eMedicine Specialties > Urology > Stones

Hypocitraturia

Author: George Bennett Stackhouse IV, MD, Assistant Professor of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD; Director, Endourology, Walter Reed Army Medical Center, Washington, DC
Coauthor(s): Howard H Woo, MD, Consulting Staff, Clinical Instructor, Department of Urology, Ochsner Urology Institute
Contributor Information and Disclosures

Updated: Jan 27, 2010

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.¹ 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 is often associated with thiazide diuretic or acetazolamide administration. More recently, topiramate has been found to be associated with an increased risk for urinary stones² and to cause hypocitraturia by its inhibition of renal carbonic anhydrases.³
• 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.

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