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

Подождите немного. Документ загружается.

Chapter 13 / Medical Evaluation of Stone Disease 267

recurrent or complicated kidney stone disease. In the majority of patients, the simplified

step-by-step approach may be sufficient. However, in certain instances, particularly for

those presenting with complicated or severe stone disease, a more comprehensive work-

up maybe warranted to identify the pathophysiological mechanism for stone formation.

REFERENCES

1. Pak CYC, Skurla C, Harvey J. Graphic display of urinary risk factors for renal stone formation.

J Urol 1985; 134: 867.

2. Pak CYC. Medical management of nephrolithiasis. J Urol 1982; 128: 1157.

3. Marshall N, White RH, De Saintonge MC, et al. The natural history of renal and ureteric calculi.

Br J Urol 1975; 47: 117.

4. Johnson CM, Wilson DM, O’Fallon WM, et al. Renal stone epidemiology: a 25-year study in

Rochester, Minnesota. Kid Int 1979; 16: 624.

5. Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice.

Miner Electrolyte Metab 1985; 11: 267.

6. Coe FL, Keck J, Norton ER. The natural history of calcium urolithiasis. J Am Med Assoc 1977;

238: 519.

7. Fine JK, Pak CYC, Preminger GM. Effect of medical management and residual fragments on

recurrent stone formation following shock wave lithotripsy. J Urol 1995; 153: 27.

8. Crawhall JC, Purkiss P, Watts RWE, Young EP. The excretion of amino acids by cystinuric

patients and their relatives. Ann Human Genet 1969; 33:149.

9. Danpure CJ, Smith LH. The primary hyperoxalurias. In: Kidney Stones: Medical and Surgical

Management, (Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM, eds.). Lippincott Raven,

Philadelphia, PA, 1996; p. 859.

10. Pak CYC, Sakhaee K, Crowther C, Brinkley L. Evidence justifying high fluid intake in the treat-

ment of nephrolithiasis. Ann Inter Med 1980; 93: 36.

11. Borghi L, Meschi T, Amato F, et al. Urinary volume, water and recurrences in idiopathic calcium

nephrolithiasis: a 5-year randomized prospective study. J Urol 1996; 155: 839.

12. Sakhaee K, Harvey JA, Padalino PK, et al. Potential role of salt abuse on the risk of kidney stone

formation. J Urol 1991; 150: 310.

13. Robertson WG, Peacock M, Heyburn PJ. Risk factors in calcium stone disease of the urinary tract.

Br J Urol 1978; 50: 449.

14. Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Ann Intern Med, 1989; 111: 1006.

15. Pak CYC. Should patients with single renal stone formation undergo diagnostic evaluation? J Urol

1982; 127: 854.

16. Consensus Conference: prevention and treatment of kidney stones. J Am Med Assoc 1988; 260: 977.

17. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. Family history and risk of kidney stone. J Am

Soc Nephrol 1997; 8:1568.

18. Rudman D, Dedonis JL, Fountain MT, et al. Hypocitraturia in patients with gastrointestinal mal-

absorption. N Eng J Med 1980; 303: 657.

19. Smith LH, Fromm H, Hofmann AF. Acquired hyperoxaluria, nephrolithiasis and intestinal dis-

ease: description of a syndrome. N Eng J Med 1972; 286:1371.

20. Griffith DP, Musher DM. Prevention of infected urinary stone by urase inhibition. Invest Urol

1973; 11: 228.

21. Hwang TIS, Hill K, Schneider V, Pak CYC. Effect of prolonged bedrest on propensity for renal

stone formation. J Clin Endo Metab 1988, 66: 109.

22. Klugman V, Pak CYC, Favus MJ. Nephrolithiasis in primary hyperparathyroidism. In: The Par-

athyroids: Basic and Clinical Concepts, 2nd Ed., (Bilezikian JP, Marcus R, Levine MA, eds.).

Academic Press, San Diego, CA, 2001; pp. 437–450.

23. Reddy, S.T., Wang, C.Y., Sakhaee, K. et al.: Effect of low-carbohydrate high-protein diets on acid-

base balance, stone-forming propensity, and calcium metabolism. Am J Kid Dis, 2002; 40: 265.

24. Wabner CL, Pak CYC. Effect of orange juice consumption on urinary stone risk factors. J Urol

1993; 149: 1405.

268 Odvina and Pak

25. Higashihara E, Nutahara K, Takeuchi T, et al. Calcium metabolism in acidotic patients induced by

carbonic anhydrase inhibitors: responses to citrate. J Urol 1991; 145: 942.

26. Auer BL. Auer D, Rodger AL. Relative hyperoxaluria, crystalluria and haematuria after megadose

ingestion of vitamin C. Eur J Clin Invest 1998; 28: 695.

27. Ettinger B, Oldroyd NO, Sorgel F. Triamterene nephrolitiasis. J Am Med Assoc 1980; 244: 2443.

28. Berns JS, Cohen RM, Silverman M, Turner J. Acute renal failure due to indinavir crystalluria and

nephrolithiasis: report of 2 cases. Am J Kidney Dis 1997; 30: 558.

29. Pak CYC, Asplin JR, Ogawa Y, et al. Evaluation of stone-forming patients. Paris Consultation on

Stone Disease. Paris, France. July 4–5, 2001.

30. Pak CYC. Medical management of nephrolithiasis: a new, simplified approach for general prac-

tice. Am J Med Sci 1997; 313: 215.

31. Pak CYC, Resnick MI. Medical therapy and new approaches to management of urolithiasis. Urol

Clin North Am 2000; 27: 243.

32. Pak CYC, Peterson R, Pondexter JR. Adequacy of a single stone risk analysis in the medical

evaluation of urolithiasis. J Urol 2001; 165: 378.

33. Levy FL, Adams-Huet B, Pak CYC. Ambulatory evaluation of nephrolithiasis: an update of a 1980

protocol. Am J Med 1995; 98: 509.

34. Pak CYC, Kaplan RA, Bone H, et al. A simple test for the diagnosis of absorptive, resorptive and

renal hypercalciurias. N Engl J Med 1975; 292:497.

35. Pietchmann F, Breslau NA, Pak CYC. Reduced vertebral bone density in hypercalciuric nephroli-

thiasis. J Bone Min Res 1992; 7:1383.

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 269

269

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

Pharmacologic Prophylaxis

of Calcium Stones

Yeh Hong Tan, MD and Glenn M. Preminger, MD

CONTENTS

INTRODUCTION

PATHOPHYSIOLOGY OF HYPERCALCIURIA

MANAGEMENT OF HYPERCALCIURIA

PATHOPHYSIOLOGY OF HYPERURICOSURIC CALCIUM

OXALATE NEPHROLITHIASIS

MANAGEMENT OF HYPERURICOSURIC CALCIUM

OXALATE NEPHROLITHIASIS

PATHOPHYSIOLOGY OF HYPEROXALURIA

MANAGEMENT OF HYPEROXALURIA

PATHOPHYSIOLOGY OF HYPOCITRATURIC CALCIUM

OXALATE NEPHROLITHIASIS

PATHOPHYSIOLOGY OF HYPOMAGNESURIA

DRUG-INDUCED CALCIUM NEPHROLITHIASIS

CONCLUSIONS

REFERENCES

Key Words: Nephrolithiasis; medical management; prophylaxis; calcium;

diuretic.

INTRODUCTION

The management of nephrolithiasis forms an important part of urologic practice. The

recurrence rate after forming an initial stone is reported to be as high as 50% at 5 yr and

80–90% at 10 yr, highlighting the importance of medical prophylactic therapy. A better

understanding of pathophysiology and formulation of diagnostic criteria for different

270 Tan and Preminger

etiologies of nephrolithiasis have made feasible the adoption of selective treatment

programs. The objectives of medical stone management should be:

1. Correct the underlying physicochemical and physiologic derangements

2. Prevent new stone formation

3. Avoid nonrenal complications of the disease process

4. Be free of serious side-effects

The background for the selection of certain medical treatment programs is the

assumption that specific physicochemical and physiological abnormalities identified

with a given disorder are etiologically important in the formation of renal stones, and

that the correction of these disturbances would prevent stone formation. Moreover, it

is assumed that such a selective treatment program would be more effective and safe

than a “random” treatment approach.

These hypotheses appear reasonable and logical. For many pharmacologic treatment

programs recommended for the prevention of recurrent nephrolithiasis, sufficient infor-

mation is now available to characterize their physicochemical and physiological actions.

PATHOPHYSIOLOGY OF HYPERCALCIURIA

Hypercalciuria is defined as the excretion of urinary calcium exceeding 200 mg/24 h

(or an excess of 4 mg of calcium/kg/24 h). The association of hypercalciuria with recur-

rent calcium nephrolithiasis has long been recognized, although the exact nature of this

relationship continues to be investigated. Nephrolithiasis resulting from hypercalciuria

is heterogeneous in origin, and comprises several entities.

Absorptive Hypercalciuria

The primary abnormality in absorptive hypercalciuria is increased intestinal absorp-

tion of calcium (1). The exact cause for the hyperabsorption of calcium is not fully

understood. A subsequent increase in serum calcium concentration enhances the renal

filtered load and suppresses parathyroid function (Fig. 1). The combination of an

increase in the filtered load and a decrease in renal tubular reabsorption of calcium,

caused by parathyroid suppression, results in development of hypercalciuria and poten-

tial stone formation. The excessive renal loss of calcium compensates for the intestinal

hyperabsorption, thereby maintaining serum calcium in the normal range.

Absorptive hypercalciuria type I (AH-I) is the most severe form of absorptive

hypercalciuria, characterized by a urine calcium level >200mg/d, with high or low

dietary calcium intake. In AH-I, patients have normal serum levels of calcium and

phosphorus and a normal or low serum PTH level. Fasting urinary calcium is normal,

whereas an oral calcium load results in exacerbated hypercalciuria. Absorptive hyper-

calciuria Type II (AH-II) is a mild to moderate form of this disorder in which hyper-

calciuria only occurs with high calcium intake. These patients have normal urinary

calcium excretion either while fasting or on a restricted calcium diet.

Renal Hypercalciuria

The underlying abnormality in renal hypercalciuria (or “renal leak” hypercalciuria)

is thought to be impairment of renal tubular reabsorption of calcium (1). The consequent

reduction in serum calcium concentration stimulates parathyroid function (Fig. 2). Par-

athyroid hormone (PTH) excess results in mobilization of calcium from bone and

enhanced intestinal absorption of calcium, with ensuing stimulation of renal synthesis

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 271

of 1,25-(OH)

D. These events lead to an increase in the circulating concentration and

renal filtered load of calcium, often causing significant hypercalciuria, even during the

fasting state. Unlike primary hyperparathyroidism, patients with renal hypercalciuria

have normal serum calcium level. As the elevated PTH (secondary hyperparathyroid-

ism) is a response to the renal calcium leak, an oral calcium load may suppress the

hyperparathyroidism in these individuals.

Resoprtive Hypercalciuria

Primary hyperparathyroidism is the cause of resorptive hypercalciuria. The initial

event in this condition is hypersecretion of PTH, resulting in excessive bone resorption

and an increase in serum calcium levels (Fig. 3). Intestinal absorption of calcium is often

secondarily elevated owing to PTH-dependent stimulation of renal synthesis of 1,25-

(OH)

D. These effects cause significant hypercalciuria through an increase in the circu-

Fig. 2. Renal hypercalciuria.

Fig. 1. Absoptive hypercalciuria.

Fig. 3. Resorptive hypercalciuria.

272 Tan and Preminger

lating concentration and renal filtered load of calcium. Elevated PTH also enhances renal

reabsorption of calcium and the excretion of phosphate. Fasting urinary calcium levels

remain elevated as in patients with renal hypercalciuria.

Differential Diagnosis of Hypercalciuria

Different forms of hypercalciuria can be differentiated from their biochemical and

physiological pictures (Table 1). Although the serum calcium is normal in absorptive

hypercalciuria and renal hypercalciuria, patients with resorptive hypercalciuria have

elevated circulating calcium levels. Serum PTH concentration is primarily elevated in

resorptive hypercalciuria and secondarily elevated in renal hypercalciuria, whereas

parathyroid activity is normal or suppressed in absorptive hypercalciuria. Fasting uri-

nary calcium is normal in patients with absorptive hypercalciuria but is elevated in renal

hypercalciuria and resorptive hypercalciuria. Finally, all three forms of hypercalciuria

are accompanied by an intestinal hyperabsorption of calcium. However, this disturbance

is a primary defect in patients with absorptive hypercalciuria and a secondary defect in

renal hypercalciuria and resorptive hypercalciuria.

Some patients may present with fasting hypercalciuria and normal serum PTH

(unclassified hypercalciuria) (2). This disorder exhibits features of both absorptive

and renal hypercalciuria. However it lacks the characteristics required for clear differ-

entiation. Fasting hypercalciuria suggests a renal calcium leak, although hyperpara-

thyroidism is not evident. A lack of PTH elevation resembles absorptive hypercalciuria,

but the fasting urinary calcium is elevated. The picture of unclassified hypercalciuria

is most commonly caused by inadequate dietary preparation.

MANAGEMENT OF HYPERCALCIURIA

Sodium Cellulose Phosphate

Sodium cellulose phosphate can be used in selected patients with absorptive

hypercalciuria (3,4). However, sodium cellulose phosphate is not routinely used for

prevention of stone recurrence (5). This medication is more commonly used as a diag-

nostic tool in patients with absorptive hypercalciuria.

Sodium cellulose phosphate may decrease urinary magnesium, increase urinary

oxalate, and have a limited hypocalciuric action or cause negative calcium balance in the

absence of increased calcium absorption or in the presence of renal calcium leak (4).

Table 1

Differential Diagnosis of Hypercalciuria

Absorptive Renal Resorptive

• Serum calcium Normal Normal Elevated

• Parathyroid function Suppressed Stimulated Stimulated

(secondarily) (primarily)

• Fasting urinary calcium Normal Elevated Elevated

• Intestinal calcium absorption Elevated Elevated Elevated

(primarily) (secondarily) (secondarily)

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 273

When sodium cellulose phosphate is administered, this nonabsorbable resin binds cal-

cium and inhibits intestinal calcium absorption. However, this inhibition is caused by

limiting the amount of intraluminal calcium available for absorption, not by correcting

the basic disturbance in calcium transport.

The common side effects of cellulose phosphate are hyperoxaluria, hypomagnesiuria

and diarrhea (6). The potential complications of sodium cellulose phosphate therapy can

be explained by its mechanism of action. First, this medication may cause a negative

calcium balance and parathyroid stimulation when used in patients with normal intesti-

nal calcium absorption or with renal or resorptive hypercalciuria. Second, the treatment

may cause magnesium depletion by binding magnesium in the gut. Finally, sodium

cellulose phosphate may produce secondary hyperoxaluria by binding divalent cations

in the intestinal tract, reducing divalent cation-oxalate complexation, and making more

oxalate available for absorption. These complications may be overcome by using the

drug only in documented cases of absorptive hypercalciuria Type I, providing oral

magnesium supplementation (given independent from sodium cellulose phosphate), and

imposing a moderate dietary restriction of oxalate (4).

When these precautions are followed, sodium cellulose phosphate at a dosage of 10–

15 g/d (given with meals) has been shown to reduce urinary calcium and the saturation

of calcium salts (calcium phosphate as well as calcium oxalate), maintain stable bone

density and to be clinically effective.

Thiazides

Thiazide diuretics are ideally indicated for the treatment of renal hypercalciuria.

Several studies have demonstrated the beneficial effects of thiazide in preventing stone

recurrence. Thiazides have been demonstrated to correct the renal leak of calcium by

augmenting calcium reabsorption in the distal tubule and by causing extracellular vol-

ume depletion and stimulating proximal tubule reabsorption of calcium (7–9). The

subsequent correction of secondary hyperparathyroidism restores normal serum 1,25-

(OH)

D and intestinal calcium absorption. Thiazides provide a sustained correction of

hypercalciuria commensurate with a restoration of normal serum 1,25-(OH)

D and

intestinal calcium absorption for up to 10 yr of therapy. Physicochemically, the urinary

environment becomes less saturated with respect to calcium oxalate and brushite during

thiazide treatment, largely because of the reduced calcium excretion. In addition, urinary

inhibitor activity, as reflected in the limit of metastability, is increased. The above effects

are shared by hydrochlorothiazide (50 mg twice per day), chlorothalidone (50 mg/d) or

indapamide (1.5 mg/d). Potassium supplementation (approx 40 meq/d) is required to

prevent hypokalemia and attendant hypocitraturia with all of these agents. Potassium

citrate has been shown to be effective in averting hypokalemia and in increasing urinary

citrate when administered to patients with calcium nephrolithiasis who are taking

thiazides (10,11).

Concurrent use of triamterene, a potassium-sparing agent, should be

undertaken with caution because of recent reports of triamterene stone formation (12,13).

Thiazide is contraindicated in primary hyperparathyroidism because of potential aggra-

vation of hypercalcemia.

Thiazide is not considered a selective therapy for absorptive hypercalciuria, because

it does not decrease intestinal calcium absorption in this condition. However, this drug

has been used widely to treat absorptive hypercalciuria because of its hypocalciuric

action and the high cost and inconvenience of alternative therapy (sodium cellulose

phosphate).

274 Tan and Preminger

Current studies indicate that thiazide may have a limited long-term effectiveness in

AH-I (14). Despite an initial reduction in urinary calcium excretion, the intestinal cal-

cium absorption remains persistently elevated. These studies suggest that the retained

calcium may be accreted in bone at least during the first few years of therapy. Bone

density may increase during thiazide treatment in AH (15). With continued treatment,

however, the rise in bone density stabilizes and the hypocalciuric effect of thiazide

becomes attenuated. These results suggest that thiazide treatment has caused a low

turnover state of bone that interferes with a continued calcium accretion in the skeleton.

The “rejected” calcium would then be excreted in urine. In contrast, bone density is not

significantly altered in renal hypercalciuria, where thiazide causes a decline in intestinal

calcium absorption commensurate with a reduction in urinary calcium.

Besides hypokalemia, the side effects of thiazide include erectile dysfunction, gout

raised serum cholesterol and glucose intolerance.

Guidelines for the Use of Sodium Cellulose Phosphate

or Thiazides in Absorptive Hypercalciuria Type I

There is currently no treatment program capable of correcting the basic abnormality

of AH-I. Neither sodium cellulose phosphate nor thiazides corrects the basic, underlying

physiologic defect in AH. Some guidelines are offered until more selective therapy can

be developed.

Sodium cellulose phosphate might be used in patients with severe AH-I (urinary

calcium greater than 350 mg/d) or in those resistant to or intolerant of thiazide therapy.

In patients with AH-I who may be at risk for bone disease (growing children, postmeno-

pausal women) or who already have bone loss, thiazides may be the first choice. If

thiazides lose their hypocalciuric action (after long-term treatment), sodium cellulose

phosphate may be temporarily substituted for approx 6 mo; thiazide treatment may then

be resumed. Continued monitoring of urinary calcium excretions is essential to assure

that the hypocalciuric action of thiazides persist.

Orthophosphate

(Including Slow-Releasing Potassium Phosphate)

The most common form of absorptive hypercalciuria is secondary to increased

intestinal calcium absorption. Various theories exist regarding the exact pathophysi-

ology of absorptive hypercalciuria including both vitamin D dependent as well as

vitamin D independent absorptive hypercalciuria. It is believed that in a significant

subset of patients, increased 1-25 (OH)

D (vitamin D) levels may be responsible for

enhanced intestinal calcium absorption in patients with absorptive hypercalciuria.

There are two types of orthophosphate (acidic and neutral) that have been used clini-

cally in patients with nephrolithiasis. Previous studies have demonstrated that neutral

phosphates may indeed be a useful preparation to reduce serum vitamin D levels as well

as to inhibit urinary calcium excretion in patients with AH (16). However, there are a

number of problems available with current forms of orthophosphate therapy. These

preparations provide rapid-release of neutral phosphate that may cause gastrointestinal

upset and diarrhea from an increased osmotic load. The side effects include diarrhea,

nausea, vomiting and abdominal colic. In addition, many orthophosphate preparations

provide an inadequate hypocalciuric response as compared to thiazides or sodium cell-

ulose phosphate preparations owing to the renal effect of sodium contained in most

Chapter 14 / Pharmacologic Prophylaxis of Calcium Stones 275

currently available orthophosphate preparations (see section on dietary sodium intake).

Finally, previous studies have also demonstrated that orthophosphate preparations may

increase the urinary saturation of calcium phosphate (brushite) owing to a substantial

rise in urinary pH, caused by the increased alkalinity of most available orthophosphate

preparations.

A new formulation of slow-release, neutral potassium phosphate has been developed

to obviate the problems with currently available orthophosphate preparations (17,18).

This potassium phosphate preparation (UroPhos-K) is prepared in a wax matrix to pro-

vide slow release of the orthophosphate. This restricted release limits the amount of GI

upset found with most current orthophosphate preparations. In addition, UroPhos-K

contains phosphate salts of potassium and no sodium. Therefore, this preparation does

not provide a sodium load that could offset the hypocalciuric action of the orthophos-

phate. Finally, this medication is designed to yield a pH of 7.0 as compared to 7.3 for

some available orthophosphate preparations. Therefore, it is less likely that the crystal-

lization of calcium phosphate may occur in the urine.

Randomized prospective double-blind trials were performed to assess the impact of

this new medication on patients with documented stone formation and AH-I (18,19).

Patients received either UroPhos-K or placebo in a double-blinded fashion. No signifi-

cant gastrointestinal side effects were noted with the slow-release potassium phosphate

preparation nor was there a significant increase in fasting serum potassium or phospho-

rus. However, the UroPhos-K treatment did significantly reduce urinary calcium with-

out altering oxalate excretion. Moreover, the urinary saturation of calcium oxalate was

significantly reduced without altering brushite saturation. Also noted was a significant

increase of inhibitor activity secondary to increased urinary citrate and pyrophosphate,

thereby inhibiting the potential crystallization of calcium oxalate in the urine.

PATHOPHYSIOLOGY OF HYPERURICOSURIC

CALCIUM OXALATE NEPHROLITHIASIS

Hyperuricosuria is found in about 10% of patients with calcium oxalate nephrolithi-

asis. The features of hyperuricosuric calcium oxalate nephrolithiasis include elevated

urinary uric acid >600mg/d, a normal serum calcium level, normal urinary calcium and

oxalate levels, normal fasting and calcium load response, and urinary pH typically >5.5

(20,21).

Although excessive uric acid excretion can be found in primary gout, it may also be

seen in secondary conditions of purine overproduction (e.g., myeloproliferative disease,

glycogen storage disease and malignancy). Excessive dietary intake of purine-rich foods

is another potential cause for this condition. It is believed that monosodium urate is

formed in a supersaturated environment in hyperuricosuric patients. Monosodium urate

(colloidal or crystalline) may then initiate calcium stone formation through direct induc-

tion of heterogeneous nucleation of calcium oxalate or by adsorption of certain macro-

molecular inhibitors of stone formation (22).

MANAGEMENT OF HYPERURICOSURIC

CALCIUM OXALATE NEPHROLITHIASIS

Allopurinol

Allopurinol (300 mg/d), a xanthine oxidase inhibitor, is the drug of choice in

hyperuricosuric calcium oxalate nephrolithiasis resulting from uric acid overproduction

276 Tan and Preminger

because of its ability to reduce uric acid synthesis and lower urinary uric acid (23).

Besides reducing urate production and the serum urate concentration, allopurinol also

decreases urate excretion in urine. Its use in hyperuricosuria associated with excessive

dietary purine intake may be necessary if dietary purine restriction cannot be achieved.

Changes ensuing from restoration of normal urinary uric acid include an increase in the

urinary limit of metastability of calcium oxalate. Thus, the spontaneous nucleation of

calcium oxalate is retarded by treatment, probably via inhibition of monosodium urate-

induced calcium oxalate crystallization. Because sodium could exaggerate monosodium

urate-induced calcium oxalate crystallization, a moderate sodium restriction (100 meq/

d) is also advisable. The side effects from allopurinol are not common and these include

hypersensitivity reaction, skin rash, drowsiness, nausea and diarrhea.

Potassium Citrate

Potassium citrate represents an effective alternative to allopurinol in the treatment of

hyperuricosuria (24,25). Administration of potassium citrate (at a dose of 40-60 meq/d

in divided doses) to patients with hyperuricosuric calcium oxalate nephrolithiasis may

reduce the urinary saturation of calcium oxalate (by complexing calcium), and inhibit

urate-induced crystallization of calcium oxalate. Potassium citrate may be particularly

useful in patients with mild-to-moderate hyperuricosuria (<800 mg/d) in whom

hypocitraturia is also present. However, allopurinol is probably preferred in patients

with more marked hyperuricosuria, especially if hyperuricemia coexists.

PATHOPHYSIOLOGY OF HYPEROXALURIA

Hyperoxaluria is defined by urinary oxalate excretion in excess of 45 mg/d. A mild-

to-moderate elevation (45–80 mg/d) may be caused by dietary hyperoxaluria. At levels

>80 mg/d, the diagnosis of nephrolithiasis is likely caused by either enteric or primary

hyperoxaluria.

Dietary Hyperoxaluria

The majority (80–90%) of urinary oxalate is synthesized in the liver, whereas the rest

is derived from dietary oxalate or ascorbic acid (vitamin C). Therefore, dietary intake in

oxalate-rich foods or excessive ascorbic acid ingestion can contribute to hyperoxaluria

through intestinal absorption of oxalate. However, controversy persists regarding the

importance of dietary ascorbic acid. Recent studies have demonstrated that high doses

of vitamin C do not increase the risk of calcium oxalate stone disease. Ascorbate excre-

tion increases when vitamin C ingestion is initiated, but will level out after 24 h, suggest-

ing that once the metabolic pool is saturated, ingested ascorbic acid is excreted

unmetabolized in the urine (26,27). In addition, no association between serum ascorbic

acid levels and the prevalence of kidney stones has been found in women or men (28).

Moreover, a prospective study of 85,557 women with 14-yr follow up demonstrated that

vitamin C intake was not associated with risk of stone formation. Routine restriction of

vitamin C to prevent stone formation appears unwarranted (29). Studies suggest that a

daily intake of up to 4 gm of vitamin C can be allowed with no significant risk of stone

formation (30). However, recurrent stone formers and patients with renal failure who

have a defect in ascorbic acid or oxalate metabolism should probably restrict daily

vitamin C intakes to approx 100 mg