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Unpublished Data - Cincinnati Children’s Hospital Medical Center 2012

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VSDTOF

TGAHLHS

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 Failure

Circulatory 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 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”