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

Kidney Int. 2007 Dec;72(12):1483-92. doi: 10.1038/ Epub 2007 Oct 10.


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.

Publication types

  • Comment
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / blood
  • Animals
  • Blood Pressure / drug effects
  • Body Weight
  • Diuretics / toxicity*
  • 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 / drug effects
  • Potassium, Dietary / blood
  • Potassium, Dietary / pharmacology
  • Proteinuria / etiology
  • Proteinuria / metabolism
  • Proteinuria / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / metabolism
  • Urine
  • Vasodilation / drug effects


  • Diuretics
  • Insulin
  • Potassium, Dietary
  • Hydrochlorothiazide
  • Nitric Oxide
  • Aldosterone
  • Sodium
  • Magnesium