Thiazide and thiazide-like diuretics (sequential nephron blockade)
AMT in HFrEF · Class IIaAMT in HFpEF · Class IIaRemoval by dialysis
What each drug's prescribing information says about removal by (haemo)dialysis. Where the label is silent, this page says so rather than inferring from protein binding.
- HydrochlorothiazideRemoval not studied
“The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.”
Hydrochlorothiazide tablets USP 12.5/25/50 mg, prescribing information, Accord Healthcare Inc. (2026)· OVERDOSAGE Source
- MetolazoneNot removed (or not meaningfully removed)
“There is no specific antidote available but immediate evacuation of stomach contents is advised. Dialysis is not likely to be effective.”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· OVERDOSAGE, Treatment Source
- ChlorthalidoneLabel does not address dialysis removal
The chlorthalidone label contains no statement on dialysis.
After starting: what a change in creatinine, eGFR or potassium means
Rising creatinine: check for hypovolaemia, stop nephrotoxins, withhold an MRA if eGFR falls below 20, and stop a concomitant thiazide. Small transient creatinine rises during effective decongestion are not associated with poor outcome.
“Check for hypovolaemia/dehydration.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 17, Table S7 Source“Withhold an MRA (if eGFR drops below 20 mL/min/1.73 m2).”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 17, Table S7 Source“Possible worsening kidney function should be evaluated in the context of diuretic response, because small and transient rises in serum creatinine during diuretic therapy are not associated with poor outcome if decongestion is achieved.”
A hemodynamic eGFR dip of up to 30% after starting an SGLT2 inhibitor, RAAS inhibitor, MRA or ARNI is expected and should not lead to discontinuation; above 30%, look for other causes of AKI (KDIGO). ESC accepts a creatinine rise of less than 50% above baseline as long as eGFR stays above 15.
“Hemodynamic fluctuations in eGFR up to 30% can be seen and should not lead to discontinuation”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10“If >30%, other causes of AKI should be evaluated”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10“An increase in serum creatinine of <50% above baseline, as long as eGFR remains >15 mL/min/1.73 m2, is considered acceptable.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 66, Section 10.3 Source“Worsening kidney function alone is not an independent determinant of outcomes in patients with acute HF.”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 11
Drugs and doses
| Drug | Brands | Start | Target | Kidney dosing |
|---|---|---|---|---|
| Hydrochlorothiazide | Microzide (discontinued), generic | 25 mg (ESC Table S7). DHF add-on dosed by eGFR: >50 -> 25 mg, 20-50 -> 50 mg, <20 -> 100 mg daily (ESC Figure 15, CLOROTIC) | Usual 12.5-100 mg (ESC); label edema 25-100 mg/day; ESC Table S13 maximum 200 mg | Paradoxically, the dose goes UP as eGFR falls in the ESC/CLOROTIC DHF protocol. Label: contraindicated in anuria; use with caution in severe renal disease (may precipitate azotemia, cumulative effects). |
| Metolazone | Zaroxolyn, generic | 2.5 mg (ESC Table S7); ESC text 2.5-5 mg; label edema of cardiac failure 5-20 mg once daily | Usual 2.5-10 mg (ESC Table S7); maximum 20 mg (ESC Table S13, AHA Table 12) | Unlike thiazides, may still produce diuresis at GFR <20 mL/min (label); ESC names it the thiazide-like option for eGFR <30. Use caution in severely impaired renal function (accumulation). Contraindicated in anuria. Zaroxolyn-type and Mykrox-type formulations are not interchangeable. |
| Chlorthalidone | Thalitone, generic | Label edema: 50-100 mg daily or 100 mg on alternate days (Thalitone); ESC Table S13 starting 25 mg; AHA Table 12 12.5-25 mg once | ESC Table S13 usual 25-200 mg; label maximum 200 mg daily for edema; AHA Table 12 maximum 100 mg | Label: contraindicated in anuria; patients with CKD, HF or volume depletion are at particular risk of acute renal failure; monitor renal function. The CLICK trial (stage 4 CKD hypertension, not HF) showed efficacy at eGFR 15-29 with more creatinine rises when combined with loop diuretics. |
Status by kidney stage
| Stage | Initiate | Continue |
|---|---|---|
| G1 | Use with caution Only as a short-term add-on to a loop diuretic for diuretic resistance (DHF Class IIa for eGFR-dosed HCTZ, 25 mg at eGFR >50); not as chronic monotherapy in stable HF. Close K+/Na+/creatinine monitoring. | Not recommended Chronic use in stable HF should be avoided (electrolyte disturbances). |
| G2 | Use with caution As G1 (HCTZ 25 mg at eGFR >50; 50 mg at eGFR 20-50 in DHF). | Not recommended Avoid long-term use; usually needed only briefly. |
| G3a | Use with caution Short-term add-on; HCTZ 50 mg in DHF if eGFR 20-50. Expect more creatinine rise and hypokalaemia. | Not recommended Avoid chronic continuation; stop the thiazide if creatinine rises during combined therapy. |
| G3b | Use with caution Short-term add-on; ESC CVD-CKD gives IIb for upfront thiazide in DHF + CKD and notes smaller weight-loss effect and more hypokalaemia than acetazolamide. | Not recommended Avoid chronic continuation in HF. |
| G4 | Use with caution May still work (ESC names metolazone for eGFR <30; HCTZ 50-100 mg by eGFR in DHF; CLICK showed chlorthalidone works in stage 4 CKD), but response is less reliable and ESC flags eGFR <30 for specialist advice. Acetazolamide may be preferred in advanced CKD. | Not recommended Avoid chronic continuation in HF; if used, short courses with careful eGFR/electrolyte monitoring. |
| G5 | Use with caution Only short-term as part of sequential nephron blockade in a non-anuric patient: metolazone keeps activity at GFR <20 (label); ESC DHF protocol uses HCTZ 100 mg at eGFR <20. Contraindicated in anuria; accumulation risk. | Not recommended Avoid chronic continuation; stop if azotemia/oliguria worsen. |
| dialysis | No data No guideline or trial supports thiazides for HF congestion on maintenance dialysis; all DHF recommendations are restricted to patients 'not on KRT'. Contraindicated if anuric. | No data No authoritative statement; contraindicated once anuric. |
| aki | Not recommended Do not add a thiazide during AKI; KDIGO advises against diuretics in AKI except for volume overload, and ESC advises stopping the thiazide when creatinine rises. | Not recommended Stop the thiazide component if kidney function worsens; continue the loop diuretic as needed. |
| transplant | No data No transplant-specific statement found. | No data No transplant-specific statement found. |
Cutoffs recorded from the sources
- egfr > 50 mL/min/1.73m2 → HCTZ 25 mg daily (initiate; hydrochlorothiazide)“Acetazolamide (500 mg i.v. once daily) or hydrochlorothiazide (if eGFR >50 mL/min/1.73 m2: 25 mg daily; eGFR 20–50 mL/min/1.73 m2: 50 mg daily; and eGFR <20 mL/min/1.73 m2: 100 mg daily).” — esc2026, p. 49
- egfr between 20,50 mL/min/1.73m2 → HCTZ 50 mg daily (initiate; hydrochlorothiazide)“Acetazolamide (500 mg i.v. once daily) or hydrochlorothiazide (if eGFR >50 mL/min/1.73 m2: 25 mg daily; eGFR 20–50 mL/min/1.73 m2: 50 mg daily; and eGFR <20 mL/min/1.73 m2: 100 mg daily).” — esc2026, p. 49
- egfr < 20 mL/min/1.73m2 → HCTZ 100 mg daily (initiate; hydrochlorothiazide)“Acetazolamide (500 mg i.v. once daily) or hydrochlorothiazide (if eGFR >50 mL/min/1.73 m2: 25 mg daily; eGFR 20–50 mL/min/1.73 m2: 50 mg daily; and eGFR <20 mL/min/1.73 m2: 100 mg daily).” — esc2026, p. 49
- egfr < 30 mL/min/1.73m2 → metolazone 2.5-5 mg can be used (with careful eGFR/electrolyte monitoring) (initiate; metolazone)“Thiazide-like diuretics—particularly oral metolazone (2.5–5 mg)—can be used in patients with advanced HF who exhibit diuretic resistance, as part of a sequential nephron blockade approach, or in those with an eGFR <30 mL/min/1.73 m2.” — esc2026, p. 48
- egfr < 30 mL/min/1.73m2 → caution / seek specialist advice (initiate; hydrochlorothiazide, chlorthalidone, metolazone)“Significant renal dysfunction (eGFR <30 mL/min/1.73 m2)—may be made worse by diuretic or patient may not respond to diuretic (especially” — esc2026-supp, p. 16
- egfr >= 30 mL/min/1.73m2 → thiazides generally preferred over loop for BP; below 30 loop preferred but thiazides can still be used (initiate; hydrochlorothiazide, chlorthalidone, metolazone)“Thiazides/thiazide-like diuretics are generally preferred over loop diuretics if eGFR is ≥30 mL/min/1.73 m2, and can augment the albuminuria-lowering effect of ACEI/ARB treatment.” — esc2026-ckd, p. 25
- other < 20 mL/min GFR → metolazone may still produce diuresis (unlike thiazides) (initiate; metolazone)“However, unlike thiazides, metolazone may produce diuresis in patients with glomerular filtration rates below 20 mL/min.” — fda-metolazone, CLINICAL PHARMACOLOGY
- potassium <= 3.5 mmol/L → caution (initiate; hydrochlorothiazide, chlorthalidone, metolazone)“Significant hypokalaemia (K+ ≤3.5 mmol/L)—may be made worse by diuretic.” — esc2026-supp, p. 16
- other <= 200 mg/day HCTZ (metolazone 20 mg/day) → dose ceiling (uptitrate; hydrochlorothiazide, metolazone)“HCTZ: 200 mg Metolazone: 20 mg” — esc2026-supp, p. 24
- other <= 200 mg/day chlorthalidone → dose ceiling (AHA Table 12 lists 100 mg) (uptitrate; chlorthalidone)“The recommended initial dosage is 50 to 100 mg daily or 100 mg on alternate days. Depending on response, dosage can be decreased or increased up to a maximum of 200 mg daily.” — fda-chlorthalidone, 2.3 Edema
Trial evidence (informational)
- CLOROTIC · Acute HF on i.v. furosemide (n=230), eGFR 14-109Weight loss at 72 h; dyspnoea: 2.3 vs 1.5 kg; no difference in dyspnoea, mortality or rehospitalization“Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo [2.3 vs. 1.5 kg;” — trullas2023, Abstract, Methods and Results
- CLOROTIC eGFR post hoc · As above, by eGFR groupDiuretic response across eGFR: Effect present across eGFR, attenuated weight-loss effect at eGFR <45 (interaction NS)“The addition of eGFR-adjusted doses of oral HCTZ to loop diuretics in patients with AHF improved diuretic response across the eGFR spectrum.” — trullas2023-egfr, Abstract, Conclusion
- CLICK (not HF) · Stage 4 CKD with uncontrolled hypertension (eGFR 15-29), 60% on loop diuretics24-h ambulatory systolic BP at 12 weeks: -11.0 vs -0.5 mmHg; difference -10.5 mmHg (95% CI -14.6 to -6.4)“The adjusted change in the 24-hour ambulatory systolic blood pressure from baseline to 12 weeks was −11.0 mm Hg in the chlorthalidone group and −0.5 mm Hg in the placebo group, for a mean difference of −10.5 mm Hg (95% CI, −14.6 to −6.4) (P<0.001), and similar reductions were observed during the day and night.” — agarwal2021, Results
- ADVOR and CLOROTIC (ESC summary) · DHFHard endpoints: No benefit on death/HF rehospitalization“Both ADVOR and CLOROTIC did not show benefit of non-loop diuretics on hard endpoints.” — esc2026, p. 48
Acute kidney injury
Stop the thiazide component when creatinine rises during combined loop + thiazide therapy (ESC Table S7). KDIGO AKI suggests not treating AKI with diuretics except for volume overload. Labels warn of acute renal failure risk in CKD/HF/volume depletion. CLOROTIC: HCTZ more often worsened kidney function.
“If using concomitant loop and thiazide diuretic, stop thiazide diuretic.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 17 Source“Treatment with hydrochlorothiazide was associated with greater 24 h diuresis but also more likely worsened kidney function and hypokalaemia, warranting caution.”
“If azotemia and oliguria worsen during treatment of patients with severe renal disease, metolazone should be discontinued.”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· WARNINGS, Azotemia Source
Dialysis
No source supports thiazide-type diuretics for HF on maintenance dialysis; anuria is a labelled contraindication for all three agents.
“Anuria, hepatic coma or precoma, known allergy or hypersensitivity to metolazone.”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· CONTRAINDICATIONS Source“THALITONE is contraindicated in patients with anuria or hypersensitivity to chlorthalidone or other sulfonamide-derived drugs.”
THALITONE (chlorthalidone) tablets, prescribing information, Casper Pharma LLC (2026)· 4 CONTRAINDICATIONS Source
Kidney transplant
No kidney-transplant-specific statement found.
No verbatim statement found for this cell.
Albuminuria
Hypertension context only: ESC CVD-CKD notes thiazides can augment the albuminuria-lowering effect of ACEI/ARB at eGFR >=30. Not an HF-congestion criterion.
“Thiazides/thiazide-like diuretics are generally preferred over loop diuretics if eGFR is ≥30 mL/min/1.73 m2, and can augment the albuminuria-lowering effect of ACEI/ARB treatment.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 25 Source
Monitoring
Thiazide add-on needs close biochemistry: serum electrolytes (K+, Na+, Mg2+) and creatinine/eGFR; in DHF at least every 24 h. Rapid severe hyponatraemia/hypokalaemia can occur after initial doses. Combined loop + thiazide: risk of hypovolaemia, hypotension, hypokalaemia and renal impairment.
“Combination with other diuretics (e.g. loop plus thiazide)—risk of hypovolaemia, hypotension, hypokalaemia, and renal impairment.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 16 Source“Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics.”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· WARNINGS Source“Unusually large or prolonged losses of fluids and electrolytes may result when metolazone is administered concomitantly to patients receiving furosemide”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· WARNINGS, Furosemide Source“THALITONE can cause hypokalemia, hyponatremia, hypochloremic alkalosis, and hypomagnesemia.”
THALITONE (chlorthalidone) tablets, prescribing information, Casper Pharma LLC (2026)· 5.3 Electrolyte Abnormalities Source
In-hospital initiation
DHF: oral HCTZ dosed by eGFR (25/50/100 mg), added short term to i.v. loop diuretics in patients previously on loop diuretics (ESC IIa B1); thiazides are used orally only in DHF (chlorothiazide i.v. exists in the US).
“In the CLOROTIC trial, oral hydrochlorothiazide (dose adjusted for eGFR) was compared with placebo in patients receiving i.v. furosemide.”
“Only PO use in decompensated HF, thiazides are not recommended for daily ambulatory use in chronic stable HF.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 25 Source
Outpatient
Temporary add-on (e.g. metolazone 2.5-5 mg) for worsening HF or diuretic resistance, especially in advanced HF or eGFR <30, with careful eGFR/electrolyte monitoring; avoid chronic daily use in stable HF.
“Thiazide-like diuretics—particularly oral metolazone (2.5–5 mg)—can be used in patients with advanced HF who exhibit diuretic resistance, as part of a sequential nephron blockade approach, or in those with an eGFR <30 mL/min/1.73 m2. This strategy requires careful monitoring of eGFR and electrolytes.”
“Long-term use of thiazide diuretics should be avoided, as this often induces severe electrolyte disturbances that could go undetected in the ambulatory setting.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 16 Source
Where sources disagree
Chronic (maintenance) thiazide use in HF
“The chronic use of thiazide diuretics in stable patients should be avoided, as this often induces severe electrolyte disturbances that could go undetected in the ambulatory setting.”
“For patients with HF and congestive symptoms, addition of a thiazide (e.g., metolazone) to treatment with a loop diuretic should be reserved for patients who do not respond to moderate- or high-dose loop diuretics to minimize electrolyte abnormalities”
“Chlorthalidone is indicated in adults as adjunctive therapy in edema associated with heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome.”
THALITONE (chlorthalidone) tablets, prescribing information, Casper Pharma LLC (2026)· 1.2 Edema Source
Tool uses esc2026: The labels permit chronic use for edema but give no HF-specific preference; ESC 2026 (primary framework) advises against chronic use in stable HF, and AHA restricts it to loop non-responders. Engine: initiate = caution (short-term add-on), continue = not-recommended for chronic stable use. AHA 2022 also notes thiazides may be considered for HF with hypertension and mild fluid retention (not quotable verbatim: two-column extraction).
Thiazide efficacy and use at eGFR <30
“Significant renal dysfunction (eGFR <30 mL/min/1.73 m2)—may be made worse by diuretic or patient may not respond to diuretic (especially”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 16 Source“Acetazolamide (500 mg i.v. once daily) or hydrochlorothiazide (if eGFR >50 mL/min/1.73 m2: 25 mg daily; eGFR 20–50 mL/min/1.73 m2: 50 mg daily; and eGFR <20 mL/min/1.73 m2: 100 mg daily).”
“Below this level, loop diuretics are generally preferred although thiazides/thiazide-like diuretics can still safely be used.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 25 Source“Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia.”
Hydrochlorothiazide tablets USP 12.5/25/50 mg, prescribing information, Accord Healthcare Inc. (2026)· WARNINGS, Renal Disease Source
Tool uses esc2026: No source forbids use; the label asks for caution. Status 'caution' at G4/G5 with eGFR-based HCTZ dosing from ESC Figure 15, metolazone named for eGFR <30, and a note that acetazolamide may be preferable in advanced CKD (ESC p. 49; ESC CVD-CKD p. 42).
Metolazone dose
“Thiazide-like diuretics—particularly oral metolazone (2.5–5 mg)—can be used in patients with advanced HF who exhibit diuretic resistance, as part of a sequential nephron blockade approach, or in those with an eGFR <30 mL/min/1.73 m2.”
“Metolazone: starting dose 2.5 mg, usual dose 2.5–10 mg”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 16 Source“Edema of cardiac failure: Metolazone tablets 5 to 20 mg once daily.”
Metolazone tablets USP (Zaroxolyn-equivalent), prescribing information, Mylan Pharmaceuticals Inc. (2024)· DOSAGE AND ADMINISTRATION Source
Tool uses fda-metolazone: Label > guideline for the 20 mg/day ceiling (also ESC Table S13 and AHA Table 12). Starting dose: the label's 5-20 mg 'initial dosage range' predates sequential-blockade practice; propose showing the ESC 2.5-5 mg start as the guideline value, with the label range alongside. Owner to confirm.
Chlorthalidone maximum dose
“The recommended initial dosage is 50 to 100 mg daily or 100 mg on alternate days. Depending on response, dosage can be decreased or increased up to a maximum of 200 mg daily.”
THALITONE (chlorthalidone) tablets, prescribing information, Casper Pharma LLC (2026)· 2.3 Edema Source“Chlorthalidone 12.5–25 mg once 100 mg 24–72 h”
“Metolazone: 2.5/2.5– 10 mgc Chlorthalidone: 25/ 25–200 mgc”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 24 Source
Tool uses fda-chlorthalidone: Label > guideline: 200 mg/day maximum for edema (ESC Table S13 usual range also reaches 200 mg); AHA's 100 mg is a chronic-HF table value.
Open questions
- Status for the DHF short-term HCTZ add-on: the vocabulary implies 'recommended' for Class IIa + RCT, but the electrolyte/WRF safety signal and chronic-use advice suggest 'caution'. Set to 'caution'. Owner to confirm.
- Should 'continue' for thiazides be 'not-recommended' (ESC: avoid chronic use) even when a patient has HF plus hypertension and preserved eGFR (ACC/AHA would allow)?
- Dialysis: set to 'no-data' (no source) rather than 'not-recommended'. Engine should still flag anuria as contraindicated.
- Metolazone formulation non-interchangeability (Zaroxolyn vs Mykrox) may warrant a UI note.