Biomarkers for optimal management of heart failure. Cardiorenal syndrome. Veli-Pekka Harjola Helsinki University Central Hospital Helsinki, Finland

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1 Biomarkers for optimal management of heart failure Cardiorenal syndrome Veli-Pekka Harjola Helsinki University Central Hospital Helsinki, Finland

2 Presenter Disclosure Information V-P Harjola The following relationships exist related to this presentation: No relationships to disclose

3 Cardiorenal syndrome introduction pathophysiology role of biomarkers management of HF

4 Cardiorenal syndrome introduction pathophysiology role of biomarkers management of HF

5 Prevalence of renal failure in HF - mild/moderate/severe = GFR 60-90/30-60/<30 Ml/min Any Renal failure Moderate/severe egfr<90 ml/min (%) egfr <60 ml/min(%) Chronic HF Acute HF Smith GL JACC 2006

6 Glomerular filtration rate and risk Death Cardiovascular event Hospitalization Risk (%) > <15 GFR (ml/min/1.73 m²) Go AS et al. NEJM 2004; 351.

7 RIFLE criteria for ARF Mehta Crit Care 2007:11:R31

8 Cardiorenal syndrome introduction pathophysiology role of biomarkers management of HF

9 CRS 1 AHF-ARF House AA et al. Am J Kidney Dis 56:

10 CRS2 CHF-CRF House AA et al. Am J Kidney Dis 56:

11 Cardiorenal syndrome introduction pathophysiology role of biomarkers management of HF

12 Acute kidney injury biomarkers hours Vaidya VS et al. Annu Rev Pharmacol Toxicol 2008;48. Plasma Cystatin C 12 hours

13 Glomerular filtration rate = function (5.5 =TnT) Damman K. Heart Fail Rev 2011

14 Relationship between serum creatinine and estimated GFR: effect of change in serum creatinine 70-year old white male Conversion of Serum creatinine 1mg/dl = 88.4 umol/l

15 Comparison of creatinine and cystatin C as markers of GFR Lassus J. Heart Fail Rev 2011.

16 PRIDE: 1-year mortality vs. quartiles of NT-proBNP and creatinine clearance in AHF The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please

17 FINN-AKVA 1-year mortality risk in AHF & cysc and NT-proBNP % in the first tertile of both biomarkers (n = 77) % % in the third tertile (n = 76) of both markers CystatinC >1.55 mg/l 10 CystatinC mg/l 0 NT-ProBNP >6341pg/ml NT-ProBNP pg/ml NT-ProBNP <2617 pg/ml CystatinC <1.13 mg/l Lassus J. Eur Heart J 2007: 28,

18 Effect on survival of patients with normal crea and elevated cysc both normal 1-yr mortality 12.6% normal crea but elevated cystatin C 1-year mortality 40.4%. Lassus J. Eur Heart J 2007: 28,

19 Glomerular permeabilty Damman K. Heart Fail Rev 2011

20 The early detection of AKI markers of (tubulointerstitial) injury Damman K. Heart Fail Rev 2011

21 The early detection of AKI NGAL neutrophil gelatinase-associated lipocalin expressed in neutrophilial cells and epithelial tissues upregulated in post-ischemic kidney can be measured both in plasma and urine

22 P-NGAL is an early biomarker for AKI in an adult ICU population Cruz DN. Intensive Care Med (2010) 36:

23 Cardiorenal syndrome introduction pathophysiology role of biomarkers management of HF

24 Approach to the patient with CRS 1. Anticipate 2. Optimize HF therapy 3. Evaluate renal structure and function (US) 4. Optimize diuretic dosing 5. Consider renal-specific therapies a. Renal-dose dopamine b. Nesiritide c. Ultrafiltration and/or hemodialysis 6. Investigational therapies a. Hypertonic saline high-dose loop diuretics?? b. Vasopressin antagonists c. Adenosine antagonists (rolofyllin) Liang. Crit Care Med 2008; 36[Suppl.]:S75 S88

25 Management of renal failure Check for hypovolaemia/dehydration Exclude use of nephrotoxic agents, e.g. NSAIDs Withhold aldosterone antagonist If using loop and thiazide diuretic stop thiazide (uneffective when GFR<30) Consider reducing dose of ACEI/ARB Consider ultrafiltration Dickstein K et al. ESC HF Guidelines 2008

26 Diuretic strategies in AHF Furosemide bolus or infusion? high or low dose? Felker G NEJM 2011 March 3

27 Ultrafiltration should be considered to reduce fluid overload in selectedpatients correct hyponatraemia in symptomatic patients refractory to diuretics UNLOAD (Costanza MR JACC 2007) AHF: UF vs diuretics in AHF UF group less HF hospitalisation and unscheduled visits No serum creatinine or mortality differences

28 Vasopressin V2 antagonism vasopressin = ADH anatgonism increased excretion of water without excretion of Na EVEREST trial, AHF tolvaptan vs pla 60 days: mortality, hospitalisations N.S. improvements in day 1 dyspnea, weight P-Na in hyponatraemic patients Konstam MA. JAMA 2007: 12:1319.

29 Pharmacological Management of Cardiorenal Syndrome 2 House AA International Journal of Nephrology 2011

30 HF management and biomarkers of cardiorenal syndrome cardiorenal syndrome common in HF strongly linked to morbidity and mortality old biomarkers and CysC measure function new biomarkers detect injury earlier renal markers currently mostly used for safety not yet any renal-marker guided-therapy no specific kidney-healer either current trials will give insight to new markers in HF management

31 HF management and biomarkers of cardiorenal syndrome Thank you!

32 Thank you!

33 Diuretic resistence High-dose loop diuretic U-Na tubuloglomerular feedback release of adenosine afferent arteriolar constriction GFR proximal tubular Na-reabsorption Decreased circulatory volume RAAS ja SNS distal tubular cell hypertrophy Na-reabsorption Diuretic resistence (despite persisting hypervolemia)

34 Future biomarkers for CRS Cystatin C (Cys C), erythropoietin (EPO), fatty acid binding protein (FABP), interleukin (IL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L- FABP), N-acetyl-β-D-glucosaminidase (NAG), natriuretic peptides (NP). Maisel konsensus

35 NGAL ja Krea päivystyspotilailla AnnIntMed 2008 Nickolas et al

36 Markers of renal function Glomerular filtration rate creatinine estimated CrCl tai GFR Cockcroft-gault MDRD (Urine CrC) Cystatin C

37 Management of heart failure patients with renal dysfunction ON THE OTHER HAND (more nephrological point of view) No absolute level of creatinine which precludes the use of ACEIs/ARBs. if crea >250 μmol/l (~2.5 mg/dl), specialist supervision crea > 500 μmol/l (~5 mg/dl), haemofiltration or dialysis may be needed Dickstein K et al. ESC HF Guidelines 2008

38 introduction pahophysioogy and definition diagnosis of CRS & current biomarkers management in chronic heart failure management in acute heart failure dosing of drugs based on Crea / egfr safety limits for ACEI/ARB, MRAs: spironolacrone increase in S-crea only after decrease in GFR over 50% vrt TnT BNP ; NGAL cysc -> crea KATSO MUISTIINPANOT PROTECR ei toiminut; fluids, hemodynamic optimation in ARF, CRF >RAAS-ihi weight, urine output (ml/h; ml/kg/min), CVP, CO, PCWP cut off rajat

39 Initiation of ACEI/ARB and kidneys some WRF initially halve the dose, if crea μmol/l (~ mg/dl) stop immediately, if even higher Dickstein K et al. ESC HF Guidelines 2008

40 Management of heart failure patients with renal dysfunction thiazide diuretics ineffective when GFR <30 ml/min impaired clearance of many drugs (e.g. digoxin) Dickstein K et al. ESC HF Guidelines 2008