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CardioNerds, Amit Goyal and Daniel Ambinder, join Duke University CardioNerds Ambassador and Correspondent, Dr. Kelly Arps for the diuretic showdown of a lifetime. Join us for this Cardiology vs. Nephrology discussion and respective approach to volume overload and diuretic strategies with Dr. Michael Felker (Professor of Medicine with tenure in the Division of Cardiology at Duke University School of Medicine), and Dr. Matt Sparks (Founding member of the Nephrology Social Medial Collective and #NephJC and Associate Professor of Medicine and Program Director for the Nephrology Fellowship Program at Duke University School of Medicine). Episode introduction, audio editing and Approach to Diuretic Resistance infographic by Dr. Gurleen Kaur (Director of the CardioNerds Internship).
Volume overload is a common indication for hospitalization in patients with heart failure. Loop diuretics are first line therapy for volume overload in heart failure, with assessment for adequate response within 3-6 hours after administration. Elevation in creatinine is common with venous congestion as well as during decongestion. While other causes of renal injury should be considered, an elevated creatinine in this context should not automatically trigger avoidance or cessation of diuresis. Diuretic resistance is an exaggerated form of natural safety mechanisms in the face of diuresis. Strategies for addressing diuretic resistance include optimizing dose and frequency of loop diuretic administration, adding adjunctive medication for sequential nephron blockade (i.e., thiazide diuretic, potassium sparing diuretic, acetazolamide, tolvaptan, SGLT2 inhibitor), and, in refractory cases, hemodialysis with ultrafiltration. In the outpatient setting, transition to a more potent loop diuretic (i.e., torsemide or bumetanide from furosemide), addition of a mineralocorticoid antagonist, or intermittent dosing of thiazide diuretic may augment maintenance diuretic therapy for patients with diminished response to loop diuretics.
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The CardioNerds Heart Success Series is developed in collaboration with the Heart Failure Society of America. The Heart Failure Society of America is a multidisciplinary organization working to improve and expand heart failure care through collaboration, education, research, innovation, and advocacy. Its members include physicians, scientists, nurses, nurse practitioners, and pharmacists. Learn more at hfsa.org.
Pearls – Cardiology vs Nephrology: A Diuretic Showdown
- Elevation in creatinine is expected in both congested states and during diuresis. Do not avoid or stop diuresis in a patient who is clearly volume overloaded based on an elevated creatinine. There may be a role for right heart catheterization if the fluid and/or hemodynamic status is unclear.
- Alkalosis in the setting of loop diuretic administration and diuretic resistance may represent a natural response to loop diuretics and not volume depletion. Ensure adequate potassium repletion and try using a mineralocorticoid antagonist to correct this alkalosis. Acetazolamide is rarely necessary but may be of use.
- Currently available evidence does not support extreme fluid or salt restriction in hospitalized patients with volume overload. Consider permissive restrictions and focus on choosing appropriate diuretic dosing for each individual patient.
- Diuretic resistance is an exaggerated form of diuretic braking, the kidney’s natural response to prevent dangerous degrees of sodium loss from the NKCC2-blocking effects of loop diuretics.
- Torsemide has improved bioavailability and duration of action compared to furosemide and may be a good choice for outpatient therapy in patients with limited diuretic response.
Quotable – Cardiology vs Nephrology: A Diuretic Showdown
Eventually the…body recognizes that, Hey, if we’re going to live without this very important, cotransporter in KCC2, we’re going to have to kick on things in the distal nephron to basically have a steady state. – Dr. Sparks
I would rather the patient feel good with a creatinine of 2 than terrible with creatinine of 1 and a half. – Dr. Felker
I think it’s pretty clear that in the long run, if they’re accompanied by effective decongestion, [minor elevations in creatinine] are actually if anything, a favorable prognostic indicator in terms of heart failure, prognosis, as opposed to an adverse one. – Dr. Felker
I think we hit a record for that. The most number of times a cardiologist has mentioned urine and measuring something in the urine. – Dr. Sparks
I can tell you my experience and it’s biased because I take care of people with pretty bad heart failure, but nine times out of 10, if we do a right-heart cath, because we’re not sure if the patient is still volume overloaded, they still are. – Dr. Felker
The more, when you look at the data, the more high quality, the study design, so randomized versus non-randomized, uh, the worst sodium and fluid restriction look. The one thing we are guaranteed to do though, is create unhappy patients. – Dr. Felker
Show notes – Cardiology vs Nephrology: A Diuretic Showdown
1. Approach to diuretic therapy for inpatients with volume overload
- Evaluate for non-cardiac sources of edema (nephrotic syndrome, hepatic dysfunction, VTE, etc).
- Choose a starting dose of loop diuretic. The effective home dose is a helpful guide.
- Evaluate diuretic response within 2-3 hours of each dose.
- If inadequate response, double the next dose of loop diuretic
- If inadequate or diminishing response to high-dose loop diuretic, consider additional pharmacotherapies (discussed below)
- Consider right heart catheterization when
- Concerned for low output state
- Exam is unclear for volume status
2. Initial dose of diuretic therapy for hospitalized patients
The kidney alters its compensatory mechanisms to avoid being poisoned by too much blockade of important transporters like NKCC-2 (loop diuretic) and NCC (thiazide diuretics).
- Start with at least double the patient’s maintenance dose of diuretic
- Patients on chronic high-dose diuretics need higher initial IV doses
- Patients with CKD need higher doses of diuretic
3. Evaluating for adequate response to diuretic in a hospitalized patient
- 2-3 hours after the dose:
- Urine output: should be >150 mL / hour in the 2-3 hours after an adequate diuretic dose.
- Spot urine sodium: should be >50-70 mmol/L after an adequate diuretic dose
- Daily: assess for improvement in jugular venous distension, lower extremity edema, weight, calculated ratio of fluid intake to output, and symptoms (orthopnea, dyspnea on exertion).
4. Approach to elevated creatinine in a volume overloaded patient
- Evaluate for alternative causes of hypercreatinemia: urinary obstruction, nephrotoxic agents (i.e. IV contrast, antibiotics, NSAIDs).
- If exam and/or invasive hemodynamic data are consistent with volume overload, renal vascular congestion may be contributing to elevated creatinine, and is expected to improve with euvolemia.
5. Approach to ‘contraction alkalosis’ in a patient undergoing diuresis
Alkalosis in the setting of loop diuretic administration and diuretic resistance may not indicate volume depletion.
- Diuretics increase delivery of sodium to the distal nephron, which accelerates potassium and proton secretion and results in bicarbonate reclamation, resulting in hypokalemic metabolic alkalosis.
- Diuresis triggers activation of the renin-angiotensin system, which increases apical ATPase activity, increasing hydrogen ion secretion into the urine.
- Repleting potassium (with potassium chloride, not potassium citrate) can correct metabolic alkalosis.
- Use of mineralocorticoid receptor antagonists can improve this metabolic alkalosis.
- Acetazolamide may be used in refractory cases with severe metabolic alkalosis.
6. Approach to hyponatremia in heart failure
- Consider reasonable degree of fluid restriction (available evidence does not support extreme fluid restriction.
- Pharmacotherapy options for extreme hyponatremia includes urea and tolvaptan.
7. Causes of diuretic resistance
- Processes outside the nephron: venous congestion, low-output heart failure, hypoalbuminemia, increased intraabdominal pressure
- Intra-renal causes (response to sodium loss, caused by NKCC2 blockade by loop diuretics): reflexive upregulation of sodium intake in the proximal tubule, increased expression of sodium reabsorption channels (e.g., ENAC, NCC, pendrin)
8. Treatment options for diuretic resistance
- Increase dose +/- frequency of loop diuretic
- Thiazide diuretic (and monitor electrolytes closely)
- Potassium sparing diuretic (i.e., spironolactone, amiloride)
- SGLT2 inhibitor (“a diuretic enabler”)
Oral loop diuretics
|PO: IV conversion||~2:1||1:1||1:1|
|Dose ratio (to furosemide)||—||1:40||1:2|
|Bioavailability in oral dosing||Widely variable||Nearly 100%||Nearly 100%|
References – Cardiology vs Nephrology: A Diuretic Showdown
Ellison DH, Felker GM. Diuretic Treatment in Heart Failure [published correction appears in N Engl J Med. 2018 Feb 1;378(5):492]. N Engl J Med. 2017;377(20):1964-1975. doi:10.1056/NEJMra1703100
Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(10):1178-1195. doi:10.1016/j.jacc.2019.12.059
3T trial: 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
ASCEND-HF trial: O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure [published correction appears in N Engl J Med. 2011 Aug 25;365(8):773. Wilson, W H [corrected to Tang, W H W]]. N Engl J Med. 2011;365(1):32-43. doi:10.1056/NEJMoa1100171
ATHENA trial: Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol. 2017;2(9):950-958. doi:10.1001/jamacardio.2017.2198
BNP trial: McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation. 2002;106(4):416-422. doi:10.1161/01.cir.0000025242.79963.4c
DOSE trial: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805. doi:10.1056/NEJMoa1005419
EVEREST trial: Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331. doi:10.1001/jama.297.12.1319
ROPA-DOP trial: Sharma K, Vaishnav J, Kalathiya R, et al. Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine: The ROPA-DOP Trial. JACC Heart Fail. 2018;6(10):859-870. doi:10.1016/j.jchf.2018.04.008
ROSE trial: Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533-2543. doi:10.1001/jama.2013.282190
TRANSFORM-HF trial: Greene SJ, Velazquez EJ, Anstrom KJ, et al. Pragmatic Design of Randomized Clinical Trials for Heart Failure: Rationale and Design of the TRANSFORM-HF Trial [published online ahead of print, 2021 Mar 10]. JACC Heart Fail. 2021;S2213-1779(21)00061-5. doi:10.1016/j.jchf.2021.01.013
Dr. Michael Felker is a Professor of Medicine in the Division of Cardiology at Duke University and head of Cardiovascular Research at the Duke Clinical Research Institute. Dr. Felker obtained his medical degree from Duke University School of Medicine, completed internal medicine residency training at the Johns Hopkins Osler program where he served as ACS, and finally cardiology fellowship at Duke University where he remained for an illustrious career including having served as Chief of the Heart Failure Section and numerous other roles.
Dr. Matt Sparks is the Nephrology Fellowship Program and Director of medical student research at Duke University. In addition to clinical, research, and educational roles locally at Duke University, Dr. Sparks is internationally recognized as a founding member of the Nephrology Social Media Collective (NSMC) and the widely popular nephrology journal club (#NephJC) with the goals of leveraging social media to enhance free online medical education. In addition to the NephJC, they’ve created several impactful education projects including the AJKD nephrology blog, NephMadness, the Renal Fellow Network.