Cardiorenal Syndromes Chronic Kidney Disease in the Fontan Patient: What Does it Tell Us?

1. Cardiorenal SyndromesChronic Kidney Disease in the Fontan Patient: What Does it Tell Us? Bradley S. Marino MD, MPP, MSCE Associate Professor PediatricsDirector, Heart Institute Research Core Attending Physician, Cardiac Intensive Care Unit Divisions of Cardiology and Critical Care MedicineCincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of Medicine

2. Overview • Single Ventricle Palliation Culminating in the Fontan Completion • Fontan Outcomes and Multisystem Organ Dysfunction • Special Physiologic Considerations in the Fontan Circulation Leading to Various Types of Cardiorenal Syndrome • Chronic Kidney Disease in Fontan Survivors • Renal Biomarkers Can Predict Cardiac Index by MRI in Fontan Survivors? • Multi-Center Retrospective Study • Multi-Center Prospective Study

3. Stage I Reconstruction: Modified Norwood Procedure RV-PA conduit BTS Operative Cardiac Surgery (5th Edition). Editors: TJ Gardner and TL Spray, 2004

4. Mortality After Norwood Palliation Unpublished Data - Cincinnati Children’s Hospital Medical Center 2012

6. Superior Cavopulmonary Connection with Takedown of BT or RV-PA Shunt Removes Volume Load on Single Ventricle Hemi-Fontan Bidirectional Glenn

8. Lateral Tunnel Fenestrated Fontan after Hemi-Fontan Jonas R: Op Tech Card ThoracSurg2:229,1997

9. Extracardiac Fontan after Bidirectional Glenn Reddy M et al: Op Tech Card ThoracSurg2:221,1997

11. The Total Cavopulmonary Connection - Fontan Physiology • Cavopulmonary connections divert systemic venous return into pulmonary vasculature • The single ventricle ejects blood to systemic circuit • Pulmonary blood flow returns passively to pulmonary vascular bed • Fontan pressures 2-3x the normal CVP • Increased renal vein pressure and decreased renal perfusion pressure • Chronic heart failure is common

12. Increasing Population of CHD SurvivorsQuebec CHD Mortality Khairy et al, JACC, 2010

13. The Fontan Circulation: A Spectrum of Heart Failure Anatomic Risk Factors Procedural Risk Factors Circulatory Risk Factors Underlying 1V Anatomy Staged Procedures Fontan Circulation Primary Prevention Compensated Heart Failure Early Intervention Decompensated Heart Failure End-Stage “Failing Fontan Physiology” Late Intervention Mortality Intervention

14. Dysfunction Cardiac Functional Impairments Vascular “Failing Fontan Physiology” Neuro-developmental Pulmonary Reduced Quality of Life Hepatic Multi-system Organ Dysfunction Psychosocial Renal Physical Intestinal Endocrine Hematopoietic

15. The Fontan Circulation Results in Chronic Heart Failure and Various Types of Cardiorenal Syndrome • Early Contributing Factors • Multiple episodes of AKI • Chronic Volume Load • Cyanosis • Late Contributing Factors • Ventriculo-arterial uncoupling • Systolic Dysfunction • Diastolic Dysfunction • Activation of Renin-Angiotensin-Aldosterone System and increased SVR

16. Types of Cardiorenal SyndromesIn Fontan Survivors Type I: Acute Cardiorenal Syndrome Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or acutely decompensated CHF) leading to acute kidney injury Type II: Chronic Cardiorenal Syndrome Chronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and potentially permanent chronic kidney disease Type III: Acute Renocardiac Syndrome Abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia) Type IV: Chronic Renocardiac Syndrome Chronic kidney disease (e.g. chronic glomerular or interstitial disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events Type V: Secondary Cardiorenal Syndrome Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction

17. Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients

18. Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients (n=1,102) 50% of ACHD Survivors will have Mild or Moderate-Severe Chronic Renal Dysfunction GFR < 89 ml/min/1.73m2 50% of Fontan Survivors will have Mild or Moderate-Severe Chronic Renal Dysfunction GFR < 89 ml/min/1.73m2 Figure 1. Renal dysfunction in patients with ACHD. Distribution of GFR values across the spectrum of ACHD

19. Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients

20. Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors Background Patients with “failing Fontan” physiology often have multi-system organ dysfunction Identifying biomarkers that predict declining CI prior to clinical manifestations of “failing Fontan” physiology could potentially improve patient outcome by pre-emptively introducing interventions to augment CI A simple non-invasive measure associated with lower CI is needed to maximize outcome in Fontan survivors Serum biochemical and hematopoietic markers are minimally invasive, widely available and may be useful for serial monitoring of Fontan hemodynamics

21. Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors Study Design Multi-center retrospective case series comparing MRI-derived CI to serum biomarkers Inclusion Criteria Fontan patients age ≥ 6 years of age Fontan patients who had an MRI with phase contrast CO measured in the vena cavae and/or pulmonary arteries Fontan patients who had biochemical and hematopoietic biomarkers obtained ± 12 months from MRI Patient Data Collection Medical history and biomarker values obtained by chart review Biomarkers analyzed: LFTS, serum creatinine, CBC with mean corpuscular volume (MCV) MRI Data Collection Phase contrast technique-derived CO measurements were obtained by the cardiologist/radiologist at each respective site

22. Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors Statistical Analysis Normal serum biochemical/hematopoietic values vary by gender and age Normal serum biomarker data from QUEST Diagnostics was used to create age and gender specific LMS curves to calculate age-specific z-scores for each biomarker eCrCl was calculated by the Schwartz formula utilizing the serum creatinine Associations between biomarker z-scores and CI were assessed by Spearman Rank correlation Biomarkers that were significantly correlated with CI (i.e. Total Alk Phos, eCrCl, MCV) had Receiver Operating Curves generated separately and as a composite with corresponding AUC estimated Composite index derived from multivariate logistic regression incorporating all three independently significant variables

23. Retrospective Fontan Biomarker Cohort • 85 Fontansurvivors from 8 tertiary care centers • Median age at MRI – 15 years (6-33 years) • 57% Male, 75% Caucasian • Original Single Ventricle CHD Diagnosis • HLHS - 31% • Tricuspid atresia - 21% • DORV/TGA - 15% • Other SV anatomies - 33%

24. Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors

25. Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index Marino et al, JACC (Abstract), 2011

26. Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index Marino et al, JACC (Abstract), 2011

27. Prospective Cross-Sectional Fontan Biomarker Study • Funded by Children’s Heart Foundation • 12 centers – 125 Fontan Survivors • Lower CI will be associated with: • Heart- Higher Brain Natriuretic Peptide • Bone- Lower Bone-specific Alkaline Phosphatase • Bone Marrow - Higher Mean Corpuscular Volume • Kidney-Lower glomerular filtration rate as measured by Cystatin-C • Liver - Higher Gamma-Glutamyl Transpeptidase • Intestine- Higher Stool Alpha-1 Antitrypsin

28. Summary • Successful SV palliation has resulted in a growing population of Fontan survivors • 50% will have evidence of chronic renal dysfunction and suffer from Cardio-renal syndrome • eCrCl may be a member of a potential “biomarker panel” to risk stratify Fontan survivors for Lower CI • More research on primary prevention of cardiorenal syndrome and long-term renal dysfunction in this high-risk population is needed • Longitudinal follow-up of renal biomarkers may allow for early intervention to prevent the “Failing Fontan Physiology”