Associations Between Characteristics of Individuals With Fontan Circulation With Blood and Urine Biomarkers of Kidney Injury and Dysfunction

Abstract

Background Fontan circulation is associated with kidney injury and dysfunction, often unappreciated until Fontan circulatory failure. We hypothesized that cystatin C-estimated glomerular filtration rate (eGFR) would identify chronic kidney disease more frequently and that urine kidney injury biomarkers would be higher with declining Fontan physiological features. Methods and Results We enrolled 100 ambulatory individuals. Blood and urinary laboratory measurements were compared with demographics and clinically obtained data. Different eGFR equations were used for individuals aged ≥19 years and <19 years. Chronic kidney disease was defined as eGFR <90 mL/min per 1.73 m². Median (25th-75th percentile) age was 19 (14-26) years, and 43% were female patients. Cystatin C eGFR detected chronic kidney disease (37%) in more patients than creatinine eGFR (11%). Cystatin C eGFR was positively associated, and skeletal muscle mass was negatively associated, with creatinine eGFR in both univariate (cystatin C eGFR β=0.44±0.12, P=0.0006; skeletal muscle mass β=-0.72±0.32, P=0.03) and multivariable analysis (cystatin C eGFR β=0.43±0.12, P=0.0005; skeletal muscle mass β=-0.69±0.29, P=0.02). Urine neutrophil gelatinase-associated lipocalin concentration correlated with Fontan pressure (r=0.28; P=0.04), ventricular end-diastolic pressure (r=0.28; P=0.04), and body fat mass (r=0.26; P=0.03). Conclusions Cystatin C eGFR identified more kidney dysfunction, likely attributable to creatinine eGFR being confounded by skeletal muscle mass. Elevated urine neutrophil gelatinase-associated lipocalin was associated with worse Fontan hemodynamics and higher percentage body fat, suggesting that higher venous pressure and higher adiposity are associated with ongoing kidney injury.

Keywords: Fontan operation; adult congenital heart disease; chronic kidney disease; creatinine; cystatin C; hemodynamics; novel urine markers of kidney injury.

Figure 1. Cystatin C– vs creatinine–estimated glomerular filtration rate (eGFR).

Scatterplot of cystatin C eGFR vs creatinine eGFR for 100 patients with a Fontan circulation. The red line represents the best fit, or trend, line identified using linear regression. The blue dashed lines represent eGFR <90mL/min per 1.73 m², a commonly used clinical cutoff that indicates chronic kidney disease (CKD). There was a positive correlation between cystatin C eGFR and creatinine eGFR (Spearman ρ=0.42; P=0.0006). Of the 100 patients, 37 had cystatin C eGFR <90 mL/min per 1.73 m², whereas only 11 patients had a creatinine eGFR <90 mL/min per 1.73 m². There were 26 patients with CKD by cystatin C, who would be classified as having normal eGFR by creatinine (bottom right quadrant, highlighted in yellow).

Figure 2. Comparison of urine biomarkers of kidney injury between age groups among 100 individuals with a Fontan circulation.

Median values of kidney injury molecule‐1 (KIM‐1; pg/mL), N‐acetyl glucosaminidase (NAG; U/L), and neutrophil gelatinase‐associated lipocalin (NGAL; ng/mL) are presented, along with error bars representing the 25th and 75th percentiles. Comparisons are between those aged <19 years (<19; children) and those aged ≥19 years (≥19; adults) for each urine biomarker of kidney injury using the Wilcoxon rank sum test (P values for each comparison are presented above each set of columns).