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Kidney Week

Abstract: FR-PO507

Lithium-Associated Tubulointerstitial Nephropathy, Role of Collecting Duct Cell Proliferation

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Himbert, Marie, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Try, Mélanie, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Cheval, Lydie, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Lasaad, Samia, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Morla, Luciana, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Vidal-Petiot, Emmanuelle, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
  • Flamant, Martin, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
  • Vrtovsnik, Francois, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
  • Crambert, Gilles, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
  • Tabibzadeh, Nahid, Centre de Recherche des Cordeliers, Paris, Île-de-France, France
Background

Lithium salts are the main treatment for bipolar disorder, a common and serious illness. However, their effectiveness is offset by their renal toxicity, especially microcystic tubulointerstitial nephropathy, which can lead to end-stage renal failure.
The aim of this project is to determine the mechanisms involved in this nephropathy, and to identify predictive biomarkers of renal outcome, especially GDF15, a growth factor known to be involved in the proliferation of intercalary A cells in an acid environment.

Methods

The project is based on a model of lithium exposure, for 1 month, of mice expressing or not GDF15, followed prospectively in a metabolic cage, allowing the analysis of urine, including the dosage of GDF15, by ELISA test. Cell proliferation was studied by immunofluorescence analysis of mouse kidneys collected at sacrifice. The role of GDF15 was also clarified in humans, from a prospective cohort of lithium treated patients, in whom GDF15 was measured in the urine and correlated with the clinico-biological phenotype.

Results

Plasma levels of GDF15 are increased in lithium treated mice (p=0.019). The phenotype of GDF15-/- mice is not different from WT lithium carbonate treated mice, while in lithium chloride treated mice, diuresis and cell proliferation are significantly lower in GDF15-/- mice (p=0.0159 and p=0.0147 respectively).
In patients, GDF15 urinary excretion is positively correlated with diuresis (p<0.0001) and natremia (p<0.0001), but negatively with eGFR (p<0.0001).

Conclusion

GDF15 is both increased in lithium treated mice and patients, suggesting it as a prognostic marker of nephropathy. There is a differential causal relation depending on the associated anion, requiring more investigations. It could be a protective mechanism to limit polyuria by increasing the proliferation of the principal cells.

Funding

  • Government Support – Non-U.S.