Sum and Substance_____________________________

Etiology and Treatment of Urolithiasis. Charles Y. C. Pak, MD. Am I Kidney Dis 1991; 18:624-637. (Center for
Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, 5323
Harry Hines Blvd, Dallas, TX 75235-8885.)

N EPHROLITHIASIS is a heterogeneous disorder, with known, although infection may precede the onset of
varying chemical composition and pathophysio- stone disease: It is not due to a high dietary sodium in-
logic background. Approximately 500,000 Americans ex- take, since fasting hypercalciuria has been shown to per-
perience stone episodes yearly, and up to 12 million sist following sodium restriction.
Americans will develop stones in their lifetime. Primary hyperparathyroidism accounts for only 2% of
Stone disease is a surgical and a medical problem. stone disease. Patients with stones could not be distin-
When stones cause obstruction of the urinary tract, in- guished from those without stones on the basis of levels
tractable pain, or bleeding, surgical removal may become of serum parathyroid hormone, 1,25-(OH)2vitamin D,
mandatory. A medical prophylactic program is also mdi- intestinal calcium absorption, or urinary calcium.
cated, since nephro!ithiasis is characterized by a high The cause of stone formation may be ascertained in
rate of recurrence. most patients with the reliable diagnostic protocols that
Major progress has been made recent!y in the tech- are available for the identification of these disturbances.
niques of stone removal and in the medical prevention Effective medical treatments capable of correcting un-
of new stone formation. The introduction of extracorpo- derlying nutritional or physiologic disturbances have
real shock wave lithotripsy has considerably reduced the been formulated. They include treatment with sodium
morbidity of stone removal, often eliminating the need cellulose phosphate, thiazide, and orthophosphate for
for surgery. hypercalciuric nephro!ithiasis; potassium citrate for hy-
Pathophysiologic disturbances responsible for or asso- pocitraturic calcium nephrolithiasis; acetohydroxamic
ciated with stone formation have been largely clarified. It acid for infection stones; and D-penicillamine and mer-
is now possib!e to prevent recurrence of stones in most captopropionylglycine for cystinuria. With use of these
patients by using a variety of treatment programs di- treatments, new stone formation can now be prevented
rected at correcting the underlying disturbances. Im- in most patients.
provements in methods of stone removal have not di- Some hypercalciuric patients (hypercalciuria may be
minished the need for the application of an effective partly skeletal in origin) have fasting hyperca!ciuria with
prophylactic program. normal levels of serum parathyroid hormone, despite
Although kidney stones are generally composed of proper dietary preparation. In one-fourth to one-third of
calcium oxalate or calcium phosphate, they may also patients with increased calcium absorption without para-
consist of uric acid, magnesium-ammonium phosphate, thyroid stimulation, serum 1,25-(OH)2vitamin D concen-
or cystine. For nonca!careous stones, the stone composi- tration is increased, presumably from enhanced produc-
tion sometimes discloses the underlying physiologic dis- tion rate of calcitrol, which may result from impaired
turbance responsible for stone formation. For example, renal tubular reabsorption of phosphate (renal phos-
the presence of uric acid suggests undue urinary acidity phate leak). The ensuing calcitro! excess produces hyper-
from gouty diathesis or chronic diarrhea! syndrome, calciuria by stimulating intestinal calcium absorption
whereas the presence of struvite is pathognomonic of and bone resorption.
infection of the urinary tract with urea-splitting organ- In cases of hypercalciuria with normal serum parathy-
isms, and the detection of cystine indicates cystinuria. roid hormone levels, abnormalities such as rena! calcium
Kidney stones have been classified according to underly- leak, renal phosphate leak, and overproduction of 1,25-
ing urinary biochemical abnormalities, including altered (OH)2vitamin D may occur in combination. Such cases
metabolism or hormonal derangement and certain nutri- might also be the result of excess of the prostag!andin
tiona! disturbances. PGE, which has been shown to stimulate bone resorp-
Metabolic causes of stone formation include varying tion, enhance 1,25-(OH)2vitamin D synthesis, increase
forms of hypercalciuria, hypocitratuna, undue urinary renal blood flow, and reduce renal tubular reabsorption
acidity, hyperuricosuna, hyperoxaluria, infection with of calcium, but this scheme has not been validated.
urease-producing organisms, and cystinuria. Hypocitraturia, a common abnormality that occurred
Hypercalciuria, occurring in approximately 60% of in approximately 30% of patients with recurrent stone
patients with stones, raises urinary calcium concentra- disease, is an important determinant for calcium stone
tion and saturation levels of calcium oxalate and calcium formation because of the loss of the inhibitor activity of
phosphate. Absorptive hypercalciuria, the most common citrate. Citrate retards calcium stone formation by reduc-
variant, results from the primary enhancement of intesti- ing urinary saturation of calcium salts, which inhibits
na! calcium absorption and has an unknown cause. The spontaneous precipitation and agglomeration of calcium
majority of patients with absorptive hypercalciuria gave oxalate and prevents crystal growth of calcium phos-
a positive family history of stones; an automsomal domi- phate. Low citrate excretion therefore promotes stone
nant mode of inheritance has been shown. Rena! hyper- formation. The principal cause for hypocitraturia in pa-
calciuria, due to an impaired renal tubular reabsorption tients with nephrolithiasis is acidosis or acid retention,
of calcium, leads to secondary hyperparathyroidism that which reduces levels of urinary citrate by both enhanc-
may cause compensatory intestinal hyperabsorption of ing renal tubular reabsorption and impairing peritubu!ar
calcium by stimulating the rena! synthesis of 1,25- uptake and synthesis of citrate. In this study, a direct
(OH)2vitamin D. The cause of renal calcium leak is not measurement of citrate absorption with the intestinal
washout technique demonstrated nearly complete ab-
sorption of citrate in patients with hypocitraturia and
See also Radioloe,y 1991; 178:694. (Continues OH p 352)

336 Radiology
#{149} November 1992
(continuedfrom p 336) Dietary calcium restriction is recommended in absorptive hy-
nephrolithiasis, equivalent to that found in healthy sub- percalciuria (unless bone loss is present) and in primary hyper-
jects. parathyroidism with intestinal hyperabsorption of calcium. A
Urinary pH is unusually acid ( < 5.5) in approximately one- moderate restriction of animal proteins may be useful, espe-
third of patients with nephro!ithiasis. Because this level is less cially in the presence of hyperuricosuria or hypocitraturia.
than the dissociation constant for uric acid, urinary content of Specific treatment of primary hyperparathyroidism is par-
undissociated uric acid is high, leading to uric acid stone for- athyroidectomy. There is no treatment that corrects the basic
mation. Once a uric acid stone is formed, it could induce for- abnormality of increased calcium absorption. Sodium cellulose
mation of calcium oxa!ate stones by epitaxy, heterogeneous phosphate is appropriate for patients with severe absorptive
nucleation, or binding of macromolecular inhibitors. Uric acid hypercalciuria type I (urinary calcium > 8.75 mmo!/d) and for
could subserve the above functions itself or by transformation patients resistant to or intolerant of thiazide therapy. In ab-
to sodium urate, which would then induce calcium oxalate sorptive hypercalciuria type II, a low-calcium diet (iO-i5
crystallization by similar mechanisms. Thus, persistent undue mmo!/d) and a high fluid intake (sufficient to maintain urine
acidity could lead to both uric acid and calcium stones. Patients output > 2 L/d) are appropriate. Thiazide is the treatment of
susceptible to undue urinary acidity include those with chronic choice for renal hypercalciuria. In cases of renal phosphate
diarrhea! states and gouty diathesis. leak, orthophosphate, indomethacin, or thiazide with potas-
Other metabolic causes of hypercalciuric states in patients sium citrate may be appropriately used.
with stone formation include hyperuncosuria, hyperoxaluria, Treatment of nonhypercalciuric calcium nephrolithiasis in-
hypomagnesiuria, and miscellaneous causes such as infection volves potassium citrate therapy for distal renal tubular acido-
with urease-producing organisms and cystinuria. No metabolic sis; such therapy corrects both metabolic acidosis and hy-
disturbance can be found in iO%-i5% of patients with stones, pokalemia. In mild to moderate cases of chronic diarrhea!
who may present with low urine volume. syndrome, potassium citrate is generally effective in restoring
Diagnostic criteria for major forms of stone disease include normal urinary citrate and pH levels (levels of urinary calcium
absorptive hypercalciuria type I, which is characterized by nor- generally remain low). In more severe cases, even high doses
ma! fasting urinary calcium, an exaggerated urinary calcium of potassium citrate may be ineffective in restoring norma! un-
level after administration of a i-g calcium load, normal serum nary citrate levels. Thiazide-induced hypokalemia may cause
parathyroid hormone, and high urinary ca!cium on both re- hypocitratuna and may thereby attenuate the beneficial hypo-
stricted and random diets. Patients with absorptive hypercalci- calciuric effect of therapy on renal stone formation; treatment
uria type II have an exaggerated calciuric response to oral cal- with potassium citrate is usual!y effective in preventing hy-
cium load but normal levels of urinary calcium on the pokalemia and maintaining normal urinary citrate levels. Idio-
restricted diet. pathic hypocitraturic calcium oxalate nephro!ithiasis can be the
Hypocitraturic calcium nephrolithiasis refers to the condition result of isolated hypocitratunia occurring in conjunction with
in which hypocitraturia is present alone without other physio- absorptive and renal hypercalciunia or with hyperunicosunic
logic derangements. Complete distal renal tubular acidosis is calcium oxalate nephrolithiasis and can be treated with potas-
characterized by hyperch!oremic metabolic acidosis in the ab- sium citrate.
sence of infection of the urinary tract. Incomplete renal tubular In patients with gouty diathesis, potassium citrate, which
acidosis is characterized by normal serum electrolyte levels but increases the solubility of uric acid and prevents uric stone for-
an impaired ability to acidify the urine following ammonium mation, is the treatment of choice. Sodium alkali therapy and
chloride load. Both complete and incomplete forms may be as- al!opurinol can also be used.
sociated with hypercalciuria, hypocitraturia, calcium nephroli- A low methionine diet has been recommended for the con-
thiasis, and nephroca!cinosis. trol of cystine nephrolithiasis because methionine is a precur-
In chronic diarrheal states, the degree of hypocitraturia is sor for cystine. High fluid intake and administration of alkali
generally proportional to the severity of intestinal fluid loss. should also be attempted. Potassium citrate is advantageous
The invariant feature in gouty diathesis is the persistent pas- over sodium citrate because potassium citrate does not cause
sage of an unusually acid urine without bowel disease or ani- hypercalciuria, is !ess likely to promote development of cal-
mal protein excess: Some patients may form pure uric acid cium stones, and is devoid of sodium-induced enhancement of
stones on one occasion and calcium stones on another occa- cystine excretion. Treatment with penicillamine should reduce
sion. Uric acid stones are radiolucent. Struvite stones are radi- total cystine excretion by complexing cysteine, the monomeric
opaque and sometimes may attain a large (staghorn) size; they form of cystine; unfortunately, such treatment is associated
usually occur as mixtures with calcium carbonate apatite or less with frequent and sometimes severe side effects, including
commonly with calcium oxa!ate. nephrotic syndrome, dermatitis, and pancytopenia. Alpha-
For a simple evaluation, a multichannel blood screen test mercaptopropionylg!ycine has similar biochemical and clinical
should be performed to identify primary hyperparathyroidism action compared with penicillamine, but it has a lower toxicity
(from hypercalcemia), renal phosphate leak (from electrolytes), profile.
and gouty diathesis (from hyperuricemia). A fresh spot urine In the treatment of patients with infection stones, it is diffi-
sample should be cultured for urea-splitting organisms and cult to obtain long-standing control of infection with urea-split-
examined for pH (with a pH electrode). A qualitative examina- ting organisms with use of antibiotics. If a struvite stone is
tion of urine for cystine provides a clue to the presence of present, it is difficult to eradicate infection completely because
cystinuria. Available stone should be analyzed for stone corn- the stone may harbor the organisms within its interstices; these
position. A careful history should be obtained for predisposing organisms can cause reinfection. Therefore, surgical removal of
conditions, medications, dietary aberrations, and insufficient the struvite stones is usually recommended; treatment with
fluid intake. acetohydroxamic acid may prevent stone growth and some-
The primary objective of medical treatment of nephrolithia- times causes dissolution of existing stones.
sis is the prevention of recurrent stone formation. Conservative Careful follow-up is necessary. At each visit, a careful history
management to be used in all patients includes fluid intake suf- should be taken for stone episodes, complications of treatment,
ficient to ensure a minimum urine level of 2 L/d. Dietary so- and compliance with drug therapy or dietary recommenda-
dium restriction is recommended, since a high sodium intake tions. Follow-up should occur every 4 months initially and
increases urinary calcium and lowers citrate levels, promotes then every 6-i2 months after satisfactory control has been es-
sodium urate-induced calcium oxalate crystallization, and tablished. U

blunts hypocalciuric response to thiazide. Oxalate restriction is

useful in patients with calcium oxa!ate stones and is essential PHYLLIS HooD
in patients taking sodium cellulose phosphate or in those with RSNA Publications
intestinal hyperabsorption of oxalate (enteric hyperoxaluria).

352 Radiolrntv
#{149} November 1992