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Diabetes Insipidus

Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus (DI) is a condition in which the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). In CDI, the amount of antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH) produced by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus or released from the pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland is decreased. In nephrogenic DI, the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy fail to respond to circulating ADH. Both conditions result in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy being unable to concentrate urine, leading to polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation, nocturia, and polydipsia. Central and NDI are differentiated based on measured serum sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia and urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation levels and response to a water-deprivation test. Central DI is treated with desmopressin Desmopressin Hemophilia, while nephrogenic DI is treated with diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication and dietary salt restriction.

Last updated: May 17, 2024

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology

  • Total prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 1 in 25,000 people
  • Central  diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus (CDI) is more common than nephrogenic diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus (NDI). 
  • Only 1 in 10 cases of DI is congenital Congenital Chorioretinitis.
  • Men and women are equally affected.
  • 20% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship undergoing neurosurgery Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. Neurosurgery will develop some degree of DI.

Pathophysiology

Role of antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH)

Antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia is also called vasopressin.

Function:

Antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia regulates serum osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation and blood pressure.

Production:

Adh regulation and production

Regulation and pathway of ADH production

Image by Lecturio.

Central DI

Central  diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus is caused by the insufficient production of ADH from the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus or insufficient release from the posterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types gland.

  • Idiopathic Idiopathic Dermatomyositis
    • Most common (30%50%)
    • Assumed to be caused by autoimmune damage to ADH-producing cells
  • Acquired
    • Autoimmune 
    • Pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types or secondary tumors
      • Craniopharyngioma Craniopharyngioma Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure that arise from the remnants of Rathke’s pouch along the pituitary stalk, in the suprasellar region. Craniopharyngiomas are histologically benign but tend to invade surrounding structures; thus, they should be treated as low-grade malignancies. Craniopharyngioma 
      • Adenoma
    • Neurosurgery Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. Neurosurgery or head trauma Head trauma Head trauma occurs when external forces are directed to the skull and brain structures, resulting in damage to the skull, brain, and intracranial structures. Head injuries can be classified as open (penetrating) or closed (blunt), and primary (from the initial trauma) or secondary (indirect brain injury), and range from mild to severe and life-threatening. Head Trauma
    • Infiltrative disease
      • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
      • Langerhans cell histiocytosis
    • Hypoxic encephalopathy Encephalopathy Hyper-IgM Syndrome 
    • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
    • Alcohol intoxication Alcohol intoxication An acute brain syndrome which results from the excessive ingestion of ethanol or alcoholic beverages. Alcohol Use Disorder
  • Congenital Congenital Chorioretinitis (rare)
    • Congenital Congenital Chorioretinitis hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism 
    • Wolfram syndrome

Nephrogenic DI

Nephrogenic diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus is caused by an insufficient response of the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy to ADH.

  • Acquired
    • Long-term lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly therapy
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
    • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • Other drugs (antivirals, antifungals, antibiotics, antineoplastic drugs) 
    • Acute or chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
      • Autosomal dominant polycystic kidney disease Autosomal dominant polycystic kidney disease Polycystic kidney disease (PKD) is an inherited genetic disorder leading to the development of numerous fluid-filled cysts in the kidneys. The 2 main types of PKD are autosomal dominant polycystic kidney disease (ADPKD), which is often diagnosed in adulthood, and autosomal recessive polycystic kidney disease (ARPKD), which is often diagnosed antenatally or shortly after birth. Autosomal dominant polycystic kidney disease (ADPKD) ( ADPKD ADPKD Polycystic kidney disease (PKD) is an inherited genetic disorder leading to the development of numerous fluid-filled cysts in the kidneys. The 2 main types of PKD are autosomal dominant polycystic kidney disease (ADPKD), which is often diagnosed in adulthood, and autosomal recessive polycystic kidney disease (ARPKD), which is often diagnosed antenatally or shortly after birth. Autosomal dominant polycystic kidney disease (ADPKD))
      • Renal amyloidosis Renal Amyloidosis Ankylosing Spondylitis
      • Bardet-Biedl syndrome
      • Bartter syndrome Bartter syndrome Bartter syndrome is a rare autosomal recessive disorder that affects the kidneys and presents either antenatally with severe or life-threatening manifestations or in childhood or adulthood with a milder course, depending on the genetic defect. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb of the loop of Henle. Bartter Syndrome
      • Sjögren’s syndrome
    • Mild form is often found in elderly individuals (decline in kidney function with age).
  • Congenital Congenital Chorioretinitis (most common)

Clinical Presentation and Diagnosis

Clinical presentation

Central  diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus and NDI present with the same symptoms:

  • Polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation
    • Defined as > 3 L urine output/day
  • Nocturia (leading to daytime sleepiness Daytime sleepiness Narcolepsy)
  • Polydipsia (secondary to increased serum sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia and plasma osmolality Plasma osmolality Volume Depletion and Dehydration)
  • Neurologic symptoms may occur secondary to hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia.
    • Irritability
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, if severe

Diagnosis

  • Water deprivation test
  • Additional testing:
    • Head computed tomography (CT) or magnetic resonance imaging (MRI) (if CDI is suspected)
    • Review of current medications ( lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly salts, foscarnet Foscarnet An antiviral agent used in the treatment of cytomegalovirus retinitis. Foscarnet also shows activity against human herpesviruses and HIV. Antivirals for Herpes Virus, clozapine Clozapine A tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2a/2c receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. Second-Generation Antipsychotics)
Craniopharyngioma

Head CT of a craniopharyngioma (calcified cystic mass): Diabetes insipidus is estimated to occur in up to 35% of patients before surgery and 70%–90% after surgery.

Image: “Craniopharyngioma1” by Matthew R Garnett, Stéphanie Puget, Jacques Grill, Christian Sainte-Rose. Craniopharyngioma. Orphanet Journal of Rare Diseases.. License: CC BY 2.0

Management

Central DI

  • Medical therapy:
  • Nutritional:
    • Low-sodium, reduced-protein diet
    • Hydration
    • If electrolyte abnormalities do not normalize through oral water intake: IV dextrose Dextrose Intravenous Fluids plus water or IV hypo-osmolar fluids
    • Special consideration in children:
      • Early treatment important due to harmful effects of hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia
      • Give water every 2 hours (day and night).
      • Monitor food intake and growth.
      • Low-protein diet not recommended

Nephrogenic DI

  • Medical therapy:
    • Hydrochlorothiazide Hydrochlorothiazide A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It is used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. Thiazide Diuretics
    • Indomethacin Indomethacin A non-steroidal anti-inflammatory agent (nsaid) that inhibits cyclooxygenase, which is necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
    • Amiloride Amiloride A pyrazine compound inhibiting sodium reabsorption through sodium channels in renal epithelial cells. This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct. Negative potential reduces secretion of potassium and hydrogen ions. Amiloride is used in conjunction with diuretics to spare potassium loss. Liddle Syndrome
    • Avoidance of offending agent (most commonly lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly) → kidney function may return to normal after discontinuation.
  • Nutritional: same as for central DI

Differential Diagnosis

  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus: a chronic metabolic disorder characterized by resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin ( type 2 Type 2 Spinal Muscular Atrophy) or insufficient production of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin ( type 1 Type 1 Spinal Muscular Atrophy) resulting in hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus and resultant polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation due to osmotic diuresis Osmotic diuresis Volume Depletion and Dehydration. Also presents with polydipsia due to increased diuresis. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship would be expected to have elevated serum glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance and glucosuria Glucosuria Diabetes Mellitus
  • Psychogenic polydipsia: excessive fluid intake without an identifiable organic cause, often seen in individuals with schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders, or anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa nervosa. This excessive drinking of fluids results in polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation and, in severe cases, hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia. Water-deprivation test would show an increase in urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation after fluid restriction, which differentiates it from DI.

References

  1. Tabibzadeh N. et al. (2019). Complications métaboliques et rénales chroniques du traitement par sels de lithium [Chronic metabolic and renal disorders related to lithium salts treatment]. Rev Med Interne.
  2. Ghirardello, S. et al. (2006). Diabetes insipidus in craniopharyngioma: postoperative management of water and electrolyte disorders. Journal of pediatric endocrinology & metabolism: JPEM, 19 Suppl 1, 413–421. 
  3. Hui C., Radbel J.M. Diabetes Insipidus. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved Oct 8, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK470458/
  4. Bendz, H., Aurell, M. (1999). Drug-Induced Diabetes Insipidus. Drug-Safety, 449–456.

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