Case: 74 year old male with a history of heart failure with reduced ejection fraction (EF 20%) diagnosed 10 years ago comes in with subacute progressive lower extremity edema, orthopnea, and 10 kg weight gain. Patient reports good compliance with his long-standing home furosemide dose of 120 mg PO BID, but notes he hasn’t been producing as much urine with his furosemide as previously. In the hospital, he is treated with furosemide 120 mg IV BID, with only 2 L urine output daily.
This scenario is a common one in the hospital. Patients with heart failure are chronically treated with loop diuretics to prevent retention of fluid. These medications work by increasing sodium excretion. Loop diuretics do so by inhibiting the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb of the loop of Henle, thereby preventing uptake of sodium back into the circulation and resulting in natriuresis with a corresponding reduction in extracellular fluid volume.1
However, over the course of long-term therapy, the natriuretic response to loop diuretics decreases, a phenomenon termed “diuretic resistance.”2 Direct evidence in animal studies and indirect evidence in human studies suggest that diuretic resistance arises from increased sodium uptake in the distal convoluted tubules. For example, a study published in 1985 sought to examine the histological changes present in the nephrons of rats treated with loop diuretic therapy. This study examined under light and electron microscopy the distal convoluted tubules (DCT) of rats that were treated with furosemide for six days. They found these rats developed hypertrophy of their DCT compared to rats given placebo.3 This finding suggests remodeling of the DCT may play a role in eventually overcoming diuresis.
Studies in humans have not used biopsy to search for evidence of DCT hypertrophy, but instead sought findings suggestive of DCT involvement using less invasive measures. One placebo-controlled study in 1989 treated participants with either furosemide, chlorothiazide, furosemide with spironolactone, or placebo twice daily for one month. After one month, patients were given either an intravenous bolus of furosemide, or intravenous bolus of furosemide with intravenous chlorothiazide. Urine sodium excretion, sodium fractional excretion (FENa), and furosemide excretion were measured during and after the treatment. The researchers found lower responses to intravenous furosemide in the chronically treated group compared to the placebo group, as measured by FENa, despite greater excretion of furosemide in these patients. Treatment with both intravenous furosemide with intravenous chlorothiazide restored FENa to levels similar to the placebo-treated furosemide-naive patients. Patients treated with spironolactone 36 hours prior to the intravenous furosemide dose did not have increased sodium excretion. This suggests that the site of action of chlorothiazide, as opposed to spironolactone, is responsible for diuretic resistance.4
A more recent 2017 study sought to find the site of diuretic resistance in a different way. The investigators took patients with heart failure who were receiving high dose loop diuretics. They measured FENa as well as fractional excretion of lithium (FELi), an established proxy for the measurement of sodium reabsorption in the proximal convoluted tubule and loop of Henle only. Importantly, FELi is not affected by distal reuptake. In these patients, FELi was elevated, indicating low sodium reabsorption in the proximal convoluted tubule and loop of Henle, but had lower FENa.5 This suggested that a segment of the nephron distal to the loop of Henle was responsible for the increased sodium uptake.
Given those findings, it is likely diuretic resistance arises distal to the loop of Henle, in the hypertrophied distal convoluted tubule, at chlorothiazide’s site of action. Chlorothiazide is a thiazide diuretic, which acts on the NaCl cotransporter (NCC) in the DCT.1,6 Commonly used thiazide diuretics include chlorothiaizde and hydrochlorothiazide, and commonly used thiazide-like diuretics include chlorthalidone, indapamide, and metolazone.6 In patients chronically treated with loop diuretics, we can use thiazide and thiazide-like diuretics (which I will refer to collectively as “thiazides” for brevity) synergistically with loop diuretics to overcome the diuretic resistance arising from DCT-hypertrophy, a strategy termed “sequential nephron blockade.” Metolazone is most commonly the diuretic of choice to pair with loop diuretics.7–9 Multiple case series in the 1970s through the 1990s showed the clinical utility of sequential nephron blockade in overcoming diuretic resistance.9–12
It is unclear, however, why metolazone became the preferred thiazide to overcome loop diuretic resistance. It possibly relates to a combination of its potency and duration of action. Metolazone is the newest of the commonly used thiazides, and was approved by the FDA in 1973, compared to 1957 for chlorothiazide, 1959 for hydrochlorothiazide, and 1960 for chlorthalidone.13–16 Metolazone and chlorthalidone both have long half-lifes that allow for once-daily dosing, compared to twice daily dosing for hydrochlorothiazide and chlorothiazide.1 In addition, a 1972 study found that metolazone is a more potent diuretic than chlorothiazide.17
Despite the common use of metolazone in sequential nephron blockade, there have been studies showing efficacy of other thiazides to overcome diuretic resistance in congestive heart failure. For example, one study showed the addition of hydrochlorothiazide to furosemide significantly increased daily urine output from an average of 1899 mL to 3065 mL.18 Another study, this time in 1994, compared bendrofluazide, also a thiazide diuretic, to metolazone, when added to loop diuretics in hospitalized patients with diuretic-resistant CHF. Again, greater diuresis was achieved with the addition of a thiazide compared to loop diuresis alone. However, the urine output achieved from the addition of bendrofluazide was equal to the urine output with the addition of metolazone.19
More modern studies have found similar results. A retrospective cohort study in 2016 compared intravenous chlorothiazide to oral metolazone. They found urine output of patients in acute decompensated heart failure with diuretic resistance given oral metolazone to be non-inferior to urine output of patients given IV chlorothiazide.20 Lastly, the 3T randomized controlled trial published in March 2020 compared the addition of oral metolazone, intravenous chlorothiazide, or tolvaptan to intravenous loop diuretic in hospitalized patients with acute heart failure and diuretic resistance. They found no significant differences in weight loss between the three groups. While the chlorothiazide group had greater natriuresis compared to the metolazone group at 24 hours, this difference disappeared after 48 hours.21 One 2017 review concluded that there is no evidence suggesting one thiazide diuretic is more efficacious than the others.22
In many patients with heart failure, development of loop diuretic resistance appears inevitable. Unfortunately, there are no high-quality data to suggest initiating use of thiazide diuretics earlier in patients with heart failure, as opposed to first maximizing loop diuretic doses, as discussed in a recent State-of-the-Art Review in JACC regarding diuretics in heart failure.23 The authors point out that caution should be employed when using a thiazide with a loop diuretic given the association in an observational study between sequential nephron blockade and hyponatremia, hypokalemia, and increased mortality.7,23 However, lacking any data from prospective randomized control trials, such observational data will remain limited by possible confounding despite use of propensity-matching. Randomized control trials comparing maximizing loop diuretic dosing versus early initiation of thiazide use are necessary to guide treatment algorithms.
In summary, in patients with congestive heart failure presenting with loop-diuretic resistance, there is good direct evidence from animal studies and indirect evidence from human studies isolating the cause of resistance to the distal convoluted tubule. The DCT hypertrophy can be overcome with the addition of thiazides. However, other than metolazone’s long half-life, there appears to be little evidence, other than routine practice, to argue for its preferential use. It is reasonable to consider the use of other thiazides in sequential nephron blockade.
Dr. Joshua Novack is a 3rd year resident at NYU Langone Health
Reviewed by David Goldfarb, MD, Professor, Department of Medicine at NYU Grossman School of Medicine, Professor, Department of Neuroscience and Physiology at NYU Grossman School of Medicine, Chief, Nephrology at NY Harbor VA Medical Center
Image courtesy of Wikimedia Commons, source: Blausen Medical Communications, Inc.
- Ellison DH. Clinical Pharmacology in Diuretic Use. Clin J Am Soc Nephrol. 2019;14(8):1248-1257. doi:10.2215/CJN.09630818 https://pubmed.ncbi.nlm.nih.gov/30936153/
- Iyengar S, Abraham WT. Diuretic resistance in heart failure. Curr Heart Fail Rep. 2006;3(1):41-45. doi:10.1007/s11897-006-0030-x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431570/
- Kaissling B, Bachmann S, Kriz W. Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment. Am J Physiol. 1985;248(3 Pt 2):F374-381. doi:10.1152/ajprenal.1985.248.3.F374 https://pubmed.ncbi.nlm.nih.gov/3976898/
- Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired natriuretic response to furosemide during prolonged therapy. Kidney Int. 1989;36(4):682-689. doi:10.1038/ki.1989.246 https://pubmed.ncbi.nlm.nih.gov/2811065/
- Rao VS, Planavsky N, Hanberg JS, et al. Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure. J Am Soc Nephrol JASN. 2017;28(11):3414-3424. doi:10.1681/ASN.2016111178 https://pubmed.ncbi.nlm.nih.gov/28739647/
- Subramanya AR, Ellison DH. Distal Convoluted Tubule. Clin J Am Soc Nephrol. 2014;9(12):2147-2163. doi:10.2215/CJN.05920613
- Brisco‐Bacik Meredith A., ter Maaten Jozine M., Houser Steven R., et al. Outcomes Associated With a Strategy of Adjuvant Metolazone or High‐Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. J Am Heart Assoc. 2018;7(18):e009149. doi:10.1161/JAHA.118.009149
- Sica DA. Metolazone and Its Role in Edema Management. Congest Heart Fail. 2003;9(2):100-105. doi:10.1111/j.1527-5299.2003.01907.x
- Ghose RR, Gupta SK. Synergistic action of metolazone with “loop” diuretics. Br Med J Clin Res Ed. 1981;282(6274):1432-1433.
- Gunstone RF, Shani HGP, Njemo D, Wing AJ, Sabuka EMW. Clinical experience with metolazone in fifty-two African patients: synergy with frusemide. Postgrad Med J. 1971;47(554):789-793. doi:10.1136/pgmj.47.554.789
- Kiyingi A, Field MJ, Pawsey CC, Yiannikas J, Lawrence JR, Arter WJ. Metolazone in treatment of severe refractory congestive cardiac failure. The Lancet. 1990;335(8680):29-31. doi:10.1016/0140-6736(90)90148-X
- Grosskopf I, Rabinovitz M, Rosenfeld J. Combination of furosemide and metolazone in the treatment of severe congestive heart failure. Isr J Med Sci. 1986;22(11):787—790.
- National Center for Advancing Translational Sciences. NCATS Inxight: Drugs — CHLOROTHIAZIDE. Inxight: Drugs. Accessed October 22, 2020. https://drugs.ncats.io/drug/77W477J15H
- National Center for Advancing Translational Sciences. NCATS Inxight: Drugs — CHLORTHALIDONE. Inxight: Drugs. Accessed October 22, 2020. https://drugs.ncats.io/drug/Q0MQD1073Q
- National Center for Advancing Translational Sciences. NCATS Inxight: Drugs — HYDROCHLOROTHIAZIDE. Inxight: Drugs. Accessed October 22, 2020. https://drugs.ncats.io/drug/0J48LPH2TH
- National Center for Advancing Translational Sciences. NCATS Inxight: Drugs — METOLAZONE. Inxight: Drugs. Accessed October 22, 2020. https://drugs.ncats.io/drug/TZ7V40X7VX
- Steinmuller SR, Puschett JB. Effects of metolazone in man: Comparison with chlorothiazide. Kidney Int. 1972;1(3):169-181. doi:10.1038/ki.1972.24
- Dormans TPJ, Gerlag PGG. Combination of high-dose furosemide and hydrochlorothiazide in the treatment of refractory congestive heart failure. Eur Heart J. 1996;17(12):1867-1874. doi:10.1093/oxfordjournals.eurheartj.a014805
- Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart failure: a randomised controlled trial. Br Heart J. 1994;71(2):146-150. doi:10.1136/hrt.71.2.146
- Shulenberger CE, Jiang A, Devabhakthuni S, Ivaturi V, Liu T, Reed BN. Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance. Pharmacotherapy. 2016;36(8):852-860. doi:10.1002/phar.1798
- Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020;8(3):157-168. doi:10.1016/j.jchf.2019.09.012
- Shah N, Madanieh R, Alkan M, Dogar MU, Kosmas CE, Vittorio TJ. A perspective on diuretic resistance in chronic congestive heart failure. Ther Adv Cardiovasc Dis. 2017;11(10):271-278. doi:10.1177/1753944717718717
- Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for Patients With Heart Failure. J Am Coll Cardiol. 2020;75(10):1178-1195. doi:10.1016/j.jacc.2019.12.059