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
Divisions of Cardiology and Critical Care Medicine
Cincinnati Children’s Hospital Medical Center
University 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
Stage I Reconstruction: Modified Norwood
Procedure
BTS
RV-PA
conduit
Operative Cardiac Surgery (5th Edition). Editors: TJ Gardner and TL Spray, 2004
Mortality After Norwood Palliation
Mortality %
100
80
60
HLHS
TGA
TOF
VSD
40
20
0
1970's
1980's
1990's
2000's
Unpublished Data - Cincinnati Children’s Hospital Medical Center 2012
Superior Cavopulmonary Connection with
Takedown of BT or RV-PA Shunt Removes
Volume Load on Single Ventricle
Bidirectional Glenn
Hemi-Fontan
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 Survivors
Quebec CHD Mortality
Khairy et al, JACC, 2010
The Fontan Circulation: A Spectrum of Heart Failure
Anatomic
Risk Factors
Procedural
Risk Factors
Circulatory
Risk Factors
Underlying
1V Anatomy
Staged
Procedures
Fontan
Circulation
Compensated
Heart Failure
Primary
Prevention
Decompensated
Heart Failure
Early
Intervention
End-Stage
“Failing Fontan
Physiology”
Late
Intervention
Intervention
Mortality
Dysfunction
Cardiac
“Failing Fontan
Physiology”
Multi-system
Organ
Dysfunction
Functional
Impairments
Vascular
Pulmonary
Neurodevelopmental
Hepatic
Psychosocial
Renal
Intestinal
Physical
Endocrine
Hematopoietic
Reduced
Quality
of Life
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 Syndromes
In 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
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)
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
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 multisystem 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 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
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”