David A. Bushinsky Fredric L. Coe Orson W. Moe
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Introduction, 1299 |
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Epidemiology, 1299 |
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Human Genetics, 1300 |
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Familial Aggregation, 1301 |
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Inheritance Pattern, 1301 |
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Twin Studies, 1301 |
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Association and Linkage, 1301 |
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Pathogenesis, 1302 |
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Saturation, 1302 |
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Clinical Manifestations, 1305 |
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Pain, 1305 |
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Hematuria, 1305 |
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Loin Pain Hematuria Syndrome, 1305 |
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Asymptomatic Stone Disease, 1305 |
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Clinical Evaluation, 1305 |
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Basic Evaluation, 1306 |
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Comprehensive Evaluation, 1308 |
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General Therapy, 1308 |
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Fluid Intake, 1308 |
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Salt Intake, 1309 |
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Protein Intake, 1309 |
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Calcium Intake, 1309 |
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Recurrence after a Single Stone, 1310 |
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Calcium Stones, 1310 |
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Idiopathic Hypercalciuria, 1310 |
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Genetic Causes of Hypercalciuria, 1319 |
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Primary Hyperparathyroidism, 1319 |
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Hyperoxaluria, 1326 |
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Hypocitraturia, 1328 |
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Hyperuricosuria, 1331 |
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Calcium Phosphate Stones and Renal Tubular Acidosis, 1332 |
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Uric Acid Stones, 1333 |
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Epidemiology, 1334 |
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Pathogenesis and Etiology, 1335 |
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Diagnosis and Evaluation, 1336 |
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Treatment, 1337 |
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Struvite Stones, 1337 |
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Urease-Producing Bacteria, 1338 |
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Therapy, 1338 |
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Cystine Stones, 1339 |
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Cystine Supersaturation, 1339 |
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Renal Pathology, 1340 |
INTRODUCTION
Our skeleton is composed primarily of apatite (Ca10[PO4]6[OH]2) and is, by far, the largest repository of calcium in the body. [4] [5] Growth and pregnancy necessitate substantial absorption of dietary calcium. Once skeletal formation is complete, nonpregnant humans must excrete any absorbed calcium in the urine; however, absorption is not precisely regulated, and it increases with additional dietary intake regardless of need. [6] [7] The ions that are most often complexed with calcium in kidney stones, oxalate and phosphate, are respectively an end product of metabolism or another principle component of bone whose absorption is also poorly regulated. The need to conserve water by terrestrial humans often results in excretion of these unneeded ions, calcium, oxalate and phosphate, in relatively small volumes of urine. Ion excretion in scant urine leads to a substantial supersaturation with respect to various solid phases of calcium oxalate and calcium phosphate. Whereas inhibitors of crystallization retard stone formation, if supersaturation overwhelms inhibitor capacity, a solid phase forms, increases in size, and often causes pain as it enters, obstructs, or migrates down the ureter into the bladder. Nephrolithiasis, although rarely causing kidney failure or life-threatening illness, is responsible for substantial morbidity. The focus of this chapter is to review the mechanisms of kidney stone formation and medical treatments directed at prevention of stone formation and recurrence.
Nephrolithiasis, with a lifetime risk of 7% to 13%, results in significant morbidity as well as substantial economic costs, not only directly from medical treatment but also indirectly through time lost from work. [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] The yearly economic cost of kidney stones has been estimated to approach $5.3 billion in the United States alone.[24]
Kidney stones have been observed in prehistoric humans[25] and are composed of crystals, often of several different types, in a protein matrix. The majority of crystals are composed of calcium (>80%) complexed with oxalate and or phosphate ( Table 37-1 ). [14] [16] [17] [20] [22] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] Other stones are composed of uric acid, magnesium ammonium phosphate (struvite), or cystine, either alone or in combination. Previously in industrialized countries, lower urinary tract stones were more common than upper tract stones and are still more common in less-developed countries. [40] [41]
TABLE 37-1 -- Types of Renal Stones Formed and Frequency of Occurrence
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Calcium Oxalate and Calcium Phosphate |
Calcium Oxalate |
Calcium Phosphate |
Uric Acid |
Calcium Oxalate and Uric Acid |
Cystine |
Struvite |
Number of Stones |
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Nordin and Hodgkinson[26] |
46 |
15 |
8 |
3 |
— |
3 |
25 |
243 |
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Lagergren[27] |
44 |
15 |
8 |
2 |
2 |
1 |
28 |
460 |
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Melick and Henneman[28] |
30 |
27 |
21 |
13 |
— |
3 |
15 |
155 |
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Prien[29] |
34 |
33 |
5 |
5 |
1 |
3 |
19 |
1,000 |
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Sutor et al[30] |
36 |
29 |
7 |
1 |
1 |
2 |
24 |
810 |
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Mandel and Mandel[31] |
10 |
49 |
9 |
10 |
2 |
1 |
12 |
10,163 |
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Koide et al[32] |
55 |
25 |
7 |
4 |
2 |
1 |
6 |
2,724 |
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Pak et al[33] |
25 |
53 |
9 |
4 |
3 |
2 |
3 |
1,960 |
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Oxalates |
Phosphates |
Uric Acid |
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Cystine |
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Number of Stones |
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Herring[34] |
73 |
17 |
7 |
1 |
10,000 |
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Schneider[35] |
69 |
10 |
14 |
1 |
100,000 |
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Brien[36] |
72 |
14 |
11 |
1 |
10,000 |
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Leusmann[37] |
45 |
25 |
7 |
1 |
5,035 |
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Numbers represent the percentage of each stone type in the series. |
EPIDEMIOLOGY
Kidney stones are common in industrialized nations with an annual incidence of 0.5% to 1.9% [13] [42] and a lifetime incident rate of up to approximately 13% in men and approximately 7% in women. [13] [14] [22] [42] [43] [44] [45] In a recent study, the mean age at the incident stone event was 45 years of age in men and 41 years of age in women, and the overall incident ratio of men to women was 1.73.[42] In the United States, the lifetime prevalence of nephrolithiasis in adults 20 to 74 years of age has increased from 3.2% in the years from 1976 to 1980 to 5.2% in the years 1988 to 1994.[13] During both time periods, men had a greater prevalence of kidney stones at ages older than 40 years of age ( Fig. 37-1 ).[13] In all age groups, the overall prevalence in men (6.3%) is greater than that in women (4.1%). By the ages of 70 to 74 in men the prevalence of nephrolithiasis was 13.3%, whereas it was 6.9% in women. Outside of the United States, in the Middle East, the lifetime prevalence of stone disease has been reported to be up to 25%.[46]
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FIGURE 37-1 A and B, Percentage (%) of patients with kidney stones as a function of gender, race, and age. (From Stamatelou KK, Francis ME, Jones CA, et al: Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int 63:1817–1823, 2003.) |
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In addition to age and gender, race, geography, and body mass index are a factor in the prevalence of kidney stones. Non-Hispanic whites have more kidney stones than non-Hispanic blacks at all age ranges (see Fig. 37-1 ) and Mexican Americans. [13] [47] Prevalence among Hispanics and Asian men was intermediate between that of whites and blacks.[47] The age-adjusted prevalence of kidney stones increases from the North to the South and from the West to the East.[47] This increased risk of nephrolithiasis in the Southeast has been postulated to be linked to the greater sunlight exposure in this area, leading to an increase in insensible losses through sweating, resulting in more concentrated urine. The sun exposure enhances vitamin D production, leading to an increase in intestinal calcium absorption and subsequent urine calcium excretion. [43] [47] Increased urine calcium excretion in a smaller urine volume markedly increases urine supersaturation with respect to the calcium-containing solid phases that constitute the majority of kidney stones. However, another report has not found significant differences in the urinary risk factors for stone disease in five regions of the United States.[48]
Obese men and women have a greater risk of kidney stones. [13] [49] [50] Individuals who weighed more than 220 pounds have a significantly greater chance of forming a kidney stone than those weighing less than 150 pounds.[49] A body mass index greater than 30, compared with a body mass index between 21 and 22.9, was also associated with an increased risk of stone formation as was a weight gain of 35 pounds since young adulthood and an increased waist circumference.
HUMAN GENETICS
This section summarizes and discusses the genetic contribution to nephrolithiasis as a whole, whereas specific monogenic causes of kidney stones such as distal renal tubular acidosis (RTA), primary hyperoxaluria, and cystinuria are covered under the relevant sections. Epidemiologic studies constitute the bulk of the data. The current approaches are based purely on demonstrating correlative, rather than causative, relationships. Two types of epidemiologic studies with statistical modeling of phenotype frequencies have been performed—familial aggregation and twin studies. In addition, attempts have been made to perform genotype-phenotype association or linkage with either candidate genes and fewer attempts with whole genome linkage studies.
Familial Aggregation
The rationale for studying familial aggregation is based on finding statistically different frequencies of stone formers in family members of affected versus unaffected individuals, as illustrated in Figure 37-2 .
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FIGURE 37-2 Familial clustering of kidney stones. The proband is shown as the arrow and his family is in yellow (case). The spouse in this example serves as the negative control, and her family is shown in blue (control). Filled symbols denote affected individuals. |
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Familial aggregations of nephrolithiasis were noted as early as the 19th century.[51] The study of Gram in the 1930s probably represents the first detailed definition of kindreds in stone formers.[52] Retrospective case-control studies have commonly been used to determine the relative importance of heredity and environment in idiopathic nephrolithiasis. The first large-scale retrospective case-control study was performed by McGeown,[53] who studied 174 patients with renal stones and 174 age- and gender-matched controls, and found a significant increase in the number of parents and siblings with kidney stones among the stone formers compared with controls. This case-control design has been the basis of many studies since. Two frequently cited studies were performed by Resnick and co-workers[54] and Trinchieri and co-workers,[55] which used the spouses of stone formers as a control group and demonstrated relative risk of kidney stones of threefold to fourfold when one has an affected family member. A large number of studies have indicated 20% to 40% of stone formers have positive family histories of stones, including large databases like Nurses Health Cohort and Health Professional Follow-up Study with a relative risk in the neighborhood of two- to fourfold. [56] [57] [58] [59]
Inheritance Pattern
An early attempt to model the segregation of nephrolithiasis by tracking four generations of renal stone formers led to the conclusion of an autosomal-dominant pattern.[52] This view was espoused by several others in subsequent studies, [60] [61] [62] although the phenotypic definition has varied from nephrolithiasis, to calcium oxalate stones, and hypercalciuria. This variation will no doubt impact on the conclusion. The discussion of genetic determinants of hypercalciuria will be covered in more detail in a later section. The aforementioned conclusions were largely de facto based on the fact that the pattern did not match a recessive pattern and male-to-male transmission ruled out X-linked loci. Because stone disease frequently does not manifests till midlife and asymptomatic stones are not uncommon, one has to exercise caution in constructing pedigrees. Attempting to arrive at a specific Mendelian pattern is not justified given the current body of knowledge. The current notion is that nephrolithiasis is a complex trait with polygenic contribution (determined by many genes), loci heterogeneity (different genetic stones formers affected by different genes), incomplete penetrance (positive genotype but negative phenotype), and extensive phenocopy (nongenetic factors causing the same phenotype). [63] [64] [65]
Twin Studies
Another useful statistical method in the analysis of the genetics of stones disease is twin studies. Liew and colleagues[66] recently pointed out that this technique dated back to 1922. Several twin registries have provided valuable data on dissecting the inheritable component of diseases. [67] [68] [69] The basis of the analysis is founded on the simple principle that monozygotic twins share identical genetic information, and if the twins are reared together, they likely share similar environmental factors. Some of these factors, if identifiable, can be monitored and corrected in the analysis. Prevalence of a certain trait such as kidney stones in a concordance or discordance fashion can be harnessed and statistical models can be constructed to ascertain the genetic contribution of heritability of certain traits ( Fig. 37-3 ).
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FIGURE 37-3 Twin studies. Twin pairs are analyzed for whether they both have or not have the trait (concordance), or only one of them have the trait (discordance). |
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Surprisingly, this method has not been applied to stones disease until recently when Goldfarb and co-workers studied the Vietnam Era Twin Registry, which included about 7500 male-male twin pairs born between 1939 and 1955 and collected data from approximately 2000 monozygotic and approximately 1400 dizygotic twins.[70] These investigators observed a 32% concordance rate in monozygotic and 17% concordance rate in dizygotic twins. One of the major strength of the study is attempt to account for phenocopy. For the discordant twin pairs, part of the sparing effect in the unaffected twin can potentially be attributed to dietary factors. This twin study concluded that half of the propensity to kidney stones can be attributed to heredity, which is remarkably similar to the familial clustering studies.
Association and Linkage
Candidate genes have been examined using the association approach, which is another form of case-control study in which specific gene sequence variations are studied in affected versus unaffected individuals. Genes along the vitamin D axis were popular candidates. Some studies have a demonstrated association of polymorphism of vitamin D axis genes with one form of phenotypic parameter or another. [71] [72] [73] [74] [75] [76] [77] [78] Despite this persistent perennial emergence of positive associations, no definitive model has emerged to elucidate the biology of the relationship between the vitamin D axis and the human genetics of kidney stones. Moreover, other studies have found no difference in the phenotype of vitamin D receptor expression, induction, allelic frequ-encies, coding region sequence between controls, and well-characterized hypercalciuric stone formers. [79] [80] There is also using conflicting conclusions from genotyping different regions of the vitamin D receptor in the same population. [76] [81] One encouraging outcome has been the identification of potential susceptibility locus in the vicinity of the vitamin D receptor gene in 47 French Canadian kindreds using sibpair analysis.[82]
As opposed to association, linkage detects genotype-phenotype cosegregation within pedigrees and has been the workhorse for disease-locus discovery in monogenic diseases. [83] [84] Nonparametric linkage analysis takes advantage of a model-free test to avoid a priori assumption of a particular inheritance pattern. The Hospital Maisonneuve-Rosemont group from Montreal used in large numbers of French Canadian concordant affected sib-pairs on a large number of candidate genes including the vitamin D receptor, 1-a-hydroxylase, the calcium-sensing receptor, and crystallization modifiers such as osteopontin, Tamm-Horsefall protein, and osteocalcin-related gene. [82] [85] [86]Similarly, Reed and co-workers [87] [88] from Dallas performed a whole-genome linkage analysis of three large kindreds with absorptive hypercalciuria using nonparametric testing and found one locus with a candidate in this region, which is the soluble adenylyl cyclase. The significance of these efforts in linkage analysis has not yet led to definitive conclusion to date.
In summary, the data supporting genetic influence in nephrolithiasis are strong, with up to 50% contribution to the phenotype. Nephrolithiasis as a phenotype is complex trait with polygenic influence, loci heterogeneity, incomplete penetrance, and strong environmental modification.
PATHOGENESIS
Saturation
Consider a flask of water containing an ample amount calcium oxalate crystals, which is well mixed and at a stable temperature.[21] The crystals have been bathed in the solution for a long time and neither grow nor shrink. The calcium and oxalate concentrations in the solution must also be unchanging, because the crystals are of a stable mass. The system is at equilibrium. The product of the free ionized calcium and oxalate concentrations in such a solution is called the equilibrium solubility product. A lower free ion activity product will cause the crystals to dissolve. Such a solution is called undersaturated. A higher free ion activity product will cause the crystals to grow.
Now remove the crystals from the equilibrium system and raise the ion activity product by adding calcium, oxalate, or both. The elevated activity product would have caused growth of preformed crystals had they been left in the beaker, but in the absence of solid phase, nothing appears to happen: the solution remains clear, free of crystals. A solution that will cause growth of preformed crystals but not the appearance of new solid phase is called metastable. Increase the activity product sufficiently, however, and new crystals will appear. This point is often called the formation product, or the upper limit of metastability. Above the formation product, a solution is unstable, prone to creating new crystal nuclei. Urine may be undersaturated, metastable, or unstable with respect to calcium oxalate or the stone-forming calcium phosphate crystals.
Factors Influencing Saturation
Renal excretion of calium, oxalate, phosphate, and water are primary determinants of saturation. However, complexation of calcium and oxalate, and urine pH, which influences the relative amounts of mono- and dihydrogen phosphate, alter free ion concentrations drastically, and have an importance in regulating saturation at least equal to that of the total concentrations. Ion binding also complicates the measurement of urine saturation; simple concentration measurements give little clue to the actual activity product. For example citrate readily complexes calcium, reducing the ionized calcium levels[89]; a similar relationship exists for Mg2+ and oxalate.[90] For this reason, among others, hypercalciuria, oxaluria, hypocitraturia, unduly alkaline urine, and chronic dehydration seem to increase the risk of calcium stone formation but are not sufficient to ensure that stones will form.
Urine Saturation Measurements
Pak and colleagues[91] measured urine saturation by comparing urine chemistries to their equilibrium concentration for a given crystal. They add seed crystals to an aliquot of urine and incubated at 37°C, with stirring, at constant pH, for 2 days. By that time, equilibrium is attained; the crystal mass has become stable. If the activity coefficients for calcium, oxalate, and phosphate—essentially the fractions of each that are free to react—remain stable throughout the incubation, the ratio of the concentration product at the start of incubation to the concentration product after incubation, at equilibrium, must equal the activity product ratio (APR), even though the concentration products themselves do not equal the activity products. Pak and colleagues[91] have shown that the assumption of stable activity coefficients is valid, so the empirical concentration product ratio is a valid estimation of the APR, provided the calcium concentration is less than 5.0 μM and oxalate less than 0.5 μM. The upper limit of metastability can be determined by raising the activity product by adding ligand and noting the APR at which solid phase begins to appear.
Others have developed a simpler approach using computer programs to calculate urine free ion activities for calcium, oxalate, and phosphate from their concentrations and their known tendencies to form soluble complexes with each other and with other ligands such as citrate and sulfate. [91] [92] [93] If a calculated free ion activity product, such as the calcium oxalate ion product, is divided by the corresponding equilibrium solubility product, estimated in the same way, the resulting APR estimates the degree of saturation. A ratio higher than 1 connotes oversaturation; less than 1 is undersaturation. The validity of this approach has been confirmed by two studies that showed a strong correlation between the type of stone a patient forms and the prevailing supersaturations found in two or three 24-hour urine samples as estimated by the computer program Equil2. [94] [95]
Observed Urine Saturation
Robertson, Pak, and Weber and their colleagues, using different measurements, have accumulated considerable evidence that urine from stone formers is more supersaturated than normal. [96] [97] [98] [99] [100] Probably because of the differences in methods, absolute values differ for the three investigative groups. However, stone formers, whether hypercalciuric, without detectable metabolic disorder (idiopathic), or hyperparathyroid, had higher average values of urine saturation than did normal subjects, whether saturation was measured with respect to calcium oxalate, brushite, octocalcium phosphate, or hydroxyapatite. In the study by Weber and associates,[100] supersaturation for calcium oxalate was higher among hypercalciuric than among normocalciuric patients. Another important observation common to both experimental approaches is that normal urine, on average, is above the equilibrium solubility product, that is, supersaturated, with respect to calcium oxalate. In the case of the data of Pak and of Weber and co-workers, [99] [100] this is a visible fact: Added crystals grow in urine from most normal persons. Urine supersaturation with brushite is more variable, being highly dependent on urine pH and calcium. The use of urine measurements to assess supersaturation may be insufficient to reveal the full crystallization potential that exists in the renal tubule. Hautmann and colleagues[101] have studied calcium and oxalate concentrations in tissue from cortex, medulla, and papilla of seven human kidneys. The calcium-oxalate concentration product in the papillae (1 × 10-4 M2) exceeded that of urine (5 × 10-7 M2) and those of the medulla and cortex (8 × 10-7 M2 and 6 × 10-7 M2, respectively).[101] In addition, high calcium phosphate supersaturation appears to be a frequent event in the tip of the loop of Henle because tubule fluid pH and calcium concentrations are high due to water extraction on the descending limb.[102]
Limits of Metastability
Urine APR describes whether preexistent crystals, once formed, will grow or shrink while suspended in it; but the APR gives incomplete information about the ability of that urine to produce new crystals. In simple salt solutions, the upper limit of metastability for calcium oxalate has been found to occur at an APR of 8.5 by Pak and Holt[99] and 10.0 by Robertson and associates.[93] The small difference in upper limit is mainly methodologic in origin.
Pak and Holt[99] have measured the actual upper limits for calcium oxalate and brushite in human urine samples from normal subjects and from hypercalciuric, normocalciuric, and hyperparathyroid stone formers and have found surprising variability. The APR at the upper limit of metastability (ULM) is higher in normal urine than in a salt solution. The ULM in urine from stone formers is lower than normal, and in primary hyperparathyroidism, it may be below 8.5, the value observed in simple salt solution. Recently, Coe and colleagues have reported studies in which the ULM of calcium oxalate and brushite was measured in urine from calcium stone formers and sex- and age-matched control subjects. [103] [104] They found that the distance between prevailing supersaturation of the urine and the ULM was reduced in stone formers, although the defect was more dramatic for brushite than for calcium oxalate. The closer urine supersaturation is to the ULM, the more likely crystallization and stone formation will occur.
The reduced ULM likely represents a defect of crystallization inhibition in calcium stone formers. Despite their differences, these studies yield similar conclusions. Urine is abnormally saturated in stone formers. Values of APR lie close enough to the ULM, for calcium oxalate and calcium phosphate, that new crystal formation could be expected. Most urine, even from normal persons, is metastable with respect to calcium oxalate, so growth of crystal nuclei into a significant mass is predictable.
Nucleation
Homogeneous nucleation, the spontaneous formation of new crystal nuclei in an oversaturated solution, is uncommon.[21] Usually, particles of dust or debris in solution, irregularities on the surface of the container, or other crystals furnish a surface on which crystal nuclei begin to form at a lower APR than is required for homogeneous nucleation. The very existence of the metastable zone reflects the greater free energy change required to create new nuclei than to enlarge preformed nuclei, so any surface that can serve as a substrate for ions in solution to organize on may act as a heterogeneous nucleus, abridge the costly process of creating a solid phase de novo, and lower the apparent ULM.
The efficiency of heterogeneous nucleation depends on the similarity between the spacing of charged sites on the preformed surface and in lattice of the crystal that is to grow on that surface. This kind of matching is referred to as epitaxis, and its extent is usually referred to as a good or poor epitaxial relationship.[105] In order to achieve homogeneous nucleation, all potential heterogeneous nuclei must be excluded, an unreasonably difficult task when human urine is under study. It is probable that the apparent urine formation product ratio for any given crystal is conditioned by preformed heterogeneous nuclei and nuclei of other crystals that form because the APR is raised during the experimental determination itself.
A number of urine crystals have good epitaxial matching and behave toward one another as heterogeneous nuclei. Monosodium urate and uric acid are excellent heterogeneous nuclei for calcium oxalate, [106] [107] so uric acid or urate could, by crystallizing, lower the ULM for calcium oxalate. Heterogeneous nucleation may be the mechanism linking hyperuricosuria to calcium oxalate stones, [108] [109] [110] [111] a matter discussed later in this chapter. Epitaxial overgrowth of calcium oxalate on a surface of uric acid has been experimentally documented.[112]
Brushite can nucleate calcium oxalate,[113] but in vivo, it is more likely to transform, above pH 6.9, to hydroxyapatite, which is also an effective nucleating surface for calcium oxalate.[114] Calcium phosphate plaques found in the renal papilla, so-called Randall plaques, may act as nucleating sites for calcium oxalate stones.[115]
The Randall plaque is formed in the interstitium of the papilla but can erode through the papillary epithelium to be exposed to the urine. The plaque provides a preferred nucleating site, lowering the free energy needed for crystallization of calcium oxalate. At the same time, the plaque provides an anchoring site, allowing the new crystal to be retained in the kidney and have sufficient time to grow to a clinically significant size. Apatite is frequently found at the core of calcium oxalate stones,[34] and there is increased prevalence and severity of Randall plaques in stone formers as compared to non-stone formers.[116] Coe, Evan, and colleagues have extensively studied Randall plaque formation in patients with various types of nephrolithiaisis [117] [118] [119] [120] [121] [122] and this information is presented in the relevant sections below.
Crystal Growth and Aggregation
Once present, crystal nuclei will grow if suspended in urine with an APR higher than 1. Growth and aggregation are critical to stone disease, because microscopic nuclei are too small to cause obstruction or produce symptoms. Crystals are regular lattices, composed of repeating subunits, and they grodw by incorporation of calcium and oxalate, or phosphate, into new subunits on their surfaces. In metastable solutions, at 37°C, growth rates of calcium oxalate and the stone-forming calcium phosphate crystal are rapid; appreciable changes in macroscopic dimensions occur over hours to days. Growth rate increases with the extent of oversaturation and tends be most rapid in urines having the highest values of APR. Small crystals aggregate into larger crystalline masses by electrostatic attraction from the charged surface of the crystals. This process can rapidly increase particle size, producing a crystal that can lodge in the urinary tract. Stone-former urine contains larger crystal aggregates than urine from non-stone formers.[123]
Cell-Crystal Interactions
Finlayson and Reid[124] have proposed that crystals cannot grow or aggregate fast enough to anchor in the urinary tract to cause obstruction of renal tubules during the normal transit time through the nephron. Crystals must anchor to the renal tubule epithelium or urothelium to grow large enough to be of clinical significance—the fixed particle theory. Although Randall plaques may offer an anchoring or nucleating site, it is also clear that not all stone formers have Randall plaques,[116] so an alternative mechanism has been invoked. In vitro studies have shown adherence of calcium oxalate crystals to rat collecting duct epithelial cells,[125] and adherence and subsequent endocytosis of calcium oxalate crystals by monkey kidney epithelial cells.[125] The adherence and uptake of crystals appear to be crystal specific, greater for calcium oxalate than for calcium phosphate. [126] [127] The crystals bind to anionic sites on the cell membrane in a stereospecific fashion.[128] Cells may even act as nucleating sites for crystal formation.[129] Bigelow and associates have shown that phosphatidylserine appears to be a preferred binding site and that enrichment of cell membranes with phosphatidylserine increases calcium oxalate crystal binding by renal epithelial cells in culture.[130] The binding of crystals to the cells can be inhibited by a variety of anionic compounds normally found in urine, which may be part of the normal defense against kidney stones.[131] The importance of the cell-crystal interaction in the pathogenesis of human kidney stone disease is not clear at this time.
Inhibitors of Stone Formation
Urine is generally supersaturated with respect to the common stone solid phases of calcium oxalate, calcium phosphate, sodium urate, or uric acid; however, a solid phase often does not form. [96] [97] [98] [99] [100] That a solid phase does not form once urine becomes supersaturated implies that there are inhibitors to stone formation present in normal urine.[132] The upper limit of metastability is the supersaturation at which the solid phase forms.[21] That the upper limit of metastability is lower in patients who form stones compared with matched controls [117] [133] implies that these inhibitors are less effective in stone formers compared with controls.
There are at least four types of inhibitors in urine: multivalent metallic cations such as magnesium, small organic anions such as citrate, small inorganic anions such as pyrophosphate, or macromolecules such as osteopontin and Tamm-Horsfall protein.[43]
Magnesium
Magnesium (Mg) has been touted as a kidney stone inhibitor for centuries.[134] It is present in urine in millimolar concentrations, where it readily binds to oxalate. Li and colleagues[135] found that Mg inhibited both nucleation and growth of calcium oxalate crystals. Wilson and associates,[136] using a seeded crystal growth system of constant composition, found that Mg was a weak inhibitor. Fifty-five stone formers who were given 500 mg of Mg2+ daily in the form of Mg(OH)2 had a decrease in stone rate from 0.8 to 0.08 stones per year[134]; 85% of treated patients remained free of stone recurrence, whereas 59% of untreated control patients continued to form stones. However, more recent controlled clinical studies suggest that Mg2+ does not alter the recurrence rates for calcium oxalate stone formation, perhaps owing to its poor absorption.[137]
Citrate
Citrate inhibits the nucleation, growth, and aggregation of calcium oxalate crystals. [135] [138] [139] [140] [141] Nicar and co-workers[142] have shown that citrate inhibits crystallization not only by complexing with calcium but also by directly inhibiting crystallization as well, although the latter effect is smaller in magnitude. Tiselius and colleagues [144] [145] [146] [147] [148] [149] [150] confirmed that citrate directly inhibits crystallization.[143] Citrate (as the potassium salt) has been shown, in the majority of clinical studies, to effectively inhibit recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, in those with distal RTA[150] and in normocitrauric stone formers.[145]Greischar and associates[151] demonstrated that citrate increased the upper limit of metastability by increasing both urine citrate and pH. During metabolic acidosis, there is an increase in proximal citrate reabsorption, reducing the amount of citrate excreted in the urine.[152] A reduction of urinary citrate, due to increased the acid load generated from dietary protein ingestion, can promote formation of both calcium oxalate and uric acid stones. [153] [154] [155] [156]
Pyrophosphate
Pyrophosphate has been shown to retard the growth of calcium phosphate and calcium oxalate crystals. [111] [157] Russell and Fleisch[111] found that the average urine pyrophosphate concentration was sufficient to significantly inhibit crystal growth. Schwille and co-workers[158] found a reduced pyrophosphate-to-creatinine ratio in half of stone formers, suggesting that a lack of pyrophosphate may predispose to nephrolithiasis.
Macromolecules
Macromolecules are potent inhibitions of calcium oxalate crystallization.[159] These inhibitory molecules are generally highly anionic and contain large amounts of acidic amino acids that undergo post-translational modification with negatively charged side chains.[21]
Osteopontin, previously termed uropontin, is an acidic phosphorylated glycoprotein that was initially isolated from bone. [160] [161] [162] [163] [164] Osteopontin inhibits formation of hydroxyapatite during normal bone formation. [165] [166] [167] [168] [169] Osteopontin is also expressed in cells of the thick ascending limb of Henle loop and the distal convoluted tubules, and secreted into the tubules with about 4 mg/day present in the final urine. [161] [163] [170]Osteopontin inhibits the nucleation, growth, and aggregation of calcium oxalate stones in vitro. [160] [161] [171] Osteopontin knockout mice develop calcium oxalate kidney stones when given ethylene glycol, a nephrotoxin that leads to hyperoxaluria, at doses that do not induce stone formation in wild-type mice. [160] [172] Osteopontin is up-regulated at sites of stone formation in genetic hypercalciuric stone-forming rats.[173]
Tamm-Horsfall protein is the most abundant protein found in the urine of humans, with approximately 100 mg excreted per day. It is also synthesized in the thick ascending limb of Henle loop and, owing to self aggregation, is the principle component of urinary casts.[174] Tamm-Horsfall protein inhibits calcium oxalate crystal aggregation but does not alter growth or nucleation. [175] [176] [177] Tamm-Horsfall protein knockout mice spontaneously form calcium crystals in the lumen of tubules in the papilla and medulla.[162] When these knockout mice are given ethylene glycol to induce calcium oxalate stone formation, there is a marked induction of renal osteopontin at sites of crystal formation.[162]
Urinary prothrombin fragment 1 (crystal matrix protein), which is a fragment of prothrombin that is made within the kidney,[178] is a potent inhibitor of calcium oxalate growth, aggregation, and nucleation, [179] [180] and is present within kidney stones.[181] There is evidence for differences in urinary prothrombin fragment 1 between stone formers and non-stone formers.[182]
Bikunin is the light chain of the inter-a-trypsin inhibitor, which inhibits both calcium oxalate growth and nucleation.[183] It is found in the epithelial cells of the proximal tubule and in the thin descending segment near the loop of Henle.[184] Bikunin and the heavy chains of the inter-a-trypsin inhibitor have been isolated form kidney stones, indicating that multiple fragments of this inhibitor may be active in preventing stone formation.[185] Marengo et al demonstrated differences in the electrophoretic mobility pattern between stone formers and non-stone formers.[186]
Nephrolcalcin is a 14-KD glycoprotein that was the first urinary protein found to have crystal inhibitory properties. [175] [176] [187] [188] [189] [190] It contains γ-carboxyglutamic acid (Gla) and has been shown to inhibit crystal growth, nucleation, and aggregation. Nephrocalcin from some stone-forming patients lacks Gla and has diminished ability to inhibit nucleation and growth of calcium oxalate crystals. [175] [177] [191]
Urinary trefoil factor 1 has potent inhibitory activity against calcium oxalate crystal growth, similar to that of nephroclacin.[192] Concentrations of urinary trefoil factor 1 have been shown to be greater in stone formers compared with those of controls. Calgranulin has been isolated from urine and from calcium oxalate kidney stones, and is a potent inhibitor of growth and aggregreation.[193]
Recently, Bergsland and colleagues[194] compared the inhibitory proteins in urine from 50 stone-forming and 50 non-stone-forming matched first-degree relatives of calcium stone-forming patients. They found that profiles of inhibitory proteins were more effective in discriminating relatives of stone formers from non-stone formers than conventional measurements of supersaturation. Clinical use of inhibitor profiles is hampered by the difficulty and thus the expense of these measurements.
CLINICAL MANIFESTATIONS
The most characteristic symptoms of nephrolithiasis are pain often associated with hematuria, nausea, and vomiting. Other presentations include urinary tract infection and acute renal failure, if stones cause bilateral renal tract obstruction or unilateral obstruction in a single functioning kidney.
Pain
The classic presentation of pain in patients with nephrolithiasis is severe ureteral colic. This pain is often of abrupt onset and intensifies over time into an excruciating, severe flank pain that resolves with stone passage or removal. The pain may migrate anteriorly along the abdomen and inferiorly to the groin, penis, or labia majora as the stone moves toward the ureterovesical junction. Gross hematuria, urinary urgency, frequency, nausea, and vomiting may be also present. Stones smaller than 2 mm have a 97% likelihood of spontaneous passage, at 3 mm a 14% chance for passage, at 4 to 6 mm a 50% chance, and if the stone is larger than 6 mm, it has only a 1% chance of spontaneous passage and will almost certainly require urologic intervention. [117] [195] [196] [197] [198] [199] [200] [201] The pain is thought to be secondary to hydrostatic pressure causing renal capsular distention; relief of the obstruction often relieves the pain, even if the stone remains in place.[195]
Ureteral pain is not exclusive to stone disease and may also occur with the passage of clots from hematuria of many causes (so-called clot colic) or obstruction due to sloughing of a papilla. As well as colic, nephrolithiasis may provoke less-specific loin pain that may be poorly localized to the kidney and, therefore, has a wide differential diagnosis, particularly if it is not associated with other urinary symptoms. The finding of a stone on radiologic examination does not preclude the concurrent presence of other significant pathology.
Hematuria
Stone disease commonly causes hematuria, both microscopic and macroscopic.[195] In general, macroscopic hematuria occurs most commonly with large calculi and during urinary infection and colic. Although typically associated with loin pain or ureteric colic, nephrolithiasis may cause hematuria in the absence of pain. The clinical differential of hematuria is therefore wide and includes tumor, infection, and stones, as well as glomerular and interstitial renal parenchymal disease. Painless microscopic hematuria in children may occur with hypercalciuria in the absence of demonstrable stones.
Loin Pain Hematuria Syndrome
The combination of loin pain with hematuria syndrome (LPHS) in the absence of renal stones is a poorly understood condition that must always be considered in the differential diagnosis of patients presenting with the clinical manifestations of nephrolithiasis.[17] This diagnosis is reached by exclusion when the patients, who are often young to middle-aged females, present with loin pain and persistent microscopic or intermittent macroscopic hematuria.[202] Careful evaluation is required to exclude small stones, tumor, and urinary tract infection as a cause of the pain. Inconsistent angiographic abnormalities implying intrarenal vasospasm or occlusion have been reported, as have renal biopsy abnormalities typified by deposition of complement C3 in arteriolar walls. Recently, 43 consecutive patients with clinical manifestations of LPHS were evaluated by renal biopsy after excluding other causes of their symptoms.[203] Nine were found to have immunoglobulin A glomerulonephritis. Two thirds of the remainder had glomerular basement membranes that were either unusually thick or thin on electron microscopy, and half had a history of kidney stones, although none had obstructing stones at the time of assessment. The investigators postulated that the abnormal glomerular basement membrane led to rupture of the glomerular capillary walls, with consequent hemorrhage into the renal tubules causing tubular obstruction. Local and global renal parenchymal edema follow, ultimately resulting in stretching of the renal capsule and in severe flank pain. This condition requires reassurance and careful management of analgesia. LPHS usually remits after several years. Denervation of the kidney by autotransplantation is rarely successful,[204] and although nephrectomy has been attempted, often the pain recurs promptly in the contralateral kidney.
Asymptomatic Stone Disease
Even obstructive uropathy caused by large staghorn calculi may be painless; thus, nephrolithiasis should always be considered in the differential diagnosis of unexplained renal failure.
CLINICAL EVALUATION
It is important to emphasize that although nephrolithiasis is considered a “diagnosis” in diagnostic codes used for reimbursement, its occurrence alone confers little information about the underlying defect. The presence of a kidney stone can be a sentinel for a diverse range of underlying diagnoses. Therefore, nephrolithiasis per se is not much more of a “diagnosis” than for example high blood pressure, ascites, or fever. As in many scenarios in medicine when the database is incomplete, the term “idiopathic” is applied in stone disease to enable practitioners and researchers to empirically group certain entities that bear similarities but most likely are heterogeneous in their etiology. Because there is sometimes confusion in the nomenclature of kidney stones, Table 37-2 provides a cross-reference of the chemical and common names of the frequently encountered types of stones.
TABLE 37-2 -- Chemical and Common Names of Kidney Stones
|
Chemical Name |
Chemical Formula |
Common Name |
|
Calcium oxalate monohydrate |
CaC2O4•H2O |
Whewellite |
|
Calcium oxalate dehydrate |
CaC2O4•2H2O |
Weddellite |
|
Calcium phosphate |
Ca10(PO4)6(OH)2 |
Hydroxyapatite Apatite |
|
Calcium hydrogen phosphate |
CaHPO4•2H2O |
Brushite |
|
Calcium pyrophosphate |
Ca9(Mg, Fe[2]+)(PO4)6 (PO3OH) |
Whitlockite |
|
or |
||
|
Ca9(Mg, Fe)H(PO4)7 |
||
|
Magnesium ammonium phosphate hexahydrate |
MgNH4PO4• 6H2O |
Struvite |
|
Magnesium acid phosphate trihydrate |
MgHPO4•3H2O |
Newberryite |
|
Uric acid monohydrate |
|
None |
|
Uric acid dihydrate |
|
None |
|
Monosodium urate (exist only in conjunction with calcium stones) |
|
None |
The clinical approach to evaluating kidney stones can vary considerably depending on the region; hence, the prevalence of different kinds of stones, and the resources available to and the philosophy of the practitioner and patient. On one end, in situations with highly limited resources, one can subscribe to the argument that virtually all crystalline precipitation can be abrogated and prevented by urinary dilution using one of the cheapest universally available nonprescription drug—water. This view will propound that no evaluation is necessary. On the other hand, one can take the stance that every stone stems from some identifiable and potentially treatable etiology (some of which may be serious), and it is the clinician's duty to exhaustively unveil the underlying pathophysiology in every single patient. Although both strategies are supported by justifiable rationales to some extent, in most circumstances, one can find an approach between these extremes.
For organizational purposes, one can envision the clinical manifestations of kidney stones in three broadly categories as features of the underlying condition predisposing to nephrolithiasis, symptoms stemming from the stone itself, and finally manifestations of complications from the kidney stones. Symptoms and signs can be organized in a likewise fashion.
Basic Evaluation
The prevalence of kidney stones is rising[205] and is conferring a significant fiscal encumbrance on the health care system.[206] After the first episode of a stone, the 10-year recurrence rate is about 50%.[207] This has led to a dichotomous “half full versus half empty” approach. One can interpreted that half of these patients are clinically cured after the debut passage, whether the underlying pathophysiology is still present or not, and submit that no evaluation is necessary until the time recurrence as the second passage heralds further and more frequent relapses.[208] Our view is that this approach is not justified because the second episode is preventable once the risk factors are identified. Furthermore, there may be underlying diagnoses such as primary hyperparathyroidism, whose diagnoses should not be deferred. The metabolic profile of single stone formers evaluated at a University referral clinic is not different from that of recurrent stone formers.[209]
History and Physical Examination
A well-conducted history provides the platform and direction for decision about more detailed evaluation. Age of the patient and family history is important for inherited causes or possibility of underlying structural abnormalities. States of volume contraction and oliguria, such as low fluid intake, excessive sweating, and diarrhea, should be noted. A careful nutritional history of estimated dietary contents of calcium, oxalate, sodium, acid (protein), potassium-rich citrus fruits, and purine can be conducted in a semiquantitative fashion by a physician before or without a consultation with a dietician. Gastrointestinal diseases such as any chronic diarrhea states, ileal resection, jejunoileal bypass, or weight reduction surgery are all important in the history. Underlying conditions that lead to hypercalcemia and hypercalciuria include immobilization, metastatic diseases, multiple myeloma, primary hyperparathyroidism, a history of bone pain, nontraumatic fractures, and systemic symptoms of hyper-calcemia are important features. Distal RTA can present solely with kidney stones, although in more severe cases in children, stunted growth may be noted. Recurrent urinary tract infection with urease positive organisms can cause kidney stones. Gout, diabetes, obesity, and the metabolic syndrome are risk factors for kidney stone formation and, particularly, uric acid stones. Medication history should be documented, with careful attention paid to the drugs listed in Table 37-3 .
TABLE 37-3 -- Medications Associated with Increased Stone Risk
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Drug |
Effect |
|
Corticosteroids |
Hypercalciuria |
|
Vitamin C |
Hyperoxaluria+ |
|
Vitamin D |
Hypercalciuria |
|
Vitamin B6 |
Hyperoxaluria[*] |
|
Calcium supplements/antacids[*] |
Hypercalciuria |
|
Carbonic anhydrase inhibitors |
Hypocitraturia, hypercalciuria, high urine pH |
|
Insoluble drugs |
Indinavir, triamterene |
|
+Some degree of controversy exists. |
|
* |
Usually associated with very high doses and may be accompanied by other underlying defects. |
Laboratory Studies
In addition to a careful history and physical examination, a minimal set of laboratory studies should be performed. A simple urinalysis can offer important information. Urine crystals are of variable assistance in the diagnosis, because crystalluria can be encountered in the absence of kidney stones. However, the presence of distinctive hexagonal cystine stones is extremely valuable in prompting the diagnosis of cystinuria and cystine stones. A pictorial display of crystalluria is present in the section of urinalysis in Chapter 23 . Specific gravity and osmolality provide a clue in the habitual fluid intake of a given individual. A low urinary pH (<5.5) signifies the possibility of uric acid stones. A moderately high pH (6.5–7.2) may reflect complete or incomplete distal RTA. An extremely high pH (>7.4) usually indicates splitting of urea into ammonium and bicarbonate. A positive nitrite test and a culture will reveal the microbiologic diagnosis. Plasma tests should include at least electrolytes, calcium, phosphorus, and uric acid. The level of calcitropic hormones (parathyroid hormone [PTH], 25- and 1,25-[OH]2 vitamin D3) can be included in the initial evaluation, especially if there are abnormalities of calcium and phosphorus.
Although some prefer to defer this laboratory test to the level of comprehensive evaluation, we believe that this test can be included in the basic evaluation because of its simplicity and wealth of information. This is the outpatient 24-hour urine analysis on a random diet. The patient should be instructed to perform an accurate 24-hour urine collection, and the specimen should be preserved with thymol and refrigerated. The chemistry includes calcium, phosphorus, oxalate, uric acid, sodium, potassium, pH, bicarbonate, sulfate, ammonium, titratable acid, citrate, and creatinine, and calculates relative supersaturation ratios of calcium oxalate, calcium phosphate, monosodium urate, and concentration of undissociated uric acid. This simple test enlightens the clinician not only on the underlying diagnosis but also provides guidelines for therapy.
Stone Analysis
All attempts should be made to encourage the patient and the primary care physician to capture the stone and submit it for analysis. This is one pathologic specimen that is completely stable with time. Dame Kathleen Lonsdale has made clinical diagnoses based on postmortem stone analyses of patients hundreds of years after their demise.[210] Because different kidney stones herald completely different underlying pathophysiology, stone analysis assumes a central role in the evaluation of stone formers. Most, but not all the time, knowledge of the stone composition can disclose the underlying diagnosis or at least streamline the diagnostic process.[33] For example, a cystine stone is definitive for congenital cystinuria, a struvite or carbonate stone indicated urinary tract infection with urease-positive organisms, triamterene and indinavir stones are pathognomonic for the precipitation of these drugs. [211] [212]Identification of calcareous stones is less definitive in terms of narrowing down the diagnosis but is still helpful. Mixed urate/calcium stones may suggest hyperuricosuric calcium urolithiasis, and primarily calcium phosphate stones may suggest acidification defects such as RTA and carbonic anhydrase inhibitors.
In addition to diagnosis, stone analysis can also assist in prognosis and treatment. A higher recurrence rate has been described for calcareous stones with higher calcium phosphate content, and with recurrent stone formation, the proportion of calcium phosphate also increases in the stone. [213] [214]
Radiologic Evaluation
Still a very common radiologic procedure is the plain film of the abdomen. Certain characteristics of stones that help differentiate different stone types are listed in Table 37-4 . Note that the overall accuracy using the plain radiograpsh is less than satisfactory.[215] Bowel gas, skeletal structures, and phleboliths can interfere with the interpretation. Ultrasonography is less useful because it often yields suboptimal visualization in the kidney and is almost useless for ureteral stones, although it is excellent in detecting obstruction caused by kidney stones. In the pediatric population, a sonogram is used much more often to spare the child irradiation.
TABLE 37-4 -- Appearance on Plain Radiographs
|
Characteristics |
Crystal |
|
Radioopaque Well circumscribed |
Calcium oxalate-monohydrate |
|
Calcium oxalate-dehydrate |
|
|
Calcium phosphate (apatite; brushite) |
|
|
Radiolucent rarely staghorn |
Uric acid |
|
Can be staghorn |
Struvite (magnesium ammonium phosphate) |
|
Mildly opaque |
Cystine |
|
“Ground-glass” look |
|
|
Can be staghorn |
Although the intravenous pyelogram has served well and been the standard procedure for decades, unenhanced computer tomography (CT) scan is currently the diagnostic procedure of choice. [216] [217] Under idealized conditions, spiral CT is far superior to conventional CT, but one needs to consider the higher dose of radiation delivered and the increased expense.[217] CT has the added advantage of the utility of Hounsfield unit to predict fragility of the stone for subsequent therapeutic attempts. In addition to locating the stone by imaging, another component of the diagnostic effort is to discern why the patient formed the stone so that recurrences can be prevented and due attention can be devoted to any underlying conditions. Examples of these conditions include anatomic abnormalities of the urinary tract, medullary sponge kidney, and autosomal-dominant polycystic kidney disease.
Comprehensive Evaluation
The tests described above should and easily be performed on all stone formers. For given individuals with more complicated presentations and depending on the infrastructure of the medical facility and whether research protocol are being conducted, more comprehensive evaluations are often conducted. If such tests are not readily available, the practitioner should consider referring the patient to specialty clinics rather than forgoing critical information. Certain patient characteristics should prompt more comprehensive evaluation. Recurrent stone formation deserves more elaborate investigation. It is unclear whether any one factor alone can predict recurrence before the stones actually recur. [207] [209] [218] Degree of hypercalciuria, low urinary volume, hyperuricouria, and hypocitraturia have all been suggested to have some predictive power. [208] [218] [219] Any first stone formers who have biochemical evidence of hyperparathyroidism, enteric or primary hyperoxaluria, distal RTA, struvite stones, cystinuria, and any hypercalcemic states such as myeloma, sarcoidosis, and so on should have a comprehensive evaluation.
In a clinical research setting the Dallas group has proposed that outpatient 24-hour urine collection can be performed as described above for stone risk factors but under dietary manipulation.[220] An instructed diet of 400 mg (10 mmoles)/day calcium and 100 mEq/day sodium for 4 to 7 days can be prescribed before the collection. In addition, lowering of dietary oxalate and protein can also be prescribed. This provides information as to how responsive the patient is to dietary manipulation. Urine collection under dietary manipulation is a research tool that is rarely done in clinical practice. If there is evidence of cystine crystal on urinalysis, a quantitative 24-hour cystine excretion rate can be determined. This protocol is best done only at stone research institutions.
The “idiopathic hypercalciuria” in fact stems from diverse pathophysiology. One can envision hypercalciuria as absorptive, resorptive, renal leak, or a combination of two or three of the components.[220] A test that is usually performed only in selected research centers is the “fast and load” calcium test that can help distinguish absorptive from renal hypercalciuria.[221] This test entails a 2-hour fasting urinary calcium in the morning along with a serum sample for calcium, creatinine, and PTH, followed by a 1-gm oral calcium load.[221] Subsequent to the load, a 4-hour urine collection is obtained for calcium and creatinine. The fasting sample allows calculation of fractional excretion of calcium in the absence of calcium in the gut and unveils urinary calcium leak. The post-load urinary calcium-creatinine ratio allows one to evaluate the intestinal contribution. A normal value is less than 0.2 mg calcium mg of creatinine.
Bone loss frequently accompanies hypercalciuric states whether the primary defect is renal, absorptive, or resorptive. In the long run, the patients are at risk of not only kidney stones but osteoporosis. Radial shaft bone density is low in renal hypercalciuria from hyperparathyroidism, and low spinal density has been described in patients with absorptive hypercalciuria. [222] [223]
More complicated tests are performed usually in a research setting for patients suspected of monogenic causes of kidney stones including genotyping and specific metabolic tests such as ammonium chloride loading and urine-blood carbon dioxide tension during bicarbonaturia (RTA), aminoaciduria (Dent disease), and parathyroid suppression by calcium infusion (activating mutation of calcium-sensing receptor). Consenting affected and nonaffected members of the kindred are frequently included.
GENERAL THERAPY
Therapy to minimize stone recurrence should ideally be guided by measurements of urinary supersaturation and determination of stone type. [17] [22] However, passage of a single stone in an apparently healthy young adult often does not lead to extensive metabolic evaluation,[18] and the stone may not be available for analysis. Patients such as these, and patients with a strong familial history of nephrolithiasis who have yet to pass a stone, are often given general advice on fluid and dietary modification aimed at lowering urinary supersaturation with the goal of preventing future stone formation. With this general advice, in the absence of pharmacologic therapy, stone recurrence rates have been 60% over 5 years and this condition is termed the “stone clinic effect.”[224]
These nonpharmacologic measures include an increase in fluid intake, which will concomitantly increase urine volume; restriction of dietary sodium, which leads to a reduction of urine calcium excretion; restriction of animal protein, which also leads to an reduction of urine calcium excretion and an increase in excretion of the calcification inhibitor citrate; and ingestion of an age and gender appropriate amount of dietary calcium. [44] [154] [155] [156] [224] [225] [226] [227] [228] [229] [230] [231] [232] [233]
Fluid Intake
An increase in fluid intake resulting in a urine volume, ideally to greater than 2 to 2.5 L daily, is of proven efficacy in reducing the incidence of stone formation. [224] [230] [231] [234] [235] Borghi and colleagues[234] studied 199 patients after their first idiopathic calcium stone episode ( Fig. 37-4 ). These patients were randomized into two groups and followed for 5 years. Neither group was told to alter their dietary food intake. In group 1, the patients were instructed to increase their fluid intake, whereas group 2 were not told to alter their fluid intake. Within 5 years, more than twice as many patients in group 2 formed stones than in group 1; the average interval to stone formation was 38.7 months in group 1 and 25.1 months in group 2.
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FIGURE 37-4 After a baseline study period 199 stone formers were randomized into two groups and were followed prospectively for 5 years. Patients in group 1 were advised to increase water intake without any change in diet and patients in group 2 were not advised to change fluid intake or diet. (From Borghi L, Meschi T, Amato F, et al: Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 155:839–843, 1996.) |
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For any quantity of ion excretion, an increase in urine volume will reduce urinary supersaturation relative to all of the stone solid phases. Additionally, increased urine flow rats will increase the upper limit of metastability with respect to calcium oxalate.[236] Although there are no careful studies as to when in the day urine supersaturation is greatest, in general, urine volume is least at night, when there is little to no fluid intake. This decreased volume almost certainly results in a period of maximum supersaturaton and thus risk for stone formation. Patients should be encouraged to drink enough fluid in the evening to provoke nocturia and then to drink more fluid before returning to bed. [17] [22]
Salt Intake
Increasing renal sodium excretion leads to a direct increase in renal calcium excretion ( Fig. 37-5 ). [226] [227] [237] Hypercalciuric patients appear to have a greater calciuric response to a sodium load than nonhypercalciuric control subjects[228] and to increase urine calcium excretion in response to salt even in the presence of marked hypercalciuria. [238] [239] Restriction of dietary sodium with the consequent decrease in urinary sodium will lead to a reduction of urine calcium excretion and urine supersaturation with respect to calcium-containing solid phases. A high sodium intake is associated with an increase in nephrolithiasis, and a reduction of intake lessens recurrent stone formation,[240] especially when combined with a diet adequate in calcium and moderate in protein.[233] Patients are generally counseled to limit their daily sodium intake to 2000 mg (approximately 87 mmol). [44] [226] [233]
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FIGURE 37-5 Calcium clearance as a function of sodium clearance in dogs. (From Walser M: Calcium clearance as a function of sodium clearance in the dog. Am J Physiol 200:1099–1104, 1961.) |
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Protein Intake
The ingestion of animal protein increases renal stone formation [241] [242] [243] [244] by a number of mechanisms. The metabolism of a number of amino acids generate hydrogen ions, which leads to calcium release from bone and an increase in the filtered load of calcium. [245] [246] [247] [248] Acidosis directly decreases renal tubule calcium reabsorption, [249] [250] which coupled to an increased filtered load, leads to increased urine calcium excretion[246] ( Fig. 37-6 ). As mentioned above, citrate, a base, forms soluble complexes with calcium and is beneficial in lowering calcium oxalate and calcium phosphate superaturation. Metabolic acidosis leads to an increase in proximal tubule citrate reabsorption and a decrease in renal citrate excretion.[152] Apart from the protein-generating metabolic acids, dietary protein may increase urine calcium excretion through as yet undefined mechanisms.[43] Thus, a diet rich in animal protein intake results in increased urine calcium excretion into urine in which the calcium is less soluble because of the excess sulfate and reduced citrate. Reduction of dietary protein in conjunction with a low-salt diet and adequate dietary protein reduces stone formation.[233] Correction of acidosis with potassium citrate or potassium bicarbonate reduces urine calcium excretion [245] [246] [251] and stone formation.[150]
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FIGURE 37-6 Delta urine calcium excretion as a function of delta urine net acid excretion in humans. (From Lemann J Jr, Bushinsky DA, Hamm LL: Bone buffering of acid and base in humans. Am J Physiol Renal Physiol 285:F811–F832, 2003.) |
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Not only is excess dietary protein a risk for calcium containing kidney stones but for uric acid stones as well. Dietary protein, especially from meat, leads to an increase in uric acid excretion, and the increased protein also results in a lower urine pH. [43] [252] [253] [254] Uric acid nephrolithiasis is promoted because the increased uric acid excretion is less soluble in the acidic urine. [252] [254] Stone formers are generally counseled to consume a diet moderate in total protein (0.8–1.0 g/kg daily) and especially those proteins derived from animal sources. [17] [22] [44] [233]
Calcium Intake
Despite conventional wisdom that patients forming calcium-containing renal stones should refrain from consuming calcium, recent studies have clearly demonstrated a decrease in the incidence of stone formation when people consume diets adequate in calcium. [230] [243] [255] [256] Indeed, consuming a low-calcium diet can actually increase the rate of stone formation. [14] [233] Hypercalciuric rats and in humans placed on a low-calcium diet have a continuously distributed wide variation of urine calcium excretion, with many subjects excreting more calcium than they consume. [21] [117] [257] [258] Placing patients such as these on a low calcium diet engenders the risk of bone demineralization, by far the largest repository of body calcium. [258] [259] [260] Ingested calcium binds intestinal oxa-late, reducing oxalate absorption and consequent renal excretion. [23] [230] [255]
Support for the use of an age- and gender-appropriate amount of dietary calcium to prevent recurrent calcium oxalate stone formation in hypercalciuric men was recently provided Borghi and co-workers[233] in a randomized prospective study comparing the rate of stone formation in men assigned to a low-calcium diet with those assigned to a normal calcium, low-sodium, and low-animal protein diet ( Fig. 37-7 ). Both groups were instructed to restrict oxalate intake and drink 2 to 3 liters of water daily. Stone formation in the 60 men assigned to the low-calcium diet was twice as likely over the 5-year study compared with those on the normal-calcium, low-sodium, and low-animal protein diet. Urinary calcium oxalate supersaturation also diminished more rapidly in those on the higher calcium diet and remained lower than that of men on the low-calcium diet for most of the study. The reduction in supersaturation was due to a greater fall in urinary oxalate in the men eating the normal-calcium, low-sodium, and low-animal protein diet. [23] [233]
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FIGURE 37-7 Results of a randomized prospective study comparing the rate of stone formation in men assigned to a low calcium diet with those assigned to a normal calcium, low sodium and low animal protein diet. (From Borghi L, Schianchi T, Meschi T, et al: Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 346:77–84, 2002.) |
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Kidney stones can be also be promoted by excessive dietary calcium intake. Increasing dietary calcium increases urinary calcium. [6] [7] [261] [262] [263] A recent large prospective study demonstrated that postmenopausal women given calcium supplements and vitamin D had an increased risk of stone formation compared with those on a free choice diet.[264] Some have postulated that the increase in stone formation may be due to taking the supplemental calcium apart from meals, which would enhance calcium absorption without reducing oxalate absorption.
Pak and colleagues, in a retrospective review, found that stone-forming patients with elevated urinary calcium excretion (>275 mg/day) could be given a low-calcium diet without a resultant elevation in urinary oxalate, as long as they were also instructed to eat a low-oxalate diet.[265] They contend that patients with no evidence of bone loss, excessive absorption of calcium, and severe hypercalciuria may benefit from dietary calcium restriction. However, because most patients are not stratified by excessive intestinal calcium absorption versus those who have a reduction in renal calcium reabsorption, nor do we routinely obtain estimates of bone mineral density (BMD), this strategy would be difficult to implement.
An age-appropriate amount of calcium (for both men an women, 1000 mg of elemental calcium from ages 19 to 50, and then 1200 mg of calcium thereafter[266] without supplements) appears most prudent. [230] [233] [243] [256] [264]As detailed earlier, a lower calcium diet not only increases stone formation but increases the risk for bone demineralization, and a higher calcium diet also increases nephrolithiasis without substantially improving BMD.
Recurrence after a Single Stone
Sutherland and associates[267] followed the course of patients in a single private practice, none of whom had received any prevention modalities and all of whom had presented with a single stone ( Fig. 37-8 ). By 5 years, about 40% had formed at least one more stone. Borghi and co-workers[234] performed a prospective open trial of marked hydration verusus conservative treatment in patients with a single stone (see Fig. 37-8 ) and found that by 5 years, 30% of the latter had formed a new stone versus only 10% of those highly hydrated.
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FIGURE 37-8 Recurrence of stones in patients who have formed a single stone. Untreated, 50% of patients (Parks) relapsed by 5 years. (From Sutherland JW, Parks JH, Coe FL: Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab 11:267–269, 1985.) Given marked hydration in an open prospective trial, 30% relapsed by 5 years (open circles) versus 10% who achieved a urine volume higher than 2.5 liters (closed circles). (From Borghi L, Meschi T, Amato F, et al: Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 155:839–843, 1996.) |
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CALCIUM STONES
Idiopathic Hypercalciuria
Overview of Calcium Balance
A detailed account of whole organism calcium homeostasis and renal calcium handling is covered in Chapters 5 and 16 and also in some recent reviews.[268] In this section, a brief overview of intestinal and to some extent renal calcium transport will be presented. Calcium balance is maintained for a wide range of intakes (500 to 1200 mg/day or 12 to 300 mmoles/day) by integrating the absorption of calcium with tissue requirements, turnover with bone, and losses in the sweat and urine. Total body calcium by mass is about 2% of total body weight (1.4 × 106 mg; 3.5 × 104 mmoles) Approximately 99% of total body calcium is in bone, with 1% distributed in the teeth, soft tissues, and the extracellular space. As one peruses the three main compartments of interest that are in equilibrium, one can easily appreciate the vast difference in content and composition and the challenge posed to the homeostatic systems ( Table 37-5 ). The magnitude of the fluxes and size of various pools are shown in Figure 37-9 .
TABLE 37-5 -- Body Distribution of Calcium
|
|
Bone |
ECF |
ICF |
|
Content |
1.3 × 106 mg |
103 mg |
<0.1 mg |
|
Aqueous concentration |
— |
10-3 M |
10-7 M |
|
ECF, extracellular fluid; ICF, intracellular fluid. |
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FIGURE 37-9 Relative rates of calcium flux between the extracellular fluid (ECF) pool and the three principal organs of calcium homeostasis. Flux rates are per 24 hours. Net flux between bone and ECF is normally zero. Pool size is shown in blue. |
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From the point of view of understanding the pathophysiology of kidney stones, several points are noteworthy at this juncture.[269]
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1. |
At the steady state of constant bone mineral mass, any increase in intestinal calcium absorption results in hypercalciuria. |
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2. |
A small degree of dysequilibrium between bone formation and bone resorption (e.g., resorption > formation by 1 mmole/day) will not lead to discernible change in bone mass for a long time, but the 1 mmole release will be excreted in the urine resulting in a 20% increase in calciuria. |
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3. |
A primary disturbance in one organ will lead to compensatory changes in the other two. A primary renal leak in calcium will result in increased intestinal absorption and bone resorption, so the overall defect appears like a multiorgan disease. |
Three pools of calcium have overlapping but diverse functions (see Table 37-5 ). Calcium is the principal cation used in biomineralization of both endoskeletons and exoskeletons. Calcium salts of phosphate and carbonate provide strength for the skeleton, and the reversible and extensive interaction between calcium crystals and biomolecules allows the ability of the bone to undergo constant active remodeling. The skeleton also provides a sink and a buffer to disturbance in extracellular calcium. Extracellular calcium provides the immediate exchangeable pool and also acts as an endocrine hormone. Intracellular calcium is largely a signaling molecule for a host of intracellular processes. The internal flux of calcium between organs and between the organism and the environment is achieved by calcium transporting epithelia.
Epithelial Calcium Transport
When millimoles of calcium traverses an epithelial cell with an obligatory intracellular ionized calcium activity in the 100 μM range, it is difficult to fathom how the cell survives without succumbing to calcium-induced cell death. Two modes of transport achieve this objective. First, calcium can be transported in a paracellular fashion, hence never invading the sanctity of the intracellular pool. Second, transcellular calcium transport can be attained as long as there are ample safeguards against flooding the cytoplasmic free calcium pool. Both of these are used in the intestine and the kidney, and they are illustrated in Figure 37-10 .
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FIGURE 37-10 Generic model of epithelial calcium transport. Paracellular calcium transport (bottom) requires an electrochemical gradient (Δμ) between the lumen and the interstitium-plasma compartments. Transcellular calcium transport is more complex. Apical calcium entry proceeds by means of a downhill free energy gradient and is mediated by calcium channels. Basolateral calcium extrusion is an energetically uphill process using the sodium and voltage gradient (secondary active) and direct coupling to adesnosine triphosphate (ATP) hydrolysis (primary active). In the kidney, both Na+-Ca2+ exchange and Ca2+-ATPase supports basolateral efflux. In the intestine, only the Ca2+-ATPase is present. In the cell, several processes are in place to ensure protection of cytoplasmic calcium activity at acceptable levels including cellular calcium buffering proteins, negative feedback on apical entry, and organellar storage of calcium. The apical entry step in the intestine is mainly TRPV6, whereas in the kidney, TRPV5 predominates. The calcium-binding protein in the gut is calbindin-9K and in the renal distal nephron, it is calbindin-28K. |
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Paracellular calcium transport has two requisites: a paracellular ionic permeability to calcium and an electrochemical driving force (Δμ) for calcium (see Fig. 37-10 ). In this mode, calcium never traverses the intracellular compartment. Various other cation and anion transport pathways will provide the shunt to complete charge movement. Transcellular calcium transport is more complex and requires apical entry pathways, primary and secondary active basolateral extrusion mechanisms, and most important of all, means to prevent killing the cell with calcium overload. The apical entry step for calcium is down the electrochemical gradient (chemical 104 M; electrical 70 mV) so all that is required is a calcium channel. In the intestine, this is transient receptor potential vallinoid (TRPV) 6, and in the kidney, it is TRPV5 with some contribution from TRPV6.[268] TRPs are members of a large superfamily of channels with diverse functions.[270] By the same analysis, basolateral calcium extrusion is an energetically uphill process that requires primary coupling to ATP hydrolysis (plasma membrane calcium pump PMCA1b) and secondary active transport (Na+-Ca2+ exchanger; NCX1).[268] Intercalated between these two membranes is a host of processes in the cytoplasm that shield the cell from calcium overload. Free Ca2+ feeds back negatively to shut off apical calcium entry.[268] The calbindin molecules cater not only a diffusible carrier function for calcium but also buffer free calcium to keep it low. Organellar storage of calcium also contributes to keeping cytosolic calcium activity at the physiologic range while transcellular flux is high. Very little is known about the nature of regulation of paracellular calcium permeability except that in the thick ascending limb, claudin-16 appears to confer calcium permeability.
Intestinal Calcium Transport
Figure 37-11 shows intestinal transport resolved into a saturable component with Michaelis-Menton substrate kinetics (red) that represents transcellular transport and a nonsaturable linear component (blue) that represents paracellular transport. [271] [272] The transcellular process is clearly active in the duodenum and proximal jejunum, whereas the paracellular process predominates in the distal jejunum and ileum. [272] [273] The chime, however, spends proportionately more time in the distal than the proximal small bowel. A full discussion of intestinal calcium absorption is beyond the scope of this chapter. A few highlights relevant to kidney stone disease are provided.
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FIGURE 37-11 Intestinal calcium transport. Transcellular route is saturable and regulated by 1,25(OH)2-vitamin D3 and dietary calcium, whereas paracellular transport is driven solely by electrochemical gradients. The availability of calcium in the lumen is determined largely by formation of calcium complexes. Axial differences exist for the relative proportion of these two transport modes from proximal to distal small bowel. |
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The single most important hormone that regulates intestinal calcium transport is 1,25-(OH)2-vitamin D3. It has been estimated that 80% to 90% of the intestinal transport is regulated by 1,25-(OH)2-vitamin D3,[272] which increases the apical calcium channel. [274] [275] One modeling effort predicted that for luminal calcium concentration ranging from 1 to 150 μM, 99% and 94% of transcellular calcium flux is carried by calbindin-D9K[276] respectively. Calbindin-D9K is up-regulated by 1,25-(OH)2-vitamin D3. [277] [278] [279] The extrusion step is also vitamin D dependent but it has been questioned as to whether it is rate limiting. [276] [279] [280] The role of heightened 1,25-(OH)2-vitamin D3 bioactivity in the intestine in absorptive hypercalciuria is discussed later.
Another pivotal regulator of calcium absorption is luminal calcium. First of all, the ionic milieu of luminal calcium is extremely important in affecting its transport. Only free ionized calcium can be absorbed but not the soluble, and definitely not the insoluble complexes. High concentrations of phosphate accompanying high pH will retard calcium absorption. Carbonate and bicarbonate salts of calcium are also prevalent in high pH environments and are highly insoluble. Calcium oxalate interaction, which is a major component of kidney stones, also occurs in the intestinal lumen. Dietary calcium can affect oxalate absorption, and likewise, dietary oxalate can affect calcium absorption. Because calcium complexation is an equilibrated process, the continuous removal of calcium from the lumen through high-affinity transport processes will create a dysequilibrium situation in which complexed calcium can be released and be available for absorption.
Calcium flux across the intestine is regulated by acute luminal load as well as an adaptation to chronic changes in dietary calcium. Increasing luminal load of calcium is accompanied by an increase in calcium absorption, but the process is not linear. [220] [281] In the intact organism, as the acute oral calcium load increases, the percentage absorption decreases such that a near-plateau effect of absolute absorption is reached.[281] This is mostly likely mediated by reduction in transcellular calcium transport. A similar phenomenon is observed in the isolated perfused duodenal loops. When loops were infused with 1 μM, 25 μM, and 100 μM of calcium, 90%, 30%, and 15% of the load is absorbed in 20 minutes, respectively.[271] In the chronic setting, when food is high in calcium, the transcellular pathway is down-regulated, and conversely, when dietary calcium is low, transcellular calcium transport is up-regulated.[272] A significant part of this effect is mediated by changes in 1,25-(OH)2-vitamin D3 and its effect on the calcium-transporting epithelial cell.[271] It is unknown if the calcium-sensing receptor regulates calcium transport by the gastrointestinal tract. Some have postulated that the ability of organic molecules such as polyamines and L-amino acids to activate the calcium-sensing receptor may provide potential mechanisms by which diet can modify calcium gut absorption.[282]
Renal Calcium Transport
Renal calcium transport is covered in detail in Chapters 5 and 16 and receives limited attention in this chapter with emphasis focusing on concepts important for understanding the pathophysiology of hypercalciuria. Ionized and complexed calcium in the plasma are freely filtered (approximately 60% of total calcium), and up to 90% of calcium is reabsorbed in the proximal tubule and thick ascending limb ( Fig. 37-12 ). Although there are hormonal actions on proximal tubule and thick limb calcium transport, the most important regulator of proximal calcium flux is sodium and fluid absorption. In states of high sodium intake, proximal sodium and water reabsorption is decreased and calcium reabsorption decreases accordingly.[237] In the thick ascending limb, calcium transport is driven by the luminal positive voltage generated by potassium uptake by the Na+-K+-2Cl- cotransporter-apical potassium channel ensemble. Inhibition of this mechanism by high plasma calcium concentration is mediated by the basolateral calcium sensing receptor.[283] Inhibition of the apical membrane potassium entry-recycling ensemble either by natriuretics or genetic lesions reduces calcium absorption and increases calciuria. The thick ascending limb is one locale where one of the proteins mediating paracellular calcium transport has been identified. Inactivating mutations of claudin-16 (paracellin) impairs calcium transport in the thick ascending limb.[284]
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FIGURE 37-12 Renal calcium transport. Calcium transport by the proximal tubule and thick ascending limb are high capacity and occurs primarily through the paracellular route. The driving force in the proximal tubule is primarily chemical, owing to luminal concentration of calcium from isotonic water and solute absorption. In the thick ascending limb, it is mostly electrical due to luminal diffusion potential generated by potassium. The distal nephron (distal convoluted tubule, connecting tubule, and collecting duct) has much lower transport capacity, but transepithelial calcium movement proceeds by means of the transcellular mechanisms. |
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Contrary to the proximal tubule and ascending limb, distal calcium transport is dissociated from sodium transport.[285] In the distal nephron, calcium is transported exclusively through transcellular mechanisms, as illustrated in Figures 37-10, 37-12, and 37-13 [10] [12] [13]. There are numerous regulators of distal renal calcium transport, which includes PTH, the calcium-sensing receptor, and 1,25-(OH)2-vitamin D3. [268] [282] [285] [286] [287] The mechanisms by which these hormones regulate distal calcium transport are not fully understood. More detailed discussion can be found in Chapter 5 .
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FIGURE 37-13 Gating of distal apical calcium channel TRPV5 by luminal and cell pH. Top panels show that the current carried by TRPV5 is inhibited by low pH both from the luminal and cellular side. The bottom panels show that luminal inhibition by H+ can be sensitized by cellular H+and vice versa. |
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From the point of view of nephrolithiasis, an important cause of hypercalciuria is acid loading whether this load causes detectable systemic metabolic acidosis or not. In the clinical setting, the most common scenario is acid load from dietary protein. Although there are non-acid-related components that can lead to hypercalciuria, the acid effects are best studied.[288] The hypercalciuria likely results from a combination of increased gut absorption, increased bone calcium release, and renal leak with potential actions on the proximal tubule, thick ascending limb, and distal tubule.[288]
One aspect of the physiology of distal calcium transport is the direct gating of the TRPV5 channel by both luminal and intracellular pH. Figure 37-13 summarizes the data from Yeh, Huang, and associates, who defined the pH sensitivity of the TRPV5 channel. [289] [290] TRPV5 activity is inhibited by H+ from both the luminal and intracellular side of the channel. In addition to this bilateral direct pH gating, luminal acidification synergizes gating by intracellular acidification and likewise, intracellular acidification sensitizes the effect of luminal pH. This enables conditions that either acidify the lumen or the cell in the distal tubule to independently and synergistically contribute to hypercalciuria.
Bone Resorption
Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total body calcium. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [38] The source of this additional urine calcium almost certainly is the skeleton, which is by far the largest repository of calcium in the body. [258] [259] [260] Idiopathic hypercalciuria has been associated with markers of increased bone turnover. [133] [291] [292] Urinary hydroxyproline is increased in unselected patients with idiopathic hypercalciuria,[291] and serum osteocalcin levels are elevated in stone formers who have a defect in renal tubule calcium reabsorption but not in those with excessive intestinal calcium absorption.[133] Bone turnover studies with 47Ca confirm the increased formation and resorption.[293] Cytokines known to increase bone resorption have also been shown to be elevated in patients with idiopathic hypercalciuria (IH). [294] [295] [296] [297] Pacifici and colleagues[294] have shown that interleukin-1 (IL-1) is elevated in the monocytes of patients with fasting hypercalciuria but not in those with excessive intestinal calcium absorption. Weisinger and co-workers[295] confirmed the elevation in IL-1 and also demonstrated that IL-6 and tumor necrosis factor-α were elevated. These observations have been confirmed by others. [296] [297]
A number of studies using a variety of methods including radiologic densitometry, quantitative CT, dual-energy x-ray absorptiometry and single-photon absorptiometry confirm that patients with nephrolithiasis have a generally mild reduction in BMD compared with matched controls. [22] [23] [153] [223] [258] [297] [298] [299] [300] [301] Pietschmann and colleagues[223] found lower spinal BMD in hypercalciuric compared with normocalciuric patients. Jaeger and associates[298] found that stone formers were slightly shorter and had a significantly lower BMD at the tibial diaphysis and the tibial epiphysis compared with controls. Giannini and co-workers[299] found that 49 recurrent stone formers with idiopathic hypercalciuria had a lower lumbar spine Z-score than normal controls. Silva and colleagues[297] examined bone formation and resorption parameters in 40 stone formers and classified 10 as osteopenic. Tasca and associates[300] found a more negative Z-score in L1 to L2 in hypercalciuric patients than in controls. After adjusting for a large number of variables an analysis of the third National Health and Nutrition Examination Survey (NHANES III) demonstrated that men with a history of kidney stones have a lower femoral neck BMD than those without a history of stones.[302] An analysis of almost 6000 older man again demonstrated an association of kidney stones with decreased BMD.[303]
Bone mineral density is correlated inversely with urine calcium excretion in both men[304] and women.[305] This relationship was confirmed in stone formers but not in non-stone formers.[260] Stone formers have been shown to have an increased risk of fractures. [302] [306] In NHANES III there was an increased risk of wrist and spine fractures in stone formers,[302] and in a retrospective analysis, stone formers had an increased incidence of vertebral fractures but not fractures at other sites.[306]
Synthesis of the Pathophysiology
Excess urine calcium excretion is most likely to occur when there is dysregulation of calcium transport at sites of substantial calcium fluxes, which are the intestine, kidney, and bone. [17] [22] [39] [257] [307] Increased intestinal calcium absorption may be mediated either by direct enhanced calcium absorption or through excess 1,25(OH)2D3-mediated calcium absorption. Decreased renal mineral reabsorption of either calcium of phosphorus, the latter through a hypophosphatemia-induced increase in 1,25(OH)2D3, will also lead to hypercalciuria. Enhanced bone mineral dissolution also increases serum calcium, suppresses PTH, and results in hypercalciuria. Each result in hypercalcemia and an increased filtered load of calcium, which, in conjunction of a calcium induced suppression of PTH, results in hypercalciuria.
Although we use ion and hormone measurements to help differentiate between these alternative mechanisms, we must realize that small changes from the normal range may be well beyond our ability to detect owing not only to our failure to measure precisely but to excellent homeostatic control mechanisms. We must often stress the system, perhaps by withholding a particular ion such as calcium, as noted earlier, to better understand mechanisms. Even then, it is likely that given the polygenic nature of hypercalciuria, dysregulation at multiple sites may be involved to pro-duce the phenotype. [43] [117] [307]
Increased Intestinal Calcium Absorption
With the ingestion of calcium, a primary increase in intestinal calcium absorption will result in an increase in postprandial serum calcium, resulting in a decrease in the serum levels of PTH and 1,25(OH)2D3. The filtered load of calcium will increase, which in the presence of decreased PTH induced tubular calcium reabsorption, will result in hypercalciuria. With fasting, serum and urine calcium move into the normal range because the intestine no longer contains adequate calcium for the excess absorption to be manifest; a low-calcium diet produces the same effect.
With an excess of 1,25(OH)2D3, intestinal calcium increases, as does serum calcium, but PTH will again fall. After an overnight fast, urine calcium remains elevated because excess 1,25(OH)2D3 stimulates bone resorption. Serum calcium and phosphorus remain normal to elevated depending on the subtle interplay of renal tubule calcium reabsorption and bone mineral resorption. On a low-calcium diet, with excess 1,25(OH)2D3, urine calcium excretion will remain elevated due to bone resorption.
Decreased Renal Tubule Mineral Reabsorption
A defect in renal calcium reabsorption directly leads to hypercalciuria, which is maintained by the subsequent fall in serum calcium and an increase in serum PTH and 1,25(OH)2D3, the latter leading to increased intestinal calcium absorption. The increase in urine calcium excretion persists after an overnight fast or while consuming a low-calcium diet.
A defect in renal phosphorus reabsorption decreases serum phosphorus and stimulates an increase in serum 1,25(OH)2D3, leading to enhanced calcium absorption and an increase in the filtered load of calcium, which in the presence of a calcium-induced suppression of PTH, results in hypercalciuria.
Enhanced Bone Demineralization
Enhanced bone demineralization leads to an increase in serum calcium concentration and an increase in the filtered load of calcium, which in the presence of a calcium-induced decrease in PTH, results in hypercalciuria.
These predictions of hormone and ion levels directly lead to testable hypotheses ( Table 37-6 ). Intestinal calcium absorption is low only with enhanced bone resorption. Serum PTH should be elevated and fasting serum calcium suppressed only with a defect in renal calcium reabsorption, and fasting serum phosphorus should be depressed only with a defect in renal phosphorus reabsorption. On a low-calcium diet, fasting urine calcium excretion normalizes only with a direct increase in intestinal calcium absorption.
TABLE 37-6 -- Predictions of Alternative Mechanisms for Hypercalciuria
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Increased Intestinal Calcium Absorption |
Decreased Renal Reabsorption |
Increased Bone Resorption |
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Parameter |
Direct |
1,25(OH)2D3 |
Calcium |
Phosphorus |
|
|
|
Ca Absorption |
Primary ↑ |
↑ |
↑ |
↑ |
↓ |
|
|
S 1,25(OH)2D3 |
↓ |
Primary ↑ |
↑ |
↑ |
↓ |
|
|
S PTH |
↓ |
↓ |
↑ |
↓ |
↓ |
|
|
Bone Ca |
nl |
nl to ↓ |
nl to ↓ |
nl to ↓ |
Primary ↓ |
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|
Fasting SCa |
nl |
nl to ↑ |
↓ |
nl to ↑ |
nl to ↑ |
|
|
Fasting SP |
nl |
nl to ↑ |
nl to ↑ |
↓ |
nl to ↑ |
|
|
Fasting UCa |
nl |
↑ |
primary ↑ |
↑ |
↑ |
|
|
UCa on LCD |
nl |
nl to ↑ |
↑ |
nl to ↑ |
↑ |
|
|
S, serum; U, urine; Ca, calcium; P, phosphorus; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; PTH, parathyroid hormone; LCD, low calcium diet; ↑, increased; nl, normal; ↓, decreased. |
Human Data to Support Alternate Mechanisms
Pak and colleagues developed an outpatient protocol to distinguish between reduced renal tubule calcium reabsorp-tion (renal hypercalciuria) and increased intestinal calcium absorption (absorptive hypercalciuria). [46] [221] [308]Patients are placed on a low-calcium diet (400 mg calcium and 100 mEq NaCl per day). After 7 days, a 24-hour urine is collected. Fasting urine calcium excretion is measured and again after a 1-gm oral calcium load. Renal hypercalciuria is defined as an elevated fasting urine calcium level (>0.11 mg/100 mL glomerular filtration) and an elevated PTH level. Absorptive hypercalciuria is divided into two groups: Group I is defined as normal fasting urine calcium, elevated urine calcium after the oral calcium load, normal PTH, and hypercalciuria on the calcium-restricted diet. Group II is similar except for normal urinary calcium on the calcium-restricted diet. In 241 consecutive stone-forming patients, they found 24% with group I absorptive hypercalciuria, 30% with group II absorptive hypercalciuria, and 8% with renal hypercalciuria.[308]
Parathyroid Hormone.
Several studies have demonstrated an elevated PTH in hypercalciuric stone formers, strongly suggesting the mechanism of decreased renal tubule calcium reabsorption. [309] [310] However in most studies, fasting PTH levels are not elevated in the majority of patients, and some are even low, suggesting that most patients do not have decreased tubule calcium reabsroption. [153] [309] [310] [311] [312] Bataille and colleagues[153] found that only 1 of 42 patients with idiopathic hypercalciuria had fasting hypercalciuria and an elevated PTH, again suggesting that this subtype of idiopathic hypercalciuria is unusual. However, most of these studies were done before assays specific for the biologically intact hormone were perfected.
Calcitriol.
Serum levels of 1,25(OH)2D3 in patients with idiopathic hypercalciuria have been measured in a number of studies. [21] [153] [258] [259] [311] [313] [314] [315] [316] [317] In general, the levels are elevated, suggesting either a primary increase in calcitriol leading to hypercalciuria or a secondary response to decreased tubule reabsorption of calcium or phosphorus. Elevated levels of calcitriol are inconsistent with enhanced bone resorption as a primary mechanism for hypercalciuria. The elevated levels of calcitriol suggest that enhanced intestinal calcium absorption is responsible for hypercalciuria in the majority of patients with idiopathic hypercalciuria, which is consistent with the data of Pak and co-workers.[308]
Excess Urinary Phosphorus.
Nine of 59 members of a Bedouin tribe had hypophosphatemic rickets, elevated levels of calcitriol, hypercalciuria, and hyperphosphaturia.[318] Almost half of the remaining patients had idiopathic hypercalciuria with a mild reduction in levels of serum phosphate and a mild increase in levels of calcitriol, indicating that a loss of urinary phosphate could be associated with hypercalciuria. A polymorphism in the gene coding for the proximal tubule sodium phosphate cotransporter has been proposed to cause renal phosphorus wasting and hypercalciuria but the functional consequence of this polymorphism is unclear.[319] However, a recent study of 98 pedigrees with multiple hypercalciuric stone formers found that although variants of this gene are not rare, it did not appear to be associated with clinically significant renal phosphate or calcium-handling anomalies.[320]
Evidence of a Systemic Dysregulation of Calcium Transport
In an attempt to determine the mechanism of hypercalciuria, Coe and colleagues[258] studied 24 patients with idiopathic hypercalciuria and nine control subjects fed a low-calcium diet (2 mg/kg per day) for more than a week. There was no difference in serum calcium or in calcitriol levels; however, the hypercalciuric patients had a mild decrease in PTH levels. On this low-calcium diet, the controls excreted less calcium then they ingested, whereas 16 of the 24 hypercalciuric patients excreted more calcium than they consumed, indicating a probable loss of bone mineral. There was not a clear demarcation between those who retained calcium, suggesting enhanced intestinal calcium absorption, and those who lost calcium, suggesting a failure of the kidney to adequately reabsorb calcium. This smooth continuum in urine calcium excretion and in net calcium retention suggested that there were not specific, well-demarcated pathophysiologic etiologies of hypercalciuria. Furthermore, on some days, patients retained calcium and on others they lost calcium, suggesting that even in a carefully done clinical study, it was not possible to consistently place patients into defined groups. These data suggest that because patients cannot be accurately classified, the prescription of a diet low in calcium to those who you believe absorb excessive amounts of dietary calcium can potentially lead to a dangerous reduction of BMD, especially in women. [258] [259] [260] [321] Furthermone, a diet low in calcium promotes, rather than retards, stone formation. [230] [233]
Adams and co-workers[322] demonstrated that administering calcitriol to normal men on a normal or high-calcium diet led to an increase in both intestinal calcium absorption and urine excretion, in the absence of hypercalcemia, paralleling observations in patients with idiopathic hypercaliuria. When normal men were fed an extremely low-calcium diet, administration of calcitriol also led to an increase in intestinal calcium absorption and urine calcium excretion but also to a marked decrease in calcium retention,[323] which can only result from enhanced bone resorption. These studies indicate that critical physiologic aspects of idiopathic hypercalciuria can be modeled by calcitriol administration, suggesting that an excess of this hormone, or its activity, may be responsible, at least in part, for this clinical disorder.
As noted later, the genetic hypercalciuric rats, whose physiology closely parallels that of patients with idiopathic hypercalciuria, have an excess number of receptors for calcitriol. [257] [324] [325] [326] [327] [328] Recently, Favus and associates[329] have found that there is an increased number of vitamin D receptors in peripheral blood monocytes from male patients with idiopathic hypercalciuria, in the absence of elevated levels of calcitriol, compared with age-matched controls.
Thus, evidence points to a systemic dysregulation of calcium transport, rather than a specific organ-centered defect, in most patients with idiopathic hypercalciuria. That a small excess of calcitriol can mimic many aspects of this disorder suggests that slight excesses of this hormone, or its receptor, may be integral in the pathophysiology of idiopathic hypercalciuria.
Idiopathic Calcium Oxalate Stones: Site of Initial Solid Phase
One must distinguish among calcium oxalate stone formers. A vast majority of such patients form their stones with no systemic disorders apart from genetic, or idiopathic, hypercalciuria. These are usually named idiopathic calcium oxalate stone formers, and this section concerns them. Patients with hyperparathyroidism, obesity bypass surgery, sarcoidosis, hyperthyroidism, primary hyperoxaluria, and many other systemic disorders of calcium or oxalate metabolism can form calcium oxalate stones, and the mechanisms responsible may not be the same as for idiopathic calcium oxalate stone formers.
Calcium oxalate stones appear to grow on the renal papillae, detach, and then pursue their clinical course of growth and passage.[120] The attachment site is always over interstitial deposits of apatite named Randall plaque after the person who first described it. [115] [330] Plaque appears to form in the basement membranes of the thin loops of Henle ( Fig. 37-14 ) as myriads of microparticles in which apatite crystals and organic layers alternate in tree-ring fashion.[121] In the interstitium, individual plaque particles fuse, forming a lake of organic material with floating islands of crystal.[118] At least one component of the organic layer is osteopontin, which localizes at the apatite crystal surface.[118] Plaque makes its way to the suburothelial layer, and it is over this plaque accumulation that CaOx stones appear to form (see Fig. 37-14 ).
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FIGURE 37-14 Endoscopic and histologic images of Randall plaque in idiopathic calcium oxalate stone formers. A, An example of a papilla from a CaOx-stone former that was video recorded at the time of their percutaneous nephrolithotomy for stone removal. Several sites of Randall plaque (arrows) are noted as irregular white areas beneath the urothelium. Two small stones (asterisks) appear attached sites of Randall plaque. B, A low-magnification light microscopic image of a papillary biopsy specimen show numerous sites of calcium deposits (arrow) stained black by the Yasue metal substitution method for calcium histochemistry. The calcium deposits are surrounding several ducts of Bellini. C, The initial sites of calcium deposits (arrows) by light microscopy to be localized to the basement membranes (BM) of the thin loops of Henle deep within the inner medulla. These deposits then appear to form in the interstitial space, and along with the deposits in the BM, they migrate to the papillary tip to be positioned beneath the basal surface of the urothelial cells, as seen in B. D, A high-magnification transmission electron micrograph showing immunogold label indicating osteopontin localization at the interface of the crystalline material and organic layer of a single crystal found in the BM of a loop of Henle. The insert in D shows the multiple layers of crystal and matrix material that form a single crystal. E and F, show osteopontin localization (arrows) in the crystalline material found in the interstitial space. Magnification, ×600 (B); ×1100 (C); ×50,000; ×35,000 (E); ×14,000 (F). (All plates courtesy of Andrew P. Evan, PhD, Department of Anatomy and Cell Biology, Indiana University School of Medicine.) |
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The abundance of plaque, which can be quantified using intraoperative imaging, varies with urine calcium excretion ( Fig. 37-15 ) and inversely with urine pH and volume.[122] A multivariable score using volume and calcium excretion, and one using all three variables account for increasing fractions of the variation in plaque abundance (lower panels on Fig. 37-15 ). Although the details of the physiology remain to be elucidated, these findings suggest that plaque is fostered by calcium concentrations, in the loop fluid or interstitium that are themselves increased by water conservation and increased movement of calcium through the nephron. That plaque abundance varies inversely with urine pH suggests that it is fostered by interstitial fluid alkalinity, because collecting duct cells must tend to increase medullary interstitial pH as they lower the pH of the final urine.
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FIGURE 37-15 Pathophysiologic correlates of interstitial plaque abundance. The fraction of papillary surface occupied by plaque, as quantified by intraoperative imaging (y-axes of all five panels) varies with urine calcium excretion (upper left panel) and inversely with urine volume and pH (upper middle and left panels). Multivariable scores using volume and calcium excretion, or all three variables (lower panels), correlate strongly with plaque abundance. (Adapted from Kuo RL, Lingeman JE, Evan AP, et al: Urine calcium and volume predict coverage of renal papilla by Randall's plaque. Kidney Int 64:2150–2154, 2003.) |
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It is unclear why the initial solid phase forms in distinct locations and why the initial crystals apparently are only calcium phosphate.[331] The basement membrane of the thin limb appears an unlikely site for the initial crystallization in patients with idiopathic hypercalciuria. It is not the vectorial transport of either calcium or phosphorus,[332] and because the transtubular permeabilities of these ions are extremely low,[332] it is difficult to link supersaturation within the thin limbs[102] to the surrounding interstitium. However, the thin limbs are in very close proximity to the vasa recta and the collecting ducts, and all are situated in a highly concentrated, hypertonic environment. One could hypothesize the following sequence of events, which might lead to increased supersaturation and subsequent crystal formation.[331] Following ingestion and absorption of dietary calcium, the renal filtered load of calcium increases, resulting in increased tubular calcium concentration.[5] The medullary countercurrent mechanism concentrates the calcium extracted from the thick ascending limb into the hypertonic papilla. The vasa rectum, also with an increased calcium concentration, does not readily remove calcium from the interstitium. The increased serum calcium stimulates the calcium receptor and decreases reabsorption of water in the collecting duct,[333] further concentrating the hypertonic interstitium. Vectorial proton transport into the collecting duct alkalinizes the interstitium. The pH of the vasa recta also increases following gastric proton secretion, the so-called “alkaline tide,” resulting in less bicarbonate removal from the medullary interstitium. The increased pH leads to a decrease in the solubility of calcium phosphate complexes. Local collagen fibrils might provide the initial nucleating sites, allowing for heterogeneous nucleation, which occurs with a lower degree of supersaturation than homogeneous nucleation. Future studies will be necessary to test these speculative hypotheses.[331]
Pharmacologic Treatment
Thus far, seven prospective trials have been published. For patients with idiopathic hypercalciuria and calcium stones, three trials have employed thiazide-type agents ( Fig. 37-16 ): chlorthalidone,[334] indapamide,[335] and hydrochlorothiazide.[336] Another prospective, randomized open trial showed the greater benefit of a high-calcium, reduced-sodium, and reduced-protein diet versus a low-calcium diet.[233] For those with low urine citrate, oral potassium citrate [144] [145] has proven effective. A third trial, however, did not show an effect.[146] Finally, for those with hyperuricosuria and calcium stones, allopurinol was effective in a single controlled double-blind trial.[337] In this figure, the number of patients who completed the trial is shown on the x-axis; the number with a recurrence while on treatment is shown on the y-axis. The remarkable elevation of the placebo points (filled symbols) above the gray points (active drugs) gives a strong visual image of the rather notable treatment effects.
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FIGURE 37-16 Summary of prospective treatment trials. Numbers of patients who finished the trial (x-axis) overlap for placebo (dark circles) and active drug groups (light circles), but among those receiving active drug, fewer formed a new stones with treatment (y-axis). CTD, chlorthalidone 25 mg daily, 73 people entered[334]; Ctz, hydrochlorothiazide 25 mg twice daily, 50 people entered[336]; Ind, indapamide, 2.5 mg daily, 75 people entered[335]; Cit1, potassium citrate 30-60 mEq daily, 55 people entered[144]; Cit 2 potassium magnesium citrate 60 mEq daily, 64 people entered[145]; Cit 3, potassium citrate, variable dose, 50 people entered[146]; Allo, allopurinol 300 mg daily, 62 entered[337]; diet, low-calcium diet (dark circles) verusus high-calcium, reduced-protein, and reduced-sodium diets (light circles), 120 entered.[233] All trials are 3 years in duration, except for the diet study (5 years). |
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Genetic Causes of Hypercalciuria
The genetics of human kidney stones was discussed earlier. This section addresses specifically genetic causes of hypercalciuria. A comprehensive review of this topic is beyond the scope of this chapter. The reader is referred to several recent reviews that cover the genetics of hypercalciuria in humans and animals in more detail. [257] [269] [338] [339] [340]
Several general concepts deserve attention in the consideration of the genetics of hypercalciuria. Hypercalciuria is not an “on-off” phenotype but rather a continuous variable not unlike body weight and blood pressure. Although all clinical laboratories have utilitarian quantitative definitions of hypercalciuria to facilitate practitioners to care for patients, there is still no true and universally accepted single cut-off value for hypercalciuria. The conventional usage of the term hypercalciuria in clinical and scientific parlance should carry these notions in mind. Hypercalciuria can result from primary genetic lesions in the intestine (hyperabsorption), bone (resorption), kidney (renal leak), and as noted earlier, may often result from a combination of the three. The underlying pathophysiology is extremely varied and complex. Regardless of the pathophysiologic mechanism, the genetic cause of hypercalciuria can be monogenic or polygenic in origin. Furthermore, the impact of any genetic factor is heavily affected by environmental influence. In addition, even considering just the genetic component, no one gene can singularly monopolize urinary calcium excretion to the exclusion of other. Modifier genes always have to be considered. Hypercalciuria is a penultimate complex trait with polygenic and multiple nongenetic determinants.[341] There is loci heterogeneity among different individuals with polygenic hypercalciuria. It is overwhelmingly likely that sequences of genes that control calciuria cannot be definitively categorized into wild type versus mutant. There are likely multiple alleles with functional diversity that can influence the amount of calcium in the urine.
Table 37-7 lists the monogenic causes of hypercalciuria.[269] This table illustrates the immense complexity and diversity of lesions that can cumulate in hypercalciuria. Even in the simplified scenarios in which only monogenic lesions are singled out, the list is formidable one with diverse pathophysiology. These conditions can lead to absorptive, resorptive, or renal hypercalciuria, or a combination of the above. Table 37-8 summarizes some animal models that have been shown to cause hypercalciuria. Akin to the human monogenic diseases, hypercalciuria can result from a myriad of single gene defects. In fact, in a number of these instances, hypercalciuria emerged as an unanticipated finding.
TABLE 37-7 -- Monogenic Hypercalciuria in Humans
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Disease |
OMIM |
Gene/Gene Product |
Phenotype |
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Renal |
Gastrointestinal |
Bone |
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Dent's Disease (X-linked recessive nephrolithiasis, X-linked hypophosphatemic rickets, low-molecular weight proteinuria) |
300009 |
CLC5/Chloride channel 5 |
Hypercalciuria. Hyperphosphaturia. Tubular proteinuria. Fanconi syndrome. Nephrocalcinosis, Renal calculi. |
Rickets |
|||||||||||||
|
Lowe oculocerebrorenal syndrome |
309000 |
OCRL/Inositol polyphosphate 5 phosphatase |
Hypercalciuria. Aminoaciduria. Phosphaturia. Fanconi syndrome. Nephrocalcinosis. Renal calculi. |
Vitamin D-resistant rickets |
|||||||||||||
|
Bilateral macular coloboma with hypercalciuria |
248190 |
Unknown probably autosomal recessive |
Hypercalciuria |
||||||||||||||
|
Wilson disease |
277900 |
ATP7B/copper-transporting ATP-ase |
Hypercalciuria, renal calculi, hyperphosphaturia, partial fanconi, syndrome, proteinuria, distal tubular acidosis |
Liver disease |
Osteoporosis |
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|
Tyrosinemia type 1 |
276700 |
FAH/fumarylaceto-acetase |
Hypercalciuria, Fanconi syndrome, nephrocalcinosis, renal calculi |
Hepatomegaly, liver disease |
Rickets |
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|
Glycogen storage disease type 1a |
232200 |
G6PC/glucose-6-phosphatase |
Hypercalciuria, Fanconi syndrome, hypocitraturia, nephrocalcinosis, proteinuria |
Hepatomegaly, poor growth, hypoglycemia |
Osteopenia, fracture |
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|
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis |
248250 |
PCLN-1/paracellin-1 or claudin 16 |
Hypercalciuria, magnesium wasting, nephrocalcinosis |
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|
Bartter syndrome: |
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|
Type 1 |
601678 |
NKCC2/sodium-potassium-chloride co-transporter |
Hypercalciuria, nephrocalcinosis, metabolic alkalosis |
Osteopenia |
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Type 2 |
241200 |
ROMK/Renal outer-medullary potassium channel |
Hypercalciuria, nephrocalcinosis, metabolic alkalosis |
Osteopenia |
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|
Type 3 |
607364 |
CLC-Ka-β Chloride channels |
Less severe hypercalciuria. No nephrocalcinosis |
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Type 4 |
602522 |
Barttin |
Congenital deafness |
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Overlap between autosomal dominant hypocalcemia and Bartter syndrome |
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Type 5 |
601199 |
CaSR/Calcium-sensing receptor |
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Autosomal-dominant Hypocalcemia |
601198 |
CaSR/Calcium-sensing receptor (activating mutations) |
Hypercalciuria |
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Familial isolated hypoparathyroidism |
146200 |
|
Hypercalciuria |
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Familial hypertensive hyperkalemia or pseudohypoaldosteronism type 2 |
145260 |
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|
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Renal tubular acidosis: |
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|
267300 |
ATP6V1B1 / V-ATP-ase, beta subunit |
Nephrocalcinosis, hypercalciuria |
Hyperabsorption |
Acidosis-related bone resorption |
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|
602722 |
ATP6V0A4 / V-ATP-ase, alpha subunit |
Nephrocalcinosis, hypercalciuria |
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179800 |
SLC4A1 / Anion exchanger |
Nephrocalcinosis, renal stones |
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259730 |
CAII / Carbonic anhydrase II |
Nephrocalcinosis, urolithiasis |
Osteopetrosis, brain calcifications |
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Liddle syndrome |
177200 |
SCNN1B and SCNN1G / epithelial sodium channel, beta and gamma subunits |
Hypercalciuria and nephrocalcinosis |
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Congenital lactase deficiency |
223000 |
Unknown. Autosomal recessive. Locus linked to 2q21 |
Hypercalciuria, nephrocalcinosis, Hypercalcemia |
|
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Congenital sucrase-isomaltase deficiency |
222900 |
SI / Sucrase-isomaltase |
Hypercalciuria, Nephrocalcinosis, Hypercalcemia |
Hyperabsorption, Chronic diarrhea, failure to thrive |
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Glucose / Galactose malabsorption |
606824 |
SLC5A1 / Sodium-glucose cotransporter |
Hypercalciuria, renal calculi, nephrocalcinosis hypercalcemia, glucosuria |
Severe diarrhea |
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|
Blue diaper syndrome |
211000 |
Unknown. Autosomal- recessive or X-linked. Possibly SLC16A10 / T-type aminoacid transporter |
Hypercalciuria, nephrocalcinosis, hypercalcemia, indicanuria |
Defect in intestinal tryptophan transport |
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Hypophosphatemia and absorptive hypercalciuria (type 3) |
182309 |
SLC34A1/NPT2A/Sodium-phosphate cotransporter IIa |
Phosphate wasting, hypercalciuria, renal calculi |
Vitamin D-mediated calcium hyperabsorption |
Osteoporosis |
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Hereditary hypophosphatemic rickets with hypercalciuria |
241530 |
SLC34A3/NPT2C/odium phosphate cotransporter |
Phosphate wasting, hypercalciuria |
Vitamin D-mediated calcium hyperabsorption |
Rickets/osteomalacia |
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Williams-Beuren syndrome (not monogenic) |
194050 |
|
Hypercalciuria |
Calcium hyperabsorption |
Rickets |
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Hyperabsorptive hypercalciuria (not monogenic) |
607258 |
4q33-qter deletion |
Hypercalciuria, nephrocalcinosis |
Calcium hyperabsorption |
Facial and skeletal abnormalities |
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|
Down syndrome (not monogenic) |
190685 |
Trisomy 21 |
Hypercalciuria |
Calcium hyperabsorption |
Low mineral bone density |
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|
Osteogenesis imperfecta type 1 |
166200 |
COL1A1 and COL1A2/collagen type 1, alpha 1 and 2 |
Hypercalciuria |
Fractures |
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|
MEN1 syndrome with hyperparathyroidism |
131100 |
MEN1 / Menin |
Hyperparathyroidism, with hypercalciuria, nephrocalcinosis, renal stones. |
Increased bone turnover |
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|
Neonatal self-limited primary hyperparathyroidism |
239199 |
Gene unknown. Autosomal recessive |
Hypercalciuria, nephrocalcinosis, renal tubular acidosis |
Increased bone turnover |
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|
Metaphysal chondrodysplasia jansen type |
156400 |
PTHR / Parathyroid hormone receptor-1 |
Hypercalciuria. Hyperphosphaturia, high urinary cAMP |
High bone resorption with metaphyseal deformitites |
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|
Infantile hypophosphatasia |
241500 |
ALPL / Alkaline phosphatase |
Hypercalcemia, hypercalciuria, nephrocalcinosis |
Rickets, craniosynostosis |
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|
McCune-Albright syndrome |
174800 |
GNAS1 / guanine nucleotide binding protein (G protein), α-stimulating activity polypeptide 1 |
Hypercalciuria, nephrocalcinosis, hyperphosphaturia |
Fibrous dysplasia, rickets. craniofacial/hyperostosis, deformity of femur. |
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|
Cystic fibrosis |
219700 |
CFTR / cystic fibrosis transmembrane conductance regulator |
Microscopic nephrocalcinosis, hypercalciuria |
||||||||||||||
|
Beta-thalassemia |
141900 |
HBB / beta globin |
Hypercalciuria, proximal, tubulopathy. |
Decreased bone mineral density, osteomalacia |
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|
Beckwith-Wiedemann syndrome |
130650 |
|
Hypercalciuria, nephrocalcinosis. |
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|
Phenylketonuria |
261600 |
PKU1/Phenylalanine hydroxylase |
Hypercalciuria |
Osteopenia |
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From Moe OW, Bonny O: Genetic hypercalciuria. J Am Soc Nephrol 16:729–745, 2005.
TABLE 37-8 -- Animal Models of Monogenic Hypercalciuria
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Gene |
Animal Model |
Phenotype |
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Renal |
Gastrointestinal |
Bone |
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CLC5 |
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NPT2 |
Mouse KO[629] |
Hypercalciuria, Hyperphosphaturia, Renal calcifications |
Higher alkaline phosphatase |
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|
Retarded secondary ossification |
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|
NHERF-1 |
Mouse KO[630] |
Male: Normal overall renal function, hypercalciuria, hyperphosphaturia, hypermagnesuria. |
Female: Bone fracture. 25%–30% reduced bone mineral density. 40% reduced bone mineral content. Low serum alkaline phosphatase |
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|
TRPV5 |
Mouse KO[631] |
Hypercalciuria, Hyperphosphaturia |
Increased intestinal calcium absorption |
Reduced trabecular and cortical thickness of bones |
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|
VDR |
Mouse KO [630] [632] |
Hypercalciuria on high-calcium and high-lactose diet |
Rickets |
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Calbindin-D28k |
Mouse KO |
Normocalciuria, Normocalcemia,[633] Hypercalciuria, [634] [635]Normocalciuria[636] |
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|
Calbindin-D28k and VDR |
Mouse double KO[637] |
Hypercalciuria, Hyperphosphaturia |
Reduced food intake |
Severe rickets |
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|
NKCC2 |
Mouse KO[638] |
Hypercalciuria, Polyuria Hydronephrosis, proteinuria |
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|
Caveolin-1 |
Mouse KO[639] |
Hypercalciuria in man, bladder stone. |
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|
AKr1b1 |
Mouse KO[640] |
Hypercalciuria, hypercalcemia, hypermagnesemia, increased urine volume and decreased urine osmolarity |
||||||||||||||
|
CaSR |
Chemical mutagenesis. CaSR activating mutation[641] |
Ectopic calcifications, no hypercalciuria by calcium/creatinine |
Ectopic calcifications |
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Although dissecting monogenic causes of hypercalciuria is of extreme importance, the real challenge is to identify loci in polygenic hypercalciuria. As discussed earlier, the effort in studying polygenic hypercalciuria in humans has received modest success. Most of the knowledge gained in this front comes from a genetic strain of rats created by Bushinsky and co-workers.[257]
Genetic Hypercalciuric Stone-Forming Rats
To help understand the mechanism of idiopathic hypercalciuria in humand, Bushinsky and colleagues have developed an animal model of this disorder. [173] [257] [325] [326] [327] [328] [342] [343] [344] [345] [346] [347] [348] [349] [350] [351] [352] [353] [354] [355] [356] [357] [358] Through more than 67 generations of successive inbreeding of the most hypercalciuric progeny of the most hypercalciuric Sprague-Dawley rats found in a large screening, they have established a strain of rats that excrete 8 to 10 times as much urinary calcium as controls whose excretion has not changed with time ( Fig. 37-17 ). Compared with the control rats, the genetic hypercalciuric rats absorb far more dietary calcium at lower levels of calcitriol, [257] [354] similar to observations in humans. [17] [22] The increase in intestinal calcium absorption is due to a significant increase in the mucosal to serosal (absorptive) calcium flux with no change in the serosal to mucosal (secretory) flux.[354] When the hypercalciuric rats are fed a diet essentially devoid of calcium, urinary calcium excretion remains significantly elevated compared with that of similarly treated controls, indicating a defect in renal tubule calcium reabsorption or an increase in bone resorption, or both,[353] again similar to observations in humans. [258] [359] Cultured bone from the hypercalciuric rats released more calcium than the bone of control rats when exposed to increasing amounts of calcitriol.[328] Administration of a bisphosphonate, which significantly inhibits bone resorption, to hypercalciuric rats fed a low-calcium diet significantly reduces urinary calcium excretion.[347] Using clearance studies, a primary defect in renal calcium reabsorption is observed.[348] Thus, these hypercalciuric rats have a systemic abnormality in calcium homeostasis; they absorb more intestinal calcium, they resorb more bone, and they do not adequately reabsorb filtered calcium ( Fig. 37-18 ). As each of the hypercalciuric rats forms renal stones, they have been called genetic hypercalciuric stone-forming (GHS) rats. [257] [344] The bone, kidney and intestine of the GHS rats have an increased number of vitamin D receptors, [324] [325] [327] [328] suggesting a potential mechanism for the hypercalciuria. As noted earlier in a recent clinical study, circulating monocytes from humans with idiopathic hypercalciuria were shown to have an increased number of receptors for calcitriol.[329]
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FIGURE 37-17 Urine calcium excretion in control rats (generation 0) and in subsequent generations of inbred genetic hypercalciuric stone-forming (GHS) rats. Values are mean ± SEM. Urine calcium excretion for all generations is greater than that observed in generation 0. (From Bushinsky DA, Frick KK, Nehrke K: Genetic hypercalciuric stone-froming rats. Curr Opinion Nephrol Hyperten 15:403–418, 2006.) |
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FIGURE 37-18 Dysregulation of calcium transport in the genetic hypercalciuric stone-forming (GHS) rats. Compared with control rats fed comparable dietary calcium (DCa), GHS rats have increased intestinal absorption of calcium (αCa), increased bone resorption (BrCa), and decreased renal reabsorption (frCa), resulting in increased urine calcium (UCa). (From Bushinsky DA, Frick KK, Nehrke K: Genetic hypercalciuric stone-froming rats. Curr Opinion Nephrol Hyperten 15:403–418, 2006.) |
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Primary Hyperparathyroidism
PTH has a critical role in regulating the level of serum calcium, and an elevation of PTH promptly and significantly increases blood calcium. Primary hyperparathyroidism is due to chronic, excess secretion of PTH, [5] [21] [360] and it, along with malignancy, are the two most common causes of hypercalcemia. [5] [21] Primary hyperparathyroidism is relatively common, with an incidence of 1 in 500 to 1 in 1000,[361] and it is associated with nephrolithiasis.[5] A single benign adenoma is present in 75% to 80% of patients, four-gland hyperplasia in approximately 20% of patients, and parathyroid carcinoma in less than 1% of patients. [362] [363]
The principle regulator of PTH secretion is the level of blood ionized calcium with increases leading to a fall in PTH. [364] [365] Calcium is sensed by the calcium-sensing receptor, which is a member of the G protein-linked receptor family with seven plasma membrane-spanning domains. [366] [367] [368] The PTH response to blood ionized calcium is sigmoidal in shape with the steepest portion of PTH secretion occurring in the physiologic range of calcium.[369]Each parathyroid cell secretes a minimal amount of PTH such that markedly enlarged glands secrete biologically significant amounts of PTH, even at elevated levels of blood ionized calcium.[364] Excess phos-phate inhibits PTH secretion directly and indirectly by lowering 1,25(OH)2D3 and thus serum calcium.[364] 1,25(OH)2D3 does not effect PTH secretion but does lower PTH gene transcription. [370] [371]
PTH increases blood calcium through increasing renal tubular calcium reabsorption, increasing bone resorption and increasing intestinal calcium absorption through increasing 1,25(OH)2D3. PTH increases renal tubular calcium reabsorption primarily in the distal convoluted tubule and connecting tubule; reabsorption in these segments is predominantly active, transcellular transport under hormonal regulation by PTH. [22] [372] [373] [374] [375] [376] [377] [378] [379] [380] [381] Here, calcium enters the cell at the apical surface through both facilitated diffusion and a dihydropyridine-sensitive calcium channel, which is stimulated by PTH. [377] [382] [383] The identity of the apical calcium channel in distal tubule remains somewhat controversial, although Trpv5 and TrpV6 are present. [383] [384] [385] [386] [387] Calcium then binds to the vitamin D-dependent calcium-binding protein, calbindin D28K, which serves as a shuttle to transport calcium across the cell. [375] [376] Basolateral calcium transport occurs through both NCX and Ca2+-ATPase (PMCA), which have been estimated to transport 70% and 30% of calcium, respectively. [388] [389]
PTH receptors are found on osteoblasts and osteoblast precursors but not on osteoclasts.[360] PTH administration increases both bone formation and bone resorption. Osteoclastic bone resorption is induced by expression of osteoblastic surface expression of macrophage colony-stimulating factor (M-CSF) and RANK ligand, which stimulate osteoclastic precursors into mature bone resorbing osteoclasts. [390] [391] [392] Continuous exogenous administration of PTH leads to net bone resorption, whereas intermittent administration can result in bone formation.[360] PTH does not directly effect intestinal calcium transport; however, it induces transcription of the 25-hydroxyvitamin D 1a hydroxylase gene, which stimulates the converstion of 25-(OH)D3 to 1,25(OH)2D3. [393] [394] 1,25(OH)2D3 leads to a substantial increase in intestinal calcium transport.[395]
Effect on Urine Calcium Excretion
In primary hyperparathyroidism, the elevation in serum calcium appears due, in large part, to the PTH-induced increased in distal tubular calcium reabsorption coupled with the increase in intestinal calcium absorption; bone reabsorption appears to play a minor role ( Fig. 37-19 ).[396] In spite of the action of PTH to increase renal tubular calcium reabsorption, primary hyperparathyroidism generally leads to an increase in urine calcium excretion.[397]However, urine calcium excretion appears to be lower at a similar level of serum calcium in patients with primary hyperparathyroism compared with those with hypercalcemia for other disorders such as bone metastasis, sarcoidosis, vitamin D intoxication, or myeloma. [396] [397] [398]
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FIGURE 37-19 Urinary calcium excretion as a function of serum calcium concentration in normal subjects (center solid line +/- 1 SD) and in patients with hypoparathyroidism (open circles) and with hyperparathyroidism (closed circles). (From Nordin BEC, Peacock M: Role of kidney in regulation of plasma-calcium. Lancet 2:1280–1283, 1969.) |
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Parks and associates[399] found that urine calcium excretion may be substantially elevated even in those patients who have slight elevations in serum calcium. In 48 stone-forming patients with documented hyperparathyroidism, 30 had mild hypercalcemia with serum calcium in the range of 10.1 to 11.0 mg/dL. Urine calcium excretion exceeded the upper limit of normal in the majority of patients. However, Pak and co-workers[400] could find no difference in levels of serum calcium, PTH, 1,25(OH)2D3, or urinary calcium in those hyperparathyroid patients who formed stones compared with those who did not.
The hypercalciuria observed in patients with primary hyperparathyroidism appears secondary to the increased filtered load of calcium and to the hypercalcemia activating the calcium-sensing receptor on the basolateral membrane of the thick ascending loop leading to a suppression of potassium secretion in the lumen, a decrease in the lumen positive charge, and thus a decrease in calcium reabsorption in this segment. [21] [307] [401]
The kidney stones in patients with primary hyperparathyroidism are composed of hydroxyapatite, calcium oxalate, or brushite.[402] Pak and colleagues[403] have found that as the phosphate content of the stones increased from calcium oxalate to mixed calcium oxalate-calcium apatite and finally to calcium apatite the percentage of patients with primary hyperparathyroidism increases from 2% to 10%. Some patients, for unknown reasons, present with nephrocalcinosis.
Diagnosis
With the advent of routine measurements of blood chemistry, the majority of patients with primary hyperparathyroidism are diagnosed incidentally, that is, without overt signs and symptoms of hypercalcemia.[404] In Olmstead County, Minnesota only 2% of patients had classic symptoms at the time of diagnosis.[404] Women are affected approximately 3 times more commonly than men, the peak incidence is between 50 and 60 years of age, and the serum calcium elevation is generally less then 1 mg/dL higher than the upper range of the laboratory normal. [361] [405] Diagnosis is generally made by the finding of hypercalcemia, the exclusion of other causes of hypercalcemia ( Table 37-9 ),[373] and the finding of an elevated level of serum PTH. When compared with the 1970s and 1980s, the incidence of nephrolithiasis in patients with primary hyperparathyroidism appears to be decreasing. [361] [405] [406] [407]However, nephrolithaisis is the most common overt complication patients with primary hyperparathyroidism and is present in 10 to 25% of patients. [361] [405] [408] The incidence of nephrolithiasis appears not to increase with time in untreated patients. [407] [409]
TABLE 37-9 -- Principal Causes of Hypercalcemia
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Primary hyperparathyroidism |
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Malignancy |
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Vitamin intoxication |
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Renal failure |
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Following renal transplant |
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Thiazide diuretics |
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Lithium |
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Immobilization |
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Granulomatous disease |
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Milk-alkali syndrome |
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Familial hypocalciuric hypercalcemia |
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Thyrotoxicosis |
From Bushinsky DA: Disorders of calcium and phosphorus homeostasis. In Greenberg A (ed): Primer on Kidney Diseases, 4th ed. San Diego, Academic Press, 2005, pp 120–130.
Immunometic assays that measure intact PTH molecule using two antibodies are very effective in separating those patients with primary hyperparathyroidism from those with hypercalcemia of malignancy. [410] [411] [412] Urinary excretion of cyclic adenosine monophosphate, which is increased by PTH, has not proven to be useful in differentiating patients between primary hyperparathyroidism and other hypercalcemic disorders owing to broad overlap of its excretion with the different disorders. [413] [414] [415]
It is often particularly difficult to separate patients with primary hyperparathyroidism from those with familial hypocalciuric hypercalcemia.[416] This autosomal-dominant disorder is due to a mutation of the calcium-sensing receptor gene, [367] [374] leading to a decrease in the sensitivity of the receptor for calcium[417] and excessive secretion of PTH, at physiologically normal blood ionized calcium. The decrease in sensitivity of the calcium-sensing receptor in the thick ascending limb leads to excessive renal tubular calcium reabsorption and relative hypocalciuria. The distinction is critical, because hypercalcemia always recurs after parathyroidectomy in patients with familial hypocalciuric hypercalcemia and is thus contraindicated. Marx found that the excretion ratio of calcium clearance to creatinine clearance as a function of creatinine clearance provided reasonable, but not complete, separation between the two groups of patients.[418] Patients generally have a reduced calcium clearance such that even in the presence of overt hypercalcemia, urinary calcium excretion is generally less than 200 mg/day.[419] The ratio of calcium clearance to creatinine clearance in patients with familial hypocalciuric hypercalcemia is generally less than 0.013, whereas it is greather in patients with routine primary hyperparathyroidism ( Fig. 37-20 ).[419] Bilezikian et al[405] suggest that the distinction can be made on the following four criteria: (1) family history, (2) onset of hypercalcemia early in life, (3) exceedingly low urinary calcium excretion, and (4) a specific gene abnormality. If there is any question, the diagnosis of primary hyperparathyroidism often can be supported by the finding of a single enlarged gland on imaging studies.
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FIGURE 37-20 Urinary calcium clearance-to-creatinine clearance ratio as a function of creatinine clearance in subjects with familial hypocalciuric hypercalcemia (closed circles) and patients with primary hyperparathyroidism (open circles). (From Marx SJ, Spiegel AM, Brown EM, et al: Divalent cation metabolism: famalial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. Am J Med 65:235–242, 1978.) |
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Whether to Operate
Surgery to remove the adenomal or hyperplastic gland is curative. However, especially in older asymptomatic patients, surgery is not always necessary. Two NIH consensus conferences, one in 1990[420] and one in 2002,[421] were held to address optimal treatment for patients with primary hyperparathyroidism. Recommendations from the latter conference are presented in Table 37-10 . [360] [421] Thus, in patients with primary hyperparathyroidism, surgery is recommended for all with nephrolithiasis, whether they are symptomatic or if a stone found on a radiograph.
TABLE 37-10 -- Primary Hyperparathyroidism—Indications for Surgery
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Clinically symptomatic disease |
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Creatinine clearance < 30% |
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Urinary calcium excretion > 400 mg/24 hours |
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Serum calcium concentration > 1 mg/dL over the upper limit of normal |
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Age < 50 years |
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Bone mineral density (T score) < -2.5 at any site |
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Patient requests surgery |
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Complicated medical monitoring |
Modified from Bringhurst FR, Demay MB, Kronenberg HM: Hormones and disorders of mineral metabolism. In Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (eds): Williams Textbook of Endocrinology, 10th ed. Philadelphia, Saunders, 2002, pp 1303–1371; and Bilezikian JP, Potts JT Jr, El-Hajj Fuleihan G, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidsim: a perspective for the 21st century. J Bone Miner Res 17:N2–N11, 2002.
Successful surgery requires a surgeon experienced and skilled in this difficult procedure. There are a variety of surgical approaches from minimally invasive parathyroidectomy under local anesthesia following localization of the parathyroid gland with technetium-99m-sestamibi and ultrasound to a full neck exploration under general anesthesia. In general, patients who do not require surgery do well with careful medical follow-up.[409] Biochemical measurements and BMD remain constant. However, over 10 years 25% of these previously asymptomatic patients will develop symptoms, patients younger than 50 years of age have a greater likelihood of progression to symptoms, and symptomatic patients, who initially should have had surgery, often do not do well.
Effect of Surgery
Following successful surgery, serum calcium and urine calcium excretion normalize [422] [423] and formation of kidney stones decrease markedly. [399] [409] [424] [425] [426] [427] [428] [429] Mollerup et al followed 674 consecutive patients after surgical parathyroidectomy.[429] They found that the relative risk of stone formation was 40 before surgery and 16 after surgery, although 10 years after surgery, the relative risk of stone formation was no different from controls. Stone-free survival 20 years after surgery was 90.4%. Parks and associates[399] found that following successful surgery in 48 patients, stone formation recurred in only one patient who remained hypercalciuric. Silverberg and co-workers[409] found that of 20 patients with primary hyperparathyroidism, the 12 who had surgery did not have stone recurrence, whereas there was recurrence in six of the eight who did not have surgery. Pratley and colleagues[427] found that after successful parathyroid surgery, eight of 54 patients had residual renal disease manifested by stones, nephrocalcinosis or increasing blood urea nitrogen. Britton and associates[428] also found that 32 of 52 patients had evidence of recurrent renal or stone disease following surgery.
Hyperoxaluria
Intestinal and Renal Oxalate Transport
Hyperoxaluria is as important as hypercalciuria in conferring stone risk.[430] Although one primarily encounters renal pathology (nephrolithiasis, oxalosis, and so on) in oxalate-related diseases, the pathogenesis is as much of gastrointestinal or systemic than renal in origin. The levels of oxalate in plasma in normal subjects ranges from 1.3 to 3.1 μM (mean 2.03 μM), with women having slightly higher levels (mean 2.25 μM) than men (mean 1.87 μM).[431] Plasma oxalate is higher in patients with primary hyperoxaluria or chronic renal failure.[172]
Oxalate is the simplest dicarboxylic acid with pK1 = 4.2 and pK2 = 1.2, so it exists largely as a divalent anion in plasma and urine. The only body fluid in which there is significant undissociated oxalic acid is in the gastric lumen. Oxalate is a complex anion to consider in terms of external balance and determinants of urinary excretion. It is present in the diet, absorbed, secreted, and degraded in the intestine; synthesized by humans from precursors; and filtered, reabsorbed, and secreted by the kidneys ( Fig. 37-21 ). [432] [433] The only fate that oxalate seems to elude is metabolism by the body. Several factors contribute to the hurdles in understanding and the physiology of this metabolite. Because of intestinal metabolism and endogenous production, it is very difficult to establish a state of balanced flux. The contribution of dietary to urinary oxalate ranges from 25 to 50 percent.[434] The simultaneous use of paracellular, transcellular carrier-mediated, and putative nonionic diffusive pathways renders the modeling of the epithelia extremely difficult. The bidirectional transport with highly variable net flux in both intestinal and renal epithelia further adds to the complexity. Finally, the lack of definitive identification of candidate transporters and specific reagents precludes unequivocal conclusions to be drawn. Despite these limitations, due considerations are necessary because of its important role in increasing risk for kidney stone formation.
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FIGURE 37-21 Oxalate transport and metabolism. White arrows, oxalate addition; grey arrows, oxalate removal. |
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Intestinal Transport and Metabolism
A full discussion of this topic is beyond the scope of this chapter. The reader is referred to a recent review.[433] A few highlights relevant to kidney stones are presented to complement the section on hyperoxaluria. There is no evidence of de novo intraluminal generation of oxalate in the intestine. Dietary oxalate comes from a wide range of substances. The usual food chart lists rhubarb, spinach, beetroot, parsley, okra, soy products, sesame seeds, pepper, chocolate products, and tea. It is important to note that precursors of oxalate, such as animal product containing collagen, which is rich in hydroxyproline, can also cause “dietary hyperoxaluria.”
Oxalate is both absorbed and secreted in the gastrointestinal tract ( Fig. 37-21 ). Both paracellular and transcellular pathways are believed to contribute to oxalate movement. Paracellular permeability can be documented in vitro when intestinal epithelia are mounted on Ussing chambers and quantitative estimates for paracellular flux have been offered ranging from 70% to 400% of the total net flux. [435] [436] [437] Although these are valuable measures, paracellular oxalate transport cannot be confirmed in the intact organism to date. Transcellular transport of oxalate is definitely present in the intestine. In the gastric lumen, where the pH is low enough to titrate part of dietary oxalate into small hydrophobic molecules, undissociated oxalic acid can theoretically diffuse through the lipid bilayer, and there is some circumstantial evidence for this “gastric phase” of nonionic oxalic acid absorption. [433] [438] [439] It is not clear whether acid in the colon such as that generated by certain bacteria on carbohydrate substrate can contribute quantitatively significant nonionic absorption of oxalic acid.[440]
The remainder of oxalate transport is mediated by transcellular movement of ionized oxalate, which is likely the most important component. Definitive cell models of intestinal oxalate transport have not materialized because of lack of data. In vitro measurements using inhibitor transport of isolated bowel segments have shown dependence on adenosine triphosphate (ATP) (metabolic inhibitors), anion exchange (stilbenes), and coupling with other cation exchangers (amiloride analogs). [436] [437] [441] [442] Candidate anion exchangers are selected on the basis of two requisites—expression in the intestine, and ability to transport oxalate based on primary on heterologous expression in Xenopus oocytes. Table 37-11 summarizes some members of the SLC26 family that are potential contenders for oxalate transport in the gut and kidney. Similar to the handling of many organic solutes in the proximal tubule, which can be reabsorptive or secretory, the intestine can also absorb or secrete oxalate. In vitro studies suggest that there is axial heterogeneity in this function in that net secretion predominates in the proximal small intestine and the transport mode shifts to net absorption in the colon. [433] [435] [436] [437] [443] It is unclear if this is indeed the case in the intact animal. The fact that probiotics can decrease serum serum and oxalate in primary hyperoxaluria and in animal models suggests that there is significant secretion in the colon as well. [444] [445]
TABLE 37-11 -- SLC26 Family of Anion Exchangers Relevant to Intestinal and Renal Oxalate Transport
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SLC26 member |
Synonym |
Substrate[*] |
Expression |
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A1 |
Sat-1 |
Sulfate, oxalate |
Renal proximal tubule basolateral membrane[1] |
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A2 |
DTDST |
Sulfate, chloride, oxalate |
Colonic cells[2] |
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A3 |
DRA, CLD |
Sulfate, chloride, bicarbonate, hydroxyl, oxalate |
Duodenum and colon. |
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Surface and crypt cells [2] [3] |
|||
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A6 |
PAT-1, CFEX |
Sulfate, chloride, bicarbonate, hydroxyl, formate, oxalate |
Renal proximal tubule apical membrane, stomach, intestine [8] [9] [10] |
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A7 |
— |
Sulfate, chloride, oxalate |
Proximal tubule subapical membrane, thick limb basolateral membrane [11] [12] |
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* |
Assayed when expressed in Xenopus oocytes and sf9 insect cells. In vivo evidence for oxalate secretion in intestine. CFEX, chloride formate exchanger; CLD, congenital chloride diarrhea; DRA, down-regulated in adenoma; DTDST, diastrophic dysplasia sulfate transporter; PAT-1, pancreatic anion transporter; Sat-1, sulfate anion transporter 1. |
The most definitive evidence to date of intestinal oxalate secretion and of the role of a specific transporter comes from the slc26a6-deleted mouse, where the hyperoxaluria and calcium oxalate cystoliths result from impaired intestinal oxalate secretion. [446] [447] [448]
A number of factors can affect oxalate absorption in terms of relevance to stone disease. Because oxalate complexes are not substrates for absorption, luminal calcium can clearly decrease oxalate absorption by lowering free oxalate. This has been touted as the reason why high dietary calcium intake does not necessarily increase stone forming risk. [243] [256] [449] [450] [451] [452] Sequestration of calcium by fatty acids may also contribute to enhanced oxalate absorption. A similar explanation has been given to explain the urinary oxalate-lowering effects of dietary magnesium. [449] [452] Bile acids have been shown to increase bidirectional flux of oxalate in vitro through paracellular pathways and increase transcellular secretion in colon. [453] [454] [455] This has been postulated to increase paracellular oxalate absorption in malabsorptive states.
Microbial Metabolism of Luminal Oxalate
In addition to the complexity introduced by bidirectional flux, variable luminal oxalate metabolism also greatly complicates the assessment of oxalate transport. A number of microbial species have been shown to use oxalate as a substrate.[456] Of these, Oxalobacter formigenes has been the center of focus. O. formigenes degrades oxalate through oxalate decarboxylase, and it has an obligatory dependence on oxalate for trophic growth. When luminal oxalate falls, the O. formigenes count also falls, and for it to be an effect agent, recolonization and regrowth are absolutely necessary on reintroduction of oxalate. There is circumstantial evidence supporting the role of O. formigenes in lowering hyperoxaluria. This includes association between lower fecal and urinary oxalate with O. formigenes colonization, correlation between host colonization and stone recurrence, lower in vitro oxalate degradation in patients with enteric hyperoxaluria, and lowering of urinary oxalate in patients with primary hyperoxaluria. [457] [458] [459] [460] [461] The potential therapeutic role of this probiotic remains to be determined.
Renal Transport
This is still a rather poorly understood area. The actual numerical value of the ratio of oxalate clearance to creatinine clearance (or fractional excretion FEoxalate) varies from 0.5 to 3, indicating net tubular absorption or secretion of oxalate ( Fig. 37-22 ). [172] [462] [463] [464] [465] What determines the net fate of oxalate at the renal tubule is unclear. Reduction of glomerular filtration rate (GFR) increases FEoxalate in some but not all studies. [462] [463] [465] Primary hyperoxaluria appears to increase FEoxalate. Plasma oxalate may be placing the tubular into a secretory mode in primary hyperoxaluria but the hyperoxalemia in chronic kidney disease may be the result rather than the cause of reduced oxalate excretion. Plasma oxalate is 86% ultrafiltrable,[172] thus, there is unlikely regulation at the filtration step.
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FIGURE 37-22 Renal handling of oxalate. Oxalate clearance can be greater than glomerular filtration rate (GFR) (FE >1) or less than GFR (FE < 1). The controlling factors are unknown. |
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The tubular handling of oxalate is still not well defined. When measured in the tubule in situ by in vivo micropuncture and stop flow capillary perfusion techniques, oxalate flux showed that both luminal or basolateral uptake are possible and are mediated by anion exchangers on both sides of the membrane. [466] [467] [468] The contenders at the moment are likely SLC26A1 at the basolateral membrane and SLC26A6 at the apical membrane, based on localization and substrate profiles (see Table 37-11 ). It is not known whether these transporters are really the key controllers of oxalate reabsorption and secretion. And if they are indeed the key transporters, how are they regulated to alter FEoxalate over such a large range?
Enteric Hyperoxaluria
Hyperoxaluria with or without nephrolithiasis is often observed in patients with bowel disease such as Crohn disease, celiac sprue, pancreatic insufficiency, and small bowel bypass surgery for obesity. [469] [470] [471] [472] [473] [474]Pardi and co-workers[475] have estimated that the risk of nephrolithiasis in patients with inflammatory bowel disease is 10 to 100 times that of the normal population. These patients often have multiple stones composed of calcium oxalate generally with ileal involvement and uric acid when the patients have large amounts of diarrhea. [475] [476] [477]
The mechanism by which these disorders enhance urine oxalate excretion involves dietary fat malabsorption with steatorrhea. Increased luminal free fatty acids appear critical and there is a positive correlation between fecal fat and hyperoxaluria. [469] [478] [479] [480] Increased luminal concentration of bile acids and long-chain fatty acids enhance the absorption of oxalate by increasing the permeability of the colon to oxalate. [455] [481] [482] The free fatty acids also bind calcium, making more oxalate available for absorption. Diarrhea results in loss of base, metabolic acidosis and reduced citrate excretion.
Animal studies have shown that that endogenous digestive microflora can metabolize oxalate, which should reduce oxalate available for absorption.[483] Initial studies have demonstrated that the provision of a lactic acid bacteria mixture can, at least transiently, lower oxalate excretion in humans. [444] [484] [485] [486]
Site of the Initial Solid Phase
In this form of calcium oxalate stone-forming disease, stones do not form on Randall plaque, but rather appear to form through nucleation and growth in the urine itself. The renal papillae show no evidence of plaque ( Fig. 37-23 ). Instead, the inner medullary collecting ducts are filled with apatite plugs that resemble those found in calcium phosphate stone formers but are sparser. Although the apatite plugging proves that the inner medullary collecting duct lumen fluid must have been at a pH above 6, the average urine pH of these patients was below 5.5,[121] meaning that tubule fluid and urine pH were not the same. Although stones were always pure calcium oxalate in these patients, and among the large numbers of patients with this syndrome we have reported elsewhere,[487] no tubule contained any calcium oxalate crystals.
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FIGURE 37-23 Endoscopic and histologic images showing intraluminal crystal deposition in medullary tissue of intestinal bypass patients for obesity with kidney stones. A, An example of a papilla from an intestinal bypass stone former that was video recorded at the time of stone removal. Distinct sites of Randall plaque material are not found on the papilla of these patients; instead, several nodular-appearing structures (arrowheads) were noted near the opening of the ducts of Bellini. B, A low magnification light microscopic image of a papillary biopsy specimen from an intestinal bypass patient showing crystal deposition in the lumens of a few collecting ducts as far down as the ducts of Bellini (asterisk). No other sites of deposits were found. Note dilated collecting ducts (arrows) with cast material and regions of fibrosis around crystal deposit-filled collecting ducts. C, A 1-mm plastic section of a collecting duct showing complete crystallization of the tubular lumen and lining cells. In D, an electron micrograph of a region of the collecting duct seen in C is shown (see rectangle). No cellular detail remains; only crystalline material is found. Magnification, ×100 (B); ×550 (C); ×4,000 (D). (All plates courtesy of Andrew P. Evan, PhD, Department of Anatomy and Cell Biology, Indiana University School of Medicine.) |
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Treatment
Therapy directed at the underlying disorder, if possible, reduces intestinal lumen free fatty acid and the propensity for stone formation. For example the provision of a gluten-free diet should reduce hyperoxaluria in patients with sprue. However, to date, no trials substantiate treatment effects in this disease. [230] [473] [479] [487] [488] [489] [490] [491] [492] Foremost is to reduce oxalate ( Table 37-12 ) and fat in the diet, so as to reduce oxalate absorption. Use of calcium supplements (e.g., one to two calcium carbonate antacid tablets toward the end of each meal) can reduce oxalate absorption because the calcium binds dietary oxalate in the gut lumen. Cholestyramine, 2 to 4 gm with each meal, is even more effective as an oxalate binder but has the drawback of unpleasant taste and possible vitamin K deficiency. Because malabsorption itself causes bowel losses of bicarbonate, urine pH and citrate will be low; sodium or potassium citrate supplementation can be beneficial. The higher pH prevents possible uric acid crystallization, and the higher urine citrate binds urine calcium and reduces calcium oxalate supersatuation, and also inhibits calcium oxalate crystallization directly. Finally, high fluid intake is important as in all stone formation states.
TABLE 37-12 -- Foods High in Oxalate [17] [22] [642]
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Beans (green and dried) |
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Beer—draft, stout, lager, pilsner |
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Beets |
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Berries (blackberries, blueberries, raspberries, strawberries, juice containing berries) |
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Black tea |
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Black pepper |
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Celery |
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Chocolate, cocoa |
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Eggplant |
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Figs, dried |
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Greens (collard greens, dandelion greens, endive, escarole, kale, leeks, mustard greens, parsley, sorrel, spinach, Swiss chard, watercress) |
|
Green peppers |
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Lemon, lime and orange peel |
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Nuts |
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Pecans, peanuts, peanut butter |
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Okra |
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Rhubarb |
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Sweet potato |
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Tofu |
Hypocitraturia
Urinary Citrate and Renal Citrate Handling
Citrate has multiple functions in mammalian urine, and the two most important ones are as a chelator for urinary calcium and as a physiologic urinary base. [148] [493] Citrate is freely filtered at the glomerulus, and 65% to 90% is reabsorbed in the proximal tubule.[152] In physiologic urine pH, bivalent (citrate2-) and trivalent citrate (citrate3-) exist in equilibrium citrate2-/3- (pK of the citrate2-/citrate3- pair 5.4–5.7). It is a component of the tricarboxylic acid cycle, and the majority of citrate reabsorbed by the kidney is oxidized to electroneutral end products so H+ must be consumed in the process, making citrate a major urinary base. Calcium associates with all species of citrate with a one-to-one stoichiometry—the highest affinity being a monovalent anionic CaCitrate- complex. CaCitrate- is extremely soluble in an aqueous environment so with adequate amounts of citrate in the urine, most calcium will not be free to bind with other less soluble complexes.[493] In addition to forming a soluble complex, citrate also inhibits the spontaneous nucleation of calcium oxalate and brushite (CaHPO4•2H2O),[142] and retards agglomeration of preformed calcium oxalate.[494] Finally, citrate may also increase the inhibitory activity of urine macromolecules. Hess and co-workers showed that citrate increases the calcium oxalate aggregation inhibition of Tamm-Horsfall protein in vitro. [176] [495]
The final urinary excretion of citrate is determined by reabsorption in the proximal tubule. The most important regulator of citrate reabsorption is proximal tubule cell pH. Acidosis increases citrate absorption by four mechanisms. Acutely, low lumimal pH titrates citrate3- to citrate2-, which is the preferred transported species.[496] The Na-citrate transporter is also gated by pH such that low pH stimulates its activity.[497] More chronically, intracellular acidosis increases expression of the transporter, as well as stimulates enzymes that metabolize citrate in the cytoplasm and mitochondria. [498] [499] [500] An appropriate response of the proximal tubule to cellular acidification is hypocitraturia.
Clinical Hypocitraturia
Hypocitraturia has been described in 15% to 60% of stone formers. [149] [501] [502] [503] [504] [505] The wide range in the reported prevalence of hypocitraturia reflects differences in the populations studied, differences in dietary background, and differences in the laboratory definition of hypocitraturia. Although isolated hypocitraturia may not be common, hypocitraturia accompanied by other defects such as hypercalciuria is very common in stone formers. Some groups report differences in normal subjects related to age and sex [502] [506] [507]; others have not found such differences. [505] [508] [509] A rigid cut-off of this continuous variable into a range of “hypocitraturia” is impossible and physiologically inappropriate.[148] A utilitarian guideline can be arbitrarily set at 320 mg/day (1.68 mmoles/day), assuming the excretion of about 1 L of urine.
Causes of hypocitraturia in the context of nephrolithia-sis are listed in Table 37-13 . All conditions acidify the proximal tubule cell by one way or another. Take caution that frank metabolic acidosis (low plasma [HCO3-]) is not always detectable in these settings. Some of these conditions, such as RTA, have obvious systemic metabolic acidosis, whereas most of the other conditions have normal plasma [HCO3-], and in K+ depletion plasma [HCO3-] and pH may even be high. Occasionally, no underlying defect can be uncovered and the patient is defaulted into the diagnosis of idiopathic hypocitraturia.
TABLE 37-13 -- Causes of Hypocitraturia
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Condition |
Cause |
||||||||||||||||||
|
Acid overproduction |
|
||||||||||||||||||
|
Acid underexcretion |
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||||||||||||||||||
|
Acid shift |
K depletion |
||||||||||||||||||
|
Idiopathic |
|
ACE, angiotensin-converting enzyme. |
Treatment
The basis of therapy for hypocitraturia is correction of any underlying disorder that reduces urine citrate, such as acidosis, acid load, or hypokalemia. Any alkali supplement will increase urine citrate levels. However, sodium alkali will increase urine calcium excretion, offsetting the benefits of increased urine citrate. [510] [511] Either potassium bicarbonate or potassium citrate may be used. Citrate requires less frequent dosing than bicarbonate because it is metabolized to bicarbonate in the liver. Citrate is the most frequently used alkali for hypocitraturic patients and has been proven to be efficacious in hypocitraturia caused by distal RTA,[150] chronic diarrheal syndrome,[149] thiazide-induced hypokalemia,[512] hyperuricosuric calcium nephrolithiasis,[513] and uric acid nephrolithiasis.[514] The maximal recommended dose is 60 mEq/day, whereas milder cases can be started on 30 to 40 mEq/day. There are three randomized trials of citrate therapy in calcium oxalate stone formers.
Barcelo and co-workers[144] conducted a 3-year double-blind trial of potassium citrate in patients with hypocitraturic calcium oxalate stones. The placebo group had no change in the stone formation rate, whereas the potassium citrate-treated group had their stone formation rate decreased from 1.2 to 0.1 stone per patient-year (P < .001) (see Figs. 37-16 and 37-24 [16] [24]). Only 20% of the placebo group remained stone free compared with 72% of the treated group during the study. A 3-year double-blind study of potassium magnesium citrate also showed a reduced calcium oxalate stone formation rate with therapy[145](see Fig. 37-16 ). The patients in this study had a variety of metabolic abnormalities as the cause of the stones, with only 20% having hypocitraturia. The benefit of citrate therapy was not limited to the patients with hypocitraturia. A third 3-year randomized study using sodium-potassium citrate did not reveal any reduction in stone recurrence in a group of calcium oxalate stone formers.[146] The majority of patients did have hypocitraturia on entry into the study, and the treated group did show an increase in citrate during therapy. The reason for the different outcomes in these studies is not clear; possibly the use of a mixed sodium-potassium salt blunted the antilithogenic response to citrate.[146] In summary, there are two positive controlled trials and uncontrolled trials showing reduction in stone formation by citrate therapy.
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FIGURE 37-24 Effect of potassium citrate therapy (upper panel) versus placebo (lower panel) on hypocitraturic calcium oxalate stone disease. Each line represents a single patient and each dot represents a new stone formation. (From Barcelo P, Wuhl O, Servitge E, et al: Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 150:1761–1764, 1993.) |
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An new formulation of potassium magnesium citrate emerged as an alternative to potassium citrate. The stoichiometry is 4K+: 2Mg2+: 2 citrate3- and delivers 7, 3.5, and 10.5 mEq of K+, Mg2+, and citrate3-, respectively, per tablet. Potassium magnesium citrate is effective in treating thiazide-induced electrolyte deficits [515] [516] and preventing stone recurrence,[145] and is more effective than potassium citrate in raising urinary pH.[517] No study has been performed yet to document clinical outcome comparing potassium magnesium citrate with potassium citrate.
Hyperuricosuria
In common clinical parlance, hyperuricosuria refers to an excess of the sum of urate and uric acid in the urine regardless of the relative partition between these two species. Although hyperuricosuria is an obvious cause of uric acid nephrolithiasis, it is also a well-documented risk factor for calcium oxalate stones. About 5% of stones analyzed have mixed calcium-uric acid.[34] In patients with gout and uric acid nephrolithiasis, 17% of stones contain calcium.[518] In more than 800 calcium stone formers, 15% have hyperuricosuria as the sole abnormality and 14% have combined hyperuricosuria and hypercalciuria.[519] In fact, the majority of pure uric acid stones are not secondary to hyperuricosuria but rather are due to unduly acidic urine. The excess H+ titrate urate to the sparingly soluble uric acid causing precipitation of uric acid. The relative impact of urinary pH versus hyperuricosuria on uric acid precipitation is discussed later under uric acid nephrolithiasis. When urine pH is not low, hyperuricosuria leads to excessive urate rather than uric acid in the urine. Although urate is much more soluble than uric acid, it is not infinitely soluble. The most abundant cation in urine is usually sodium, and sodium urate has a lower solubility than potassium urate. In the presence of hyperuricosuria and absence of excessively acidic urine, sodium urate becomes the culprit in lithogenesis.
Pathogenesis of Hyperuricosuria Calcium Urolithiasis
Although the clinical entity of hyperuricosuric calcium urolithiasis is well established, the mechanism of how this transpires is not well established. The role of hyperuricosuria in calcium stone formation can be attributed to several of its effects on the urinary milieu, although the exact mechanism is not definitely proven.[520] One mechanism that has been touted for many years is heterogeneous nucleation or epitaxy. The crystal lattice dimension for uric acid, sodium urate, calcium oxalate monohydrate, and calcium oxalate dehydrate are remarkably similar so the presence of one in solid phase will promote the precipitation of the other. [521] [522] Work from Coe and co-workers[107] and Pak and co-workers[106] showed that in vitro, it is sodium urate rather than uric acid that is responsible for epitaxic crystal growth. Another in vitro study by Grover and co-workers [523] [524] showed that urate-induced calcium oxalate crystallization does not decrease urate concentration in solution and the authors proposed a discount of the epitaxy theory.
A second model is the “salting out” phenomenon. Whereas epitaxy requires a solid phase to initiate the crystallization, “to salt out” refers to the ability of urate to lower the formation product of calcium oxalate by yet unknown mechanisms. [523] [524] [525] This was supported by studying clinical samples in which formation product of calcium oxalate increased with allopurinol therapy. [526] [527] A third model proposes that uric acid or sodium urate sequesters calcium crystallization inhibitors. Sodium urate addition to urine lowers the activity of inhibitors, [528] [529] and sodium urate has been shown to bind to polyanionic macromolecules, many of which are functional crystallization inhibitors.[530] This finding is not universally consistent, because Ryall and co-workers [531] [532] showed in undiluted urine that sodium urate crystals did not have an effect on metastable limits, size, and growth rate of calcium oxalate crystals on oxalate challenge.
Causes
Because urinary uric acid excretion is a continuous variable, one does not and should not have rigid definitions of hyperuricosuria. Gutman and Yü[518] provided some guidelines for clinicians (750 mg or 4.5 mmoles/day for adult women; 800 mg or 4.8 mmoles/day for adult men). It is important to note that hyperuricosuria is not an all-or-none diagnosis. At the steady state, that is, constant plasma uric acid level, uric acid production equals the sum of urinary uric acid excretion and intestinal uricolysis. A primary increase in uric acid production is compensated by increased renal excretion and intestinal uricolysis, and usually is accompanied by hyperuricemia ( Fig. 37-25 ). A primary increase in renal excretion should be accompanied by some degree of hypouricemia in the absence of changes in production and intestinal degradation. Table 37-14 provides a list of conditions that cause hyperuricosuria. The single most prevalent cause of hyperuricosuric kidney stones is excessive dietary purine.
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FIGURE 37-25 Two mechanisms that cause hyperuricosuria. In overproduction, there is adaptive increase in renal excretion and intestinal uricolysis. The result is less severe hyperuricemia. The increase in urinary uric acid is an underestimation of the elevated production because intestinal uricolysis is not measured. In primary renal uric acid leak, there may or may not be hypouricemia. Finally, a combination of two mechanisms can occur. |
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TABLE 37-14 -- Causes of Hyperuricosuria
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Condition |
Pathogenesis |
Etiology |
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|
Purine overproduction |
Hypoxanthine-guanine phosphoribosyl transferase deficiency |
Lesch-Nyhan syndrome—complete Kelley-Seegmiller syndrome—Partial |
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Phosphoribosylopyrophosphate synthetase superactivity |
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Normal purine metabolic enzymes but increased flux though purine pathways—increased nucleotide/nucleoside turnover |
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Renal leak |
URAT1 mutation |
Hereditary renal hypouricemia |
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Glycogen storage disease type I |
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Inhibition of urate transporters |
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Treatment
Because hyperuricosuria is frequently not a singular risk factor, it is important to address all causative factors of nephrolithiasis in any given individual. In about 70 percent of hyperuricosuric patients, high purine intake is the cause of hyperuricosuria, as evident by their response to dietary purine restriction. [109] [533] Therefore, dietary modification should still be the first line of therapy, although compliance may be variable. The noncompliant patients, along with the 30 percent who represent true nonresponders, require alternative approaches.
The cornerstone of xanthine oxidase inhibition is still allopurinol since its approval by the Food and Drug Administration (FDA) in 1966 for treatment of gout.[534] Allopurinol is oxidized by xanthine oxidase to its active metabolite oxypurinol, which inhibits xanthine oxidase. At low concentrations, allopurinol is a substrate for the enzyme, as well as its competitive inhibitor. At high concentrations, it functions as a noncompetitive inhibitor. Major drawbacks of allopurinol include rash, gastrointestinal upset, abnormal liver enzymes, and prolonged elimination in renal disease.
A number of novel xanthine oxidase inhibitors have more favorable toxicology profiles, improved bioavailability, and more potent and persistent action than allopurinol.[535] Febuxostat is a thiazolecarboxylic acid derivative that does not resemble a purine or pyrimidine but still has substantial activity as a xanthine oxidase inhibitor. [536] [537] Although xanthine oxidase inhibitors are effective in reducing hyperuricosuria as well as stone recurrence,[538] the ability to reduce stone recurrence in patients with combined hyperuricosuria and hypercalciuria is less well established.
Other measures targeted at calcium such as thiazides and potassium citrate are effective in reducing calcium stone recurrence in patients with or without hyperuricosuria. [232] [513]
Calcium Phosphate Stones and Renal Tubular Acidosis
Mechanisms of Calcium Phosphate Stone Formation
Coe and others [538] [539] have noticed that some patients stand out among calcium stone formers by virtue of forming predominantly calcium phosphate stones. Why they form calcium phosphate stones is clear enough; compared with patients whose stones are mainly calcium oxalate, their urine is of higher pH and therefore higher in calcium phosphate supersaturation ( Fig. 37-26 ). Urine pH and calcium phosphate supersaturation increase progressively as the fraction of calcium phosphate salts in formed stones increases (see Fig. 37-26 , upper and middle left panels). As a group, patients with predominantly calcium phosphate stones are as hypercalciuric as other stone formers, perhaps more so (upper right panel), and have higher urine volumes (lower left panel). Urine phosphate and citrate excretions (lower middle and right panels) are not remarkable.
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FIGURE 37-26 Urine stone risk factors with increasing stone CaP%. CaP SS rose with the percent of calcium phosphate in passed stones (CaP%) (left upper panel, y- and x-axes, respectively), among men (blue circles) and women (red circles; values are mean ± SEM). Urine pH rose progressively (upper middle panel), which would increase CaP SS. Urine calcium excretion (upper right panel) rose to a plateau in men but rose and fell in women. Urine volumes were higher at high CaP% values in both sexes, although mean values for CaOx and CaP patients did not differ. Urine phosphorus excretion was variable, with no specific pattern (lower middle panel). Urine citrate excretion was lowest when CaP% was highest, but SEM values were very wide and generally overlapping. (Adapted from Parks JH, Worcester EM, Coe FL: Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int 64:2150–2154, 2004.) |
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Renal Pathology of Calcium Phosphate Stones
The mechanism of the higher urine pH among patients whose phosphate stones contain brushite (calcium monohydrogen phosphate) seems evident from the renal pathology ( Fig. 37-27 ). Renal papillae are grossly and variably deformed with dilated terminal ducts of Bellini, out of whose mouths one can often find projections of calcium phosphate plugs. Histologic examination reveals massive dilation of ducts of Bellini filled with apatite crystals. Epithelial cells are damaged and, in some cases, obliterated. The surrounding interstitium is often fibrotic, and in the cortex, one finds glomerular obsolescence.[119] With so much inner medullary collecting duct damage, one might expect reduced acidification ability. However, the sequence of events in brushite stone disease is not established from the pathology. Clearly, in order to produce the inner medullary collecting duct apatite deposits, the tubule fluid must have already had a higher pH; the search for the initial events requires new research.
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FIGURE 37-27 A to F, Endoscopic and histologic images showing three distinct papillary patterns of crystal deposits in brushite patients. A and C, examples of papilla from brushite patients who were video recorded at the time of their percutaneous nephrolithotomy for stone removal. Both panels show the irregular white areas of crystalline deposits (arrows) (type 1 crystal pattern) beneath the urothelium that we described for calcium oxalate patients (see Fig. 37-14 ). These papilla show yellowish crystalline deposits at the openings of dilated ducts of Bellini (asterisk) (type 2 crystal pattern). A third crystal pattern was noted in the brushite papilla and appeared as yellowish mineral deposition within lumens of medullary collecting ducts just like that described for the type 2 pattern, except that these collecting ducts are located just beneath the urothelium. Sites of type 3 deposits ranged from large areas of crystalline material in collecting tubules that formed a spke-and-wheel-like pattern around the circumference of the papilla (C, double arrows) to small, single sites of yellowish material in focal regions of a collecting duct. D confirms that these sites of type 3 deposits are in medullary collecting tubules (asterisk) positioned just beneath the urothelium lining (arrow) of the renal pelvis. Several sites of Yasue-positive material are noted in the interstitial space (double arrow) adjacent to a filled collecting tubule. In E and F, a unique histologic finding is seen in the papillary biopsies of the brushite stone formers as focal regions of damaged collecting tubules filled with Yasue-positive material (arrow). Mineral was occasionally noted filling the lumens of nearby thin loops of Henle (asterisk). Magnification, ×100 (B); ×250 (D); ×700 (E); ×1100 (F). (All plates courtesy of Andrew P. Evan, PhD, Department of Anatomy and Cell Biology, Indiana University School of Medicine.) |
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Renal Tubular Acidosis
One initiating mechanism is hereditary or acquired RTA. The hereditary disorders, discussed elsewhere in this book in Chapter 40 , are caused by mutations in critical membrane transporter units. Autosomal-dominant RTA is caused by defects in SLC4A1; its protein product, AE1, is a chloride-bicarbonate exchanger on the basolateral surfaces of type A intercalated cells. Stones and nephrocalcinosis are common. [540] [541] [542] Autosomal-recessive RTA with and without hearing loss is caused by defects of the B1 and α4 subunits of vacuolar ATPase of intercalated cells, and causes stones and nephrocalcinosis. [543] [544] In these rare diseases, formation of apatite within the inner medullary collecting duct is not an unreasonable event, and after it forms, a vicious circle of cell injury and interstitial inflammation, and calcium deposition is inevitable.
A more subtle problem is how acquired RTA actually occurs. Some cases reflect direct cell injury from diseases such as Sjögren syndrome,[545] hyper-gamma globulinemic diseases, [546] [547] sickle cell disease,[548] lithium treatment,[548] and obstructive uropathy.[549] But for the most part, increased urine pH with apatite or brushite stones seems to occur without any particular inciting cause. Often, one finds low urine excretion of citrate associated with a urine pH above 6, suggesting some abnormality of acid base homeostasis but without serum abnormalities, and affixes the label of “incomplete RTA.” If challenged with an acid load, such patients frequently cannot lower urine pH[550] to the normal extent (below 5.5). The problem with pathogenesis is illustrated precisely by our biopsy findings; calcium phosphate stone formers, at least those with brushite in their stones, have obvious inner medullary collecting duct damage and would be expected to display less than normal acidification.
Clinical Management
A majority of calcium phosphate stone formers are hypercalciuric, and lowering urine calcium is a priority. Because acid loading causes hypercalciuria, [154] [246] it is attractive to consider alkali supplements in patients with overt RTA; blood bicarbonate will increase, and urine calcium and calcium phosphate supersaturation will fall. Also, urine citrate, reduced by metabolic acidosis,[551] will increase, which is a protective response because citrate raises the upper limit of metastability for calcium phosphate.[151] Unfortunately urine calcium often does not fall, because the cause of high calcium is not merely acidosis, so early follow-up measurements are mandatory. Given persistent hypercalciuria thiazide treatment, as in idiopathic hypercalciuria, is appropriate. Alkali supplements may be beneficial in increasing urine citrate, but they may also increase urine pH, worsening calcium phosphate supersaturation. Therefore, monitoring should include measurements of calcium phosphate supersaturation, and the overall effect of treatment must be to minimize that supersaturation. There are no high-quality trials of treatment for calcium phosphate stones per se.
URIC ACID STONES
Uric acid stones in the setting of gout first appeared in the literature in 1776.[552] Uric acid was isolated from urine by Scheele in 1776 and later identified in voided urinary concretions by Wollaston in 1810. [552] [553] The high incidence of renal and bladder uric acid stones from pre-World War I United Kingdom were likely due to mostly dietary causes. This ailment was particularly common among affluent elderly men. Both bladder and kidney uric acid stones were noted to be associated with tophaceous gout. Although diet is still a contributing factor, uric acid nephrolithiasis from sheer gluttony is not as common today.
Although uric acid stones are caused by hyperuricosuria in most mammals, [554] [555] [556] the majority of uric acid stones in humans are not associated with hyperuricosuria but rather unduly low urinary pH. [252] [254] [557] [558] To our present knowledge, this condition is unique to humans. Acidic urine pH and low urinary NH4+ has been described in patients with uric acid nephrolithiasis, [518] [559] [560] [561] [562] although these findings have not always been universal [561] [563] [564] [565] and sometimes are dependent on the underlying conditions. [564] [565] The reason for the low urinary pH was unknown until recently. It is now clear that uric acid nephrolithiasis is part of a cluster of metabolic disturbances. Presentation of a uric acid stone may be a sentinel for a systemic metabolic syndrome. Conversely, patients with the metabolic syndrome are at heightened risk for uric acid nephrolithiasis.
Epidemiology
Uric acid nephrolithiasis comprises about 8% to 10% of kidney stones in the United States.[31] The proportion of uric acid stones among stone formers is significantly higher in the Middle East,[566] in Okinawa, Japan,[567] and in certain regions in Germany.[568] In the United States, a high prevalence of uric acid nephrolithiasis was reported in the Hmong population in Minnesota, a Laotian ethnic group with Chinese ancestry.[403] As a group, the Hmong have increased risk for nephrolithiasis in general, with more than 50% of the stones containing uric acid.
Taylor and co-workers[569] analyzed three databases of 200,000 participants from the Nurses' Health Study I and II, and the Health Professionals Follow-up Study and found a relative risk of kidney stone to be 1.3 ot 1.6 in diabetics versus non-diabetics. However, stone composition was not part of the database. Using data from two centers, Pak and co-workers[570] found a fivefold higher rate of uric acid stones in stone formers with type 2 diabetes mellitus. This finding was confirmed in 4700 stone analyses from France, where a threefold higher proportion of pure uric acid or mixed calcium and uric acid stones was found in diabetic patients compared with nondiabetics ( Fig. 37-28 ).[571] [572] In addition to diabetes, obesity is associated with a higher prevalence of uric acid nephrolithiasis because 63% of their stones were composed of uric acid.[573] The proportion of uric acid stones in obese patients (body mass index > 30 kg/m2) is 4 times higher than lean nephrolithiasis patients (body mass index < 25 kg/m2).[574] Epidemiologic data support the link between uric acid stones, type 2 diabetes, and obesity.
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FIGURE 37-28 Relative distribution of kidney stones from approximately 4700 stone analyses. (Based on data from Daudon M, Lacour B, Jungers P: High prevalence of uric acid calculi in diabetic stone formers. Nephrol Dial Transplant 20:468–469, 2005.) |
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Pathogenesis and Etiology
Humans and higher primates have no uricase, so they maintain relatively high levels of uric acid in the plasma and in the urine, and the theoretical evolutionary origin and selective advantage of this phenomenon has been discussed elsewhere. [253] [575] Thus, compared with nonprimate mammals, the “physiologic uricosuria” of humans plants the seed for uric acid precipitation in urine. Both hyperuricosuria and low urinary volume can theoretically increase the supersaturation of uric acid and cause crystallization. The causes of hyperuricosuria were discussed earlier. Once again, it is important to note that uric acid excretion is not elevated in the majority of patients with uric acid nephrolithiasis. [576] [577] The principal defect is excessively low urinary pH. The H+ on N at position 9 is dissociable at physiologic pH (pK 5.75) ( Fig. 37-29 ). The physicochemical consequence of this titration is highly significant.
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FIGURE 37-29 Uric acid. The nitrogen in position 3 of the purine ring has a H+ that dissociates at physiologic pH. |
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Figure 37-30 shows the relative contribution of hyperuricosuria and pH to the concentration of undissociated uric acid. At UpH = 6.5, it takes a lot of total uric acid (uric acid + urate) to exceed the solubility of uric acid. In contrast, at urine pH of 5.5, even physiologic amounts of uric acid in the urine can easily exceed solubility. Although it is uncommon to have total uric acid higher than 1000 mg/L, it is not unusual to have urine pH go to 5.5 or lower. Theoretically, even transient physiologic diurnal dips in urine pH[578] can titrate urate to uric acid to exceed its solubility and initiate the process of crystallization.
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FIGURE 37-30 Undissociated uric acid (vertical axis) plotted as a function of total uric acid (uric acid + urate) and urinary pH (UpH). The solubility of undissociated uric acid is about 97 mg/L At UpH of 5.5, solubility can be exceeded with a total uric acid concentration slightly above 200 mg/L. At UpH 6.5, urine can accommodate total uric acid of above 1000 mg/L. (Adapted from Maalouf NM, Cameron MA, Moe OW, Sakhaee K: Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 13:181–189, 2004.) |
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Table 37-15 shows the list of causes of low urine pH. These causes must be sorted and ruled out, and often there are no overtly identifiable causes. Although low UpH in uric acid nephrolithiasis has been known for a long time, the reason for this phenomenon is unknown until recently. Epidemiologic data presented earlier provide strong suggestive evidence that states of insulin resistance, such as that associated with type 2 diabetes and obesity, underlies normouricosuric uric acid nephrolithiasis.
TABLE 37-15 -- Causes of Low Urinary pH
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Several lines of evidence support a relationship between uric acid nephrolithiasis and insulin resistance. [570] [571] [572] Cross-sectional data demonstrated that idiopathic uric acid stone formers have many features of the metabolic syndrome, including obesity, dyslipidemia, and glucose intolerance, all of which are linked to insulin resistance. More than half of uric acid stone formers exhibit glucose intolerance or type 2 diabetes mellitus.[576] Patients with obesity or type 2 diabetes mellitus have a higher proportion of uric acid stones when compared with lean or nondiabetic subjects. [571] [572] [573] [574]
The pathogenic link between insulin resistance and excessively acidic urine is currently being investigated. An inverse relationship was demonstrated between body weight and urine pH in a large population of stone-forming subjects.[578] Urine pH has been demonstrated to directly correlate with glucose disposal rate, a measure of peripheral insulin resistance determined by the hyperinsulinemic, euglycemic clamp method.[579] Compared with normal individuals, individuals with type 2 diabetes with the same dietary acid intake have increased endogenous acid production and a preference for excreting acid as titratable acidity rather than ammonium.[580] A model is presented inFigure 37-31 .
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FIGURE 37-31 Working model of unduly acidic urine pH in patients with uric acid nephrolithiasis. Increased endogenous acid generation is compensated for by increased renal net acid excretion. Instead of carrying the H+ with high-pK, high-capacity open buffer such as NH3, H+ is carried by low-pK, low-capacity closed buffers, which include a wide variety of H+ acceptors, urate being one of them. |
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There appears to be two disturbances in uric acid nephrolithiasis and the metabolic syndrome. The mechanisms for escalation and what type of endogenous acid generation are not resolved at the moment. These individuals are in acid-base balance in the sense that this heightened production is matched by a commensurate increase in renal acid excretion at steady state. The second defect is that instead of carrying most of the increased H+ with high pK high-capacity open buffer such as NH3, H+ is carried by low pK low-capacity closed buffers, which includes a wide variety of H+ acceptors. This mandates a lower urinary pH. One of these low pK buffer happens to be urate, which when titrated, yields the highly insoluble uric acid. The mechanism of the renal reticence to recruit the ammonium acid excretory system is unclear at present.
Diagnosis and Evaluation
As with all nephrolithiasis, definitive diagnosis stems from stone analysis, which will reveal either pure or mixed uric acid. The evaluation of a uric acid stone former should include a complete history and physical with a focus on secondary factors described earlier that contribute to either hyperuricosuria (see Table 37-14 ), low urinary volume, or low urinary pH (see Table 37-15 ). A review of medications and diet should be included. Identification of an underlying cause will guide future management.[581]
Uric acid stones are radiolucent on plain radiographs but are visualized by CT.[43] It is important to note that xanthine and 2,8-dihyroxyadenine (2,8-DHA) stones are also radiolucent and should not be confused with uric acid stones. Xanthine calculi can be seen in patients receiving allopurinol or in rare congenital conditions such as Lesch-Nyhan syndrome or xanthine oxidase deficiency.[582] 2,8-DHA stones are seen in patients with adenine phosphoribosyltransferase deficiency.[583] Both stone types are extremely insoluble regardless of urinary pH and are resistant to urinary alkalinization.
The most important and invariant chemical finding in uric acid nephrolithiasis is low urinary pH. A 24-hour urine collection should be obtained on all subjects to evaluate for urine volume and pH, hyperuricosuria, and markers of excessive purine and acid load (urea, sulfate, net acid excretion). Hyperuricosuria is a risk factor for both calcium and uric acid stones, but calcium nephrolithiasis is more commonly encountered with hyperuricosuria.[527] Close to 80% of hyperuricosuric stone formers have calcium oxalate stones and 10% have calcium phosphate stones.[33] These patients differ from uric acid stone formers because they have a normal serum uric acid concentration and a normal urine pH. [33] [576]
Treatment
Fluid and dietary modifications should be recommended to all patients with uric acid stones to maintain a urinary volume of approximately 2 liters per day, and animal protein consumption should be decreased to less than 0.8 g/kg/day. Even though most uric acid stone formers have normal or even low urinary uric acid, they frequently have hyperuricemia which can benefit from dietary purine restriction. For those patients with hyperuricosuria refractory to dietary modification, xanthine oxidase inhibitors should be tried. The use of this class of drugs is discussed under hyperuricosuic calcium urolithiasis.
Table 37-16 summarizes the various ways to alkalinize urine. Either potassium citrate or sodium alkali therapy can effectively increase urine pH to prevent stone recurrence, and in some cases, to dissolve existing calculi. [514] [584] [585] Potassium citrate is preferred because it is the only agent that reduces urinary calcium, thereby decreasing the risk for calcium oxalate stone formation. [514] [584] It also has an advan-tage over sodium alkali therapy because potassium urate is more soluble than sodium urate in urine, attenuating the risk of epistaxis of calcium oxalate salts.[514] Sodium citrate or sodium bicarbonate can be used in patients intolerant to potassium salts or with impaired renal potassium excretion, such as impaired renal function or documented hyperkalemic responses to angiontensin-converting enzyme inhibitors or angiotensin receptor blockers. The initial recommended alkali dose is 30 to 40 mEq per day. Twenty-four-hour urine pH should be monitored frequently and the alkali dose titrated to maintain urinary pH above 6.1, but less than 7.0 to avoid complications of calcium phosphate stones.
TABLE 37-16 -- Urinary Alkalinization
|
Urine |
K3 Citrate |
Na3Citrate |
KHCO3 |
NaHCO3 |
Orange Juice |
CA Inhibitors |
|
pH |
↑ |
↑ |
↑ |
↑ |
↑ |
↑ |
|
Citrate |
↑ |
↑ |
↑ |
↑ |
↑ |
↓ |
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Calcium |
↔ |
↑ |
↔ |
↑ |
↔/↑ |
↑ |
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Oxalate |
↔ |
↔ |
↔ |
↔ |
↑ |
↔ |
|
Side effects |
Nausea |
Nausea |
Bloating |
Bloating |
Glucose Load |
Acidosis |
Carbonic anhydrase inhibitors (acetazolamide, topiramate) may be used as alternative alkalinizing agents.[586] This treatment is effective in significantly increasing the urine pH. However, the risk of calcium phosphate stones may increase because of lower urinary citrate[587] owing to proximal tubule cellular acidification and a pH-dependent increase in insoluble calcium phosphate complex formation.
In those subjects who are intolerant to or adverse to pharmacologic therapy, orange and grapefruit juice may be used. These agents have been shown to exert both citraturic and alkalinizing effects. [588] [589] [590] Not all citrus juices are equivalent. Only citrate salts of inorganic cations such as potassium lead to hypercitraturia; lemon juice, which contains mainly citric acid, is not effective.[590] Juices present a considerable caloric load and can increase urinary oxalate and calcium excretion. [588] [589] [591]
The therapies described thus far merely attempt to empirically alter the urinary chemistry. Ultimately, the definitive therapy is to attack the underlying metabolic defect including the escalated acid production, insulin resistance, lipotoxicity, and glycotoxicity.
Uric acid nephrolithiasis is part of a systemic metabolic disease and diverse manifestations. Two of its features, namely, an increase in endogenous acid production and the propensity of the kidney not to use ammonium to excrete acid beget the foundation for uric acid precipitation as an innocent bystander. From a pathophysiologic point of view, uric acid nephrolithiasis provides a window to glimpse into the renal effects of the metabolic syndrome.
STRUVITE STONES
Struvite (MgNH4PO4•6H2O) stones make up only 10% to 15% of all kidney stones and are often also composed of carbonate apatite (Ca10[PO4]6•CO3) as well. These rapidly growing stones branch and enlarge, and may fill the renal collecting system to form staghorn calculi. Struvite stones form only in urine infected by urea splitting bacteria. These stones are difficult to treat because surgical removal is successful only if every infected stone fragment is removed. Any remaining fragments generally contain the infecting bacteria and are a nidus for further stone growth. The propensity of these stones to grow rapidly in size, to recur despite attempts at therapy, and to result in significant morbidity (and potential mortality) has led to the appellation stone cancer. [17] [22] These stones have also be called triple phosphate stones, magnesium ammonium phosphate stones, and infection stones.
In contrast to other types of kidney stones, struvite stones occur more frequently in women than in men largely because of the increased incidence of urinary tract infections in women. [17] [22] Chronic urinary stasis or infections predispose patients to struvite stones so that the elderly and those with neurogenic bladders, indwelling urinary catheters, and anatomic abnormalities of the urinary tract and spinal cord lesions are particularly at risk. The presence of large stones in an infected alkaline urine should altert the clinician to the potential presence of struvite. Given their potential for rapid growth and substantial morbidity, early detection and eradication are essential.[592]
The urease of urea splitting organisms hydrolyzes the conversion of urea (CO[NH2]2)] to 2 NH3 + CO2. Ammonia (NH3+) hydrolyzes spontaneously to form the base, ammonium hydroxide (NH4OH). The CO2 hydrates to form carbonic acid (H2CO3) which, in the now alkaline urine, loses a proton to become bicarbonate (HCO3-) and then another proton to become carbonate (CO3-). The phosphate and magnesium combines with the NH4 to form struvite and the calcium and phosphate with the carbonate to form carbonate apatite. Ammonium can bind to the charged sulfates on the glycosaminoglycans that line the urothelium.[593] This binding impairs the the hydrophilic activity of the glycoaminoglycans, increasing adhesion of crystals to the urothelium, which can then rapidly increase in size fixed to the urothelium.
The conditions produced by urea splitting organisms are unique. Generally, NH3 is increased only during acid loads or potassium depletion. Only during infections with urease-producing organisms will there be a simultaneous elevation in urine NH4+, pH, and carbonate concentration. With successful antimicrobial treatment of the underlying infection, the struvite can actually dissolve as the urine is generally undersaturated with respect to struvite. [594] [595] However, urine is generally not undersaturated with respect to carbonate apatite,[595] so successful antimicrobial therapy would not be expected to result in dissolution of this component of an infection stone. Whether a stone dissolves with prolonged antibiotic aministration depends on the amount of carbonate apaptite in the stone.[21]
Urease-Producing Bacteria
Although several hundred types of bacteria, both gram negative and gram positive, as well as Mycoplasm and yeast species, have been shown to produce urease, the majority of urease-producing infections are caused by Proteus mirabilis. In addition to proteus species Haemophilus, Corynebacterium, and Ureaplasma are also frequently shown to cause struvite stones. All of these bacteria use urease to split urea and supply their need for nitrogen (in the form of NH3), which is incorporated into glutamate and glutamine. Colony counts may be low so that the laboratory should be specifically instructed to identify any bacteria and determine sensitivities no matter how low the number of colony-forming units. If routine urinary cultures are negative yet a urease producer is suspected, the laboratory should be specifically instructed to culture for the mucobacterium Ureaplasma urealyticum, which can also split urea.[593] The common urinary pathogen, Escherichia coli, does not produce urease.
Therapy
Surgery
Struvite staghorn calculi generally require surgical removal [21] [596] and, if not properly treated, may result in nephrectomy in up to 50% of cases. [597] [598] Initially, struvite stones were treated with open surgical stone removal. Almost one quarter of patients so treated had recurrence following surgery, and almost half had recurrent urinary tract infections.[599] However, if the open nephrectomy was followed by aggressive lavage of the renal pelvis with hemiacidrin, a mixture of citric acid, gluconic acid, magnesium hydrocarbonate and magnesium acid citrate at an acidic pH of 3.9 for chemolysis, the procedure resulted in a reduction in the recurrence rate to 2%. [593] [599]
Rather than open surgical stone removal, percutaneous nephrolithotomy can completely remove sturvite stones in up to 90% of cases, [201] [600] with a recurrence rate approaching only 10% in kidneys rendered stone free.[601]Extracorporeal shock wave lithotripsy with ureteral stenting alone will result in stone-free rates of 50% to 75%. [602] [603] In 1994, a panel of the American Urological Association suggested that a combined approach of percutaneous nephrolithotomy and shock wave lithotripsy was preferred.[596] Since then, retrograde ureteroscopy with homium:YAG laser stone disruption has become available. Using this approach, Grasso and associates[604] have reported fragmentation of almost all minor staghorn stones with a recurrence rates of 60% at 6 months.
Antimicrobials
Without ongoing infection with urease-producing bacterial struvite, stones cannot grow and, if urine can be sterilized, may actually regress in size. [593] [605] Long-term, culture-specific antimicrobials must be used. Optimally, the urine will be sterilized; however, this will rarely occur because it is difficult to eradicate infections in the presence of a foreign body, the stuvite stone, owing to bacteria lodging in sites relatively inaccessible to antibiotics and white cells. However, the reduction of bacterial counts will result in reduced urease production and should reduce stone growth.[606]
After surgery, the urine should be cultured, as should stone fragments. After 1 to 2 weeks of full-dose antibiotic therapy, the urine may become sterilized; the dose of antibiotics can then be decreased by 50%. This dose of antibiotics should be continued with monthly urine cultures, and they can be discontinued when there are three successive negative monthly urine cultures. The urine should continue to be cultured on a monthly basis for another year, with retreatment of any recurrent infection. [593] [607] In patients who cannot tolerate surgery, chronic suppressive antibiotics can be used in an effort to retard stone gowth.
Often, antibiotics are generally concentrated in the urine so that a sensitivity testing that measures efficacy in the serum are misleading when applied to the urine.[593] Specific testing of urine sensitivities are often required. The quinolones and ampicillin are often effective against the urease-splitting organisms found in the urine. With continued treatment, resistance may develop, making antimicrobial therapy less efficacious.
Lavage Chemolysis
In addition to antimicrobial therapy, medical treatment may involve chemolysis of the formed stone. [593] [608] In chemolysis, the stone is dissolved by irrigating the renal collecting system through a nephrostomy tube or uretereal catheter with an acidic solution containing citrate and more recently magnesium. The lowered pH dissolves the stone, and the citrate binds the released calcium, keeping it soluble for excretion. Magnesium appears to reduce pelvic irritation.
This technique was first used in the 1930s. [609] [610] With modern extracorporeal shock-wave lithotripsy (ESWL) and advanced percutaneous techniques, this form of therapy is currently rarely used, although it may have a role in dissolution of residual stone fragments. The most commonly used solution is hemiacidrin, which has a pH of 3.9 and contains citric acid, calcium carbonate, gluconic acid, magnesium hydrocarbonate, and magnesium acid citrate.[593] Initially, there were reports of successful dissolution of calculi; however, four deaths were reported after renal pelvic irrigation with a 10% hemiacidrin solution, perhaps caused by infection. [611] [612] Subsequently, a number of investigators have reported successful stone dissolution with close monitoring of serum magnesium levels and inflow, outflow, and intrapelvic pressures, and absence of infection or extravasation, [613] [614] [615] [616] again this technique is rarely used in current urologic practice. [617] [618]
Urease Inhibitors
The ability of urease to split urea is necessary for struvite stone formation and subsequent growth. Although inhibition of bacterial urease has been shown to retard stone growth and to prevent new stone formation, it cannot eradicate existing stone, nor is it antimicrobial. [17] [22] [593] [608] However, when combined with antimicrobial therapy, urease inhibition provides palliative care for patients who cannot undergo definitive surgical management.
Acetohydroxamic acid (AHA) is most commonly used, although hydroxyurea is also available. Three randomized double-blind clinical trials using AHA have been reported, and in each, there was a reduction of stone growth or formation. [619] [620] [621] However, AHA requires adequate renal clearance for therapeutic efficacy and is contraindicated in patients with a serum creatinine level higher than 2 mg/dL. The kidney containing the stone, in the case of unilateral disease, must also have adequate renal function. Chronic kidney disease not only limits drug excretion but can increase the incidence of side effects, which are numerous and often lead to discontinuation of this form of therapy. Principle side effects include neurologic symptoms, GI upset, hair loss, hemolytic anemia, and rash, which resolve with discontinuation of the drug. AHA is also teratogenic. The starting dose of AHA is 250 mg by mouth twice a day. If it is well tolerated for about 1 month, the dose is increased to 250 mg by mouth three times a day.[593]
CYSTINE STONES
This stone-forming state occurs because inherited defects of a crucial transporter of dibasic amino acids lead to excessive urine excretion of cystine, a sparingly soluble amino acid. At least 100 mutations of SL3A1 and 60 mutations of SCLC7A9 have been identified. Urine cystine supersaturation is increased, and cystine crystallizes to form stones. The nature of the transporter defects is discussed in Chapter 9 .
Cystine Supersaturation
Cystine solubility rises markedly with urine pH above 6.5, and past nomograms have attempted to calculate cystine supersaturation from urine pH; however, more modern direct measurements have shown that such calculations are not accurate. [622] [623] In clinical practice,[624] such methods have proved effective in providing supersaturation estimates that can be used for guiding treatment. The goal is a sufficient volume of urine and sufficiently high pH to maintain urine cystine supersaturation below 1. This almost always requires more than 4 liters of urine volume, and a urine pH above 7, the latter achieved through potassium citrate 40 to 80 mEq daily. Reduction of protein and sodium intake can reduce urine cystine excretion. Routine urine stone risks should be assessed during treatment because incidental hypercalciuria combined with such a high pH from alkali supplements could raise calcium phosphate supersaturation and promote calcium phosphate stones or calcium phosphate overgrowths on cystine stones (so-called egg shell stones).
D-Penicillamine or α-mercaptopropionyglycine form solu-ble heterodimers with cysteine and thereby reduce the cystine available for crystallization, but both can produce loss of taste (remediable through zinc supplementation), fever, proteinuria, serum sickness reactions, and even nephritic syndrome. For these reasons, water and alkali with diet changes are always preferred and invariably tried before using drugs. Drugs are added if stone formation continues despite achievement of these conservative treatment goals.
Renal Pathology
As one might suspect, the gross papillary changes in patients with cystinuria are variable, from almost no abnormality to severe scarring and retraction ( Fig. 37-32 ). Biopsy reveals plugging of the terminal Belini ducts with crystal masses, which are composed of cystine. Presumably, the same forces that create cystine stones lead to collecting duct plugging. In the inner medullary collecting duct are additional crystal plugs, but of apatite, not cystine, and plugging with apatite extend upward even into the thin limbs of Henle (see Fig. 37-27 ). The fact that these deposits exists proves that significant calcium phosphate supersaturation must be present in the inner medullary collecting duct, presumably because of high pH, but mechanisms are not at all clear. One hypothesis is that ducts of Belini plugging leads to local obstructive uropathy with subsequent loss of normal acidification, and the resulting increase of tubule fluid pH permits apatite crystallization. As in the case of brushite stones and bypass patients, apatite crystal deposits are associated with cell injury and loss as well as interstitial fibrosis. Overall, renal function of patients with cystinuria is well known to be below normal,[625] and these histologic findings certainly provide an explanation for functional loss.
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FIGURE 37-32 Endoscopic and histologic images from cystine stone formers. Papillary morphlology of the cystine stone formers varied from normal to flattened with greatly enlarged openings (arrows, A) of the ducts of Bellini. Small sites of suburothelial white plaque (arrowhead, A), termed Randall plaque were noted. Some dilated ducts of Bellini contained protruding plugs (B) of crystalline material (double arrow). At the time of percutaneous nephrolithotomy (PNL), large masses of crystalline material were seen to lie under the urothelium (arrow, C) and, when unroofed, exposed a deposit (double arrow, C) located within a tubular lumen. C, A whole papillary biopsy that was imaged by micro computed tomography (mCT) so that sites of mineral deposit could be localized within the tissue space of the papilla. The large, dense triangular deposit was determined to have an attenuation value of 8500, a value consistent with cystine. This large deposit is similar to the deposit seen in B. Surrounding the large deposit in D are several smaller regions of mineral (double arrow) that all had an attenuation value of 22,000, a value consistent with apatite. The papillary histopathology of the cystine patients varied from normal to regions of plugging, dilation and injury of inner medullary collecting ducts (IMCD). Intraluminal plugging with crystals was noted in thin loops of Henle (arrow, E) and IMCD (double arrows, E). Cell injury was common in these crystal-filled tubules. Isolated sites of interstitial Randall plaque were observed. Transmission electron microscopy revealed tubular cell injury that ranged from an unusual amount of cellular debris admixed with crystals (asterisk, F) in the tubular lumens to frank necrosis exposing the tubular basement membrane (double arrow). Note the presence of crystalline material within the basement membrane (arrowhead, F) and in the interstitial space. Magnification, ×900 (D); ×700 (E); ×5500 (F). (All plates courtesy of Andrew P. Evan, PhD, Department of Anatomy and Cell Biology, Indiana University School of Medicine.) |
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References
1. Karniski LP, Lotscher M, Fucentese M, et al: Immunolocalization of sat-1 sulfate/oxalate/bicarbonate anion exchanger in the rat kidney. Am J Physiol 1998; 275:F79-F87.
2. Haila S, Hastbaka J, Bohling T, et al: Slc26a2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types. J Histochem Cytochem 2001; 49:973-982.
3. Jacob P, Rossman H, Lamprecht G, et al: Downregulated in adenoma mediates apical Cl-/HCO3 exchange in rabbit, rat, and human duodenum. Gastroenterology 2002; 122:709-724.
4. Widdowson EM, McCance RA, Spray CM: The chemical composition of the human body. Clin Sci 1951; 10:113-125.
5. Bushinsky DA, Monk RD: Calcium. Lancet 1998; 352:306-311.
6. Lemann Jr J, Favus MJ: Intestinal absorption of calcium, magnesium and phosphate. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 4th ed. Kelseyville: California, American Society for Bone and Mineral Research; 1999:63-67.
7. Lemann Jr J, Adams ND, Gray RW: Urinary calcium excretion in human beings. N Engl J Med 1979; 301:535-541.
8. Knauf F, Yang CL, Thomson RB, et al: Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc Natl Acad Sci USA 2001; 98:9425-9430.
9. Petrovic S, Wang Z, Ma L, et al: Colocalization of the apical Cl-/HCO3- exchanger PAT1 and gastric H-K-ATPase in stomach parietal cells. Am J Physiol 2002; 283:G1207-G1216.
10. Wang Z, Petrovic S, Mann E, Soleimani M: Identification of an apical Cl-/HCO3- exchanger in the small intestine. Am J Physiol 2002; 282:G573-G579.
11. Vincourt JB, Jullien D, Kossida S, et al: Molecular cloning of SLC26A7, a novel member of the SLC26 sulfate/anion transporter family, from high endothelial venules and kidney. Genomics 2002; 79:249-256.
12. Dudas PL, Mentone S, Greineder CF, et al: Immunolocalization of anion transporter Slc26a7 in mouse kidney. Am J Physiol 2006; 290:F937-F945.
13. Stamatelou KK, Francis ME, Jones CA, et al: Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003; 63:1817-1823.
14. Bushinsky DA: Renal Lithiasis. In: Humes HD, ed. Kelly's Textbook of Internal Medicine, 4th ed. New York: Lippincott Williams & Wilkins; 2000:1243-1248.
15. Bushinsky DA, Parker WR, Alexander KM, Krieger NS: Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release. Am J Physiol 2001; 281:F1058-F1066.
16. Bushinsky DA: Nephrolithiasis. J Am Soc Nephrol 1998; 9:917-924.
17. Monk RD, Bushinsky DA: Nephrolithiasis and Nephrocalcinosis. In: Johnson R, Frehally J, ed. Comprehensive Clinical Nephrology, 2nd ed. London: Mosby; 2003:731-744.
18. Consensus Conference: Prevention and treatment of kidney stones. JAMA 1988; 260:977-981.
19. Pak CYC: Pathophysiology of Calcium Nephrolithiasis. In: Seldin DW, Giebisch G, ed. The Kidney: Physiology and Pathophysiology, 2nd ed. New York: Raven Press; 1992:2461-2480.
20. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of kidney stones. N Engl J Med 1992; 327:1141-1152.
21. Coe FL, Favus MJ, Asplin JR: Nephrolithiasis. In: Brenner BM, ed. The Kidney, 7th ed. Philadelphia: W.B. Saunders; 2004:1819-1866.
22. Monk RD, Bushinsky DA: Kidney Stones. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, ed. Williams Textbook of Endocrinology, 10th ed. Philadelphia: W.B. Saunders; 2003:1411-1425.
23. Bushinsky DA: Recurrent hypercalciuric nephrolithiasis-Does diet help?. N Engl J Med 2002; 346:124-125.
24. Saigal CS, Joyce G, Timilsina AR: Direct and indirect costs of nephrolithiasis in an employed population: Opportunity for disease management?. Kidney Int 2005; 68:1808-1814.
25. Shattock SG: Prehistoric or predynastic Egyptian calculus. Trans Path Sci Lond 1905; 56:275-290.
26. Nordin BEC, Hodgkinson A: Urolithiasis. Adv Intern Med 1967; 13:155-182.
27. Lagergren C: Biophysical investigations of urinay calculi. Acta Radiol Scand Suppl 1956; 133:1-71.
28. Melick RA, Henneman PH: Clinical and laboratory studies of 207 consecutive patients in a kidney-stone clinic. N Engl J Med 1958; 259:307-314.
29. Prien EL: Studies in urolithiasis. J Urol 1949; 61:821-836.
30. Sutor DJ, Wooley SE, Illingworth JJ: Some aspects of the adult urinary stone problem in Great Britain and Northern Ireland. Br J Urol 1974; 46:275-288.
31. Mandel NS, Mandel GS: Urinary tract stone disease in the United States veteran population. II. Geographical analysis of variations in composition. J Urol 1989; 142:1516-1521.
32. Koide T, Oka T, Takaha M, et al: Urinary tract stone disease in modern Japan. Eur Urol 1986; 12:403-407.
33. Pak CYC, Poindexter JR, Adams-Huet B, Pearle MS: Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am J Med 2003; 115:26-32.
34. Herring LC: Observations on the analysis of ten thousand urinary calculi. J Urol 1962; 88:545-562.
35. Schneider HJ, Berg C: Epidemiologische aussagen zum harsteinleiden auf der grundlage von 100,000 harnsteinanalysen. Untr besonderer berucksichtigung der rezidive. Fortschr rep Urol Nephrol 1981; 17:34-39.
36. Brien G, Schubert G, Bick C: 10,000 analyses of urinary calculi using X-ray diffraction and polarizing microscopy. Eur Urol 1982; 8:251-256.
37. Leusmann DB, Blaschke R, Schmandt W: Results of 5035 stone analysis: A contribution to epidemiology stone disease. Scan J Urol Nephrol 1990; 24:205-210.
38. Coe FL, Bushinsky DA: Pathophysiology of hypercalciuria. Am J Physiol (Renal Fluid Electrolyte Physiol) 1984; 247:F1-F13.
39. Bushinsky DA: Calcium Nephrolithiasis. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. Washington, DC: American Society of Bone and Mineral Research; 2006:456-460.
40. Ellis H: A history of bladder stones, Oxford, Blackwell Science Publications, 1969.
41. Sutor DJ, Wooley SE, Illingworth JJ: A geographical and historical survey of the composition of urinary stones. Br J Urol 1974; 46:393-407.
42. Lieske JC, Pena de la Vega LS, Slezak JM, et al: Renal stone epidemiology in Rochester, Minnesota: An update. Kidney Int 2006; 69:760-764.
43. Moe OW: Kidney stones: Pathophysiology and medical management. Lancet 2006; 367:333-344.
44. Monk RD: Clinical approach to adults. Semin Nephrol 1996; 16:375-388.
45. Bushinsky DA: Kidney stones. Adv Intern Med 2001; 47:219-238.
46. Pak CY: Kidney stones. Lancet 1998; 351:1797-1801.
47. Soucie JM, Thun MJ, Coates RJ, et al: Demographic and geographic variability of kidney stones in the United States. Kid Int 1994; 46:893-899.
48. Harvey JA, Hill KD, Pak CY: Similarity of urinary risk factors among stone-forming patients in five regions of the United States. J Lithotr Stone Dis 1990; 2:124-132.
49. Taylor EN, Stampfer MJ, Curhan GC: Obesity, weight gain, and the risk of kidney stones. JAMA 2005; 293:455-462.
50. Hamano S, Nakatsu H, Suzuki N, et al: Kidney stone disease and risk factors for coronary heart disease. Int J Urol 2005; 12:859-863.
51. Clubbe WH: Family disposition to urinary concretions. Lancet 1874; 1:823.
52. Gram HC: The heredity of oxalic urinary calculi. Acta Med Scand 1932; 78:268-281.
53. McGeown MG: Heredity in renal stone disease. Clin Sci 1960; 19:465-471.
54. Resnick M, Pridgen DB, Goodman HO: Genetic predisposition to formation of calcium oxalate renal calculi. N Engl J Med 1968; 278:1313-1318.
55. Trinchieri A, Mandressi A, Luongo P, et al: Familial aggregation of renal calcium stone disease. J Urol 1988; 139:478-481.
56. Ljunghall S, Danielson BG, Fellstrom B, et al: Family history of renal stones in recurrent stone patients. Br J Urol 1985; 57:370-374.
57. Curhan GC, Willett WC, Knight EL, Stampfer MJ: Dietary factors and the risk of incident kidney stones in younger women: Nurses' Health Study II. Arch Intern Med 2004; 164:855-891.
58. Curhan GC, Willett WC, Rimm EB, Stampfer MJ: Family history and risk of kidney stones. J Am Soc Neph 1997; 8:1568-1573.
59. Edvardsson V, Elidottir H, Indridason OS, Palsson R: High incidence of kidney stones in Icelandic children. Pediatr Nephrol 2005; 20:940-944.
60. Coe FL, Parks JH, Moore ES: Familial idiopathic hypercalciuria. N Engl J Med 1979; 300:337-340.
61. Mehes K, Szelid Z: Autosomal dominant inheritance of hypercalciuria. Eur J Pediatr 1980; 133:239-242.
62. Pak CYC, McGuire J, Peterson R, et al: Familial absorptive hypercalciuria in a large kindred. J Urol 1981; 126:717-719.
63. Favus MJ: Familial forms of hypercalciuria. J Urol 1989; 141:719-722.
64. Goodman HO, Holmes RP, Assimos DG: Genetic factors in calcium oxalate stone disease. J Urol 1995; 153:301-307.
65. Griffin DG: A review of the heritablility of idiopathic nephrolithiasis. J Clin Pathol 2004; 57:793-796.
66. Liew SH, Elsner H, Spector TD, Hammond CJ: The first “classical” twin study? Analysis of refractive error using monozygotic and dizygotic twins published in 1922. Twin Res Hum Genet 2005; 8:198-200.
67. Kyvik KO, Christensen K, Skytthe A, et al: The Danish Twin Register. Dan Med Bull 1996; 43:467-470.
68. Kaprio J, Pulkkinen L, Rose RJ: Genetic and environmental factors in health-related behaviours: Studies on Finnish twins and twin families. Twin Res 2002; 5:366-371.
69. Yang H, Li X, Cao W, et al: Chinese National Twin Registry as a resource for genetic epidemiologic studies of common and complex diseases in China. Twin Res 2002; 5:347-351.
70. Goldfarb DS, Fischer ME, Keich Y, Goldberg J: A twin study of genetic and dietary influences on nephrolithiasis: A report from the Vietnam Era Twin (VET) Registry. Kidney Intl 2005; 67:1053-1061.
71. Dawson-Hughes B, Harris SS, Finnerman S: Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J Clin Endocrinol Metab 1995; 80:3657-3661.
72. Wishart JM, Horowitz M, Need AG, et al: Relations between calcium intake calcitrol, polymorphisms of the vitamin D receptor gene, and calcium absorption in premenopausal women. Am J Clin Nutr 1997; 65:798-802.
73. Jackman SV, Kibel AS, Ovuworie CA, et al: Familial calcium stone disease: Taql polymorphism and the vitamin D receptor. J Endourol 1999; 13:313-316.
74. Nishijima S, Sugaya K, Naito A, et al: Association of vitamin D receptor gene polymorphism with urolithiasis. J Urol 2002; 167:2188-2191.
75. Heilberg IP, Teixeira SH, Martini LA, Boim MA: Vitamin D receptor gene polymophism and bone mineral density in hypercalciuric calcium-stone-forming patients. Nephron 2002; 90:51-57.
76. Chen WC, Chen HY, Lu HF, et al: Association of the vitamin D receptor gene start codon Fok I polymorphism with calcium oxalate stone disease. BJU International 2001; 87:168-171.
77. Vezzoli G, Soldati L, Proverbio MC, et al: Polymorphism of vitamin D receptor gene start codon in patients with calcium kidney stones. J Nephrol 2002; 15:158-164.
78. Mossetti G, Vuotto P, Redina D, et al: Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 2003; 253:194-200.
79. Zerwekh JE, Hughes MR, Reed BY, et al: Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. J Clin Endocrinol Metab 1995; 80:2960-2965.
80. Zerwekh JE, Reed BY, Heller HJ, et al: Normal vitamin D receptor concentration and responsiveness to 1,25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria. Miner Electrolyte Metab 1998; 24:307-313.
81. Chen WC, Chen HY, Hsu CD, et al: No association of vitamin D receptor gene BsmI polymorphisms with calcium oxalate stone formation. Mol Urol 2001; 5:7-10.
82. Scott P, Ouimet D, Valiquette L, et al: Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation. J Am Soc Nephrol 1999; 10:1007-1013.
83. Haseman J, Elston R: The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 1972; 2:3-19.
84. Risch N: Linkage strategies for geneticall complex trait. I. Multilocus models. Am J Hum Genet 1990; 46:222-228.
85. Scott P, Ouimet D, Proulx Y, et al: The 1 alpha-hydroxylase locus is not linked to calcium stone formation or calciuric phenotypes in French-Canadian families. J Am Soc Nephrol 1998; 9:425-432.
86. Lerolle N, Coulet F, Lantz B, et al: No evidence for point mutations of the calcium-sensing receptor in familial idiopathic hypercalciuria. Nephrol Dial Transplant 2001; 16:2317-2322.
87. Reed BY, Heller HJ, Gitomer WL, Pak CY: Mapping a gene defect in absorptive hypercalciuria to chromosome 1q23.3-q24. J Clin Endocrinol Metab 1999; 84:3907-3913.
88. Reed BY, Gitomer WL, Heller HJ, et al: Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab 2002; 87:1476-1485.
89. Milliner DS: The primary hyperoxalurias: An algorithm for diagnosis. Am J Nephrol 2005; 25:154-160.
90. Hallson PC, Rose GA, Sulaiman S: Magnesium reduces calcium oxalate crystal formation in human whole urine. Clin Sci (Lond) 1982; 62:17-19.
91. Pak CYC, Hayashi Y, Finlayson B: Estimation of the state of saturation of brushite and calcium oxalate in urine: A comparison of three methods. J Lab Clin Med 1977; 89:891-909.
92. Robertson WG, Peacock M, Nordin BEC: Activity products in stone-forming and non-stone-forming urine. Clin Sci 1968; 34:579-594.
93. Werness PG, Brown CM, Smith LH, Finlayson B: Equil2: A BASIC computer program for the calculation of urinary saturation. J Urol 1985; 134:1242-1244.
94. Asplin J, Parks J, Lingeman J, et al: Supersaturation and stone composition in a network of dispersed treatment sites. J Urol 1998; 159:1821-1825.
95. Parks JH, Coward M, Coe FL: Correspondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Int 1997; 51:894-900.
96. Robertson WG, Peacock M, Nordin BEC: Calcium oxalate crystaluria and urine saturation in recurrent renal stone formers. Clin Sci 1971; 40:365-374.
97. Robertson WG, Peacock M, Marshall RW, et al: Saturation-inhibition index as a measure of the risk of calcium oxalate stone formation in the urinary tract. N Engl J Med 1976; 294:249-252.
98. Marshall RW, Cochran M, Robertson WG, et al: The relation between the concentration of calcium salts in the urine and renal stone composition in patients with calcium-containing renal stones. Clin Sci 1972; 43:433-441.
99. Pak CYC, Holt K: Nucleation and growth of brushite and calcium oxalate in urine of stone formers. Metabolism 1976; 25:665-673.
100. Weber DV, Coe FL, Parks JH, et al: Urinary saturation measurements in calcium nephrolithiasis. Ann Intern Med 1979; 90:180-184.
101. Hautmann R, Lehmann A, Komor S: Calcium and oxalate concentrations in human renal tissue: The key to the pathogenesis of stone formation. J Urol 1980; 123:317-319.
102. Asplin JR, Mandel NS, Coe FL: Evidence for calcium phosphate supersaturation in the loop of Henle. Am J Physiol 1996; 270:F604-F613.
103. Asplin JR, Parks JH, Chen MS, et al: Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int 1999; 59:1505-1516.
104. Asplin JR, Parks JH, Nakagawa Y, et al: Reduced crystallization inhibition by urine from women with nephrolithiasis. Kidney Int 2002; 61:1821-1829.
105. Nielson AE: Kinetics of precipitation. In: Belcher R, Gordon L, ed. International Series of Monographs on Analytical Chemistry, 1st ed. New York: Pergamon Press; 1964:72-85.
106. Pak CY, Arnold LH: Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate. Proc Soc Exp Biol Med 1975; 149:930-932.
107. Coe FL, Lawton RL, Goldstein RB, Tembe V: Sodium urate accelerates precipitation of calcium oxalate in vitro. Proc Soc Exp Biol Med 1975; 149:926-929.
108. Coe FL, Raisen L: Allopurinol treatment of uric-acid disorders in calcium-stone formers. Lancet 1973; 1:129-131.
109. Coe FL: Hyperuricosuric calcium oxalate nephrolithiasis. Kidney Int 1978; 13:418-426.
110. Fleisch H, Bisaz S: Isolation from urine of pyrophosphate, a calcification inhibitor. Am J Physiol 1962; 203:671-675.
111. Russell RGG, Fleisch H: Inhibitors in urinary stone disease: Role of pyrophosphate in urinary calculi. In: Cifuentes-Delatte L, Rapado A, Hodgkinson A, ed. Urinary Calculi, New York: S Karger; 1973:307-312.
112. Deganello S, Coe F: Epitaxy between uric and whewellite: Experimental verification. Neves Jb Miner Monat 1983; 6:270-276.
113. Meyer JL, Bergert JH, Smith LH: Epitaxial relationships in urolithiasis: The brushite-whewellite system. Clin Sci (Colch) 1977; 52:143-148.
114. Meyer JL, Bergert JH, Smith LH: Epitaxial relationships in urolithiasis: The calcium oxalate monohydrate-hydroxyapatite system. Clin Sci Molec Med 1975; 49:369-374.
115. Randall A: The origin and growth of renal calculi. Ann Surg 1937; 105:1009-1027.
116. Low RK, Stoller ML: Endoscopic mapping of renal papillae for Randall's plaques in patients with urinary stone disease. J Urol 1997; 158:2062-2064.
117. Coe FL, Evan A, Worcester E: Kidney stone disease. J Clin Invest 2005; 115:2598-2608.
118. Evan AP, Coe FL, Rittling SR: Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: Osteopontin localization. Kidney Int 2005; 68:145-154.
119. Evan AP, Lingeman JE, Coe FL: Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kid Int 2005; 67:576-591.
120. Evan AP, Coe FL, Lingeman J, Worcester EA: Insights on the pathology of kidney stone formation. Urol Res 2005; 33:383-389.
121. Evan AP, Lingeman JE, Coe FL, et al: Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest 2003; 111:607-616.
122. Kuo RL, Lingeman JE, Evan AP, et al: Urine calcium and volume predict coverage of renal papilla by Randall's plaque. Kidney Int 2003; 64:2150-2154.
123. Robertson WG, Peacock M, Nordin BEC: Inhibitors of the growth and aggregation of calcium oxalate crystals in vitro. Clin Chim Acta 1973; 43:31-37.
124. Finlayson B, Reid F: The expectation of free and fixed particles in urinary stone disease. Invest Urol 1978; 15:442-448.
125. Lieske JC, Walsh-Reitz MM, Toback FG: Calcium oxalate monohydrate crystals are endocytosed by renal epithelial cells and induce proliferation. Am J Physiol 1992; 262:F622-F630.
126. Lieske JC, Toback FG: Regulation of renal epithelial cell endocytosis of calcium oxalate monohydrate crystals. Am J Physiol 1993; 264:F800-F807.
127. Kohjimoto Y, Ebisuno S, Tamura M, et al: Interactions between calcium oxalate monohydrate crystals and Madin-Darby canine kidney cells. Urol Res 1996; 24:193-199.
128. Lieske JC, Toback FG, Deganello S: Face selective adhesion of calcium oxalate dihydrate crystals to renal eptithelial cells. Calcif Tissue Int 1996; 58:195-200.
129. Lieske JC, Toback FG, Deganello S: Direct nucleation of calcium oxalate dihydrate crystals onto the surface of living renal epithelial cells in culture. Kidney Int 1998; 54:796-803.
130. Bigelow MW, Wiessner JH, Kleinman JG, et al: Surface exposure of phosphatidylserine increases calcium oxalate attachment to IMCD cells. Am J Physiol 1997; 272:F55-F62.
131. Lieske JC, Leonard R, Toback FG: Adhesion of calcium oxalate monohydrate crystals to renal epithelial cells is inhibited by specific anions. Am J Physiol 1995; 268:F604-F612.
132. Daudon M, Hennequin C, Bader C, et al: Inhibitors of crystallization. Adv Nephrol Necker Hosp 1995; 24:167-216.
133. Urivetzky M, Anna PS, Smith AD: Plasma osteocalcin levels in stone disease: A potential aid in the differential diagnosis of calcium nephrolithiasis. J Urol 1988; 139:12-14.
134. Johansson G, Backman U, Danielson BG, et al: Effects of magnesium hydroxide in renal stone disease. J Am Coll Nutr 1982; 1:179-185.
135. Li MK, Blacklock NJ, Garside J: Effects of magnesium on calcium oxalate crystallization. J Urol 1985; 133:123-125.
136. Wilson JW, Werness PG, Smith LH: Inhibitors of crystal growth of hydroxyapatite: A constant composition approach. J Urol 1985; 134:1255-1258.
137. Massey L: Magnesium therapy for nephrolithiasis. Magnes Res 2005; 18:123-126.
138. Robertson WG, Scurr DS: Modifiers of calcium oxalate crystallization found in urine. J Urol 1986; 135:1322-1326.
139. Rodgers AL, Garside J: The nucleation and growth kinetics of calcium oxalate in the presence of some synthetic urine constituents. Invest Urol 1981; 18:484-488.
140. Hallson PC, Kasidas GP: The inhibitory activity of some citrate analogues upon calcium crystalluria: Observations using an improved evaporation technique. Urol Int 1996; 57:43-47.
141. Hess B: Simultaneous measurements of calcium oxalate crystal nucleation and aggregation: Impact of various modifiers. Urol Res 1995; 23:231-238.
142. Nicar MJ, Hill K, Pak CYC: Inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro. J Bone Miner Res 1987; 2:215-220.
143. Tiselius HG, Fornander A, Nilsson M: The effects of citrate and urine on calcium oxalate crystal aggregation. Urol Res 1993; 21:363-366.
144. Barcelo P, Wuhl O, Servitge E, et al: Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993; 150:1761-1764.
145. Ettinger B, Pak CY, Citron JT, et al: Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urology 1997; 158:2069-2073.
146. Hofbauer J, Hobarth K, Szabo N, Margerger M: Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis-A prospective randomized study. Br J Urol 1994; 73:362-365.
147. Whalley NA, Meyers AM, Martins M, Margolius LP: Long-term effects of potassium citrate therapy on the formation of new stones in groups of recurrent stone formers with hyprocitraturia. Br J Urol 1996; 78:10-14.
148. Pak CY: Citrate and renal calculi: An update. Min Electrolyte Metab 1994; 20:371-377.
149. Pak CYC, Fuller C, Sakhaee K, et al: Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol 1985; 134:11-19.
150. Preminger GM, Sakhaee K, Skurla C, Pak CY: Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985; 134:20-23.
151. Greischar ANY, Coe FL: Influence of urine pH and citrate concentration on the upper limit of metastability for calcium phosphate. J Urol 2003; 169:867-870.
152. Hamm LL: Renal handling of citrate. Kidney Int 1990; 38:728-735.
153. Bataille P, Achard JM, Fournier A, et al: Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers. Kidney Int 1991; 39:1193-1205.
154. Lemann Jr J, Litzow JR, Lennon EJ: The effects of chronic acid loads in normal man: Further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. J Clin Invest 1966; 45:1608-1614.
155. Allen LH, Oddoye EA, Margen S: Protein-induced hypercalciuria: A longer term study. Am J Clin Nutr 1979; 32:741-749.
156. Licata A, Bou E, Bartter FC, Cox J: Effects of dietary protein on urinary calcium in normal subjects and in patients with nephrolithiasis. Metabolism 1979; 28:895-900.
157. Meyer JL, Smith LH: Growth of calcium oxalate crystals: II. Inhibition by natural urinary crystal growth inhibitors. Invest Urol 1975; 13:36-39.
158. Schwille PO, Rumenapf G, Wolfel G, et al: Urinary pyrophosphate in patients with recurrent urolithiasis and in healthy controls: A reevaluation. J Urol 1988; 140:239-245.
159. Ito H, Coe FL: Acidic peptide and polyribonucleotide crystal growth inhibitors in human urine. Am J Physiol 1977; 233:F455-F463.
160. Mazzali M, Kipari T, Ophascharoensuk V, et al: Osteopontin-A molecule for all seasons. QJM 2002; 95:3-13.
161. Wesson JA, Johnson RJ, Mazzali M, et al: Osteopontin Is a Critical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules. J Am Soc Nephrol 2003; 14:139-147.
162. Mo L, Huang HY, Zhu XH, et al: Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kid Int 2004; 66:1159-1166.
163. Min W, Shiraga H, Chalko C, et al: Quantitative studies of human urinary excretion of uropontin. Kid Int 1998; 53:189-193.
164. Shiraga H, Min W, VanDusen WJ, et al: Inhibition of calcium oxalate crystal growth in vitro by uropontin: another member of the aspartic acid-rich protein superfamily. Proc Natl Acad Sci U S A 1992; 89:426-430.
165. Hunter GK, Hauschka PV, Poole AR, et al: Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochem J 1996; 317:59-64.
166. Goldberg HA, Warner KJ, Stillman MJ, Hunter GK: Determination of the hydroxyapatite-nucleating region of bone sialoprotein. Conn Tiss Res 1996; 35:385-392.
167. Goldberg HA, Hunter GK: The inhibitory activity of osteopontin on hydroxyapatite formation in vitro. Ann N Y Acad Sci 1995; 760:305-308.
168. Hunter GK, Kyle CL, Goldberg HA: Modulation of crystal formation by bone phosphoproteins: Structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem J 1994; 300:723-728.
169. Hunter GK, Goldberg HA: Nucleation of hydroxyapatite by bone sialoprotein. Proc Natl Acad Sci U S A 1993; 90:8562-8565.
170. Kleinman JG, Beshensky A, Worchester EM, Brown D: Expression of osteopontin, a urinary inhibitor of stone mineral crystal growth, in rat kidney. Kidney Int 1995; 47:1585-1596.
171. Asplin J, Arsenault D, Parks JH, et al: Contribution of human uropontin to inhibition of calcium oxalate crystallization. Kidney Int 1998; 53:194-199.
172. Constable AR, Joekes AM, Kasidas GP, et al: Plasma level and renal clearance of oxalate in normal subjects and in patients with primary hyperoxaluria or chronic renal failure or both. Clin Sci (Lond) 1979; 56:299-304.
173. Evan AP, Bledsoe SB, Smith SB, Bushinsky DA: Calcium oxalate crystal localization and osteopontin immunostaining in genetic hypercalciuric stone-forming rats. Kidney Int 2004; 65:154-161.
174. Serafini-Cessi F, Malagolini N, Cavallone D: Tamm-Horsfall glycoprotein: Biology and clinical relevance. Am J Kidney Dis 2003; 42:658-676.
175. Asplin J, Deganello S, Nakagawa YN, Coe FL: Evidence that nephrocalcin and urine inhibit nucleation of calcium oxalate monohydrate crystals. Am J Physiol 1991; 261:F824-F830.
176. Hess B, Nakagawa Y, Coe FL: Inhibition of calcium oxalate monohydrate crystal aggregation by urine proteins. Am J Physiol 1989; 257:F99-F106.
177. Worcester EM, Nakagawa Y, Wabner CL, et al: Crystal adsorption and growth slowing by nephrocalcin, albumin, and Tamm-Horsfall protein. Am J Physiol 1988; 255:F1197-F1205.
178. Stapleton AM, Timme TL: Gene expression of prothrombin in the human kidney and its potential relevance to kidney stone disease. Br J Urol 1998; 81:666-671.
179. Doyle IR, Marshall VR, Dawson CJ, Ryall RL: Calcium oxalate crystal matrix extract: The most potent macromolecular inhibitor of crystal growth and aggregation yet tested in undiluted human urine in vitro. Urol Res 1995; 23:53-62.
180. Stapleton AM, Ryall RL: Blood coagulation proteins and urolithiasis are linked: Crystal matrix protein is the F1 activation peptide of human prothrombin. Br J Urol 1995; 75:712-719.
181. Stapleton AM, Dawson CJ, Grover PK, et al: Further evidence linking urolithiasis and blood coagulation: urinary prothrombin fragment 1 is present in stone matrix. Kidney Int 1996; 49:880-888.
182. Durrbaum D, Rodgers AL, Sturrock ED: A study of crystal matrix extract and urinary prothrombin fragment 1 from a stone-prone and stone-free population. Urol Res 2001; 29:83-88.
183. Ebisuno S, Nishihata M, Inagaki T, et al: Bikunin prevents adhesion of calcium oxalate crystal to renal tubular cells in hyman urine. J Am Soc Neph 1999; 10:S436-S440.
184. Okuyama M, Yamaguchi S, Yachiku S: Identification of bikunin isolated from human urine inhibits calcium oxalate crystal growth and its localization in the kidneys. Int J Urol 2003; 10:530-535.
185. Dawson CJ, Grover PK, Kanellos J, et al: Inter-a-trypsin inhibitor in calcium stones. Clin Sci 1998; 95:187-193.
186. Marengo SR, Resnick M, Yang L: Differential expression of urinary inter-alpha-trypsin inhibitor trimers and dimers in normal compared to active calcium oxalate stone forming men. J Urol 1998; 159:1444-1450.
187. Nakagawa Y, Abram V, Kezdy FJ, et al: Purification and characterization of the principal inhibitor of calcium oxalate monohydrate crystal growth in human urine. J Biol Chem 1983; 258:12594-12600.
188. Nakagawa Y, Otsuki T, Coe FL: Elucidation of multiple forms of nephrocalcin by 31P-NMR spectrometer. FEBS Lett 1989; 250:187-190.
189. Nakagawa Y, Ahmed M, Hall SL, et al: Isolation from human calcium oxalate renal stones of nephrocalcin, a glycoprotein inhibitor of calcium oxalate crystal growth. Evidence that nephrocalcin from patients with calcium oxalate nephrolithiasis is deficient in gamma-carboxyglutamic acid. J Clin Invest 1987; 79:1782-1787.
190. Hess B, Nakagawa Y, Coe FL: A new spectrophotometric method for measuring calcium oxalate monohydrate crystal aggregation in the absence of supersaturation: inhibitory effects of urinary glycoproteins. Urol Res 1989; 17:149-150.
191. Nakagawa Y, Parks JH, Kezdy FJ, Coe FL: Molecular abnormality of urinary glycoprotein crystal growth inhibitor in calcium nephrolithiasis. Trans Assoc Am Physicians 1985; 98:281-289.
192. Chutipongtanate S, Nakagawa Y, Sritippayawan S, et al: Identification of human urinary trefoil factor 1 as a novel calcium oxalate crystal growth inhibitor. J Clin Invest 2005; 115:3613-3622.
193. Pillay SN, Asplin JR, Coe FL: Evidence that calgranulin is produced by kidney cells and is an inhibitor of calcium oxalate crystallization. Am J Physiol 1998; 275:F255-F261.
194. Bergsland KJ, Kelly JK, Coe BJ, Coe FL: Urine protein markers distinguish stone-forming from non stone-forming relatives of calcium stone formers. Am J Physiol Renal Physiol 2006; 291:F530-F536.
195. Teichman JMH: Acute renal colic from ureteral calculus. N Engl J Med 2004; 350:684-693.
196. Hubner WA, Irby P, Stroller ML: Natural history and current concepts for the treatment of small ureteral calculi. Eur Urol 1993; 24:172-176.
197. Miller OF, Kane CJ: Time to stone passage for observed uretral calculi: a guide for patient education. J Urol 1999; 162:688-691.
198. Ueno A, Kawamura T, Wgawa A, Takayasu H: Relation of spontaneous passage of ureteral calculi to size. Urology 1977; 10:544-546.
199. Morse RM, Resnick MI: Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol 1991; 145:263-265.
200. Segura JW, Preminger GM, Assimos DG, et al: Ureteral Stones Clinical Guidelines Panel summary report on the management of ureteral calculi. J Urol 1997; 158:1915-1921.
201. Segura JW, Patterson DE, LeRoy AJ, et al: Percutaneous removal of kidney stones: Review of 1000 cases. J Urol 1985; 134:1077-1081.
202. Weisberg LS, Bloom PB, Simmons RL, Viner ED: Loin pain hematuria syndrome. Am J Nephrol 1993; 13:229-237.
203. Spetie DN, Nadasdy T, Nadasdy G, et al: Proposed pathogenesis of idiopathic loin pain-hematuria syndrome. Am J Kidney Dis 2006; 47:419-427.
204. Sheil AG, Chui AK, Verran DJ, et al: Evaluation of the loin pain/hematuria syndrome treated by renal autotransplantation or radical renal neurectomy. Am J Kidney Dis 1998; 32:215-220.
205. Stamatelou K, Francis ME, Jones CA, et al: Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kid Int 2003; 63:1817-1823.
206. Shuster J, Scheaffer RL: Economic impact of kidney stones in white male adults. Urology 1984; 24:327-331.
207. Trinchieri A, Ostini F, Nespoli R, et al: A prospective study of recurrence rate and risk factor for recurrence after a first renal stone. J Urol 1999; 162:27-30.
208. Strauss AL, Coe FL, Deitsch L, et al: Factors that predict relapse of calcium nephrolithasis during treatment: A prospective study. Am J Med 1982; 72:17-24.
209. Pak CY: Should patients with single remal stone occurrence undergo diagnostic evaluation?. J Urol 1982; 127:855-858.
210. Lonsdale K: Human stones. Science 1968; 159:1199-1207.
211. Wu DS, Stoller ML: Indinavir urolithiasis. Curr Opin Urol 2000; 10:557-561.
212. White DJ, Nancollas GH: Triamterene and renal stone formation: the influence of triamterene and triamterene stones on calcium oxalate crystallization. Calcif Tissue Int 1987; 40:79-84.
213. Tiselius HG, Larsson L: Calcium phosphate: An important crystal phase in patients with recurrent stone formation?. Urol Res 1993; 21:175-180.
214. Mandel N, Madel I, Fryjoff K, et al: Conversion of calcium oxalate to calcium phosphate with recurrent stone episodes. J Urol 2003; 169:2026-2029.
215. Ramakumar S, Patterson DE, LeRoy AJ, et al: Prediction of stone composition from plain radiographs: a prospective study. J Endourol 1999; 13:397-401.
216. Smith RC, Verga M, McCarthy S, Rosenfield AT: Diagnosis of acute flank pain: value of unenhanced helical CT. Am J Roentgenol 1996; 166:97-101.
217. Heneghan JP, McGuire KA, Leder RA, et al: Helical CT for nephrolithiasis and ureterolithiasis: comparison of conventional and reduced radiation-dose techniques. Radiology 2003; 229:575-580.
218. Yagisawa T, Chandhoke PS, Fan J: Metabolic risk factors in patients with first-time and recurrent stone formation as determined by comprehensive metabolic evaluation. Urology 1998; 52:750-755.
219. Coe FL, Keck J, Norton ER: The natural history of calcium urolithiasis. JAMA 1977; 238:1519-1523.
220. Pak CYC, Ohata M, Lawrence EC, Snyder W: The hypercalciurias: causes, parathyroid functions, and diagnostic criteria. J Clin Invest 1974; 54:387-400.
221. Pak CYC, Kaplan R, Bone H: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med 1975; 292:497-500.
222. Lawoyin S, Sismilich S, Browne R, Pak CY: Bone mineral content in patients with calcium urolithiasis. Metabolism 1979; 28:1250-1254.
223. Pietschmann F, Breslau NA, Pak CYC: Reduced vertebral bone density in hypercalciuric nephrolithiasis. J Bone Miner Res 1992; 7:1383-1388.
224. Hosking DH, Erickson SB, Van Den Berg CJ, et al: The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1983;1115-1118.
225. Lemann Jr J, Litzow JR, Lennon EJ: Studies of the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man. J Clin Invest 1967; 46:1318-1328.
226. Muldowney FP, Freaney R, Moloney MF: Importance of dietary sodium in the hypercalciuria syndrome. Kidney Int 1982; 22:292-296.
227. Breslau NA, McGuire JL, Zerwekh JE, Pak CYC: The role of dietary sodium on renal excretion and intestinal absorption of calcium and on vitamin D metabolism. J Clin Endocrinol Metab 1982; 55:369-373.
228. Lemann Jr J, Worcester EA, Gray RW: Hypercalciuria and stones. (Finlayson colloquium on urolithiasis). Am J Kidney Dis 1991; 17:386-391.
229. Uribarri J, Oh MS, Carroll HJ: The first kidney stone. Kidney Int 1989; 111:1006-1009.
230. Lemann Jr J, Pleuss JA, Worcester EA, et al: Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996; 49:200-208.(Erratum: Kidney International: 50:341,1996)
231. Meschi T, Schianchi T, Ridolo E, Adorni G, et al: Body weight, diet and water intake in preventing stone disease. Urol Int 2004; 72:29-33.
232. Meschi T, Maggiore U, Fiaccadori E, et al: The effect of fruits and vegetables on urinary stone risk factors. Kidney Int 2004; 66:2402-2410.
233. Borghi L, Schianchi T, Meschi T, et al: Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002; 346:77-84.
234. Borghi L, Meschi T, Amato F, et al: Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: A 5-year randomized prospective study. J Urol 1996; 155:839-843.
235. Brand E, Harris MM, Billion S: Cystinuria: Excretion of a cystine complex which decomposes in the urine with the liberation fo free cystine. J Biol Chem 1930; 86:315-331.
236. Pak CY, Sakhaee K, Crowther C, Brinkley L: Evidence justifying a high fluid intake in treatment of nephrolithiasis. Ann Intern Med 1980; 93:36-39.
237. Moe OW, Preisig PA: Hypothesizing on the evolutionary origins of salt-induced hypercalciuria. Curr Opin Nephrol Hypertens 2005; 14:368-372.
238. Phillips MJ, Cooke JN: Relation between urinary calcium and sodium in patients with idiopathic hypercalciuria. Lancet 1967; 1:1354-1357.
239. Timio F, Kerry SM, Anson KM, et al: Calcium urolithiasis, blood pressure and salt intake. Blood Press 2003; 12:122-127.
240. Sakhaee K, Harvey JA, Padalino PK, et al: The potential role of salt abuse on the risk for kidney stone formation. J Urol 1993; 150:310-312.
241. Amanzadeh J, Gitomer WL, Zerwekh JE, et al: Effect of high protein diet on stone-forming propensity and bone loss in rats. Kid Int 2003; 64:2142-2149.
242. Reddy ST, Wang CY, Sakhaee K, et al: Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kid Dis 2002; 40:265-274.
243. Curhan GC, Willett WC, Rimm EB, Stampfer MJ: A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993; 328:833-838.
244. Robertson WG, Heyburn PJ, Peacock M, et al: The effect of high animal protein intake on the risk of calcium stone-formation in the urinary tract. Clini Sc 1979; 57:285-288.
245. Frassetto L, Morris Jr RC, Sebastian A: Long-term persistence of the urine calcium-lowering effect of potassium bicarbonate in postmenopausal women. J Clin Endocrinol Metab 2005; 90:831-834.
246. Lemann Jr J, Bushinsky DA, Hamm LL: Bone buffering of acid and base in humans. Am J Physiol Renal Physiol 2003; 285:F811-F832.
247. Allen LH, Bartlett RS, Block GD: Reduction of renal calcium reabsorption in man by consumption of dietary protein. J Nutr 1979; 109:1345-1350.
248. Bushinsky DA: Acid-base balance and bone health. In: Holick MF, Dawson-Hughes B, ed. Nutrition and Bone Health, Totowa, NJ: Totowa Humana Press, Inc.; 2004:279-304.
249. Sutton RAL, Wong NLM, Dirks JH: Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney. Kidney Int 1979; 15:520-533.
250. Sutton RAL: Renal filtration and reabsorption of calcium. In: Coe FL, Favus MJ, Pak CYC, et al ed. Kidney Stones: Medical and Surgical Management, Philadelphia: Lippincott-Raven; 1996:223-238.
251. Sebastian A, Harris ST, Ottaway JH, et al: Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med 1994; 330:1776-1781.
252. Moe OW, Abate N, Sakhaee K: Pathophysiology of uric acid nephrolithiasis. Endo Clin North Am 2002; 31:895-914.
253. Moe OW: Uric acid nephrolithiasis: Protonation of an essential molecule?. Curr Opin Nephrol Hypertens 2006; 15:366-373.
254. Asplin JR: Uric acid stones. Semin Nephrol 1996; 16:412-424.
255. Stauffer JQ: Hyperoxaluria and intestinal disease: the role of steatorrhea and dietary calcium in regulating intestinal oxalate absorption. Digest Dis 1977; 22:921-928.
256. Curhan GC, Willett WC, Speizer FE, et al: Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med 1997; 126:497-504.
257. Bushinsky DA, Frick KK, Nehrke K: Genetic hypercalciuric stone-froming rats. Curr Opinion Nephrol Hyperten 2006; 15:403-418.
258. Coe FL, Favus MJ, Crockett T, et al: Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects. Am J Med 1982; 72:25-32.
259. Monk RD, Bushinsky DA: Pathogenesis of idiopathic hypercalciuria. In: Coe F, Favus M, Pak C, et al ed. Kidney Stones: Medical and Surgical Management, Philadelphia: Lippincott-Raven; 1996:759-772.
260. Asplin JR, Bauer KA, Kinder J, et al: Bone mineral density and urine calcium excre-tion among subjects with and without nephrolithiasis. Kidney Int 2003; 63:662-669.
261. Favus MJ, Bushinsky DA, Lemann Jr J: Regulation of calcium, magnesium and phosphate metabolism. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. Durham, NC: American Society of Bone and Mineral Research; 2006:76-83.
262. Lemann Jr J: Composition of the diet and calcium kidney stones. N Engl J Med 1993; 328:880-882.
263. Lemann Jr J: The urinary excretion of calcium, magnesium and phosphorus. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Kelseyville, CA: American Society for Bone and Mineral Research; 1990:36-39.
264. Jackson RD, LaCroix AZ, Gass M, et al: Calcium plus vitamin d supplementation and the risk of fractures. N Engl J Med 2006; 354:669-683.
265. Pak CYC, Odvina CV, Pearle MS, et al: Effect of dietary modification on urinary stone risk factors. Kidney Int 2005; 68:2264-2273.
266. Committee on Dietary Reference Intakes: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride, Washington, DC, National Academy Press, 1997.
267. Sutherland JW, Parks JH, Coe FL: Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab 1985; 11:267-269.
268. Hoenderop JGJ, Nilius B, Bindels RJM: Calcium absorption across epithelia. Physiol Revs 2005; 85:373-422.
269. Moe OW, Bonny O: Genetic hypercalciuria. J Am Soc Nephrol 2005; 16:729-745.
270. Huang CL: The transient receptor potential superfamily of ion channels. Am Soc Nephrol 2004; 15:1689-1690.
271. Bronner F, Pansu D, Stein WD: An analysis of intestinal calcium transport across the rat intestine. Am J Physiol (Gastroint and Liver Physiol) 1986; 250:G561-G569.
272. Bronner F: Mechanisms and functional aspects of intestinal calcium absorption. J Exp Zool 2003; 300:47-52.
273. Pansu D, Bellaton C, Roche C: Duodenal and ileal calcium absorption in the rat and effects of vitamin D. Am J Physiol 1983; 244:G695-G700.
274. Van Cromphaut SJ, Dewerchin M, Hoenderop JG, et al: Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci U S A 2001; 98:13324-13329.
275. Woods RJ, Tchack L: Taparia: 1,25-Dihydroxyvitamin D3 increase the expression of the CaT 1 epithelial calcium channel in the Caco-2 human intestinal cell line. BMC Physiology 2001; 1:11-18.
276. Slepchenko B, Bronner F: Modeling of transcellular calcium transport in rat duodenum points to coexistence of two mechanism of calcium entry. Am J Physiol 2001; 281:C270-C281.
277. Desplan C, Brehier A, Perret C, Thomasset M: Rat duodenal calcium binding protein mRNA: induction by 1,25-dihydroxyvitamine D3. J Steroid Biochem 1983; 19:1577-1582.
278. Duflos C, Bellaton C, Baghdassarian N, et al: 1,25-Dihydroxycholecalciferol regulates rat intestinal calbindin D9k posttranscriptionally. J Nutr 1996; 126:834-841.
279. Wasserman RH, Fullmer CS: Vitamin D and calcium transport: facts, speculations and hypothesis. J Nutr 1995; 125:1971S-1979S.
280. Wasserman RH, Smith CA, Brindak ME, et al: Vitamin D and mineral deficiencies increase the plasma membrane calcium pump of chicken intestine. Gastroenterology 1992; 102:886-894.
281. Norman DA, Fordtran JS, Brinkley LJ, et al: Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D. J Clin Invest 1981; 67:1599-1603.
282. Hebert SC, Cheng S, Geibel J: Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. Cell Calcium 2004; 35:239-247.
283. Ba J, Friedman PA: Calcium-sensing receptor regulation of renal mineral ion transport. Cell Calcium 2004; 35:229-237.
284. Simon DB, Lu Y, Choate KA, et al: Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999; 285:103-106.
285. Friedman PA: Codependence of renal calcium and sodium transport. Annu Rev Physiol 1998; 60:179-197.
286. Friedman PA: Mechanisms of renal calcium transport. Exp Nephrol 2000; 8:343-350.
287. Hemmingsen C: Regulation of renal calbindin-D28k. Pharmacol Toxicol 2000; 87(suppl3):5-30.
288. Moe OW, Huang CL: Hypercalciuria from acid load: renal mechanisms. J Neph 2006; 19:S53-S61.
289. Yeh BI, Sun TJ, Lee JZ, et al: Mechanism and molecular determinant for regulation of rabbit transient receptor potential type 5 (TRPV5) channel by extracellular pH. J Biol Chem 2003; 278:51044-51052.
290. Yeh BI, Kim YK, Jabbar W, Huang CL: Conformational changes of pore helix coupled to gating of TRPV5 by protons. EMBO Journal 2005; 24:3224-3234.
291. Sutton RAL, Walker VR: Bone resorption and hypercalciuria in calcium stone formers. Metabolism 1986; 35:485-488.
292. Heilberg IP, Weisinger JR: Bone disease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 2006; 15:394-402.
293. Liberman UA, Sperling O, Atsmon A, et al: Metabolic and calcium kinetic studies in idiopathic hypercalciuria. J Clin Invest 1968; 47:2580-2590.
294. Pacifici R, Rothstein M, Rifas L, et al: Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic and hypercalciuria. J Clin Endocrinol Metab 1990; 71:138-145.
295. Weisinger JR, Alonzo E, Bellorin-Font E, et al: Possible role of cytokines on the bone mineral loss in idiopathic hypercalciuria. Kid Int 1996; 49:244-250.
296. Ghazali A, Fuentes V, Desaint C, et al: Low bone mineral density and peripheral blood monocyte activation profile in calcium stone formers with idiopathic hypercalciuria. J Clin Endocrinol Metab 1997; 82:32-38.
297. Misael da Silva AM, dos Reis LM, Pereira RC, et al: Bone involvement in idiopathic hypercalciuria. Clin Nephrol 2002; 57:183-191.
298. Jaeger P, Lippuner K, Casez JP, et al: Low bone mass in idiopathic renal stone formers: magnitude and significance. J Bone Min Res 1994; 9:1525-1532.
299. Giannini S, Nobile M, Sartori L, et al: Bone density and skeletal metabolism are altered in idiopathic hypercalciuria. Clin Nephrol 1998; 50:94-100.
300. Tasca A, Cacciola A, Ferrarese P, et al: Bone alterations in patients with idiopathic hypercalciuria and calcium nephrolithiasis. Urology 2002; 59:865-869.
301. Heilberg IP, Martini LA, Teixeira SH, et al: Effect of etidronate treatment on bone mass of male nephrolithiasis patients with idiopathic hypercalciuria and osteopenia. Nephron 1998; 79:430-437.
302. Lauderdale DS, Thisted RA, Wen M, Favus M: Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J Bone Miner 2001; 16:1893-1898.
303. Cauley JA, Fullman RL, Stone KL, et al: Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 2005; 16:1525-1537.
304. Vezzoli G, Soldati L, Ardila M, et al: Urinary calcium is a determinant of bone mineral density in elderly men participating in the InCHIANTI study. Kid Int 2005; 67:2006-2014.
305. Giannini S, Nobile M, Dalle Carbonare L, et al: Hypercalciuria is a common and important finding inpostmenopausal women with osteoporosis. Eur J Endocrinol 2003; 149:209-213.
306. Melton LJI, Crowson CS, Khosla S, et al: Fracture risk among patients with urolithiasis: a population based cohort study. Kidney Int 1998; 53:459-464.
307. Frick KK, Bushinsky DA: Molecular mechanisms of primary hypercalciuria. J Am Soc Neph 2003; 14:1082-1095.
308. Pak CYC, Britton F, Peterson R, et al: Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med 1980; 69:19-30.
309. Coe FL, Canterbury JM, Firpo JJ, Reiss E: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 1973; 52:134-142.
310. Bordier P, Ryckewart A, Gueris J, Rasmussen H: On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med 1977; 63:398-409.
311. Shen FH, Baylink DJ, Nielsen RL, et al: Increased serum 1,25-dihydroxyvitamin D in idiopathic hypercalciuria. J Lab Clin Med 1977; 90:955-962.
312. Burckhardt P, Jaeger P: Secondary hyperparathyroidism in idiopathic renal hypercalciuria: fact or theory?. J Clin Endocrinol Metab 1981; 55:550-555.
313. Haussler MR, Baylink DJ, Hughes MR: The assay of 1,25-dihydroxy vitamin D3: physiologic and pathologic modulation of circulating hormone levels. Clin Endocrinol Metab 1976; 5:1515-1655.
314. Kaplan RA, Haussler MR, Deftos LJ, et al: The role of 1,25 dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Invest 1977; 59:756-760.
315. Gray RW, Wilz DR, Caldas AE, Lemann Jr J: The importance of phosphate in regulating plasma 1,25(OH)2 vitamin D levels in humans: studies in healthy subjects, in calcium stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 1977; 45:299-306.
316. Broadus AE, Insogna KL, Lang R, et al: Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria. N Engl J Med 1984; 311:73-80.
317. Insogna KL, Broadus AE, Dreyer BE, et al: Elevated production rate of 1,25-dihydroxyvitamin D in patients with absorptive hypercalciuria. J Clin Endocrinol Metab 1985; 61:490-495.
318. Tieder M, Modai D, Shaked U, et al: “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets: two phenotypical expressions of a common genetic defect. N Engl J Med 1987; 316:125-129.
319. Prie D, Huart V, Bakouh N, et al: Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 2002; 347:983-991.
320. Lapointe JY, Tessier J, Paquette Y, et al: NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kid Int 2006; 69:2261-2267.
321. Freundlich M, Alonzo E, Bellorin-Font E, Weisinger JR: Reduced bone mass in children with idiopathic hypercalciuria and in their asymptomatic mothers. Nephrol Dial Transplant 2002; 17:1396-1401.
322. Adams ND, Gray RW, Lemann JJ: Effects of calcitriol administration on calcium metabolism in healthy men. Kidney Int 1982; 21:90-97.
323. Maierhofer WJ, Gray RW, Cheung HS, Lemann Jr J: Bone resorption stimulated by elevated serum 1,25-(OH)2-vitamin D3 concentrations in healthy men. Kidney Int 1983; 24:555-560.
324. Karnauskas AJ, van Leeuwen JP, van den Bemd GJ, et al: Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. J Bone Min Res 2005; 20:447-454.
325. Yao J, Karnauskas AJ, Bushinsky DA, Favus MJ: Regulation of renal calcium-sensing receptor gene expression in response to 1,25(OH)2D3 in genetic hypercalciuric stone forming rats. J Am Soc Nephrol 2005; 16:1300-1308.
326. Yao J, Kathpalia P, Bushinsky DA, Favus MJ: Hyperresponsiveness of vitamin D receptor gene expression to 1,25-dihydroxyvitamin D3: A new characteristic of genetic hypercalciuric stone-forming rats. J Clin Invest 1998; 101:2223-2232.
327. Li XQ, Tembe V, Horwitz GM, et al: Increased intestinal vitamin D receptor in genetic hypercalciuric rats: a cause of intestinal calcium hyperabsorption. J Clin Invest 1993; 91:661-667.
328. Krieger NS, Stathopoulos VM, Bushinsky DA: Increased sensitivity to 1,25(OH)2D3 in bone from genetic hypercalciuric rats. Am J Physiol (Cell Physiol) 1996; 271:C130-C135.
329. Favus MJ, Karnauskas AJ, Parks JH, Coe FL: Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria. J Clin Endocrinol Metab 2004; 89:4937-4943.
330. Matlaga BR, Williams Jr JC, Kim SC: Endoscopic evidence of calculus attachment to Randall's plaque. J Urol 2006; 175:1720-1724.
331. Bushinsky DA: Nephrolithiasis: site of the initial solid phase. J Clin Invest 2003; 111:602-605.
332. Rocha AS, Magaldi JB, Kokko JP: Calcium and phosphate transport in isolated segments of rabbit Henle's loop. J Clin Invest 1977; 59:975-983.
333. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor in divalent mineral ion homeostasis. J Exp Biol 1997; 200:295-302.
334. Ettinger B, Citron JT, Livermore B, Dolman LI: Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol 1988; 139:679-684.
335. Borghi L, Meschi T, Guerra A, Novarini A: Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol 1993; 22:S78-S86.
336. Laerum E, Larsen S: Thiazide prophylaxis of urolithiasis: A double-blind study in general practice. Acta Med Scand 1984; 215:383-389.
337. Ettinger B, Tang A, Citron JT, et al: Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986; 315:1386-1389.
338. Gambaro G, Vezzoli G, Casari G, et al: Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 2004; 44:963-986.
339. Langman CB: The molecular basis of kidney stones. Curr Opin Pediatr 2004; 16:188-193.
340. Knohl SJ, Scheinman SJ: Inherited hypercalciuric syndromes: Dent's disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1). Semin Nephrol 2004; 24:55-60.
341. Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994; 265:2037-2048.
342. Bushinsky DA, Asplin JR, Grynpas MD, et al: Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2002; 61:975-987.
343. Bushinsky DA, Grynpas MD, Asplin JR: Effect of acidosis on urine supersaturation and stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2001; 59:1415-1423.
344. Bushinsky DA, Parker WR, Asplin JR: Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2000; 57:550-560.
345. Scheinman SJ, Cox JPD, Lloyd SE, et al: Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 2000; 57:232-239.
346. Hoopes RR, Reid R, Sen S, et al: Quantitative trait loci for hypercalciuria in a rat model of kidney stone disease. J Am Soc Nephrol 2003; 14:1844-1850.
347. Bushinsky DA, Neumann KJ, Asplin J, Krieger NS: Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats. Kidney Int 1999; 55:234-243.
348. Tsuruoka S, Bushinsky DA, Schwartz GJ: Defective renal calcium reabsorption in genetic hypercalciuric rats. Kidney Int 1997; 51:1540-1547.
349. Asplin JR, Bushinsky DA, Singharetnam W, et al: Relationship between supersaturation and crystal inhibition in hypercalciuric rats. Kidney Int 1997; 51:640-645.
350. Bushinsky DA, Bashir MA, Riordon DR, et al: Increased dietary oxalate does not increase urinary calcium oxalate saturation in hypercalciuric rats. Kidney Int 1999; 55:602-612.
351. Bushinsky DA, Grynpas MD, Nilsson EL, et al: Stone formation in genetic hypercalciuric rats. Kidney Int 1995; 48:1705-1713.
352. Bushinsky DA, Kim M, Sessler NE, et al: Increased urinary saturation and kidney calcium content in genetic hypercalciuric rats. Kidney Int 1994; 45:58-65.
353. Kim M, Sessler NE, Tembe V, et al: Response of genetic hypercalciuric rats to a low calcium diet. Kidney Int 1993; 43:189-196.
354. Bushinsky DA, Favus MJ: Mechanism of hypercalciuria in genetic hypercalciuric rats: inherited defect in intestinal calcium transport. J Clin Invest 1988; 82:1585-1591.
355. Bushinsky DA: Genetic hypercalciuric stone forming rats. Semin Nephrol 1996; 16:448-457.
356. Bushinsky DA: Genetic hypercalciuric stone-forming rats. Curr Opin Nephrol Hypertens 1999; 8:479-488.
357. Bushinsky DA: Bench to bedside: Lessons from the genetic hypercalciuric stone forming rat. Am J Kidney Dis 2000; 36:61-64.
358. Bushinsky DA, Asplin JR: Thiazides reduce brushite, but not calcium oxalate, supersaturation and stone formation in genetic hypercalciuric stone-forming rats. J Am Soc Nephrol 2005; 16:417-424.
359. Pak CY: Nephrolithiasis. Current Ther Endo Metab 1997; 6:572-576.
360. Bringhurst FR, Demay MB, Kronenberg HM: Hormones and disorders of mineral metabolism. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, ed. Williams Textbook of Endocrinology, 10th ed. Philadelphia: Saunders; 2002:1303-1371.
361. Bilezikian JP, Silverberg SJ: Primary hyperparathyroidism. In: Favus M, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. Washington, D.C.: ASBMR; 2006:181-185.
362. Weber CJ, Sewell CW, McGarity WC: Persistent and recurrent sporadic primary hyperparathyroidism: Histopathology, complications, and results of reoperation. Surgery 1994; 116:991-998.
363. Rosen IB, Yong JEM, Archibald SD, et al: Parathyroid cancer: clinical variations and relationships to autotransplantation. Can J Surg 1994; 37:465-469.
364. Sherwood LM, Mayer GP, Ramberg Jr CF: Regulation of parathyroid hormone secretion: proportional control by calcium, lack of effect of phosphate. Endocrinology 1968; 83:1043-1051.
365. Brown EM: PTH secretion in vivo and in vitro. Regulation by calcium and other secretagogues. Min Elect Metab 1982; 8:130-150.
366. Brown EM, MacLeod RJ: Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001; 81:239-297.
367. Brown EM, Pollock M, Hebert SC: The extracellular calcium-sensing receptor: its role in health and disease. Ann Rev Med 1998; 49:15-29.
368. Brown EM, Gamba G, Riccardi D, et al: Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 1993; 366:575-580.
369. Brown EM: Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983; 56:572-581.
370. Silver J, Naveh-Many T, Mayer H, et al: Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986; 78:1296-1301.
371. Silver J, Russell J, Sherwood LM: Regulation by vitamin D metabolites of messenger ribonucleic acid for pre-proparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A 1985; 82:4270-4273.
372. Bushinsky DA: Calcium, magnesium, and phosphorus: renal handling and urinary excretion. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 5th ed. Washington, D.C.: American Society for Bone and Mineral Research; 2003:97-105.
373. Bushinsky DA: Disorders of calcium and phosphorus homeostasis. In: Greenberg A, ed. Primer on Kidney Diseases, 4th ed. San Diego: Academic Press; 2005:120-130.
374. Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG: Genetic disorders of renal electrolyte transport. N Engl J Med 1999; 340:1177-1187.
375. Reilly RF, Ellison DH: Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 2000; 80:277-313.
376. Hoenderop JG, Nilius B, Bindels RJ: Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol 2002; 64:529-549.
377. Friedman PA, Gesek FA: Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181-F198.
378. Hoenderop JG, Muller D, Van der Kemp AW, et al: Calcitriol controls the epithelial calcium channel in kidney. J Am Soc Neph 2001; 12:1342-1349.
379. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia: Measurement, mechanisms and regulation. Physiol Rev 1995; 75:429-471.
380. Magaldi AJ, vanBaak AA, Rocha AS: Calcium transport across rat inner medullary collecting duct perfused in vitro. Am J Physiol 1989; 257:F738-F745.
381. Bengele HH, Alexander EA, Lechene CP: Calcium and magnesium transport along the inner medullary collecting duct of the rat. Am J Physiol 1980; 239:F24-F29.
382. Suki WN, Rouse D: Renal transport of calcium, magnesium, and phosphate. In: Brenner BM, ed. The Kidney, 5th ed. Philadelphia: W.B. Saunders; 1996:472-515.
383. Hoenderop JGJ, Bindels RJM: Epithelial Ca2+ and Mg2+ channels in health and disease. J Am Soc Nephrol 2005; 16:15-26.
384. Hoenderop JG, Vennekens R, Muller D, et al: Function and expression of the epithelial Ca2+ channel family: comparison of mammalian ECaC1 and 2. J Physiol 2001; 537:747-761.
385. Peng JB, Chen XZ, Berger UV, et al: Human calcium transport protein CaT1. Biochem Biophys Res Commun 2000; 278:326-332.
386. Peng JB, Chen XZ, Berger UV, et al: A rat kidney-specific calcium transporter in the distal nephron. J Biol Chem 2000; 275:28186-28194.
387. Peng JB, Brown EM, Hediger MA: Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics 2001; 76:99-109.
388. Shimizu T, Yoshitomi K, Nakamura M, Imai M: Effects of PTH, calcitonin, and cAMP on calcium transport in rabbit distal nephron segments. Am J Physiol 1990; 259:F408-F414.
389. Bindels RJM, Hartog A, Timmermans J, Van Os CH: Active Ca2+ transport in primary cultures of rabbit kidney CCD: stimulation by 1,25-dihydroxyvitamin D3 and PTH. Am J Physiol 1991; 261:F799-F807.
390. Suda T, Takahashi N, Udagawa N, et al: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endo Rev 1999; 20:345-357.
391. Suda T, Takahashi N, Martin TJ: Modulation of osteoclast differentiation. Endo Rev 1992; 13:66-80.
392. Hofbauer LC, Heufelder AE: The role of receptor activator of nuclear factor-kB ligand and osteoprotegerin in the pathogenesis and treatment of metabolic bone diseases. J Clin Endocrinol Metab 2000; 85:2355-2363.
393. Murayama A, Takeyama K, Kitanaka S, et al: Positive and negative regulations of the renal 25-hydroxyvitamin D3 1a-hydroxylase gene by parathyroid hormone, calcitonin, and 1 a,25(OH)2D3 in intact animals. Endocrinology 1999; 140:224-2231.
394. Weisinger JR, Favus MJ, Langman CB, Bushinsky DA: Regulation of 1,25-dihydroxyvitamin D3 by calcium in the parathyroidectomized, parathyroid hormone-replete rat. J Bone Miner Res 1989; 4:929-935.
395. Woodhouse NJY, Doyle FH, Joplin GF: Vitamin-D deficiency and primary hyperparathyroidism. Lancet 1971; 2:283-286.
396. Nordin BEC, Peacock M: Role of kidney in regulation of plasma-calcium. Lancet 1969; 2:1280-1283.
397. Transbol I, Hornum I, Hahnemann S, et al: Tubular reabsorption of calcium in the differential diagnosis of hypercalcemia. Acta Med Scand 1970; 188:505-522.
398. Kleeman CR, Bernstein D, Rockney R, et al: Studies on the renal clearance of diffusible calcium and the role of the parathyroid glands in its regulation. Yale J Biol Med 1961; 34:1-30.
399. Parks JH, Coe FL, Favus MJ: Hyperparathyroidism in nephrolithiasis. Arch Intern Med 1980; 140:1479-1481.
400. Pak CYC, Nicar MJ, Peterson R, et al: A lack of unique pathophysiologic background for nephrolithiasis of primary hyperparathyroidism. J Clin Endocrinol Metab 1981; 53:536-542.
401. Riccardi D, Lee WS, Lee K, et al: Localization of the extracellular Ca2+-sensing receptor and PTH/PTHrP receptor in rat kidney. Am J Physiol 1996; 271:F951-F956.
402. Hodgkinson A, Marshall RW: Changes in the composition of urinary tract stones. Invest Urol 1975; 13:F951-F956.
403. Portis AJ, Hermans K, Culhane-Pera KA, Curhan GC: Stone disease in the Hmong of Minnesota: initial description of a high-risk population. J Endourol 2004; 18:853-857.
404. Wermers RA, Khosla S, Atkinson EJ, et al: The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965-1992. Ann Intern Med 1997; 126:433-440.
405. Bilezikian JP, Brandi ML, Rubin J, Silverberg SJ: Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005; 257:6-17.
406. Mallette LE, Bilezikian JP, Heath DA, Aurbach GD: Primary hyperparathyroidism: clinical and biochemical features. Medicine 1974; 53:127-146.
407. Silverberg SJ, Shane E, Jacobs TP, et al: Nephrolithiasis and bone involvement in primary hyperparathyroidism, 1985-1990. Am J Med 1990; 89:327-334.
408. Klugman VA, Favus M, Pak CYC: Nephrolithiasis in primary hyperparathyroidism. In: Bilezikian JP, ed. The Parathyroids: Basic and Clinical Concepts, New York: Academic Press; 2001:437-450.
409. Silverberg SJ, Shane E, Jacobs TP: Primary hyperparathyroidism: 10-year course with or without parathyroid surgery. N Engl J Med 1999; 341:1249-1255.
410. Nussbaum SR, Potts JTJ: Immunoassays for parathyroid hormone 1-84 in the diagnosis of hyperparathyroidism. J Bone Miner Res 1991; 6:S43-S50.
411. Brown RC, Aston JP, Weeks I, et al: Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay. J Clin Endocrinol Metab 1987; 65:407-414.
412. Blind E, Schmidt-Gayk H, Scharla S, et al: Two-site assay of intact parathyroid hormone in the investigation of primary hyperparathyroidism and other disorders of calcium metabolism compared with a midregion assay. J Clin Endocrinol Metab 1988; 67:353-360.
413. Kaminsky NI, Broadus AE, Hardman JG, et al: Effects of parathyroid hormone on plasma and urinary adenosine 3′, 5′-monophosphate in man. J Clin Invest 1970; 49:2387-2395.
414. Neelon FA, Birch BM, Drezner M, et al: Urinary cyclic adenosine monophosphate as an aid in the diagnosis of hyperparathyroidism. Lancet 1973; 1:631-633.
415. Lafferty FW: Differential diagnosis of hypercalcemia. J Bone Miner Res 1991; 6:S59.
416. Mark SJ, Spiegel AM, Brown EM, et al: Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1978; 47:1190-1197.
417. Khosla S, Ebeling PR, Firek AF, et al: Calcium infusion suggests a “set-point” abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab 1993; 76:715-720.
418. Marx SJ, Attie MF, Levine M, et al: The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine 1981; 60:397-412.
419. Marx SJ, Spiegel AM, Brown EM, et al: Divalent cation metabolism: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. Am J Med 1978; 65:235-242.
420. National Institutes of Health: Consensus development conference statement on primary hyperparathyroidism. J Bone Miner Res 1991; 6:s9-s13.
421. Bilezikian JP, Potts Jr JT, El-Hajj Fuleihan G, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidsim: a perspective for the 21st century. J Bone Miner Res 2002; 17:N2-N11.
422. Pyrah LN, Hodgkinson A, Anderson CK: Primary hyperparathyroidism. Br J Surg 1966; 53:245-316.
423. Anderson J, Osborn SC, Tomlinson RWS, et al: Calcium dynamics of the gastrointestinal tract and bone in primary hyperparathyroidism. Q J Med 1964; 33:421-438.
424. Edvall CA: Renal function in hyperparathyroidism: A clinical study of 30 cases with special reference to selective renal clearance and renal vein catherterization. Acta Chir Scand Suppl 1958; 299:1-55.
425. McGeown MG: Effect of parathyroidectomy on the incidence of renal calculi. Lancet 1961; 1:586-587.
426. Pak CYC: Effect of parathyroidectomy on crystallization of calcium salts in urine of patients with primary hyperparathyroidism. Invest Urol 1979; 17:146-148.
427. Pratley SK, Posen S, Reeve TS: Primary hyperparathyroidism: Experience with 60 patients. Med J Aust 1973; 1:421-426.
428. Britton DC, Thompson MH, Johnston IDA, et al: Renal function following parathyroid surgery in primary hyperparathyroidism. Lancet 1971; 2:74-75.
429. Mollerup CL, Vestergaard P, Frokjaer VG, et al: Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. Br Med J 2002; 325:807-810.
430. Pak CYC, Adams-Huet B, Poindexter J, et al: Relative effect of urinary calcium and oxalate on saturation of calcium oxalate. Kid Int 2004; 66:2032-2037.
431. Kasidas GP, Rose GA: Measurement of plasma oxalate in healthy subjects and in patients with chronic renal failure using immobilized oxalate oxidase. Clin Chim Acta 1986; 154:49-58.
432. Jaeger P, Robertson WG: Role of dietary intake and intestinal absorption of oxalate in calcium stone formation. Nephron Phys 2004; 98:64-71.
433. Hatch M, Freel RW: Intestinal transport of an obdurate anion: Oxalate. Urol Res 2005; 33:1-16.
434. Holmes RP, Goodman HO, Assimos DG: Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int 2001; 59:270-276.
435. Hatch M, Freel RW, Vaziri ND: Intestinal excretion of oxalate in chronic renal failure. J Am Soc Neph 1994; 5:1339-1343.
436. Hatch M, Freel RW, Vaziri ND: Characteristics of the transport of oxalate and other ions across rabbit proximal colon. Pfleugers Arch 1993; 423:206-212.
437. Hatch M, Freel RW, Vaziri ND: Mechanisms of oxalate absorption and secretion across the rabbit distal colon. Pfleugers Arch 1994; 426:101-109.
438. Hautmann RE: The stomach: a new and powerful oxalate absorption site in man. J Urol 1993; 149:1401-1404.
439. Chen Z, Ye Z, Zeng L, Yang W: Clinical investigation on gastric oxalate absorption. Chin Med J 2003; 116:1749.
440. Diamond KL, Fox CC, Barch DH: Role of cecal pH in intestinal oxalate absorption in the rat. J Lab Clin Med 1988; 112:352-356.
441. Hatch M, Freel RW, Goldner AM, Earnest DL: Oxalate and chloride absorption by the rabbit colon: sensitivity to metabolic and anion transport inhibitors. Gut 1984; 25:232-237.
442. Knickelbein RG, Aronson PS, Dobbins JW: Oxalate transport by anion exchange across rabbit ileal brush border. J Clin Invest 1986; 77:170-175.
443. Freel RW, Hatch M, Earnest DL, Goldner AM: Oxalate transport across the isolated rat colon. Biochem Biophys Acta 1980; 600:838-843.
444. Hoppe B, von Unruh G, Laube N, et al: Oxalate degrading bacteria: new treatment option for patients with primary and secondary hyperoxaluria?. Urol Res 2005; 33:372-375.
445. Hatch M, Cornelius M, Allison H, Sidhu H: Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion. Kidney Int 2006; 69:691-698.
446. Wang Z, Wang T, Petrovic S, et al: Renal and intestinal transport defects in Slc26a6-null mice. Am J Physiol Cell Physiol 2005; 288:C957-C965.
447. Jiang Z, Asplin JR, Evan AP, et al: Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet 2006; 38:474-478.
448. Freel RW, Hatch M, Green M, Soleimani M: Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice. Am J Physiol 2006; 290:G719-G728.
449. Barilla DE, Notz C, Kennedy D, Pak CY: Renal oxalate excretion folowing oral oxalate loads in patients with ileal disease and with renal and absorptive hypercalciurias. Effect of calcium and magnesium. Am J Med 1978; 64:579-585.
450. Jaeger P, Portmann L, Jacquet AF, Burckhardt P: Influence of the calcium content of the diet on the incidence of mild hyperoxaluria in idiopathic renal stone formers. Am J Nephrol 1985; 5:40-44.
451. Hess B, Jost C, Zipperle L, et al: High calcium intake abolishes hyperoxaaluria and reduces urinary crystallization during a 20-fold normal oxalate load in humans. Nephrol Dial Transplant 1998; 13:2241-2247.
452. Liebman M, Costa G: Effects of calcium and magnesium on urinary oxalate excretion after oxalate loads. J Urol 2000; 163:1565-1569.
453. Hatch M, Freel RW, Goldner AM, Earnest DL: Effect of bile salt on active oxalste transport in the colon. In: Kasper H, Goebell H, ed. Colon and Nutrition, Lancaster: MTP Press Ltd; 1981:299-305.
454. Hatch M, Freel RW, Goldner AM, Earnest DL: Comparison of effects of low concentrations of ricinoleate and taurochenodeoxycholate on colonic oxalate and chloride absorption. Gastroenterology 1983; 84:1181.
455. Kathpalia P, Favus MJ, Coe FL: Evidence for size and charge permselectivity of rat ascending colon: Effects of ricinoleate and bile salts on oxalic acid and neutral sugar transport. J Clin Invest 1984; 74:805-811.
456. Allison MJ, Daniel SL, Cornick NA: Oxalate-degrading bacteria. In: Khan SR, ed. Calcium Oxalate in Biological Systems, Boca Raton: CRC; 1995:131-168.
457. Doane LT, Liebman M, Caldwell DR: Microbial oxalate degradation: effects on oxalate and calcium balance in humans. Nutr Res 1989; 9:957-964.
458. Sidhu H, Hoppe B, Hesse A, et al: Absence of oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria. Lancet 1998; 352:1026-1029.
459. Neuhaus TJ, Belzer T, Blau N, et al: Urinary oxalate excretion in urolithiasis and nephrocalcinosis. Arch Dis Child 2000; 82:322-326.
460. Troxel SA, Sidhu H, Kaul P, Low RK: Intestinal oxaalobacter formigenes colonization in calcium oxalate stone formers and its relation to urinary oxalate. J Endourol 2003; 17:173-176.
461. Kleinschmidt K, Mahlmann A, Houtmann R: Microbial degradiation of dietary oxalate in the human gut and urinary oxalate concentrations in patients with calcium oxalate concentrations in patients with calcium oxalate urolithiasis and control persons. Invest Urol 1994; 5:222-224.
462. Kasidas GP, Nemat S, Rose GA: Plasma oxalate and creatinine and oxalate/creatinine clearance ratios in normal subjects and in primary hyperoxaluria. Evidence for renal hyperoxaluria. Clin Chim Acta 1990; 191:67-77.
463. Boer P, Prenen JA, Koomans HA, Dorhout Mees EJ: Fractional oxalate clearance in subjects with normal and impaired renal function. Nephron 1985; 41:78-81.
464. Chen SM, Chen TW, Lee YH, et al: Renal excretion of oxalate in patients with chronic renal failure or nephrolithiasis. J Formos Med Assoc 1990; 89:651-656.
465. Prenen JA, Dorhout Mees EJ, Boer P: Plasma oxalate concentration and oxalate distribution volume in patients with normal and decreased renal function. Eur J Clin Invest 1985; 15:45-49.
466. Ullrich KJ, Rumrich G, Kloss S: Contraluminal sulfate transport in the proximal tubule of the rat kidney. I. Kinetics, effects of K+, Na+, Ca2+, H+, and anions. Pflugers Arch 1984; 402:264-271.
467. Wareing M, Green R: Effect of formate and oxalate on fluid reabsorption from the proximal convoluted tubule of the anaesthetized rat. J Physiol 1994; 477:347-354.
468. Brandle E, Bernt U, Hautmann RE: In situ characterization of oxalate transport across the basolateral membrane of the proximal tubule. Pflugers Arch 1998; 435:840-849.
469. Dobbins JW, Binder HJ: Importance of colon in enteric hyperoxaluria. N Engl J Med 1977; 296:298-301.
470. Chadwick VS, Modha K, Dowling RH: Mechanism for hyperoxaluria in patients with ileal dysfunction. N Engl J Med 1973; 289:172-176.
471. Dowling RH, Rose GA, Sutor DJ: Hyperoxaluria and renal calculi in ileal disease. Lancet 1971; 1:1103-1106.
472. Smith LH, Frueth AJ, Hoffman AF: Acquired hyperoxaluria, nephrolithiasis and intestinal disease. N Engl J Med 1972; 286:1371-1375.
473. Hylander E, Jarnum S, Nielsen K: Calcium treatment of enteric hyperoxaluria after jejunoileal bypass for morbid obesity. Scand J Gastroent 1980; 15:349-352.
474. Canos HJ, Hogg GA, Jeffery JR: Oxalate nephropathy due to gastrointestinal disorders. Can Med Assoc J 1981; 124:729-733.
475. Pardi DS, Tremaine WJ, Sandborn WJ, McCarthy JT: Renal and urolog complications of inflammatory bowel disease. Am J Gastroenterol 1998; 93:504-514.
476. Clarke AM, McKenzie RG: Ileostomy and the risk of urinary uric acid stones. Lancet 1969; 2:395-397.
477. Rudman D, Dedonis JL, Fountain MT, et al: Hypocitraturia in patients with gastrointestinal malabsorption. N Engl J Med 1980; 303:657-661.
478. Earnest DL, Johnson G, Williams HE, et al: Hyperoxaluria in patients with ileal resection: An abnormality in dietary oxalate absorption. Gastroenterology 1974; 77:1114-1122.
479. McLeod RS, Churchill DN: Urolithiasis complicating inflammatory bowel disease. J Urol 1992; 148:974-978.
480. Modigliani R, Labayle D, Aymes C, Denvil R: Evidence for excessive absorption of oxalate by the colon in enteric hyperoxaluria. Scand J Gastroent 1978; 13:187-192.
481. Saunders DR, Sillery J, McDonald GB: Regional differences in oxalate absorption by rat intestine: evidence for excessive absorption by the colon in steatorrhea. Gut 1975; 16:543-548.
482. Marangella M, Fruttero B, Bruno M, Linari F: Hyperoxaluria in idiopathic calcium stone disease: Further evidence of intestinal hyperabsorption of oxalate. Clin Sci 1982; 63:381-385.
483. Argenzio RA, Liacos JA, Allison MJ: Intestinal oxalate-degrading bacteria reduce oxalate absorption and toxicity in guinea pigs. J Nutr 1988; 118:787-792.
484. Lieske JC, Goldfarb D, DeSimone C, Regnier C: Use of a probiotic to decrease enteric hyperoxaluria. Kid Int 2005; 68:1244-1249.
485. Campieri C, Campieri M, Bertuzzi V, et al: Reduction of oxaluria after an oral course of lactic acid bacteria at high concentration. Kid Int 2001; 60:1097-1105.
486. Hoppe B, Beck B, Gatter N, et al: Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney Int 2006; 70:1305-1311.
487. Parks JH, Worcester EM, O'Connor RC, Coe FL: Urine stone risk factors in nephrolithiasis patients with and without bowel disease. Kidney Int 2003; 63:255-265.
488. Worcester EM: Stones from bowel disease. Endocrinol Metabol Clin N Am 2002; 31:979-999.
489. Stauffer JQ: Hyperoxaluria and intestinal disease. The role of steatorrhea and dietary calcium in regulating intestinal oxalate absorption. Am J Dig Dis 1977; 22:921-928.
490. Andersson H, Bosaeus I: Hyperoxaluria in malabsorptive states. Urol Int 1981; 36:1-9.
491. Parivar F, Low RK, Stoller ML: The influence of diet on urinary stone disease. J Urol 1996; 155:432-440.
492. Nordenvall B, Backman L, Larsson L, Tiselius HG: Effects of calcium, aluminum, magnesium and cholestyramine on hyperoxaluria in patients with jejunoileal bypass. Acta Chir Scand 1983; 149:93-98.
493. Moe OW, Preisig PA: Duel role of citrate in mammalian urine. Curr Opin Nephrol Hypertens 2006; 15:419-424.
494. Kok DJ, Papapoulos SE, Bijvoet OL: Excessive crystal agglomeration with low citrate excretion in recurrent stone-formers. Lancet 1986; 10:1056-1058.
495. Tiselius HG, Bek-Jensen H, Fornander AM, Nilsson MA: Crystallization properties in urine from calcium oxalate stone formers. J Urol 1995; 154:940-946.
496. Brennan S, Hering-Smith K, Hamm LL: Effect of pH on citrate reabsorption in the proximal convoluted tubule. Am J Physiol 1988; 255:F301-F306.
497. Wright SH, Kippen I, Wright EM: Effect of pH on the transport of Krebs cycle intermediates in renal brush border membranes. Biochem Biophys Acta 1982; 684:287-290.
498. Aruga S, Wehrli S, Kaissling B, et al: Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney Int 2000; 58:206-215.
499. Melnick JZ, Srere P, Elshourbagy NA, et al: Adenosine triphosphate citrate lyase mediates hypocitraturia in rats. J Clin Invest 1996; 98:2381-2387.
500. Melnick JZ, Preisig PA, Moe OW, et al: Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia. Kidney Int 1998; 54:160-165.
501. Rudman D, Kutner MH, Redd SC, et al: Hypocitraturia in calcium nephrolithiasis. J Clin Endocrinol Metab 1982; 55:1052-1057.
502. Minisola S, Rossi W, Pacitti MT, et al: Studies on citrate metabolism in normal subjects and kidney stone patients. Miner Electrolyte Metab 1989; 15:303-308.
503. Menon M, Mahle CJ: Urinary citrate excretion in patients with renal calculi. J Urol 1983; 129:1158-1160.
504. Nicar MJ, Skurla C, Sakhaee K, Pak CYC: Low urinary citrate excretion in nephrolithiasis. Urology 1983; 21:8-14.
505. Hosking DH, Wilson JW, Liedtke RR: Urinary citrate excretion in normal persons and patients with idiopathic calcium urolithiasis. J Lab Clin Med 1985; 106:682-689.
506. Parks JH, Coe FL: A urinary calcium-citrate index for the evaluation of nephrolithiasis. Kidney Int 1986; 30:85-90.
507. Sarada B, Satyanarayana U: Urinary composition in men and women and the risk of urolithiasis. Clin Biochem 1991; 24:487-490.
508. Nikkila M, Koivula T, Jokela H: Urinary citrate excretion in patients with urolithiasis and normal subjects. Eur Urol 1989; 16:382-385.
509. Marangella M, Bianco O, Grande ML, et al: Patterns of citrate excretion in healthy subjects and patterns with idiopathic stone disease. Contrib Nephrol 1987; 58:34-38.
510. Lemann Jr J, Gray RW, Pleuss JA: Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 1989; 35:688-695.
511. Lemann Jr J, Pleuss JA, Gray RW, Hoffmann RG: Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults. Kidney Intl 1991; 39:973-983.
512. Pak C, Peterson R, Sakhaee K, et al: Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis. Am J Med 1985; 79:284-288.
513. Pak CY, Peterson R: Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate. Arch Intern Med 1986; 146:863-867.
514. Pak CYC, Sakhaee K, Fuller C: Successful management of uric acid nephrolithiasis with potassium citrate. Kid Int 1986; 30:422-428.
515. Odvina CV, Mason RP, Pak CY: Prevention of thiazide-induced hypokalemia without magnesium depletion by potassium-magnesium-citrate. Am J Ther 2006; 13:101-108.
516. Ruml LA, Pak CY: Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magnesium loss. Am J Kidney Dis 1999; 34:107-113.
517. Pak CY, Koenig K, Khan R, et al: Physicochemical action of potassium-magnesium citrate in nephrolithiasis. J Bone Min Res 1992; 7:281-285.
518. Gutman A, Yü TF: Urinary ammonium excretion in primary gout. J Clin Invest 1965; 44:1474-1481.
519. Millman S, Strauss AL, Parks JH, et al: Pathogenesis and clinical course of mixed calcium oxalate and uric acid nephrolithiasis. Kidney Int 1982; 22:366-370.
520. Sorensen CM, Chandhoke PS: Hyperuricosuric calcium nephrolithiasis. Endocrinol Metab Clin N Am 2002; 31:915-925.
521. Modlin M: The aetiology of renal stone: a new concept arising from studies on a stone-free population. Ann R Coll Surg Engl 1967; 40:155-178.
522. Lonsdale K: Epitaxy as a growth factor in urinary calculi and gallstones. Nature 1968; 217:56-58.
523. Grover PK, Ryall RL, Marshall VR: Effect of urate on calcium oxalate crystallization in human urine: evidence for a promotory role of hyperuricosuria in urolithiasis. Clin Sci (Lond) 1990; 79:9-15.
524. Grover PK, Ryall RL, Marshall VR: Calcium oxalate crystallization in urine: role of urate and glycosaminoglycans. Kidney Int 1992; 41:149-154.
525. Kallistratos G, Timmerman A, Fenner O: Influence of the salting-out effect on the formation of calcium oxalate crystals in human urine. Natturwissenschaften 1970; 57:198.
526. Pak CY, Waters CO, Arnold L, et al: Mechanism for calcium urolithiasis among patients with hyperuricosuria. J Clin Invest 1977; 59:426-431.
527. Pak CY, Barilla DE, Holt K, et al: Effect of oral purine load and allopurinol on the crystallization of calcium salts in urine of patients with hyperuricosuric calcium urolithiasis. Am J Med 1978; 65:593-599.
528. Fellstrom B, Backman U, Danielson BG, et al: Inhibitory activity of human urine on calcium oxalate crystal growth: effects of sodium urate and uric acid. Clin Sci (Lond) 1982; 62:509-514.
529. Zerwekh JE, Holt K, Pak CY: Natural urinary macromolecular inhibitors: Attenuation of inhibitory activity by urate salts. Kidney Int 1983; 23:838-841.
530. Hesse A, Wurzel H, Krampitz G, Vahlensieck W: Experimental determination of the kinetics of calcium-binding with chondroitin sulphate and the effects of uric acid on this process. Urol Res 1987; 15:93-97.
531. Ryall RL, Hibberd CM, Mazzachi BC, Marshall VR: Inhibitory activity of whole urine: a comparison of urines from stone formers and healthy subjects. Clin Chim Acta 1986; 154:59-67.
532. Ryall RL, Hibberd CM, Marshall VR: The effect of crystalline monosodium urate on the crystallization of calcium oxalate in whole human urine. Urol Res 1986; 14:63-65.
533. Coe FL, Parks JH: Hyperuricosuria and calcium nephrolithiasis. Urol Clin North Am 1981; 8:227-244.
534. Terkeltaub RA: Clinical practice. Gout. N Engl J Med 2003; 349:1647-1655.
535. Pacher P, Nivorozhkin A, Szabo C: Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58:87-114.
536. Takano Y, Hase-Aoki K, Horiuchi H, et al: Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 2005; 76:1835-1847.
537. Terkeltaub R, Bushinsky D, Becker M: Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther 2006; 8(Suppl 1):54.
538. Coe FL: Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder. Ann Intern Med 1977; 87:404-410.
539. Parks JH, Worcester EM, Coe FL: Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int 2004; 66:777-783.
540. Karet FE, Gainza FJ, Gyory AZ, et al: Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc Natl Acad Sci U S A 1998; 95:6337-6342.
541. Devonald MA, Smith AN, Poon JP, et al: Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nat Genet 2003; 33:125-127.
542. Quilty JA, Cordat E, Reithmeier RA: Impaired trafficking of human kidney anion exchanger (kAE1) caused by hetero-oligomer formation with a truncated mutant associated with distal renal tubular acidosis. Biochem J 2002; 368:895-903.
543. Karet FE, Finberg KE, Nelson RD, et al: Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 1999; 21:84-90.
544. Stehberger PA, Schulz N, Finberg KE, et al: Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis. J Am Soc Nephrol 2003; 14:3027-3038.
545. Aasarod K, Haga HJ, Berg KJ, et al: Renal involvement in primary Sjogren's syndrome. QJM 2000; 93:297-304.
546. Seux-Levieil ML, Joly V, Yeni P, et al: Evaluation of renal acidification in HIV-infected patients with hypergammaglobulinemia. Nephron 1997; 75:196-200.
547. Spruce BA, Baylis PH, Kerr DN, Morley AR: Idiopathic hypergammaglobulinaemia associated with nephrogenic diabetes insipidus and distal renal tubular acidosis. Postgrad Med J 1984; 60:493-494.
548. Kurtzman NA: Acquired distal renal tubular acidosis. Kidney Int 1983; 24:807-819.
549. Sharma RK, Jha R, Bhatia VL: Secondary distal renal tubular acidosis in association with urological abnormalities. Nephrol Dial Transplant 1997; 12:233.
550. Pongchaiyakul C, Domrongkitchaiporn S, Stichantrakul W, et al: Incomplete renal tubular acidosis and bone mineral density: a population survey in an area of endemic renal tubular acidosis. Nephrol Dial Transplant 2004; 19:3029-3033.
551. Hamm LL, Alpern RJ: Regulation of acid-base balance, citrate, and urine pH. In: Coe FL, Favus M, Pak CYC, ed. Kidney Stones: Medical and Surgical Management, Philadelphia: Lippincott-Raven; 1996:289-302.
552. Scheele K: Examen chemicum calculi urinari. Opuscula 1776; 2:73.
553. Wollaston WH: On cystic oxide: a new species of urinary calculus. Trans Roy Soc London 1810; 1:376-377.
554. Sonmez G: Organic distribution and interrelationships of lesions occurring in laying hens suffering from gout and urolithiasis. Adv Exp Med Biol 1991; 309A:247-250.
555. Tomlinson MJ, Perman V, Westlake RL: Urate nephrolithiasis in ranch mink. J Am Vet Med Assoc 1982; 180:622-626.
556. Kozhevnikov EM, Voitov LI, Efimova MN, Samokhina RF: Uric acid diathesis in chickens. Vetrinariia 1978; 2:84-86.
557. Riese RJ, Sakhaee K: Uric acid nephrolithiasis: Pathogenesis and treatment. J Urol 1992; 148:765-771.
558. Maalouf NM, Cameron MA, Moe OW, Sakhaee K: Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 2004; 13:181-189.
559. Henneman PH, Wallach S, Dempsey EF: The metabolism defect responsible for uric acid stone formation. J Clin Invest 1962; 41:537-542.
560. Metcalfe-Gibson A, McCallum FM, Morison RBI, Wrong O: Urinary excretion of hydrogen ion in patients with uric acid calculi. Clin Sci 1965; 28:325-342.
561. Rapoport A, Crassweller PO, Husdan H, et al: The renal excretion of hydrogen ion in uric acid stone formers. Metabolism 1967; 16:176-188.
562. Yu TF, Gutman AB: Uric acid nephrolithiasis in gout. Ann Intern Med 1967; 67:1133-1148.
563. Barzel US, Sperling O, Frank M, deVries A: Renal ammonium excretion and urinary pH in idiopathic uric acid lithiasis. J Urol 1964; 92:1-5.
564. Plante GE, Durivage J, Lemieux G: Renal excretion of hydrogen in primary gout. Metabolism 1968; 17:377-385.
565. Falls WF: Comparison of urinary acidification and ammonium excretion in normal and gouty subjects. Metabolism 1972; 21:433-445.
566. El-Reshaid K, Mughal H, Kapoor M: Epidemiological profile, mineral metabolic pattern and crystallographic analysis of urolithiasis in Kuwait. Eur J Epidemiol 1997; 13:229-234.
567. Hossain RZ, Ogawa Y, Hokama S, et al: Urolithiasis in Okinawa, Japan: a relatively high prevalence of uric acid stones. Int J Urol 2003; 10:411-415.
568. Hesse A, Schneider HJ, Berg W, Hienzsch E: Uric acid dihydrate as urinary calculus component. Invest Urol 1975; 12:405-409.
569. Taylor EN, Stampfer MJ, Curhan GC: Diabetes mellitus and the risk of nephrolithiasis. Kidney Int 2005; 68:1230-1235.
570. Pak CYC, Sakhaee K, Moe OW, et al: Biochemical profile of stone-forming patients with diabetes mellitus. Urology 2003; 61:523-527.
571. Daudon M, Lacour B, Jungers P: High prevalence of uric acid calculi in diabetic stone formers. Nephrol Dial Transplant 2005; 20:468-469.
572. Daudon M, Traxer O, Conort P, et al: Type 2 diabetes increases the risk for uric acid stones. J Am Soc Neph 2006; 17:2026-2033.
573. Ekeruo WO, Tan YH, Young MD, et al: Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol 2004; 172:159-163.
574. Daudon M, Lacour B, Jungers P: Influence of body size on urinary stone composition in men and women. Urol Res 2006; 34:193-199.
575. Balinsky JB: Phylogenetic aspects of purine metabolism. S Afr Med J 1972; 46:993-997.
576. Sakhaee K, Adams-Huet B, Moe OW, Pak CY: Pathyophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int 2002; 62:971-979.
577. Alvarez-Nemegyei J, Medina-Escobedo M, Villanueva-Jorge S, Vasquez-Mellado J: Prevalence and risk factors for urolithiasis in primary gout: is a reappraisal needed?. J Rheumatol 2005; 32:2189-2191.
578. Maalouf NM, Sakhaee K, Parks JH, et al: Association of urinary pH with body weight in nephrolithiasis. Kidney Int 2004; 65:1422-1425.
579. Abate N, Chandalia M, Cabo-Chan AV, et al: The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 2004; 65:386-392.
580. Cameron MA, Maalouf NM, Adams-Huet B, et al: Urine composition in type 2 diabetes: predispostiion to uric acid nephrolithiasis. J Am Soc Nephrol 2006; 17:1422-1428.
581. Cameron MA, Pak CYC: Approach to the patient with the first episode of nephrolithiasis. Clin Rev Bone Miner Metab 2004; 2:265-278.
582. Pais Jr VM, Lowe G, Lallas CD, et al: Xanthine urolithiasis. Urology 2006; 67:1084-2011.
583. Cameron JS, Moro F, Simmonds HA: Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993; 7:105-118.
584. Sakhaee K, Nicar M, Hill K, Pak CY: Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 1983; 24:348-352.
585. Freed SZ: The alternating use of an alkalizing salt and acetazolamide in the management of cystine and uric acid stones. J Urol 1975; 113:96-99.
586. Welch BJ, Graybeal D, Moe OW, et al: Biochemical and stone risk profiles with topiramate treatment. Am J Kid Dis 2006; 48:555-563.
587. Gordon EE, Sheps SG: Effect of acetazolamide on citrate excretion and formation of renal calculi. N Engl J Med 1957; 256:1215-1219.
588. Wabner CL, Pak CYC: Effect of orange juice consumption on urinary stone risk factors. J Urol 1993; 149:1405-1408.
589. Goldfarb DS, Asplin JR: Effect of grapefruit juice on urinary lithogenicity. J Urol 2001; 166:263-267.
590. Odvina CV: Comparative value of orange juice versus lemonade in reducing stone-forming risk. Clin J Am Soc Nephrol 2006; 1:1269-1274.
591. Lemann Jr J, Piering WF, Lennon EJ: Possible role of carbohydrate-induced calciuria in calcium oxalate kidney-stone formation. N Engl J Med 1969; 280:232-237.
592. Rodman JS: Struvite stones. Nephron 1999; 81:50-59.
593. Wong HY, Riedl CR, Griffith DP: Medical management and prevention of struvite stones. In: Coe FL, Favus MJ, Pak CYC, ed. Kidney Stones: Medical and Surgical Management, Philadelphia: Lippincott-Raven; 1996:941-950.
594. Elliot JS, Sharp RA, Lewis L: The solubility of struvite in urine. J Urol 1959; 81:366-368.
595. Robertson WG, Peacock M: Calcium oxalate crystalluria and inhibitors of crystallization in recurrent renal stone formers. Clin Sci (Colch) 1972; 43:499-506.
596. Segura JW, Preminger GM, Assimos DG, et al: Nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. J Urol 1994; 151:1648-1651.
597. Wojewski A, Zajaczkowski T: The treatment of bilateral stagehorn calculi of the kidneys. Int Urol Nephrol 1974; 5:249-260.
598. Singh M, Chapman R, Tressider GC, et al: The fate of the unoperated stagehorn calculus. Br J Urol 1973; 45:581-585.
599. Griffith DP, Gibson JR, Clinton C, et al: Acetohydroxamic acid: Clinical studies of a urease inhibitor in patients with staghorn renal calculi. J Urol 1978; 119:9-15.
600. Kerlan RK, Kahn RK, Laberge JM, et al: Percutaneous removal of renal stagehorn calculi. Am J Roentgenol 1985; 145:797-801.
601. Patterson DE, Segura JW, LeRoy AJ: Long-term follow-up of patients treated by percutaneous ultrasonic lithotripsy for struvite staghorn calculi. J Endourol 1987; 1:177-180.
602. Michaels EK, Fowler JEJ: Extracorporeal shock wave lithotripsy for struvite renal calculi: Prospective study with extended followup. J Urol 1991; 146:728-732.
603. Miller K, Bachor R, Sauter T, et al: ESWL monotherapy for large stones and staghorn calculi. Urol Int 1990; 45:95-98.
604. Grasso M, Conlin M, Bagley D: Retrograde ureteropyeloscopic treatment of 2 cm or greater upper urinary tract and minor staghorn calculi. J Urol 1998; 160:346-351.
605. Griffith DP, Moskowitz PA, Carlton Jr CE: Adjunctive chemotherapy of infection-induced staghorn calculi. J Urol 1979; 121:711-715.
606. Griffith DP: Infection (urease) stones. Miner Electrolyte Metab 1987; 13:278-285.
607. Michaels EK: Surgical management of struvite stones. In: Coe FL, Favus MJ, Pak CYC, et al ed. Kidney Stones: Medical and Surgical Management, Philadelphia: Lippincott-Raven; 1966:951-970.
608. Sant GR, Blaivas JG: Hemiacidrin irrigation in the management of struvite calculi: Long-term results. J Urol 1983; 130:1048-1050.
609. Hellstrom J: The significance of staphylococci in the development and treatment of renal and ureteric stones. Br J Urol 1938; 10:348-372.
610. Albright F, Sulkowitch HW, Chute R: Nonsurgical aspects of the kidney stone problem. JAMA 1939; 113:2049-2053.
611. Shortliffe LMD, Spigelman SS: Infection stones: evaluation and management. Urol Clin North Am 1986; 13:717-726.
612. Jacobs SC, Gittes RF: Dissolution of residual renal calculi with hemiacidrin. J Urol 1976; 115:2-4.
613. Nemoy NJ, Stamey TA: Surgical, bacteriological, and biochemical management of “infection stones.”. JAMA 1971; 215:1470-1476.
614. Brock WA, Nachtseim DA, Parsons CL: Hemiacidrin irrigation of renal pelvic calculi in patients with ileal conduit urinary diversion. J Urol 1980; 123:345-347.
615. Dretler SP, Pfister RC, Newhouse JH: Renal stone dissolution via percutaneous nephrostomy. N Engl J Med 1979; 300:341-343.
616. Angermeier K, Streem SB, Yost A: Simplified infusion method for 10% hemiacidrin irrigation of the renal pelvis. Urology 1993; 41:243-246.
617. Bernardo NO, Smith AD: Chemolysis of urinary calculi. Urol Clin North Am 2000; 27:355-365.
618. Dormia E, Dormia G, Malagola G, Minervini S: Experience with instrumental chemolysis for urolithiasis. J Urol 2003; 170:1105-1110.
619. Griffith DP, Khonsari F, Skurnick JH: Randomized, double-blind trial of lithostat (acetohydroxamic acid) in palliative treatment of infection-induced urinary stones in spinal cord injury patients. J Urol 1988; 140:318-324.
620. Griffith DP, Gleeson MJ, Lee H, et al: Randomized, double-blind trial of lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. Eur Urol 1991; 20:243-247.
621. Williams JJ, Rodman JS, Peterson CM: A randomized double-blind study of acetohydroxamic acid in struvite nephrolithiasis. N Engl J Med 1984; 311:760-764.
622. Nakagawa Y, Asplin JR, Goldfarb DS: Clinical use of cystine supersaturation measurements. J Urol 2000; 164:1481-1485.
623. Nakagawa Y, Coe FL: A modified cyanide-nitroprusside method for quantifying urinary cystine concentration that corrects for creatinine interference. Clin Chim Acta 1999; 289:57-68.
624. Goldfarb DS, Coe FL, Asplin JR: Urinary cystine excretion and capacity in patients with cystinuria. Kid Int 2006; 69:1041-1047.
625. Assimos DG, Leslie SW, Ng C: The impact of cystinuria on renal function. J Urol 2002; 168:27-30.
626. Luyckx VA, Leclercq B, Dowland LK, Yu AS: Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proc Natl Acad Sci U S A 1999; 96:12174-12179.
627. Piwon N, Gunther W, Schwake M, et al: CLC-5 Cl-channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 2000; 408:369-373.
628. Wang SS, Devuyst O, Courtoy PJ, et al: Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 2000; 9:2937-2945.
629. Beck L, Karaplis AC, Amizuka N, et al: Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A 1998; 95:5372-5377.
630. Shenolikar S, Voltz JW, Minkoff CM, et al: Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. PNAS 2002; 99:11470-11475.
631. Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al: Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 2003; 112:1906-1914.
632. Li YC, Pirro AE, Amling M, et al: Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94:9831-9835.
633. Yoshizawa T, Handa Y, Uematsu Y, et al: Mice lacking the vitamin D Receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 1997; 16:391-396.
634. Airaksinen MS, Eilers J, Garaschuk O, et al: Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin D28Kgene. Proc Natl Acad Sci U S A 1997; 94:1488-1493.
635. Lee CT, Huynh VM, Lai LW, et al: A-induced hypercalciuria in calbindin-D28k knockout and wild-type mice. Kidney Int 2002; 62:2055-2061.
636. Sooy K, Kohut J, Christakos S: The role of calbindin and 1,25 dihydroxyvitamin D3 in the kidney. Curr Opin Nephrol Hypertens 2000; 9:341-347.
637. Zheng W, Xie Y, Li G, et al: Critical role of calbindin-D28k in calcium homeostasis revealed by mice lacking both vitamin D receptor and calbindin-D28k. J Biol Chem 2004; 279:52406-52413.
638. Takahashi N, Chernavvsky DR, Gomez RA, et al: Uncompensated polyuria in a mouse model of Bartter's syndrome. Proc Natl Acad Sci U S A 2000; 97:5434-5439.
639. Cao G, Yang G, Timme TL, et al: Disruption of the caveolin-1 gene impairs renal calcium reabsorption and leads to hypercalciuria and urolithiasis. Am J Pathol 2003; 162:1241-1248.
640. Aida K, Ikegishi Y, Chen J, et al: Disruption of aldose reductase gene (Akr1b1) causes defect in urinary concentrating ability and divalent cation homeostasis. Biochem Biophys Res Commun 2000; 277:281-286.
641. Hough TA, Bogani D, Cheeseman MT, et al: Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci U S A 2004; 101:13566-13571.
642. Wainer L, Resnik BA, Resnick MI: Nutritional aspects of stone disease. In: Pah CY, ed. Renal Stone Disease: Pathogenesis, Prevention, and Treatment, Boston: Martinus-Nijhoff; 1987:143-164.
643. Walser M: Calcium clearance as a function of sodium clearance in the dog. Am J Physiol 1961; 200:1099-1104.
