Volume Status and Diuretic Therapy in Systolic Heart Failure, and the Detection of Early...

Volume Status and Diuretic Therapy in Systolic Heart Failure, and the

Detection of Early Abnormalities in Renal and Tubular Function

Kevin Damman, Marie J. Ng Kam Chuen, Robert J. MacFadyen, Gregory YH Lip, David Gaze, Paul O. Collinson, Hans L. Hillege, Wim van Oeveren, Adriaan A. Voors, and Dirk J. van Veldhuisen

University Medical Center Groningen, Groningen, The NetherlandsUniversity of Birmingham, Birmingham, United KingdomSt George’s Hospital, London, United Kingdom

Background

Renal failure is prevalent in acute and chronic heart failure

Renal failure is the most important predictor of outcome in patients with heart failure

Pathophysiology of reduced glomerular filtration rate (GFR):

Decreased renal blood flow (RBF)

Increaed central venous pressure (CVP)

J Am Coll Cardiol 2011;57:2233-41

Background

Especially in situations of reduced RBF, increased CVP is associated with reduced GFR

Damman et al. Eur J Heart Fail 2007

Background Higher CVP associated with lower eGFR along the whole

spectrum of cardiovascular disease

CVP predicts worsening renal function (WRF)

Damman et al. JACC 2009, Mullens et al. JACC 2009

Background

Diuretics are the cornerstone of treatment of symptoms and signs of congestion in heart failure.

However, the efficacy of diuretics to decrease morbidity and mortality in heart failure has never been established.

Higher doses of diuretics have been associated with worsening renal function


Background

Metra et al. Eur J Heart Fail 2008

High dose of IV diuretics associated with occurence of WRF

Background

Felker et al. NEJM 2011

High dose of IV diuretics associated with occurence of WRF

WRF occurred significantly more in high vs low dose Diuretic regime: 23 vs 14%, P = 0.04

DOSE study

Worsening renal function, at any point in time, is associated with poor prognosis

Background

Damman et al. Eur J Heart Fail 2009. Damman et al. J Card Fail 2007

Background

Tubular Damage is prevalent in Heart Failure

Damman et al. Heart 2010

Summary

Higher central venous pressure associated with impaired GFR, tubular damage and poor outcome

Diuretics improve QoL and congestion, but may be associated with WRF and worse outcome


Summary

Diuretic therapy

Worsening renalfunction

Diuretic therapy

ImprovingCongestion

PrognosisJ Am Coll Cardiol 2011;57:2233-41

Aim and Hypothesis

Aim:

To investigate the effect modulation of congestion by diuretics (witdrawal and re-initiation) on markers of renal and tubular function in heart failure.

Hypothesis:

Diuretic therapy reduces central and renal venous pressure, improving GFR and tubulo-interstitial damage


Methods

Prospective cohort, Birmingham, UK

Patient population (N = 30):

chronic systolic heart failure (EF < 40%)

presumed euvolemic state

on oral loop diuretic regimen (Furosemide 40 / 80 mg )

treated according to guidelines


Methods

7 day Study Protocol

Baseline Diuretic withdrawal Diuretic resumption

Day1

Tue2

Wed3

Thurs4

Fri5

Sat6

Sun7

Mon

Usual dose of furosemide

X50 mg IV

furosemideX X X

Blood and urine biomarkers

0, 4, 8 h X X 0, 4, 8 h X


Methods Outcome measures:

- Markers of Volume overload: ANP, BNP

- Markers of glomerular filtration: serum creatinine

- Markers of tubulo-interstitial damage (urine):

- KIM-1 (Kidney Injury Molecule 1)

- NAG (N-acetyl-beta-D-glucosaminidase)

- NGAL (Neutrophil Gelatinase Associated Lipocalin)


Variable Value

Age 70 7

Gender (N male (%)) 26 (87)

BMI (Kg/m2) 26 6

SBP (mmHg) 136 22

DBP (mmHg) 77 12

LVEF (%) 25 8

NYHA class (I, II, III (%)) 3 / 87 / 10

Etiology of Heart failure (%)

Coronary Artery Disease 67

Hypertension 3

Idiopathic 17

Other 13

Baseline Characteristics


Baseline Characteristics

Variable Value

Serum creatinine (mg/dL) 1.3 (1.0 – 1.6)

eGFR (mL/min/1.73m2) 44 (27 - 54)

Hemoglobin (g/dL) 9.1 1.2

BNP (pg/mL) 154 (95 -293)

ANP (pg/mL) 794 (264 – 2543)

Medication

ACE-inhibitor (n (%)) 20 (67)

ARB (n (%)) 10 (33)

Beta-Blocker (n (%)) 23 (77)

Lipid lowering (n (%)) 23 (77)

Furosemide (n (%)) 30 (100)

Furosemide 40 mg (n (%)) 20 (67)

Furosemide 80 mg (n (%)) 10 (33)

Spironolacton (n (%)) 10 (33)


Results

Variable Baseline

uKIM-1 (ng/gCr) 562 (99 – 1379)

uNAG (U/gCr) 8.5 (5.7 – 14.0)

uNGAL (µg/gCr) 25 (0 – 26)

sNGAL (ng/mL) 470 (330 – 601)


Results: Creatinine

Mean ± SEMs are presented * P < 0.001 vs Day 1, baseline, † P < 0.05 vs Day 4


Results: ANP/BNP

Day 1

Baseline

Day 1,

8 hoursDay 2 Day 3 Day 4 Day 7

ANP (pg/mL)794

(264 – 2543)

898*

(358 – 2665)

937*

(347 – 2748)

879*

(384 – 2845)

880*

(343 – 2704)

1183*

(421 – 2794)

BNP (pg/mL)157

(104 – 92)

166

(96 – 283)

143

(66 – 218)

152

(96 – 290)

221†

(102 – 350)

149#

(70 – 346)

* P < 0.01 vs baseline, † P < 0.05 vs baseline, # P < 0.05 vs Day 4

Diuretic withdrawal and reinitiation


Results: ANP/BNP

Mean ± SEMs are presented. * P < 0.01 vs Day 1, baseline, † P < 0.05 vs Day 1, # P < 0.05 vs Day 4


Results: Tubular markersDiuretic withdrawal

Median and IQRs are presented. * P < 0.01, † P = 0.075 vs Day 1, baselineJ Am Coll Cardiol 2011;57:2233-41

Results: Tubular markersDiuretic withdrawal


Results: Tubular markersDiuretic Reinitiation

Median and IQRs are presented. * P < 0.05 vs Day 4, 0 hoursJ Am Coll Cardiol 2011;57:2233-41

Results: Tubular markers

Diuretic Reinitiation


Results: Tubular markers

Absolute Changes

Diuretic Withdrawal Diuretic Reinitiation


Results: correlations No significant correlation between changes in

Natriuretic Peptides and changes in tubular damage markers

No significant correlations between changes in tubular markers and changes in serum creatinine


Results: findings

Diuretic withdrawal lead to:

an increase in ANP apparent after 4 hours

an increase in BNP apparent at day 4

no significant alterations in serum creatinine

an increase in urinary KIM-1, apparant after 8 hours, which was sustained through day 4

an increase in urinary NAG, apparent at day 3

no change in either serum or urinary NGAL levels


Results: findings

Diuretic reinitiation lead to:

no decrease in ANP, but further increase

a decrease in BNP to baseline levels

no change in serum creatinine

a decrease in urinary KIM-1, apparant after 4 hours, which was sustained through day 7

a decrease in urinary NAG, apparent after 8 hours, and which was sustained through day 7

no change in either serum or urinary NGAL levels


Conclusion

Diuretic withdrawal leads to increased markers of volume overload and this was paralleled by an increase in urinary levels of markers of tubular damage, especially KIM-1 and NAG

Reinitiation of diuretics leads to reduction of both urinary KIM-1 and NGAL

There was no effect of diuretic manipulation on NGAL levels


Discussion

Modulation of volume (overload), even in HF patients with a presumed euvolemic state caused changes in tubular damage markers, but not serum creatinine

These markers are much more sensitive to small changes in glomerular and tubular function/integrity, and may therefore serve as early and specific markers of impaired renal function.

On the other hand, elevated tubular markers also indicate tubulo-interstitial damage.


Discussion

How does diuretic therapy influence (renal) tubular function?

2 Hypotheses:

(renal) Congestion causes tubular damage and renal interstitial fibrosis in heart failue. Diuretics directly improve congestion, therefore tubular function

Diuretic therapy decreases workload of the proximal tubule (less salt retained), which induces favourable conditions: less oxygen consumption, decreased renal hypoxia.


Discussion

Future studies are needed to:

Investigate placebo-controlled effects of diuretics on renal function and outcome

Identify high risk individuals for the development of WRF, using specific new tubular markers, such as KIM-1 / NAG/NGAL

Investigate the ability of these new markers to monitor and guide therapy in heart failure, especially diuretic therapy


Acknowledgments

Birmingham, UK:

Dr. R MacFadyen

Dr. JMNK Chuen

Dr. GYH Lip

Dr. L Fransisco

Groningen, NL:

Prof. dr. DJ van Veldhuisen

Prof. dr. HL Hillege

Prof. dr. G Navis

Prof. dr. AA Voors

W. Van Oeveren


Volume Status and Diuretic Therapy in Systolic Heart Failure, and the Detection of Early...

Documents

Transcript of Volume Status and Diuretic Therapy in Systolic Heart Failure, and the Detection of Early...