DIVERSIFIED RENAL TUBULAR EPITHELIAL REMODELING AND WATER BALANCE IN GITELMAN'S SYNDROME AND THIAZIDE-TREATED HYPERTENSIVE PATIENTS

Abstract

Objective: Mutations leading to loss of function of NaCl cotransporter (NCC) in the distal convoluted tubule is the basis defect of Gitelman's Syndrome (GS), which is clinically characterized by hypokaliemic metabolic alkalosis, hypomagnesemia, hypocalciuria and normal or low blood pressure with increased renin activity and high aldosterone levels. NCC is the target of thiazide diuretics (TZ) and clinical and laboratory findings of GS patients resemble those on chronic thiazide diuretics treatment. From a physiopathological perspective, this similarity in term of site of defect or site of action (NCC in distal convoluted tubule) for GS or TZ-treated patients respectively, should not alter their urine-concentrating or diluting ability. We aimed to study water balance pathways in these 2 clinical settings. Design and method: We investigated two groups of patients: 1) GS (n = 5, age range 21–43, 2 females and 3 males, mean concentration of blood potassium 2.9 mmol/L, bicarbonate 34 mmol/L and magnesium 1.2 mg/dl, normotensive) and 2) TZ hypertensive patients (n = 11, age range 26–48, 4 female and 7 males, blood pressure normalized with chronic thiazide type or like diuretics including hydrochlorothiazide, chlortalidone and indapamide maintained for at least 2 months) to evaluate their water balance pathway by determining plasma and urine osmolarity and to assess through urine aquaporin 2 (AQP2)/creatinine ratio their sensitivity to antidiuretic hormone. These measurements were repeated three times in the same patients. Results: Four out of five GS patients showed a urinary AQP2/creatinine ratio lower than TZ-treated patients (mean value of AQP2/creatinine of GS vs TZ-treated p < .05), associated with lower urine osmolarity (p = 0.03). Conclusions: Our study shows that water balance in these two groups may be differently handled: A diversified renal tubular epithelial remodeling of medullary collecting duct cells related to TZ treatment could be suggested, leading to an increased prevalence of principal cells on intercalated cells, thus increasing free water reabsorption.