The Basics of Diuretic Resistance in Heart Failure

The Basics of Diuretic Resistance in Heart Failure Posted By:
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Increasing severity of congestion is the main reason patients with heart failure (HF) seek medical care. Extracellular fluid volume expansion is central to the pathophysiology of HF. The pivotal role of congestion in HF makes diuretics one of the cornerstones of HF therapy, and loop diuretics are widely used to manage that congestion. However, diuretic resistance (DR) is a major challenge that portends poor outcomes and can develop in a third of patients with HF.

What is Diuretic Resistance?

Diuretic resistance can be simply defined as the loss of or reduction in response to diuretics. It is an inadequate rate/quality of natriuresis despite an adequate diuretic regimen. The qualitative description of DR consists of: (1) presence and degree of hypervolemia, (2) adequacy of diuretic regimen, and (3) rate of net negative urine and sodium balance. The challenge is that there is no established and precise measure of diuretic response or efficiency because it can be subjective and varies with clinical context.

More recently, quantification of diuretic response by urinary sodium level has gained attention. It has been shown that a post-diuretic spot urinary sodium of <50 to 70 mmol is associated with higher risk for worsening renal function, HF, and other long-term adverse events. The use of urinary sodium as a quantitative measure of DR has great potential in providing a more precise definition, but it needs further validation in larger scale studies.

Mechanisms of Diuretic Resistance

The mechanisms of DR can be broadly classified as prerenal and intrarenal. There is also a growing appreciation that the mechanisms may vary on the basis of clinical context and patient population.

  • Prerenal mechanisms: Hemodynamic cardiorenal interactions in HF contribute to DR. Several physiologic changes that occur in HF can also cause alterations in drug pharmacokinetics such as alterations in absorption, distribution, metabolism, and elimination of loop diuretics. Hypoalbuminemia is also thought to be a part of the mechanism because all loop diuretics are 90% protein bound. The complex relationship between sodium and HF plays a role in DR; in patients with dietary sodium indiscretion, loop diuretics can initially cause pronounced natriuresis but this may can be followed by a post-diuresis increase in sodium reabsorption.
  • Intrarenal mechanisms: These mechanisms occur at the renal level. Increased proximal tubule sodium reabsorption, reduced glomerular filtration rate (GFR), compensatory distal tubule sodium reabsorption, and hypochloremic alkalosis all play a role in DR at this level.

How to Manage Diuretic Resistance?

Management of DR depends on its mechanism in the individual patient, but the goal is to relieve congestion and achieve a net negative sodium and fluid balance. In a hemodynamically stable, hypervolemic patient with HF exhibiting DR, the following strategies have been suggested:

  • Exclude non-adherence with prescribed medications, dietary changes, and sodium/fluid intake restrictions.
  • Exclude causes of pseudoresistance such as drug interactions (eg, with NSAIDs), urinary tract obstruction, and total body euvolemia with edema secondary to lymphedema or hypoalbuminemia.
  • Up-titration of diuretic doses (ideally by IV administration). Assessment of diuretic response must occur between 2 and 6 hours of diuretic administration. If not meeting diuretic goals, consider doubling the diuretic dose for the next scheduled dose.
    NOTE: many patients with HF have some degree of renal dysfunction that makes it necessary to increase diuretic dose to adequately deliver the drug at its site of action.
  • Combination diuretic therapy should be considered (eg, combination of loop diuretic and thiazide diuretic such as metolazone or chlorothiazide). Loop and thiazide diuretics each act on a different part of the renal tubules thus, using them together causes a synergistic diuretic action.
  • If there is persistent or refractory DR, consider hemodynamic-guided diuretic/medical therapy. Addition of other types of diuretics such as spironolactone or acetazolamide should be considered in the appropriate clinical context.
  • Consult with nephrology and an advanced HF specialist for further guidance, especially when advanced HF therapies are needed.
References
  • Cox ZL, Testani JM. Loop diuretic resistance complicating acute heart failure. Heart Fail Rev. 2020;25:133-145.
  • Felker GM, Ellison DH, Mullens W, et al. Diuretic therapy for patients with heart failure: JACC state-of-the-art review. JACC. 2020;75:1178-1195.
  • Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21:137-155.
  • Shah N, Madanieh R, Alkan M, et al. A perspective on diuretic resistance in chronic congestive heart failure. Ther Adv Cardiol Dis. 2017;11:271-278.

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Filed under: Cardiometabolic

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