IN-DEPTH REVIEW

Etiology and Treatment of Urolithiasis Charles Y. C. Pak, MD • Nephrolithiasis is a heterogeneous disorder, with varying chemical composition and pathophysiologic background. Although kidney stones are generally composed of calcium oxalate or calcium phosphate, they may also consist of uric acid, magnesium-ammonium phosphate, or cystine. Stones develop from a wide variety of metabolic or environmental disturbances, including varying forms of hypercalciuria, hypocitraturia, undue urinary acidity, hyperuricosuria, hyperoxaluria, infection with urease-producing organisms, and cystinuria. The cause of stone formation may be ascertained in most patients using the reliable diagnostic protocols that are available for the identification of these disturbances. Effective medical treatments, capable of correcting underlying derangements, have been formulated. They include sodium cellulose phosphate, thiazide, and orthophosphate for hypercalciuric nephrolithiasis; potassium citrate for hypocitraturic calcium nephrolithiasis; acetohydroxamic acid for infection stones; and D-penicillamine and a-mercaptopropionylglycine for cystinuria. Using these treatments, new stone formation can now be prevented in most patients. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Nephrolithiasis; hypercalciuria; hypocitraturia.

N

EPHROLITHIASIS is a common disorder. Approximately 500,000 Americans suffer from stone episodes yearly, and up to 12 million Americans will develop stones in their lifetime. It is customarily believed that the southeastern United States is a "stone belt," with a high concentration of stone disease. However, a recent study, has shown that stone-forming patients residing in the stone belt carry environmental and metabolic risk factors identical in severity and frequency to those of patients residing elsewhere in the United States. I Stone disease is a surgical as well as a medical problem. When stones cause obstruction of the urinary tract, intractable pain, or bleeding, surgical removal may become mandatory. A medical prophylactic program is also indicated, since nephrolithiasis is characterized by a high rate of recurrence. Major progress has been made recently in the techniques of stone removal and in the medical prevention of new stone formation. The introduction of extracorporeal shock wave lithotripsi

has considerably reduced the morbidity of stone removal, often eliminating the need for surgery. Pathophysiological disturbances responsible for or associated with stone formation have been largely clarified. 3 It is now possible to prevent recurrence of stones in most patients, using a variety of treatment programs directed at correcting the underlying disturbances. Improvements in methods of stone removal have not diminished the need for the application of an effective prophylactic program. Despite this progress, many practicing physicians lack sufficient skills to apply an appropriate preventive program rationally. It is the objective of this review to provide them with a background knowledge that would be useful in the management of patients with stones. First, a detailed discussion of pathophysiology of nephrolithiasis will be given, since its understanding is critical for the selection of appropriate therapy. Second, practical guidelines in the diagnostic categorization of different causes of stones will be provided. Last, various therapeutic options for the prevention of stone formation will be discussed.

From the Center for Mineral Metabolism and Clinical Research. University of Texas Southwestern Medical Center at Dallas, Dallas, TX. Supported by US Public Health Service Grant No. POlDK20543. Address reprint requests to Charles Y. C. Pak, MD, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-8885. © 1991 by the National Kidney Foundation, Inc. 0272-6386/91/1806-0002$3.00;0

CLASSIFICATION OF NEPHROLITHIASIS

624

Kidney stones are heterogeneous with respect to chemical composition4 and pathophysiological background responsible for stone formation. 3 Most stones are calcareous. Such calcium-containing stones are composed of calcium oxalate, hydroxyapatite, and much less commonly brushite (CaHP04 • 2H 20) (Table 1). Less common are noncalcareous stones composed of uric

American Journal of Kidney Diseases, Vol XVIII. No 6 (December). 1991: pp 624-637

625

ETIOLOGY AND TREATMENT OF UROLITHIASIS

Table 1. Stones Composition and Corresponding Pathophysiology

Calcareous stones Calcium oxalate Hydroxyapatite Brushite Noncalcareous stones Uric acid Struvite Cystine Triamterene 2,8-dihydroxyadenine Silica

Relative Occurrence (%)

Causes

60

Hypercalciuria, hypocitraturia, undue urinary acidity, hyperuricosuria, hyperoxaluria Hypercalciuria, hypocitraturia, hyperuricosuria Hypercalciuria, hypocitraturia, hyperuricosuria

20 2

7 7

3 5 mmol/d [>200 mg/d]) on both restricted and random diets. Absorptive hypercalciuria type II has an exaggerated calciuric response to an oral calcium load, but normal urinary calcium on the restricted diet. Fasting hypercalciuria in the setting of normocalcemia does not prove the presence of renal hypercalciuria. Serum PTH must be elevated as well to diagnose renal hypercalciuria. Parathyroid function is normal in fasting hypercalciuria with normal serum PTH. Hyperuricosuria (> 15.0 mmol/d [>600 mg/d]) is present with calcium stones in hyperuricosuric calcium nephrolithiasis. Hypocitraturic calcium nephrolithiasis in the pure presentation refers to the condition in which hypocitraturia (urinary citrate < 1.7 mmol/d [6.8) in the absence of infection of the urinary tract. Incomplete renal tubular acidosis is characterized by normal serum electrolytes, but an impaired ability to acidify the urine following ammonium chloride load. Both complete and incomplete forms may be associated with hypercalciuria, hypocitraturia, calcium nephrolithiasis, and nephrocalcinosis. Stone

Table 2. Diagnostic Criteria

Serum calcium Phosphate PTH Urinary calcium Fasting 1-g calcium load 24-h (restricted diet) Oxalate Uric acid Citrate pH

AH-I

AH-II

RH

PHPT

PL

1,25

EH

HUCN

Idiop Hypocit

RTA

GO

N N N

N N N

N N

t

N

N N

t

N

t

N N

t

t

N N N

N N N

N N N

N N N

N

N

t t

t

t t t

t t t

t t t

t t t

N N N N

N N N N N

t

N N N N

N N N N

N N N N N

N N N N

t

N N N N

N N N N

N N N N

t

t t t

t

t t t

t

N N

t

N

N

t

N N

t t

NIt N

t

NOTE. Pure presentations are depicted. Abbreviations: AH-I, absorptive hypercalciuria type I; AH-II, absorptive hypercalciuria type II; RH, renal hypercalciuria; PHPT, primary hyperparathyroidism; PL, renal phosphate leak; 1,25, primary 1,25-(OH)2vitamin D excess; EH, enteric hyperoxaluria; HUCN, hyperuricosuric calcium nephrolithiasis; Idiop Hypocit, idiopathic hypocitraturia; RTA, distal renal tubular acidosiS; GD, gouty diathesiS; N, normal; t, increase; t, decrease.

632

analysis typically shows preponderance of hydroxyapatite with calcium oxalate as a minor constituent. Chronic diarrheal states capable of producing hypocitraturia and calcium nephrolithiasis include ileal disease or ileal resection, gastrectomy, ulcerative colitis, and colectomy. The degree of hypocitraturia is generally proportional to the severity of intestinal fluid loss. In severe diarrheal states, urinary citrate may be very low «0.3 mmoljd [ 7.5). Struvite stones are radiopaque and sometimes may attain a large (staghorn) size; they usually occur as mixtures with calcium carbonate apatite or less commonly with calcium oxalate. Simple Evaluation

A multichannel blood screen should be performed to identify primary hyperparathyroidism (from hypercalcemia), renal phosphate leak (from electrolytes), and gouty diathesis (from hyperur-

CHARLES Y. C. PAK

icemia). A fresh spot urine sample should be cultured for urea-splitting organisms and examined for pH (with a pH electrode). A qualitative examination of urine for cystine provides a clue to the presence of cystinuria. Available stone should be analyzed for stone composition. A careful history should be taken for predisposing conditions, medications, dietary aberrations, and insufficient fluid intake. MEDICAL THERAPY OF NEPHROLITHIASIS

Conservative Management

The primary objective of medical treatment is the prevention of recurrent stone formation. All patients with stones should be offered a conservative treatment program. It alone may' be necessary in patients with mild disease, those with a single stone episode, or those without metabolic disturbance. It should always accompany specific drug therapies in patients with more severe recurrent disease. Fluid intake should be sufficient to assure a minimum urine level of 2 L/d. Dietary sodium restriction (100 mEq/d) is recommended, since a high sodium intake increases urinary calcium, lowers citrate, promotes sodium urate-induced calcium oxalate crystallization, and blunts hypocalciuric response to thiazide. Oxalate restriction is useful in all patients with calcium oxalate stones, and is essential in patients taking sodium cellulose phosphate or in those with intestinal hyperabsorption of oxalate (enteric hyperoxaluria). Dietary calcium restriction is recommended in absorptive hypercalciuria (unless bone loss is present) and in primary hyperparathyroidism with intestinal hyperabsorption of calcium. A moderate restriction of animal proteins may be useful, especially in the presence of hyperuricosuria orhypocitraturia. Specific Treatment

A more specific medical treatment is indicated in patients who continue to form stones or who are recalcitrant to conservative therapy. Treatment of each metabolic condition will be discussed (Table 3). Primary hyperparathyroidism. Parathyroidectomy is the optimal treatment. There is no established medical treatment for the nephrolithiasis of this condition. Although orthophosphates have been recommended for disease of mild to

633

ETIOLOGY AND TREATMENT OF UROLITHIASIS Table 3. Treatment Programs Indication Primary hyperparathyroidism

Absorptive hypercalciuria type I

Parathyroidectomy

• Urinary Ca 4- 1.25-(OH),O

Orthophosphate

Allopurinol

• Urinary Ca t Urinary citrate and pyrophosphate • Intestinal Ca absorption • Urinary Ca = Intestinal Ca absorption Urinary Ca (transient) 4- Urinary citrate +Intestinal Ca absorption 4- Urinary Ca +Urinary Ca (sustained) +Intestinal Ca absorption +1.25(OH)2D +Intestinal Ca absorption +Urinary Ca t Urinary citrate and pyrophosphate .. Urinary uric acid

Potassium citrate

t

• Oxalate intake Potassium citrate

• Urinary t Urinary t Urinary t Urinary

Sodium cellulose phosphate Thiazide Low Ca diet

Absorptive hypercalciuria type II Renal hypercalciuria

Thiazide

Renal phosphate leak

Orthophosphate

Hyperuricosuric Ca nephrolithiasis

Enteric hyperoxaluria

Masgnesium gluconate Calcium citrate Hypocitraturic Ca nephrolithiasis

Potassium citrate

Gouty diathesis

Potassium citrate

Cystinuria

Penicillamine or MPG

Infection stones

Acetohydroxamic acid

Abbreviations: • • decrease;

Physicochemical Action

Physiological Action

Treatment

+

t

Urinary citrate

oxalate citrate pH Mg

Urinary citrate

t Urinary pH

t t

urinary citrate Urinary pH +/= Urinary Ca Urinary pH +Undissociated uric acid Urinary citrate Mixed disulfide with cysteine +Urinary cystine Urease activity

t t

+ +NW +pH'

+Urinary saturation of calcium salts • Promoter activity • Urinary saturation of Ca oxalate Inhibitor activity • Urinary saturation of Ca oxalate • Ca phosphate saturation +Urinary saturation of Ca salts

t

.. Urinary saturation of Ca oxalate and Ca phosphate • Urinary saturation 01 Ca salts

+Urinary saturation of Ca oxalate t

Inhibitor activity

.. Urate-induced crystallization 01 Ca salts +Urinary saturation of 'Ca oxalate +Urate-induced crystallization of Ca salts +Urinary saturation of Ca oxalate .. Urinary saturation of Ca oxalate t Inhibitor activity .. Urinary saturation 01 Ca oxalate

t

Inhibitor activity

+Urinary saturation t

Inhibitor activity

t

Urinary saturation of uric acid

+Ca oxalate crystallization

+Urinary saturation of cystine

+Urinary saturation of struvite

+. increase; =. no change.

moderate severity,39 their safety and efficacy have not yet been proved. The use of estrogen in postmenopausal women with this condition has shown some promise. 4o A medical approach should be applied only when parathyroid surgery cannot be undertaken. Absorptive hypercaiciuria. There is no treatment that corrects the basic abnormality of increased calcium absorption. When administered orally, sodium cellulose phosphate binds calcium, inhibits calcium absorption, and lowers urinary calcium. 41 However, it may also lower urinary magnesium (by binding magnesium) and enhance oxalate excretion (by reducing complexation of oxalate by divalent cations). Thiazide is ineffective in restoring normal calcium absorption. Thus, hypocalciuric action, disclosed during first 2 years of treatment, may become attenuated thereafter.

The following guidelines in the use of these two agents are recommended until more selective therapies are found. Sodium cellulose phosphate is appropriate for patients with severe absorptive hypercalciuria type I (urinary calcium> 8.75 mmol/d [>350 mgjd]) and for patients resistant to or intolerant of thiazide therapy. In patients at risk for bone disease (growing children, postmenopausal women, or elderly men), thiazide is the first choice. When thiazide becomes ineffective in lowering urinary calcium, this treatment may be temporarily substituted by sodium cellulose phosphate or orthophosphate (for -6 months). Restoration of hypocalciuric response to thiazide may then ensue, permitting resumption of thiazide therapy. Potassium citrate (eg, 15 to 20 mEq twice a day) should be given along with thiazide (eg, trichlormethiazide 4 mgjd) to prevent hypokalemia and to augment citrate excretion.42

634

In absorptive hypercalciuria type II, a low calcium diet (10 to 15 mmol/d [400 to 600 mg/d]) and a high fluid intake (sufficient to maintain urine output >2 L/d) are appropriate, since normocalciuria can be restored by dietary calcium restriction alone and because increased urine volume reduces urinary saturation of calcium oxalate, brushite, and monosodium urate, and inhibits spontaneous nucleation of calcium oxalate. Renal hypercalciuria. Thiazide is the treatment of choice. This agent corrects the renal leak of calcium directly by augmenting calcium reabsorption in the distal tubule and by causing extracellular volume depletion, which stimulates proximal tubular reabsorption of calcium. The ensuing correction of secondary hyperparathyroidism restores to normal serum 1,25-(OH)zvitamin D and intestinal calcium absorption. 17 These effects are shared by hydrochlorothiazide (50 mg twice a day), chlorthalidone (50 mg/d), and trichlormethiazide (4 mg/d). Trichlormethiazide is generally best tolerated. Potassium citrate supplementation (15 to 20 mEq twice a day) is recommended to prevent hypokalemia and attendant hypocitraturia. Concurrent use of triamterene, a potassium-sparing agent, should be undertaken with caution because of the possibility of triamterene stone formation. 43 Amilioride may be used with thiazide, since it may also exert a hypocalciuric action, exaggerate the hypocalciuric action of thiazide, and may prevent hypokalemia. 44 However, amiloride does not augment citrate excretion, and may cause hyperkalemia if potassium supplements are also given. Thus, in patients with hypercalciuric nephrolithiasis and hypocitraturia, in whom the use of potassium citrate is contemplated, it is probably wise to use thiazide alone without a potassium-sparing diuretic. Renal phosphate leak. Orthophosphate (neutral or alkaline salt of sodium and/or potassium, 0.5 g phosphorus three to four times per day) appears to be a logical treatment because of its potential for inhibiting 1,25-(OH)zvitamin D syntheSiS. II ,4S Indomethacin (25 mg three times a day) may control hypercalciuria in documented PGEz excess. In other miscellaneous conditions, thiazide with potassium citrate is probably appropriate.

Nonhypercalciuric Calcium Nephrolithiasis Renal tubular acidosis (distal). Potassium citrate therapy is capable of correcting both metabolic acidosis and hypokalemia. 46 Moreover, it

CHARLES Y. C. PAK

may restore normal urinary citrate, although large doses (up to 120 mEq/d) may be required in severe acidotic states. Urinary calcium typically declines with the correction of acidosis. The overall increase in urinary pH is small, since urinary pH is high to begin with; the urinary pH is generally less than 7.5 during treatment unless a urinary tract infection is present. Thus, potassium citrate treatment produces a sustained decline in the urinary saturation of calcium oxalate (from reduction in urinary calcium and rise in citrate complexation of calcium). The urinary saturation of calcium phosphate does not increase because the rise in phosphate dissociation is relatively small (due to a modest increase in pH) and is adequately compensated. by a decline in ionic calcium concentration. Moreover, inhibitor activity against the crystallization of calcium oxalate and calcium phosphate is augmented due to the direct action of citrate. The decrease in urinary calcium is generally accompanied by an increase in intestinal calcium absorption, averting bone 10ss.47 Chronic diarrheal syndrome. In patients with mild to moderate severity of intestinal fluid loss in whom hypocitraturia is not severe (urinary citrate in the range of 0.5 to 1.5 mmol/d [100 to 300 mg/d]), potassium citrate (40 to 60 mEq/d in three to four divided doses in a liquid form) is generally effective in restoring normal urinary citrate and pH. Urinary calcium generally remains low. In those with severe hypocitraturia (with urinary citrate < 0.5 mmol/d [500 mgjd]), in whom conservative management alone is not likely to be effective, penicillamine therapy (together with conservative measures) may be begun. Penicillamine shares with cysteine a free sulfhydryl group. Thus, it undergoes thioldisulfide exchange with cystine to form penicillamine-cysteine disulfide, which is much more soluble than cystine. Following oral administration, a sufficient amount of penicillamine can be excreted in urine to complex cysteine and thereby lower cystine excretion. Unfortunately, penicillamine therapy is associated with frequent, and sometimes severe, side effects, including nephrotic syndrome, dermatitis, and pancytopenia. Alpha-mercaptopropionylglycine (MPG) shares with penicillamine similar biochemical and clinical action. 50 However, it has a lower toxicity profile than penicillamine. Injection Stones Iflong-standing control of infection with ureasplitting organisms can be achieved, new stone formation may be averted, and some existing

636

CHARLES Y. C. PAK

stones may be dissolved. Unfortunately, such control is difficult to obtain with antibiotic therapy. If a struvite stone is present, it is difficult to eradicate infection completely because the stone may harbor the organisms within its interstices. Even if "sterilization" of urine can be achieved by antibiotic therapy, reinfection could occur from organisms harbored by the stones. For this reason, surgical removal of the struvite stones is usually recommended. Acetohydroxamic acid, a urease inhibitor, reduces urinary saturation of struvite by preventing the formation of ammonium and hydroxyl ions. 51 It may prevent stone growth and sometimes cause dissolution of existing stones. However, it may cause hemolytic anemia, thrombophlebitis, and

nonspecific neurological symptoms (disorientation, tremulousness, and headache). Guidelines for Follow-Up

A careful follow-up is mandatory after initiation of therapy, in order to gauge treatment response and to detect side effects of therapy. We recommend that patients be routinely monitored every 4 months initially. At each visit, a careful history should be taken for stone episodes, complications of treatment, and compliance to drug therapy or dietary recommendations. Key urinary risk factors should be measured. When a satisfactory control is obtained, patients can be monitored less frequently (eg, every 6 to 12 months).

REFERENCES I. Harvey JA, Hill KD, Pak CYC: Similarity of urinary risk factors among stone-forming patients in five regions of the United States. J Lith Stone Dis 2:124-132,1990 2. Chaussy CH, Brendel W, Schmiedt E, et al: Extracorporeally induced destruction of kidney stones by shock waves. Lancet 2:1265-1268, 1980 3. Pak CYC: Medical management of nephrolithiasis in Dallas: Update 1987. J Urol 140:461-467, 1988 4. Prien EL, Prien EL Jr: Composition and structure of urinary stone. Am J Med 45:654-672, 1968 5. Pak CYC, Sakhaee K, Fuller e: Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int 30:422-428, 1986 6. Griffith DP, Musher DM: Prevention of infected urinary stones by urease inhibition. Invest Urol 11 :228-233, 1973 7. Zerwekh JE, Hwang TIS, Poindexter J, et al: Modulation by calcium of the inhibitor activity of citrate, chondroitin sulfate and urinary glycoprotein against calcium oxalate crystallization. Kidney Int 33: 1005-1008, 1988 8. Pak CYe: Pathogenesis of hypercalciuria, in Peck WA (ed): Bone and Mineral Research, vol 4. New York, NY, Elsevier, 1985, pp 9. Pak CYC, Ohata M, Lawrence EC, et al: The hypercalciurias: Causes, parathyroid functions and diagnostic criteria. J C1in Invest 54:387-400, 1974 10. Kaplan RA, Haussler MR, Deftos U, et al: The role of 1a,25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. JClin Invest 59:756-760, 1977 11. Barilla DE, Zerwekh JE, Pak CYe: A critical evaluation of the role of phosphate in the pathogenesis of absorptive hypercalciuria. Miner Electrolyte Metab 2:302-309, 1979 12. Zerwekh JE, Pak CYC, Kaplan RA, et a1: Pathogenetic role of la,25-dihydroxyvitamin D in sarcoidosis and absorptive hypercalciuria: Different response to prednisolone therapy. J C1in Endocrinol Metab 51 :381-386, 1980 13. Coe FL, Parks, JH, Moore ES: Familial idiopathic hypercalciuria. N Engl J Med 300:337-340, 1979 14. Pak CYC, Nicar MJ, Krejs GJ: Intestinal absorption of calcium, magnesium, phosphate and oxalate: Deviation

from normal in idiopathic urolithiasis, in Schwille PO, Smith, LH, Robertson WG, et al (eds): Urolithiasis and Related Clinical Research. New York, NY, Plenum, 1985, pp 127-133 15. Coe FL, Canterbury JM, Firpo JJ, et al: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 52:134-141, 1973 16. Pak CYe: Physiological basis for absorptive and renal hypercalciurias. Am J Physiol 237:F415-F423, 1979 17. Zerwekh JE, Pak CYC: Selective effects of thiazide therapy on serum 1a,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias. Metabolism 29: 13-17, 1980 18. Broadus AE, Horst RL, Lang R, et al: The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. N Engl J Med 302:421-426, 1980 19. Patron P, Gardin J-P, Paillard M: Renal mass and reserve of vitamin: Determinants of plasma 1,25(OH)zD3 in primary hyperparathyroidism. Kidney Int 31:1174-1180, 1987 20. Pak CYC, Nicar MJ, Peterson R, et al: A lack of unique pathophysiologic background for nephrolithiasis of primary hyperparathyroidism. J Clin Endocrinol Metab 53:536-542, 1981 21 . Pacifici R, Rothstein M, Rifas L, et al: Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria. J Clin Endocrinol Metab 71 : 138-145, 1990 22. Insogna KL, Broadus AE, Dreyer BE, et al: Elevated production rate of 1,25-dihydroxyvitamin D in patients with absorptive hypercalciuria. J Clin Endocrinol Metab 61:490495, 1985 23. Gray RW, Wilz DR, Caldas AE, et al: The importance of phosphate in regulating plasma 1,25-(OH)2vitamin D levels in humans: Studies in healthy subjects, in calcium-stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 45:299-306, 1977 24. Coe FL, Favus MJ, Crockett T, et al: Effects of lowcalcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)zD3Ievels in patients with idiopathic hypercalciuria and in normal SUbjects. Am J Med 72:25-32, 1982

ETIOLOGY AND TREATMENT OF UROLITHIASIS

25. Buck AC, Lote CJ, Sampson WF: The influence of renal prostaglandins on urinary calcium excretion in idiopathic urolithiasis. J UroI129:421-426, 1983 26. Pak CYC: Citrate and renal calculi. Miner Electrolyte Metab 13:257-266, 1987 27. Jenkins AD, Dousa TP, Smith LH: Transport of citrate across renal brush border membrane: effects of dietary acid and alkali loading. Am J Physiol 249:F590-F595, 1985 28. Rudman D, Dedonis JL, Fountain MT, et a1: Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med 303:657-661, 1980 29. Fourman P, Robinson JR: Diminished urinary excretion of citrate during deficiencies of potassium in man. Lancet 2:656-657, 1953 30. Breslau NA, Brinkley L, Hill KO, et al: Relationship role of animal protein-rich diet to kidney stone formation and calcium metabolism. J C1in Endocrinol Metab 66:140-146, 1988 31. Cowley DM, McWhinney BC, Brown JM, et al: Chemical factors important to calcium nephrolithiasis: Evidence for impaired hydroxycarboxylic acid absorption causing hyperoxaluria. Clin Chern 33:243-247, 1987 32. Coe FL: Uric acid and calcium oxalate nephrolithiasis. Kidney Int 24:392-403, 1983 33. Coe FL: Hyperuricosuric calcium oxalate nephrolithiasis. Kidney Int 13:418-426, 1978 34. Pak CYC, Waters 0, Arnold L, et al: Mechanism for calcium urolithiasis among patients with hyperuricosuria: Supersaturation of urine with respect to monosodium urate. J Clin Invest 59:426-432, 1977 35. Smith LH, Fromm H, Hofmann AF: Acquired hyperoxaluria, nephrolithiasis and intestinal disease: Description ofa syndrome. N Engl J Med 286:1371-1374,1972 36. Smith LH: Enteric hyperoxaluria and other hyperoxaluric states. Nephrology 5:43-71, 1980 37. Pak CYC, Kaplan RA, Bone H, et a1: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med 292:497-500, 1975 38. Pak CYC, Britton F, Peterson R, et a1: Ambulatory evaluation of nephrolithiasis: Classification, clinical presentation and diagnostic criteria. Am J Med 69: 19-30, 1980 39. Broadus AE, Magee JS, Mallette LE, et al: A detailed evaluation of oral phosphate therapy in selected patients with

637 primary hyperparathyroidism. J Clin Endocrinol Metab 56: 953-961, 1983 40. Selby PL, Peacock M: Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. N Engl Med 314:1481-1485, 1986 41. Pak CYC: A cautious use of sodium cellulose phosphate in the management of calcium nephrolithiasis. Invest Urol 19:187-190, 1981 42. Pak CYC, Peterson R, Sakhaee K, et al: Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med 78:284-288, 1985 43. Ettinger B, Oldroyd NO, Sorge F: Triamterene nephrolithiasis. JAMA 244:2443-2445, 1980 44. Leppla D, Browne R, Hill K, et al: Effect of amiloride with or without hydrochlorothiazide on urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab 57:920924, 1983 45. van den Berg CJ, Kumar R, Wilson DM; et al: Orthophosphate therapy decreases urinary calcium excretion and serum 1,25-dihydroxyvitamin D concentrations in idiopathic hypercalciuria. J Clin Endocrinol Metab 51 :998-100 1, 1980 46. Preminger GM, Sakhaee K, Skuria C, et a1: Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 134:20-23, 1985 47. Preminger GM, Sakhaee K, Pak CYe: Hypercalciuria and altered intestinal calcium absorption occurring independently of vitamin D in incomplete distal renal tubular acidosis. Metabolism 36:176-179,1987 48. Pak CYC, Fuller C: Idiopathic hypocitraturic calcium oxalate nephrolithiasis successfully treated with potassium citrate. Ann Intern Med 104:33-37, 1986 49. Sakhaee K, Nicar M, Hill K, et al: Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salt. Kidney Int 24:348-352, 1983 50. Pak CYC, Fuller C, Sakhaee K, et al: Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine (Thiola). J Urol 136:1003-1008, 1986 51. Griffith DP: Struvite stones. Kidney Int 13:372-382, 1978