Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus.

Abstract

To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.

• Authors: Theun de Groot, Anne P Sinke, Marleen L A Kortenoeven, Mohammad Alsady, Ruben Baumgarten, Olivier Devuyst, Johannes Loffing, Jack F Wetzels, Peter M T Deen
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 27 Issue 7 Pg. 2082-91 (Jul 2016) ISSN: 1533-3450 [Electronic] United States
• PMID: 26574046 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• Aquaporin 2
• Diuretics
• Lithium Compounds
• Sodium Chloride Symporter Inhibitors
• Amiloride
• Acetazolamide

Topics

• Acetazolamide (therapeutic use)
• Amiloride (therapeutic use)
• Animals
• Aquaporin 2 (metabolism)
• Diabetes Insipidus, Nephrogenic (chemically induced, drug therapy)
• Diuretics (therapeutic use)
• Female
• Lithium Compounds (adverse effects)
• Mice
• Mice, Inbred C57BL
• Sodium Chloride Symporter Inhibitors (therapeutic use)