Dietary and medical management of recurrent nephrolithiasis
ABSTRACTDietary approaches and medical treatment can prevent recurrence of urinary stones. Some interventions are appropriate for all types of stones, but there are particular risk factors that may need directed therapy.
KEY POINTS
- Nephrolithiasis is common and widespread, and its incidence and prevalence are increasing.
- Calcium stones are the most common type, and of these, calcium oxalate stones predominate.
- The most common risk factors for recurrent calcium stones are low urinary output, hypercalciuria, hyperoxaluria, hypocitraturia, and hyperuricosuria.
- Less common types of stones are usually associated with genetic abnormalities, infections, or medications.
Increasing citrate excretion
Hypocitraturia is a well-known risk factor for the formation of kidney stones. It is usually defined as a citrate excretion of less than 320 mg/day for adults.
Citrate prevents formation of calcium crystals by binding to calcium, thereby lowering the concentration of calcium oxalate below the saturation point.45
Diet therapy. Patients with calcium oxalate stones and hypocitraturia should be encouraged to increase their intake of fruits and vegetables, which enhances urinary citrate excretion, and to limit their intake of nondairy animal protein.11
The use of citrus products in preventing stones in patients with hypocitraturia is controversial, however, and needs to be studied more.
One study46 demonstrated that lemon juice was beneficial in hypocitraturic nephrolithiasis: 4 oz/day of lemon juice concentrate in the form of lemonade was associated with an increase in urinary citrate excretion to 346 mg/day from 142 mg/day in 11 of 12 patients who participated.
Odvina47 compared the effects of orange juice with those of lemonade on the acid-base profile and urinary stone risk under controlled metabolic conditions in 13 volunteers. Orange juice was reported to have greater alkalinizing and citraturic effects and was associated with lower calculated calcium oxalate supersaturation compared with lemonade.
Lemonade therapy may be used as adjunctive treatment in patients who do not comply with or cannot tolerate alkali therapy. However, we advise caution about recommending citrus products, as they can increase oxalate excretion.
Pharmacotherapy includes alkali therapy. Barcelo et al48 compared the effects of potassium citrate and placebo in 57 patients with calcium oxalate stones and hypocitraturia. Patients treated with potassium citrate had a rate of stone formation of 0.1 event per patient per year, compared with 1.1 in the placebo group.
Many forms of alkaline citrate are available. Potassium citrate is preferred over sodium citrate since the latter may increase urine calcium excretion.49 Treatment is usually started at 30 mEq/day and is titrated to a maximal dose of 60 mEq/day for a urinary citrate excretion greater than 500 mg/day.
Common side effects are abdominal bloating and hyperkalemia (especially with renal insufficiency), and in such cases sodium-based alkali, sodium citrate, or sodium bicarbonate can be prescribed.
PREVENTING CALCIUM PHOSPHATE STONES
Risk factors for calcium phosphate stones are similar to those for calcium oxalate stones (other than hyperoxaluria), but calcium phosphate stones are formed in alkaline urine (usually urine pH > 6.0), often the result of distal renal tubular acidosis. Preventive measures are similar to those for calcium oxalate stones.
Alkali therapy should be used with caution because of its effect on urinary pH and the risk of precipitation of calcium phosphate crystals.50 Use of potassium citrate was found to be associated with increases in both urinary citrate excretion and calcium phosphate supersaturation in hypercalciuric stone-forming rats.51 It is therefore challenging to manage patients with calcium phosphate stones and hypocitraturia. Alkali administration in this setting may diminish the formation of new stones by correcting hypocitraturia, but at the same time it may increase the likelihood of calcium phosphate stone formation by increasing the urinary pH. When the urine pH increases to above 6.5 with no significant change in urine citrate or urine calcium excretion, we recommend stopping alkali therapy.
PREVENTING URIC ACID STONES
Clinical conditions associated with uric acid stones include metabolic syndrome, diabetes mellitus, gout, chronic diarrheal illness, and conditions that increase tissue turnover and uric acid production, such as malignancies. Other risk factors for uric acid stone formation are low urine volume, low uric pH, and hyperuricosuria.
Abnormally acidic urine is the most common risk factor. Metabolic syndrome and diabetes mellitus reduce ammonia production, resulting in a lower urinary pH, which predisposes to uric acid stone formation. Chronic diarrhea also acidifies the urine by loss of bicarbonate. Similarly, in gout, the predisposing factor in uric acid stone formation is the persistently acidic urine due to impaired ammonium excretion.52 Uric acid precipitates to form uric acid stones in a low urinary pH even with normal excretion rates of 600 to 800 mg/day and a urinary volume of 1 to 1.5 L.53
Therefore, apart from increasing fluid intake, urinary alkalization is the cornerstone of management of uric acid stones. Potassium citrate is the preferred alkali salt and is started at a dose of 30 mEq/day for a goal urinary pH of 6 to 6.5.47
Patients with hyperuricosuria are also advised to restrict their protein intake to no more than 0.8 to 1 mg/kg/day.
If the above measures fail, patients are treated with a xanthine oxidase inhibitor, ie, allopurinol or febuxostat, even if their uric acid excretion is normal.54
PREVENTING STRUVITE STONES
Struvite stones contain magnesium ammonium phosphate and are due to chronic upper urinary tract infection with urea-splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and enterococci. Urea hydrolysis releases hydroxyl ions, resulting in alkaline urine that promotes struvite stone formation. Early detection and treatment are important, since struvite stones are associated with morbidity and rapid progression.
Medical treatment of struvite stones is usually unsuccessful, and the patient is referred to a urologist for surgical removal of the stones, the gold standard treatment.55 Long-term use of culture-specific antibiotics to prevent new stone growth is not well studied. Medical therapy by itself is preferred in patients who refuse stone removal or cannot tolerate it. Urease inhibitors such as acetohydroxamic acid have been successful in preventing or slowing stone growth, but their use is limited by frequent side effects such as nausea, headache, rash, and thrombophlebitis.56
CYSTINE STONES
Cystine stones occur in people with inherited defects of renal tubular and intestinal transport of cysteine and dibasic amino acids that cause excessive excretion of urinary cystine, ie, 480 to 3,600 mg/day.
Cystine is formed from two cysteine molecules linked by a disulfide bond. The solubility of cystine is pH-dependent, with increased solubility at higher urinary pH. The goal is to maintain a urinary cystine concentration below its solubility level by keeping the cystine concentration below 243 mg/L and the urine cystine supersaturation (the ratio of the urine cysteine concentration to the cysteine solubility in the same sample) less than 0.6.57 Therapy is aimed at increasing daily urinary volume to 3 L and urine alkalization to pH above 7, in order to increase cystine solubility by 300%.58
Overnight dehydration should be prevented, and patients should be encouraged to wake up at least once a night to void and drink additional water. Sodium restriction to 100 mmol/day (2,300 mg/day) and moderate protein restriction to 0.8 to 1 g/kg/day are associated with decreased cystine excretion, but long-term studies demonstrating their benefit in preventing cystine stones are lacking.59
A thiol-containing drug, eg, D-penicillamine (0.5–2 g/day) or tiopronin (400–1,200 mg/day), should be added to the conservative measures if they have not been effective for 3 months or if there is history of noncompliance.60 Thiol-containing drugs have a sulfhydryl group that reduces the disulfide bond, and they form soluble disulfide cysteine-drug complexes with greater ability to solubilize cystine in alkaline urine. They must always be used in conjunction with fluid and alkali therapy.61
Both drugs have severe and common adverse effects including leukopenia, aplastic anemia, fever, rash, arthritis, hepatotoxicity, pyridoxine deficiency, and proteinuria (membranous nephropathy). However, tiopronin seems to have a lesser incidence of side effects.62 Regular monitoring of complete blood cell counts, liver enzymes, and urine protein should be done.
Captopril contains a sulfhydryl group, and the captopril-cysteine disulfide is more soluble than cysteine alone. The amount of captopril that appears in the urine is low, and doses of 150 mg/day are usually required to reduce cysteine excretion, which can lead to hypotension. The efficacy of captopril in treating cystine stones is unproven, and this drug is used only if patients cannot tolerate other thiol-containing drugs.63
