Nephrogenic diabetes insipidus (NDI) is characterized by the inability to concentrate urine due to the resistance of the renal distal tubules to arginine vasopressin (AVP), resulting in polyuria, polydipsia, and chronic dehydration [1]. Repeated episodes of hypernatremia, dehydration, and polyuria can lead to various complications, including irreversible brain injury, behavioral problems, growth failure, megacystis, and hydronephrosis. Among the various causes, primary NDI is a rare disorder with an estimated prevalence of approximately 1 in 100,000 individuals and is primarily attributed to mutations in two genes [2]. The X-linked form, accounting for about 90% of hereditary cases, is caused by mutations in the vasopressin V2 receptor gene (AVPR2). The remaining cases are due to mutations in the aquaporin-2 water channel gene (AQP2), which are typically inherited in an autosomal recessive pattern, while the autosomal dominant form is extremely rare [3]. Patients with hereditary NDI are at risk of developing disease-related complications from a very early age. Therefore, early diagnosis and treatment are important because timely management can reduce these complications, improve the quality of life, and enable catch-up growth in patients with NDI [4]. The current treatment approach is not curative but aims to alleviate symptoms [5]. Although possible therapeutic strategies have been proposed to overcome the dysfunctional pathway from the AVP-vasopressin V2 receptor to the aquaporin-2 water channel, they are beyond the scope of this review [6]. Here, we discuss the general management and current drug therapies used in pediatric patients with hereditary NDI.

An adequate water supply is required for patients with NDI, especially in cases of febrile illness, gastroenteritis, or surgery, to prevent dehydration. In cases of hypernatremic dehydration, oral water supplementation is preferable, whenever possible. However, this can be challenging for infants who rely on caregivers for water intake [1]. If intravenous fluid therapy is required, hypotonic fluid (usually 5% dextrose with 0.225% sodium chloride) is recommended, starting at an infusion rate that is slightly greater than the urine output [7]. Most guidelines recommend an initial treatment with an isotonic solution for patients with severe dehydration, regardless of their serum sodium levels [8]. However, free water loss is typically observed during dehydration in patients with NDI. Therefore, replenishing fluid deficiency with isotonic fluid may worsen hypernatremia [9]. Isotonic fluid should only be reserved for acute volume expansion during hypovolemic shock, which is rare in patients with NDI [10]. During fluid therapy, fluid intake, fluid output, and serum sodium levels should be monitored and adjusted accordingly. In cases of severe dehydration accompanied by severe hypernatremia, the serum sodium level should be reduced at a rate no greater than 0.5 mEq/L per hour, to prevent treatment-associated neurologic complications [11].

To manage the diet of pediatric patients with NDI, it is essential to minimize obligatory water excretion by reducing the osmotic load resulting from the metabolism of nutrients obtained through food intake [12]. Simultaneously, the diet must ensure adequate caloric and protein intakes to support normal growth and development. Dietary management strategies for pediatric patients with hereditary NDI are summarized in Table 1. The osmotic load consists of osmotically active substances excreted in the urine. In healthy individuals, the urine output can be regulated by adjusting the urine concentration (i.e., urine osmolality) through the action of AVP, depending on the solute load applied to the kidney tubules. However, in patients with NDI, AVP does not function appropriately, and the urine osmolality remains fixed [13]. When the urine osmolality is kept constant, the urine output is proportional to the renal osmotic load. For example, if the osmotic load from an individual’s diet is 800 mOsm and urine osmolality is 800 mOsm/kg, 1 L of urine is required to excrete the solute. However, if the maximum urine osmolality is 100 mOsm/kg, a minimum of 8 L of urine output is required [10]. The osmotic load is usually determined by the amount of dietary protein and salt (Na and K), which is calculated as follows: 2×(Na+K, mmol) + 4×protein (g), using a protein-to-urea conversion of 4 mmol/g protein [14]. Unlike proteins, the metabolic byproducts of lipids and carbohydrates do not require renal excretion and therefore do not contribute to the osmotic load. While a low-salt, low-protein diet can reduce the urine output, protein restriction may further impair growth in children. Thus, salt restriction alone is often recommended [15]. A reasonable goal for the renal solute load in the diet of a child with NDI is approximately 15 mOsm/kg/day [16]. For example, a normal-protein diet providing 2.0–2.5 g/kg/day results in a solute load of 8–10 mOsm/kg/day. Accordingly, dietary sodium and potassium should be adjusted to yield an additional 5–7 mOsm/kg/day, allowing the total renal solute load to remain within the target range. In their review, Duicu et al. [17] presented different renal solute loads for various infant formulas. For example, breastmilk contains a solute load that is 20% to 30% lower than that of standard formula, whereas cow’s milk has approximately 3.3 times the solute load of human milk.

In addition, to balance the provision of appropriate nutrients within a limited osmotic load and ensure adequate hydration, procedures such as nasogastric tube feeding or percutaneous endoscopic gastrostomy, under the guidance of a pediatric dietitian, may be necessary. Several studies have reported the use of tube feeding in pediatric patients with NDI when the catch-up growth is inadequate [2,18]. In a cohort study of 66 patients with congenital NDI from 16 centers in the United States, patients were diagnosed at a median age of 4.2 months and followed up until 72 months of age; 36% of patients underwent gastrostomy at a median age of 6.7 months, and gastrostomy tubes were removed at a median age of 51.1 months [18]. In another study involving 315 patients from 22 countries in Europe, 59 (18.7%) received nasogastric tubes and 23 (7.3%) underwent gastrostomy, with procedures starting in the neonatal period and tube removal occurring at approximately 2 years of age [2]. There are still no established guidelines for the indications and duration of tube feeding in pediatric patients with NDI, and research on long-term outcomes related to catch-up growth and development in these patients when such interventions are used is limited. Observational and interventional studies are warranted, particularly those investigating early implementation of gastrostomy or tube feeding to improve nutritional support for young pediatric patients with NDI.

Commonly used medications for NDI include thiazide diuretics, potassium-sparing diuretics (PSD) such as amiloride, and prostaglandin inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) [18,19]. The mechanisms of action, dosage, and common side effects of the three drug types are summarized in Table 2.

When combined with a low-solute diet, thiazides can reduce the urine output by up to 70% in patients with NDI [10]. The mechanism involves inhibition of the sodium-chloride cotransporter in the distal convoluted tubule, leading to mild salt loss and a subsequent reduction in the intravascular volume. This reduction in volume triggers the compensatory activation of the renin-angiotensin-aldosterone system (RAAS), which enhances sodium and water reabsorption in the proximal tubule. By increasing the proximal reabsorption, the fluid volume delivered to the distal nephron is significantly reduced [19,20]. Because the collecting ducts in patients with NDI are unresponsive to antidiuretic hormone, reduced downstream fluid delivery leads to a marked decrease in urine output. This mechanism underscores the paradoxical antidiuretic effect of thiazides in conditions such as NDI, despite their classification as diuretics. The initial dose of hydrochlorothiazide in pediatric patients with NDI is typically 1–2 mg/kg, which can be gradually increased to 3–4 mg/kg/day based on the clinical response and tolerability [7]. Common side effects of thiazides include electrolyte imbalances such as hypokalemia, hyponatremia, hypomagnesemia, and hypercalcemia, which may necessitate monitoring and management. Other adverse effects include hyperglycemia, hyperlipidemia, and hyperuricemia, which can increase the risk of gout and photosensitivity [21]. In some cases, thiazides may lead to orthostatic hypotension owing to volume depletion, as well as fatigue, dizziness, and muscle cramps [22]. Close monitoring of electrolyte levels, renal function, and clinical symptoms is essential to mitigate these risks, particularly in pediatric patients with NDI.

PSDs, such as amiloride, are typically not used alone but are utilized to counteract hypokalemia, a common side effect of thiazides. Amiloride specifically inhibits the epithelial sodium channels (ENaC) located in the principal cells of the collecting duct in the kidney. Blocking ENaC prevents sodium reabsorption at this site, which reduces the electrochemical gradient that drives potassium excretion, thereby conserving potassium levels. This reduction in sodium reabsorption decreases the extracellular fluid volume and stimulates the RAAS [23]. Although activation of the RAAS promotes sodium and water reabsorption in other parts of the nephron, the net effect of amiloride is a reduction in potassium excretion, preservation of plasma potassium levels, and a modest reduction in urine output. The dosage of amiloride is 0.1–0.3 mg/kg/day, but doses up to 0.6 mg/kg/day have been reported [10,17]. Common side effects include hyperkalemia, which is the most significant concern, particularly in patients with impaired renal function [19]. Other potential side effects include nausea, vomiting, diarrhea, abdominal pain, headache, and dizziness. Regular monitoring of electrolyte levels and renal function is essential to minimize the risk of adverse effects.

In patients with NDI, potassium supplementation can be used as an alternative to PSDs to compensate for thiazide-induced hypokalemia. However, this approach has the potential drawback of increasing the osmotic load due to the additional solutes introduced with potassium salts [10]. An elevated osmotic load may lead to increased water excretion, which could counteract the desired effect of thiazides in reducing the urine output. Additionally, excessive potassium supplementation may increase the risk of gastrointestinal (GI) side effects such as nausea and abdominal discomfort.

NSAIDs inhibit cyclooxygenase (COX), thereby suppressing prostaglandin synthesis in the kidneys, and are frequently used in combination with thiazides to treat NDI [24]. Although the exact mechanism of action of NSAIDs in patients with NDI remains unclear, several studies suggest that their target prostaglandins, particularly prostaglandin E2 (PGE2), play a role in modulating the renal response to antidiuretic hormones [7,25]. PGE2 inhibits adenylate cyclase activity, a key component of the AVP signaling pathway, resulting in the decreased expression of AQP2 channels in the collecting ducts. This contributes to impaired water reabsorption. Furthermore, PGE2 can reduce the expression of the Na-K-2Cl cotransporter in the ascending limb of the loop of Henle, thereby decreasing the medullary osmotic gradient required for effective urine concentration. These mechanisms collectively exacerbate the AVP resistance observed in patients with NDI [26-28]. Among NSAIDs, the most widely used, indomethacin, is more effective than alternatives, such as ibuprofen, in reducing urine output. Indomethacin is usually administered at 1–2 mg/kg/day, divided into two or three doses, with a maximum of 3 mg/kg/day. The combination of indomethacin with thiazides can decrease the urine output by an additional 25% to 50% compared with thiazide therapy alone [17]. This significant reduction makes NSAIDs an essential component of NDI management, particularly in patients with an incomplete response to thiazides alone.

However, the use of NSAIDs, particularly indomethacin, requires careful monitoring owing to the potential side effects. Indomethacin can cause a rapid decrease in serum sodium levels, especially when combined with thiazides, which may lead to hyponatremic seizures, a serious complication in pediatric patients [29]. The long-term use of NSAIDs is associated with decreased renal function, necessitating regular monitoring of serum creatinine levels and the glomerular filtration rate to identify early signs of renal impairment. GI symptoms such as abdominal pain, nausea, and bleeding are common, especially after prolonged use [30]. These symptoms can often be mitigated by administering medications with food or co-prescribing proton pump inhibitors to reduce GI irritation.

For pediatric patients who are intolerant to indomethacin, selective COX-2 inhibitors such as celecoxib may be a safer alternative. COX-2 inhibitors are associated with a lower risk of GI side effects, while retaining efficacy in reducing the urine output in patients with NDI [4]. However, the long-term safety profile of COX-2 inhibitors in children with NDI warrants further investigation, and their use should be guided by clinical judgment and individual patient tolerance.

For the management of symptoms in patients with NDI, thiazides are often combined with PSD and/or NSAIDs. The most commonly used combination therapy is thiazides with PSD, followed by the subsequent addition of NSAIDs [18,31]. This approach is taken because, while NSAIDs are effective in reducing urine output, their long-term use raises concerns due to potential GI complications and renal impairment. All pharmacological treatments are most effective when combined with a low-solute diet.

To manage NDI, an integrated approach that combines pharmacological and dietary strategies is essential. Although thiazides, PSDs, and NSAIDs significantly reduce the urine output and improve hydration, their side effects require vigilant monitoring. Dietary adjustments that minimize the osmotic load while ensuring the provision of adequate nutrients and water for normal growth are critical. In particular, a low-salt diet reduces the renal solute load and improves the hydration status without compromising growth and development. Multidisciplinary teams, including nephrologists and dietitians, play a pivotal role in providing personalized care. Advancements in therapeutic options hold promise for addressing the molecular basis of NDI and pave the way for more effective and targeted treatments.