Continuing Education Activity

Hypocitraturia is characterized by low citrate levels in the urine and is a significant metabolic abnormality linked to the formation of renal calculi. 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. This condition is often associated with various dietary, metabolic, and genetic factors, making its management crucial for preventing recurrent kidney stone episodes and maintaining overall renal health. Hypocitraturia is diagnosed through a 24-hour urine test, often confirmed with a second test. Treatment includes optimizing potassium citrate supplementation and addressing underlying causes when possible. Management involves pharmacological interventions, dietary modifications, and lifestyle changes to increase urinary citrate levels, effectively preventing up to half of symptomatic kidney stones. 

This activity offers an in-depth exploration of hypocitraturia, its role in the pathogenesis of renal calculi, and contemporary, evidence-based treatment options, including pharmacological interventions, dietary modifications, and lifestyle changes to increase urinary citrate levels and prevent stone formation. In addition, this activity provides healthcare providers with insight into the latest diagnostic techniques, treatment modalities, and preventative strategies for hypocitraturia and kidney stones. This activity also highlights the role of an interprofessional healthcare team in improving patient outcomes through enhanced personalized treatment plans and comprehensive, collaborative care. This activity underscores that an interprofessional healthcare team is essential in optimizing patient outcomes through personalized treatment plans and collaborative care.

Objectives:

• Identify the clinical signs and risk factors associated with hypocitraturia and renal calculi to improve diagnostic accuracy.
• Implement evidence-based treatment protocols, including potassium citrate supplementation and dietary modifications, to manage hypocitraturia effectively.
• Apply updated guidelines and best practices for managing hypocitraturia and renal calculi to improve patient care and outcomes.
• Collaborate with an interprofessional healthcare team to provide comprehensive patient care and address all aspects of hypocitraturia and renal calculi management.

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

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]

• 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]

• 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]

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

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.

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.

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] 

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] 

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]

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] 

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.

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.

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.

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Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.

Disclosure: Khalid Bashir declares no relevant financial relationships with ineligible companies.