Diabetes insipidus (DI) is a condition in which the kidneys 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 (ADH) produced by the hypothalamus or released from the pituitary gland is decreased. In nephrogenic DI, the kidneys fail to respond to circulating ADH. Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Central and NDI are differentiated based on measured serum sodium and urine osmolality levels and response to a water-deprivation test. Central DI is treated with desmopressin, while nephrogenic DI is treated with diuretics and dietary salt restriction.
Total prevalencePrevalenceThe 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[4,15]
Central diabetesDiabetesDiabetes 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 diabetesDiabetesDiabetes 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 DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus is congenitalCongenitalChorioretinitis.
Men and women are equally affected.
20% of patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship undergoing neurosurgeryNeurosurgeryNeurosurgery 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 DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus.
20% of people who undergo cranial surgery will develop transient DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus during recovery.
About 30% of diagnosed cases do not have a known underlying cause.
Pathophysiology
A position statement published in the January 2023 issue of the Journal of Clinical Endocrinology & Metabolism suggested renaming “diabetesDiabetesDiabetes 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.” The proposal is to rename CDI to “arginineArginineAn essential amino acid that is physiologically active in the l-form.Urea Cycle vasopressin deficiency” and NDI to “arginineArginineAn essential amino acid that is physiologically active in the l-form.Urea Cycle vasopressin resistanceResistancePhysiologically, 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.”[1]
Role of antidiuretic hormoneAntidiuretic hormoneAntidiuretic 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)[5,18]
Antidiuretic hormoneAntidiuretic hormoneAntidiuretic 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 arginineArginineAn essential amino acid that is physiologically active in the l-form.Urea Cycle vasopressin (AVP).
Function:
Antidiuretic hormoneAntidiuretic hormoneAntidiuretic 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 osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation and blood pressure.
Increased free water absorptionAbsorptionAbsorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation.Digestion and Absorption resulting in:
Synthesized in the supraoptic nuclei of the hypothalamusHypothalamusThe 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
Stored and secreted by the posterior pituitaryPituitaryA 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
Detected by osmoreceptorsOsmoreceptorsRenal Sodium and Water Regulation (vasopressin type 2Type 2Spinal Muscular Atrophy; V₂) in the hypothalamusHypothalamusThe 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
ThresholdThresholdMinimum voltage necessary to generate an action potential (an all-or-none response)Skeletal Muscle Contraction for release is about 280‒290 mOsm/kg.[18]
Central DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus[5,12,19,20]
Central diabetesDiabetesDiabetes 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 hypothalamusHypothalamusThe 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 pituitaryPituitaryA 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.
Assumed to be caused by autoimmune damage to ADH-producing cells
Acquired
Autoimmune
PituitaryPituitaryA 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
CraniopharyngiomaCraniopharyngiomaCraniopharyngiomas 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
NeurosurgeryNeurosurgeryNeurosurgery 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 traumaHead traumaHead 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
SarcoidosisSarcoidosisSarcoidosis 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
MeningitisMeningitisMeningitis 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 intoxicationAlcohol intoxicationAn acute brain syndrome which results from the excessive ingestion of ethanol or alcoholic beverages.Alcohol Use Disorder
CongenitalCongenitalChorioretinitishypopituitarismHypopituitarismHypopituitarism 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 syndromeWolfram syndromeA hereditary condition characterized by multiple symptoms including those of diabetes insipidus; diabetes mellitus; optic atrophy; and deafness. This syndrome is also known as didmoad (first letter of each word) and is usually associated with vasopressin deficiency. It is caused by mutations in gene wfs1 encoding wolframin, a 100-kda transmembrane protein.Diabetes Insipidus
Nephrogenic DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus[5,12,16,17]
Nephrogenic diabetesDiabetesDiabetes 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 kidneysKidneysThe 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 resulting in a decrease in urinary concentrating ability.
Acquired
Long-term lithiumLithiumAn 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
HypercalcemiaHypercalcemiaHypercalcemia (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
PregnancyPregnancyThe 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 (1 in 25,000)
HypokalemiaHypokalemiaHypokalemia 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 diseaseChronic Kidney DiseaseChronic 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 diseaseAutosomal dominant polycystic kidney diseasePolycystic 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) (ADPKDADPKDPolycystic 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))
Bardet-Biedl syndromeBardet-Biedl syndromeAn autosomal recessive disorder characterized by retinitis pigmentosa; polydactyly; obesity; mental retardation; hypogenitalism; renal dysplasia; and short stature. This syndrome has been distinguished as a separate entity from laurence-moon syndrome.Diabetes Insipidus
Bartter syndromeBartter syndromeBartter 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).
Mutations in the geneGeneA category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Basic Terms of Genetics encoding the vasopressin (V2) receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
X-linked inheritanceX-linked inheritanceGenetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases.Alport Syndrome
Less common:
Mutations in the geneGeneA category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Basic Terms of Genetics encoding the aquaporin (AQP) channelsChannelsThe Cell: Cell Membrane
Central diabetesDiabetesDiabetes 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:
PolyuriaPolyuriaUrination 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 in adults (age-specific in children)
PolyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation in patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus is a water diuresis (contrasted with a solute diuresis in individuals with diabetesDiabetesDiabetes 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).
NocturiaNocturiaFrequent urination at night that interrupts sleep. It is often associated with outflow obstruction, diabetes mellitus, or bladder inflammation (cystitis).Diabetes Insipidus(leading to daytime sleepinessDaytime sleepinessNarcolepsy)
PolydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus (secondary to increased serum sodiumSodiumA member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23.Hyponatremia and plasma osmolalityPlasma osmolalityVolume Depletion and Dehydration)
Neurologic symptoms may occur secondary to hypernatremiaHypernatremiaHypernatremia 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.
ComaComaComa 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 or seizuresSeizuresA seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, if severe
Table: Definition of polyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation in children[15,18]
Age
Cutoff value
Neonates
> 150 mL/kg/day
≤ 2 years
> 100–110 mL/kg/day
> 2 years
> 40–50 mL/kg day
Basic laboratory studies
Serum sodiumSodiumA member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23.Hyponatremia (Na+):[8,15]
HyponatremiaHyponatremiaHyponatremia 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 (serum Na+ < 135 mEq/L) → likely primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
HypernatremiaHypernatremiaHypernatremia 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 (serum Na+ > 145 mEq/L) → either CDI or NDI
Normal sodiumSodiumA member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23.Hyponatremia level (Na+ 135–145 mEq/L) → proceed with either:
≤ 280 mOsm/kg implies primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
Urine studies:[4,8,9,16,18,19]
A 24-hour urine collection can confirm hypotonicHypotonicSolutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid.Renal Sodium and Water RegulationpolyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation if:
> 2.5 L/day (or > 30 mL/kg/day in children)
≤ 800 mOsm/kg:
Urine osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation (Uosm) < 300 mOsm/L suggests complete CDI or NDI.
Uosm 300–800 mOsm/L suggests partial CDI or NDI.
A random urine osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation may also be obtained.
Next steps
Differentiating NDI from CDI can be a challenge. The following tests should be performed under the guidance of a specialist (e.g., endocrinology).[4]
Water-deprivation (restriction) test:[8,14,15]
Previously the gold standard
Often combined with desmopressinDesmopressinHemophilia challenge, but may also be combined with copeptin testing
This stimulates ADH to maximally concentrate the urine.
Procedure (for adults):
Serum and urine Na+ and osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation are measured before water restriction.
No water intake for 2–3 hours
Serum and urine levels are remeasured repeatedly during this interval.
If Na+ and osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation goals are not achieved → overnight fluid restriction may be considered
Uosm > 800 mOsm/kg (“normal” response) → primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
Some prefer IV to ensure reliable absorptionAbsorptionAbsorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation.Digestion and Absorption.
See your local facility’s protocol for dosing.
Observation time is about 2 hours.
A follow-up Uosm is measured and compared to the initial osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation:
If osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation increases by < 9% → primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
Results may be clouded by:
Diuretic use
Renal disease
Random copeptin level:[8,14,15]
Copeptin is the C-terminal segment of ADH → reflects circulating levels of ADH
Not universally available
Baseline copeptin level ≥ 21.4 pmol/L → NDI
Baseline copeptin < 21.4 pmol/L → there are 3 options:
Hypertonic salineHypertonic salineHypertonic sodium chloride solution. A solution having an osmotic pressure greater than that of physiologic salt solution (0. 9 g NaCl in 100 ml purified water).Hyponatremia–stimulated copeptin level (3% saline is infused to a goal serum Na+ > 150 mEq/L):
≤ 4.9 pmol/L → CDI
> 4.9 pmol/L → primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
> 3.8 pmol/L → primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus
May also be combined with a water-deprivation test, with copeptin level drawn once Na+ ≥ 145 mEq/L
Diagnostic algorithm for diabetes insipidus:[4,8,14,15] Keep in mind, the process is complicated and should be guided by a specialist.
CDI: central diabetes insipidus; NDI: nephrogenic diabetes insipidus; Uosm: urine osmolality
Image by Lecturio.
Additional evaluation[14,15,19,20]
Head computed tomography (CT) or magnetic resonance imaging (MRI) if CDI is suspected:
T1-weighted MRI:
Normal posterior pituitaryPituitaryA 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 hyperintensity is present with NDI or primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus but is very small or absent with CDI.
Note: Healthy patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with an “empty sella” may also lack hyperintensity in the posterior pituitaryPituitaryA 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.
Can identify tumors or infiltrative disease as a cause of CDI (e.g., thickening of the pituitaryPituitaryA 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 stalk)
Review of current medications (lithiumLithiumAn 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, foscarnetFoscarnetAn antiviral agent used in the treatment of cytomegalovirus retinitis. Foscarnet also shows activity against human herpesviruses and HIV.Antivirals for Herpes Virus, clozapineClozapineA 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)
Additional studies to elicit an underlying cause should be guided by the patient’s presentation and by clinical suspicion.
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
Management may vary depending on practice location. The following information is based on US, UK, and European literature and guidelines.
Mild cases of DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus do not require treatment other than fluid intake and discontinuing aggravating factors, if identified. Additional management should be guided by a specialist.
Central DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus
Initial adult dose: 5–10 µg once daily at bedtime to control nocturiaNocturiaFrequent urination at night that interrupts sleep. It is often associated with outflow obstruction, diabetes mellitus, or bladder inflammation (cystitis).Diabetes Insipidus
Assess the need for daytime dose based on control of polyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation
Maximum dose needed is typically 10 µg 2–3 times daily.
Oral:
Alternative for patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with nasal issues
Initial adult dose: 50–100 µg daily
Maximum dose needed is typically 200 µg 2–3 times daily.
Taking on an empty stomachStomachThe stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy improves absorptionAbsorptionAbsorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation.Digestion and Absorption and prolongs duration of action.
IV or SC:
For patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship who cannot take either nasally or orally (e.g., before or after nasal/pituitaryPituitaryA 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 surgery)
Initial adult dose: 1–2 µg every 12–24 hours as needed
Drugs with antidiuretic effect (rarely used; less effective with more side effects)
ThiazideThiazideHeterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics.HyponatremiadiureticsDiureticsAgents that promote the excretion of urine through their effects on kidney function.Heart Failure and Angina Medication
CarbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs
Avoid correcting Na+ by more than 0.5 mEq/L/hr (< 10 mEq/L/day).
Special consideration in children:
Early treatment important due to harmful effects of hypernatremiaHypernatremiaHypernatremia 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
High-risk patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship (those at risk for deterioration):[13]
HypernatremiaHypernatremiaHypernatremia 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 or hyponatremiaHyponatremiaHyponatremia 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
Poor thirst mechanism
Unable to communicate
Unable to self-administer medications
Nephrogenic DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus
ThiazideThiazideHeterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics.Hyponatremia diuretic: hydrochlorothiazideHydrochlorothiazideA 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 (HCTZHCTZA 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)
Blocks thiazide-sensitive cotransporter in the distal convoluted tubuleDistal convoluted tubuleThe portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule.Gitelman Syndrome → ↓ Na reabsorption
Initial natriuresis → ↓ intravascular volume → RAASRAASA blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system.Adrenal Hormones activation
↑ Na and H2O reabsorption in proximal tubuleProximal tubuleThe renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle.Tubular System → ↓ volume delivery to distal nephronNephronThe functional units of the kidney, consisting of the glomerulus and the attached tubule.Kidneys: Anatomy → antipolyuric response
Potassium-sparing diuretic: amilorideAmilorideA 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
Blocks epithelial sodium channelEpithelial sodium channelSodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure.Liddle Syndrome (ENaCENaCSodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure.Liddle Syndrome) in distal convoluted tubuleDistal convoluted tubuleThe portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule.Gitelman Syndrome and collecting ductCollecting ductStraight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla.Renal Cell Carcinoma → ↓ Na reabsorption
Reduces hypokalemiaHypokalemiaHypokalemia 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 associated with thiazideThiazideHeterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics.HyponatremiadiureticsDiureticsAgents that promote the excretion of urine through their effects on kidney function.Heart Failure and Angina Medication
Can be added to HCTZHCTZA 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 if the urine output is not reduced enough
Preferred for patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with reversible lithiumLithiumAn 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 AnomalytoxicityToxicityDosage Calculation
Beware: medical therapy (particularly combination therapy) can rapidly lower Na levels → seizuresSeizuresA seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
Additional measures:[6,18]
Avoidance of offending agent (most commonly lithiumLithiumAn 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 DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus
Table: Medication dosing for NDI[6,18]
Medication
Adult dose
Pediatric dose
HydrochlorothiazideHydrochlorothiazideA 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
25 mg once daily May increase to a maximum of twice daily, if needed
2–4 mg/kg/day divided in 2 doses
AmilorideAmilorideA 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
5 mg once daily
0.1–0.3 mg/kg/day
IndomethacinIndomethacinA 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)
DiabetesDiabetesDiabetes 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 resistanceResistancePhysiologically, 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 insulinInsulinInsulin 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 2Type 2Spinal Muscular Atrophy) or insufficient production of insulinInsulinInsulin 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 1Type 1Spinal Muscular Atrophy) resulting in hyperglycemiaHyperglycemiaAbnormally high blood glucose level.Diabetes Mellitus and resultant polyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation due to osmotic diuresisOsmotic diuresisVolume Depletion and Dehydration. Also presents with polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus due to increased diuresis. PatientsPatientsIndividuals 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 glucoseGlucoseA 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 glucosuriaGlucosuriaDiabetes Mellitus. PolyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation in diabetesDiabetesDiabetes 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 is a solute diuresis, contrasted with a water diuresisseen with CDI, NDI, or primary polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus.
Psychogenic polydipsiaPolydipsiaExcessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin.Diabetes Insipidus: excessive fluid intake without an identifiable organic cause, often seen in individuals with schizophreniaSchizophreniaSchizophrenia 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, anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorders, or anorexiaAnorexiaThe 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 polyuriaPolyuriaUrination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes.Renal Potassium Regulation and, in severe cases, hyponatremiaHyponatremiaHyponatremia 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 osmolalityOsmolalityPlasma osmolality refers to the combined concentration of all solutes in the blood.Renal Sodium and Water Regulation after fluid restriction, which differentiates it from DIDIDiabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia.Diabetes Insipidus.
References
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