University of Rochester School of Medicine and Dentistry, Nephrologv Unit, Strong Meniorial Hospital, Rochester, New York.

DISEASEOF THE MONTH Nephrolithiasi s DAVID A. BUSHINSKY University of Rochester School of Medicine and Dentistry, Nephrologv Unit, Strong Meniorial Hospital, Rochester, New York. The incidence of nephrolithiasis appears to be slightly in excess of one case per 1 000 patients per year and has been slowly increasing in recent decades ( 1,2). Kidney stones often cause severe pain, which may lead to emergent hospitalization, shock-wave lithotripsy, and/or surgery. An understanding of the mechanisms involved in kidney stone formation leads to rational treatment which has been documented to decrease the incidence of nephrobithiasis and its associated morbidity. Urinary Saturation Kidney stones are generally composed of calcium salts, uric acid, magnesium ammonium phosphate (struvite), or cystine (1,3) (Table 1). Stones form in urine that is supersaturated with respect to the ionic components of the specific stone. and saturation is dependent on chemical free ion activities. The chemical free ion activities of the components of a stone, in a solution in which the stone will neither grow nor dissolve, is at the equilibrium solubility product. A decrease in the free ion activity will cause the urine to become undersaturated, a state in which the stone will not grow and may even dissolve. An increase in the free ion activity will cause the urine to become supersaturated, a state that would favor a stone to form or increase in size. The chemical free ion activity of the components of the stone are influenced by many factors, including the concentration of the relevant ions, urine ph, and complexation with substances in the urine. The chemical free ion activity is directly related to ion concentration. Ion concentration is a function of how much of the particular ion is excreted in the volume of urine. Increased urinary ion excretion and decreased urine volume will both increase free ion activity and favor stone formation and growth. Urine ph is particularly important with respect to uric acid supersaturation. Citrate forms soluble complexes with calcium and will thus reduce its free ion activity. Stone Formation and Growth Kidney stones can form and increase in size through either homogeneous or heterogeneous nucleation ( I,4). During ho- Correspondence to Dr. David A. Bushinsky. Professor of Medicine and of Pharmacology and Physiology. University of Rochester School of Medicine and Dentistry. Chief of Nephrobogy Unit. Strong Memorial Hospital. 601 Elmwood Avenue, Box 675. Rochester, NY 14642. 1046-6673/0905-09 17$03.00/0 Journal of the American Society of Nephrobogy Copyright U 1998 by the American Society of Nephrobogy mogeneous nucleation, increasing chemical free ion activity leads to supersaturation with respect to a solid phase. Once this supersaturation reaches the formation product, the ions form clusters that can increase in size to form a permanent solid phase. With heterogeneous nucleation, crystal growth occurs on the surface of a dissimilar but complementary crystal or on another, generally foreign. substance. In vivo, heterogeneous nucleation predominates over homogeneous nucleation because the presence of a solid phase allows for crystal growth at a lower level of supersaturation, a so-called metastable solution. Microscopic crystals take longer to grow into clinically significant stones than the calculated passage time for fluid through the renal tubule (5). Crystals appear to adhere to tubular cells allowing time for further growth (6). Urine from stone formers generally is more supersaturated than urine from non-stone formers ( 1.2). However, despite similar degrees of supersaturation, some people form stones, whereas others do not. This may be due to the presence of inhibitors of crystallization. Citrate, uropontin, nephrocalcin, and pyrophosphate inhibit the formation of calcium-containing crystals (7). Although some studies have shown a decrease in inhibitor activity when the urine of stone-forming patients is compared with that of control subjects, the influence of abnormalities in the composition or amount of inhibitors in the occurrence or frequency of stone formation has not been determined. Clinicians generally determine a patient s potential for stone formation by measuring the rates of urine solute excretion, in mass per unit time, of the principal components of stones. However, it is clear that the critical determinant for crystallization is urine supersaturation and not the absolute quantity of ions excreted over a period of time ( 1 ). Computer programs are now available, such as EQUIL, that calculate saturation from measured concentrations and should be used for a more accurate determination of the lithiasis risk (8-10). Even with sophisticated calculations of saturation, variations in hourly urine output of both water and solute dictate that any mean collection will be an underestimation of the maximum supersaturation. Patient Evaluation All patients who form their first. single stone should be evaluated as suggested in Table 2 ( 1 1 ). All stones should be analyzed and if a patient forms only a single stone, then 24-h urine testing is not recommended. The emphasis is to understand whether medical or environmental risk factors predispose the patient to stone formation. Patients who form a second stone, those whose stones are

918 Journal of the American Society of Nephrology Table 1. Types and percentages of renal stones Type Percentage Calcium oxalate and 37 calcium phosphate Calcium oxalate 26 Calcium phosphate 7 Uric acid S Struvite 22 Cystine 2 increasing in size, and all children with even a single stone should undergo a more complete evaluation. These patients should be studied as recommended for the single stone evabuation and, in addition, have a workup as suggested in Table 3 ( 1 1 ). The cornerstone of this more extensive evaluation is the 24-h urine collection. Two or three 24-h urine collections are generally recommended while the patient is eating his normal diet and taking his usual medications. Determinations of saturation should be used for initial management and to guide Table 2. Approach to patients with a single stone Collect and analyze all stones History medical risk factors family history malignant neoplasm skeletal disease inflammatory bowel disease intestinal bypass urinary tract infection environmental risk factors fluid restriction urine volume diet climate occupation immobilization medications Physical examination Laboratory analysis urinalysis ± culture urine for cystine blood calcium ± parathyroid hormone phosphorus uric acid electrolytes creatinine Radiobogic analysis kidney, ureters, and bladder ± intravenous urography ± tomograms Table 3. Approach to children and patients with a second or multiple stones or growing stones As for single stone, plus: 24-h urine volume ph calcium phosphate sodium uric oxalate citrate acid creatinine repeat 24-h urine to monitor compliance and effectiveness of treatment specialized testing is not recommended for most patients therapy. Specialized testing is not recommended for most patients with nephrolithiasis, even those with multiple stones. CALCIUM STONES Approximately 70% of all kidney stones contain calcium and are composed of calcium oxalate or calcium phosphate or both (Table 1 ). Pure calcium oxalate stones occur more frequently than pure calcium phosphate stones. Once a patient forms a calcium-containing stone, another stone will generally form in less than 7 years, with a decreasing time interval to subsequent stone events (3). Pregnancy increases urine calcium excretion but does not increase stone formation ( 12). Calcium stones may form in urine that is supersaturated secondary to excess calcium, oxalate, or uric acid excretion, or the stones may form without a discernible cause. Excess Calcium Excretion Idiopathic Hvpercalciuria Patients with idiopathic hypercalciuria have a normal concentration of serum calcium; however, their urine calcium excretion exceeds the maximum of 300 mg/24 h in men, 250 mg/24 h in women, or 4 mg/kg in either sex (13). These patients lack a definable disorder that would cause the observed elevation of urine calcium excretion. Idiopathic hypercalciuria tends to be familial, it is more prevalent in men, and initial stone formation often occurs in the third decade of life. Although the cause of idiopathic hypercalciuria is obviously not known, it may result from disordered regulation of calcium handling at sites where large fluxes of calcium must be tightly regulated (1,14-16) (Figure 1). This disordered regulation may occur in the intestine, the kidney, or in the bone, resulting in an increase in urine calcium excretion (Table 4). Increased intestinal calcium absorption may occur either by a direct mechanism or through excess 1,25-dihydroxyvitamin D3 ( 1,2S(OH),D3)-mediated calcium absorption. The increase in intestinal calcium absorption will result in a slight increase in serum calcium, a fall in parathyroid hormone, and an increase in the calcium filtered by the gbomerulus and entering the renal

Nephrolithiasis 919 Calcium Da aca 4 mmoles ECFa 25 mmoles frca 266 mmoles 270 mmoles GFR 16 mmoles Brca 14 mmoles Bfa 14 mmoles Kidney Intestine Uca 4 mmoles 19,900 mmoles Figure 1. Flux of calcium within compartments in the body (40). Ca, calcium; D. dietary: a, absorption; ECF, extracellular fluid: Br. bone resorption; Bf, bone formation: fr. fractional reabsorption: U. urine. 1 mmob of calcium equals 40 mg of calcium. tubule. Because parathyroid hormone increases renal tubule calcium reabsorption. a fall in parathyroid hormone coupled to an increase in the filtered load of calcium will result in hypercalciuria. Decreased renal reabsorption of either calcium or phosphorus. the latter through a hypophosphatemia-induced increase in l,25(oh),d3, will result in hypercalcemia. A primary increase in bone mineral resorption will increase serum calcium, suppress parathyroid hormone, and result in hypercalciuria. Patients with idiopathic hypercalciuria cannot easily be characterized into any of these specific diagnostic groups ( 13). Although there are expected serum and urine values for the alternative mechanisms of hypercalciuria (Table 4). in formal metabolic studies there has been enough collection-to-collection variation among individual patients to preclude specific categorization (17). Among large groups of patients, there appear to be smooth transitions in various metabolic parameters between the patients, which again precludes biologically significant grouping. However, several general concepts have emerged from studies of patients with idiopathic hypercalciuria. Most investigators agree that patients have an increase in net intestinal calcium absorption, have increased 1,25(OH)1D3 levels. have increased intestinal calcium absorption relative to the l,25(oh),d3 levels, and have mild decreases in bone mineral density (1,14,18). These abnormalities appear to point to a systemic disregubation ofthe effect of l.2s(oh),d3 acting on the intestine, bone, and possibly kidney. Genetic Hypercalciuric Stone-Forming Rats. To more fully understand idiopathic hypercalciuria in humans, we have developed an animal model of this disorder (15,16,19-25). Through more than 46 generations of successive inbreeding of the most hypercalciuric progeny of hypercalciuria Sprague Dawley rats, we have established a strain of rats, each of which excrete abnormally barge amounts of urinary calcium (Figure 2). As in humans, the principal mechanism for the excessive calcium excretion in these rats appears to be an increase in intestinal calcium absorption (IS). The increased intestinal calcium absorption appears to be mediated not by an increase in the serum level of l.25(oh)2d3. but by an increase in the number of intestinal vitamin D receptors (25). When these hypercalciuric rats are fed a very low calcium diet, their urine calcium excretion remains elevated compared with that of similarly treated control rats, indicating a defect in renal cabcium reabsorption and/or an increase in bone resorption (24), again similar to observations in humans (2). When exposed to increasing amounts of 1.2S(OH),D1 (22), the bone of these hypercalciuric rats releases more calcium compared with bone of control rats. In addition, a primary defect in renal calcium reabsorption is observed during clearance studies (2 1 ). We have shown that both the bone and kidney of hypercalciuric

920 Journal of the American Society of Nephrology Table 4. Expected serum and urine values in alternative mechanisms of idiopathic hypercalciuria normal. Parameter Increa sed Iiitestinal Ca Absorption Decreased Ren al Reabsorption Direct Excess l.25(oh),d Calcium Phosphorus Enhanced Bone Deminerabization Ca absorption Primary I I Serum l,2s(oh),d Primary f )f. j, SerumPTH 1 Bone Ca nb nl to ni to j. nl to Primary J, Fasting serum Ca nl to ni to ni to nl to Fasting serum P nb nl to ni to ni to Fasting urine Ca ni Primary I I Urine Ca after low Ca diet nl nl to I I nl to I I a Ca. calciuiii: l.2s(oh)2d. 1.25 dihydroxyvitamin D; PTH. parathyroid hormone: P. phosphorus:. increase:. decrease: ni. rats also have an increased number of vitamin D receptors (22,25). Thus, these hypercalciuric rats appear to have a systemic abnormality in calcium homeostasis: they absorb more intestinal calcium. they resorb more bone. and they fail to adequately reabsorb filtered calcium. Because each of these hypercalciuric rats forms renal stones. we have termed the rats genetic hypercalciuric stone-forming (GHS) rats (16.19). Additional studies in GHS rats may help elucidate the mechanism of idiopathic hypercalciuria in humans. Treatment. The treatment of patients with idiopathic hypercalciuria involves reduction of urine calcium excretion, especially using long-acting thiazide diuretics, in association with increasing fluid intake. both in an effort to decrease supersaturation with respect to the calcium-containing solid phases (2,3,13.14). Oral fluids, especially water, should be increased so that patients excrete more than 2 L of urine each day. and periods of dehydration must be avoided. Most clinicians use a long-acting thiazide diuretic such as chlorthalidone to reduce calcium excretion. Indapamide may he preferable in patients at risk for arterial plaque formation because it does not increase serum lipids. Patients should be monitored for hypokalemia and. if necessary, supplemented with potassium or a potassium-sparing diuretic such as amiloride. Triamterene should be avoided as it may, itself, cause stones. Limitation of sodium and protein intake has theoretical advantages in decreasing urine calcium excretion. Limitation of calcium intake. in general, is not prudent because intestinal calcium will not be present to bind oxalate, resulting in enhanced oxalate absorption, excretion, and an increased propensity for stone formation. In a large epidemiologic study, decreased calcium intake was associated with increased stone formation (26). In addition, patients with nephrolithiasis are often found to have decreased bone mineral density, and limitation of calcium intake could potentially worsen this osteopenia ( 14). For these reasons, age- and gender-appropriate cabcium intake should be maintained. Often, the recommendation that the patient consume calcium requires extensive reeduca- E 8 C.) 6 a) - 2 0 0 4 10 19 40 46 GHS Generation Figure 2. Urine calcium excretion in control rats (generation 0) and in selected subsequent generations of genetic hypercalciuric stone-forming (GHS) rats. All rats were fed a similar diet before collecting two successive 24-h urines. Urine calcium excretion at generation 0 is plotted as the mean + 2 SD. whereas all other generations are plotted as the mean + SEM. Urine calcium excretion fcr all generations is greater than that observed in generation 0.

Nephrolithiasis 921 tion, because many have been advised, on numerous occasions, to studiously avoid calcium. Hormonal Hypercalciuria Patients with hyperparathyroidism have an elevated serum calcium concentration and urine calcium excretion and a decrease in serum phosphorus concentration due to an increase in the serum level of parathyroid hormone (27). The elevation in serum calcium may be very slight and may be in the upper range of normal; measurement of ionized calcium is often helpful to support the diagnoses. Especially in the presence of any degree of renal insufficiency, it is important to use the newer, immunoradiornetric assays to determine the serum level of parathyroid hormone, because older methods may give false elevations due to the accumulation of biologically inactive metabolites (28). This disorder is most common in elderly women, and at surgery they are generally found to have a single parathyroid adenoma (29). Patients with hyperparathyroidism most commonly form hydroxyapatite or calcium oxabate stones. Parathyroid hormone increases renal tubular calcium reabsorption. increases bone resorption, and increases the synthesis of 1,2S(OH),D3 (27). Excess, unregulated secretion of parathyroid hormone will result in hypercalcemia leading to an increase in the filtered load of calcium. When the increased filtered load of calcium exceeds threshold for renal tubule calcium reabsorption, which is increased by parathyroid hormone, hypercalciuria ensues. Parathyroid hormone also decreases the threshold for renal tubule phosphate reabsorption, resulting in hyperphosphaturia and hypophosphaternia despite the increased 1,25(OH),D3-mediated phosphate absorption. A reduction in serum phosphate results in further elevations of I,25(OH),D3-mediated calcium absorption, worsening the hypercalcemia and hypercalciuria. There are other hormonalby mediated. hypercalcemic disorders that can occasionally lead to stone formation. Granubomatous tissue found in sarcoidosis and tuberculosis converts 25- hydroxyvitamin D3 to I,2S-dihydroxyvitamin D3, resulting in hypercalcemia and hypercalciuria; however, levels of parathyroid hormone are depressed (30). Excess vitamin D supplementation, especially with ample calcium intake, will result in hypercalciuria. Levels of parathyroid hormone again will be depressed. Lithium therapy may directly increase parathyroid hormone secretion and result in hypercalcemia and hypercalciuria. Malignant cells can secrete parathyroid hormone-related peptide, which acts in a similar manner to parathyroid hormone; however, it is not detected on standard parathyroid hormone assays (3 1 ). Specific assays for parathyroid hormonerelated peptide are currently available. Renal Tubular Acidosis Approximately two-thirds of patients with classical distal renal tubular acidosis (type I). either of the spontaneous or inherited variety, appear to have nephrocalcinosis or nephrolithiasis or both (32). The stones are generally composed of calcium phosphate. Patients with proximal renal tubular acidosis (type II) generally do not have nephrocalcinosis or stones, but appear to have osteomabacia or rickets. The mechanism of stone formation in patients with distal renal tubular acidosis is multifactorial; patients have increased urine calcium and phosphorus excretion, have a high urine ph. and decreased citrate excretion (33). Increased urine calcium excretion appears due to a direct effect of acidosis to decrease renal tubule calcium reabsorption (34). There is no concomitant increase in intestinal calcium absorption so that the increased urine calcium excretion must be derived from the bone mineral (35,36). Increased urine ph decreases the solubility of calcium phosphate complexes. resulting in greater urine supersaturation at any urine calcium and phosphorus concentration. Citrate is freely filtered by the glomerulus and reabsorbed in the proximal tubule. Acidosis increases proximal tubule citrate absorption and decreases its excretion. Citrate binds urine calcium, lowering its concentration. and acts as an inhibitor of crystallization. Thus. an acidosis-induced reduction in urinary citrate excretion not only increases the available calcium, raising supersaturation with respect to calcium phosphate complexation, but decreases an important crystallization inhibitor. Alkali administration reduces nephrocalcinosis and nephrolithiasis by decreasing calcium and increasing citrate excretion despite maintenance of an elevated urine ph. Decreased Citrate Excretion Urinary citrate is decreased in many patients who form calcium stones (37,38). The decreased urinary citrate excretion is often secondary to excessive dietary protein intake, which beads to increased endogenous acid production and increased net acid excretion. Patients with chronic diarrhea have an ongoing loss of base and often have decreased urinary citrate excretion. Decreasing dietary protein intake and, if necessary. administering base such as potassium bicarbonate or potassium citrate will increase citrate excretion and may help prevent stone formation. The sodium salt of the base should be avoided because sodium, but not potassium. will increase urine calcium excretion (39). Patients often prefer tablets to potassium-contaming liquids. Excess Oxalate Excretion Hvperoxaluria The majority of patients who form calcium oxalate stones excrete similar amounts of urinary oxabate (<4() mg/d) as do non-stone formers (2). However, there are patients who excrete excessive amounts of oxalate. leading to supersaturation with respect to calcium oxalate and to stone formation. Excessive urinary oxalate comes either from enhanced intestinal absorption, so-called enteric hyperoxaluria, or from enhanced endogenous production. Oxalate is an end product of metabolism. Healthy humans absorb less than 5% of dietary oxalate; however, foods that are rich in oxalate, such as spinach, chocolate, peanuts. and cocoa, can increase urine oxalate excretion by 25 to 50% (2). Intestinal oxalate absorption, mainly in the colon. is increased by a reduction of luminal calcium as oxalate forms insoluble salts with calcium. which can then not be absorbed. Conversely. oxalate absorption is

922 Journal of the American Society of Nephrology decreased by oral calcium administration. Gastrointestinal disorders, such as Crohn s disease, celiac sprue, and intestinal bypass surgery, which result in dietary fat malabsorption, lead to enhanced oxalate absorption as (1) the long-chain fatty acids and bile increase cobonic permeability to oxalate and (2) these fats bind calcium, freeing the oxabate for absorption. Binding the fatty and bile acids with cholestyramine and increasing dietary calcium will decrease oxalate absorption and excretion and lower urinary supersaturation. Oxalate is produced by oxidation of ascorbic acid and by oxidation of glycobate (3). Supplementation of dietary ascorbic acid will increase urine oxalate in some individuals. Glycolate oxidation produces the bulk of urine oxalate. There are two types of hereditary hyperoxaluria, and in both cases oxalate production is increased. The more common, type I, is an autosomal recessive disease in which the excretion of glyoxylate and glycolate, as well as oxabate, are increased. In type II, excretion of L-glyceric acid is increased. Pyridoxine administration will decrease oxalate excretion in both. A not uncommon cause of acute calcium oxalate crystal deposition, in the form of nephrolithiasis or nephrocalcinosis, is the ingestion, either accidental or intentional, of the antifreeze ethylene glycob, which is metabolized to oxalate (40). Excess Uric Acid Excretion Hyperuricosuria Compared with non-stone formers, there is an increased frequency of hyperuricosuria (defined as >800 mg/d in men and >750 mg/d in women) in patients who form calcium stones ( 1,2). In general, excess uric acid excretion is a result of increased dietary purine intake derived from meat, poultry, and fish. Reduction of uric acid excretion with allopurinol has been shown to decrease calcium oxalate stone formation. The mechanism by which hyperuricosuria promotes calcium oxalate stone formation is not yet certain. The dimensions of uric acid crystals closely match those of calcium oxalate, and it has been suggested that the uric acid crystals promote heterogeneous nucleation of calcium oxalate from a metastable urine (4). Alternatively, the excess uric acid may adsorb inhibitors of calcium oxalate crystallization, allowing stone formalion to occur at modest degrees of supersaturation. Idiopathic Even after extensive evaluation, there remains a group of patients in whom a clear etiology for stone formation cannot be found (4 1,42). Excretion of calcium, oxalate, and uric acid are normal, and the urine is not supersaturated with respect to solid phases of calcium oxalate or calcium phosphate. Determination of a mechanism for stone formation is not possible. and decisions regarding treatment to prevent recurrence are speculative. In this case, the results of stone analysis, if available, must be an important guide to treatment. These patients may benefit from general stone clinic advice aimed at lowering urinary supersaturation such as increasing fluid intake and decreasing sodium and protein intake. URIC ACID STONES Urine ph is a major determinant of uric acid supersaturation and subsequent stone formation ( 1.43). Uric acid is a weak acid in which two W may, in theory, be dissociated. However, because the pk of the first H dissociation is 5.5 and the second is 10.0, only the first W can be dissociated at a physiologically attainable urine ph. Uric acid, with two H, is far less soluble than urate, with one H. indicating that an increase in urine ph will increase sobubility. At an acid urine ph of 5, even the normal male uric acid excretion of <800 mg/24 h per L of urine may result in supersaturation with respect to uric acid and will increase the potential for stone formation. Urine ph is determined by the absolute amount of endogenously produced net acid and the proportion of this net acid that is excreted as NH4 compared with that excreted as titratable acidity. The more net acid that can be excreted as the base NH4, the higher the urine ph. Uric acid stone formers appear to excrete less net acid as NH4 and more as titratabbe acidity resulting in a lower urine ph, a greater supersaturation with respect to uric acid, and a greater propensity for nephrolithiasis (43). In addition to urine ph, the main determinants of supersaturation with respect to uric acid are endogenous uric acid production and subsequent excretion and urine volume. In healthy individuals, uric acid production is directly related to consumption of dietary purine from meat, poultry, and fish. Increasing purine intake will increase uric acid excretion. Some patients with gout have mild overproduction of uric acid, whereas others with genetic defects of purine reutilization, such as the Lesch.-Nyhan syndrome, have substantial overproduction of uric acid. Patients with myeloproliferative disorders often overproduce uric acid and may have massive release of preformed uric acid during effective treatment, the so-called tumor lysis syndrome. Renal excretion is responsible for more than 50% of daily uric acid elimination; the remainder is degraded in the intestine (43). Some patients have a relative decrease in renal tubule uric acid reabsorption, resulting in increased uric acid excretion and decreased intestinal degradation. Approximately 25% of patients with clinical gout have uric acid nephrolithiasis (43). These patients tend to have excess uric acid excretion even while consuming a low purine diet and have a very acidic urine ph. Patients with chronic diarrhea are particularly at risk for uric acid stones because they are often dehydrated and the alkaline diarrheal fluid causes chronic metabolic acidosis and an acidic urine. Both probenecid and barge doses of salicylates promote uric acid excretion and predispose to stone formation. Treatment. The main principles of treatment for uric acid nephrobithiasis are hydration, dietary purine moderation, unnary alkalization, and, if necessary, allopurinol administration (3). Increasing fluid intake and decreasing the amount of dietary purine will decrease urine supersaturation. Alkalinization with bicarbonate or a bicarbonate precursor such as citrate should be aimed at maintaining a urine ph >6.0, but <7.0, throughout the day and night. During the day, multiple doses of

Nephrolithiasis 923 bicarbonate, to match the endogenous acid production of approximately I meqlkg per 24 h, can be used. If nocturnal urine ph falls, then acetazolamide may be administered. However, one must avoid a urine ph greater than approximately 7.0 to avoid increasing the risk for calcium oxalate nephrolithiasis. Albopurinal can be added ifthese measures, in combination, are not successful in reducing supersaturation and stone formation. MAGNESIUM AMMONIUM PHOSPHATE (STRUVITE) STONES These so-called infection stones form only when the unnary tract is infected with a urea-splitting bacteria (44). Most Proteus and Providencia species possess urease, which splits urea, as do some species of Kiebsiella pneumnoniae and Serratia marcescens. Bacterial urease hydrolyzes urea to form NH3, CO,, and H,O, consuming during the hydrolysis and resulting in an increase in urine ph. In the now alkaline urine. NH3 spontaneously hydrolyzes to form NH4OH, and CO2 is hydrated to form HCO1, which then becomes CO. The concentrations of NH4OH and CO increase, and any phosphate present is deprotonated (POt). Struvite (MgNH4PO4 H,O) stones are formed on the PO backbone, as are carbonate apatite (Ca1()(P04)6. CO3) stones. The carbonate apatite is usually found within the struvite. This cascade of events is totally dependent on bacterial urease (44). Struvite stones may occur secondary to another stone that causes obstruction and subsequent infection. In the presence of bacteria, local supersaturation occurs and crystals form around the bacteria. The infection is difficult to control because normal urine flow, which can wash away bacteria, is disrupted. The struvite stones rapidly increase in size and can fill the renal collecting system resulting in staghorn calculi. Hematuria is common, and renal insufficiency and failure can result from obstruction and infection. Treatment. Surgical stone removal is difficult because any retained stone fragments will generally contain bacteria and be the nidus for new calculi formation. Percutaneous nephrolithotomy can often be used to completely remove struvile stones. Chronic antibiotic therapy may slow the progression of the disease but is rarely curative. Bacterial urease can be inhibited by acetohydroxamic acid, and this has been shown to be effective in reducing the rate of stone growth; however, this compound has numerous side effects. Unfortunately. treatment of struvite stones is often frustrating for the patient as well as the physician. CYSTINE STONES Cystinuria is a rare, but important hereditary disorder in which there is a tubular defect in dibasic amino acid transport resulting in increased urine excretion of cystine. ornithine, lysine, and arginine (45). Nephrolithiasis usually presents by the fourth decade. although a later presentation has been reported. Due to the sulfur content of the cystine molecule, the stones are visible on plane radiographs and will often present as staghorn calculi or multiple bilateral stones. Cystinuria. in which cystine accumulates only in the lumen of the renal tubules, is distinct from cystinosis, in which there is widespread intracellular cystine accumulation. Cystine is poorly soluble at approximately 3(X) mgfl at a neutral ph. The normal cystine excretion of approximately 30 to SO mg/d is readily soluble in the typical daily urine volume, which exceeds I L. However, homozygote cystinuric patients generally excrete between 250 and 1000 mg ofcystine per day, with heterozygotes excreting an intermediate amount. There are at least three distinct types of cystinuria that can be classified by intestinal transport studies. Treatment. Treatment of cystinuria must be directed at decreasing the urinary cystine concentration below the limits of sobubility (45). The metabolic precursor ofcystine. methionine, is an essential amino acid; thus, it is impractical to reduce its intake and subsequent excretion of cystine. Increasing urinary volume so that cystine remains below the limits of solubility is the first approach to treatment and is generally practical; however, sometimes it is necessary to excrete 4 L of urine per day. Increasing urine ph above 7.5 will increase cystine solubility, but this ph is often difficult to maintain on a chronic basis. Tiopronin or D-penicillamine will both bind cystine and reduce urine supersaturation; however, side effects limit their use. Acknowledgments This work was supported in part by National Institutes of Health Grants AR-39906 and DK-4763 I. References I. Bushinsky DA: Renal lithiasis. In: Ke/lv s Textbook (?f Medicine, edited by Kelly WF, New York. Lippincott. 1996. pp 1024-1028 2. Asplin JR. Favus Mi, Coe FL: Nephrolithiasis. In: The Kidney, edited by Brenner BM. Philadelphia. W. B. Saunders. 1996. pp I 893-1935 3. Coe FL. Parks JH. Asplin ir: The pathogenesis and treatment of kidney stones. N EngI J Med 327: 1 141-1 152. 1992 4. Mandel N: Mechanism of stone formation. Semimi Nephro/ 16: 364-374. 1996 5. Finlayson B. Reid F: The expectation of free and fixed particles in urinary stone disease. Invest Uro! 15: 442-448, 1978 6. Lieske ic. Toback FG: Interaction of urinary crystals with renal epithelial cells in the pathogenesis of nephrolithiasis. Semin Nephro/ 16: 458-473. 1996 7. Coe FL, Parks ih: New insights into the pathophysiology and treatment of nephrolithiasis: New research venues. J Bone Miner Res 12: 522-533. 1997 8. Brown CM. Ackermann DK. Punch DL: EQUIL93: A tool for experimental and clinical urolithiasis. Urol Res 22: 1 19-126, I 994 9. Finlayson B: Calcium stones: Some physical and clinical aspects. In: Ca/cium Metaholisimi in Remia! Failure (111(1 Nephrolithia.sis. edited by David DS. New York. Wiley. 1977, pp 337-382 10. Werness PG. Brown CM. Smith LH, Finlayson B: Equil2: A basic computer program for the calculation of urinary saturation. J Uro! 134: 1242-1244, 1985 1 1. Consensus conference: Prevention and treatment of kidney stones. JAMA 260: 977-981, 1988 12. Maikranz P. Coe FL. Parks I. Lindeimer MD: Nephrolithiasis in pregnancy. Am J Kidney Dis 9: 354-358. 1987

924 Journal of the American Society of Nephrology 13. Parks ih. Coe FL: Pathogenesis and treatment of calcium stones. Semimi Nephro/ I6: 398-4 1 1, 1996 14. Monk RD. Bushinsky DA: Pathogenesis of idiopathic hypercalciuria. In: Kidney Stones: Medica! and Surgical Management, edited by Coe F, Favus Mi, Pak C, Parks J, Preminger G. New York, Raven, 1996, pp 759-772 15. Bushinsky DA. Favus Mi: Mechanism of hypercabciuria in genetic hypercalciuric rats: Inherited defect in intestinal calcium transport. J C/in latest 82: 1585-1591. 1988 16. Bushinsky DA, Nilsson EL, Nakagawa Y, Coe FL, Grynpas M: Stone formation in genetic hypercalciuric rats. Kidney fat 48: 1705-1713. 1995 17. Coe FL, Favus MI, Crockett T, Strauss AL. Parks JH. Porat A, Gantt C, Sherwood LM: Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum l,25(oh),d3 levels in patients with idiopathic hypercalciuria and in normal subjects. Am J Med 72: 25-32. 1982 18. Coe FL, Bushinsky DA: Pathophysiology of hypercalciuria. Ani J Physiol 247: Fl-F13, 1984 19. Bushinsky DA: Genetic hypercalciuric stone forming rats. Semin Nephro/ 16: 448-457. 1996 20. Asplin JR. Bushinsky DA, Singharetnam W. Riordon D. Parks il-i, Coe FL: Relationship between supersaturation and crystal inhibition in hypercalciuric rats. Kidney Im 51: 640-645, 1997 21. Tsuruoka S. Bushinsky DA, Schwartz Gi: Defective renal calcium reabsorption in genetic hypercalciuric rats. Kidney Int S 1: 1540-1547, 1997 22. Krieger NS, Stathopoubos VM, Bushinsky DA: Increased sensitivity to l,25(oh)2d3 in bone from genetic hypercalciuric rats. Am J Phvsio/ 271: C130-Cl35, 1996 23. Bushinsky DA. Kim M, Sessler NE, Nakagawa Y. Coe FL: Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. Kidney fat 45: 58-65, 1994 24. Kim M, Sessler NE. Tembe V. Favus MI, Bushinsky DA: Response of genetic hypercalciuric rats to a low calcium diet. Kidney hit 43: 189-196, 1993 25. Li X-Q, Tembe V. Horwitz GM, Bushinsky DA. Favus Mi: Increased intestinal vitamin D receptor in genetic hypercalciuric rats: A cause of intestinal calcium hyperabsorption. J C/in lns est 91: 661-667, 1993 26. Curhan GC, Willett WC, Rimm EB, Stampfer MJ: A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N EngI J Med 328: 833-838, 1993 27. Bushinsky DA, Krieger NS: Integration of calcium metabolism in the adult. In: Disorders of Bone and Minera! Metabolism, edited by Coe FL, Favus MI. New York, Raven, 1992, pp 4 17-432 28. Mallette LE, Gagel RF: Parathyroid hormone and calcitonin. In: Primer on the Metabolic Bone Diseases amid Disorders of Mimiera! Metabolism, edited by Favus Mi, Philadelphia, Lippincott- Raven. 1996. pp 96-105 29. Bibezikian ip: Primary hyperparathyroidism. In: Primer on the Metabo/ic Bone Diseases amid Disorders ofminera! Metabolism, edited by Favus MJ, Philadelphia. Lippincott-Raven, 1996, pp 18 1-186 30. Adams is: Hypercalcemia due to granuboma-forming disorders. In: Primer on the Metabolic Bone Diseases and Disorders of Minera! Metabolism, edited by Favus MJ, Philadelphia, Lippincott-Raven, I 996, pp 206-209 3 1. Strewler GJ: Parathyroid hormone-related protein. In: Primer on the Metabo/ic Bone Diseases amid Disorders of Minera! Metabolism, edited by Favus MI, Philadelphia, Lippincott-Raven, 1996, pp 7 1-73 32. Brenner RI, Spring DB, Sebastian A, McSherry EM, Genant HK, Palubinskas Al, Morris RC Jr: Incidence of radiographically evident bone disease, nephrocalcinosis, and nephrolithiasis in various types of renal tubular acidosis. N Engl J Med 307: 217-221, 1982 33. Bushinsky DA: Internal exchanges of hydrogen ions: Bone. In: The Regulation of Acid-Base Balance, edited by Sebdin DW, Giebisch G, New York, Raven, 1989, pp 69-88 34. Sutton RAL: Disorders of renal calcium excretion. Kidney fat 23: 665-673, 1983 35. Lemann J Jr, Adams ND, Gray RW: Urinary calcium excretion in human beings. N Eng! J Med 301: 535-541, 1979 36. Bushinsky DA: The contribution of acidosis to renal osteodystrophy. Kidney 1w 47: 1816-1832, 1995 37. Pak CYC: Pathophysiology of calcium nephrolithiasis. In: The Kidney: Physiology and Pathophvsio!ogv, edited by Seldin DW, Giebisch G, New York, Raven, 1992, pp 2461-2480 38. Alpern RT: Trade-offs in the adaptation to acidosis. Kidney fin 47: 1205-1215, 1995 39. Lemann i ir, Gray RW, Pleuss IA: Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Im 35: 688-695. 1989 40. Bushinsky DA, Krieger NS: Role of the skeleton in calcium homeostasis. In: The Kidney: Phvsio!ogy amid Pathophysiology, edited by Sebdin DW, Giebisch G, New York, Raven, 1992, pp 2395-2430 41. Monk RD: Clinical approach to adults. Semin Nephro! 16: 375-388, 1996 42. Stapleton FB: Clinical approach to children with urolithiasis. Semnin Nephro! 16: 389-397. 1996 43. Asplin JR: Uric acid stones. Semnin Nephro! 16: 412-424, 1996 44. Cohen TD, Preminger GM: Struvite calculi. Semimi Nephro! 16: 425-434. 1996 45. Sakhaee K: Pathogenesis and medical management of cystinuria. Semin Nephro! 16: 435-447, 1996