2.

DIABETES INSIPIDUS Definition : Diabetes Insipidus (DI) is a heterogeneous clinical syndrome of disturbance in water balance, characterized by polyuria (urine output > 5 ml/kg/hr), polydypsia (water intake > 2 L/m2/d) and failure to thrive which results from either vasopressin deficiency (central DI) or vasopressin insensitivity at the level of the kidney (nephrogenic DI). Both central DI and nephrogenic DI can arise from inherited defects of congenital or neonatal onset or can be secondary to a variety of causes .

In children three pathophysiologic mechanisms give rise to polydypsia and polyuria: Central (vasopressin sensitive, hypothalamic, neurogenic) DI caused by defective vasopressin synthesis and/or secretion. Nephrogenic (vasopressin resistant) DI caused by defective renal tubular response to vasopressin action. Primary polydypsia due to compulsive water drinking (psychogenic) or defective thirst mechanism (dipsogenic).

In children, Nephrogenic DI (NDI) is more common than Central DI (CDI) and is most often acquired X linked NDI accounts for 90% of all the congenital forms of NDI.

Table 552-1 -- DIFFERENTIAL DIAGNOSIS OF POLYURIA AND POLYDIPSIA Diabetes insipidus (DI) Central DI Genetic (autosomal dominant) Acquired Trauma (surgical or accidental) Congenital malformations Neoplasms Infiltrative, autoimmune, and infectious diseases Drugs Nephrogenic DI Genetic (X-linked, autosomal recessive, autosomal dominant) Acquired Hypercalcemia, hypokalemia Drugs Kidney disease

Primary polydipsia Diabetes mellitus

The triphasic response following surgery refers to an initial phase of transient DI, lasting 12-48 hr, followed by a 2nd phase of syndrome of inappropriate antidiuretic hormone secretion (SIADH), lasting up to 10 days, which may be followed by permanent DI. The initial phase may be the result of local edema interfering with normal vasopressin secretion; the 2nd phase results from unregulated vasopressin release from dying neurons, whereas in the 3rd phase, permanent DI results if more than 90% of the neurons have been destroyed.

Vasopressin, 9-amino-acid peptide, has both antidiuretic and vascular pressor activity .

synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. transported to the posterior pituitary via axonal projections, where it is stored awaiting release into the systemic circulation. half-life of vasopressin in the circulation is 5 min. In addition to responding to osmotic stimuli, vasopressin is secreted in response to significant decreases in intravascular volume and pressure (minimum of 8% decrement) via afferent baroreceptor pathways arising from the aortic arch (carotid sinus) and volume receptor pathways in the cardiac atria and pulmonary veins. Osmotic and hemodynamic stimuli interact synergistically. The thirst threshold is approximately 10 mOsm/kg higher (i.e., 293 mOsm/kg) than the osmotic threshold for vasopressin release. Therefore, under conditions of hyperosmolality, vasopressin is released before thirst is initiated, allowing ingested water to be retained. Chemoreceptors present in the oropharynx rapidly down-regulate vasopressin release following water ingestion.

ACTIONS :Vasopressin exerts its principal effect on the kidney via V2 receptors located primarily in the collecting tubule, the thick ascending limb of the loop of Henle, and the periglomerular tubules. The human V2 receptor gene is located on the long arm of the X chromosome (Xq28) at the locus associated with congenital, X-linked, vasopressin-resistant diabetes insipidus.

Activation of the V2 receptor results in increases in intracellular cyclic adenosine monophosphate (cAMP) ----- insertion of the aquaporin-2 water channel into the apical (luminal) membrane ----- water movement along its osmotic gradient into the hypertonic inner medullary interstitium from the tubule lumen ----- excretion of concentrated urine.

APPROACH TO DIAGNOSIS
Clinical features
Polyuria, polydypsia, defined as water intake of more than 2 L/m2/d (or more than 5 L/d) failure to thrive or growth retardation are essential features of DI] signs and symptoms of DI vary with the etiology, the loss of excess of free water, excessive thirst, dehydration, and hypernatremia manifests differently in different age groups depending on their ability to replenish water. Infants may present with a vigorous suck, vomiting, recurrent episodes of fever without an apparent cause, excessive crying, irritability, weight loss, constipation, and excessively wet diapers. Younger children often manifest with primary enuresis and difficulty in toilet training. Older children characteristically have high urine output and nocturia leading to disturbed sleep and easy fatigability.

Seizures due to severe hypernatremia, hyperosmolar dehydration and potential hypoxia may lead to neurological sequel in the form of intracranial bleed and developmental delay. Death due to hypovolemic shock or hypernatremic seizure has been reported.

Investigations: CONFIRM POLYURIA :

24 hour urine output >5ml/kg/hr or >2L/m2/day

POLYURIA

Further investigations

1. Urine examination for: WBCs: UTI Sugar: D.M Specific gravity: <1.005 D.I Urine Osmolality: <300 mOsm/kg- D.I 2. Blood : Urea, Creatinine Serum Electrolytes Calcium Blood gas analysis Blood glucose Plasma Osmolality

DI LIKELY IF: High Plasma Osmolality >300 mOsm/kg Low Urine Osmolality <300 mOsm /kg Urine Sp.gravity < 1.005 Serum Sodium > 145 mmol/L DI UNLIKELY IF : Serum Osmolality <270 Urine Osmolality >600 mOsm/kg Urine Sp.gravity >1.010 OTHER TEST:

1. MRI of hypothalamic-pituatary region in case of suspected central DI 2. Renal imaging for renal DI 3. Water deprivation test-Determines ability of kidneys to concentrate urine. Indication- If plasma osmolality is normal with low urinary osmolality. Prerequisite- rule out renal failure and RTA Procedure Begin the test after a 24-hr period of adequate hydration & stable weight. Obtain a baseline weight after bladder emptying. Restrict fluids for 7 hours. Measure body weight and urine specific gravity and volume hourly. Check serum Na+ and urine and serum osmolality every 2 hr. Terminate the test if weight loss approaches 5%.

- Test is stopped when urine osmolality >700 which excludes DI or plasma osmolality >300mOsm/kg diagnostic of DI.

5. Gene testing
Gene testing for the familial forms of CDI and NDI are not commercially available 6. NEWER TESTS : - Measurement of Aquaporin-2 excretion is being used to differentiate NDI and CDI. The urinary excretion of Aquaporin-2 increases following desmopressin administration in CDI, while there is no increase in NDI - plasma copeptin levels have been studied as a surrogate marker of AVP. Copeptin, the Cterminal part of the AVP precursor, co-secreted with AVP is much easier to measure. It was demonstrated that plasma copeptin is a valuable surrogate of AVP release in patients with the DI.

TREATMENT :
The therapeutic goals are primarily to reduce polyuria and decrease the thirst so that the child is able to grow adequately and maintain a normal life style. The specific therapy depends on the etiology. 1. 2. 3. 4. 5. Providing free access to water Dietary management to optimize free water excretion. Therapy with vasopressin analogue desmopressin in CDI Therapy with drugs to enhance water reabsorption in NDI Treatment of the underlying cause as in NDI.

Free access to water :

facilitates maintenance of tonicity if the thirst mechanism is intact; inconvenient to drink lots of fluids. Long standing excess fluid intake may cause hydronephrosis and hydroureter and may also lead to fluorosis if the florid content of the water is high. Fluids alone can be a management strategy in very young infants and neonates. As they have a high obligatory oral fluid intake, vasopressin therapy may cause hyponatremia. Hence it is better to manage them with fluids alone.

Dietary management :
Diet with low sodium, low protein with high calories providing a high calorie: solute ratio is recommended. restrict oral sodium intake to 1 meq/kg/d and protein intake 2 g/kg/d. more prudent to restrict salt than proteins which are essential for growth

Vasopressin and its analogue :

older children --- DDAVP is available in an intranasal preparation (onset 5-10 min) and as tablets (onset 15-30 min). The intranasal preparation of DDAVP (10 g/0.1 mL) can be administered by rhinal tube (allowing dose titration) or by nasal spray. Use of DDAVP oral tablets requires at least a 10-fold increase in the dosage compared with the intranasal preparation. Oral dosages of 25-300 g every 8-12 hr are safe and effective in children. The appropriate dosage and route of administration is determined empirically based on the desired length of antidiuresis and patient preference. To prevent water intoxication, patients should have at least 1 hr of urinary breakthrough between doses each day. Dilutional hyponatremia, headache, hypertension and nasal congestion are some of the side effects occasionally seen.

Perioperative management of Central DI

Aqueous Vasopressin

Central DI of acute onset following neurosurgery is best managed with continuous administration of synthetic aqueous vasopressin (pitressin). total fluid intake must be limited to 1 L/m2/24 hr during antidiuresis. dosage for intravenous vasopressin therapy is 1.5 mU/kg/hr, which results in a blood vasopressin concentration of approximately 10 pg/mL and titrated every 10 minute as to maintain a urine output of less than 2 ml/kg/hr following hypothalamic (but not transsphenoidal) surgery, higher initial concentrations of vasopressin may be required to treat acute DI, which has been attributed to the release of a vasopressin inhibitory substance. Vasopressin concentrations >1,000 pg/mL should be avoided because they can cause cutaneous necrosis, rhabdomyolysis, cardiac rhythm disturbances, and hypertension.

Postneurosurgical patients treated with vasopressin infusion should be switched from intravenous to oral fluids as soon as possible to allow thirst sensation, if intact, to help regulate osmolality.

A known case of diabetes insipidus undergoing surgery :

prolonged oral fluid restriction. the usual dose of desmopressin is withheld prior to surgery. The child is kept on 1 L/m2/d of restricted intravenous fluids. When the effect of the previous desmopressin dose wanes off and CDI sets in, intravenous aqueous vasopressin is started as per the perioperative CDI protocol described above.

Other management in Central DI

glucocorticoids are essential for insertion of water channels independent of vasopressin, cortisol deficiency inhibits free water clearance and adequate replacement if required helps achieve better control of DI. Decreased bone mineral density has been reported in children with CDI central diabetes insipidus which shows significant improvement in bone mineral density (BMD) after treatment with oral alendronate.

Treatment of Nephrogenic DI :
acquired NDI --- eliminating underlying disorder, such as offending drugs, hypercalcemia, hypokalemia, or ureteral obstruction. Congenital nephrogenic diabetes insipidus -- difficult to treat Despite adequate control, growth retardation and mental retardation is often found on long term follow up.

Pharmacologic approaches : Thiazide diuretics : decrease the overall urine output. induce a state of mild volume depletion by enhancing sodium excretion at the expense of water and by causing a decrease in the glomerular filtration rate, which results in proximal tubular sodium and water reabsorption. a dose of 2 - 4 mg/kg/day in divided doses Indomethacin : (2 mg/kg/d) further enhances proximal tubular water reabsorption, but has significant side effects. Amiloride (0.3 mg/kg/d) may be used in combination with thiazides to further reduce polyuria. High-dose DDAVP therapy, in combination with indomethacin --- genetic defects in the V2 receptor associated with a reduced binding affinity for vasopressin. The combination of thiazide and amelioride is the most commonly used regimen..