria is a long-term consequence of Roux-en-Y Gastric bypass: a 2-year prospective longitudinal study. Journal of the American College of Surgeons. 2010 Jul:211(1):8-15. doi: 10.1016/j.jamcollsurg.2010.03.007. Epub     [PubMed PMID: 20610243]

[70]

Tarplin S, Ganesan V, Monga M. Stone formation and management after bariatric surgery. Nature reviews. Urology. 2015 May:12(5):263-70. doi: 10.1038/nrurol.2015.67. Epub 2015 Apr 7     [PubMed PMID: 25850790]

[71]

Jhagroo RA, Wertheim ML, Penniston KL. Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia. British journal of clinical pharmacology. 2016 Jan:81(1):131-6. doi: 10.1111/bcp.12751. Epub 2015 Dec 10     [PubMed PMID: 26297809]

[72]

Merino-Salas S, Arrabal-Polo MA, Cano-Garcia Mdel C, Arrabal-Martin M. Calcium nephrolithiasis induced by topiramate. Archivos espanoles de urologia. 2014 Apr:67(3):284-7     [PubMed PMID: 24840594]

Level 3 (low-level) evidence

[73]

Dell'Orto VG, Belotti EA, Goeggel-Simonetti B, Simonetti GD, Ramelli GP, Bianchetti MG, Lava SA. Metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review. British journal of clinical pharmacology. 2014 Jun:77(6):958-64. doi: 10.1111/bcp.12283. Epub     [PubMed PMID: 24219102]

Level 1 (high-level) evidence

[74]

Otto BJ, Bozorgmehri S, Kuo J, Canales M, Bird VG, Canales B. Age, Body Mass Index, and Gender Predict 24-Hour Urine Parameters in Recurrent Idiopathic Calcium Oxalate Stone Formers. Journal of endourology. 2017 Dec:31(12):1335-1341. doi: 10.1089/end.2017.0352. Epub     [PubMed PMID: 29084490]

[75]

Hosking DH, Wilson JW, Liedtke RR, Smith LH, Wilson DM. Urinary citrate excretion in normal persons and patients with idiopathic calcium urolithiasis. The Journal of laboratory and clinical medicine. 1985 Dec:106(6):682-9     [PubMed PMID: 4067380]

Level 2 (mid-level) evidence

[76]

Trinchieri A, Mandressi A, Luongo P, Rovera F, Longo G. Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones. Scandinavian journal of urology and nephrology. 1992:26(4):379-86     [PubMed PMID: 1292077]

[77]

Hess B, Hasler-Strub U, Ackermann D, Jaeger P. Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 1997 Jul:12(7):1362-8     [PubMed PMID: 9249770]

[78]

Shorr E, Bernheim AR, Taussky H. THE RELATION OF URINARY CITRIC ACID EXCRETION TO THE MENSTRUAL CYCLE AND THE STEROIDAL REPRODUCTIVE HORMONES. Science (New York, N.Y.). 1942 Jun 12:95(2476):606-7     [PubMed PMID: 17745023]

[79]

Beara-Lasic L, Goldfarb DS. Nephrolithiasis in women: how different from men? Current opinion in nephrology and hypertension. 2020 Mar:29(2):201-206. doi: 10.1097/MNH.0000000000000577. Epub     [PubMed PMID: 31789849]

Level 3 (low-level) evidence

[80]

Reinstatler L, Khaleel S, Pais VM Jr. Association of Pregnancy with Stone Formation among Women in the United States: A NHANES Analysis 2007 to 2012. The Journal of urology. 2017 Aug:198(2):389-393. doi: 10.1016/j.juro.2017.02.3233. Epub 2017 Feb 24     [PubMed PMID: 28238670]

[81]

Zacchia M, Preisig P. Low urinary citrate: an overview. Journal of nephrology. 2010 Nov-Dec:23 Suppl 16():S49-56     [PubMed PMID: 21170889]

Level 3 (low-level) evidence

[82]

Melnick JZ, Srere PA, Elshourbagy NA, Moe OW, Preisig PA, Alpern RJ. Adenosine triphosphate citrate lyase mediates hypocitraturia in rats. The Journal of clinical investigation. 1996 Nov 15:98(10):2381-7     [PubMed PMID: 8941657]

Level 3 (low-level) evidence

[83]

Fegan J, Khan R, Poindexter J, Pak CY. Gastrointestinal citrate absorption in nephrolithiasis. The Journal of urology. 1992 May:147(5):1212-4     [PubMed PMID: 1569651]

[84]

Brennan TS, Klahr S, Hamm LL. Citrate transport in rabbit nephron. The American journal of physiology. 1986 Oct:251(4 Pt 2):F683-9     [PubMed PMID: 3766744]

Level 3 (low-level) evidence

[85]

Simpson DP. Citrate excretion: a window on renal metabolism. The American journal of physiology. 1983 Mar:244(3):F223-34     [PubMed PMID: 6338740]

Level 3 (low-level) evidence

[86]

Minisola S, Rossi W, Pacitti MT, Scarnecchia L, Bigi F, Carnevale V, Mazzuoli G. Studies on citrate metabolism in normal subjects and kidney stone patients. Mineral and electrolyte metabolism. 1989:15(5):303-8     [PubMed PMID: 2811789]

[87]

Pattaras JG, Moore RG. Citrate in the management of urolithiasis. Journal of endourology. 1999 Nov:13(9):687-92     [PubMed PMID: 10608522]

[88]

HODGKINSON A. The relation between citric acid and calcium metabolism with particular reference to primary hyper-parathyroidism and idiopathic hypercalciuria. Clinical science. 1963 Apr:24():167-78     [PubMed PMID: 13963792]

[89]

Menon M, Mahle CJ. Urinary citrate excretion in patients with renal calculi. The Journal of urology. 1983 Jun:129(6):1158-60     [PubMed PMID: 6854790]

[90]

Rodgers A, Allie-Hamdulay S, Jackson G. Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2006 Feb:21(2):361-9     [PubMed PMID: 16249202]

[91]

Caudarella R, Vescini F. Urinary citrate and renal stone disease: the preventive role of alkali citrate treatment. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2009 Sep:81(3):182-7     [PubMed PMID: 19911682]

[92]

Kamphuis GM, Wouter van Hattum J, de Bie P, Somani BK. Method of alkalization and monitoring of urinary pH for prevention of recurrent uric acid urolithiasis: a systematic review. Translational andrology and urology. 2019 Sep:8(Suppl 4):S448-S456. doi: 10.21037/tau.2019.05.01. Epub     [PubMed PMID: 31656751]

Level 1 (high-level) evidence

[93]

Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney international. 1986 Sep:30(3):422-8     [PubMed PMID: 3784284]

Level 3 (low-level) evidence

[94]

Hess B, Zipperle L, Jaeger P. Citrate and calcium effects on Tamm-Horsfall glycoprotein as a modifier of calcium oxalate crystal aggregation. The American journal of physiology. 1993 Dec:265(6 Pt 2):F784-91     [PubMed PMID: 8285211]

[95]

Hess B. Tamm-Horsfall glycoprotein and calcium nephrolithiasis. Mineral and electrolyte metabolism. 1994:20(6):393-8     [PubMed PMID: 7783702]

[96]

Hess B, Jordi S, Zipperle L, Ettinger E, Giovanoli R. Citrate determines calcium oxalate crystallization kinetics and crystal morphology-studies in the presence of Tamm-Horsfall protein of a healthy subject and a severely recurrent calcium stone former. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2000 Mar:15(3):366-74     [PubMed PMID: 10692522]

[97]

Hess B. Tamm-Horsfall glycoprotein--inhibitor or promoter of calcium oxalate monohydrate crystallization processes? Urological research. 1992:20(1):83-6     [PubMed PMID: 1736492]

[98]

Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, Song L, Maalouf NM. Nephrolithiasis. Endotext. 2000:():     [PubMed PMID: 25905296]

[99]

Abou Chakra M, Dellis AE, Papatsoris AG, Moussa M. Established and recent developments in the pharmacological management of urolithiasis: an overview of the current treatment armamentarium. Expert opinion on pharmacotherapy. 2020 Jan:21(1):85-96. doi: 10.1080/14656566.2019.1685979. Epub 2019 Nov 12     [PubMed PMID: 31714803]

Level 3 (low-level) evidence

[100]

Welshman SG, McGeown MG. Urinary citrate excretion in stone-formers and normal controls. British journal of urology. 1976 Feb:48(1):7-11     [PubMed PMID: 1268467]

[101]

Höbarth K, Hofbauer J. Value of routine citrate analysis and calcium/citrate ratio in calcium urolithiasis. European urology. 1991:19(2):165-8     [PubMed PMID: 2022221]

[102]

Nikkilä M, Koivula T, Jokela H. Urinary citrate excretion in patients with urolithiasis and normal subjects. European urology. 1989:16(5):382-5     [PubMed PMID: 2776809]

[103]

Cupisti A, Morelli E, Lupetti S, Meola M, Barsotti G. Low urine citrate excretion as main risk factor for recurrent calcium oxalate nephrolithiasis in males. Nephron. 1992:61(1):73-6     [PubMed PMID: 1528345]

[104]

Gouru VR, Pogula VR, Vaddi SP, Manne V, Byram R, Kadiyala LS. Metabolic evaluation of children with urolithiasis. Urology annals. 2018 Jan-Mar:10(1):94-99. doi: 10.4103/UA.UA_98_17. Epub     [PubMed PMID: 29416283]

[105]

Carnes K, Howe A, Feustel PJ, Listman JA, White M, Kogan BA. 24-Hour urine collection for first time pediatric stone formers: Is it worth it? Journal of pediatric urology. 2021 Jun:17(3):387.e1-387.e7. doi: 10.1016/j.jpurol.2020.12.001. Epub 2020 Dec 5     [PubMed PMID: 33762156]

[106]

Ubetagoyena Arrieta M, Areses Trapote R, Mendia Ubetagoyena J, Pérez Revuelta MS, Letona Luqui M. Renal lithiasis in pediatric patients: correlation of methods that depend on 24-hour collections with simpler methods that do not require timed urine. Actas urologicas espanolas. 2021 Mar:45(2):146-153. doi: 10.1016/j.acuro.2020.09.006. Epub 2020 Nov 5     [PubMed PMID: 33160758]

[107]

Haleblian GE, Leitao VA, Pierre SA, Robinson MR, Albala DM, Ribeiro AA, Preminger GM. Assessment of citrate concentrations in citrus fruit-based juices and beverages: implications for management of hypocitraturic nephrolithiasis. Journal of endourology. 2008 Jun:22(6):1359-66. doi: 10.1089/end.2008.0069. Epub     [PubMed PMID: 18578663]

[108]

Penniston KL, Nakada SY, Holmes RP, Assimos DG. Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. Journal of endourology. 2008 Mar:22(3):567-70. doi: 10.1089/end.2007.0304. Epub     [PubMed PMID: 18290732]

[109]

Seltzer MA, Low RK, McDonald M, Shami GS, Stoller ML. Dietary manipulation with lemonade to treat hypocitraturic calcium nephrolithiasis. The Journal of urology. 1996 Sep:156(3):907-9     [PubMed PMID: 8709360]

[110]

Kang DE, Sur RL, Haleblian GE, Fitzsimons NJ, Borawski KM, Preminger GM. Long-term lemonade based dietary manipulation in patients with hypocitraturic nephrolithiasis. The Journal of urology. 2007 Apr:177(4):1358-62; discussion 1362; quiz 1591     [PubMed PMID: 17382731]

Level 2 (mid-level) evidence

[111]

Wabner CL, Pak CY. Effect of orange juice consumption on urinary stone risk factors. The Journal of urology. 1993 Jun:149(6):1405-8     [PubMed PMID: 8501777]

Level 1 (high-level) evidence

[112]

Patel RM, Jiang P, Asplin J, Granja I, Capretz T, Osann K, Okhunov Z, Landman J, Clayman RV. Coconut Water: An Unexpected Source of Urinary Citrate. BioMed research international. 2018:2018():3061742. doi: 10.1155/2018/3061742. Epub 2018 Nov 1     [PubMed PMID: 30515390]

[113]

Levine BS, Rodman JS, Wienerman S, Bockman RS, Lane JM, Chapman DS. Effect of calcium citrate supplementation on urinary calcium oxalate saturation in female stone formers: implications for prevention of osteoporosis. The American journal of clinical nutrition. 1994 Oct:60(4):592-6     [PubMed PMID: 8092096]

[114]

Sakhaee K, Baker S, Zerwekh J, Poindexter J, Garcia-Hernandez PA, Pak CY. Limited risk of kidney stone formation during long-term calcium citrate supplementation in nonstone forming subjects. The Journal of urology. 1994 Aug:152(2 Pt 1):324-7     [PubMed PMID: 8015062]

[115]

Pak CY, Peterson R. Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Archives of internal medicine. 1986 May:146(5):863-7     [PubMed PMID: 3963975]

[116]

Nicar MJ, Peterson R, Pak CY. Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. The Journal of urology. 1984 Mar:131(3):430-3     [PubMed PMID: 6699979]

[117]

Pak CY, Sakhaee K, Fuller CJ. Physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. Transactions of the Association of American Physicians. 1983:96():294-305     [PubMed PMID: 6679957]

[118]

Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney international. 1983 Sep:24(3):348-52     [PubMed PMID: 6645208]

Level 1 (high-level) evidence

[119]

Song Y, Hernandez N, Shoag J, Goldfarb DS, Eisner BH. Potassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis. Urolithiasis. 2016 Apr:44(2):145-8. doi: 10.1007/s00240-015-0819-8. Epub 2015 Nov 18     [PubMed PMID: 26582172]

[120]

Sorokin I, Pearle MS. Medical therapy for nephrolithiasis: State of the art. Asian journal of urology. 2018 Oct:5(4):243-255. doi: 10.1016/j.ajur.2018.08.005. Epub 2018 Sep 3     [PubMed PMID: 30364650]

[121]

Kessler T, Hesse A. Cross-over study of the influence of bicarbonate-rich mineral water on urinary composition in comparison with sodium potassium citrate in healthy male subjects. The British journal of nutrition. 2000 Dec:84(6):865-71     [PubMed PMID: 11177203]

Level 1 (high-level) evidence

[122]

Pinheiro VB, Baxmann AC, Tiselius HG, Heilberg IP. The effect of sodium bicarbonate upon urinary citrate excretion in calcium stone formers. Urology. 2013 Jul:82(1):33-7. doi: 10.1016/j.urology.2013.03.002. Epub 2013 Apr 18     [PubMed PMID: 23602798]

Level 1 (high-level) evidence

[123]

Phillips R, Hanchanale VS, Myatt A, Somani B, Nabi G, Biyani CS. Citrate salts for preventing and treating calcium containing kidney stones in adults. The Cochrane database of systematic reviews. 2015 Oct 6:2015(10):CD010057. doi: 10.1002/14651858.CD010057.pub2. Epub 2015 Oct 6     [PubMed PMID: 26439475]

Level 1 (high-level) evidence

[124]

Sakhaee K, Pak C. Superior calcium bioavailability of effervescent potassium calcium citrate over tablet formulation of calcium citrate after Roux-en-Y gastric bypass. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2013 Sep-Oct:9(5):743-8. doi: 10.1016/j.soard.2011.11.011. Epub 2011 Dec 3     [PubMed PMID: 22222299]

Level 1 (high-level) evidence

[125]

Shenoy C. Hypocitraturia despite potassium citrate tablet supplementation. MedGenMed : Medscape general medicine. 2006 Jul 13:8(3):8     [PubMed PMID: 17406150]

Level 3 (low-level) evidence

[126]

Stern KL, Canvasser N, Borofsky M, Gleason VM, Kamphuis G, El Tayeb MM, Hsi R, Scotland KB. Alkalinizing Agents: A Review of Prescription, Over-the-Counter, and Medical Food Supplements. Journal of endourology. 2020 Jan:34(1):1-6. doi: 10.1089/end.2019.0292. Epub 2019 Sep 25     [PubMed PMID: 31333065]

[127]

Johnson BA, Steinberg RL. Over-the-Counter Remedies for Recurrent Stone Formers: Where Is the Evidence? The Journal of urology. 2023 Jun:209(6):1043-1044. doi: 10.1097/JU.0000000000003398. Epub 2023 Apr 29     [PubMed PMID: 37119210]

[128]

Hedelin H, Grenabo L, Hugosson J, Pettersson S. The influence of zinc and citrate on urease-induced urine crystallisation. Urological research. 1989:17(3):177-80     [PubMed PMID: 2749946]

[129]

McLean RJ, Downey J, Clapham L, Nickel JC. Influence of chondroitin sulfate, heparin sulfate, and citrate on Proteus mirabilis-induced struvite crystallization in vitro. The Journal of urology. 1990 Nov:144(5):1267-71     [PubMed PMID: 2122009]

[130]

Wang YH, Grenabo L, Hedelin H, McLean RJ, Nickel JC, Pettersson S. Citrate and urease-induced crystallization in synthetic and human urine. Urological research. 1993 Mar:21(2):109-15     [PubMed PMID: 8503146]

[131]

Wang YH, Grenabo L, Hedelin H, Pettersson S. The effects of sodium citrate and oral potassium citrate on urease-induced crystallization. British journal of urology. 1994 Oct:74(4):409-15     [PubMed PMID: 7820416]

[132]

Cicerello E, Merlo F, Gambaro G, Maccatrozzo L, Fandella A, Baggio B, Anselmo G. Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients. The Journal of urology. 1994 Jan:151(1):5-9     [PubMed PMID: 8254832]

Level 1 (high-level) evidence

[133]

Fine JK, Pak CY, Preminger GM. Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. The Journal of urology. 1995 Jan:153(1):27-32; discussion 32-3     [PubMed PMID: 7966783]

Level 2 (mid-level) evidence

[134]

Fuselier HA, Moore K, Lindberg J, Husserl FE, Cole FE, Kok DJ, Whitehead D, Galliano DJ, Erwin DT. Agglomeration inhibition reflected stone-forming activity during long-term potassium citrate therapy in calcium stone formers. Urology. 1998 Dec:52(6):988-94     [PubMed PMID: 9836542]

[135]

Fuselier HA, Ward DM, Lindberg JS, Allen JM, Husserl FE, Marcucci PA, Cole FE, Turnipseed J, Alam J, Kok DJ. Urinary Tamm-Horsfall protein increased after potassium citrate therapy in calcium stone formers. Urology. 1995 Jun:45(6):942-6     [PubMed PMID: 7771027]

[136]

Moussa M, Papatsoris AG, Abou Chakra M, Moussa Y. Update on cystine stones: current and future concepts in treatment. Intractable & rare diseases research. 2020 May:9(2):71-78. doi: 10.5582/irdr.2020.03006. Epub     [PubMed PMID: 32494553]

[137]

Jaipakdee S, Prasongwatana V, Premgamone A, Reungjui S, Tosukhowong P, Tungsanga K, Suwantrai S, Noppawinyoowong C, Maskasame S, Sriboonlue P. The effects of potassium and magnesium supplementations on urinary risk factors of renal stone patients. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2004 Mar:87(3):255-63     [PubMed PMID: 15117041]

Level 1 (high-level) evidence

[138]

Reddy SV, Shaik AB, Bokkisam S. Effect of potassium magnesium citrate and vitamin B-6 prophylaxis for recurrent and multiple calcium oxalate and phosphate urolithiasis. Korean journal of urology. 2014 Jun:55(6):411-6. doi: 10.4111/kju.2014.55.6.411. Epub 2014 Jun 16     [PubMed PMID: 24955227]

[139]

Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. The Journal of urology. 1997 Dec:158(6):2069-73     [PubMed PMID: 9366314]

Level 1 (high-level) evidence

[140]

Pak CY, Koenig K, Khan R, Haynes S, Padalino P. Physicochemical action of potassium-magnesium citrate in nephrolithiasis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1992 Mar:7(3):281-5     [PubMed PMID: 1585829]

[141]

Herrmann U, Schwille PO, Schmiedl A, Fan J, Manoharan M. Acute effects of calcium sodium citrate supplementation of a test meal on mineral homeostasis, oxalate, and calcium oxalate crystallization in the urine of healthy humans--preliminary results in patients with idiopathic calcium urolithiasis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 1999 Jun:53(5-6):264-73     [PubMed PMID: 10424248]

[142]

Reungjui S, Prasongwatana V, Premgamone A, Tosukhowong P, Jirakulsomchok S, Sriboonlue P. Magnesium status of patients with renal stones and its effect on urinary citrate excretion. BJU international. 2002 Nov:90(7):635-9     [PubMed PMID: 12410738]

Level 2 (mid-level) evidence

[143]

Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CY. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. The Journal of urology. 1993 Dec:150(6):1761-4     [PubMed PMID: 8230497]

Level 1 (high-level) evidence

[144]

Hofbauer J, Höbarth K, Szabo N, Marberger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis--a prospective randomized study. British journal of urology. 1994 Apr:73(4):362-5     [PubMed PMID: 8199822]

Level 1 (high-level) evidence

[145]

Mattle D, Hess B. Preventive treatment of nephrolithiasis with alkali citrate--a critical review. Urological research. 2005 May:33(2):73-9     [PubMed PMID: 15875173]

[146]

Preminger GM, Harvey JA, Pak CY. Comparative efficacy of "specific" potassium citrate therapy versus conservative management in nephrolithiasis of mild to moderate severity. The Journal of urology. 1985 Oct:134(4):658-61     [PubMed PMID: 3897582]

Level 2 (mid-level) evidence

[147]

Manzo BO, Cabrera JD, Emiliani E, Sánchez HM, Eisner BH, Torres JE. Impact of the adherence to medical treatment on the main urinary metabolic disorders in patients with kidney stones. Asian journal of urology. 2021 Jul:8(3):275-279. doi: 10.1016/j.ajur.2020.07.002. Epub 2020 Aug 6     [PubMed PMID: 34401334]

[148]

Dai JC, Maalouf NM, Hill K, Antonelli JA, Pearle MS, Johnson BA. Alkali Citrate Content of Common Over-the-Counter and Medical Food Supplements. Journal of endourology. 2023 Jan:37(1):112-118. doi: 10.1089/end.2022.0274. Epub 2022 Oct 19     [PubMed PMID: 35972746]

[149]

Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, Monga M, Penniston KL, Preminger GM, Turk TM, White JR, American Urological Assocation. Medical management of kidney stones: AUA guideline. The Journal of urology. 2014 Aug:192(2):316-24. doi: 10.1016/j.juro.2014.05.006. Epub 2014 May 20     [PubMed PMID: 24857648]

[150]

Parfitt AM. Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis; relationship to citrate and calcium excretion. Archives of internal medicine. 1969 Dec:124(6):736-40     [PubMed PMID: 5353483]

[151]

Parfitt AM. Acetazolamide and renal stone formation. Lancet (London, England). 1970 Jul 18:2(7664):153     [PubMed PMID: 4194537]

Level 3 (low-level) evidence

[152]

Rimer JD, Sakhaee K, Maalouf NM. Citrate therapy for calcium phosphate stones. Current opinion in nephrology and hypertension. 2019 Mar:28(2):130-139. doi: 10.1097/MNH.0000000000000474. Epub     [PubMed PMID: 30531474]

Level 3 (low-level) evidence

[153]

Goldfarb DS, Asplin JR. Effect of grapefruit juice on urinary lithogenicity. The Journal of urology. 2001 Jul:166(1):263-7     [PubMed PMID: 11435883]

Level 1 (high-level) evidence