Congenital nephrogenic diabetes insipidus

82

Indian Journal of Nephrology

Indian J Nephrol 2001;11: 82-86

ARTICLE

Congenital nephrogenic diabetes insipidus KD Phadke, A Bagirath Childrens Kidney Care Centre, Department of Paediatrics, St Johns Medical College Hospital, Bangalore-34

Introduction The ‘renal type of Diabetes insipidus’ was appreciated as a separate entity more than 45years ago when it was first described independently by two investigatorsForssman in Sweden1 and Warnig in United States2. In 1947, Williams and Henry coined the term Nephrogenic Diabetes Insipidus (NDI) .It is synonymous with the terms Vasopressin or ADH (Antidiuretic hormone) resistant Diabetes insipidus or Diabetes Insipidus Renalis.

but are rare and often occur during therapy. Obstination, enuresis and nocturia are common complaints later in childhood.

In this article we discuss and review the molecular biology, approach to evaluation and management strategies for Nephrogenic diabetes insipidus.

Most untreated patients fail to grow normally. Treated patients are still small for age and remain so until adulthood. Weight for the height has been seen to be generally low during the first year of life but normalizes thereafter. The reasons for failure to thrive are initial feeding problems, ingestion of large amounts of low calorie fluid resulting in decreased appetite and repeated episodes of dehydration. Mental retardation is an important complication of untreated NDI due to recurrent episodes of severe brain cellular dehydration and cerebral edema caused by a hyperosmolar state4. Psychological development is influenced by persistant desire for drinking, frequent voiding which may be misinterpreted as hyperactivity, easy distractability, short attention span and restlessness5. Affected children frequently develop dilatation and functional obstruction of the urinary tract probably secondary to the large urinary volume.

Clinical manifestations

Genetics

As a consequence of insensitivity of the distal nephron to antidiuretic hormone, the kidney loses its ability to concentrate urine which leads to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia). The defect is present since birth and manifestations generally emerge during the first weeks oflife3.

In 90% of cases, the transmission is an X linked recessive trait with mutations in Vasopressin2 Receptor (V2R) gene. In 10% the transmission is autosomal recessive as a result of mutation in Aquaporin2 (AQP2) gene.The severity and occurrence of complications are related to the time of diagnosis and treatment and not influenced by the type of NDI. There are no clear clinical differences in the two types. The differentiation between the autosomal type and the X linked type is complicated. The DDAVP (1 desamino 8 D arginine vasopressin) infusion test, with measurement of extrarenal coagulation, fibrinolytic and vasodilatory responses is recommended3,6.

Congenital Nephrogenic Diabetes Insipidus is a rare disorder of the kidney constituted by the failure to concentrate urine despite normal or elevated plasma concentration of ADH .The marked urinary concentration defect resulting in polyuria,extreme thirst, growth retardation, developmental delay and the difficulties encountered in effectively treating this disorder have challenged nephrologists and paediatricians for decades.

Babies on human milk with low salt and protein content have a low renal osmolar load. With cows milk the osmolar load increases resulting in increased demand for free water predisposing to hypernatremic dehydration. Irritability, poor feeding , poor weight gain are the initial symptoms. Infants are eager to suck but may vomit after feeds. Dehydration is evidenced by dryness of skin, sunken eyes, depressed anterior fontanelle and scaphoid abdomen. Intermittent high fever is a common complication of a dehydrated state. Seizures can occur Address for Correspondence: Dr Kishore D Phadke Paediatric Nephrologist and Associate Professor Childrens Kidney Care Center Department of Paediatrics St Johns Medical College Hospital, Bangalore-34 Copyright © 2001 by The Indian Society of Nephrology

Molecular biology of Nephrogenic Diabetes Insipidus The conservation of water by the human kidney is a function of the renal tubules within the renal medulla. The principal cells of the renal collecting tubules are responsive to the neurohypophyseal antidiuretic hormone ,Vasopressin. The major action of ADH is to facilitate urinary concentration by allowing water to be transported passively down an osmotic gradient between


the tubular fluid and the surrounding interstitium7. The first step in the antidiuretic action of ADH is its binding to the vasopressin V2 receptor located on the basolateral membrane of the collecting duct cells –See Figure 1. This initiates a cascade of events- receptor linked activation of G protein, activation of adenyl cyclase (AC), production of cAMP and stimulation of protein kinase A (pKa) – that leads to the final step in the antidiuretic action of AVP. There is an exocytic insertion of specific water channels in the luminal membrane thereby increasing the water permeability of that membrane. These water channels are members of an integral group of membrane proteins that facilitate water transport3,8. Aquaporin1 (AQP1) was the first protein shown to function as a molecular water channel and is expressed in the red cells, renal proximal tubules and descending limbs of loop of Henle. Aquaporin 2 (AQP2) is the vasopressin regulated water channel in the renal collecting duct. Aquaporin 3 (AQP3) and Aquaporin 4(AQP4) are the water channels in the basolateral membranes of the renal medullary collecting ducts. These two aquaporins are assumed to function as an exit pathway for water and urea in the basolateral membrane during antidiuresis. AQP3 has a more prominent role in the urinary concentrating mechanism and expression of AQP3 is upregulated by dehydration in contrast to AQP49,10,11,12. In Congenital NDI, the renal collecting ducts are resistant to the antidiuretic action of ADH secondary to either mutation in the AVPR2 gene which codes for vasopressin V2R or to mutation in AQP2 gene which codes for vasopressin dependent water channel. Long term adaptation to circulating ADH levels, in a dehydrated state, is accomplished by increasing the expression of AQP2 and mRNA protein.The cAMP dependent transcriptional regulation of this gene may be of major importance in the long term regulation of water permeability13.

Characteristics of individual types of NDI

Congenital nephrogenic diabetes insipidus

83

Autosomal recessive NDI : Nineteen different mutations in the AQP2 gene have been detected in autosomal recessive nephrogenic diabetes insipidus. Impaired routing of the AQP2 mutation protein from the endoplasmic reticulum to the plasma membrane is the most likely general molecular cause of NDI with recessive mutations16. Autosomal dominant NDI : A single missense mutation in AQP2 gene has been identified in two families in which NDI showed male to male transmission.The impaired routing of the mutations from the Golgi apparatus to the plasma membrane is the underlying defect17,18.

Approach to evaluation Plasma sodium and osmolality are maintained within normal limits by a thirst ADH – renal axis.Thirst and ADH release both stimulated by increased osmolality, have been termed a ‘double negative feed back’ system19. Thus even when ADH limb of this double negative regulatory feed back system is lost , the thirst mechanism still preserves the plasma sodium and osmolality within normal range. In practice one needs to differentiate between central diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia. The diagnosis of congenital nephrogenic diabetes insipidus could be rapidly confirmed by a short dehydration test followed by vasopressin administration. Water deprivation test : Begin test in the morning after a 24hours period of adequate hydration and stable weight record. Patient should be on empty stomach and the bladder emptied too. Restrict fluids for 7 hrs. Measure body weight and urine specific gravity and volume hourly. Check the serum sodium and urine and serum osmolality every 2 hrs. Monitor carefully to assure that fluids are not ingested during the test. Terminate the test if the weight loss is more than 5%.

X linked NDI : The vasopressin type 2 receptor is the prime candidate for defective step in the ADH mediated response .In addition to the antidiuretic action, the vasodilatory, coagulation and fibrinolytic responses to V2 receptor specific agonist DDAVP are lacking14.

Interpretation - Normal individuals who are water deprived will concentrate their urine between 500 and 1400mmol/l and plasma osmolality will range between 288-291 mmol/l. In a normal child and those with psychogenic diabetes insipidus urine specific gravity rises to 1.010 and greater.

To date, more than 84 distinct disease causing mutations in V2 receptor gene have been identified. The mutations are not clustered in one domain of V2 receptor but are found throughout in the protein.The mutations consist of point mutations, small deletions and insertions, splice site mutations or large deletions.The finding of so many diverse mutations in V2 recptor gene in patients with X linked nephrogenic diabetes insipidus demonstrates that this disease is highly heterogenous at the molecular level, as expected for a typical X linked disorder showing reduced reproductive fitness in males15.

The urine to plasma osmolality ratio is more than 2 and urine volume decreases and there should be no appreciable weight loss. Specific gravity remains below 1.005 in patients with NDI. Urine osmolality remains less than 150 mmol/l with no reduction of urine volume. A loss of weight of up to 5% occurs and serum osmolality more than 290mmol/l with serum sodium more than 150 meq /l provide evidence that the patient with NDI did not receive water during the test. To confirm the concentrating defect and to distinguish the renal form of Copyright © 2001 by The Indian Society of Nephrology

84

Indian Journal of Nephrology


NDI from central form a vasopressin test is performed. Vasopressin test : DDAVP or vasopressin in a dose of 10micro grams for infants and 20 micrograms for children is administered subcutaneously and urine is collected in the subsequent 5-6 hrs. The maximum urine osmolality in any collected aliquot is chosen as a measure of concentrating capacity. After DDAVP addministration, NDI patients are unable to increase urine osmolality, which remains below 200 mmol/l 0f H2O with no reduction in volume of urine.

to ADH.

Summary of approach to diabetes insipidus ·

Measure plasma osmolality and sodium concentration under condition of ad libitum fluid intake. If they are greater than 295 mmol/l and 143meq/l respectively then the diagnosis of primary polydipsia is excluded.

·

Perform a dehydration test. If urine concentration does not occur before plasma osmolality and sodium reaches 295mmol/l and143meq/l respectively then the diagnosis of primary polydypsia is excluded.

·

Determine the ratio of urine to plasma osmolality at the end of dehydration test . If it is less than 1.5 the diagnosis of primary polydipsia is excluded.

·

Perform a hypertonic saline infusion with measurement of plasma vasopressin and osmolality at intervals during the procedure. If the relation between the 2 variables is subnormal the diagnosis of diabetes insipidus is established.

·

The figure 2 depicts the differences between various causes of polyuria20.

Perform a vasopressin infusion test. If urine osmolality is more than 150mmol/l above the value obtained at the end of the dehydration test, NDI is excluded.

·

The distinction between central diabetes insipidus and nephrogenic diabetes insipidus may not be as clear as one might expect due to

Measure urine osmolality and plasma vasopressin at the end of dehydration . If the relation is normal diagnosis of NDI is excluded.

The Table 1 summarises the diagnosis of polyuria

Interpretation : Patients with ADH deficient diabetes insipidus concentrate urine to 1.010 or greater and have decreased urine volumes and low fluid intake. Patients with NDI have no significant change in intake , volume or specific gravity. A constant intake associated with decreased output, increased specific gravity suggests psychogenic diabetes insipidus.The measurement of urine osmolality after dehydration or vasopressin administration is referred as the ‘indirect test’.The ‘direct test’ consists of assessment of vasopressin assay during the dehydration test plotted on a normogram depicting the normal relation between plasma sodium or osmolality and plasma ADH in normal individuals. If this relation is discordant, it is diagnosed as central diabetes insipidus3.

1. Chronic polyuria due to any cause interferes with maintenance of medullary concentrating ability of the kidney due to medullary wash out of urea . 2. Partial Central diabetes insipidus patients have a small capacity to secrete AVP during severe dehydration and urine osmolality may then increase to greater than plasma osmolality 3. Many patients with congenital nephrogenic diabetes insipidus have incomplete defect in their response

Management of NDI Hydration : The primary therapy of NDI is to provide adequate water to prevent dehydration. However most infants with NDI cannot drink the required amounts of water3. Diet : Low solute diet with low sodium (1mmol/kg/day) and low protein (1g/kg/day) content, has been recommended to reduce renal osmolar load which helps to decrease obligatory water excretion. However, in view

Table 1 - Interpretation of water deprivation and vasopressin test Cause of polyuria

Urine osmolality with water deprivation (mosmol/kg of H2O)

Plasma ADH after dehydration

Increase in urine osmolality with exogenous ADH

Normal

>800

>2pg/ml

No increase

Complete central DI