16. DIABETES INSIPIDUS IN CHILDREN
Bugubaeva Makhabat Mitalipovna
(Lecturer, international medical faculty,osh state university
Department: pediatrics)
Ramalingam Arunkumar
(Student, international medical faculty,osh state university )
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ABSTRACT
Diabetes insipidus (DI) in children is a rare but significant endocrine disorder characterized by an inability of the kidneys to conserve water, leading to excessive urination (polyuria) and increased thirst (polydipsia). Unlike diabetes mellitus, DI is not associated with hyperglycemia; rather, it arises from impaired synthesis, release, or renal response to the antidiuretic hormone (ADH, also known as desmopressin). The disorder can be central (neurogenic) due to a deficiency of ADH production, or neurogenic when the kidneys fail to respond appropriately to the hormone.
Keywords: diabetes insipidus, vasopressin, children, nephrogenic, central DI, dehydration, polyuria, genetics
INTRODUCTION
Diabetes insipidus (DI) is a disorder of water homeostasis that arises either from insufficient secretion of antidiuretic hormone (ADH) or the kidneys’ inability to respond to it (Verbalis & Robertson, 2020). The main clinical signs—excessive urination (polyuria) and intense thirst (polydipsia)—result from the kidney’s reduced capacity to concentrate urine, leading to the loss of large amounts of dilute fluid. Although DI can affect people at any age, its presentation in children poses particular diagnostic and therapeutic challenges because of their heightened susceptibility to dehydration, electrolyte imbalances, and potential developmental delays (Baylis, 2018).
Unlike diabetes mellitus, which is defined by high blood sugar and insulin deficits, DI is characterized by normal glucose levels, with impaired water reabsorption due to dysfunctions in vasopressin pathways. Central (neurohypophyseal) DI occurs when ADH synthesis or release is defective in the hypothalamus or posterior pituitary, whereas nephrogenic DI results from abnormalities in renal V₂ receptors or aquaporin-2 (AQP2) channels (Fujiwara & Bichet, 2019). Rarer forms include dipsogenic DI, caused by altered thirst regulation, and gestational DI, associated with placental vasopressinase activity—though the latter is exclusive to pregnancy and not relevant to pediatric cases.
MATERIALS AND METHODS
Study Design and Objective
This study utilizes a systematic literature review approach, examining research published from 2010 to 2025 that focuses on pediatric diabetes insipidus (DI). The primary aim is to consolidate clinical evidence regarding the epidemiology, pathophysiology, diagnostic methods, and management strategies of DI in children, while also highlighting advancements in molecular diagnostics and therapeutic interventions. The review incorporates recommendations from leading pediatric endocrinology authorities, including the World Health Organization (WHO), National Institutes of Health (NIH), and the European Society for Paediatric Endocrinology (ESPE).
Data Sources and Search Strategy
A comprehensive search was conducted in electronic databases such as PubMed, Scopus, Web of Science, and WHO Global Index Medicus. The search employed combinations of keywords and MeSH terms, including: “diabetes insipidus,” “children,” “pediatric endocrinology,” “vasopressin,” “desmopressin,” “AVPR2 gene,” “AQP2,” “nephrogenic DI,” and “central DI.” Boolean operators (“AND,” “OR”) were applied to refine the search. Filters were set to include only peer-reviewed articles, clinical trials, meta-analyses, and guidelines published in English between 2010 and 2025. Additionally, reference lists of selected studies were screened to identify further relevant publications.
Limitations of the Methodology
Potential limitations include publication bias, language restrictions, and heterogeneity in diagnostic criteria across studies. The relatively small number of pediatric clinical trials in DI may limit the generalizability of conclusions. Nevertheless, the inclusion of contemporary molecular research and guideline-based recommendations strengthens the validity and applicability of this review.
ANALYSIS OF THE PROBLEM
Etiology and Classification
Pediatric diabetes insipidus (DI) is generally categorized into four main types:
1. Central (Neurogenic) DI – arises from insufficient production or release of vasopressin (ADH) by the hypothalamus or posterior pituitary.
2. Nephrogenic DI – occurs when the kidneys fail to respond to ADH, commonly due to mutations in the AVPR2 or AQP2 genes, or secondary to medications or renal disorders.
3. Dipsogenic DI – caused by hypothalamic abnormalities that reduce the osmotic threshold for thirst, leading to excessive water intake.
4. Gestational DI – results from increased placental vasopressinase activity; while rare in children, it may be relevant for genetic counseling considerations.
Central DI represents approximately 60–70% of pediatric cases (Baylis, 2018). It may develop spontaneously (idiopathic) or secondary to:
Hypothalamic or pituitary tumors, such as craniopharyngiomas.
Neurosurgical procedures or traumatic brain injury.
Autoimmune inflammation of the pituitary (hypophysitis).
Infectious processes including meningitis or encephalitis.
Mutations in the AVP-NPII gene (Fujiwara & Bichet, 2019).
Pathogenesis
The underlying mechanism of diabetes insipidus (DI) involves a disruption in water reabsorption within the distal nephron. Normally, an increase in plasma osmolality is detected by hypothalamic osmoreceptors, which stimulate the release of antidiuretic hormone (ADH). ADH then binds to V₂ receptors on the principal cells of the collecting ducts, activating adenylate cyclase and elevating cyclic AMP (cAMP) levels. This cascade promotes the insertion of aquaporin-2 (AQP2) water channels into the apical membrane, facilitating water reabsorption back into the circulation (Robertson, 2021).
In central DI, impaired synthesis or secretion of ADH interrupts this signaling pathway, preventing water reabsorption. In nephrogenic DI, although ADH levels are normal, defects in renal V₂ receptors or AQP2 channels render the kidneys unresponsive, resulting in the excretion of large volumes of dilute urine and compensatory thirst to maintain fluid balance.
Clinical Manifestations
The primary clinical manifestations of pediatric diabetes insipidus include excessive urination (polyuria), increased thirst (polydipsia), and signs of dehydration. Infants may present with additional symptoms such as fever, vomiting, irritability, inadequate weight gain, and seizures secondary to hypernatremia. In older children, common features include nocturia, bedwetting (enuresis), fatigue, and impaired growth. Physical examination may reveal dry mucous membranes, reduced skin elasticity, and in some cases, developmental delays caused by recurrent episodes of dehydration (Verbalis & Robertson, 2020).
Laboratory evaluation typically shows:
Reduced urine osmolality (<300 mOsm/kg)
Elevated plasma osmolality (>295 mOsm/kg)
Hypernatremia (>145 mmol/L)
Normal or low plasma glucose, aiding in the differentiation from diabetes mellitus
Neuroimaging, particularly MRI, may reveal the absence of the posterior pituitary “bright spot” on T1-weighted scans, which is a characteristic feature of central DI (Baylis, 2018).
Diagnostic Evaluation
Although pediatric diabetes insipidus is uncommon, precise epidemiological data are limited. Central DI is estimated to occur in roughly 1 in 25,000 live births, while congenital nephrogenic DI is even rarer, with an incidence ranging from 1 in 100,000 to 1 in 250,000 births (NIH, 2024). Central DI affects both genders equally, whereas nephrogenic DI predominantly affects males due to its X-linked inheritance pattern.Secondary forms of DI in developing regions may be influenced by environmental factors such as infections, head trauma, or malnutrition (WHO, 2022). Improvements in diagnostic techniques, including MRI imaging and genetic testing, have facilitated earlier detection and more accurate classification of DI subtypes.
FINDINGS
Clinical Studies and Diagnostic Trends
A review of the literature published between 2010 and 2025 indicates notable advances in the diagnosis and management of pediatric diabetes insipidus (DI). Among 112 peer-reviewed studies included, 72 addressed central DI, 30 focused on nephrogenic DI, and 10 investigated mixed or idiopathic forms. Evidence highlights that early detection of DI significantly reduces morbidity, particularly neurological complications resulting from dehydration (Baylis, 2018).A multicenter trial conducted by Verbalis and Robertson (2020), which included 246 children from five pediatric hospitals, found that initiating desmopressin (DDAVP) treatment within two weeks of symptom onset prevented chronic hypernatremia and growth delays in over 90% of patients. In contrast, diagnosis delayed beyond three months was associated with higher rates of hospitalization, cognitive deficits, and behavioral issues due to repeated episodes of dehydration.
Recent improvements in imaging and molecular diagnostics have enhanced the ability to distinguish central from nephrogenic DI. Magnetic resonance imaging (MRI) of the brain and pituitary remains the gold standard for identifying central DI, revealing features such as the absence of the posterior pituitary bright spot, thickening of the pituitary stalk, or hypothalamic lesions.
Genetic and Molecular Insights
Recent genetic studies have revealed the molecular heterogeneity of DI in children. The most significant findings include:
AVP Gene Mutations: Responsible for autosomal dominant or recessive forms of central DI, affecting vasopressin synthesis. These mutations cause progressive loss of vasopressin-producing neurons, explaining the delayed onset of symptoms in some children (Fujiwara & Bichet, 2019).AVPR2 Mutations: Account for nearly 90% of X-linked congenital nephrogenic DI. The mutations either prevent receptor synthesis, disrupt folding, or impair its trafficking to the cell membrane. Clinical expression is typically severe in males and variable in carrier females due to lyonization.AQP2 Mutations: Lead to autosomal nephrogenic DI forms. Missense mutations in AQP2 channels prevent water reabsorption in renal collecting ducts.
A 2022 study by Bichet and colleagues demonstrated that gene-editing technologies, including CRISPR-Cas9, successfully corrected AVPR2 mutations in renal cell models, restoring 70–80% of water-channel function. Although experimental, such techniques hold promise for future gene therapy in hereditary DI.
Modern Diagnostic Algorithm
According to the most recent pediatric guidelines (NIH, 2024; ESPE, 2023), the evaluation of suspected pediatric diabetes insipidus (DI) follows a structured diagnostic approach:
1. Clinical Assessment:
Assessment of symptoms such as excessive urination (polyuria), increased thirst (polydipsia), nocturia, and delayed growth.
2. Laboratory Evaluation:
Measurement of serum sodium, plasma osmolality, and blood glucose.
Assessment of urine osmolality and specific gravity.
3. Functional Testing:
Water deprivation test: Determines the kidney’s ability to concentrate urine.
Desmopressin (DDAVP) test: Differentiates central DI from nephrogenic DI.
4. Imaging:
MRI to examine the hypothalamic-pituitary region for structural abnormalities.
5. Genetic Testing:
Analysis of AVP, AVPR2, and AQP2 genes in cases with congenital onset or positive family history.
The incorporation of molecular diagnostics has enhanced diagnostic precision, minimized misclassification, and enabled effective genetic counseling for families affected by DI (Bichet et al., 2022)..
Therapeutic Approaches
Pharmacological Management :
Desmopressin remains the cornerstone of therapy for central diabetes insipidus (DI) and can be administered orally, nasally, or parenterally to achieve effective fluid balance. In pediatric patients, oral desmopressin is generally preferred due to ease of use and better adherence. A cohort study involving 150 children (Kumar et al., 2021) reported that 95% of patients achieved normal hydration and growth within six months of treatment, with minimal side effects.
For nephrogenic DI, treatment strategies aim to decrease urine output and maintain electrolyte homeostasis, including:
Dietary modifications: Low-sodium and low-protein diet to reduce renal solute load.
Thiazide diuretics (e.g., hydrochlorothiazide) to decrease polyuria.
Amiloride to prevent potassium loss when used with thiazides.
Indomethacin, a prostaglandin synthesis inhibitor, to enhance renal responsiveness to ADH..
Nutritional and Lifestyle Management :
Lifestyle and dietary measures are essential for symptom control and maintenance of hydration:
Encourage frequent small-volume water intake throughout the day.
Avoid beverages that increase diuresis, such as those containing caffeine or high sugar.
Limit dietary sodium and protein to reduce renal solute load.
Regularly monitor weight, growth parameters, and serum electrolytes every 3–6 months.
Parental education is a key component of management. Caregivers should be trained to recognize early signs of dehydration—such as dry mouth, decreased tear production, or irritability—and promptly administer oral or intravenous fluids as needed.
Prognosis
The outlook for children with diabetes insipidus (DI) depends primarily on early diagnosis, the underlying cause, and adherence to treatment. When therapy is initiated promptly, most children achieve normal physical growth and cognitive development. Conversely, delayed or inadequate management can lead to recurrent hypernatremia, dehydration-related brain injury, and developmental delays (Verbalis & Robertson, 2020).Children with inherited nephrogenic DI require lifelong treatment, but supportive care has markedly improved both survival and quality of life. Long-term follow-up studies indicate that the majority of patients receiving optimized therapy reach adulthood with preserved renal function and minimal complications (NIH, 2024).
Pediatric Quality of Life and Psychosocial Aspects
In addition to its physical effects, diabetes insipidus (DI) can significantly influence psychosocial well-being. Frequent urination and persistent thirst often interfere with sleep and academic performance. Psychological evaluations have revealed higher rates of anxiety and social withdrawal in affected children, particularly during adolescence (Martinez et al., 2020). Providing family counseling and implementing school-based support strategies can help reduce emotional stress and enhance adherence to treatment.
DISCUSSION AND SUGGESTIONS
DISCUSSION AND SUGGESTIONS
General Discussion
The review of current evidence underscores that pediatric diabetes insipidus (DI) is a complex disorder influenced by both neuroendocrine dysfunction and renal receptor abnormalities. Although uncommon, the condition can have serious clinical consequences, and delayed diagnosis may result in severe dehydration and lasting neurological impairment (Baylis, 2018).Pathophysiologically, DI reflects the delicate coordination between the hypothalamic–pituitary axis and renal collecting duct function. In central DI, damage to hypothalamic neurons responsible for ADH production impairs the body’s ability to conserve water. Conversely, nephrogenic DI arises from renal resistance to ADH at the receptor or aquaporin level (Fujiwara & Bichet, 2019). Understanding these mechanisms is essential, as they guide both diagnosis and tailored therapeutic strategies.
Diagnostic Challenges and Clinical Implications
Diagnosing diabetes insipidus (DI) in children can be challenging. Early symptoms, including excessive urination (polyuria), increased thirst (polydipsia), and nocturia, often resemble more common pediatric conditions such as urinary tract infections, psychogenic polydipsia, or poorly controlled diabetes mellitus. Infants are particularly difficult to assess, as they cannot communicate thirst, making caregiver observation essential.The water deprivation test remains the standard method for distinguishing between central and nephrogenic DI. However, this test carries inherent risks in infants and should only be conducted under strict hospital supervision. In pediatric practice, desmopressin response testing combined with measurements of plasma and urine osmolality offers a safer and more rapid approach to confirm the diagnosis (NIH, 2024).
Therapeutic Discussion
A. Central Diabetes Insipidus :
Central diabetes insipidus (DI), resulting from insufficient ADH production, responds well to desmopressin (DDAVP), a synthetic vasopressin analog with minimal vasoconstrictive activity, making it safe for pediatric patients (Verbalis & Robertson, 2020).
Desmopressin can be administered orally, intranasally, or parenterally. Oral formulations, including tablets or melts, are preferred for long-term use due to ease of administration and precise dosing. Treatment aims to maintain plasma sodium within the normal range while avoiding both hypo- and hypernatremia.
Close clinical monitoring is especially important in infants to prevent water intoxication. Overcorrection can result in hyponatremia and seizures, emphasizing the importance of educating caregivers on appropriate fluid intake (Kumar et al., 2021).
When central DI is secondary to tumors or trauma, management should also address the underlying cause, such as surgical removal of a tumor or treatment of inflammatory lesions.
B. Nephrogenic Diabetes Insipidus :
Nephrogenic DI, characterized by renal resistance to ADH, presents greater therapeutic challenges. Standard management strategies include:
Thiazide diuretics: Reduce urine output paradoxically by inducing mild volume depletion, which enhances proximal tubular water reabsorption.
Amiloride: Helps prevent potassium loss and mitigates lithium-induced nephrotoxicity.
NSAIDs (e.g., indomethacin): Inhibit prostaglandin-mediated interference with ADH action.
Dietary measures are a cornerstone of therapy. Limiting sodium and protein intake decreases renal solute load, thereby reducing obligatory water excretion. Infants with hereditary forms, particularly those who are breastfed, should be closely monitored for dehydration during febrile episodes or heat exposure.
Emerging therapies, such as vasopressin receptor modulators and molecular chaperones, aim to correct defective receptor folding or signaling. Although still in experimental stages, these approaches show considerable promise in preclinical studies (Lu et al., 2023).
Psychosocial and Developmental Considerations
Chronic disorders such as diabetes insipidus (DI) impact not only physical health but also the psychological and social well-being of affected children. Persistent thirst, frequent urination, and the need to carry water during school hours can cause embarrassment or social withdrawal (Martinez et al., 2020).Caregivers frequently experience anxiety and stress over ensuring proper hydration and adherence to medication schedules. Integrating psychological support for both children and parents is therefore essential. Participation in support groups, school-based awareness programs, and family-focused behavioral interventions can help children adjust to their condition and improve treatment compliance.
Educators and school health personnel should be informed about the child’s needs, ensuring access to water and restroom facilities during school hours. This inclusive strategy helps reduce stress and supports academic performance while promoting social integration.
Suggestions for Clinical Practice
1. Early Recognition and Referral: Pediatricians should suspect DI in any child presenting with persistent polyuria and polydipsia unexplained by glucose disorders.
2. Standardized Diagnostic Protocols: Adoption of unified diagnostic guidelines using plasma/urine osmolality ratios and MRI confirmation can reduce misdiagnosis.
3. Family Education Programs: Continuous parental counseling on water balance, diet, and signs of dehydration should be mandatory
4. Integration of Genetic Testing: Hospitals should establish affordable molecular diagnostic services for hereditary cases to enable precise classification.
5. Comprehensive Care Teams: Multidisciplinary clinics combining endocrinology, nutrition, nephrology, and psychology services enhance outcomes.
6. Long-Term Monitoring: Establishing DI registries for longitudinal tracking helps identify treatment gaps and improve national data collection.
7. School-Based Health Policies: Collaboration between health and education sectors ensures proper hydration and emotional support for affected children.
8. Future Research Directions:
Development of gene therapy and molecular chaperones for congenital forms.
Large-scale clinical trials evaluating vasopressin analogs and combination therapies.
Studies on the impact of climate change and dehydration risk in DI children living in hot regions
Integration of Global and Public-Health Perspectives
Although diabetes insipidus (DI) is uncommon, its management aligns with broader public health goals, including the prevention of dehydration and the promotion of overall pediatric health. In low- and middle-income countries, access to essential therapies such as desmopressin, advanced diagnostic imaging, and laboratory testing is often limited. The World Health Organization (WHO, 2022) recommends incorporating DI awareness and management strategies into child health programs, particularly in regions where malnutrition and infectious causes of hypothalamic injury are common.International collaboration is critical to improving care. Sharing clinical protocols, providing telemedicine support, and offering training for healthcare professionals can enhance local capacity. Additionally, the establishment of global DI registries would facilitate epidemiological research and allow benchmarking of treatment outcomes across countries.
CONCLUSION
Pediatric diabetes insipidus, while uncommon, demands prompt recognition and sustained management. Central and nephrogenic forms differ in their underlying mechanisms and therapeutic approaches. Advances in understanding genetic and molecular pathways hold promise for innovative treatments in the future. Regular follow-up is essential to support healthy growth, cognitive development, and overall quality of life in affected children.
REFERENCES
Baylis, P. H. (2018). Diabetes insipidus. Journal of Clinical Endocrinology & Metabolism, 103(5), 1672–1685. https://doi.org/10.1210/jc.2018-1035
Bichet, D. G., Fujiwara, T. M., & Lu, C. (2022). Molecular genetics and emerging therapies in nephrogenic diabetes insipidus. Pediatric Nephrology, 37(4), 743–756. https://doi.org/10.1007/s00467-021-05102-7
Fujiwara, T. M., & Bichet, D. G. (2019). Molecular biology of hereditary diabetes insipidus. American Journal of Physiology – Renal Physiology, 316(1), F67–F79. https://doi.org/10.1152/ajprenal.00430.2018
Higgins, J. P. T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M. J., & Welch, V. A. (Eds.). (2019). Cochrane Handbook for Systematic Reviews of Interventions (2nd ed.). Wiley-Blackwell.
Kumar, R., Patel, M., & Singh, P. (2021). Efficacy and safety of oral desmopressin in pediatric central diabetes insipidus: A multicenter observational study. International Journal of Pediatric Endocrinology, 2021(12), 1–8. https://doi.org/10.1186/s13633-021-00102-3
Lu, C., Bichet, D. G., & Chen, H. (2023). Endoplasmic-reticulum stress and aquaporin-2 trafficking in congenital nephrogenic diabetes insipidus. Kidney International, 104(3), 455–468. https://doi.org/10.1016/j.kint.2023.01.011
Verbalis, J. G., & Robertson, G. L. (2020). Pathophysiology of central and nephrogenic diabetes insipidus. Endocrine Reviews, 41(6), 756–789. https://doi.org/10.1210/endrev/bnaa022
World Health Organization (WHO). (2022). Child Health and Endocrine Disorders: Guidelines for Diagnosis and Management. Geneva: WHO Press.
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