Journal Article

Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia

Nakagawa, T., Patel, J.M., Hu, H., Roncal, C.A., Croker, B.P., Simoni, J., Byer, K., Srinivas, T., Johnson, R.J., Sitprija, V., Reungjui, S., Mu, W., Wesson, D.

2007

Overview

Hydrochlorothiazide (HCTZ) is used to manage hypertension and heart failure; however, its side effects include mild hypokalemia, metabolic abnormalities, and volume depletion, which might have deleterious effects on renal and endothelial function. We studied whether HCTZ cause renal injury and/or altered vasoreactivity and if these changes are hypokalemia-dependent. Rats were given a normal diet or a diet moderately low in potassium (K+) with or without HCTZ. Animals fed either a low K+ diet alone or HCTZ developed mild hypokalemia. There was no significant difference in systolic blood pressure in the different treatment groups. All three groups with hypokalemia had mild proteinuria; low K+-HCTZ rats had reduced creatinine clearance. HCTZ-treated rats displayed hypomagnesemia, hypertriglyceridemia, hyperglycemia, insulin resistance, and hyperaldosteronism. No renal injury was observed in the groups without HCTZ; however, increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress were seen with HCTZ treatment. Endothelium-dependent vasorelaxation was reduced in all hypokalemic groups and correlated with reduced serum K+, serum, and urine nitric oxide. Our results show that HCTZ is associated with greater renal injury for the same degree of hypokalemia as the low K+ diet, suggesting that factors such as chronic ischemia and hyperaldosteronism due to volume depletion may be responsible agents. We also found impaired endothelium-dependent vasorelaxation was linked to mild hypokalemia.

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: Aldosterone - blood / Animals / Blood Pressure - drug effects / Body Weight / Diuretics - toxicity / endothelial function / Hydrochlorothiazide - toxicity / Hypertension, Renal - drug therapy / Hypertension, Renal - metabolism / Hypertension, Renal - pathology / Hypokalemia - chemically induced / Hypokalemia - complications / Hypokalemia - metabolism / Immunohistochemistry / Insulin - blood / Insulin Resistance / Kidney - metabolism / Kidney - pathology / Magnesium - metabolism / Male / Muscle, Skeletal - metabolism / Nitric Oxide - metabolism / Organ Size / oxidative stress / Oxidative Stress - drug effects / potassium restriction / Potassium, Dietary - blood / Potassium, Dietary - pharmacology / Proteinuria - etiology / Proteinuria - metabolism / Proteinuria - pathology / Rats / Rats, Sprague-Dawley / renal injury / Sodium - metabolism / thiazides / Urine / Vasodilation - drug effects