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

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Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 277

Enteric Hyperoxaluria

The cause of calcium stone formation in the majority of hyperoxaluric patients is

enteric hyperoxaluria (31,32). Ileal disease is responsible for increased intestinal absorp-

tion of oxalate that leads to hyperoxaluria. This disorder may be encountered in patients

with inflammatory bowel disease, gastric or small bowel resection, or jejunoileal bypass

(33).

Two processes are likely responsible for the intestinal hyperabsorption of oxalate.

Bile salts and fatty acids increase the permeability of the intestinal mucosa that results

in a primary increase in the intestinal transport of oxalate. Fat malabsorption, character-

istic of ileal disease, leads to calcium soap formation. This factor limits the amount of

free calcium that can complex with oxalate, thereby raising the oxalate pool available for

absorption and promoting the development of stones.

In enteric hyperoxaluria, stone formation may also be the result of additional factors

such as low urinary output from intestinal fluid loss, low urinary citrate caused by

hypokalemia and metabolic acidosis, and low urinary magnesium caused by impaired

intestinal magnesium absorption.

Primary Hyperoxaluria

Primary hyperoxaluria type I is an autosomal recessive disorder due in a defect of the

hepatic enzyme alanine-glyoxylate aminotransferase (AGT). In the normal liver, AGT

functions in catalyzing the transamination of glyoxylate to glycine in hepatic peroxi-

somes. The deficiency, or altered migration of this enzyme, in primary hyperoxaluria

type I results in the conversion of glyoxylate to oxalate, leading to increased urinary

excretion of oxalic, glycolic, and glyoxylic acids (34,35).

This condition is characterized by nephrocalcinosis, oxalate deposition in tissues

(oxalosis), and renal failure resulting in death before the age of 20 when untreated (36).

The diagnosis can definitively be made by assaying the amount and distribution of AGT

in liver specimens obtained by percutaneous biopsy.

Primary hyperoxaluria type II is very rare and results in deficiencies in the hepatic

enzymes

D-glycerate dehydrogenase and glyoxylate reductase, leading to increased

urinary oxalate and glycerate excretion (37). Both types of primary hyperoxaluria cause

stone formation beginning in childhood, with subsequent development of nephrocalci-

nosis, tubulointerstitial nephropathy, and chronic renal failure. In addition to high levels

of urinary oxalate, serum oxalate levels are also elevated.

MANAGEMENT OF HYPEROXALURIA

Dietary Hyperoxaluria

Less than 10–15% of urinary oxalate is usually derived from dietary sources. Food-

stuffs that are rich in oxalate include spinach, chocolate, nuts, and tea. Although general

advice on a restricted oxalate intake might be given to patients with recurrent nephroli-

thiasis, a low oxalate diet would be most useful in patients with enteric hyperoxaluria or

those with underlying bowel abnormalities.

Enteric Hyperoxaluria

Oral administration of large amounts of calcium (0.25–1.0 g four times per day) or

magnesium has been recommended for the control of calcium nephrolithiasis of ileal

278 Tan and Preminger

disease. Although urinary oxalate may decrease (probably from binding of oxalate by

divalent cations), the concurrent rise in urinary calcium may obviate the beneficial effect

of this therapy, at least in some patients. Cholestyramine does not cause a sustained

reduction in urinary oxalate. The replacement of dietary fat with medium chain triglyc-

erides may be helpful in those patients who also have malabsorption.

Patients may exhibit hypomagnesiuria caused by impaired intestinal absorption of

magnesium. Because magnesium has been shown to complex oxalate, hypomagnesiuria

may increase the urinary saturation of calcium oxalate. Although oral magnesium supple-

ments may correct hypomagnesiuria, they may also provoke further diarrhea. Treatment

with potassium citrate (60–120 meq/d) may correct the hypokalemia and metabolic

acidosis and in some patients, increase urinary citrate toward normal. A liquid form of

potassium citrate is preferable owing to the rapid gastrointestinal transit time in many

individuals with enteric hyperoxaluria.

A high fluid intake is recommended to assure adequate urine volume in patients with

enteric hyperoxaluria. Because excessive fluid loss may be present, an antidiarrheal

agent may be necessary before sufficient urine output can be achieved. Calcium citrate

may theoretically have a role in management of enteric hyperoxaluria. This treatment

may lower urinary oxalate by binding oxalate in the intestinal tract. Calcium citrate may

also raise the urinary citrate and pH by providing an alkali load. Finally, calcium citrate

may correct the malabsorption of calcium and adverse effects on skeleton by providing

an efficiently absorbed calcium supplement.

Primary Hyperoxaluria

Overall, the prognosis of patients with primary hyperoxaluria has been unfavorable.

These patients usually develop renal failure and early death. Routine renal transplanta-

tion fails because of progressive systemic oxalosis (38). An alternate option of combined

liver and kidney transplantation, aims to replace the deficient enzyme, peroxisomal

AGT, and to re-establish normal kidney function. However, this treatment carries sig-

nificant operative morbidity and mortality (39). Bilateral nephrectomies of native kid-

neys, which are a major source of oxalate, have to be considered because of persistent

systemic oxalosis (40).

Currently, pharmacologic therapy plays little part in treatment of primary hyper-

oxaluria. Pyridoxine is useful only in a minority of patients. Long-term administration

of orthophosphate and pyridoxine might decrease urinary oxalate crystallization and

might preserve renal function in selected patients. In addition, long-term administration

of alkali citrate might be beneficial in some patients (41,42). The key to success-

ful management of primary hyperoxaluria is early diagnosis, testing for pyridoxine

response and early planning for definitive therapy when renal function deteriorates.

PATHOPHYSIOLOGY OF HYPOCITRATURIC

CALCIUM OXALATE NEPHROLITHIASIS

Hypocitraturic calcium nephrolithiasis may exist as an isolated abnormality (10%) or

in combination with other metabolic disorders (50%). Acid–base disorder, especially

acidosis, is the most important factor that affects the renal handling of citrate, with

increased acid levels resulting in diminished endogenous citrate production (43,44).

Citrate lowers urinary saturation of calcium salts by forming soluble complexes with

calcium, as well as directly inhibiting the crystallization of calcium salts (45,46). In the

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 279

setting of hypocitraturia, the urinary environment is more supersaturated with respect to

calcium salts, thus promoting nucleation, growth, and aggregation, resulting in stone

formation. Mean normal urinary citrate excretion is 640 mg/d, whereas the lower limit

of normal is 320 mg/d.

In patients with hypocitraturic calcium oxalate nephrolithiasis, potassium citrate treat-

ment is capable of restoring normal urinary citrate, lowering the urinary saturation and

inhibiting crystallization of calcium salts (10,47,48). Moreover, a recent study demon-

strates that potassium citrate therapy might have beneficial effect in preventing age

dependent bone loss (49). Because hypocitraturia is found in a number of different

conditions, each will be addressed individually.

Distal Renal Tubular Acidosis

One of the more common causes of hypocitraturia is distal renal tubular acidosis (RTA).

Acidosis impairs urinary citrate excretion by enhancing renal tubular reabsorption of

citrate as well as by reducing its synthesis (50). Distal RTA may occur in a complete or

incomplete form. The complete form is characterized by hyperchloremic metabolic acido-

sis, hypokalemia, and elevated urinary pH, whereas the incomplete form is characterized

by normal serum electrolyte levels and an inability to acidify urine following an ammo-

nium chloride load. Hypercalciuria and profound hypocitraturia may be associated with

either complete or incomplete RTA. In combination with alkaline urine, the patient is at

risk for developing calcium oxalate or calcium phosphate stones (51).

Potassium citrate therapy may correct the metabolic acidosis and hypokalemia found

in patients with distal renal tubular acidosis. In addition, it is capable of restoring normal

urinary citrate, although large doses (up to 120 meq/d) may be required in severe acidotic

states (51). With correction of the acidosis, urinary calcium should decline into the

normal range. Because urinary pH is generally high to begin with in patients with renal

tubular acidosis, the overall rise in urinary pH is usually small.

Potassium citrate therapy may produce a sustained decline in the urinary saturation

of calcium oxalate (from reduction in urinary calcium and from citrate complexation of

calcium). The urinary saturation of calcium phosphate does not increase because the rise

in phosphate dissociation is relatively small and is adequately compensated by a decline

in ionic calcium concentration. In addition, the inhibitory activity against the crystalli-

zation of calcium oxalate and calcium phosphate is augmented owing to the direct action

of citrate.

Chronic Diarrheal Syndromes

Patients with these conditions lose alkali in the form of bicarbonate via their gas-

trointestinal tract. This bicarbonate loss results in metabolic acidosis with a subsequent

impairment in citrate synthesis (52). Decreased citrate production is responsible for the

lower urinary concentration of citrate. Besides hypocitraturia, patients with chronic

diarrheal syndrome may have additional risk factors for stone formation such as low

urine volumes and hyperoxaluria.

Potassium citrate therapy in patients with hypocitraturia secondary to chronic diar-

rheal states has been shown to significantly reduce the stone formation rate and produce

remission in 70% of patients (45,53). The dose of potassium citrate will be dependent

on the severity of hypocitraturia in these patients. Dosages of potassium citrate range

from 60 meq in three to four divided doses to 120 meq/d.

280 Tan and Preminger

It is recommended that a liquid preparation of potassium citrate be used rather than

the slow-release tablet preparation because the slow-release medication may be poorly

absorbed owing to rapid intestinal transit time. In addition, frequent dose schedules

(three to four times per day) for the liquid preparation are necessary because this form

of the medication has a relatively short duration of biological action. A less frequent dose

schedule (two to three times per day) is acceptable if the solid preparation is used because

of its slow-release characteristic.

Thiazide-Induced Hypocitraturia

Thiazide diuretics can produce hypokalemia that leads to intracellular acidosis. The

acidotic state inhibits the synthesis of citrate, resulting in hypocitraturia. The essential

mechanism is the inhibition of citrate production that is a consequence of chronic aci-

dosis (10,11). Therefore, potassium supplementation, preferably in the form of potas-

sium citrate, should be administered to patients receiving thiazides during treatment of

hypercalciuria. Potassium citrate is equally effective as potassium chloride in correcting

thiazide-induced hypokalemia, except in severe chloride deficiency. Moreover, potas-

sium citrate will enhance citrate excretion.

Idiopathic Hypocitraturia

This entity includes hypocitraturia occurring alone, as well as in conjunction with

other abnormalities (i.e., hypercalciuria or hyperuricosuria). Mechanisms that account

for hypocitraturia in this condition include a high animal protein diet (with an elevated

acid-ash content), strenuous physical exercise (causing lactic acidosis), high sodium

intake, and intestinal malabsorption of citrate.

Stones formed in this condition are predominantly composed of calcium oxalate.

Potassium citrate therapy has been shown to produce a sustained increase in urinary

citrate excretion from initially low values to within normal limits (54).

Thus, potassium citrate can be used in a variety of conditions. A liquid preparation of

potassium citrate with a frequent dose schedule (three to four times per day) is recom-

mended in chronic diarrheal states. In other conditions, a solid preparation given on a

twice-daily schedule is generally preferred.

PATHOPHYSIOLOGY OF HYPOMAGNESURIA

Hypomagnesuric calcium oxalate nephrolithiasis occurs in less than 5% of patients

with recurrent calcium stones. Hypomagnesuria is defined as urinary magnesium excre-

tion <50 mg/d. This condition may co-exist with hypocitraturia in approx 65% of

patients, and low urine volume (<1 L/d) in approx 40% of patients (55). Many patients

with nephrolithiasis will report a limited intake of magnesium-rich foods such as nuts

and chocolate, suggesting the dietary basis of this condition.

Magnesium is known to be an inhibitor of calcium nephrolithiasis by apparently

increasing the solubility product of calcium oxalate and calcium phosphate. Magne-

sium forms complexes with oxalate, thereby reducing the supersaturation with calcium

oxalate. Magnesium has some direct inhibitory effect on crystal growth of calcium

phosphate and oxalate. Besides, the urinary excretion of magnesium and citrate is

increased, whereas the pH is elevated.

Magnesium hydroxide and oxide have been used clinically to treat stone recurrence.

However, both preparations are poorly absorbed and produce slight increase in urinary

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 281

magnesium. Besides, the administration of magnesium produces an increase in urinary

calcium(56). In a randomized trial, the use of magnesium hydroxide did not significantly

reduce the recurrence rate of calcium nephrolithiasis (9). However, in a recent prospec-

tive study, potassium-magnesium citrate reduced the 3-yr recurrence rate of calcium

oxalate formation (57). Magnesium therapy may results in side effects in gastrointestinal

(diarrhea) and central nervous systems (paresis and sleepiness). At the present moment,

their clinical application as a monotherapy is rather limited other than in patients with

hypomagnesuric calcium oxalate nephrolithiasis. Moreover, some suggest that the pro-

tective effect of magnesium administration may be due primarily to magnesium’s effect

on urinary citrate excretion (58).

DRUG-INDUCED CALCIUM NEPHROLITHIASIS

Certain medications (e.g., acetazolamide and lithium) used to treat other medical

conditions are known to be associated with calcium stone formation. If possible, these

medications should be discontinued or alternative therapy should be employed.

Acetazolamide

Acetazolamide is used to manage elevated intraocular pressure in glaucoma, and is

also used to prevent acute mountain sickness (altitude sickness). This medication can

also be a component of treatment plans for congestive heart failure and seizure disor-

ders. Long-term use of acetazolamide is known to cause nephrolithiasis and nephrocal-

cinosis (59,60). Acetazolamide, a carbonic anhydrase inhibitor, may raise the urinary

pH initially because of renal bicarbonate loss. However, the resultant metabolic acidosis

often results in lowering urinary pH with hypocitraturia, eventually causing the forma-

tion of renal calculi. Long-term treatment with acetazolamide markedly decreases uri-

nary citrate, which will result in an increased ion-activity product of calcium phosphate

and decreased inhibition of calcium phosphate crystallization. Treatment with aceta-

zolamide has also been shown to increase urinary oxalate, which together with

hypocitraturia, might further increase the risk of calcium oxalate crystallization (61).

The use of alkali to buffer acidosis and prevent the urinary abnormalities associated

with these medications is often inadequate. The concurrent use of sodium bicarbonate

further potentiates the risk of stone formation.

Lithium

Lithium carbonate has proved to be a highly effective medication to manage bipolar

mood disorders and an increasing number of patients are receiving long-term lithium

therapy. However, the long-term use of lithium has been associated with hyperparathy-

roidism and hypercalcemia. Because of the first report of lithium-induced hyperparathy-

roidism in 1973, more than 40 cases have been uncovered (62–65). However,

nephrolithiasis has rarely been reported. Renal calculi

and hypercalciuria are common

with primary hyperparathyroidism,whereas calculi and renal calcium excretion is vari-

able in the lithium-induced state (66). The exact mechanism is not well studied. By

interfering with adenylate cyclase, lithium affects thyroid and parathyroid function,

causing hyperparathyroidism, hypercalcemia, and hypothyroidism. Although primary

hyperparathyroidism is usually associated with hypercalciuria, there is decreased uri-

nary calcium excretion in patients taking lithium. Lithium may act independently of

parathyroid hormone on the renal tubule to increase calcium absorption. The hypo-

282 Tan and Preminger

calciuric effect probably results in the low risk of nephrolithiasis of lithium-induced

hyperparathyroidism (67).

CONCLUSIONS

Significant progress has been made over last decades in the metabolic evaluation

and management of nephrolithiasis. In addition to conservative measures like dietary

and fluid regimens, selective medical therapy is effective in preventing new stone

formation. Remission rate of greater than 80% and overall reduction in individual

stone formation rate of greater than 90% can be achieved in patients with recurrent

nephrolithiasis. Despite initial higher cost of diagnostic protocols and medical therapy,

an effective pharmacologic prophylactic program could significantly reduce the need

for stone removal, thereby potentially reducing the long-term costs associated with

recurrent nephrolithiasis.

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Chapter 15 / Diet and Urolithiasis 285

285

From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Diet and Urolithiasis

William K. Johnston, III, MD and Roger K. Low, MD

CONTENTS

INTRODUCTION

FLUIDS

PROTEIN

CARBOHYDRATE

FAT

CALCIUM

OXALATE

SODIUM

VITAMINS

STONE-SPECIFIC DIETARY RECOMMENDATIONS

CONCLUSION

REFERENCES

Key Words: Nephrolithiasis; diet; fluid; calcium; protein; sodium.

INTRODUCTION

Nephrolithiasis is a common disorder affecting approx 8–13% of the US population

(1,2). After experiencing renal colic and/or treatment for urinary stones, nearly every

patient expresses interest in diet and specific dietary changes useful in lowering the risk

for future stones.

The pathophysiology of nephrolithiasis is complex and involves multiple factors.

Diet plays a major role in the concentration of a number of urinary solutes and inhibitors

involved in crystallization and stone growth. Determining the impact of one’s diet on

future stone risk begins with a dietary history and subsequent metabolic testing. Meta-

bolic testing usually reveals that an individual’s risk is caused by a combination of

metabolic and environmental factors, many of which can be improved with dietary

modification. In this chapter, we will outline how diet impacts urinary stone formation

and offer dietary recommendations for individuals with specific types of urinary stone.

286 Johnston and Low

FLUIDS

Patient inquiries on the influence of fluid intake on stone formation are perhaps the

most common during discussion of stone prevention. Many patients come with a precon-

ceived notion that forcing oral fluids not only decreases stone risk but also influences

spontaneous stone passage. Little evidence supports this practice during the acute phase

of stone passage; however, the importance of fluid intake on the prevention of future

stones recurrences cannot be overemphasized.

Current theories on stone formation are based on crystal formation caused by super-

saturation of urinary salts. Saturation, determined by the concentration of urinary salts,

is proportional to excreted substrate and inversely proportional to urinary volume. In

theory, increasing urinary volume should decrease the supersaturation capabilities of

urine and increasing oral fluid intake should be beneficial to patients with all types of

stones. Evidence supporting this practice is less convincing. Although some studies do

demonstrate a lower oral fluid intake (3,4) in stone formers vs controls, others do not (5–

7). There is also a concern that hydration may actually be detrimental by diluting inhibi-

tors present within the urine.

Despite less than convincing evidence, there is a consensus that fluid intake to achieve

a daily urine output in excess of 2 L should be recommended to all patients with a history

of urolithiasis (8). For most patients, this requires a daily fluid intake of more than 3 L/

d. This daily intake of fluid typically requires 12 oz of fluid to be ingested with meals,

in between meals, at bedtime, and again during the night. It is useful to explain to patients

the utility of using the appearance of their urine as a gauge as to the adequacy of hydra-

tion. Fluid consumption to produce urine nearly free of coloration is encouraged.

Although hydration is encouraged to all patients, successful incorporation of this dietary

change is often challenging because of patients’ social and occupational lifestyles.

Most would agree that water is the preferred fluid for stone formers to consume. Does

water “hardness” influence the risk of forming stones? Water “hardness” relates to the

amount of dissolved calcium and magnesium. Numerous population studies have

attempted to attribute regional differences in urolithiasis incidence to differences in

water hardness. The small concentration differences of calcium and magnesium between

“hard” and “soft” water relative to those found in the urine make this factor probably

unimportant (9).

Although much is made about the risk of specific types of beverages on stone risk,

most studies indicate a benefit to consumption of nearly any fluid. Beverages such as

coffee, tea, and alcohol have been found to reduce stone formation (4,10). Although

alcoholic beverage consumption promotes urinary calcium and uric acid excretion, stud-

ies suggest a negative correlation between consumption and stone risk. Krieger et al.

found the consumption of as little as 8 oz of beer per week reduces the risk of having a

stone event (11). The beneficial effects of caffeinated coffee and alcohol may be attrib-

utable to induction of diuresis from either blunting of the effects of antidiuretic hormone

or limiting its secretion (12).

With the exception of grapefruit and apple juice, consumption of fruit juices produce

no increased stone risk (10). This increased risk may be caused by their high oxalate

content. In general, citrus juices tend to be beneficial to stone formers by alkalinizing the

urine and promoting an increase in urinary citrate, a known inhibitor of calcium stone

formation. In a study of 12 patients with a history of refractory hypocitraturia, Seltzer

et al. found lemonade consumption of 2 L/d increased urinary citrate an average of 204