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Lithium increases ammonium excretion leading to altered urinary acid-base buffer composition

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Abstract

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Francesco Trepiccione, Birgitte Mønster Christensen & Sebastian Frische

  2. Department of Cardio-Thoracic and Respiratory Science, University of Campania “Luigi Vanvitelli”, Via Pansini 5, 80131, Naples, Italy

    Francesco Trepiccione, Claudia Altobelli & Giovambattista Capasso

  3. Istituto di Ricerche Gaetano Salvatore, Biogem S.c.a.r.l., Naples, Italy

    Giovambattista Capasso

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  1. Francesco Trepiccione
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Correspondence to Francesco Trepiccione.

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Ethical statement

This study does not involve humans.

Animal care

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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40620_2017_460_MOESM1_ESM.tif

Figure S1: Time course of the urinary lithium excretion. Lithium excretion during the 7 days of treatment. As expected urinary Li+ was detected exclusively in rats treated either with LiCl or LiCitrate. Li+ excretion was similar in these two group showing equal intake of lithium (*** is for p-value < 0.001 One-way ANOVA followed by Tukey’s multiple comparison test was used for statistics) (TIF 193 KB)

40620_2017_460_MOESM2_ESM.tif

Figure S2: Time-course of acid-base urinary parameters including all the groups. Treatment with NaCl or NaCitrate did significantly affect the urinary acid-base parameters (TIF 1073 KB)

40620_2017_460_MOESM3_ESM.tif

Figure S3: Pendrin expression after 7 days of treatment. Immunohistochemistry of kidney sections from rats treated for 7 days with LiCl enriched diet, LiCitrate enriched diet or normal food. Sections are labelled with an anti-pendrin antibody. The upper panel shows localization of pendrin exclusively in the renal CTX/OSOM. The lower panel shows the expected distribution of pendrin on the apical plasma membrane domain (TIF 2557 KB)

40620_2017_460_MOESM4_ESM.tiff

Figure S4: Time course of urinary potassium excretion and food intake. Time course of urinary potassium over creatinine excretion (A) and food intake (B) in control rats black circle) and in rats receiving food enriched with LiCl 40 mmole/Kg of dry food (open square) or equivalent lithium amount of LiCitrate (open triangle). * is for significant difference between control and LiCl group, § between Ctr and LiCitrate group. For panel A, One-way ANOVA followed by Tukey’s multiple comparison test was used for statistics, while Two-way ANOVA has been performed for food intake (TIFF 174 KB)

40620_2017_460_MOESM5_ESM.tif

Figure S5: Blue Comassie staining. Representative pictures from Comassie Blue gel from Cortex, ISOM and IM samples (TIF 850 KB)

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Trepiccione, F., Altobelli, C., Capasso, G. et al. Lithium increases ammonium excretion leading to altered urinary acid-base buffer composition. J Nephrol 31, 385–393 (2018). https://doi.org/10.1007/s40620-017-0460-4

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