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MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
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UROLITHIASIS
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MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS Charles Y. C. Pak, MD, and Martin I. Resnick, MD
The introduction of extracorporeal shockwave lithotripsy (ESWL.) has revolutionized the urologic practice in urolithiasis.' This technology has reduced considerably the morbidity of stone disease, by allowing relatively noninvasive removal of stones. Unfortunately, the facilitated removal of stones by ESWL has led some urologists to abandon or disparage the medical approach to stone management. This development is unfortunate, because the need for medical diagnosis and prevention has not diminished. Renal stone disease is characterized by a high rate of rec~rrence.~ The propensity for stone recurrence is not altered by removal of stones with ESWL.5 Ample evidence has accumulated, however, showing that a variety of medical treatments can prevent recurrence of stones? There have been notable advances in the medical management of urolithiasis. A method for the analysis of urinary-stone risk factors in a 24-hour urine sample was described in 1985.14A graphic display of stone risk factors is now available commercially. A Supported by USPHS grants Pol-DK20543 and M01RR00633
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step-by-step approach to diagnosis and treatment of different causes of urolithiasis was described in 1996.15A simplified, nonselective treatment program was recommended in 1997." Despite this progress, many urologists are confused by current guidelines on medical diagnosis and prevention. It is the objective of this article to offer practical guidelines in medical management of urolithiasis. Although borrowing from prior recommendations,", 14, l5 the current guidelines represent a simpler version directed at a practicing urologist. Described here in stepwise fashion is the approach that a practicing urologist might take in medically diagnosing and managing patients with stones, summarized as follows: Step 1. History and minimum diagnostic tests Step 2. 24-hour urinary stone risk profile (customary diet) Identification of abnormal dietary risk factors Short-term dietary modification Step 3. Repeat stone risk profile after dietary modification Step 4. Elucidation of causes and construction of treatment options for abnormal risk factms ~
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From the Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical School, Dallas, Texas (CYCP) and the Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, Ohio (MIR)
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 27 NUMBER 2 MAY 2000
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Relevant history and minimum diagnostic test results first are obtained. A full 24-hour stone risk profile is measured on a random diet and fluid intake. Another stone risk profile is obtained after a short-term dietary modification. From these simplified tests, potential causes are discerned and treatment options are constructed for each abnormal stonerisk factor and combined derangements. SIMPLE DIAGNOSTIC APPROACH Initial Visit
The first step, to be undertaken during the initial visit, is to take a careful history and conduct minimum diagnostic tests: History Secondary causes Dietary aberrations Stone-provoking drugs Minimum diagnostic tests Abdominal radiograph of the kidneys, ureter, and bladder Urinary sediment (crystals) Serum calcium, potassium, electrolytes, and uric-acid levels History
In all patients with stones, a careful history should be taken. The history should include prior stone occurrences, family history of stones, and history of gout, bowel disease, fluid loss, or urinary-tract infection; dietary aberrations; and use of stone-provoking medications. Gout, bowel disease, urinary-tract infection, and excessive fluid loss represent potential secondary causes of stones. Dietary aberrations include low intake of fluids or citrus fruits and a high intake of calcium, oxalate, sodium or animal proteins. Drugs that can cause stones include those that can increase urinary calcium (acetazolamide, calcium-channel blockers, calcium or vitamin D preparations, phosphorus-binding antacids, furosemide, and theophylline), oxalate (vitamin C), uric acid (uricosuric agents), and those than can enhance urinary excretion of poorly soluble substances (triamterene). Minimum Diagnostic Tests
The following tests should be obtained in any patient presenting with stones, for the
first time or after prior stone episodes: Urinalysis and culture; radiograph of kidneys, ureter, and bladder; stone analysis; and measurement of serum calcium, phosphorus, electrolyte, uric-acid, and creatinine levels. The finding of calcium oxalate crystals is not overly useful, because they can be found in normal urine. The detection of cystine or struvite (magnesium-ammonium phosphate) crystals, however, is diagnostic of cystinuria or infection stones, respectively. A positive culture for urea-splitting organisms is indicative of infection stones. Radioopaque stones imply the presence of calcium oxalate, calcium phosphate, struvite, or cystine. Radiolucency suggests that stones might be composed of uric acid. The finding of cystine and struvite on stone analysis is diagnostic of cystinuria and infection stones, respectively. Uric-acid stones are indicative of conditions that cause low urinary pH (e.g., such as gout or chronic diarrheal states) or marked hyperuricosuria. Stones composed largely of calcium phosphate (hydroxyapatite) are suggestive of primary hyperparathyroidism, renal tubular acidosis, and sodium alkali therapy. Of lesser diagnostic importance are common stones of calcium oxalate. They are encountered with hypercalciuria, hyperoxaluria, hypocitraturia, hypomagnesiuria, or low urine volume. Presence of hypercalcemia and hypophosphatemia is indicative of primary hyperparathyroidism. Hypokalemia and high serum bicarbonate concentration are suggestive of renal tubular acidosis. Hyperuricemia indicates gouty diathesis. Twenty-four-hour Urinary Stone Risk Profile on the Customary Diet
The second step, to be undertaken in recurrent stone formers and first-time stone formers with increased risk (i.e., family history of stones, bone or bowel disease, gout, chronic urinary-tract infection, or nephrocalcinosis), is to obtain a 24-hour urine sample, while patients maintain their customary diets and fluid intakes, for the analysis of full stone risk pr0fi1e.I~The metaboZic factors include calcium, oxalate, uric acid, citrate, and pH. Environmental factors comprise total volume, sodium, sulfate, phosphorus, and magnesium. Physicochemical factors are urinary saturation of calcium oxalate, brushite (CaHP0,.2H20), monosodium urate, and uric acid, expressed
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
relative to mean values in normal subjects without stones. Identification of Abnormal Dietary Risk Factors
Aberrations in diet and fluids can produce abnormal environmental factors cited previously. They also could exaggerate disturbances in metabolic factors. From the stone risk profile, it is important to identify aberrant environmental risk factors and try to correct them with dietary modification. Short-term Dietary Modification
If urinary total volume is less than 2 L/d, patients should increase fluid intake. If urinary sodium exceeds 200 mEq/d, sodium intake should be restricted. In general, this goal may be achieved by avoidance of salt shakers and obviously salty foods. If urinary oxalate exceeds 45 mg / d, one should impose dietary oxalate restriction, that is, limitation or avoidance of tea, spinach, and other dark roughage; nuts; and chocolate. Vitamin C in excess of 500 mg/d is not advisable because it can be converted to oxalate. If urinary calcium exceeds 250 mg / d in a patient taking a high-calcium diet, a moderate calcium restriction might be imposed, for example, 1 glass of milk and a small serving of another dairy product per day. If urinary uricacid and sulfate levels exceed 700 mg/d and 30 mmol/ d, respectively, one should restrict animal proteins by limiting the intake of beef, poultry, and fish to two servings per day. If urinary pH, citrate, and potassium are low, patients should be told to increase the intake of potassium-rich citrus fruits (e.g., orange, grapefruit, and cranberry). Repeat 24-hour Profile After Short-term Dietary Modification: Identification of Abnormal Environmental and Metabolic Risk Factors
In the third step, another 24-hour urine is to be collected for a stone risk profile, after the dietary modification described previously for 1 week. From a stone risk profile so obtained it is important to identify abnormal environmental and metabolic risk factors. The stone risk profile obtained following dietary modification is compared with that
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measured on a random diet. The correction of aberrant risk factors by dietary modification suggests that such abnormalities are environmental in origin. If risk factors considered to be clearly environmental remain abnormal (e.g., low urine volume or high urinary sodium level), the dietary modification may have been inadequate or poorly followed. In contrast, the persistence of abnormal metabolic stone risk factors would confirm that the derangements were metabolic in origin. In the fourth step, potential causes are discerned and treatment guidelines are constructed, for each abnormal urinary risk factor and combination of deranged risk factors. This task is aided by history, minimum diagnostic tests, and stone risk profiles.
CAUSESANDTREATMENTOF INDIVIDUAL ABNORMAL STONE RISK FACTORS Long-term Dietary Modification
In all patients with stones, dietary modification should be continued in the long term:
High fluid intake: At least ten 10-02glasses per day Sodium restriction: Avoidance of salt shakers and salty foods Oxalate restriction: Avoidance of nuts, dark roughage, chocolate, tea, vitamin C Restriction of animal proteins: Limited servings of meat products Increased citrus fruits: Potassium-rich products preferable The high fluid intake and restriction of sodium and oxalate should be maintained, without fear of adverse effects on health. In most patients, purine restriction is difficult to maintain. Adequate intake of fruits and vegetables to balance the intake of animal proteins should be encouraged. Potassium-rich citrus fruits, such as orange, grapefruit and cranberry, are preferable to low-potassium citrus fruits, such as lime and lemon. Orange juice, for example, represents a natural form of potassium citrate and possesses alkalinizing and citraturic action." Lime juice, on the other hand, is composed largely of citric acid, and does not affect acid-base balance appreciably.20Thus, it does not alter urinary pH and only modestly increases urinary citrate (from the renal clearance of a small
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parathyroidism should be suspected if serum PTH is high.
amount of absorbed citrate that escapes oxidation in vivo). If long-term restriction of calcium is contemplated, it is important to make sure that the patient does not suffer from excessive bone loss. Measurement of bone density, particularly in the spine, is recommended. Treatment options are discussed here for each risk factor and combination of factors (Table 1).
Associated with Hypercalcemia
Associated with Sodium Excess One should check urinary sodium in order to estimate the increment in urinary calcium produced by excessive sodium intake. If the urinary sodium level exceeds 100 mEq/d, every increment in sodium of 100 mEq can increase urinary calcium by about 50 mg/d?l One should re-emphasize the importance of sodium restriction, by avoidance of the use of salt shakers and ingestion of salty foods. Recommended sodium intake is 100 mEq/d or one teaspoonful of table salt per day.
One should check serum calcium and phosphorus levels from step 1. If the serum calcium level is high, one should obtain serum parathyroid hormone (PTH). Primary hyper-
Absorptive or Renal Hypercalciuria If a high serum calcium or urinary sodium level cannot account for hypercalciuria, the
Hypercalciuria (More Than 250 mg/d)
Table 1. CAUSES AND TREATMENT OPTIONS FOR INDIVIDUAL METABOLIC RISK FACTORS ~~~~
Condition
Hypercalciuria With hypercalcemia With high urinary sodium Absorptive and renal hypercalciuria Hyperoxaluria Mild Moderate-severe Ileal disease Primary/ metabolic Hypocitraturia Severe Chronic diarrhea Distal RTA Infection Mild-moderate Dietary Incomplete RTA Hypokalemia of thiazide Hyperuricosuria With normouricemia Mild-moderate Normal urinary citrate Hypocitraturia Severe (>go0 mg/d) With hyperuricemia Low urinary pH Gouty diathesis Chronic diarrhea Physical exercise Severe high-protein diet High urinary pH pH 7.0-7.5 Distal RTA Vegetarian diet pH >7.5 Infection stones RTA = renal tubular acidosis.
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Causes
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Dispositiodlreatment
Primary hyperparathyroidism High sodium intake Metabolic causes
Check parathyroid status Sodium restriction Thiazide and potassium citrate
Dietary causes
Restrict dietary oxalate
Increased oxalate absorption Enzymatic disturbances
Oxalate restriction, calcium citrate Pyridoxine
Metabolic acidosis Renal acidification defect Enzymatic degradation
Potassium-sodium citrate Potassium citrate Antibiotic, urea% inhibitor
Animal-protein excess Renal acidification defect Intracellular acidosis
Potassium citrate Potassium citrate Potassium citrate
Dietary purine excess Dietary purine excess Dietary purine excess Primary gout
None Potassium citrate Allopurinol Allopurinol
Defective ammoniagenesis Intestinal bicarbonate loss Lactic acidosis Dietary acid excess
Potassium citrate Potassium-sodium citrate Balanced electrolyte fluids Potassium citrate
Renal acidification defect Dietary alkali
Potassium citrate Oxalate restriction
Urea-splitting infection
Antibiotic, urease inhibitor
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
patient probably has absorptive or renal hypercalciuria. Absorptive hypercalciuria is caused by enhanced intestinal absorption of calcium, whereas renal hypercalciuria results from the impaired renal tubular reabsorption (renal leak) of calcium.'O The two conditions can be distinguished by normal or low serum F"H levels in the former and high serum PTH levels in the latter. Diagnostic separation is not necessary for the initiation of medical treatment. Treatment should be considered initially with trichlormethiazide 4 mg/d with potassium citrate 20 mEq twice daily." The long duration of action of trichlormethiazide allows it to be given on a once-daily schedule. Trichlormethiazide generally is tolerated better than short-acting thiazides. Most patients prefer a tablet formulation of potassium citrate rather than liquid formulations. The tablet formulation may be given with meals in order to reduce minor gastrointestinal side effects, without sacrificing the physiologic action.16 The objective of thiazide treatment is to reduce urinary calcium level by an effect on the renal handling of calcium." In patients with renal hypercalciuria, a long-term correction of hypercalciuria may be achieved with thiazide. Some patients with absorptive hypercalciuria show a loss of thiazide's hypocalciuric action after about 2 years of treatment.I7 A temporary withdrawal of therapy may be necessary. It is critical to restrict sodium intake, because a high sodium intake could blunt thiazide's hypocalciuric action. The objective of adjunctive potassium citrate treatment is to rovide potassium to avert development of ypokalemia, and to confer an alkali load to increase urinary citrate? an inhibitor of stone formation. The dose of potassium citrate may be adjusted based on serum potassium and urinary citrate levels measured after 4 to 6 months of treatment.
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Hyperoxaluria (More Than 45 mg/d) Mild Hyperoxaluria (Urinary Oxalate Less Than 60 mg/d) Mild hyperoxaluria generally is caused by dietary factors. One should suspect overconsumption of oxalate-rich foods, such as spinach and dark roughage, tea, chocolate, and nuts. Vitamin C supplementation of more than 500 mg/ d could raise the urinary oxalate level by serving as a substrate. Patients suffer-
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ing from absorptive hypercalciuria maintained on calcium restriction could have mild hyperoxaluria, because of the insufficient amount of calcium left in the bowel to bind oxalate. Dietary oxalate restriction should be emphasized, and vitamin C supplementation limited to no less than 500 mg/d. There is no evidence that long-term oxalate restriction is hazardous to health. Moderate to Severe Hyperoxaluria (Urinary Oxalate Greater Than or Equal to 60 mg/d)
If this level of urinary oxalate is encountered, the presence of bowel disease should be suspected. In patients with intestinal malabsorption offat, inflammatory diseases, or resection of the small bowel, oxalate absorption can be increased substantially by two mechanism^.^ The nonabsorbed bile salts and fatty acids may stimulate mucosal permeability to oxalate directly. Oxalate absorption also may be stimulated indirectly from an enlarged pool of absorbable oxalate. Nonabsorbed fatty acids bind calcium and magnesium in the bowel, leaving an insufficient amount of divalent cations to bind oxalate. Patients suffering from small-bowel disease without functioning colons may not develop hyperoxaluria, because the colon is the principal site of oxalate absorption. A rigid restriction of dietary oxalate is critical. Solubilized calcium citrate (e.g., Citracal Liquitab) may help to lower urinary oxalate by binding oxalate. Hyperoxaluria often coexists with low urinary citrate and magnesium levels, pH, and volume (discussed in a subsequent section). Moderate hyperoxaluria (up to 70 mg/d) may be encountered in patients with absorptive hypercalciuria taking sodium cellulose phosphate.6 The amount of free calcium in the bowel can be reduced severely from enhanced absorption of calcium and binding of calcium to the drug, increasing the absorbable oxalate pool. A rigid control of oxalate intake is critical. This situation seldom is encountered now because of infrequent use of sodium cellulose phosphate. In the absence of bowel disease or the use of sodium cellulose phosphate, one might consider mild metabolic hyperoxaluria or primary hyperoxaluria to explain moderate to severe hyperoxaluria. Suppression of oxalate synthesis in vivo is necessary. Pyridoxine 100 to 200 mg / d may be useful.
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Hypocitraturia (Less Than 320 mud) Severe Hypocitraturia (Less Than 700 mdd)
In this situation, one should suspect bowel disease. Any chronic diarrheal state that produces metabolic acidosis can cause hypocitraturia.19 Thus, gastrectomy and ulcerative colitis may produce hypocitraturia, though not hyperoxaluria. After application of treatments directed at diarrhea, it is important to provide alkali therapy to correct or ameliorate metabolic acidosis. A liquid formulation of potassium and sodium citrate is preferable. In patients with severe bowel disease, a full correction of hypocitraturia ma not be possible. A partial amelioration of ypocitraturia, however, may bring a substantial improvement in stone disease. Another cause of severe hypocitraturia is complete distal renal tubular acidosis. Patients typically have low serum potassium, high serum bicarbonate, hypercalciuria, and high urinary pH (near 7). Treatment is potassium citrate at a dose sufficient to correct metabolic acidosis (2040 mEq twice daily). Some patients may have renal impairment. Potassium citrate should be used with caution, with frequent monitoring of serum potassium concentration. Finally, severe hypocitraturia may be found in infection stones (magnesium and ammonium phosphate or carbonate apatite). Citrate may be used as a substrate by bacterial enzymes.
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Mild to Moderate Hypocitraturia (700-320mdd)
A mild to moderate decrease in urinary citrate is usually dietary in origin (relative acid excess).= Affected patients may show a preference for animal proteins (i.e., beef, poultry, and fish) over vegetables and fruits. Urinary uric-acid and sulfate levels may be high. If patients are willing, dietary restriction of animal proteins may be useful. In most patients, it probably is easier to apply treatment with potassium citrate (initial dose of 20 mEq twice daily). The dose should be adjusted based on urinary citrate obtained at 4 to 6 months of treatment. A minority of patients with mild to moderate hypocitraturia may have incomplete renal tubular acidosis (RTA). Unlike in complete
RTA, serum electrolytes are normal and urinary pH may be normal. A defect in renal acidification is shown by inadequate acidification of urine upon ammonium chloride challenge. A definitive diagnosis is not necessary, however, for a satisfactory treatment. The treatment of choice is potassium citrate, as in acquired (dietary) mild to moderate hypocitraturia. In complete and incomplete forms of distal RTA, potassium citrate treatment may exert a beneficial extrarenal action. This treatment may prevent bone loss, by reducing urinary calcium and increasing intestinal calcium absorption.18 Mild to moderate hypocitraturia also may develop from hypokalemia of thiazide treatment for hypercalciuric nephrolithiasis.8 Hypokalemia may produce hypocitraturia by producing intracellular acidosis. Thus, it is advisable to always provide potassium supplementation with thiazide treatment. Potassium citrate is preferable to potassium chloride because it can raise urinary citrate (inhibitor of stone formation) to above the prethiazide range.8
Low Normal Urinary Citrate Level (320-400mdd) The low range of normal for urinary citrate is wide (low normal limit of 320 mg/d and mean normal of 640 mg/d). It may be advisable to treat patients with urinary citrate levels in the lower end of the normal range. A small dose of potassium citrate (10 mEq twice daily) may be sufficient. Hyperuricosuria (>700 mg/d) With Normouricemia
In most patients, hyperuricosuria is caused by dietary excess of purines (animal proteins)? Urinary sulfate levels may be high. Serum uric-acid level tends to be high normal but rarely is increased above the normal range. In committed patients, a balanced diet might be recommended, with a reduced intake of animal proteins and increased intake of vegetables and fruits. The long-term compliance with dietary modification, however, is generally poor in most patients. Allopurinol and potassium citrate are potentially useful in preventing the formation of calcium oxalate stones in patients with hyperuricosuria. Allopurinol does so by re-
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
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ducing uric-acid synthesis and excretion. The induced hypercitratria from alkali therapy can retard urate-induced calcium oxalate crystallization.12In general, allopurinol (300 mg/ d) is indicated for patients with marked hyperuricosuria (more than 800 mg/d). In those with mild to moderate hyperuricosuria (no more than 800 mg/d), only conservative treatment may be necessary if urinary citrate levels are normal. If hypocitraturia coexists, potassium citrate alone may be sufficient.
dose of 20 mEq twice daily) at a dose sufficient to keep urinary pH at about 6.0 to 6.5. Low urinary pH also is encountered in metabolic acidosis of chronic diarrheal states (see section on hypocitraturia). Finally, low urinary pH may develop during strenuous physical exercise from lactic acidosis.22It is important to remind stone-forming patients who wish to participate in an exercise program to take adequate fluids containing balanced electrolytes before and after exercise.
With Hyperuricemia
High Urinary pH (>7)
If serum uric acid is elevated frankly, suspect gouty diathesis (i.e., stone disease of primary g o ~ t )Urinary .~ pH is typically low, and the serum triglyceride level may be high. Allopurinol (300 mg/d) is indicated to reduce serum uric acid in order to lower the risk of gouty arthritis. If urinary pH is low, potassium citrate also is required (discussed subsequently).
Urinary pH Between 7.0 and 7.5 For patients with high urinary pH, one should suspect distal RTA. Urinary citrate is expected to be low as well (see section on hypocitraturia). The treatment is potassium citrate. This degree of rise in urinary pH also may be encountered in patients who are kept on a vegetarian diet (e.g., low in proteins and high in vegetables and fruits). Their urinary citrate levels, however, are expected to be high, unlike in patients with RTA. Other clues might be low urinary uric acid and sulfate and high urinary oxalate levels.
Low Urinary pH (Less Than 5.5)
Excessive acid intake from the diet rarely can cause a decline in 24-hour urinary pH to below 5.5. It may exaggerate the decline in pH produced by other factors, however. If urinary pH is less than 5.5 in a 24-hour urine specimen, one should suspect gouty diathes ~ schronic ,~ diarrheal state,l9 or strenuous physical exercise.22 Gouty diathesis represents fully manifested primary gout or an early phase of primary Unfortunately, this condition often is understood poorly by many practicing urologists, even though it is easy to treat with an invariably satisfactory response. The low urinary pH is believed to be the result of impaired renal ammoniagenesis. Uric-acid stones develop from the impaired dissociation of uric acid, which increases the amount of sparingly soluble, undissociated uric acid. Calcium-containing stones may develop as well from the urate-induced crystallization of calcium oxalate. Thus, stones formed by patients with gouty diathesis are composed of uric acid alone, calcium oxalate alone, or both. Secondary to primary gout, serum uric acid and trigyceride levels may be elevated, and some patients may have a personal history or present with a family history of gouty arthritis. The treatment is potassium citrate (initial
Urinary pH > 7.5 The action of normal urinary buffers does not allow urinary pH to exceed 7.5. If pH exceeds this value, one should suspect infection of the urinary tract with urea-splitting organisms. Urinary pH even may exceed 8, from the release of hydroxyl ions upon hydrolysis of urea. Other abnormal findings from stone risk profile might be increased urinary ammonium and saturation of struvite.
Low Urine Volume (Less Than 2 Ud) Mild to Moderate Reduction in Urine Volume ( 1 -2 U d) If 24-hour urine volume ranges from 1 to 2 L, one should consider reduced fluid infake as a cause. In a 70-kg human being, insensible loss from feces and sweat is normally about 1 L/d. Thus, to produce a urine output of 2 L / d a subject must drink about 3 L / d of fluids total. That amount translates to about nine 10-02 glasses of water or other beverages, assuming that about one glassful of water is contained in solid food. If a subject sweats excessively, more fluids must be drunk to achieve urine output of 2 L/d.
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Any patient with fluid consumption below this level may have a low urine output. Increased fluid intake above that level is recommended to keep urine output above 2 L/d. Desired fluids are potassium-containing fruit juices, citrate-containing soft drinks, and water. Potassium-containingfruit juices (e.g., orange, grapefruit, cranberry) exert citraturic action by conferring an alkali load. Citratecontaining soft drinks (e.g., Sprite, 7-Up, Slice) are similar to diluted orange juice with respect to the content of potassium and citrate. Less desirable are tea (because of high oxalate content) and milk (because of high calcium content). Very Low Urine Volume (Less Than 1 Ud)
Very low urine output can be caused by inadequate fluid ingestion. It also may be encountered in patients with chronic diarrheal conditions, even if they are imbibing adequate amounts of fluids. Besides a history of diarrhea and low urine output, clues to excessive intestinal fluid loss are low urinary pH, sodium, potassium, and citrate. High Urinary Sodium (>200 mEq/day)
Under steady-state conditions, a high urinary sodium level is indicative of an excessive intake of sodium. High sodium intake contributes to stone formation in several ways.** First, it increases the urinary calcium level by reducing renal tubular reabsorption of calcium. Second, high sodium intake can cause a mild reduction in urinary citrate level by provoking mild bicarbonaturia and metabolic acidosis. Third, it can increase urinary saturation of monosodium urate, causing urateinduced calcium oxalate crystallization. Fourth, sodium excess could attenuate the hypocalciuric action of thiazide, rendering this treatment ineffective in the management of hypercalciuric nephrolithiasis. The desired sodium intake of 100 mEq/d generally can be achieved by avoidance of salt shakers and salty foods. It is important to remember, however, that foods served in most restaurants, particularly “fast foods,” are notoriously rich in sodium. To stress the importance of dietary sodium restriction, it is sometimes useful to show patients a display of salt shaker with the amount of table salt corresponding to the sodium content of their
own urine samples. A patient with urinary sodium of 300 mEq/d may become alarmed if shown a salt shaker nearly half full, and told that he or she had consumed all of that salt in a single day. High Urinary Sulfate Levels (More Than 30 mmol/d)
Animal products (i.e., beef, poultry, and fish) contain sulfur containing amino acids. In metabolized in vivo, the released sulfate is not degraded further and appears in urine. High urinary sulfate, therefore, is indicative of an excessive intake of animal proteins and signals exaggerated delivery of acid. This disturbance may be associated with hyperuricosuria and hypocitraturia. If dietary modification is not followed or possible, potassium citrate should overcome acid load and stoneforming propensity. CAUSESANDTREATMENTOF COMBINED DISTURBANCES
The majority of patients with stones present with more than one abnormal stone risk factor, involving a mixture of metabolic and environmental factors. This multiple presentation has posed a major confusion for many practicing urologists in medically managing patients with stones. In the following discussion, key examples of multiple presentation, selected from actual patient referrals, are discussed in detail (Table 2). Hypercalciuria, Hyperuricosuria, and Hypocitraturia
A 40-year-old man with calcium oxalate stones had a urinary calcium level of 350 to 400 mg/d, uric acid level of 790 mg/d, and citrate level of 300 mg/d. Urinary sodium and sulfate levels also were high, 300 mEq/d and 35 mmol/d, respectively. This presentation is perhaps the commonest picture describing a patient with absorptive kpercalciuria with dietary abuse. Excessive intake of sodium is indicated by high urinary sodium levels. Assuming that the urinary sodium level is nearly equal to the intake at steady state, the patient’s daily sodium intake was 200 mEq above the recommended amount of 100 mEq. This dietary
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Table 2. CAUSES AND TREATMENT OF COMBINED DISTURBANCES Findings 1. Hypercalciuria
Hyperuricosuria Hypocitraturia High urinary sodium 2. Low urinary pH Hyperuricosuria Hypocitraturia 3. Hypocitraturia
Hyperoxaluria Low urinary pH Low urine volume 4. Hyperuricosuria Hyperphosphaturia Hypercalciuria Low urinary pH Hypocitraturia 5. Hypocitraturia High urinary pH Hypercalciuria 6. High urinary pH Hyperoxaluria Normal uMary citrate
Condition
Treatment
Absorptive hypercalauria with dietary abuse
Thiazide Potassium citrate Sodium restriction
Gouty diathesis with dietary abuse
Potassium citrate Allopurinol if serum uric acid is high Sodium restriction Potassium-sodium citrate
Crohn’s disease
Exaggerated animal-protein excess
Potassium citrate
Incomplete renal tubular acidosis
Potassium citrate
Vegetarian diet with supplements
Dietary modification
sodium excess could increase urinary calcium by about 100 mg/ d. Even after this correction, the urinary calcium level still would be high at about 300 mg/d. The patient, therefore, had a metabolic background for hypercalciuria. The high urinary uric acid and sulfate levels indicated that the patient had ”purine gluttony.” The resulting acid load could explain a modest decline in urinary citrate. The recommended treatment for this patient is trichlormethiazide (4 mg/d) and potassium citrate (20 mEq twice daily), with sodium restriction. Thiazide can lower urinary calcium levels by enhancing renal tubular reabsorption of calcium, even though this action may become attenuated after 2 years of treatment in some patient^.'^ Sodium restriction is critical, because high sodium intake blunts the ability of thiazide to lower urinary calcium. Potassium citrate can not only prevent thiazide-induced hypokalemia but also neutralize the acid load from a diet high in animal protein and increase the urinary citrate level. Low Urinary pH, Hyperuricosuria, and Hypocitraturia
A 45-year old man had a urinary pH (in a 24-hour specimen) of 5.0, urinary uric-acid
level of 650 mg/d, and urinary citrate level of 310 mg/ d. His urinary sulfate level was 32 mmol/d. The serum uric acid level was 7.0 mg / dL, and the serum triglyceride level was 350 mg/dL. He denied having had gouty arthritis, bowel disease, or chronic diarrheal condition. Analysis of one stone disclosed calcium oxalate but another contained uric acid. This patient probably suffered from gouty diathesis with dietary abuse.7 The key abnormality is low urinary pH, which cannot be explained by intestinal loss of bicarbonate or a high-acid diet. The patient did not suffer from diarrhea. He probably was ingesting a diet high in animal protein, indicated by high urinary uric acid, citrate, and sulfate levels. The amount of acid load from such a diet, however, is probably insufficient to produce a urinary pH of 5.0. By a process of exclusion, the diagnosis is gouty diathesis. Low urinary pH is the hallmark of primary gout, the underlying disturbance for stone formation in gouty diathesis. This diagnosis is supported by the findings of uric acid on stone analysis and hypertriglyceridemia. Gouty diathesis is still a likely diagnosis even if uric acid is not found on stone analysis. Calcium oxalate stones frequently are found among patients with primary gout. Some patients with gouty diathesis present with calcium oxalate ~ t o n e s . ~ Hypertriglyceridemia commonly is encoun-
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tered in primary gout. The patient probably had latent gout, in which the disease is manifested mainly with defective ammoniagenesis and low urinary pH. This explanation could account for the absence of marked hyperuricemia and gouty arthritis. The treatment is potassium citrate at a dose sufficient to increase and maintain urinary pH between 6.0 and 6.5 (initial dose of 20 mEq twice daily). There is no need to add allopurinol in the absence of hyperuricemia. Urinary alkalinization (by potassium citrate) is much more effective than reduction in urinary uric acid (by allopurinol) in decreasing the amount of sparingly soluble undissociated uric acid. Dietary sodium restriction is recommended to avoid complication of calcium-stone f~rmation.'~ Hypocitraturia, Hyperoxaluria, Low Urinary pH, and Low Urine Volume A 30-year-old woman had severe hypocitraturia of 60 mg/d, severe hyperoxaluria of 100 mg/d, low urinary pH of 5.3, and low urine volume of 800 mL / d. She also had low urinary sodium (40 mEq/d), potassium (30 mEq/d), calcium (80 mg/d) and magnesium (30 mg/d) levels. She had fat malabsorption and frequent watery bowel movements secondary to Crohn's disease. Her stones were composed of uric acid and calcium oxalate. This patient had enteric hyperox~luria.~ Patients with inflammatory disease or resection of ileum are at increased risk of developing stones of uric acid and calcium oxalate from multiple disturbances. Urinary citrate and pH are low because metabolic acidosis from intestinal bicarbonate loss. Hyperoxaluria develops from enhanced intestinal absorption of oxalate. Urinary volume is low because of intestinal fluid loss, increasing the urinary concentration of stone-forming substances. Calcium oxalate saturation is increased by hyperoxaluria and low urine volume. The saturation of undissociated uric acid is high because of low urinary pH and volume. Some stone-forming patients with ileal disease may not show all of these urinary stone risk factors. For example, hyperoxaluria may not be present in all patients, and urine volume may be relatively normal. Most patients, however, display hypocitraturia and low urinary pH. The treatment has been discussed previously.
Hyperuricosuria, Hyperphosphaturia, Hypercalciuria, Low Urinary pH, and Hypocitraturia
A 36-year-old woman had a urinary uric acid level of 750 mg/d, a phosphorus level of 1400 mg/d, a calcium level of 270 mg/d, pH of 5.4, and a citrate level of 250 mg/d. Her urinary sulfate level was high at 36 mmol/d, but urinary oxalate level was low normal at 20 mg/d. She had been on a weight-reducing diet for 1 month, emphasizing animal proteins with severely limited intake of fruits and vegetables. She formed a stone composed of uric acid. This picture represents the characteristic presentation of markedly exaggerated animal protein excess. Hyperuricosuria results from purine load, and hyperphosphaturia from high phosphate content of meat products. Low urinary pH, hypocitraturia, and hypercalciuria are produced by acid load. Urinary oxalate sometimes is reduced because of low content of oxalate in meat products. These derangements theoretically could be prevented by potassium citrate therapy. Hypocitraturia, High Urinary pH, and Hypercalciuria
A 50-year-old woman had severe hypocitraturia of 50 mg/d, pH of 7.0, and hypercalciuria of 250 mg/d. She had formed stones composed of hydroxyapatite. An abdominal radio raph disclosed nephrocalcinosis. Althoug serum electrolyte levels were normal, her urinary pH did not decline below 5.4 on ammonium chloride challenge. She had incomplete distal RTA. The treatment is potassium citrate.
a
High Urinary pH, Hyperoxaluria with Normal Urinary Citrate
A 40-year-old man had urinary pH of 7.0, urinary oxalate level of 70 mg/d, and urinary calcium level of 260 mg/ d. His urinary citrate level was high normal at 750 mg/d, as was his uric acid level at 480 mg/d. His urinary ammonium level was low normal at 20 mmol/d. His wife had imposed a "healthy diet" composed of limited intake of meat products (one serving per day) with plentiful intake of vegetables and fruits and many multivitamins and minerals. Diet history dis-
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
closed a high intake of oxalate. He also was found to be taking 1.5 g / d vitamin C and 1.5 g / d calcium. He formed a calcium oxalate stone. He probably had an alkali load from his vegetarian diet, indicated by high urinary pH, high normal urinary citrate level, and low normal urinary ammonium and uric acid levels. This presentation alone probably did not cause stone formation. He also had taken calcium supplements and vitamin C, which led to hypercalciuria and hyperoxaluria. SUMMARY A simple, step-by-step approach to diagnosis and medical treatment of stone disease is described. It uses urinary stone risk profile obtained before and after dietary modification, history, and minimum diagnostic tests. For each abnormal stone risk factor, potential causes are discussed and treatment options are presented. The article concludes with diagnosis and treatment of combined disturbances.
References 1. Chaussey C, Schridt E, Brendel W Extracorporeally
2. 3. 4. 5.
6. 7.
induced destruction of kidney stones by shock waves. Lancet ii:1265-1268, 1980 Coe FL: Hyperuricosuric calcium oxalate nephrolithiasis. Kidney Int 13:418426, 1978 C w FL, Keck J, Norton R The natural history of calcium nephrolithiasis. JAMA 238:1519-1523, 1977 Earnest DL, Williams HE, Admirand WH: A physicochemical basis for treatment of enteric hyperoxaluria. Trans Assoc Am Phys 88:224-234, 1975 Fine JK, Pak CYC, Preminger G M Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 153:27-33, 1995 Hayashi Y, Kaplan RA, Pak CYC: Effect of sodium cellulose phosphate therapy on crystallization of calcium oxalate in urine. Metabolism 241273-1278,1975 Khatchadurian J, Preminger GM, Whitson PA, et al: Clinical and biochemical presentation of gouty diath-
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esis: Comparison of uric acid versus pure calcium stone formation. J Urol 154:166%1669,1995 8. Nicar MJ, Peterson R, Pak CYC: Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 131:430433,1984 9. Pak CYC Medical prevention of renal stone disease. Nephron, in press 10. Pak CYC: Physiologicalbasis for absorptive and renal hypercalciurias. Am J Physiol237F415-F423, 1979 11. Pak CYC Southwestern Internal Medicine Conference: Medical management of nephrolithiasis: A new, simplified approach- for general practice. Am J Med Sci 313:215-219, 1997 12. Pak CYC, Peterson R Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 146:863-868, 1986 13. Pak CYC, Sakhaee K, Fuller C: Successful treatment of uric acid nephrolithiasis with potassium citrate. Kidney Int 30422428,1986 14. Pak CYC, Skurla C, Harvey J: Graphic display of urinary risk factors for renal stone formation. J Urol 134:867-870, 1985 15. Pak CYC, Griffith DP, Menon M, et al: Urolithiasis. Current Practice Medicine. 4133-134,1996 16. Pak CYC, Oh MS, Baker S, et al: Effect of meal on the physiological and physicochemical actions of potassium citrate. J Urol 146:803-805, 1991 17. Preminger GM, Pak CYC Eventual attenuation of hypocalciuric response to hydrochlorothiazide in absorptive hypercalciuria. J Urol 1371104-1109, 1987 18. Preminger GM, Sakhaee K, Pak CYC: Hypercalciuria and altered intestinal calcium absorption occurring independently of vitamin D in incomplete renal tubular acidosis. Metabolism 36176-179, 1987 19. Rudman D, Dedonis JL, Fountain MT, et al: Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med 303:657-661, 1980 20. Sakhaee K, Alpern R, Poindexter J, et al: Citraturic response to oral citric acid load. J Urol 147975-976, 1992 21. Sakhaee K, Harvey JA, Padalino PK, et al: Potential role of salt abuse on the risk of kidney stone formation. J UrollW310-312, 1991 22. Sakhaee K, Nigam S, Snell P, et al: Assessment of the pathogenetic role of physical exercise in renal stone formation. J Clin Endocrinol Metab 653974-979, 1987 23. Sakhaee K, Williams RH, Oh MS, et ak Alkali absorption and citrate excretion in calcium nephrolithiasis. J Bone Miner Res 8787-792, 1993 24. Wabner CL, Pak CYC: Effect of orange juice consumption on urinary stone risk factors. J Urol 149:1405-1408, 1993 25. Yendt ER, Guay GF, Garcia D A Use of thiazides in the prevention of renal calculi. Can Med Assoc J 102614-620, 1970
Address reprint requests to Charles Y. C. Pak, MD Center for Mineral Metabolism and Clinical Research University of Texas Southwestern Medical School 5323 Harry Hines Boulevard Dallas, TX 75390-8885
UROLITHIASIS
+ .OO
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS Charles Y. C. Pak, MD, and Martin I. Resnick, MD
The introduction of extracorporeal shockwave lithotripsy (ESWL.) has revolutionized the urologic practice in urolithiasis.' This technology has reduced considerably the morbidity of stone disease, by allowing relatively noninvasive removal of stones. Unfortunately, the facilitated removal of stones by ESWL has led some urologists to abandon or disparage the medical approach to stone management. This development is unfortunate, because the need for medical diagnosis and prevention has not diminished. Renal stone disease is characterized by a high rate of rec~rrence.~ The propensity for stone recurrence is not altered by removal of stones with ESWL.5 Ample evidence has accumulated, however, showing that a variety of medical treatments can prevent recurrence of stones? There have been notable advances in the medical management of urolithiasis. A method for the analysis of urinary-stone risk factors in a 24-hour urine sample was described in 1985.14A graphic display of stone risk factors is now available commercially. A Supported by USPHS grants Pol-DK20543 and M01RR00633
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step-by-step approach to diagnosis and treatment of different causes of urolithiasis was described in 1996.15A simplified, nonselective treatment program was recommended in 1997." Despite this progress, many urologists are confused by current guidelines on medical diagnosis and prevention. It is the objective of this article to offer practical guidelines in medical management of urolithiasis. Although borrowing from prior recommendations,", 14, l5 the current guidelines represent a simpler version directed at a practicing urologist. Described here in stepwise fashion is the approach that a practicing urologist might take in medically diagnosing and managing patients with stones, summarized as follows: Step 1. History and minimum diagnostic tests Step 2. 24-hour urinary stone risk profile (customary diet) Identification of abnormal dietary risk factors Short-term dietary modification Step 3. Repeat stone risk profile after dietary modification Step 4. Elucidation of causes and construction of treatment options for abnormal risk factms ~
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From the Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical School, Dallas, Texas (CYCP) and the Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, Ohio (MIR)
UROLOGIC CLINICS OF NORTH AMERICA VOLUME 27 NUMBER 2 MAY 2000
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Relevant history and minimum diagnostic test results first are obtained. A full 24-hour stone risk profile is measured on a random diet and fluid intake. Another stone risk profile is obtained after a short-term dietary modification. From these simplified tests, potential causes are discerned and treatment options are constructed for each abnormal stonerisk factor and combined derangements. SIMPLE DIAGNOSTIC APPROACH Initial Visit
The first step, to be undertaken during the initial visit, is to take a careful history and conduct minimum diagnostic tests: History Secondary causes Dietary aberrations Stone-provoking drugs Minimum diagnostic tests Abdominal radiograph of the kidneys, ureter, and bladder Urinary sediment (crystals) Serum calcium, potassium, electrolytes, and uric-acid levels History
In all patients with stones, a careful history should be taken. The history should include prior stone occurrences, family history of stones, and history of gout, bowel disease, fluid loss, or urinary-tract infection; dietary aberrations; and use of stone-provoking medications. Gout, bowel disease, urinary-tract infection, and excessive fluid loss represent potential secondary causes of stones. Dietary aberrations include low intake of fluids or citrus fruits and a high intake of calcium, oxalate, sodium or animal proteins. Drugs that can cause stones include those that can increase urinary calcium (acetazolamide, calcium-channel blockers, calcium or vitamin D preparations, phosphorus-binding antacids, furosemide, and theophylline), oxalate (vitamin C), uric acid (uricosuric agents), and those than can enhance urinary excretion of poorly soluble substances (triamterene). Minimum Diagnostic Tests
The following tests should be obtained in any patient presenting with stones, for the
first time or after prior stone episodes: Urinalysis and culture; radiograph of kidneys, ureter, and bladder; stone analysis; and measurement of serum calcium, phosphorus, electrolyte, uric-acid, and creatinine levels. The finding of calcium oxalate crystals is not overly useful, because they can be found in normal urine. The detection of cystine or struvite (magnesium-ammonium phosphate) crystals, however, is diagnostic of cystinuria or infection stones, respectively. A positive culture for urea-splitting organisms is indicative of infection stones. Radioopaque stones imply the presence of calcium oxalate, calcium phosphate, struvite, or cystine. Radiolucency suggests that stones might be composed of uric acid. The finding of cystine and struvite on stone analysis is diagnostic of cystinuria and infection stones, respectively. Uric-acid stones are indicative of conditions that cause low urinary pH (e.g., such as gout or chronic diarrheal states) or marked hyperuricosuria. Stones composed largely of calcium phosphate (hydroxyapatite) are suggestive of primary hyperparathyroidism, renal tubular acidosis, and sodium alkali therapy. Of lesser diagnostic importance are common stones of calcium oxalate. They are encountered with hypercalciuria, hyperoxaluria, hypocitraturia, hypomagnesiuria, or low urine volume. Presence of hypercalcemia and hypophosphatemia is indicative of primary hyperparathyroidism. Hypokalemia and high serum bicarbonate concentration are suggestive of renal tubular acidosis. Hyperuricemia indicates gouty diathesis. Twenty-four-hour Urinary Stone Risk Profile on the Customary Diet
The second step, to be undertaken in recurrent stone formers and first-time stone formers with increased risk (i.e., family history of stones, bone or bowel disease, gout, chronic urinary-tract infection, or nephrocalcinosis), is to obtain a 24-hour urine sample, while patients maintain their customary diets and fluid intakes, for the analysis of full stone risk pr0fi1e.I~The metaboZic factors include calcium, oxalate, uric acid, citrate, and pH. Environmental factors comprise total volume, sodium, sulfate, phosphorus, and magnesium. Physicochemical factors are urinary saturation of calcium oxalate, brushite (CaHP0,.2H20), monosodium urate, and uric acid, expressed
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
relative to mean values in normal subjects without stones. Identification of Abnormal Dietary Risk Factors
Aberrations in diet and fluids can produce abnormal environmental factors cited previously. They also could exaggerate disturbances in metabolic factors. From the stone risk profile, it is important to identify aberrant environmental risk factors and try to correct them with dietary modification. Short-term Dietary Modification
If urinary total volume is less than 2 L/d, patients should increase fluid intake. If urinary sodium exceeds 200 mEq/d, sodium intake should be restricted. In general, this goal may be achieved by avoidance of salt shakers and obviously salty foods. If urinary oxalate exceeds 45 mg / d, one should impose dietary oxalate restriction, that is, limitation or avoidance of tea, spinach, and other dark roughage; nuts; and chocolate. Vitamin C in excess of 500 mg/d is not advisable because it can be converted to oxalate. If urinary calcium exceeds 250 mg / d in a patient taking a high-calcium diet, a moderate calcium restriction might be imposed, for example, 1 glass of milk and a small serving of another dairy product per day. If urinary uricacid and sulfate levels exceed 700 mg/d and 30 mmol/ d, respectively, one should restrict animal proteins by limiting the intake of beef, poultry, and fish to two servings per day. If urinary pH, citrate, and potassium are low, patients should be told to increase the intake of potassium-rich citrus fruits (e.g., orange, grapefruit, and cranberry). Repeat 24-hour Profile After Short-term Dietary Modification: Identification of Abnormal Environmental and Metabolic Risk Factors
In the third step, another 24-hour urine is to be collected for a stone risk profile, after the dietary modification described previously for 1 week. From a stone risk profile so obtained it is important to identify abnormal environmental and metabolic risk factors. The stone risk profile obtained following dietary modification is compared with that
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measured on a random diet. The correction of aberrant risk factors by dietary modification suggests that such abnormalities are environmental in origin. If risk factors considered to be clearly environmental remain abnormal (e.g., low urine volume or high urinary sodium level), the dietary modification may have been inadequate or poorly followed. In contrast, the persistence of abnormal metabolic stone risk factors would confirm that the derangements were metabolic in origin. In the fourth step, potential causes are discerned and treatment guidelines are constructed, for each abnormal urinary risk factor and combination of deranged risk factors. This task is aided by history, minimum diagnostic tests, and stone risk profiles.
CAUSESANDTREATMENTOF INDIVIDUAL ABNORMAL STONE RISK FACTORS Long-term Dietary Modification
In all patients with stones, dietary modification should be continued in the long term:
High fluid intake: At least ten 10-02glasses per day Sodium restriction: Avoidance of salt shakers and salty foods Oxalate restriction: Avoidance of nuts, dark roughage, chocolate, tea, vitamin C Restriction of animal proteins: Limited servings of meat products Increased citrus fruits: Potassium-rich products preferable The high fluid intake and restriction of sodium and oxalate should be maintained, without fear of adverse effects on health. In most patients, purine restriction is difficult to maintain. Adequate intake of fruits and vegetables to balance the intake of animal proteins should be encouraged. Potassium-rich citrus fruits, such as orange, grapefruit and cranberry, are preferable to low-potassium citrus fruits, such as lime and lemon. Orange juice, for example, represents a natural form of potassium citrate and possesses alkalinizing and citraturic action." Lime juice, on the other hand, is composed largely of citric acid, and does not affect acid-base balance appreciably.20Thus, it does not alter urinary pH and only modestly increases urinary citrate (from the renal clearance of a small
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parathyroidism should be suspected if serum PTH is high.
amount of absorbed citrate that escapes oxidation in vivo). If long-term restriction of calcium is contemplated, it is important to make sure that the patient does not suffer from excessive bone loss. Measurement of bone density, particularly in the spine, is recommended. Treatment options are discussed here for each risk factor and combination of factors (Table 1).
Associated with Hypercalcemia
Associated with Sodium Excess One should check urinary sodium in order to estimate the increment in urinary calcium produced by excessive sodium intake. If the urinary sodium level exceeds 100 mEq/d, every increment in sodium of 100 mEq can increase urinary calcium by about 50 mg/d?l One should re-emphasize the importance of sodium restriction, by avoidance of the use of salt shakers and ingestion of salty foods. Recommended sodium intake is 100 mEq/d or one teaspoonful of table salt per day.
One should check serum calcium and phosphorus levels from step 1. If the serum calcium level is high, one should obtain serum parathyroid hormone (PTH). Primary hyper-
Absorptive or Renal Hypercalciuria If a high serum calcium or urinary sodium level cannot account for hypercalciuria, the
Hypercalciuria (More Than 250 mg/d)
Table 1. CAUSES AND TREATMENT OPTIONS FOR INDIVIDUAL METABOLIC RISK FACTORS ~~~~
Condition
Hypercalciuria With hypercalcemia With high urinary sodium Absorptive and renal hypercalciuria Hyperoxaluria Mild Moderate-severe Ileal disease Primary/ metabolic Hypocitraturia Severe Chronic diarrhea Distal RTA Infection Mild-moderate Dietary Incomplete RTA Hypokalemia of thiazide Hyperuricosuria With normouricemia Mild-moderate Normal urinary citrate Hypocitraturia Severe (>go0 mg/d) With hyperuricemia Low urinary pH Gouty diathesis Chronic diarrhea Physical exercise Severe high-protein diet High urinary pH pH 7.0-7.5 Distal RTA Vegetarian diet pH >7.5 Infection stones RTA = renal tubular acidosis.
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Causes
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Dispositiodlreatment
Primary hyperparathyroidism High sodium intake Metabolic causes
Check parathyroid status Sodium restriction Thiazide and potassium citrate
Dietary causes
Restrict dietary oxalate
Increased oxalate absorption Enzymatic disturbances
Oxalate restriction, calcium citrate Pyridoxine
Metabolic acidosis Renal acidification defect Enzymatic degradation
Potassium-sodium citrate Potassium citrate Antibiotic, urea% inhibitor
Animal-protein excess Renal acidification defect Intracellular acidosis
Potassium citrate Potassium citrate Potassium citrate
Dietary purine excess Dietary purine excess Dietary purine excess Primary gout
None Potassium citrate Allopurinol Allopurinol
Defective ammoniagenesis Intestinal bicarbonate loss Lactic acidosis Dietary acid excess
Potassium citrate Potassium-sodium citrate Balanced electrolyte fluids Potassium citrate
Renal acidification defect Dietary alkali
Potassium citrate Oxalate restriction
Urea-splitting infection
Antibiotic, urease inhibitor
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
patient probably has absorptive or renal hypercalciuria. Absorptive hypercalciuria is caused by enhanced intestinal absorption of calcium, whereas renal hypercalciuria results from the impaired renal tubular reabsorption (renal leak) of calcium.'O The two conditions can be distinguished by normal or low serum F"H levels in the former and high serum PTH levels in the latter. Diagnostic separation is not necessary for the initiation of medical treatment. Treatment should be considered initially with trichlormethiazide 4 mg/d with potassium citrate 20 mEq twice daily." The long duration of action of trichlormethiazide allows it to be given on a once-daily schedule. Trichlormethiazide generally is tolerated better than short-acting thiazides. Most patients prefer a tablet formulation of potassium citrate rather than liquid formulations. The tablet formulation may be given with meals in order to reduce minor gastrointestinal side effects, without sacrificing the physiologic action.16 The objective of thiazide treatment is to reduce urinary calcium level by an effect on the renal handling of calcium." In patients with renal hypercalciuria, a long-term correction of hypercalciuria may be achieved with thiazide. Some patients with absorptive hypercalciuria show a loss of thiazide's hypocalciuric action after about 2 years of treatment.I7 A temporary withdrawal of therapy may be necessary. It is critical to restrict sodium intake, because a high sodium intake could blunt thiazide's hypocalciuric action. The objective of adjunctive potassium citrate treatment is to rovide potassium to avert development of ypokalemia, and to confer an alkali load to increase urinary citrate? an inhibitor of stone formation. The dose of potassium citrate may be adjusted based on serum potassium and urinary citrate levels measured after 4 to 6 months of treatment.
x
Hyperoxaluria (More Than 45 mg/d) Mild Hyperoxaluria (Urinary Oxalate Less Than 60 mg/d) Mild hyperoxaluria generally is caused by dietary factors. One should suspect overconsumption of oxalate-rich foods, such as spinach and dark roughage, tea, chocolate, and nuts. Vitamin C supplementation of more than 500 mg/ d could raise the urinary oxalate level by serving as a substrate. Patients suffer-
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ing from absorptive hypercalciuria maintained on calcium restriction could have mild hyperoxaluria, because of the insufficient amount of calcium left in the bowel to bind oxalate. Dietary oxalate restriction should be emphasized, and vitamin C supplementation limited to no less than 500 mg/d. There is no evidence that long-term oxalate restriction is hazardous to health. Moderate to Severe Hyperoxaluria (Urinary Oxalate Greater Than or Equal to 60 mg/d)
If this level of urinary oxalate is encountered, the presence of bowel disease should be suspected. In patients with intestinal malabsorption offat, inflammatory diseases, or resection of the small bowel, oxalate absorption can be increased substantially by two mechanism^.^ The nonabsorbed bile salts and fatty acids may stimulate mucosal permeability to oxalate directly. Oxalate absorption also may be stimulated indirectly from an enlarged pool of absorbable oxalate. Nonabsorbed fatty acids bind calcium and magnesium in the bowel, leaving an insufficient amount of divalent cations to bind oxalate. Patients suffering from small-bowel disease without functioning colons may not develop hyperoxaluria, because the colon is the principal site of oxalate absorption. A rigid restriction of dietary oxalate is critical. Solubilized calcium citrate (e.g., Citracal Liquitab) may help to lower urinary oxalate by binding oxalate. Hyperoxaluria often coexists with low urinary citrate and magnesium levels, pH, and volume (discussed in a subsequent section). Moderate hyperoxaluria (up to 70 mg/d) may be encountered in patients with absorptive hypercalciuria taking sodium cellulose phosphate.6 The amount of free calcium in the bowel can be reduced severely from enhanced absorption of calcium and binding of calcium to the drug, increasing the absorbable oxalate pool. A rigid control of oxalate intake is critical. This situation seldom is encountered now because of infrequent use of sodium cellulose phosphate. In the absence of bowel disease or the use of sodium cellulose phosphate, one might consider mild metabolic hyperoxaluria or primary hyperoxaluria to explain moderate to severe hyperoxaluria. Suppression of oxalate synthesis in vivo is necessary. Pyridoxine 100 to 200 mg / d may be useful.
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Hypocitraturia (Less Than 320 mud) Severe Hypocitraturia (Less Than 700 mdd)
In this situation, one should suspect bowel disease. Any chronic diarrheal state that produces metabolic acidosis can cause hypocitraturia.19 Thus, gastrectomy and ulcerative colitis may produce hypocitraturia, though not hyperoxaluria. After application of treatments directed at diarrhea, it is important to provide alkali therapy to correct or ameliorate metabolic acidosis. A liquid formulation of potassium and sodium citrate is preferable. In patients with severe bowel disease, a full correction of hypocitraturia ma not be possible. A partial amelioration of ypocitraturia, however, may bring a substantial improvement in stone disease. Another cause of severe hypocitraturia is complete distal renal tubular acidosis. Patients typically have low serum potassium, high serum bicarbonate, hypercalciuria, and high urinary pH (near 7). Treatment is potassium citrate at a dose sufficient to correct metabolic acidosis (2040 mEq twice daily). Some patients may have renal impairment. Potassium citrate should be used with caution, with frequent monitoring of serum potassium concentration. Finally, severe hypocitraturia may be found in infection stones (magnesium and ammonium phosphate or carbonate apatite). Citrate may be used as a substrate by bacterial enzymes.
K
Mild to Moderate Hypocitraturia (700-320mdd)
A mild to moderate decrease in urinary citrate is usually dietary in origin (relative acid excess).= Affected patients may show a preference for animal proteins (i.e., beef, poultry, and fish) over vegetables and fruits. Urinary uric-acid and sulfate levels may be high. If patients are willing, dietary restriction of animal proteins may be useful. In most patients, it probably is easier to apply treatment with potassium citrate (initial dose of 20 mEq twice daily). The dose should be adjusted based on urinary citrate obtained at 4 to 6 months of treatment. A minority of patients with mild to moderate hypocitraturia may have incomplete renal tubular acidosis (RTA). Unlike in complete
RTA, serum electrolytes are normal and urinary pH may be normal. A defect in renal acidification is shown by inadequate acidification of urine upon ammonium chloride challenge. A definitive diagnosis is not necessary, however, for a satisfactory treatment. The treatment of choice is potassium citrate, as in acquired (dietary) mild to moderate hypocitraturia. In complete and incomplete forms of distal RTA, potassium citrate treatment may exert a beneficial extrarenal action. This treatment may prevent bone loss, by reducing urinary calcium and increasing intestinal calcium absorption.18 Mild to moderate hypocitraturia also may develop from hypokalemia of thiazide treatment for hypercalciuric nephrolithiasis.8 Hypokalemia may produce hypocitraturia by producing intracellular acidosis. Thus, it is advisable to always provide potassium supplementation with thiazide treatment. Potassium citrate is preferable to potassium chloride because it can raise urinary citrate (inhibitor of stone formation) to above the prethiazide range.8
Low Normal Urinary Citrate Level (320-400mdd) The low range of normal for urinary citrate is wide (low normal limit of 320 mg/d and mean normal of 640 mg/d). It may be advisable to treat patients with urinary citrate levels in the lower end of the normal range. A small dose of potassium citrate (10 mEq twice daily) may be sufficient. Hyperuricosuria (>700 mg/d) With Normouricemia
In most patients, hyperuricosuria is caused by dietary excess of purines (animal proteins)? Urinary sulfate levels may be high. Serum uric-acid level tends to be high normal but rarely is increased above the normal range. In committed patients, a balanced diet might be recommended, with a reduced intake of animal proteins and increased intake of vegetables and fruits. The long-term compliance with dietary modification, however, is generally poor in most patients. Allopurinol and potassium citrate are potentially useful in preventing the formation of calcium oxalate stones in patients with hyperuricosuria. Allopurinol does so by re-
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
249
ducing uric-acid synthesis and excretion. The induced hypercitratria from alkali therapy can retard urate-induced calcium oxalate crystallization.12In general, allopurinol (300 mg/ d) is indicated for patients with marked hyperuricosuria (more than 800 mg/d). In those with mild to moderate hyperuricosuria (no more than 800 mg/d), only conservative treatment may be necessary if urinary citrate levels are normal. If hypocitraturia coexists, potassium citrate alone may be sufficient.
dose of 20 mEq twice daily) at a dose sufficient to keep urinary pH at about 6.0 to 6.5. Low urinary pH also is encountered in metabolic acidosis of chronic diarrheal states (see section on hypocitraturia). Finally, low urinary pH may develop during strenuous physical exercise from lactic acidosis.22It is important to remind stone-forming patients who wish to participate in an exercise program to take adequate fluids containing balanced electrolytes before and after exercise.
With Hyperuricemia
High Urinary pH (>7)
If serum uric acid is elevated frankly, suspect gouty diathesis (i.e., stone disease of primary g o ~ t )Urinary .~ pH is typically low, and the serum triglyceride level may be high. Allopurinol (300 mg/d) is indicated to reduce serum uric acid in order to lower the risk of gouty arthritis. If urinary pH is low, potassium citrate also is required (discussed subsequently).
Urinary pH Between 7.0 and 7.5 For patients with high urinary pH, one should suspect distal RTA. Urinary citrate is expected to be low as well (see section on hypocitraturia). The treatment is potassium citrate. This degree of rise in urinary pH also may be encountered in patients who are kept on a vegetarian diet (e.g., low in proteins and high in vegetables and fruits). Their urinary citrate levels, however, are expected to be high, unlike in patients with RTA. Other clues might be low urinary uric acid and sulfate and high urinary oxalate levels.
Low Urinary pH (Less Than 5.5)
Excessive acid intake from the diet rarely can cause a decline in 24-hour urinary pH to below 5.5. It may exaggerate the decline in pH produced by other factors, however. If urinary pH is less than 5.5 in a 24-hour urine specimen, one should suspect gouty diathes ~ schronic ,~ diarrheal state,l9 or strenuous physical exercise.22 Gouty diathesis represents fully manifested primary gout or an early phase of primary Unfortunately, this condition often is understood poorly by many practicing urologists, even though it is easy to treat with an invariably satisfactory response. The low urinary pH is believed to be the result of impaired renal ammoniagenesis. Uric-acid stones develop from the impaired dissociation of uric acid, which increases the amount of sparingly soluble, undissociated uric acid. Calcium-containing stones may develop as well from the urate-induced crystallization of calcium oxalate. Thus, stones formed by patients with gouty diathesis are composed of uric acid alone, calcium oxalate alone, or both. Secondary to primary gout, serum uric acid and trigyceride levels may be elevated, and some patients may have a personal history or present with a family history of gouty arthritis. The treatment is potassium citrate (initial
Urinary pH > 7.5 The action of normal urinary buffers does not allow urinary pH to exceed 7.5. If pH exceeds this value, one should suspect infection of the urinary tract with urea-splitting organisms. Urinary pH even may exceed 8, from the release of hydroxyl ions upon hydrolysis of urea. Other abnormal findings from stone risk profile might be increased urinary ammonium and saturation of struvite.
Low Urine Volume (Less Than 2 Ud) Mild to Moderate Reduction in Urine Volume ( 1 -2 U d) If 24-hour urine volume ranges from 1 to 2 L, one should consider reduced fluid infake as a cause. In a 70-kg human being, insensible loss from feces and sweat is normally about 1 L/d. Thus, to produce a urine output of 2 L / d a subject must drink about 3 L / d of fluids total. That amount translates to about nine 10-02 glasses of water or other beverages, assuming that about one glassful of water is contained in solid food. If a subject sweats excessively, more fluids must be drunk to achieve urine output of 2 L/d.
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Any patient with fluid consumption below this level may have a low urine output. Increased fluid intake above that level is recommended to keep urine output above 2 L/d. Desired fluids are potassium-containing fruit juices, citrate-containing soft drinks, and water. Potassium-containingfruit juices (e.g., orange, grapefruit, cranberry) exert citraturic action by conferring an alkali load. Citratecontaining soft drinks (e.g., Sprite, 7-Up, Slice) are similar to diluted orange juice with respect to the content of potassium and citrate. Less desirable are tea (because of high oxalate content) and milk (because of high calcium content). Very Low Urine Volume (Less Than 1 Ud)
Very low urine output can be caused by inadequate fluid ingestion. It also may be encountered in patients with chronic diarrheal conditions, even if they are imbibing adequate amounts of fluids. Besides a history of diarrhea and low urine output, clues to excessive intestinal fluid loss are low urinary pH, sodium, potassium, and citrate. High Urinary Sodium (>200 mEq/day)
Under steady-state conditions, a high urinary sodium level is indicative of an excessive intake of sodium. High sodium intake contributes to stone formation in several ways.** First, it increases the urinary calcium level by reducing renal tubular reabsorption of calcium. Second, high sodium intake can cause a mild reduction in urinary citrate level by provoking mild bicarbonaturia and metabolic acidosis. Third, it can increase urinary saturation of monosodium urate, causing urateinduced calcium oxalate crystallization. Fourth, sodium excess could attenuate the hypocalciuric action of thiazide, rendering this treatment ineffective in the management of hypercalciuric nephrolithiasis. The desired sodium intake of 100 mEq/d generally can be achieved by avoidance of salt shakers and salty foods. It is important to remember, however, that foods served in most restaurants, particularly “fast foods,” are notoriously rich in sodium. To stress the importance of dietary sodium restriction, it is sometimes useful to show patients a display of salt shaker with the amount of table salt corresponding to the sodium content of their
own urine samples. A patient with urinary sodium of 300 mEq/d may become alarmed if shown a salt shaker nearly half full, and told that he or she had consumed all of that salt in a single day. High Urinary Sulfate Levels (More Than 30 mmol/d)
Animal products (i.e., beef, poultry, and fish) contain sulfur containing amino acids. In metabolized in vivo, the released sulfate is not degraded further and appears in urine. High urinary sulfate, therefore, is indicative of an excessive intake of animal proteins and signals exaggerated delivery of acid. This disturbance may be associated with hyperuricosuria and hypocitraturia. If dietary modification is not followed or possible, potassium citrate should overcome acid load and stoneforming propensity. CAUSESANDTREATMENTOF COMBINED DISTURBANCES
The majority of patients with stones present with more than one abnormal stone risk factor, involving a mixture of metabolic and environmental factors. This multiple presentation has posed a major confusion for many practicing urologists in medically managing patients with stones. In the following discussion, key examples of multiple presentation, selected from actual patient referrals, are discussed in detail (Table 2). Hypercalciuria, Hyperuricosuria, and Hypocitraturia
A 40-year-old man with calcium oxalate stones had a urinary calcium level of 350 to 400 mg/d, uric acid level of 790 mg/d, and citrate level of 300 mg/d. Urinary sodium and sulfate levels also were high, 300 mEq/d and 35 mmol/d, respectively. This presentation is perhaps the commonest picture describing a patient with absorptive kpercalciuria with dietary abuse. Excessive intake of sodium is indicated by high urinary sodium levels. Assuming that the urinary sodium level is nearly equal to the intake at steady state, the patient’s daily sodium intake was 200 mEq above the recommended amount of 100 mEq. This dietary
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
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Table 2. CAUSES AND TREATMENT OF COMBINED DISTURBANCES Findings 1. Hypercalciuria
Hyperuricosuria Hypocitraturia High urinary sodium 2. Low urinary pH Hyperuricosuria Hypocitraturia 3. Hypocitraturia
Hyperoxaluria Low urinary pH Low urine volume 4. Hyperuricosuria Hyperphosphaturia Hypercalciuria Low urinary pH Hypocitraturia 5. Hypocitraturia High urinary pH Hypercalciuria 6. High urinary pH Hyperoxaluria Normal uMary citrate
Condition
Treatment
Absorptive hypercalauria with dietary abuse
Thiazide Potassium citrate Sodium restriction
Gouty diathesis with dietary abuse
Potassium citrate Allopurinol if serum uric acid is high Sodium restriction Potassium-sodium citrate
Crohn’s disease
Exaggerated animal-protein excess
Potassium citrate
Incomplete renal tubular acidosis
Potassium citrate
Vegetarian diet with supplements
Dietary modification
sodium excess could increase urinary calcium by about 100 mg/ d. Even after this correction, the urinary calcium level still would be high at about 300 mg/d. The patient, therefore, had a metabolic background for hypercalciuria. The high urinary uric acid and sulfate levels indicated that the patient had ”purine gluttony.” The resulting acid load could explain a modest decline in urinary citrate. The recommended treatment for this patient is trichlormethiazide (4 mg/d) and potassium citrate (20 mEq twice daily), with sodium restriction. Thiazide can lower urinary calcium levels by enhancing renal tubular reabsorption of calcium, even though this action may become attenuated after 2 years of treatment in some patient^.'^ Sodium restriction is critical, because high sodium intake blunts the ability of thiazide to lower urinary calcium. Potassium citrate can not only prevent thiazide-induced hypokalemia but also neutralize the acid load from a diet high in animal protein and increase the urinary citrate level. Low Urinary pH, Hyperuricosuria, and Hypocitraturia
A 45-year old man had a urinary pH (in a 24-hour specimen) of 5.0, urinary uric-acid
level of 650 mg/d, and urinary citrate level of 310 mg/ d. His urinary sulfate level was 32 mmol/d. The serum uric acid level was 7.0 mg / dL, and the serum triglyceride level was 350 mg/dL. He denied having had gouty arthritis, bowel disease, or chronic diarrheal condition. Analysis of one stone disclosed calcium oxalate but another contained uric acid. This patient probably suffered from gouty diathesis with dietary abuse.7 The key abnormality is low urinary pH, which cannot be explained by intestinal loss of bicarbonate or a high-acid diet. The patient did not suffer from diarrhea. He probably was ingesting a diet high in animal protein, indicated by high urinary uric acid, citrate, and sulfate levels. The amount of acid load from such a diet, however, is probably insufficient to produce a urinary pH of 5.0. By a process of exclusion, the diagnosis is gouty diathesis. Low urinary pH is the hallmark of primary gout, the underlying disturbance for stone formation in gouty diathesis. This diagnosis is supported by the findings of uric acid on stone analysis and hypertriglyceridemia. Gouty diathesis is still a likely diagnosis even if uric acid is not found on stone analysis. Calcium oxalate stones frequently are found among patients with primary gout. Some patients with gouty diathesis present with calcium oxalate ~ t o n e s . ~ Hypertriglyceridemia commonly is encoun-
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tered in primary gout. The patient probably had latent gout, in which the disease is manifested mainly with defective ammoniagenesis and low urinary pH. This explanation could account for the absence of marked hyperuricemia and gouty arthritis. The treatment is potassium citrate at a dose sufficient to increase and maintain urinary pH between 6.0 and 6.5 (initial dose of 20 mEq twice daily). There is no need to add allopurinol in the absence of hyperuricemia. Urinary alkalinization (by potassium citrate) is much more effective than reduction in urinary uric acid (by allopurinol) in decreasing the amount of sparingly soluble undissociated uric acid. Dietary sodium restriction is recommended to avoid complication of calcium-stone f~rmation.'~ Hypocitraturia, Hyperoxaluria, Low Urinary pH, and Low Urine Volume A 30-year-old woman had severe hypocitraturia of 60 mg/d, severe hyperoxaluria of 100 mg/d, low urinary pH of 5.3, and low urine volume of 800 mL / d. She also had low urinary sodium (40 mEq/d), potassium (30 mEq/d), calcium (80 mg/d) and magnesium (30 mg/d) levels. She had fat malabsorption and frequent watery bowel movements secondary to Crohn's disease. Her stones were composed of uric acid and calcium oxalate. This patient had enteric hyperox~luria.~ Patients with inflammatory disease or resection of ileum are at increased risk of developing stones of uric acid and calcium oxalate from multiple disturbances. Urinary citrate and pH are low because metabolic acidosis from intestinal bicarbonate loss. Hyperoxaluria develops from enhanced intestinal absorption of oxalate. Urinary volume is low because of intestinal fluid loss, increasing the urinary concentration of stone-forming substances. Calcium oxalate saturation is increased by hyperoxaluria and low urine volume. The saturation of undissociated uric acid is high because of low urinary pH and volume. Some stone-forming patients with ileal disease may not show all of these urinary stone risk factors. For example, hyperoxaluria may not be present in all patients, and urine volume may be relatively normal. Most patients, however, display hypocitraturia and low urinary pH. The treatment has been discussed previously.
Hyperuricosuria, Hyperphosphaturia, Hypercalciuria, Low Urinary pH, and Hypocitraturia
A 36-year-old woman had a urinary uric acid level of 750 mg/d, a phosphorus level of 1400 mg/d, a calcium level of 270 mg/d, pH of 5.4, and a citrate level of 250 mg/d. Her urinary sulfate level was high at 36 mmol/d, but urinary oxalate level was low normal at 20 mg/d. She had been on a weight-reducing diet for 1 month, emphasizing animal proteins with severely limited intake of fruits and vegetables. She formed a stone composed of uric acid. This picture represents the characteristic presentation of markedly exaggerated animal protein excess. Hyperuricosuria results from purine load, and hyperphosphaturia from high phosphate content of meat products. Low urinary pH, hypocitraturia, and hypercalciuria are produced by acid load. Urinary oxalate sometimes is reduced because of low content of oxalate in meat products. These derangements theoretically could be prevented by potassium citrate therapy. Hypocitraturia, High Urinary pH, and Hypercalciuria
A 50-year-old woman had severe hypocitraturia of 50 mg/d, pH of 7.0, and hypercalciuria of 250 mg/d. She had formed stones composed of hydroxyapatite. An abdominal radio raph disclosed nephrocalcinosis. Althoug serum electrolyte levels were normal, her urinary pH did not decline below 5.4 on ammonium chloride challenge. She had incomplete distal RTA. The treatment is potassium citrate.
a
High Urinary pH, Hyperoxaluria with Normal Urinary Citrate
A 40-year-old man had urinary pH of 7.0, urinary oxalate level of 70 mg/d, and urinary calcium level of 260 mg/ d. His urinary citrate level was high normal at 750 mg/d, as was his uric acid level at 480 mg/d. His urinary ammonium level was low normal at 20 mmol/d. His wife had imposed a "healthy diet" composed of limited intake of meat products (one serving per day) with plentiful intake of vegetables and fruits and many multivitamins and minerals. Diet history dis-
MEDICAL THERAPY AND NEW APPROACHES TO MANAGEMENT OF UROLITHIASIS
closed a high intake of oxalate. He also was found to be taking 1.5 g / d vitamin C and 1.5 g / d calcium. He formed a calcium oxalate stone. He probably had an alkali load from his vegetarian diet, indicated by high urinary pH, high normal urinary citrate level, and low normal urinary ammonium and uric acid levels. This presentation alone probably did not cause stone formation. He also had taken calcium supplements and vitamin C, which led to hypercalciuria and hyperoxaluria. SUMMARY A simple, step-by-step approach to diagnosis and medical treatment of stone disease is described. It uses urinary stone risk profile obtained before and after dietary modification, history, and minimum diagnostic tests. For each abnormal stone risk factor, potential causes are discussed and treatment options are presented. The article concludes with diagnosis and treatment of combined disturbances.
References 1. Chaussey C, Schridt E, Brendel W Extracorporeally
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induced destruction of kidney stones by shock waves. Lancet ii:1265-1268, 1980 Coe FL: Hyperuricosuric calcium oxalate nephrolithiasis. Kidney Int 13:418426, 1978 C w FL, Keck J, Norton R The natural history of calcium nephrolithiasis. JAMA 238:1519-1523, 1977 Earnest DL, Williams HE, Admirand WH: A physicochemical basis for treatment of enteric hyperoxaluria. Trans Assoc Am Phys 88:224-234, 1975 Fine JK, Pak CYC, Preminger G M Effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. J Urol 153:27-33, 1995 Hayashi Y, Kaplan RA, Pak CYC: Effect of sodium cellulose phosphate therapy on crystallization of calcium oxalate in urine. Metabolism 241273-1278,1975 Khatchadurian J, Preminger GM, Whitson PA, et al: Clinical and biochemical presentation of gouty diath-
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esis: Comparison of uric acid versus pure calcium stone formation. J Urol 154:166%1669,1995 8. Nicar MJ, Peterson R, Pak CYC: Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 131:430433,1984 9. Pak CYC Medical prevention of renal stone disease. Nephron, in press 10. Pak CYC: Physiologicalbasis for absorptive and renal hypercalciurias. Am J Physiol237F415-F423, 1979 11. Pak CYC Southwestern Internal Medicine Conference: Medical management of nephrolithiasis: A new, simplified approach- for general practice. Am J Med Sci 313:215-219, 1997 12. Pak CYC, Peterson R Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 146:863-868, 1986 13. Pak CYC, Sakhaee K, Fuller C: Successful treatment of uric acid nephrolithiasis with potassium citrate. Kidney Int 30422428,1986 14. Pak CYC, Skurla C, Harvey J: Graphic display of urinary risk factors for renal stone formation. J Urol 134:867-870, 1985 15. Pak CYC, Griffith DP, Menon M, et al: Urolithiasis. Current Practice Medicine. 4133-134,1996 16. Pak CYC, Oh MS, Baker S, et al: Effect of meal on the physiological and physicochemical actions of potassium citrate. J Urol 146:803-805, 1991 17. Preminger GM, Pak CYC Eventual attenuation of hypocalciuric response to hydrochlorothiazide in absorptive hypercalciuria. J Urol 1371104-1109, 1987 18. Preminger GM, Sakhaee K, Pak CYC: Hypercalciuria and altered intestinal calcium absorption occurring independently of vitamin D in incomplete renal tubular acidosis. Metabolism 36176-179, 1987 19. Rudman D, Dedonis JL, Fountain MT, et al: Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med 303:657-661, 1980 20. Sakhaee K, Alpern R, Poindexter J, et al: Citraturic response to oral citric acid load. J Urol 147975-976, 1992 21. Sakhaee K, Harvey JA, Padalino PK, et al: Potential role of salt abuse on the risk of kidney stone formation. J UrollW310-312, 1991 22. Sakhaee K, Nigam S, Snell P, et al: Assessment of the pathogenetic role of physical exercise in renal stone formation. J Clin Endocrinol Metab 653974-979, 1987 23. Sakhaee K, Williams RH, Oh MS, et ak Alkali absorption and citrate excretion in calcium nephrolithiasis. J Bone Miner Res 8787-792, 1993 24. Wabner CL, Pak CYC: Effect of orange juice consumption on urinary stone risk factors. J Urol 149:1405-1408, 1993 25. Yendt ER, Guay GF, Garcia D A Use of thiazides in the prevention of renal calculi. Can Med Assoc J 102614-620, 1970
Address reprint requests to Charles Y. C. Pak, MD Center for Mineral Metabolism and Clinical Research University of Texas Southwestern Medical School 5323 Harry Hines Boulevard Dallas, TX 75390-8885