2. Diabetes A metabolism disorder that causes excessive amounts of urine production.

3. Diabetes insipidus DI is a disorder resulting from deficiency of anti-diuretic hormone ( ADH ) or its action. It is characterized by the passage of copious amounts of dilute urine.

4. DI must be differentiated from other polyuria states (ex. Primary polydipsia, osmotic diuresis) Primary polydipsia : excessive water intake by mentally ill patients. ( phenothiazine) Osmotic diuresis : high blood sugar / mannitol

5. Anti-diuretic hormone ( ADH ) Octapeptide Also called vasopressin Synthesized in the supraoptic nuclei in the hypothalamus. realeased from the posterior pituitary

6. ADH functions Primary effect : 1)v2 receptors: -acts on the cells of distal tubules and collecting ducts of the kidneys -Promotes reabsorption of water -Enhances reabsorption of urea  increasing tonicity of the renal medulla  more water absorption 2) v1 receptors : -Acts on blood vessels causing vasoconstriction  Elevated BP ( balanced by inhibitory effect on sympathetic cardiac stimuli)

7. ADH regulation ADH is secreted as a result of: Plasma osmolality > 280 mOsm/l Hypovolemia ( to maintain tissue perfusion ) Stress During sleep

10. Types of DI Central DI : failure of the pituitary gland to secrete ADH. Nephrogenic DI : failure of the kidneys tubules to respond to circulating ADH. * In both types, the resulting renal concentration defect leads to the loss of large volumes of dilute urine (polyuria). This causes cellular and extracellular dehydration and hypernatremia.

11. 1.Post surgical. (Transient) 2.Idiopathic (autoimmune) 3.Tumors (i.e Craniopharyngioma) 4.Trauma 5.Infiltration 6.Vascular (hemorrhage) 7.Infection 8.Genetic defect: - Dominant (AVP gene mutation) - Recessive (Wolfram syndrome– association of diabetes insipidus with diabetes mellitus, optic atrophy, deafness) Causes of Cranial DI

12. Causes of Nephrogenic DI 1.Familial ( defect in vasopressin receptor gene or Aquaporin-2 gene) 2.Metabolic (low K+, High Ca++) 3.Drugs (lithium, demeclocyine ”Antibiotic”, Colchicine, Fluoride, Cidofovir ) 4.Chronic Renal Disease 5.Sickle cell disease

14. Signs and Symptoms Polyuria (5-20 L urine in 24 Hours.) Nocturia Polydipsia Dehydration develops in: -unconscious patients -impaired thirst mechanism * Mild Hypernatremia  If there is associated cortisol deficiency, then diabetes insipidus may not be manifest until glucocorticoid replacement therapy is given

15. Diagnosis If a patient presents with polyuria and polydipsia, consider the following first in the differential diagnosis: Diabetes Mellitus Diuretic use Diabetes Insipidus Primary polydipsia

16. Diagnosis Tests to do & their Findings: 24-h urine volumes > 3 L/day (5-15 L/day) Blood & dipstick urine for glucose → to distinguish it from DM Electrolyte levels → ↑Ca2+ ↓K+ in nephrogenic DI Electrolyte levels → ↑Na+ → Hypernatremia as dehydration develops

17. Diagnosis Urinalysis → dilute urine (Urine osmol < 100 mmol/L) & low urine specific gravity (SG < 1.005) Serum & Urine osmolalities → High plasma osmolality (Plasma osmol >295 mOsm/kg) with low urine osmolality ( U:P ratio < 2 ) Note: Normal plasma osmolality is 285-295 mOsmol/kg, and urine can be concentrated to more than twice this concentration. Significant DI is excluded if U:P osmolality ratio is more than 2:1, provided plasma osmolality is no greater than 295 mOsmol/kg. In DI despite raised plasma osmolality, urine is dilute.

18. Diagnosis ADH Level (not the test of choice ; takes a long time to get results) → Low ADH levels in central DI → Normal or elevated in nephrogenic DI Water deprivation test (dehydration test) Aims to test the ability of kidneys to concentrate urine for diagnosis of DI, and then to localize the cause (The test of choice which is required to make the diagnosis) Note: it is often difficult to differentiate primary polydipsia from partial DI

19. Water deprivation test Stage 1 Fluid deprivation (0-8 hours): for diagnosis of DI. start at 8:00 Empty bladder, then no drinks and only dry food. Weigh hourly. If >3% weight lost during test, order urgent serum osmolality. If >300 mOsmol/kg, proceed to stage 2. if <300 continue test Collect urine every 2h; measure its volume & osmolality Venous sample for osmolality every 4h Stop test after 8h (16:00) if urine osmolality >600 mOsmol/kg stop the test (DI is excluded)

20. Water deprivation test Stage 2 Differentiate cranial from nephrogenic DI proceed if urine still dilute-ie urine osmolality <6oo mOsmol/kg Give desmopressin 2μg IM. Water can be drunk now. Measure urine osmolality hourly for the next 4h.

21. Water deprivation test Response to water deprivation test Normal: urine osmolality >600 mOsmol/kg in stage 1 U:P ratio >2 (normal concentrating ability) Primary polydipsia: urine concentrates but less than normal, >400-600 mOsmol/kg Cranial DI: urine osmolality increases to >600 mOsmol/kg after desmopressin (if equivocal an extended deprivation test may be tried ( no drinking from 18:00 the night before)) * Nephrogenic DI: no increase in urine osmolality after desmopressin

23. MANAGEMENT

24. Treatment of Cranial DI Find the cause—MRI (head); test anterior pituitary function. Give Desmopressin (DDAVP), a synthetic analogue of ADH. Currently the DOC for long term therapy of CDI. It is more patent than Vasopressin & has longer duration of action (8-10 h vs 2-3 h).

25. DDAVP Usually given Intranasally, Oral formulation is also available but bioavailability is low and rather unpredictable. For comatose patients or during surgery DDAVP should be given I.M. The initial aim of therapy is to reduce nocturia, after that is achieved control of daily diuresis is the goal. Safe during pregnancy for both the mother and the fetus. Potential risks of DDAVP include water retention & hyponatremia, this can avoided by giving the Ideal dose: minimum daily dose required to control polyuria.

26. TREATMENT OF NEPHROGENIC DI Correction of underlying cause (If possible) and replace free water deficit. Provision of adequate fluids & calorie. Low-sodium & low-protein diet.

27. TREATMENT OF NEPHROGENIC DI If it persists, we give Thiazide Diuretics:  Bendroflumethiazide (5-10 mg/24h).  Add Amiloride (5-10 mg/24h) a potassium- sparing diuretic to prevent hypokalemia.  NSAIDS (e.g. Indometacin)(15mg 3 times daily) : carries a risk of reducing GFR.

28. TREATMENT OF NEPHROGENIC DI  Are we treating extreme diuresis with a diuretic ?? I.Thiazide diuretics will decrease distal convoluted tubule reabsorption of sodium and water causing diuresis. II.This will decrease plasma volume & GFR. III.Enhancing the absorption of sodium and water in the proximal nephron. IV.Less fluid reaches the distal nephron, so overall fluid conservation is obtained.

29. Emergency Management Do urgent plasma U&E, and serum and urine osmolalities. Monitor urine output carefully and check U&E twice a day initially. IVI to keep up with urine output. If severe hypernatremia, do not lower Na+ rapidly as this may cause cerebral edema and brain injury. If Na+ is ≳ 170, use 0.9% saline initially—this contains 150mmol/L of sodium.

31. Thank you