Hypopituitarism, Diabetes Insipidus, and Syndrome of Inappropriate Antidiuretic Hormone Secretion after Pituitary Macroadenoma Surgery with Indocyanine Green Dye.

(1) Background: Pituitary adenomas are benign tumors comprising about 18% of all intracranial tumors, and they often require surgical intervention. Differentiating pituitary tissue from adenoma during surgery is crucial to minimize complications. We hypothesized that using ICG dye would reduce the hormonal complication rates. (2) Methods: A prospective randomized study (February 2019-October 2023) included 34 patients with non-functional macroadenomas of the pituitary gland randomly assigned to receive intraoperative ICG or be in the control group. All underwent endoscopic endonasal transsphenoidal surgery. Pituitary function was assessed preoperatively, immediately postoperatively, and 3-6 months postoperatively. Adenohypophysis function was evaluated with hormonal tests (Cosyntropin stimulation test, TSH, fT3, fT4, prolactin, IGF-1, FSH, LH, and testosterone in men) and neurohypophysis function with fluid balance, plasma and urine osmolality, and serum and urinary sodium. (3) Results: Of the 34 patients (23 men, 11 women; average age 60.9 years), 5.9% in the ICG group developed diabetes insipidus postoperatively, compared to 23.5% in the control group. Adenohypophysis function worsened in 52.9% of the ICG group and in 35.3% of the control group. (4) Conclusions: Our study did not confirm the benefits of using ICG in these surgeries. Further research with a larger sample is needed.

Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Predictive factors and scoring system for delayed symptomatic hyponatremia following endoscopic endonasal surgery: A single-center retrospective study.

BACKGROUNDS: Delayed symptomatic hyponatremia (DSH) is one of the common complications following endoscopic endonasal surgery (EES). Currently, published studies have predominantly focused on delayed postoperative hyponatremia, while there is relatively limited research on DSH. METHODS: We analyzed 175 consecutive cases from a single center between 2019 and 2023, involving patients who underwent endoscopic endonasal surgery (EES) for pituitary adenoma or Rathke's cleft cyst (RCC), all histopathologically confirmed. We collected preoperative, intraoperative, and postoperative data, and performed statistical analysis to determine the incidence of postoperative diabetes insipidus (DI) and identify significant predictive factors. Based on these factors, we developed a simplified scoring system. RESULTS: There were 29 cases (16.6%) of DSH occurrence. In the binary logistic regression analysis, Knosp grade ≥3 (OR, 4.19; 95% CI, 1.26-13.92; P=0.019), intraoperative cerebrospinal fluid leaks (OR, 3.93; 95% CI, 1.49-10.34; P=0.006), serum sodium on the second day after surgery (OR, 0.88; 95% CI, 0.78-1.00; P=0.049), and postoperative diabetes insipidus (OR, 2.88; 95% CI, 1.10-7.53; P=0.031) were factors with independent predictive value for DSH. The scoring system achieved a maximum area under the ROC curve (AUC) of 0.789 (95% CI, 0.697-0.881), with a cutoff value of 1, sensitivity of 86.2%, and specificity of 59.6%. CONCLUSION: The incidence rate of DSH after EES in patients was 16.8%. Knosp grade ≥3, intraoperative cerebrospinal fluid leaks, serum sodium concentration on the second day after surgery, and postoperative diabetes insipidus were associated with the occurrence of DSH.

Desmopressin dose requirements in patients with permanent arginine vasopressin deficiency: a tertiary center experience.

PURPOSE: The desmopressin daily dose requirement is highly variable among patients with arginine vasopressin (AVP) deficiency (i.e. central diabetes insipidus) and few studies to date have evaluated this topic, with often inconclusive results. The aim of our study was to identify clinical and biochemical predictors of such dose requirements in a cohort of patients with a confirmed diagnosis of permanent AVP deficiency who have good and stable control under substitutive treatment. METHODS: We retrospectively analyzed data of all patients with permanent AVP deficiency undergoing regular follow-up at our Division. Inclusion criteria were the presence of stable disease under therapy for at least 12 months and in good biochemical and clinical control. Patients with AVP deficiency who lacked intact thirst or had a disease duration of less than 12 months were excluded from the analysis. RESULTS: Out of the 132 patients initially screened, 96 patients (M/F 44/52; age 51 [37-63] years) met the inclusion criteria. Patients on nasal spray therapy (n = 8) had a significantly longer disease duration (p = 0.002) than patients treated with oral lyophilizate (n = 88). In the bivariate analysis, considering only patients treated with the sublingual formulation, the drug dose was correlated positively with estimated glomerular filtration rate (eGFR) and weight (r = 0.410, p < 0.001; r = 0.224, p = 0.036, respectively) and negatively with age (r = - 0.433, p < 0.001). In the multivariate regression analysis taking into account age, weight, and eGFR, only age emerged as a significant predictor of the required sublingual desmopressin dose (ß = - 1.426, p = 0.044). CONCLUSION: Our data suggest that patient age appears to be the primary factor associated with the daily sublingual desmopressin dose required to achieve adequate clinical and biochemical control in patients with permanent AVP deficiency.

Acute lymphoblastic leukemia with nephrogenic diabetes insipidus as the first symptom: a case report.

BACKGROUND: Acute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs. CASE PRESENTATION: This is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made. CONCLUSIONS: Renal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed.

Cognitive function in pituitary adenoma patients: A cross-sectional study.

Various factors may affect cognition in patients with pituitary adenoma, including size and extension of the tumor, degree of pituitary hormone deficiencies, and treatment of the tumor, most often being transsphenoidal surgery (TSS). The aim of this cross-sectional study was to evaluate cognitive function in patients with clinically significant pituitary adenoma and to identify factors influencing cognition. Sixty-eight patients with pituitary adenoma were included. Of these, 31 patients were evaluated before TSS and 37 patients 12 months following TSS. Cognitive function was evaluated by using the Repeatable Battery for the Assessment of Neuropsychological Status. Patients had lower mean scores on cognitive assessment compared to age-adjusted normative data. Variability in cognition, analyzed by linear regression analysis, was explained by sex, educational level, and self-perceived fatigue, but not by pituitary hormone deficiencies, diabetes insipidus, or surgical treatment. Our results are in line with previous findings, namely that pituitary adenoma affects cognition. To better evaluate the factors affecting cognition, longitudinal studies are recommended. Such studies would allow for within-individual comparisons, effectively controlling for the considerable influence of sex and education on test results.

Dexmedetomidine: a real-world safety analysis based on FDA adverse event reporting system database.

Objective: Using the FDA adverse event reporting system (FAERS) database to analyze the safety profile of Dexmedetomidine and provide guidance for clinical application. Methods: Data from the FAERS database from the first quarter of 2004 to the third quarter of 2023 were collected. Reporting odds ratio (ROR), the proportional reporting ratio (PRR), and the Bayesian confidence propagation neural network (BCPNN) were employed to detect and assess adverse events associated with Dexmedetomidine. Results: A total of 1910 reports of Dexmedetomidine as the primary suspect drug were obtained. After screening, 892 preferred terms were obtained, including 52 new preferred terms not mentioned in the drug insert. The common adverse events of Dexmedetomidine include bradycardia, cardiac arrest, hypotension, diabetes insipidus, arteriospasm coronary and agitation. Notably, cardiac disorders exhibited the highest number of reports and the highest signal intensity in the system organ class. Among the new preferred terms, those with high signal intensity include transcranial electrical motor evoked potential monitoring abnormal, acute motor axonal neuropathy, trigemino-cardiac reflex, glossoptosis, floppy iris syndrome, phaeochromocytoma crisis, postresuscitation encephalopathy and diabetes insipidus. Conclusion: This study mined and evaluated adverse events associated with Dexmedetomidine and also identified new adverse events. This could help alert clinicians to new adverse events not mentioned in the drug inserts, reducing the risk of drug.

Intraoperative Transient Central Diabetes Insipidus Status Post-Cerebellopontine Meningioma Resection: A Case Report.

Central diabetes insipidus (CDI) is a neurological pathological condition in which vasopressin synthesis has been compromised. A 52-year-old male presented with a cerebellopontine angle mass not involving the hypothalamic-pituitary axis. Despite vasopressin therapy, the patient produced a total of 8650 mL of urine, with the urine-specific gravity measured at 1.002 near hour 8. A literature review found associations with certain anesthetic drugs that have an increased incidence of CDI, including alpha-2 agonists and sevoflurane. Reports have recommended administering desmopressin over vasopressin, especially for neurosurgery cases that warrant a more extended operative period, given that desmopressin has a longer context-sensitive half-life.

Lithium-induced apoptotic cell death is not accompanied by a noticeable inflammatory response in the kidney.

Lithium (Li+) therapy is a valuable tool in psychiatric practice that remains underutilized due to safety concerns. Excessive plasma Li+ levels are nephrotoxic and can trigger a local immune response. Our understanding of the immunomodulatory effects of Li+ in the kidney is fragmentary. Here, we studied how immune mechanisms contribute to the development of Li+-induced adverse effects in the kidneys of C57BL/6NJ mice placed on a 0.3% lithium carbonate diet for 28 days. We combined histochemical techniques, immunoblotting, flow cytometry, qPCR and proteome profiler arrays to characterize renal tissue damage, infiltrating immune cells and cytokine markers, activation of pyroptotic and apoptotic cascades in the kidneys of mice receiving Li+-containing and regular diets. We found that biomarkers of tubular damage, kidney injury marker, KIM-1, and neutrophil gelatinase-associated lipocalin, NGAL, were elevated in the renal tissue of Li+-treated mice when compared to controls. This correlated with increased interstitial fibrosis in Li+-treated mice. Administration of Li+ did not activate the pro-inflammatory NLRP3 inflammasome cascade but promoted apoptosis in the renal tissue. The TUNEL-positive signal and levels of pro-apoptotic proteins, Bax, cleaved caspase-3, and caspase-8, were elevated in the kidneys of Li+-treated mice. We observed a significantly higher abundance of CD93, CCL21, and fractalkine, accumulation of F4.80+ macrophages with reduced M1/M2 polarization ratio and decreased CD4+ levels in the renal tissue of Li+-treated mice when compared to controls. Therefore, after 28 days of treatment, Li+-induced insult to the kidney manifests in facilitated apoptotic cell death without an evident pro-inflammatory response.

Erdheim-Chester Disease Presenting as Bilateral Facial Masses: A case report and review of literature.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis with unknown aetiology. It is recently recognised to be neoplastic with genetic mutations affecting the mitogen-activating protein kinase pathway. We report a 49-year-old female patient who initially presented in 2012 to a tertiary care centre in Muscat, Oman, with bilateral facial masses. These were removed but later recurred over a period of 10 years. She then presented with xanthelasmas, bone lesions, secondary infertility due to hypothalamic hypogonadism, diabetes insipidus and Hashimoto's hypothyroidism. The facial masses were biopsied and they showed classic morphological features in the form of diffuse infiltration by foamy histiocytes with scattered Touton type of giant cells, patchy lymphocytic infiltrates and dense fibrosis. The patient is stable and is being followed-up. The presented ECD case is particularly interesting due to the recurrent bilateral facial masses. To the best of the authors' knowledge, this is the first documented case in Oman.

Autosomal dominant nephrogenic diabetes insipidus in one family caused by a novel AQP2 mutation.

A 9-month-old male presented with vomiting and dehydration with mild hypernatremia in the context of failure to thrive. He was later diagnosed with nephrogenic diabetes insipidus (NDI) during this hospitalisation and was also found to have eosinophilic esophagitis (EoE). He has since been growing well after EoE and NDI were properly managed. Molecular genetic testing revealed an unreported deletion in AQP2 which was deemed pathogenic and of autosomal dominant inheritance when correlated with his clinical findings and family history. This case report describes the clinical course of this patient in comparison to his family members and reviews current literature on autosomal dominant NDI caused by AQP2 mutations.

Challenges in Diagnosing and Managing Severe Hypernatremia in Patients With Major Depressive Disorder: A Case Report.

Hypernatremia, characterized by a plasma sodium concentration above 145 mmol/L, is frequently observed in critically ill patients, often due to factors such as gastrointestinal losses, dehydration, and diabetes insipidus. Psychiatric patients, particularly those with major depressive disorder, are also at risk of developing hypernatremia due to abnormalities in thirst sensation, mineralocorticoid excess, or medication side effects. Severe hypernatremia in psychiatric patients is associated with a high mortality rate, presenting challenges in diagnosis and management. The treatment of chronic hypernatremia (>48 hours) typically involves administering isotonic saline to hypovolemic patients until normalization of vital signs, followed by dextrose 5% in water (D5W) based on water deficit and losses. The goal is to decrease plasma sodium by 8-10 mmol/day. Acute hypernatremia (<48 hours) is corrected with a plasma sodium reduction of 1 mmol/L/hour in the first six to eight hours. While there are no clear guidelines for sodium correction in severe hypernatremia, the literature suggests a safe correction rate of 8-10 mmol/day for chronic hypernatremia and 1 mmol/L/hour for acute cases. In a specific case, a 51-year-old female with severe depression and reduced oral intake was admitted. She exhibited signs of dehydration and was found to have severe hypernatremia (191 mmol/L) with acute kidney injury. Treatment involved D5W, followed by D5W/half-normal saline at 150 mL/hr. Within 24 hours, her plasma sodium decreased to 178 mmol/L and gradually normalized to 143 mmol/L without neurological complications. This case highlights the challenges and underscores the importance of early recognition and management of severe hypernatremia in psychiatric patients. The primary treatment approach addresses water deficits and losses and administers D5W. Recent findings suggest that rapid correction of the condition is acceptable.

Retrospective analysis of the outcomes of endoscopic transsphenoidal surgery for Cushing's disease.

Background: The first-line surgical management of an adrenocorticotropic hormone (ACTH)--secreting pituitary adenoma causing Cushing's disease (CD) is endoscopic transsphenoidal resection of the tumor. This study was performed to assess postoperative (postop) complications and remission in endoscopic surgically resected cases of CD. Methods: Data of patients who underwent endoscopic transsphenoidal surgery (ETSS) for CD were collected from the neurosurgery department at a tertiary care center in a retrospective manner from January 2015 to February 2022 and analyzed. Postoperative remission was categorized as - early morning serum cortisol <138 nmol/L within 7 days of the surgery, as per the Endocrine Society Guidelines, with significant clinical improvement in features of hypercortisolism in the operated patient and strict cutoff rate of <50 nmol/L at postop day 3 was also utilized, to look for the early identification of remission. Results: A total of 41 patients were identified who underwent 44 ETSS during the same timeframe. Preoperative magnetic resonance imaging localized an adenoma in all 41 patients, out of which 32 were microadenoma, and nine were macroadenoma (2 with cavernous sinus invasion). Intrapetrosal sinus sampling was performed in 35 (85%) patients. The rate of remission for the initial surgery was 85.4% using the standard criteria and 68.3% using strict criteria. Three patients underwent early repeat surgery for the persistent disease as the day 3 cortisol was high (306-555 nmol/L). Once the outcome of this surgery was also included, the overall rate of remission was 90.2% (37/41). None of the patients had meningitis, cerebrospinal fluid leakage, visual deterioration, or vascular injury. Permanent and transient diabetes insipidus (DI) occurred in 9.75% and 26.8% following the first ETSS, respectively. We also noted a single case of CD recurrence in 9 months during the total follow-up period of 84 months. Conclusion: ETSS has satisfactory rates of remission for the primary treatment of CD, with rates being higher for microadenomas. A long follow-up period is needed to assess the rates of recurrence. Patients must be counseled regarding the risk of postop DI, whether transient or permanent, as a possible complication.

Hyponatremia due to preserved non-osmotic arginine vasopressin secretion in adipsic diabetes insipidus: a case report with review of literature.

Adipsic diabetes insipidus (ADI) is characterized by central diabetes insipidus and an impaired thirst response to hyperosmolality, leading to hypernatremia. Hyponatremia observed in patients with ADI has been considered a complication of desmopressin therapy. Herein, we present a case of impaired thirst sensation and arginine vasopressin (AVP) secretion without desmopressin therapy, in which hyponatremia developed due to preserved non-osmotic AVP secretion. A 53-year-old woman with hypopituitarism, receiving hydrocortisone and levothyroxine, experienced hyponatremia three times over 5 months without desmopressin treatment. The first hyponatremic episode (120 mEq/L) was complicated by a urinary tract infection with a plasma AVP level of 33.8 pg/mL. Subsequent hyponatremia episodes occurred after administration of antipsychotic (124 mEq/L) and spontaneously (125 mEq/L) with unsuppressed plasma AVP levels (1.3 and 1.8 pg/mL, respectively). Hypertonic saline infusion did not affect AVP or copeptin levels. Regulating water intake using a sliding scale based on body weight prevented the recurrence of hyponatremia without the use of desmopressin. Except during infection, plasma AVP levels (1.3 ± 0.4 pg/mL) were not significantly correlated with serum sodium levels (rs = -0.04, p = 0.85). In conclusion, we present a unique case of impaired thirst sensation and AVP secretion in which hyponatremia developed without desmopressin therapy. Preserved non-osmotic AVP secretion, possibly stimulated by glucocorticoid deficiency, may contribute to the development of hyponatremia in patients with ADI.

Wrong Tissue at the Wrong Place: A Rare Case of Hypopituitarism Secondary to Metastatic Renal Cell Carcinoma.

Metastasis to the pituitary gland is a very rare occurrence. The most common primary cancer that metastasizes to the pituitary are breast cancer and lung cancer. Most of the pituitary metastases are asymptomatic. The most commonly reported symptoms include anterior pituitary dysfunction, visual field defects, headaches, and diabetes insipidus. Metastasis from renal cell carcinoma (RCC) is very rare. Here, we present the case of a 59-year-old male who presented with vision changes, fatigue, low libido, a low appetite, and excessive thirst. The hormonal evaluation was consistent with panhypopituitarism, and he was started on hydrocortisone, levothyroxine, testosterone, and desmopressin. Brain MRI showed a suprasellar enhancing mass that progressively increased in size. He underwent endoscopic endonasal transplanum and transtuberculum approach for tumor removal. Biopsy of the tumor was reported as metastatic RCC. He was later scheduled for a gamma knife. Metastatic RCC to pituitary is rare, with most being asymptomatic, leading to a delay in diagnosis. Treatment of pituitary metastases is not standardized and should be tailored to patients' clinical conditions, histology, and the presence of extrapituitary metastases. More prospective studies are needed to formulate guidelines for the management of pituitary metastases.

Hyponatremia-Induced Epileptic Seizure Provoked by Levetiracetam and Pain Medication Intake in a Patient with Central Diabetes Insipidus.

Introduction: Causes of epileptic seizures are often multifactorial but for an effective therapy, they should be uncovered in detail. Case Presentation: We present a 67-year-old male patient with a central diabetes insipidus, who experienced a generalized tonic-clonic seizure. The patient was treated with levetiracetam for prevention of further seizures, opioids and non-steroidal anti-inflammatory drugs, i.e., ibuprofen because of severe back pain due to vertebral compression fractures. In this setting, he developed significant hyponatremia and experienced another epileptic seizure. After stopping analgesics and switching from levetiracetam to lacosamide, sodium levels returned to normal and the patient remained free of seizures since then. Conclusion: The interrelationships of medical therapy, sodium levels and epileptic seizures in the context of central diabetes insipidus are discussed.

Approach to the patient with suspected hypotonic polyuria.

Investigation and management of hypotonic polyura is a common challenge in clinical endocrinology. The three main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), AVP-resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis as management differs for each. This new nomenclature more accurately reflects pathophysiology, and has now been adopted by the Systemised Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use three patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature.

Comparison of clinical and radiological characteristics of inflammatory and non-inflammatory Rathke cleft cysts.

PURPOSE: Rathke cleft cysts are commonly encountered sellar lesions, and their inflammation induces symptoms and recurrence. Cyst wall enhancement is related to inflammation; however, its range and frequency have not yet been investigated. This study aimed to investigate the clinical and radiological differences between inflammatory and non-inflammatory Rathke cleft cysts. METHODS: Forty-one patients who underwent cyst decompression surgery for Rathke's cleft cysts between January 2008 and July 2022 were retrospectively analyzed. Based on the pathological reports, patients were divided into inflammatory and non-inflammatory groups. Clinical assessments, endocrinological evaluations, cyst content analysis, and imaging metrics (mean computed tomographic value, maximum diameter, mean apparent diffusion coefficient [ADC] value, and qualitative features) were analyzed. Receiver operating characteristic curve analysis was performed, to determine ADC cutoff values, for differentiating inflammatory group from non-inflammatory group. RESULTS: Totally, 21 and 20 cases were categorized into the inflammatory and non-inflammatory groups, respectively. The inflammatory group displayed a higher incidence of central diabetes insipidus (arginine vasopressin deficiency) (p = 0.04), turbid cyst content (p = 0.03), significantly lower mean ADC values (p = 0.04), and more extensive circumferential wall enhancement on magnetic resonance imaging (MRI) (p < 0.001). In the inflammatory group, all cases revealed circumferential wall enhancement, with some exhibiting thick wall enhancement. There were no significant differences in other radiological features. The ADC cutoff value for differentiating the two groups was 1.57 × 10-3 mm2/s, showing a sensitivity of 81.3% and specificity of 66.7% CONCLUSION: Inflammatory Rathke cleft cysts tended to show a higher incidence of central diabetes insipidus and turbid cyst content. Radiologically, they exhibited lower mean ADC values and greater circumferential wall enhancement on MRI.

Copeptin as a surrogate marker for arginine vasopressin: analytical insights, current utility, and emerging applications.

Copeptin is a 39-amino-acid long glycosylated peptide with a leucine-rich core segment in the C-terminal part of pre-pro-vasopressin. It exhibits a rapid response comparable to arginine vasopressin (AVP) in response to osmotic, hemodynamic, and nonspecific stress-related stimuli. This similarity can be attributed to equimolar production of copeptin alongside AVP. However, there are markedly different decay kinetics for both peptides, with an estimated initial half-life of copeptin being approximately two times longer than that of AVP. Like AVP, copeptin correlates strongly over a wide osmolality range in healthy individuals, making it a useful alternative to AVP measurement. While copeptin does not appear to be significantly affected by food intake, small amounts of oral fluid intake may result in a significant decrease in copeptin levels. Compared to AVP, copeptin is considerably more stable in vitro. An automated immunofluorescent assay is now available and has been used in recent landmark trials. However, separate validation studies are required before copeptin thresholds from these studies are applied to other assays. The biological variation of copeptin in presumably healthy subjects has been recently reported, which could assist in defining analytical performance specifications for this measurand. An established diagnostic utility of copeptin is in the investigation of polyuria-polydipsia syndrome and copeptin-based testing protocols have been explored in recent years. A single baseline plasma copeptin >21.4 pmol/L differentiates AVP resistance (formerly known as nephrogenic diabetes insipidus) from other causes with 100% sensitivity and specificity, rendering water deprivation testing unnecessary in such cases. In a recent study among adult patients with polyuria-polydipsia syndrome, AVP deficiency (formerly known as central diabetes insipidus) was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. Glucagon-stimulated copeptin has been proposed as a potentially safe and precise test in the investigation of polyuria-polydipsia syndrome. Furthermore, copeptin could reliably identify those with AVP deficiency among patients with severe hypernatremia, though its diagnostic utility is reportedly limited in the differential diagnosis of profound hyponatremia. Copeptin measurement may be a useful tool for early goal-directed management of post-operative AVP deficiency. Additionally, the potential prognostic utility of copeptin has been explored in other diseases. There is an interest in examining the role of the AVP system (with copeptin as a marker) in the pathogenesis of insulin resistance and diabetes mellitus. Copeptin has been found to be independently associated with an increased risk of incident stroke and cardiovascular disease mortality in men with diabetes mellitus. Increased levels of copeptin have been reported to be independently predictive of a decline in estimated glomerular filtration rate and a greater risk of new-onset chronic kidney disease. Furthermore, copeptin is associated with disease severity in patients with autosomal dominant polycystic kidney disease. Copeptin predicts the development of coronary artery disease and cardiovascular mortality in the older population. Moreover, the predictive value of copeptin was found to be comparable with that of N-terminal pro-brain natriuretic peptide for all-cause mortality in patients with heart failure. Whether the measurement of copeptin in these conditions alters clinical management remains to be demonstrated in future studies.