1. 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 Netherlands University of Birmingham, Birmingham, United Kingdom St George’s Hospital, London, United Kingdom

2. 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

3. Background Especially in situations of reduced RBF, increased CVP is associated with reduced GFR Damman et al. Eur J Heart Fail 2007

4. 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

5. 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 J Am Coll Cardiol 2011;57:2233-41

6. Background Metra et al. Eur J Heart Fail 2008 High dose of IV diuretics associated with occurence of WRF

7. 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

8. 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

9. Background Tubular Damage is prevalent in Heart Failure Damman et al. Heart 2010

10. 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 J Am Coll Cardiol 2011;57:2233-41

11. Summary Diuretic therapy Worsening renal function Diuretic therapy Improving Congestion Prognosis J Am Coll Cardiol 2011;57:2233-41

12. 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 J Am Coll Cardiol 2011;57:2233-41

13. 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 J Am Coll Cardiol 2011;57:2233-41

14. Methods 7 day Study Protocol BaselineDiuretic withdrawalDiuretic resumption Day 1 Tue 2 Wed 3 Thurs 4 Fri 5 Sat 6 Sun 7 Mon Usual dose of furosemide X 50 mg IV furosemide XXX Blood and urine biomarkers 0, 4, 8 hXX X J Am Coll Cardiol 2011;57:2233-41

15. 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) J Am Coll Cardiol 2011;57:2233-41

16. Variable Value Age 70  7 Gender (N male (%))26 (87) BMI (Kg/m 2 ) 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 Disease67 Hypertension3 Idiopathic17 Other13 Baseline Characteristics J Am Coll Cardiol 2011;57:2233-41

17. Baseline Characteristics Variable Value Serum creatinine (mg/dL)1.3 (1.0 – 1.6) eGFR (mL/min/1.73m 2 )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) J Am Coll Cardiol 2011;57:2233-41

18. Results VariableBaseline 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) J Am Coll Cardiol 2011;57:2233-41

19. Results: Creatinine Mean ± SEMs are presented * P < 0.001 vs Day 1, baseline, † P < 0.05 vs Day 4 J Am Coll Cardiol 2011;57:2233-41

20. Results: ANP/BNP Day 1 Baseline Day 1, 8 hours Day 2Day 3Day 4Day 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 J Am Coll Cardiol 2011;57:2233-41

21. 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 J Am Coll Cardiol 2011;57:2233-41

22. Results: Tubular markers Diuretic withdrawal Median and IQRs are presented. * P < 0.01, † P = 0.075 vs Day 1, baseline J Am Coll Cardiol 2011;57:2233-41

23. Results: Tubular markers Diuretic withdrawal J Am Coll Cardiol 2011;57:2233-41

24. Results: Tubular markers Diuretic Reinitiation Median and IQRs are presented. * P < 0.05 vs Day 4, 0 hours J Am Coll Cardiol 2011;57:2233-41

25. Results: Tubular markers Diuretic Reinitiation J Am Coll Cardiol 2011;57:2233-41

26. Results: Tubular markers Absolute Changes Diuretic WithdrawalDiuretic Reinitiation J Am Coll Cardiol 2011;57:2233-41

27. 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 J Am Coll Cardiol 2011;57:2233-41

28. 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 J Am Coll Cardiol 2011;57:2233-41

29. 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 J Am Coll Cardiol 2011;57:2233-41

30. 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 J Am Coll Cardiol 2011;57:2233-41

31. 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. J Am Coll Cardiol 2011;57:2233-41

32. 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. J Am Coll Cardiol 2011;57:2233-41

33. 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 J Am Coll Cardiol 2011;57:2233-41

34. 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 J Am Coll Cardiol 2011;57:2233-41