Effects of Reduced Glomerular Filtration Rate on Responsiveness to Chlorothiazide and Mercurial Diuretics

Abstract

Clearance experiments have been performed in 24 subjects with different levels of glomerular filtration, suffering from renal disease without edema, in order to compare the diuretic, saluretic, and kaliuretic responses to a single intravenous injection of meralluride, chlorothiazide, or both together. The inulin clearances of these patients ranged from 5.9 to 135 ml. per minute. The effects of the drugs were studied under constant loading with saline over 3 hours after injection. Our results indicate that over a wide range (15 to 20 ml. per minute up to normal values) a permanent reduction of the glomerular filtration rate has little influence on the diuretic and saluretic effects of meralluride or chlorothiazide. Below 15 to 20 ml. per minute a further reduction results in a sharp decrease in the diuretic and saluretic actions. This can be best explained by assuming that the diuretic agents block an increasing fraction or the tubular reabsorption of water, sodium, and chloride related to the decrease in glomerular filtration rate. This fraction, however, seems to be limited to 30 to 40 per cent of the filtered load. Some dispersion in the glomerulo-tubular activity may account for the splay of the experimental curves. The kaliuretic effect of chlorothiazide is proportional to the glomerular filtration rate. This effect can be blocked by meralluride. At high levels of glomerular filtration the diuretic and saluretic actions of meralluride and chlorothiazide are additive. At lower levels of filtration, such a summation effect is not demonstrable. Apparently, both drugs given together cannot block the reabsorption of more than 30 to 40 per cent of the filtered load. A single injection of chlorothiazide does not lower the arterial blood pressure of hypertensive subjects, loaded with saline, but produces a slight decrease in the glomerular filtration rate, averaging 7 per cent.

Use of Metolazone, a New Diuretic, in Patients with Renal Disease

“…The magnitude of the response varied with the GFR. R eubi and C ottier [18] in their studies with chloro thiazide and mercurial diuretics in patients with different degrees of renal impairment, showed a sharp reduction in the diuretic and natriuretic action of these drugs when the GFR was below 15-20 inl/min. However, M u tii [13,14] was able to consistently induce a diuresis with frusemide in the presence of a creatinine clearance below 20 ml/min.…”

Thiazides in advanced chronic kidney disease

“…One such trial from 1961 epitomizes the early evidence base [14]. In this study chlorothiazide 500 mg was administered intravenously once to subjects who were then closely monitored for the subsequent 3 hours while on a constant intravenous saline infusion [14]. Urine flow and the sodium excretion rate increased in all 7 subjects with inulin clearance 60 mL/min or less.…”

“…Secondly, small early studies of chlorothiazide in CKD appeared to support the theoretical concerns [13;14]. One such trial from 1961 epitomizes the early evidence base [14]. In this study chlorothiazide 500 mg was administered intravenously once to subjects who were then closely monitored for the subsequent 3 hours while on a constant intravenous saline infusion [14].…”

Pharmacological Classification and Renal Actions of Diuretics

“…They have proved especially effective in patients with reduced glomerular filtration rates, as the thiazide group of drugs is often ineffective in these patients [13]. Used in combination with other agents to provide sequential neph- [14], These drugs have been utilized less often as first-line agents for the treatment of hypertension.…”