Urolithiasis
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) .
Hypercalciuria (More Than 250 mg/d)
Associated with Hypercalcemia
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 hyperparathyroidism should be suspected if serum PTH is high.
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. [21] 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.
Absorptive or Renal Hypercalciuria
If a high serum calcium or urinary sodium level cannot account for hypercalciuria, the 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. [10] The two conditions can be distinguished by normal or low serum PTH 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. [11] 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. [25] 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. [17] 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 provide potassium to avert development of hypokalemia, and to confer an alkali load to increase urinary citrate, [8] 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.
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 suffering 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 of fat, inflammatory diseases, or resection of the small bowel, oxalate absorption can be increased substantially by two mechanisms. [4] 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.
Hypocitraturia (Less Than 320 mg/d)
Severe Hypocitraturia (Less Than 100 mg/d)
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 may not be possible. A partial amelioration of hypocitraturia, 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 (20-40 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.
Mild to Moderate Hypocitraturia (100-320 mg/d)
A mild to moderate decrease in urinary citrate is usually dietary in origin (relative acid excess). [23] 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 completeRTA, 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 (320-400 mg/d)
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). [2] 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 reducing uric-acid synthesis and excretion. The induced hypercitratria from alkali therapy can retard urate-induced calcium oxalate crystallization. [12] In 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.
With Hyperuricemia
If serum uric acid is elevated frankly, suspect gouty diathesis (i.e., stone disease of primary gout). [7] 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).
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 diathesis, [7] chronic diarrheal state, [19] or strenuous physical exercise. [22]
Gouty diathesis represents fully manifested primary gout or an early phase of primary gout. [7] 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 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. [22] It 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.
High Urinary pH (>7)
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.
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 L/d)
Mild to Moderate Reduction in Urine Volume (1-2 L/d)
If 24-hour urine volume ranges from 1 to 2 L, one should consider reduced fluid intake 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-oz 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.
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-containing fruit juices (e.g., orange, grapefruit, cranberry) exert citraturic action by conferring an alkali load. Citrate-containing 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 L/d)
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. [21] 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 stone-forming propensity.
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