Amiloride modifies the progression of lithium‐induced renal interstitial fibrosis
The main action of lithium appears to be on the principal cells of the collecting duct, which has been well described by numerous authors, and which leads to NDI.1 Lithium enters these cells via the epithelial sodium channel ENaC, situated on the apical (luminal) membranes.8 Within the principal cells, the initial effect of lithium is to inhibit arginine vasopressin stimulated aquaporin‐2 (AQP2) translocation to, and its insertion into, the apical cell membrane. Longer term, lithium also down‐regulates AQP2 synthesis.6 The lack of AQP2 creates a barrier to the passive movement of water down its osmotic gradient, leading to the excretion of a large volume of dilute urine, manifest as NDI. Amiloride acts to block lithium uptake through ENaC.8 The relatively short‐term administration of amiloride has been shown to partially correct the lithium‐induced NDI in both animal and human studies.10 However, to date, there are no long‐term studies examining whether or not partial correction of the lithium‐induced NDI with amiloride modifies the progressive chronic interstitial fibrosis, tubular atrophy, and glomerular sclerosis often evident with long‐term lithium exposure. In a clinical setting, amiloride administration is not usually commenced at the time of initiation of lithium therapy, rather only if the lithium‐induced NDI becomes a clinical problem. Therefore, using our rat model of chronic lithium exposure,4 amiloride treatment was commenced after the establishment of lithium‐induced NDI, in order to reflect usual clinical practice. In this study, 5 months of lithium therapy is shown to partially correct the lithium‐induced NDI and limit the further progression of lithium‐induced kidney fibrosis. This improvement was associated with decreased expression of the profibrotic cytokine connective tissue growth factor (CTGF), along with reduced myofibroblast infiltration and decreased collagen deposition around the distended cortical collecting ducts.