Vasopressin Function in the Syndrome of Inappropriate Antidiuresis

Zerbe, Robert L.; Stropes, Linda L.; Robertson, Gary

doi:10.1146/annurev.me.31.020180.001531

Cited by 295 publications

(159 citation statements)

References 34 publications

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“…Importantly, our study also revealed major deviations from the original report 5 as to both subtype prevalence and phenotype: On the basis of our quantitative classification, 10% of patients (n=5) were assigned to type A SIAD, characterized by grossly elevated baseline copeptin concentrations unresponsive to osmotic regulation. Erratic and markedly elevated AVP fluctuations had previously been reported to characterize the osmoregulatory defect of type A.…”

Section: Discussioncontrasting

confidence: 50%

“…4 Zerbe et al were the first to suggest distinct types of osmotic dysregulation in SIAD based on the AVP response to hypertonic saline: a type with erratic fluctuations of high plasma AVP levels that are nonresponsive to osmotic stimulation (type A); another type, with a preserved linear correlation between AVP and serum osmolality but an abnormally low osmotic threshold ("reset osmostat" or type B); type C, with constant and nonsuppressible AVP release in the hypoosmotic range; and type D, with undetectable AVP levels. 5 Unfortunately, this subtype description was reported only as individual case examples; it has never been validated using quantitative criteria. A better understanding of the different forms of SIAD may influence future treatment strategies because response to therapy (e.g., with vaptans or fluid restriction) varies widely in SIAD.…”

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confidence: 99%

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A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

Fenske

Christ‐Crain

Hörning

et al. 2014

Journal of the American Society of Nephrology

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Hyponatremia, the most frequent electrolyte disorder, is caused predominantly by the syndrome of inappropriate antidiuresis (SIAD). A comprehensive characterization of SIAD subtypes, defined by type of osmotic dysregulation, is lacking, but may aid in predicting therapeutic success. Here, we analyzed serial measurements of serum osmolality and serum sodium, plasma arginine vasopressin (AVP), and plasma copeptin concentrations from 50 patients with hyponatremia who underwent hypertonic saline infusion. A close correlation between copeptin concentrations and serum osmolality existed in 68 healthy controls, with a mean osmotic threshold6SD of 28264 mOsM/kg H 2 O. Furthermore, saline-induced changes in copeptin concentrations correlated with changes in AVP concentrations in controls and patients. With use of copeptin concentration as a surrogate measure of AVP concentration, patients with SIAD could be grouped according to osmoregulatory defect: Ten percent of patients had grossly elevated copeptin concentrations independent of serum osmolality (type A); 14% had copeptin concentrations that increased linearly with rising serum osmolality but had abnormally low osmotic thresholds (type B); 44% had normal copeptin concentrations independent of osmolality (type C), and 12% had suppressed copeptin concentrations independent of osmolality (type D). A novel SIAD subtype discovered in 20% of patients was characterized by a linear decrease in copeptin concentrations with increasing serum osmolality (type E or "barostat reset"). In conclusion, a partial or complete loss of AVP osmoregulation occurs in patients with SIAD. Although the mechanisms underlying osmoregulatory defects in individual patients are presumably diverse, we hypothesize that treatment responses and patient outcomes will vary according to SIAD subtype.

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Section: Discussioncontrasting

confidence: 50%

mentioning

confidence: 99%

A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

Fenske

Christ‐Crain

Hörning

et al. 2014

Journal of the American Society of Nephrology

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“…At least 1 kindred has been described in which several individuals bearing this mutation did not manifest clinically recognized hyponatremia until late into adulthood. 23 The true incidence of these and similar V 2 R mutations, as well as how often they are responsible for the pattern of euvolemic hyponatremia with low or unmeasurable plasma AVP levels found in approximately 10% of patients with SIADH, 24 remains to be determined.…”

Section: Nephrogenic Syndrome Of Inappropriate Antidiuresismentioning

confidence: 99%

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Verbalis

Goldsmith

Greenberg

et al. 2007

The American Journal of Medicine

523

498

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Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. Hyponatremia is the most common disorder of electrolytes encountered in clinical practice, occurring in up to 15% to 30% of both acutely and chronically hospitalized patients. 1 Although most cases are mild and relatively asymptomatic, hyponatremia is important clinically because: (1) acute severe hyponatremia can cause substantial morbidity and mortality; (2) mortality is higher in patients with hyponatremia who have a wide range of underlying diseases; and (3) overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death.Despite knowledge of hyponatremia since the mid-20th century, this common disorder remains incompletely understood in many basic areas because of its association with a plethora of underlying disease states, and its multiple etiologies with differing pathophysiologic mechanisms. 2 Optimal treatment strategies have not been well defined, both for these reasons and because of marked differences in symptomatology and clinical outcomes based on the acuteness or chronicity of the hyponatremia. 3 Vasopressin receptor antagonists have long been anticipated as a more effective method to treat hyponatremia by virtue of their unique aquaretic effect to selectively increase solute-free water excretion by the kidneys. 4 The recent approval of the first such agent, conivaptan, for clinical use by the US Food and Drug Administration (FDA) heralds the beginning of a new era in the management of hyponatremic disorders. However, effective therapy with these agents will require intelligent guidelines for their use. To this end, a panel of experts in hyponatremia convened to review current therapies for hyponatremia and to evaluate the situations in which aquaretic agents should be considered as alternatives or supplements to accepted current therapies. This review is a summary of the conclusions of this panel.

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“…This is particularly important when considering that 10%-20% of patients diagnosed with SIADH have undetectable serum AVP levels upon water restriction, 18 suggesting that some of these patients may in fact have NSIAD due to an activating mutation in their AVPR2 gene. 3 Finally, our study demonstrates that a disease resulting from distinct mutations of the same gene may respond differently to a given therapy, highlighting the importance of a clear understanding of the functional consequences of the mutations that will allow appropriate personalized medicine.…”

mentioning

confidence: 99%

Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD

Carpentier

Greenbaum

Rochdi

et al. 2012

Journal of the American Society of Nephrology

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Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/ L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.

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Vasopressin Function in the Syndrome of Inappropriate Antidiuresis

Cited by 295 publications

References 34 publications

A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

Identification and Characterization of an Activating F229V Substitution in the V2 Vasopressin Receptor in an Infant with NSIAD

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