Cardiorenal Considerations: 5 Pearls Segment

Welcome to Core IM, a virtual medical community! Core IM strives to empower its colleagues of all levels and backgrounds with clinically applicable information as well as inspire curiosity and critical thinking. Core IM promotes its mission through podcasts and other multimodal dialogues. ACP has teamed up with Core IM to offer continuing medical education, available exclusively to ACP members by completing the CME/MOC quiz.

Pearl 1: Make sure the renal dysfunction is actually all cardiorenal!

• How do you define cardiorenal physiology?

• Classic Definition:
  •  Kidney dysfunction that is related to either a (1) low-flow state and/or (2) renal venous congestion
    • BOTH can independently lead to decreased intrarenal blood flow
    •  BOTH can lead to neurohormonal activation → Increased renin-angiotensin-aldosterone system (RAAS) activity
      • Can be detrimental to renal function!
    • NOTE: Renal venous congestion is thought to be a larger contributor to kidney dysfunction than low-flow states

• How should you think about the differential for a kidney injury in someone with heart failure?

• Be broad! Multiple processes can happen at the same time
  • Urinalysis findings:
    • Pure cardiorenal syndrome
      • “Bland” with no protein, blood, granular or other cell casts
        • May have hyaline casts
        • No signs of intrinsic injury!
    • NOTE: Screen for proteinuria in heart failure patients!
      • Urine protein to creatinine ratio (UPCR) or
      • Urine albumin to creatinine ratio (UACR)
  • Dilute urine can falsely lower proteinuria on a urine dipstick!

Pearl 2: Practical Tidbits on Loop Diuretics

• What is the “go-to” loop diuretic for someone who is hospitalized for volume overload?
  • Intravenous therapy!
    • Because gut edema may interfere with oral absorption
  • Dosing:
    •  2.5 times their equivalent daily oral home dose of diuretic
      • Benefits of this dosing:
        • Better decongestion at 72 hours
          •  By weight and symptom improvement
        • Faster transition back to oral diuretics
          •  Compared to lower IV doses
    •  Continuous vs. Bolus dosing?
      • No difference in outcomes!
        • NOTE: Patients being treated with bolus may require more escalations in dosing during their hospitalization
• What are the differences between loop diuretics?
  • IV formulations:
    • Furosemide vs. Bumetanide
      • No difference in outcomes demonstrated
        • But not largely studied!
      • Bumetanide Considerations:
        • More potent
          • Practitioners may be more comfortable with using higher equivalent doses since bumetanide doses are in the single digits
        • Severe myalgias with IV bumetanide as a continuous infusion
          • Especially with higher doses
          • Unclear if unique to bumetanide or if purely dose-related given furosemide is not typically used at equally high equivalent doses
  • PO formulations:
    • Furosemide vs. Torsemide vs. Bumetanide
      • Conversions (PO): Furosemide 40 mg = torsemide 20 mg = bumetanide 1 mg
    • Considerations when choosing PO:
      •  Bioavailability
        • Furosemide
          • Extremely variable bioavailability (10-100%)
        • Torsemide & Bumetanide
          • More consistent bioavailability (80-100%)
      • Duration of action
        • Torsemide (6-16 hours) > furosemide (6-8 hours) > bumetanide (4-6 hours)
          •  NOTE:
            • Torsemide can be dosed once daily, whereas
            • Bumetanide should be dosed at least twice daily!
    • Torsemide is preferred over furosemide since it is more predictable!
      • Caveat: The TRANSFORM-HF trial did not show significant difference in outcomes between torsemide and furosemide
        • However, there are many criticisms of the trial!
          • Significant crossover
          • Use of mortality as the primary outcome rather than other metrics

Pearl 3: Assessing Diuretic Response and Renal Function

• How to assess diuretic response?
  •  Traditionally assessment:
    • Weights
    • Exam findings
    • Urine output
  • Challenges with relying on these:
    • Inaccurate documentation and/or
    • Delay in diuretic titration
      • In case of inadequate response
  • Alternative assessment:
    • Spot urine sodium (UNa) level
      • Measures diuretic responsiveness
      • Quick assessment 1-2 hours after administering loop diuretic
      • Interpretation:
        •  UNa < 50-100 mEq/L → poor response to the current dose of loop diuretic
        • GOAL: >70 mEq/L
          • For an appropriate response
        • Causes of falsely high spot UNa:
          • Low volume of urine
          • Metabolic alkalosis
          • Medications (ex. piperacillin-tazobactam)
        • Causes of falsely low spot UNa:
          • Cirrhosis
          • High volume of urine
      • NOTE: Using a spot urine sodium AND 6-hour urine output-guided protocol to escalate loop diuretic dosing was feasible
        • Resulted in:
          • Significantly higher diuresis at 2 days
          • Shorter length of stay!
• What do you do if the response to diuretic is not adequate?
  • Double your loop diuretic dose
  • Start a drip (if at maximum dose)
  • Reassess initial diagnosis or if new insult!
• What happens to creatinine during diuresis?
  • Generally safe to see up to 30% rise in from baseline levels with active decongesion
    • Known as “rise in serum creatinine” (RSC) or”worsening renal function” (WRF) (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.030112?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed)
      • Usually does NOT reflect true renal tubular injury (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.030112?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed)
        • Even though this threshold is how acute kidney injury (AKI) is defined
      • Rise is a result of:
        • Hemodynamic or functional change in glomerular filtration
        • Hemoconcentration of creatinine (https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.111.963413?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed)
          • In patients who are being adequately decongested (https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.111.963413?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed)!
      • Alone, should NOT be a reason to stop diuresing a volume overload patient
        • NOTE: Mortality actually worse for patient’s whose serum creatinine “improved” compared to those who had “worsening” levels.
      • The rise has no predictive value for rehospitalization or mortality (https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.111.963413?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed) unless patients also had other signs of congestion at discharge
    • Still, always still do the due diligence each day!
      • Volume assessment
      • Urine output monitoring
      • Consider need to evaluate for another cause of rising serum creatinine
      • Consider more sophisticated and/or invasive measures of volume status
        • Point-of-care ultrasound (POCUS)
        • Right heart catheterization

Pearl 4: How to approach diuretic resistance

• What is diuretic resistance?
  • Failure to achieve therapeutically desired congestion relief despite using appropriate or escalating doses of diuretics.
• Consider…Is something else going on?
  • Diuretics cannot work if they are not reaching the kidney!
  • Some factors to consider:
    • Shock
    • Low-flow state
    • Elevated intra-abdominal pressure (ascites)
• How can you augment your diuresis?
  • Sequential nephron blockade!
    • Thiazide or Thiazide-Like Diuretics:
      • PO Metolazone vs. IVChlorothiazide (or Diuril)
        • Metolazone
          • Less expensive
          • Metolazone has a much longer half-life and duration of action compared to chlorothiazide
        • Chlorothiazide
          • More expensive (cost is starting to come down)
          • NOTE: Many clinicians anecdotally prefer chlorothiazide because of faster onset and IV administration
        • Effect:
          • No significant difference between two in terms of urine output measured at 24-48 hours.
      • Alternative adjusts:
        • Hydrochlorothiazide or Chlorthalidone
          • Reasonable options though more in outpatient setting
            • Commonly used as antihypertensives
        • Acetazolamide
          • Achieves successful decongestion and shortening length of stay
            • Without any differences in safety outcomes!
          • In practice: Considered especially in cases of worsening metabolic alkalosis or in COPD
            • Caution when using serum bicarbonate is low!
        • Acute SGLT2i
          • Not well-established adjunct
        • Hypertonic saline
          • Not well-established adjunct
  • What should be monitored during diuresis?
    • Electrolytes, particularly hypokalemia
      • More common with augmentation
      • Hypokalemia is an independent risk factor for development of diuretic resistance
        • Add potassium-sparing diuretics early!
          •  Long-term benefit
    • Volume Depletion
  • What about ultrafiltration (UF)?
    • CARRESS-HF Trial
      • Stepped diuretic algorithm was superior to starting with ultrafiltration
        • Preserved renal function
        • Lower rates of adverse events
      •  Criticisms:
        • May not be realistic (diuresis was not attempted in UF group)
        • Unclear if ideal rate of UF was used
    • In practice: UF only after a failing maximal medical therapy
      • Due to concerns about future renal function when starting HD and dialysis access complications

Pearl 5: Don’t be afraid of medical therapy because of CKD

• Guideline-directed medical therapy (GDMT) for heart failure
  • Also are key medical therapies that slow progression of CKD!.
    •  Benefit of medications seen in patients with:
      • Proteinuric CKD (estimated albuminuria > 300 mg/day) with or without diabetes
    •  GDMT meds are heavily underutilized in patients with concomitant heart failure and CKD
      • Despite worse outcomes!
        • Percent of patients of GDMT (RAAS inhibition, MRA, beta blocker) by eGFR at discharge
          • eGFR 30-45 → only 15% of patients!
          •  eGFR < 30 → only 5% of patients!
        • NOTE: Data from 2014-2019 heart failure registry
          • Before SGLT2 inhibitors became an established pillar in heart failure and CKD
• How should you start GDMT in advanced CKD?
  •  Expect an initial decline in eGFR based on creatinine
    • When starting RAAS inhibitors and/or SGLT2 inhibitors
      • But don’t panic!
  • Decline is usually reflective of:
    • Glomerular hemodynamic changes
    • Reduction of pathologic hyperfiltration
  • Decline is associated with:
    • Better outcomes
    • Slower annual eGFR decline afterwards
      • SGLT2i studies
  • General Advice: Tolerate up to a 30% reduction in eGFR after initiation as declines in eGFR larger than 30% are unusual with these agents!
• RAAS Inhibitors
  • Tips & Tricks
    • RAAS inhibitors should NOT be stopped solely because of declining eGFR
      • STOP-ACE Trial - no significant difference in trajectory of GFR decline or number of patients started on RRT when stopping vs. continuing RAS inhibitors at eGFR < 30
        • Signal towards worse cardiovascular outcomes, however, when these agents are stopped.
    • Hyperkalemia IS more of a reason to pause - but consider trying to treat the potassium first!
      • SGLT2 inhibitors are also protective against hyperkalemia - even more reason to have them on board if not already!
      • Consider adding potassium binders (see our episode on hyperkalemia in CKD).
• SGLT2 Inhibitors
  • Tips & Tricks
    • Currently approved for initiation at eGFR > 20
      • EMPA-CKD Trial
      • Subgroup analyses of DAPA-CKD Trial
      • There are ongoing trials where people are being safely continued on these agents even through dialysis!
• SGLT2 inhibitors can likely be continued safely even if eGFR eventually declines to < 20!
  • Mineralocorticoid Receptor Antagonists (MRA)
    • Tips & Tricks
      • All MRAs:
        • Slows CKD progression
          •  Patients with type 2 diabetes
          • Patients with proteinuric CKD
        • Improved cardiovascular outcomes and mortality
          • Primarily by reduced heart failure hospitalizations
      • NOTE: It is still extremely important to closely monitor for dangerous potassium issues and kidney function especially when initiating any MRA!
      • Finerenone:
        • New agent on the block!
      • Non-steroidal mineralocorticoid receptor antagonist
        • More selective for the mineralocorticoid receptor
          • Compared to more familiar agents like spironolactone or eplerenone (which are steroidal MRAs)
        • Reduced rates of hyperkalemia
          • Compared with nonstero

Contributors

Shreya Trivedi, MD, ACP Member – Host, Editor
Andrew Ling, MD – Host, Editor, MOC questions
Nayan Arora, MD* - Guest
Nicole Bhave, MD *- Guest

Reviewers

Nisha Bansal, MD, FACP
Larissa Kruger Gomes, MD

* Nayan Arora, MD:  AstraZeneca, Bayer – Consultant 

* Nicole Bhave, MD:  Rednvia - Consultant

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  May 13, 2024 

Expiration Date: May 12, 2027 

CME Credit 

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American College of Physicians and Core IM.  The American College of Physicians is accredited by the ACCME to provide continuing medical education for physicians.

The American College of Physicians designates this enduring material (podcast) for .5 AMA PRA Category 1 Credit™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity. 

ABIM Maintenance of Certification (MOC) Points 

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to .5 medical knowledge MOC Point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program.  Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. 

How to Claim CME Credit and MOC Points 

After listening to the podcast, complete a brief multiple-choice question quiz. To claim CME credit and MOC points you must achieve a minimum passing score of 66%. You may take the quiz multiple times to achieve a passing score.