A 12-year-old boy presents with a 2-month history of polyuria and polydipsia.

Transcription

1 A 12-year-old boy presents with a 2-month history of polyuria and polydipsia. Laboratory studies confirm a diagnosis of diabetes insipidus. On review of systems, he has no headaches, although he reports ear pain with purulent discharge and occasional leg pains. You note a rash on his wrists. Serum and cerebrospinal fluid concentrations of α-fetoprotein and hcg are undetectable. A trial of DDAVP results in successful treatment of the diabetes insipidus.

2 Which one of the following would confirm the cause of the diabetes insipidus? [ A ] MRI of the pituitary showing an ectopic posterior pituitary [ B ] Biopsy of the rash showing an accumulation of macrophages [ C ] CT showing calcifications in the region of the sella [ D ] Fluorescent in situ hybridization test revealing a V2 receptor defect [ E ] Vasopressin antibody measurement showing elevated antibody levels

3 DI / SIADH / CSW Salt and Water 101 Michael Haller, MD Fellow s Core Conference

4 Objectives 1) Physiology of Osmolarity and Volume 2) Ontogeny Arginine Vasopressin (AVP) 3) Synthesis / Processing / Storage of AVP 4) Secretion and Transport AVP 5) V2 Receptor Action 6) Define DI, SIADH, CSW 7) Discuss Normal Fluid Requirements 8) Case Discussions

5 Physiology of Volume and Osmolarity Balance Two SEPARATE systems that function to ensure Na and normal fluid status Renin / Angiotensin / Aldo -Modulates Na Retention -Restores Intravascular Volume Status - Suppressed once euvolemic Vasopressin / Thirst - Moderates water ingestion and retention - Restores Osmolarity - Activated to restore volume -When suppressed, allows Na loss in urine

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8 Stimuli for Vasopressin Release l Serum Osmolality l Depleted Intravascular Volume l Nausea l Nicotine l Hypoglycemia l Adrenal Insufficiency (increased CRH secretion > increased ADH secretion and cortisol directly inhibits ADH secretion)

9 ADH Secretion Osmoreceptors Paraventricular nucleus NaCl Supraoptic nucleus (expression of ADH genes) Vasopressin & Neurophysin II POSTERIOR PITUITARY Vasopressin Neurophysin II

10 Processing of Vasopressin Pre-pro-vasopressin H 2 N - Signal peptide H 2 N- -lys-arg- -lys-arg- - COOH Processing in rough ER (loss of signal peptide) Pro-vasopressin H 2 N- -lys-arg- -lys-arg- -COOH Processing in Golgi hydrolysis of lys-arg bonds Vasopressin Neurophysin II ADH carrier protein Glycoprotein

11 Structure of Antidiuretic Hormone AVP S S O Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-C- NH 2 Antidiuretic hormone (ADH; vasopressin) Promotes water resorption from distal renal tubules ddavp S S O Cys-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-C-X Note the removal of the amino group and addition of the D- to Arginine to for ddavp 1-deamino-8-D-arginine vasopressin

12 Stimulus-Secretion Coupling of Vasopressin Osmolality or Volume É Cell Body Granules fuse with the surface Preganglionic Fiber Vasopressin Neurophysin II Ach Action Potential Ca 2+ Depolarization Exocytosis of Vasopressin

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14 Vasopressin Receptors l V1a Smooth muscle, hepatocytes, platelets. Induces vasoconstriction and glycogenolysis l V1b (V3) Pituitary Corticotrophs. Increases ACTH release l V2 Renal Collecting ducts, periglomerular tubules, vascular endothelium. Activates adenylyl cyclase

15 Kidney Distal Tubule Cell Vesicles move to and fuse with apical membrane Aquaporin-2 H 2 O H2O H2O Adenylyl cyclase G s protein Vasopressin V 2 vasopressin receptor Basolateral membrane Phosphorylated aquaporin-2 camp ATP Cytoplasm ADP ATP PKA (active) camp PKA camp camp (inactive) camp Protein Kinase A Pathway H 2 O H 2 O H 2 O H 2 O H 2 O Apical membrane URINE

16 Vasopressin Metabolism l Half life is 5 to 10 minutes l Degraded by vasopressinase l Pregnancy increases vasopressinase so normally women make more AVP to compensate l ddavp has antidiuretic effect for 4-24 hours depending on dose/absorption

17 Since we know normal physiology.....lets Discuss Defects

18 Diabetes Insipidus l Lack of adequate AVP secretion in response to increase in osmolarity l High volume, dilute UOP l Dehydration l Hypernatremia l Need Specific Criteria..

19 Diabetes Insipidus: One Set of Diagnostic Criteria Serum sodium greater than 145 meq/l AND Four of the following criteria: Urine specific gravity < Urine output > 4 ml/kg per hour Plasma osmolality > 300 mosm/kg Urine osmolality < 300 mosm/kg Urine Sodium < 20 meq/l Also can use weight loss

20 Causes of Central DI l Trauma, Surgery l Anatomical Defects Septo-Optic Dysplasia l Tumor Mass effect l DIDMOAD (Wolfram) AR or Mitochondrial l Familial AD - (pre-pro AVP gene defect) l Infiltrative (Histiocytosis) l Infectious (TB) l Increased Metabolism (Pregnancy)

21 Causes of Nephrogenic DI Genetic l V2 Receptor Mutation - X-Linked l Aquaporin Mutations - Autosomal Recessive l Aquaporin Mutations- Dominant (RARE) Acquired l Lithium (interferes with camp) l Foscarnet, Clozapine, Ampho, Rifampin l Hypercalcemia, Hypokalemia

22 Water Deprivation Test Water Deprivation Phase l Obtain initial weight + vitals + duration of pretest water restriction l Place IV, and foley if needed l Baseline serum Na, vasopressin, urine osmolality and urine SG. l Begin water deprivation l Measure and record hourly: - Weight, HR, BP, UOP and specific gravity. - Serum sodium and urine osmolality.

23 Water Deprivation Test l If Na < 145, urine osmolality<600, and there is no clinical evidence of significant, symptomatic hypovolemia, continue water deprivation. l If urine osmolality is above 1000, or above 600 and stable over 2 measures, stop test. Patient does NOT have diabetes insipidus. l If serum osmolality is above 300 and urine osmolality is below 300, the patient HAS diabetes insipidus. Proceed to Vasopressin response phase

24 Vasopressin Response Collect blood for vasopressin Administer Pitressin, 1 unit/m2, SQ Limiting fluid intake to the volume of urine produced during the entire testing period (water deprivation and vasopressin response) 30 and 60 minutes after Pitressin, measure vital signs, urine output, and urine specific gravity, and send urine to lab for osmolality. 2X increase in urine osmolality, think central DI < 2 X increase in urine osmolality, think nephrogenic DI.

25 Nephrogenic DI Therapy l Thiazide Diuretics - decrease of urine to normal or only slightly elevated values (e.g. typically from 8 10 liters to 4 liters or less per day) l Renal sodium loss causes EC volume contraction > lowered GFR > increased proximal tubular sodium/water reabsorption.less water (and solute) gets to the distal tubule and collecting duct l Indomethacin reduces free water excretion l Low Osmotic Load

26 Central DI Therapy l No antidiuresis and water will always work if the patient has intact thirst and access to water OR l Vasopressin Drip 1.5 milliunit / kg / hr l Rhinal Tube or Nasal Spray 5-10mcg l ddavp mg qd to tid l Always start with a little and work up to effective dose

27 What are Maintenance H2O Requirements? Losses per day: - Repiratory and Skin: 500 ml/m2/d - Gastrointestinal: 100 ml/m2/d - Urine ( Osm): 1150 ml/m2/d Gains: - Water of Oxidation: 250 ml/m2/d Net: 1,500 ml/m2/d

28 Losses if Anti-Diuresed? Urine output less than 1-2 cc/kg/day - Urine: 400 ml/m2/d - GI: 100 ml/m2/d - Respiratory and Skin: 500 ml/m2/d Net: 1,000 ml/m2/d *Total insensible losses*

29 How Much H2O Do I Give in DI?? Option 1 No Vasopressin Replace normal insensible losses = 1 L/m2/d with D5 ¼ NS Replace excess UOP with D5W up to 4 L/m2/d

30 How Much H2O Do I Give in DI?? Option 2 Vasopressin l Give IV Pitressin to provide complete antidiuresis (1.5-2mU/kg/kr) l Restrict Fluids to ONLY insensible losses = 1 L/m2/d l OUR PROTOCOL uses this option

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32 SIADH Development of SIADH should be considered if two of these four criteria are evident: 1. Urine specific gravity greater than Serum Osm less than Urine output less than 1 ml/kg/hr 4. Serum sodium concentrations decreases more than 10 meq/l in 10 hours

33 Causes of SIADH CNS: Trauma, bleed, meningitis Cancer: Small Cell, Lymphoma, Ewings Pulmonary: Pneumonia, Abscess Meds: ACE, Cisplatin, Vinblastine, Haldol, Clofibrate, Fluoxetine, Tricyclics

34 SIADH Therapy l Restrict Fluids to insensible losses l ~1000 ml / m2 / day (insensible losses) l ~ 2/3 maintenance Fluid requirement depends largely on solute load.

35 SIADH -Therapy Vaprisol (Conivaptan) l High affinity for the V1A receptors in vascular smooth muscle and for the V2 receptors in the collecting ducts of the kidneys l Blocks the V2 receptors in the collecting ducts of the kidneys, resulting in aquaresis the electrolyte-sparing excretion of free water

36 Cerebral Salt Wasting Consider CSW if: 1. Urine sodium loss greater than 150 meq/l and 2. UOP is increased 3. Serum Na is falling 4. Hypovolemia 5. Elevated Atrial or Brain Naturetic Peptide (ANP or BNP)

37 CSW Treatment Preferred method is PO salt! 1 tsp of table salt is 100 meq Na Maintenance is 3-4mEq/kg/d but with CSW they will pour salt into urine! Can use NS or 3%NS IV if needed Push 3%NS only if seizing Acute reversal of acutely low Na, not at risk for pontine demyelinosis

38 Cases l 8 year old with presents peripheral field vision loss. l MRI shows large craniopharyngioma pushing down on optic chiasm l Pre op labs Na 143 l TSH < 0.01 miu/l, FT4 0.4 ng/dl l 8 AM Cortisol 3.2 l Prolactin 48

39 Post-Op l On way to recovery room Dr. Pincus calls and says I was a very bad boy.. l Pituitary stalk definitely transected l What do you do!?!?!

40 Prepare for the worst, hope for the best.. l Check Na q 1-2 hours l Exact I s and O s l Urine SG, Osmolality q 2 hours l Serum Osmolality q 2 hours l When DI Criteria are met, initiate therapy per new protocol But understand this is just ONE way to do this.

41 Labs 3 hours later - DI l Serum Na 159 l Urine Osm 140 l Serum Osm 345 l Urine Na <20 l Urine SG Start Vasopressin drip at 1.5mU/kg/hr and increase until UOP less than 2 cc/kg/hr Provide insensible losses with ~2/3 maintenance Replace fluid deficit slowly

42 24 hours later DI Controlled l Na 145 l Urine Osm 300 l Serum Osm 285 l Urine Na 45 l Urine SG All is good

43 72 hours later - SIADH Should not really see this if completely antidiuresed in first place but just to discuss. l Na 135 l Urine Osm 650 l Serum Osm 260 l Urine Na 70 l Urine SG l UOP < 1cc/kg/hr Looks like SIADH

44 SIADH l Stop Vasopressin (if not already maximally antidiuresed) l Restrict Fluids is key l Follow labs and UOP closely

45 48 hours later DI is Back l Na 150 l Urine Osm 250 l Serum Osm 315 l Urine Na < 20 l Urine SG Restart Vasopressin

46 24 hours later Stable again l Na 140 l Urine Osm 295 l Serum Osm 285 l Urine Na 35 l Urine SG Able to take PO now so switch to ddavp nasal spray. Back to regular fluid intake

47 24 hours later CSW or Too l Na 134 l Urine Osm 395 l Serum Osm 280 l Urine Na 112 l Urine SG l ANP / BNP elevated Much ddavp? Can be tough to tell.. More UOP than expected for antidiuresis and high Urine Na so suspect CSW Replace Urine Na loss as needed to maintain normal Na 1 tsp Na (100mEq per tsp) added to each feed (infant)

48 24 hours later Stable again l Na 140 l Urine Osm 495 l Serum Osm 285 l Urine Na 150 l Urine SG Continue ddavp and Na supplementation until urine Na normalizes. CSW can last days to weeks to months.

49 Questions????

50 High, Low, or Normal?????

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