14.1. Clinical Presentation

Kidney stones are composed of insoluble salts of constituents of the forming urine. The salts precipitate, and the crystals aggregate and grow and ultimately reach a mass sufficient to cause clinical symptoms. The majority of stones are composed either completely or mostly of calcium salts, including those of calcium oxalate and calcium phosphate. Uric acid, cystine, and magnesium ammonium phosphate (struvite) compose the remainder of the stones. Table 1 lists the frequency of each stone type and the shape of the major crystals that form the stone. Each of the four general stone types follows its own natural history, has its own pathogenesis, and responds to specific therapies.

Table 1. Stone type and frequency by Composition

Composition	Frequency (%)	Crystal Shape
Calcium oxalate	15-35	Dumbbell shape for calcium oxalate monohydrate; and bipyramidal for calcium oxalate dihydrate
Calcium phosphate	5-20	Elongate, narrow
Mixed Ca oxalate/ phosphate	40-45	Mixed
Uric acid	2-13	Flat, rhomboidal
Struvite	20-30	Rectangular prisms
Cystine	1-3	Hexagonal plates
Ammonium urate	0.5-1.0	Flat, rhomboidal
Mixed Calcium oxalate/uric acid	2-5	Mixed
Struvite is magnesium ammonium phosphate; CaP also known as brushite or apatite. Frequency is the incidence of the crystals found in all stones reported from five series with a total of 2,668 patients.

14.1.1. Epidemiology and Natural history

The prevalence of kidney stones in the United States varies with race, sex, and geographic location. For men, rates vary from four to nine percent, and for women, stone rates range from almost two to four percent. The incidence of nephrolithiasis tracked by the Mayo Clinic indicates an increase in stone frequency since 1950 (1). For men, the rates of new stone appearance increased from 78.5 to 123.6 cases per 100,000 per year during this time. For women, in 1974 the rate was 36 cases per 100,000 per year. For Caucasians, the risk for stone formation is several times that of African-Americans. The prevalence of a history of nephrolithiasis in the U.S. population reported in the NHANES III (1988 to 1994) survey increased from 3.8% (1976-1980) to 5.2% (2). In the United States the lifetime risk for stone formation is 12% in men and 5% in women. Recurrence rates of new stone formation are high. If untreated, stones will recur at the rate of 50% in 5 to 10 years.

Long-term follow-up of 20 to 30 years indicate recurrence rates as high as 75%; with 40% to 50% of the recurrences occurring within five years of the initial stone event (3). While there is variation in the natural history of stone disease, patients who have formed two or more stones tend to have successive shorter intervals between each new stone event (4). The accelerating pace of stone formation in recurrent stone formers cannot be predicted by their metabolic abnormality, sex, age, or any other known characteristic. Therefore, in any single stone-former, one cannot predict who will relapse. This complex natural history of stone disease and the high rate of recurrence is the basis for careful diagnostic evaluation and early treatment.

14.1.2. Clinical Manifestations

An episode of renal colic has a sudden onset, with fluctuation and intensification over 15 to 45 minutes. The pain then becomes steady and unbearable and often accompanied by nausea and emesis. As the stone passes down the ureter toward the bladder, flank pain changes in a downward direction toward the groin. As the stone lodges at the ureterovesical junction, urinary frequency and dysuria appear. The pain may clear as the stone moves into the bladder or from the calyceal system into the ureter.

Stones may obstruct the urinary tract and impair renal function. There is increased risk of infection with chronic obstruction. Bleeding may be chronic and accompany obstruction. The presence of bleeding alone does not predict a more severe outcome. Episodes of rapid onset of pain, bleeding, and then rapid clearing, often called ‘passing gravel’, is the result of passing a large amount of crystals of calcium oxalate, uric acid, or cystine.

The size, number, and metabolic composition of new stones strongly influence the natural history and complication rates. Thus, the clinical presentation can be classified by metabolic type (Table 2). Spontaneous stone passage may occur with calcium oxalate, calcium phosphate, uric acid, and cystine stones. Rarely does a struvite stone or a staghorn stone of other composition (cystine, uric acid) pass spontaneously.

Table 2. Manifestations of Stones by Composition

Stone event	Calcium	Uric acid	Struvite	Cystine
Stone passage	+	+	-	+
Crystalluria	-	+	-	+
Small, separate stone	+	+	-	
Radiodense	+	-	+	+
Staghorn	-	+	+	+
Nephrocalcinosis	+	-	-	-
Sludge and obstruction	-	+	-	+

Relationship of kidney stones to other diseases. Nephrolithiasis with loss of renal function may be a complication of obstruction by a stone lodged in the ureter, a complication of the surgical procedure to remove a stone, or from the disordered pathophysiology of some stones. Moderate reduction in renal function can increase long-term cardiovascular morbidity. Staghorn calculi caused by cystinuria, renal tubular acidosis (RTA), or chronic infection are well recognized causes of decreased renal function. The development of uric acid sludge within the renal tubules under conditions of massive cell lysis may rapidly reduce renal funciton and cause acute renal failure.

Early surgical treatment of obesity using gastro-jejunal bypass procedures resulted in hyperoxaluria, calcium oxalate nephrolithiasis, and renal insufficiency. The modern era of gastric bypass surgery approaches weight loss by reducing the size of the stomach. Whether such surgery also results in hyperoxaluria and stone formation has yet to be determined by well designed clinical studies.

In addition to the longstanding associations of nephrolithiasis with primary hyperparathyroidism, gout and inflammatory bowel disease, stones are now recognized to be strongly associated with obesity, diabetes type II, and hypertension.

14.1.3. Imaging

All patients suspected of harboring a stone in the urinary tract should undergo an imaging procedure to determine whether the new stone is located within the kidney parenchyma, renal pelvis, upper or lower ureter, or bladder, and whether there is ureteral obstruction, ,. Localization of stones is also important in choosing medications, surgery, or lithotripsy. Figure 1 demonstrates the appearance of a solitary radio-opaque stone in the lower pole of the left kidney in a patient with idiopathic hypercalciuria. Such stones may be symptomatic with bleeding, infection, or obstruction. This stone was asymptomatic and was not removed. Figure 2 shows multiple radio-opaque stones of various sizes occupying the upper and lower poles and calyces of both kidneys. Noninfused CT of the abdomen with 5 mm cuts is the most sensitive imaging technique for determining the number and location of stones within the renal parenchyma or along the upper or lower urinary tract. Using this technique, stones can be distinguished from kidney tissue or blood clots. Nephrocalcinosis can be identified as a myriad of tiny, almost microscopic specks of radiodense calcium arrayed along the calyces. Small, separate, radiodense stones of less than 1 cm in diameter suggest calcium or less commonly, cystine stones (Table 2). Radiodense stones suggest either calcium or struvite composition, but struvite stones are usually large and fill the calyceal system. Cystine stones appear to be radiodense, but less dense than calcium-containing stones. Small, radiolucent stones suggest uric acid composition. Uric acid stones appear as filling defects on intravenous pyelography. Filling defects that occupy the renal pelvis are staghorn stones and may be of struvite, uric acid, or cystine composition. Sludge may be of either uric acid or cystine, can fill the renal pelvis and cause obstruction. Plain radiographs of the abdomen can identify large stones of greater than 3 mm. Ultrasound may not accurately visualize all stones and therefore cannot be used for follow-up to determine the appearance of new stones.

Figure 1. Standard radiograph of abdomen showing opaque kidney stone in the parenchyma of the left kidney. This stone may be asymptomatic or may cause pain, hematuria, infection.

Figure 2.

14.1.4. Diagnosis

Treatment to prevent recurrence of stones is based upon knowledge of the pathogenesis of the metabolic environment that favors formation, aggregation, and growth of the crystal mass. The metabolic abnormality is reflected in the composition of the stone and is identified by selected blood and urine tests. Thus, every effort should be made to recover the stone for composition analysis. The frequency and composition of stones are listed in Tables 1 and 2. Performing a urinalysis n a first morning sample may reveal the presence of crystals and strongly suggest the type of stone (Table 1).

14.1.5. Stone analysis

The composition of every stone and stone fragment recovered should be submitted for composition. Commercial laboratories can perform such analyses using polarization microscopy with minimal expense. Infrared spectroscopy and x-ray diffraction are more precise and sensitive, but are not necessary for most stone analyses.

14.1.6. Biochemical evaluation

The NIH Consensus Conference of 1988 recommended that a single stone former should undergo blood tests to detect primary hyperparathyroidism, other causes of hypercalcemia, and level of renal function. Recurrent stone formers should have at least one set of blood measurements and one 24 hour urine collection while on their usual diet and medications. The University of Chicago Kidney Stone Clinic obtains three 24hour urine collections and three consecutive fasting blood tests while patients follow their usual diet. Each serum and urine collection (Table 3) is analyzed as indicated. In addition, each of the three urine collections is analyzed for citrate, oxalate, pH, and volume. A screening test for cystine is also performed on one urine sample. The urine concentrations of key ions and small molecules can be used to calculate supersaturation with respect to the crystals that appear spontaneously and aggregate to form stones of calcium oxalate, calcium phosphate, and uric acid. Software is available to calculate supersaturations by solving 23 simultaneous equations.

Table 3. Suggested Laboratory Evaluation of Stone Formers

Fasting Blood (one) Calcium Phosphate Magnesium Creatinine Uric acid Sodium Potassium 24 Hour urine (three consecutive days) Volume pH Calcium Phosphate Magnesium Creatinine Oxalate Uric acid Citrate Cystine* Sodium Potassium Sulfate Ammonium

Protocol used by the University of Chicago Kidney Stone Program for single and recurrent stone formers (5). Tests are obtained while the patient is eating his/her usual diet. Cystine is obtained on one urine sample in all patients.

Urine supersaturation and stone formation Kidney stones are categorized by their composition, the type of mineral found in the stones. The stone type may be determined by spectroscopic analysis of a stone or stone fragment passed. The stone type is the byproduct of the state of supersaturation in the urine at the time the stone formed (6). Because strategies to decrease stone formation are based upon effective reduction of urine supersaturation, it is important to know that urinary supersaturation may develop through one of many mechanisms. For the calcium oxalate stone, urine supersaturation with respect to calcium oxalate may occur as a result of increased urine excretion of calcium or oxalate, low urine volume, or combinations of these conditions. A number of pathogenetic processes can lead to the endpoint of over-excretions. In the example of uric acid stone formation, uric acid supersaturation may arise from uric acid overproduction, overexcretion, or low urine pH (see uric acid section below).

14.1.7. General Principles on the management of stones

Current management of stones in the renal parenchyma, collecting system, and urinary tract is based upon proposed general guidelines that emerged from the 1988 National Institutes of Health Consensus Conference on Nephrolithiasis (7, 8).

14.1.8. Shock wave lithotripsy

Surgical intervention is required for stones that cause obstruction, bleeding, severe pain, or serious infection. Depending upon their size and location, stones may be removed using cystoscopy, lithotripsy, or percutaneous nephrolithotomy. Stones that are less than 5 mm in diameter may pass through the upper and lower urinary tract spontaneously, whereas those 7 mm and greater in diameter tend not to pass. Extracorporeal shock wave lithotripsy (ESWL) fragments stones in the renal parenchyma and upper and lower urinary tracts. ESWL is effective for removing stones less than 2 cm in diameter, with success rates highest in kidneys that contain one stone. Stones less than 2 cm in the upper two-thirds of the ureter can be effectively fragmented, and cystoscopy is effective in removing stones in the lower one-third of the ureter. Stones lodged at the ureteropelvic junction or within calyceal diverticulae in the upper tract are best removed through endourologic techniques. Because too many shock waves may result in renal damage, very large stones and staghorn calculi are not treated with ESWL. Ureterolithotomy rather than ESWL is the procedure of choice for removal of stones in the lower segment of the ureter. Patients with stones larger than 2 cm require both ESWL and percutaneous nephrolithotomy. Overall, ESWL alone fails to remove stone fragments in 35% to 55% of cases. The special case of large, infected staghorn calculi, or complex anatomy, or obstruction, may require open surgery.

14.2. Calcium Stones

Calcium oxalate and calcium phosphate crystals, either alone or combined, are the most common causes of renal calculi. Among the earliest events in stone formation is supersaturation of the urine with respect to the constituents of the stone. Crystals of calcium oxalate form in supersaturated urine and then become anchored on the urothelium of the renal pelvis. Biochemical abnormalities that create supersaturation of the urine with respect to either calcium oxalate or calcium phosphate include hypercalciuria, hypocitraturia, hyperoxaluria, and hyperuricosuria. These several pathogenetic causes of calcium stone formation offer a rational basis for classification. The site of the initial crystal formation is specific for the underlying cause of the calcium stone. Randall’s plaques (see below) are deposits of interstitial crystals localized to the papillary tip. Urologists discover calcium oxalate stones in the renal pelvis attached to or anchored onto the plaques. Analysis of renal biopsies obtained at the time of stone removal (percutaneous nephrolithotomy) and taken from the plaques revealed changes specific for the several causes of calcium stones (9,10).

In IH stone formers, the investigators (9) found the initial crystals were located in the basement membrane of the thin loop of Henle with extension into the vasa recta and then into the interstitium around the terminal collecting ducts. In the most advanced cases, crystals in the interstitium extended into the papillae. The crystals were calcium phosphate or apatite while the stones were calcium oxalate. At the site of the plaques, there was evidence of erosion of the crystals through the thin layer of urothelium, thus the crystals of calcium phosphate were exposed to the urine supersaturated with respect to calcium oxalate. It is postulated that calcium oxalate deposits on the apatite crystals to create an anchored stone through the process of heterogeneous nucleation (crystal formation on the surface of another crystal).

Patients with other causes of calcium oxalate stones also underwent kidney biopsy during stone removal. Patients with hyperoxaluria resulting from intestinal bypass surgery and intestinal oxalate over-absorption had calcium oxalate stones. Biopsies revealed calcium phosphate crystals, but in contrast to the location of crystals in IH patients, the crystals were located within the tubule lumens at the level of the terminal collecting ducts. Randall plaques were not present, and there was no calcium phosphate crystal deposition in the interstitium. Biopsies from non-stone formers who had undergone nephrectomy did not have Randall’s plaques and there were no crystals within the tubules or in the interstitium. Thus, the underlying metabolic abnormality that leads to calcium oxalate stone formation is associated with a specific location of the initial crystal formation. Potential mechanisms responsible for the localization of the calcium oxalate crystals have been reviewed (9, 10) and will serve as the basis for future research.

14.2.1. Primary hyperparathyroidism

Increased parathyroid hormone (PTH) secretion is usually from a benign adenoma arising from one or more parathyroid glands or hyperplasia of two or more glands. All of the manifestations of primary hyperparathyroidism can be accounted for by exaggeration of the physiological effects of parathyroid hormone primarily on kidney and bone. These effects result in intestinal calcium hyperabsorption, increased bone turnover, low bone mass, hypercalcemia, hypercalciuria, hypophosphatemia and calcium oxalate or calcium phosphate stone formation. The diagnosis rests on demonstration of hypercalcemia and elevated serum PTH by radioimmunoassay. Current assays measure intact PTH and will differentiate primary hyperparathyroidism from other causes of hypercalcemia in 95% of cases (Table 4). Five percent of patients have PTH that is not frankly elevated but is inappropriately high for the prevailing elevated serum calcium. Urine calcium is high in most patients.

Table 4. Differential Diagnosis of Hypercalcemia

1. Primary hyperparathyroidism 2. Malignant tumors 3. With skeletal metastases 4. Without skeletal metastases 5. Arising from the marrow 6. Myeloma 7. Leukemia with blastic crisis 8. Granulomatous diseases 9. Sarcoidosis 10. Active tuberculosis 11. Histoplasmosis 12. Coccidiomycosis 13. Leprosy 14. Medications 15. Thiazide diuretics 16. Vitamin D intoxication 17. Vitamin A intoxication 18. Lithium carbonate 19. Total parenteral nutrition 20. Estrogens in breast cancer 21. Androgens in breast cancer therapy 22. Aminophylline intoxication 1. Miscellaneous 2. Immobilization 3. Pheochromocytoma 4. Vasoactive intestinal peptide-producing tumor 5. Familial hypocalciuric hypercalcemia 6. Milk-alkali syndrome

Primary hyperparathyroidism is the second most common cause of calcium kidney stones, and contributes from three to 13 percent of all stone formers (11). Metabolic disturbances that predispose to stone formation include hypercalciuria, hyperphosphaturia, and alkaline urine. Excess PTH inhibits tubule bicarbonate reabsorption with resultant urine pH above 6.5. This alkaline urine and the excess urine phosphate increase urine supersaturation for both calcium oxalate and calcium phosphate and therefore favor kidney stone formation. The most common stone is that of calcium phosphate (brushite), but calcium oxalate stones and stones that contain both calcium oxalate and calcium phosphate are also common.

Calcium nephrolithiasis is an indication for parathyroidectomy. Surgical cure of the hyperparathyroidism normalizes serum calcium and returns calcium filtered load to normal, lowers urine calcium, reduces urine phosphate, and lowers urine pH. As a result, urinary supersaturation with respect to calcium phosphate and calcium oxalate decreases, and stone-free status is achieved in over 95% of patients.

14.2.2. Idiopathic hypercalciuria

Greater than 50% of patients with calcium oxalate nephrolithiasis have idiopathic hypercalciuria (IH). IH is characterized by normocalcemia, urine calcium excretion of greater than 300 mg per 24 hr for men, 250 mg 24 hr for women, greater than 140 mg calcium per gram urine creatinine, or greater than 4.0 mg calcium per Kg body weight for either sex in the absence of known causes of normocalcemic hypercalciuria (12). The diagnosis is one of exclusion of known causes of normocalcemic hypercalciuria (Table 5). Hypercalciuria increases the risk for calcium oxalate nephrolithiasis by 10-fold and about 10% of those with hypercalciuria will form at least one calcium oxalate kidney stone (5, 13). IH is common in the general population, affecting about 7% of the population. Children and adults have the same rate of IH, strongly suggesting that hypercalciuria begins early in infancy or childhood and persists throughout life.

Table 5. Causes of Hypercalciuria with Normocalcemia

1. Idiopathic or familial hypercalciuria (IH) 2. Sarcoidosis 3. Hyperthyroidism 4. Immobilization 5. Rapidly progressive osteoporosis 6. Paget’s disease of bone 7. Glucocorticoid excess 8. Renal tubular acidosis 9. Malignant tumors

14.2.3. Genetic basis of IH

The familial pattern of IH is consistent with an autosomal dominant pattern of inheritance. Males and females are equally affected, hypercalciuria occurs in successive generations, and one-half of first degree relatives of a given proband are hypercalciuric (14, 15). The observations that spontaneous hypercalciuria and calcium stone formation can be bred in male and female genetic hypercalciuric stone-forming (GHS) rats support the concept that hypercalciuria can have a genetic basis (16). Potential genes responsible for IH have been identified using either linkage analysis or association studies. Scott et al (17) using sib-pair linkage analysis reported a potential linkage of the VDR locus to idiopathic calcium stone formation and relevant quantitative traits. Linkage analysis was also used by Reed et al (18, 19) to map a gene defect possibly responsible for absorptive hypercalciuria to chromosome 1q23.3-q24. A gene product identified in this region shares homology with the rat soluble adenylate cyclase, but the potential function of the cyclase remains to be determined. Weber et al (20) reported a potential link between a heterozygous PCLN-1 mutation and hypercalciuria in calcium stone-formers. A number of candidate genes have been assessed in association studies, including the Ca-sensing receptor (CaR, 21), VDR (22, 23), TRPV5, TRPV6, calbindins, and CLCN5. None of the studies have yielded conclusive evidence implicating any of these genes as primary causes of IH.

The largest genetic study to date was conducted in 3,773 stone formers in Iceland and The Netherlands and compared to 42,510 non-stone-formers (24). In this genome-wide association study, common variants located within the CLDN14gene 21q22 locus were associated with kidney stones (OR = 1.25 and P = 4.0 x10_^-12for the rs219780[C] SNP). Approximately 60% of the general population is homozygous for rs219780[C] which confers a 1.64 times greater risk of developing kidney stones compared to non-carriers. The CLDN14gene is expressed in the kidney where the caludin proteins are involved in regulation of paracellular permeability at epithelial tight junctions. Hypercalciuria was associated with the mutation, and the same variants were also associated with reduced bone mineral density at the hip and spine. Whether the phenotype of kidney stones and low bone mass arise directly or indirectly from the gene variation is not known at present.

14.2.4. Pathogenesis of IH

Patients with IH have high urine calcium and normal urine oxalate concentrations. Urine citrate may be normal or low., and urine pH is normal. The excess urine calcium creates a supersaturation of the urine with respect to calcium and oxalate and favors spontaneous calcium oxalate crystal formation. The aggregation of crystals and subsequent attachment of the crystal mass onto the surface of Randall’s plaques in the renal papillae are early events in what can become a clinical stone. The evidence supporting a role of hypercalciuria in the pathogenesis of calcium oxalate stones include: 1) the high frequency of hypercalciuria among calcium oxalate stone formers; 2) urine supersaturation with calcium oxalate in stone formers; 3) and the reduction in new stone formation upon reversal of the hypercalciuria as by thiazide diuretic therapy.

Patients with IH and calcium oxalate stones have a unique histopathology that centers around the presence of Randall’s plaque, which are the sites of attachment of calcium oxalate stones. The stones appear to attach and then grow while by addition of crystal. The plaque is composed of calcium phosphate or apatite. The plaque is composed of layers of apatite separated by intervening layers of a macromolecular matrix containing a number of proteins, the majority of which are yet to be identified. It is known that osteopontin and heavy chain 3 of the inter-alpha trypsin inhibitor are contained in the matrix. The plaque material extends below Randall’s plaque and forms a syncytium that curses through the interstitium. Randall’s plaques are common in stone formers and rarely found in non-stone formers. The amount of papillary surface covered with plaque varies directly with the level of urine calcium excretion and inversely with urine volume and pH. These are the same factors that predispose to urine calcium oxalate supersaturation. It is important to note that crystal deposition does not occur within the tubule lumens of the terminal collecting ducts.

Studies of the ultrastructure of the syncytium reveal that the plaque formation begins in the basement membrane of the thin limb of the Loop of Henle and then extends into the medullary interstitium. The syncytium expands downward into the papillae and eventually reaches the urothelium. For stones to grow and enlarge on the plaque, the papillary urothelium must be penetrated. At this point, the supersaturated urine is in direct contact with the plaque, both its mineral and macromolecular phases. In stones removed by percutaneous lithotomy, a plaque-stone interface can be appreciated with the mineral of the plaque extending down into the medullary interstitium. Papillary urothelial cells may be identified on the periphery of the stone at the edges of the site of urothelial penetration.

Randall’s plaque is unique to IH, as calcium oxalate stones that form in the presence of oxalate-excess states such as following ilieal by-pass surgery or in patients with genetic defects in oxalate metabolism, are not anchored by a Randall’s plaque structure. These observations emphasize the specificity of the processes involved in stone formation even when urine supersaturation may not differ.

The source of the excess urine calcium is due to both intestinal over-absorption of dietary calcium and increased bone resorption (14). Intestinal calcium hyperabsorption is found in the vast majority of IH patients at all levels of dietary calcium intake (25). Pathologic renal over-production of 1,25-dihydroxyvitamin D [1,25(OH)₂D] and high serum levels is found in about 50% of patients (26). For them, the high 1,25(OH)₂D levels can explain the high calcium absorption rates. In the other patients with normal serum 1,25(OH)₂D levels, intestinal calcium absorption rates are elevated but the cause is not known. Elevated intestinal vitamin D receptor (VDR) levels have been found in genetic hypercalciuric (GHS) rats, which serve as a model for human IH (27), and in men with urine calcium excretion over 350 mg/24 hr peripheral blood monocyte VDR levels were twice that of non-stone-formers (28). It is proposed that high tissue VDR increases the number of 1,25(OH)₂D/VDR complexes and amplifies the biologic actions of 1,25(OH)₂D. Animal experimental data demonstrate a direct relationship between tissue VDR and 1,25(OH)₂D actions.

IH patients also have an abnormality in the renal handling of calcium (30). The filtered load of calcium is not different between IH patients and normal subjects, as both have normal total and ionized blood calcium. However, tubular calcium reabsorption is reduced in IH. The mechanism for the decreased tubular calcium reabsorption is not known, but may involve over- expression and function of Ca-specific transporters or channels such as the calcium-sensing receptor and .TRPV5, or altered permeability such as may occur in the absence of functioning parafillin or caludin (24).

Under conditions of adequate calcium intake, most of the excess urine calcium is dietary in origin (14). During dietary calcium restriction, urine calcium declines. However, in about 50% of patients, urine calcium does not decrease sufficient to maintain neutral or positive calcium balance, and negative calcium balance ensues (25, 30). That is, there is more calcium in the urine than is in the diet. Prolonged low calcium intake and negative calcium balance eventually lead to clinically detectable bone loss with low bone mass and increased risk for fracture (31). Indeed, low bone density has been well documented in IH patients (25) and may be a more common phenotype than calcium oxalate stones.

14.2.5. Pathogenetic models of IH

IH may be a heterogeneous disorder, as all of the observed changes in calcium metabolism cannot be understood by any one pathophysiologic model. Elevated serum 1,25(OH)2D levels can account for the increased intestinal calcium absorption, high bone resorption, and low bone mass. The increased 1,25(OH)₂D production and high serum 1,25(OH)₂D may be due to hypophosphatemia in about one-third and elevated parathyroid hormone levels in about 5%.

Patients with normal serum 1,25(OH)₂D levels may have elevated tissue VDR levels that would amplify vitamin D biologic responses to the normal serum 1,25(OH)₂D levels. In these patients, increased intestinal calcium absorption, bone resorption, and decreased tubule calcium reabsorption would occur simultaneously and continuously. Increased peripheral blood monocytes have been shown to over-produce cytokines that stimulate bone resorption. Increased IL-1beta, TNF-alpha, and IL-6 may increase bone resorption and produce low bone mass in some patients (31,33) but do not explain the increased intestinal calcium absorption and reduced renal tubule calcium reabsorption .Increased peripheral blood monocyte VDR found in some men with IH could stimulate 1,25(OH)₂D-mediated bone resorption, intestinal calcium absorption, and reduced renal tubular calcium reabsorption.

14.2.6. Treatment of IH

Because the state of supersaturation is an accurate estimate of the risk that a solution such as urine will create and enlarge a solid phase, rational therapy to prevent stone recurrence seeks to reduce urine supersaturation with respect to the major constituents of the stone formed. In IH, calcium oxalate monohydrate and dihydrate crystals form in urine that is supersaturated with respect to the calcium and oxalate ion product. Effective therapy lowers either or both calcium and oxalate sufficient to reduce supersaturation (34, 35, 36). Estimates of supersaturation are also useful in following the efficacy of therapy, as failure to reduce urine supersaturation predicts a high risk of stone recurrence (36).

Because of the high stone rate of recurrence in IH, treatment following the initial stone is advised. A rational approach to the treatment of IH is reduction of calcium oxalate supersaturation. The thiazide class of diuretic agents reduces urine calcium excretion through a direct action on the distal tubule to increase calcium reabsorption (37). The multiple actions of thiazide agents include increased sodium excretion, volume contraction, and a resulting decrease in glomerular filtration rate (GFR). Decreased GFR enhances distal tubule calcium reabsorption, lowers urine calcium, and improves calcium balance. Although dietary calcium restriction partially reduces urine calcium excretion, calcium oxalate supersaturation is not decreased presumably because reduced dietary calcium absorption permits an increase in the intestinal availability and absorption of oxalate (38). As a result, calcium oxalate stone formation is not decreased (39). As diet calcium restriction promotes negative calcium balance and bone loss (25), a reasonable target calcium intake should be 800 to 1,000 mg per day (39). Food sources of calcium are preferable, as the rapid dissolution and absorption of calcium from calcium supplements may be rapid and increase urine calcium supersaturation which promotes calcium oxalate crystal formation even for brief periods of time.

The efficacy of thiazide therapy has been evaluated in six prospective trials (25). Long term studies of three years or longer have demonstrated efficacy in reducing new stone formation, however more brief studies of 1-2 year duration effectively reduce new stone appearance (25,40,41). The thiazide agents shown to be effective in prospective trials are listed in Table 6. As chronic thiazide use may be associated with hypokalemia, potassium supplements are often required. The preferable form of potassium replacement is potassium citrate, as increased citrate intake increases urine citrate, which in turn lowers calcium oxalate supersaturation.

Table 6. Thiazide Diuretic Therapy in Idiopathic Hypercalciuria

Agent	Dose schedule	Comments
Hydrochlorothiazide	25 to 50 mg	Short half-life of 6-8 hr requires bid dosing
Chlorthalidone	25 to 50 mg	Long half life of 23 hr permits qAM dosing
Indapamide	1.25 to 2.5 mg	Long acting permits qAM dosing
Amiloride	5 to 10 mg	QAM dose to avoid potassium wasting

A five-year, randomized study conducted in male recurrent calcium oxalate kidney stone-formers showed that recurrent stone formation was reduced by about 50% among those who ingested a diet with normal calcium (1,200 mg calcium), and low in animal protein (52 g per day) and salt (2,900 mg sodium chloride) compared to men who ate a low calcium (400 mg calcium) diet (42). Urine calcium levels were lower with both diets, but the decline in urine calcium oxalate supersaturation was greater in the men ingesting the normal calcium, low protein, and low salt diet. The decline in relative supersaturation of calcium oxalate was due to a decline in urine oxalate in those eating a normal calcium diet and rose in those who ingested a low calcium diet.

Adequate fluid intake (at least two liters daily) is part of all management plans for the prevention of calcium oxalate stones; however fluid intake alone has not been sufficient to prevent new stone formation in hypercalciuric patients (43).

14.2.7. Renal tubular acidosis

Systemic hyperchloremic acidosis, alkaline urine, medullary nephrocalcinosis, calcium phosphate nephrolithiasis, and low bone mass characterize type 1 renal tubular acidosis (RTA, 44). Alkaline urine increases the proportion of urinary phosphate in the divalent and trivalent states and raises calcium phosphate supersaturation. The state of calcium phosphate supersaturation and the lack of effect of urine pH on calcium oxalate supersaturation predict the formation of calcium phosphate or brushite stone formation. Two other major factors that contribute to stone formation are low urine citrate and hypercalciuria. Hypocitraturia is due to enhanced proximal tubule citrate reabsorption and occurs with any cause of acidosis. The hypercalciuria is due to calcium release from bone during bone buffering of the acidosis and to suppressed tubule calcium reabsorption.

Alkali therapy reverses the acidosis and reduces urine calcium excretion. Therapy for stones that occur in type 1 RTA includes modification of risk factors and alkali therapy in the form of potassium citrate.

14.2.8. Low urine citrate

Urine citrate forms soluble calcium citrate complexes and thereby reduces calcium oxalate and calcium phosphate supersaturation. As a result, calcium oxalate and calcium phosphate stone formation decreases (25). Low urine citrate removes an important inhibitory action on nucleation, growth, and aggregation of calcium oxalate and is a common cause of calcium oxalate stone formation, especially in women. Several causes of low urine citrate are known (Table 7), however the majority of men and women with low urine citrate are idiopathic. Women with calcium oxalate nephrolithiasis are more likely to have hypocitraturia than are men.

Table 7. Causes of low urine citrate

1. Systemic acidosis 2. Renal tubular acidosis 3. Chronic diarrheal states 4. Ileostomy 5. Thiazide-induced hypokalemia 6. Urinary tract infection 7. Glucocorticoid excess 8. Idiopathic

Low urine citrate is considered to be below 500 mg/24 hr

Non-stone forming women have higher urine citrate than men (600 mg/L vs 400 mg/L), which may account for the lower rate of stone formation among women (45). Normal and stone-forming men have comparable urine citrate levels, and these levels are similar to urine citrate levels found in stone-forming women.

Hypocitraturia can be corrected by multiple daily doses of potassium citrate. By increasing urine citrate excretion, such treatment is effective in reducing new calcium oxalate stone formation in men and women with hypocitraturia through reduction in calcium oxalate supersaturation (46,47).

14.2.9. Hyperoxaluric States

Non-stone formers excrete 20 to 40 mg of oxalate in the urine daily. Normal urine oxalate excretion is found in idiopathic hypercalciuria, however, a variety of genetic and acquired disorders raise urine oxalate above 45 mg per 24 hour, increase urine calcium oxalate supersaturation, and raise the risk of calcium oxalate stone formation. The causes of hyperoxaluria can be classified as either oxalate over-synthesis, or intestinal oxalate hyperabsorption (Table 8).

Table 8. Hyperoxaluric States*

Oxalate Over-production 1. Systemic acidosis 2. Hereditary types I and II 3. Ethylene glycol poisoning 4. Methoxyflurane anesthesia Intestinal Oxalate Over-absorption 1. Pancreatic insufficiency 2. Celiac sprue 3. Ileal resection 4. Small bowel bypass surgery for obesity 5. Dietary over-ingestion of oxalate-rich foods 6. Cellulose phosphate ingestion or low calcium diet

*Adapted from reference 51 (Klugman V, Favus MJ. Diagnosis and treatment of calcium kidney stones. In Advances in Endocrinology and Metabolism. Mazzaferri EL, Barr RS, Kreisberg RA, eds. Mosby, St Louis, pp117-142, 1995)

Intestinal oxalate hyperabsorption, or enteric hyperoxaluria, is the most common acquired form of hyperoxaluria (48, 49). Each of these causes (Table 8) may increase the risk of calcium oxalate stone formation 25- to 100- fold. Increased colon oxalate absorption is thought to be due to malabsorption of fatty acids and bile salts with subsequent increased distal delivery into the colon and increased colonic oxalate permeability. Also, fatty acids bind luminal calcium and form insoluble calcium soaps. As a result, in the presence of lower luminal calcium, more oxalate is available for absorption. Hyperoxaluria from small bowel malabsorption often surpasses 100 mg/24 hr, which is sufficient to raise the rate of stone formation.

Management of enteric hyperoxaluria is directed at decreasing intestinal oxalate absorption by limiting dietary oxalate and fat and increasing calcium in the form of calcium carbonate. At doses of calcium in the range of 250 mg to 1,000 mg four times daily, calcium oxalate precipitation in the intestinal lumen reduces oxalate absorption. The ion exchange resin cholestyramine, 4 to 16 g per day in four divided doses, binds intestinal luminal oxalate, fatty acids, and bile salts and thereby diminishes oxalate absorption. For those patients with malabsorption, hypocitraturia may also be present and require correction.

Excess urinary oxalate may be due to high intake of foods rich in oxalate. Dietary excesses of oxalate-rich foods such as nuts, cocoa, chocolate, tea, spinach, rhubarb, parsley, and pepper can raise urinary oxalate to 50 to 60 mg per day. However, dietary sources alone do not increase urine oxalate to the levels that occur in enteric hyperoxaluria. Dietary calcium and fiber sources can bind oxalate in the intestinal lumen of the small intestine and colon and limit its absorption. Treatment of dietary-induced hyperoxaluria is dietary modification to limit ingestion of oxalate-rich foods.

Oxalate overproduction occurs as a result of two rare inherited disorders of oxalate metabolism (50). Type 1 primary hyperoxaluria is an autosomal recessive disorder caused by decreased activity of the hepatic peroxisomal alanine glycoxylate amono-transferase. The accumulated glycoxylate is converted to oxalic acid. Type 2 primary hyperoxaluria is due to a deficiency of D-glyceric dehydrogenase. Both hereditary forms result in high urine oxalate excretion, usually in excess of 130 mg/24 hr. The natural history of untreated inherited hyperoxaluric disorders includes nephrolithiasis beginning in early childhood followed by nephrocalcinosis, renal insufficiency, and systemic oxalosis (tissue deposition of oxalate). Increased urine volume to 3 liters daily plus potassium citrate can lower urine oxalate concentration and thereby reduce urine supersaturation. Combined liver and kidney transplantation has been performed to restore the missing enzyme. As patients with extensive oxalosis have done poorly following transplantation, transplantation should be performed prior to the development of systemic oxalosis.

As pyridoxine is a cofactor in the conversion of glycoxylate to glycine, therapy for genetic hyperoxaluria types 1 and 2 includes the early use of pyridoxine 400 mg daily. Therapy must be initiated before renal insufficiency appears.

14.2.10. Hyperuricosuria

Hyperuricosuria is defined as urine uric acid of greater than 800 mg per 24 hr in men and greater than 750 mg per 24 hr in women. Excess urine uric acid excretion is a well-recognized risk factor for calcium oxalate nephrolithiasis (51, 52). Urine may become supersaturated with sodium hydrogen urate when the urine has a pH of greater than 5.5 in the presence of hyperuricosuria. Crystals of monosodium urate may facilitate crystallization of calcium oxalate and the aggregation of these crystals into a stone by heterogeneous nucleation.

Increased urine uric acid has many causes (Table 9). Over-ingestion of purine-rich foods including meat, fish, and poultry accounts for the majority of patients with hyperuricosuria who form calcium oxalate stones. A minority over-produce uric acid and hyperuricosuria persists despite ingestion of a low purine diet. Urine supersaturation with respect to uric acid may also occur through an increase in uric acid concentration during dehydration. In addition, urine pH below 6.0 reduces the solubility of uric acid, and uric acid stone formers have as a group, lower urine pH compared with patients who form calcium oxalate stones (pH 5.5 vs 6.0) (8).

Table 9. Causes of Hyperuricosuria

1. Increased dietary purine ingestion from meat, fish, poultry 2. Overproduction of uric acid Low urine pH Dehydration with low urine volumes, low pH

Hyperuricosuria is defined as urine excretion greater than 800 mg/24 hr in men, and greater than 750 mg/24 hr in women while ingesting their usual diet. These same conditions may lead to pure uric acid stone formation..

Recurrence of hyperuricosuric calcium oxalate stone formation due to uric acid overproduction can be lessened by the administration of allopurinol at a dose that is sufficient to inhibit uric acid synthesis. As a result of the treatment, urine uric acid supersaturation is diminished and new stone formation can be reduced by 50% compared to hyperuricosuric stone formers not taking allopurinol (53).

14.3. Uric Acid Stones

Uric acid stones are responsible for 5 to 10% of all stones seen in a stone clinic. Stones composed of uric acid or the sodium salt of this crystal, sodium hydrogen urate, may become clinically manifest as crystalluria, obstruction, dysuria, or bleeding. Elevated serum uric acid may cause interstitial deposition of crystals and inflammation of the renal parenchyma. Crystalluria may occur in the presence or absence of hyperuricemia or hyperuricosuria. Low urine pH may cause crystals in the urine of normal subjects. Uric acid stones occur in a variety of clinical settings (Table 10).

Table 10. Pathophysiologic Classification of Uric Acid Stone Formation

1. Idiopathic 2. Sporadic 3. Familial 4. With hyperuricemia 5. Primary gout 6. Lesch-Nyhan syndrome 7. Glycogen storage disease 8. Myeloproliferative and neoplastic disorders 9. With hyperuricosuria 10. Purine over-ingestion 11. Defective renal tubule reabsorption 12. Uricosuric medications 13. Dehydration 14. Gastrointestinal disease with fluid loss 15. Perspiration and losses through the skin

14.3.1. Gout

Uric acid stones are more frequent in patients with primary gout, and stone formation may occur prior to gouty articular symptoms (54, 55, 56). The frequency of stone formation among gouty patients is estimated to be about 35%, with increasing frequency of stones as serum or urine uric acid levels rise. Urine pH is the major determinant of urine uric acid supersaturation. Uric acid may appear in the urine as monohydrogen sodium urate as the first of two hydrogen ions dissociates from uric acid with a pK of 5.34. Urate is more soluble in the urine than uric acid, therefore urate stones are rare, and supersaturation refers to the state of uric acid.

Urine pH has a greater influence on uric acid stone formation than the 24-hour urine excretion of uric acid. A decline in urine pH from 6.0 to 5.0 increases urine uric acid concentration six-fold, while excretion due to production is increased only two-fold. Therefore, uric acid stone formation is more determined by pH than by urine volume or urine uric acid concentrations. The normal range for uric acid excretion 500 to 600 mg per 24 hour, and excretions greater than 750 mg for women and 800 mg for men are considered elevated. Clinically significant crystal and stone formation require persistent hyperuricosuria, dehydration, or marked reduction in urine pH. The cause of the low urine pH in uric acid stone-formers is not completely understood, but reduction in urine ammonium excretion appears to play an important role. Dehydration, which reduces urine volume and promotes a decline in urine pH increases urine uric acid concentration. Stone formers who over-excrete uric acid do so either as a result of excess dietary purine ingestion and conversion to uric acid, or to excess production of uric acid. Marked overproduction of uric acid may rarely be due to hereditary enzyme deficiency states such as Lesch-Nyhan syndrome (Table 10).

14.3.2. Malignancy

Treatment of a variety of disorders including myeloproliferative disorders, adult chronic granulocytic leukemia, and childhood acute leukemia may be complicated by uric acid stone formation as a result of chemotherapy-induced massive cell necrosis and release of purines. Renal precipitation may occur quickly and be extensive, leading to bilateral ureteral obstruction and acute renal insufficiency.

14.3.3. Gastrointestinal disorders

Acute diarrheal states and chronic inflammatory bowel disease may be associated with water loss and dehydration. With plasma volume contraction, urine pH falls and predisposes to stone formation. Patients with ileostomy are at increased stone risk due to intestinal bicarbonate losses. Patients with ileal resection may have hyperoxaluria and hyperuricosuria and have stones composed of both uric acid and calcium oxalate.

14.3.4. Drug-induced

Hyperuricosuria may be induced by large doses of aspirin or probenecid. In patients with high purine intake, these agents may increase urine uric acid excretion and stone formation.

14.3.5. Idiopathic

Familial uric acid nephrolithiasis occurs at a younger age and follows an autosomal dominant pattern of inheritance. Men and women are equally affected. Sporadic cases often begin in the early to mid-adult years, with high rates of recurrence. Serum and urine uric acid levels are normal in both conditions, and urine pH is low and related to reduced renal ammonium production.

14.4. Infection Stone

Struvite (magnesium ammonium phosphate) stones form only in the presence of bacteria that produce urease. The common urease-producing bacteria that may populate the urinary tract are proteus, klebsiella, pseudomonas, and enterococci. Urease-mediated splitting of urea and the generation of ammonium results in an alkaline urine. Urine pH above 7.0 normally is associated with very low urine ammonium levels of less than 10 mM per 24 hr. However, urine ammonium levels above 30 mM/24 hr and urine pH above 7.0 virtually make the diagnosis. Other constituents of the stone may include calcium carbonate and brushite (calcium phosphate), which form crystals in the very alkaline urine. Patients who form struvite stones do not pass them spontaneously, but rather are at high risk for bleeding, obstruction, and decreased renal function. Some infection stones begin as calcium oxalate stones that become infected with a urease-producing bacterium. Spread of infection to the contralateral kidney may occur.

Because untreated staghorn calculi will require nephrectomy in 50% of patients, definitive treatment is indicated. Growth of infection stones and their progressive damage to kidney tissue may be limited by ESWL and percutaneous nephrolithotomy; however definitive treatment of struvite stones is surgical removal. Open surgical removal followed by vigorous lavage of the renal pelvis to remove all fragments of the infected stone has reduced recurrence rates from 40% to 2% during seven years of follow-up (57). Extended antibiotic therapy has proven ineffective in irradicating the infection and does not substitute for complete removal of even the smallest particulate of the stone. Acetohydroxamic acid inhibits urease produced by the bacteria and has been shown to be effective in eradicating chronic infection of struvite stones (58). Use of the drug has been limited, however, as it is associated with potentially serious side effects such as hemolytic anemia and venous thromboembolic disease.

14.5. Cystine Stone

The dibasic amino acid cystine forms by the complexation of two cysteine molecules. Cystine is relatively insoluble, and appears in normal urine in small amounts that are insufficient to cause supersaturation, crystalluria, or stone formation. Cystinuria is a hereditary disorder in which a defect in intestinal and renal tubule transport of cystine and other amino acids results in a 10-fold increase in urine cystine excretion. As a result, the solubility limit of cystine in the urine is exceeded (59). Patients who are homozygous for the disease also over-excrete the other dibasic amino acids lysine, ornithine, and arginine. Heterozygous inheritance is associated variable increases in amino acid excretion and an intermediate increase in cystinuria. Renal stones form in the upper urinary tract as early as the first decade of life. The stones tend to be large, staghorn, and bilateral. Stone formation may manifest as obstruction, infection, hematuria, and renal failure. Cystine stones are visible on standard abdominal radiographs because of the relative density of the sulfur constituent of cystine.

Therapy is selected to reduce cystine excretion and increase urinary cystine solubility. Large urine volumes of 3-4 liters per day may be effective in some patients. Alkaline pH in the 7.5 range will reduce cystine solubility. However, fluid and alkali therapies are difficult to establish, especially in children. Dietary restriction of the essential amino acid methionine may cause small decreases in cystine synthesis, but is not practical because of the risk of inducing methionine deficiency. When fluid, alkali and dietary therapy fail, then pharmacologic therapy may be effective. Thiola and d-penicillamine reduce cystine synthesis by preventing cysteine-cysteine complexation. More soluble thiol-cysteine disulfides form and are readily excreted in the urine. Both agents have potentially serious side effects and therefore they are not used as first-line treatment.