Single infusion of zoledronate in Paget's disease of bone: a placebo-controlled, dose-ranging study.
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Aged↗
Biomedical subjects
A M Moses
Publications and source records attributed to A M Moses.
Reproductive dysfunction in women with Albright's hereditary osteodystrophy.
Most individuals with Albright's hereditary osteodystrophy (AHO) have deficient expression or function of G(s alpha), the alpha subunit of the guanine nucleotide binding protein that stimulates adenylyl cyclase, and are resistant to parathyroid hormone (PTH) and other hormones that act via stimulation of adenylyl cyclase. To determine the incidence and etiology of ovarian dysfunction in women with AHO, we examined the reproductive history and hypothalamic-pituitary-ovarian axis in 17 affected women aged 17-43 yr. All patients had typical PTH resistance and an approximately 50% reduction in erythrocyte G(s alpha) activity, (0.43 +/- 0.03 vs. 0.92 +/- 0.08 for normal control subjects, P < 0.001). Fourteen of the 17 patients (76%) were oligomenorrheic or amenorrheic, more than half had delayed or incomplete sexual development, and only two had a history of earlier pregnancy. Most women were mildly hypoestrogenic, with normal to slightly elevated serum gonadotropin levels. Computer analysis of 24 hour LH measurement showed that the frequency of LH peaks/24 h in AHO women varied widely, but as a group they were not statistically different from a group of normal women studied in the early follicular phase. Administration of 100 microg synthetic GnRH produced normal FSH and LH responses. We conclude that reproductive dysfunction is common in women with AHO and probably represents partial resistance to gonadotropins.
Adolescent↗
Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response.
Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 I/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to approximately 60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.
Amino Acid Sequence↗
Proposed cause of marked vasopressin resistance in a female with an X-linked recessive V2 receptor abnormality.
Almost all cases of congenital nephrogenic diabetes insipidus (NDI) are transmitted in an X-linked recessive manner by an asymptomatic carrier female to her affected son. Severe symptomatic NDI has not previously been reported in a female with X-linked recessive NDI. Each of the three members of this family has an abnormal V2 receptor gene, which results in truncation of the V2 receptor beginning at arginine-337. This prematurely terminates the receptor at the carboxy-terminal tail and very likely disrupts receptor function. The son has an abnormal V2 receptor gene on his X-chromosome, whereas the mother and daughter have one normal and one abnormal gene for the V2 receptor. The infusion of desmopressin into the mother and son reveals a total lack of antidiuretic response, whereas the daughter increases urinary osmolality normally. The plasma factor VIII concentration after the infusion of desmopressin in the son does not rise, whereas the mother and daughter have half of the normal factor VIII response, similar to asymptomatic female carriers of NDI. These responses to desmopressin in daughter and son are those of a typical carrier female and male affected with NDI. In contrast, the mother acts as an NDI patient when the urine concentration is measured, but acts as a carrier in terms of the factor VIII response to desmopressin. We postulate that the renal tubular cells of the mother demonstrate extreme lyonization of X-chromosome inactivation, whereas in the tissue that subserves the hematological response to desmopressin, X-chromosome inactivation followed a more typically random distribution.
Adult↗
Characterization of carrier females and affected males with X-linked recessive nephrolithiasis.
X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.
Adolescent↗
Acute interstitial nephritis with renal failure associated with propylthiouracil therapy.
Propylthiouracil therapy is associated with a variety of adverse reactions. Renal involvement, although rare, has occurred, but neither acute interstitial nephritis nor severe acute renal failure has been reported previously. We report a case of fulminant acute interstitial nephritis with renal failure following treatment with propylthiouracil.
Acute Disease↗
Novel mutations in the V2 vasopressin receptor gene of patients with X-linked nephrogenic diabetes insipidus.
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Amino Acid Sequence↗
Comments on some clinical implications of the release of adrenocorticotropin and vasopressin by interleukin-6 and other cytokines.
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Adrenocorticotropic Hormone↗
Hereditary vasopressin resistance in man and mouse.
The DI +/+ Severe hereditary nephrogenic diabetes insipidus mouse is resistant to the antidiuretic action of vasopressin (VP) because of failure to accumulate cAMP and subsequent inability to form intramembranous particles on the apical (luminal) surface of kidney cells that normally respond to VP. The defect is primarily, if not exclusively, due to excessive activity of specific cAMP-phosphodiesterases. The abnormality can be overcome in vitro and in vivo by the phosphodiesterase inhibitor, rolipram. Most cases of hereditary NDI in man have sex-linked recessive inheritance, which appears to be due to an abnormality of the V2 receptor. The chromosomal locus of the defect is Xq28. Sporadic cases of congenital NDI have been described in females who appear to have a defect beyond the V2 receptor and the guanine nucleotide-binding stimulatory protein. There is no information on the biochemical defect in very rare cases with other types of inheritance patterns. No abnormalities of V1a and V1b receptor function have been found in patients with NDI. Mice and patients with NDI have evidence of increased AVP synthesis. AVP release in relation to plasma osmolality is increased in patients during infusion of hypertonic saline. This is the opposite of what has been described in patients with primary polydipsia (dipsogenic diabetes insipidus) who are chronically overhydrated. Together, these studies indicate that chronic dehydration and overhydration can cause up- and downregulation of the osmotic release of AVP.
Animals↗
Impairment of osmotically stimulated AVP release in patients with primary polydipsia.
The secretion of arginine vasopressin (AVP) from the posterior pituitary is primarily and finely regulated by the osmolality of plasma. Even though a number of factors alter osmolality-induced release of AVP, there are no published data in humans that have addressed the role of chronic overhydration on this phenomenon. To address this problem we have identified eight patients with primary polydipsia using criteria not involving measurement of AVP, and have subjected them to standardized infusions of hypertonic saline. These patients had less AVP in both plasma and urine in relation to plasma osmolality than was found in normal subjects. In addition, their rate of rise of plasma and urine AVP was less than in normal subjects. Their osmotic threshold for AVP release may have been higher than normal. These data demonstrate that chronic overhydration in humans downregulates the release of AVP in response to hypertonicity. This phenomenon may explain the impairment of urine concentration in patients with primary polydipsia and emphasizes the basis of the difficulty that may occur clinically in differentiating between patients with primary polydipsia and partial central diabetes insipidus.
Adult↗
Effects of atrial natriuretic peptides on metabolism of arginine vasopressin by isolated perfused rat kidney.
Atrial natriuretic peptide (ANP) antagonizes the release and action of arginine vasopressin (AVP) both in vivo and in vitro. We have reported that ANP increases the urinary and metabolic clearances of AVP in normal subjects (A. M. Moses et al. J. Clin. Endocrinol. Metab. 70: 222-229, 1990). To clarify this effect, we perfused isolated rat kidneys in vitro and measured the clearances of AVP for 30 min after the addition of rat ANP [rANP-(1-28), 10(-7) M]. In the perfused kidney, rANP increased the urinary clearance of AVP (UCAVP) from 321 +/- 19 to 417 +/- 20 microliters/min (P less than 0.01) and increased the glomerular filtration rate (GFR) from 558 +/- 28 to 696 +/- 28 microliters/min (P less than 0.01). Fractional excretion of AVP was unchanged. Rates of AVP reabsorption were directly related to filtered AVP, and this relationship was not altered by ANP. ANP did not affect the total organ clearance or the renal metabolic clearance of AVP. The increase in GFR was associated with increases in renal vascular resistance (P less than 0.05), filtration fraction (P less than 0.01), and sodium excretion (P less than 0.001). UCAVP also increased when GFR was raised without ANP by perfusing at higher pressures. The rat ANP clearance receptor agonist [cANP- (4-23), 10(-7) M] did not change GFR or UCAVP. ANP increases UCAVP in the isolated perfused rat kidney. This appears to be a hemodynamic effect of ANP, acting through its biological receptor and not the clearance receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ectopic secretion of neurohypophyseal peptides in patients with malignancy.
A great deal of information has been accumulated on the synthesis and release of AVP, oxytocin, and their associated neurophysins under normal circumstances. In 1957, Schwartz and Bartter first described SIAD in patients with lung cancer and postulated that the clinical findings were the results of excessive vasopressin secretion. Tumors have been known since 1964 to produce vasopressin, and small cell (oat cell) carcinoma of the lung is by far the most frequent malignant cause of SIAD. The biosynthetic pathway for the synthesis of AVP and its associated neurophysin (and to a lesser extent, oxytocin and its neurophysin) is well described and is similar if not identical to the synthesis of these peptides in the hypothalamus. However, there is little reliable information on the control of peptide synthesis and release by these tumors. The clinical picture of SIAD is well described and occurs in 20% to 40% of patients with SCCL, although up to 88% of patients with extensive SCCL have elevated circulating levels of one or more neurohypophyseal peptides. This information has led to considerable interest in the use of these peptides as tumor markers for the diagnosis, evaluation, and assessment of therapy in these patients. With the recognition of the high incidence of secretion of neurohypophyseal peptides by SCCL, studies have been initiated to determine the value of radioactive vasopressin neurophysin antibodies in localizing tumors that synthesize these peptides. The studies provide potentially useful information in diagnosing and following patients with SCCL and also offer some promise that radiolabeled antineurophysins could eventually be used to treat these patients.
Biomarkers, Tumor↗
Desmopressin and indomethacin therapy for nephrogenic diabetes insipidus in patients receiving lithium carbonate.
Individuals receiving lithium carbonate commonly have nephrogenic diabetes insipidus. There is no effective and practical treatment for this condition. We have found that large doses of desmopressin (DDAVP) may provide effective therapy without adverse effects. A recent report showed that indomethacin improved nephrogenic diabetes insipidus that had persisted after the lithium therapy was discontinued. We have provided additional evidence that indomethacin may be effective, even when treatment with lithium is continued. We also have shown that indomethacin together with desmopressin can markedly decrease polyuria, though indomethacin must be used with care because it may impair renal function.
Adult↗
L-histidine augments the response to 1-deamino-8-D-arginine vasopressin in Brattleboro homozygous (di/di) rats.
Studies in vitro have shown that L-histidine increases the hydroosmotic response to vasopressin. We examined whether this phenomenon occurs also in vivo. Homozygous Brattleboro rats (di/di) were fed a regular diet (0.5% histidine) or a diet enriched with histidine and received 1 ng of 1-deamino-8-D-arginine vasopressin (dDAVP) daily. Addition of histidine (1% by weight) increased post-dDAVP urine osmolality to a level higher than that of control (502 +/- 62 vs. 316 +/- 36 mosmol/kg, P less than 0.05). Similar results were seen with 3.0% and 5.5% dietary histidine. There were significant increases in free-water reabsorption and in the ratio of free-water reabsorption to osmolar clearance, but no difference in osmolal clearance. No significant effect was found with supplemental histidine of 0.5% or less. The cause for these findings appears not to be the metabolism of histidine, since the nonmetabolizable D-histidine had a significant, albeit smaller, effect, and the isonitrogenous addition of albumin, alanine, arginine, or glutamine was ineffective. In part, histidine may operate by increasing cAMP since the renal cAMP content in response to vasopressin is increased in histidine-fed rats (13.1 +/- 0.9 vs. 9.8 +/- 0.8 nmol/g dry weight, P less than 0.01). The role of prostaglandins appears less clear. Histidine greatly decreased urinary PGE2 during baseline (1.5 +/- 0.3 vs. 7.0 +/- 2.3 micrograms/mg creatinine, P less than 0.001), but it profoundly augmented urinary prostaglandin excretion after dDAVP stimulation (40.0 +/- 4.2 vs. 7.0 +/- 2.0 micrograms/mg creatinine, P less than 0.001).
Animals↗
Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects.
Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.
Adult↗
Osmotic thresholds for AVP release with the use of plasma and urine AVP and free water clearance.
Eleven hydrated normal subjects were infused with hypertonic saline so that plasma osmolalities (POsmol) ranged from 280 to 306 mosmol/kg. Linear relationships were calculated between POsmol and plasma and urine arginine vasopressin (AVP) in the 11 individual subjects. There was an excellent linear correlation between POsmol and plasma and urine AVP, with the latter as concentration or rate of excretion. The highest correlation coefficient occurred when urine AVP was expressed as microunits of AVP per 100 milliliters of glomerular filtrate. The smallest coefficient of variation of the slopes occurred when urine AVP was expressed as microunits of AVP per minute. The osmotic thresholds obtained by abscissal intercepts from relating POsmol to urine AVP per minute or per 100 milliliters of glomerular filtrate were 285.9 and 285.5 mosmol/kg, respectively. These values did not differ from the mean osmotic threshold obtained by traditional free water clearance changes (285.8 mosmol/kg). Analysis of the relationship between plasma osmolality and plasma AVP resulted in the greatest variation in slope and osmotic threshold, with the latter being significantly lower than that obtained by free water clearance changes. The data also demonstrated a much more rapid rise of urine than of plasma AVP under the stated conditions of osmotic stimulation.
Adult↗
Two distinct pathophysiological mechanisms in congenital nephrogenic diabetes insipidus.
V1 and V2 vasopressin receptor functions were studied in 2 patients with congenital nephrogenic diabetes insipidus. V1 receptor-mediated functions (increase in urinary prostaglandin E2 excretion and plasma cortisol levels) and Gs (guanine nucleotide-binding stimulatory protein) activity of erythrocyte membranes were normal in both patients. After infusion of 0.4 micrograms/kg dDAVP, a 57-yr-old male patient had no increase in plasma factor VIII coagulant, ristocetin cofactor, or fibrinolytic activity or change in von Willebrand factor multimers. In addition, he had no vasodilatory response to dDAVP, a response that occurs in normal subjects and patients with central diabetes insipidus. In contrast, a 25-yr-old female patient had normal hemostatic and vasodilatory responses to the infusion of dDAVP. These observations indicate that the cellular abnormalities in patients with congenital nephrogenic diabetes insipidus may be either at the V2 receptor or in the postreceptor (and Gs activity) cascade of events that mediate vasopressin-induced antidiuresis. Therefore, heterogeneity exists in the biochemical cause(s) of congenital nephrogenic diabetes insipidus in man.
Adult↗