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Supplementary Online Content

Rajpal S, Alshawabkeh L, Almaddah N, et al. Association of albuminuria with major adverse outcomes in adults with congenital heart disease: results from the Boston Adult Congenital Heart Biobank. JAMA Cardiol. Published March 14, 2018. doi:10.1001/jamacardio.2018.0125.

eMethods. Supplemental Methods.

eFigure 1. Patient Enrollment and Inclusion in the Analysis.

eFigure 2. Hazard Ratios for the Combined Outcome by Estimated Glomerular Filtration Rate and Degree of Albuminuria.

eFigure 3. Risk of Adverse Outcomes for Adults with Biventricular Congenital Heart Disease, n=526, by Urinary Albumin-to-Creatinine Ratio (ACR) Value.

eFigure 4. Kaplan-Meier Plots of Albuminuria as a Predictor of Adverse Outcomes, stratified by New York Heart Association Functional Class.

eTable. Exercise Test Results by Albuminuria Status, Stratified by Type of Circulation.

This supplementary material has been provided by the authors to give readers additional information about their work.

© 2018 American Medical Association. All rights reserved.

eMethods.

Patients were classified into groups by primary diagnosis and/or pathophysiology:

1. Left sided obstructive lesions

2. Tetralogy of Fallot (TOF) with pulmonary stenosis or atresia (PA), double outlet right ventricle (DORV)

3. Single ventricle Fontan (SVF)

4. Repaired simple shunt lesions without related clinical sequelae

5. Simple shunt lesion with sequelae (e.g. arrhythmia, pulmonary hypertension, heart failure)

6. Atrioventricular septal defect (note: isolated primum atrial septal defects or inlet ventricular septal defects

were included under groups 4 or 5)

7. Transposition of the great arteries with a systemic right ventricle

8. Transposition of the great arteries with a systemic left ventricle

9. Ebstein anomaly

10. Eisenmenger syndrome, or cyanotic unrepaired single ventricle physiology, or other complex defects

11. A miscellaneous group including the following: valvar pulmonary stenosis (n=19), truncus arteriosus (n=6),

coronary anomalies (n=4), total anomalous pulmonary venous return (n=3), double chamber right ventricle

(n=3), pulmonary atresia with intact ventricular septum (n=2), and n=1 each: coronary artery fistula, cor

triatriatum, interrupted aortic arch, isolated partial anomalous pulmonary venous return, and malposed

atrial septum.

Patients with right-to-left or bidirectional shunting due to markedly elevated pulmonary vascular resistance were

classified as having Eisenmenger syndrome 1. Previous studies have shown that, even in the absence of Eisenmenger

syndrome, patients with simple shunt lesions have worse prognosis in the presence of specific disease-related

sequelae 2,3; therefore, we classified these common lesions into two groups based on presence or absence of

arrhythmia, pulmonary hypertension and/or heart failure.

Cyanosis was defined as resting oxygen saturation <92%. CHD severity was defined per 32nd Bethesda conference

recommendations, which rely mainly on anatomical complexity of disease with modification for a subset of lesions


based on additional characteristics (e.g., any defect associated with pulmonary vascular disease is classified as

severely complex) 4.

References:

1. Opotowsky AR. Clinical evaluation and management of pulmonary hypertension in the adult with

congenital heart disease. Circulation. 2015;131(2):200-210.

2. Kuijpers JM, van der Bom T, van Riel AC, et al. Secundum atrial septal defect is associated with reduced

survival in adult men. Eur Heart J. 2015;36(31):2079-2086.

3. Murphy JG, Gersh BJ, McGoon MD, et al. Long-term outcome after surgical repair of isolated atrial septal

defect. Follow-up at 27 to 32 years. N Engl J Med. 1990;323(24):1645-1650.

4. Warnes CA, Liberthson R, Danielson GK, et al. Task force 1: the changing profile of congenital heart

disease in adult life. J Am Coll Cardiol. 2001;37(5):1170-1175.


eFigure 1: Patient Enrollment and Inclusion in the Analysis.

A total of 753 patients with congenital heart disease were enrolled in Biobank during the study period. Of these, 59 were excluded due to lack of urine sample and 89 were excluded as they had urine collection after exercise, which can confound urine albumin measurement. There were 612 patients included in final analysis, 106 of whom had albuminuria (ACR≥30 mg/g).

Abbreviations: ACR- Albumin-to-creatinine ratio


eFigure 2: Hazard Ratios for the Combined Outcome by Estimated Glomerular Filtration Rate and Degree of Albuminuria.

Hazard ratios for the combined outcome by eGFR and degree of albuminuria for patients with a biventricular circulation. On the x-axis is eGFR category in mL/min/1.73m2, on the y-axis are hazard ratios for the combined outcome of death or non-elective cardiovascular hospitalization. Results are then into three groups of albuminuria based on KDIGO classification. Data for patients with ACR>300 mg/g who had eGFR<60 or 60-90 mL/min/1.73m2 were combined because of small sample size in each group (n=7). Presented hazard ratios are rounded to the nearest integer value.

Abbreviations: eGFR: estimated glomerular filtration rate, ACR: albumin-creatinine ratio, KDIGO: Kidney Disease: Improving Global Outcomes.


eFigure 3: Risk of Adverse Outcomes for Adults with Biventricular Congenital Heart Disease, n=526, by Urinary Albumin-to-Creatinine Ratio (ACR) Value.



Hazard ratios for the primary combined outcome, mortality or non-elective cardiovascular hopitalization, for adults with biventricular congenital heart disease by urinary albumin-to-creatinine Ratio (ACR). Panel A and B show the unadjusted and adjusted hazard ratios, respectively. Panel C shows the equivalent information for all-cause mortality, unadjusted. Note that the Y axis scale differs for Panel C.

The solid, thick, blue line indicates the hazard ratio and the dotted thin lines indicate 95% confidence intervals. The gray line represents the reference where the hazard ratio for ACR = 1. The multivariable model adjusted for New York Heart Association functional class and cyanosis.


eFigure 4: Kaplan-Meier Plots of Albuminuria as a Predictor of Adverse Outcomes, stratified by New York Heart Association Functional Class.

Kaplan–Meier plots curves of ACHD patients with (red line) and without (dashed black line) albuminuria according to NYHA FC. Albuminuria was especially useful in identifying high-risk subgroup in NYHA FC II ACHD patients. Abbreviations: ACHD- adult congenital heart disease. NYHA FC- New York Heart Association functional class


eTable: Exercise Test Results by Albuminuria Status, Stratified by Type of Circulation.

All Biventricular Fontan

Albumin-to-Creatinine Ratio

< 30 mg/g ≥ 30 mg/g P Value < 30 mg/g ≥ 30 mg/g P Value < 30 mg/g ≥30 mg/g P Value

N 351 53 300 38 51 15

Peak VO2 (ml/kg/min) 24.2±8.0 18.5±7.6 <0.0001 24.7±8.0 17.8±8.2 <0.0001 21.1±6.5 20.5±5.7 0.73

Peak VO2 (% predicted) 74.1±19.5 58.6±20.7 <0.0001 76.7±19.0 58.8±23.8 <0.0001 58.8±15.0 58.2±10.5 0.88

Peak Heart Rate (bpm) 153.1±23 137.8±25 <0.0001 155.5±25 135.0±26 <0.0001 139.1±25 145.4±19 0.38

VE:VCO2 Slope 27.6±5.6 31.4±8.8 <0.0001 26.7±4.9 31.5±10.0 <0.0001 32.7±6.7 31.0±4.5 0.38

Patients with albuminuria had lower peak VO2, whether indexed to body mass or as a percent of predicted values, as well as lower peak heart rate and higher VE:VCO2 slope. This pattern held for patients with a biventricular circulation, but not for those with a single ventricle Fontan circulation. Values are presented as mean±SD. A 2-sided unpaired Student’s t- or Wilcoxon rank sums test, as appropriate for distribution, was used to compare continuous variables between groups.



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