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

Abstract

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.

Long-Term Renal and Cardiovascular Outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants by Baseline Estimated GFR

“…For all CKD subtypes, the hypertension guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (36) recommend diuretics along with RAS axis inhibitors to lower BP and reduce risk for CVD. Our findings support this approach and allay concerns about long-term consequences of renal injury induced by thiazide diuretics in animal models (37). Finally, the high cardiovascular event rate associated with CKD in our study underscores the need for research into novel preventive and treatment strategies for CVD in CKD (38).…”

Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11β-HSD activity

“…These Aldo concentrations, while not entirely physiologic, have been observed and even exceeded in adrenally intact but stimulated animals (24). In other animal models, even more modest interventions like daily diuretic administration have been shown to increase Aldo levels between two and three times those observed in controls (30,37). Reungjui and co-workers (37) showed that administration of the diuretic hydrochlorothiazide over a period of 20 wk was associated with a twofold increase in Aldo concentration and fibrotic changes within the kidney.…”

“…In other animal models, even more modest interventions like daily diuretic administration have been shown to increase Aldo levels between two and three times those observed in controls (30,37). Reungjui and co-workers (37) showed that administration of the diuretic hydrochlorothiazide over a period of 20 wk was associated with a twofold increase in Aldo concentration and fibrotic changes within the kidney. Thus, such "supraphysiologic concentrations" of Aldo are achievable in vivo and overtime, they appear to play a role in the fibrotic process.…”

Kidney Stones and the Risk for Chronic Kidney Disease

“…The HR remained relatively constant adjusting for these factors, and there was little evidence that these factors explained the increased risk for CKD. Further studies are needed to determine whether the risk for CKD in community stone formers is related to medications (e.g., thiazide diuretics [31,32], citrate [33], analgesic nephropathy), stone type (8), urinary tract infections (34), shock wave lithotripsy (35,36), recurrent obstruction with high stone burden (37), or damage from chronic crystalluria (particularly calcium oxalate) (26).…”