eMedicine Specialties > Urology > Stones

Hypocitraturia

George Bennett Stackhouse IV, MD, Clinical Fellow in Endourology, Urology, University of California, San Francisco
Howard H Woo, MD, Consulting Staff, Clinical Instructor, Department of Urology, Ochsner Urology Institute

Updated: Jun 16, 2006

Introduction

Background

Hypocitraturia, a low amount of citrate in the urine, is an important risk factor for kidney stone formation. Citrate in the urine has long been recognized as an inhibitor of calcium salt crystallization. Citrate is the dissociated anion of citric acid, a weak acid that is both ingested in the diet and produced endogenously in the tricarboxylic acid cycle. The mean urinary citrate excretion is 640 mg/d in healthy individuals. Hypocitraturia usually is defined as citrate excretion of less than 320 mg/d, but this definition has been challenged as inadequate for recurrent stone formers. Severe hypocitraturia is citrate excretion of less than 100 mg/d, and mild-to-moderate hypocitraturia is citrate excretion of 100-320 mg/d. Other definitions include a urine citrate level of less than 220 mg/d for both men and women, regardless of age, or less than 115 mg/d in men and less than 200 mg/d in women.

These definitions have been called into question by several kidney stone experts and researchers. They feel that these reference range values were selected somewhat arbitrarily from statistical models and large populations of healthy subjects and do not necessarily indicate the optimal level for a calcium stone former. While hypocitraturia currently is defined as the excretion of less than 320 mg of citrate per day, most healthy people actually will have daily urinary citrate excretions of over 600 mg.

Researchers believe that the current definition ignores urinary citrate concentration, which may be far more important than the gross total 24-hour urinary citrate excretion. Further, they argue that optimal urinary citrate levels for calcium stone formers are likely to be closer to the statistical average or median of the reference group than to the lower limits of the healthy range. Using this logic, optimal daily urinary citrate levels for calcium stone formers would probably range from 500-800 mg, and one group uses 450 mg/d in men and 550 mg/d in women as cutoff values in stone formers.

Pathophysiology

The excretion of citrate in the urine is a function of filtration, reabsorption, peritubular transport, and synthesis by the renal tubular cell. The proximal tubule reabsorbs most (70-90%) of the filtered citrate, and citrate secretion is negligible. Acid-base status plays the most significant role in citrate excretion. Alkalosis enhances citrate excretion, while acidosis decreases it. In acidosis, increased citrate utilization by the mitochondria in the tricarboxylic acid cycle occurs. This results in lower intracellular levels of citrate, facilitating citrate reabsorption and hence reducing citrate excretion. Citrate excretion is impaired by acidosis, hypokalemia (causing intracellular acidosis), high–animal protein diet (with an elevated acid-ash content), and urinary tract infection (UTI).

Citrate plays several important roles in the mechanism of urinary stone formation. First, citrate complexes to calcium ions in the urine, reducing calcium ion activity, which results in lowering the urinary supersaturation of calcium phosphate and calcium oxalate. This complexing action is not completely understood and has been recently shown to involve the formation of a calcium-citrate-phosphate species. This process is pH-dependent, and increases in urinary pH levels appear to be more important in the formation of this complex than increases in available citrate per se. Second, citrate has a direct inhibitory effect on the crystallization and precipitation of calcium salts.

Citrate also increases the calcium oxalate aggregation inhibitory activity of urine macromolecules (eg, Tamm-Horsfall protein) and may reduce the expression of urinary osteopontin, which is an important component of the protein matrix of urinary stones. In addition, urinary citrate excretion can increase urinary pH, which is a factor in uric acid crystallization and uric acid stone formation, as well as in the calcium-citrate-phosphate complex formation described above.

In summary, hypocitraturia (low urine citrate excretion) enhances urine calcium salt supersaturation and reduces calcium crystallization inhibition, increasing the risk of calcium nephrolithiasis. It also may play a role in uric acid solubility and uric acid stone formation.

Frequency

United States

Hypocitraturia has been reported in 15-63% of all patients with nephrolithiasis, but it is probably a significant factor in about a third of all kidney stone patients. This condition may exist as a single abnormality (10%) or in conjunction with other metabolic disorders of calcium nephrolithiasis (50%).

International

The incidence of nephrolithiasis varies among populations; Ramello et al reported rates of 1-5% in Asia, 5-9% in Europe, 13% in North America, and 20% in Saudi Arabia. The incidence of hypocitraturia among these populations is not reported.

Mortality/Morbidity

Hypocitraturia commonly is observed in patients with nephrolithiasis, metabolic acidosis, and chronic diarrheal syndromes. Hypocitraturia itself may not be associated with significant mortality or morbidity; however, potential complications of nephrolithiasis secondary to hypocitraturia can be significant. Potential morbidity due to nephrolithiasis includes hematuria, ureteral obstruction, UTI, urosepsis, and loss of kidney function.

Race

In general, epidemiologic studies have shown that blacks in the United States experience less stone disease than whites by a ratio of approximately 1:4. A review of 1,141 stone formers showed similar rates of hypocitraturia among whites, blacks, and Asians.

Sex

Calcium-containing stones occur 3 times more often in men than in women. The 24-hour measurement of urinary citrate in non–stone-forming subjects is higher in women (mean value of 710 mg) than in men (mean value of 531 mg). However, hypocitraturia is more common in stone-forming women than in men.

Age

The incidence of stone diseases is highest in persons aged 30-50 years. Hypocitraturia is more common in premenopausal women with stone disease than in postmenopausal stone-forming women. Geriatric stone patients have a higher incidence of isolated hypocitraturia (29%) than younger stone formers (17%).

Clinical

History

Hypocitraturia is diagnosed based on a metabolic evaluation of a 24-hour urine collection in patients with nephrolithiasis. The stone chemical composition and elements of the clinical history may help to determine the cause of stone formation and identify potential patients with hypocitraturia. The important elements in the history are outlined below:

• Medical history
  • Personal history of nephrolithiasis: Previous stone passage, interventional procedures, and previous stone composition are important in history taking. A history of multiple stone passages and rapid recurrent stone formation may indicate a fundamental metabolic cause, such as primary hyperparathyroidism or renal tubular acidosis. The necessity for multiple interventional procedures, whether endoscopic or open surgical, implies the growth of larger stones. This may be indicative of a more malignant form of stone disease, such as infected lithiasis.
  • Chronic diarrhea, inflammatory bowel disease, ileostomy, and colostomy (fluid loss due to diarrhea)
  • Recurrent UTI: As many as 30% of patients with calcium oxalate stones have a history of an infection with Escherichia coli.
  • Systemic disease (eg, renal tubular acidosis [RTA])
  • Horseshoe kidney: Stones in patients with horseshoe kidney have previously been attributed solely to urinary stasis, but a more recent review shows that most have predisposing metabolic stone risk factors, and more than 50% of patients with horseshoe kidney and stones have hypocitraturia.
• Surgical history
  • Past history of shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy, or open stone surgery
  • Patients who have undergone enterocystoplasty (augmentation cystoplasty) or who have an intestinal urinary reservoir (neobladder, continent urinary diversion) are usually prone to infection stones but have also been found to have hypocitraturia associated with uninfected stone formation.
  • Obesity is related to increased risk for calcium oxalate stone formation, but not specifically to hypocitraturia. However, many surgical treatments for obesity, including jejunoileal bypass and roux-en-Y procedures, lead to hyperoxaluria and hypocitraturia, resulting in urinary stone disease.
• Diet and fluid intake
  • High meat intake increases the urinary excretion of calcium, oxalate, and uric acid and decreases urinary pH and citric excretion. The recent popularity of high-protein, low-carbohydrate diets for weight loss has led to concern about increased risk of stone formation, as these diets have been shown to be associated with decreased urinary citrate and pH levels and increased urine calcium and sodium levels in both the induction and maintenance phases.
  • An excessive amount of sodium can result in hypocitraturia.
• Stone-provoking medications
  • High sodium intake
  • Hypercalciuria can result from administration of corticosteroids, aluminum-containing antacids, loop diuretics, and vitamin D.
  • Hypocitraturia often is associated with thiazide diuretic or acetazolamide administration.
• Social history
  • Strenuous exercise
  • High sodium intake

Physical

No specific physical findings are related to hypocitraturia. However, patients with nephrolithiasis often experience acute and extremely painful episodes of renal colic, with associated costovertebral angle tenderness. Abdominal tenderness may develop during renal colic, but peritoneal signs are not found. Renal colic due to kidney stone disease prompts one of the most common reasons for visits to the emergency department for urological care.

Causes

The following are causes of hypocitraturic calcium nephrolithiasis: distal RTA, chronic diarrheal syndrome, thiazide diuretic or acetazolamide administration, diet high in animal protein, strenuous physical exercise, high sodium intake, gout or gouty diathesis, and active UTI.

• Renal tubular acidosis: RTA is a term applied to several clinical syndromes of metabolic acidosis that result from specific defects in renal tubular hydrogen ion secretion and urinary acidification. One of the more common presentations of hypocitraturia is distal RTA, which can occur in a complete or incomplete form. The complete form is characterized by hyperchloremic metabolic acidosis, hypokalemia, and elevated urine pH, while the incomplete form exhibits normal serum electrolytes but the inability to acidify urine following an ammonium chloride load. Both forms can be associated with hypercalciuria and profound hypocitraturia. Combined with alkaline urine, such abnormalities place patients at high risk for calcium phosphate or, less commonly, calcium oxalate stone formation.
• Chronic diarrheal syndrome: Chronic diarrheal syndrome results in fluid loss and intestinal alkali loss. Patients with chronic diarrhea and inflammatory bowel disease frequently have hypocitraturia due to bicarbonate loss from the intestinal tract. Hypocitraturia caused by RTA or chronic diarrheal syndrome is associated with other metabolic abnormalities (eg, hypercalciuria, hyperuricosuria) or may occur alone. In chronic diarrheal syndrome, other risk factors for stone formation often are present (eg, low urinary volume, hyperoxaluria, hypomagnesuria, low urinary pH).
• Thiazide diuretic or acetazolamide administration: Thiazide therapy may induce hypocitraturia owing to hypokalemia with resultant intracellular acidosis. Acetazolamide (a carbonic anhydrase inhibitor used in the treatment of glaucoma) produces changes in urine composition that are similar to those found in distal RTA. It results in hyperchloremic acidosis due to its action of inhibiting sodium bicarbonate reabsorption in the proximal tubule. Thus, hypocitraturia often occurs due to metabolic acidosis.
• Diet high in animal protein: A diet rich in animal protein (from elevated acid-ash content) may produce hypocitraturia. Animal proteins contain sulfate and phosphate moieties that are excreted as acids.
• Strenuous physical exercise (that causes lactic acidosis) and increased sodium intake can likewise produce hypocitraturia.
• UTI with bacteria that degrade citrate lowers urinary citrate levels.
• Gout and gouty diathesis are conditions that involve excessive serum uric acid, which often is associated with nephrolithiasis. Controlling the uric acid problem and its potential contribution to stone formation may involve limiting purine intake, controlling hepatic uric acid production, monitoring urinary uric acid levels, and checking or altering urinary acidity.

Differential Diagnoses

Bariatric Surgery
Hyperparathyroidism
Medullary Sponge Kidney
Short-Bowel Syndrome
Struvite and Staghorn Calculi

Other Problems to Be Considered

Hypomagnesuria is another metabolic abnormality contributing to nephrolithiasis.

Workup

Laboratory Studies

• Hypocitraturia, defined as less than 320 mg of citrate excreted per 24-hour urine collection, is diagnosed by 24-hour urine collection for metabolic stone risk analysis. Many laboratories have their own definitions of normal citrate levels. Other laboratory studies for stone workups may include urine analysis and culture, Sequential Multiple Analysis of 20 chemical constituents (SMA-20), serum uric acid, and parathyroid hormone (PTH) if the serum calcium is elevated.
• 24-hour urine collection
  • The collection should be undertaken in recurrent stone formers, children, patients with solitary kidneys, and selectively in first-time stone formers with either increased risk (eg, family history of stones, bone or bowel disease, gout, chronic UTI, nephrocalcinosis) or who are sufficiently motivated to follow long-term therapy for stone prophylaxis.
  • A 24-hour urine sample is obtained for analysis of a full stone risk profile while patients maintain their customary activity level, diets and fluid intakes. Some practitioners always use 2 separate 24-hour urine collections for initial evaluation to avoid clinical confusion due to spurious variations in diet or activity. Patients should not have a metabolic stone risk profile while on a controlled diet in the hospital or while they are experiencing an acute renal colic attack.
  • Several commercial laboratories provide metabolic kidney stone prevention profiles, including Dianon, LabCorp, Litholink, Mission, Nichols, and Urocor. Some analyze only 24-hour urine data, while others include serum data and/or patient-reported clinical history and medications in their analysis. They calculate the total volume from the dilution of the volume marker and analyze metabolic risk factors (eg, calcium, oxalate, uric acid, citrate, pH) as well as total volume, sodium, phosphorus, and magnesium. Supersaturation ratios are calculated, and the risk of specific stone types is presented.
  • The 24-hour urine collection usually is deferred for several weeks after stone passage, although several studies have suggested that this may be unnecessary as long as the patient is following the regular routine diet and activity.
  • If the evaluation results are normal, the 24-hour collection may be repeated twice. If the evaluation results of metabolic stone workups remain normal after 2 separate 24-hour urine collections, idiopathic nephrolithiasis is suspected. False-positive 24-hour urine collection results can be caused by the patient altering the usual diet while being tested. The issue of defining what may be within the reference range versus what is optimal for a stone former also may exist. Increased fluid output almost always is recommended for recurrent stone formers regardless of the measured amount on a 24-hour urine testing.
  • In a large database of over 20,000 stone-forming patients with computerized analysis of the urinary and serum laboratory data, less than 1% demonstrated no urinary or serum chemistry abnormality related to possible kidney stone disease.
• Urine analysis and culture
• Sequential Multiple Analysis of 20 chemical constituents - Serum calcium, phosphorus, electrolyte, uric acid, and creatinine levels
• Parathyroid hormone
• Clinical examples
  • Complete type I RTA - Urine pH greater than 6.9, high serum chloride, low serum potassium, low bicarbonate levels, hypercalciuria (may be present)
  • Incomplete type I RTA - Normal electrolytes but poor response to acid load (NH4Cl 100 mg/kg administered PO, and urine pH does not fall below 5.3), hypercalciuria (may be present)
  • Chronic diarrhea - Urine pH less than 5.5, low urine volume, hypokalemia, hypomagnesemia, hypocalciuria, hypomagnesuria
  • Uric acid lithiasis - Some patients with uric acid stones may demonstrate unusually acidic urine and normal or near-normal uric acid excretion levels. In these cases, appropriate levels of potassium citrate should be used to alkalinize the urine sufficiently to prevent uric acid stone formation. Allopurinol is reserved for cases where potassium citrate supplementation is insufficient to stop uric acid stone formation or not tolerated for some reason. It also can be used in cases of calcium nephrolithiasis, gout, hyperuricemia, and hyperuricosuria, particularly where alkalinization alone has been inadequate to stop stone formation.

Imaging Studies

• Kidneys, ureters, and bladder (KUB) radiography, intravenous pyelography (IVP), renal ultrasound, and noncontrast spiral CT scans are available to diagnose nephrolithiasis. On plain radiography, radiopaque stones imply the presence of calcium oxalate, calcium phosphate, struvite, or cystine. Radiolucency may implicate uric acid stones. Nephrocalcinosis may lead to consideration of type I RTA. Large branching stones are more likely to be infection stones or cystine stones. No imaging modality is sensitive or specific for hypocitraturia as an etiology for detected stones.
  • KUB radiography: This is the least specific but most available and inexpensive imaging modality for stone detection. KUB radiography is commonly used for follow-up of stone therapies or screening for recurrence.
  • Renal ultrasonography: This operator-dependent modality is widely available, noninvasive, and without ionizing radiation. Renal ultrasonography is typically used in pregnant women, in acute screening, and in follow-up in conjunction with KUB radiography.
  • Intravenous pyelography (IVP) or intravenous urography (IVU): These are widely available. The sensitivity and specificity of these modalities are better than those of plain KUB radiography. IVP and IVU are invasive and entail increased radiation exposure. Contrast allergy and nephropathy are associated risks.
  • Noncontrasted spiral computed tomography: The availability of this is increasing throughout the world. The radiation exposure is increased compared with KUB radiography, but this modality carries the best sensitivity and specificity for stone detection. Cross-sectional imaging also allows for evaluation of non–stone-related causes of flank or abdominal pain. Noncontrasted spiral computed tomography is typically used in the immediate evaluation of patients with colic.

Other Tests

• Stone analysis: Urinary calculi secondary to hypocitraturia are typically composed of some hydroxyapatite (calcium phosphate) along with calcium oxalate.

Treatment

Medical Care

Treatment should be aimed toward correcting the underlying disorder that reduces urine citrate. If the patient has idiopathic hypocitraturia, induce a mild metabolic alkalosis to increase urine citrate.

• Uric acid nephrolithiasis
  • Uric acid stones can form whenever elevated urinary uric acid is present or if the urinary pH drops consistently below recommended levels. Overly acidic urine can cause uric acid stones to form even with normal urinary uric acid excretion. Potassium citrate can maintain an optimal urinary pH of 6.5-7.0 to both dissolve existing stones and prevent recurrences. In these cases, monitoring the urinary pH frequently when trying to dissolve existing stones is important. Potassium citrate dosages should be adjusted accordingly and serum potassium levels checked to identify any hyperkalemia that may develop. Total urinary citrate excretion levels are less important in these situations than the pH.
  • Prophylaxis for uric acid lithiasis often may consist of a nighttime dose of potassium citrate to simulate the nightly alkaline tide that may be diminished or absent in these patients. Allopurinol can be used if the patient has gout, hyperuricemia, or hyperuricosuria.
• Distal RTA - Potassium citrate is administered in large doses. Often, patients require as much as 120 mEq/d.
  • Chronic diarrheal syndrome In mild-to-moderate severity of fluid loss and hypocitraturia, potassium citrate 40-60 mEq is administered in 3 or 4 divided doses in a liquid form or as needed to optimize urinary citrate and pH. The liquid form is preferred because of better absorption compared to slow-release tablets in conditions where rapid gastrointestinal transit may exist.
  • Severe hypocitraturia requires high doses of potassium citrate, often as much as 320 mEq/d. In these cases, care should be taken to monitor the patient for hyperkalemia while optimizing urinary citrate excretion without increasing the urinary pH beyond 7.0-7.2.
• Thiazide-induced hypokalemia
  • Potassium citrate 10-30 mEq PO is administered 2-4 times daily or as needed to optimize urinary citrate excretion without overly alkalinizing the urine.
  • For patients treated with a thiazide, potassium citrate has the added advantage of preventing or reducing hypokalemia by supplementing potassium. Potassium citrate attenuates the drop in urinary citrate associated with thiazide therapy by preventing the hypokalemia-induced intracellular acidosis that leads to hypocitraturia. Therefore, consider concurrent treatment with potassium citrate in normocitraturic stone-forming patients who are on a thiazide for hypercalciuria. Although potassium chloride also can prevent a reduction in urinary citrate because it also maintains normokalemia, urinary citrate levels are maintained only at baseline; potassium citrate increases urinary citrate above the baseline level, thereby improving the urinary stone risk profile.
• Idiopathic hypocitraturic calcium nephrolithiasis
  • The stones formed are composed predominantly of calcium oxalate.
  • Potassium citrate 10-30 mEq PO is administered 2-4 times daily or as needed to optimize the urinary citrate excretion without exceeding the recommended urinary pH levels.
  • Maintain urinary pH at 6.5-7.0.

Consultations

Consider long-term medical treatment for a patient with recurrent stone disease. Consider consultation with a urologist or a nephrologist for further management of stone disease.

Diet

• High fluid intake - Sufficient to produce 1.5 L or more of urine per day
• Sodium restriction - Patients should avoid saltshakers and processed or salty foods.
• Oxalate restriction (may be advised) - Patients should avoid nuts, dark roughage, chocolate, tea, and vitamin C.
• Restriction of animal proteins - Limited servings of meat products, especially at the same meal
• Increased citrus fruits, potassium-rich products, and alkalinizing foods
  • Orange juice is a good source of dietary citrate. Orange juice contains potassium citrate (approximately 50 mEq of potassium per L and 160 mEq of citrate per L). Wabner and Pak (1993) studied the value of orange juice consumption in kidney stone prevention in 8 healthy men and in 3 men with documented hypocitraturic nephrolithiasis. Consumption of 1.2 L of orange juice (containing 60 mEq of potassium per d and 190 mEq of citrate per d) was compared to potassium citrate tablets (60 mEq/d). Compared to potassium citrate, orange juice delivered an equivalent alkali load and caused a similar increase in urinary pH (6.48 versus 6.75 from 5.71) and urinary citrate (962 versus 944 from 571 mg/d). However, orange juice increased urinary oxalate and did not alter calcium excretion, whereas potassium citrate decreased urinary calcium without altering urinary oxalate.
  • Similarly, Seltzer et al (1996) used lemonade therapy in 12 patients who could not or would not take potassium citrate. Ingestion of 4 o. of lemon juice in 2 L of water daily raised urinary citrate levels from an average pretreatment level of 142 mg/d to 346 mg/d (P <.001). Daily total urinary volumes were similar (2.7 L pretreatment vs 2.9 L on lemonade therapy). Seven of 12 patients developed normal citrate levels while consuming lemonade. Urinary calcium excretion decreased an average of 39 mg while on lemonade. No change in urinary oxalate excretion was seen.
  • Kessler and Hesse evaluated the effects of bicarbonate-rich mineral water versus sodium potassium citrate in an equimolar fashion regarding alkali load in 24 healthy male volunteers using a crossover design study and found that the alkali load was sufficient to raise urinary citrate and pH levels regardless of the treatment arm. Urinary sodium levels were not reported in this study, so whether sodium levels were elevated in the mineral-water arm is unclear.

Activity

No limitation of activity level is necessary, but dehydration should be avoided, especially with outdoor activities in warm dry environments.

Medication

Currently, preferred treatment of hypocitraturia is with potassium citrate (eg, Urocit-K, Polycitra-K) supplementation. The sodium-containing forms of citrate (eg, Bicitra, Polycitra) and sodium bicarbonate do not have the same beneficial effects because the excess sodium in these preparations actually aggravates both hypercalciuria and hyperuricosuria.

Calcium citrate may be used in patients with enteric hyperoxaluria and hypocitraturia, as the calcium is available to bind oxalate in the intestinal lumen. This therapy can raise urinary citrate levels and lower urinary oxalate levels but can raise urinary calcium levels. Potassium citrate is often used in addition to calcium citrate in these patients to further elevate urinary citrate and pH levels.

Calcium citrate is often recommended for calcium supplementation in postmenopausal women and others at risk for osteoporosis. It increases urinary citrate levels in non–stone-forming patients but also raises urine calcium excretion and does not significantly increase or decrease the relative supersaturation of calcium oxalate. Calcium citrate has not been well studied as therapy for hypocitraturia in idiopathic calcium oxalate stone formers and is not typically used for this purpose. Natural sources of citrate are citrus fruits. Lemons contain the most concentrated form of citrate and, when provided as lemonade, can increase both fluid volume and citrate excretion.

Two agents have been used for the treatment of hypocitraturia—sodium potassium citrate, which commonly is used in Europe, and potassium citrate, either in liquid form or as a wax matrix tablet, which is used in the United States. The usual therapeutic dose is 30-60 mEq/d, administered in 3 divided doses or as a single evening dose. Potassium citrate is preferred because it appears to decrease urinary calcium excretion. Sodium citrate does not lower urinary calcium excretion, perhaps because of the increased sodium load associated with therapy.

Potassium citrate is available in 5- or 10-mEq tablets (eg, Urocit-K) or as a liquid, powder, or syrup combining potassium citrate and citric acid (eg, Polycitra-K). The powder and syrup are mixed with water before ingestion. The tablet formulation has been shown to produce less variability in the level of urinary citrate throughout the day, but the liquid form is better in short bowel syndromes where absorption is a problem and in more severe cases because of its higher citrate dose.

Alkalinizing agents

The increase in urinary pH decreases calcium ion activity by increasing calcium complexation to dissociated anions and increases ionization of uric acid to more soluble urate ion.

Potassium citrate is an excellent alkalinizing agent for the treatment of patients with uric acid stones. The urinary pH should be checked regularly with Nitrazine paper and drug dosages adjusted to maintain a urinary pH of 6.5-7.0. Uric acid stones can be dissolved completely using this regimen, but dissolution may require 3-4 months of intensive medical therapy.

Increased citrate complexation of calcium is opposed by the rise in pH-dependent dissociation of phosphate; thus, urinary saturation of calcium phosphate is unaltered by potassium citrate therapy. Calcium phosphate stones are more stable in alkaline urine, such as pH 8. Therefore, a urinary pH is checked regularly and drug dosages adjusted to avoid calcium phosphate precipitation.

Potassium citrate (Urocit-K)

Citrate salt of potassium. Empirical formula is K₃ C₆ H₅ O₇.H₂ 0. White, granular, water-soluble powder (154 g/100 mL) that is almost insoluble in alcohol and is insoluble in organic solvents. Urocit-K is supplied as wax matrix tablets containing 5 mEq (ie, 540 mg) potassium citrate and 10 mEq (ie, 1080 mg) potassium citrate each for oral administration. Also available as the following: Cystopurin (England), K-Lyte (Canada), Kajos (Sweden, Norway), Kation (Italy), Nitrocit (United States).
Administered orally. Absorbed citrate is metabolized to produce an alkaline load that, in turn, increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafiltrable serum citrate. Urinary potassium is increased by approximately the amount contained in the medication, and some patients experience a transient reduction in urinary calcium. Potassium citrate produces urine that is less conducive to crystallization of stone-forming salts (eg, calcium oxalate, calcium phosphate, uric acid).
The increased citrate in the urine complexes with calcium, decreasing its ion activity and reducing saturation of calcium oxalate. Citrate also inhibits the spontaneous nucleation of calcium oxalate and calcium phosphate (brushite).

Dosing

Adult

10-20 mEq PO tid with meals; may administer up to 100 mEq qd; while higher doses sometimes may be needed to optimize levels, they have not been studied adequately and therefore should be used cautiously with appropriate monitoring
Severe hypocitraturia (urinary citrate <150 mg/d): Initially, 20 mEq PO tid or 15 mEq PO qid
Mild-to-moderate hypocitraturia (urinary citrate >150 mg/d): Initially, 10 mEq PO tid
Use 24-h urinary citrate and urinary pH measurements to determine adequacy of initial dosage and evaluate effectiveness of any dosage change; measure urinary citrate and/or pH q2-3mo until stable, then q4-6mo once optimized

Pediatric

Not established

Interactions

Increased drug effect/toxicity with potassium-containing medications; potassium-sparing diuretics, ACE inhibitors, or cardiac glycosides could lead to toxicity; drugs that slow GI transit time (eg, anticholinergics) are expected to increase GI irritation by potassium salts

Contraindications

Severe renal insufficiency; sodium-restricted diet (sodium citrate); untreated Addison disease; severe myocardial damage; acute dehydration; hyperkalemia; delayed gastric emptying; esophageal compression; intestinal obstruction or stricture; taking anticholinergic medication; active UTI

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Frequent monitoring of serum potassium concentration is recommended; caution in CHF, hypertension, edema, or any condition sensitive to sodium or potassium intake; conversion of citrate to bicarbonate in the liver may be blocked by severe illness, shock, or hepatic failure; patients may find intact matrices in feces; associated with GI distress; bradycardia; hyperkalemia, metabolic alkalosis; neuromuscular and skeletal weakness; dyspnea

Polycitra-K crystals

Polycitra-K crystals is a pleasant-tasting oral systemic alkalizer containing potassium citrate and citric acid in a sugar-free base.
Each unit dose packet contains potassium citrate monohydrate 3300 mg and citric acid monohydrate 1002 mg. Each unit dose packet, when reconstituted, supplies the same amount of active ingredients as is contained in 15 mL (1 tablespoonful) Polycitra-K oral solution and provides 30 mEq potassium ion and is equivalent to 30 mEq bicarbonate.
Potassium citrate is absorbed and metabolized to potassium bicarbonate, thus acting as a systemic alkalizer. The effects are essentially those of chlorides before absorption and those of bicarbonates subsequently. Oxidation is virtually complete so that <5% of the potassium citrate is excreted in the urine unchanged.
Polycitra-K crystals is highly concentrated and, when administered after meals and before bedtime, allows one to maintain an alkaline urinary pH at all times, usually without the necessity of a 2 am dose. Polycitra-K crystals alkalinizes the urine without producing a systemic alkalosis in recommended dosage.

Dosing

Adult

Take crystals mixed in cool water or juice according to directions, followed by additional water, if desired
Contents of 1 packet reconstituted with at least 6 oz of cool water or juice, after meals and at bedtime, or as directed by physician

Pediatric

Not recommended for pediatric use; dosage can be regulated more easily using Polycitra-K oral solution

Interactions

Increased drug effect/toxicity with potassium-containing medications, potassium-sparing diuretics, ACE inhibitors, or cardiac glycosides

Contraindications

Severe renal impairment with oliguria or azotemia; untreated Addison disease; adynamia episodica hereditaria; acute dehydration; heat cramps; anuria; severe myocardial damage; hyperkalemia from any cause

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Frequent monitoring of serum potassium concentration is recommended; caution in CHF, hypertension, edema, or any condition sensitive to sodium or potassium intake; conversion of citrate to bicarbonate in the liver may be blocked by severe illness, shock, and hepatic failure; patients may find intact matrices in feces; associated with GI distress; bradycardia; hyperkalemia, metabolic alkalosis; neuromuscular and skeletal weakness; dyspnea

Polycitra-K oral solution

Polycitra-K is a stable and pleasant-tasting oral systemic alkalizer containing potassium citrate and citric acid in a sugar-free base.
Each teaspoonful (5 mL) contains potassium citrate monohydrate 1100 mg and citric acid monohydrate 334 mg. Each mL contains 2 mEq potassium ion and is equivalent to 2 mEq bicarbonate.

Dosing

Adult

3-6 teaspoonfuls (15-30 mL) diluted with 1 glass of water PO after meals and at bedtime, or as directed by physician

Pediatric

1-3 teaspoonfuls (5-15 mL) diluted with half a glass of water PO qid

Interactions

Increased drug effect/toxicity with potassium-containing medications, potassium-sparing diuretics, ACE inhibitors, or cardiac glycosides

Contraindications

Severe renal impairment with oliguria or azotemia; untreated Addison disease; adynamia episodica hereditaria; acute dehydration; heat cramps; anuria; severe myocardial damage; hyperkalemia from any cause

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Frequent monitoring of serum potassium concentration is recommended; caution in CHF, hypertension, edema, or any condition sensitive to sodium or potassium intake; conversion of citrate to bicarbonate in the liver may be blocked by severe illness, shock, and hepatic failure; patients may find intact matrices in feces; associated with GI distress; bradycardia; hyperkalemia, metabolic alkalosis; neuromuscular and skeletal weakness; dyspnea

Follow-up

Further Inpatient Care

• When necessary, inpatient care should be directed at only the stone disease. Treatment of underlying hypocitraturia is best accomplished on an outpatient basis after convalescence. Diet and medication should be modified in an atmosphere as close as possible to the patient's normal environment.

Further Outpatient Care

• The objective of treatment with Urocit-K or Polycitra-K is to provide potassium citrate in sufficient dosage to restore normal urinary citrate (ie, >320 mg/d and as close to the normal mean of 640 mg/d as possible) and to increase urinary pH to a level of 6.0-7.0. Urinary citrate and/or urinary pH measurements should be evaluated every 4 months. Those results should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. Note that doses of Urocit-K greater than 100 mEq/d have not been studied and should be avoided when possible. Obviously, risk of hyperkalemia is increased when these higher dosages are used, so serum potassium levels should be monitored as well, particularly in cases of renal failure. The pH change after institution of potassium citrate therapy generally is small, although reduced doses may be required, with frequent pH monitoring, to maintain the pH below 7-7.2. At pH levels above 7.2, the risk of calcium phosphate crystallization increases significantly. Calcium phosphate can coat an otherwise dissolvable uric acid stone and prevent it from dissolving, so avoiding overalkalinization when trying to dissolve pure uric acid calculi is particularly important.
• Initial visit
  • A careful history is taken, and minimum diagnostic tests are conducted.
  • History: Secondary causes include dietary aberrations and stone-provoking drugs. The patient's interest and motivation to follow a course of preventive therapy should be assessed.
  • Minimum diagnostic tests
    • Abdominal radiograph of the KUB
    • Urinary stone/sediment analysis
    • Serum calcium, potassium, electrolytes, creatinine, and uric acid levels
    • Urine analysis and culture
• A 24-hour urinary stone risk profile on the patient's customary diet
• Identification of abnormal dietary risk factors
• Short-term dietary modification
• Repeat 24-hour profile after short-term dietary modifications.
• Identification of abnormal environmental and metabolic risks factors
• Long-term dietary modification with the addition of appropriate supplements and medications, if necessary.

Inpatient & Outpatient Medications

• Severe hypocitraturia ( <100 mg/d)
  • Chronic diarrheal states - Liquid formulation of potassium citrate
  • Complete distal RTA - Potassium citrate 20-40 mEq PO 2-4 times daily as needed to optimize urinary citrate excretion
  • Infection stones (magnesium and ammonium phosphate or carbonate apatite) - Potassium citrate, antibiotics, stone removal (Potassium citrate should be used cautiously in these situations because alkalinization will increase struvite [infection] stone formation.)
• Mild-to-moderate hypocitraturia (100-320 mg/d)
  • Dietary causes - Dietary restriction of animal protein and supplemental potassium citrate (initial dose 20 mEq PO bid-tid) is recommended therapy. The dose is adjusted based on urinary pH and citrate levels obtained at 2-3 months of treatment. Once stabilized, repeat testing can be performed at 4- to 6-month intervals and then yearly if stable. Performing a complete, 24-hour urine metabolic screening that includes serum potassium, as well as urinary volume, calcium, uric acid, oxalate, phosphate, sodium, and magnesium in addition to citrate, is important. New problems may develop as diets are adjusted. An adequate fluid volume needs to be maintained even if this means dilution of the citrate concentration. When this occurs, appropriate adjustment of the potassium citrate dosage should be achieved to ensure an optimal concentration of roughly 300 mg of citrate per liter.
  • Incomplete RTA - Potassium citrate supplementation as appropriate
• Hypokalemia of thiazide treatment – Administer potassium citrate and stop or replace thiazide if possible. When initiating long-term thiazide therapy for hypercalciuria, a potassium citrate supplement often is recommended, even if urinary citrate levels initially are normal.
• Low-normal urinary citrate level (320-400 mg/d) – Administer potassium citrate (10 mEq PO bid-tid). Consider optimizing 24-hour citrate to 600 mg per 24 hours.

Deterrence/Prevention

• Adequate amount of hydration to maintain 1.5-2 L or more of urine output per day is a well-accepted stone prevention measure.

Complications

• Hyperkalemia
• Abdominal discomfort
• Vomiting
• Diarrhea
• Peptic ulcer disease
• Formation of urinary stones
• Meta-analysis shows that up to 48% of patients in long-term studies discontinue oral potassium citrate therapy because of side effects.

Prognosis

• Approximately 80-90% of patients with hypocitraturia are treated successfully with potassium citrate to raise their urine citrate levels. This reduces the risk of recurrent stone formation.
• Barcelo and colleagues randomized hypocitraturic stone formers to potassium citrate (30-60 mEq/d, with an average of 45 mEq qd) or placebo for 3 years. Thirty-eight patients completed 3 years of study, 18 in the treatment arm and 20 in the placebo group. Among treated patients, 72% had no further stone formation, compared to 20% in the placebo group. All patients in the treatment group had a decline in their individual stone formation rate.
• Pak showed remission rates after potassium citrate therapy of 67% (in patients with chronic diarrheal syndromes) to 92% (in those with idiopathic hypocitraturia); all patients showed a reduction in their rate of stone formation.

Patient Education

• Diet and behavioral modification
• Risks and benefits of treatment with potassium citrate
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Kidney Stones.

Miscellaneous

Medicolegal Pitfalls

• See Complications and avoid these undesirable problems in clinical practice.
• Potassium-containing medications should be used with caution in patients with renal insufficiency or in those receiving potassium-sparing diuretics.
• Citrate therapy may be counterproductive in patients with infection stones.

Special Concerns

• Potassium-magnesium-citrate has been investigated and may be more effective than potassium citrate in the prevention of stones because it not only increases urinary citrate but also urinary magnesium, which is another well-known inhibitor of stone formation. It is available over-the-counter and on the Internet but has not yet been widely embraced by the urologic community.

References

1. Annuk M, Backman U, Holmgren K. Urinary calculi and jejunoileal bypass operation. A long-term follow-up. Scand J Urol Nephrol. May 1998;32(3):177-80. [Medline].

2. Breslau NA, Brinkley L, Hill KD. Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism. J Clin Endocrinol Metab. Jan 1988;66(1):140-6. [Medline].

3. Conway NW, Maitland ATK, Rennie JB. The urinary citrate excretion in patients with renal calculi. Br J Urol. 1979;21:30.

4. Edin-Liljegren A, Grenabo L, Hedelin H. Concrement formation and urease-induced crystallization in urine from patients with continent ileal reservoirs. Br J Urol. Jul 1996;78(1):57-63. [Medline].

5. Evans BM, MacIntyre I, MacPherson CR. Alkalosis in sodium and potassium depletion. Clin Sci. 1957;16:53-64.

6. Gentle DL, Stoller ML, Bruce JE. Geriatric urolithiasis. J Urol. Dec 1997;158(6):2221-4. [Medline].

7. Hamm LL. Renal handling of citrate. Kidney Int. Oct 1990;38(4):728-35. [Medline].

8. Hess B, Zipperle L, Jaeger P. Citrate and calcium effects on Tamm-Horsfall glycoprotein as a modifier of calcium oxalate crystal aggregation. Am J Physiol. Dec 1993;265(6 Pt 2):F784-91. [Medline].

9. Kessler T, Hesse A. Cross-over study of the influence of bicarbonate-rich mineral water on urinary composition in comparison with sodium potassium citrate in healthy male subjects. Br J Nutr. Dec 2000;84(6):865-71.

10. Leslie S. Potassium Citrate and Potassium Citrate Therapy. In: Savitz G, Leslie S, eds. The Kidney Stones Handbook: A Patient's Guide to Hope, Cure, and Prevention. 2nd ed. Roseville, Calif:. Published by Four Geez Press;1999:90-92.

11. Maloney ME, Springhart WP, Ekeruo WO. Ethnic background has minimal impact on the etiology of nephrolithiasis. J Urol. Jun 2005;173(6):2001-4.

12. Mattle D, Hess B. Preventive treatment of nephrolithiasis with alkali citrate--a critical review. Urol Res. May 2005;33(2):73-9.

13. Menon M, Mahle CJ. Urinary citrate excretion in patients with renal calculi. J Urol. Jun 1983;129(6):1158-60. [Medline].

14. Menon M, Mahle CJ. Prevalence of hyperoxaluria in idiopathic calcium oxalate urolithiasis: relationship to other metabolic abnormalities (Abstract 458). Presented at American Urological Association. Las Vegas;1983.

15. Menon M, Parulkar BG, Drach GW. Urinary lithiasis: etiology, diagnosis, and medical management. In: Campbell's Urology. 7th ed. Philadelphia, Pa: WB Saunders;1998:2661-2733.

16. Mosby-Year Book. Mosby's GenRx: The Complete Reference for Generic and Brand Drugs. 9th ed. Mosby-Year Book, Inc;1999:1807.

17. Nicar MJ, Skurla C, Sakhaee K. Low urinary citrate excretion in nephrolithiasis. Urology. Jan 1983;21(1):8-14. [Medline].

18. Nicar MJ, Peterson R, Pak CY. Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol. Mar 1984;131(3):430-3. [Medline].

19. Pak CY. Citrate and renal calculi. Miner Electrolyte Metab. 1987;13(4):257-66. [Medline].

20. Pak CY, Fuller C, Sakhaee K. Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol. Jul 1985;134(1):11-9. [Medline].

21. Pak CY. Hypercalciuric calcium nephrolithiasis.In: Resnick MI, Pak CYC, eds. Urolithiasis: A Medical and Surgical Reference. Philadelphia, Pa:. WB Saunders;1990:79-88.

22. Pak CY, Skurla C, Harvey J. Graphic display of urinary risk factors for renal stone formation. J Urol. Nov 1985;134(5):867-70. [Medline].

23. Preminger GM, Sakhaee K, Skurla C. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol. Jul 1985;134(1):20-3. [Medline].

24. Preminger GM, Pak CY. Eventual attenuation of hypocalciuric response to hydrochlorothiazide in absorptive hypercalciuria. J Urol. Jun 1987;137(6):1104-9. [Medline].

25. Raj GV, Auge BK, Assimos D. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys. J Endourol. Mar 2004;18(2):157-61.

26. Ramello A, Vitale C, Marangella M. Epidemiology of nephrolithiasis. J Nephrol. Nov-Dec 2000;13 Suppl 3:S45-50. [Medline].

27. Reddy ST, Wang CY, Sakhaee K. Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kidney Dis. Aug 2002;40(2):265-74. [Medline].

28. Robertson WG, Woodhouse CR. Metabolic factors in the causation of urinary tract stones in patients with enterocystoplasties. Urol Res. Mar 8 2006.

29. Rodgers A, Allie-Hamdulay S, Jackson G. Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor. Nephrol Dial Transplant. Feb 2006;21(2):361-9.

30. Rudman D, Dedonis JL, Fountain MT. Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med. Sep 18 1980;303(12):657-61. [Medline].

31. Ruml LA, Pearle MS, Pak CY. Medical therapy, calcium oxalate urolithiasis. Urol Clin North Am. Feb 1997;24(1):117-33. [Medline].

32. Sakhaee K, Alpern R, Jacobson HR. Contrasting effects of various potassium salts on renal citrate excretion. J Clin Endocrinol Metab. Feb 1991;72(2):396-400. [Medline].

33. Sakhaee K, Harvey JA, Padalino PK. The potential role of salt abuse on the risk for kidney stone formation. J Urol. Aug 1993;150(2 Pt 1):310-2. [Medline].

34. Sakhaee K, Williams RH, Oh MS. Alkali absorption and citrate excretion in calcium nephrolithiasis. J Bone Miner Res. Jul 1993;8(7):789-94. [Medline].

35. Sakhaee K, Poindexter JR, Griffith CS. Stone forming risk of calcium citrate supplementation in healthy postmenopausal women. J Urol. Sep 2004;172(3):958-61.

36. Scott WW, Huggins C, Selman BC. Metabolism of citric acid in urolithiasis. J Urol. 1943;50:202.

37. Seltzer MA, Low RK, McDonald M. Dietary manipulation with lemonade to treat hypocitraturic calcium nephrolithiasis. J Urol. Sep 1996;156(3):907-9. [Medline].

38. Siener R, Glatz S, Nicolay C. The role of overweight and obesity in calcium oxalate stone formation. Obes Res. Jan 2004;12(1):106-13.

39. Wabner CL, Pak CY. Effect of orange juice consumption on urinary stone risk factors. J Urol. Jun 1993;149(6):1405-8. [Medline].

40. Yasui T, Sato M, Fujita K. Effects of citrate on renal stone formation and osteopontin expression in a rat urolithiasis model. Urol Res. Feb 2001;29(1):50-6. [Medline].

Keywords

citrate, citric acid, nephrolithiasis, calcium nephrolithiasis, calcium oxalate, calcium phosphate, alkalinization, uric acid, potassium citrate

Contributor Information and Disclosures

Author

George Bennett Stackhouse IV, MD, Clinical Fellow in Endourology, Urology, University of California, San Francisco
George Bennett Stackhouse IV, MD is a member of the following medical societies: Alpha Omega Alpha and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Howard H Woo, MD, Consulting Staff, Clinical Instructor, Department of Urology, Ochsner Urology Institute
Howard H Woo, MD is a member of the following medical societies: American Urological Association
Disclosure: Nothing to disclose.

Medical Editor

Leonard Gabriel Gomella, MD, FACS, Director of Urologic Oncology, Bernard W Godwin Associate Professor of Prostate Cancer, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University
Leonard Gabriel Gomella, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Urological Association, Sigma Xi, Society for Basic Urologic Research, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf, Jr, MD, FACS, David A Bloom Professor of Urology, Director, Division of Minimally Invasive Urology, Department of Urology, University of Michigan Medical Center
J Stuart Wolf, Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Stephen W Leslie, MD, FACS, Founder and Medical Director of the Lorain Kidney Stone Research Center, Clinical Assistant Professor, Department of Urology, Medical College of Ohio
Stephen W Leslie, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, National Kidney Foundation, and Ohio State Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Beng Jit Tan, MD, PhD, to the development and writing of this article.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)