Continuing Education Activity

Renal calculi are one of the most common cases that physicians encounter. It has been estimated that half of all symptomatic kidney stones could be prevented with proper diagnosis and prophylactic treatment of underlying chemical nephrolithiasis risk factors. This activity outlines the role of the interprofessional team in the evaluation and management of renal calculi.

Objectives:

• Describe the etiology of renal calculi.
• Review the diagnostic approach for clinicians to diagnose hypocitraturia.
• Summarize the initial treatment options for patients with hypocitraturia.
• Outline the ongoing management options available for hypocitraturia.

Introduction

It's been 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 dramatically lowered in nephrolithiasis patients, even in those with asymptomatic stones.[4]

Direct and indirect costs are estimated at over $10 billion yearly, which is predicted to exceed $15 billion by 2030. This is due to the increasing incidence of stone disease from other associated disorders that contribute to nephrolithiasis, such as diabetes and obesity, general population growth, and global warming.[5] 

Low urinary citrate excretion (hypocitraturia) is one of the most common, treatable causes of kidney stones. Boothby and Adams first reported this in 1934 and later confirmed by Kissin and Locks in 1941. This information was largely ignored or attributed to the bacterial consumption of citrate until 1962, when Hodgkinson first suggested hypocitraturia as a unique urinary chemical disorder in nephrolithiasis patients.[6]

Hypocitraturia is officially defined as less than 320 mg of urinary citrate excretion a day, but this definition has been questioned by many experts as it is based on statistical analyses of large numbers of 24-hour urine tests from the general population and not on 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 like citrate are not reported in standard laboratory reports. 

It is estimated that hypocitraturia is found in about 30% (10% to 60%) of all stone formers, but this will vary according to the particular definition of hypocitraturia used and the stone type.[9] It is the sole identifiable stone-promoting chemical abnormality in about 10% of all calcium stone-forming patients and is a contributing factor associated with other metabolic problems in about half.

Long-term optimization of potassium citrate supplementation can reduce calcium nephrolithiasis by 80%.[10] 

Etiology

In normal individuals, urinary citrate excretion is directly related to the net gastrointestinal absorption of alkali.[11] Low urinary citrate is most often associated with poor dietary choices, such as high meat and high sodium intake with low fruit (citrus) ingestion. Thiazides, ACE inhibitors, topiramate, and acetazolamide can all cause hypocitraturia. Low urinary citrate is also found in irritable bowel syndrome (IBS), colitis, short bowel syndrome, chronic diarrhea, and after Roux-en-Y gastric bypass surgery.

Urinary citrate is increased in females and metabolic alkalosis as well as by estrogens, parathyroid hormone, growth hormone, and vitamin D.  It is decreased by testosterone in males, in starvation, and all types of acidosis; whether dietary, metabolic, uremic, or diabetic.[12] The ethnic background does not seem to significantly affect urinary citrate excretion, but genetic factors appear to play an important primary or contributing role in at least some nephrolithiasis patients.[13][14][15][16][17][18]

Specific causes of hypocitraturia include:

• Acetazolamide therapy (by creating a hyperchloremic acidosis through its effect on reducing bicarbonate reabsorption in the proximal renal tubule. This is similar to the mechanism in distal renal tubular acidosis.)[19]
• Angiotensin-converting enzyme inhibitors (by increasing adenosine triphosphate (ATP) citrate lyase activity.)[20]
• Chronic diarrhea syndrome, colitis, and irritable bowel syndrome (due to alkali loss in the stool. This is also responsible for the burning rectal sensation in patients with chronic diarrhea who are actually experiencing a mild chemical alkali burn.)[21][22][23]
• Chronic renal failure. A reduced glomerular filtration rate results in less filtered citrate. This effect is compensated by increased fractional citrate excretion, so hypocitraturia is not typically apparent until relatively advanced renal failure has developed.[24] This presents a problem in treatment as it is important to avoid hyperkalemia from excessive potassium citrate supplementation in chronic renal failure patients.[25] Therefore, the use of low potassium citrate supplements is preferred in chronic renal failure. 
• Citrate GI malabsorption. Some patients may demonstrate a blunted response to oral citrate supplementation due to a primary intestinal absorptive defect.[26][27]
• Dietary factors (typically, high animal protein, high sodium, low citrus, and low alkali diet)[28]
• Distal renal tubular acidosis.[29][30][31]
• Ethacrynic acid.[28] 
• Gastric bypass surgery; particularly Roux-en-Y procedures.[21][32][33][34][35]
• Genetic factors.[15][16][17][18]
• Gout, hyperuricosuria, and gouty diathesis.[36]
• Glycogen storage disease, type 1.[37] 
• High animal protein diet (from the high acid ash load. Animal proteins are high in sulfates and phosphates, which are excreted as acids. A low animal protein diet can increase urinary citrate by an average of 25%.)[38][39]
• High sodium intake (due to sodium-induced hypokalemia); a high sodium diet can decrease urinary citrate by 20%.[11][20][38][40][41]
• Horseshoe kidneys. (Over 50% of nephrolithiasis patients with a horseshoe kidney will demonstrate hypocitraturia.)[42]
• Hypokalemia (from increased intracellular acidosis).[43][44]
• Ketogenic diets.[28]
• Medullary sponge kidney.[45][46][47][48]
• Primary hyperaldosteronism (secondary to the chronic hypokalemia produced by this disorder.)[49]
• Thiazide diuretics (from the hypokalemia associated with thiazide medications)[50]
• Topiramate therapy (due to the induced metabolic acidosis.)[51][52][53][54]
• Starvation (increases citrate absorption by stimulating cellular transporters directly and by increasing acidosis)[55]
• Strenuous physical exercise (due to lactic acidosis).
• Urinary tract infections (from direct bacterial breakdown of citrate. Up to 30% of calcium oxalate stone formers will have a history of E. coli urinary tract infections.)

Chronic Diarrheal States, Colitis, and Irritable Bowel Syndrome (IBS)

The overall risk of nephrolithiasis is markedly increased by up to 38% in patients with chronic diarrheal states, colitis, and irritable bowel syndrome compared to the general population.[56] Chronic diarrhea causes significant bicarbonate loss resulting in 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 notorious for their tendency to develop dehydration, metabolic acidosis, and severe hypocitraturia resulting in a high risk for urinary stone disease, particularly uric acid calculi.[56]

Among IBS patients, those with Crohn's disease tend to have the highest incidence of hypocitraturia and nephrolithiasis, especially if they've also had intestinal surgical resections. Urolithiasis develops in up to 28% of Crohn's patients who've had a resection of the terminal ileum.[57] In Crohn's disease, the urine pH appears to be an important urolithiasis risk factor as those patients with a urine pH of 6 or less developed eight times more urinary stones than those with a urinary pH of 6.5 or more.[58] Enteric hyperoxaluria, due to intestinal calcium malabsorption, and relative dehydration from chronic diarrhea, also contributes to an increased risk of nephrolithiasis in this group.[23] The use of liquid citrate preparations is recommended for treatment over tablets in this population.

Distal Tubular Acidosis (Type 1)

Of the various types of metabolic acidotic conditions due to kidney disorders, only distal renal tubular acidosis (Type 1) has been associated with nephrolithiasis, usually producing calcium phosphate stones.[59] It can be either complete or incomplete, genetic (typically in children), or acquired (usually in adults). The most common etiologies of acquired distal tubular acidosis are Sjogren syndrome and rheumatoid arthritis. 

Distal renal tubular acidosis is characterized by persistent urinary alkalinity, hypercalciuria, hypocitraturia, nephrocalcinosis, calcium phosphate nephrolithiasis, hypokalemia, and osteoporosis. The underlying cause is a failure of hydrogen ion excretion in the distal renal tubule resulting in metabolic acidosis, which is partially buffered by the release of calcium from bone, thus causing osteoporosis. This effect, together with increased intestinal calcium absorption and reduced renal calcium reabsorption, results in hypercalciuria. The degree of hypercalciuria is roughly equivalent to the severity of acidemia.[31][60][61]

Hypocitraturia results from increased citrate reabsorption in the proximal renal tubule caused by metabolic acidosis, while the elevated urinary pH is directly due to the kidney's inability to excrete excess acid.[31][60][61] 

Hypokalemia in distal renal tubular acidosis comes from renal potassium wasting.[62][63]

The combination of chronically alkaline urine together with hypercalciuria and hypocitraturia results in nephrocalcinosis and calcium phosphate stone production.

The metabolic acidosis, hypercalciuria, and hypokalemia can be corrected with appropriate potassium citrate therapy, reversing osteoporosis, halting nephrocalcinosis, and reducing calcium phosphate stone production.[64]

Gastric Bypass Surgery (Roux-en-Y)

While Roux-en-Y gastric bypass surgery is no longer the most commonly performed bariatric procedure performed in the US (gastric sleeve has become more popular), it is still considered the most effective and comprises a significant portion of all weight-loss surgeries.[35] There were over 1 million Roux-en-Y surgeries done in the US in the decade leading up to 2015.[65] Kidney stone risk after Roux-en-Y surgery is known to be increased, roughly three times the risk compared to obese, age-matched controls, affecting 18.6% of all Roux-en-Y patients within their first two post-op years.[33] It is highest among those who had a history of kidney stones before their bariatric surgery, which is roughly double the risk of gastric bypass patients without a prior history of nephrolithiasis.[33] 

Patients undergoing Roux-en-Y gastric bypass surgery will typically average a 40% reduction in urinary citrate, which, along with a 50% or more increase in urinary oxalate and a 30% decrease in their daily urinary volumes, dramatically increases their nephrolithiasis risk.[33][66] Urinary citrate levels tend to decrease over time after their surgery. Liquid citrate preparations are generally preferred for treatment in these patients due to their rapid intestinal transit time, which reduces absorption from tablets.[67]  

Topiramate Therapy

Topiramate is a carbonic anhydrase inhibitor, like acetazolamide, increasingly used in epilepsy, as an anticonvulsant, and for migraines. It is also used, off-label, for weight loss and pain management.[52][68][69] It causes a mild metabolic acidosis utilizing a mechanism similar to distal renal tubular acidosis, which ultimately results in hypocitraturia, hypercalciuria, hypokalemia, urinary alkalinity, and an increased risk of kidney stones, particularly those composed primarily of calcium phosphate.[70] The degree of hypocitraturia from topiramate varies, but in general, the starting dose of topiramate reduces urinary citrate by about 40%, although this can go up to 65% at higher dosages.[51][52] For those kidney stone patients who take topiramate and demonstrate hypocitraturia, potassium citrate therapy can increase urinary citrate levels and reverse its other undesirable chemical effects.[52][68][69]

Epidemiology

The exact number of patients with hypocitraturia varies greatly depending on the precise definition used. However, what is clear is that the incidence of hypocitraturia is increasing, particularly among more obese patients and with the increasing use of topiramate.[32] 

There does not appear to be any significant difference in the rate of hypocitraturia between Whites, Blacks, or Asians despite the significantly higher reported rate of nephrolithiasis in Caucasians.[13]

Older stone-forming patients are more likely to have hypocitraturia than younger nephrolithiasis patients.[71] 

While women generally have higher citrate levels than men, hypocitraturia is more common in female stone formers than in their male stone-forming counterparts. Among female stone formers, hypocitraturia is more common in pre-menopausal women than in those who are post-menopausal.[72][73][74] In women, the highest urinary citrate levels correspond with their estrogen peak during the menstrual cycle.[75]

The incidence of stones among women is increasing. The reasons for this are unclear but are thought to be due to more women in the workplace, which introduces changes in activity level, diet, and stress that are similar to men. Additionally, women tend to have more obesity, diet more often, and have more bariatric surgeries than men, all activities that increase kidney stone risk.[76] Women also are at higher risk for stones after being pregnant. For women less than 50 years of age, a single prior pregnancy increases their incidence of stones by almost 100%, and additional pregnancies further increase their overall nephrolithiasis risk.[77]

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. The apical membrane cotransporter NaDC activity regulates the absorption of citrate, while cellular metabolism is mediated by ATP citrate lyase and mitochondrial enzymes in the proximal tubules. In chronic acidosis, both citrate transport and cellular metabolism are increased, causing hypocitraturia. Conversely, an alkaline load causes a reduction in these cellular activities and results in higher urinary citrate excretion.[78]

Renal cells contain large amounts of adenosine triphosphate citrate lyase (ATP citrate lyase). This enzyme will convert intracellular citrate into acetyl CoA.[79] The activity of ATP citrate lyase is increased by metabolic acidosis, potassium deficiency, insulin, glucose metabolites, and dietary factors such as high carbohydrate intake.[79] The use of a competitive inhibitor that blocks the activity of ATP citrate lyase (4S-hydroxycitrate) has been shown to quadruple urinary citrate in chronic metabolic acidosis.[79] 

Dietary citrate intake averages only about 4 grams daily, but it is readily absorbed from the intestine in both healthy individuals and hypocitraturic stone formers.[80][81] Serum citrate is filtered in the renal glomerulus and reabsorbed in the proximal tubule, but only about 25% (10% to 35%) of filtered citrate is ultimately excreted in the urine.[82][83][84] Hormones that affect bone health, such as estrogens, vitamin D, and parathyroid hormone, all tend to increase urinary citrate excretion.[85][86]

Hypocitraturia affects stone disease in several ways: 

• Urinary citrate forms a soluble complex with calcium. This reduces ionic (free) calcium's availability to form urinary crystals and stones. This effect is somewhat pH-dependent as it becomes more pronounced as the urinary pH increases.[87]
• Urinary citrate directly inhibits calcium crystallization and crystal aggregation in the urine.[88] 
• Urinary citrate increases pH, which drastically increases uric acid solubility as the pH approaches 6.5 to 7. Uric acid stones will generally not form with a sustained urinary pH of 6.5 or greater.[89][90]
• Hypocitraturia reduces urinary osteopontin, an important constituent of the matrix component of urinary calculi.[88] 
• Hypocitraturia decreases the inhibitory effect of urinary macromolecules (primarily Tamm-Horsfall protein) on nephrolithiasis.[91][92][93]
• Hypocitraturia increases urinary viscosity by reducing calcium binding in the urine, increasing viscosity as free calcium interacts with urinary macromolecules such as Tamm-Horsfall protein.[94]

History and Physical

There are no specific physical findings or medical history associated with hypocitraturia. However, patients taking acetazolamide or topiramate are at risk, as well as patients with a history of nephrocalcinosis or kidney stones, especially if composed of calcium phosphate. Other risk factors to be noted from the medical history would be gastric bypass surgery (especially the Roux-en-Y type), irritable bowel syndrome, chronic diarrhea, prior intestinal surgery, gout, a personal or family history of nephrolithiasis, and prior kidney stone surgeries. Previous 24-hour urine tests for nephrolithiasis prophylaxis and chemical stone composition analyses of prior renal calculi will also be helpful.

Evaluation

By definition, the diagnosis of hypocitraturia requires a 24-hour urine test. Some practitioners will recommend a second, 24-hour urine test if the original is "normal." This is intended to avoid any clinical confusion due to spurious, anecdotal, or incidental changes in diet, activities, fluid intake, or personal routine. Many stone clinics will frequently order a second 24-hour urine test 3 months after starting initial therapy. Not only does this allow the clinician to catch any "spurious" readings, but final adjustments to the patient's therapy can also be done.[95]

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. 24-hour testing for stone prophylaxis should always be done on an outpatient basis and never performed in the hospital where diet and fluid intake are controlled. For optimal results, the patient must be back on their regular diet and activities after hospitalization or surgery. Many experts prefer to wait 30 days after the last kidney stone event or surgery before performing the 24-hour urine test. The urine chemistry may not change that much, but some patients who were very eager for preventive testing right after surgery are having second thoughts about making a serious long-term commitment to follow therapy when discussing testing again after 30 days. 

The "official" hypocitraturia definition of 320 mg citrate/24 hours used by many laboratories has been questioned by numerous experts as it was picked arbitrarily from statistical analyses, did not consider age, gender, body mass, or stone composition, and was not based on solute concentrations, pH, normal median totals, supersaturation ratios nor any determination of what "optimal" urinary citrate levels should be for stone formers.[7][8][95][95] While 24-hour urine chemistry totals are provided in these commercial tests, the urinary concentrations are generally not. Laboratories are only required to provide "normal" ranges for urine chemistries and not "optimal" or "target" levels, which makes it particularly difficult for many practitioners to determine which stone formers actually have hypocitraturia and would benefit from treatment. 

A group of patients will also have normal or even high urinary citrate levels but still need supplemental alkalinization therapy. These patients will demonstrate significant aciduria (low pH) even with above-average urinary citrate levels. Many of these patients will form uric acid stones based on their persistent aciduria despite high urinary citrate levels.

Many experts, therefore, recommend using an alternate level of urinary citrate as a target. Since the median daily average of urinary citrate in healthy, non-stone-forming adults is 640 mg. The minimum recommended daily urinary output for nephrolithaisis patients is 2,000 ml; 320 mg/liter of urine would seem to be a reasonable "optimal" concentration. This would suggest that many calcium stone-forming patients with marginal 24-hour urinary citrate totals between 320 mg and 640 mg would benefit from some degree of citrate supplementation therapy. 

Another consideration is the urinary pH. Persistent, severely acidotic urine, especially in uric acid stone formers, should be aggressively treated with alkalinization (citrate) therapy sufficient to normalize their aciduria regardless of total urinary citrate levels. In other words, aciduria should also be treated in addition to just low urinary citrate levels, particularly in uric acid nephrolithiasis patients. The goal is to optimize the urinary citrate level and pH, if possible.[96][97] 

The citrate/creatinine ratio or the calcium/citrate ratio may also be used to help identify patients who would benefit from citrate supplementation therapy. Still, the gold standard remains 24-hour urine testing.[98][99][100][101][102] A ratio of <180 mg citrate/1,000 mg creatinine or >0.33 mg calcium mg/citrate mg 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.[103][104]

Summary of Diagnostic Criteria for Hypocitraturia

24-hour urine citrate of 320 mg or more. The "optimal" level should be 640 mg or more. Citrate supplemental therapy should generally be considered if the daily urinary citrate is <500 mg.

24-hour urinary citrate concentration should "optimally" be 320 mg/L or more. Consider treatment if the citrate concentration is <250 mg/L.

Consider citrate supplementation if citrate mg/creatinine g is <180 or calcium/citrate is >0.33. 

Urine pH: For most stone formers, the optimal pH is from 6 to 6.5.

• In uric acid stone formers, the optimal pH would be 6.5 for maintenance and prophylaxis; 7 for stone dissolution.
• For cystinuria, the optimal pH is 7.5.

Treatment / Management

Treatment of low urinary citrate is targeted, when possible, on the underlying etiology, such as improving dietary intake and stopping carbonic anhydrase-inhibiting medications. When this is not possible, or the cause is idiopathic, treatment is primarily by oral urinary alkalinizing medications.

Dietary measures alone can help raise urinary citrate levels, but very large amounts are usually required for any significant improvement.[105][106] Citrus is generally high in citrate, with lemons having a particularly high citrate concentration, which, when converted to lemonade, has been shown to improve urinary citrate levels as well as overall urinary volume.[106][107][108] Orange juice contains 160 mEq/L of citrate and 50 mEq/L of potassium. The problem with orange juice is that it's relatively high in sugar, increases oxaluria, and does not reduce hypercalciuria, all of which is accomplished by potassium citrate supplementation.[109] Coconut water has been shown to increase urinary citrate effectively. While not particularly high in citrate, it carries a very high alkaline load with 50% fewer calories and 60% less sugar than grapefruit and orange juice.[110] In one study, drinking coconut water instead of tap water increased urinary citrate by 29% but this required drinking 1.92 Liters of coconut water a day.[110]

Calcium citrate has not been adequately evaluated as a urinary citrate booster, although it is recommended as a calcium supplement due to its increased solubility compared to other calcium boosters. 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.[111][112]

Potassium citrate supplementation is generally the treatment of choice for hypocitraturia. Dietary measures alone are often insufficient and require very large quantities to affect significant improvements. Potassium citrate decreases the supersaturation ratio of calcium oxalate without significantly increasing the supersaturation of calcium phosphate.[113][114][115] Patients already on potassium supplements can easily be switched to potassium citrate, but serum potassium levels need to be followed, particularly for patients with renal failure, those on potassium-sparing diuretics, or those taking very large amounts of potassium citrate (over 100 mEq per day). Potassium citrate tablets are readily available, well-tolerated, relatively inexpensive, and generally provide a reasonably predictable result. Further, potassium citrate tends to eliminate hypokalemia as a potential source of hypocitraturia and, as a bonus, may tend to lower urinary calcium excretion.[116] Potassium citrate therapy has been shown to lower urinary calcium excretion by 30% in one study of hypocitraturic calcium oxalate stone formers.[117] This was explained as a result of increased gastrointestinal calcium binding to citrate resulting in reduced calcium absorption, a reduction in bone turnover due to improved acid buffering from the additional alkali, and/or a direct hypocalciuric effect on the distal renal tubule.[117][118]

Sodium citrate products and sodium bicarbonate have significant alkalinizing effects, but the excess sodium increases hyperuricosuria and worsens hypercalciuria.[119][120] 

Citrate absorption will depend on renal and gastrointestinal factors such as intestinal transit time, GI bypass surgery, and other absorptive characteristics and the presence and degree of any underlying metabolic and renal disorders such as acidosis, medullary sponge kidney, and renal failure. Potassium citrate therapy, while still useful, should be used somewhat cautiously in patients with struvite (triple phosphate or infection) stones, which generally require alkaline urine to grow. 

Potassium citrate tablets are available in 5, 10, and 15 mEq dosages. These tablets are typically designed using a wax matrix for slow release, so patients should be informed that if they see the whole tablets appear in the stool, it does not mean the medication is not working.[31] A number of patients arbitrarily stop their potassium citrate therapy when they see the tablets in their stool and erroneously believe the medication is not being absorbed. These events can be eliminated by informing the patient that seeing the tablet ghost carrier in the stool is normal and expected as the actual medication is extracted during the intestinal passage.

Potassium citrate supplementation should be titrated until optimal urinary citrate and pH levels are obtained. This can be difficult to achieve as it requires significant patient compliance to periodically repeat the 24 urine testing and continue taking medication multiple times daily for which no immediate benefit is seen or felt. There are also limitations based on patient tolerance due to GI upset or just physically being able to swallow many relatively large tablets. Patient compliance is a serious issue, with 48% of patients stopping therapy in long-term studies due to cost and side effects.[121] Patients can easily monitor their urinary pH with urinary dipsticks that are readily available online at a nominal cost. Multiple urine pH readings are suggested initially when adjusting citrate supplementation for pH. After stabilization at the recommended level, dipstick pH measurements can be performed much less often.

The amount of citrate needed can be estimated from the following formula: 30 mEq of potassium citrate daily will increase urinary citrate by about 200 mg/24 hours. (Potassium citrate package insert.)

Serum potassium levels should be checked periodically, especially in patients with renal failure or a history of hyperkalemia. If patients develop hyperkalemia, no additional potassium should be administered. Sodium bicarbonate can be used to increase urinary citrate as it has no potassium and is quite inexpensive. Still, it also has a considerable sodium load, which can contribute to fluid retention and hypercalciuria. Besides its sodium load, sodium citrate has a minimal effect on calcium oxalate supersaturation compared to potassium citrate.[14] 

Liquid potassium citrate preparations are preferred in Roux-en-Y gastric bypass patients and those with short bowel syndrome, chronic diarrhea, and irritable bowel syndrome, as well as those who fail to respond adequately to potassium citrate tablets.[122][123] Liquid citrate supplements are better and more quickly absorbed than tablets. They may also carry higher citrate concentrations than tablets, but availability is sometimes a problem, and bad taste can make compliance difficult.[80][122][123] 

Some patients may develop gastrointestinal upset, abdominal discomfort, or diarrhea from potassium citrate supplementation. These side effects can be minimized by taking the potassium citrate with food or altering the form of the potassium citrate supplement.[118] 

Citrate supplements with lower potassium content are available. They include various combinations of potassium citrate, sodium citrate, magnesium citrate, citric acid, and sodium bicarbonate. There are several formulations available, both prescription and OTC. One popular formulation comes as a 10 mEq citrate packet. It contains 5 mEq of potassium citrate, 2.5 mEq of sodium bicarbonate, and 2.5 mEq of magnesium citrate. It has the equivalent citrate of a standard 10 mEq potassium citrate tablet with half the potassium content. It has other advantages, including better absorption, liquid formulation (so no large or difficult tablets to swallow), fewer overall side effects, lower cost, and no taste when consumed.[124] It is optimal for use in children due to its lack of taste, so it can easily be added to routine beverages in pediatric hypocitraturic patients. It can be ordered online and does not require a prescription. However, non-prescription urinary alkalinizing agents have varying alkalinizing abilities, and it is unclear how they compare to standard prescription potassium citrate products. They are generally recommended when their cost, formulation, reduced potassium content, or other advantages make them preferable to standard potassium citrate therapy for individual patients.

In distal renal tubular acidosis, treatment with potassium citrate directly corrects the metabolic acidosis, hypercalciuria, and hypokalemia while also reversing osteoporosis, halting nephrocalcinosis, and reducing calcium phosphate stone production. However, relatively large amounts of potassium citrate may be required.[64] 

Citrate also inhibits struvite stone formation despite an increase in pH due to its chelation effect on magnesium, complexing with calcium, and coating of struvite crystal surfaces.[125][126][127][128] Potassium citrate therapy also prevents the recurrence of struvite stones after extracorporeal shockwave lithotripsy (ESWL) and actually appears to improve the residual fragment clearance rate of calcium oxalate and struvite stones.[129][130] 

About 20% of patients with hypocitraturia appear to be relatively resistant to citrate supplementation therapy. This is why a follow-up 24-hour urine test is recommended for all patients placed on potassium citrate therapy, as this "resistant" group will require more aggressive medical treatment to achieve optimal urinary citrate and pH levels.[14][131][132]

Like uric acid stones, cystine becomes progressively more soluble in urine as the pH increases. Cystine stone formers generally require a urinary pH of at least 7, with 7.5 being "optimal." This may require very high levels of potassium citrate, up to 3 or 4 mg/kg/day, in divided doses.[133] Acetazolamide has sometimes been used to help maintain the pH, especially overnight, but it comes with a number of undesirable side effects, such as metabolic acidosis, bone demineralization, hypocitraturia, and an increased risk of calcium phosphate stones. Daily urinary volumes of 3 liters or more are recommended as well.[133]

Potassium magnesium citrate may be superior to potassium citrate alone in increasing urinary citrate and pH as well as kidney stone prevention.[134] It increases urinary pH and decreases urinary saturation ratios of uric acid and calcium oxalate more than potassium citrate.[135][136][137][138] Potassium magnesium citrate also increases urinary magnesium levels, which independently increases urinary citrate and has a generally beneficial effect on nephrolithiasis that does not occur with potassium citrate alone.[139] Magnesium will form complexes with urinary citrate, which interferes with the NaDC citrate transport mechanism and increases citrate excretion.[139] For these reasons, potassium magnesium citrate is considered a superior urinary citrate supplement compared to potassium citrate.[84] Its main problem is that it requires multiple dosing throughout the day, has not been extensively studied, optimal dosing has not been determined, and it's not generally available.

Suggested Recommended Therapy Targets for Hypocitraturic Stone Formers

Optimal urinary citrate levels for most stone formers should be at least 640 mg/24 hours or 320 mg/L. (There is no direct harm in having higher urinary citrate levels as long as the urinary pH and serum potassium levels are acceptable.)[95]

For calcium stone formers, the optimal urine pH is 6 to 6.5. For uric acid stone prophylaxis, maintenance therapy is generally considered optimal at a urinary pH of 6.5, regardless of the total citrate level.[89][90] 

For cystine stone formers, the optimal urinary pH is 7.5. As this may be hard to achieve, a pH of at least 7 is necessary to allow a reasonable solubility of 250 mg of cystine/liter of urine. (This goes up to 500 mg/liter at a pH of 7.5.) [140] 

Urinary pH levels above 7.2 are not generally recommended (except in cystinuria), as this will tend to promote calcium phosphate precipitation.

Differential Diagnosis

• Carbonic anhydrase inhibitors
• Distal 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 stomach upset limit potassium citrate administration, a lower potassium alkalinizing supplement or plain sodium bicarbonate can be used. For those with poor absorption from tablets, liquid preparations can be substituted. Nephrolithiasis patients with irritable bowel problems typically improve when their bowel issues are successfully managed. 

Randomized controlled trials looking at citrate therapy for hypocitraturic stone formers have generally found significant reductions in new stone formation in subjects who receive treatment compared to controls.[136][141][142][143]

Over two-thirds (69%) of untreated stone formers will continue to manufacture stones compared to only 2% of patients receiving optimized prophylactic medical therapy.[144] 

Overall compliance with citrate supplementation is somewhat less than optimal at an overall 73.3% after six months. This is due to the need for a dosage schedule that is usually three or four times a day, the large size of the tablet formations, poor absorption requiring increasing doses, hyperkalemia, the appearance of "ghost" tablets appearing in the stool which some patients incorrectly interpret as being ineffective, and the lack of any appreciable clinical benefit. If patients deliberately or accidentally stop therapy briefly, there is no immediate or obvious clinical effect or harm. Clinicians should make every effort to reinforce the many benefits of continuing therapy long-term even if there is no obvious clinical improvement and no apparent harm if therapy is temporarilystopped.[145] It is best to do this before starting therapy and after each yearly 24-hour urine recheck.

In general, with proper treatment, hypocitraturia can be successfully managed, if not completely reversed, and patients can expect substantially fewer new renal calculi while taking adequate citrate therapy.

Complications

Some patients on potassium citrate therapy will develop hyperkalemia, which limits their dosage. Potassium citrate therapy may also develop side effects from the treatment, including stomach upset, abdominal pain, and diarrhea. Calcium phosphate stones can develop if the urine pH is consistently above 7.2. Patients with chronic renal failure are at higher risk of hyperkalemia and so should be monitored carefully. The citrate from liquid potassium citrate preparations is better and more quickly absorbed than from tablets, but some of the liquid forms have significantly more gastrointestinal side effects, and many patients object to the taste.[10] (The OTC citrate supplement mentioned earlier (supplied as dissolvable crystals in a packet containing potassium citrate, magnesium citrate, and sodium bicarbonate) may be an exception as there is generally minimal stomach upset with its use, and it is virtually tasteless.)

Deterrence and Patient Education

The American Urological Association now recommends that all nephrolithiasis patients be told about 24-hour urine testing for prophylactic treatment to prevent future stones. This will ultimately result in more kidney stone patients being tested and hence, even more patients being identified as hypocitraturic.

Pearls and Other Issues

Acetazolamide and topiramate are carbonic anhydrase inhibitors. Their effect is to produce alkaline urine (which may sometimes be useful in uric acid urolithiasis) while decreasing citrate excretion.[146][147] Their use in stone disease is usually limited to situations like 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.

Consider using 20 mEq potassium citrate (two 10 mEq tablets) at bedtime or with dinner for these patients where a 24-hour urine determination is not available.

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

Uric acid stone patients 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 urinary pH levels and their therapy titrated accordingly.

Urinary citrate is a potent inhibitor of calcium phosphate crystal growth and stone formation; it's responsible for about fifty percent of the normal, total chemical urinary inhibitory effect on calcium phosphate precipitation in normal urine.[148]

Hypocitraturia: Summary and Clinical Tips

Potassium citrate is the mainstay of urinary citrate supplementation and alkalinization therapy.

Use dietary therapy (lemonade, orange juice, powdered lemonade). Grapefruit juice is not recommended, despite its high citrate levels, as it inhibits CYP 450 enzymes and does not seem to reduce overall urinary risk factors for stone formation.[149]

Every 30 mEq of potassium citrate is expected to increase urinary citrate by 200 mg. Failure to do so indicates poor citrate absorption, for some reason. Consider switching to liquid citrate therapy and/or sodium bicarbonate.

Optimal urinary citrate significantly reduces the formation of all common stone types (calcium oxalate, calcium phosphate, cystine, struvite, and uric acid). This means the clinician doesn't have to know the stone's chemical composition to use citrate therapy.

Monitor serum potassium periodically, especially in patients with renal failure and those taking 60 mEq or more of potassium citrate. Consider a low potassium citrate alternative if hyperkalemia develops. 

Nephrolithiasis patients on acetazolamide, thiazides, or topiramate, as well as post-Roux-en-Y gastric bypass patients, can generally be assumed to have some level of hypocitraturia, even without formal 24-hour urine testing.  Consider empiric citrate therapy, which can be monitored by urinary pH in patients unable or unwilling to do 24-hour urine testing. 

Warn patients that seeing undissolved potassium citrate tablets in the stool is normal, and they should not be concerned or stop treatment. They see the wax matrix ghost carrier after the medication has been released.

Urinary alkalinization is the preferred treatment for uric acid stones, but using allopurinol or similar agents is recommended and will be very helpful in patients with elevated serum or urine uric acid levels. 

Potassium citrate can also be used in calcium phosphate stone formers as long as the urinary pH is maintained below 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 is recommended if the daily citrate total is <500 mg.
• 24-hour urinary citrate concentration should be 320 mg/L or more. Consider supplemental therapy if the citrate concentration is <250 mg/L.
• Dosage of potassium citrate can be estimated as 30 mEq will roiughly increase daily urinary citrate by 200 mg.
• Urine pH: For most stone formers, the optimal pH is 6 to 6.5. In uric acid stone formers, the optimal urinary pH would be 6.5 for maintenance and 7 for stone dissolution.
• For cystinurics, the optimal urinary pH is 7 to 7.5, depending on cystine concentration.
• pH levels above 7.2 are not generally recommended (except in cystinuria), as this will promote calcium phosphate precipitation.

Enhancing Healthcare Team Outcomes

Renal calculi are a very common condition encountered by doctors in primary care centers around the world. In an extensive clinical database of almost 50,000 nephrolithiasis patients, less than 1% showed no abnormal or sub-optimal chemistries.  A significant portion had abnormal or sub-optimal urinary citrate levels. Interprofessional teamwork is the key to early diagnosis and active management of kidney stone disease, of which hypocitraturia is an important part since it is the easiest urinary chemical abnormality to treat.

24-hour urine testing and treatment can significantly improve urinary chemistry risk factors and reduce the reoccurrence of nephrolithiasis.[150]

According to the current AUA guidelines, all patients with nephrolithiasis should be offered access to a 24-hour urine test for kidney stone prophylaxis, especially for patients with multiple stones or who have a high surgical risk. All members of the healthcare team should cooperate in communicating this information to their nephrolithiasis patients. Optimal management of kidney stone disease requires a team approach for early diagnosis of acute renal colic, prompt urologic surgical removal of significant stones, ensuring that all kidney stone patients are aware of their option to minimize future stone production by having 24-hour urine testing with the prophylactic treatment of conditions like hypocitraturia by urology, nephrology, primary care and other members of the healthcare team.