1. Chronic Heart Failure: Fluid Overload, Hyponatremia, and Increased Creatinine
John Lynn Jefferies, MD, MPH, FACC, FAHA
Director, Advanced Heart Failure and Cardiomyopathy
Associate Professor, Pediatric Cardiology and Adult Cardiovascular Diseases
Associate Professor, Division of Human Genetics
The Heart Institute
Cincinnati Children’s Hospital Medical Center

2. Heart Failure and Worsening Renal Function
Outcomes remain poor following admission for acute heart failure
Increased risk with concomitant decreased renal function
Increased risk with development of worsening renal function (WRF)
Increased area of focus in heart failure
Goal of therapy should be adequate decongestion without causing renal dysfunction

3. Patient Selection and Treatment
Congestion at Rest No
Yes
Warm & Dry
PCWP normal
CI normal
(compensated)
Warm & Wet
PCWP elevated
CI normal
Diuretics
Vasodilators
Ultrafiltration
Aquaretics No
Low
Perfusion
at Rest
Cold & Dry
PCWP low/normal
CI decreased
Cold & Wet
PCWP elevated
CI decreased
Yes
Patient Selection and Treatment
This quadrant diagram depicts hemodynamic profiles of patients with advanced HF.
Signs and symptoms of congestion: orthopnea/paroxysmal nocturnal dyspnea, jugular venous distension, hepatomegaly, edema, rales (rare in chronic HF), elevated PA pressure, and valsalva square wave.
Signs and symptoms of low perfusion: narrow pulse pressure, sleepy/obtunded, low serum sodium, cool extremities, hypotension with ACE inhibitor, renal dysfunction.
The majority of patients with HF are volume overloaded or wet. These patients may have cardiac index that is unchanged or decreased. Most patients with decreased cardiac index have elevated systemic vascular resistance; however, a minority have unchanged or low SVR. Vasodilators can reduce filling pressures and improve cardiac output without risks of arrhythmia. Can transition to oral vasodilator regimen.
Patients with signs of systemic hypoperfusion who are dry would be expected to have therapeutic benefits with volume loading and/or inotropic agents.
Stevenson LW. Eur J Heart Fail. 1999;1:251
Normal SVR
High SVR
Inotropic Drugs
Stevenson LW. Eur J Heart Fail. 1999;1:251

4. Pharmacologies in Heart Failure Management
Myocardial Injury
Fall in LV Performance
Activation of RAAS and SNS
(endothelin, AVP, cytokines)
Myocardial Toxicity
Change in Gene Expression
ANP
BNP
Peripheral Vasoconstriction Sodium/Water Retention
Remodeling and
Progressive
Worsening of
LV Function
Morbidity and Mortality
HF Symptoms
Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2

5. Decongestive Therapy and Worsening Renal Function
Goldsmith et al. Circ Heart Fail 2014;7:

6. Causes of Worsening Renal Function
Underdiuresis
Progression of underlying disease
Overdiuresis
Transient reduction in intravascular volume
“Plasma refill rate” or the rate that the intravascular volume is replenished by the extravascular space

7. Treatment Strategies
Diuretics
Ultrafiltration
“Aquaretics”

8. Diuretics

9. Diuretics and the Cardiorenal Syndrome
Treatment of symptoms is an important consideration in management of ADHF
Typically involves use of intravenous diuretics
Diuretics may worsen renal function
Continued use of diuretics may result in further kidney injury
Ronco et al. J Am Coll Cardiol 2012;60:
Felker GM, Mentz RJ. J Am Coll Cardiol 2012;59:

10. Diuretics
Felker et al. NEJM 2011;364:

11. Ultrafiltration

12. Ultrafiltration
Ultrafiltration (UF) is a potentially attractive treatment strategy for patients with volume overload with CRS
Results are rapid
Volume removed is easily controlled and predictable
Restores responsiveness to diuretics in patients with diuretic resistance
Invasive with associated technical limitations

13. Ultrafiltration Additional advantages that may be of benefit in ADHF
Little to no activation of the neurohormonal system that diuretics
No significant deleterious effects on electrolytes
Schrier RW. J Am Coll Cardiol 2006;47:1-8.

14. Ultrafiltration in Heart Failure
Initial data was generated in heart failure with low ejection fraction (HFLEF)
Costanzo et al. reported on 200 patients randomized to intravenous diuretics or ultrafiltration
No differences in serum creatinine between the two treatments
Costanzo et al. J Am Coll Cardiol 2007;49:

15. Ultrafiltration
Costanzo et al. J Am Coll Cardiol 2007;49:

17. Bart et al. N Engl J Med 2012;367:2296-304.

18. Diuretics Versus Ultrafiltration
Bart et al. N Engl J Med 2012;367:

19. Ultrafiltration in Heart Failure
Evidence primarily in HFLEF population
Some patients in UNLOAD had LVEF>40%
Suggested that therapy may be an option in heart failure with preserved ejection fraction (HFPEF)
Single center study comparing ultrafiltration in HFLEF versus HFPEF
Jefferies et al. Circ Heart Fail 2013;6:

20. Weight Change in HFLEF and HFPEF
Jefferies et al. Circ Heart Fail 2013;6:

21. Changes in Serum Sodium and Creatinine After Ultrafiltration
Jefferies et al. Circ Heart Fail 2013;6:

22. Decongestive Therapy and Renal Function
Both diuretics and ultrafiltration use may be associated with worsening renal function
Diuretics result in direct neurohormonal stimulation
Increased renin levels
Ultrafiltration can lead to transient intravascular volume depletion
Necessitates a newer strategy with less likelihood of causing WRF

23. V2 Receptor Antagonists “Aquaretics”

24. Arginine Vasopressin Receptor Antagonism
Vaptans are competitive antagonists of the vasopressin receptor
Primarily directed at the V2 receptor
Currently approved for treatment of euvolemic or hypervolemic hyponatremia
Tolvaptan (selective V2RA), conivaptan (V1/V2RA)
Increasing amount of interest in utility of these drugs for decongestion
V1 receptor does not have any sig important physiologic effects

25. Vasopressin V2 Receptor Activation
Increased aquaporin formation at the apical membrane which results in increased permeability of water from the collecting duct
Finley et al Circulation 2008;118:

26. Arginine Vasopressin Receptor Antagonism
V2-receptor blockade in the renal collecting ducts results in:
Increase in free water clearance (aquaresis)
Increase in serum sodium
Decrease in urine osmolality
No significant changes in urinary sodium or potassium excretion
No effect on serum potassium

27. Arginine Vasopressin Receptor Antagonism
Different than diuretics or UF that rely on changes in hydrostatic pressure to move fluid from extravascular to intravascular space after fluid leaves the intravascular space. Diuretics and UF do not impact serum osmolality so plasma refill can be slow or delayed.
Goldsmith et al. Circ Heart Fail 2014;7:

28. Arginine Vasopressin Receptor Antagonism
Tolvaptan enhances diuresis safely and significantly when added to diuretics
Tolvaptan shown not to result in neurohormonal stimulation
As monotherapy compared to diuretic, tolvaptan results in lower levels of aldosterone
Tolvaptan improved renal blood flow and GFR compared to furosemide
Konstam et al. JAMA 2007;297:
Udelson et al. J Cardiac Fail 2011;17:
Costello-Boerrigter et al. Am J Physiol Renal Physiol 2006;290:F273-F278.

29. Maisel AS and Choudhary R. Nat Rev Cardiol 2012;9:478-490.

30. Best Decongestive Strategy?
Prospective randomized study in adults with acute heart failure and volume overload
Three arms of therapy
Usual care
Usual care + tolvaptan
Ultrafiltration

31. Best Decongestive Strategy?
Primary endpoint: Net change in weight
Secondary endpoints:
30 day all cause readmission
30 day all cause death
Serum creatinine change (baseline to peak and baseline to discharge)
Serum sodium and potassium changes
Length of stay and dyspnea score
Net volume loss
Changes in urine nGAL (AKI biomarker)

32. Conclusions
Management of volume overload in acute heart failure continues to offer unique challenges
Increasingly common to have concomitant electrolyte derangement or renal dysfunction
Use of diuretics continues to be the most widely available option
Unfavorable impacts have prompted interest in alternative modalities

33. Conclusions Mixed results for ultrafiltration in adult populations
Ongoing assessment with different biomarkers may help define institution and duration of ultrafiltration
Different populations such as HFPEF and pediatric patients may offer insights into optimal use of this technology
Improved surveillance techniques needed to avoid intravascular depletion

34. Conclusions
Aquaretic therapy either alone or in combination with other therapies may be a viable opportunity
May result in safer and more effective decongestion without negatively impacting renal function or electrolytes
Underscores need for individualized therapies