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Cardiorenal Syndromes Chronic Kidney Disease in the Fontan Patient: What Does it Tell Us? . Bradley S. Marino MD, MPP, MSCE Associate Professor Pediatrics Director, Heart Institute Research Core Attending Physician, Cardiac Intensive Care Unit - PowerPoint PPT Presentation
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Cardiorenal Syndromes
Chronic 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 UnitDivisions of Cardiology and Critical Care MedicineCincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of Medicine
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
BTSRV-PA
conduit
Operative Cardiac Surgery (5th Edition). Editors: TJ Gardner and TL Spray, 2004
Stage I Reconstruction: Modified Norwood Procedure
Mortality After Norwood Palliation
Unpublished Data - Cincinnati Children’s Hospital Medical Center 2012
0
20
40
60
80
100
Mor
talit
y %
1970's 1980's 1990's 2000'sVSD
TOFTGA
HLHS
Bidirectional Glenn Hemi-Fontan
Superior Cavopulmonary Connection with Takedown of BT or RV-PA Shunt Removes
Volume Load on Single Ventricle
Lateral Tunnel Fenestrated Fontan after Hemi-Fontan
Jonas R: Op Tech Card Thorac Surg 2:229,1997
Extracardiac Fontan after Bidirectional Glenn
Reddy M et al: Op Tech Card Thorac Surg 2:221,1997
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
Increasing Population of CHD SurvivorsQuebec CHD Mortality
Khairy et al, JACC, 2010
Underlying 1V Anatomy
Fontan Circulation
Staged Procedures
Compensated Heart Failure
Decompensated Heart Failure
Anatomic Risk Factors
Procedural Risk Factors
MortalityIntervention
Primary Prevention
Early Intervention
Late Intervention
The Fontan Circulation: A Spectrum of Heart FailureCirculatory
Risk Factors
End-Stage “Failing Fontan
Physiology”
“Failing Fontan Physiology”
Multi-system Organ
Dysfunction
Reduced Quality of Life
Neuro-developmental
Vascular
Intestinal
Renal
Endocrine
Hepatic
Cardiac
Psychosocial
Physical
Dysfunction
Hematopoietic
Pulmonary
Functional Impairments
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
Types of Cardiorenal SyndromesIn Fontan Survivors
Type I: Acute Cardiorenal SyndromeAbrupt worsening of cardiac function (e.g. acute cardiogenic shock or acutely decompensated CHF) leading to acute kidney injury
Type II: Chronic Cardiorenal SyndromeChronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and potentially permanent chronic kidney disease
Type III: Acute Renocardiac SyndromeAbrupt 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 SyndromeChronic 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 SyndromeSystemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction
Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients
Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients (n=1,102)
Figure 1.Renal dysfunction in patients with ACHD. Distribution of GFR values across the spectrum of ACHD
50% of ACHD Survivors will have Mild or Moderate-Severe Chronic Renal DysfunctionGFR < 89 ml/min/1.73m2
50% of Fontan Survivors will have Mild or Moderate-Severe Chronic Renal DysfunctionGFR < 89 ml/min/1.73m2
Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients
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
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 MRIPatient 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
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
Retrospective Fontan Biomarker Cohort• 85 Fontan survivors 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%
Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors
Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index
Marino et al, JACC (Abstract), 2011
Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index
Marino et al, JACC (Abstract), 2011
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
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”