Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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164 Abrahams, Meng, and Stoller

fragments after SWL (57). This was compared to a 35% and 17% reduction in those who

discontinued their medical therapy, respectively. In another study, 40 patients with

residual calcium stone fragments received sodium potassium citrate therapy. Seventy-

five percent (75%) cleared their residual stones compared to only 32% of controls (58).

Citrate decreased the rate of stone growth and fragment reaggregation (5% in citrate

group vs 47% in the control group). Residual fragments grew in 16% in those that were

compliant with potassium citrate as opposed to 55% in patients not taking their pre-

scribed medication. A third recent study evaluated the use of potassium citrate to prevent

recurrence and aid in stabilization of lower pole fragments after SWL (59). Patients who

were stone free after lower pole SWL had lower recurrence rates with potassium citrate

than those without treatment (0 vs 28.5%, p < 0.05). Patients with residual lower pole

fragments after SWL had higher remission rates with therapy (44.5 vs 12.5%) than

untreated patients (p < 0.05). These studies demonstrate the use of potassium citrate to

help dissolve, clear and prevent recurrent nephrolithiasis.

Tekin et al documented the use of potassium citrate for children with hypocitraturic

(<320 mg/1.73 m

/24 h), calcium-based stones. Sixty-four hypocitraturic children (ages

1–15, median 7.2 yr), including 20 that had recurrent nephrolithiasis, were treated with

potassium citrate tablets or liquid (1meq/kg in 3 divided doses) for an average of 22

mos(60). No adverse reactions were observed. Daily urinary citrate levels increased

from 197 ± 72 to 632 ± 218 mg/1.73 m

(p < 0.01). Mean urinary calcium levels

decreased from 3.5 ± 2.7 to 2.5 ± 2.7 mg/kg (p < 0.05). The children with recurrent stone

disease experienced a decrease in stone recurrence from 0.32 to 0.17 stones per patient-

year. The overall recurrence rate was 0.07 per patient-year and none of the 44 first-time

stone formers recurred. Although no control group was included in this study, the authors

concluded that potassium citrate therapy was beneficial and safe in children with

hypocitraturic calcium-based stones.

The efficacy of potassium citrate is mainly related to the alkali load presented to the

proximal renal tubular cells. This alkali load invokes changes in the cells that result in

decreased reabsorption of citrate from the filtrate and peritubular fluid, thus increasing

urinary citrate concentrations. Potassium citrate is almost entirely absorbed from the

gastrointestinal tract (11). The citrate component is largely oxidized through the citric

acid cycle to carbon dioxide and water, although Pak suggests that up to 20% of the

citraturic response to citrate therapy may be caused by direct excretion in the urine (61).

Potassium citrate therapy causes sustained increases in urinary pH and urinary citrate

levels (61), which lead to a lower level of ionized calcium and therefore lower urinary

saturation levels of calcium oxalate and uric acid. Crystallization is therefore inhibited

by numerous mechanisms. The increase in urinary pH can induce precipitation of cal-

cium phosphate crystals (62) but does not cause precipitation of magnesium ammonium

phosphate (63).

Potassium citrate is available in liquid, crystal and wax matrix tablet formulations

(Table 3). Most clinicians use three divided daily doses for wax matrix tablets and liquid

preparations; crystal preparations are typically given twice per day. Single evening

dosing of sodium potassium citrate has been tested and might be applicable to potassium

citrate (see Sodium Potassium Citrate Section) (64). The crystal form may encourage

increased fluid intake caused by the need to dissolve the crystals in fluid. Many formu-

lations have a bitter taste and this may further increase fluid intake (64).

The tablet preparation, however, is more convenient for many, raises urinary citrate

levels and pH for a longer time (65), and may offer less gastrointestinal upset (66). The

Chapter 9 / Urinary Stone Inhibitors 165

tablet is large and therefore may not be effective in children or adults who have difficulty

swallowing. The wax matrix tablet passes through the gastrointestinal tract and therefore

is typically seen in the stool. Patients should be informed that the potassium citrate is

fully absorbed despite the remaining wax matrix appearing as an intact tablet. Rarely, in

patients with rapid intestinal transit times, the potassium citrate may not be adequately

absorbed. These rare patients should be changed to the liquid or crystal preparation.

Dosing regimens of potassium citrate are typically 30–60 meq/d, depending on pre-

treatment citrate levels and clinical response. Some recommend increasing the dosage

(up to 1 meq/kg) until urinary pH and/or urinary citrate concentrations reach the desired

level (66). The most common side effect of potassium citrate therapy is gastrointestinal

irritation (diarrhea, dyspepsia, nausea). Potassium citrate efficacy is considered to be

equal when taken on an empty stomach or with meals (65), but is probably tolerated

better when taken with meals (66). Potential complications associated with potassium

citrate include hyperkalemia, especially in those patients on potassium-sparing diuret-

ics and those with renal insufficiency, and gastric erosions or rarely intestinal obstruc-

tion in those taking the wax matrix tablet. Potassium citrate can be used as an alternative

to potassium chloride supplementation in patients taking potassium-wasting diuretics.

Patients with renal failure should be started on one-third or one-half the usual dose and

monitored with serial serum electrolytes. Aluminum absorption has been reported to

increase secondary to oral citrate therapy (67,68). However, Sakhaee and colleagues

showed no increase in total body aluminum retention in those with normal renal function

(69).

The role of intermittent alkali therapy has been reviewed recently. The rationale is that

one may be able to replicate the body’s normal urinary pH fluctuations by giving three

to seven doses per week (70,71). Potential indications for intermittent therapy are

asymptomatic large stones and prophylaxis regimens. Potential advantages include fewer

side effects, avoidance of systemic alkalosis, lower risk of calcium phosphate crystal-

lization, and improved compliance (70). There are no prospective trials regarding inter-

mittent potassium citrate therapy. One retrospective study comparing regular medical

prophylaxis (64 patients, mean duration of therapy 27.8 ± 4.8 mo), intermittent medical

Table 3

Potassium Citrate Preparations Available in the United States

Drug Trade name

Potassium citrate/sodium citrate Citrolith Tablets

Potassium citrate/citric acid K Liquid

Potassium citrate/citric acid Cytra Polycitra K Liquid

Potassium citrate/citric acid/sodium citrate Polycitra LC Liquid

Potassium citrate/citric acid/sodium citrate Polycitra Syrup

Potassium citrate/citric acid/sodium citrate Cytra 3 Syrup

Potassium citrate Polycitra Crystals

Potassium citrate Urocit-K (wax matrix tablet)

Sodium citrate/citric acid Bicitra

(Source: Internet search, June, 2006.)

166 Abrahams, Meng, and Stoller

therapy (80 patients, mean duration of treatment 7.9 ± 4.9 mo) and no medical therapy

(169 patients) demonstrated that regular medical treatment with potassium citrate mark-

edly reduced the stone recurrence rate compared to the intermittent group (7.8% vs 30%)

(71). Kaplan–Meier curves and log-rank tests revealed that patients on intermittent

therapy had statistically similar recurrence rates to those patients who refused therapy

altogether. This study, therefore, suggests that patients who occasionally are compliant

with their potassium citrate likely will recur as often as those without any therapy. The

findings do not suggest, however, that a standardized intermittent regimen of potassium

citrate would be ineffective. Theoretically, if urinary pH and citrate were occasionally

elevated, calculogenesis may be inhibited. Prospective standardized trials are necessary

to adequately ascertain whether intermittent therapy is efficacious.

Sodium citrate and sodium potassium citrate supplementation are more commonly

used in Europe than in North America (72). Potassium citrate has many advantages over

sodium citrate. Potassium replacement is a necessary treatment for patients with RTA,

diarrheal syndromes and thiazide-induced hypocitraturia. Correcting the hypokalemia

reduces the acidosis and leads to a less pronounced hypocitraturic state. In contrast,

sodium citrate does not treat the underlying potassium deficit. In addition, potassium

citrate lowers urinary calcium levels in patients with RTA and may temporarily reduce

urinary calcium in other diseases (73,74). Conversely, sodium citrate may increase

urinary calcium and cause sodium-urate crystallization of calcium oxalate (53). A global

dietary recommendation for patients with calcium-based stones is a decreased sodium

intake in order to reduce urinary calcium excretion via the sodium dependent calcium

pumps (75). Therefore, a nonsodium-based alkali supplement is advantageous. The

sodium load is also a central issue in patients with cardiac failure, renal failure, hyper-

tension, or pulmonary edema in relation to their overall fluid homeostasis.

A single daily dose of sodium potassium citrate (1 g = 3.6 mmol citrate, 4.4 mmol

potassium, and 4.4 mmol sodium) was tested in healthy volunteers and calcium stone

forming patients (64). The volunteer group was given a single dose (men 5 g and women

3.5 g) at 8

PM. Urinary pH remained elevated until 10 AM the following morning but

urinary citrate levels did not increase. In the stone formers, a single evening dose at 8 pm

(3.75 g, 5 g, or 7.5 g) raised the urinary citrate levels from 1.7 ± 1.2 mmol/24 h to 3.0 ±

1.3 mmol/24 h (p < 0.001). Urinary calcium decreased from 6.6 ± 3.2 mmol/24 h to 5.6

±2.5 mmol/24 h (p < 0.001). Stone formation rates decreased from 0.35 ± 1.14 to 0.16

±0.36 over the mean treatment length of 3.5 ± 1.7 yr, but this decrease was not statis-

tically significant. Stone occurrence rates before treatment were lower in this study

than other similar studies and this might account for the lack of statistical significance.

In a prospective randomized trial of 50 patients with calcium oxalate stone disease

treated with either sodium potassium citrate or dietary changes, stone recurrence rates

were the same with or without medical treatment (76). In the control group, stone rates

decreased from 1.8/yr to 0.7. In the treatment group, stone rates were 2.1 and 0.9/yr

before and after treatment, respectively. An objective benefit of alkali citrate could not

be established. This study had a substantial decrease in stone rates in the control group

and this dramatic “clinic effect” may explain the lack of difference between the treatment

and control groups.

Calcium citrate has not been investigated as a therapy for urolithiasis. Long term use

of calcium citrate raises urinary citrate levels marginally and raises urinary calcium but

does not alkalinize the urine (77,78). As a calcium supplement, calcium absorption may

be higher than with calcium carbonate preparations (79). Calcium citrate is therefore not

Chapter 9 / Urinary Stone Inhibitors 167

recommended for a citrate supplement in patients with hypocitraturic calcium-based

nephrolithiasis.

Urinary citrate can be elevated with the use of natural citrus juices. Lemons, grape-

fruit, pineapples, and oranges all have a high concentration of citrate. Seltzer and col-

leagues showed the use of drinking 2 L/d of reconstituted lemonade (80). Of the 12

patients, 11 had increased urinary citrate levels (average increase of 204 mg/d). Average

levels increased from 142 mg daily (range <10–293) at baseline to 346 mg daily (range

89–814) after treatment (p <.001). Urinary oxalate was unchanged and urinary calcium

decreased, although not in a significant amount. Patients were compliant with this

nonpharmacologic mode of citrate supplementation. In a similar study, Wabner and Pak

compared the effect of ingesting 1.2 L of orange juice per day with standard potassium

citrate supplementation (81). Urinary citrate levels and pH increased with orange juice

to the same degree as with potassium citrate. However, urinary oxalate levels also

increased, either because of the oxalate content of orange juice or the conversion of

ascorbic acid (vitamin C) to oxalate. The saturation of calcium oxalate was unchanged

with orange juice but decreased significantly with potassium citrate therapy. Similar

effects were seen in a recent study detailing the effect of grapefruit juice on urine chem-

istries (82). An acute load of grapefruit juice was given to 7 healthy volunteers. Three

hours after ingestion, urinary citrate increased from 18.7 mg/h to 25.8 mg/h and urinary

calcium increased from 3.3 mg/h to 6.7 mg/h. No long-term studies are available detail-

ing the urinary effects of citrus juice therapy.

MAGNESIUM

The significance of urinary magnesium in preventing stone formation has been de-

bated for decades. Most data evaluating urinary magnesium is based on older animal

studies (83). In 1962, Gersoff and Andrus first noted that diets low in magnesium in-

creased calcium oxalate deposits in rat kidneys in their ethylene glycol rat model (84).

Lyon followed with the finding that high magnesium diets prevented calcium oxalate

encrustation of zinc disks implanted into rat bladders (85). Robertson demonstrated that

magnesium binds oxalate in human urine (86). In superphysiologic concentrations,

magnesium can inhibit nucleation and growth of calcium oxalate crystals (84,87). A

more recent animal study involving rats on an ethylene glycol induced hyperoxaluric diet

showed no change in renal calcifications with the addition of magnesium oxide (88).

Some studies have shown increased urinary calcium when magnesium is supplemented.

The overall importance of urinary magnesium may relate to its enhancement of urinary

citrate concentrations (83,89,90).

One reason why magnesium has not been considered an important inhibitor is the low

incidence of hypomagnesuria in stone formers (4.3–11%) (91). Normal urinary magne-

sium levels according to Litholink

laboratory are 30–120 mg/24 h (26). Parks and Coe

documented urinary magnesium levels of 84 ± 5 mg in 27 nonstone forming females and

99 ± 6 mg in 33 nonstone forming males (92). Mean urinary magnesium levels in stone

formers older than 65 years of age were 77 mg/24 h (standard deviation, SD, 39) and 83

mg/24 h (SD, 39) in stone patients younger than 65 yr (32). Urinary magnesium levels

in 78 calcium stone forming children were the same as control children, using a defini-

tion of hypomagnesuria of less than 1.2 mg/kg in 24 h (33).

Most patients with low urinary magnesium also have hypocitraturia, thereby confus-

ing the significance of magnesium levels (91). It has been suggested that the magnesium-

168 Abrahams, Meng, and Stoller

to-calcium ratio may be more important (93). Melnick sited a low urinary magnesium

level in patients of the “stone belt,” and related this to low soil magnesium content in this

region (94).

Magnesium replacement therapy for prophylaxis in urinary stone patients was first

introduced by Moore and Bunce in 1964 (95). Gershoff and Prien reported that magne-

sium oxide reduced stone rates from 1.3/patient year to 0.1 (96). Melnick also found

similar results over a 4-yr trial (94). Selikowitz and Olsson compared the efficacy of

magnesium oxide, hydrochlorothiazide, methylene blue, and sodium phosphate to pre-

vent and treat CaOx stones in a rat model (97). Magnesium oxide prevented renal stone

formation entirely and limited the area of parenchymal calcification. Randomized trials

by Wilson (1984) (98) and Ettinger (1988) (99) found no difference in stone formation

between patients treated with magnesium hydroxide and those without treatment.

Lindburg documented only a minimal increase in urinary magnesium with magnesium

citrate and magnesium oxide unless taken with food (100). The latter produced a

decrease in the supersaturation of calcium oxalate and brushite. Urinary citrate levels did

increase with magnesium citrate and magnesium oxide. This study included only 11

patients, making conclusions unreliable. Preminger has documented the use of oral

magnesium citrate in those patients with hypomagnesuric calcium stones (91). Intrave-

nous magnesium sulfate was given to stone formers and controls in another recent study

from Thailand. Urinary citrate increased with supplementation, leading to the idea that

magnesium’s effect on stone formation may be indirect (89).

The combined use of potassium, magnesium and citrate has gained much attention in

the last decade (11,101,102). In a comparison study of potassium citrate and potassium

magnesium citrate including five normal volunteers and five calcium stone formers,

urinary pH, urinary magnesium and urinary citrate rose higher with potassium magne-

sium citrate therapy (102). Calcium oxalate saturation and agglomeration declined and

calcium phosphate inhibition rose to a greater extent with the potassium magnesium

citrate preparation. Both treatment regimens had the same dose of potassium but the

magnesium potassium citrate preparation contained 50% more citrate. Another com-

parison study demonstrated equal potassium delivery with potassium citrate, potassium

chloride and potassium magnesium citrate and equal magnesium delivery with magne-

sium citrate and potassium magnesium citrate (103). Of these four preparations, potas-

sium magnesium citrate produced the largest citraturic response (125 mg/d increase).

Potassium magnesium citrate also may be useful for correcting thiazide-induced hypo-

kalemia (101,104), hypomagesuric calcium oxalate nephrolithiasis (91), and chronic

diarrheal states in which patients are often hypocitraturic, hypomagnesuric and hypo-

kalemic. The major side effect of magnesium replacement is gastrointestinal symptoms.

CONCLUSIONS

This chapter has focused on two inhibitors of urinary stone formation: citrate and

magnesium. The former is of true clinical importance whereas the latter is potentially of

historic interest only. From a clinical standpoint, citrate is the most important inhibitor.

There is limited prospective data regarding the use of citrate replacement. It is clear,

however, that citrate supplementation will decrease stone recurrence. Multiple prepara-

tions are available, allowing the therapy to be tailored to the patient. Any patient with

acidosis will likely have hypocitraturia and correction of the acidosis will increase

urinary citrate levels. Magnesium may act indirectly by increasing urinary citrate levels.

Chapter 9 / Urinary Stone Inhibitors 169

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Chapter 9 / Urinary Stone Inhibitors 173

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