What is the definition and management of diuretic resistance (reduced responsiveness to diuretics)?

From the Guidelines

Diuretic resistance is defined as a reduced responsiveness to diuretics, particularly loop diuretics, and can be managed by optimizing the current loop diuretic, adding a thiazide diuretic, or combining loop diuretics with other agents, as well as addressing underlying causes and ensuring adequate sodium restriction. To manage diuretic resistance, the following strategies can be employed:

• Optimizing the current loop diuretic by increasing the dose or changing to continuous infusion, as seen in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1
• Adding a thiazide diuretic like metolazone 2.5-10mg once daily or chlorothiazide 500-1000mg intravenously to create sequential nephron blockade, enhancing diuretic effect
• Combining loop diuretics with acetazolamide 250-500mg daily or spironolactone 25-50mg daily to overcome resistance through complementary mechanisms
• Ensuring adequate sodium restriction (less than 2g daily) and monitoring for electrolyte imbalances, particularly hypokalemia and hypomagnesemia, which can worsen diuretic resistance
• Addressing underlying causes such as NSAID use, poor renal perfusion, or hypoalbuminemia, as highlighted in the 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults 1 In severe cases, ultrafiltration may be necessary to achieve adequate control of fluid retention. The use of mechanical methods of fluid removal can produce meaningful clinical benefits in patients with diuretic-resistant heart failure and may restore responsiveness to conventional doses of loop diuretics. It is essential to define the patient's dry weight and use it as a continuing target for the adjustment of diuretic doses, and many patients can modify their own diuretic regimen in response to changes in weight that exceed a predefined range. The restriction of dietary sodium and fluid intake can greatly assist in the maintenance of volume balance, and enrollment in a heart failure program can provide close surveillance and education needed for the early recognition and treatment of volume overload. Diuretic resistance occurs because of compensatory distal tubular sodium reabsorption, decreased renal perfusion, and activation of the renin-angiotensin-aldosterone system, which is why combination therapy targeting different nephron segments is often effective. Some key points to consider when managing diuretic resistance include:
• The most commonly used loop diuretic for the treatment of heart failure is furosemide, but some patients respond more favorably to other agents in this category, such as bumetanide or torsemide, due to their increased oral bioavailability 1
• Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium, are taking agents that can block the effects of diuretics, or have significant impairment of renal function or perfusion
• Diuretic therapy is commonly initiated with low doses, and the dose is increased until urine output increases and weight decreases, generally by 0.5 to 1.0 kg daily
• The ultimate goal of diuretic treatment is to eliminate clinical evidence of fluid retention, such as jugular venous pressure elevation and peripheral edema.

From the FDA Drug Label

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide diuretics [see Drug Interactions (7. 3)] . Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone and acetylsalicylic acid are used concomitantly, spironolactone may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained [see Clinical Pharmacology (12.3)] .

The definition of diuretic resistance is not explicitly stated in the provided drug labels. However, it can be inferred that diuretic resistance refers to a reduced responsiveness to diuretics. The management of diuretic resistance is not directly addressed in the labels, but it is mentioned that when certain drugs (such as NSAIDs or acetylsalicylic acid) are used concomitantly with diuretics (like spironolactone), the diuretic effect may be reduced, and the patient should be closely monitored to determine if the desired effect is obtained 2 2. Key considerations for managing diuretic resistance include:

• Monitoring the patient's response to diuretic therapy
• Adjusting the diuretic dose as needed
• Avoiding or minimizing the use of drugs that can reduce diuretic efficacy (such as NSAIDs or acetylsalicylic acid) However, the exact management strategy for diuretic resistance is not provided in the labels.

From the Research

Definition of Diuretic Resistance

• Diuretic resistance is defined as a failure to increase fluid and sodium output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level 3
• It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death, but is difficult to diagnose unequivocally 3

Pathophysiological Mechanisms of Diuretic Resistance

• Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics 3
• Pathophysiological mechanisms include an inappropriately high daily salt intake, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves 3
• Nephron mechanisms include tubular tolerance, enhanced reabsorption in the proximal tubule, and adaptive increase in reabsorption in the downstream distal tubule and collecting ducts 3

Management of Diuretic Resistance

• One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade" 4
• Combination diuretic therapy using thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution 4
• Hypertonic saline solution added to high doses of furosemide can improve dose-response curves in worsening refractory congestive heart failure 5
• A new urinary sodium-based definition of diuretic efficiency has been proposed to identify diuretic resistant patients 6
• The BAN-ADHF score can be used to estimate diuretic resistance and guide loop diuretic dosing in treatment of acute heart failure 7

Diuretic Resistance in Acute Heart Failure

• Diuretic resistance is a relevant clinical issue in acute heart failure, but a standardized, quantitative definition is still missing 6
• The BAN-ADHF score correlated with diuretic resistance and prognosis, and may capture the risk of diuretic resistance compared to traditional measures like CKD or NT-proBNP 7