Urinary Cyclic Adenosine Monophosphate Research Articles

Idiopathic hypercalciuria: Association with isolated hematuria and risk for urolithiasis in children

A prospective multicenter study was designed to determine the frequency and prognostic importance of hypercalciuria in children with hematuria. Urinary calcium excretion was examined in 215 patients with unexplained isolated hematuria (no proteinuria, urolithiasis, infection or systemic disorder). Hypercalciuria (urinary calcium excretion greater than 4 mg/kg/day) was identified in 76 patients (35%). Compared to patients with normal urinary calcium excretion, children with hematuria and hypercalciuria were characterized by male preponderance, white race, family history of urolithiasis, gross hematuria and calcium oxalate crystals. Renal biopsies were performed in 10 patients with urinary calcium excretion 0.4 to 2.5 mg/kg/day; three had IgA glomerulonephritis, three had glomerular basement membrane thinning, one had proliferative glomerulonephritis and three were normal. Renal biopsies in three patients with hypercalciuria showed focal segmental glomerulosclerosis, hereditary nephritis or no abnormalities. Oral calcium loading tests showed renal hypercalciuria in 26 patients, absorptive hypercalciuria in 15 patients and were not diagnostic in 35 patients. Serum parathyroid hormone, bicarbonate and phosphorus and urinary cyclic adenosine monophosphate concentrations were similar in the three groups of hypercalciuric patients. Urinary calcium excretion after one week of dietary calcium restriction was higher (5.8 mg/kg/day) in renal hypercalciuria than in other hypercalciuric patients (3.4 mg/kg/day), P less than 0.01. One to four years follow-up was available for 184 patients. Eight of 60 hypercalciuric patients developed urolithiasis or renal colic compared to 2 of 124 patients with normal urinary calcium excretion (P less than 0.001). Hypercalciuria is commonly associated with isolated hematuria and represents a risk factor for future urolithiasis in children with hematuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperparathyroidism, Hypothyroidism, and Impaired Renal Function After 10 to 20 Years of Lithium Treatment

Of 19 patients who had been receiving a therapeutic dosage of lithium carbonate for 10 to 20 years, 8 (42%) were found to have some laboratory evidence of hyperparathyroidism. Of the 3 who had parathyroid surgery, 2 had hyperplasia and 1 had a solitary adenoma, an unusually high incidence of hyperparathyroidism. Unusual features of lithium-induced hyperparathyroidism in this series include (1) low urinary calcium excretion and the absence of nephrolithiasis, (2) normal urinary cyclic adenosine monophosphate excretion, and (3) normal plasma inorganic phosphate. Eight patients (42%) required treatment for hypothyroidism. Three patients (16%) had impaired kidney function. While these observations do not contraindicate the continued use of lithium carbonate in manic depression, they strongly emphasize the need for close laboratory surveillance.

Renal Hypercalciuria and Acidification Defect in Kidney Stone Patients

Calcium metabolism and renal acidification ability were examined in renal stone patients. On a random diet 33 of 52 patients excreted more than 4mg. per kg. body weight per day of urinary calcium and were entered into a second study on a 300mg. calcium diet. Absorptive and renal hypercalciuria was differentiated by fasting urinary calcium (mg. per 100ml. glomerular filtration). Every absorptive hypercalciuria patient tested and 5 renal hypercalciuria patients had a normal renal acidification ability, and the serum parathyroid hormone and urinary cyclic adenosine monophosphate levels were normal. By calcium restriction urinary calcium decreased more in absorptive hypercalciuria than in renal hypercalciuria (2.48 ± 0.14 versus 3.34 ± 0.27mg. per kg. body weight per day, p less than 0.05). However, urinary calcium remained high in 76 per cent of the patients with absorptive hypercalciuria. Nine patients had a defect in renal tubular acidification and the calcium metabolism was similar to those with renal hypercalciuria. Present studies show that renal hypercalciuria and renal tubular acidification defect cannot be differentiated without an ammonium chloride test.

Clinical and Laboratory Approaches for Evaluation of Nephrolithiasis

The initial part of this presentation deals with the sensitivity of tests commonly used in the diagnosis of primary hyperparathyroidism. Total serum calcium levels often are normal in patients with small parathyroid adenomas but levels of serum ultrafilterable and/or ionized calcium usually are elevated in these patients. The recent introduction of improved radioimmunoassays for measurement of circulating parathyroid hormone has led to greatly improved sensitivity of this test for the diagnosis of primary hyperparathyroidism. However, measurement of total urinary cyclic adenosine monophosphate, even when expressed as a function of glomerular filtration rate, is an extremely insensitive test in patients who have parathyroid adenomas weighing less than 1 gm. Consequently, this test no longer is used for diagnostic purposes in our laboratory.Data relating to the prevalence and causes of hyperoxaluria in patients with idiopathic calcium oxalate stones also are presented. Hyperoxaluria (more than 450 μmol. per 24 hours) was found in 21 of 99 consecutive untreated male patients. Approximately a third of the patients with high normal or increased urinary oxalate excretion also have increased urinary glycolate excretion, which is indicative of increased endogenous oxalate production. This metabolic abnormality was unresponsive to pyridoxine administration but preliminary findings suggest that it may be corrected by restricting dietary protein.

Idiopathic Hypercalciuria

Idiopathic hypercalciuria, defined as the urinary excretion of more than 300 mg. calcium per day in men or more than 250 mg. calcium per day in women, or more than 4 mg. calcium per kg. per day, is observed in about 50 per cent of the patients with calcium oxalate/apatite nephrolithiasis and is one of the risk factors for stone formation. These patients do not exhibit hypercalcemia, elevated serum parathyroid hormone concentrations or urinary cyclic adenosine monophosphate excretion nor clinical evidence of sarcoidosis, other granulomas or a malignancy. Hypophosphatemia may be present. Augmented rates of intestinal absorption of dietary calcium account for most of the increments in urinary calcium. Serum 1,25-dihydroxyvitamin D concentrations are in the upper normal range or elevated among many patients and are normal but not suppressed in the others. Activation of 1,25-dihydroxyvitamin D formation may be secondary to hypophosphatemia or other, as yet undefined, factors. Since, 1,25-dihydroxyvitamin D apparently can up-regulate its own receptor, small increments in its synthesis and blood levels could amplify the effect of the hormone to stimulate intestinal calcium absorption. Calcium balances are slightly but significantly negative and urinary hydroxyproline excretion may be increased so that a generalized disorder of calcium homeostasis also involving bone may be present. Additional studies are required to determine the genetic basis for the occurrence of idiopathic hypercalciuria in families, the cause of greater expression of idiopathic hypercalciuria in men and whether environmental factors (high dietary sodium chloride, protein and purified carbohydrate intakes) contribute to the expression of idiopathic hypercalciuria. Although thiazide diuretics, inorganic phosphate, magnesium hydroxide and potassium citrate have provided effective therapy, prospective studies are needed to determine optimum therapy and the optimum duration of treatment.

Monitoring calcium intake in osteoporosis by assay of nephrogenous cyclic AMP

We studied the relationship between urinary and nephrogenous cyclic adenosine monophosphate (CAMP) and intake of calcium in patients with clinical osteoporosis. Serum and urinary Ca, alkaline phosphatase, and CAMP were measured by standard techniques. Lumbar mineral density was assessed by dual photon absorptiometry. Mean (+/- SD) urinary and nephrogenous CAMP was 4.6 +/- 1.4 mumol/g creatinine (0.52 +/- 0.16 mumol/mmol creatinine) and 15 +/- 8.0 nmol/L GF in patients using an extra gram of Ca carbonate daily and 6.5 +/- 2.6 mumol/g creatinine and 32 +/- 18 nmol/L GF in patients consuming dietary Ca (p less than 0.05). Serum Ca was increased (p less than 0.05) in the supplemented group (9.8 +/- 0.4 vs 9.3 +/- 0.6 mg/dL [2.4 +/- 0.099 vs 2.32 +/- 0.14 mmol/L]) but urinary Ca and serum alkaline phosphatase were similar. Bone mineral density was the same in both (0.88 +/- 0.19 vs 0.87 +/- 0.08 g/cm2). We concluded that CAMP is greater in patients with no supplemental Ca in the diet. This test may be useful to assess patient compliance and biological availability of dietary or supplemental Ca.

Monitoring calcium intake in osteoporosis by assay of nephrogenous cyclic AMP

We studied the relationship between urinary and nephrogenous cyclic adenosine monophosphate (CAMP) and intake of calcium in patients with clinical osteoporosis. Serum and urinary Ca, alkaline phosphatase, and CAMP were measured by standard techniques. Lumbar mineral density was assessed by dual photon absorptiometry. Mean (+/- SD) urinary and nephrogenous CAMP was 4.6 +/- 1.4 mumol/g creatinine (0.52 +/- 0.16 mumol/mmol creatinine) and 15 +/- 8.0 nmol/L GF in patients using an extra gram of Ca carbonate daily and 6.5 +/- 2.6 mumol/g creatinine and 32 +/- 18 nmol/L GF in patients consuming dietary Ca (p less than 0.05). Serum Ca was increased (p less than 0.05) in the supplemented group (9.8 +/- 0.4 vs 9.3 +/- 0.6 mg/dL [2.4 +/- 0.099 vs 2.32 +/- 0.14 mmol/L]) but urinary Ca and serum alkaline phosphatase were similar. Bone mineral density was the same in both (0.88 +/- 0.19 vs 0.87 +/- 0.08 g/cm2). We concluded that CAMP is greater in patients with no supplemental Ca in the diet. This test may be useful to assess patient compliance and biological availability of dietary or supplemental Ca.

The effect of uninephrectomy on mineral metabolism in normal human kidney donors.

A longitudinal prospective study of 17 normal human kidney donors before and after uninephrectomy revealed changes in mineral metabolism during compensation for loss of renal mass. Increases in carboxy terminal parathyroid hormone (PTH) and urinary cyclic adenosine monophosphate (AMP) occurred at 1 week and persisted for up to 3 years after surgery. 1,25(OH)2D levels fell from 26.5 +/- 2.0 to 18.6 +/- 1.7 pg/mL (P less than 0.05) at 1 week. Tubular reabsorption of phosphate (TRP) fell from 83.4% to 72.3% at 1 month and remained at this level throughout the study. At 6 months, several changes developed that were suggestive of increased PTH effect: hypocalciuria, a decrease in serum phosphate, and the return of 1,25(OH)2D levels to baseline or above. 1,25(OH)2D levels showed an inverse correlation with serum phosphate at 6 months (r = 0.75, P less than 0.005) and 1 year (r = 0.60, P less than 0.01). In addition, at 6 months, an increase in bone mineral content by forearm photon absorptiometry was indirect evidence for a period of positive calcium balance. The compensatory changes demonstrated in this study after loss of renal mass took place over the course of several months and persisted for up to 3 years.

Hypercalcemia and abnormal 1,25-dihydroxyvitamin D concentrations in leprosy

Two patients with lepromatous leprosy and hypercalcemia are presented. Serum immunoreactive parathyroid hormone and urinary cyclic adenosine monophosphate concentrations were suppressed. Serum 1,25-dihydroxyvitamin D [1,25-(OH) 2D] concentrations were elevated in one patient and normal in the other. Urinary hydroxyproline excretion was slightly high in both patients. Hypercalcemia resolved with prednisone therapy. Abnormal 1,25-(OH) 2D production and/or metabolism may play a role in the pathogenesis of hypercalcemia in some patients with leprosy.

Effect of phosphorus intake in total parenteral nutrition infusates in premature neonates

Phosphorus intake was evaluated in 27 appropriate weight for gestational age, critically ill neonates who required total parenteral nutrition for 2 weeks. All received approximately 30 mg/kg/d elemental calcium. The low P intake group (1.01 mmol/kg/d, 30 mg/kg/d) showed signs of phosphate depletion: hypercalciuria, hypophosphatemia, and absence of phosphaturia. The high P intake group (1.67 mmol/kg/d, 50 mg/kg/d) did not have signs of P depletion; however, they had high urinary cyclic adenosine monophosphate excretion and marked phosphaturia, suggesting secondary hyperparathyroidism. The moderate P intake group (1.34 mmol/kg/d, 40 mg/kg/d) had evidence of neither phosphate depletion nor secondary hyperparathyroidism. This phosphorus dose appears to be appropriate for the very sick, poorly growing infant receiving total parenteral nutrition.

Arginine infusion blocks the action of parathyroid hormone but not arginine vasopressin on the renal tubule in man.

Six male volunteers were infused with arginine (0.5 g/kg body weight) over 30 min, after an overnight fast and water deprivation. There was a significant decrease in renal phosphate clearance (P less than 0.025) and urinary cyclic adenosine monophosphate (cAMP) output (P less than 0.025) during the 60- to 90-min period after the beginning of the infusion; both returned to the preinfusion basal levels within 150 min. The plasma levels of parathyroid hormone (PTH) were not affected by the infusion and remained unchanged during the subsequent 150 min. Plasma levels of arginine vasopressin (AVP) were also not significantly affected although plasma osmolality increased by 6-9 mmol/kg in all subjects. The infusion resulted in a diuresis, and a fall in urine osmolality but a decrease in free-water clearance; creatinine clearance was not affected. Six other subjects were given a bolus of 230 i.u. PTH intravenously, and 20 days later this was repeated during an infusion of arginine (0.5 g/kg body weight). There was a significant decrease in urinary phosphate (P less than 0.025) and cAMP excretion (P less than 0.05) when PTH was given with arginine. It is suggested that arginine blocks the action of PTH on the proximal renal tubule but not that of vasopressin on the distal nephron and collecting ducts.

Urinary cyclic adenosine monophosphate discriminates subsets of patients with osteoporosis.

To assess the biologic activity of the parathyroid hormone in osteoporosis, 32 patients with radiologic and clinical evidence of this disease were studied. Measurements of urinary cyclic adenosine monophosphate (cAMP), serum calcitriol (1,25 dihydroxyvitamin D), calcium, phosphorus, albumin, creatinine, and estimated glomerular filtration were obtained. The high cAMP group averaged 5.68 µmol cAMP/g (SEM, 0.35) and the low cAMP group, 2.89 µmol cAMP/g (SEM, 0.22) of creatinine. Mean urinary calcium levels were lower (P

Chronic DOCA treatment increases Ca absorption: role of hypercalciuria and vitamin D.

To examine the effects of mineralocorticoidism on calcium (Ca) absorption and to define the mechanism, rats received a high-salt diet and injections of vehicle or deoxycorticosterone acetate (DOCA). Net (44.2 vs. 31.4 mg/day) and percent Ca absorption (28.1 vs. 20.1%) was increased after 5 days of DOCA. This was associated with increased duodenal 45Ca uptake. Thus despite the hypercalciuria, Ca balance was similar. Although the hypercalciuria persisted chronically, the gut effects were sustained, which maintained normal ionized Ca, bone Ca, and Ca balance. Urinary cyclic adenosine monophosphate was elevated by DOCA. Compared with appropriate controls, neither DOCA alone nor polydipsia (elicited by dextrose) produced similar magnitudes of hypercalciuria as DOCA plus high-salt diet. These maneuvers also failed to increase Ca absorption. Neutralization of the metabolic alkalosis neither attenuated the DOCA-induced hypercalciuria nor abolished the Ca hyperabsorption. In vitamin D-deprived rats, the hypercalciuria but not the intestinal effects of DOCA were reproduced. Serum 1,25-dihydroxyvitamin D3 levels were increased during chronic DOCA treatment (224 vs. 139 pg/ml). These data best fit the hypothesis that increased Ca absorption is secondary to the calciuric effects of DOCA and high-salt diet and is mediated via the increased parathyroid hormone and 1,25-dihydroxyvitamin D3 activities.

Kenny syndrome: Evidence for idiopathic hypoparathyroidism in two patients and for abnormal parathyroid hormone in one

We report three unrelated patients with Kenny syndrome. Clinical symptoms included severe dwarfism, with internal cortical thickening and medullary stenosis of the tubular bones, normal bone age, macrocephaly, absent diploic space, delayed closure of the anterior fontanel, and normal intelligence; two of the patients had hyperopia and papillary edema. The patients also had episodic hypocalcemic tetany and low serum levels of magnesium. In two patients the diagnosis of idiopathic hypoparathyroidism was established on the basis of undetectable serum parathyroid hormone (PTH) levels (N- and C-terminal RIAs); one of these had normal urinary cyclic adenosine monophosphate (cAMP) response to exogenous PTH. Circulating calcitonin was undetectable in either patient. In a third patient, who had abnormal body proportions, serum levels of PTH were increased in an RIA detecting predominantly intact PTH (N-RIA) and undetectable in another RIA recognizing carboxy-terminal fragments (C-RIA). Administration of PTH promptly increased urinary cAMP excretion. In this patient, serum levels of calcitonin were increased, whereas values for 25-OHD and 1,25(OH)2D were normal.

Calcium homeostasis during therapeutic plasma exchange.

Because the removal of substantial quantities of plasma calcium during plasma exchange is rarely attended by clinically significant hypocalcemia, we evaluated calcium homeostasis during this procedure. Twenty-one procedures were performed on 10 patients with various neurological disorders. The reduction by plasma exchange in the serum concentrations of total calcium, ionized calcium, magnesium, and phosphate was significantly less than predicted (p less than 0.001) based on plasma volume of the patient and size of the exchange. However, N-terminal parathomone (PTH) levels increased to 242 +/- 120 percent midway into the procedure and were 207 +/- 84 percent after plasma exchange; urinary cyclic adenosine monophosphate (cAMP) levels rose by 165 +/- 35 percent. These data demonstrate a rapid compensatory response in N-terminal PTH and urinary cAMP to the reduction by plasma exchange of serum concentrations of total calcium, ionized calcium, and phosphate. The routine administration of supplemental calcium during plasma exchange may therefore be unnecessary in patients with normal parathyroid function.

Functional mediastinal parathyroid cyst. Dynamics of parathyroid hormone secretion during cyst aspirations and surgery

A patient presented with a large neck mass, hypercalcemia, and elevated serum parathyroid hormone levels. Aspiration of the cystic mass yielded 100 ml of fluid that contained a low concentration of thyroxine, but large amounts of parathyroid hormone, as measured by bioassay or with three different radioimmunoassays. After each of four aspirations, the serum calcium level declined significantly. Serial measurements showed that serum amino-terminal and mid-region parathyroid hormone levels and urinary cyclic adenosine monophosphate values declined after aspiration. Surgical resection of the cervical-mediastinal cyst restored normal serum calcium and parathyroid hormone levels, and these have been maintained for nine months. Calculations suggest that parathyroid hormone traversing the cyst lumen might contribute significantly to the excess circulating parathyroid hormone.

A model for malignancy-associated humoral hypercalcemia.

Tumor tissue from a patient with squamous cell carcinoma of the lung and hypercalcemia has been serially implanted into athymic mice. Tumor-bearing mice develop cachexia, hypercalcemia without bone metastases, hypophosphatemia, increased urinary cyclic adenosine monophosphate (cAMP) to creatinine ratio, and undetectable human immunoreactive parathyroid hormone levels. Radiographs of spines in the tumor-bearing mice demonstrate demineralization, suggesting skeletal resorption as the source of the hypercalcemia. Within 4-8 hours following tumor removal, hypercalcemia is reversed, suggesting that a relatively short-acting humoral substance is responsible for the hypercalcemia. The animals gain weight and become essentially normal within 4 days following tumor removal. The studies demonstrate that this animal model is similar in many aspects to human malignancy-associated humoral hypercalcemia (MAHH) and can provide a useful tool for further investigation of the pathogenesis and treatment of this syndrome.

Intraoperative urinary cyclic adenosine monophosphate as a guide to successful reoperative parathyroidectomy.

Sixty patients with persistent or recurrent primary hyperparathyroidism underwent reexploration during which urinary cyclic adenosine monophosphate (UcAMP) levels were determined at half-hour intervals by radioimmunoassay. Retrospective analysis of the data allowed us to develop UcAMP criteria for surgical success. Following removal of parathyroid tissue, if an individual UcAMP level dropped 50% from the median baseline level, or if elevated levels dropped to less than 4.0 nmol/dl glomerular filtrate, surgery was predicted to be successful. Eight unsuccessful procedures in seven patients produced no decline in UcAMP, and the intraoperative results accurately predicted surgical failure. Fifty-three patients underwent successful procedures and in every case UcAMP fell. Ninety-eight per cent of these successful procedures were predicted by our criteria. Levels of UcAMP fell 1.5 +/- 0.5 hours (means +/- SD) following abnormal parathyroidectomy. In 19 of 36 successful cases diagnosed before surgery as adenoma, the operative procedure was terminated before a significant drop in UcAMP. In 16 of 17 successful cases diagnosed before surgery as hyperplasia or uncertain histology, UcAMP fell during the operation. Intraoperative determination of UcAMP is helpful in reoperative parathyroid surgery. The criteria established allow intraoperative prediction of success with remarkable accuracy. Urinary cyclic AMP is especially helpful in reoperation for multigland disease; when enough pathologic tissue has been removed, the criteria will be met and the procedure may be terminated with confidence.

Idiopathic Hypercalciuria: Renal and Absorptive Subtypes in Children

• Twelve children with urolithiasis or unexplained episodes of gross hematuria, hypercalciuria, and normal serum calcium levels were examined with an oral calcium loading test. Eight patients displayed elevated fasting urinary calcium excretion, consistent with renal hypercalciuria; four exhibited normal fasting calcium excretion, which increased excessively with calcium loading, suggesting hyperabsorption of intestinal calcium. Evidence of secondary hyperparathyroidism was detected in three children with renal hypercalciuria on the basis of urinary cyclic adenosine monophosphate (cAMP) excretion. Serum calcium concentrations obtained four hours after loading increased significantly in children with renal hypercalciuria and were directly correlated with fasting urinary calcium excretion. Among patients with renal hypercalciuria, serum calcium level was higher in patients with normal fasting cAMP excretion. These results suggest that hyperabsorption of intestinal calcium occurs in renal hypercalciuria and may account for the lower-than-predicted incidence of secondary hyperparathyroidism in these patients. Idiopathic hypercalciuria may arise from one fundamental metabolic disturbance with varying degrees of expression, rather than from two separate pathogenic mechanisms. ( AJDC 1984;138:176-180)

Potential Pitfalls of the 2-Hour Calcium-to-Creatinine Ratio and Urinary Cyclic Adenosine Monophosphate Excretion in the Differential Diagnosis of Idiopathic Hypercalciuria

We studied 44 patients with calcium urolithiasis on high (900mg. daily) and low (400mg. daily) calcium diets. With 24-hour urinary data, we categorized the patients as normocalciuric or hyper-calciuric and subdivided the hypercalciuric patients into absorptive and renal types. Abbreviated tests, including the 2-hour fasting urinary calcium-to-creatinine ratio and 24-hour urinary (nephro-genous) cyclic adenosine monophosphate, did not predict accurately whether hypercalciuria was of the idiopathic, absorptive or renal type. However, 24-hour urinary calcium excretions on the low calcium diet had a sensitivity and specificity of more than 90 per cent for reproducing the categorized diagnoses.