Morning ReportPediatric Nephrology Service

May 24, 2004

Sapna Sutaria, M.D. (PL3)

Diabetes Insipidus

Background

Diabetes insipidus (DI) is a disease characterized by polyuria and polydipsia

Central DI: results from a lack of circulating arginine vasopressin (ADH) due to an abnormality in either synthesis or secretion

Nephrogenic DI: results from a failure of AVP-sensitive epithelial cells of the kidney collecting duct to respond normally to ADH

Normal Physiology

Vasopressin in synthesized by the supraoptic and paraventricular nuclei of the hypothalamus

It is then transported to the posterior pituitary where stored until its release

Vasopressin release from posterior pituitary is primarily regulated by changes in plasma osmolality

The primary site of vasopressin action in the kidney is at the collecting duct

Vasopressin receptors are classified as V1 and V2

Etiologies of Central DI

Primary inherited forms—rare – Autosomal Dominant form– Wolfram syndrome– septo-optic dysplasia

Etiologies of Central DI

Secondary or acquired causes—more common– tumors of the suprasellular and chiasmatic regions

(craniopharyngiomas, optic gliomas, germinomas)– Head injury (basal skull fx)– Operations (near pituitary or hypothalamus)– Systemic diseases (encephalitis, histiocytosis,

turberculosis, leukemia)– Autoantibodies to vasopressin-producing cells

Etiologies of Central DI

In the newborn, DI has been reported in association with asphyxia, IVH, intravascular coagulopathy, Listeria monocytogenes sepsis, and GBBS meningitis

Approx 20% of cases of DI are idiopathic

Etiologies of Nephrogenic DI

Primary inherited causes– Mutations that affect the V2 receptor as well as

the AQP 2 water channel– The V2 receptor gene is localized the the X

chromosome– V2 receptor mutations may also appear de novo– Inherited autosomal recessive forms of

nephrogenic DI also reported (mutation localized to chromosome 12)

Etiologies of Nephrogenic DI

Secondary or acquired forms– More common than primary forms– Drugs (lithium, ampho B, demeclocycline)– Can be associated with prolonged intervals of

hypercalcemia or hypokalemia– Can be present in conjunction with inherited

disorders of renal development (Polycystic kidney disease, renal dysplasia)

– Disease processes that injure the collecting duct & surrounding tubules (sickle cell anemia, chronic pyelonephritis, urinary tract obstruction)

Patient History

How much pt drinks per day Voiding patterns Dietary intake Drugs/meds

Clinical Manifestations

POLYURIA POLYDIPSIA Signs and symptoms of chronic dehydration Infants: irritability, poor feeding, growth failure,

intermittent high fevers In children who have acquired bladder control,

enuresis may be the first symptom

Clinical Manifestations

Central DI– Hypothalamic tumors: growth disturbances,

progressive cachexia or obesity, hyperpyrexia, sleep disturbance, sexual precocity, or emotional disorders

– Lesions initially causing DI may eventually destroy the anterior pituitary and its associated endocrine axes

Labs

Urine is usually pale and colorless UA and urine electrolytes Urine SG varies b/w 1.001 and 1.010 Uosm usually 50-300 mOsm/kg Sosm may vary widely, depending on

hydration status Other renal fxn studies usually nl Serum AVP measurement

Imaging

Imaging– RUS– MRI

Tumors—calcifications; enlargement of sella turcica; increased width of suture lines

“Bright spot”—differentiates between posterior pituitary and anterior pituitary; present in normal pts; absent or ectopic in pts with hypothalamic-neurohypophyseal tract lesions

Diagnosis

Administration of DDAVP– In central DI, DDAVP will raise Uosm and

suppress UOP– In nephrogenic DI, DDAVP produces no

increase in Uosm and no suppression of UOP– In normal individuals, DDAVP administration

can cause a vasodilatory response (flushing, fall in diastolic BP, rise in HR), believed to be mediated by extrarenal V2 receptors

Diagnosis

Water deprivation test– In pts with severe DI, a 3 hr interval of

water deprivation may result in elevation of Sosm, whereas Uosm remains at less that plasma values

Treatment

The cause of the underlying condition should be treated when possible

Treatment

Central DI– Administration of DDAVP, usually intranasally– DDAVP binds almost exclusively to V2 receptors

and is more resistant to degradation by body peptidases than endogenous vasopressin

– Therefore, the antidiuretic effects of DDAVP last 8-10 hr, compared with 1-3 hr for endogenous vasopressin

– Dose: 5-10 mcg IN, given in single or divided doses; < 2 y/o: 0.15-0.5 mcg/kg/24 hr

– IV/SQ therapy also available

Treatment

Nephrogenic DI– Ensure a sufficient intake of water to replace

the large urinary water losses– Stop causative medications, if applicable– Low sodium diet– Drugs that reduce polyuria

Thiazide diuretics (hydrochlorothiazide) Prostaglandin synthesis inhibitors (indomethacin) Potassium-sparing diuretics (amiloride)

Management

Check serum electrolytes frequently After episodes of dehydration, these patients

usually require replacement of large quantities of water, but not sodium (**remember this when choosing IV fluids**)

Involve endocrine and nephrology services (and genetics, if indicated, for genetic counseling)

Prognosis

Central DI– Prognosis often determined by the

underlying etiologic process – Central DI may be transient or long-standing– Uncomplicated central DI can be managed

effectively; permits a high quality of life for affected patients

Prognosis

Nephrogenic DI– Good prognosis, if careful clinical and

laboratory monitoring– There are isolated reports of CRF in pts

with nephrogenic DI

The End