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CHAPTER 30 Kidney Stones ANIRBAN BOSE • REBECA D. MONK • DAVID A. BUSHINSKY Epidemiology of Stone Formation, 1365 Pathogenesis of Stone Formation, 1366 Clinical Presentation and Evaluation, 1370 Therapy, 1375 KEY POINTS • Numerous factors, including sex, age, race and the patient’s geographic location, determine the prevalence of kidney stones • Kidney stones form when urine becomes supersaturated with respect to the specific components of the stone’s constituents • A multitude of monogenic hereditary disorders that result in changes of either calcium handling at the level of kidney, bone and gut, or calcium sensing at the calciumsensing receptor on the parathyroid glands and renal tubular cells, can lead to hypercalciuria and stone formation. • All patients, even those with a single stone, should undergo at least a basic evaluation in order to rule out a systemic etiology of stone formation. • Increasing fluid intake is a simple measure that has considerable impact on reducing stone growth and new stone formation. Nephrolithiasis is a common disorder with an incidence greater than 1 case per 1000 patients per year. In the year 2000, this resulted in nearly 2 million physician office visits with an estimated annual cost between $2 billion and $5.5 billion in the United States alone.1,2 The prevalence in industrialized nations is approximately 6% in women and 12% in men and appears to be rising over time.3 Its incidence peaks when patients are in their 30s and 40s. The prevalence increases with age until about the seventh decade of life.3-6 Stones may be composed of calcium oxalate, calcium phosphate, uric acid, magnesium ammonium phosphate (struvite), or cystine, alone or in combination. A variety of pathogenic mechanisms determine the type of stone formed. Symptomatic stones tend to localize in the renal tubules and collecting system but are also commonly found within the ureters and bladder.7 The recurrence rate of calcium oxalate stones is about 50% at 5 to 10 years and higher for cystine, uric acid, and struvite stones.8 Kidney stones result in substantial morbidity. The severe pain of renal colic can lead to frequent hospitalization, shock wave lithotripsy, or invasive surgical procedures. Though rarely a cause of end-stage renal disease (ESRD), nephrolithiasis has been associated with chronic kidney disease (CKD) in various populations,9-13 and even mild CKD is associated with significant adverse cardiovascular events.14-16 Insight into the mechanisms involved in stone formation can help direct appropriate therapy, which is known to significantly decrease the incidence of stone formation and its associated morbidity. If this morbidity also includes cardiovascular disease, then stone prevention may have more significant overall health benefits for patients than merely controlling the pain and consequences of renal colic. EPIDEMIOLOGY OF STONE FORMATION Numerous factors determine the prevalence of stones, including sex, age, race, and geographic distribution. Men are two to four times as likely to get nephrolithiasis as women.3-6,17 In the United States, blacks, Hispanics, and Asian Americans are much less likely to have stones than whites. Geography also appears to influence stone formation in the United States, with a decreasing prevalence from south to north and, to some degree, from east to west.17 The greater exposure to sunlight in the southeastern United States may be responsible for the increased rates of nephrolithiasis in that area. Sun exposure can lead to more concentrated urine by increasing insensible fluid losses due to sweating.18,19 Although increased sun exposure should increase levels of serum 25(OH)D (25-hydroxyvitamin D), there is no evidence for a subsequent increase in the level of 1,25(OH)2D (1,25-dihydroxyvitamin D), nor is there any evidence that hypercalciuria will worsen. Along with geography, genetic predisposition can influence the type of stone formed.18,20 For example, uric acid stones are seen in up to 75% of all cases in Mediterranean and Middle Eastern countries but constitute fewer than 10% of cases in the United States. By contrast, more than 70% of stones formed in the United States are calciumbased. Less common are magnesium ammonium phosphate (struvite or infection) stones, which account for about 10% to 25% of stones formed, and cystine stones, which are due to an autosomal recessive disorder and constitute only about 2% of all stones formed (Fig. 30-1).4,21,22 Diet and pharmacologic agents can also significantly impact stone formation. In a dramatic example, an outbreak of nephrolithiasis in Chinese infants was attributed to ingestion of melamine in infant formulas and milk powder. Melamine, intentionally added to raise the apparent protein content of the concentrates, led to the formation of large particles in the kidney and resulted in many cases of nephrolithiasis and renal failure due to obstructive uropathy.23-25 A variety of other dietary factors can have a significant impact on both the formation and prevention of kidney stones (see later discussion). 1365 1366 SECTION VII Mineral Metabolism Struvite, 15%-22% Uric acid, 5%-10% Calcium phosphate, 5%-10% Cystine, 1%-2% Calcium oxalate, 25%-35% Calcium oxalate and calcium phosphate, 35%-37% Figure 30-1 Frequency of different types of kidney stones. PATHOGENESIS OF STONE FORMATION Physiology Kidney stones form when urine becomes supersaturated with respect to the specific components of the stone. Saturation is dependent on chemical free ion activities of the stone constituents. Factors that affect chemical free ion activity include urinary ion concentration, pH, and the combination of the constituent ion with other substances. For example, an increase in the urinary calcium concentration or a decrease in urine volume increases the free ion activity of calcium ions in the urine. Urinary pH can also modify chemical free ion activity. A low urinary pH increases the free ion activity of uric acid ions. However, a high urine pH promotes the complexation of calcium with phosphorus, which decreases the free ion activity of both calcium and phosphorus. Citrate combines with calcium ions to form soluble complexes and will decrease the free ion activity of unbound citrate and calcium. When the chemical free ion activities are increased, the urine becomes supersaturated (also termed oversaturated). In this setting, new stones may form and established stones may grow. In the event of decreased free ion activity, urine becomes undersaturated, and stones do not grow and can even dissolve. The equilibrium solubility product is the chemical free ion activity of the stone components in a solution at which the stone neither grows nor dissolves. Stones form through the processes of homogeneous or heterogeneous nucleation. In homogeneous nucleation, progressive supersaturation eventually results in formation of small clusters secondary to the aggregation of identical molecules. These clusters grow to form a permanent solid phase, or crystals. Heterogeneous nucleation refers to crystal formation on the surface of a different crystal type or on other dissimilar substances, such as cells. In vivo, this type of nucleation is more common than homogeneous nucleation because crystals form at a lower level of supersaturation in the presence of a solid phase. The small crystals may then aggregate into larger clinically significant stones. Crystals generally anchor to renal tubular epithelium; this allows more time for growth. This anchoring of crystals occurs at the renal papillae, over areas of interstitial calcium phosphate present in the form of apatite termed Randall plaques (Fig. 30-2).26-28 The apatite crystals appear to originate at the basement membrane of tubular cells in the thin loop of Henle and extend into the interstitium without damaging the cells themselves or filling the tubular lumens. A combination of apatite crystal and organic material extends from the loop of Henle tubular basement membrane to the papillary uroepithelial Figure 30-2 An attached stone (paired arrows) is seen resting on a region of white plaque (single arrows) and intermixed with small areas of white (single arrow) and yellow plaques (arrowheads). (From Evan AP, Lingeman JE, Worcester EM, et al. Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease. Kidney Int. 2010;78:310-317.) surface, where calcium oxalate crystals or other crystals can adhere and form stones. If the stone breaks this anchor to the urothelial surface, it will then be carried by the urine through the ureter and into the bladder. If the stone is small (generally ≤5 mm in diameter) it may pass with only minor discomfort; however, if it has grown sufficiently, this migration may be extremely painful, and if the stone is of sufficient size, it may even completely obstruct the ureter, leading to nonfunction of the unilateral kidney. An important factor in the development of kidney stones may be the absence of adequate levels or activity of crystallization inhibitors in the urine. Uropontin, pyrophosphate, citrate, and nephrocalcin are endogenously produced substances that have been shown to inhibit calcium crystallization. Differences in the amount or activity of inhibitors are thought to account for the variability in stone formation among people with similar degrees of urinary supersaturation.22,29 Clinically, most physicians evaluate the lithogenic potential of the urine from stone formers by measuring the rate of excretion of the principal stone-forming elements in mass per unit time (e.g., milligrams or millimoles per 24 hours). It is clear, however, that the lithogenic potential of urine is better determined by the degree of supersaturation. Computer programs that calculate saturation from concentrations of various elements in the urine and the urinary pH are now available (e.g., both Quest Diagnostics and Litholink are commercial laboratories that measure urine ion excretion and calculate supersaturation) and more accurately determine the risk of stone formation. Any calculation of mean saturation underestimates the maximum supersaturation, which may drive stone formation, because of hourly variations in water and solute excretion throughout the day. Diet Dietary factors have a great influence on the concentration of excreted ions. Simply instructing patients to increase fluid intake appears to have a considerable impact on CHAPTER 30 Kidney Stones reducing stone growth and formation.30-32 Renal calcium excretion is augmented by increased sodium excretion,33 and hypercalciuric patients tend to have a greater calciuric response to a sodium load than control subjects.34 Dietary sodium restriction with the consequent decrease in urinary sodium excretion reduces calcium excretion and lowers supersaturation with respect to calcium-containing kidney stones. Patients are counseled to limit their daily sodium intake to a maximum of 3000 mg (~130 mEq) to reduce hypercalciuria.4,33,35 A moderate reduction in animal protein (~1.0 mg/kg per day) is known to be beneficial in patients with nephrolithiasis. Animal protein contributes to stone formation via multiple mechanisms.35 A mild metabolic acidosis develops when animal proteins are metabolized. In order to buffer the excess hydrogen ions, calcium is resorbed from bone, which leads to an increased filtered load of calcium.36 Metabolic acidosis also directly decreases renal tubular calcium reabsorption, which further enhances hypercalciuria.36 In addition, metabolism of amino acids contained in animal protein generates sulfate ions, which couple with calcium ions to form insoluble complexes.36,37 Citrate, a base, acts as a urinary inhibitor of stone formation. Citrate forms soluble complexes with calcium and lowers calcium oxalate and calcium phosphate supersaturation. During metabolic acidosis, citrate is reabsorbed proximally, reducing the amount excreted in the urine.38 Hypokalemia can also lead to reduced citrate excretion. An animal protein–induced reduction in urinary citrate can promote formation of both calcium oxalate and uric acid stones.34,39 Fructose has become a ubiquitous sweetener in American processed foods. In large food questionnaire studies this sugar has been associated with a significant risk of developing nephrolithiasis. Though the mechanism is not known, fructose is the only carbohydrate that can increase uric acid production, and fructose metabolism may increase stone formation.40 Several studies have demonstrated the benefits of a diet containing an age- and gender-appropriate amount of calcium in patients with kidney stones.31,35,41,42 Ingested calcium binds intestinal oxalate, reducing its absorption and consequent renal excretion.31 In a long-term prospective trial, Borghi and colleagues randomized hypercalciuric male stone formers to either a low-calcium diet or to a diet with a normal amount of calcium but low in sodium and animal protein.35 Both groups of men were instructed to restrict oxalate intake and drink 2 to 3 L of water daily. The group of men on a normal-calcium, low-sodium, and low– animal protein diet had a significantly lower recurrence of nephrolithiasis and a greater reduction in oxalate excretion and calcium oxalate supersaturation compared with the men on the low-calcium diet.35 Thus, patients should be maintained on an age- and gender-appropriate intake of calcium.42 Dietary calcium restriction should be strongly discouraged because it not only increases risk of recurrent stone formation but also engenders a significant risk of bone demineralization and development of osteoporosis.43,44 Note that although dietary calcium intake has been associated with a reduced incidence of kidney stones, calcium intake in the form of supplements can exacerbate stone formation in older women. The recommended dietary intake for men and women is 1000 mg of elemental calcium from ages 19 through 50 years and 1200 mg of calcium thereafter.45 Teenagers should consume 1300 mg of calcium per day. Excess calcium should be avoided, because the combination of calcium and vitamin D supplementation has recently been shown to significantly increase the risk of kidney stones in postmenopausal women.46 1367 Pathogenesis of Idiopathic Hypercalciuria Idiopathic hypercalciuria (IH) is defined as excessive urinary calcium excretion in the setting of normocalcemia and the absence of secondary causes of hypercalciuria. IH is the most common cause of calcium-containing kidney stones. The disorder is familial; it was initially thought to exhibit an autosomal dominant pattern of inheritance but is almost certainly polygenic.47 The mechanism by which IH leads to hypercalciuria is not known. It has been postulated that IH comprises three distinct disorders: excessive intestinal calcium absorption, decreased renal tubular calcium reabsorption, and enhanced bone demineralization. In a genetic strain of hypercalciuric stone-forming rats, hypercalciuria appears to be due to an excessive number of enteric vitamin D receptors leading to a generalized disorder of calcium transport at all sites of calcium transport including the kidney, intestine, and bone.48 In humans, recent observations also suggest that IH may be a systemic disorder of calcium homeostasis with dysregulation of calcium transport.49 An understanding of calcium homeostasis helps elucidate the potential mechanisms involved in IH. Calcium Homeostasis (Also See Chapter 28) Urinary calcium homeostasis is regulated in the gastrointestinal (GI) tract, the kidneys, and bone by parathyroid hormone (PTH) and 1,25(OH)2D. Approximately 99% of the calcium in the body is contained within the bone mineral. Daily bone resorption and bone formation, which in healthy, nonpregnant, nonosteoporotic adults should be equal, allow less than 1% of bone calcium to be exchanged with that in the extracellular fluid. Both PTH and 1,25(OH)2D at high concentrations stimulate release of calcium from the bone mineral through osteoclast-mediated bone resorption. Net calcium influx into the extracellular fluid is achieved by absorption from the GI tract, which occurs through 1,25(OH)2D-dependent and -independent mechanisms. Although PTH appears to have no direct effect on GI calcium absorption, increased levels of the hormone stimulate production of 1,25(OH)2D, which in turn leads to enhanced absorption. Increased serum levels of calcium and 1,25(OH)2D provide negative feedback to the parathyroid glands, resulting in reduced PTH secretion. The roughly 60% of calcium in the extracellular fluid is not protein bound and is freely filtered by the renal glomeruli. Approximately 80% to 85% of this amount is passively reabsorbed in the proximal tubule. Most of the remaining calcium is reabsorbed in the thick ascending limb (TAL) of Henle and distal cortical tubules under PTH stimulation. Ultimately, these reabsorptive mechanisms result in a urinary calcium excretion that is less than 2% of the daily filtered load of calcium.50 Except during pregnancy and lactation, in healthy, nonosteoporotic adults, urinary calcium excretion (and any calcium lost in sweat) precisely equals net intestinal calcium absorption. Potential Mechanisms for the Development of Idiopathic Hypercalciuria Dysregulation of calcium transport in the intestine, kidney, or bone can lead to hypercalciuria. For example, excessive calcium absorption by the GI tract leads to a transient increase in the serum calcium. This increase in serum calcium suppresses secretion of PTH that, along with the increased filtered load of calcium to the kidneys, results in hypercalciuria. Excessive 1,25(OH)2D has a similar effect of 1368 SECTION VII Mineral Metabolism increasing intestinal calcium absorption but also results in an influx of calcium into the extracellular fluid because of enhanced bone resorption. The result is hypercalciuria even in the setting of a low-calcium diet or an overnight fast. The excess 1,25(OH)2D also suppresses PTH secretion, thereby further reducing renal tubular reabsorption of calcium. If a primary defect in renal calcium reabsorption leads to hypercalciuria, there is a fall in the serum calcium concentration that stimulates synthesis of PTH and 1,25(OH)2D. Increased 1,25(OH)2D results in enhanced intestinal calcium absorption and bone resorption. The renal loss of calcium persists even with a low-calcium diet or overnight fast. Hypercalciuria can also develop as a result of a defect in renal phosphate reabsorption. The resultant hypo­ phosphatemia leads to enhanced 1,25(OH)2D production, which stimulates intestinal absorption of phosphorus and calcium. The increased serum calcium and 1,25(OH)2D suppresses PTH synthesis and release. The increased filtered load of calcium in the setting of suppressed PTH leads to hypercalciuria. Enhanced bone resorption due to excessive 1,25(OH)2D increases the serum calcium concentration, which in turn suppresses PTH production further. The increase in the filtered load of calcium in this setting results in hypercalciuria. Thus, there are several potential mechanisms for hypercalciuria.49 Do human or animal data support one mechanism above all others? From a clinical therapeutic standpoint, is it worth differentiating among the various potential mechanisms in each patient with suspected IH? Human Data Lemann51 compiled the results of numerous calcium balance studies on patients with IH and normocalciuric control subjects and normalized the results for calcium intake. He found that intestinal calcium absorption was significantly higher in the subjects with IH. Coe and colleagues, also collecting data from published metabolic balance studies, compared net intestinal calcium absorption and urinary calcium excretion in hypercalciuric and normocalciuric adults.52 They also noted an increase in intestinal calcium absorption in subjects with IH but found that urinary excretion of calcium was increased to an even greater degree, thus placing many of these patients in net negative calcium balance. Although these data confirm that enhanced intestinal absorption of calcium probably plays a role in the pathogenesis of IH, the investigators could not clarify whether this is the primary defect or if it is secondary to another lesion, such as a primary dysregulation of renal tubular calcium reabsorption. Others suggested that the increase in intestinal calcium absorption, in combination with a decrease in renal calcium reabsorption, indicated a more generalized defect in calcium homeostasis. Nonetheless, the finding of enhanced calcium absorption makes enhanced bone resorption an unlikely primary mechanism of IH, because the increase in serum calcium concentration resulting from bone resorption would suppress 1,25(OH)2D-mediated intestinal calcium absorption. In most published studies, patients with IH have higher serum levels of 1,25(OH)2D than normocalciuric control subjects.7,49,53 Kaplan and colleagues53 determined that 1,25(OH)2D levels were higher than control values in approximately one third of patients with IH and that intestinal calcium absorption was inappropriately high for the level of 1,25(OH)2D. These studies support either 1,25(OH)2D-mediated intestinal calcium absorption or a primary defect in renal tubular calcium reabsorption as a primary mechanism of hypercalciuria in IH. PTH levels in patients with IH have been reported as normal or slightly lower than those in control subjects.39,43 This finding argues against a reduction in renal tubular calcium reabsorption as the primary defect in IH, because with this mechanism the hypercalciuria would lead to low serum calcium levels and stimulation of PTH secretion. This finding also does not support the hypothesis that an elevated level of PTH is the stimulus for the increased levels of serum 1,25(OH)2D observed in many studies. It is, however, consistent with the other potential mechanisms for IH. Bone mass in patients with IH has been assessed by a number of methods, including radiologic densitometry, quantitative computed tomography (CT), dual-energy x-ray absorptiometry (DXA), single-photon absorptiometry, and others. Studies of patients with IH have generally shown a mild reduction of bone mineral density compared with values in control subjects.39,43,54 The studies were unable to reveal a unifying mechanism for the mild reduction in bone mineral density. Altered 1,25(OH)2D regulation would be consistent with this finding because the effects of 1,25(OH)2D on bone resorption would be mitigated by the increased intestinal calcium absorption stimulated by the hormone. Previously it was considered essential to determine whether a patient with IH tended to have excessive GI calcium absorption (absorptive hypercalciuria) or excessive renal excretion (renal leak).55,56 Patients with excessive renal calcium excretion were prescribed thiazide diuretics, and those thought to have a predominantly absorptive defect were prescribed a low-calcium diet. Coe and colleagues43 undermined the validity of this approach in a study in which 24 patients with IH and 9 control subjects were given a low-calcium diet (2 mg/kg/day) for more than 1 week. Urine and blood tests revealed normal serum calcium levels, a mild decrease in PTH levels in the patients with IH, and no difference in 1,25(OH)2D levels. The striking finding was that, whereas all the normocalciuric subjects excreted less calcium than they ingested on the low-calcium diet, 16 of the 24 subjects with IH had urinary calcium excretion that exceeded their intake. Thus, most of the patients with IH receiving a low-calcium diet were in net negative calcium balance. There was no clear demarcation between the patients who excreted excessive amounts of calcium and those who did not. Instead, there was a smooth continuum of urinary calcium excretion among patients with and without IH that appeared not to be influenced by calcemic hormones. From a therapeutic standpoint, these findings have rendered obsolete both the need to clinically distinguish IH mechanisms in humans and the prescription of a low-calcium diet in any of these patients. This approach to diet is important because a lowcalcium diet can result in a dangerous reduction in bone mineral density, especially in women.43,44,49,54 As mentioned earlier (see “Pathogenesis of Stone Formation”), a lowcalcium diet also appears to increase recurrent stone formation.31,35 Thus, there is no benefit, and a number of well-documented risks, to advising a low-calcium diet to prevent recurrent stone formation in patients with IH. Genetic Hypercalciuric Stone-Forming Rats To explain more fully the mechanism of IH in humans, we have developed an animal model of this disorder.48,57-61 Through more than 100 generations of successive inbreeding of the most hypercalciuric progeny of hypercalciuric Sprague-Dawley rats, we have established a strain of rats CHAPTER 30 Kidney Stones Urine calcium (mg/24 h) 12 8 4 0 0 10 20 30 40 50 60 70 80 90 100 GHS Generation All data from published studies. Figure 30-3 Hypercalciuria in subsequent generations of genetic hypercalciuric stone-forming (GHS) rats. that excrete 8 to 10 times as much urinary calcium as control Sprague-Dawley rats (Fig. 30-3). Compared with control Sprague-Dawley rats, the genetic hypercalciuric rats absorb far more calcium at lower dietary levels of 1,25(OH)2D.48,62 When these hypercalciuric rats were fed a diet very low in calcium, their urinary calcium excretion remained elevated compared with that of similarly treated control rats, indicating a defect in renal calcium reabsorption or an increase in bone resorption, or both,63 again similar to observations in humans.43,64 Bone from these hypercalciuric rats released more calcium than the bone of control rats when exposed to increasing amounts of 1,25(OH)2D,65 and their bone mineral densities were lower than those of control rats.66 The administration of a bisphosphonate to the genetic hypercalciuric rats fed a low-calcium diet significantly reduced urinary calcium excretion.67 In addition, a primary defect in renal calcium reabsorption was observed during clearance studies.68 We have shown that besides the intestine, both the bone and kidney of the hypercalciuric rats have an increased number of vitamin D receptors and calcium receptors.57,61,65,69,70 Thus, hypercalciuric rats appear to have a systemic abnormality in calcium homeostasis. They absorb more intestinal calcium, they resorb more bone, and they do not adequately reabsorb filtered calcium. Because every one of the hypercalciuric rats forms renal stones, we have described them as genetic hypercalciuric stone-forming (GHS) rats.48,59 These studies suggest that an increased number of vitamin D and calcium receptors may be the underlying mechanism for hypercalciuria in these rats70 and perhaps in humans as well.48,59,69 Circulating monocytes from humans with IH have been shown to have an increased number of vitamin D receptors.71 Genetics of Idiopathic Hypercalciuria in Humans The difficulty in ascertaining the genetics of IH arises, in part, from the numerous other factors that influence stone formation, such as diet, environment, and gender. Because half of patients with IH report a family history of stones and male patients often have fathers or sons with the disorder, inheritance is not believed to be recessive or X-linked. A multitude of monogenic hereditary disorders (see later discussion) can lead to hypercalciuria because they are caused by a variety of mutations resulting in changes in calcium handling at the level of kidney, bone, gut, and the calcium-sensing receptor in the kidneys and parathyroid glands. Given the evidence that IH is a complex trait with 1369 multiple pathways for developing the hypercalciuria phenotype, it is most likely a polygenic disorder, with heterogeneity of loci and possibly polygenic modifiers. Although attempts to diagnose the exact cause of IH in a particular patient might not be critical from a therapeutic standpoint, determining the cause of IH in a particular family is essential for researchers attempting to clarify the genetics of IH.19,27,47,72 Recently a team of investigators using the technique of genome-wide association studies have found that a member of the claudin family, claudin 14, is associated with stone formation in Iceland.73 Whether this association will be found in other populations, thus supporting its link to stone formation, remains to be determined. Other Genetic Causes of Stones and Nephrocalcinosis Numerous monogenic disorders cause hypercalciuria that leads to nephrolithiasis or nephrocalcinosis.19,27,47,72,74-76 Disorders that lead to hypercalciuria by augmenting bone resorption include osteogenesis imperfecta type 1, multiple endocrine neoplasia type 1 (MEN1) syndrome with hyperparathyroidism, McCune-Albright syndrome, and infantile hypophosphatemia. Disorders that result in hypercalciuria because of excessive intestinal absorption of calcium include hereditary hypophosphatemic rickets due to disordered sodium phosphate cotransporter SCL34A3, Down syndrome, and congenital lactate deficiency. Others include autosomal dominant hypocalcemia (which is caused by an activating mutation of the calcium-sensing receptor), Lowe oculocerebrorenal syndrome, and Wilson disease. Next, we describe in more detail several disorders that result in hypercalciuria via their effect on genes expressed in the kidney. X-Linked Hypercalciuric Nephrolithiasis (Dent Disease and Others) Several families around the world were discovered to have a variable combination of disorders including hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis or stones, hypophosphatemic rickets, and renal failure.74,75 Some affected persons demonstrate evidence of defects in proximal tubular reabsorption of amino acids, glucose, or phosphate. PTH tends to be quite low and 1,25(OH)2D high in the majority of patients. The abnormalities completely resolve in the patients who receive renal transplants, a finding that suggests a renal tubular disorder rather than a systemic process. In all families, the pattern of inheritance is consistent with an X-linked recessive disorder, with male patients affected to a greater extent than female patients. The latter are often minimally affected but transmit the disorder to half of their male offspring. Over time, the various disorders—X-linked recessive nephrolithiasis in the United States, Dent disease in the United Kingdom, X-linked recessive hypophosphatemic rickets in Italy, and low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis in Japan—have all been linked to mutations affecting the CLCN5 gene on the Xp11.22 locus of the X chromosome.77 This gene encodes the CLC-5 protein, which is one of the nine members of the CLC family of voltage-gated hydrogen chloride exchangers. How defects in this channel lead to the array of disorders listed here, including hypercalciuria, stones, and renal failure, is not yet understood. Bartter Syndrome Bartter syndrome is caused by at least five genetic mutations, predominantly autosomal recessive, that lead to 1370 SECTION VII Mineral Metabolism sodium chloride wasting at the TAL of the loop of Henle.27,28,47,76,78 Defects can arise in NKCC2 (sodium potassium chloride cotransporter), ROMK (renal outer medullary potassium channel), the CLC-Kb (basolateral chloride channel), or in a chloride channel subunit known as barttin. These genes, all expressed in the TAL, cause a defect in sodium transport that leads to a reduction in the transtubular potential difference, resulting in a decrease in paracellular calcium reabsorption in the TAL. The ensuing reduction in intravascular volume also induces an aldosterone-mediated metabolic alkalosis. Bartter syndrome, therefore, resembles high-dose furosemide administration (that targets NKCC2) and differs from Gitelman syndrome in that hypercalciuria, nephrocalcinosis, and nephrolithiasis are seen with Bartter but not with Gitelman. An autosomal dominant form of Bartter syndrome results from a gain-of-function mutation in the calciumsensing receptor in renal tubular cells. This mutation leads to reduced calcium reabsorption and hypocalcemia caused by low PTH levels. Therapy with vitamin D and calcium supplementation can exacerbate stone disease in this disorder. Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder that results in hypomagnesemia, hypercalciuria, nephrolithiasis, and distal renal tubular acidosis (dRTA). Polyuria and severe nephrocalcinosis also ensue, and progressive renal failure is common by late childhood.27,28 The genetic disorder results in defective production of either of the tight junction proteins, claudin 16 and claudin 19, that bind together to facilitate paracellular calcium and magnesium transport in the TAL as well as renal sodium reabsorption.79,80 Distal Renal Tubular Acidosis dRTA is caused by dysfunctional α-intercalated cells, resulting in defective acid excretion.27,28,47,72,81 This inability to adequately acidify the urine results in metabolic acidosis, hypocitraturia, hypokalemia, hypercalciuria, nephrocalcinosis, and stones. The metabolic acidosis leads to resorption of both calcium and phosphate from bone. The increased filtered load of calcium and phosphate, along with the elevated urine pH and hypocitraturia, results in favorable conditions for calcium phosphate stone formation. Although there are secondary causes of dRTA such as Sjögren syndrome and use of carbonic anhydrase inhibitors (e.g., acetazolamide), there are also a number of hereditary causes of dRTA.82 Some are autosomal recessive and can also result in hearing loss; others are autosomal dominant. One form of dRTA that targets carbonic anhydrase II results in osteopetrosis and brain calcifications.82 Patients with dRTA fail to lower their urine pH below 5.5 following ingestion of an acid load. Their urine citrate is extremely low despite mildly reduced or even normal serum bicarbonate levels. Hereditary Hypophosphatemic Rickets With Hypercalciuria Hereditary hypophosphatemic rickets with hypercalciuria is an autosomal form of hypophosphatemic rickets that is manifested clinically by hypophosphatemia secondary to renal phosphate wasting.83,84 These patients have a hypophosphatemia-induced increase in levels of 1,25(OH)2D, which leads to increased intestinal calcium absorption and hypercalciuria. The bone pain, muscle weakness, limb deformities, and rickets remit completely with administration of oral phosphate. This disorder is caused by mutations in the gene for the renal sodium phosphate cotransporter, NaPi-IIc. Primary Hyperoxaluria and Cystinuria Primary hyperoxaluria (PHO) and cystinuria are each discussed later in their respective sections under “Therapy.” CLINICAL PRESENTATION AND EVALUATION Kidney stones vary in clinical presentation from those discovered asymptomatically on routine imaging, to their painful passage through the ureters, to large, obstructing staghorn calculi that can significantly impair renal function and even lead to ESRD.6,85 The severity of stone disease depends on the pathogenic factors contributing to the rate of stone formation as well as the stone type, size, and location. In its most classic form, nephrolithiasis manifests as renal colic. This discomfort of abrupt onset intensifies over time into excruciating, severe flank pain that resolves only with stone passage or removal. The pain often migrates anteriorly along the abdomen and inferiorly to the groin, testicles, or labia majora as the stone moves toward the ureterovesical junction. Gross hematuria, urinary urgency and frequency, nausea, and vomiting may be present. Nephrolithiasis can also result in a dull, poorly localizing abdominal pain. The probability of passing a stone without intervention depends on its size and varies from 97% for stones less than 2 mm, to 50% for stones 4 to 6 mm, and less than 1% for stones larger than 6 mm.86,87 There is increasing evidence that nephrolithiasis is associated with a twofold increase in CKD that is independent of other risk factors, such as diabetes and hypertension found in stone formers.88-90 A French study estimated the incidence rate of ESRD caused by nephrolithiasis to be about 3.1 cases per 1 million population per year,91 and a Canadian study demonstrated that although only 0.8% of patients with ESRD had nephrolithiasis, any stone episode previously was associated with a increased risk of ESRD (hazard ratio 2.16).92 The common reasons for loss of a single kidney in stone formers were staghorn calculi, high stone burden, infection, and ureteral obstruction.93 The development of CKD from stone disease is thought to be from ureteral obstruction leading to parenchymal damage.88 Most data are derived from animal models and suggest that unilateral ureteral obstruction causes intense renal vasoconstriction that reduces renal blood flow and glomerular filtration rate (GFR).94 Brushite (CaHPO4) stone formers have an increased risk of cortical fibrosis,95 and the formation of Randall plaques in such patients was associated with duct plugging, collecting duct cell death, and inflammation.96 Renal biopsy specimens in patients with staghorn calculi demonstrate extensive inflammation and macrophage infiltration.97 Other stone-forming diseases such as PHO, cystinuria, and Dent disease have all been associated with crystal formation in the renal parenchyma that presumably triggers subsequent inflammation and CKD.98 Certain disorders can lead to diffuse renal parenchymal calcifications termed nephrocalcinosis.6,28,81,99 The calcifications, usually calcium phosphate or calcium oxalate, may be present in the cortex or medulla. Among the most CHAPTER 30 Kidney Stones common causes of stone-related nephrocalcinosis are PHO and medullary sponge kidney. Metabolic Evaluation of Stone Formers Although it is uniformly accepted that patients with multiple stones merit a thorough investigation into the cause of nephrolithiasis, the need for evaluation of the patient with a single stone is controversial. This is probably due to the difficulty in determining the cost-to-benefit ratio of stone evaluations and wide differences in reported rates of stone recurrence. The National Institutes of Health has convened several consensus conferences to resolve such issues related to the prevention and treatment of kidney stones.5 These panels determined that all patients, even those with a single stone, should undergo at least a basic evaluation in order to rule out a systemic etiologic mechanism. Patients with an increase in number or size of stones (metabolically active stones), all children, all noncalcium oxalate stone formers, and those in demographic groups not typically susceptible to stone formation warrant a more complete metabolic evaluation.5 The Basic Evaluation Elements of the basic evaluation are listed in Table 30-1. History In addition to the medical history typically obtained from new patients, the evaluation of the stone former includes a stone history and a thorough review of diet, fluid intake, and lifestyle. Specific laboratory studies and radiographic tests are also required. Stone History. The stone history begins with a chronologic account of stone events: age of incidence of first stone, size and number of stones formed, frequency of passage, stone TABLE 30-1 The Basic Evaluation of Stone Formers History Stone history Medical history Family history Medications Occupation and lifestyle Diet and fluid intake Physical examination Laboratory tests Urinalysis Urine culture and sensitivity Cystine screening Blood tests Sodium, potassium, chloride, bicarbonate Calcium, phosphorus, uric acid, creatinine Intact parathyroid hormone if calcium is elevated or at upper limit of normal Tetrahydrodeoxycortisol, urinary free cortisol, and 25(OH)D levels as appropriate Stone analysis Radiology (choose appropriate study as indicated; see text) Unenhanced helical (spiral) computed tomography Kidneys, ureter, and bladder examination Intravenous pyelography Ultrasonography Data from Monk RD. Clinical approach to adults. Semin Nephrol. 1996;16: 375-388; Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Frehally J, Floege J, Johnson RJ, eds. Comprehensive Clinical Nephrology, 3rd ed. London, UK: Mosby; 2007:641-655. 1371 type if known, and whether the stones occur equally in both kidneys or unilaterally. Also helpful is a report of the patient’s symptoms with each episode as well as the need for and response to surgical intervention. This information is useful to judge not only the severity of the stone disease but also clues to the origin of the patient’s nephrolithiasis. For example, nephrolithiasis that begins at a young age may be attributable to an inherited metabolic disorder such as PHO or cystinuria. Large staghorn calculi that are difficult to eradicate and tend to recur despite frequent surgical intervention are more likely to be composed of struvite (NH4MgPO4 ⋅ 6H2O) instead of calcium oxalate. Cystine stones are not disintegrated thoroughly with the use of lithotripsy, and alternative surgical modalities are generally required for stone removal. In patients who tend to form stones in only one kidney, the possibility of congenital abnormalities of that kidney, such as megacalyx or medullary sponge kidney, should be explored. Medical History. Systemic disorders that can contribute to nephrolithiasis are sought in the medical history. For example, any disorder that can result in hypercalcemia, such as sarcoidosis or certain malignancies, may also lead to hypercalciuria. A variety of GI disorders associated with malabsorption (e.g., sprue, Crohn disease) can cause calcium oxalate nephrolithiasis on the basis of enteric hyperoxaluria. Patients with gout or insulin resistance are more likely to have uric acid stones19,20 (Tables 30-2 and 30-3). TABLE 30-2 Causes of Calcium Stone Formation Hypercalciuria Cushing syndrome Granulomatous diseases Hypercalcemic disorders Idiopathic hypercalciuria Immobilization Malignancy Milk-alkali syndrome Primary hyperparathyroidism Sarcoid Thyrotoxicosis Medications (see Table 30-4) Hyperoxaluria Biliary obstruction Chronic pancreatitis Crohn disease Dietary hyperoxaluria (urine oxalate secretion 40-60 mg/day) Enteric oxaluria (urine oxalate 60-100 mg/day) Jejunoileal bypass Malabsorptive disorders Primary hyperoxaluria types 1 and 2 (oxalate 80-300 mg/day) Sprue (celiac disease) Hyperuricosuria (see Table 30-3) Hypocitraturia Androgens Exercise Hypokalemia Hypomagnesemia Infection Metabolic acidosis Starvation Renal tubular acidosis (distal, type 1) Anatomic genitourinary tract abnormalities Congenital megacalyx Medullary sponge kidney Tubular ectasia Data from Monk RD. Clinical approach to adults. Semin Nephrol. 1996;16: 375-388; Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Frehally J, Floege J, Johnson RJ, eds. Comprehensive Clinical Nephrology, 3rd ed. London, UK: Mosby; 2007:641-655; Bushinsky DA, Monk RD. Calcium. Lancet. 1998;352:306-311. 1372 SECTION VII Mineral Metabolism TABLE 30-3 TABLE 30-4 Factors Associated With Noncalcium Stone Formation Medications Associated With Renal Lithiasis and Nephrocalcinosis Uric Acid Stones Cushing syndrome Diarrhea Diet high in animal protein Excessive dietary purine Excessive insensible losses Genetic predisposition Glucose-6-phosphatase deficiency Gout Hemolytic anemia Hyperuricemia Hyperuricosuria Inadequate fluid intake Inborn errors of metabolism Insulin resistance Intracellular to extracellular uric acid shift Lesch-Nyhan syndrome Low urine pH (<5.5) Low urine volume Malabsorptive disorders Medications (see Table 30-4) Metabolic syndrome Myeloproliferative disorders Obesity Tumor lysis Struvite Stones Urease-producing bacteria Proteus, Pseudomonas, Haemophilus, Yersinia, Ureaplasma, Klebsiella, Corynebacterium, Serratia, Citrobacter, Staphylococcus, and others Never Escherichia coli—not a urease producer High urine pH (~6.5) Indwelling urinary catheter Neurogenic bladder Cystine Stones Autosomal recessive trait Excessive excretion of cystine, ornithine, lysine, and arginine Low solubility of cystine (<250 mg/L) Data from Monk RD. Clinical approach to adults. Semin Nephrol. 1996;16: 375-388; Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Frehally J, Floege J, Johnson RJ, eds. Comprehensive Clinical Nephrology, 3rd ed. London, UK: Mosby; 2007:641-655. Family History. As noted earlier, a number of stone disorders are inherited, making the family history an important component of the basic evaluation. IH appears to be a familial disorder. Although the exact chromosomes and genes have not yet been identified, the pattern of inheritance is almost certainly polygenic. Stones arising in childhood or young adulthood can be related to autosomal recessive disorders such as cystinuria and primary oxaluria. These genetic disorders are reviewed later in the sections on treatment of cystine and oxalate stones. The high prevalence of uric acid stones in certain areas of the world is suggestive of genetic as well as environmental risk factors. Genes that cause either excessively acidic urine or hyperuricosuria have been implicated.4,6,20,27,99-102 Medications Medications can contribute to stone formation in several ways. Calcium-containing supplements, for example, can increase the amount of calcium absorbed and subsequently excreted.46 Loop diuretics can directly promote renal tubular excretion of calcium and are associated with nephrocalcinosis in neonates who have received the drug.103,104 Acetazolamide, a weak diuretic, induces a mild metabolic Medications That Promote Calcium Stone Formation Acetazolamide Amphotericin B Antacids (calcium and noncalcium antacids) Calcium supplements Glucocorticoids Loop diuretics Theophylline Vitamin C? Vitamin D Medications That Promote Uric Acid Lithiasis Allopurinol (associated with xanthene stones) Probenecid Salicylates Medications That Can Precipitate Into Stones or Crystals Acyclovir (when infused rapidly intravenously) Indinavir Nelfinavir Sulfonamides Triamterene Data from Monk RD. Clinical approach to adults. Semin Nephrol. 1996;16: 375-388; Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Frehally J, Floege J, Johnson RJ, eds. Comprehensive Clinical Nephrology, 3rd ed. London, UK: Mosby; 2007:641-655. acidosis and alkaline urine, favorable conditions for the development of calcium phosphate stones. Other uricosuric medications, such as salicylates and probenecid, have been implicated in uric acid lithiasis.105 Certain crystals or stones can consist completely of precipitated medication. Such medications include intravenously administered acyclovir, triamterene, indinavir, and various sulfonamides, such as sulfadiazine. Oxalate is a metabolic end product of vitamin C, and large doses increase oxalate excretion and may predispose to stone formation (Table 30-4).106,107 Lifestyle and Diet Occupation and lifestyle are aspects of the social history that can be relevant to stone formation. Surgeons and traveling salespeople, for example, tend to minimize fluid intake in order to avoid frequent micturition throughout the day. Insensible losses of fluid can also exacerbate nephrolithiasis and may be related to employment (e.g., construction work) or hobbies (running, gardening). The evaluation proceeds with a thorough review of the patient’s diet and fluid intake. Patients are asked to review what they eat at all meals and snacks. Particular attention is paid to ingestion of foods high in sodium (fast foods, canned foods, added salt, or soy sauce) and the quantity of animal protein consumed (see later discussion). Patients are also asked to list four or five favorite foods or snacks to assess whether they may be consuming foods high in oxalate or purine as well. Many patients are erroneously counseled by physicians to avoid calcium-containing foods. As noted earlier, doing so is not only associated with increased risk of stone formation but it may also result in bone demineralization, a grave concern in women with stones.31,35,41 Physical Examination For most patients with nephrolithiasis, physical findings are normal. In some patients, however, the findings may CHAPTER 30 Kidney Stones reveal a systemic disorder related to the stone disease. An enterocutaneous fistula, for example, may be associated with Crohn disease, a common cause of enteric hyperoxaluria. A paraplegic patient with an indwelling catheter may be susceptible to frequent urinary tract infections with urease-producing organisms and consequent struvite stone formation. Hyperuricosuria and uric acid stone formation may be seen in patients with tophi related to gout.4,6 Laboratory Tests Although valuable information is gleaned from the history and physical examination, it is often difficult to determine the metabolic cause of a patient’s nephrolithiasis without laboratory data. The urinalysis is an easy and inexpensive test that provides a great deal of information. Often, the presence of different kinds of crystals can suggest the type of underlying stone (Fig. 30-4). Uric acid and calcium oxalate stones, for example, grow more favorably at an acidic pH, and a consistently high urinary pH may suggest calcium phosphate or struvite nephrolithiasis. The specific gravity, if high, can confirm suspicions of inadequate fluid intake. Hematuria is often present in active stone disease. Microscopic examination of the urine in this case might reveal characteristic crystals. Bacteria and pyuria noted in conjunction with a high urinary pH (~6.5) are characteris- 1373 tic of struvite stone disease. Urine specimens for culture should be obtained in this setting. Because enough urease may be produced to form struvite stones even when colony counts are low (~50,000 colony-forming units), the microbiology laboratory should be instructed specifically to identify the organism and to check for urease-producing bacteria despite low colony counts.108 Qualitative cystine screening should be performed on a urine specimen. Urine turns purple-red when sodium nitroprusside is added to a specimen containing cystine at a concentration greater than 75 mg/L.100 Recommended blood tests in the basic evaluation include electrolytes (sodium, potassium, chloride, bicarbonate), uric acid, calcium, phosphorus, and serum creatinine to determine renal function.4,5 If the serum calcium level is elevated or at the upper limit of normal or if the serum phosphorus level is reduced or at the lower limit of normal, a serum intact PTH level is also determined to rule out primary hyperparathyroidism. Low serum bicarbonate levels suggest a hypocitraturic disorder such as RTA or acetazolamide ingestion. Stone Analysis Stone analysis should be performed, whenever possible, in patients with a new history of nephrolithiasis or in patients with long-standing stone disease who note a difference in A B C D Figure 30-4 Crystals seen in urine of stone formers. A, Calcium oxalate. B, Urate. C, Cystine. D, Struvite. 1374 SECTION VII Mineral Metabolism clinical presentation or in the color, shape, or texture of any stone passed. Knowing the constituents of a stone can help the physician target certain elements of the medical history and specific urine studies. In most cases, the stone must be sent to an outside laboratory for examination. X-ray diffraction crystallography and infrared spectroscopy are currently the most accurate methods available for stone analysis.109 Radiologic Evaluation Various radiologic tests can help determine the location and extent of the stone burden and might elucidate genitourinary abnormalities contributing to stone formation (Table 30-5). For acute renal colic, spiral (or helical) CT without contrast (unenhanced) has replaced intravenous pyelogram (IVP) as the optimal test for detection and localization of kidney stones. Helical CT has proved to be at least as sensitive and specific as IVP in detecting stones of all types in both the kidneys and ureters. In addition, it can more accurately reveal causes of flank pain and hematuria not related to stones and circumvents the use of intravenous contrast material. Radiation exposure is a disadvantage of both CT and IVP, and the exposure to patients undergoing helical CT may be triple that of IVP. As such, it should be used judiciously, especially in young patients with frequent episodes of renal colic. Helical CT takes less time to perform, a potential advantage in an emergency department setting, but it tends to be more expensive.85,110-112 CT should be followed by a plain film (radiograph) of the abdomen that includes the kidneys, ureter, and bladder (KUB). Plain films can assist in determining stone composition. Stones composed of calcium, cystine, and struvite are radiopaque and visible on KUB, whereas radiolucent stones, such as those composed of uric acid and xanthine, are not (Fig. 30-5). IVPs are useful in detecting certain genitourinary abnormalities that can predispose to nephrolithiasis, such as medullary sponge kidney and caliceal abnormalities. Another advantage of IVP is that the osmotic diuresis generated by the administered contrast agent may aid in excretion of the offending stone during an episode of acute renal colic. A major disadvantage of IVP is exposure to TABLE 30-5 Radiologic Evaluation of Nephrolithiasis Procedure Advantage Disadvantage Abdominal radiograph Intravenous pyelography Simple, easily available More sensitive (64-87%) and specific (92-94%) May even help stone move along ureter because of strong osmotic effect Ultrasound Easily performed No radiation Very sensitive in detecting obstruction Safe in pregnant women Very sensitive (95-98%) and specific (98%) Based on radiologic characteristic the type of stone can be diagnosed Can assess for other causes of abdominal pain at the same time Low sensitivity (45-59%) and specificity (71-77%) Can miss nonobstructing stones Risk of contrast in patients with chronic kidney disease Radiation exposure Often reimaging is needed for high-grade obstruction because of inadequate contrast concentration Poor sensitivity, especially for ureteral stone (19%) Noncontrast helical computed tomography A Radiation exposure is significantly higher More expensive B Figure 30-5 Renal stones on abdominal radiograph and computed tomography scan. A, Radiolucent kidney stone can be seen on the KUB (kidneys, ureter, and bladder) radiograph at the ureterovesical junction. B, Large stone is seen in the renal pelvis of the right kidney.