Complete Central Diabetes Insipidus Research Articles

Anterior and Posterior Pituitary Function in Patients with Sheehan Syndrome - Combining the use of Insulin Tolerance Test and Copeptin Assay.

Sheehan syndrome (SS) typically involves the loss of anterior pituitary cells and rarely affects the posterior pituitary. The water deprivation test (WDT) is the gold standard for diagnosing central diabetes insipidus (CDI), but it is cumbersome. Serum copeptin measurements are an alternative for CDI diagnosis. In this study, we measured hypoglycaemia-stimulated serum copeptin in SS patients to assess posterior pituitary function alongside anterior pituitary hormone levels. This study recruited 43 patients with SS on stable hormonal replacement except for growth hormone (GH), 18 patients with CDI, and 19 body mass index (BMI) and parity-matched controls. All patients with SS and four patients with CDI underwent an insulin tolerance test (ITT), and hypoglycaemia-stimulated copeptin levels were measured at 0, 30, 45, and 90 minutes after insulin injection. The mean serum copeptin level among patients with SS (26.01 ± 12.41 pmol/L) was significantly lower than that in healthy controls (31.92 ± 7.85 pmol/L) and higher than that in patients with CDI (1.81 ± 0.14 pmol/L). Using pre-defined cut-offs for CDI, basal serum copeptin <2.69 pmol/L and stimulated levels <4.92 pmol/L for complete central DI, and basal copeptin levels >2.69 pmol/L and stimulated copeptin <4.92 pmol/L for partial central DI, 9.2% (n = 4) of patients with SS had CDI, of which half had complete CDI and half had partial CDI. A significant number of patients with SS who are on hormone replacement therapy show involvement of the posterior pituitary, despite not displaying symptoms.

Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction. The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate. RESULTS: Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3-CXCR6+ CD4+ T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells. We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis.

SUN-409 Diabetes Insipidus Central: Idiophatic versus Autoinmune?

BACKGROUND Central diabetes insipidus (CDI) is a rare disorder characterized by the excretion of abnormally large volumes of hypotonic urine due to a lack of AVP. The etiology of CDI is unknown in over one third of the cases and is classified as idiopathic. Autoimmunity has been found to be the cause of several endocrine diseases previously classified as idiopathic, but no specific clinical, immunological, and/or radiological pattern has been unequivocally associated with autoimmunity in patients with CDI. CLINICAL CASE A 28 years old woman attended with five-month illness time characterized by polydipsia, associated with polyuria at night and asthenia. Throbbing frontal headache is added 8/10 that decreases with liquid fluids intake. Was evaluated by a doctor, prescribing acetaminophen 500mg conditional to pain. 2 months before admission, an endocrinologist in a clinic, found serum sodium: 158mg/dL, so she was referred. Medical history: 3 previous pregnancies, last delivery 10 months ago, without uterine dynamics, normal breastfeeding. Blood tests: basal glucose: 98mg/dL, FSH: 6.03mU/mL (follicular phase: 3.3-11.3), Estradiol: 67.17pg/mL (follicular phase: 10-178), TSH: 2.08uU / mL (0.27-4.2), T4L: 1.55ng / dL (0.9-1.7), prolactin: 17.02ng / mL (4.79-23.3), insulin: 6.4, urinary sodium: 14.1, urinary chlorine: 13.1, urinary potassium: 7.51. A water deprivation test was performed , with the following baseline values: weight 65kg, serum sodium 142mg/dL, serum osmolarity 288.1mmol / kg, presenting excess thirst. Two hours after starting the test, sensation :weight: 64kg, accumulated urinary volume: 710cc, serum sodium 146mg / dL, serum osmolarity 296.7mmol / kg, urinary osmolarity 158mOsm/kg. The test was stopped, suspended anding the test and 10ug of and intranasal desmopressin was administered, obtaining a a positive results with a post-desmopressin urine osmolarity at of 573mOsm/kg and 2 hours later, 512mOsm/kg, indicating CDI as the diagnosis. The pituitary MRI was reported as “absence of posterior pituitary and absence of T1 signal increase”. No other injuries were seen. Currently, the patient is on treatment with Intranasal Desmopressin 10ug intranasal every 24hrs, with complete improvement of symptoms. CONCLUSIONS The most common causes of CDI are idiopathic and are associated with autoinmmune process. The autoimmune CDI is associated with AVP antibodies (AVPcAb). It is most prevalent in women and the age of onset before 30 years, is an independent factor associated with AVPcAb in 53% of cases. Likewise, the duration of the disease over 5 months, complete CDI and the absence of bright neurohypophyseal spots at MRI, are conditions present in the patient that can tip the diagnosis towards the autoimmune etiology.

A Combined Outpatient and Inpatient Overnight Water Deprivation Test is Effective and Safe in Diagnosing Patients with Polyuria-Polydipsia Syndrome

The water deprivation test (WDT) is widely used for the differential diagnosis of the polyuria-polydipsia syndrome (PPS). However, it is inconvenient and may not always be precise in differentiating partial forms of diabetes insipidus (DI) from primary polydipsia (PP). The aim of this study was to evaluate the results of a combined outpatient and inpatient overnight WDT protocol that included an overnight unsupervised period concerning its feasibility and safety. We performed a retrospective analysis of clinical data and laboratory results of 52 patients with PPS undergoing WDT at a single center. PP was the most frequent diagnosis, followed by complete central DI (cCDI), partial central DI (pCDI), and nephrogenic DI (NDI). Over 90% of the patients showed an expected increase in serum osmolality at the end of the dehydration period. There were no reports of complications during the overnight deprivation period. Post-dehydration urine osmolality and urine-to-serum osmolality ratio significantly differentiated all the groups ( P<.05), except for cCDI and NDI, which could be differentiated by basal and post-dehydration vasopressin (AVP) levels ( P<.05 for both). Although these measurements were useful for differentiating patients according to their allocation groups, results from WDT and direct AVP levels may often require a comprehensive diagnostic approach, particularly in the challenging groups of PP and pCDI. A combined outpatient and inpatient overnight WDT protocol is safe and feasible when the test is performed with special care at experienced centers. Newer diagnostic tools are expected to improve the accuracy of PPS diagnosis. AQP2 = aquaporin-2; AVP = vasopressin; CDI = central diabetes insipidus; cCDI = complete central diabetes insipidus; DDAVP = desmopressin; DI = diabetes insipidus; IQR = interquartile range; MRI = magnetic resonance imaging; Na+ = sodium; NDI = nephrogenic diabetes insipidus; pCDI = partial central diabetes insipidus; PP = primary polydipsia; PPS = polyuria-polydipsia syndrome; S_osm = serum osmolality; U_osm = urine osmolality; WDT = water deprivation test.

Plasma Apelin Concentrations in Patients With Polyuria-Polydipsia Syndrome.

Apelin and arginine vasopressin are antagonists in the regulation of body fluid and osmotic homeostasis. There are no data about apelin levels in patients with polyuria-polydipsia syndrome (PPS). To investigate plasma apelin levels and plasma apelin to copeptin ratios in patients with PPS and healthy volunteers using copeptin as a surrogate marker for arginine vasopressin. We included 41 patients with PPS in this post hoc analysis of a prospective study performed in tertiary care hospitals in Switzerland and Germany and 113 healthy volunteers as a control group. Plasma apelin and copeptin levels were measured in 15 patients with complete central diabetes insipidus (DI), seven patients with complete nephrogenic DI, 19 patients with primary polydipsia (PP), and 113 healthy volunteers. Plasma apelin levels were highest in patients with complete nephrogenic DI (413 pmol/L; interquartile range, 332-504 pmol/L; P = .01) and lower in patients with PP (190 [172-215] pmol/L; P < .001) or complete central DI (209 [174-241] pmol/L; P = .02) as compared to healthy volunteers (254 [225-311] pmol/L). Plasma apelin to copeptin ratio in patients with PP (53 [38-92] pmol/pmol; P > .9) was similar to healthy volunteers (57 [37-102] pmol/pmol). In contrast, the apelin to copeptin ratio was higher in patients with complete central DI (89 [73-135] pmol/pmol; P = .02) and lower in patients with complete nephrogenic DI (7 [6-10] pmol/pmol; P < .001) compared to healthy volunteers. In PP, normal plasma apelin to copeptin ratio attests a normal water homeostasis. In contrast, in patients with central or nephrogenic DI, the increased or decreased apelin to copeptin ratio, respectively, reflects a disturbed osmotic and body fluid homeostasis.

Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study.

The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging. The objective was to evaluate the accuracy of copeptin, a stable peptide stoichiometrically cosecreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome. This was a prospective multicenter observational cohort study from four Swiss or German tertiary referral centers of adults >18 years old with the history of polyuria and polydipsia. A standardized combined water deprivation/3% saline infusion test was performed and terminated when serum sodium exceeded 147 mmol/L. Circulating copeptin and AVP levels were measured regularly throughout the test. Final diagnosis was based on the water deprivation/saline infusion test results, clinical information, and the treatment response. Fifty-five patients were enrolled (11 with complete central DI, 16 with partial central DI, 18 with PP, and 10 with nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with a 100% sensitivity and specificity, rendering a water deprivation testing unnecessary in such cases. A stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with a 94.0% specificity and a 94.4% sensitivity. A stimulated AVP >1.8 pg/mL differentiated between the same categories with a 93.0% specificity and a 83.0% sensitivity. This study was limited by incorporation bias from including AVP levels as a diagnostic criterion. Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary Funding Sources: Swiss National Science Foundation, University of Basel.

Circulating Levels of Human salusin-β,a Potent Hemodynamic and Atherogenesis Regulator

Using bioinformatics analysis, we previously identified salusin-β, an endogenous bioactive peptide with diverse physiological activities. Salusin-β is abundantly expressed in the neuroendocrine system and in systemic endocrine cells/macrophages. Salusin-β acutely regulates hemodynamics and chronically induces atherosclerosis, but its unique physicochemical characteristics to tightly adhere to all types of plastic and glassware have prevented elucidation of its precise pathophysiological role. To quantitate plasma total salusin-β concentrations, we produced rabbit and chicken polyclonal antibodies against the C- and N-terminal end sequences, circumvented its sticky nature, and successfully established a sandwich enzyme-linked immunosorbent assay (ELISA). Salusin-β was abundantly present in the plasma of healthy volunteers, ranging from 1.9 to 6.6 nmol/L. Reverse phase-high performance liquid chromatography analysis showed that a single immunoreactive salusin-β peak coincided with synthetic authentic salusin-β. Plasma salusin-β concentrations were unaffected by postural changes and by potent vasopressin release stimuli, such as hypertonic saline infusion or smoking. However, salusin-β concentrations showed significant circadian variation; concentrations were high during the daytime and reached the lowest concentrations in the early morning. Plasma salusin-β levels in subjects with diabetes mellitus, coronary artery disease, and cerebrovascular disease showed distinctly higher levels than healthy controls. Patients with panhypopituitarism combined with complete central diabetes insipidus also showed significantly higher plasma salusin-β levels. Therefore, the ELISA system developed in this study will be useful for evaluating circulating total salusin-β levels and for confirming the presence of authentic salusin-β in human plasma. The obtained results suggest a limited contribution of the neuroendocrine system to peripheral total salusin-β concentrations and a role for plasma total salusin-β concentrations as an indicator of systemic vascular diseases.

Copeptin in the Differential Diagnosis of the Polydipsia-Polyuria Syndrome—Revisiting the Direct and Indirect Water Deprivation Tests

The water deprivation test (WDT) with direct or indirect measurement of plasma arginine vasopressin (AVP) is the method of choice for the differential diagnosis of the polydipsia-polyuria syndrome. In theory, direct measurement of AVP is highly attractive but is hampered by technical difficulties. The aim of the study was to evaluate the utility of copeptin, a surrogate of AVP secretion, in the diagnostic work-up of the polyuria-polydipsia syndrome and to compare its performance with the current diagnostic standard. In two tertiary referral centers, 20 healthy subjects and 50 patients with polydipsia-polyuria syndrome underwent WDT with measurements of both plasma AVP and copeptin levels. The reference diagnosis was based on clinical information and treatment response. Twenty-two patients (44%) were diagnosed with primary polydipsia, 17 (34%) with partial central diabetes insipidus (DI), nine (18%) with complete central DI, and two (4%) with nephrogenic DI. The indirect WDT led to a correct diagnosis in 35 of 50 patients (70%). The direct WDT with AVP or copeptin measurement correctly diagnosed 23 patients (46%) or 36 patients (72%), respectively. Baseline copeptin values greater than 20 pmol/liter identified patients with nephrogenic DI, and concentrations below 2.6 pmol/liter indicated complete central DI. The ratio between Δ copeptin (0800 to 1600 h) and serum sodium concentration at 1600 h yielded optimal diagnostic accuracy, allowing us to also discern partial central DI from primary polydipsia (sensitivity 86%, and specificity 100%). Copeptin holds promise as a diagnostic tool in the polyuria-polydipsia syndrome, improving significantly the diagnostic accuracy of the direct WDT.

Solitary Fibrous Tumor of the Sella Mimicking Pituitary Adenoma: An Uncommon Tumor in a Rare Location—A Case Report

Solitary fibrous tumor (SFT) is rarely located in the central nervous system, and sella turcica involvement was reported in only two patients. We report the case of a 28-year-old man with a SFT of the sella turcica mimicking a pituitary nonfunctioning macroadenoma. He presented with optic nerve compression caused by a heterogeneous tumor located in the sellar and suprasellar area. At surgery, the tumor was hard and infiltrated the sellar diaphragm, so that resection resulted in a cerebrospinal fluid fistula. His postoperative course was also complicated by complete central diabetes insipidus, hypopituitarism, and two episodes of meningitis. After surgical resection, the diagnosis of SFT was reached on the basis of histological and immunohistochemical studies. He was discharged after 49 days. Ten months after surgery, he was clinically well, and magnetic resonance images showed no evidence of residual or recurrent tumor. SFT should be considered in the differential diagnosis of sellar and parasellar tumors.

Longitudinal study of vasopressin-cell antibodies and of hypothalamic-pituitary region on magnetic resonance imaging in patients with autoimmune and idiopathic complete central diabetes insipidus.

Diagnosis of autoimmune central diabetes insipidus (CDI) is based on the presence of autoantibodies to AVP-secreting cells (AVPcAb) or the coexistence of other autoimmune polyendocrine syndromes; moreover, it can be also suggested by the presence of lymphocytic infundibulo-neurohypophysitis, evidenced by biopsy of pituitary stalk and/or by pituitary stalk thickening on magnetic resonance imaging (MRI). However, so far, in clinical CDI patients with lymphocytic infundibulo-neurohypophysitis, AVPcAb have not been investigated and in those with or without autoimmune polyendocrine syndromes (APS), longitudinal studies on the behavior of AVPcAb alone, or of both AVPcAb and hypothalamic pituitary imaging on MRI are lacking. Aim of this work was to investigate in these patients the occurrence of AVPcAb (by indirect immunofluorescence) and of pituitary stalk thickening (by MRI) and their longitudinal changes during a follow-up period. We studied 22 patients, aged 29-53, with APS and complete CDI, grouped as follows: 10 with recent onset (< or =1.5 yr) of CDI (group 1a) and 12 with CDI of long-term duration (> or = 7 yr) (group 1b); moreover, a group of 13 patients with apparent idiopathic CDI of recent onset (<1.5 yr) were studied. They were divided, on the basis of the detection of AVPcAb as follows: 5 AVPcAb positive patients (aged 19-26) classified as isolated autoimmune CDI (group 2) and 8 AVPcAb negative patients (aged 21-26), classified as true idiopathic CDI (group 3). All patients were evaluated yearly, along 5 yr, for AVPcAb and for hypothalamic-pituitary region imaging. At study entry, 8/10 (80%) of patients in group 1a and 7/12 (58.3%) in group 1b were positive for AVPcAb and persisted positive subsequently, during all the follow-up period, even if at lower titers. All patients in group 2 were positive and all those in group 3 were negative for AVPcAb and persisted positive and negative, respectively, for all the follow-up study. Among the AVPcAb-positive patients, only 5 in group 1a and 2 in group 2 showed also pituitary stalk thickening at the first observations, which however spontaneously disappeared subsequently indicating a possible lymphocytic infundibulo-neurohypophysitis. All patients in the studied groups showed loss of the hyperintense signal of the neurohypophysis on MRI at entry and during all the follow-up period. Results of this longitudinal study suggest: 1) AVPcAb, frequently present at high titers in recent phases of CDI, persist subsequently, even if at lower titers, several years after the onset of disease. 2) The occurrence of a lymphocytic infundibulo-neurohypophysitis suggested by the pituitary stalk thickening on MRI only in patients positive for AVPcAb confirms a further autoimmune variant of CDI also in these cases. 3) The longitudinal behavior of patients in group 3 suggests that the absence of AVPcAb at the onset of clinical idiopathic CDI is able to exclude a subsequent appearance of these antibodies and consequently an autoimmune involvement in CDI of these patients. Instead the finding of AVPcAb in several patients with only CDI, thought at first clinical observation as idiopathic, indicates that the prevalence of autoimmune CDI must be considered much higher than that so far reported.

Longitudinal Study of Vasopressin-Cell Antibodies and of Hypothalamic-Pituitary Region on Magnetic Resonance Imaging in Patients with Autoimmune and Idiopathic Complete Central Diabetes Insipidus

Longitudinal Study of Vasopressin-Cell Antibodies and of Hypothalamic-Pituitary Region on Magnetic Resonance Imaging in Patients with Autoimmune and Idiopathic Complete Central Diabetes Insipidus

A patient with partial central diabetes insipidus: Clarifying pathophysiology and designing treatment

Studies were undertaken in a 32-year-old man who developed polyuria (4 L[sol ]d) a few days after a basal skull fracture; the condition persisted 1 year after the accident. The other major features were thirst, a plasma sodium of 143 mmol[sol ]L, 24-hour urine osmolality of 221 mOsm[sol ]kg H2 O, and levels of vasopressin in plasma that were less than 0.5 pg[sol ]mL on 20 separate occasions. The 24-hour urine volume implied that the diagnosis was partial rather than complete central diabetes insipidus; however, several random urine samples had a much higher osmolality. An infusion of hypertonic saline led to the release of vasopressin and the excretion of concentrated urine. We propose that the basis for the lesion may be the transection of some, but not all, of the fibers connecting the osmostat and vasopressin release center. This partial transection could permit vasopressin to be secreted in response to a larger rise in plasma sodium concentration. This pathophysiologic analysis provided the basis for therapy to minimize the degree of polyuria.

A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus.

Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37-48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI.

Central diabetes insipidus in dogs: 20 cases (1986–1995)

Objective— To assess clinical signs, biochemical findings, results of modified water deprivation and other diagnostic tests, response to treatment, and survival time in dogs with central diabetes insipidus (CDI). Design— Retrospective study. Animals— 20 dogs with CDI. Procedure— Signalment, history, physical examination, results of diagnostic tests, response to treatment, and survival time were extracted from the medical record of each dog and supplemented with information obtained from owners via telephone. Results— Isosthenuria or hyposthenuria was a consistent finding. Seven dogs with complete CDI and 13 dogs with partial CDI were identified on the basis of results of a modified water deprivation test. Dogs treated with desmopressin acetate responded well to treatment. Seven dogs were alive 18 to 72 months (median, 36 months) after diagnosis, and 10 dogs died or were euthanatized 1 week to 2 years (median, 2 months) after diagnosis. Seven of 10 dogs that died developed neurologic signs after diagnosis of CDI. Computed tomography revealed a mass in the region of the pituitary gland in 5 of 7 dogs. Necropsy of 6 dogs, including 2 dogs on which computed tomography had been performed, revealed neoplasia in the pituitary gland. Clinical Implications— Onset of neurologic signs after diagnosis of CDI in middle- to old-aged dogs indicates that CDI may not be a benign disease that is treated easily. Brain imaging is recommended after diagnosis of CDI in middle- to old-aged dogs. Also, because many dogs are isosthenuric on initial examination, CDI cannot be ruled out as a cause of polyuria and polydipsia on the basis of lack of hyposthenuria. (J Am Vet Med Assoc 1996;209:1884–1888)

Urinary arginine vasopressin (AVP) measurement in children: Water deprivation test incorporating urinary AVP

The value of a water deprivation test incorporating urinary arginine vasopressin (AVP) measurement was investigated in 13 patients with polydipsia and/or polyuria (complete central diabetes insipidus [CCDI] in four; incomplete central diabetes insipidus [ICDI] in five; secondary nephrogenic diabetes insipidus [NDI] in three; compulsive water drinking [CWD] in one) and a group of 25 control subjects (C). Urine samples were collected after water deprivation during sleep and the urinary osmolalities and AVP concentrations were measured. Analysis of the results of 104 urine samples from the 25 control subjects demonstrated a close correlation between urinary osmolality and AVP (r = 0.89, P < 0.001). After water deprivation during sleep, the respective mean maximal urinary osmolalities and AVP concentrations were: 127.4 +/- 34.4 mOsm/kg and 1.1 +/- 0.5 pg/mL in the patients with CCDI (14 samples, four children); 410.3 +/- 101.8 and 6.1 +/- 3.5 in those with ICDI (16 samples, five children); 348.7 +/- 71.2 and 100 +/- 45.1 in those with NDI (nine samples, three children); 541.5 +/- 143.5 and 43.6 +/- 33.2 in the patient with CWD (two samples, one child) and 898.8 +/- 186.3 and 97.4 +/- 50.4 in group C (54 samples, 18 children). Furthermore, the urinary AVP level relative to the osmolality in each patient varied depending on the AVP secretion status and renal concentrating ability. Each patient, except the one with CWD, could be discriminated from the normal subjects using this test. It seems that this test is easy to perform and useful for diagnosis and follow-up of patients with partial/complete posterior pituitary function defects and those with renal concentration impairment.

1-Deamino-8- d-arginine vasopressin in the treatment of central diabetes insipidus in childhood

The effectiveness of therapy with carbamazepine and clofibrate (oral therapy), intramuscular pitressin-in-oil, and intranasal 1-deamino-8-D-arginine vasopressin has been compared in 15 children with partial or complete central diabetes insipidus. Mean daily urine volume without therapy was 5.4 l and dropped to 1.1 and 1.6 l/day while receiving pitressin and DDAVP, respectively. Oral agents decreased the daily urine volume to 2.2 l in patients with partial DI, with good symptomatic control except for some nocturia. These agents had no effect in patients with complete DI and did not alter pitressin requirements. Duration of pitressin action was 24 to 36 hours with a significant incidence of hyponatremia. The duration of DDAVP effect was 8 to 20 hours, varying in individual patients. Children with partial DI required smaller doses of DDAVP and the duration of action was longer than in those with complete DI. Control of serum electrolytes was excellent using two doses per day and nocturia was eliminated. All patients who had received pitressin had growth hormone antibodies, but continued to grow normally unless there was pre-existing growth hormone deficiency. These antibodies gradually disappeared after approximately one year of therapy with oral agents or DDAVP. DDAVP did not alter growth hormone, cortisol, or prolactin levels during sleep. DDAVP is the antidiuretic therapy of choice in children with either complete or partial DI; to date, no side effects have been demonstrated.

DDAVP (l-Desamino-8-D-arginine-vasopressin) Treatment of Central Diabetes Insipidus—Mechanism of Prolonged Antidiuresis*

DDAVP, 1-desamino-8-D-arginine-vasopressin, is a synthetic analog of arginine vasopressin which produces prolonged antidiuresis after intranasal administration to patients with complete central diabetes insipidus. We have studied the mechanism of the prolonged antidiuretic effect by specific radioimmunossay of DDAVP in plasma of patients and by in vitro studies on the adenylate cyclase-cylic AMP system of the rat outer renal medulla. When DDAVP was administredd to patients, all responded, but the duration of response among patients varied from 5-21 h. The peak level of DDAVP in plasma was achieved up to 4 h after administration indicating a slow absorption from the nasal mucosa. The disappearance time of DDAVP from plasma correlated significantly with the duration of antidiuresis, P less than 0.001. On a molar basis DDAVP was 3-fold greater than AVP in its stimulation of outer medullary adenylate cyclase activity and 10-fold greater than AVP in its stimulation of cyclic AMP content. The prolonged antidiuresis of intranasally administered DDAVP is due to slow absorption, presistence in plasma, and enchanced effect on the kidney.

DDAVP in the treatment of central diabetes insipidus.

DDAVP, 1-desamino-8-d-arginine-vasopressin, is a synthetic analogue of vasopressin with increased antidiuretic activity and decreased pressor activity. Whereas the antidiuretic-to-pressor ratio of arginine vasopressin is 1, the antidiuretic-to-pressor ratio of DDAVP is 4000. When administered as an intranasal spray, 5 to 20 mug of DDAVP produced eight to 20 hours of antidiuresis in patients with complete central diabetes insipidus. The minimum recommended therapeutic dose resulted in a maximum antidiuresis in most patients. No side effects of the drug were noted in clinical trials. DDAVP thus gives promise of becoming the standard treatment of severe central diabetes insipidus.