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

• Published in: Kidney international Vol. 72; no. 12; pp. 1483 - 1492
• Main Authors: Reungjui, S., Hu, H., Mu, W., Roncal, C.A., Croker, B.P., Patel, J.M., Nakagawa, T., Srinivas, T., Byer, K., Simoni, J., Wesson, D., Sitprija, V., Johnson, R.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2007; Elsevier Limited
• Subjects: 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; endothelial function; potassium restriction; thiazides; oxidative stress; renal injury
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/sj.ki.5002564

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.