Vasopressin-Dependent Disorders: What Is New in Children?

Arginine vasopressin (AVP)-mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP's chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.

Acquired forms of central diabetes insipidus: Mechanisms of disease.

Most cases of acquired central diabetes insipidus are caused by destruction of the neurohypophysis by: 1) anatomic lesions that destroy the vasopressin neurons by pressure or infiltration, 2) damage to the vasopressin neurons by surgery or head trauma, and 3) autoimmune destruction of the vasopressin neurons. Because the vasopressin neurons are located in the hypothalamus, lesions confined to the sella turcica generally do not cause diabetes insipidus because the posterior pituitary is simply the site of the axon terminals that secrete vasopressin into the bloodstream. In addition, the capacity of the neurohypophysis to synthesize vasopressin is greatly in excess of the body's needs, and destruction of 80-90% of the hypothalamic vasopressin neurons is required to produce diabetes insipidus. As a result, even large lesions in the sellar and suprasellar area generally are not associated with impaired water homeostasis until they are surgically resected. Regardless of the etiology of central diabetes insipidus, deficient or absent vasopressin secretion causes impaired urine concentration with resultant polyuria. In most cases, secondary polydipsia is able to maintain water homeostasis at the expense of frequent thirst and drinking. However, destruction of the osmoreceptors in the anterior hypothalamus that regulate vasopressin neuronal activity causes a loss of thirst as well as vasopressin section, leading to severe chronic dehydration and hyperosmolality. Vasopressin deficiency also leads to down-regulation of the synthesis of aquaporin-2 water channels in the kidney collecting duct principal cells, causing a secondary nephrogenic diabetes insipidus. As a result, several days of vasopressin administration are required to achieve maximal urine concentration in patients with CDI. Consequently, the presentation of patients with central diabetes insipidus can vary greatly, depending on the size and location of the lesion, the magnitude of trauma to the neurohypophysis, the degree of destruction of the vasopressin neurons, and the presence of other hormonal deficits from damage to the anterior pituitary.

GENETICS IN ENDOCRINOLOGY Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus.

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.

Diagnosis and differential diagnosis of diabetes insipidus: Update.

The two main differential diagnoses of central diabetes insipidus are nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between those entities is essential as treatment differs substantially with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the indirect water deprivation test had several pitfalls, resulting in a low diagnostic accuracy. With the introduction of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of diabetes insipidus was new evaluated. While unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, a stimulation test is needed to differentiate patients with central diabetes insipidus from patients with primary polydipsia. Stimulation can either be achieved through hypertonic saline infusion or arginine infusion. While the former showed high diagnostic accuracy and superiority over the indirect water deprivation test in a recent validation study, the diagnostic accuracy for arginine-stimulated copeptin was slightly lower, but superior in test tolerance. In summary of the recent findings, a new copeptin based diagnostic algorithm is proposed for the reliable diagnosis of diabetes insipidus.

Gestational diabetes insipidus: Diagnosis and management.

In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.

Management of central diabetes insipidus.

The treatment of central diabetes insipidus has not changed significantly in recent decades, and dDAVP and replacement of free water deficit remain the cornerstones of treatment. Oral dDAVP has replaced nasal dDAVP as a more reliable mode of treatment for chronic central diabetes insipidus. Hyponatraemia is a common side effect, occurring in one in four patients, and should be avoided by allowing a regular break from dDAVP to allow a resultant aquaresis. Hypernatraemia is less common, and typically occurs during hospitalization, when access to water is restricted, and in cases of adipsic DI. Management of adipsic DI can be challenging, and requires initial inpatient assessment to establish dose of dDAVP, daily fluid prescription, and eunatraemic weight which can guide day-to-day fluid targets in the long-term.

Diabetes insipidus.

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must be differentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be due to an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed to ensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.

[The pathway of vasopressin as a pharmacological target in nephrology: a narrative review].

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

Vasopressin, Central Autonomic Control and Blood Pressure Regulation.

PURPOSE OF REVIEW: We present recent advances in understanding of the role of vasopressin as a neurotransmitter in autonomic nervous system control of the circulation, emphasizing hypothalamic mechanisms in the paraventricular nucleus (PVN) involved in controlling sympathetic outflow toward the cardiovascular system. RECENT FINDINGS: Suggest that somato-dendritically released vasopressin modulates the activity of magnocellular neurons in the PVN and SON, their discharge pattern and systemic release. Advances have been made in uncovering autocrine and paracrine mechanisms controlling presympathetic neuron activity, involving intranuclear receptors, co-released neuroactive substances and glia. It is now obvious that intranuclear release of vasopressin and the co-release of neuroactive substances in the PVN, as well as the level of expression of vasopressin receptors, modulate sympathetic outflow to the cardiovascular system and determine vulnerability to stress. Further research involving patho-physiological models is needed to validate these targets and foster the development of more efficient treatment.

Extracellular volume depletion and resultant hypotonic hyponatremia: A novel translational approach.

Although several methods currently exist to determine that a person is hypovolemic, it often remains very challenging to accurately estimate the effective circulating volume or amount of intravascular volume depletion in a non-controlled setting. This depletion of intravascular volume can have many causes and is frequently accompanied by hypotonic hyponatremia as a result of hypovolemia-induced release of arginine vasopressin (AVP) from the posterior pituitary gland. Here, we derive a novel, comprehensible equation that provides a theoretical insight into the complex interrelationship between the degree of isotonic volume depletion and the resultant change in plasma sodium concentration. We believe that the presented model can prove to be a valuable tool for the analysis of fluid and electrolyte imbalances.

Central and peripheral roles of vasopressin in the circadian defense of body hydration.

Vasopressin is a neuropeptide synthesized by specific subsets of neurons within the eye and brain. Studies in rats and mice have shown that vasopressin produced by magnocellular neurosecretory cells (MNCs) that project to the neurohypophysis is released into the blood circulation where it serves as an antidiuretic hormone to promote water reabsorption from the kidney. Moreover vasopressin is a neurotransmitter and neuromodulator that contributes to time-keeping within the master circadian clock (i.e. the suprachiasmatic nucleus, SCN) and is also used as an output signal by SCN neurons to direct centrally mediated circadian rhythms. In this chapter, we review recent cellular and network level studies in rodents that have provided insight into how circadian rhythms in vasopressin mediate changes in water intake behavior and renal water conservation that protect the body against dehydration during sleep.

[Small cell lung cancer associated with multiple paraneoplastic syndromes].

We report the case of a patient presenting with multiple severe electrolyte disturbances who was subsequently found to have small cell lung cancer. Upon further evaluation, she demonstrated three distinct paraneoplastic processes, including the syndrome of inappropriate antidiuretic hormone, Fanconi syndrome, and an inappropriate elevation in fibroblast growth factor-23 (FGF23). The patient underwent one round of chemotherapy, but she was found to have progressive disease. After 36 days of hospitalization, the patient made the decision to enter hospice care and later she expired.

Small cell lung cancer associated with multiple paraneoplastic syndromes / Cáncer de pulmón de células pequeñas asociado a múltiples síndromes paraneoplásicos

Abstracts We report the case of a patient presenting with multiple severe electrolyte disturbances who was subsequently found to have small cell lung cancer. Upon further evaluation, she demonstrated three distinct paraneoplastic processes, including the syndrome of inappropriate antidiuretic hormone, Fanconi syndrome, and an inappropriate elevation in fibroblast growth factor-23 (FGF23). The patient underwent one round of chemotherapy, but she was found to have progressive disease. After 36 days of hospitalization, the patient made the decision to enter hospice care and later she expired.

Resumen Se reporta el caso de una paciente que ingresó al hospital para evaluación de múltiples trastornos electrolíticos y, posteriormente, se le hizo el diagnóstico de cáncer de pulmón de células pequeñas. Tras la evaluación médica, se detectaron tres síndromes paraneoplásicos: síndrome de secreción inadecuada de hormona antidiurética, síndrome de Fanconi y elevación inapropiada del factor 23 de crecimiento de fibroblastos. Se le administró quimioterapia sin éxito, por lo cual se decidió darle tratamiento paliativo y, un tiempo después, falleció.

Cord blood copeptin concentrations in fetal macrosomia.

BACKGROUND/AIM: Excessive fetal growth is associated with increased adiposity and reduced insulin sensitivity at birth. Copeptin, a surrogate marker of arginine vasopressin (AVP) secretion, is upregulated in states of hyperinsulinemia and is considered one of the mediators of insulin resistance. We aimed to investigate cord blood concentrations of copeptin (C-terminal fragment of AVP pro-hormone) in healthy large-for-gestational-age (LGA) infants at term. METHODS: This prospective study was conducted on 30 LGA (n=30) and 20 appropriate-for-gestational-age (AGA, n=20) singleton full-term healthy infants. Cord blood copeptin and insulin concentrations were determined by ELISA and IRMA, respectively. Infants were classified as LGA or AGA, based on customized birth-weight standards adjusted for significant determinants of fetal growth. RESULTS: Cord blood copeptin concentrations were similar in LGA cases, compared to AGA controls, after adjusting for delivery mode. However, in the LGA group, cord blood copeptin concentrations positively correlated with birth-weight (r=0.422, p=0.020). In the AGA group, cord blood copeptin concentrations were elevated in cases of vaginal delivery vs elective cesarean section (p=0.003). Cord blood insulin concentrations were higher in LGA cases, compared to AGA controls (p=0.036). No association was recorded between cord blood copeptin concentrations and maternal age, parity, gestational age or fetal gender in both groups. CONCLUSIONS: Cord blood copeptin concentrations may not be up-regulated in non-distressed LGA infants. However, the positive correlation between cord blood copeptin concentrations and birth-weight in the LGA group may point to the documented association between AVP release and increased fat deposition. Vaginal delivery vs elective cesarean section is accompanied by a marked stress-related increase of cord blood copeptin concentrations.

Altered agonist sensitivity of a mutant v2 receptor suggests a novel therapeutic strategy for nephrogenic diabetes insipidus.

Loss-of-function mutations of the type 2 vasopressin receptor (V2R) in kidney can lead to nephrogenic diabetes insipidus (NDI). We studied a previously described, but uncharacterized, mutation of the V2R (N321K missense mutation) of a patient with NDI. The properties of the mutant receptor were evaluated. We constructed a highly sensitive Epac-based bioluminescence resonance energy transfer biosensor to perform real-time cAMP measurements after agonist stimulation of transiently transfected HEK293 cells with V2Rs. ß-Arrestin binding of the activated receptors was examined with luciferase-tagged ß-arrestin and mVenus-tagged V2Rs using the bioluminescence resonance energy transfer technique. Cell surface expression levels of hemagglutinin-tagged receptors were determined with flow cytometry using anti-hemagglutinin-Alexa 488 antibodies. Cellular localization examinations were implemented with fluorescent tagged receptors visualized with confocal laser scanning microscopy. The effect of various vasopressin analogs on the type 1 vasopressin receptor (V1R) was tested on mouse arteries by wire myography. The N321K mutant V2R showed normal cell surface expression, but the potency of arginine vasopressin for cAMP generation was low, whereas the clinically used desmopressin was not efficient. The ß-arrestin binding and internalization properties of the mutant receptor were also different than those for the wild type. The function of the mutant receptor can be rescued with administration of the V2R agonist Val(4)-desmopressin, which had no detectable side effects on V1R in the effective cAMP generating concentrations. Based on these findings we propose a therapeutic strategy for patients with NDI carrying the N321K mutation, as our in vivo experiments suggest that Val(4)-desmopressin could rescue the function of the N321K-V2R without significant side effects on the V1R.

Alcohol abuse and the injured host: dysregulation of counterregulatory mechanisms review.

Traumatic injury ranks as the number one cause of death for the younger than 44 years age group and fifth leading cause of death overall (www.nationaltraumainstitute.org/home/trauma_statistics.html). Although improved resuscitation of trauma patients has dramatically reduced immediate mortality from hemorrhagic shock, long-term morbidity and mortality continue to be unacceptably high during the postresuscitation period particularly as a result of impaired host immune responses to subsequent challenges such as surgery or infection. Acute alcohol intoxication (AAI) is a significant risk factor for traumatic injury, with intoxicating blood alcohol levels present in more than 40% of injured patients. Severity of trauma, hemorrhagic shock, and injury is higher in intoxicated individuals than that of sober victims, resulting in higher mortality rates in this patient population. Necessary invasive procedures (surgery, anesthesia) and subsequent challenges (infection) that intoxicated trauma victims are frequently subjected to are additional stresses to an already compromised inflammatory and neuroendocrine milieu and further contribute to their morbidity and mortality. Thus, dissecting the dynamic imbalance produced by AAI during trauma is of critical relevance for a significant proportion of injured victims. This review outlines how AAI at the time of hemorrhagic shock not only prevents adequate responses to fluid resuscitation but also impairs the ability of the host to overcome a secondary infection. Moreover, it discusses the neuroendocrine mechanisms underlying alcohol-induced hemodynamic dysregulation and its relevance to host defense restoration of homeostasis after injury.

[The syndrome of inappropriate antidiuresis]. / Syndrome d'antidiurèse inappropriée (sécrétion inappropriée d'hormone antidiurétique).

The syndrome of inappropriate antidiuresis (SIAD; formerly the syndrome of inappropriate secretion of antidiuretic hormone) is the most frequent cause of hyponatremia. A strong association exists between mortality and hyponatremia, which reflects the severity of the underlying disease. In SIAD, hyponatremia is associated with normovolaemia but the assessment of extracellular volume can be difficult. Clinical features are mainly neurological and can lead to death but mechanisms of adaptation can limit cerebral oedema. The notion of mild asymptomatic hyponatremia was questioned by the observation of subclinical neurocognitive impairment, a greater risk of falls and fractures. Aetiologies are classified into six groups: neurologic disorders, infections mainly cerebral, meningeal and pulmonary, drugs in particular antidepressants, tumors, genetic causes, and idiopathic. Symptomatic acute hyponatremia is a therapeutic emergency that is not specific of SIAD. When hyponatremia is asymptomatic, fluid restriction with salt intake is generally sufficient but urea can be an alternative. In chronic SIAD, there is currently no recommendation. Fluid restriction is not always feasible; urea has proved its efficacy, its good tolerance and its long-term harmlessness. Vaptans have demonstrated their good tolerance and their efficacy on the correction of hyponatremia from SIAD in studies subgroups, for moderate hyponatremia and asymptomatic patients. In the only study having compared vaptans and urea, efficacy and tolerance were similar. Because of the cost difference between vaptans and urea and while waiting for follow-up studies, urea appears at present as the first-line treatment of hyponatremia in SIAD.

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the "syndrome of inappropriate antidiuresis", is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.