Therapeutic roles of thiazides and loop diuretics in blood pressure control and renal protection against chronic kidney disease

Abstract

Fluid overload secondary to loss of functional nephron mass can elevate blood pressure, which is characteristic of hypertension shown in chronic kidney disease (CKD). Therefore, it is logical to use diuretics at appropriate dose to lower blood pressure in patients with CKD and hypertension. Despite the theoretical background on the use of diuretics in CKD, there have been no definitive data on the effectiveness or safety of diuretics as first-line therapy for the management of hypertension in patients with CKD. Results from some clinical trials have demonstrated that diuretics would not lower blood pressure. They could even worsen electrolyte imbalance and kidney function when they are administered in patients with CKD. Major clinical practice guidelines on management of blood pressure or CKD have stated that evidence for benefits of thiazide diuretics is not conclusive yet in patients with advanced CKD, although loop diuretics are often effective for volume control at lower glomerular filtration rate. Recently, evidence for diuretics as effective blood pressure lowering agents in patients with advanced CKD is increasing. Renoprotective effect of thiazide or loop diuretics might represent a consequence of their influence on blood pressure or their ability to potentiate the effect of renin-angiotensin system blockade by making intraglomerular pressure more renin-angiotensin system-dependent, although their direct benefit on renal function remains controversial. This review summarizes recent data on the possible role of diuretics in lowering blood pressure, slowing the progression of kidney disease, and reducing cardiovascular risk in CKD patients.

Keywords: Antihypertensive agents; Chronic renal insufficiency; Diuretics; Hypertension; Kidney tubules.

Fig. 1

Schematic view of volume overload-induced hypertension in chronic kidney disease. Reduced glomerular filtration rate in chronic kidney disease eventually produces sodium retention and a fall in plasma renin level with minimal dependence of systemic angiotensin II, causing volume expansion and subsequent increased arterial pressure. In this situation, blockades of renin-angiotensin system are less effective in controlling systemic blood pressure

Fig. 2

Price comparison of angiotensin receptor blocker alone or in fixed dose combination with hydrochlorothiazide (HCTZ) in Korea. Data on list prices of selected medicines were collected using a publicly available website provided by the Ministry of the Interior and Safety, Republic of Korea (https://www.data.go.kr/data/15067459/fileData.do). Brands for each agent were chosen based on the original drug developer that work in the Republic of Korea. The price of generic HCTZ 25 mg was KRW 10 in 2022. Price data were reported in 2022 KRW, and the KRW-US dollar rate was KRW 1,296/dollar in December 2022, based on the daily exchange rates provided by Woori Bank (https://spib.wooribank.com/pib/Dream?withyou=ENENG0358)

Fig. 3

Proposed mechanisms responsible for blood pressure lowering effect with thiazide diuretics. After administration of thiazide diuretics, blood pressure is initially lowered due to a reduction in extracellular volume and subsequent cardiac output. However, within weeks, compensatory reabsorption of sodium and water can lead to return of the extracellular volume towards baseline. Antihypertensive effects of chronic thiazide therapy might be dependent of a fall of total peripheral resistance, a slight volume reduction and action on the vasculature. NCC, Na-Cl cotransporter; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system