Lithium increases ammonium excretion leading to altered urinary acid-base buffer composition
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Previous reports identify a voltage dependent distal renal tubular acidosis (dRTA) secondary to lithium (Li+) salt administration. This was based on the inability of Li+-treated patients to increase the urine–blood (U–B) pCO2 when challenged with NaHCO3 and, the ability of sodium neutral phosphate or Na2SO4 administration to restore U–B pCO2 in experimental animal models. The underlying mechanisms for the Li+-induced dRTA are still unknown. To address this point, a 7 days time course of the urinary acid-base parameters was investigated in rats challenged with LiCl, LiCitrate, NaCl, or NaCitrate. LiCl induced the largest polyuria and a mild metabolic acidosis. Li+-treatment induced a biphasic response. In the first 2 days, proper urine volume and acidification occurred, while from the 3rd day of treatment, polyuria developed progressively. In this latter phase, the LiCl-treated group progressively excreted more NH4 + and less pCO2, suggesting that NH3/NH4 + became the main urinary buffer. This physiological parameter was corroborated by the upregulation of NBCn1 (a marker of increased ammonium recycling) in the inner stripe of outer medulla of LiCl treated rats. Finally, by investigating NH4 + excretion in ENaC-cKO mice, a model resistant to Li+-induced polyuria, a primary role of the CD was confirmed. By definition, dRTA is characterized by deficient urinary ammonium excretion. Our data question the presence of a voltage-dependent Li+-induced dRTA in rats treated with LiCl for 7 days and the data suggest that the alkaline urine pH induced by NH3/NH4 + as the main buffer has lead to the interpretation dRTA in previous studies.
KeywordsLithium Distal renal tubular acidosis Ammonium Acid-base homeostasis Collecting duct
The authors thank Inger Merete Skrubbeltrang Poulsen and Helle Hoyer for excellent technical assistance with immunohistochemistry and western blotting and Mogen Koed for manufacturing the bicarbonate analyser. Financial support for this study was provided by the Danish National Research Foundation (Grundforskningsfonden), the Marie Curie Research Program (EU’s Sixth Framework Programme), the Lundbeck Foundation, The Danish Council for Independent Research—Medical Sciences, Aarhus University Research Foundation and AU-center: MEMBRANES.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest.
This study does not involve humans.
This study involves only animal models, particularly rats. As stated in the method section, all the experiments have been performed in accordance to the license #2005/561–1032 issued by the Animal Experiments Inspectorate, Denmark.
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