International Journal of
Molecular Sciences Article
The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity Lucia Pacifico 1, *, Enea Bonci 2 , Gian Marco Andreoli 1 , Michele Di Martino 3 , Alessia Gallozzi 1 , Ester De Luca 1 and Claudio Chiesa 4 1 2 3 4
*
Policlinico Umberto I Hospital, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] (G.M.A.); [email protected] (A.G.); [email protected] (E.D.L.) Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] Department of Radiological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133 Rome, Italy; [email protected] Correspondence: [email protected]; Tel.: +39-06-4997-9215
Academic Editor: Giovanni Tarantino Received: 25 June 2016; Accepted: 21 July 2016; Published: 27 July 2016
Abstract: The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ě5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m2 . Abnormal albuminuria was defined as urinary excretion of ě30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m2 was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16–5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. Keywords: nonalcoholic fatty liver disease; renal function; obesity; children
1. Introduction Concurrent with the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD) is becoming one of the most prevalent chronic liver disorders in both adults and children. It is now known that NAFLD is not only a risk factor for hepatic failure and hepatic carcinoma, but it is also associated with a spectrum of extrahepatic diseases generally linked to metabolic syndrome (MetS) such as type 2 diabetes, and cardiovascular disease [1,2]. Recent studies in the pediatric obese population have demonstrated that the prevalence of prediabetes and MetS is significantly increased in subjects with increased hepatic fat content, and that liver steatosis, independently of visceral and intramyocellular lipid content, is a key determinant of the impairment of liver, muscle, and adipose insulin sensitivity [3,4]. Several studies have reported associations between NAFLD and
Int. J. Mol. Sci. 2016, 17, 1218; doi:10.3390/ijms17081218
www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2016, 17, 1218
2 of 10
subclinical atherosclerosis and between NAFLD and cardiac function alterations, independently of established risk factors [5–7]. In addition, emerging evidence suggests that subjects with NAFLD have an increased risk of chronic kidney disease (CKD), defined by a decline in the estimated glomerular filtration rate (eGFR) and/or microalbuminuria and/or overt proteinuria [8–12]. However, no data are available in children regarding a possible association between NAFLD and impaired renal function. Recognition of the influence of NAFLD on renal function in the early age would enable us to better understand the association of NAFLD and CKD, since there is less potential for confusion with adult-onset complications. Thus, in this study we sought to determine whether children with overweight/obesity and NAFLD show signs of renal functional alterations, as assessed by eGFR and urinary albumin excretion, compared to children with overweight/obesity but without NAFLD as well as to healthy normal-weight controls. 2. Results 2.1. Clinical and Laboratory Data from the Study Population Clinical and laboratory data from the study population are presented in Table 1. None of the enrollees had type 2 diabetes mellitus. Patients with NAFLD were on average older than those without NAFLD and healthy controls, and had higher waist circumference (WC) as well as higher values for systolic and diastolic blood pressure (BP), higher triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid, fasting glucose, insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) values, and lower high-density lipoprotein-cholesterol (HDL-C) concentrations. Patients with NAFLD had significantly lower whole-body insulin sensitivity index (WBISI) than those without NAFLD. Obese children with NAFLD and obese subjects without NAFLD had significantly higher eGFR compared to healthy controls (median, 115 (interquartile range, 104–134) and 115 (96–132) vs. 108 (100–118) mL/min/1.73 m2 ; p < 0.0001), whereas no differences were found between patients with and without NAFLD. However, a greater frequency of reduced eGFR ( 139 mL/min/1.73 m2 , n (%) Microalbuminuria, n (%)
Normal Weight
NO NAFLD
NAFLD
p Value *
130 10.6 (3.5) 61 (46.9) 0.17 (0.85) 65 (10) 102 (11) 63 (7) 166 (145–186) 92 (72–118) 56 (50–83) 62 (50–83) 22 (20–30) 16 (13–20) 0.21 (0.18–0.25) 83 (7) 7.5 (4.3–10.5) 1.58 (0.90–2.20) 108 (100–118) 1 (0.77) 6 (4.6) 0
328 10.1 (2.9) 151 (46.0) 1.85 (0.45) a 82 (12) a 107 (12) b 65 (9) c 161 (139–187) 94 (76–115) 51 (44–60) a 70 (50–99) 23 (20–27) c 18 (14–23) b 0.25 (0.22–0.29) a 83 (7) 11.1 (7.5–15.4) a 2.30 (1.55–3.22) a 6.5 (4.5–9.0) 115 (104–134) a 22 (6.7) b 56 (17.0) a 13 (4.0) a
268 11.2 (2.9) d 166 (61.9) a,d 2.0 (0.45) a,d 92 (13) a,d 114 (12) a,d 69 (8) a,d 159 (137–181) 94 (74–111) 46 (38–53) a,d 89 (58–127) a,d 26 (21–35) a,d 31 (19–54) a,d 0.28 (0.24–0.34) a,d 85 (11) 15.2 (10.1–23.2) a,d 3.23 (2.05–5.0) a,d 3.5 (2.4–5.6) d 115 (96–132) a 47 (17.5) a,d 46 (17.2) a 25 (9.3) a,d
Molecular Sciences Article
The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity Lucia Pacifico 1, *, Enea Bonci 2 , Gian Marco Andreoli 1 , Michele Di Martino 3 , Alessia Gallozzi 1 , Ester De Luca 1 and Claudio Chiesa 4 1 2 3 4
*
Policlinico Umberto I Hospital, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] (G.M.A.); [email protected] (A.G.); [email protected] (E.D.L.) Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] Department of Radiological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; [email protected] Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133 Rome, Italy; [email protected] Correspondence: [email protected]; Tel.: +39-06-4997-9215
Academic Editor: Giovanni Tarantino Received: 25 June 2016; Accepted: 21 July 2016; Published: 27 July 2016
Abstract: The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ě5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m2 . Abnormal albuminuria was defined as urinary excretion of ě30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m2 was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16–5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. Keywords: nonalcoholic fatty liver disease; renal function; obesity; children
1. Introduction Concurrent with the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD) is becoming one of the most prevalent chronic liver disorders in both adults and children. It is now known that NAFLD is not only a risk factor for hepatic failure and hepatic carcinoma, but it is also associated with a spectrum of extrahepatic diseases generally linked to metabolic syndrome (MetS) such as type 2 diabetes, and cardiovascular disease [1,2]. Recent studies in the pediatric obese population have demonstrated that the prevalence of prediabetes and MetS is significantly increased in subjects with increased hepatic fat content, and that liver steatosis, independently of visceral and intramyocellular lipid content, is a key determinant of the impairment of liver, muscle, and adipose insulin sensitivity [3,4]. Several studies have reported associations between NAFLD and
Int. J. Mol. Sci. 2016, 17, 1218; doi:10.3390/ijms17081218
www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2016, 17, 1218
2 of 10
subclinical atherosclerosis and between NAFLD and cardiac function alterations, independently of established risk factors [5–7]. In addition, emerging evidence suggests that subjects with NAFLD have an increased risk of chronic kidney disease (CKD), defined by a decline in the estimated glomerular filtration rate (eGFR) and/or microalbuminuria and/or overt proteinuria [8–12]. However, no data are available in children regarding a possible association between NAFLD and impaired renal function. Recognition of the influence of NAFLD on renal function in the early age would enable us to better understand the association of NAFLD and CKD, since there is less potential for confusion with adult-onset complications. Thus, in this study we sought to determine whether children with overweight/obesity and NAFLD show signs of renal functional alterations, as assessed by eGFR and urinary albumin excretion, compared to children with overweight/obesity but without NAFLD as well as to healthy normal-weight controls. 2. Results 2.1. Clinical and Laboratory Data from the Study Population Clinical and laboratory data from the study population are presented in Table 1. None of the enrollees had type 2 diabetes mellitus. Patients with NAFLD were on average older than those without NAFLD and healthy controls, and had higher waist circumference (WC) as well as higher values for systolic and diastolic blood pressure (BP), higher triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid, fasting glucose, insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) values, and lower high-density lipoprotein-cholesterol (HDL-C) concentrations. Patients with NAFLD had significantly lower whole-body insulin sensitivity index (WBISI) than those without NAFLD. Obese children with NAFLD and obese subjects without NAFLD had significantly higher eGFR compared to healthy controls (median, 115 (interquartile range, 104–134) and 115 (96–132) vs. 108 (100–118) mL/min/1.73 m2 ; p < 0.0001), whereas no differences were found between patients with and without NAFLD. However, a greater frequency of reduced eGFR ( 139 mL/min/1.73 m2 , n (%) Microalbuminuria, n (%)
Normal Weight
NO NAFLD
NAFLD
p Value *
130 10.6 (3.5) 61 (46.9) 0.17 (0.85) 65 (10) 102 (11) 63 (7) 166 (145–186) 92 (72–118) 56 (50–83) 62 (50–83) 22 (20–30) 16 (13–20) 0.21 (0.18–0.25) 83 (7) 7.5 (4.3–10.5) 1.58 (0.90–2.20) 108 (100–118) 1 (0.77) 6 (4.6) 0
328 10.1 (2.9) 151 (46.0) 1.85 (0.45) a 82 (12) a 107 (12) b 65 (9) c 161 (139–187) 94 (76–115) 51 (44–60) a 70 (50–99) 23 (20–27) c 18 (14–23) b 0.25 (0.22–0.29) a 83 (7) 11.1 (7.5–15.4) a 2.30 (1.55–3.22) a 6.5 (4.5–9.0) 115 (104–134) a 22 (6.7) b 56 (17.0) a 13 (4.0) a
268 11.2 (2.9) d 166 (61.9) a,d 2.0 (0.45) a,d 92 (13) a,d 114 (12) a,d 69 (8) a,d 159 (137–181) 94 (74–111) 46 (38–53) a,d 89 (58–127) a,d 26 (21–35) a,d 31 (19–54) a,d 0.28 (0.24–0.34) a,d 85 (11) 15.2 (10.1–23.2) a,d 3.23 (2.05–5.0) a,d 3.5 (2.4–5.6) d 115 (96–132) a 47 (17.5) a,d 46 (17.2) a 25 (9.3) a,d
