Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

hyponatremia treatment guidelines: 2012 and beyond Joseph G. Verbalis, MD Professor of Medicine and Physiology Chief, Endocrinology and Metabolism Director, Georgetown-Howard Universities Center for Clinical and Translational Science Georgetown University Washington, DC USA

Joseph G. Verbalis: disclosures consultant: Astellas, Ferring, Cardiokine, Otsuka advisory board: Astellas, Otsuka data safety board: Ferring grant support: NHLBI, NIA, NCATS, Otsuka

1

Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

body fluid compartments water is the largest component of our body; since the major determinant of body water is AVP-regulated water excretion by the kidneys, it follows logically that AVP must be the most important hormone in the body

AVP stimulation and effects

hyperosmolality, hypovolemia, angiotensin II

+

–

baroreceptors, natriuretic peptides

AVP V1a Receptors vasoconstriction

V2 Receptors renal H2O reabsorption

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

receptor-mediated effects of AVP receptor subtype site of action vascular smooth muscle cells platelets V1a lymphocytes and monocytes liver

activation effects vasoconstriction platelet aggregation cytokine release glycogenolysis

V1b

anterior pituitary

ACTH and β -endorphin release

V2

renal collecting duct principal cells

free water absorption

AVP

Collecting Duct Cell

AQP3

H2O ATP GTP (Gs) AVP V2 Receptor

AQP2 cAMP

Exocytic Insertion

PKA AQP2

AQP4 Basolateral membrane

Recycling vesicle

Collecting duct

Vasa recta

AVP regulation of water reabsorption from renal tubular cells

H2O

Endocytic Retrieval

Luminal membrane

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

prevalence of dysnatremias at initial presentation to a health care provider (data from 303,577 samples on 120,137 patients available for analysis) 30

Acute hospital care Ambulatory hospital care Community care

28.2

Prevalence (%)

25 21

20 15 10

7.2

5 0

1.43

0.49 0.17 0.03

Na < 116

Na < 135

0.53 0.72

0.06 0.01 0.01

Na > 145

Na > 165

Hawkins. Clin Chim Acta 337:169-172, 2003

relationship between hospital admission serum [Na+] and in-hospital mortality

Predicted Probability of In-Hospital Mortality

0.20

0.15

0.10

0.05

110

115

120

125

130

135

140

145

Admission Serum [Na+] Concentration (mEq/L)

Wald et al. Arch Intern Med 170:294-302, 2010

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

chronic hyponatremia is also associated with increased adverse outcomes

increased mortality over a 12-year period of outpatient follow-up

significantly increased risk of fracture

Hoorn et al. J Bone Mineral Res 26:1822-8, 2011

hyponatremic disorders hypovolemia/dehydration polydipsia SIADH extracellular fluid volume expansion congestive heart failure hepatic cirrhosis bilateral ureteral obstruction

5

Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

hyponatremia can be caused by dilution from retained water, or by depletion from electrolyte losses in excess of water

6

Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

U-Na+ excretion for identification of EABV with diuretics

without diuretics

Fenske W. et al, JCEM 92:2991- 2997, 2008

SIADH: essential criteria • •

true plasma hypoosmolality

• •

clinical euvolemia, no diuretic therapy

•

normal thyroid, adrenal and renal function

urine concentration inappropriate for plasma osmolality (Uosm > 100 mOsm/kg H2O) absent renal sodium conservation (UNa > 30 mmol/L)

modified from Bartter & Schwartz, Am J Med 42:790-806, 1967

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

Plasma Vasopressin, pg/mL

plasma AVP levels are inappropriately elevated in >95% of patients with SIADH 11 10 9 8 7 6 5 4 3 2 1 0

Normal Range

230

240

250 260 270 280 290 300 Plasma Osmolality, mOsm/kg H2O

310

Robertson et al. Am J Med 72:339, 1982

stimuli to AVP secretion related to fluid independent of homeostasis: fluid homeostasis: hyperosmolality nausea hypotension hypoxia hypovolemia hypercarbia angiotensin II hypoglycemia stress: cytokines physical activity

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

plasma osmolality (mOsm/kg H2O) 296

thirst osmotic threshold

plasma AVP (pg/ml) 9

294

8

292

7

290

6 5

288 286

4

urine osmolality (mOsm/kg H2O) 1000 800

250 500

3 600

AVP osmotic threshold

maximal urine excretion rate (ml/h)

284

2

282

1

300

280

0

100

400

1000

200 0

278

0

250

500

750

1000

Urine volume (ml/h)

276

nephrogenic SIAD caused by an activating mutation of the AVP V2R at the same site that also can cause DI via an inactivating mutation

Feldman et al. New Engl J Med 352:1884-90, 2005

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Diabetes Insipidus and SIADH Joseph G. Verbalis, MD

Clinical Endocrinology: 2007

acute hyponatremia is associated with high morbidity and mortality acute patients duration serum [Na+] stupor or coma seizures mortality low [Na+] deaths

14 < 12 hrs 112 ± 2 100% 29% 50% 36%

chronic 52 3 days 118 ± 1 6% 4% 6% 0%

Arieff et al. Medicine 56:121, 1976 (hospital consults in one year; [Na+]