Nephrogenic syndrome of inadequate antidiuresis

In 2005, Feldman et al. described two unrelated infants who clinically exhibited SIADH (syndrome of inadequate ADH secretion), but in whom undetectable ADH levels (arginine vasopressin = AVP) were found. They called this new syndrome "Nephrogenic Syndrome of Inadequate Antidiuresis (NSIAD)" (Feldman 2005).

NSIAD is a rare cause of hyponatremia (Powlson 2016).

Mutation in the vasopressin V2 receptor gene (Morin 2012) can lead to two different diseases:

• nephrogenic diabetes insipidus (R137H affected).
• NSIAD (R137L and R137C affected) (Decaux 2007).

NSIAD represents a subtype of SIADH (Feldman 2005).

Very rarely occurring disease. Since the description of the clinical picture in 2005, 30 cases have been reported so far (Hague 2018). The NSIAD mainly affects the male sex, but is not limited to this sex, as was initially suspected (Decaux 2007). In the female sex, asymptomatic hyponatremia is present in most cases (Hague 2018).

NSIAD is an X chromosomal (recessive) inheritance in which the male affected individuals are index cases (Hague 2018).

There is an activating mutation in NSIAD (the altered gene develops a new qualitative effect [Speer 2001]) of the arginine vasopressin (AVP) receptor type 2 (V2R) (Herold 2020).

AVP is synthesized in the paraventricular and supraoptic nuclei and acts on 3 different ATP receptors:

• V1a receptor
• V1b- receptor
• V2- Receptor (V2R)

After stimulation with AVP, the V2 receptor prevents excessive tubular reabsorption of water in healthy individuals. This is only possible to a very limited extent with the activating mutation of the V2 receptor. The mechanism that leads to this has not yet been fully clarified (Morin 2012).

NSIAD can occur from infancy into old age (Morin 2012).

There is a great heterogeneity in the patients with regard to the severity of the disease and also with regard to the age at diagnosis.

Female patients usually have an asymptomatic genotype, but there are also few known cases of severe clinical symptoms in women (Hague 2018)

The following symptoms in particular are found in infants:

• Hypotension
• Irritability
• Seizures

In adults, there are mostly less specific symptoms such as:

• vertigo
• intermittent confusion
• Tiredness
• Headaches (Hague 2018)
• Nausea (Powlson 2016)

In case of childhood hyponatremia, the diagnosis of NSIAD should always be considered. This is especially true if a high urinosmolality is also present (Morin 2012).

Water load test: The water load test is used to check the kidneys' ability to dilute urine. The patient drinks a defined amount of water (20 ml / kg bw) under medical supervision (because of the risk of hyponatremia). The amount of urine excretion is measured up to 240 min after ingestion. Normally, between 78% - 82% of the water load is excreted within 4 h. In patients with NSIAD the excreted amount of water is significantly reduced. At the same time there is a

- Hyponatremia

- increased urine molality

- undetectable serum co-eptin (released together with AVP) (Hague 2018)

The water load test can also be helpful in differentiating between NSIAD and SIADH by directly measuring AVP (Hague 2018). It can also be used to identify female carriers in the siblings of affected persons (Morin 2012)

Molecular diagnostics: AVPR2 sequencing enables the final diagnosis (Powlson 2016)

Plasma AVP mirrors: these are low or not detectable

plasma sodium level: this indicates severe hyponatremia

Urine: high osmolarity (Powlson 2016)

SIADH (syndrome of inadequate ADH secretion) (Hague 2018)

If severe hyponatremia persists, there is a risk of brain damage (Morin 2012).

• Fluid restriction (the amount varies individually and should be based on the maximum amount of fluid possible to keep the sodium level in the lower normal range (Hague 2018)
• possibly administration of 30 % - 50 % urea solution orally (Morin 2012)

With early diagnosis and appropriate fluid restriction, the prognosis is good.

1. Decaux G et al (2007) Nephrogenic Syndrome of Inappropriate Antidiuresis in Adults: High Phenotypic Variability in Men and Women from a Large Pedigree. JASN 18: 606 - 612
2. Feldman B J et al (2005) Nephrogenic Syndrome of Inappropriate Antidiuresis. N Engl J Med 352: 1884 - 1890
3. Hague J et al (2018) Adult female with symptomatic AVPR2- related nephrogenic syndrome of inappropriate antidiuresis (NSAID). Endocrinology, Diabetes and Metabolism case reports. ID: 17 - 0139 DOI: http://doi.org/10.1530/EDM-17-0139
4. Herold G et al (2020) Internal medicine. Herold Publisher S 805
5. Morin D et al (2012) Nephrogenic Syndrome of Inappropriate Antidiuresis. Int J Pediatr 937175
6. Powlson A S et al (2016) Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2. Clin Endocrinol (Oxf) 85: 306 - 312
7. Speer C P et al (2001) Pediatrics Springer Verlag S 57