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Néphrologie & Thérapeutique

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Immunity and tubular dysfunction in case of systemic disease Volume 17, issue 3, Etats des lieux dans l'HDF en 2022

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Background and aim

The current study investigated the effects of treatment with 300 mg/kg valproic acid on rhabdomyolysis and acute kidney injury induced by intramuscular injection of hypertonic glycerol in rats.

Methods

Four groups of male wistar rats: control and hypertonic glycerol, valproic acid and valproic acid + hypertonic glycerol treated groups were used. Blood urea nitrogen, serum creatinine, creatinine kinase (CK) and CK MB, myoglobin and renal reduced glutathione (GSH) levels were measured. Histopathological examination of the kidneys was carried out to evaluate the degree of renal injury in each group. The expression of interleukin-1 beta “IL-1β” in renal tissue was detected using immunohistochemistry.

Results

Hypertonic glycerol administration led to severe renal tubular damage with a significant elevation of blood urea nitrogen, serum creatinine, creatinine kinase, CK MB and myoglobin levels and overexpression of IL-1β compared to control group. Valproic acid administration attenuated both the muscle injury and the acute kidney injury induced by hypertonic glycerol, estimated through a significant reduction of creatinine kinase, myoglobin, and serum creatinine. Valproic acid administration caused a significant increase in GSH in the hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group. A significant decrease in tubular necrosis grade, and expression of IL-1β in hypertonic glycerol + valproic acid group compared to the hypertonic glycerol group was observed.

Conclusion

This study demonstrates, for the first time to the best of our knowledge, that valproic acid could ameliorate the rhabdomyolysis and the related acute kidney injury in rats.

Les atteintes tubulaires associées aux maladies auto-immunes sont connues de longue date, mais leur prévalence reste imprécise. Elles impliquent l’action d’effecteurs humoraux et cellulaires des immunités adaptative et innée, sur diverses cibles du système tubulaire rénal : canaux protéiques, systèmes de co- ou de contre-transport, enzymes luminales ou cytosoliques, jonctions serrées. Des variants génétiques et épigénétiques sont également en cause. Leurs manifestations sont diverses et rendent leur diagnostic parfois difficile. Elles peuvent précéder le diagnostic de l’affection causale, qu’elles aggravent. Le modèle princeps en est l’acidose tubulaire distale hypokaliémique du syndrome de Sjögren, qui illustre le concept d’épithélite auto-immune. D’autres modes d’action de l’immunité cellulaire sont décrits, comme la néogenèse lymphoïde tertiaire au cours du lupus. L’immunité humorale, par le biais des auto-anticorps, cible diverses structures protéiques à l’origine de dysfonctions spécifiques. Elle est également impliquée dans la transition épithélio-mésenchymateuse des cellules tubulaires. L’immunité innée, via les cytokines, intervient aussi. La thérapeutique repose sur la correction des anomalies hydro-électrolytiques et les traitements immunosuppresseurs. Le choix de la molécule devrait idéalement être conditionné par le mécanisme physiopathologique dominant.

The immune renal tubular diseases are known since five decades, but their prevalence remains to be defined. They are caused by humoral and cellular effectors of innate and adaptative immunities on several targets of the renal tubule: protein channels, co or counter transporters, luminal or cytosolic enzymes, tight junctions. Genetic or epigenetic variations are also involved. Clinical manifestations are various and make the diagnosis difficult. They can precede the causal affection and they worsen the prognosis. The classical model consists in hypokalemic tubular distal acidosis observed in Sjögren's syndrome which illustrates the auto-immune epithelitis concept. Cellular immunity can act through other ways, like tertiary lymphoid neogenesis in systemic lupus. Humoral immunity through autoantibodies targets several membrane, cytosolic or nuclear proteins, causing specific tubular dysfonctions. It is also implied in the epithelial-mesenchymal transition of tubular cells. Innate immunity through cytokines may be involved. Treatment consists in electrolytic disorders correction and immunosupppressive medication: the choice should be guided at best by physiopathology.