Lithium-induced NDI: acetazolamide reduces polyuria but does not improve urine concentrating ability.

Abstract

Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium-induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long-term (pre)clinical studies.

• Authors: Theun de Groot, Joan Doornebal, Birgitte M Christensen, Simone Cockx, Anne P Sinke, Ruben Baumgarten, Jennifer J Bedford, Robert J Walker, Jack F M Wetzels, Peter M T Deen
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 313 Issue 3 Pg. F669-F676 (09 01 2017) ISSN: 1522-1466 [Electronic] United States
• PMID: 28615247 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 the American Physiological Society.

Chemical References

• Aqp2 protein, mouse
• Aquaporin 2
• Diuretics
• Lithium Chloride
• Acetazolamide

Topics

• Acetazolamide (adverse effects, therapeutic use)
• Aged
• Animals
• Aquaporin 2 (metabolism)
• Blood Pressure (drug effects)
• Diabetes Insipidus, Nephrogenic (chemically induced, drug therapy, physiopathology)
• Disease Models, Animal
• Diuretics (adverse effects, therapeutic use)
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Kidney (drug effects, metabolism, physiopathology)
• Kidney Concentrating Ability (drug effects)
• Lithium Chloride
• Male
• Mice, Inbred C57BL
• Middle Aged
• Netherlands
• New Zealand
• Osmolar Concentration
• Pilot Projects
• Polyuria (chemically induced, drug therapy, physiopathology)
• Prospective Studies
• Time Factors
• Treatment Outcome