Diabetes Insipidus (Wonders)

Physiology of Water Homeostasis: Vasopressin

Arginine vasopressin=antidiuretic hormone=ADH=AVP=vasopressin -Peptide hormone produced in the hypothalamus and stored in the posterior pituitary for release -*Primary determinant of body water excretion* -Release of ADH regulated by baroreceptors, osmoreceptors, and ATII -AVP acts on 2 receptors: 1. V1: vasoconstriction, enhances corticotropin release and renal prostaglandin synthesis - Meh. 2. *V2: mediates antidiuretic response in kidneys* -ADH has many mechanisms to maintain water - many ways body regulates homeostasis but main way is vasopressin -As said before, hypo makes ADH, stored in posterior pituitary - then told by hypo to be secreted -V1R causes vasoconstriction, V2R causes fluid reabsorption (increased resistance and BV leads to increased arterial pressure!)

Pharmacologic Tx of DI

Central DI: 1. Desmopressin 2. CBZ 3. Chlorpropamide 4. Indapamide 5. Thiazides Nephrogenic DI: 1. Desmopressin 2. Amiloride 3. NSAIDs 4. Thiazides Dipsogenic DI: 1. Ice chips/sour candies Gestational DI: 1. Desmopressin

CDI Tx: Desmopressin Acetate - Know Dosage Forms!

Desmopressin acetate (DDAVP, DDAVP Rhinal Tube, Stimate (nasal spray)) *MoA: synthetic analog of ADH arginine vasopressin* -Increases cAMP in renal tubular cells, increasing AQP and allowing reabsorption of water FDA Indications: 1. Neurophyophyseal diabetes insipidus (CDI) 2. Hemophilia A and Von Willebrand dz 3. Primary nocturnal enuresis Offlabel Uses: 1. Hemorrhage 2. Nocturia 3. Urinary incontinence 4. Urine concentration test -Excretion primarily through urin - PK - prolonged halfife in renal impairment ADRs: 1. Hyponatremia 2. Hypoosmolality 3. Water intoxication syndrome 4. Seizure 5. MI 6. Dizziness 7. Chills 8. Flushing Caution: 1. Hx of CVD 2. Conditions with associated fluid/electrolyte imbalance 3. Mild renal impairment may increase toxic rxns *CI: hyponatremia, CrCl<50mL/min* *Available as: oral tablet, nasal soln, nasal spray, IV soln* Pregnancy Category: B DDIs: 1. Analgesics 2. NSAIDs 3. SSRIs 4. TCAs 5. CBZ 6. Chlorpromazine -Titrate to adequate urinary concentration to prevent nocturia, daily urine volume of 1,5-2L, a serum Na of 137-142 mEq/L -Followup measure serum Na q3-4days during initial period then q2-4mos

Overview

Diabetes Insipidus (DI) is NOT the same as DM -Both cause excess urine output -DM urine tastes sweet due to glucose, DI urine is tasteless Epidemiology: -3-4 in 100k; no gender or ethnic differences in incidence -X-linked nephrogenic DI is very rare but males are at greater risk

Focus

Diabetes Insipidus: 5 questions a. Recognize different causes of diabetes Insipidus and the preferred treatments b. MOA of treatments

Differentiating between the Diabetes (DI vs. DM)

Diabetes insipidus: 1. Pituitary disorder (vasopressin disorder) 2. Deficiency or decrease in response to ADH 3. No rise in BG 4. Urine osmolality very low (dilute) 5. Enormous urine output 6. No ketone bodies Diabetes mellitus 1. Pancreatic disorder (insulin disorder) 2. Deficiency or decrease in response to insulin 3. Rise in BG 4. Urine osmolality normal 5. Increased urine output (nowhere near as much as DI) 6. Ketone bodies when uncontrolled

Tests to Diagnose and Monitor

Diagnosis: 1. History and physical exam 2. Urinalysis and blood testing 3. Fluid deprivation and desmopressin challenge 4. Magnetic resonance imaging (MRI) - not really dx but for etiology

NDI Tx: Thiazides

Hydrochlorothiazide, chlorthalidone -Enhances sxs relief -Like CDI, it's given commonly along with desmopressin

NDI Tx: NSAIDs

Medications: ibuprofen, naproxen, indomethacin, diclofenac MoA: NSAIDs inhibit renal prostaglandin synthesis (PGs antagonize action of ADH), increasing concentrating ability of the kidneys Indomethacin has been shown to have the greatest effect compared to ibuprofen or other NSAIDs ADEs: HA, vomiting, postoperative hemorrhage, dizziness, pruritus Pregnancy Category: C DDI: CYP2C19, 2C9

NDI Tx: Amiloride

MoA: closes Na channels in the luminal membrane of the collecting tubules, thus blocking the reentry of filtered Li into the cells (*most beneficial for Li-induced DI*) Dose: 5-10mg daily FDA indications: CHF, HTN Offlabel uses: Edema - *beneficial in pts with reversible Li-induced nephrogenic DI* ADEs: N/V/D, HA, hyperkalemia (K-sparing), encephalopathy Pregnancy Category: C Interactions: Meds that may lower BP or increase K+

CDI Tx: Carbamazepine

MoA: increases renal sensitivity to ADH effect; in vivo, decreased urinary volume and increased urinary osmolality by increasing AQP2 expression (help kidneys become more sensitive) FDA indications: 1. Seizure 2. BPD 3. Trigeminal neuralgia 4. Glossopharyngeal neuralgia -Alternative uses: diabetes insipidus, restless leg syndrome Dose: 100-300 mg orally BID ADEs: lots of S/E - last resort Pregnancy Category: D -Many DDIs -Special note: *increased risk of rash in patients with genotype HLA *1502**. Recommend screening pts of Asian descent prior to initiation.*

CDI Tx: Indapamide

MoA: unkown - may increase urinary osmolality and decrease serum osmolality via hypovolemia-induced proximal sodium and water reabsorption FDA Indications: HTN, HF Alternative uses: Ca nephrolithiasis ADEs: agitation, anxiety, dizziness, datigue, HA, irritability, lethargy, malaise Pregnancy Category: B DDI: BP lowering agents (like thiazides)

Questions

NSAIDs inhibt PG synthesis, allowing kidneys to concentrate urine via ADH Desmopressin preferred route is IN via nasal spray pump due to bioavailability - avoid if nose problems

CDI Tx: Desmopressin Acetate - Oral Tablet

Oral Tablets: 0.1 and 0.2 mg tabs -Initial dosing: 0.05 mg PO BID (should be individualized) -Antidiuretic effect occurs 1h after ingestion with peak 4-7h after (need multiple daily dosing) -*Low F compared to intranasal - so IN is preferred route* -Ideal for pts with chronic rhinitis or fear of needles -Fluid restriction should be observed

Types of Diabetes Insipidus and Treatment Modalities

Previous tx: used to give pts pituitary from cattle - had vasopressin in it Non-Pharmacological Tx: 1. *Hydration!*: don't be dehydrated leading to seizures, cardiac collapse, etc. 2. Diet and nutrition doesn't play a role in causing or preventing diabetes insipidus 3. Eat a low solute (Na and protein) diet - because if you need to excrete a lot of these then you'll lose even more fluid doing so

CDI Tx: Chlorpropamide

Really potent - can be used for T2DM (offlabel: DI) but not well tolerated due to S/E

Physiology of Water Homeostasis: Thirst

Thirst: the physiologic urge to drink water -*4 major stimuli to thirst*: 1. Hypertonicity: cellular dehydration acts via osmoreceptors in the hypothalamus (osmoreceptors sense water and serum concentration - sends out signals for thirst) 2. Hypovolemia: low volume is sensed from low BP via baroreceptors in the large veins and right atrium 3. Hypotension: sensed via low pressure in baroreceptors in the carotid sinus and aorta arteries 4. Angiotensin II: produced when the kidneys release renin (i.e. response to renal hypotension) - ACEIs and ARBs work on these -AHHH

Physiology of Water Homeostasis: *Deprivation Test Interpretation*

Urine osmolality: 1. *If >750 after fluid deprivation, and doesn't change after demopressin (concentrated), then it's primary polydypsia* 2. *If <300 after fluid deprivation, and increases to >750 after desmopressin (concentrated via desmopressin), then its central DI* 3. *If it's <300 after fluid deprivation and desmopressin (didn't respond to ADH), then it's nephrogenic DI*

Physiology of Water Homeostasis: MRI

-*Cannot diagnose diabetes insipidus* -Can show if the pt has issues with the hypothalamus or pituitary gland though (tumor, swelling, injury)

Central Diabetes Insipidus: Causes

-*Most common form of DI, hyposecretion of ADH* Acquired CDI: damage to the pituitary disrupting the storage and release of ADH -Principal Causes: 1. Idiopathic (20-50%): most common 2. Tumors of the brain or pituitary (2nd most common) 3. Cranial surgery 4. Head trauma 5. Other causes: stroke, infection, inflammation, pituitary surgery, hypoxic encephalopathy Hereditary/Familial CDI (10%): 1. 55 mutations in familial neurohypophyeal CDI, mostly autosomal dominant pattern of inheritance 2. Mutations in AVP-NP2 gene - mutant prohormone that is toxic to neuron

NDI Tx: Desmopressin Acetate

-*Used for sxs relief! Kidneys might respond a little* -Nasal soln preferred over oral tab, nasal spray, IV soln (same as before) CIs: hyponatremia, CrCl<50mL/min

Dipsogenic Diabetes Insipidus

-Also called *primary polydypsia* -*A defect or damage in the thirst mechanism in the hypothalamus* -Abnormal increase in thirst and fluid intake suppressing ADH secretion and increasing urine output Treatment: *NONE currently 1. Ice chips/sour candies to suppress thirst*

Nephrogenic Diabetes Insipidus: Causes

-Decreased kidney response to ADH Acquired: 1. Metabolic (hypokalemia, hypercalcemia) 2. Renal dz e.g. sickle cell dz, amyloidosis 3. Pregnancy (transient) 4. Hyperglycemia (osmotic diuresis) 5. *Drug-induced: -Lithium (most common!)* -Foscarnet -Clozapine -Amphotericin B -AMGs -Didanosine -Orlistat -Cidofovir Hereditary, Familial: 1. Rare, X-linked disorder (males): mutation in AVPR2 - resistance to ADH 2. Autosomal recessive/autosomal dominant - mutation in AQP2 gene - also very rare

Prognosis

-Depends on underlying cause of disorder; if genetic, no cure but it can be transient -No severe or longterm complications if managed properly -*Pts tend to have normal ECF volume as long as they are conscious and have free access to water* -Typically have serum Na concentration of *141-145 mEq* when normal is 135-145 (high end of normal) -*Normally have daily urine volume >3L* when normal is 800-2000mL (so need to replace that water)

Pathophysiology

-Disruption of the body's mechanism for maintaining water homeostasis -Caused by *hyposecretion or response failure to antidiuretic hormone (ADH)* -ADH is secreted from the posterior pituitary gland -ADH=arginine vasopressin -ADH non-response or non-secretion leads to excessive free water loss (polyuria due ADH not reabsorbing) and an increase in thirst accompanied by free water intake (polydypsia) -Urine output ranging from 4L to 30L in a 24h period leading to dehydration *What is normal urine output*? 1. Polyuria is characterized by age -At birth: ~150mL/kg/24h -Age<2: 100-110 mL/kg/24h -Age>2: 40-50mL/kg/24h -Decreases with age - this polyuria is much higher than DM polyuria

CDI Tx: Desmopressin Acetate: Injection Soln

-Given IV or SQ -Antidiuretic effect occurs 30 mins after administration with peak after 1.5-2h ADRs: 1. Anaphylaxis 2. Can change BP Clinical Pearl: 1. Parenteral dose (IV/SQ) is 1/10th IN dose 2. Refrigerated

Physiology of Water Homeostasis

-Maintenance of water balance in healthy individuals is controlled by three inter-related factors: *1. Thirst 2. ADH (vasopressin) 3. Kidneys* 1. When too much salt or sweating, water content of the blood is LOW 2. The brain senses this and produces MORE ADH 3. ADH puts more aquaporin channels to reabsorb water in the kidney 4. Reabsorption of water via ADH causes LOW urine output (small volume of concentrated urine) 5. Water content of the blood returns to normal Conversely, 1. When too much water drunk by pt, water content of the blood is HIGH 2. Brain produces LESS ADH in response 3. Less ADH means less AQP channels so less water reabsorption; therefore more water excretion 4. Urine output is HIGH (large volume of dilute urine) 5. Water content of the blood returns to normal

CDI Tx: Desmopressin Acetate - Nasal Spray Pump/Rhinal Tube Delivery System

-Nasal Pump=Stimate -Dosing is individualized and adjusted based on pattern of response -Antidiuretic effect occurs 15-30 mins after administration with peak after 1h (so multiple daily dosing) -CI: nasal scarring, edema, or other nasal dz -Clinical Pearl: 1. *Nasal spray pump ONLY delivers dosing in multiples of 10mcg, rhinal tube delivery system preferred for atypical regimens* 2. *Stimate Nasal Spray: each 2.5mL bottle delivers 25 sprays of 150mcg each; inform pt to discard bottle after 25 sprays* -Prime Stimate 4 times before 1st use -Make sure to tilt pump so drawing up from deepest part of container -One dose in one nostril (if two doses, use other nostril for 300mcg) -Prime if haven't been used for a week DDAVP Rhinal Tube: *keep refrigerated all times - 3 weeks stability if closed*

Gestational Diabetes Insipidus

-Occurs only during pregnancy - more urine output -*Enzyme (vasopressinase) produced by the placenta increases the metabolism of ADH in the mother* -ADH to replace the ones destroyed by vasopressinase - *the desmopressin acetate isn't broken down by the baby vasopressinase* Treatment: 1. Desmopressin acetate (IN or SQ) -*Resistant to degradation by vasopressinase* -No adverse maternal or fetal effects from desmopressin use during pregnancy reported (Cat B) -*Dose is usually slightly higher than those used to treat central DI in nonpregnant pts* Tx Monitoring: 1. Daily wt monitoring 2. Urine output hourly (report UOP>200mL/h) 3. Serum Na, K, Ca 4. S/Sxs of dehydration

Physiology of Water Homeostasis: Kidneys

-Vasopressin increases water permeability in the collecting duct and distal convoluted tubule in the kidneys by inducing the *translocation of the aquaporin water channels* 1. AQP channels are normally located in vesicles near the basolateral membrane of cells in collecting duct 2. Once vasopressin stimulates V2 receptors, the AQP translocates to the basolateral membrane so that water is reabsorbed through the cell (goes through apical side too but those water channels are always there) MoA: ADH binding to V2 cuses cAMP and signal cascade to cause AQP2 to translocate

Central Diabetes Insipidus: Treatment

1. *Desmopressin: 1st line therapy due to it being caused by not enough ADH* 2. Thiazides 3. Carbamazepine 4. Indapamide 5. Chlorpropamide

Treatment Goals

1. *Treat the underlying cause*: remove the tumor, remove offending med, etc. 2. Correct serum Na to 145 mEq/L -Correct slowly or if too fast, then it can cause cerebral edema -Prevent recurrence of hypernatremia and correct hypercalcemia and hypokalemia if necessary 3. Resolve sxs associated with hypovolemia: -Fluid resuscitation if dehydrated (administer fluids at a rate no greater than 500-750mL/h; aim at reducing serum Na approximately 0.5mEq/L/h 4. Alleviate sxs of polyuria and nocturia (decrease amt of urine excreted)

*Types of DI - Know!*

1. Central: hyposecretion of vasopressin (can be hyposecretion (partial central DI) or NO secretion (complete central DI) 2. Nephrogenic: kidneys inappropriately responding to vasopressin (producing enough ADH that works but kidney doesn't recognize the ADH) 3. Dipsogenic (primary polydypsia): disorder of the thirst mechanism (doesn't have to deal with vasopressin - people drink too much so excrete lots of urine) 4. Gestational: fetal placenta secreting vasopressinase that destroys the mother's vasopressin - net decrease of ADH in the body (returns to normal after birth)

NDI Tx: Treatment Options

1. Desmopressin 2. Amiloride 3. NSAIDs 4. Thiazides

CDI Tx: Thiazides

1. Hydrochlorothiazide 2. Chlorthalidone -Adjunct really, desmopressin is best but these can be combined with others is desmopressin isn't tolerated *MoA: paradoxical reaction - thiazides decrease distal tubule Na reabsorption that increases urinary excretion which leads to low extracellular volume - this in turn increases proximal Na and water reabsorption that decreases urine output* -Can be used to enhance sxs relief - often given along with desmopressin FDA Indications: edema, HTN Off-label use: Li-induced diabetes insipidus (most common med DI) ADEs: monitor for electrolyte imbalance

Diagnosis: History and Physical Exam

1. Medication list (medication-induced?) - matches with onset of sxs? 2. FHx 3. Physical exam: -Dehydration (how severe? need hospitalization?) -Bladder enlargement

Physiology of Water Homeostasis: Deprivation Test and Desmopressin Challenge

1. Miller-Moses test: depriving pt of water to see how much is actually excreted -24-h urine volume test to confirm polyuria -Used to ensure adequate dehydration and subsequnt stimulation: basically ask pt not to drink to induce dehydration and then give them desmopressin to distinguish the types of DI -*Helps to distinguish between causes of polyuria: primary polydypsia vs. central DI vs. nephrogenic DI* Deprivation Test: 1. Fluid cessation 2. Wait 2-12h 3. Measure urine volume and osmolality q12h; measure plasma Na and osmolality q12h 4. Monitor for endpoints (~7+ h) Endpoints: 1. Urine osmolality>600mOsm/kg: *NORMAL response, ADH intact* - it can be primary polydypsia (just drinking too much because body can concentrate urine) 2. Urine osmolality remains steady, plasma osmolality rising (due to con't high excretion)-> desmopressin challenge, give ADH 4mcgSQ -> monitor urine osmolality and volume q30min over next 2h (if continue to lose water, see if response) 3. Plasma Na>145mEq/L or plasma osmolality 295-300mOsm/kg - give them free water and try again -*Basically if they concentrate urine after dehydration - primary polydypsia -If they don't concentrate, and you challenge with ADH, and they respond, then it's central DI -If they don't respond to ADH, it's nephrogenic DI* Terminate the test if one of the following is attained: 1. Urine SG>=1.020 2. Urine osmolality >=600 mOsm/kg 3. Plasma osm>295-300mOsm/kg or plasma Na>145mEq/L 4. Pt has lost >5% starting BW or exhibits signs of volume depletion 5. If a period of water restriction reaches: -6h in infants<6mos old -8h in children 6mos-2yo -12h in children and adults>2yo

Physiology of Water Homeostasis: Urinalysis and Blood Testing

1. Physical and chemical examination of urine (check for glucose) 2. Blood testing (BG, plasma osmolality, electrolytes - chem7 panel) 3. Can rule out primary polydypsia (type of DI that doesn't have any dysregulation in ADH) Examine urine osmolar excretion rate: 1. If urine >1000 mOsm/d: -Osmotic diuresis secondary to hyperglycemia OR -Urea, mannitol, high Na load 2. If urine <1000 mOsm/d: -*Primary polydypsia: serum Na<140mEq/L and urine osmol <100 mOsm/kg* OR -*Diabetes insipidus: serum Na>140 mEq/L and urine osmol<100 mosm/kg* Basically, if urine is low osmolarity, then can be primary or polydypsia - to tell the difference, polydypsia has low Na levels while DI has high Na levels -Primary polydypsia (drinking a lot so diluting Na levels so low even if excreting); DI: just excreting so still high Na

Clinical Presentation of DI

1. Polyuria -Dilute urine (SG<1.006) ->3L/24h (<300mOsm/kg); up to 20L 2. Polydypsia: extreme thirst 3. Nocturia -Enuresis in children 4. Hypernatremia/dehydration: lethargy, altered mental status, hyperreflexia, seizure (dehydrated and blood very concentrated) Sxs in infants/children: 1. Crying 2. Irritability 3. Vomiting 4. Diarrhea 5. Growth retardation 6. Hyperthermia 7. Wt loss Serious Complications: 1. Hypernatremia 2. Tachycardia, hypotension -> CV collapse