Disorders of Water Balance: Central Diabetes Insipidus, Nephrogenic Diabetes Insipidus, and SIADH

Introduction

Maintaining water homeostasis is essential for preserving plasma osmolality and electrolyte balance. The hormone arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), plays a pivotal role in this process by regulating renal water reabsorption in response to plasma osmolality. Disorders of AVP production or action can lead to contrasting syndromes: diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Central and nephrogenic DI are characterized by hypotonic polyuria and hypernatremia, whereas SIADH results in impaired free water excretion and hyponatremia. Understanding the pathophysiology and clinical distinctions of these syndromes is critical for proper diagnosis and treatment.

Central Diabetes Insipidus

Central diabetes insipidus arises from a deficiency in AVP production due to damage or dysfunction in the hypothalamus or posterior pituitary. It can be idiopathic or caused by trauma, neurosurgery, tumors (e.g., craniopharyngioma), infections (e.g., encephalitis), or infiltrative diseases like sarcoidosis.

Patients with central DI present with polyuria, polydipsia, and hypernatremia if fluid intake does not compensate for water loss. The urine is characteristically dilute with low specific gravity and osmolality. A hallmark feature is an inability to concentrate urine despite hyperosmolar plasma.

The water deprivation test, followed by desmopressin (DDAVP) administration, is used diagnostically. In central DI, urine osmolality increases significantly after DDAVP, indicating intact renal responsiveness to AVP. Treatment involves desmopressin, a synthetic AVP analog, administered intranasally, orally, or parenterally to replace the deficient hormone and restore normal water balance.

Nephrogenic Diabetes Insipidus

Nephrogenic DI results from renal resistance to AVP, despite normal or elevated hormone levels. It can be inherited (often due to mutations in the AVPR2 gene encoding the V2 receptor) or acquired secondary to medications (e.g., lithium, demeclocycline), hypercalcemia, hypokalemia, or chronic kidney disease.

Clinically, nephrogenic DI presents similarly to central DI with polyuria, polydipsia, and risk of dehydration and hypernatremia. However, in nephrogenic DI, the kidneys do not respond to desmopressin, and there is minimal or no increase in urine osmolality after its administration.

Management involves addressing the underlying cause (e.g., discontinuing lithium), low-sodium and low-protein diets, thiazide diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, which reduce urine output by decreasing renal prostaglandin synthesis and enhancing sodium and water reabsorption.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

In contrast to DI, SIADH is caused by excessive AVP release or action, leading to water retention, dilutional hyponatremia, and inappropriately concentrated urine despite low plasma osmolality. Common causes include CNS disorders (e.g., stroke, trauma, meningitis), pulmonary diseases (e.g., pneumonia, small cell lung carcinoma), medications (e.g., SSRIs, carbamazepine), and ectopic AVP production by tumors.

Patients with SIADH often present with euvolemic hyponatremia, fatigue, nausea, headache, and in severe cases, confusion, seizures, or coma due to cerebral edema. Laboratory findings include hyponatremia, low serum osmolality, elevated urine osmolality (>100 mOsm/kg), and elevated urine sodium (>30 mmol/L) in the setting of normal renal, adrenal, and thyroid function.

Treatment of SIADH includes fluid restriction, salt tablets, and in moderate-to-severe cases, hypertonic saline infusion with careful monitoring. Vasopressin receptor antagonists (vaptans), such as tolvaptan or conivaptan, are second-line therapies that block AVP at the V2 receptor, promoting aquaresis. Identifying and treating the underlying cause is essential for long-term resolution.

Key Differences

The table below summarizes the major clinical and laboratory distinctions:

Feature	Central DI	Nephrogenic DI	SIADH
Serum sodium	High or normal	High or normal	Low
Serum osmolality	High	High	Low
Urine osmolality	Low	Low	High
Response to DDAVP	Positive (↑ urine osmolality)	Minimal or no response	Not applicable
Treatment	Desmopressin	Thiazides, NSAIDs	Fluid restriction, vaptans

Conclusion

Central diabetes insipidus, nephrogenic diabetes insipidus, and SIADH are disorders of water regulation with distinct pathophysiological mechanisms and clinical implications. Central and nephrogenic DI lead to impaired water reabsorption, while SIADH results in inappropriate water retention. Careful assessment of clinical symptoms, serum and urine osmolality, and response to desmopressin is crucial for accurate diagnosis. Management strategies must be tailored to the underlying cause and pathogenesis to restore fluid and electrolyte balance.

References

1. Verbalis JG. Disorders of water balance. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine, 20th ed. McGraw-Hill Education; 2018.

2. Christ-Crain M, Bichet DG, Fenske WK. Diabetes insipidus. Nat Rev Dis Primers. 2019;5(1):54. doi:10.1038/s41572-019-0103-2

3. Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072. doi:10.1056/NEJMra070256

4. Decaux G, Soupart A, Vassart G. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet. 2008;371(9624):1624-1632. doi:10.1016/S0140-6736(08)60673-0

   
   

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