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Periodic Report Summary 1 - LITHIOPATHIES (Towards gene identification and personalized prophylactic medication for lithiopathies in lithium-using patients)


Lithium is widely prescribed and the mainstay treatment for bipolar disorders. Unfortunately, lithium treatment often leads to adverse side effects (lithiopathies) including nephrogenic diabetes insipidus (NDI), hypercalcaemia and chronic kidney disease (CKD). As the lithiopathies are largely irreversible, medication for the lithiopathies should be administered with the start of lithium treatment. However, prophylactic administration of these medications to lithium-using patients is undesirable, because not all patients develop lithiopathies. Therefore, to target for lithiopathy-specific personalized prophylactic medication, the aim of this study is to identify the susceptibility genes for development of the lithiopathies.

Project objectives

1) Identify susceptibility gene clusters for the development of lithiopathies in mice.
2) Isolate the responsible gene within the cluster.
3) Rationally hypothesize the role of the gene in lithiopathy development.

Update work progress and results

1) Identify susceptibility gene clusters for the development of lithiopathies in mice.

To identify the susceptibility genes for the different lithiopathies, haplotype association mapping (HAM) is performed using 29 different mouse strains that were treated with a control or lithium diet. Phenotype data was collected at day 9-10, day 27-28 and day 364-365 by housing the mice in metabolic cages to collect urine (all time points), isolating blood (all time points) and isolate the kidneys (only at end experiment).

a. Nephrogenic Diabetes Insipidus (NDI): Large variability among the inbred strains was observed in urine output and urine osmolality between control and lithium-treated mice at all time points. In many strains a significant increase in urine output was noted in the lithium-treated mice compared to the control groups at all time points. However there were also strains without a change in urine output after lithium treatment. The urine osmolality ratio between control and lithium-treated mice was strongly related to the urine output ratio. In most strains an increased urine output was also accompanied by an increased water intake.

b. Hypercalcaemia: Ionized calcium (iCa2+) was significantly increased in 4 out of 29 strains, while there were no significant differences at day 28.

c. Chronic Kidney Disease (CKD): The development of CKD was evaluated by analyzing albuminuria in time and by performing histological analyses at the end of the experiment. The albuminuria analyses did not demonstrate any lithium-induced renal damage in time. In contrast, the histological analysis demonstrated that 8 strains demonstrated an increased interstitial fibrosis and tubular atrophy, characteristics also observed in humans with lithium-induced CKD.

2) Isolate the responsible gene within the cluster.

HAM analysis was restricted to the NDI and CKD data, as the number of strains with differences in hypercalcaemia was too little. At all time points highly significant associations with NDI development were found in over 20 regions, while the genetic analysis for CKD remains to be fully analyzed. Using literature and the NIH proteome databases of native inner medullary collecting duct cells and cortical collecting duct cells, the renal expression of the NDI candidate genes was assessed. In addition, we performed immunoblotting and immunofluorescence to investigate the renal expression of several of our candidates.

3) Rationally hypothesize the role of the gene in lithiopathy development.

To further understand the development of NDI, and the potential of the different candidate genes, different additional analyses were performed. The analyses included the urinary Prostaglandin E2 (PGE2) and lactate levels, and different analysis to evaluate acid-base homeostasis. No differences between the different mouse strains were found in the effect of lithium on PGE2 levels, while urinary lactate levels were significantly increased in different lithium-treated mouse strains, which also significantly associated with the development of NDI. In most strains there were no differences in blood pH and urinary acid excretion.

Based on this information, the strength of association in the HAM analysis, the expression of the candidate genes in principal cells, different candidates (details see full report period 1 and 2) were selected as primary candidates that will be further investigated in the last period.

Expected final results and potential impact

Based on the results obtained in the first two years of this project the expected final results will be:
1) An overview of novel candidate genes that play a role in lithium-induced NDI and CKD.
2) The identification of the mechanisms by which some candidates play a role in lithium-induced NDI and CKD.

The obtained results already gave us and the whole scientific community a much broader insight on the essential role of genetics in the development of lithium-induced NDI and CKD. The obtained overview of candidate genes for both diseases already lead to an increased understanding of the pathological processes taking place in the kidney of lithium-treated mice, but also resulted in a first list of genetic candidates that determine the susceptibility towards these lithium-induced side effects. If these genes or molecular pathways are similar in men, the first steps can be made towards predicting the susceptibility of lithium-treated patients towards the development of side effects.


Maarten van Langen, (Legal advisor)
Tel.: +31 243619791


Life Sciences
Record Number: 187620 / Last updated on: 2016-08-22
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