Physiological basis for absorptive and renal hypercalciurias.

Physiological basis for absorptive renal hypercalciurias

and

PAK, CHARLES Y. C. Physiological basis for absorptive and renal hypercalciurias. Am. J. Physiol. 237(6): F415-F423, 1979 or Am. J. Physiol.: Renal Fluid Electrolyte Physiol. 6(6): F415-F423, 1979.-Idiopathic hypercalciuria constitutes two major variants -absorptive hypercalciuria, characterized by a primary intestinal hyperabsorption of calcium, and renal hypercalciuria, in which renal tubular reabsorption of calcium is primarily impaired. The two forms of hypercalciuria may be distinguished from each other, since a) parathyroid function is -stimulated in renal hypercalciuria, but normal or suppressed in absorptive hypercalciuria, b) the renal leak of calcium is present in renal hypercalciuria, but not in absorptive hypercalciuria, c) intestinal calcium absorption is probably increased primarily in absorptive hypercalciuria, and secondarily in renal hypercalciuria (from parathyroid hormone excess), d) the increased calcium absorption in renal hypercalciuria probably results from the parathyroid hormone-dependent stimulation of 1,25-dihydroxyvitamin D synthesis, whereas that in absorptive hypercalciuria may be vitamin D-independent, e) the response of the two conditions to certain treatments is unique, and f) the sequelae of parathyroid hormone excess, such as low bone density and negative calcium balance, may be present in renal hypercalciuria, but not in absorptive hypercalciuria. These findings provide a physiological basis for the consideration of absorptive and renal hypercalciurias as distinct and separate entities. nephrolithiasis;

calcium

absorption;

vitamin

OFHYPERCALCIURIA with calciumurolithiasis was first recognized in 1939 by Flocks (18). Fourteen years later, a group of patients with hypercalciuria, normocalcemia, and a history of recurrent passage of calcium-containing renal stones was reported by Albright et al. (1). The term “idiopathic hypercalciuria” was used to describe their condition, since the cause of the hypercalciuria was not known. Since then, many reports have appeared implicating either an increased intestinal calcium absorption (15, 17, 36, 47) or an impaired renal tubular reabsorption of calcium (14, 23, 25) for the hypercalciuria. The controversy prevailed mainly because idiopathic hypercalciuria was thought to be homogeneous, accountable by a single etiology. In 1974, it was suggested that this condition may be heterogeneous, composed of absorptive and renal hypercalciurias as two major variants (42). Although the suggestion has been challenged, this classification is supported by substantial experimental data. Furthermore, this separation has a practical value because of the unique response of each subgroup to certain treatment programs. This Editorial Review summarizes physiologically relevant data that justify consideration of absorptive and renal hypercalciurias as distinct and separate entities.

THE ASSOCIATION

0363-6127/79/oooO-0000$01.25

Copyright

0 1979 the American

Physiological

D

Basic Scheme for Absorptive and Renal Hypercakiurias In absorptive hypercalciuria, the basic abnormality is presumed to be the intestinal hyperabsorption of calcium (36, 42). The consequent rise in the circulating concentration of calcium augments the renal filtered load of calcium and suppresses parathyroid function. Hypercalciuria ensues from the increased renal filtered load of calcium and reduced renal tubular reabsorption of calcium consequent to parathyroid suppression. The excessive renal loss of calcium compensates for the high calcium absorption from the intestinal tract and maintains serum calcium concentration in the normal range. In renal hypercalciuria, the primary abnormality is the impairment in the renal tubular reabsorption (renal leak) of calcium (14, 41). The consequent reduction in the circulating concentration of calcium stimulates parathyroid function. There may be an excessive mobilization of calcium from bone and an enhanced intestinal absorption of calcium associated with the parathyroid hormone (PTH) excess. These effects restore serum calcium to the normal range. If the above schemes are valid, it is anticipated that Society

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C. Y. C. PAK

F416

the conditions of absorptive and renal hypercalciurias could be distinguished from each other on the basis of following criteria. a) Parathyroid function should be stimulated in renal hypercalciuria, but not in absorptive hypercalciuria. b) Renal leak of calcium should be demonstrable in renal hypercalciuria, but not in absorptive hypercalciuria. c) The intestinal calcium absorption should be primarily increased in absorptive hypercalciuria, although it may be raised secondarily in renal hypercalciuria. d)‘ There may be a variable pathogenetic role of vitamin D metabolism in the two forms of hypercalciuria. e) The response of the two conditions to certain treatments may be unique. f) Sequelae of PTH excess may be present in renal hypercalciuria, but absent in absorptive hypercalciuria. g) The two conditions may present with different demographic and clinical pictures.

Evidence for Renal Calcium Leak

Studies of renal calcium clearance have been performed in patients with idiopathic hypercalciuria (47, 51). One report concluded that an impaired renal tubular reabsorption of calcium was present (51). Another report found a tubular reabsorption of calcium similar to that in normal subjects (47). However, some patients with stones displayed a different pattern, a finding suggesting that a heterogeneous population had been evaluated. Similar studies have not been conducted in documented cases of absorptive or renal hypercalciuria. The presence of a renal leak of calcium may be detected from the fasting urinary calcium (36,41,46). If the duration of fast is sufficient, the absorbed calcium (from the intestinal tract) provides a limited contribution to urinary calcium. In normocalcemic patients in whom renal filtered load of calcium is probably not increased, Parathyroid Function a high fasting urinary calcium indicates that a renal leak Parathyroid function has been assessedfrom the mea- of calcium may be present. A high fasting urinary calcium surement of serum immunoreactive PTH and of urinary has been found to be invariably present in patients with cyclic AMP. With the use of different antisera and assay renal hypercalciuria in whom th .e diagnosis was reached systems, the circulating concentration of immunoreactive indepe ndently ’ (4 9 10, 41). In contrast, urinary calcium PTH has been shown to be increased in renal hypercalduring fasting was shown to be usually within the normal ciuria (4, 10, 14, 39, 42), and normal or reduced in ab- range in patients with absorptive hypercalciuria (4, 10, sorptive hypercalciuria (4, 10, 39, 42, 50). 34, 41). These results suggested that the renal tubular Total urinary cyclic AMP (fasting and 24-h determireabsorption of calcium may be impaired in renal hypernations, expressed relative to urinary creatinine or glo- calciuria but not in absorptive hypercalciuria. merular filtration rate), as well as nephrogenous cyclic In a minority of patients with absorptive hypercalciAMP, have been reported to be high in renal hypercaluria, fasting urinary calcium may be increased (39). It ciuria (4, 10, 39, 41, 42), and normal or low in absorptive has therefore been suggested that a concurrent renal leak hypercalciuria (4, 10, 34, 39, 41, 42). In renal hypercalciof calcium may be present. However, an inhibition of uria, the total urinary cyclic AMP, which had been high calcium absorption by a prior treatment with sodium during fast, was found typically to decrease to the normal cellulose phosphate restored normal urinary calcium (39) range following an oral ingestion of a large amount of (Fig. 1). In normal subjects, an inverse relationship becalcium (e.g., 1 g) (41). This finding suggested that para- tween fasting urinary calcium and fasting urinary cyclic AMP was found. Prior to sodium cellulose phosphate thyroid function was suppressible by the small increment in serum calcium resulting from absorbed calcium, and treatment, values in absorptive hypercalciuria were losupported a probable existence of secondary hyperparacated on the left part of this regression line, toward thyroidism. However, Broadus et al. (10) were unable to higher fasting urinary calcium and lower cyclic AMP. document a restoration of normal nephrogenous cyclic Following sodium cellulose phosphate preparation, valAMP subsequent to oral calcium load in two patients ues were shifted to the right of the regression line defined with renal hypercalciuria. This conflicting report proba- for the normal group. The results suggested that there bly reflects peculiarities of the patients examined rather may be an incomplete renal excretion of absorbed calthan a consequence of the mode of expression of cyclic cium (39). Because of an increased calcium absorption, AMP (12). In certain patients with renal hypercalciuria, some of the absorbed calcium may be left in the circulasome degree of parathyroid “autonomy” may be expected tion during the period of fast to provide suppression of from a long-term stimulation of parathyroid glands (7). parathyroid function and increased calcium excretion. Alternatively, an oral calcium load may provide an in- Accordingly, the high fasting urinary calcium encounsufficient challenge to parathyroid suppression if there is tered in some patients with absorptive hypercalciuria a prompt excretion of absorbed calcium or a limited may be the result of an incomplete renal excretion of calcium absorption. It is noteworthy that the increment absorbed calcium and not a concurrent primary defect in in serum calcium following calcium ingestion was small renal calcium absorption. in the two patients with renal hypercalciuria evaluated The above relationship between fasting urinary calby Broadus et al. (10). cium and cyclic AMP is the basis for the derivation of In absorptive hypercalciuria, both total urinary and the fasting Ca-CAMP discriminant score (39). A positive nephrogenous cyclic AMP were shown to decrease fol- value, indicative of renal calcium leak and secondary lowing an oral calcium load (10, 41), a pattern similar to hyperparathyroidism, was present in renal hypercalciuria the one observed in control subjects. The overall results (39) (Fig. 2). In contrast, the Ca-CAMP discriminant with serum immunoreactive PTH and urinary cyclic score was negative in absorptive hypercalciuria as it was AMP are compatible with parathyroid stimulation in- in normal subjects, a finding which indicated that a renal volving renal hypercalciuria and not absorptive hyperleak of calcium and parathyroid stimulation were not calciuria. present.


EDITORIAL

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REVIEW

0

Pre-SCP Post -SCP

6

7

0

o

1 Fasting

2 Urinary

3

4 Cyclic

5 AMP

~moles/100mI

8

9

10

GF

FIG. 1. Effect of sodium cellulose phosphate (SCP) treatment on fasting urinary calcium and urinary cyclic AMP in 10 patients with absorptive hypercalciuria. The dashed diagonal line represents mean + SE of estimate for control patients.

+6r +5 t +4 k 0+3 %

1

be renal in origin (29, 32). Lemann et al. (30) found an exaggerated calciuric response to carbohydrate ingestion in patients with idiopathic hypercalciuria and their relatives. In a recent study, the exaggerated augmentation of urinary calcium was shown to be selective, involving renal hypercalciuria but not absorptive hypercalciuria (4) . Broadus et al. (10) reported that the increment in serum calcium following an oral calcium load was less prominent in renal hypercalciuria than in absorptive hypercalciuria, and suggested that this blunted calcemic response was caused by an underlying renal leak of calcium. However, in a study involving a larger number of patients, the calcemic response to a calcium load was not found to be significantly different in the two forms of hypercalciuria, even though the mean value was lower in renal hypercalciuria. The increment in serum calcium following a l-g calcium load was 0.33 t 0.32 (SD) mg/dl in renal hypercalciuria (n = 14), and 0.62 t 0.40 mg/dl in absorptive hypercalciuria (n = 21) (P > 0.5). This finding was not unexpected, since a renal leak of calcium may develop secondarily to the parathyroid suppression following calcium load in absorptive hypercalciuria. It is not known whether other abnormalities in renal tubular function are present in renal hypercalciuria. In patients with idiopathic hypercalciuria, an impaired renal concentrating ability, reflected by a low maximal urinary osmolarity, has been reported (20, 52). This defect was correctable by a restoration of normal urinary calcium in one (20) but not in another study (52). A partial defect in renal acidification was shown in a small fraction of patients with idiopathic hypercalciuria (2). Unfortunately, these studies did not segregate hypercalciuric patients into the two major subgroups. Intestinal

A further support for an impaired renal tubular reabsorption of calcium in renal . hypercalciuria was obtained from the calciuric response to the oral carbohydrate load (4). The increment in calcium excretion following an ingestion of metabolizable carbohydrates is believed to

Calcium

Absorption

In idiopathic hypercalciuria, an enhanced intestinal calcium absorption has been shown by several techniques, including calcium balance (net calcium absorption) (15, 23, 25, 33), radiocalcium kinetic analysis (31), and forearm counting (54). Since the diagnostic separation into the two hypercalciuric forms, the intestinal calcium absorption has been assessed from the fecal recovery of orally administered radiocalcium (fractional calcium absorption) (42), forearm counting (50), calciuric response to the oral calcium load (10, 41), and from selective intestinal perfusion (8). The fractional calcium absorption was typically performed with 47Ca in a lOO-mg-calcium carrier (42). This method provided a measure principally of luminal-toserosal transport of calcium. An indirect measure of intestinal calcium absorption was obtained from the extent of urinary calcium excretion following an oral administration of an excessive amount of calcium (e.g., 1 g Ca) (10, 41). In the original version of the test (41), the total urinary calcium, obtained during a 4-h period immediately following the calcium load, was determined and expressed relative to the corresponding urinary creatinine level. In the presence of normal fasting urinary calcium, a postload value exceeding 0.2 mg calcium/mg creatinine indicated that


C. Y. C. PAK

F418 the intestinal calcium absorption was increased. This test has a limited value in the assessment of calcium absorption in patients with a high fasting urinary calcium. In the modified version, Broadus et al. (10) introduced the following changes: a) urinary calcium was determined in a Z-h sample obtained over the third and fourth hours postload, during which a peak calcium excretion was expected; b) urinary calcium was expressed relative to 100 ml of glomerular filtration; and c) the calcium load response was calculated as an increment over basal (fasting) urinary calcium. An increment exceeding 0.2 mg/lOO ml glomerular filtration indicated that the intestinal calcium absorption was increased. This modified approach is applicable for the study of calcium absorption even in the presence of a high fasting urinary calcium (as in renal hypercalciuria), since the basal value is subtracted. However, it offers no advantage over the original version in the detection of increased calcium absorption in patients with absorptive hypercalciuria. In a recently completed study (48), the two methods were equally reliable in the detection of increased calcium absorption in patients in whom the diagnosis of absorptive hypercalciuria was made independently. The results from both methods should be interpreted with caution in patients with a rapid bone turnover or a disturbance in renal tubular handling of calcium. For example, calcium excretion following an oral calcium load may be attenuated by the drug-induced augmentation of renal calcium reabsorption in patients who are receiving thiazide or orthophosphate (11). In the intestinal perfusion technique (8, 36), synthetic media containing known amounts of calcium are infused through a defined segment of the small bowel (e.g., proximal jejunum or midileum) via a triple-lumen tube. Bidirectional fluxes as well as net calcium absorption rate may be measured. In patients with absorptive hypercalciuria in whom a high urinary calcium (>200 mg/day) was documented on a diet with a daily composition of 400 mg calcium and 100 meq sodium, the fractional calcium absorption, obtained from the fecal recovery of orally administered radiocalcium in a lOO-mg-calcium carrier was found to be typically increased (42). Moreover, these patients were shown to have an exaggerated calcium excretion following an oral load of 1 g calcium, a finding indicating indirectly that they probably also hyperabsorb calcium from a higher calcium load (4, 10, 34). Some patients have a less classic presentation (absorptive hypercalciuria Type II) (40). The fractional calcium absorption from a lOO-mg-calcium carrier is not always increased. However, all patients show an exaggerated calcium excretion following an oral load of 1 g calcium. Urinary calcium on a calcium-restricted diet (400 mg calcium and 100 meq sodium per day) is within the normal range (~200 mg/day), though usually high normal. These results suggest that the Type II presentation may be a less severe form of absorptive hypercalciuria, characterized by a relatively normal intestinal absorption and renal excretion of calcium on a low calcium intake, but having abnormal responses on a high calcium intake. Thus, the intestinal calcium absorption, measured as fractional calcium absorption and/or from the response to the oral

calcium load, was shown to be invariably elevated in absorptive hypercalciuria. This conclusion was supported by measurement of calcium absorption utilizing forearm counting (50). However, the intestinal calcium absorption is increased in some but not all patients with renal hypercalciuria. A high fractional calcium absorption was found in 70% (37), and an exaggerated increment in urinary calcium after calcium load in 57% (48). The results suggested that the increased calcium absorption of renal hypercalciuria may not represent a primary derangement, but probably indicates a secondary event. The studies of intestinal perfusion have been performed in absorptive hypercalciuria (8, 36). An increased calcium absorption (from l-20 mM calcium in the perfusate) was found in the jejunum; however, the calcium absorption in the ileum was normal (see below for implications) (8). Similar studies have not been performed in renal hypercalciuria. Role of Vitamin

D Metabolism

Because of the well-known action of vitamin D on intestinal calcium transport and the recognition that an increased calcium absorption is invariably or frequently encountered in hypercalciurias, the pathogenetic role of vitamin D was investigated. In renal hypercalciuria, the fractional calcium absorption was found to be directly correlated with the circulating concentration of 1,25-dihydroxyvitamin D (55) (Fig. 3), as in primary hyperparathyroidism (11, 26). Parathyroid hormone has been shown to stimulate the renal synthesis of 1,25-dihydroxyvitamin D (19). Accordingly, the probable scheme for the increased calcium absorption is: renal leak of calcium + stimulation of PTH secretion + enhanced renal synthesis of 1,25-dihydroxyvitamin D + increased calcium absorption. The validity of this hypothesis was shown by the restoration of normal serum 1,25-dihydroxyvitamin D and intestinal calcium absorption following the correction of renal calcium leak with thiazide therapy (55) (see below). In absorptive hypercalciuria, the fractional calcium absorption was not found to be correlated with the serum concentration of 1,25-dihydroxyvitamin D (26). However, several reports have shown increased serum values for

- r ‘;3 4.0

so.4

r = .768 p< 0.04

I-

4 6 8 2 SERUM la, 25-(OH), D (ng/dl) FIG. 3. Relationship between fractional rum concentration of 1,25-dihydroxyvitamin tients with renal hvnercalciuria.

10

calcium absorption D ( lcw,25- (OH)zD)

and sein pa-


EDITORIAL

REVIEW

the vitamin D metabolite in approximately one-third to one-half of the patients (21, 26, 50). To explain this rise, a scheme implicating an important role of hypophosphatemia was proposed (7, 21, 28, 50). It was assumed that certain patients with absorptive hypercalciuria may have a primary “renal leak” of phosphate. The ensuing hypophosphatemia would then stimulate the renal synthesis of 1,25dihydroxyvitamin D, as has been shown in experimental animals (24). Thus, the enhanced calcium absorption develops secondarily to the hypophosphatemiainduced synthesis of 1,25dihydroxyvitamin D rather than as a primary event. The above scheme is supported by studies showing that a) serum phosphorus concentration and renal tubular threshold concentration for phosphate (TmP) are lower in absorptive hypercalciuria than in the control group (28, 50), b) phosphate deprivation stimulates 1,25-dihydroxyvitamin D (16), and c) plasma concentration of 1,25-dihydroxyvitamin D is inversely correlated with serum phosphorus concentration (in a mixed group consisting of stone formers, patients with primary hyperparathyroidism, and control subjects) (21). However, there are substantial data that do not support the validity of this scheme, at least in the vast majority of our patients with absorptive hypercalciuria. First, serum phosphorus concentration was not lower than in the control group if patients with absorptive hypercalciuria were evaluated under the same dietary and study setting as the control subjects (5, 38). For reasons heretofore unexplained, serum phosphorus was found to be higher in an inpatient setting than in an ambulatory setting in both the absorptive hypercalciuria and control group. When appropriately compared, hypophosphatemia and reduced TmP were found to be infrequent in absorptive hypercalciuria, occurring in only 3 of 56 patients (5). Second, the serum concentration of 1,25-dihydroxyvitamin D was not found to be correlated with serum phosphorus or TmP if only patients wit.h absorptive hypercalciuria were considered (5). Third, the fractional calcium absorption was not correlated with serum phosphorus or TmP (5, 35). Finally, orthophosphate therapy failed to restore normal intestinal calcium absorption even though it reduced the serum concentration of 1,25-dihydroxyvitamin D (see below) (5). Studies of intestinal perfusion provided a further insight in the potential pathogenetic role of vitamin D in absorptive hypercalciuria. Calcium absorption was found to be increased in jejunum but normal in ileum (8). Magnesium absorption in jejunum was normal (8,9). The increased calcium absorption in jejunum was not attenuated by magnesium. The addition of magnesium (5 mM) to the test solution did not modify calcium absorption (from 5 mM calcium perfusate) in the jejunum in eight patients with absorptive hypercalciuria (0.29 t 0.02 (SE) vs. 0.28 t 0.04 mmol30 cm-‘. h-’ in the presence of magnesium, P > 0.1). However, treatment with lcx-hydroxyvitamin D or 1,25-dihydroxyvitamin D was shown to stimulate calcium absorption in both jejunum and ileum (45,49,53) and to augment magnesium absorption in jejunum (in chronic renal failure) (49). Moreover, magnesium was shown to inhibit calcium absorption in the jejunum (of normal subjects) (9). These results, therefore, do not support an important etiologic role of

F419 1,25-dihydroxyvitamin D for the increased calcium in absorptive hypercalciuria. It is unlikely that 25-hydroxycholecalciferol or 24,25-dihydroxyvitamin D is pathogenetically involved, since normal values for these metabolites were reported in calcium-stone formers (13). The results suggest that the selective abnormality in absorptive hypercalciuria, involving increased absorption of calcium (not magnesium) in jejunum (not ileum), may be vitamin D-independent (8). A confirmation of this conclusion requires the demonstration that 1,25-dihydroxycholecalciferol stimulates absorption of calcium and magnesium in both intestinal segments in normal subjects (instead of in patients with chronic renal failure), and the provision of an adequate explanation for the increased serum 1,25-dihydroxyvitamin D occurring in some patients with this condition. Moreover, it is critical to perform similar perfusion studies in patients with renal hypercalciuria with an enhanced endogenous production of 1,25-dihydroxyvitamin D. Different

Responses

to Treatment

Absorptive hypercalciuria and renal hypercalciuria may be differentiated from each other on the basis of their unique responses to certain treatments. In renal hypercalciuria, thiazide therapy “corrected” the renal calcium leak (14) and restored normal parathyroid function (14), serum 1,25-dihydroxyvitamin D concentration (55), and fractional calcium absorption (3) (Fig. 4). In absorptive hypercalciuria, however, the serum concentration of 1,25-dihydroxyvitamin D remained unchanged (55) and the intestinal hyperabsorption of calcium persisted (3, 55) despite a reduction in urinary calcium. Sodium cellulose phosphate, a nonabsorbable resin with a high affinity for calcium, inhibits intestinal calcium absorption when given orally (15, 33, 42). It caused 8.0 r

1 T

S.Oi1~,25-(0H)~D (ng/dI)

1

4 o * t

0.8 0.6 FRACTIONAL Co ABSORPTION

o 4 *

0.2 I

J

PRE -THERAPY

FIG. 4. Effect dihydroxyvitamin tion in absorptive

POST - THERAPY of thiazide treatment on serum concentration of 1,25D (la,25(0H)zD) and on fractional calcium absorphypercalciuria (AH) and renal hypercalciuria (RH).


F420 a more prominent reduction in urinary calcium in absorptive hypercalciuria than in renal hypercalciuria. In absorptive hypercalciuria, urinary calcium declined from 264 t 52 (SD) to 98 t 34 mg/day during treatment with sodium cellulose phosphate (5 g with meals, or 15 g/day for 4 days), while the patients were maintained on a constant diet with a daily composition of 400 mg calcium, 100 meq sodium, and 800 mg phosphorus (P < 0.001). In renal hypercalciuria, urinary calcium decreased from 275 t 50 to 198 t 40 mg/day (P < 0.05). The results emphasize an important contribution of absorbed calcium to calcium excretion in absorptive hypercalciuria. Moreover, the fasting urinary Ca-CAMP discriminant score became more negative with sodium cellulose phosphate treatment in absorptive hypercalciuria (Fig. 1)) whereas it remained positive in renal hypercalciuria (39) (see above, Evidence for Renal Calcium Leak). Absorptive hypercalciuria and sarcoidosis share certain features, such as the occurrence in at least some patients of high serum 1,25-dihydroxyvitamin D concentration (6,44), intestinal hyperabsorption of calcium, and hypercalciuria. In sarcoidosis, prednisone (50 mg/day for 8 days) typically lowered serum 1,25-dihydroxyvitamin D levels (6, 44), intestinal calcium absorption, and urinary calcium, findings which suggested an important pathogenetic role for vitamin D metabolism. In contrast, prednisone therapy in absorptive hypercalciuria did not significantly alter the serum concentration of 1,25-dihydroxyvitamin D or intestinal calcium absorption, and it augmented urinary calcium (unpublished observations). The results supported a vitamin D-independent process for the increased absorption of absorptive hypercalciuria. This conclusion is supported by the inability of orthophosphate therapy to significantly alter the hyperabsorptive state for calcium in absorptive hypercalciuria, despite its ability to lower serum concentration of 1,25dihydroxyvitamin D (5) (see above, RoZe of Vitamin D Metabolism). Although different responses may be expected, similar studies with prednisone and orthophosphate have not been performed in renal hypercalciuria, in which an important pathogenetic role for vitamin D has been implicated. Sequelae of PTH Excess A recognized action of parathyroid hormone is the stimulation of bone resorption. Bone disease may therefore appear in states of hyperparathyroidism. With use of the technique of ?-photon absorptiometry (22, 43), osteitis, subperiosteal resorption, osteoporosis, and reduced bone density have been reported in primary hyperparathyroidism and in secondary hyperparathyroidism of chronic renal failure. It is anticipated that bone diseaseis more likely to develop in secondary hyperparathyroidism of renal hypercalciuria than in absorptive hypercalciuria, in which parathyroid function is normal or suppressed. Calcium balance has been reported to be negative, positive, or in balance in patients with idiopathic hypercalciuria (15, 23, 24, 31, 33). This variable response may partly be the result of the failure to separate the group into the two principal variants. Alternatively, conflicting data may reflect intrinsic difficulty of the balance tech-

C. Y. C. PAK

nique in assessingsmall changes in balance. No study of calcium balance has been performed in documented cases of absorptive or renal hypercalciuria. Calcium balance can be estimated from the difference between absorbed calcium (Ca,) and urinary calcium (Cau) (42). CaA represents the product of fractional calcium absorption and dietary calcium. Ordinarily, the fractional calcium absorption was obtained from a lOOmg-calcium carrier contained in one meal of a synthetic diet. Since patients ingested four such meals a day, CaA was the fractional calcium absorption x 400 mg. The CaA indicated principally the luminal-to-serosal calcium absorption and not the net calcium absorption. Thus, CaA - Cau exceeded calcium balance by the amount of net secreted calcium (endogenous fecal calcium). In patients with absorptive hypercalciuria, CaA - Cau was typically positive (42), and averaged 55 t 33 (SD) mg/day. Since this value approximates the endogenous fecal calcium expected in a setting of high calcium absorption during a low calcium diet (42), these patients probably were in calcium balance. In contrast, CaA Cau was negative in 44% of patients with renal hypercalciuria (37, 42); the mean value was 4 t 67 mg/day. Patients with negative values for CaA - Cau were usually those in whom the fractional calcium absorption was not increased. Accordingly, many patients with renal hypercalciuria were probably in negative calcium balance, especially if they had an inadequate compensatory stimulation of calcium absorption from the intestinal tract. The above conclusion was supported by results from ‘?-photon absorptiometric analysis of bone density (in the distal third of the radius) (27). Observed bone density, expressed as the ratio of bone mineral and bone width, was compared with the mean bone density for age- and sex-matched control subjects. In absorptive hypercalciuria, the mean fractional change in bone density of -0.0010 was virtually identical to and not significantly different from the control mean. In renal hypercalciuria, the mean fractional change in bone density of -0.0746 was significantly lower than the control mean (P c 0.001 by one-sample t test). The individual value for bone density was below the lower limit of the 95% prediction interval for observations from control subjects in only 1 of 117 patients with absorptive hypercalciuria, whereas it was low in 5 of 44 patients with renal hypercalciuria. In patients with hypophosphatemic absorptive hypercalciuria with presumed renal phosphate leak, it was reported that urinary hydroxyproline levels and the extent of osteoclastic surface are increased, and that the degree of osteoblastic surface is decreased (7). However, we were unable to document an increased hydroxyproline excretion in our patients with absorptive hypercalciuria, even in those with hypophosphatemia (5). Demographic and Clinical Picture Table 1 gives demographic and clinical data in 141 patients with absorptive hypercalciuria and in 26 patients with renal hypercalciuria who were evaluated by us during the past 3 yr. Absorptive hypercalciuria was characterized by a male preponderance (72.3%) and a high incidence of family history of stones (44.7%). In renal hypercalciuria, a proportionately larger fraction were


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REVIEW

1. Demographic and clinical picture

TABLE

Absorptive percalciuria NO.

Male/Female, Age,

%

yr

Urinary tract infection, % Clinical bone disease, % Family history of stones, % Duration of disease, yr

141 72.3i27.7 39t_ 11 36.2

Hy-

TABLE

2. Pertinent distinguishing features

Renal Hypercalciuria

Absorptive Hypercalciuria

26

Parathyroid function Serum iPTH Urinary cyclic AMP Ca-CAMP discriminant score Renal calcium leak Fasting urinary Ca Calciuric response to CHO Ca absorption Fractional Ca absorption (cu) Calciuric response to po Ca Jejunal calcium absorption Ileal calcium absorption Vitamin D status Serum 1,25-(OH)zD vs. CY Dependence on serum P Response to treatment Prednisone Serum 1,25-(OH)zD Urinary Ca Thiazide Parathyroid function Urinary Ca Serum 1,25- (OH)zD Orthophosphate Serum 1,25-(OH)gD

57.7142.3 42 t 16 53.9

0

0

44.7 9.5 t 8.0

38.5 8.0 t, 8.1

women (42.3 vs. 27.7%), and the incidence of urinary tract infection was higher (53.9 vs. 36.2%). A substantial portion of patients with renal hypercalciuria (38.5%) also had a family history of stones. None of the patients in either group had clinical bone disease (pathologic fractures, osteoporosis). In addition to a higher incidence of urinary tract infection, renal hypercalciuria was characterized by more frequent and severe episodes of infection. Moreover, the onset of infection more often preceded stone disease in this subgroup than in absorptive hypercalciuria. Though admittedly inconclusive, the findings support the hypothesis of Albright et al. (1) that renal leak of calcium may have resulted from pyelonephritis, at least in some patients with renal hypercalciuria. The lack of clinical bone disease is not too surprising, since most patients with renal hypercalciuria had a compensatory stimulation of intestinal calcium absorption (37). Moreover, the fractional change in bone density by photon absorptiometry, though low, was not as severely depressed as in osteoporosis (27). Conclusion From the preceding discussion, it is apparent that there is sufficient physiological basis for the consideration of absorptive and renal hypercalciurias as distinct and separate entities. Pertinent distinguishing features are summarized in Table 2. This analysis has also emphasized areas for further investigation, e.g., studies of intestinal perfusion and response to orthophosphate and prednisone in renal hypercalciuria, and elucidation of the cause for high circulating 1,25-dihydroxyvitamin D levels in

SCYP Urinary Ca Urinary cyclic AMP Ca-CAMP discriminant Sequelae of PTH excess CaA - CalI Bone density

score

Renal Hypercalciuria

normal normal normal normal T f 7 normal none none

unchanged t unchanged J unchanged i unchanged a normal + normal

Abbreviations: iPTH, immunoreactive PTH; CHO, carbohydrate; po, oral; 1,25-(OH)pD, 1,25-dihydroxyvitamin D; SCP, sodium cellulose phosphate; CaA and Ca lJ, absorbed and urinary calcium, respectively.

absorptive hypercalciuria. With continued progress, it is anticipated that additional subclassification may be required. Despite certain shortcomings, the available data provide a rational basis for the use of the terms absorptive and renal hypercalciurias, and indicate that the term “idiopathic” hypercalciuria should now be abandoned. This study was supported by Public Health AM16061, P50-AM20543, and MOl-RR-00633.

Service

Grants

ROI-

REFERENCES 1. ALBRIGHT, Idiopathic

F., P. HENNEMAN, P. H. BENEDICT, hypercalciuria. A preliminary report.

46: 1077-1081, 2. BACKMAN,

AND A. P. FORBES;. Proc. R. Sot. Med.

1953.

U. Kidney function in recurrent renal stone formers. Stand. J. UroZ. Nephrol. SuppZ. 25: l-90, 1976. 3. BARILLA, D. E., R. TOLENTINO, R. A. KAPLAN, AND C. Y. C. PAK. Selective effect of thiazide on the intestinal absorption of calcium in absorptive and renal hypercalciurias. MetaboZism 27: 125-131, 1978.

4. BARILLA, D. E., J. TOWNSEND, AND C. Y. C. PAK. An exaggerated augmentation of renal calcium excretion following oral glucose ingestion in patients with renal hypercalciuria. Inuest. UroZ. 15: 486-488, 5. BARILLA,

1978.

D. E., J. E. ZERWEKH, evaluation of the role of phosphate hypercalciuria. Miner. EZectroZyte 6. BELL. N. H.. AND P. H. STERN.

AND C. Y. C. PAK. A critical in the pathogenesis of absorptive Metab. In press. Correction of increased plasma

l&,25-dihydroxyvitamin D and hypercalcemia in sarcoid with prednisone. In: Program and Abstracts, Ann. Meeting Endocrine Society, 61st, Anaheim, CA, 1979, p. 195. 7. BORDIER, P., A. RYCKEWART, J. GUERIS, AND H. RASMUSSEN. On the pathogenesis of so-called idiopathic hypercalciuria. Am. J. Med. 63: 398-409, 8. BRANNAN,

1977.

P. G., S. MORAWSKI, C. Y. C. PAK, AND J. S. FORDTRAN. Selective jejunal hyperabsorption of calcium in absorptive hypercalciuria. Am. J. Med. 66: 425-428, 1979. 9. BRANNAN, P. G., P. VERGNE-MARINI, C. Y. C. PAK, A. R. HULL, AND J. S. FORDTRAN. Magnesium absorption in the human small intestine: results in normal subjects, patients with chronic renal disease and patients with absorptive hypercalciuria. J. CZin. Inuest. 57: 1412-1418,

10.

1976.

BROADUS, A. E., M. DOMINGUEZ, AND F. C. BARTTER. Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive hvpercalciuric subgroups.


F422 J. CZin. Endocrinol. Metab. 47: 751-760, 1978. 11. BROADUS, A., R. HURST, R. LANG, AND H. RASMUSSEN. Distinct pathophysiologic subgroups in primary hyperparathyroidism: role of serum 1,25-(OH)zD:s and response to oral phosphorus therapy. CZin. Res. 27: 363A, 1979. 12. BROADUS, A. E., J. E. MAHAFFEY, F. C. BARTTER, AND R. M. NEER. Nephrogenous cyclic adenosine monophosphate as parathyroid function test. J. CZin. Invest. 60: 771-773, 1977. 13. CALDAS, A. E., R. W. GRAY, AND J. LEMANN, JR. The simultaneous measurement of vitamin D metabolites in plasma: studies in healthy adults and in patients with calcium nephrolithiasis. J. Lab. CZin. Med. 91: 840-849, 1978. 14. COE, F. L., J. M. CANTERBURY, J. J. FIRPO, AND E. REISS. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J. CZin. Invest. 52: 134-142, 1973. 15. DENT, C. E., M. HARPER, AND A. M. PARFITT. The effect of cellulose phosphate on calcium metabolism in patients with hypercalciuria. CZin. Sci. 27: 417-425, 1964. 16. DOMINGUEZ, J. H., R. W. GRAY, AND J. LEMANN. Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25-OH-vitamin D. J. CZin. EndocrinoZ. Metab. 43: 1056-1068, 1976. 17. FINN, W. F., G. J. CERILLI, AND T. F. FERRIS. Transplantation of a kidney from a patient with idiopathic hypercalciuria. N. EngZ. J. Med. 283: 1449-1451, 1970. 18. FLOCKS, R. H. Calcium and phosphorus excretion in the urine of patients with renal or ureteral calculi. J. Am. Med. Assoc. 113: 1466-1471, 1939. 19. GARABEDIAN, M., M. F. HOLICK, H. F. DELUCA, AND I. T. BOYLE. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc. NatZ. Acad. Sci. USA 69: 1673-1676, 1972. 20. GILL, J. R., JR., AND F. C. BARTTER. On the impairment of renal concentrating ability in prolonged hypercalcemia and hypercalciuria in man. J. CZin. Invest. 40: 716-722, 1961. 21. GRAY, R. W., D. R. WILZ, A. E. CALDAS, AND J. LEMANN, JR. The importance of phosphate in regulating plasma 1,25-(OH)-vitamin D levels in humans: studies in healthy subjects, in calcium-stone formers and in patients with primary hyperparathyroidism. J. CZin. EndocrinoZ. Metab. 45: 299-306, 1977. 22. GRIFFITHS, H. F., R. E. ZIMMERMAN, G. BAILEY, AND R. SNIDER. The use of photon absorptiometry in the diagnosis of renal osteodystrophy. Radiology 109: 277-281, 1973. 23. HENNEMAN, P. H., P. H. BENEDICT, A. P. FORBES, AND H. R. DUDLEY. Idiopathic hypercalciuria. N. EngZ. J. Med. 259: 802-807, 1958. 24. HUGHES, M. R., P. F. BRUMBAUGH, M. R. HAUSSLER, J. E. WERGEDAL, AND D. J. BAYLINK. Regulation of serum la,25-dihydroxyvitamin D by calcium and phosphate in the rat. Science 190: 578580, 1975. 25. JACKSON, W. P. U., AND C. DANCASTER. A consideration of the hypercalciuria in sarcoidosis, idiopathic hypercalciuria and that produced by vitamin D. A new suggestion regarding calcium metabolism. J. CZin. EndocrinoZ. Metab. 19: 658-680, 1959. 26. KAPLAN, R. A., M. R. HAUSSLER, L. J. DEFTOS, H. BONE, AND C. Y. C. PAK. The role of la,25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J. CZin. Invest. 59: 756-760, 1977. 27. LAWOYIN, S., S. SISMILICH, R. BROWNE, AND C. Y. C. PAK. Bone mineral content in patients with primary hyperparathyroidism, osteoporosis, and calcium urolithiasis. MetaboZism. In press. 28. LEMANN, J., JR., J. H. DOMINGUEZ, AND R. W. GRAY. Idiopathic hypercalciuria: a defect in phosphate and vitamin D metabolism. In: Colloquium on Renal Lithiasis, edited by B. Finlayson and W. C. Thomas, Jr. Gainesville: Univ. of Florida Press, 1976, p. 276-290. 29. LEMANN, J., JR., E. J. LENNON, W. R. PIERING, E. L. PRIEN, JR., AND E. S. RICANATI. Evidence that glucose ingestion inhibits net renal tubular reabsorption of calcium and magnesium in man. J. Lab. CZin. Med. 75: 578-585, 1970. 30. LEMANN, J., JR., W. F. PIERING, AND E. J. LENNON. Possible role of carbohydrate-induced calciuria in calcium oxalate kidney stone formation. N. Engl. J. Med. 280: 232-237, 1969. 31. LIBERMAN, U. A., 0. SPERLING, A. ATSMON, M. FRANK, M. MODAN, AND A. DE VRIES. Metabolic and calcium kinetic studies in idiopathic hypercalciuria. J. CZin. Invest. 47: 2580-2590, 1968.

C. Y. C. PAK 32. LINDEMAN, R. D., S. ADLER, M. J. YIENGST, AND E. S. BEARD. Influence of various nutrients on urinary divalent cation excretion. J. Lab. CZin. Med. 70: 236-245, 1967. 33. NASSIM, J. R., AND B. A. HIGGINS. Control of idiopathic hypercalciuria. Br. Med. J. 1: 675-681, 1965. 34. NELSON, J. H., H. W. RIEMENSCHNEIDER, B. PFLUG, W. K. WHITEHOUSE, R. A. REHM, H. A. WISE, K. KEMPLE, AND C. C. WINTER. Oral calcium tolerance and urinary cyclic AMP in urolithiasis. Urology 12: 519-524, 1978. 35. NORDIN, B. E. C., M. PEACOCK, AND D. H. MARSHALL. Calcium excretion and hypercalciuria. In: UroZithiasis Research, edited by H. Fleisch, W. G. Robertson, and L. H. Smith. New York: Plenum, 1976. 36. NORDIN, B. E. C., M. PEACOCK, AND R. WILKINSON. Hypercalciuria and calcium stone disease. In: CZinics in Endocrinology and Metabolism, edited by I. McIntyre. Philadelphia: Saunders, 1972, p. 169-183. 37. PAK, C. Y. C., D. BARILLA, H. BONE, AND C. NORTHCUTT. Medical management of renal calculi. In: New Concepts in Endocrinology and Metabolism, edited by L. I. Rose and R. L. Lavine. New York: Grune and Stratton, 1977, p. 97-106. 38. PAK, C. Y. C., C. FETNER, J. TOWNSEND, L. BRINKLEY, C. NORTHCUTT, D. E. BARILLA, M. KADESKY, AND P. PETERS. Evaluation of calcium urolithiasis in ambulatory patients. Comparison of results with those of inpatient evaluation. Am. J. Med. 64: 979-987, 1978. 39. PAK, C. Y. C., AND R. A. GALOSY. Fasting urinary calcium and cyclic AMP: a discriminant analysis for the identification of renal and absorptive hypercalciurias. J. CZin. Endocrinol. Metab. 48: 260-265, 1979. 40. PAK, C. Y. C., AND K. HOLT. Nucleation and growth of brushite and calcium oxalate in urine of stone-formers. MetaboZism 25: 665673, 1976. 41. PAK, C. Y. C., R. A. KAPLAN, H. BONE, J. TOWNSEND, AND 0. WATERS. A simple test for the diagnosis of absorptive, resorptive, and renal hypercalciurias. N. EngZ. J. Med. 292: 497-500, 1975. 42. PAK, C. Y. C., M. OHATA, E. C. LAWRENCE, AND W. SYNDER. The hypercalciurias: causes, parathyroid functions and diagnostic criteria. J. CZin. Invest. 54: 387-400, 1974. 43. PAK, C. Y. C., A. STEWART, R. KAPLAN, H. BONE, C. NOTZ, AND R. BROWNE. Photon absorptiometric analysis of bone density in primary hyperparathyroidism. Lancet 2: 7-9, 1975. 44. PAPAPOULOS, S. E., T. L. CLEMENS, L. J. FRAHER, I. G. LEWIN, L. M. SANDLER, AND J. L. H. O’RIORDAN. 1,25-Dihydroxycholecalciferol in the pathogenesis of the hypercalcemia of sarcoidosis. Lancet 1: 627-630, 1979. 45. PARKER, T. F., P. VERGNE-MARINI, A. HULL, C. Y. C. PAK, AND J. FORDTRAN. Jejunal absorption and secretion of calcium in patients with chronic renal failure on hemodialysis. J. CZin. Invest. 54: 358365, 1974. 46. PEACOCK, M., F. KNOWLES, AND B. E. C. NORDIN. Effect of calcium administration and deprivation on serum and urine calcium in stone-forming and control subjects. Br. Med. J. 2: 729-731, 1968. 47. PEACOCK, M., AND B. E. C. NORDIN. Tubular reabsorption of calcium in normal and hypercalciuric subjects. J. CZin. PathoZ. 21: 353-358, 1968. 48. SAKHAEE, K., R. PETERSON, C. NORTHCUTT, AND C. Y. C. PAK. A critical appraisal of oral calcium load test for the indirect assessment of intestinal calcium absorption. J. UroZ. In press. 49. SCHMULEN, C., M. LERMAN, C. Y. C. PAK, J. ZERWEKH, P. VERGNEMARINI, S. MORAWSKI, AND J. S. FORDTRAN. Effect of 1,25-dihydroxyvitamin D therapy on intestinal absorption of magnesium in patients with chronic renal disease. Am. J. Physiol. In press. 50. SHEN, F. H., D. J. BAYLINK, R. L. NIELSEN, D. J. SHERRARD, J. L. IVEY, AND M. R. HAUSSLER. Increased serum 1,25-dihydroxyvitamin D in idiopathic hypercalciuria. J. Lab. CZin. Med. 955-962, 1977. 51. SMITH, D. A., AND J. C. MACKENZIE. In: Calcified Tissues, edited by H. Fleisch, H. J. J. Blackwood, and M. Owen. Berlin: Springer, 1965, p. 211. 52. SUKI, W. N., G. EKNOYAN, N. SAMAAN, C. DICHOSO, P. C. JOHNSON, AND M. MARTINEZ-MALDONADO. Idiopathic hypercalciuria: its diagnosis, pathogenesis and treatment. In: CorneZZ Seminars in Nephrology, edited by E. L. Becker. New York: Wiley, 1973, p. 229245. 53. VERGNE-MARINI, P., T. F. PARKER, C. Y. C. PAK, A. R. HULL, H.


EDITORIAL

F423

REVIEW

F. DELUCA, AND J. S. FORDTRAN. Jejunal and ileal calcium absorption in patients with chronic renal disease. Effect of la-hydroxycholecalciferol. J. CZin. b-west. 57: 861-866, 1976. 54. WILLS, M. R., E. ZISMAN, J. WORTSMAN, R. G. EVENS, C. Y. C. PAK, AND F. C. BARTTER. The measurement of intestinal calcium absorption by external radioisotope counting: application to study

of nephrolithiasis. CZin. Sci. 39: 95-106, 1970. 55. ZERWEKH, J. E., AND C. Y. C. PAK. Selective effects of thiazide therapy on serum l&,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias. MetaboZism. In press.

Charles Y. C. Pak Section on Mineral Metabolism, Department of Internal University of Texas Health Science Center at Dallas, Dallas, Texas 75235

Medicine,


Fasting urinary calcium and adenosine 3',5'-monophosphate: a discriminant analysis for the identification of renal and absorptive hypercalciurias.

Physiological basis of stress.

Physiological and pharmacological basis for the chemotherapy of enuresis.

Physiological basis of ischemic enteropathy.

Selective effects of thiazide on intestinal absorption of calcium and adsorptive and renal hypercalciurias.

A physiological basis for the treatment of essential hypertension.

The physiological basis of therapies for cerebellar ataxias.

Physiological basis for an animal model of the renal Fanconi syndrome: use of succinylacetone in the rat.

The physiological basis of implosive therapy.

The physiological basis of bird flight.

Biochemical Basis of Sestrin Physiological Activities.

[Physiological basis of the microcirculation: vascular adaptation].

Physicochemical and Nutritional Requirements for Axenic Replication Suggest Physiological Basis for Coxiella burnetii Niche Restriction.

Physiological basis of visual acuity and its development in kittens.

Dynamic tuning of lymphocytes: physiological basis, mechanisms, and function.

The physiological basis and clinical significance of lung volume measurements.

Renal ectopia and fusion. Embryologic Basis.

Sustained and Transient Vestibular Systems: A Physiological Basis for Interpreting Vestibular Function.

Physiological and genetic basis for self-aggregation of a thermophilic hydrogenotrophic methanogen, Methanothermobacter strain CaT2.

Physiological and biochemical analysis to reveal the molecular basis for black widow spiderling toxicity.

Fecal coliform elevated-temperature test: a physiological basis.

Modeling: optimal marathon performance on the basis of physiological factors.

On the physiological basis of vitamin A-stimulated growth.

Calcium absorptive consistency.