Heart Failure and Cardio-Renal Syndrome 1: Pathophysiology. Biomarkers of Renal Injury and Dysfunction

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1 CRRT 2011 San Diego, CA February 2011 Heart Failure and Cardio-Renal Syndrome 1: Pathophysiology Biomarkers of Renal Injury and Dysfunction Dinna Cruz, M.D., M.P.H. Department of Nephrology San Bortolo Hospital, Vicenza, Italy

2 Increase in All-Cause Mortality in AKI with worse RIFLE Class Ref. N=71,527 patients

3 Increase in All-Cause Mortality with worse RIFLE Class (by patient population) Crude Mortality (%) Non-AKI Risk Injury Failure 0 All Gen ICU Gen ICU Cr only Cardiac Surg Other ICU Non-ICU N=71,527 patients

4 Acute Kidney Injury Biomarkers NGAL Cystatin C

Neutrophil Gelatinase- Associated Lipocalin (NGAL) 25 kda polypeptide member of lipocalin superfamily originally described in neutrophils Normally very small amounts in kidney tubules One

5 Neutrophil Gelatinase- Associated Lipocalin (NGAL) 25 kda polypeptide member of lipocalin superfamily originally described in neutrophils Normally very small amounts in kidney tubules One of the most upregulated genes in the kidney by gene expression profiling, soon after ischemic or nephrotoxic AKI Protein product highly over-expressed in the kidney during early phases of AKI

Cystatin C Cysteine protease inhibitor produced at constant rate by all nucleated cells Freely filtered by glomerulus, then reabsorbed and metabolized by proximal tubule cells Not affected by age,

6 Cystatin C Cysteine protease inhibitor produced at constant rate by all nucleated cells Freely filtered by glomerulus, then reabsorbed and metabolized by proximal tubule cells Not affected by age, gender, race, or muscle mass Can be measured in blood or urine Superior to Cr for earlier detection of GFR (CKD) When PCT cells are injured, they may not metabolize cystatin C properly Cys C then released into urine

7 Conceptual Model of AKI Cystatin C NGAL Measures a protein Indicates DAMAGE Increases before scr Cystatin C Super creatinine Measures GFR Indicates renal FUNCTION Creatinine Measures GFR Indicates renal FUNCTION Affected by age, sex, drugs, etc.

9 Cardiorenal Syndrome (CRS) General Definition: Pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ induces acute or chronic dysfunction in the other CRS Type I (Acute Cardiorenal Syndrome) Abrupt worsening of cardiac function leading to acute kidney injury CRS Type II (Chronic Cardiorenal Syndrome) Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease CRS Type III (Acute Renocardiac Syndrome) Abrupt worsening of renal function (e.g. acute kidney ischaemia or glomerulonephritis) causing acute cardiac disorders (e.g. heart failure, arrhythmia, ischemia) CRS Type IV (Chronic Renocardiac Syndrome) Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events CRS Type V (Secondary Cardiorenal Syndrome) Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction

10 CRS Subtypes CRS Type I (Acute Cardiorenal Syndrome) Abrupt worsening of cardiac function leading to Acute Kidney Injury (AKI) Ronco C, McCullough P, Anker SD, et al Eur Heart J. 2010;31(6):

11 CSA-AKI: A popular model for AKI biomarker studies Cardiac surgery associate-aki (CSA-AKI), radiocontrastinduced nephropathy Timing of renal insult is known Can compare biomarker values pre-insult and post-insult One [big] hit to kidneys CSA-AKI in pediatric populations Exclusion criteria included: Preexisting renal insufficiency, DM, use of nephrotoxic drugs before or during the study period Homogeneous population of children Few major confounding variables Only obvious renal insult = ischaemia/ reperfusion injury after CPB

12 S- and U-NGAL in children after cardiopulmonary bypass (n=71) Mishra J et al. Lancet 2005;365.

13 AUC=0 998 S- and U-NGAL in children after cardiopulmonary bypass (n=71). AUC=0 906 Mishra J et al. Lancet 2005;365.

14 Accuracy of NGAL in Diagnosis and Prognosis in AKI: A Systematic Review and Meta-analysis 19 studies, 8 countries Data from 2,538 patients included (mean sample size 123 [67-179]) and approx. 20% developed AKI AKI setting: 10x cardiac surgery, 5x ICU, 3x CIN, 1x ED 12x adult setting, 6x pediatric setting, 1x mixed 10x urine NGAL, 5x plasma/serum NGAL, 4x both NGAL Meta-analysis Investigator Group: AJKD 2009, 54(6):

15 NGAL to predict AKI across settings Sensitivity AUC-ROC: ( ) DOR 18.6 ( ) Cut-off: >190 ( ) ng/ml Specificity.2 0 Study estimate HSROC curve Summary point 95% confidence region NGAL Meta-analysis Investigator Group: AJKD 2009, 54(6):

16 Diagnostic value of NGAL in subgroups NGAL to predict AKI (no of events/total patients; no of studies/datasets) Sensitivit y (95%CI) Specificit y (95%CI) Diagnostic Odds Ratio (95%CI) AUC-ROC (95%CI) NGAL cut-off (ng/ml) Across all settings >190.2 (487/2538; N=19/23) ( ) ( ) ( ) ( ) ( ) After cardiac surgery >273.6 (307/1204; N=10/13) ( ) ( ) ( ) ( ) ( ) In critically ill patients >155.0 (123/602; N=5/5) ( ) ( ) ( ) ( ) ( ) After contrast infusion >100.0 (34/191; N=3/4) ( ) ( ) ( ) ( ) ( ) Cut-off across all settings ranged between > ng/ml NGAL Meta-analysis Investigator Group: AJKD 2009, 54(6):

17 NGAL to predict AKI in children vs. adults AUC-ROC DOR Sensitivity Specificity Cut-off, ng/ml (95%CI) (95%CI) (95%CI) (95%CI) (95%CI) Children (N=6) ( ) ( ) ( ) ( ) ( ) Adults (N=12) ( ) ( ) ( ) ( ) ( ) Excluding the study by Xin et al. NGAL Meta-analysis Investigator Group: AJKD 2009, 54(6):

18 In an observational study, 100 adults operated on cardiopulmonary bypass for coronary revascularization or valve surgery Serum creatinine peaked at 67.9 ± 45.4 hrs postoperatively AKI AKI No AKI No AKI

19 Comparison - Novel vs. Conventional Markers On arrival in ICU Incidence of AKI AUC-ROC (95% CI) NGAL 0.80 ( ) Creatinine 0.68 ( ) Cystatin C 0.83 ( ) Urea 0.60 ( ) P=0.035 P=0.038 Value of novel renal biomarkers >> conventional biomarkers Interpretation of AUC-ROCs: >0.7 = useful risk predictor (Swets JA. Measuring the accuracy of diagnostic systems. Science 1988) Haase-Fielitz, et al. Crit Care Med 2009

21 In an observational study, 100 adults operated on cardiopulmonary bypass for coronary revascularization or valve surgery Serum creatinine peaked at 67.9 ± 45.4 hrs postoperatively AKI AKI No AKI No AKI P=0.026

23 In ADHF: CRS Type 1 is associated with higher all-cause mortality No AKI AKI Goldberg, Am Heart J 2005;150:330-7

24 In AMI: CRS Type 1 AKI affects long-term mortality AKI: 79-93% vs non-aki 68% Pairkh et al, Arch Int Med 2008

25 Aghel et al, J Cardiac Failure, Vol. 16 No

26 Aghel et al, J Cardiac Failure, Vol. 16 No

27 236 patients with acute post-mi HF NGAL correlated with Nt-proBNP R=0.15, p=0.03 Yndestad et al, European Heart Journal (2009) 30,

28 Q1-3 Q4 Cystatin C on hospital admission predicts death or re-hospitalization after Acute Heart Failure N=240 Campbell C et al. Am J Cardiol 2009

29 CRS Subtypes CRS Type II Chronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and permanent chronic kidney disease Ronco C, McCullough P, Anker SD, et al Eur Heart J. 2010;31(6):

30 CRS Subtypes CRS Type IV CKD contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events Ronco C, McCullough P, Anker SD, et al Eur Heart J. 2010;31(6):

31 N=90 ambulatory CHF patients Greater urinary albumin and NGAL levels suggest structural tubular damage in CHF pts

32 ungal correlates with NT-pro-BNP in chronic heart failure Venous congestion Impaired cardiac systolic function

33 Yndestad et al, Eur Heart J 2009 N=150 pts with chronic HF Serum/ plasma NGAL in CHF N=46 elderly pts with chronic HF Bolignano et al, Rejuvenation Res 2009

34 Yndestad et al, Eur Heart J 2009 composite endpoint = nonfatal MI, cardiovascular death, allcause death & stroke Bolignano et al, Rejuvenation Res 2009

N=203 pts hospitalized for ACS Followed for 6 mos AUC 0.62 AUC 0.

35 N=203 pts hospitalized for ACS Followed for 6 mos AUC 0.62 AUC In ACS: Cys C performs slightly better than Cr for prediction of CV complications (MI, CV death)

36 Cys C, NT-pro-BNP & Troponin T in Patients with Acute Heart Failure N=138 pts admitted for AHF Endpoint of mortality or re-hospitalization Manzano et al, Am J Cardiol 2009

Cardiorenal Biomarkers and Heart Failure. Nicholas Wettersten, MD April 7 th, 2017

Cardiorenal Biomarkers and Heart Failure Nicholas Wettersten, MD April 7 th, 2017 Disclosures Still none, but looking for some Acute Kidney Injury Biomarkers 547 in 2015 4112 as of March 2017 Case 1 60