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154 Chin
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Chapter 9 / Urinary Stone Inhibitors 157
157
From: Current Clinical Urology, Urinary Stone Disease:
A Practical Guide to Medical and Surgical Management
Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ
9
Urinary Stone Inhibitors
Citrate and Magnesium
Harrison M. Abrahams, MD, Maxwell V. Meng, MD,
and Marshall L. Stoller, MD
CONTENTS
INTRODUCTION
CITRATE
MAGNESIUM
CONCLUSIONS
REFERENCES
Key Words: Nephrolithiasis; stone inhibition.
INTRODUCTION
It is intriguing that despite marked abnormal urinary factors, most humans will not
form stones. Alternatively, some patients develop stones despite normal urinary compo-
sition. The key element, therefore, appears to be inhibition of the steps in calculogenesis
(nucleation, crystal growth, aggregation, and crystal/stone retention). Urolithiasis will
not develop if any one of these steps is blocked. Despite this simple fact, it is unclear
exactly why many people form stones. Numerous molecules have been identified that
inhibit crystallization in vitro but many stone formers have normal levels of these sub-
stances; others will continue to develop stones despite replacement of these known
inhibitors. The formation of urinary calculi requires a complex combination of factors,
both promoting and inhibiting stone formation. Fortunately, there are many patients who
can be helped because of our existing knowledge about two specific urinary inhibitors:
citrate and magnesium. This chapter will discuss the in vitro and in vivo evidence
regarding citrate and magnesium as inhibitors of urinary stone disease.
158 Abrahams, Meng, and Stoller
CITRATE
Background
Citrate is the most well-studied inhibitor of calcium-based stones. It is therefore
appropriate to detail the investigations leading to this discovery and outline the proof of
its use in the treatment and prevention of urolithiasis.
Sabatini is credited as first discovering the ability of citrate to bind to calcium in the
1930s (1). Hypocitraturia was noted in two patients with urinary stones by Boothby and
Adams in 1934 but the significance of this report was not fully appreciated (2).
Hypocitraturia was again noted by Kissin and Locks in 1941 who first postulated that
citrate replacement might treat and/or prevent calcium-based calculi (3). Howard first
described the clinical use of citrate as an alkalinizing agent for the treatment of
noncalcium stones in 1954 (4).
Scientific interest in urinary citrate was rekindled in the early 1980s as numerous
studies verified hypocitraturia in stone patients (5–7). Citrate replacement therapy for
prevention of calcium-based nephrolithiasis was introduced in 1981 by Butz and Dulce
(8). They noted that a combination of sodium citrate and potassium citrate lowered
urinary calcium levels and raised urinary citrate concentrations. Dissolution of existing
calcium-based stones with potassium citrate was reported by Pak and colleagues in 1983
(9). These reports spurred countless investigations and led to the approval of potassium
citrate by the United States Food and Drug Administration in 1985.
Chemistry
Citrate is a tricarboxylic acid (Fig.1) and is entirely ionized above a pH of 6.5 at 37C
(10,11). Citrate is almost entirely absorbed by the gastrointestinal tract (12). Plasma
concentrations range from 0.05 to 0.3 mM (13). Assuming a normal glomerular filtration
rate of 125 mL/min, citrate is filtered at rates ranging from 6.25 to 37.5 µmol/min.
Approximately 75% is reabsorbed by the proximal convoluted tubule (Fig. 2) (14). Ten
to 35% (by volume) of oral citrate is excreted in the urine unchanged and is dependent
on the renal acid/base status. Renal tubular cells can additionally extract citrate from the
peritubular fluid at a rate of 0.5 to 3 µmol/min (11). Therefore, the citrate concentration
in the renal cortex can exceed that of peripheral serum.
Urinary citrate excretion is strongly dependent on the acid-base status of renal tubu-
lar cells. When the cells are in an acidotic state, as much as 95% of the filtered citrate
is sequestered by proximal tubular mitochondria as an additional source of energy in
the Krebs cycle (also known as citric acid cycle and tricarboxylic acid cycle) (11,15).
Fig. 1. Chemical composition of citrate.
Chapter 9 / Urinary Stone Inhibitors 159
This is the common pathway that cells use to liberate energy from the final steps of
oxidation, generating carbon dioxide (CO
2
) and water. Citrate extraction from the
peritubular fluid is also increased via a sodium-citrate co-transporter which is activated
in an acidotic state (15,16). This results in significantly lower urinary citrate levels as
the citrate is sequestered in the proximal tubular cell. Conversely, in an alkalotic state,
up to 50% of filtered citrate may be excreted in the urine as the reabsorption of citrate
into the proximal tubular cells is dramatically reduced.
Any condition that results in intracellular acidosis, including hypokalemia, high pro-
tein diet, and exercise, will cause a decrease in urinary citrate concentrations (Table 1).
Androgens, acetozolamide, angiotensin converting enzyme inhibitors, volume expan-
sion and starvation are thought to lower urinary citrate levels through similar mecha-
nisms (14,17,18).
Fig. 2. Citrate handling under normal, acidotic, and alkalotic states. (A) Normal state: approx
75% of filtered citrate is reabsorbed. (B) Acidotic state: to preserve citrate for the citric acid cycle,
the proximal tubular cells increase reabsorption from the filtrate and from the peritubular fluid.
Overall, as much as 95% of filtered citrate is reabsorbed. (C) Alkalotic state: when the cells have
an excess of alkali, reabsorption is reduced, thereby increasing urinary citrate levels.
160 Abrahams, Meng, and Stoller
Other clinical states may result in decreased urinary citrate levels (Table 2). For
example, organic acids such as malate, succinate, and fumarate provide an alkali load
and therefore stimulate intrarenal citrate synthesis and decrease sequestration from both
the filtrate and the peritubular fluid (19,20). The spice tamarind may also increase uri-
nary citrate levels through its high levels of tartaric acid (20). Increases in urinary citrate
concentration have been documented during pregnancy and during the latter half of the
menstrual cycle (21). These increases are likely related to the elevated estrogen and
progesterone levels. The hypercalciuria of pregnancy may be offset by the concomitant
increase in urinary citrate excretion. This may protect pregnant women from developing
urinary stones despite the marked increased urinary calcium. Parathormone (PTH),
magnesium, lithium, calcitonin, and vitamin D also have been found to increase urinary
citrate levels (14).
Citrate: “Normal” Levels
Urinary citrate levels vary substantially throughout the day, and from day to day.
“Normal” levels, therefore, are difficult to define. Pak has created a “functional” defi-
nition of hypocitraturia based on 24-h urinary citrate levels of patients with renal tubular
acidosis (22). These patients had urinary citrate levels less than 320 mg/d. He concluded,
therefore, that normal patients should have a urinary citrate level greater than 320 mg/
d. Parks and Coe found a urinary citrate level of 729 ± 47 mg/24 h in a group of normal
females and 547 ± 31 mg/24 h in normal males. Others have used a cutoff of 115 mg in
males and 200 mg in females as a cutoff for hypocitraturia (23). A recent comparison of
male and female stone patients shows no difference in urinary citrate levels until the
seventh decade when citrate levels fell in women (24). Premenopausal and postmeno-
Table 1
Conditions and Compounds Known to Decrease Urinary Citrate
• Intracellular acidosis • Hypokalemia
• Renal tubular acidosis • Chronic diarrhea
• High protein diet • High sodium diet
• Exercise • Androgens
• Acetozolamide • Angiotension converting enzyme inhibitors
• Thiazides • Volume expansion
• Starvation • Active urinary tract infection
(Adapted from refs. 11,14,17,18, and 34.)
Table 2
Conditions and Compounds Known to Increase Urinary Citrate
• Organic acids • Tamarind/Tartaric acid
(malate, succinate, and fumarate) (spice)
• Pregnancy • Last portion of the menstrual cycle
• Parathormone (PTH) • Magnesium
• Lithium • Calcitonin
• Vitamin D
(Adapted from refs. 11,14,19–21.)
Chapter 9 / Urinary Stone Inhibitors 161
pausal women had similar levels. In another study, 28 postmenopausal women taking
estrogen replacement had higher urinary citrate levels than 41 postmenopausal women
that were not taking estrogen therapy (576.6 ±237.9 vs 306.2 ± 209.9 mg./24 h, p <0.001)
(25). Litholink
®
, a commercial laboratory evaluating 24-h urine collections, suggests
that “normal” urinary citrate levels are 450 mg/d for men and 550 mg/d for women (26).
Obviously, this dramatic range of “normal” values demonstrates that an optimal level
remains ill-defined. Therapeutic citrate supplementation may be warranted in more
patients than previously thought owing to the ambiguity of “normal” urinary citrate
levels.
Hypocitraturia: Incidence
Seventeen to 63% of stone patients have hypocitraturia as a risk factor, depending on
its definition (27–31). Gentle et al evaluated 24-h urine collections from 5942 patients.
Hypocitraturia (<320 mg/24 h) was found as an isolated abnormality in 18.6% of the
patients whereas another 9.3% of the patients had hypocitraturia in conjunction with
another urinary abnormality (hypocitraturia with hyperoxaluria, 2.9%; hypocitraturia
with hypercalciuria, 1.9%; hypocitraturia with hyperuricosuria, 2.3%; hypocitraturia
with multiple other defects, 2.2%) (32). Among patients younger than 65 years of age,
17% were found to have hypocitraturia as the sole metabolic defect. Hypocitraturia was
associated with other metabolic defects in an additional 10% of these patients. In con-
trast, there was a higher incidence of hypocitraturia as a sole urinary abnormality in stone
patients older than 65 (29%). An additional 7% of these geriatric patients had hypo-
citraturia in conjunction with other urinary defects. In a smaller study, 8.5% of 31 stone
patients with no other demonstrable metabolic abnormality had hypocitraturia (<322
mg/24 h) (30). More than 50% of 194 patients with other metabolic abnormalities had
urinary citrate levels below the lowest level for controls (320 mg/24 h).
The incidence of hypocitraturia in children with calcium-based renal stones has
recently been investigated (33). Seventy-eight stone forming children (age 1–15 yr)
were examined and compared with 24 controls. Median urinary citrate levels for the
stone forming children was 261 ± 256 mg/24 h compared with 491 ± 490 mg/24 h in
the control group (p = 0.002). Sixty-four percent (64%) of the stone forming children
had urinary citrate levels less than 320 mg/24 h compared with 29% of the controls.
Hypocitraturia: Disease Associations
Hypocitraturia is associated with many clinical entities, most commonly renal tubular
acidosis (RTA) type I (distal). In this disorder, impaired hydrogen excretion causes
intracellular acidosis and reduced urinary citrate by the mechanisms described above
(see Chapter 8). Clinically, patients with calcium-based stones and a quantitative urinary
citrate of less than 50 mg/24 h can be assumed to have type I RTA. These patients require
aggressive citrate supplementation to help prevent future calculi. Although hypocitraturia
may be seen in other forms of RTA, it is not clinically important, as stones do not
typically form in these patients. Patients taking acetazolamide may have an RTA-like
pattern, with hypocitraturia caused by the blockade of proximal tubule bicarbonate
reabsorption.
Other common entities associated with hypocitraturia include chronic diarrheal syn-
dromes, thiazide induced hypocitraturia and idiopathic hypocitraturia (11). Chronic
diarrheal syndromes result in intestinal loss of alkali leading to a metabolic acidosis and
162 Abrahams, Meng, and Stoller
therefore hypocitraturia. These include patients who have undergone gastrectomy, bowel
resection, intestinal bypass, or those with inflammatory bowel diseases. Thiazide diure-
tics can result in hypocitraturia from the renal loss of potassium and the resultant intra-
cellular acidosis. Some “idiopathic” stone formers may have hypocitraturia caused by
a high sodium diet (34), rigorous exercise (35) or active urinary tract infection (11). In
the latter situation, bacteria may use citrate to augment their energy needs, thus effec-
tively consuming urinary citrate. Pak reported that a small subset of patients will show
a blunted response to citrate replacement. Such patients have hypocitraturia without
acidosis, leading to the proposition of a rare genetic alteration in the sodium-citrate
transport gene (36). Impaired gastrointestinal uptake is no longer considered a probable
cause of hypocitraturia (37).
Citrate: Mechanism of Action?
Citrate inhibits many of the steps in calculogenesis. One mechanism of action is the
binding of urinary calcium in solution, thus effectively lowering ionic calcium concen-
trations. This leads to lower saturations of calcium oxalate and calcium phosphate (38).
Dissolution of calcium salts may theoretically occur once the urine concentration of
these salts is lower than the saturation level (11). However, this mechanism of complexing
calcium may be minimal (39). Ashby and Sleet mixed equal concentrations of citrate and
oxalate and added calcium oxalate crystals until a steady state was reached (40). The
supersaturation of calcium oxalate in the solution only varied by less than 1% despite
varied citrate concentrations. This study suggests that inhibition of calcium oxalate by
citrate is mainly caused by mechanisms other than calcium complexation.
Citrate lowers the spontaneous nucleation of calcium oxalate (41)
and prevents the
heterogeneous nucleation of calcium oxalate by urate crystals (42,43). By this mecha-
nism, the generation of a stone nidus may be inhibited. However, if calcium phosphate
crystals precipitate as a result of over-alkalinization, calcium phosphate nucleation may
occur. Aggregation of calcium oxalate and calcium phosphate crystals is diminished at
normal physiologic citrate concentrations (44–46). Citrate reduces crystal growth rates
of calcium oxalate by 33% in a seeded metastable in vitro growth system (38) and when
tested in urine from stone formers (47–49). Calcium phosphate (apatite) crystal growth
rates are decreased in the presence of citrate in a similar manner (50). These effects are
independent of the urinary pH changes brought about by potassium citrate supplemen-
tation. Citrate inhibits multiple steps in stone formation including nucleation, aggrega-
tion, and crystal growth.
There is debate as to which inhibitory mechanism is most important in the prevention
of calcium-based stones. Citrate is likely most powerful because of its high urinary
concentration, and is actually less powerful on a molar basis than other potential urinary
inhibitors (51).
Citrate: Supplementation
Potassium citrate is the most common formulation of citrate supplementation studied.
Other forms of citrate replacement include sodium citrate, sodium potassium citrate,
calcium citrate, citrus juices, potassium magnesium citrate, and combination prepara-
tions. These formulations will be discussed separately.
Potassium citrate is used for both the treatment and prevention of urinary stone dis-
ease. Barcelo and colleagues performed a randomized, placebo controlled prevention
Chapter 9 / Urinary Stone Inhibitors 163
trial of potassium citrate therapy in patients with hypocitraturic calcium nephrolithiasis
(52). Fifty-seven patients with moderately severe urinary stone disease (two or more
stones in the last 2 yr) and low (<342 mg/24 h) or low normal (<642 mg/24 h) urinary
citrate levels were randomized. Sixteen patients were noncompliant and two discontin-
ued therapy secondary to gastrointestinal side effects. Eighteen patients received potas-
sium citrate tablets (30–60 meq/d) for 3 yr. Urinary citrate levels increased from 1.9 ±
0.5 mmol/d (359 ± 95 mg/d) to 2.8-3.5 mmol/d (529–661 mg/d). Urinary pH levels
increased from 5.4 ± 0.5 to 6.1–6.7. Stone formation rates dropped dramatically from 1.2
± 0.6 before treatment to 0.1 ± 0.2 per patient year (p < 0.0001) after treatment. Thirteen
(72%) of these patients did not form any stones during the trial period. No patient with
existing renal stones showed significant stone growth while on potassium citrate therapy.
In contrast, the 20 patients taking placebo for 3 yr showed no significant change in stone
formation rate (1.1 ± 0.4 – 1.1 ± 0.3 per patient year). Twenty percent (20%) of controls
showed remission of stone production during the trial. Three patients demonstrated
significant stone growth in the placebo arm. There was no comment regarding potassium
citrate and stone dissolution. There are multiple anecdotal reports regarding potassium
citrate therapy but this remains the only randomized, placebo-controlled trial.
The use of potassium citrate for hyperuricosuric calcium oxalate nephrolithiasis was
validated by Pak and Peterson in 1986. Nineteen patients were treated with 60–80 meq
of potassium citrate per day (43). The treatment raised urinary pH by 0.55–0.85 and
increased urinary citrate levels by 249–402 mg/d to a mean of 643 mg/d. It also decreased
stone formation from 1.55 ± 2.70 per patient-year to 0.38 ± 1.22 per patient-year during
the 2.4-yr average treatment period. This study documents the use of potassium citrate
in patients with nonhypocitraturic forms of calcium nephrolithiasis.
Potassium citrate is also beneficial in uric acid stone disease as first reported by Pak
and colleagues in 1986. Eighteen patients with uric acid stones were treated with potas-
sium citrate for an average of 2.8 yr (53). Urinary citrate levels rose from 503 ± 225 mg/
d to 852–998 mg/d, urinary pH increased from 5.30 ± 0.31 to 6.19–6.46, and new stone
formation rate declined from 1.20 ± 1.68 stones/yr to 0.01 ± 0.04 stones/yr (p < 0.001).
Potassium citrate has become the hallmark method of urinary alkalinization. Treatment
of uric acid stone formers is centered on increasing urinary pH. Potassium citrate, there-
fore, is effective therapy to dissolve and prevent uric acid nephrolithiasis.
The use of potassium citrate for the prevention of cystine stone formation was reviewed
by Hess in 1990 (54). The solubility of cystine increases dramatically above a pH of 7.0,
reaching 1000 mg/L at a urine pH of 8.0. Although sodium bicarbonate could be used
for alkalinization, potassium citrate is preferred because the sodium load will raise
urinary calcium and may actually increase the urinary cystine levels (53). A recent
comparison of potassium citrate and sodium bicarbonate therapy for patients with
homozygous cystinuria demonstrated equal alkalinization with the two therapies (55).
Average urinary cystine and urinary citrate levels were similar with both medications.
Urinary sodium increased significantly with sodium bicarbonate but not with potassium
citrate. There was a linear correlation between urinary sodium and urinary cystine
excretion, thereby making potassium citrate the recommended medication. This corre-
lation is likely caused by the presence of sodium dependent cystine pumps (56).
Potassium citrate has been used more recently to dissolve fragments remaining after
shockwave lithotripsy (SWL). In one study, specific medical therapy (allopurinol or
potassium citrate) was given to 80 patients after SWL. Medical therapy reduced the stone
formation rate by 91% in patients who were stone free and by 81% in those with residual