Estimated glomerular filtration rate and urine biomarkers in patients with single-ventricle Fontan circulation

Abstract

Objectives To define whether adults with a Fontan circulation, who have life-long venous congestion and limited cardiac output, have impaired glomerular filtration rate (GFR) or elevated urinary biomarkers of kidney injury. Methods We measured circulating cystatin C and creatinine (n=70) and urinary creatinine, albumin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl glucosaminidase (NAG)(n=59) in ambulatory adult Fontan patients and 20 age- and sex- matched controls. Urinary biomarkers were normalized to urine creatinine concentration. Survival free from non-elective cardiovascular hospitalization was compared, by estimated GFR and urinary biomarker levels using survival analysis. Results Cystatin C GFR was lower in the Fontan group compared with controls (114.2±22.8 vs. 136.3±12.8mL/min/1.73m2, p<0.0001); GFR<90mL/min/1.73m2 in 14.3% vs. 0% of controls. Albumin-to-creatinine ratio (ACR), KIM-1 and NAG were elevated compared with controls; ACR=23.2 [7.6–38.3] vs. 3.6 [2.5–5.7]mg/g, p<0.0001; NAG=1.8 [1.1–2.6] vs. 1.1 [0.9–1.6]U/g, p=0.02; KIM-1=0.91 [0.52–1.45] vs. 0.33 [0.24–0.74]ng/mg, p=0.001. Microalbuminuria, ACR>30mg/g, was present in 33.9% of the Fontan patients but in none of the controls. Over median 707 [IQR 371–942] day follow-up, 31.4% of patients had a clinical event. Higher KIM-1 and NAG were associated with higher risk of non-elective hospitalization or death (HR/+1SD=2.1, 95%CI=1.3–3.3, p=0.002; HR/+1SD=1.6, 95%CI=1.05–2.4, p=0.03, respectively); cystatin C GFR was associated with risk of the outcome (HR/+1SD=0.66, 95%CI=0.48–0.90, p=0.009) but creatinine-based GFR was not (HR/+1SD=0.91, 95%CI=0.61–1.38, p=0.66). Neither ACR nor NGAL were associated with events. Conclusions The Fontan circulation is commonly associated with reduced estimated GFR and evidence for glomerular and tubular injury. Those with lower cystatin C GFR and tubular injury are at increased risk of adverse outcomes.

Renal dysfunction is associated with higher central venous pressures in patients with Fontan circulation

“…Renal function is significantly dependent on a favorable preglomerular and postglomerular pressure gradient, and therefore, may be affected in patients with Fontan circulation. Indeed, there is a growing body of evidence supporting the hypothesis that the hemodynamic effects of the Fontan circulation may adversely affect kidney health . In this study, we sought to evaluate relationship of CVP and estimated glomerular filtration rate (eGFR) in the patients with Fontan circulation.…”

Creatinine‐based estimation of glomerular filtration rate in patients with a Fontan circulation

“…24,25 In contrast to creatinine, cystatin C is not affected by muscle mass, and could be the key to accurate estimation of GFR independent of altered body composition in Fontan patients. 6 However, it has been hypothesized that this biomarker may be associated with unfavorable hemodynamics in general and may not more accurately estimate GFR in Fontan patients when compared to serum creatinine. 6 However, it has been hypothesized that this biomarker may be associated with unfavorable hemodynamics in general and may not more accurately estimate GFR in Fontan patients when compared to serum creatinine.…”

“…22 Equations incorporating this biomarker may improve accuracy of eGFR compared to creatinine-based equations, with a recent study by Opotowsky et al demonstrating an association between cystatin C-based eGFR and risk of adverse outcomes in Fontan patients (and no such relationship observed between creatinine-based eGFR and adverse outcomes). 6 Further studies comparing cystatin C-based eGFR calculations, including those incorporating both cystatin C and serum creatinine, with directly measured GFR are required to establish the accuracy of these methods in the Fontan population. 6 Further studies comparing cystatin C-based eGFR calculations, including those incorporating both cystatin C and serum creatinine, with directly measured GFR are required to establish the accuracy of these methods in the Fontan population.…”

“…6 At this stage, their role in routine care is unclear. 6 At this stage, their role in routine care is unclear.…”

“…These inherent properties of the circulation, in addition to the use of multiple nephrotoxic medications, prolonged cardiopulmonary bypass, exposure to intravenous contrast agents, and longstanding cyanosis place the kidneys of a Fontan patient at undeniable risk. 6,7 Nonetheless, the use of cystatin C in Fontan has not been completely validated, and creatinine-based methods remain the mainstay of routine GFR estimation at many centers worldwide. 5 Data are emerging on the use of cystatin C-based equations in Fontan patients, which may more accurately reflect true GFR in the Fontan cohort when compared to creatinine-based equations, possibly due to reduced lean muscle mass in these patients.…”