Assessment Of Kidney Function in Survivors Following Fontan Palliation

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Sheena Sharma, MD,* Rebecca L Ruebner, MD,* Susan L Furth, MD,* Kathryn M Dodds, CRNP,† Jack Rychik, MD,† and David J Goldberg, MD†

*Division of Nephrology and † Division of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, Pa, USA

Abstract

Objective. The Fontan operation is a palliative procedure for congenital single ventricle heart disease. Long-term kidney function in this cohort is not well-known. Our aim was to evaluate renal function in long-term survivors post-Fontan palliation, and we hypothesize that this cohort will have a higher prevalence of chronic kidney disease (CKD) compared to controls. Design. We performed a retrospective cohort study of 68 subjects evaluated through the Single Ventricle Survivorship Program at the Children’s Hospital of Philadelphia between July 2010 and December 2014 compared to 70 healthy children similar in age and sex. Primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 using creatinine and cystatin C–based estimating equations. Secondary outcomes included proteinuria and elevated intact parathyroid hormone. Results. The Fontan cohort included 68 subjects with a median age of 13 years (IQR 9.0, 17.3) who were median 11.1 years (IQR 6.5, 15.7) post-Fontan palliation. This cohort was compared to 70 healthy individuals (median age 15.5 years (IQR 12.5, 18.3). Although median eGFRs were comparable: 102.6 vs. 101.9 mL/min/1.73 m2 (P 5 .89) in Fontan vs. healthy subjects <18 years of age (Full CKiD equation), and 128.5 vs. 129.7 mL/min/1.73 m2 (P 5 .56) in Fontan vs. healthy subjects  18 years of age (CKD-EPI creatinine and cystatin formula); 10% of Fontan subjects had an eGFR<90 mL/min/1.73 m2 . Median intact parathyroid hormone level was higher at 59.4 pg/mL (IQR 43.0, 83.1) in the Fontan group compared to 23.4 pg/mL (IQR 16.7, 30.0) in controls (P  .001). Proteinuria was present in 10% of the Fontan group compared to 4.7% in controls (P 5 .27). Conclusion. Ten percent of long-term survivors post-Fontan palliation had eGFR <90 ml/min/1.73 m2, and higher median parathyroid hormone levels compared to controls. Taken together, these measures may indicate early kidney disease. Future studies will focus on longitudinal assessment of kidney function and evaluation of risk factors for CKD post-Fontan palliation.

Key Words. Chronic Kidney Disease; Single Ventricle Heart Disease; Fontan Palliation

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Introduction

Single ventricle type of congenital heart disease affects approximately 1 per 2000 live births.1 The Fontan operation is a palliative procedure for children born with functional single ventricles. It is the third in a series of staged surgical procedures in which a cavopulmonary connection is created allowing blood to return passively to the lungs from the systemic veins in the attempt to eliminate hypoxemia and ventricular overload. It is commonly performed after the age of 2 years when pulmonary vascular resistance is at a nadir, in order to optimize the potential for passive pulmonary blood flow. Due to improvement in prenatal diagnosis and advancements in surgical techniques, a greater number of children are surviving into adulthood with this unique cardiovascular physiology. Long-term survival is approximately 75–80% in the 20 years postprocedure.2,3

Abnormalities in the circulatory system commonly develop over time in post-Fontan palliation patients as a result of the lack of a subpulmonary ventricle. Given the absence of a “pump” and ventricular thrust to propel blood through the pulmonary vasculature, patients with Fontan physiology have an obligatory elevation in central venous pressure and reduced cardiac output.4,5 Over time, these fundamental characteristics of Fontan physiology can lead to a host of secondary consequences including liver fibrosis/cirrhosis, abnormal bone and muscle development, poor linear growth, protein-losing enteropathy, and plastic bronchitis.6–8 These consequences of Fontan physiology have the potential to substantially impact long-term quality and duration of life.

The kidneys receive approximately 20–25% of total cardiac output, and therefore, these circulatory abnormalities eventually impact the renal system.9 Decrease in cardiac output leading to poor renal perfusion, use of nephrotoxic medications, and chronic cyanosis resulting in cyanotic nephropathy are amongst several factors which may contribute to kidney injury.9–11 However, studies focusing on long-term kidney function in this cohort are limited.

The Single Ventricle Survivorship Program (SVSP) at the Children’s Hospital of Philadelphia is a unique program in which post-Fontan palliation patients are referred for multi-disciplinary care.12 The program focuses on a comprehensive assessment of end-organ consequences related to the circulatory deficiencies manifest after Fontan palliation. We performed a retrospective cohort study to assess the prevalence and degree of CKD in a cohort of pediatric and young adult Fontan patients referred to the SVSP compared to healthy controls. We also evaluated for proteinuria and hyperparathyroidism which may be additional signs of kidney injury. Lastly, we studied the prevalence of pre-, peri-, and postoperative factors to determine potential risk factors for the development of CKD.

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Methods

Study Design

We performed a retrospective cohort study of all patients who had undergone Fontan palliation and attended the SVSP at the Children’s Hospital of Philadelphia between July 1, 2010, and December 5, 2014. There were no exclusion criteria. Control subjects were recruited from within the Children’s Hospital of Philadelphia general pediatric practices and were of similar age and sex. This study was approved by the institutional review board at the Children’s Hospital of Philadelphia (CHOP IRB 14-011593). The primary endpoint was the prevalence of CKD, defined as estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2, using age-appropriate creatinine and cystatin C–based estimating equations. For subjects, less than 18 years of age, the traditional Schwartz, bedside CKiD, CKiD cystatin C, and Full CKiD formulas were used.13 For patients greater than or equal to 18 years of age, the CKD-epidemiology (EPI) creatinine, CKD-EPI cystatin, and CKD-EPI creatinine and cystatin formulas were used.14 Creatinine was measured by enzymatic assay. Cystatin C was measured by immunonephelometric assay (Associated Regional and University Pathologists, Salt Lake City, UT, the USA for the Fontan cohort, and University of Pennsylvania Translational Core Lab, Philadelphia, PA, the USA for the control cohort). All other laboratory studies were performed in the clinical laboratories of the Children’s Hospital of Philadelphia. Secondary outcomes included proteinuria and elevated parathyroid hormone levels. Proteinuria was defined as urine protein to urine creatinine ratio >=0.2 or >= 11 proteinurias on urine dipstick.

We compared the prevalence of risk factors including preoperative (gestational age at diagnosis, age at Fontan palliation, type of congenital heart disease, known urologic conditions), peri-operative (need for extracorporeal membrane oxygenation and/or hemodialysis), and postoperative (use of angiotensin-converting enzyme inhibitors [ACE inhibitors], angiotensin receptor blockers [ARBs], diuretics, aspirin) in those with eGFR <90 mL/min/ 1.73 m2 to those with eGFR  90 mL/min/1.73 m2 within the Fontan cohort using the Full CKID or CKD-EPI creatinine and cystatin formulas.

Analytic Approach

Statistical analyses were performed using STATA/ IC 13.1 (Stata Corporation, College Station, TX, USA). Continuous variables were reported as median with interquartile range (IQR, 25th–75th percentile) and compared using Wilcoxon rank-sum test. Categorical variables were reported as percentages and compared using the chi-square test. A P value <.05 was the threshold for statistical significance.

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Results

A total of 68 Fontan patients and 70 control patients were included in this study. The baseline demographic characteristics of the study population and control cohort are shown in Table 1. The median age of Fontan subjects was 13 years (IQR 9.0, 17.3). The median age of control subjects was similar to the Fontan group at 15.5 years (IQR 12.5, 18.3). In the Fontan cohort, 42 (61%) were male and 58 (85%) were white compared to the control group where 39 (56%) were male and 42 (60%) were white. Seventeen (32%) Fontan subjects compared to no control subjects had heights below the 3rd percentile for gender and age. Four (6%) Fontan subjects were underweight (body mass index <5th percentile for subjects less than 19 years of age or <18.5 kg/m2 in those greater than or equal to 20 years of age) compared to 1 subject (1%) within the control group. The median age at the time of Fontan surgery was 25 months (IQR 20.8, 38.8), and the most common congenital heart anomaly was hypoplastic left heart syndrome in 38 subjects (56%). Within the Fontan cohort, 63 (93%) were on aspirin, 42 (61%) were on one or more ACE inhibitors and/or ARBs, and 22 (32%) were on one or more diuretic(s) at the time of study visit. Patients were on aspirin for surgical indications and not for any other conditions.

The results of the laboratory values for both the Fontan and healthy control participants are shown in Table 2. The Fontan group had slightly higher serum hemoglobin levels with a median of 14.8 g/dL (IQR 14.0, 15.5) compared to the control group of 14.0 g/dL (IQR 13.2, 15.1). The Fontan group had slightly higher serum phosphorus levels with a median of 4.7 mg/dL (IQR 4.0, 5.0) compared to 4.3 mg/dL (IQR 4.0, 4.8) within the control group. The median serum intact parathyroid hormone level was more than twice as high within the Fontan cohort at 59.4 pg/mL (IQR 43.0, 83.1), compared to healthy controls at 23.4 pg/mL (IQR 16.7, 30.0) (P .001). Two participants with CKD stage 2 had an elevated intact parathyroid hormone as defined by The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines with normal serum 25-OH vitamin D levels. Within the Fontan group, 10.2% (5/50 participants) had proteinuria compared to 4.6% (3/64 participants) within the control group (P5 .27). Of the five participants within the Fontan cohort with proteinuria, three were on one or more ACE inhibitors and/or ARBs. All five subjects had eGFR >= 90 mL/min/1.73 m2.

Among the Fontan subjects, median serum creatinine concentration was 0.6 mg/dL (IQR 0.5, 0.7) and median serum cystatin C concentration was higher at 0.7 mg/L (IQR 0.6, 0.8). Among controls, median serum creatinine concentration was 0.7 mg/dL (IQR 0.6, 0.8) and median serum cystatin C concentration was also 0.7 mg/L (IQR 0.6, 0.7). Results of eGFR calculated with multiple creatinine and cystatin C–based estimating equations for both Fontan and control cohorts are summarized in Table 3. Within the pediatric subjects, there was a trend toward higher eGFR among the Fontan cohort compared to controls using creatinine-based estimating equations, with a statistically significantly higher median eGFR using the bedside CKiD formula. Estimated GFR was similar when using the CKiD cystatin alone equation. Among adult subjects, eGFR was similar for Fontan subjects and controls using creatinine-based equations. There was a trend toward lower eGFR using the CKD-EPI cystatin alone equation, although this did not reach statistical significance.

Table 4 shows the seven Fontan subjects with eGFR <90 mL/min/1.73 m2 compared to those with eGFR  90 mL/min/1.73 m2 . These seven subjects were slightly older at the time of Fontan surgery with a median age of 38 months compared to 25 months in those with eGFR  90 mL/min/ 1.73 m2 (P 5 .59). The seven participants had a median time from surgery to follow-up of 10.8 years which was slightly earlier compared to a median of 13 years in those with eGFR >= 90 mL/ min/1.73 m2. No subjects within the Fontan cohort had pre-existing urologic issues or required hemodialysis or extracorporeal membrane oxygenation in the postoperative period. In those with eGFR <90 mL/min/1.73 m2 , 100% were on aspirin compared to 92% on aspirin within the group whose eGFR was  90 mL/min/1.73 m2 (P 5 .43), 100% were on an ACE inhibitor(s) or ARB(s) compared to 57% on an ACE inhibitor(s) or ARB(s) (P 5 .03), and 57% were on diuretic(s) compared to 30% on diuretic(s) (P 5 .14).

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Discussion

In this retrospective cohort study of pediatric and young adult Fontan recipients, we found that approximately 90% had an eGFR >90 mL/min/ 1.73 m2 using age-appropriate creatinine and cystatin C–based estimating equations. Although this study demonstrated that renal function was similar to similarly aged controls across the full cohort, there were still a significant number of patients within the Fontan cohort with impaired renal function. We also found that subjects in the Fontan group had a median intact parathyroid hormone level greater than twice that among controls, and 10% of Fontan subjects had proteinuria. These are other markers that may indicate an increased risk of CKD in this population. To our knowledge, this is the largest single-center study of kidney function in long-term survivors after Fontan palliation with comparison to a control group.

Prior studies have evaluated kidney function after Fontan. Anne et al. described 21 subjects who had undergone Fontan palliation.15 These participants were similar to our cohort in age and length of time since Fontan palliation. Using the Schwartz formula, they found that all patients had a normal eGFR and that 43% of Fontan subjects had microalbuminuria. Only pre- and post-Fontan pulmonary vascular resistance were found to be positively associated with the development of microalbuminuria. The use of ACE inhibitors was protective, and participants who received a lisinoprilequivalent dose greater than 0.4 mg/kg/day had no proteinuria. Esch et al examined 211 subjects for the development of acute kidney injury within the first three days after Fontan surgery.11 At least one creatinine was obtained at a median of 373 days (IQR 9 days to 3.8 years) for 94% of these patients. The median creatinine clearance at follow-up was 111 mL/min/1.73 m2 but 8% (16 patients) had an eGFR of <80 mL/min/1.73 m2 . Of these 16 patients, 25% had pre-Fontan renal dysfunction. Acute kidney injury was not associated with the development of long-term kidney dysfunction.

In this study, we found that although median serum creatinine concentration was slightly lower among Fontan subjects compared to controls, they had a higher median cystatin C level. There was also a greater proportion of Fontan subjects with lower height and BMI. This may indicate that Fontan subjects have poor muscle mass or nutritional status, and creatinine may not be a reliable indicator of kidney function in this population. This has been highlighted in several studies.16–18 In the study by Ylinen et al, eGFR of 52 pediatric patients with various renal conditions was determined via 51Cr-EDTA clearance and compared to cystatin C and creatinine.19 A strong correlation was found between the reciprocal of cystatin C and eGFR measured using 51Cr-EDTA clearance. In addition, in patients with reduced renal function, the correlation between eGFR and the reciprocal cystatin C (r 5 0.90) was stronger (P 5 .08) than that between GFR and the reciprocal creatinine (r 5 0.75). Therefore, calculating GFR using creatinine onlybased on estimating equations may give a falsely elevated estimate of kidney function in this group. Cystatin C is independent of muscle mass and may therefore provide a more accurate estimate of kidney function within this population, especially among pediatric patients and those with significant muscle wasting. Tanner staging was performed in approximately half of the Fontan cohort and was overall consistent with expected pubertal development. Therefore, the pubertal delay is less likely to be a contributing factor to reduced muscle mass.

This study has several limitations. First, creatinine and cystatin C values were obtained at a single time point. We were therefore not able to comment on the risk of CKD over time in this cohort. Longitudinal assessment of GFR over many years would be useful to evaluate changes in kidney function as the duration of time with Fontan physiology increases. In addition, the Fontan subjects included in this study were enrolled in the SVSP at the Children’s Hospital of Philadelphia. These patients are referred nationwide at the discretion of their primary cardiologist for further care in a multidisciplinary clinic setting. Therefore, there is a potential selection bias as these patients may be inherently more complex or ill, although all were seen in an outpatient clinic setting at the time of evaluation. As a consequence, our results may possibly not be generalizable to all patients who have undergone Fontan palliation. In addition, as these patients were largely referred to CHOP, there is a lack of information in their operative course which is important to note. In this study, the urine samples obtained were not all first-morning specimens, and therefore, there is a potential that orthostatic proteinuria in the older participants may be a contributing factor. Although proteinuria was assessed differently within the Fontan and control cohorts, many studies have demonstrated a good correlation between urine dipsticks and urine protein to urine creatinine ratios.20,21 Finally, we evaluated potential risk factors for the development of CKD after Fontan, but given the relatively small sample size of Fontan subjects with low eGFR, we were not able to make any statistically significant conclusions. Risk factors for the development of CKD should be studied further in larger studies of Fontan subjects.

In summary, we found that approximately 90% of long-term survivors following Fontan palliation had normal kidney function. As long-term survival after Fontan continues to improve, CKD may be another important comorbidity that affects this population. Although we did not find a significant difference in eGFR using creatinine and cystatin C–based equations among Fontan subjects compared to a group of healthy controls, the increased prevalence of proteinuria and hyperparathyroidism may be other indicators of abnormal kidney function in the Fontan population. Cystatin C may provide a more accurate estimate of GFR than serum creatinine in this population given the risk of decreased muscle mass. Future studies will focus on longitudinal assessment of GFR over time and evaluation of risk factors for CKD among patients after Fontan.

Author Contributions

SS was responsible for data analysis, drafting the article, and statistics. RLR was responsible for statistical analysis, data interpretation, critical revision of the article, and approval of the article. SLF was responsible for the critical revision of the article and approval of the article. KMD was responsible for data collection, critical revision, and approval of the article. JR was responsible for designing the study, data analysis, critical revision, and approval of the article. DJG was responsible for designing the study, data analysis, critical revision, and approval of the article.

Acknowledgments

Dr. Rychik and investigational research related to the Single Ventricle Survivorship Program project is supported by the Robert and Dolores Harrington Endowed Chair in Pediatric Cardiology.

Corresponding Author:

Sheena Sharma, MD, Division of Nephrology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.

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