"More Americans than ever are developing kidney stones, and the demographics of those at increased risk are changing, a study published online January 14 in the Clinical Journal of the American Society of Nephrology has shown.
Mechanism of Action
When Urocit®-K (potassium citrate extended-release tablets) is given orally, the metabolism of absorbed citrate produces an alkaline load. The induced alkaline load in turn increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafilterable serum citrate. Thus, Urocit®-K (potassium citrate extended-release tablets) therapy appears to increase urinary citrate principally by modifying the renal handling of citrate, rather than by increasing the filtered load of citrate. The increased filtered load of citrate may play some role, however, as in small comparisons of oral citrate and oral bicarbonate, citrate had a greater effect on urinary citrate.
In addition to raising urinary pH and citrate, Urocit®-K (potassium citrate extended-release tablets) increases urinary potassium by approximately the amount contained in the medication. In some patients, Urocit®-K (potassium citrate extended-release tablets) causes a transient reduction in urinary calcium.
The changes induced by Urocit®-K (potassium citrate extended-release tablets) produce urine that is less conducive to the crystallization of stone-forming salts (calcium oxalate, calcium phosphate and uric acid). Increased citrate in the urine, by complexing with calcium, decreases calcium ion activity and thus the saturation of calcium oxalate. Citrate also inhibits the spontaneous nucleation of calcium oxalate and calcium phosphate (brushite).
The increase in urinary pH also decreases calcium ion activity by increasing calcium complexation to dissociated anions. The rise in urinary pH also increases the ionization of uric acid to the more soluble urate ion.
Urocit®-K (potassium citrate extended-release tablets) therapy does not alter the urinary saturation of calcium phosphate, since the effect of increased citrate complexation of calcium is opposed by the rise in pH-dependent dissociation of phosphate. Calcium phosphate stones are more stable in alkaline urine.
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 urinary citrate at a higher, more constant level throughout the day. When the treatment is withdrawn, urinary citrate begins to decline toward the pretreatment level on the first day.
The rise in citrate excretion is directly dependent on the Urocit®-K (potassium citrate extended-release tablets) dosage. Following long-term treatment, Urocit®-K (potassium citrate extended-release tablets) at a dosage of 60 mEq/day raises urinary citrate by approximately 400 mg/day and increases urinary pH by approximately 0.7 units.
In patients with severe renal tubular acidosis or chronic diarrheal syndrome where urinary citrate may be very low ( < 100 mg/day), Urocit®-K (potassium citrate extended-release tablets) may be relatively ineffective in raising urinary citrate. A higher dose of Urocit®-K (potassium citrate extended-release tablets) may therefore be required to produce a satisfactory citraturic response. In patients with renal tubular acidosis in whom urinary pH may be high, Urocit®-K (potassium citrate extended-release tablets) produces a relatively small rise in urinary pH.
The pivotal Urocit®-K (potassium citrate extended-release tablets) trials were non-randomized and non-placebo controlled where dietary management may have changed coincidentally with pharmacological treatment. Therefore, the results as presented in the following sections may overstate the effectiveness of the product.
Renal tubular acidosis (RTA) with calcium stones
The effect of oral potassium citrate therapy in a non-randomized, non-placebo controlled clinical study of five men and four women with calcium oxalate/calcium phosphate nephrolithiasis and documented incomplete distal renal tubular acidosis was examined. The main inclusion criterion was a history of stone passage or surgical removal of stones during the 3 years prior to initiation of potassium citrate therapy. All patients began alkali treatment with 60-80 mEq potassium citrate daily in 3 or 4 divided doses. Throughout treatment, patients were instructed to stay on a sodium restricted diet (100 mEq/day) and to reduce oxalate intake (limited intake of nuts, dark roughage, chocolate and tea). A moderate calcium restriction (400-800 mg/day) was imposed on patients with hypercalciuria.
X-rays of the urinary tract, available in all patients, were reviewed to determine presence of pre-existing stones, appearance of new stones, or change in the number of stones.
Potassium citrate therapy was associated with inhibition of new stone formation in patients with distal tubular acidosis. Three of the nine patients continued to pass stones during the on-treatment phase. While it is likely that these patients passed preexisting stones during therapy, the most conservative assumption is that the passed stones were newly formed. Using this assumption, the stone-passage remission rate was 67%. All patients had a reduced stone formation rate. Over the first 2 years of treatment, the on-treatment stone formation rate was reduced from 13±27 to 1±2 per year.
Hypocitraturic calcium oxalate nephrolithiasis of any etiology
Eighty-nine patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis with or without calcium nephrolithiasis participated in this non-randomized, non-placebo controlled clinical study. Four groups of patients were treated with potassium citrate: Group 1 was comprised of 19 patients, 10 with renal tubular acidosis and 9 with chronic diarrheal syndrome, Group 2 was comprised of 37 patients, 5 with uric acid stones alone, 6 with uric acid lithiasis and calcium stones, 3 with type 1 absorptive hypercalciuria, 9 with type 2 absorptive hypercalciuria and 14 with hypocitraturia. Group 3 was comprised of 15 patients with history of relapse on other therapy and Group 4 was comprised of 18 patients, 9 with type 1 absorptive hypercalciuria and calcium stones, 1 with type 2 absorptive hypercalciuria and calcium stones, 2 with hyperuricosuric calcium oxalate nephrolithiasis, 4 with uric acid lithiasis accompanied by calcium stones and 2 with hypocitraturia and hyperuricemia accompanied by calcium stones. The dose of potassium citrate ranged from 30 to 100 mEq per day, and usually was 20 mEq administered orally 3 times daily. Patients were followed in an outpatient setting every 4 months during treatment and were studied over a period from 1 to 4.33 years. A three-year retrospective pre-study history for stone passage or removal was obtained and corroborated by medical records. Concomitant therapy (with thiazide or allopurinol) was allowed if patients had hypercalciuria, hyperuricosuria or hyperuricemia. Group 2 was treated with potassium citrate alone.
In all groups, treatment that included potassium citrate was associated with a sustained increase in urinary citrate excretion from subnormal values to normal values (400 to 700 mg/day), and a sustained increase in urinary pH from 5.6-6.0 to approximately 6.5. The stone formation rate was reduced in all groups as shown in Table 1.
Table 1: Effect of Urocit®-K (potassium citrate extended-release tablets) In Patients With Calcium
Stones Formed Per Year
|Group||Baseline||On Treatment||Remission *||Any Decrease|
|I (n=19)||12 ± 30||0.9 ± 1.3||58%||95%|
|II (n=37)||1.2 ± 2||0.4 ± 1.5||89%||97%|
|III (n=15)||4.2 ± 7||0.7 ± 2||67%||100%|
|IV (n=18)||3.4 ± 8||0.5 ± 2||94%||100%|
|Total (n=89)||4.3 ±15||0.6 ± 2||80%||98%|
|* Remission defined as “the percentage of patients remaining free of newly formed stones during treatment”.|
Uric acid lithiasis with or without calcium stones
A long-term non-randomized, non-placebo controlled clinical trial with eighteen adult patients with uric acid lithiasis participated in the study. Six patients formed only uric acid stones, and the remaining 12 patients formed mixed stones containing both uric acid and calcium salts or formed both uric acid stones (without calcium salts) and calcium stones (without uric acid ) on separate occasions.
Eleven of the 18 patients received potassium citrate alone. Six of the 7 other patients also received allopurinol for hyperuricemia with gouty arthritis, symptomatic hyperuricemia, or hyperuricosuria. One patient also received hydrochlorothiazide because of unclassified hypercalciuria. The main inclusion criterion was a history of stone passage or surgical removal of stones during the 3 years prior to initiation of potassium citrate therapy. All patients received potassium citrate at a dosage of 30-80 mEq/day in three-to-four divided doses and were followed every four months for up to 5 years.
While on potassium citrate treatment, urinary pH rose significantly from a low value of 5.3 ± 0.3 to within normal limits (6.2 to 6.5). Urinary citrate which was low before treatment rose to the high normal range and only one stone was formed in the entire group of 18 patients.REFERENCES
1. Pak, C. (1987). Citrate and Renal Calculi. Mineral and Electrolyte Metabolism 13, 257-266.
2. Pak, C. (1985). Long-Term Treatment of Calcium Nephrolithiasis with Potassium Citrate. The Journal of Urology 134, 11-19.
3. Preminger, G.M., K. Sakhaee, C. Skurla and C.Y.C. Pak. (1985). Prevention of Recurrent Calcium Stone Formation with Potassium Citrate therapy in Patients with Distal Renal Tubular Acidosis. The Journal of Urology 134, 20-23.
4. Pak, C.Y.C., K. Sakhaee and C. Fuller. (1986). Successful Management of Uric Acid Nephrolithiasis with Potassium Citrate. Kidney International 30, 422-428.
5. Hollander-Rodriguez, J et al. (2006). Hyperkalemia, American Family Physician, Vol.73/No. 2.
6. Greenberg, A et al. (1998). Hyperkalemia: treatment options. Semen Nephrol. Jan; 18 (1): 46-57.
Last reviewed on RxList: 1/21/2010
This monograph has been modified to include the generic and brand name in many instances.
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