New Approach to Combat Lithium-Induced Diabetes Insipidus

University of Pittsburgh researchers have discovered a novel application for Nrf2 activation using Bardoxolone methyl (CDDO-Me) to treat lithium-induced nephrogenic diabetes insipidus (Li-NDI). Lithium, a common treatment for bipolar disorder, often leads to adverse renal effects, including NDI. This invention leverages the Nrf2 signaling pathway to prevent the development of polyuria in Li-NDI, offering a new therapeutic approach distinct from existing treatments. The activation of Nrf2 induces antioxidant and cytoprotective responses, potentially reducing the progression to chronic kidney disease (CKD) and kidney failure.

Nrf2 hyperactivation protects against development of Li-induced nephrogenic diabetes insipidus (Li-NDI). (A) Schematic of model of Li-NDI showing groups and n per group. (B) Animal weight changes as a function of time, normalized to starting weight.

Description

Nrf2 activation using Bardoxolone methyl (CDDO-Me) represents a significant advancement in the treatment of Li-NDI. Lithium therapy, while effective for bipolar disorder, frequently results in nephrogenic diabetes insipidus, characterized by excessive urination and thirst. Current treatments target sodium-chloride cotransporters, epithelial sodium channels, carbonic anhydrase, or use non-steroidal anti-inflammatory drugs. In contrast, Bardoxolone methyl activates the Nrf2 transcription factor, engaging antioxidant and cytoprotective processes in the kidney. This novel mechanism has shown promise in reducing polydipsia and polyuria in murine models, suggesting potential therapeutic benefits for human patients.

Applications

• Treatment of lithium-induced nephrogenic diabetes insipidus
• Prevention of chronic kidney disease progression
• Therapeutic intervention for disorders of solute/fluid homeostasis

Advantages

This invention offers a unique therapeutic approach by activating the Nrf2 signaling pathway, which has not been previously explored for Li-NDI. Bardoxolone methyl’s ability to reduce the severity of water loss and potentially slow the progression to CKD provides a significant advantage over existing treatments. The activation of Nrf2 induces antioxidant and cytoprotective responses, enhancing kidney health and function.

Invention Readiness

The invention has demonstrated efficacy in vivo, with genetic and pharmacologic activation of Nrf2 showing protective effects against Li-NDI in murine models. Bardoxolone methyl has been specifically tested, revealing its potential to reduce polydipsia and polyuria. The technology is supported by extensive research and development, with promising results indicating readiness for further validation and potential clinical trials.

IP Status

https://patents.google.com/patent/WO2021021520A1