An Unfiltered Look at X-Linked Congenital Nephrogenic Diabetes Insipidus (NDI)

My buddy has a swimming pool, and taking care of it is kind of a nightmare. He’s always skimming leaves, scrubbing the bottom, testing the pH, adding chlorine, checking alkalinity, measuring calcium, repairing the cleaning robot, fixing hoses, inspecting the pump, adding water, and repeating the whole process ad infinitum. One of the biggest challenges he faced as a pool owner came when the filter system broke. The pump kept pulling dirty water out of the pool, but the filter housing failed,causing water to leak out around the filter rather than circulate back into the pool, effectively draining it. He called in a professional to fix it, spent a fortune refilling the pool, and has been worried about water intrusion affecting the house foundation ever since. This has been stressful, but it's nothing compared to X-linked congenital nephrogenic diabetes insipidus.

X-linked congenital nephrogenic diabetes insipidus (NDI) is a disease with a ridiculous name and ridiculous effects. If you were paying attention in your high school biology class, you might notice the name gives us clues as to what the disease is and what causes it:

• X-linked means the condition is due to a defect on the X (sex) chromosome; in this case it’s more common in males
• Congenital indicates that the disease is present from birth
• Nephrogenic describes the kidney tissue, the source of the problem
• Diabetes is from the ancient Greek word for a “passer through,” indicating excessive urine
• Insipidus is Latin for “without taste,” indicating that the excessive urine does not have high levels of sugar

Together, the name tells us that NDI is a chromosomal disorder, present from birth, that affects kidney tissue to make excessive, non-sugary urine. It is rare, and almost all sufferers are male.^[1,2] Those with the disease urinate incredible amounts of liquid, up to 5 gallons a day in severe cases.^[1,3] Along with the debilitating effect of frequent urination, those with NDI experience thirst, dehydration, electrolyte imbalance, and must constantly drink water.^[3]

Much like my buddy’s swimming pool issues, the problem is with the filter. The kidneys act as a filter for our blood, which is mostly water. Kidney management of water is critical, in large part because we are 60-75% water by weight.^[1] Blood flows through approximately 1-2 million tiny structures called nephrons, which pull water out of the blood, push important nutrients back into the blood, concentrate waste, and return clean water to the blood.^[4] Unfortunately, with NDI, that last step breaks down. Urine does not become concentrated in the kidneys and instead, literal gallons of relatively clean, dilute, “tasteless” water pass into the bladder and are urinated out.^[1,2]

Though the filter is the point of failure in NDI and the swimming pool, the actual cause of failure in NDI is a bit more complex. The body relies on the hormone arginine-vasopressin to regulate functions such as thirst, kidney function, blood pressure, and other autonomic processes.^[5] In the kidneys, arginine-vasopressin in the blood normally binds with an arginine-vasopressin receptor that detects levels of the hormone and sends a signal to open special “aquaporin-2” water channels that reabsorb the water.^[1,2] With X-linked congenital NDI, the gene responsible for coding arginine-vasopressin receptors has mutated in a way that makes it unable to bind with arginine-vasopressin or unable to send the downstream signal.^[5] As a result, aquaporin-2 water channels don’t open, and the water in the kidneys can’t get out except through the bladder.

So, what can be done? Unfortunately, tailor-made medications for X-linked congenital NDI are scarce. Currently approved therapies include the use of thiazide diuretics like hydrochlorothiazide (HCTZ) and chlorothiazide, which have a paradoxical long-term anti-diuretic effect for those with NDI.^[6,7] NSAIDs (non-steroidal anti-inflammatory drugs) may help concentrate urine and reduce output, but come with side effects that get worse over time.^[6] Other than these treatments, people with NDI may need to be on a salt-restricted diet and may need specialized IV fluids during rehydration, hospitalizations, or surgeries, even when those medical events are unrelated to their NDI.^[6]  Thankfully, there is a new flow to NDI treatment from the world of clinical research. Researchers are exploring new ways to activate the aquaporin-2 channels using direct medications, bypassing the faulty arginine-vasopressin receptors altogether.^[2] If these trials are successful, those with NDI may be able to dive into a new world of treatment.

Creative Director Benton Lowey-Ball, MWC, BS, BFA

References:

[1] 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

[3] 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

[4] Marieb EN, Hoehn K. The urinary system. Human anatomy & physiology. [11th Edition]. [Hoboken, New Jersey]: Pearson; [2019]. p. 974–1011.

[5] 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

[6] 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/

[7] 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