Nephrogenic diabetes insipidus: potential treatments and their mechanisms of action.

Siraj Alabeedi; Mohamed  Elkawafi

doi:10.54361/LJME.19.1.13

Authors

Siraj W A Alabeedi1 Programme of Medicine, Faculty of Medical and Health sciences, Libyan International Medical University Author
Mohamed K A Elkawafi Programme of Basic Medical sciences, Faculty of Medical and Health sciences, Libyan International Medical University Author

DOI:

https://doi.org/10.54361/LJME.19.1.13

Keywords:

Aquaporins, Nephrogenic diabetes insipidus, AQP2, Statins, Secretin agonists

Abstract

Nephrogenic diabetes insipidus (NDI) is a rare disease caused by the complete or partial resistance of the kidneys to antidiuretic hormone (ADH). NDI associated with excessive urine production and severe thirst. There are two types of NDI; acquired NDI and congenital NDI. Acquired NDI is the most common type among adults, with several factors that can cause acquired NDI, for instance, lithium therapy and electrical disorders. Congenital NDI can occur due to mutations in either the arginine vasopressin receptor 2 (AVPR2) gene or the aquaporin-2 (AQP2) gene. New effective treatments for NDI are required because the disease can be life treating if left untreated. Current animal studies showed that rolipram and metformin are two potential treatments for congenital NDI by upregulation the apical expression of AQP2 channels. Other animal studies illustrated that the combination of different drugs, such as, secretin agonist and fluvastatin could be an effective method to treat XNDI. Furthermore, some agents were found to be able to treat more than one type of NDI, for example, sildenafil citrate could be potently used to treat acquired NDI and XNDI, while statins could be promising treatments for congenital NDI and autosomal NDI. However, further investigation and human trials are needed before it can be decided if these drugs can be clinically used as a treatment for NDI.

References

Kalra, S., Zargar, A.J., Jain, S.M., Sethi, B., Chowdhury, S., Singh., A.K., Thomas, N., Unnikrishnan, A.G., Thakkar, P.B., and Malve, H. 2016. Diabetes insipidus: The other diabetes. Indian Journal of Endocrinology and Metabolism. 20(1), pp. 9 – 21.

Bech, P.A., Wetzels, J.F.M., and Nijenhuis, T.2018. Effects of sildenafil, metformin, and simvastatin on ADH-independent urine concentration in healthy volunteers. Physiological Reports. 16(7), pp. 1-7.

Rare diseases. 2016. Nephrogenic Diabetes Insipidus. [Online]. [Accessed 15 November 2024]. Available from: https://rarediseases.org/rare-diseases/nephrogenic-diabetes-insipidus/.

Bockenhauer, D., and Bichet, D.G. 2014. Urinary concentration: different ways to open and close the tap. Pediatric Nephrology. 29(8), pp. 1297 – 1303.

Bonfrate, L., Procino, G., Wang, D.Q.H., Svelto, M., and Portincasa, P. 2015. A novel therapeutic effect of statins on nephrogenic diabetes insipidus. Journal of Cellular and Molecular Medicine. 19(2), pp. 265-282

Milano, S., Carmosino, M., Gerbino, A., Svelto, M., and Procino, G. 2017. Hereditary nephrogenic diabetes insipidus: pathophysiology and possible treatment. an update. International Journal of Molecular Sciences. 18(11), pp. 2385-2441.

Wesche, D., Deen, P.M.T., and Knoers., N.V.A.M. 2012. Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol.27(12), pp. 2183 – 2204.

Moeller, H.B., Rittig, S., and Fenton, R.A. 2013. Nephrogenic Diabetes Insipidus: Essential Insights into the Molecular Background and Potential Therapies for Treatment. Endocrine Reviews. 34(2):278–301.

Dollerup, P., Thomsen, T.M., Nejsum, L.N., Færch, M., Österbrand, M., Gregersen, N., Rittig, S., Christensen, J.H., and Corydon, T.J. 2015. Partial nephrogenic diabetes insipidus caused by a novel AQP2 variation impairing trafficking of the aquaporin-2 water channel. BMC nephrology. 16(1), pp.217 – 228.

Fricka, A., Erikssona, U.K., de Mattiab, F., Öberga, F., Hedfalka, K., Neutzea, R., de Gripc, W., Deenb, P.M.T., and Törnroth-Horsefielda, S. 2014. X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking. Proceedings of the National Academy of Sciences. 111(17), pp. 6305 – 6310.

Li, W., Zhang, Y., Bouley, R., Chen, Y., Matsuzaki, T., Nunes, P., Hasler, U., Brown, D., and Lu, H.A.J. 2011. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. American Journal of Physiology–Renal Physiology. 301(2), pp. F309 - F318.

Soh, J.F., Torres-Platas, S.G., Beaulieu, S., Mantere, O., Platt, R., Mucsi, I., Saury, S Renaud, S., Levinson, A., Andreazza, A.C., Mulsant., B.H., Müller, D., Schaffer, A., Dols., A., Cervantes, P., Low, N.C., Herrmann, N., Christensen, B.M., Trepiccione, F., Rajji, T., and Soham Rej, S. 2018. Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial. BMC Psychiatry. 8, pp. 2-7.

Procino, G., Maiolo, D., Barbieri, C., Milano, S., Squatrito, S., Svelto, M., and Gullo, D. 2014. Fluvastatin Increases AQP2 Urine Excretion in a Dyslipidemic Patient with Nephrogenic Diabetes Insipidus: An In Vivo and In Vitro Study. Journal of Diabetes and Metabolism. 5(7), pp.408- 414.

Procino, G., Milano, S., Carmosino, M., Barbieri, C., Nicoletti, M.C., Li, J. H., Wess, J., and Svelto, M. 2014. Combination of secretin and fluvastatin ameliorates the polyuria associated with x-linked nephrogenic diabetes insipidus in mice. Kidney International. 86(1), pp. 127–138.

Klein, J.D., Wang, Y., Blount, M.A., Molina, P.A., LaRocque, L.M., Ruiz, J.A., and Sands, J.M. 2016. 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. 310(10), pp. F1008 - F1012.

Efe, D., Klein, J.D., Lauren M. LaRocque, L.M., Ren, H., and Sands, J.M. 2016. Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus. JCI insight. 1(11), pp. 1-11.

Sohara, E., Rai, T., Yang, S., Uchida, K., Nitta, K., Horita, S., Ohno, M., Harada, A., Sasaki, S., and Uchida, S. 2006. Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. Proceedings of the National Academy of Sciences. 103(38), pp. 14217 – 14222.

Sanches, T.R., Volpini, R.A., Shimizu, M.H.M., de Bragança, A.C., Oshiro-Monreal, E., Seguro, A.C., and Andrade, L. 2012. Sildenafil reduces polyuria in rats with lithium-induced NDI. American Journal of Physiology–Renal Physiology. 302(1), pp. F216–F225.

Assadi, F., and Sharbaf, F.G. 2015. Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus. American Journal of Nephrology. 42(1), pp. 65 – 69.

Low, N.C., Herrmann, N., Christensen, B.M., Trepiccione, F., Rajji, T., and Rej, S. 2018. Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial. BMC Psychiatry. 18(1), pp. 1-7.