Hypocitraturia Despite Potassium Citrate Tablet Supplementation

Abstract

Citrate supplementation is widely used in the prevention of recurrent nephrolithiasis with hypocitraturia. Potassium citrate is the most commonly used citrate agent for this indication. In patients with chronic diarrheal syndromes, the absorption of potassium citrate can be affected. We describe a patient who presented with recurrent nephrolithiasis and chronic diarrhea and was found to have severe hypocitraturia despite citrate supplementation with potassium citrate tablets, likely due to inadequate gastrointestinal absorption of citrate from the slow-release wax-matrix tablets.

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Introduction

Citrate inhibits renal stone recurrence by preventing crystal growth, aggregation, and nucleation. It is a strong chelator of calcium and one of the most common therapeutic agents used to prevent calcium oxalate, uric acid, or cystine stones because of its ability to alkalinize urine and decrease urinary supersaturation for calcium oxalate. Gastrointestinal absorption of citrate is less efficient from a tablet preparation of potassium citrate than from a liquid preparation. Chronic diarrhea leads to decreased absorption and increased loss of the citrate from the gastrointestinal tract, leading to decreased urinary excretion. We describe a patient with nephrolithiasis and chronic diarrhea who had severe hypocitraturia despite citrate supplementation by the slow-release tablet preparation and a normal urinary citrate level after she was switched to the liquid preparation. We hypothesize that the decreased gastrointestinal transit time from her diarrhea led to inadequate absorption of citrate from the slow-release wax-matrix tablets.

Case Report

A 35-year-old female teacher was referred to the nephrology department of a tertiary care center by her primary care physician for further evaluation of recurrent nephrolithiasis after an episode of renal colic. She had her first episode of nephrolithiasis about 5 years ago and has since had several episodes where she passed noticeably large stones. Her past medical history was also significant for chronic diarrhea diagnosed as irritable bowel syndrome. She had 5 to 6 loose bowel movements a day.

At the time of the referral, the patient was on hydrochlorothiazide 25 mg daily and 60 mEq of potassium citrate in the form of UROCIT-K (Mission Pharmacal Company, San Antonio, Texas) 2 tablets of 1080 mg 3 times a day, both of which she had been taking for more than a year. She was drinking more than 3 L of water daily and had about 2 L of urine output a day. She was compliant with her medications. She mentioned that she had noticed intact pills of UROCIT-K in her feces.

Laboratory investigations showed that her electrolytes and renal function were normal. Analysis of a stone passed by her showed the presence of 80% of calcium oxalate and 20% of calcium phosphate. Her 24-hour urinary volume was 2400 mL. Her 24-hour urinary calcium was normal at 264 mg (normal range 100-300 mg/24 hours). The 24-hour urine citrate was significantly low at 49 mg (normal range 320-1240 mg/24 hours). The 24-hour uric acid, the 24-hour oxalic acid, the 24-hour sodium, and the 24-hour creatinine were normal.

With her history of chronic diarrhea and her hypocitraturia despite the potassium citrate tablet supplementation, she was switched to an equivalent dose of the liquid form of the potassium citrate (Polycitra-K; Alza Pharmaceuticals, Mountain View, California). She was asked to follow-up in a month, and at that visit, the 24-hour urine citrate was 455 mg. She was seen again 6 months later; her 24-hour urine citrate was 410 mg and she reported no episodes of nephrolithiasis after switching to the liquid preparation of the citrate.

Discussion

Citrate is a byproduct of normal oxidative pathways in the body that is normally excreted in the urine. Tubular absorption of citrate varies with the mitochondrial pH gradient; alkalosis increases and acidosis decreases the urinary citrate output. Therapeutic agents affecting citrate excretion work by producing an alkaline load.[1] The induced alkaline load in turn increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafilterable serum citrate.

The mean normal urinary citrate excretion is 640 mg/24 hours. Hypocitraturia (< 320 mg/24 hours) occurs in between 13% and 63% of patients with recurrent calcium nephrolithiasis[2–5]; it typically occurs in these patients in the absence of changes in acid-base balance, which is termed idiopathic hypocitraturia. Hypocitraturia may be the only cause of renal stones in 5% to 10% of patients.

Possible etiologies include distal renal tubular acidosis, intestinal diseases with malabsorption and diarrhea, enteric hyperoxaluria, hypokalemia, excessive dietary intake of animal proteins, and extreme physical exercise. Fegan and colleagues[6] measured the gastrointestinal absorption of citrate in patients with nephrolithiasis and idiopathic hypocitraturia to determine if citrate malabsorption could account for the low urinary citrate. They found no significant difference in gastrointestinal citrate absorption between nephrolithiasis patients with hypocitraturia and normal volunteers, suggesting that hypocitraturia might not be due to impaired gastrointestinal citrate absorption.

Alkaline citrate supplements have been shown to dramatically decrease the recurrence of nephrolithiasis and are widely used for the prevention of recurrent nephrolithiasis with calcium stones.[5,7–10] Administration of alkaline citrate increases both the urinary citrate and the urinary pH. The increased urinary citrate complexes with calcium and decreases calcium ion activity and, thus, the urinary supersaturation and crystallization of calcium oxalate and calcium phosphate.[11] The increase in urinary pH decreases calcium ion activity by increasing calcium complexation to dissociated anions and increases the ionization of uric acid to more soluble urate ion, leading to fewer uric acid stones.

Citrate supplements are available as sodium and potassium salts, but potassium is the preferred citrate compound because the sodium salt can increase urinary calcium excretion.[12] In the United States, potassium citrate is available in 3 preparations as tablets, crystals for oral solution, and oral solution. Patients often prefer tablets to potassium-containing liquids. The gastrointestinal absorption of citrate is less efficient from a tablet preparation of potassium citrate than from a liquid preparation. In their study, Fegan and colleagues[6] compared the gastrointestinal citrate absorption of the tablet and the liquid preparation of potassium citrate and noted that citrate absorption from the tablets was 91% compared with 98% for a liquid preparation.[6] They proposed this was probably due to a delayed release of citrate from the wax matrix.[6]

UROCIT-K is a patented formulation of potassium citrate that is available in slow-release wax-matrix tablets containing 5 mEq (540 mg) and 10 mEq (1080 mg) strengths.[13] The active ingredient of the UROCIT-K dissolves out of the matrix. The package insert mentions that the wax matrix itself may not disintegrate completely, and a remnant of the wax might be noticed in the stool normally.[13] According to the information on the drug's Web site,[14] even when this happens, it is not a cause of concern because all the medication in the drug has been dissolved and absorbed, and the patient has received the full therapeutic dose.

The rise in urinary citrate excretion is directly dependent on the dosage of the oral potassium citrate. In the setting of normal renal function, the rise in urinary citrate following a single dose begins by the first hour and lasts for 12 hours. With multiple doses, the rise in citrate excretion reaches its peak by the third day and averts the normally wide circadian fluctuation in urinary citrate, thus maintaining the urinary citrate at a higher, more constant level throughout the day. For patients with calcium stone formation, urinary citrate levels should be maintained at or above 350 mg/L. After multiple doses, the potassium citrate tablet (UROCIT-K) at a dosage of 60 mEq/day raises the urinary citrate by approximately 400 mg/day.[13]

Patients with chronic diarrhea have an ongoing loss of base and often have decreased urinary citrate excretion from impaired gastrointestinal absorption, but they respond well to citrate supplementation. Our patient's urinary citrate level was low despite supplementation with the slow-release potassium citrate tablet preparation and increased to the normal range when she was switched to an equivalent dose of the liquid preparation. Therefore, we hypothesize that she was unable to absorb potassium citrate adequately from the tablet preparation, likely due to her chronic diarrhea.

Conclusion

In patients with chronic diarrheal syndromes, the absorption of potassium citrate from the slow-release wax-matrix tablet preparations can be affected. Though patients prefer the tablet preparation of potassium citrate to the liquid preparation, those with chronic diarrhea should be prescribed the liquid preparation to ensure adequate absorption of citrate.