RARE DISEASE
Arginine vasopressin deficiency
Arginine vasopressin deficiency
Arginine vasopressin deficiency
Synonyms: CDI, Neurogenic diabetes insipidus
Synonyms: CDI, Neurogenic diabetes insipidus
Synonyms: CDI, Neurogenic diabetes insipidus
Drug discovery
0
drugs
With orphan designations
Overview
Arginine Vasopressin Deficiency (AVP-D) is a rare disorder of water homeostasis caused by deficient synthesis or secretion of antidiuretic hormone (AVP), leading to uncontrolled diuresis (3-30 L/day) and polydipsia. Etiologies include genetic mutations, hypothalamic-pituitary lesions (trauma, tumors), or idiopathic causes. Diagnosis involves urine/plasma osmolality, water deprivation tests, and hypertonic saline-stimulated copeptin measurements. Treatment focuses on desmopressin replacement (intranasal/oral/IV) with careful sodium monitoring to prevent hyponatremia [1][12][18].
Burden
Chronic dehydration risks: Hypernatremia, hypovolemic shock, and cognitive impairment if untreated [2][8].
Lifetime management required; 30% of untreated cases develop acute kidney injury [4][14].
Economic burden: Frequent hospitalizations and complex monitoring (e.g., sodium levels, urine output) [14][16].
Therapies
Desmopressin: First-line synthetic AVP analog (oral/IV/nasal); dosage adjusted to prevent breakthrough polyuria or hyponatremia [3][13][16].
Adjunctive measures: Thiazides for partial AVP-D; strict fluid balance protocols during acute illness [6][13].
Emerging diagnostics: Copeptin-based testing (e.g., hypertonic saline/arginine stimulation) improves diagnostic accuracy [12][18].
Categories: rare endocrine diseases
Research Papers
425 drug discovery papers about Arginine vasopressin deficiency, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
425 drug discovery papers about Arginine vasopressin deficiency, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-04 | Open-Label, Balanced, Randomized, Single-Dose, Three-Treatment, Three-Sequence, Three-Period, Three-Way Crossover Oral Bioequivalence Study of Desmopressin Acetate Oral Solution.
Desmopressin is first-line therapy for central diabetes insipidus, also known as arginine vasopressin deficiency, but presents dosing challenges due to its narrow therapeutic index. This open-label, randomized, three-way crossover study evaluated the bioequivalence of a new desmopressin acetate oral solution (50 mcg/mL) compared to desmopressin acetate tablets (200 mcg) in 75 healthy adults. In a balanced, three-sequence, three-period design with 14-day washout periods, participants received a single 600-mcg dose of test product and reference product under fasted conditions. Plasma desmopressin concentrations were measured using a validated liquid chromatography-electrospray ionization tandem mass spectrometry method, and primary pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the last measurable concentration [AUC0-t], AUC from time 0 extrapolated to infinity [AUC0-∞]) were derived from resulting concentration-time profiles. Bioequivalence was assessed using analysis of variance on log-transformed parameters, with 90% confidence intervals (CIs) for geometric mean ratios 80%-125%. Results demonstrated bioequivalence between formulations, with geometric mean ratios of 101.9% (93.9%-110.5%) for Cmax, 103.7% (94.8%-113.5%) for AUC0-t, and 103.7% (94.9%-113.3%) for AUC0-∞. Both formulations exhibited similar pharmacokinetic profiles with 1.0 h median time to maximum concentration, ∼3.6 h mean elimination half-life, and 30%-33% intrasubject variability. Five adverse events were reported by five participants (6.7%), including two cases of hyponatremia (reference group) and one case of vomiting (test group); all were mild to moderate and resolved completely. This study establishes bioequivalence between desmopressin acetate oral solution and tablets, supporting regulatory approval of the oral solution formulation.
2026-07-12 | Sustained remission of chronic post-traumatic arginine vasopressin deficiency despite absent posterior pituitary bright spot on MRI: a case series.
Absence of the posterior pituitary bright spot (PPBS) on T1-weighted MRI is often observed in chronic post-traumatic arginine vasopressin deficiency (AVP-D), but its association with permanent AVP-D remains unclear. We report five patients with chronic-phase post-traumatic AVP-D (156-965 days post-injury) who were transferred to our rehabilitation center. All patients had received long-term desmopressin therapy and exhibited persistent absence of the PPBS on T1-weighted MRI at admission. Despite these findings, desmopressin therapy was successfully tapered and discontinued in all five cases. Case 3 presented a diagnostic challenge, in which resolution of post-traumatic AVP-D was obscured by concomitant adrenal insufficiency and was confirmed only after stabilization of glucocorticoid replacement. In Cases 3, 4, and 5, detectable plasma arginine vasopressin levels (1.0-1.9 pg/mL) were observed following desmopressin withdrawal despite persistent radiologic absence of the PPBS. All patients maintained stable water balance without desmopressin therapy, with no recurrence of polyuria or clinically significant hypernatremia during follow-up. Endogenous vasopressin secretion may be retained in selected patients with chronic TBI, even when MRI suggests persistent neurohypophyseal abnormalities. Our cases demonstrate that absence of the PPBS is not a definitive marker of lifelong post-traumatic AVP-D. These observations support periodic reassessment and supervised trial discontinuation of desmopressin therapy in the neurorehabilitation setting, suggesting that preserved endogenous vasopressin function may remain unrecognized years after the initial insult.
2026-06-01 | Arginine Vasopressin Deficiency Concealed by Progressive Kidney Injury
Background Arginine vasopressin deficiency (AVPD), formerly central diabetes insipidus, is characterized by polyuria and hypernatremia due to inadequate vasopressin production. Most cases are acquired—commonly after pituitary surgery or hypothalamic injury—and require lifelong desmopressin therapy. We report a case of long-standing AVPD in which progression to severe kidney failure and dialysis masked classical manifestations, creating the appearance of disease resolution. Case Presentation A 67-year-old woman with AVPD secondary to olfactory groove meningioma resection had required high-dose desmopressin for over 20 years, with prior hospitalizations for hypernatremia during missed doses. She also had chronic kidney disease (CKD) stage 3b. She presented with progressive confusion and was found to have severe acute kidney injury (creatinine 11 mg/dL), metabolic acidosis, hyperkalemia, and sepsis, ultimately requiring hemodialysis for uremic encephalopathy. Desmopressin was withheld on admission due to normal serum sodium; however, she remained oliguric (150–400 mL/day), and serum sodium and osmolality stayed within normal limits throughout hospitalization, with no biochemical or clinical evidence of AVPD. Discussion This case highlights that advanced kidney failure can mask AVPD. Impaired free water excretion and altered sodium handling in severe renal dysfunction may prevent hypernatremia, obscuring classical AVPD signs. Conclusion / Learning Point AVPD may become clinically silent in advanced kidney disease. Desmopressin therapy should not be considered dogmatic in this setting and may require careful reassessment.
2026-06-01 | Axis-Specific Peripartum Management for Radiation-Induced Panhypopituitarism With Arginine Vasopressin Deficiency: A Case Report.
We report the perinatal course and practical, axis-specific management of a 34-year-old woman with panhypopituitarism and arginine vasopressin deficiency (AVP-D) consequent to cranial irradiation and ifosfamide, cisplatin, and etoposide chemotherapy for a germinoma who conceived via in vitro fertilization. Care was organized by endocrine axis with coordinated obstetric collaboration. Subcutaneous growth hormone was discontinued upon pregnancy confirmation. Central hypothyroidism was managed using free thyroxine targets with trimester-appropriate oral levothyroxine dose adjustments. Secondary adrenal insufficiency was addressed with oral hydrocortisone and a predefined intrapartum stress-dose intravenous hydrocortisone plan. AVP-D was managed by continuing oral desmopressin with symptom-guided monitoring. Labor was electively induced at term, and the peripartum course was uncomplicated. Maternal and umbilical cord endocrine profiles at delivery were documented to contextualize axis physiology. The newborn had reassuring adaptation and normal early pediatric assessments. This case illustrates that a pragmatic, axis-wise strategy centered on free thyroxine-guided thyroid replacement, explicit glucocorticoid stress coverage, and disciplined AVP-D monitoring can be safely implemented in collaboration with reproductive medicine and obstetrics after cranial irradiation and ifosfamide, cisplatin, and etoposide chemotherapy. A reproducible, axis-specific pathway may support safe pregnancy and delivery in women with complex pituitary sequelae, provided that monitoring plans and intrapartum stress-dose coverage are defined in advance.
2026-05-05 | Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial.
Arginine vasopressin (AVP) and oxytocin (OXT) are both hormones released from the posterior pituitary. While AVP primarily regulates water reabsorption in the kidneys, OXT plays a key role in socioemotional functioning. Due to the anatomical proximity, disruptions of the AVP system leading to AVP deficiency (AVP-D) may also affect the OXT system, possibly resulting in an additional OXT deficiency. This hypothesis was recently proven by using the 3,4-methylenedioxymethamphetamine stimulation tests and identifying OXT deficiency in patients with AVP-D, linked to increased anxiety and impaired emotion recognition. Despite these findings, OXT replacement therapy is not currently established as a treatment for AVP-D and long-term replacement therapy remains unexplored. This is a randomised, double-blind, placebo-controlled, parallel-group trial enrolling adults with AVP-D. Participants are randomised 1:1 to receive intranasal OXT (Syntocinon, 24 IU twice daily) or placebo for 28 days. The primary endpoint is a composite binary outcome defined as a clinically meaningful improvement in either trait anxiety (≥5-point reduction in State-Trait Anxiety Inventory-Trait Score) or emotion recognition (≥4-point increase in EmBody/EmFace task performance). Secondary outcomes include empathy, stress reactivity, neuroimaging markers of amygdala activity, additional psychological measures, metabolic parameters and safety outcomes, including hyponatraemia. Analyses will follow the intention-to-treat principle, with Fisher's exact test used for the primary outcome and mixed-effects models for secondary endpoints. The study has been approved by the competent ethics committees and regulatory authorities in Switzerland and the European Union. The following institutions granted ethical approval: Ethikkommission Nordwest- und Zentralschweiz (EKNZ), project number EKNZ 2023-01010 and the Erasmus MC MERC, EU-CT number 2024-5 16 813-19-00. Results will be published in open-access, peer-reviewed journals and disseminated via scientific meetings, media communication and lay summaries provided to participants. De-identified individual participant data will be made available on reasonable request following publication. NCT06036004.
small molecules
2026-08-03 | Arginine vasopressin deficiency following SARS-CoV-2 infection: a rare pituitary complication.
We describe a rare case of arginine vasopressin deficiency (AVP-D) in a female in her 40s that developed two weeks following symptomatic COVID-19 infection. Symptoms included polydipsia, nocturia and polyuria of 9.1 L per day. A water deprivation test demonstrated an ongoing high urine output despite increasing plasma osmolality, confirming the diagnosis. Desmopressin was commenced with good effect and titrated to clinical response. This demonstrates the importance of awareness of potential pituitary complications following COVID-19 infection, including AVP-D.
2026-06-08 | Synaptic alterations are preceding the axonal loss in optic atrophy of Wolfram syndrome mouse model.
Wolfram syndrome is a rare autosomal recessive disorder characterized by antibody-negative early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine-vasopressin deficiency, and progressive neurodegeneration of the brainstem and cerebellum. It is caused primarily by pathogenic variants in the WFS1 gene, which encodes a transmembrane endoplasmic reticulum-resident protein involved in the unfolded protein response and cellular calcium homeostasis. Although multiple rodent models of Wolfram syndrome have been developed and shown to exhibit visual defects, some studies have reported significant vision loss prior to any detectable axonal degeneration or myelin abnormalities, and the mechanisms underlying these early visual deficits remain poorly understood. Recent in vitro studies have demonstrated altered synaptic contacts and aberrant neurite morphology in WFS1-deficient cerebral organoids and human iPSC-derived neurons, respectively. These findings prompted us to investigate, for the first time in vivo, whether synaptic and dendritic abnormalities occur in the retina of Wfs1 knockout mice. Using confocal microscopy, we examined retinal and optic nerve histology in Wfs1 knockout mice at 4 and 7 months of age. Our analysis reveals progressive synaptic alterations in the inner plexiform layer, driven by early presynaptic compartment failure. These changes represent the earliest detectable phenotype associated with vision loss in this model and precede overt axonal degeneration. These findings identify early synaptic preservation as a promising therapeutic target for vision loss in Wolfram syndrome.
2026-03-12 | [Analysis of stimulating factors for serum copeptin based on liquid chromatography-tandem mass spectrometry].
Copeptin， as a stable surrogate biomarker for arginine vasopressin （AVP）， plays an important role in the differential diagnosis of polyuria-polydipsia syndromes. Current guidelines recommend dynamic monitoring of copeptin levels during stimulation tests to assist in differentiating AVP deficiency （AVP-D） from primary polydipsia. Although these methods are well-established， they have certain limitations. Therefore， safer and more feasible stimulants with reliable effects are of clinical interest. Additionally， the currently available copeptin assay， which is based on time-resolved immunofluorescence assay， can be subject to interference from autoantibodies or hemolysis. This study aims to evaluate the effects of four common stimulants used in growth hormone function tests， namely levodopa， insulin， glucagon， and octreotide， on copeptin levels using a reliable liquid chromatography-tandem mass spectrometry （LC-MS/MS） method developed in our laboratory. A total of 62 subjects undergoing growth hormone function tests were retrospectively enrolled and stratified by stimulation type： levodopa （n=28）， insulin-induced hypoglycemia （n=7）， glucagon （n=20）， and octreotide （n=7）. Blood samples were collected at baseline， 30， 60， 90， and 120 min （for the glucagon stimulation test， samples were collected at 120 and 180 min） for growth hormone determination. Copeptin levels at each time point were measured using LC-MS/MS. The effects of stimulation and correlations were analyzed using the Wilcoxon paired signed-rank test， Mann-Whitney test， and Spearman correlation analysis. The results demonstrated that copeptin levels increased under levodopa stimulation by a maximum of 8.47-fold of baseline （p<0.000 1）， under insulin stimulation by a maximum of 5.85-fold of baseline （p=0.031 2）， under glucagon stimulation by a maximum of 1.43-fold of baseline （p<0.000 1）， and decreased under octreotide to 43% of baseline （p<0.05）. No significant correlation was observed between copeptin level changes and those in growth hormone levels. In the levodopa-stimulation group， the maximum value of copeptin in patients with AVP deficiency was significantly lower than that in non-AVP deficiency patients （p=0.000 2）， and the area under the receiver operating characteristic curve was 0.98 （95% confidence interval 0.94-1.00， p=0.002 1）. Our results demonstrate that levodopa and insulin can effectively stimulate copeptin secretion， whereas octreotide exhibits a suppressive effect. These findings offer important physiological insights into AVP regulation and indicate that certain GH stimulation agents may have extended utility in copeptin-based diagnostic strategies. The LC-MS/MS method for detecting copeptin has potential clinical value in the diagnosis of patients with AVP deficiency and can provide a new detection method for clinical practice. However， the relatively small sample sizes restrict the statistical power， and larger prospective studies are warranted.
2026-03-07 | Altered social-emotional processing and decision-making in Central Diabetes Insipidus: The role of vasopressin deficiency.
Arginine vasopressin (AVP) regulates homeostasis and social behavior. Damage to AVP neurons causes central diabetes insipidus (CDI), now termed arginine vasopressin deficiency (AVP-D), a rare disorder potentially linked to social deficits. This study examined how AVP deficiency affects social, emotional, and psychological functioning in AVP-D patients. Twelve AVP-D patients and twelve matched controls participated. Blood samples measured copeptin and other hormones. Participants completed behavioral tasks assessing social exclusion (Cyberball paradigm), emotion recognition (Reading the Mind in Films), prosocial behavior (Social Discounting Task), fairness (Ultimatum Game), and approach-avoidance (Stop Distance Paradigm). Questionnaires assessed mood, anxiety, aggression, alexithymia, and empathy. Hormone analysis showed AVP-D patients had lower copeptin and lower ACTH levels. Psychometric tests indicated increased depression, aggression, and alexithymia. Both groups felt negative after social exclusion, but AVP-D patients adjusted less emotionally, showing smaller changes in insecurity and team spirit. AVP-D patients also struggled more with emotion recognition, linked to lower copeptin and higher alexithymia. Fairness sensitivity differences were minor and not significant. Both groups donated less as social distance grew, though AVP-D patients' decline was less steep. In approach-avoidance behavior, AVP-D patients kept greater distances from human faces with friendly or aggressive expressions, unlike with animal targets. AVP-D patients exhibit socioemotional impairments like poor emotion recognition and depression, highlighting the need for routine screening. Early detection enables targeted interventions, and addressing central AVP pathways is crucial, underscoring the need for treatments beyond hormone replacement.
2026-03-01 | 785: BATTLE AT THE NEPHRON: A CASE OF METASTATIC SMALL CELL LUNG CANCER COMPLICATED BY AVP-D AND SIADH
Introduction: Syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by hyponatremia and low urine output. Conversely, arginine vasopressin deficiency (AVP-D) is characterized by hypernatremia and polyuria. This case involves an active smoker with suspected COPD who had a low dose lung CT in 2021 revealing suspicious lung nodules. Description: A 60 year old female with suspected COPD, HTN, and hypothyroidism presented with shortness of breath and was admitted for acute hypoxic respiratory failure. CT thorax showed a large hilar mass compressing the R mainstem bronchus and SVC, and a large R pleural effusion. She was admitted to the medical ICU due to significant oxygen requirements and underwent thoracentesis with 1.4 L fluid removed. She improved with high-dose steroids and empiric antibiotics for COPD exacerbation and possible pneumonia. Workup revealed SCLC with diffuse metastasis. Oncology was consulted and she started carboplatin and etoposide, and had palliative radiation to the brain and lung. On hospital day 28, the patient developed polyuria with Uosm 157, Posm 295, PNa 146, and copeptin < 2.8. Brain MRI showed metastasis to the dorsum sella with pituitary encroachment. Nephrology was consulted for management of AVP-D and the patient was started on ddAVP. There was initial improvement in urine output and sodium levels, however she subsequently developed hyponatremia so ddAVP was stopped. Despite discontinuation, she remained hyponatremic with elevated urine osmolality, consistent with SIADH. Throughout her hospitalization, she continued to have alternating hypernatremia and hyponatremia and was ultimately discharged on 50 mcg ddAVP daily. Discussion: AVP-D is rarely caused by pituitary metastasis, with most cases being asymptomatic. Presentations vary based on lesion size/location, magnitude of trauma, and degree of neurohypophysial destruction. This case illustrates a rare but clinically significant scenario in which a patient with metastatic SCLC developed both AVP-D due to pituitary metastasis and SIADH, a frequent paraneoplastic complication of SCLC. It provides a valuable opportunity to review the pathophysiology of sodium and fluid balance as well as highlights the importance of involving specialists to aid in the diagnosis and management strategies for complex cases.
cell therapies
2022-10-19 | Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state.
Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.
2019-03-11 | Functional ectopic neural lobe increases GAP-43 expression via PI3K/AKT pathways to alleviate central diabetes insipidus after pituitary stalk lesion in rats.
Central diabetes insipidus can occur after hypothalamic-hypophyseal tract injury. This injury is linked with a deficit in circulating vasopressin and oxytocin, which are produced in the supraoptic nuclei and the hypothalamic paraventricular nuclei. Previous studies indicate that an ectopic neural lobe forms after pituitary stalk lesion in rats, and while the relationship between an ectopic neural lobe and CDI outcomes is unclear, the underlying mechanisms are also unknown. Here, we report that two different CDI characteristics are shown in rats that underwent pituitary stalk electric lesion and are defined by two different groups classified as the recovery group and the no-recovery group. Rats showed an enlarged functional ectopic neural lobe at the lesion site with a low CDI index. Moreover, growth associated protein-43, p-PI3K and p-AKT were up-regulated in the unmyelinated fibers of the ectopic neural lobe. Our findings suggest that the enlarged structure formed a functional ectopic neural lobe after the pituitary stalk lesion, and its regeneration might influence the CDI outcome. This regeneration might be due to an increase in GAP-43 expression through the PI3K/AKT pathway.
1992-03-24 | Fiber outgrowth from fetal vasopressin neurons of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and medial amygdaloid nucleus transplanted into adult Brattleboro rats.
Outgrowth of fibers from different types of vasopressin (AVP) neurons was compared in the brains of AVP-deficient Brattleboro rats. Fetal grafts of the suprachiasmatic nucleus (SCN), the bed nucleus of the stria terminalis (BST), and the medial amygdaloid nucleus (MA) were implanted into the lateral ventricle. AVP-immunoreactive fibers from all grafts entered the host tissue in the lateral septum. SCN fibers were confined to the lateral margin of the septum. In contrast, MA and BST fibers formed equally dense networks spanning the width of the lateral septum. The data suggest that these transplanted neurons show specific outgrowth, and that the phylogenetically related BST and MA neurons follow similar cues to reach their targets.
1988-04-21 | Organization and efferent connections of transplanted suprachiasmatic nuclei.
The hypothalamic suprachiasmatic nucleus (SCh) is the principal brain structure involved in the generation of circadian rhythms. In the present study, we have employed immunohistochemical techniques to evaluate the development of the fetal SCh following its transplantation to the brain of adult host animals. Donor hypothalami were obtained from normal Long-Evans fetuses and transplanted to the lateral, third, or fourth ventricle of Brattleboro rats. Neuronal aggregations exhibiting the organotypic features of the SCh were present in over 90% of the grafts recovered at each transplantation site. Like the normal endogenous SCh, SCh-like cell groups identified within the transplants contained a prominent population of parvicellular (9-13 micron), neurophysin-containing neurons that were immunopositive for vasopressin (VP) but not oxytocin. These SCh-like cell groups also invariably contained similar small neurons that were immunoreactive for vasoactive intestinal polypeptide (VIP). Typically, VP and VIP immunoreactive perikarya were concentrated in contiguous, complementary parts of the grafted SCh, but fibers immunoreactive for either peptide were distributed throughout the extent of the nucleus. Because the brain of the Brattleboro rat is deficient in vasopressin, it was possible to evaluate the projection of the vasopressinergic component of the transplanted SCh to the host brain. Although SCh were identified in grafts recovered from each intraventricular transplantation site, an appreciable input to the host brain could be identified only when the fetal tissue was grafted to the third ventricle. Here, grafted SCh established efferent connections with periventricular diencephalic structures which ordinarily receive a projection from the in situ SCh. Specifically, VP immunoreactive fibers originating from transplanted SCh were identified in the medial preoptic area, the periventricular and dorsomedial hypothalamic nuclei, the paraventricular nuclei of the thalamus and hypothalamus, and in the retrochiasmatic area, arcuate nucleus, and suprachiasmatic nucleus of the host brain. These results demonstrate that the fetal SCh not only survives transplantation but also retains its distinguishing cytological features and the capacity to form an appropriately restricted set of efferent connections with the brain of adult host animals.
antibodies
2026-06-10 | Severe IL-6-dominant immune-mediated inflammatory response complicated by probable arginine vasopressin deficiency following ivonescimab-based therapy in advanced EGFR-mutant lung squamous cell carcinoma: a case report.
Ivonescimab, a novel PD-1/VEGF bispecific antibody, has shown promising efficacy in advanced lung cancer. Yet severe immune-related adverse events are not well studied outside clinical trials. We report a 72-year-old man with stage IV squamous NSCLC harboring an EGFR mutation and PD-L1 tumor proportion score of 90% who developed persistent fever shortly after first exposure to ivonescimab combined with nab-paclitaxel and carboplatin. His prior treatments included concurrent chemoradiotherapy, osimertinib, the investigational EGFR inhibitor BH-30643, afatinib, and recent gamma knife for cerebellar metastases plus palliative radiotherapy for bone metastases. After cycle 1, he developed persistent high fever with markedly elevated IL-6 and no response to antimicrobials. Corticosteroids brought rapid relief, pointing to an IL-6-mediated process. Re-exposure to ivonescimab triggered a more severe reaction. He then developed sudden polyuria with low urine osmolality and elevated serum osmolality. Brain MRI showed no typical hypophysitis features. Symptoms improved with corticosteroids, tocilizumab, and desmopressin, consistent with probable arginine vasopressin deficiency (AVP-D), possibly secondary to hypophysitis-though pituitary metastasis cannot be ruled out without biopsy. Ivonescimab can trigger severe IL-6-dominant inflammatory reactions and endocrine toxicity presenting as AVP-D in susceptible patients. Advanced age, EGFR-mutant/PD-L1-high tumor biology, recent radiotherapy, and Parkinsonism may have contributed to the inflammatory environment, though none can be proven causal in a single case and each deserves prospective study. Early recognition of persistent steroid-responsive fever, serial IL-6 monitoring, thorough endocrine workup, and timely IL-6 blockade are critical.
2024-12-27 | A 4-year-old Boy Positive for Anti-rabphilin-3A Antibody and Diagnosed With Lymphocytic Infundibuloneurohypophysitis.
Lymphocytic infundibuloneurohypophysitis (LINH) is a disease with an etiology involving an autoimmune mechanism, characterized by lymphocytic inflammation of the posterior pituitary and infundibular stalk, resulting in arginine vasopressin deficiency. It is difficult to distinguish from pituitary neoplasm or infiltrative diseases, and biopsy is necessary for a definitive diagnosis, but this is highly invasive. In children, it is especially important to distinguish LINH from tumors such as germ cell tumors. Recently, the usefulness of anti-rabphilin-3A antibody as a serum marker for LINH has been reported. To date, only a limited number of pediatric cases have been reported. We present a 4-year-old boy with arginine vasopressin deficiency. Magnetic resonance imaging of the head showed thickening of the pituitary stalk without a posterior pituitary bright spot, and anti-rabphilin-3A antibody was positive. Consequently, pituitary biopsy was not performed because of the strong suspicion of LINH. Five months after symptom onset, the pituitary stalk thickening had resolved. This case represents the first report of probable or definitive LINH with anti-rabphilin-3A antibody positivity in a 4-year-old child, making it the youngest positive case reported to date. Our case highlights the importance of noninvasive approaches and careful follow-up to avoid invasive interventions for children with LINH.
2024-05-01 | ARGININE VASOPRESSIN DEFICIENCY INDUCES DECREASED CARDIAC FIBROSIS RATE AND MEAN ARTERIAL BLOOD PRESSURE IN RATS WITH EXPERIMENTAL ABDOMINAL AORTIC STENOSIS
Cardiac fibrosis (CF) involves the accumulation of extracellular matrix proteins in the interstitial space, often seen in various cardiac pathologies. Each year, cardiovascular diseases claim the lives of 17.9 million people worldwide. Cardiac fibroblasts and myofibroblasts, equipped with vasopressin receptors (AVP), play a crucial role in regulating cell signaling pathways associated with CF development. AVP, an immunomodulatory hormone, influences immune responses, and its deficiency results in a decrease in immune activity. Abdominal aortic stenosis (AS) serves as an experimental model for left cardiac overload hypertension and CF. Neurointermediate pituitary lobectomy (NIL) induces a permanent decrease in circulating AVP levels, showcasing regression of hepatic fibrosis in liver damage models. The quest for effective alternative treatments for cardiac fibrosis poses a substantial challenge for researchers. In this experiment, groups of male Wistar rats weighing approximately 250 g (8/group) were categorized into: 1) Intact Control (IC), 2) Abdominal Aortic Stenosis (AS), 3) Neurointermediate pituitary lobectomy (NIL), and 4) AS+NIL. The AS and AS+NIL groups underwent abdominal aortic stenosis surgery on day one of the experiment. By week 5, the NIL and NIL+AS groups underwent NIL surgery. Prior to sacrifice at week 10, intracarotid mean blood pressure (MBP) was assessed in all groups. Following sacrifice, the hearts were removed, fixed in neutral formalin, and processed in paraffn for histopathological examination using H-E, Masson's trichrome, and Sirius red staining. Results revealed an elevated MBP in the AS group (156 ± 27.1 vs. 114 ± 30 mmHg in the IC), normalized in the AS+NIL group (110 ± 40.9 mmHg), and a mild decrease in the NIL group (87 ± 7.6 mmHg). The evaluation of CF in histological slides concurred with the MBP findings; a significant increase in CF occurred in the AS group compared to the IC, NIL, and AS+NIL groups, with almost complete reversion of CF observed in the AS+NIL group. In summary, this study demonstrates that AVP deficiency induces arterial hypotension, and in the AS+NIL group, AVP deficiency led to: 1) a decrease in blood pressure to normal levels and 2) reversion of cardiac fibrosis. Further experiments are warranted to determine if the decrease in blood pressure and cardiac overload are suffcient to inhibit profibrogenic mechanisms and/or activate antifibrogenic mechanisms. Additionally, investigations are needed to explore whether AVP deficiency, beyond inhibiting the inflammatory process, promotes the activation of antifibrogenic mechanisms. The present results offer new avenues for a deeper understanding of the molecular and cellular mechanisms through which AVP deficiency or the use of AVP receptor antagonists significantly influences fibrosis regulation in organ fibrotic diseases. Funding by Autonomous University of Aguascalientes (PIFF22-1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2016-04-11 | Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis.
Neurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months. A 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI. Clinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation. Infliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.
2002-08-12 | Calcyclin is an early vasopressin-induced gene in the renal collecting duct. Role in the long term regulation of ion transport.
Long-term effects of arginine vasopressin (AVP) in the kidney involve the transcription of unidentified genes. By subtractive hybridization experiments performed on the RCCD(1) cortical collecting duct cell line, we identified calcyclin as an early AVP-induced gene (1 h). Calcyclin is a calcium-binding protein involved in the transduction of intracellular signals. In the kidney, calcyclin was localized at the mRNA level in the glomerulus, all along the collecting duct, and in the epithelium lining the papilla. In RCCD(1) cells and in m-IMCD(3) inner medullary collecting duct cells, calcyclin was evidenced in the cytoplasm. Calcyclin mRNA levels were progressively increased by AVP treatment in RCCD(1) (1.7-fold at 4 h) and m-IMCD(3) (2-fold at 7.5 h) cells. In RCCD(1) cells, calcyclin protein levels were increased by 4 h of AVP treatment. In vivo, treatment of genetically vasopressin-deficient Brattleboro rats with AVP for 4 days induced an increase in both calcyclin and aquaporin-2 mRNA expression. Finally, introduction of anti-calcyclin antibodies into RCCD(1) cells by permeabilizing the plasma membrane prevented the long-term (but not short-term) increase in short-circuit current induced by AVP. Taken together, these results suggest that calcyclin is an early vasopressin-induced gene that participates in the late phase of the hormone response in transepithelial ion transport.
proteins
2026-08-04 | Open-Label, Balanced, Randomized, Single-Dose, Three-Treatment, Three-Sequence, Three-Period, Three-Way Crossover Oral Bioequivalence Study of Desmopressin Acetate Oral Solution.
Desmopressin is first-line therapy for central diabetes insipidus, also known as arginine vasopressin deficiency, but presents dosing challenges due to its narrow therapeutic index. This open-label, randomized, three-way crossover study evaluated the bioequivalence of a new desmopressin acetate oral solution (50 mcg/mL) compared to desmopressin acetate tablets (200 mcg) in 75 healthy adults. In a balanced, three-sequence, three-period design with 14-day washout periods, participants received a single 600-mcg dose of test product and reference product under fasted conditions. Plasma desmopressin concentrations were measured using a validated liquid chromatography-electrospray ionization tandem mass spectrometry method, and primary pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the last measurable concentration [AUC0-t], AUC from time 0 extrapolated to infinity [AUC0-∞]) were derived from resulting concentration-time profiles. Bioequivalence was assessed using analysis of variance on log-transformed parameters, with 90% confidence intervals (CIs) for geometric mean ratios 80%-125%. Results demonstrated bioequivalence between formulations, with geometric mean ratios of 101.9% (93.9%-110.5%) for Cmax, 103.7% (94.8%-113.5%) for AUC0-t, and 103.7% (94.9%-113.3%) for AUC0-∞. Both formulations exhibited similar pharmacokinetic profiles with 1.0 h median time to maximum concentration, ∼3.6 h mean elimination half-life, and 30%-33% intrasubject variability. Five adverse events were reported by five participants (6.7%), including two cases of hyponatremia (reference group) and one case of vomiting (test group); all were mild to moderate and resolved completely. This study establishes bioequivalence between desmopressin acetate oral solution and tablets, supporting regulatory approval of the oral solution formulation.
2026-07-12 | Sustained remission of chronic post-traumatic arginine vasopressin deficiency despite absent posterior pituitary bright spot on MRI: a case series.
Absence of the posterior pituitary bright spot (PPBS) on T1-weighted MRI is often observed in chronic post-traumatic arginine vasopressin deficiency (AVP-D), but its association with permanent AVP-D remains unclear. We report five patients with chronic-phase post-traumatic AVP-D (156-965 days post-injury) who were transferred to our rehabilitation center. All patients had received long-term desmopressin therapy and exhibited persistent absence of the PPBS on T1-weighted MRI at admission. Despite these findings, desmopressin therapy was successfully tapered and discontinued in all five cases. Case 3 presented a diagnostic challenge, in which resolution of post-traumatic AVP-D was obscured by concomitant adrenal insufficiency and was confirmed only after stabilization of glucocorticoid replacement. In Cases 3, 4, and 5, detectable plasma arginine vasopressin levels (1.0-1.9 pg/mL) were observed following desmopressin withdrawal despite persistent radiologic absence of the PPBS. All patients maintained stable water balance without desmopressin therapy, with no recurrence of polyuria or clinically significant hypernatremia during follow-up. Endogenous vasopressin secretion may be retained in selected patients with chronic TBI, even when MRI suggests persistent neurohypophyseal abnormalities. Our cases demonstrate that absence of the PPBS is not a definitive marker of lifelong post-traumatic AVP-D. These observations support periodic reassessment and supervised trial discontinuation of desmopressin therapy in the neurorehabilitation setting, suggesting that preserved endogenous vasopressin function may remain unrecognized years after the initial insult.
2026-06-01 | Arginine Vasopressin Deficiency Concealed by Progressive Kidney Injury
Background Arginine vasopressin deficiency (AVPD), formerly central diabetes insipidus, is characterized by polyuria and hypernatremia due to inadequate vasopressin production. Most cases are acquired—commonly after pituitary surgery or hypothalamic injury—and require lifelong desmopressin therapy. We report a case of long-standing AVPD in which progression to severe kidney failure and dialysis masked classical manifestations, creating the appearance of disease resolution. Case Presentation A 67-year-old woman with AVPD secondary to olfactory groove meningioma resection had required high-dose desmopressin for over 20 years, with prior hospitalizations for hypernatremia during missed doses. She also had chronic kidney disease (CKD) stage 3b. She presented with progressive confusion and was found to have severe acute kidney injury (creatinine 11 mg/dL), metabolic acidosis, hyperkalemia, and sepsis, ultimately requiring hemodialysis for uremic encephalopathy. Desmopressin was withheld on admission due to normal serum sodium; however, she remained oliguric (150–400 mL/day), and serum sodium and osmolality stayed within normal limits throughout hospitalization, with no biochemical or clinical evidence of AVPD. Discussion This case highlights that advanced kidney failure can mask AVPD. Impaired free water excretion and altered sodium handling in severe renal dysfunction may prevent hypernatremia, obscuring classical AVPD signs. Conclusion / Learning Point AVPD may become clinically silent in advanced kidney disease. Desmopressin therapy should not be considered dogmatic in this setting and may require careful reassessment.
2026-06-01 | Axis-Specific Peripartum Management for Radiation-Induced Panhypopituitarism With Arginine Vasopressin Deficiency: A Case Report.
We report the perinatal course and practical, axis-specific management of a 34-year-old woman with panhypopituitarism and arginine vasopressin deficiency (AVP-D) consequent to cranial irradiation and ifosfamide, cisplatin, and etoposide chemotherapy for a germinoma who conceived via in vitro fertilization. Care was organized by endocrine axis with coordinated obstetric collaboration. Subcutaneous growth hormone was discontinued upon pregnancy confirmation. Central hypothyroidism was managed using free thyroxine targets with trimester-appropriate oral levothyroxine dose adjustments. Secondary adrenal insufficiency was addressed with oral hydrocortisone and a predefined intrapartum stress-dose intravenous hydrocortisone plan. AVP-D was managed by continuing oral desmopressin with symptom-guided monitoring. Labor was electively induced at term, and the peripartum course was uncomplicated. Maternal and umbilical cord endocrine profiles at delivery were documented to contextualize axis physiology. The newborn had reassuring adaptation and normal early pediatric assessments. This case illustrates that a pragmatic, axis-wise strategy centered on free thyroxine-guided thyroid replacement, explicit glucocorticoid stress coverage, and disciplined AVP-D monitoring can be safely implemented in collaboration with reproductive medicine and obstetrics after cranial irradiation and ifosfamide, cisplatin, and etoposide chemotherapy. A reproducible, axis-specific pathway may support safe pregnancy and delivery in women with complex pituitary sequelae, provided that monitoring plans and intrapartum stress-dose coverage are defined in advance.
2026-05-05 | Oxytocin substitution therapy in patients with AVP deficiency (central diabetes insipidus): study protocol of a double-blind, randomised placebo-controlled trial.
Arginine vasopressin (AVP) and oxytocin (OXT) are both hormones released from the posterior pituitary. While AVP primarily regulates water reabsorption in the kidneys, OXT plays a key role in socioemotional functioning. Due to the anatomical proximity, disruptions of the AVP system leading to AVP deficiency (AVP-D) may also affect the OXT system, possibly resulting in an additional OXT deficiency. This hypothesis was recently proven by using the 3,4-methylenedioxymethamphetamine stimulation tests and identifying OXT deficiency in patients with AVP-D, linked to increased anxiety and impaired emotion recognition. Despite these findings, OXT replacement therapy is not currently established as a treatment for AVP-D and long-term replacement therapy remains unexplored. This is a randomised, double-blind, placebo-controlled, parallel-group trial enrolling adults with AVP-D. Participants are randomised 1:1 to receive intranasal OXT (Syntocinon, 24 IU twice daily) or placebo for 28 days. The primary endpoint is a composite binary outcome defined as a clinically meaningful improvement in either trait anxiety (≥5-point reduction in State-Trait Anxiety Inventory-Trait Score) or emotion recognition (≥4-point increase in EmBody/EmFace task performance). Secondary outcomes include empathy, stress reactivity, neuroimaging markers of amygdala activity, additional psychological measures, metabolic parameters and safety outcomes, including hyponatraemia. Analyses will follow the intention-to-treat principle, with Fisher's exact test used for the primary outcome and mixed-effects models for secondary endpoints. The study has been approved by the competent ethics committees and regulatory authorities in Switzerland and the European Union. The following institutions granted ethical approval: Ethikkommission Nordwest- und Zentralschweiz (EKNZ), project number EKNZ 2023-01010 and the Erasmus MC MERC, EU-CT number 2024-5 16 813-19-00. Results will be published in open-access, peer-reviewed journals and disseminated via scientific meetings, media communication and lay summaries provided to participants. De-identified individual participant data will be made available on reasonable request following publication. NCT06036004.
small molecules
2026-08-03 | Arginine vasopressin deficiency following SARS-CoV-2 infection: a rare pituitary complication.
We describe a rare case of arginine vasopressin deficiency (AVP-D) in a female in her 40s that developed two weeks following symptomatic COVID-19 infection. Symptoms included polydipsia, nocturia and polyuria of 9.1 L per day. A water deprivation test demonstrated an ongoing high urine output despite increasing plasma osmolality, confirming the diagnosis. Desmopressin was commenced with good effect and titrated to clinical response. This demonstrates the importance of awareness of potential pituitary complications following COVID-19 infection, including AVP-D.
2026-06-08 | Synaptic alterations are preceding the axonal loss in optic atrophy of Wolfram syndrome mouse model.
Wolfram syndrome is a rare autosomal recessive disorder characterized by antibody-negative early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine-vasopressin deficiency, and progressive neurodegeneration of the brainstem and cerebellum. It is caused primarily by pathogenic variants in the WFS1 gene, which encodes a transmembrane endoplasmic reticulum-resident protein involved in the unfolded protein response and cellular calcium homeostasis. Although multiple rodent models of Wolfram syndrome have been developed and shown to exhibit visual defects, some studies have reported significant vision loss prior to any detectable axonal degeneration or myelin abnormalities, and the mechanisms underlying these early visual deficits remain poorly understood. Recent in vitro studies have demonstrated altered synaptic contacts and aberrant neurite morphology in WFS1-deficient cerebral organoids and human iPSC-derived neurons, respectively. These findings prompted us to investigate, for the first time in vivo, whether synaptic and dendritic abnormalities occur in the retina of Wfs1 knockout mice. Using confocal microscopy, we examined retinal and optic nerve histology in Wfs1 knockout mice at 4 and 7 months of age. Our analysis reveals progressive synaptic alterations in the inner plexiform layer, driven by early presynaptic compartment failure. These changes represent the earliest detectable phenotype associated with vision loss in this model and precede overt axonal degeneration. These findings identify early synaptic preservation as a promising therapeutic target for vision loss in Wolfram syndrome.
2026-03-12 | [Analysis of stimulating factors for serum copeptin based on liquid chromatography-tandem mass spectrometry].
Copeptin， as a stable surrogate biomarker for arginine vasopressin （AVP）， plays an important role in the differential diagnosis of polyuria-polydipsia syndromes. Current guidelines recommend dynamic monitoring of copeptin levels during stimulation tests to assist in differentiating AVP deficiency （AVP-D） from primary polydipsia. Although these methods are well-established， they have certain limitations. Therefore， safer and more feasible stimulants with reliable effects are of clinical interest. Additionally， the currently available copeptin assay， which is based on time-resolved immunofluorescence assay， can be subject to interference from autoantibodies or hemolysis. This study aims to evaluate the effects of four common stimulants used in growth hormone function tests， namely levodopa， insulin， glucagon， and octreotide， on copeptin levels using a reliable liquid chromatography-tandem mass spectrometry （LC-MS/MS） method developed in our laboratory. A total of 62 subjects undergoing growth hormone function tests were retrospectively enrolled and stratified by stimulation type： levodopa （n=28）， insulin-induced hypoglycemia （n=7）， glucagon （n=20）， and octreotide （n=7）. Blood samples were collected at baseline， 30， 60， 90， and 120 min （for the glucagon stimulation test， samples were collected at 120 and 180 min） for growth hormone determination. Copeptin levels at each time point were measured using LC-MS/MS. The effects of stimulation and correlations were analyzed using the Wilcoxon paired signed-rank test， Mann-Whitney test， and Spearman correlation analysis. The results demonstrated that copeptin levels increased under levodopa stimulation by a maximum of 8.47-fold of baseline （p<0.000 1）， under insulin stimulation by a maximum of 5.85-fold of baseline （p=0.031 2）， under glucagon stimulation by a maximum of 1.43-fold of baseline （p<0.000 1）， and decreased under octreotide to 43% of baseline （p<0.05）. No significant correlation was observed between copeptin level changes and those in growth hormone levels. In the levodopa-stimulation group， the maximum value of copeptin in patients with AVP deficiency was significantly lower than that in non-AVP deficiency patients （p=0.000 2）， and the area under the receiver operating characteristic curve was 0.98 （95% confidence interval 0.94-1.00， p=0.002 1）. Our results demonstrate that levodopa and insulin can effectively stimulate copeptin secretion， whereas octreotide exhibits a suppressive effect. These findings offer important physiological insights into AVP regulation and indicate that certain GH stimulation agents may have extended utility in copeptin-based diagnostic strategies. The LC-MS/MS method for detecting copeptin has potential clinical value in the diagnosis of patients with AVP deficiency and can provide a new detection method for clinical practice. However， the relatively small sample sizes restrict the statistical power， and larger prospective studies are warranted.
2026-03-07 | Altered social-emotional processing and decision-making in Central Diabetes Insipidus: The role of vasopressin deficiency.
Arginine vasopressin (AVP) regulates homeostasis and social behavior. Damage to AVP neurons causes central diabetes insipidus (CDI), now termed arginine vasopressin deficiency (AVP-D), a rare disorder potentially linked to social deficits. This study examined how AVP deficiency affects social, emotional, and psychological functioning in AVP-D patients. Twelve AVP-D patients and twelve matched controls participated. Blood samples measured copeptin and other hormones. Participants completed behavioral tasks assessing social exclusion (Cyberball paradigm), emotion recognition (Reading the Mind in Films), prosocial behavior (Social Discounting Task), fairness (Ultimatum Game), and approach-avoidance (Stop Distance Paradigm). Questionnaires assessed mood, anxiety, aggression, alexithymia, and empathy. Hormone analysis showed AVP-D patients had lower copeptin and lower ACTH levels. Psychometric tests indicated increased depression, aggression, and alexithymia. Both groups felt negative after social exclusion, but AVP-D patients adjusted less emotionally, showing smaller changes in insecurity and team spirit. AVP-D patients also struggled more with emotion recognition, linked to lower copeptin and higher alexithymia. Fairness sensitivity differences were minor and not significant. Both groups donated less as social distance grew, though AVP-D patients' decline was less steep. In approach-avoidance behavior, AVP-D patients kept greater distances from human faces with friendly or aggressive expressions, unlike with animal targets. AVP-D patients exhibit socioemotional impairments like poor emotion recognition and depression, highlighting the need for routine screening. Early detection enables targeted interventions, and addressing central AVP pathways is crucial, underscoring the need for treatments beyond hormone replacement.
2026-03-01 | 785: BATTLE AT THE NEPHRON: A CASE OF METASTATIC SMALL CELL LUNG CANCER COMPLICATED BY AVP-D AND SIADH
Introduction: Syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by hyponatremia and low urine output. Conversely, arginine vasopressin deficiency (AVP-D) is characterized by hypernatremia and polyuria. This case involves an active smoker with suspected COPD who had a low dose lung CT in 2021 revealing suspicious lung nodules. Description: A 60 year old female with suspected COPD, HTN, and hypothyroidism presented with shortness of breath and was admitted for acute hypoxic respiratory failure. CT thorax showed a large hilar mass compressing the R mainstem bronchus and SVC, and a large R pleural effusion. She was admitted to the medical ICU due to significant oxygen requirements and underwent thoracentesis with 1.4 L fluid removed. She improved with high-dose steroids and empiric antibiotics for COPD exacerbation and possible pneumonia. Workup revealed SCLC with diffuse metastasis. Oncology was consulted and she started carboplatin and etoposide, and had palliative radiation to the brain and lung. On hospital day 28, the patient developed polyuria with Uosm 157, Posm 295, PNa 146, and copeptin < 2.8. Brain MRI showed metastasis to the dorsum sella with pituitary encroachment. Nephrology was consulted for management of AVP-D and the patient was started on ddAVP. There was initial improvement in urine output and sodium levels, however she subsequently developed hyponatremia so ddAVP was stopped. Despite discontinuation, she remained hyponatremic with elevated urine osmolality, consistent with SIADH. Throughout her hospitalization, she continued to have alternating hypernatremia and hyponatremia and was ultimately discharged on 50 mcg ddAVP daily. Discussion: AVP-D is rarely caused by pituitary metastasis, with most cases being asymptomatic. Presentations vary based on lesion size/location, magnitude of trauma, and degree of neurohypophysial destruction. This case illustrates a rare but clinically significant scenario in which a patient with metastatic SCLC developed both AVP-D due to pituitary metastasis and SIADH, a frequent paraneoplastic complication of SCLC. It provides a valuable opportunity to review the pathophysiology of sodium and fluid balance as well as highlights the importance of involving specialists to aid in the diagnosis and management strategies for complex cases.
cell therapies
2022-10-19 | Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state.
Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.
2019-03-11 | Functional ectopic neural lobe increases GAP-43 expression via PI3K/AKT pathways to alleviate central diabetes insipidus after pituitary stalk lesion in rats.
Central diabetes insipidus can occur after hypothalamic-hypophyseal tract injury. This injury is linked with a deficit in circulating vasopressin and oxytocin, which are produced in the supraoptic nuclei and the hypothalamic paraventricular nuclei. Previous studies indicate that an ectopic neural lobe forms after pituitary stalk lesion in rats, and while the relationship between an ectopic neural lobe and CDI outcomes is unclear, the underlying mechanisms are also unknown. Here, we report that two different CDI characteristics are shown in rats that underwent pituitary stalk electric lesion and are defined by two different groups classified as the recovery group and the no-recovery group. Rats showed an enlarged functional ectopic neural lobe at the lesion site with a low CDI index. Moreover, growth associated protein-43, p-PI3K and p-AKT were up-regulated in the unmyelinated fibers of the ectopic neural lobe. Our findings suggest that the enlarged structure formed a functional ectopic neural lobe after the pituitary stalk lesion, and its regeneration might influence the CDI outcome. This regeneration might be due to an increase in GAP-43 expression through the PI3K/AKT pathway.
1992-03-24 | Fiber outgrowth from fetal vasopressin neurons of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and medial amygdaloid nucleus transplanted into adult Brattleboro rats.
Outgrowth of fibers from different types of vasopressin (AVP) neurons was compared in the brains of AVP-deficient Brattleboro rats. Fetal grafts of the suprachiasmatic nucleus (SCN), the bed nucleus of the stria terminalis (BST), and the medial amygdaloid nucleus (MA) were implanted into the lateral ventricle. AVP-immunoreactive fibers from all grafts entered the host tissue in the lateral septum. SCN fibers were confined to the lateral margin of the septum. In contrast, MA and BST fibers formed equally dense networks spanning the width of the lateral septum. The data suggest that these transplanted neurons show specific outgrowth, and that the phylogenetically related BST and MA neurons follow similar cues to reach their targets.
1988-04-21 | Organization and efferent connections of transplanted suprachiasmatic nuclei.
The hypothalamic suprachiasmatic nucleus (SCh) is the principal brain structure involved in the generation of circadian rhythms. In the present study, we have employed immunohistochemical techniques to evaluate the development of the fetal SCh following its transplantation to the brain of adult host animals. Donor hypothalami were obtained from normal Long-Evans fetuses and transplanted to the lateral, third, or fourth ventricle of Brattleboro rats. Neuronal aggregations exhibiting the organotypic features of the SCh were present in over 90% of the grafts recovered at each transplantation site. Like the normal endogenous SCh, SCh-like cell groups identified within the transplants contained a prominent population of parvicellular (9-13 micron), neurophysin-containing neurons that were immunopositive for vasopressin (VP) but not oxytocin. These SCh-like cell groups also invariably contained similar small neurons that were immunoreactive for vasoactive intestinal polypeptide (VIP). Typically, VP and VIP immunoreactive perikarya were concentrated in contiguous, complementary parts of the grafted SCh, but fibers immunoreactive for either peptide were distributed throughout the extent of the nucleus. Because the brain of the Brattleboro rat is deficient in vasopressin, it was possible to evaluate the projection of the vasopressinergic component of the transplanted SCh to the host brain. Although SCh were identified in grafts recovered from each intraventricular transplantation site, an appreciable input to the host brain could be identified only when the fetal tissue was grafted to the third ventricle. Here, grafted SCh established efferent connections with periventricular diencephalic structures which ordinarily receive a projection from the in situ SCh. Specifically, VP immunoreactive fibers originating from transplanted SCh were identified in the medial preoptic area, the periventricular and dorsomedial hypothalamic nuclei, the paraventricular nuclei of the thalamus and hypothalamus, and in the retrochiasmatic area, arcuate nucleus, and suprachiasmatic nucleus of the host brain. These results demonstrate that the fetal SCh not only survives transplantation but also retains its distinguishing cytological features and the capacity to form an appropriately restricted set of efferent connections with the brain of adult host animals.
antibodies
2026-06-10 | Severe IL-6-dominant immune-mediated inflammatory response complicated by probable arginine vasopressin deficiency following ivonescimab-based therapy in advanced EGFR-mutant lung squamous cell carcinoma: a case report.
Ivonescimab, a novel PD-1/VEGF bispecific antibody, has shown promising efficacy in advanced lung cancer. Yet severe immune-related adverse events are not well studied outside clinical trials. We report a 72-year-old man with stage IV squamous NSCLC harboring an EGFR mutation and PD-L1 tumor proportion score of 90% who developed persistent fever shortly after first exposure to ivonescimab combined with nab-paclitaxel and carboplatin. His prior treatments included concurrent chemoradiotherapy, osimertinib, the investigational EGFR inhibitor BH-30643, afatinib, and recent gamma knife for cerebellar metastases plus palliative radiotherapy for bone metastases. After cycle 1, he developed persistent high fever with markedly elevated IL-6 and no response to antimicrobials. Corticosteroids brought rapid relief, pointing to an IL-6-mediated process. Re-exposure to ivonescimab triggered a more severe reaction. He then developed sudden polyuria with low urine osmolality and elevated serum osmolality. Brain MRI showed no typical hypophysitis features. Symptoms improved with corticosteroids, tocilizumab, and desmopressin, consistent with probable arginine vasopressin deficiency (AVP-D), possibly secondary to hypophysitis-though pituitary metastasis cannot be ruled out without biopsy. Ivonescimab can trigger severe IL-6-dominant inflammatory reactions and endocrine toxicity presenting as AVP-D in susceptible patients. Advanced age, EGFR-mutant/PD-L1-high tumor biology, recent radiotherapy, and Parkinsonism may have contributed to the inflammatory environment, though none can be proven causal in a single case and each deserves prospective study. Early recognition of persistent steroid-responsive fever, serial IL-6 monitoring, thorough endocrine workup, and timely IL-6 blockade are critical.
2024-12-27 | A 4-year-old Boy Positive for Anti-rabphilin-3A Antibody and Diagnosed With Lymphocytic Infundibuloneurohypophysitis.
Lymphocytic infundibuloneurohypophysitis (LINH) is a disease with an etiology involving an autoimmune mechanism, characterized by lymphocytic inflammation of the posterior pituitary and infundibular stalk, resulting in arginine vasopressin deficiency. It is difficult to distinguish from pituitary neoplasm or infiltrative diseases, and biopsy is necessary for a definitive diagnosis, but this is highly invasive. In children, it is especially important to distinguish LINH from tumors such as germ cell tumors. Recently, the usefulness of anti-rabphilin-3A antibody as a serum marker for LINH has been reported. To date, only a limited number of pediatric cases have been reported. We present a 4-year-old boy with arginine vasopressin deficiency. Magnetic resonance imaging of the head showed thickening of the pituitary stalk without a posterior pituitary bright spot, and anti-rabphilin-3A antibody was positive. Consequently, pituitary biopsy was not performed because of the strong suspicion of LINH. Five months after symptom onset, the pituitary stalk thickening had resolved. This case represents the first report of probable or definitive LINH with anti-rabphilin-3A antibody positivity in a 4-year-old child, making it the youngest positive case reported to date. Our case highlights the importance of noninvasive approaches and careful follow-up to avoid invasive interventions for children with LINH.
2024-05-01 | ARGININE VASOPRESSIN DEFICIENCY INDUCES DECREASED CARDIAC FIBROSIS RATE AND MEAN ARTERIAL BLOOD PRESSURE IN RATS WITH EXPERIMENTAL ABDOMINAL AORTIC STENOSIS
Cardiac fibrosis (CF) involves the accumulation of extracellular matrix proteins in the interstitial space, often seen in various cardiac pathologies. Each year, cardiovascular diseases claim the lives of 17.9 million people worldwide. Cardiac fibroblasts and myofibroblasts, equipped with vasopressin receptors (AVP), play a crucial role in regulating cell signaling pathways associated with CF development. AVP, an immunomodulatory hormone, influences immune responses, and its deficiency results in a decrease in immune activity. Abdominal aortic stenosis (AS) serves as an experimental model for left cardiac overload hypertension and CF. Neurointermediate pituitary lobectomy (NIL) induces a permanent decrease in circulating AVP levels, showcasing regression of hepatic fibrosis in liver damage models. The quest for effective alternative treatments for cardiac fibrosis poses a substantial challenge for researchers. In this experiment, groups of male Wistar rats weighing approximately 250 g (8/group) were categorized into: 1) Intact Control (IC), 2) Abdominal Aortic Stenosis (AS), 3) Neurointermediate pituitary lobectomy (NIL), and 4) AS+NIL. The AS and AS+NIL groups underwent abdominal aortic stenosis surgery on day one of the experiment. By week 5, the NIL and NIL+AS groups underwent NIL surgery. Prior to sacrifice at week 10, intracarotid mean blood pressure (MBP) was assessed in all groups. Following sacrifice, the hearts were removed, fixed in neutral formalin, and processed in paraffn for histopathological examination using H-E, Masson's trichrome, and Sirius red staining. Results revealed an elevated MBP in the AS group (156 ± 27.1 vs. 114 ± 30 mmHg in the IC), normalized in the AS+NIL group (110 ± 40.9 mmHg), and a mild decrease in the NIL group (87 ± 7.6 mmHg). The evaluation of CF in histological slides concurred with the MBP findings; a significant increase in CF occurred in the AS group compared to the IC, NIL, and AS+NIL groups, with almost complete reversion of CF observed in the AS+NIL group. In summary, this study demonstrates that AVP deficiency induces arterial hypotension, and in the AS+NIL group, AVP deficiency led to: 1) a decrease in blood pressure to normal levels and 2) reversion of cardiac fibrosis. Further experiments are warranted to determine if the decrease in blood pressure and cardiac overload are suffcient to inhibit profibrogenic mechanisms and/or activate antifibrogenic mechanisms. Additionally, investigations are needed to explore whether AVP deficiency, beyond inhibiting the inflammatory process, promotes the activation of antifibrogenic mechanisms. The present results offer new avenues for a deeper understanding of the molecular and cellular mechanisms through which AVP deficiency or the use of AVP receptor antagonists significantly influences fibrosis regulation in organ fibrotic diseases. Funding by Autonomous University of Aguascalientes (PIFF22-1). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2016-04-11 | Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis.
Neurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months. A 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI. Clinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation. Infliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.
2002-08-12 | Calcyclin is an early vasopressin-induced gene in the renal collecting duct. Role in the long term regulation of ion transport.
Long-term effects of arginine vasopressin (AVP) in the kidney involve the transcription of unidentified genes. By subtractive hybridization experiments performed on the RCCD(1) cortical collecting duct cell line, we identified calcyclin as an early AVP-induced gene (1 h). Calcyclin is a calcium-binding protein involved in the transduction of intracellular signals. In the kidney, calcyclin was localized at the mRNA level in the glomerulus, all along the collecting duct, and in the epithelium lining the papilla. In RCCD(1) cells and in m-IMCD(3) inner medullary collecting duct cells, calcyclin was evidenced in the cytoplasm. Calcyclin mRNA levels were progressively increased by AVP treatment in RCCD(1) (1.7-fold at 4 h) and m-IMCD(3) (2-fold at 7.5 h) cells. In RCCD(1) cells, calcyclin protein levels were increased by 4 h of AVP treatment. In vivo, treatment of genetically vasopressin-deficient Brattleboro rats with AVP for 4 days induced an increase in both calcyclin and aquaporin-2 mRNA expression. Finally, introduction of anti-calcyclin antibodies into RCCD(1) cells by permeabilizing the plasma membrane prevented the long-term (but not short-term) increase in short-circuit current induced by AVP. Taken together, these results suggest that calcyclin is an early vasopressin-induced gene that participates in the late phase of the hormone response in transepithelial ion transport.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.