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Genetic background determines renal response to chronic lithium treatment in female mice
Physiological Genomics  (IF3.107),  Pub Date : 2021-08-11, DOI: 10.1152/physiolgenomics.00149.2020
Theun de Groot, Rosalinda Doty, Lars Damen, Ruben Baumgarten, Steffi Bressers, Joline Kraak, Peter M.T. Deen, Ron Korstanje

Background Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose and duration of treatment are important risk factors, while genetic background might also play an important role. Methods In order to investigate the role of genetics, female mice of 29 different inbred strains were treated for one year with control or lithium chow and urine, blood and kidneys were analysed. Results Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, while in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, while eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, while the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (B2M) levels, an indicator of proximal tubule damage. Conclusion Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary B2M levels indicates B2M as a promising biomarker for chronic renal damage induced by lithium.