In this week's episode, we explore a rare genetic disorder that results in excessive urination. X-Linked Congenital Nephrogenic Diabetes Insipidus (NDI) is a disease where sufferers produce excessive amounts of urine, causing dehydration, electrolyte imbalance, and other issues. We explore what causes this disease, why it results in so much extra urine production, and what treatments are available and coming down the pipeline.

References:

• Wesche D, Deen PM, Knoers NV. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatric nephrology. 2012 Dec;27(12):2183-204. https://doi.org/10.1007/s00467-012-2118-8
• Klein JD, Wang Y, Blount MA, Molina PA, LaRocque LM, Ruiz JA, Sands JM. Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts. American Journal of Physiology-Renal Physiology. 2016 May 15;310(10):F1008-12. https://doi.org/10.1152/ajprenal.00102.2016
• National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes insipidus [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; [updated 2025 Oct 3; cited 2026 Jul 17]. https://www.niddk.nih.gov/health-information/kidney-disease/diabetes-insipidus
• Marieb EN, Hoehn K. The urinary system. Human anatomy & physiology. [11th Edition]. [Hoboken, New Jersey]: Pearson; [2019]. p. 974–1011.
• Bichet, D.G. and Bockenhauer, D., 2016. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant). Best Practice & Research Clinical Endocrinology & Metabolism, 30(2), pp.263-276. https://doi.org/10.1016/j.beem.2016.02.010
• Knoers N, Lemmink H.Hereditary nephrogenic diabetes insipidus. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026 [updated 2020 Feb 27]. https://www.ncbi.nlm.nih.gov/books/NBK1177/
• Perrine AL, Reechaye D, Banerjee I, Robinson J, Banerjee I. Paradoxical Anti-diuretic Effects of Thiazide and Thiazide-Like Diuretics in Diabetes Insipidus: A Systematic Review. Cureus. 2025 Apr 14;17(4). https://doi.org/10.7759/cureus.82247

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