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Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. It is not only associated with liver-related mortality and morbidity but is a multisystem disease that affects multiple extra-hepatic organ systems, such as the kidneys and cardiovascular system. Our study was conducted to evaluate the possible relationship between NAFLD and the risk of chronic kidney disease (CKD) development. This is a comparative cross-sectional study. The study was conducted on 100 patients who were diagnosed with NAFLD by abdominal ultrasound, CKD was diagnosed either by estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 or by the presence of albuminuria (albumin creatinine ratio >30 mg/g).These patients were classified into two groups, the CKD group and the non-CKD group, and the two groups were compared according to different parameters. The data were collected, presented, and statistically analyzed with the computer program IBM SPSS Statistics version 23. Among 100 NAFLD patients, there were 19 patients developed CKD diagnosed either by eGFR or by the presence of albuminuria. These CKD patients were older, have abdominal obesity, higher body mass index, higher cholesterol level, higher low-density lipoprotein level, higher triglycerides levels, higher systolic and diastolic blood pressure, and higher fatty liver index and a higher degree of fatty liver by ultrasound. Our current study suggests that NAFLD may be associated with a high risk of CKD.
Introduction 
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in Western countries affecting about 35% of the general population and about 75%–90% of specific groups, such as obese and diabetic people.[1] Globally, it is estimated that a quarter of the world’s adult population currently suffers from NAFLD.[2] The prevalence of NAFLD in parallel to obesity has increased worldwide over the past 30 years.[3] The prevalence of NAFLD is increasing rapidly owing to the global epidemics of obesity and type 2 diabetes mellitus (DM), and it is now regarded as the hepatic manifestation of metabolic syndrome.[4]
NAFLD has become the most common chronic liver disease in high-income countries, affecting up to one-third of the general adult population, and is expected to become the most common indication for liver transplantation.[5] The term NAFLD includes a wide spectrum of conditions, from simple accumulation of fat (fatty liver or steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis with its clinical consequences like hepatocellular carcinoma.[6]
The natural history of NAFLD, at least in some people, is the progression toward endstage liver disease. For this reason, NAFLD was the main cause of morbidity and mortality during the past 20 years and would become the first cause of liver transplants in the future.[7] It is now increasingly clear that NAFLD not only affects the liver but can also increase the risk of developing extra-hepatic diseases, including type 2 DM, cardiovascular disease, and chronic kidney disease (CKD).[8],[9] NAFLD is also the most rapidly growing indication for simultaneous liver-kidney transplantation, which contributes to growing evidence indicating that NAFLD is not only associated with liver-related mortality and morbidity but is a multisystem disease that affects multiple extrahepatic organ systems, such as the kidneys and cardiovascular system.[10]
NAFLD and CKD share multiple risk factors (such as abdominal obesity, insulin resistance, dyslipidemia, and hypertension).The existence of mechanistic pathways linking the liver and kidneys is also supported by the presence of hepato-renal syndrome, which can develop in cirrhotic patients with portal hypertension.[6]
Accumulating evidence indicates that NAFLD exacerbates insulin resistance, predisposes to atherogenic dyslipidemia and releases a variety of proinflammatory factors, prothrombotic factors, and profibrogenic molecules that can promote vascular and renal damage.[5]
Subjects and Methods The study aims to evaluate the possible relationship between NAFLD and CKD.
Study design
This is a comparative cross-sectional study.
Place and duration of the study The study was conducted on patients recruited from outpatient clinics and inpatient wards of Tanta University Hospitals from October 2018 to October 2019.
Study approval
Permission was obtained from Research Ethics Committee as a part of the Quality Assurance Unit of our university hospitals to conduct this study and to use the facilities in the hospitals.
Consent
Informed written consent was obtained from all participants in this research after explanation of the benefits and possible risks of the study and how we will overcome these risks. Privacy of all patients’ data was granted by a special code number for every patient’s file that includes all investigations.
Inclusion criteria
One hundred patients with NAFLD diagnosed by abdominal ultrasound were selected from the inward and outpatient clinics of Tanta University Hospitals. The four known criteria for diagnosis of NAFLD by abdominal ultrasound are the following: Hepato-renal echo contrast, liver brightness, vascular blurring of the hepatic vein, and attenuation of the echo level in the deep region of the liver.
Exclusion criteria
Alcohol consumption of ≥30 g/day in men or ≥20 g/day in women, diabetic patients, patients with liver disease for any other causes, treatment with drugs known to affect renal function or cause hepatic steatosis and pregnancy or lactation.
Study population and sample size
Among 100 NAFLD patients, there were 19 patients diagnosed as CKD either by estimated glomerular filtration rate (eGFR) or by the presence of albuminuria.
The patients were classified into two groups CKD and non-CKD groups.
Group I: Includes 19 patients diagnosed with CKDGroup II: Includes 81 patients classified as non-CKD.Every patient in this study was subjected to the following: history taking, including present history, smoking, alcohol intake, past medical history, any previous medical treatment if present. Assessment of vital signs of the patient was made also, and chest, cardiac and abdominal examination to exclude subjects with any abnormal findings. Measurement of body weight and height with the calculation of body mass index (BMI) and waist circumference.
Laboratory investigations were done including complete blood count (CBC), fasting and 2 h postprandial blood glucose levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), albumin, bilirubin, urea, creatinine, eGFR, albumin creatinine ratio (ACR), lipid profile, hepatitis C antibody (HCV Ab), and hepatitis B surface antigen (HBs Ag).
Blood sampling and processing: 10 mL venous blood sample was collected in plain tubes and 2 mL were added to ethylenediaminetetraacetic acid for CBC. Serum was separated from the other 8 mL of blood to be assayed for fasting blood glucose, 2 h PP blood glucose, total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), highdensity lipoprotein (HDL), ALT, AST, bilirubin, albumin, GGT, urea, creatinine, HBsAg and HCV Ab.
eGFR was determined according to the abbreviated Modification of Diet in Renal Disease equation.
eGFR (mL/min/1.73 m2) = 186.3 × (serum creatinine in mg/dL)−1.154× (Age)–0.203× (0.742 if female) × (1.212 if African American).
ACR was calculated by dividing the urinary albumin concentrations by the urinary creatinine concentrations, and is expressed in mg/g.
Fatty liver index (FLI) is an algorithm combining BMI, waist circumference (WC), GGT, and TG levels, and has been demonstrated to be a useful tool to predict the presence of NAFLD.
FLI was calculated according to the following algorithm:
FLI = [e0.953×loge (TG) + 0.139 × BMI + 0.718 × loge(GGT) + 0.053 × WC –15.745) / [1+e0.953 × loge(TG) + 0.139 × BMI + 0.718 × loge(GGT) + 0.053 × WC– 15.745] × 100.
Abdominal ultrasound
Abdominal ultrasound was performed by high-resolution ultrasound probe (Siemens machine with a convex probe 7 MHz). The four known criteria for diagnosis of NAFLD by abdominal ultrasound are the following: hepato-renal echo contrast, liver brightness, vascular blurring of the hepatic vein, and attenuation of the echo level in the deep region of the liver.
Statistical Analysis The data were collected, presented, and statistically analyzed with the computer program IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA).
Results This study was conducted to assess the possible relationship between NAFLD and CKD.
The study included 100 patients, 40 males and 60 females, who were diagnosed with NAFLD by abdominal ultrasound. CKD was diagnosed either by eGFR (≤60 mL/min/1.73 m2) or presence of albuminuria (CR >30 mg/g). These patients were classified into two groups, CKD group that included 19 patients and non-CKD group that included 81 patients. The two groups were compared according to different parameters.
There was significant difference between the two studied groups regarding age as the mean age of CKD group was (51.58 ± 4.91) and non CKD group was (38.12 ± 8.57) with P <0.001.
There was no statistically significant difference between the two studied groups regarding sex or smoking with P value of 0.466 and 0.125, respectively.
There was a significant difference between the two studied groups according to abdominal obesity as 100% of the CKD group have abdominal obesity, while 51.9 % of non-CKD have abdominal obesity with P = 0.002.
There was a significant difference in BMI between the two studied groups. The mean BMI of the CKD group was (43.58 ± 4.82) and non-CKD group was (37.73 ± 3.09) with P <0.001.
There is no significance between the two studied groups in the CBC parameters, liver enzymes, serum bilirubin, and GGT levels.
Albumin was significantly lower in CKD patients in comparison to non-CKD patients as the mean serum albumin level of the CKD group was 3.79 ± 0.35 and the non-CKD group was 4.13 ± 0.37 with P = 0.001, as shown in [Table 1].
Table 1: Comparison between the two studied groups according to liver function tests.Regarding lipid profile, there was a significant difference between the two studied groups regarding total cholesterol level as it showed the mean level of the CKD group was 253 ± 27.07 and non-CKD group was 207.28 ± 17.64 with P <0.001. Furthermore, there was a significant difference between the two studied groups regarding HDL level as it showed the mean HDL level of the CKD group was 41.84 ± 3.98 and non-CKD group was 50.19 ± 3.53 with P <0.001. LDL level was significantly higher in CKD patients in comparison to non-CKD patients as the mean LDL level of the CKD group was 160.68 ± 22.82 and non-CKD group was 124.74 ± 11.78 with P <0.001. TG was significantly higher in CKD patients in comparison to non-CKD patients as the mean TG level of the CKD group was 319.05 ± 62.62 and non-CKD group was 210.48 ± 35.70 with P <0.001, as shown in [Table 2].
Table 2: Comparison between the two studied groups according to lipid profile.FLI was significantly higher in CKD patients in comparison to non-CKD patients as the mean FLI of the CKD group was 96.63 ± 3.04 and non-CKD group was 76.69 ± 6.62 with P = 0.001.
In a comparison between two studied groups according to the degree of fatty liver by abdominal ultrasound, it shows that degree of fatty liver by abdominal ultrasound was 9%, 37%, 29%, and 25% for average, mild, moderate, and marked degree of fatty liver, respectively, with risk of CKD 0%, 5.3%, 42%, 52.6% for average, mild, moderate, and marked degree of fatty liver, respectively, with P = 0.001 as shown in [Table 3].
Table 3: Comparison between the two studied groups according to the degree of fatty liver by abdominal ultrasound.Multiple regression analysis of factors affecting the risk of CKD in NAFLD shows that age and total cholesterol level were the most independent factors affecting the risk of CKD in NAFLD, as shown in [Table 4] and [Table 5].
Table 4: Univariate analysis for the parameters affecting risk of chronic kidney disease in nonalcoholic fatty liver disease.
Table 5: Multivariate analysis for the parameters affecting risk of chronic kidney disease in nonalcoholic fatty liver disease. Discussion NAFLD is now one of the most common causes of chronic liver disease worldwide. The prevalence of NAFLD is constantly increasing due to the recent unhealthy dietary and lifestyle patterns.
CKD is a worldwide health problem that results in high morbidity, mortality, and health care costs. The high morbidity, mortality, and health-care costs associated with CKD have led investigators to seek novel modifiable risk factors contributing to the development of CKD. An increasing number of studies have focused on the association between NAFLD and CKD over the past decade.
The aim of the work of this study is to evaluate the possible relationship between NAFLD and the risk of CKD development.
In our study, there was a significant difference between CKD and non-CKD group according to age which was in agreement with Ahn et al[11] who found that NAFLD was significantly associated with CKD in Koreans aged 50 years or older. Furthermore, in agreement with our study a study conducted by Sirota et al[12] which showed that the mean age of the CKD group was higher than non-CKD group. In contrast to our study, Yasui et al[13] demonstrated that there was no significant difference between CKD and non-CKD group according to age in their study.
As regards gender, males represented 40% and females 60% of the patients with NAFLD in our study. The study shows that NAFLD is more common among females rather than males and this was in agreement with that of Koehler et al[14] which showed females represent 61.8% of NAFLD patients in their study. Our study showed that there was no significant difference between CKD and non-CKD group according to sex which is in agreement with Li et al.[15] Against our study is the one by Sirota et al[12] that showed that the risk of CKD was more common among females rather than males.
Our study also demonstrated that there was no significant difference between CKD and non-CKD groups according to smoking in agreement with Arase et al.[16] In contrast to our study Sesti et al[17] which demonstrated that smoking was risk factor for developing CKD in NAFLD patients and smokers in CKD group was more than the non-CKD group. The study explained that by increased cardio-renal risk factors and NAFLD fibrosis scores among smokers and they found individuals with high liver fibrosis scores have lower eGFR compared with individuals with low of liver fibrosis scores.
As regards abdominal obesity in our study, there was a significant difference between CKD and non-CKD groups in agreement with Chen et al[18] which showed that the risk of CKD was associated with abdominal obesity as it showed that the mean WC of the CKD group was higher than the non-CKD group. Against our study Zeng et al[19] which demonstrated that there was no significant difference between CKD and non-CKD groups according to abdominal obesity.
Considering BMI in our study there was a significant difference between CKD and non-CKD group in agreement with Yasui et al[13] that showed the risk of CKD was associated with higher BMI. In contrast to our study Zeng et al[19] who demonstrated that was no significant difference between CKD and non-CKD group according to BMI. This may be due to different ethnic groups and also, the BMI of patients included in that study was much lower than the BMI of patients included in our study.
As regards serum albumin in our study there was a significant difference between CKD and non-CKD groups in agreement with Zeng et al[19] who demonstrated that the CKD group has lower albumin levels than non-CKD group. Against our study Huh et al[20] who demonstrated that there was no significant difference between CKD and non-CKD groups according to serum albumin level. The difference between our study and that study may be due to differences in the number of patients included and different dietary habits. Furthermore, 60% of the patients included in this study did not have NAFLD (FLI <30).
The current study demonstrated that there was no significant difference between CKD and non-CKD group according to liver enzymes in agreement with Xuet al.[21] In contrast to our study Sesti et al[17] who demonstrated that the CKD group has higher AST levels than the non-CKD group. They explained these findings as patients with elevated liver enzymes have a higher NAFLD fibrosis score and that was associated with an increased risk of CKD.
In our study, we found there was no significant difference between CKD and non-CKD group according to GGT level in agreement with Chen et al.[18] In contrast to our study Chang et al[22] who showed that the association between NAFLD and incident CKD was more evident in the NAFLD group with elevated GGT level than in the NAFLD group with normal GGT level. This study assumed elevated GGT is associated with increased oxidative stress and inflammation that play an important role in renal injury and the development of CKD.
Considering lipid profile in our study, there was a significant difference between CKD and non-CKD groups according to total cholesterol levels in agreement with Xu et al[21] who demonstrated that the risk of CKD was associated with a higher level of total cholesterol. Against our study, Chen et al[18] who demonstrated that there was no significant difference between CKD and non-CKD groups according to total cholesterol level.
In our study, there was a significant difference between CKD and non-CKD group according to HDL level in agreement with El Azeem et al[23] in which the CKD group has lower HDL levels than the non-CKD group. In contrast to our study Arase et al[16] who demonstrated that there was no significant difference between CKD and non-CKD groups according to HDL level.
As regards LDL level in our study there was a significant difference between CKD and non-CKD group in agreement with Xu et al[21] who demonstrated that the risk of CKD was associated with a higher level of LDL. In contrast to our study Chen et al[18] who demonstrated that there was no significant difference between CKD and non-CKD group according to LDL level.
As regards TG level in our study there was a significant difference between CKD and non CKD groups in agreement with Huh et al[20] who demonstrated that the CKD group has higher TG levels than the non-CKD group in their study. In contrast to our study Zengetal[19] who demonstrated that there was no significant difference between CKD and non-CKD group according to TG level. The variations between our study and other studies regarding lipid profile elements may be due to the difference in the number of patients included in each study, different ethnic compositions, different dietary habits of each population, and duration for each study. Furthermore, patients in these studies had much lower levels of cholesterol, LDL, and TG than our patients.
As regards FLI in our study, there was a significant difference between CKD and non-CKD groups in agreement with Zeng et al[19] who demonstrated that the risk of CKD was associated with higher FLI.
Considering the degree of fatty liver, there was a significant difference between CKD and non-CKD group in our study as CKD was more among moderate and marked fatty liver rather than average and mild fatty liver in agreement with Sirota et al[12] who demonstrated a higher prevalence of CKD among moderate and severe NAFLD than mild NAFLD.
Our present study has several limitations. First, owing to the cross-sectional study design, we are unable to draw conclusions about the causality of NAFLD and CKD. Second, liver biopsy is the best diagnostic tool for quantification of NAFLD and it is most sensitive and specific for providing important prognostic information. However, because it is an invasive procedure, it cannot be easily implemented in normal people. Thus, our NAFLD diagnosis was based on ultrasound imaging. The ability of ultrasound to detect NAFLD is limited. Finally, we used an eGFR instead of directly measured GFR to define CKD.
Conflict of interest: None declared.
References 
Correspondence Address:
Abdelkader K Elgakhow
Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Gharbia Governorate
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367817
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