Clinical Guidance

AVPR2. A minority of AVPR2 pathogenic variants result in partial insensitivity to AVP or DDAVP®, and disease onset may be later in childhood. At present, 18 AVPR2 pathogenic variants resulting in partial NDI have been reported. These include:

• , , , ; reach the cell surface with impaired ligand capacity and partial AVP/DDAVP binding. See review in ,

• ; decreased ligand-binding affinity and decreased coupling to Gs

• ; decreased number of cell surface AVPR2 receptors

• and ; reduced cell surface expression and decreased binding affinity for AVP

• , , and ; impaired intracellular trafficking

• ; decreased AVP binding most likely due to conformational changes

• and (splice site); identified in individuals with partial NDI

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Diagnostic Criteria

Suggestive Findings

Hereditary nephrogenic diabetes insipidus (NDI) should be suspected in an individual with the following clinical and laboratory findings.

Clinical

• Polyuria (excessive urine production)

• Polydipsia (excessive drinking)

• Family history of NDI

• Note: In the first few months after birth, polyuria and polydipsia may not be immediately noticed; infants with NDI usually present with poor feeding, failure to thrive, and irritability.

Laboratory

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Differential Diagnosis

Diabetes insipidus is the excretion of abnormally large volumes (i.e., 50 mL/kg body weight in 24 hours) of dilute urine (i.e., specific gravity 1.010 or osmolality 300 mOsm/kg). In addition to hereditary nephrogenic diabetes insipidus (NDI), causes of diabetes insipidus include the following:

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hereditary nephrogenic diabetes insipidus (NDI), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Nephrogenic Diabetes Insipidus

System/Concern | Evaluation | Comment

Nephrology

| Kidney ultrasound exam | To evaluate for hydronephrosis, dilatation of urinary tract, megacystis

Other

| • Consultation w/clinical geneticist /or genetic counselor

• Developmental eval in children w/history of episode of severe dehydration or delay in diagnosis

|

Treatment of Manifestations

Management is usually best accomplished by a team consisting of a nutritionist, a pediatric (or adult) nephrologist or endocrinologist, and a clinical geneticist. General management. The essence of management is the provision of free access to drinking water and to toilet facilities. Infants, who are naturally unable to seek out water when thirsty, must be offered water between regular feedings. Children and adults who are heavy sleepers may need to be awakened at night by a family member or an alarm clock in order to drink water and to urinate. As long as an individual's thirst mechanism remains intact and the person is otherwise well, these measures prevent hypernatremic dehydration.

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Clinical Guidance

Water intake must not be restricted.

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Therapies Under Investigation

In a few individuals with a milder AVPR2 pathogenic variant resulting in a partial response to AVP and DDAVP®, high doses of DDAVP® in combination with a thiazide diuretic significantly decreased urinary volume . Effectiveness and safety of this treatment in partial NDI need to be explored further. Because of the known gastrointestinal safety of selective cyclooxygenase (COX)-2 inhibitors compared to nonselective COX inhibitors (e.g., indomethacin), use of these drugs has been proposed for the treatment of hereditary NDI. The effectiveness of a specific COX-2 inhibitor in decreasing free water losses was demonstrated in male infants with hereditary NDI .

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"

Surveillance Guidelines

There are no published guidelines available on recommended surveillance for children or adults with hereditary NDI. The frequency of follow up should take into consideration the medications being used and compliance with medications and diet recommendations.

Table 3.

Recommended Surveillance for Individuals with Hereditary Nephrogenic Diabetes Insipidus

System/Concern | Evaluation | Frequency

Constitutional

| Monitoring of growth development | At least every:

• 3 mos in infants

• 6 mos in older children

Renal

| Measurement of serum sodium concentration to identify unrecognized hyperosmolality early dehydration1 | At least every:

• 3 mos in infants

• 6 mos in older children

Annually in adults or only as needed, as determined on an individual basis

Kidney ultrasound exam to monitor for hydronephrosis megacystis | Annually

1. Urine output and urine specific gravity are useless as indicators of hydration status.

Source: GeneReviews — "Hereditary Nephrogenic Diabetes Insipidus"