Mechanism Of Action
When Urocit® -K 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 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 increases urinary potassium by approximately
the amount contained in the medication. In some patients, Urocit® -K causes a transient reduction in
The changes induced by Urocit® -K produce urine that is less conducive to the crystallization of stoneforming
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
Urocit® -K 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 When the treatment is withdrawn, urinary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 pre-treatment level on the first day.
The rise in citrate excretion is directly dependent on the Urocit® -K dosage. Following long-term
treatment, Urocit® -K 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 may be relatively ineffective in raising urinary citrate. A higher
dose of Urocit® -K 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 produces a relatively small rise
in urinary pH.
The pivotal Urocit® -K 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 preexisting
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 pre-existing 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 prestudy
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 In Patients With Calcium Oxalate
|Stones Formed Per Year
||12 ± 30
||0.9 ± 1.3
||1.2 ± 2
||0.4 ± 1.5
||4.2 ± 7
||0.7 ± 2
||3.4 ± 8
||0.5 ± 2
||0.6 ± 2
|* Remission defined as "the percentage of patients remaining free of newly formed
stones during treatment".
Uricacid 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.