These stones are produced by urinary tract infection with urease-producing bacteria, and cannot be treated without a combined medical—surgical approach. Usually they are too large (>2 cm) for ESWL and must be removed via percutaneous lithotomy or, in some instances, ureteroscopic laser lithotripsy. The surgery must create a stone-free kidney in that infected fragments can readily reform a large new stone. Antibiotics are useful in the immediate perioperative and postoperative periods, but chronic use has no basis. Acetohydroxamic acid (AHA) inhibits bacterial urease and can prevent growth and formation of struvite stones, but significant side effects, such as headache and thrombotic events, make it less useful. The usual organisms that cause struvite stones are Proteus, Klebsiella, Pseudomonas, and Enterobacter spp., often highly resistant to antibiotics. Repeated treatments for urinary infection and prior urologic procedures can lead to their colonization of the urinary tract. Loss of renal function can occur because of persistent obstruction and infection. Struvite stone formers may have passed prior stones due to other causes, such as cystinuria, low urine pH with uric acid stones, or calcium stones from any one of their causes. Therefore, they should be evaluated fully, in the sequence below, to find preventable causes of stone recurrence.
Only autosomally recessive inherited abnormalities of the dibasic amino acid transporter found in the proximal tubule of the kidney cause these stones. Two types of cystinuria have been identified clinically. Recent genetic studies have linked Type A (or Type I) to a defect in rBAT, the heavy unit of the heteromeric amino acid transporter; Type B (type non-I) is linked to abnormalities of b0,+AT, the light subunit of the transporter. The clinical presentations of these two groups are the same. Cystinuria is detected via stone analysis and spot urine cystine screening tests. If the latter is positive a 24-hour urine must be collected for creatinine and cystine to confirm either the heterozygote—usually non-stone-forming- or homozygous-stone-forming—state. Urine cystine levels above 300 mg daily are almost always the latter. Treatment is with urine volumes above 3 L daily, up to 5 L depending on the urine cystine excretion. As a general rule, 300 mg/L can be dissolved and it is preferable to achieve about a 2-fold more urine volume than is necessary, ie, 2 L for 300 mg/day of cystine and 4 L for 600 mg of cystine daily. Cystine dissolves more readily in urine of pH >7; potassium citrate, 20–30 mEq twice daily, is a reasonable starting dose; follow-up urine testing is needed to be sure of pH and volume. Serum potassium must be tested, ideally at 1 week of treatment, to be sure hyperkalemia has not occurred. Any elevation of serum creatinine requires special caution in the use of potassium alkali.
Because urine pH is increased by treatment, and because cystinuric patients may harbor abnormalities that foster calcium stones and can be worsened by high urine pH, all patients must be studied fully with 24-hour urine testing for stone risk factors. If they are present, follow-up testing must include risk factors and an assessment of their changes with treatment to prevent overgrowth of calcium salts on cystine stones (eggshell stones). Cystine stones are difficult to fracture with ESWL so other modalities are usually preferred.
When fluid and alkalinization alone are unsuccessful in preventing recurrence, chelating agents may be used. These drugs form a mixed thiol-cysteine disulfide that is more soluble than cystine. d-Penicillamine has been used in the past, but because of side effects, it has largely been supplanted by α-mercaptopropionylglycine (tiopronin), which appears to be somewhat better tolerated. The usual dose is 100 mg tablets, three to six daily in divided doses, which may be increased up to 1200 mg/day; side effects include loss of taste—remedied in part by supplemental zinc—and occasionally serious reactions including fever, proteinuria and serum sickness syndromes. Captopril also binds cysteine, but fall in blood pressure and allergic reactions limit its use, and its efficacy is controversial.
In all cases, these stones occur because of low (<5.6) 24-hour urine pH; low urine volume may be a contributing factor in some cases, such as patients with chronic diarrhea. High urine uric acid excretion is almost never of importance. Any uric acid in stones is sufficient grounds to perform 24-hour urine stone risk testing, which will reveal not only urine pH but other possible abnormalities that might cause conversion to calcium stones when pH is raised in treatment.
Treatment of uric acid stones consists of raising urine pH to 6, avoiding very high pH values (>6.5) that can promote calcium phosphate stones. Potassium citrate 10–30 mEq twice daily is a reasonable starting dose. Follow-up at 6 weeks can be used to gauge the need for adjusting the dose. Allopurinol is specifically not indicated for uric acid stones, as it is not sufficient or necessary.
Uric acid stone formers are often obese or diabetic, conditions that lower urine pH via insulin resistance. Stone management in obese persons, and preservation of renal tissue in patients with diabetes make stone prevention especially important in this population. Even one uric acid stone is sufficient for complete evaluation and treatment. Given the wide range of urine pH and given that response to treatment cannot be predicted, there is no basis for empirical treatment with an arbitrary dose of alkali without urine testing. As well, in patients with diabetes, and those with other disorders of potassium handling, follow-up must include serum potassium. Our practice is to check this at 1 week if baseline potassium is even high normal, or serum creatinine is above normal, or if drugs that reduce renal potassium excretion are being used. We also check serum potassium any time urine retesting is performed.
Ammonium acid urate stones are different in cause. This salt precipitates at a higher pH (about 5.7) when urine ammonia is high. In humans, the cause is almost always chronic diarrhea, organic or from laxative abuse, with hypokalemia, which stimulates ammonia production. Treatment requires correction of the underlying intestinal problem.
Unlike the situation for struvite, cystine, or uric acid stones, where even one stone requires specific treatment, patients who have formed only one calcium stone have two practical and medically sound options. In patients who avoid dehydration and maintain a reasonable urine volume of 2 L or so daily, only one-third will experience stone recurrence within 5 years. Massive hydration, with urine flows near 3 L, and sustained, will lower that rate to about 10%, an impressive reduction. Patients who are well educated about stone disease play a major role in their own treatment, as they often decide which conservative medical measure they will use. We have known some patients who are content with the odds, while others, perhaps more squeamish, prefer more active protection. A very high intake of fluids is reasonable for them. If they desire more, they can be managed as if they had multiple stones. In labeling someone a single stone former, we include radiography; single means only one stone, clinically and by x-ray.
The Most Abundant Stone Formers
Struvite, cystine, and uric acid stone formers together scarcely match even a fraction of those with multiple calcium stones. In clinical practice well over half, even two-thirds of cases will be calcium stones. Even so, we would not enlarge our comments except that causes of calcium stones are most diverse, and treatments vary. Evaluation is similar to that for all stone formers, except that at least two complete stone risk urines (Table 40–1) are advisable to detect the cause of stones and guide treatment (Table 40–4). In all multiple calcium stone formers, the highest urine volume achievable for a given patient is the proper clinical goal. We will not repeat this clinical maxim, but always practice it.
Table 40–4. Causes of Calcium Stones.1 ||Download (.pdf)
Table 40–4. Causes of Calcium Stones.1
Hypercalciuria + normocalcemia + clinical exclusions
Hypercalciuria + hypercalcemia + clinical exclusions
Low urine citrate
High urine uric acid
Low serum HCO3, urine pH >6.5, low serum K
High urine oxalate
High urine oxalate + small bowel malabsorption
High urine oxalate + clinical exclusions
Colon resection, ileostomy
Idiopathic Hypercalciuria (IH)
High urine calcium (>250 or 300 mg/day, women and men, or >4 mg/kg/day, either sex), normal serum calcium, and exclusion of hyperparathyroidism, hyperthyroidism, vitamin D excess, calcium supplement excess, rapidly progressive bone disease, malignancy, sarcoidosis, and immobilization make the diagnosis. Almost all stone formers with hypercalciuria have IH. The etiology is not yet understood, but the familial nature of the disorder points to a genetic predisposition. Patients have increased calcium absorption from food, and increased loss of calcium in the urine. Although protocols to divide patients into “absorptive” and “renal leak” subtypes have been proposed, in practice, the two groups are not clearly differentiated. In addition, recent studies document the occurrence of bone mineral loss and increased fractures in patients with kidney stones, and this suggests some risk of bone mineral loss in all hypercalciuric patients. Thus, low calcium diet is seldom used in the treatment of hypercalciuria, as it may worsen bone mineral loss; in addition, it has not been found to be effective.
Treatment of IH is aimed at lowering urine calcium loss, and thereby decreasing urine supersaturation. Three treatment trials document the efficacy of thiazide diuretics to reduce urine calcium excretion and reduce stone recurrence. Trial drugs have included chlorthalidone 25–50 mg daily, hydrochlorothiazide, 25 mg twice daily, and indapamide 2.5 mg daily, and stone reductions have decreased, on average, from a 3 year recurrence rate of 50–70% to about 15–20%. Dietary factors are known to influence calcium excretion in IH. One study has documented excellent outcomes with a reduced sodium-reduced protein diet in males versus poorer outcomes from a low calcium diet.
Thiazide use is conventional; potassium wasting is minimized by lowering diet sodium intake. Replacement is best with potassium citrate if urine citrate is low, but a potassium chloride salt is preferable if urine pH is above 6.2 because the citrate can increase pH and promote conversion to phosphate stone formation. Follow-up urine testing is recommended to be sure of a reduction of urine calcium, and to adjust diet sodium as needed. Serum potassium must be measured and hypokalemia treated. Amiloride 5 mg tablets, one or two daily, can be used if needed to reduce potassium losses. Potassium depletion can reduce urine citrate (see below) and this is corrected with potassium repletion.
Hypercalciuria with hypercalcemia suggests this disease. Reduced serum phosphate is supportive. Serum parathyroid hormone (PTH) should be measured, and the diagnosis requires the PTH be not reduced. A normal or high PTH with high serum calcium is sufficient for the diagnosis provided thiazide is excluded—which can raise serum calcium—and lithium use, which causes abnormal parathyroid regulation.
Similarly, hyperthyroidism also produces this result. Sarcoidosis, most malignant hypercalcemic states, and vitamin D excess all suppress serum PTH. The elevation of serum calcium can be modest (10.5 or less) so multiple blood samples are prudent given a scattering of borderline high results. This disease requires surgical treatment at the present time. The new calcimimetic agents are not as yet proven remedies, and are extremely expensive.
Low urine citrate (below 450 and 350 mg/day, women and men, respectively) is not uncommon and could promote calcium stones because citrate binds calcium ions and inhibits calcium salt crystallization. Three trials of potassium citrate have led to conflicting results. Two well done trials show positive results almost identical to those of thiazide for IH. The third showed no effect of citrate, mainly because recurrence in the placebo arm was as low as with thiazide or citrate. Sodium citrate salts have never been used in a trial and have the theoretical disadvantage of possibly increasing blood pressure and urine calcium. Typical products include many generic potassium citrate powders that must be dissolved in water as a beverage and used at 25–30 mEq twice daily. Only one proprietary pill form (Urocit K, Mission Pharmacal) exists, 10 mEq tablets, one or two to be taken two or three times daily. Follow-up urine testing is needed to confirm results. As with uric acid stone formers, serum potassium requires testing at appropriate intervals for safety. Potassium salts should be used with extreme care if renal function is reduced, or if drugs are being given that impair potassium excretion.
Hyperuricosuria with Calcium Oxalate Stones
Daily urine uric acid excretion above 750 or 800 mg in women and men, respectively, appears to promote CaOx stones, perhaps by fostering CaOx crystallization. In one trial allopurinol 200 mg daily reduced stone recurrence with the same efficiency as cited for thiazide and potassium citrate. Hyperuricosuria is a dietary phenomenon, related to high intakes of meat, and can be reduced by diet. No trials document benefits of diet, and it can be hard to accomplish. If stones are a serious clinical problem allopurinol is a reasonable alternative.
Distal Renal Tubular Acidosis (RTA)
This is a rare condition of reduced renal ability to lower urine pH normally, which may be genetic or acquired. Acid excretion is reduced causing metabolic acidosis. Hypokalemia is usual, as is hypocitraturia. Urine calcium can be elevated because of the acidosis, and the high urine pH fosters calcium phosphate stones and nephrocalcinosis. Potassium citrate, 2–4 mEq/kg/day in divided doses, can correct the acidosis and hypokalemia and may reverse the hypercalciuria. If urine calcium remains high, thiazides can be used. Genetic RTA need not cause progressive renal disease if treated. Sjögren syndrome is a more common cause of RTA with stones, and is an immune disorder that can cause chronic renal failure. Other causes of RTA include any hyperglobulinemic state, including the rheumatoid and collagen vascular diseases.
In dietary hyperoxaluria oxalate is usually between 50 and 80 mg daily (normal oxalate <50 mg daily) and variable. Sources of preformed oxalate are of plant origin, and spinach, nuts, cocoa, and pepper excess are very common in practice. High protein intakes stimulate endogenous oxalate production. Perhaps the most common situation is a low calcium diet, which permits diet oxalate to be absorbed instead of precipitated in the gut lumen. Dietary management includes a normal calcium intake (800–1000 mg) from foods, not supplements, reduced protein intake, and avoidance of excessive high oxalate foods. No trials substantiate these measures, however.
Enteric hyperoxaluria is a syndrome of small bowel malabsorption from any cause, but usually from Crohn's disease, bowel resection, or intestinal bypass for obesity, and subsequent excessive colonic oxalate absorption. Urine oxalate levels can range from 50 to 150 mg daily, and the diagnosis is based on the clinical setting. In addition to avoidance of high oxalate foods and excessive protein intake, calcium carbonate supplements—500–1000 mg—can be used during each meal to precipitate diet oxalate. Reduced diet fat content can reduce binding of calcium by undigested fatty acids, and reduce urine oxalate. Cholestyramine 2–4 g with each meal will adsorb both fatty acids and oxalate and reduce urine oxalate. Potassium citrate will offset the enteric bicarbonate loss usually encountered, and raise urine pH and citrate levels. These measures can reduce stones in our experience, although no trials prove that assertion. Enteric hyperoxaluria can cause renal damage including end-stage renal disease, so treatment must be aggressive and persistent.
Primary Hyperoxaluria (PHO)
PHO Types I and II arise from genetic mutations of one of two genes that control oxalate production, mainly by the liver. The urine oxalate can range from 80 mg to 300 mg daily. Patients can present with stones beginning even in childhood, and renal failure is a common outcome because of damage from the high oxalate. A fraction of patients lower their urine oxalate in response to pyridoxine, in doses ranging from 10 mg to 300 mg daily; it is best to try this in all cases, beginning at the lowest doses and working up. Very high urine volume, and perhaps potassium citrate and neutral potassium phosphate (Neutraphos, 1–2 g daily in divided doses), may lower urine oxalate. However, in practice, no one should attempt to manage this condition without continued guidance from a stone referral center, which usually means patients must travel. Preemptive liver and kidney transplantation is the definitive treatment for Type I PHO as renal disease begins to progress, because systemic oxalosis can damage blood vessels, nerves, and the heart.
Colon resection, often with ileostomy, causes diarrhea with resulting low urine volume, bicarbonate loss, and consequent low urine pH and citrate levels, and thereby leads to calcium oxalate and uric acid stones. Management is obvious: Fluids, sodium or potassium alkali replacement, and dietary measures to minimize the diarrhea. These goals are difficult to achieve in practice.
With or without a metabolic stone-forming abnormality, some people are predisposed to conditions of low fluid intake and/or dehydrating environments and tend to become stone formers. Simple habitual low urine volume is not rare and is difficult to treat. Dehydration at work arises from many causes, such as hot environments, frequent air flight, deliberate fluid restriction—in school teachers and surgeons, for example—and outdoor workers. Such people may change their habits briefly when their 24-hour urines are to be collected, so you do not know their true habits and they may not tell you unless you ask. Treatment is obvious but can be challenging.
The Problem of Calcium Phosphate Stones
Calcium will crystallize with phosphate instead of oxalate when urine pH is persistently high, that is, above 6.3 on a 24-hour basis. Calcium monohydrogen phosphate (brushite) is one form, and such stones are associated with plugging of terminal collecting ducts with crystals and significant renal disease. Apatite is the other usual stone, and its renal pathology has not yet been determined. All stones should, therefore, be analyzed and if a calcium phosphate phase is predominant, or if any brushite is present, alkali supplements should be avoided; they will not be needed to raise urine pH as it is certainly already high. Hypocitraturia with alkaline urine pH poses a common and special problem, sometimes referred to as incomplete RTA in that blood is normal but low citrate with high urine pH suggests an acidification defect. We have become skeptical of this formulation, and leery of alkali; if potassium citrate can raise urine citrate in such circumstances without an increase in urine pH, we use it. If not, we use fluids and other means.
Abate N et al: The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin
resistance. Kidney Int 2004;65(2):386.
Evan AP et al: Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int 2005;67:576.
Parks JH et al: Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int 2004;66(2):777.