Single ventricle congenital heart disease (CHD) is a group of complex congenital cardiac defects where only one of the ventricles is adequately developed. Staged surgical procedures culminating in Fontan palliation have allowed survival in many single ventricle patients [
We performed a cross-sectional analysis of a two-center cohort approved by the institutional review boards at both the Ann & Robert H. Lurie Children’s Hospital of Chicago and the Lucile Packard Children’s Hospital Stanford with a waiver of informed consent (IRB 2016-342)
We included all single ventricle CHD patients who had undergone Fontan palliation, attending outpatient pediatric cardiology or adult CHD clinic for their routine outpatient follow up, and who had concurrent Scr assessment at one of the two participating tertiary care cardiac centers between January 2008 and December 2016. We excluded patients with known congenital structural renal anomalies. Data pertaining to renal function for patients who had undergone Fontan completion but had a subsequent heart transplant were collected from their last routine outpatient clinic visit before receiving their heart transplant.
Data were collected for each patient during their most recent routine outpatient clinic visit that included a concurrent Scr assessment. Data sources consisted of electronic medical records, surgical, echocardiography and catheterization databases, including clinic notes, laboratory test results, and echocardiogram reports performed within six months of the clinic visit. Hemodynamic data were obtained from the cardiac catheterization reports prior to their Fontan surgery (Pre-Fontan cath) and after their Fontan surgery (Post-Fontan cath), if available.
Independent variables included demographic characteristics, cardiac morphologic diagnoses, surgical factors, anthropometric measurements, laboratory data, clinical symptoms, medications (diuretics, sildenafil, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), echocardiographic findings, and catheterization-based hemodynamics as listed in
Patient Characteristics | Overall Cohort | RD* |
No RD* |
||
---|---|---|---|---|---|
Estimated GFR (ml/min/1.73 m2) | 402 | 102 ± 22.9 | 74.4 ± 12.3 | 113.3 ± 15.9 | <0.001 |
Age (Median; range in years) | 402 | 13.7 (2.3–49.9) | 12.9 (2.7–49.2) | 13.9 (2.3–49.9) | ns |
Age at time of initial Fontan(years) | 385 | 4.4 ± 2.9 | 4.7 ± 3.1 | 4.3 ± 2.9 | ns |
Years since completion of Fontan | 385 | 11.4 ± 8.9 | 9.7 ± 8.4 | 12.1 ± 9.0 | 0.01 |
Race, No. (%) | 402 | ns | |||
White | 209 (52%) | 65 (59%) | 144 (49%) | ||
African American | 38 (10%) | 11 (10%) | 27 (9%) | ||
Asian | 28 (7%) | 10 (9%) | 18 (6%) | ||
Other† | 122 (30%) | 24 (22%) | 98 (34%) | ||
Missing | 5 (1%) | 0 (0%) | 5 (2%) | ||
Single ventricle with RV morphology | 402 | 189 (47%) | 66 (60%) | 123 (42%) | 0.006 |
Prior Stage 1 Norwood operation | 349 | 119 (34%) | 49 (49%) | 70 (28%) | <0.001 |
Initial Fontan Type (%) | 402 | ns | |||
Extracardiac Fontan | 282 (70%) | 87 (79%) | 195 (67%) | ||
Lateral Tunnel Fontan | 58 (14.5%) | 12 (11%) | 46 (16%) | ||
Atrio-pulmonary Fontan | 58 (14.5%) | 10 (9%) | 48 (16%) | ||
Missing | 4 (1%) | 1 (1%) | 3 (1%) | ||
Present Fontan Type (%) | 391 | ns | |||
Extracardiac Fontan | 339 (84.3%) | 96 (87.2%) | 243 (83.3%) | ||
Lateral Tunnel Fontan | 54 (13.4%) | 11 (10%) | 43 (14.7%) | ||
Atrio-pulmonary Fontan | 5 (1.3%) | 2 (1.8%) | 3 (1%) | ||
Missing | 4 (1%) | 1 (1%) | 3 (1%) | ||
Creation of fenestration with Fontan | 61 (16%) | 12 (11%) | 49 (17%) | ns |
Note: *RD defined by FAS creatinine-based eGFR <90 ml/min/1.73 m2; ns: non-significant
Patient Characteristics | N Available | Overall Cohort | RD* |
No RD* |
|
---|---|---|---|---|---|
Vital Signs | |||||
Weight (kilograms) | 399 | 46.6 ± 25.1 | 39.8 ± 21.5 | 49.2 ± 25.9 | <0.001 |
Body Mass Index | 399 | 20.0 ± 6.5 | 18.8 ± 5.2 | 20.5 ± 6.8 | 0.02 |
Systolic blood pressure (mmHg) | 388 | 106 ± 12 | 106 ± 11 | 107 ± 12 | ns |
Diastolic blood pressure(mmHg) | 388 | 65 ± 9 | 64 ± 9 | 65 ± 9 | ns |
Pulse Oximetry (%) | 354 | 93.6 ± 4.5 | 93.5 ± 4.6 | 93.7 ± 4.5 | ns |
Laboratory Data | |||||
Hemoglobin (g/dl) | 334 | 14.7 ± 1.8 | 14.2 ± 1.8 | 14.8 ± 1.8 | 0.01 |
Hematocrit (%) | 334 | 43.7 ± 5.4 | 42.7 ± 5.4 | 44.1 ± 5.4 | 0.04 |
Clinical History** | |||||
Protein Losing Enteropathy | 367 | 39 (10%) | 17 (16%) | 22 (8%) | 0.019 |
Ascites | 367 | 20 (5%) | 13 (12%) | 7 (2%) | <0.001 |
Plastic bronchitis | 367 | 10 (3%) | 6 (5%) | 4 (1%) | 0.02 |
“Failing Fontan Physiology”*** | 367 | 54 (14%) | 26 (24%) | 28 (10%) | <0.001 |
Medications | |||||
Diuretics | 402 | 186 (47%) | 64 (59%) | 122 (43%) | 0.004 |
ACE inhibitors/ARB | 402 | 217 (55%) | 60 (55%) | 157 (55%) | ns |
Sildenafil | 402 | 39 (10%) | 20 (18%) | 19 (7%) | <0.001 |
Echocardiographic Findings | |||||
≥Moderate AV Valve Regurgitation | 367 | 32 (95%) | 15 (15%) | 17 (6%) | 0.01 |
≥Moderate Ventricular Dysfunction | 367 | 10 (3%) | 6 (6%) | 4 (1%) | 0.018 |
Note: *RD defined by FAS creatinine based eGFR<90 ml/min/1.73 m2. ns: non-significant
Patient Characteristics | N Available | Overall Cohort | RD* | No RD* | |
---|---|---|---|---|---|
Pre-Fontan catheterization hemodynamic data | |||||
SVC mean pressure (mmHg) | 176 | 9.8 ± 2.7 | 10.7 ± 2.4 | 9.4 ± 2.8 | 0.004 |
RPA mean pressure (mmHg) | 175 | 9.5 ± 2.6 | 10.2 ± 2.4 | 9.2 ± 2.6 | 0.017 |
RPA wedge pressure (mmHg) | 134 | 5.7 ± 2.4 | 6.0 ± 2.1 | 5.5 ± 2.5 | ns |
Right atrial mean pressure (mmHg) | 177 | 5.3 ± 2.8 | 5.7 ± 2.3 | 5.1 ± 2.9 | ns |
SVEDP (mmHg) | 190 | 6.5 ± 2.8 | 6.7 ± 2.5 | 6.4 ± 2.9 | ns |
SV systolic pressure (mmHg) | 191 | 82.1 ± 12.1 | 82.2 ± 12.6 | 82.1 ± 11.9 | ns |
Aortic Mean Pressure (mmHg) | 179 | 60.1 ± 9.3 | 60.3 ± 9.3 | 60.0 ± 9.3 | ns |
Indexed PVR (Woods Units) | 153 | 1.4 ± 0.6 | 1.6 ± 0.7 | 1.4 ± 0.6 | 0.07 |
Indexed SVR (Woods Units) | 168 | 12.9 ± 5.5 | 13.2 ± 5.8 | 12.8 ± 5.3 | ns |
Post-Fontan catheterization hemodynamic data | |||||
Aortic oxygen saturation | 192 | 92.8 ± 5.5 | 92.1 ± 6.2 | 93.2 ± 5.2 | ns |
Systemic venous oxygen saturation | 171 | 70.6 ± 9.4 | 69.8 ± 8.4 | 71.0 ± 9.8 | ns |
SVC mean pressure (mmHg) | 164 | 12.6 ± 3.9 | 12.9 ± 3.5 | 12.5 ± 4.2 | ns |
Fontan mean pressure (mmHg) | 175 | 12.2 ± 4.2 | 12.3 ± 4.0 | 12.2 ± 4.2 | ns |
RPA mean pressure (mmHg) | 177 | 12.0 ± 4.0 | 12.4 ± 3.6 | 11.9 ± 4.2 | ns |
RPA wedge pressure (mmHg) | 157 | 8.1 ± 3.6 | 8.0 ± 3.1 | 8.1 ± 3.8 | ns |
SV systolic pressure (mmHg) | 182 | 92.2 ± 17.7 | 86.3 ± 15.3 | 94.7 ± 18.1 | 0.003 |
SVEDP (mmHg) | 183 | 8.0 ± 3.5 | 7.9 ± 2.7 | 8.1 ± 3.8 | ns |
Aortic Mean Pressure (mmHg) | 174 | 68.4 ± 12.7 | 65.2 ± 10.9 | 70.0 ± 13.2 | 0.02 |
Indexed PVR (Woods Units) | 157 | 1.5 ± 0.8 | 1.4 ± 0.8 | 1.6 ± 0.8 | ns |
Indexed SVR (Woods Units) | 175 | 18.1 ± 8.1 | 14.8 ± 4.5 | 19.6 ± 8.9 | <0.001 |
Note: *RD defined by FAS creatinine-based eGFR<90 ml/min/1.73 m2. ns: non-significant
The primary outcome was the prevalence of RD in Fontan survivors. We defined RD as a reduced eGFR of less than 90 mL/min/1.73 m2. We calculated eGFR for each patient using the Scr-based FAS equation, which adjusts for age and height [
Variables with a discrete distribution were summarized as counts and percentages, while those with a continuous distribution were presented as mean and standard deviation, or median and range. The study cohort was divided based on eGFR into RD or no-RD groups. Univariate analyses were performed for an initial comparison of candidate factors between these two groups using the Chi-square test for categorical variables and the two-sample
A total of 402 Fontan survivors were included, with baseline demographic characteristics shown in (
The median age of Fontan survivors was 13.7 (2.3–49.9) years, 68% were younger than 18 years, and 61% were male. Nearly half (47%) of the cohort had a single ventricle with right ventricular morphology of their single ventricle (single RV), 70% had an extracardiac-type of Fontan palliation as their initial Fontan, and 84% were non-fenestrated. Out of the 58 patients with initial atrio-pulmonary or similar type of Fontan palliation, 53 had undergone a Fontan conversion surgery to an extracardiac non-fenestrated Fontan. At the time of data collection, 84% had an extracardiac Fontan, 13% had a lateral tunnel Fontan, and only five patients (1.3%) had an atrio-pulmonary Fontan.
RD was noted in 27.4% (110/402) of our cohort. Most patients with RD had mild RD (94/110; 85.5%), and a small percentage had moderate RD (13/110; 11.8%) or severe RD (3/110; 2.7%).
Comparison of demographic, cardiac morphologic, and surgical characteristics between groups with and without RD is shown in
Although groups did not differ significantly in age, patients with RD were shorter, weighed less, and had lower body mass index as compared to those without RD. Blood pressure and pulse oximetry recorded during the clinic visit were not different in patients with or without RD. Although the hemoglobin and hematocrit were slightly lower in the RD group, the difference in the mean values (14.2 g/dl
A comparison of catheter-based hemodynamic variables between the two groups is shown in
Pre-Fontan catheterization hemodynamic data were available in approximately half of the patients (191/402). The group with RD had higher pre-Fontan mean pressures in the superior vena cava (SVC) and right pulmonary artery, as well as a trend towards higher pulmonary vascular resistance (PVR) as compared to those without RD. Univariate linear regression analysis further evaluating the relationship between these pre-Fontan catheter-based hemodynamic factors and eGFR is shown in
Post-Fontan cardiac catheterization data after Fontan palliation was typically acquired for hemodynamic evaluation in patients with clinical concerns or for hemodynamic assessment before planned surgical or catheter-based procedures at the two participating institutions Post-Fontan catheterization data were available in approximately half of the patients (192/402). Fontan survivors with RD had lower systemic ventricular systolic pressure, lower aortic mean pressure, and lower systemic vascular resistance as compared to those without RD documented on the post-Fontan cath. Univariate linear regression analysis further evaluating the relationship between these post-Fontan catheter-based hemodynamic factors and eGFR is shown in
Independent risk factors derived by multivariable logistic regression analyses associated with RD are listed in
Patient Characteristics | Odds Ratio | 95% CI | |
---|---|---|---|
Single ventricle with right ventricular morphology | 2.04 | 1.26–3.30 | 0.004 |
Ascites | 2.99 | 1.04–8.59 | 0.042 |
Use for Sildenafil Therapy | 2.22 | 1.05–4.67 | 0.037 |
≥Moderate Ventricular Dysfunction | 3.24 | 0.84–12.42 | 0.087 |
Association of Predicted Probabilities and Observed Responses C = 0.65 |
Having a single RV was associated with a more than 2-fold increase in odds of having RD. The presence of ascites was associated with an almost 3-fold increase in odds of having RD. Patients on sildenafil therapy had more than a 2-fold increase in the odds of experiencing RD. Although it did not reach statistical significance, there was a trend for higher risk for RD in patients with moderate or greater ventricular systolic dysfunction.
Independent risk factors that negatively correlate with eGFR are listed in
Patient Characteristics | Estimate | Standard Error | |
---|---|---|---|
Prior Stage 1 Norwood palliation | −7.55 ml/min/1.73 m2 | 2.51 | 0.003 |
“Failing Fontan physiology”: Ascites/PLE/plastic bronchitis | −8.94 ml/min/1.73 m2 | 3.49 | 0.011 |
≥Moderate ventricular dysfunction | −16.68 ml/min/1.73 m2 | 7.35 | 0.024 |
≥Moderate AV regurgitation | −7.68 ml/min/1.73 m2 | 4.40 | 0.082 |
Note: PLE = Protein-Losing Enteropathy; AV = Atrioventricular
A history of prior Stage 1 Norwood palliation was associated with an average reduction in eGFR by 7 ml/min/1.73 m2 while having symptoms of “failing Fontan physiology” was associated with an almost 9 ml/min/1.73 m2 reduction in eGFR. The most considerable eGFR reduction was predicted in patients with moderate or greater ventricular dysfunction, with eGFR being 16.7 ml/min/1.73 m2 lower than those with no or only mild ventricular dysfunction. There was a trend for lower eGFR in patients with moderate or greater regurgitation of the atrioventricular valve, which did not reach statistical significance.
We present the largest study to date that evaluates the prevalence and risk factors for RD after Fontan palliation showing that with a median follow-up duration of 10 years, at least one out of four Fontan patients develop RD. We have identified several independent factors associated with the presence of RD in Fontan survivors, including the right ventricular morphology of the single ventricle, clinical symptoms of “failing Fontan physiology,” and being on sildenafil therapy. As identified by our study, independent factors that negatively correlate with eGFR included prior Stage 1 Norwood palliation, symptoms of “failing Fontan physiology,” such as either protein-losing enteropathy, ascites, and/or plastic bronchitis; and the presence of moderate or greater ventricular dysfunction.
Our study showed that RD is common in Fontan survivors. In our study, 27% of Fontan survivors had RD defined by reduced Scr-based eGFR at the time of the study. Previous single-center or smaller cohort studies have reported a wide range of RD prevalence ranging from 10% up to 55% based on either estimated or measured GFR, as summarized in
Author—Journal | Age (years) | Criteria for RD | Reported Prevalence of RD | |
---|---|---|---|---|
Sharma et al.; Cong Heart Dis 2016 [ |
68 | 13 (IQR 9.0,17.3) | eGFRCys+Cr |
10% |
Opotowsky et al.; Heart 2017 [ |
70 | 30.7 ± 9.8 | eGFRCys (CKD-EPI) |
12.9% |
Wilson et al.; Int J Cardiol 2018 [ |
152 | 19.8 ± 9.3 | MGFR | 37% |
Lee et al.; Int J Cardiol 2018 [ |
81 | 28.4 ± 9.3 | eGFRCr (EPI equation) |
12% |
Broda et al.; Cong Heart Dis 2018 [ |
67 | 5.1–19.9 | eGFRCr (Bedside Schwartz/MDRD) | 22% |
Khuong et al.; Int J Card 2020 [ |
328 | 16–25 | MDRD | 21% |
Patel et al.; (Our study) | 402 | 13.7 (2.3–49.9) | eGFRCr |
27% |
Note: eGFRCr = Estimated GFR based on serum creatinine-based equation; eGFRCys+Cr = Estimated GFR based on serum creatinine and cystatin-based equation; mGFR = measured GFR; MDRD = Modification of Diet in Renal Disease Study equation; CKD-EPI = Chronic Kidney Disease-EPI equation
The current study evaluated a larger cohort than seen in previous studies, included children, adolescents, and adult Fontan survivors, and used a Scr-based FAS equation for eGFR. Our study provides additional evidence that RD is common in Fontan survivors, and the prevalence of RD in Fontan survivors is significantly higher as compared to the general population [
Our study identified several cardiac morphologic, clinical, echocardiographic, and hemodynamic factors associated with RD and is the first to demonstrate that having a single RV is independently associated with the presence of RD in Fontan survivors. Previous studies have reported that having a single RV is a risk factor for Fontan failure defined as death, transplantation, New York Heart Association III/IV symptoms, protein-losing enteropathy, plastic bronchitis, and/or ascites [
Clinical risk factors associated with RD in Fontan survivors include symptoms of ascites, any signs or symptoms of “failing Fontan physiology” or need for sildenafil therapy. One of the possible etiologies for “failing Fontan physiology” is having elevated pulmonary vascular resistance (PVR) and resulting in elevated central venous pressure (CVP) [
Echocardiographic risk factors for RD in our cohort of Fontan survivors included moderate or greater systolic dysfunction of the single ventricle. As described above, having a single RV is also an independent risk factor for RD. These two factors are possibly interrelated, as previous studies have shown that the single RV has reduced myocardial contractility as compared to the single LV. Therefore, Fontan patients with a single RV are at a higher risk of developing systolic ventricular dysfunction [
Catheter-based hemodynamic risk factors for RD in Fontan survivors include factors that lead to a higher CVP and a lower aortic pressure. In our cohort, Fontan survivors with RD had a higher SVC mean pressure, a higher pulmonary arterial mean pressure and a trend towards a higher PVR noted during their pre-Fontan catheterization and a lower peak systolic pressure of the single ventricle and a lower aortic mean pressure noted at post-Fontan catheterization as compared to those without RD. By definition, Fontan survivors have an elevated CVP from the moment the Fontan operation is completed. Further elevation in CVP due to the risk factors, as described above, may result in renal vein hypertension and decreased renal perfusion pressure. Prior studies have reported that higher CVP is associated with renal dysfunction in adults with biventricular CHD [
At least one out of four Fontan survivors developed RD within ten years in our two-center cohort, which included children, adolescents, and adult Fontan survivors. Our study identified several risk factors for RD, including single RV, history of a Stage 1 Norwood operation, ascites, the sildenafil therapy, any signs or symptoms of “failing Fontan physiology,” and factors that lead to elevated CVP or reduced aortic pressure.
Despite the high prevalence and known risk factors for RD in Fontan survivors, there are no guidelines for screening and ongoing evaluation of renal function in this high-risk population. Understanding the etiologies and risk factors for RD in single ventricle CHD patients will help derive strategies for primary and secondary prevention of renal complications such as chronic kidney disease and improve overall outcomes and long-term prognosis.