By David A. Bushinsky, University of Rochester School of Medicine and Dentistry, Nephrology Unit, Strong Memorial Hospital, Rochester, New York.
The incidence of nephrolithiasis appears to be slightly in excess of one case per 1000 patients per year and has been slowly increasing in recent decades   . Kidney stones often cause severe pain, which may lead to emergent hospitalization, shock-wave lithotripsy, and/or surgery. An understanding of the mechanisms involved in kidney stone formation leads to rational treatment which has been documented to decrease the incidence of nephrolithiasis and its associated morbidity.
Kidney stones are generally composed of calcium salts, uric acid, magnesium ammonium phosphate (struvite), or cystine   (Table 1) . Stones form in urine that is supersaturated with respect to the ionic components of the specific stone, and saturation is dependent on chemical free ion activities. The chemical free ion activities of the components of a stone, in a solution in which the stone will neither grow nor dissolve, is at the “equilibrium solubility product.” A decrease in the free ion activity will cause the urine to become undersaturated, a state in which the stone will not grow and may even dissolve. An increase in the free ion activity will cause the urine to become supersaturated, a state that would favor a stone to form or increase in size.
The chemical free ion activity of the components of the stone are influenced by many factors, including the concentration of the relevant ions, urine pH, and complexation with substances in the urine. The chemical free ion activity is directly related to ion concentration. Ion concentration is a function of how much of the particular ion is excreted in the volume of urine. Increased urinary ion excretion and decreased urine volume will both increase free ion activity and favor stone formation and growth. Urine pH is particularly important with respect to uric acid supersaturation. Citrate forms soluble complexes with calcium and will thus reduce its free ion activity.
Stone Formation and Growth
Kidney stones can form and increase in size through either homogeneous or heterogeneous nucleation   . During homogeneous nucleation, increasing chemical free ion activity leads to supersaturation with respect to a solid phase. Once this supersaturation reaches the “formation product,” the ions form clusters that can increase in size to form a permanent solid phase. With heterogeneous nucleation, crystal growth occurs on the surface of a dissimilar but complementary crystal or on another, generally foreign, substance. In vivo, heterogeneous nucleation predominates over homogeneous nucleation because the presence of a solid phase allows for crystal growth at a lower level of supersaturation, a so-called “metastable solution.” Microscopic crystals take longer to grow into clinically significant stones than the calculated passage time for fluid through the renal tubule  . Crystals appear to adhere to tubular cells allowing time for further growth  .
Urine from stone formers generally is more supersaturated than urine from non-stone formers   . However, despite similar degrees of supersaturation, some people form stones, whereas others do not. This may be due to the presence of inhibitors of crystallization. Citrate, uropontin, nephrocalcin, and pyrophosphate inhibit the formation of calcium-containing crystals  . Although some studies have shown a decrease in inhibitor activity when the urine of stone-forming patients is compared with that of control subjects, the influence of abnormalities in the composition or amount of inhibitors in the occurrence or frequency of stone formation has not been determined.
Clinicians generally determine a patient’s potential for stone formation by measuring the rates of urine solute excretion, in mass per unit time, of the principal components of stones. However, it is clear that the critical determinant for crystallization is urine supersaturation and not the absolute quantity of ions excreted over a period of time  . Computer programs are now available, such as EQUIL, that calculate saturation from measured concentrations and should be used for a more accurate determination of the lithiasis risk    . Even with sophisticated calculations of saturation, variations in hourly urine output of both water and solute dictate that any mean collection will be an underestimation of the maximum supersaturation.
All patients who form their first, single stone should be evaluated as suggested in Table 2  . All stones should be analyzed and if a patient forms only a single stone, then 24-h urine testing is not recommended. The emphasis is to understand whether medical or environmental risk factors predispose the patient to stone formation.
Patients who form a second stone, those whose stones are
|Calcium oxalate and calcium phosphate||37|
increasing in size, and all children with even a single stone should undergo a more complete evaluation. These patients should be studied as recommended for the single stone evaluation and, in addition, have a workup as suggested in Table 3  . The cornerstone of this more extensive evaluation is the 24-h urine collection. Two or three 24-h urine collections are generally recommended while the patient is eating his normal diet and taking his usual medications. Determinations of saturation should be used for initial management and to guide therapy.
|Collect and analyze all stones|
|medical risk factors|
|inflammatory bowel disease|
|urinary tract infection|
|environmental risk factors|
|urinalysis ? culture|
|urine for cystine|
|calcium ? parathyroid hormone|
|kidney, ureters, and bladder|
|? intravenous urography ? tomograms|
|As for single stone, plus:|
|repeat 24-h urine to monitor compliance and effectiveness of treatment|
|specialized testing is not recommended for most patients|
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