Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for greater than 3 months.1 Based on the National Health and Nutrition Survey (NHANES) data, 14.9% of the US population surveyed in 2015–2018 had CKD based on a low estimated glomerular filtration rate (eGFR) and/or proteinuria.2 CKD is an important risk factor for cardiovascular disease (CVD). Hypertension is one of the most common comorbidities affecting nearly one-third of patients with CKD.2 CKD with hypertension further increases the risk of adverse CVD and cerebrovascular events.3 The presence of hypertension in CKD may accelerate kidney injury; therefore, management of hypertension is essential to prevent further functional kidney decline.3 Multiple medications are frequently necessary to adequately control hypertension in the CKD population. Thiazide diuretics have been recommended as the first-line for the treatment of hypertension, yet their use has been discouraged in CKD stage 4 and onward, as they are suggested to be ineffective in advanced CKD. There are currently 4 thiazide diuretics which the Food and Drug Administration (FDA) has approved for the treatment of hypertension in the United States: chlorothiazide (Diuril4), hydrochlorothiazide (Microzide5), chlorthalidone (Hygroton6), and indapamide (Lozol7). The fifth thiazide diuretic, metolazone (Zaroxolyn8), is FDA approved for the treatment of edema. This review discusses the commercially available thiazide diuretics with a focus on pharmacology, clinical uses, most common adverse effects, and their efficacy and place in advanced CKD.
PHARMACOLOGY AND PHARMACOKINETICS
Thiazide diuretics are derivatives of benzothiadiazine, which include chlorothiazide, hydrochlorothiazide (HCTZ), and bendroflumethiazide.9 Chlorthalidone, indapamide, and metolazone are thiazide-like sulfonamide diuretics that have similar physiological properties to a thiazide diuretic but lack the benzothiadiazine molecular structure.9 The term “thiazide diuretics” will be used in the text to refer to all these compounds. Despite the structural variation, the primary site of action of thiazide diuretics is the Na+/Cl− co-transporter (NCCT) in the distal convoluted tubule of the nephron, which is responsible for 5% of total sodium reabsorption, resulting in natriuresis.5,6,10 Thiazide diuretics exhibit their antihypertensive effects through increasing sodium excretion, thereby reducing extracellular volume, venous return, and cardiac output.5,6,10 Counterregulatory mechanisms act to re-establish the steady state of sodium reabsorption and excretion within 3–9 days in the setting of thiazide diuretic-induced volume depletion; thus, a new steady state for plasma volume is established.11,12 Interestingly, there is evidence to suggest that thiazide diuretics may have extrarenal effects contributing to their antihypertensive effects.13 Vasodilation is one such extrarenal target and is a result of the thiazide diuretics activating the calcium-potassium channel in vascular smooth muscle.13 Both HCTZ and indapamide were found to dilate mesentery arteries in vitro.14,15 HCTZ also resulted in local vasodilation in hypertensive subjects when infused into the brachial artery.16 Other small studies of thiazide diuretics have demonstrated a reduction in peripheral vascular resistance resulting in vasodilatory effects with unchanged cardiac output and independent from their natriuretic properties.16,17 Indapamide has also been shown to chronically lower blood pressure (BP) through a different mechanism, where it inhibits norepinephrine-induced Ca2+ influx in animal arteries.18,19 Additional proposed mechanisms include inhibition of carbonic anhydrase, Rho-Ras kinase pathway inhibition, and indirect compensation as a result of systemic loss of fluid or electrolytes.20,21
All thiazide diuretics are absorbed orally and have volumes of distribution (Vd) greater than or equal to total body weight which is likely due to the extensive binding to plasma proteins; it also limits their glomerular filtration and thus requires excretion by proximal tubular secretion. The pharmacokinetic differences between the thiazide diuretics are responsible for the differences in clinical effects.22 Primarily, the differences are seen in their metabolism and excretion characteristics (Table 1), such as the onset of action ranging between 2 and 3 hours and lasting for 6–48 hours. HCTZ, the most widely used thiazide diuretic, has a bioavailability ranging from 60 to 80%, a half-life of 6–15 hours, and is relatively dose proportional. Chlorthalidone, on the other hand, exhibits an extremely long half-life of approximately 40–60 hours and also has extensive partitioning into red blood cells owing to its large volume of distribution and gradual elimination from the plasma compartment by tubular secretion.23 The red blood cells act as a reservoir that allows the drug to flow back into the plasma to exert its effect over a longer duration.22 Indapamide and metolazone are also bound to erythrocyte carbonic anhydrase, which results in a large Vd and longer half-life.22 In CKD, half-life elimination is prolonged for HCTZ, chlorthalidone, and metolazone.24
TABLE 1. -
Currently Available Thiazides in the United States
| Drug |
Chlorthiazide
4
|
Hydrochlorothiazide
5
|
Chlorthalidone
6
|
Indapamide
7
|
Metolazone
8
|
| Common dosages |
250 mg, 500 mg, 250 mg/5 mL |
12.5 mg, 25 mg, 50 mg |
25 mg, 50 mg |
1.25 mg, 2.5 mg |
2.5 mg, 5 mg, 10 mg |
| US brand names |
Diuril |
Microzide |
Hygroton, Thalitone |
Lozol |
Zaroxolyn |
| Dosage in renal impairment |
CrCl < 10 mL/min: Avoid use |
CrCl ≥ 10 mL/min: No dosage adjustment necessary CrCl < 10 mL/min: Use not recommended |
CrCl ≥ 10 mL/min: No dosage adjustment necessary |
GFR 10–50 mL/min: 1.25–2.5 mg once daily GFR < 10 mL/min: 1.25–2.5 mg once daily (limited data) Hemodialysis: 1.25–2.5 mg once daily (limited data); not dialyzable |
There are no dosage adjustments provided in the manufacturer’s labeling; use caution in patients with severe renal impairment, as most of the drug is excreted by the renal route and accumulation may occur |
| CrCl < 10 mL/min: Avoid use |
| Hemodialysis, intermittent (thrice weekly): Not dialyzable; use not recommended due to lack of efficacy |
| Peritoneal dialysis: Use not recommended due to lack of efficacy |
| Dosage in hepatic impairment |
No dosage adjustments provided in manufacturer’s labeling; use with caution |
There are no dosage adjustments provided in the manufacturer’s labeling |
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution |
There are no dosage adjustments provided in manufacturer’s labeling; use with caution |
There are no dosage adjustments provided in the manufacturer’s labeling; contraindicated in hepatic coma or precoma |
| Onset |
Oral: Within 2 hours |
~2 hours |
~2.6 hours |
1–2 hours |
~60 minutes |
| IV: 15 minutes |
| Peak |
Oral: ~4 hours |
4–6 hours |
2–6 hours |
2 hours |
8 hours |
| IV: 30 minutes |
| Duration |
Oral: ~6–12 hours |
Single dose: 6–9 hours |
Single dose: 24–48 hours |
8–12 hours |
≥24 hours |
| IV: 2 hours |
Long-term dosing: 8–15 hours |
Long-term dosing: 48–72 hours |
| Elimination half-life |
45–120 minutes |
Single dose: 12 hours |
Single dose: 40 hours; Long-term dosing: 45–60 hours |
Biphasic: 14 and 25 hours |
8–14 hours |
| Long-term dosing: 16–24 hours |
| Elimination |
Urine (10% to 15% [oral], 96% [IV] as unchanged drug) |
Urine (≥ 61% as unchanged drug) |
Urine (primarily as unchanged drug) |
Urine (~70%; 7% as unchanged drug within 48 hours); feces (23%) |
Urine (80%) |
This table was developed from each individual package insert as well as US pricing data from Lexicomp.
CLINICAL USE OF THIAZIDE DIURETICS
Hypertension in Chronic Kidney Disease
Thiazide diuretics remain the cornerstone of antihypertensive treatment due to their favorable BP-lowering efficacy, safety profile, and low cost.25 In general, thiazide diuretics result in a reduction of the systolic and diastolic BP by 10–15 and 5–10 mm Hg, respectively.26 They are beneficial in patients with low-renin hypertension, commonly seen in older adults, African Americans, or those with comorbidities such as metabolic syndrome, diabetes, or CKD.27,28 The dosing of each thiazide diuretic is influenced by the pharmacokinetic characteristics and has a flat dose-response in regards to their antihypertensive effects.29,30 This was shown in a systematic review, where dose increase did not translate to additional antihypertensive effect.31 However, when used at low doses, chlorthalidone was able to achieve a significant reduction in both daytime and nighttime BP compared to HCTZ; which is largely due to chlorthalidone’s longer duration of action.32 To be an effective antihypertensive agent, HCTZ requires twice-daily dosing to ensure sustained BP-lowering effects.32 To have equivalent BP lowering, low doses (12.5–25 mg/d) of chlorthalidone are considered to be 1.5–2 times more potent than the same dose of HCTZ.33 In terms of efficacy, multiple studies have demonstrated that chlorthalidone is superior to HCTZ in reducing BP, without increasing the incidence of hypokalemia and hyponatremia.34,35
In the setting of decreased renal function, common practice has been to avoid thiazide diuretics, particularly in advanced CKD with eGFR < 30 mL/min/1.73 m2.36Table 2 summarizes the studies of thiazide diuretics in CKD. Initial studies in the 1970s assessed the management of hypertension in CKD with metolazone as their primary thiazide diuretic, which resulted in improvement in natriuresis and BP-lowering effects.37–39 One randomized, double-blind, crossover trial indicated that chlorothiazide lowered BP in severe renal failure.40 In the 2 double-blind crossover trials assessing hypertension in patients with CKD stage 4 or 5, the pilot studies found that furosemide 60 mg and HCTZ 25 mg decreased mean BP by the same extent, with more efficient BP control with combination therapy.41,42
TABLE 2. -
Summary of Thiazide Diuretics for Treatment of
Hypertension in CKD
| Study Year, Author |
Trial Design |
Patients |
Methods |
Findings |
| 1973, Bennet et al
37
|
Observational study |
N = 20 |
Metolazone once daily 10–15 mg, all other diuretics discontinued. Dose of metolazone increased by 5 mg until a maximum dose of 25 mg |
Metolazone improved edema and had a weight reduction of 1.4 kg. Serum creatinine increased significantly from 4.7 to 5.6 mg/dL. Diastolic BP decreased by 12.5 ± 11.7 mm Hg in 12 hypertensive patients without nephrotic syndrome |
| Nephrotic syndrome (3), CKD (17) |
| 1974, Craswell et al
38
|
Observational study |
N = 12, |
Oral metolazone given in doses ranging from 2.5 to 25 mg from 2 to 20 weeks |
Metolazone had a weight reduction of 1.4 kg, improved edema, and blood pressure was reduced by 14.2/3.2 mm Hg (baseline 147/92). Serum creatinine increased from 4.7 to 5.6 mg/dL |
| CKD |
| 1977, Paton and Kane
39
|
Observational study |
N = 20 |
Before and after evaluation of administration of metolazone. Nephrotic syndrome patients received 2.5–30 mg of metolazone. CKD patients received 1.25–40 mg metolazone |
Nephrotic syndrome: baseline BP improved from 147/97 mm Hg to 137/88 mm Hg. CKD: baseline BP improved from 173/96 to 158/88 mm Hg. |
| Nephrotic Syndrome, CKD |
| 1979, Jones and Nanra
40
|
Randomized, double-blind, crossover |
N = 16 |
Chlorothiazide 0.5 mg BID versus placebo (6 weeks) |
Significant reductions in standing (13/6 mm Hg) and supine (13/5 mm Hg) blood pressure with chlorothiazide compare to placebo |
| CKD, HTN |
| 2005, Dussol et al
41
|
Double-blind, randomized crossover trial |
N = 7 |
Furosemide 60 mg/d and HCTZ 25 mg/d |
HCTZ significantly increased fractional excretion of sodium and chloride from 3.7 ± 0.9 to 5.5 ± 0.3 and from 3.9 ± 0.19 to 6.5 ± 0.3, respectively (P < 0.05). Furosemide, HCTZ and the combination of the two diuretics decreased mean Arterial blood pressure by the same extent from 112 to 97, 99 and 97 mm Hg, respectively (P < 0.05) |
| CKD and HTN |
| 2012, Dussol et al
42
|
Randomized, fixed-dose, double-blind, single-center crossover trial |
N = 23 |
Furosemide 60 mg, HCTZ 25 mg, or both diuretics |
The association of the 2 diuretics increased the fractional excretions of sodium and chloride from 3.4 ± 1.8 to 4.9 ± 2.8 and from 3.8 ± 2.0 to 6.0 ± 3.1, respectively (P < 0.05), no differences between furosemide and HCTZ with respect to natriuresis and blood pressure control in patients with hypertension and CKD |
| CKD and HTN |
| 2014, Agarwal et al
43
|
Single-center pilot study |
N = 12 |
Chlorthalidone was added to existing medications in a dose of 25 mg/d, and the dose doubled every 4 weeks if the BP remained elevated for 12 weeks |
Baseline blood pressure (143.1/75.1 mm Hg) was reduced by 10.5/3.1 mm Hg (P = 0.01/P = 0.17) |
| CKD, HTN |
| 2014, Cirillo et al
44
|
Prospective, parallel-group, single-blind, single-center study |
N = 60 |
2 groups based on eGFR values received 8-week treatment with chlorthalidone 25 mg in addition to ongoing treatment |
Decrease blood pressure in both groups at week 8 |
| CKD, HTN |
| 2020, Agarwal et al
45
|
Phase II, single institution, multicenter, double-blind randomized control trial |
N = 131 |
Chlorthalidone 12.5 mg once daily followed dose escalation. With a total of 160 patients, the study will have ≥80% power to detect a 6 mm Hg difference in systolic 24-hour ABP between the 2 treatment groups |
Ongoing |
| CKD stage 4, HTN |
BP, blood pressure; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HTN, hypertension.
While the evidence against thiazide diuretics use in advanced CKD is limited to smaller RCTs, many guidelines, including the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative, continue to recommend switching from a thiazide diuretic to a loop diuretic when GFR falls below 30 mL/min/1.73 m2.46–49 This idea has been recently challenged as more studies have been published to support the use of thiazide diuretics in patients with reduced kidney function. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines acknowledge that while many clinicians switch from a thiazide diuretic to loop diuretic, the antihypertensive benefit of thiazide diuretic may still be preserved at low levels of GFR.50 In 2014, 1 pilot trial demonstrated the potential efficacy of thiazide diuretics in advanced CKD.43 The trial enrolled 14 patients with an average eGFR of 27 mL/min/1.73 m2 (recruited eGFR ≤ 45 but >20 mL/min/1.73 m2) and hypothesized that chlorthalidone would effectively lower BP in moderate to advanced CKD with 24-hour ambulatory BP monitoring (24-h ABPM).43 At the end of 12 weeks, participants had a significant (10.5 mm Hg) reduction in 24-h ABPM.43 Additionally, a parallel-group 8-week pilot study in 2014 assessed the effects of chlorthalidone 25 mg between hypertensive patients with low kidney function and hypertensive patients with normal kidney function.44 The study enrolled 60 CKD patients with an average eGFR of 39 mL/min/1.73 m2 and an average office systolic BP of 151 mm Hg.44 Results indicated that short-term chlorthalidone effects were not reduced in those with reduced kidney function.44 In the latest Kidney Disease Outcomes Quality Initiative commentary on the 2017 ACC/AHH Hypertension Guidelines, the KDOQI workgroup disagreed with the guideline statement remarking that thiazide diuretics should not be used in advanced CKD due to lack of efficacy. They argued that thiazide diuretics should not be automatically discontinued when eGFR decreases <30 mL/min/1.73 m2 but to assess the risk and benefits associated with each patient. There are no head-to-head studies of different thiazide diuretics in CKD, but the small body of evidence available suggests chlorthalidone may be effective in BP management in patients with advanced CKD.42–44 Currently, a study is being conducted assessing the use of chlorthalidone in advanced CKD.45 Results from this trial will provide further insight regarding the safety and efficacy of thiazide diuretics in advanced CKD for hypertension.45
Cardiovascular Benefits in Chronic Kidney Disease
Thiazide diuretics first demonstrated CV morbidity and mortality benefit with BP reduction in both the severe (diastolic 115–129 mm Hg) and the mild-to-moderate (diastolic, 90–104 mm Hg) subgroups in the landmark Veterans Affair Cooperative Study in 1967.51,52 The Systolic Hypertension in the Elderly Program (SHEP) study, in which 37% subjects had eGFR below <60 mL/min/1.73 m2, assessed the efficacy of chlorthalidone and its ability to reduce the risk of nonfatal and fatal stroke in isolated systolic hypertension.53,54 Results from the study found that in those 60 years or older with isolated systolic hypertension receiving step-wise treatment with low-dose chlorthalidone as step 1 medication, stroke incidence was reduced by 36%, myocardial infarction by 27%, heart failure (HF) by 54%, and overall CV morbidity by 32%.53 In the largest randomized trial assessing hypertension mortality and morbidity, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, chlorthalidone was superior to a calcium channel blocker and ACE inhibitor in preventing one or more major forms of CVD.55 In a long-term posttrial follow-up of the ALLHAT study cohort stratified by baseline eGFR, there was no significant difference in CV mortality between chlorthalidone and amlodipine or chlorthalidone and lisinopril.56 There were no additional differences observed for mortality, coronary heart disease, CV disease, stroke, or end-stage renal disease (ESRD).56 Additionally, there were no significant differences in ESRD incidence between the amlodipine and chlorthalidone groups by the baseline eGFR level.56 In a post hoc analysis of the ALLHAT study cohort, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of ESRD or a 50% or greater decrease in eGFR.57 Furthermore, after 6 years of follow-up, there was a higher rate of HF (10.2% vs 7.7%), combined CVD (33.3% vs 30.9%), and stroke (6.3% vs 5.6%) with amlodipine versus chlorthalidone. Similarly, patients on lisinopril had more HF (8.7% vs 7.7%) than on chlorthalidone.55 In a meta-analysis analyzing safety and efficacy of various antihypertensive therapies used as first-line agents, low-dose thiazide diuretics (12.5–25 mg/d of chlorthalidone or hydrochlorothiazide) were found to be the most effective first-line treatment for preventing the occurrence of CV disease-associated morbidity and mortality.58 They also demonstrated a reduction in risk of HF by 24%, stroke by 19%, and CV disease when compared to other agents.58,59 There are a limited number of studies comparing CV mortality and morbidity between HCTZ and chlorthalidone. Studies indicate that chlorthalidone reduces CV events more than HCTZ, prompting guidelines to recommend chlorthalidone as the preferred thiazide diuretic for the treatment of hypertension.47,60–62 Chlorthalidone may also be superior to HCTZ for regression of left ventricular hypertrophy.63 Furthermore, a subgroup analysis of Systolic Blood Pressure Intervention Trial (SPRINT) study assessing nondiabetic patients receiving thiazide diuretics for hypertension revealed that those receiving thiazide diuretics had a decreased risk of HF and was associated with a decreased risk of all-cause mortality.64
Volume Overload in Chronic Kidney Disease
Diuretic therapy in edematous diseases often yields an inadequate natriuretic response despite the use of high doses of loop diuretics, due to diuretic resistance.47 This is encountered in several disease states such as CKD, congestive HF, cirrhosis, and nephrotic syndrome.65 The pathophysiology of diuretic resistance includes the imbalance between daily salt intake versus diuretic-induced salt loss, hyponatremia or hypokalemia, hyperchloremic metabolic alkalosis, and reflex activation of the renal sympathetic nerves.66 Nephron mechanisms of diuretic resistance include: decreased tubular drug secretion which limits its availability at the site of action, tubular tolerance which can develop after the renal tubules are exposed to a single dose of diuretic, or enhanced sodium reabsorption in the proximal and distal tubules.66 There are several approaches to overcome diuretic resistance: ruling out noncompliance to diuretic therapy, implementing sodium restriction, and discontinuing medications that can contribute to resistance.67
The addition of thiazide diuretics to loop diuretics has also been shown to produce diuretic synergy via sequential nephron blockade, in which multiple sites of sodium reabsorption are inhibited.67 The addition is beneficial due to the longer half-life of distally-acting thiazide diuretics, which may decrease the effectiveness of the postdose sodium retention observed with the shorter-acting loop diuretic.26,68Table 3 summarizes the studies of thiazide diuretics in volume overload in CKD. Initial studies evaluated the use of metolazone, which resulted in improvement in natriuresis and reduction in weight.69,70 The potency of combined HCTZ and furosemide was later studied in 8 patients with renal insufficiency who previously had a poor response to either medication alone.71 Results revealed that the combination of both diuretics was a potent regimen and was effective in patients with chronic renal failure compared to monotherapy.71 Soon after, larger randomized controlled trials (RCTs) were conducted assessing thiazide diuretics in CKD. Two studies confirmed the potency of utilizing a combination of a thiazide diuretic and a loop diuretic therapy in patients with advanced renal failure.72,73 Metolazone is frequently used in combination with a loop diuretic due to its long half-life and preserved activity in renal insufficiency.74 In one observational study, metolazone dosed at 20–150 mg given IV resulted in a 133% and 33% increase in sodium and potassium excretion, respectively.69 In patients with nephrotic syndrome or CKD, metolazone resulted in a reduction of 5.2 and 3.8 kg, respectively.70 A meta-analysis concluded metolazone was as effective as chlorothiazide to augment loop diuretic therapy in acute decompensated HF.75
TABLE 3. -
Summary of Thiazide Studies in Volume Overload in CKD
| Study Year, Author |
Trial Design |
Patients |
Methods |
Findings |
| 1972, Dargie et al
69
|
Observational study |
N = 14, CKD |
Metolazone given IV in doses ranging from 20 to 150 mg. Urine samples were collected at 2-hour intervals from 8 am to 10 pm, plasma samples at intervals from 9 am to 11 pm, and a further 10-hour sample of urine was collected from 10 pm to 8 am
|
Mean sodium excretion increased by 113%, potassium excretion increased by 33%. No correlation between GFR and increase in urine flow and electrolyte excretion after administration of metolazone |
| 1974, Dargie et al
70
|
Observational study |
N = 17 |
Metolazone used in doses of 5 to 200 mg for 7–180 days |
Nephrotic patients lost 5.2 kg and patients with CKD lost 3.8 kg weight |
| Nephrotic syndrome (11), CKD (6) |
| 1982, Wollam et al
71
|
Interventional study |
N = 8 |
Body weight, plasma volume, and BP were evaluated in patients receiving high-dose furosemide (320 and 480 mg/d) versus HCTZ 25 to 50 mg twice daily versus combination furosemide and HCTZ |
Combination therapy (HCTZ + furosemide) produced a marked diuresis, and a significant reduction in weight, plasma volume and mean arterial pressure (P < 0.025). Combined HCTZ-furosemide was potent and effective patients with chronic renal failure who have a poor response to furosemide alone |
| CKD |
| 1994, Fliser et al
72
|
Single-blind, placebo-controlled, crossover trial |
N = 10 |
Following a low-sodium diet of 150 mmol/d, placebo infusion was given on days 6 and 13. On days 7 and 14, patients were randomly assigned to receive either torsemide 50 mg IV, torsemide in combination with placebo infusion, or torsemide in combination with butizide 20 mg IV |
Torsemide in combination with butizide resulted in marked increase of mean cumulative sodium (156 ± 33 to 290 ± 76 mmol/24 h) and chloride excretion (from 128 ± 29 to 309 ± 99 mmol/24 h), (P < 0.01) |
| CKD |
| 1995, Knauf and Mutschler
73
|
Single-blind, randomized controlled, crossover trial |
N = 25 |
Group 1 received furosemide 80 mg and group 2 received HCTZ 25 mg with furosemide 40 mg. Study 1: pharmacodynamics of HCTZ and furosemide, Study 2: Saluretic efficacy of HCTZ and FU alone and in combination |
Doubling the dose of either HCTZ or furosemide each produced statistically insignificant increases in sodium excretion. The dose-response curves of HCTZ and furosemide were both relatively flat, doubling the dose of each produced statistically insignificant increase in sodium excretion |
| CKD (19), healthy volunteers (5) |
BP, blood pressure; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HTN, hypertension.
Hypercalciuria Kidney Stones
Thiazide diuretics have been the mainstay in the treatment of nephrolithiasis, initially discovered by Lamberg and Kuhlback.76 Thiazide diuretics can induce a positive calcium balance and reduce urinary calcium by up to 50%.77 The most commonly used agents are hydrochlorothiazide and chlorthalidone; however, indapamide can also be utilized.77 The advantage of chlorthalidone or indapamide is their longer half-life, as hydrochlorothiazide would need to be given twice a day.5–7 Numerous RCTs have examined the effects of several different thiazides on preventing calcium-containing kidney stone recurrence.78,79 Long-term use of thiazides has also been shown to reduce the incidence of recurrent renal calculi and 24-hour urinary calcium level.80 One study found a reduction of 150 mg urinary calcium per day in normal patients and 400 mg per day in hypercalciuric patients on HCTZ 50 mg BID.81 The dosing of thiazide diuretics for reducing recurrence of calcium-containing kidney stones is much higher compared to the dosing for treatment of hypertension.79,82,83 Available evidence suggests the following dosing regimen: indapamide at 2.5 mg/d, chlorthalidone at 25–50 mg daily, or HCTZ 25 mg twice a day or 50 mg daily. It is important to note that thiazide diuretics will not be effective unless dietary salt intake is limited.81,84 For every gram of daily dietary salt decrease, 24-hour urinary calcium would be expected to drop by 5.46 mg.85 Thiazide diuretics also tend to reduce serum potassium, increase uric acid levels, and lower urinary citrate excretion.86 For that reason, it is useful to add potassium citrate for these patients when they start thiazide therapy.87 Additionally, nephrolithiasis is a risk factor of the CKD, thus decreasing kidney stone development with thiazide diuretics in those with hypercalciuric kidney stones may also delay and decrease CKD progression.88–90
Adverse Effects in Chronic Kidney Disease
As a class, thiazide diuretics appear to be well-tolerated with an acceptable side effect profile. Most of the AEs associated with thiazide diuretics can be minimized with the appropriate selection of diuretic agents, dose, and careful monitoring. This section will provide a review of the evidence regarding the safety profile of the available thiazide diuretics.
Electrolyte Abnormalities
The most recognizable among the diuretic AEs are electrolyte disturbances. Hypokalemia, hyponatremia, and hypochloremic alkalosis are common in patients receiving thiazide diuretics.26 With standard doses, a mean reduction in serum potassium level of 0.3–0.4 mEq/L typically occurs.26 Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.5,6 Hypomagnesemia usually occurs concurrently with hypokalemia and may need to be corrected to achieve normokalemia.5,6 These abnormalities are dose-related but may occur even at the lowest marketed doses of thiazide diuretics. Electrolyte abnormalities, specifically hypokalemia, hyponatremia, and hyperuricemia, were common in 2 studies assessing thiazide diuretic effects in advanced CKD (eGFR 20–45 mL/min/1.73 m2) and less severe CKD (eGFR <60 mL/min/1.73 m2) at 50% and 15%, respectively.43,44 With continued use of thiazide diuretics and depletion of sodium, compensatory mechanism tends to increase this exchange and may produce an excessive loss of potassium, hydrogen, and chloride ions.10 They also decrease the excretion of calcium and uric acid. Thiazide-induced hyponatremia usually manifests within the first few days to 2 weeks of therapy, although it can develop much later.26 Several risk factors for diuretic-induced hyponatremia include older age, female sex, increased fluid intake, and use of agents known to reduce free water excretion such as antidepressants and nonsteroidal anti-inflammatory drugs.91
Hyperuricemia
Hyperuricemia is strongly associated with renal failure, hypertension, and CV disease.92,93 In CKD, there is an inverse relationship between increasing urate levels with decreasing eGFR due to a reduction in urate excretion.94 Risk factors for gout include hypertension, age, obesity, serum uric acid level, alcohol intake, high purine diet, and diuretics.95,96 Thiazide diuretics interfere with the urate transporters, specifically the organic anion transport 1 and urate/anion exchanger 1, increasing renal urate reabsorption, thus raising uric acid levels.97 Among the antihypertensive drugs, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and nonlosartan angiotensin II receptor blockers have been associated with an increased risk of gout compared to calcium channel blockers and losartan in people with hypertension.98 Hyperuricemia is more strongly associated with loop diuretics than thiazide diuretics.99 Interaction of thiazide diuretics, serum uric acid, and creatinine levels were assessed in the Hypertension Detection and Follow-up Program (HDFP) cohort.100 In those who received chlorthalidone, uric acid increase was the same with serum creatinine levels <1.5 or ≥1.5 mg/dL.100 Clinical gout was reported in 15 of 3693 patients over 5 years.100 Among individuals who were prescribed uric acid-lowering drugs, the level of serum creatinine increased just as much as in those whose uric acid level was not pharmacologically lowered.100 The expected increase in serum uric acid appears to be minimal and dose-related, with a dose of ≥50 mg of HCTZ or chlorthalidone resulting in an average increase of 1.53 mg/dL of uric acid.101 While thiazide diuretics may cause an increase in uric acid reabsorption, a history of gout should not preclude the utilization of thiazide diuretics for the treatment of hypertension in CKD. Furthermore, practitioners should be vigilant with monitoring hyperuricemia in those receiving thiazide diuretics. Urate lowering therapy should not be added readily for the sole purpose of lowering serum uric acid level in patients with CKD, as recent studies have not demonstrated it to slow the progression of CKD.102–104
Sulfa Allergy
An estimated 3 to 6% of the general population is allergic to sulfonamide, thus at risk for type 1 and other hypersensitivity reactions to sulfamethoxazole and other sulfonamide antibacterial agents.105,106 It has been theorized that a history of sulfa allergy may be associated with an increased risk of adverse events with thiazide diuretics and other nonbacterial sulfonamides. The major difference between sulfonamide antimicrobials and other sulfonamide-containing medications such as thiazide diuretics is that sulfonamide antimicrobials contain an aromatic amine group at the N4 position and an N-containing ring attached to the N1 nitrogen. Structurally, none of the thiazide diuretics exhibit both of the features shown to be responsible for sulfonamide reactions.107,108 However, there is a lack of data evaluating cross-reactivity allergic reactions among sulfonamide-containing medications. A review of medical literature and manufacturer-provided data did not find convincing evidence of broad cross-reactivity between antimicrobial and nonantimicrobial sulfonamide agents.107 Sulfa antibiotic allergy is not a contraindication to receiving a thiazide. The risk for cross-sensitivity appears to be more dependent on an underlying propensity for atopy than on any specific cross-reactivity among the classes. If a true allergy to thiazide is documented, ethacrynic acid (a non–sulfa-containing loop diuretic) can be used.109,110
Metabolic Effects
Thiazide diuretics have also been associated with metabolic toxicities. Treatment with HCTZ has been shown to worsen hepatic steatosis and reduce insulin sensitivity.111,112 In the SHEP study, there were 8.6% of new cases of diabetes mellitus in those receiving chlorthalidone compared to 7.5% in the placebo group.113 Despite these metabolic changes, chlorthalidone improved endothelial function, reversed abnormal arteriolar structure, and slowed albumin permeation in hypertensive nondiabetic patients with metabolic syndrome.114 In the ALLHAT trial, the odds of developing type 2 diabetes mellitus (T2DM) were lower in participants taking lisinopril or amlodipine compared to chlorthalidone for hypertension at 2 years.115 The odds of developing T2DM were still lower in other groups compared to chlorthalidone at 4 and 6 years.115 The study also found that among those taking chlorthalidone, there was no significant increase in CV outcomes in relation to incidence of T2DM.115 When thiazide diuretics were studied in nondiabetic patients, low doses were not associated with an increased risk for new-onset T2DM.116 In a 2015 review evaluating the various antihypertensive drug classes, the evidence against thiazide diuretics and possible metabolic derangements was insufficient.117 Furthermore, the reviewers were unable to conclude that thiazide diuretics demonstrated worsened CV or renal outcomes based on the available evidence.117 More recently, in a post hoc analysis of subgroups of patients with hypertension and T2DM, thiazide diuretics were shown to provide a significant reduction in CV events, all-cause mortality, and hospitalization for HF compared to placebo, as well as, shown to be noninferior to other antihypertensive agents.118 There is limited or no evidence of a higher incidence of metabolic side effects in CKD and thiazide diuretic use. In a pilot study (N = 7) assessing BP control with chlorthalidone in advanced CKD (20–45 mL/min/1.73 m2), hyperglycemia was noted in 1 patient.43 Therefore, benefits attributed to thiazide diuretics in terms of CV event reduction outweigh the risk of worsening glucose control in T2DM and of new-onset diabetes in nondiabetic patients.
Drug-Induced Nephrolithiasis
As a result of the electrolyte excursions associated with thiazide diuretics, particularly hypokalemia, potassium-sparing diuretics are widely utilized in combination with thiazide diuretics for their ability to protect from potassium loss.26 Such combinations provide an important alternative to increasing the dose of thiazide diuretics that can enhance BP lowering without the adverse metabolic effects of higher dosage.26 Triamterene is the most used agent, as it is readily available in fixed-dose combination with thiazide diuretics.26 However, triamterene has been linked to nephrolithiasis, with an estimated annual incidence of one per 1500 users of triamterene-HCTZ.119,120 A possible mechanism related to stone formation may be due to the saturation of the urine with triamterene, especially with sulfate ester.119 When assessing renal caliculi, triamterene was found to form the nucleus of the stone and was deposited with calcium oxalate or uric acid. One-third of the renal calculi were mostly or entirely triamterene.121 The combination use of thiazide diuretic and triamterene should be considered judiciously as nephrolithiasis is a risk factor for CKD.90
PRESCRIBING PRACTICES
Thiazide diuretics remain first-line agents for the treatment of hypertension mainly due to their proven CV mortality and morbidity benefits, safety profile, and low cost. They are beneficial in patients with low-renin hypertension, African Americans, nephrotic syndrome, and volume overload. When compared to other major classes of antihypertensive drugs, low-dose thiazides are at least as effective, while still being well-tolerated, and safe. Chlorthalidone is the preferred thiazide diuretic as is it longer-acting, more effective at BP lowering with proven CV benefits, and less electrolyte disturbances. Additionally, at higher doses, thiazide diuretics can be used for the treatment of hypercalciuric kidney stones and help to delay the progression of CKD. Electrolyte abnormalities and volume depletion can be expected and should be monitored closely at initiation and after dose modifications. Elevated uric acid levels can be expected with thiazide diuretics and should be monitored. However, a history of hyperuricemia should not preclude practitioners from utilizing these agents for hypertension management in patients with CKD. Drug-induced nephrolithiasis should also be monitored when thiazide diuretics are used in combination with triamterene. In CKD, thiazide diuretics should remain the first-line agent for the treatment of hypertension, particularly in patients with concomitant volume overload, or nephrotic syndrome. In those with advanced CKD, the combination of a thiazide diuretic and a loop diuretic can produce a synergistic effect to overcome loop diuretic resistance in those with volume overload.
REFERENCES
1. Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63:713–735.
2. United States Renal Data System. 2020 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2020.
3. Navaneethan SD, Schold JD, Arrigain S, et al. Cause-Specific Deaths in Non-Dialysis-Dependent CKD. J Am Soc Nephrol. 2015;26:2512–2520.
4. Chlorothiazide tablets [Package Insert]. Mylan Pharmaceuticals. Inc.; 2006.
5. Microzide capsules (hydrochlorothiazide) [Package Insert]. Watson Pharma Inc; 2011.
6. Thalitone (chlorthalidone) [package insert]. Casper Pharma LLC; 2021.
7. Indapamide [package insert]. Amerigen Pharmaceuticals Inc; 2016.
8. Metolazone tablets (metolazone, USP) [package insert]. Alembic Pharmaceuticals, Inc; 2020.
9. Cody RJ. Cardiac intensive care. In: Diuretics and Newer Therapies for Sodium and Edema Management in Acute Decompensated Heart Failure-Chapter 39 Elsevier Health Sciences; 2010:479–487.
10. Reilly RF, Jackson EK. Regulation of renal function and vascular volume. Hilal-Dandan R, ed. In: Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e. McGraw-Hill; 2016. Available at:
https://accessmedicine.mhmedical.com/content.aspx?bookid=1613§ionid=102159750. Accessed July 6, 2021.
11. Sica DA. Current concepts of pharmacotherapy in
hypertension: thiazide-type diuretics: ongoing considerations on mechanism of action. J Clin Hypertens (Greenwich). 2004;6:661–664.
12. Kaplan NM, Victor RG, Flynn JT. Kaplan’s Clinical
Hypertension. Vol. 11th ed. Wolters Kluwer Health; 2015.
13. Pourafshar N, Alshahrani S, Karimi A, et al. Thiazide therapy in chronic kidney disease: renal and extra renal targets. Curr Drug Metab. 2018;19:1012–1020.
14. Calder JA, Schachter M, Sever PS. Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels. Eur J Pharmacol. 1992;220:19–26.
15. Calder JA, Schachter M, Sever PS. Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries. J Cardiovasc Pharmacol. 1994;24:158–164.
16. Pickkers P, Hughes AD, Russel FG, et al. Thiazide-induced vasodilation in humans is mediated by potassium channel activation.
Hypertension. 1998;32:1071–1076.
17. Conway J, Lauwers P. Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide. Circulation. 1960;21:21–27.
18. Mironneau J, Savineau JP, Mironneau C. Compared effects of indapamide, hydrochlorothiazide and chlorthalidone on electrical and mechanical activities in vascular smooth muscle. Eur J Pharmacol. 1981;75:109–113.
19. Del Rio M, Chulia T, Gonzalez P, et al. Effects of indapamide on contractile responses and 45Ca2+ movements in various isolated blood vessels. Eur J Pharmacol. 1993;250:133–139.
20. Zhu Z, Zhu S, Liu D, et al. Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase.
Hypertension. 2005;45:233–239.
21. Alshahrani S, Rapoport RM, Zahedi K, et al. The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states. PLoS One. 2017;12:e0181376.
22. Tamargo J, Segura J, Ruilope LM. Diuretics in the treatment of
hypertension. Part 2: loop diuretics and potassium-sparing agents. Expert Opin Pharmacother. 2014;15:605–621.
23. Sica DA. Chlorthalidone: has it always been the best thiazide-type diuretic?
Hypertension. 2006;47:321–322.
24. Ellison DH. Clinical pharmacology in diuretic use. Clin J Am Soc Nephrol. 2019;14:1248–1257.
25. Moser M, Feig PU. Fifty years of thiazide diuretic therapy for
hypertension. Arch Intern Med. 2009;169:1851–1856.
26. Ernst ME, Moser M. Use of diuretics in patients with
hypertension. N Engl J Med. 2009;361:2153–2164.
27. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for
hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328:914–921.
28. Jamerson K, DeQuattro V. The impact of ethnicity on response to antihypertensive therapy. Am J Med. 1996;101:22S–32S.
29. Materson BJ, Oster JR, Michael UF, et al. Dose response to chlorthalidone in patients with mild
hypertension. Efficacy of a lower dose. Clin Pharmacol Ther. 1978;24:192–198.
30. Carlsen JE, Køber L, Torp-Pedersen C, et al. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990;300:975–978.
31. Musini VM, Nazer M, Bassett K, et al. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary
hypertension. Cochrane Database Syst Rev. 2014;(5):CD003824.
32. Pareek AK, Messerli FH, Chandurkar NB, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016;67:379–389.
33. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability.
Hypertension. 2004;43:4–9.
34. Liang W, Ma H, Cao L, et al. Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis. J Cell Mol Med. 2017;21:2634–2642.
35. Dineva S, Uzunova K, Pavlova V, et al. Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis. J Hum Hypertens. 2019;33:766–774.
36. Agarwal R, Sinha AD. Thiazide diuretics in advanced chronic kidney disease. J Am Soc Hypertens. 2012;6:299–308.
37. Bennett WM, Porter GA. Efficacy and safety of metolazone in renal failure and the nephrotic syndrome. J Clin Pharmacol. 1973;13:357–364.
38. Craswell PW, Ezzat E, Kopstein J, et al. Use of metolazone, a new diuretic, in patients with renal disease. Nephron. 1974;12:63–73.
39. Paton RR, Kane RE. Long-term diuretic therapy with metolazone of renal failure and the nephrotic syndrome. J Clin Pharmacol. 1977;17:243–251.
40. Jones B, Nanra RS. Double-blind trial of antihypertensive effect of chlorothiazide in severe renal failure. Lancet. 1979;2:1258–1260.
41. Dussol B, Moussi-Frances J, Morange S, et al. A randomized trial of furosemide vs hydrochlorothiazide in patients with chronic renal failure and
hypertension. Nephrol Dial Transplant. 2005;20:349–353.
42. Dussol B, Moussi-Frances J, Morange S, et al. A pilot study comparing furosemide and hydrochlorothiazide in patients with
hypertension and stage 4 or 5 chronic kidney disease. J Clin Hypertens (Greenwich). 2012;14:32–37.
43. Agarwal R, Sinha AD, Pappas MK, et al. Chlorthalidone for poorly controlled
hypertension in chronic kidney disease: an interventional pilot study. Am J Nephrol. 2014;39:171–182.
44. Cirillo M, Marcarelli F, Mele AA, et al. Parallel-group 8-week study on chlorthalidone effects in hypertensives with low kidney function.
Hypertension. 2014;63:692–697.
45. Agarwal R, Cramer AE, Balmes-Fenwick M, et al. Design and baseline characteristics of the chlorthalidone in chronic kidney disease (CLICK) trial. Am J Nephrol. 2020;51:542–552.
46. Chobanian AV, Bakris GL, Black HR, et al.; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572.
47. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–e248.
48. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520.
49. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on
hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 suppl 1):S1–290.
50. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2:337–414.
51. Effects of Treatment on Morbidity in
Hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202:1028–1034.
52. Effects of Treatment on Morbidity in
Hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213:1143–1152.
53. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic
hypertension. Final results of the Systolic
Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255–3264.
54. Chang AR, Lóser M, Malhotra R, et al. Blood pressure goals in patients with CKD: a review of evidence and guidelines. Clin J Am Soc Nephrol. 2019;14:161–169.
55. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.
56. Rahman M, Ford CE, Cutler JA, et al.; ALLHAT Collaborative Research Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012;7:989–1002.
57. Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:936–946.
58. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534–2544.
59. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
60. Dhalla IA, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of
hypertension in older adults: a population-based cohort study. Ann Intern Med. 2013;158:447–455.
61. Dorsch MP, Gillespie BW, Erickson SR, et al. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis.
Hypertension. 2011;57:689–694.
62. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses.
Hypertension. 2012;59:1110–1117.
63. Ernst ME, Neaton JD, Grimm RH, et al. Long-term effects of chlorthalidone versus hydrochlorothiazide on electrocardiographic left ventricular hypertrophy in the multiple risk factor intervention trial.
Hypertension. 2011;58:1001–1007.
64. Tsujimoto T, Kajio H. Thiazide use and decreased risk of heart failure in nondiabetic patients receiving intensive blood pressure treatment.
Hypertension. 2020;76:432–441.
65. Sica DA, Gehr TW. Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet. 1996;30:229–249.
66. Wilcox CS, Testani JM, Pitt B. Pathophysiology of diuretic resistance and its implications for the management of chronic heart failure.
Hypertension. 2020;76:1045–1054.
67. Bowman BN, Nawarskas JJ, Anderson JR. Treating diuretic resistance: an overview. Cardiol Rev. 2016;24:256–260.
68. Fouassier D, Blanchard A, Fayol A, et al. Sequential nephron blockade with combined diuretics improves diastolic function in patients with resistant
hypertension. ESC Heart Fail. 2020;7:2561–2571.
69. Dargie HJ, Allison ME, Kennedy AC, et al. High dosage metolazone in chronic renal failure. Br Med J. 1972;4:196–198.
70. Dargie HJ, Allison ME, Kennedy AC, et al. Efficacy of metolazone in patients with renal edema. Clin Nephrol. 1974;2:157–160.
71. Wollam GL, Tarazi RC, Bravo EL, et al. Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med. 1982;72:929–938.
72. Fliser D, Schröter M, Neubeck M, et al. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 1994;46:482–488.
73. Knauf H, Mutschler E. Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure. J Cardiovasc Pharmacol. 1995;26:394–400.
74. Brater DC, Pressley RH, Anderson SA. Mechanisms of the synergistic combination of metolazone and bumetanide. J Pharmacol Exp Ther. 1985;233:70–74.
75. Steuber TD, Janzen KM, Howard ML. A systematic review and meta-analysis of metolazone compared to chlorothiazide for treatment of acute decompensated heart failure. Pharmacotherapy. 2020;40:924–935.
76. Lamberg BA, Kuhlback B. Effect of chlorothiazide and hydrochlorothiazide on the excretion of calcium in urine. Scand J Clin Lab Invest. 1959;11:351–357.
77. Leslie SW, Sajjad H. Hypercalciuria. [Updated 2021 Apr 15]. In: StatPearls. [Internet]. StatPearls Publishing; 2021. Available at:
https://www.ncbi.nlm.nih.gov/books/NBK448183/.
78. Borghi L, Meschi T, Guerra A, et al. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol. 1993;22(suppl 6):S78–S86.
79. Scholz D, Schwille PO, Sigel A. Double-blind study with thiazide in recurrent calcium lithiasis. J Urol. 1982;128:903–907.
80. Li DF, Gao YL, Liu HC, et al. Use of thiazide diuretics for the prevention of recurrent kidney calculi: a systematic review and meta-analysis. J Transl Med. 2020;18:106.
81. Yendt ER, Cohanim M. Prevention of calcium stones with thiazides. Kidney Int. 1978;13:397–409.
82. Laerum E, Larsen S. Thiazide prophylaxis of urolithiasis. A double-blind study in general practice. Acta Med Scand. 1984;215:383–389.
83. Brocks P, Dahl C, Wolf H, et al. Do thiazides prevent recurrent idiopathic renal calcium stones? Lancet. 1981;2:124–125.
84. Reilly RF, Peixoto AJ, Desir GV. The evidence-based use of thiazide diuretics in
hypertension and nephrolithiasis. Clin J Am Soc Nephrol. 2010;5:1893–1903.
85. Martínez García M, Trincado Aznar P, Pérez Fernández L, et al. A comparison of induced effects on urinary calcium by thiazides and different dietary salt doses: Implications in clinical practice. Nefrologia (Engl Ed). 2019;39:73–79.
86. Alon US. The effects of diuretics on mineral and bone metabolism. Pediatr Endocrinol Rev. 2018;15:291–297.
87. Pak CY, Sakhaee K, Moe OW, et al. Defining hypercalciuria in nephrolithiasis. Kidney Int. 2011;80:777–782.
88. Rule AD, Bergstralh EJ, Melton LJ III, et al. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:804–811.
89. Vupputuri S, Soucie JM, McClellan W, et al. History of kidney stones as a possible risk factor for chronic kidney disease. Ann Epidemiol. 2004;14:222–228.
90. Worcester EM, Parks JH, Evan AP, et al. Renal function in patients with nephrolithiasis. J Urol. 2006;176:600–603.
91. Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf. 2010;9:243–257.
92. Iseki K, Ikemiya Y, Inoue T, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44:642–650.
93. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. JAMA. 2000;283:2404–2410.
94. Jing J, Kielstein JT, Schultheiss UT, et al.; GCKD Study Investigators. Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study. Nephrol Dial Transplant. 2015;30:613–621.
95. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987;82:421–426.
96. Choi HK, Atkinson K, Karlson EW, et al. Obesity, weight change,
hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med. 2005;165:742–748.
97. Mount DB. Molecular physiology and the four-component model of renal urate transport. Curr Opin Nephrol Hypertens. 2005;14:460–463.
98. Choi HK, Soriano LC, Zhang Y, et al. Antihypertensive drugs and risk of incident gout among patients with
hypertension: population based case-control study. BMJ. 2012;344:d8190.
99. Waller PC, Ramsay LE. Predicting acute gout in diuretic-treated hypertensive patients. J Hum Hypertens. 1989;3:457–461.
100. Langford HG, Blaufox MD, Borhani NO, et al. Is thiazide-produced uric acid elevation harmful? Analysis of data from the
Hypertension Detection and Follow-up Program. Arch Intern Med. 1987;147:645–649.
101. Handler J. Managing hypertensive patients with gout who take thiazide. J Clin Hypertens (Greenwich). 2010;12:731–735.
102. Badve SV, Pascoe EM, Tiku A, et al.; CKD-FIX Study Investigators. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382:2504–2513.
103. Weaver DJ Jr. Uric acid and progression of chronic kidney disease. Pediatr Nephrol. 2019;34:801–809.
104. Oluwo O, Scialla JJ. Uric acid and CKD progression matures with lessons for CKD risk factor discovery. Clin J Am Soc Nephrol. 2021;16:476–478.
105. Brackett CC, Singh H, Block JH. Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group. Pharmacotherapy. 2004;24:856–870.
106. Hemstreet BA, Page RL II. Sulfonamide allergies and outcomes related to use of potentially cross-reactive drugs in hospitalized patients. Pharmacotherapy. 2006;26:551–557.
107. Wulf NR, Matuszewski KA. Sulfonamide cross-reactivity: is there evidence to support broad cross-allergenicity? Am J Health Syst Pharm. 2013;70:1483–1494.
108. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of “sulfa” allergy. Drug Saf. 2001;24:239–247.
109. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349:1628–1635.
110. Lehmann DF. The metabolic rationale for a lack of cross-reactivity between sulfonamide antimicrobials and other sulfonamide-containing drugs. Drug Metab Lett. 2012;6:129–133.
111. Price AL, Lingvay I, Szczepaniak EW, et al. The metabolic cost of lowering blood pressure with hydrochlorothiazide. Diabetol Metab Syndr. 2013;5:35.
112. Eriksson JW, Jansson PA, Carlberg B, et al. Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study.
Hypertension. 2008;52:1030–1037.
113. Savage PJ, Pressel SL, Curb JD, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic
hypertension: The Systolic
Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158:741–751.
114. Dell’Omo G, Penno G, Del Prato S, et al. Chlorthalidone improves endothelial-mediated vascular responses in
hypertension complicated by nondiabetic metabolic syndrome. J Cardiovasc Pharmacol Ther. 2005;10:265–272.
115. Barzilay JI, Davis BR, Cutler JA, et al.; ALLHAT Collaborative Research Group. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–2201.
116. Ueda S, Morimoto T, Ando S, et al.; DIME Investigators. A randomised controlled trial for the evaluation of risk for type 2 diabetes in hypertensive patients receiving thiazide diuretics: diuretics in the management of essential
hypertension (DIME) study. BMJ Open. 2014;4:e004576.
117. Owen JG, Reisin E. Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications. Curr Hypertens Rep. 2015;17:558.
118. Scheen AJ. Type 2 diabetes and thiazide diuretics. Curr Diab Rep. 2018;18:6.
119. Sörgel F, Ettinger B, Benet LZ. Metabolic fate and solubility of triamterene–not an explanation for triamterene nephrolithiasis. J Pharm Sci. 1986;75:129–132.
120. Spence JD, Wong DG, Lindsay RM. Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide. Lancet. 1985;2:73–75.
121. Ettinger B, Oldroyd NO, Sörgel F. Triamterene nephrolithiasis. JAMA. 1980;244:2443–2445.
