Charles Y.C. Pak

The Hypercalciurias CAUSES, PARATHYROID FUNCTIONS, AND DIAGNOSTIC CRITERIA

The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58+/-3.63 SD mumol/g creatinine; normal, 4.02+/-0.70 mumol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (Ca(A)), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by (125)I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their Ca(A) exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion of Ca and a suppression of cAMP excretion. The urinary Ca of 453+/-154 SD mg/day was significantly higher than the control groups 211+/-42 mg/day. The urinary cAMP of 2.26+/-0.56 mumol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hypercalciuria was corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since Ca(A) was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their Ca(A) exceeded urinary Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria.

A Simple Test for the Diagnosis of Absorptive, Resorptive and Renal Hypercalciurias

A test was developed to diagnose various forms of hypercalciuria. A two-hour urine sample after an overnight fast and a four-hour urine sample after 1 g of calcium by mouth were tested for calcium, cyclic AMP and creatinine. The 24 patients with absorptive hypercalciuria had normocalcemia and normal fasting urinary calcium (less than 0.11 mg per milligram of urinary creatnine). Urinary calcium was high (greater than or equal to 0.2 mg per milligram of creatinine) after a calcium load. Of the 28 patients with primary hyperparathyroidism (resorptive hypercalciuria), 25 had hypercalcemia and 21 had high fasting urinary calcium. Urinary cyclic AMP, elevated in 30 per cent of fasting patients, was high (greater than 4.60 mu moles per gram of creatinine) in 82 per cent of cases after calcium load. Six patients with renal hypercalciuria had normocalcemia, high fasting urinary calcium, and high (greater than 6.86 mu moles per gram of creatinine) or high-normal fasting urinary cyclic AMP was normal. This simple test should facilitate the differentiation of various causes of hypercalciuria.

Ambulatory evaluation of nephrolithiasis. Classification, clinical presentation and diagnostic criteria.

Using the ambulatory protocol previously described, 241 patients with nephrolithiasis were evaluated. They could be categorized into 10 groups from the results obtained. Absorptive hypercalciuria type I (87 per cent male) comprised 24.5 per cent and was characterized by normocalcemia, normal fasting urinary calcium (less than 0.11 mg/100 ml glomerular filtration), an exaggerated urinary calcium following an oral calcium load (greater than 0.20 mg/mg creatinine), normal urinary cyclic adenosine monophosphate (AMP) (less than 5.4 nmol/100 ml glomerular filtration) and serum parathyroid hormone (PTH), and hypercalciuria (greater than 200 mg/day during a calcium- and sodium-restricted diet). Absorptive hypercalciuria type II (50 per cent male) accounted for 29.8 per cent; its biochemical features were the same as those for absorptive hypercalciuria type I, except for normocalciuria during a restricted diet and low urine volume (1.42 +/- 0.55 SD liter/day). Renal hypercalciuria (56 per cent male), disclosed in 8.3 per cent, was represented by normocalcemia and high values for fasting urinary calcium (0.160 +/- 0.054 mg/100 ml glomerular filtration), urinary cyclic AMP (6.80 +/- 2.10 nmol/100 ml glomerular filtration) and serum PTH. Primary hyperparathyroidism (57 per cent female), accounted for 5.8 per cent, typically included hypercalcemia, hypophosphatemia, hypercalciuria and high urinary cyclic AMP. Hyperuricosuric calcium urolithiasis (100 per cent male) comprised 8.7 per cent, and was characterized by hyperuricosuria (776 +/- 164 mg/day) and urinary pH exceeding pK for uric acid (5.91 +/- 0.33). In enteric hyperoxaluria (60 per cent female), encountered in 2.1 per cent of cases, urinary oxalate was increased (6.29 +/- 13.2 mg/day). Noncalcium-containing stones were found in 2.1 per cent of the patients with uric acid lithiasis (100 per cent male) and in another 2.1 per cent of the patients with infection lithiasis (60 per cent female). These conditions were typified by low urinary pH (5.29 +/- 0.12) and high urinary pH (6.69 +/- 1.16), respectively. Renal tubular acidosis was found in one patient (male, 0.4 per cent). In 10.8 per cent of the patients (81 per cent male), no metabolic abnormality could be found, although urine volume was low (1.41 +/- 0.51 liter/day). Hypercalciuria could not be differentiated between absorptive hypercalciuria and renal hypercalciuria in 5.4 per cent of the patients. Thus, this ambulatory protocol disclosed a physiologic disturbance in nearly 90 per cent of the cases and provided a definitive diagnosis in 95 per cent of the patients.

The Effects of Twelve Weeks of Bed Rest on Bone Histology, Biochemical Markers of Bone Turnover, and Calcium Homeostasis in Eleven Normal Subjects

This study was undertaken to examine the effects of 12 weeks of skeletal unloading on parameters of calcium homeostasis, calcitropic hormones, bone histology, and biochemical markers of bone turnover in 11 normal subjects (9 men, 2 women; 34 ± 11 years of age). Following an ambulatory control evaluation, all subjects underwent 12 weeks of bed rest. An additional metabolic evaluation was performed after 12 days of reambulation. Bone mineral density declined at the spine (−2.9%, p = 0.092) and at the hip (−3.8%, p = 0.002 for the trochanter). Bed rest prompted a rapid, sustained, significant increase in urinary calcium and phosphorus as well as a significant increase in serum calcium. Urinary calcium increased from a pre‐bed rest value of 5.3 mmol/day to values as high as 7.3 mmol/day during bed rest. Immunoreactive parathyroid hormone and serum 1,25‐dihydroxyvitamin D declined significantly during bed rest, although the mean values remained within normal limits. Significant changes in bone histology included a suppression of osteoblastic surface for cancellous bone (3.1 ± 1.3% to 1.9 ± 1.5%, p = 0.0142) and increased bone resorption for both cancellous and cortical bone. Cortical eroded surface increased from 3.5 ± 1.1% to 7.3 ± 4.0% (p = 0.018) as did active osteoclastic surface (0.2 ± 0.3% to 0.7 ± 0.7%, p = 0.021). Cancellous eroded surface increased from 2.1 ± 1.1% to 4.7 ± 2.2% (p = 0.002), while mean active osteoclastic surface doubled (0.2 ± 0.2% to 0.4 ± 0.3%, p = 0.020). Serum biochemical markers of bone formation (osteocalcin, bone‐specific alkaline phosphatase, and type I procollagen extension peptide) did not change significantly during bed rest. Urinary biochemical markers of bone resorption (hydroxyproline, deoxypyridinoline, and N‐telopeptide of type I collagen) as well as a serum marker of bone resorption (type I collagen carboxytelopeptide) all demonstrated significant increases during bed rest which declined toward normal during reambulation. Thus, under the conditions of this study, the human skeleton appears to respond to unloading by a rapid and sustained increase in bone resorption and a more subtle decrease in bone formation.

Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis.

In an attempt to document the efficacy of potassium citrate in stone formation, 57 patients with active lithiasis (2 or more stones during the preceding 2 years) and hypocitraturia were randomly allocated into 2 groups, with 1 group taking 30 to 60 mEq. potassium citrate daily in wax matrix tablet formation and the other group receiving placebo. In 18 patients receiving potassium citrate for 3 years stone formation significantly declined after treatment from 1.2 +/- 0.6 to 0.1 +/- 0.2 per patient year (p < 0.0001), in 13 patients (72%) the disease was in remission and all patients showed a reduced stone formation rate individually. In contrast, 20 patients taking placebo medication for 3 years showed no significant change in stone formation rate (1.1 +/- 0.4 to 1.1 +/- 0.3 per patient year) and in only 4 patients (20%) was the disease in remission. The stone formation rate during potassium citrate treatment was significantly lower than during the placebo treatment (0.1 +/- 0.2 versus 1.1 +/- 0.3 per patient year, p < 0.001). Potassium citrate therapy caused a significant increase in urinary citrate, pH and potassium, whereas placebo did not. Adverse reactions to potassium citrate were mild causing only 2 patients in the potassium citrate group and 1 in the placebo group to withdraw from the study. In summary, our randomized trial showed the efficacy of potassium citrate in preventing new stone formation in idiopathic hypocitraturic calcium nephrolithiasis.

POTASSIUM-MAGNESIUM CITRATE IS AN EFFECTIVE PROPHYLAXIS AGAINST RECURRENT CALCIUM OXALATE NEPHROLITHIASIS

PURPOSE We examined the efficacy of potassium-magnesium citrate in preventing recurrent calcium oxalate kidney calculi. MATERIALS AND METHODS We conducted a prospective double-blind study of 64 patients who were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq. potassium, 21 mEq. magnesium, and 63 mEq. citrate) daily for up to 3 years. RESULTS. New calculi formed in 63.6% of subjects receiving placebo and in 12.9% of subjects receiving potassium-magnesium citrate. When compared with placebo, the relative risk of treatment failure for potassium-magnesium citrate was 0.16 (95% confidence interval 0.05 to 0.46). Potassium-magnesium citrate had a statistically significant effect (relative risk 0.10, 95% confidence interval 0.03 to 0.36) even after adjustment for possible confounders, including age, pretreatment calculous event rate and urinary biochemical abnormalities. CONCLUSIONS Potassium-magnesium citrate effectively prevents recurrent calcium oxalate stones, and this treatment given for up to 3 years reduces risk of recurrence by 85%.

The role of 1 alpha, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria.

The cuase for the intestinal hyperabsorptionof calcium (Ca) in various forms of hypercalciurias was explored by a careful measurement of plasma 1 alpha, 25-dihydroxycholecalciferol [1 alpha, 25-(OH)I D] and by an assessment of intestinal Ca absorption and of parathyroid function. In 18 cases of primary hyperparathyroidism (PHPT), the mean plasma concentration of 1 alpha, 25-(OH)2D was significantly increased (4.9 +/- 2.2 SD ng/dl vs. 3.4 +/- 0.9 ng/dl for the control group), and was significantly correlated with fractional Ca absorption (alpha) (r = 0.80, P less than 0.001). Plasma 1 alpha, 25-(OH)2D was also correlated with urinary Ca (P less than 0.05), but not with serum Ca or phosphorus (P), P clearance, urinary cyclic AMP, or serum immunoreactive parathyroid hormone. In 21 cases of absorptive hypercalciuria (AH), plasma 1 alpha, 25-(OH)2D was elevated in one-third of cases, and the mean value of 4.5 +/- 1.1 ng/dl was significantly higher than that of the control group (P less than 0.01). Since relative hypoparathyroidism may be present, the normal absolute value of plasma 1 alpha, 25-(OH)2D, found in two-thirds of cases of AH, may be considered to be inappropriately high. Moreover, in the majority of cases of AH, the data points relating plasma 1 alpha, 25-(OH)2D and alpha fell within 95% confidence limits of values found in non-AH groups (including PHPT). The results suggest that the intestinal hyperabsorption of Ca in PHPT aw AH may be vitamin D dependent. However, the disturbance in vitamin D metabolism may not be the sole cause for the high Ca absorption in AH, since in some patients with AH, the intestinal Ca absorption appears to be inapp

Treatment of Postmenopausal Osteoporosis with Slow-Release Sodium Fluoride: Final Report of a Randomized Controlled Trial

It seems logical to use fluoride in osteoporosis, because fluoride can stimulate osteoblastic proliferation and new bone formation [1, 2]. However, clinical trials with fluoride have yielded mixed results because excessive exposure to fluoride may cause abnormal bone formation, microfractures, and gastric bleeding [3, 4]. Thus, treatment with a high dosage of plain sodium fluoride did not decrease the spinal fracture rate despite markedly increasing vertebral bone density, and it increased the rate of appendicular fractures and microfractures [4]. To overcome the complications associated with sodium fluoride, we have advocated the cyclical, intermittent use of a lower dose of less bioavailable, slow-release sodium fluoride and continuous supplementation with calcium citrate [5, 6]. This treatment has been shown to maintain serum fluoride concentrations within the narrow therapeutic window [7, 8], thus avoiding toxic peaks in serum [9], and to stimulate the formation of normally mineralized bone [5, 10] with an improved intrinsic quality of cancellous bone [11-13]. We previously reported the results of an interim analysis [6] of a placebo-controlled randomized trial (median duration of treatment for fracture analysis, 2 years). Here, we present the final report of that trial (median duration of treatment for fracture analysis, 3 years). Methods Clinical Data Demographic and baseline presentations were described in the interim report [6]. We recruited 110 women with postmenopausal osteoporosis into the trial. All had radiologic evidence of osteopenia and osteoporosis; one or more vertebral fractures believed to be nontraumatic; and no secondary cause of bone loss. They were randomly assigned to one of two groups and stratified according to estrogen treatment. All study personnel were unaware of group assignment while data were being gathered. Ninety-nine patients completed at least 1 study cycle (1 year of actual treatment). The demographic or baseline presentations of these 99 patients did not differ according to treatment group [6] (Table 1). The two groups were similar in age, time since menopause, dietary calcium intake, height, weight, and number of spinal fractures. Both groups had moderate to severe osteoporosis: The average L2-L4 bone density was approximately 30% less than of a normal 30-year-old woman, and each group had a median of two spinal fractures at baseline. Table 1. Baseline Characteristics* Treatment Patients in the fluoride group received slow-release sodium fluoride (Slow Fluoride, Mission Pharmacal Co., San Antonio, Texas), 25 mg twice daily, orally before breakfast and at bedtime in repeated 14-month cycles (12 months receiving treatment followed by 2 months not receiving treatment). They also received calcium citrate (Citracal, Mission Pharmacal), 400 mg calcium twice daily, before breakfast and at bedtime continuously throughout the study. Those in the placebo group received placebo (identical in appearance to Slow Fluoride but containing excipient only [provided by Mission Pharmacal]) on the same time schedule. The Mission Pharmacal Company had no role in the design of the study or in data retrieval, analysis, or interpretation. Thirteen of 48 patients in the fluoride group and 16 of 51 patients in the placebo group received concurrent treatment with estrogen. Nine of the 29 patients treated with estrogen were recruited at the primary site at Dallas; the other 20 were enrolled and evaluated at the Scott and White Clinic, Temple, Texas. Fracture Quantitation Before treatment and at 12 months of each cycle, a lateral spine roentgenogram was obtained for the assessment of spinal fractures. In the interim analysis [6], prevalent fractures (fractures present at baseline) were identified with the aid of radiology reports. For this final report, prevalent fractures were also analyzed using a computer program that calculated the vertebral dimensions of clearly unaffected vertebrae from landmarks (anterior and posterior corners and midpoints). By comparing these dimensions with published normal values [14], we obtained a correction factor. Using this correction factor, we estimated idealized vertebral dimensions before a fracture had occurred for the remaining vertebrae in the given baseline radiograph. A reduction in any height of more than 20% (from idealized to actual) accompanied by a decrease of at least 10% in vertebral area represented a prevalent fracture. Incident spinal fractures (fractures occurring during the trial) were identified as described previously [6], using a computer-derived method. A reduction in any vertebral height of more than 20% accompanied by a decrease in vertebral area of more than 10% from one year to the next constituted a fracture [15]. A new incident fracture was a fracture that occurred during treatment in a previously unaffected vertebrae. A recurrent fracture was one that developed on a previously fractured vertebra. Bone Mass Measurements The use of different densitometers prompted us to calculate and use percentage changes per year rather than absolute values. The method for calculating changes in L2-L4 bone mineral content and bone density of the femoral neck and the radial shaft was described previously [6]. Safety Variables Serum fluoride concentrations were measured before the morning dose of the test drug at 0, 3, 6, 9, and 12 months of each cycle, and they were analyzed using an ion-specific electrode. At the same visits, a history was taken for gastrointestinal and musculoskeletal side effects. A microfracture was defined clinically as moderate to severe lower-extremity pain that persisted for more than 6 weeks despite a reduction in treatment dose and objectively as changes on bone scan or radiograph. The relation of each side effect to treatment was assessed. A symptom was considered to be related to treatment if it was moderate to severe in intensity, had no other cause, had newly appeared and persisted during the treatment phase, or had disappeared during the withdrawal period or with dose reduction. It was considered to be unrelated if it was present at baseline or during the late withdrawal phase, or if it had newly appeared but was not persistent. The severity and frequency of side effects were also quantitated as adverse symptom scores. We identified 10 gastrointestinal items (symptoms such as nausea, vomiting, and diarrhea), 4 rheumatic items (pain in the foot, knee, hip, and other joints), and 3 skeletal items (pain in the lower, mid-, or upper back). Each item was given a numerical value of 1 to 3 for frequency (infrequent, frequent, or very frequent) and a numerical value of 1 to 3 for severity (mild, moderate, or severe). Side-effect score was the product of the value for frequency and the value for severity for each item. Thus, a constant, severe back pain yielded a score of 9 (3 3). A gastrointestinal score was derived for each patient by adding the scores of the 10 gastrointestinal items for all relevant visits and dividing the sum by the number of visits. A similar computation was done to derive rheumatic and skeletal scores for each patient. Statistical Analysis The data for incident spinal fractures were compared between the two groups-using three methods. Individual Vertebral Fracture Rate For each patient, the individual vertebral fracture rate was obtained by dividing the total number of new fractures by the duration of treatment. Because the data were skewed, this rate was compared between the two groups using the Wilcoxon rank-sum test. Fracture-Free Rate This rate was the percentage of patients without new fractures, unadjusted for covariates. The two groups were compared using the log-rank test to account for differential follow-up. Survival The Cox proportional-hazards regression model [16] was constructed to estimate the relative risk for a new spinal fracture while adjusting for covariates (treatment group, age, prevalent spinal fractures, years since menopause, height, weight, estrogen treatment, and stratum of baseline L2-L4 bone density). Time (in years) to the first fracture was considered to be the survival time. Analyses of fracture rates and logistic regression were also done [6]; the data are not presented because findings were similar to those obtained using the above methods. The arithmetic difference in height from baseline to the end of treatment for each patient was compared between groups using a two-sample t-test and a two-way analysis of variance with the following factors: 1) treatment [fluoride vs placebo] and 2) fracture status (fracture-free vs one or more new or recurrent fractures). For each patient, we calculated the percentage change per year for L2-L4 bone mineral content and bone density of femoral neck and radial shaft. The individual mean change for each patient was calculated as the average of yearly changes. The group mean was obtained by averaging the individual means. One-sample t-tests were then used to compare the percentage change to zero for each year or for the mean. Comparisons between groups were made using two-sample t-tests. Missing data precluded implementing a repeated-measures analysis of variance. For related adverse events, the frequency of each event was compared between the two groups by using the Fisher exact test. Adverse symptom scores were compared between the groups by using the Wilcoxon rank-sum test and within the groups by using the Wilcoxon signed-rank test. For nonvertebral fractures, the exact tests based on the binomial distribution using person-year data were used to compare the two groups. Most analyses were done using BMDP Statistical Software (BMDP, Los Angeles, California). Programs for analyzing person-time data were developed by the authors. Data are presented as mean SD unless otherwise indicated. All reported P values are two-sided. Results Duration of Treatment The total duration of follow-up, including withdrawal periods, was 193 patient-years in th

Hypercalcemia Associated with Increased Serum Calcitriol Levels in Three Patients with Lymphoma

A radioreceptor assay for serum 1,25-dihydroxyvitamin D (calcitriol) was used to screen patients with hypercalcemia of malignancy. Three patients with non-Hodgkins lymphoma and hypercalcemia (serum Ca, 12.0, 13.4, and 13.0 mg/dL, respectively) had increased serum calcitriol levels (56, 72, and 77 pg/mL, respectively; normal, less than 50 pg/mL). Elevated levels of calcitriol, an active vitamin D metabolite, occurred in the presence of significant renal impairment (creatinine clearance, 8 to 19 mL/min) and relative parathyroid suppression (serum immunoreactive parathyroid hormone, 17 to 39 microL-eq/mL; mean value in end-stage renal disease, 182 +/- 39 microL-eq/mL). Hypercalcemia and excessive serum calcitriol levels responded to glucocorticosteroid therapy. In two patients, the hypercalcemia and increased serum calcitriol level were related to a tumor, but not to the serum immunoreactive parathyroid hormone level. Fractional intestinal 47Ca absorption, measured in one patient, was increased (0.94; normal, less than 0.61) and varied directly with the serum calcitriol level. No patient had evidence of sarcoidosis. Hypercalcemia associated with certain lymphomas may be caused by the increased synthesis of calcitriol by lymphoma cells.

Long-Term Treatment of Calcium Nephrolithiasis with Potassium Citrate

The long-term effects of potassium citrate therapy (usually 20 mEq. 3 times daily during 1 to 4.33 years) were examined in 89 patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis, with or without calcium nephrolithiasis. Hypocitraturia caused by renal tubular acidosis or chronic diarrheal syndrome was associated with other metabolic abnormalities, such as hypercalciuria or hyperuricosuria, or occurred alone. Potassium citrate therapy caused a sustained increase in urinary pH and potassium, and restored urinary citrate to normal levels. No substantial or significant changes occurred in urinary uric acid, oxalate, sodium or phosphorus levels, or total volume. Owing to these physiological changes, uric acid solubility increased, urinary saturation of calcium oxalate decreased and the propensity for spontaneous nucleation of calcium oxalate was reduced to normal. Therefore, the physicochemical environment of urine following treatment became less conducive to the crystallization of calcium oxalate or uric acid, since it stimulated that of normal subjects without stones. Commensurate with the aforementioned physiological and physicochemical changes the treatment produced clinical improvement, since individual stone formation decreased in 97.8 per cent of the patients, remission was obtained in 79.8 per cent and the need for surgical treatment of newly formed stones was eliminated. In patients with relapse after other treatment, such as thiazide, the addition of potassium citrate induced clinical improvement. Thus, our study provides physiological, physicochemical and clinical validation for the use of potassium citrate in the treatment of hypocitraturic calcium nephrolithiasis and uric acid lithiasis with or without calcium nephrolithiasis.