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Influence of Nonalcoholic Fatty Liver Disease on the Occurrence and Severity of Chronic Kidney Disease

  • Ziwen Tao,
  • Yueyue Li,
  • Baoquan Cheng,
  • Tao Zhou and
  • Yanjing Gao* 
Journal of Clinical and Translational Hepatology   2022;10(1):164-173

doi: 10.14218/JCTH.2021.00171

Received:

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Citation: Tao Z, Li Y, Cheng B, Zhou T, Gao Y. Influence of Nonalcoholic Fatty Liver Disease on the Occurrence and Severity of Chronic Kidney Disease. J Clin Transl Hepatol. 2022;10(1):164-173. doi: 10.14218/JCTH.2021.00171.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is reported to affect 20-30% of adults and is accompanied by various metabolic comorbidities, where the economic and clinical burden of NAFLD is attributed to the progression of liver disease as well as the presence of extrahepatic diseases. Chronic kidney disease (CKD), which has a high incidence rate, high morbidity and mortality rates, and high medical costs, has been linked to NAFLD. CKD is associated with some metabolism-related risk factors that overlap with metabolic comorbidities of NAFLD. Therefore, to investigate the potential factors that influence CKD occurrence, the association between NAFLD and CKD should be clarified. Some studies have confirmed that NAFLD influences the occurrence and severity of CKD, whereas some studies have indicated that there is no correlation. In this review, the results of a few studies have been discussed, the potential risk factors for CKD in NAFLD are explored, and the respective biological mechanisms are elaborated to help clinicians identify CKD in patients much earlier than it is diagnosed now and thus help in reducing the incidence of liver and kidney transplants.

Keywords

Non-alcoholic fatty liver disease, Chronic kidney disease, Review, Risk factors

Introduction

Nonalcoholic fatty liver disease (NAFLD) includes different types of liver damage, ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to liver cirrhosis and even hepatocellular carcinoma.1,2 NAFLD is diagnosed by the presence of more than 5% fat accumulation in liver cells after excluding excessive alcohol intake in patients as well as other secondary causes of liver disease, such as drug-induced liver injury, viral and autoimmune hepatitis.3 The prevalence of NAFLD is reported to be 20–30% among the adult population in western countries.4 Due to the variety of metabolic comorbidities it accompanies, such as hypertension, insulin resistance, diabetes mellitus (DM), dyslipidemia, and central obesity, international experts decided to change its name to metabolic dysfunction-associated fatty liver disease (MAFLD).5 NAFLD is also reported to increase the risk of cardiovascular disease in patients.6 Thus, the economic and clinical burdens of NAFLD are not only associated with the progression of liver disease but also with various extrahepatic diseases.7

The diagnostic criteria for chronic kidney disease (CKD) are either the reduced estimated glomerular filtration rate (eGFR) (<60 mL/min/1.732) and/or abnormal albuminuria and/or overt proteinuria in patients for at least 3 months.8 In western countries, more than 25% of people aged >65 years are affected with CKD.9 CKD is a major risk factor for cardiovascular disease and end-stage kidney disease. It is a serious health threat that is associated with high morbidity and mortality rates and high medical costs.10 Therefore, investigating the potential influencing factors of CKD is essential to helping clinicians in their early intervention efforts for the disease. Reportedly, hypertension, dyslipidemia, obesity, and insulin resistance are considered risk factors for CKD that overlap with the metabolic comorbidities of NAFLD.11

The association between NAFLD and CKD has recently attracted the attention of many experts. NAFLD and CKD share some common pathophysiological mechanisms as well as some metabolic risk factors for cardiovascular disease.12,13 Some studies have confirmed that the presence of NAFLD increases the risk of CKD and that the degree of liver fibrosis is related to CKD stage,14,15 while other studies have found that the incidence of CKD is not affected by NAFLD.16 In addition, hepatorenal syndromes in patients with decompensated cirrhosis confirm the pathophysiological relationships between the liver and kidney.17 In this article, we have reviewed the results of studies on the relationship between NAFLD and CKD, explored the potential risk factors for CKD in NAFLD patients, and elaborated on the possible mechanisms in order to explore the possibilities of early intervention for CKD. All the data from this review are presented in Tables 1 and 2.14–16,18–43

Table 1

Data of meta-analyses included in this review

Author, yearIncluded studies, nNAFLD patients, nCKD diagnosis, nMain findings
Zou et al., 202026621,4501,211Pooled incidence of CKD among NAFLD was 9.2 per 1,000 person-years (95% CI: 5.7–14.6, p<0.01; I2=96.2%)
Mantovani et al., 201831932,8984,653NAFLD increased the risk of CKD (HR: 1.37, 95% CI: 1.20–1.53, p<0.0001; I2=33.5%); the more severe the NAFLD, the higher the risk of developing CKD (HR: 1.50, 95% CI: 1.25–1.74, p<0.0001; I2=0%)
Musso et al., 20143433NAFLD increased the risk of CKD (HR: 1.79, 95% CI: 1.65–1.95, p<0.00001). NASH and advanced fibrosis was associated with a higher incidence of CKD (HR: 2.12, 95% CI: 1.42–3.17, p=0.0002; HR: 3.29, 95% CI: 2.30–4.71, p<0.0001, respectively)
Table 2

Main findings of the included studies about relationships between NAFLD and CKD

Author, yearStudy designDiagnostic method for NAFLDDiagnostic method for CKDSample size and rate of NAFLDCKD incidence, nMain findings
Xu et al., 201614Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m2755, 100%61FIB-4 score ≥1.100 (OR: 2.660, 95% CI: 1.201–5.889, p=0.016), were independent predictors of CKD among NAFLD patients
Targher et al., 201415Retrospective, longitudinal cohort studyUltrasonographyeGFR <60 mL/min/1.73 m2 and/or macroalbuminuria261, 50.2%61NAFLD increased the risk of CKD (aHR: 2.03, 95% CI: 1.10–3.77, p<0.01) in patients with type 1 diabetes
Sirota et al., 201216Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m2 or the presence of albuminuria11,469, 36%2,891NAFLD was not associated with the occurrence of CKD (OR=1.04, 95% CI: 0.88–1.23, p=0.64)
Targher et al., 200825Prospective cohort studyUltrasonographyOvert proteinuria and/or eGFR <60 mL/min/1.73 m21,760, 73%547NAFLD increased the risk of CKD (aHR: 1.49, 95% CI: 1.10–2.20, p<0.01) in patients with type 2 diabetes
Targher et al., 200818Cross-sectional studyUltrasonographyOvert proteinuria and/or eGFR ≤ 60 mL/min/1.73 m22,103, 67%284NAFLD increased the risk of CKD (OR: 1.87, 95% CI: 1.30–4.10, p=0.02) in patients with type 2 diabetes
Targher et al., 201019Cross-sectional studyUltrasonographyAbnormal albuminuria or eGFR ≤60 mL/min/1.73 m2202, 54.9%51NAFLD increased the risk of CKD (aOR: 3.90, 95% CI: 1.50–10.10, p=0.005) in patients with type 1 diabetes
Targher et al., 201220Cross-sectional studyUltrasonographyAbnormal albuminuria or eGFR ≤60 mL/min/1.73 m2343, 53%138NAFLD increased the risk of CKD (aOR: 1.93, 95% CI: 1.10–3.60, p=0.02) in patients with type 1 diabetes
Ahn et al., 201322Cross-sectional studyUltrasonographyProteinuria or eGFR ≤60 mL/min/1.73 m21,706, 32%424NAFLD increased the risk of CKD (aOR: 1.68, 95% CI: 1.27–2.24, p=0.02)
Wilechansky et al., 201927Community-based prospective cohort studyMDCTeGFR <60 mL/min/1.73 m2987, 19%19Liver fat was not associated with the prevalence and incidence of CKD
Zhang et al., 202028Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m2 or and/or abnormal albuminuria and/or overt proteinuria60,965, 29.8%7,229NAFLD was associated with an increased risk of early stages of CKD in both Chinese and USA cohort, but not the late stages of CKD
Sinn DH et al., 201729Retrospective cohort studyUltrasonography, NAFLD severity assessed by APRI, NFS and FIB-4 scoreeGFR <60 mL/min/1.73 m241,430, 34.3%691NAFLD increased the risk of CKD (aHR: 1.22, 95% CI: 1.04–1.43, p=0.018), the degree of the risk was correlated with the severity of NAFLD
Park et al., 201930Retrospective propensity-matched cohort study1,032,497, 25.4%14,421Compared with patients without NAFLD, patients with NAFLD had a 41% increased risk of developing advanced CKD (aHR: 1.41, 95% CI: 1.36–1.46, p=0.018), patients with decompensated cirrhosis had higher risk (aHR: 2.28, 95% CI: 2.12–2.46).
Chen et al., 202032Cross-sectional studyUltrasonography, advanced liver fibrosis assessed by NFSeGFR <60 mL/min/1.73 m229,797, 44.5%6,027NAFLD was not related to CKD (OR=1.015, 95% CI: 0.954–1.081, p=0.630), but patients with advanced fibrosis tended to be more likely to have CKD (OR: 2.284, 95% CI: 1.513–3.448, p<0.001)
Zeng et al., 201723Cross-sectional studyUltrasonography, CAP, FLIeGFR <60 mL/min/1.73 m2731, 36.1%48NAFLD increased the risk of CKD regardless the diagnosis tools, when FLI ≥60 or CAP >292 dBm, eGFR was significantly reduced
Choudhary et al., 201624Retrospective cohort studyHistologyeGFR <60 mL/min/1.73 m2373, 50.1%NAFLD did not affect renal function
Jang et al., 201833Cohort studyUltrasonographyeGFR <60 mL/min/1.73 m21,525, 40.9%1,525NAFLD was associated with the progression of CKD; the decrease of eGFR was greater in NAFLD patients than those who without (−0.79 vs. 0.30% per year, p=0.002)
Targher et al., 201021Cross-sectional studyHistologyeGFR ≤60 mL/min/1.73 m2 and/or abnormal albuminuria160, 50%23NAFLD increased the risk of CKD (aOR: 6.14, 95% CI: 1.6–12.8, p<0.001), the degree of the risk was correlated with the histologic severity of NASH
Kasim et al., 202035Cross-sectional studyUltrasonography, abdominal CT scan or liver biopsyeGFR <60 mL/min/1.73 m2 and/or albuminuria134, 50%96NAFLD had higher prevalence of CKD (40.3 vs. 16.4%, p=0.002) and more grade 3 among CKD patients (37.3% vs. 9%, p=0.001) than non-NAFLD
Arase et al., 201136Retrospective cohort studyUltrasonography and liver enzymeseGFR <60 mL/min/1.73 m2 and/or overt proteinuria5,561, 100%263Diabetes (HR: 1.92, 95% CI: 1.45–2.54, p<0.001), hypertension (HR: 1.69, 95% CI: 1.25–2.29, p<0.001), age of 50 years (HR: 2.67, 95% CI: 2.06–3.46, p<0.001), elevated serum GGT of 109 IU/L (HR: 1.35, 95% CI: 1.02–1.78, p=0.038), and eGFR of 60–75 mL/min/1.73 m2 (HR: 2.75, 95% CI: 1.93–3.94, p<0.001) were risk factors of CKD among NAFLD
Luo et al., 201937Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m2 and/or albuminuria515, 100%282Obesity was a risk factor for CKD among NAFLD patients (p<0.01)
Wijarnpreecha et al., 201838Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m24,142, 100%200Advanced liver fibrosis assessed by NFS (aOR: 4.92, 95% CI: 2.96–8.15) and FIB-4 (aOR: 2.27, 95% CI: 1.05–4.52) was associated with the risk of CKD
Sesti et al., 201439Cross-sectional studyUltrasonographyeGFR <60 mL/min/1.73 m2570, 100%38Advanced liver fibrosis was independently associated with the risk of CKD
Yasui et al., 201140Cross-sectional studyHistologyeGFR <60 mL/min/1.73 m2 or overt proteinuria174, 100%24When contrasted to non-NASH NAFLD, the presence of NASH increased the incidence of CKD (21 vs. 6%, p=0.007)
Huh et al., 201741Population-based prospective cohort studyFLIeGFR <60 mL/min/1.73 m24,761, 12.62%724FLI ≥60 was associated with increased risk of CKD (HR: 1.459, 95% CI: 1.189–1.791, p=0.0012)
Chang et al., 200842Community-based cohort studyUltrasonographyeGFR <60 mL/min/1.73L m2 or the presence of proteinuria8,329, 30%324NAFLD with elevated GGT increased the risk of CKD (a RR: 2.31, 95% CI: 1.53–3.50, p=0.008)
Tsai et al., 202043Cross-sectional studyUltrasonography or FibroScaneGFR <60 mL/min/1.73 m2 or urine protein >2+90, 100%39Some nontraditional indicators, such as VCAM-1, urinary level of FABP4 and RBP4, were shown to be predictors of CKD progression

Renal function markers in NAFLD patients

Changes in different markers reflecting renal function, such as the levels of eGFR, creatinine (Cr) and blood urea nitrogen (BUN), the incidence of proteinuria, and urinary albumin-to-creatinine ratio levels in NAFLD patients were studied. Patients who had NAFLD showed lower eGFR than those without NAFLD (91±32 vs. 96±31 mL min−1 1.73 m−2, p=0.001),18 a higher incidence of proteinuria (36.4 vs. 4.4%, p<0.0001),19 and higher albumin-to-creatinine ratio levels (13.4±27.6 vs. 3.1±9.9 mmol/mol, p<0.0001).20 Other studies have also supported these results.21,44 However, no difference was reported in baseline Cr and BUN levels in patients with and without NAFLD.22,23 We hence hypothesized that Cr and BUN levels may not be the most sensitive indicators of early renal function impairment. However, Choudhary et al.24 demonstrated no difference in eGFR or Cr levels nor the incidence of proteinuria between individuals with biopsy-confirmed NAFLD and patients with normal liver histology. Therefore, to evaluate the effect of NAFLD on renal function, further studies are required.

Associations between presence of NAFLD and risk of CKD

Because NAFLD is usually accompanied by multiple metabolic comorbidities, and CKD is also affected by multiple metabolic factors, it is difficult to accurately infer their relationship. DM is a systemic disease that is closely associated with NAFLD and CKD. Studies have shown that 40–69% of DM patients develop NAFLD, and the latter is associated with poor glycemic control in DM.45,46 Meanwhile, NAFLD has also been well-demonstrated to increase the risk of DM.47 Additionally, DM is considered a cause of CKD and is reported to significantly increase the risk of CKD occurrence.48,49 To investigate the relationship between NAFLD and CKD, it is important to exclude the interference of DM.

Targher et al.18–20,25 reported that the presence of NAFLD was associated with an increased risk of CKD in both type 1 and type 2 diabetes patients and was not affected by such baseline data as body mass index, waist circumference, blood pressure, blood lipids, and glycosylated hemoglobin. Ahn et al.22 reported that NAFLD could increase the incidence of CKD by 1.68 times (95% confidence interval [CI]: 1.27–2.24), after being classified by hypertension and DM. Zou et al.26 conducted a meta-analysis involving 20,030 individuals and found that the pooled overall prevalence of CKD among NAFLD patients was 9.2 per 1,000 person-years, which when combined with the occurrence of type 1 or 2 diabetes, was observed to increase significantly (63.0 per 1,000 person-years). However, whether the presence of diabetes is associated with an increased all-cause mortality rate is unclear; more attention should be paid to the low quality of these patient’s lives and the benefits that they can reap from a hypoglycemic agent.

Hypertension, a component of metabolic syndrome, has been reported in multiple studies to increase the risk of NAFLD, independent of the obesity factor, with an estimate of 50% of patients with hypertension having NAFLD.50–53 Hypertension, as a cause for CKD, is usually primary, has a longer history than CKD, and is often accompanied by hypertensive target organ damage. A decrease in eGFR often precedes the onset of renal tubular concentrating dysfunction. Hypertension increases the production of angiotensin II by activating the renin-angiotensin-aldosterone system (RAAS), which reduces renal perfusion through the constriction of renal vessels, induces renal hyperfiltration (caused by the discordant degree of afferent and efferent arterioles contraction), and then leads to glomerulosclerosis and tubule-interstitial inflammation, ultimately leading to CKD.54,55 Hypertension caused by CKD is secondary and is attributed to various renal parenchyma and vascular lesions through the mechanisms of activation of the RAAS, the sympathetic nervous system, water and sodium retention, and endothelial dysfunction. The incidence of hypertension varies from 60% to 90% in different CKD stages.56,57 These findings indicate that exclusion of the interference of hypertension is important. No association between liver fat and CKD was reported in the Framingham Heart Study, after adjusting for blood pressure, blood lipids, DM, and other covariates.27 This study adjusted the use of drugs such as antihypertensive drugs and aspirin, suggesting that the two diseases may be linked by their common risk factors.

Sirota et al.16 reported that ultrasound-diagnosed NAFLD was not associated with CKD occurrence in American adults after adjusting for the characteristics of metabolic syndrome. Based on this result, Zhang et al.28 revealed the origin of discrepancy between eastern and western patients with respect to the relationship between NAFLD and CKD. NAFLD was an independent risk factor for CKD in the Chinese cohort; however, no such results were found in the USA cohort. The subgroup analysis found that NAFLD was associated with early stages of CKD but not with the later stages (in both groups); therefore, negative relationships were reported in the USA cohort, which mainly consisted of advanced CKD patients.

Some studies have shown that the severity of NAFLD correlates with the CKD risk.29 In a retrospective cohort study, patients with NAFLD showed an increased incidence of CKD by 41%. After adjusting for confounders, NAFLD was found to be a significant risk factor for CKD (adjusted hazard ratio [aHR]=1.58, 95% CI: 1.52–1.66), where the presence of cirrhosis increased the CKD risk (compensated cirrhosis: aHR=1.47, 95% CI: 1.36–1.59; decompensated cirrhosis: aHR=2.28, 95% CI: 2.12–2.46).30 A meta-analysis involving 96,595 patients also revealed that the more severe NAFLD was in patients, the higher was the CKD risk (hazard ratio [HR]=1.50, 95% CI: 1.25–1.74), and this risk was even greater in NAFLD patients with high-median fibrosis scores (HR=1.59, 95% CI: 1.31–1.93).31 However, Chen et al.32 found that NAFLD itself does not affect CKD occurrence, but the presence of advanced liver fibrosis increases the risk of CKD. Therefore, CKD screening should be performed in NAFLD patients with advanced fibrosis.

In addition, increased hepatic lipid content in NAFLD patients was also reported to affect the incidence of CKD. Fatty liver index (FLI) and controlled attenuation parameter are some of the noninvasive indicators for diagnosis of hepatic steatosis; when FLI was ≥60 or controlled attenuation parameter was >292 dBm, the eGFR was observed to be significantly reduced.23

Since NAFLD was recently renamed to MAFLD, their definitions are slightly different, which may have some influence on CKD recognition. A recent study of 12,571 individuals confirmed that the diagnosis of MAFLD was more accurate than that of NAFLD with respect to CKD identification. MAFLD patients showed a higher prevalence of CKD than NAFLD patients, and the severity of MAFLD was associated with a 1.34-fold increased risk of CKD.44

The majority of current studies have thus supported the conclusion that NAFLD increases the risk of CKD, and the magnitude of the risk related to CKD occurrence is associated with NAFLD severity. Components of metabolic syndrome, such as DM and hypertension, also seem to play a role in this relationship. Therefore, controlling the progression of NAFLD and other metabolic diseases may benefit the kidneys.

Effects of NAFLD on CKD severity

A growing body of research has shown that NAFLD increases the risk of CKD and is also correlated with its severity. Jang et al.33 found that among CKD patients, the decrease in eGFR was greater in NAFLD patients than in those without (−0.79% vs. 0.30% per year, p=0.002). The extent of decrease was greater in patients with higher fibrosis scores, suggesting that NAFLD severity has an impact on CKD progression.

Targher et al.21 compared the results of 80 biopsy-proven NASH patients with those of control subjects and concluded that CKD incidence was significantly higher in the NASH patients. This relationship was not affected by the components of metabolic syndrome, with eGFR levels decreasing along with the increasing histological severity (fibrosis stage). A meta-analysis of 33 studies also showed that the presence of steatohepatitis (odds ratio [OR]=2.53, 95% CI: 1.58–4.05) and advanced fibrosis (OR=5.20, 95% CI: 3.14–8.61) increased the risk of CKD, and a positive correlation was also found between NAFLD severity and CKD stages.34

Ramadhan et al.58 found that the presence of liver fibrosis increased the CKD risk by approximately 3.8 times in patients with NAFLD (95% CI: 1.07–13.79, p=0.035); meanwhile, the frequency of grades 2 and 3 CKD was higher in patients with liver fibrosis than in those without (p=0.034). Kasim et al.35 also found more grade 3 CKD patients in the NAFLD group than in the control group (37.3% vs. 9.0%).

Existing studies have shown that NAFLD itself can increase the incidence of high-grade CKD, where CKD severity is also affected by the severity of steatosis and fibrosis. Therefore, we suggest that renal function in NAFLD patients should be carefully monitored to aid in the early identification of CKD, after which relevant steps could be taken to intervene in disease progression.

Risk factors for CKD in patients with NAFLD

To stabilize the condition of NAFLD patients, delay the disease progression, and improve the quality of patient life, the search for CKD predictors is crucial. The components of metabolic syndrome are often considered first. DM is a common comorbidity of NAFLD that contributes to adverse liver outcomes through a synergistic effect.59 Studies have shown that about one-third of NAFLD patients have impaired renal functions, which is closely related to the presence of DM in patients.36,60 While obesity and NAFLD are considered as risk factors for each other, the former is also reported as a risk factor for CKD.37,61 Chon et al.62 followed up with 1,774 patients with NAFLD and confirmed that significant weight loss reduced the risk of rapid decline in renal function and presence of CKD when compared with those with minimal weight changes (HR=0.598, 95% CI: 0.458–0.782; HR=0.531, 95% CI: 0.409–0.690, respectively). Thus, weight loss can be used as one of the measures to improve long-term kidney prognosis of patients with NAFLD.

The severity of NAFLD in patients also influences CKD occurrence. High noninvasive liver fibrosis scores, such as FIB-4 and NAFLD fibrosis scores, which reflect the degree of liver fibrosis in patients with NAFLD, were associated with an increased risk of CKD.63 Both could be used clinically to exclude CKD in patients with NAFLD, and FIB-4 was found to be the most accurate one.38,39 NASH is a phase in the progression of NAFLD, which is believed to be a driving factor for the development of liver fibrosis.64,65 In contrast to non-NASH NAFLD, the presence of NASH increases the incidence of CKD (21% vs. 6%, p=0.007).40 Moreover, the predictive power of the traditional CKD prediction model significantly improves when the FLI is added, which is a predictor of the degree of hepatic steatosis. The area under receiver operating characteristic curve was observed to increase from 0.816 to 0.818 (p=0.0615).41,66 Studies have also shown that γ-glutamyl transferase concentration is not only associated with NAFLD severity but could also explain the risk of CKD in nondiabetic, nonhypertensive men, in spite of the metabolic syndrome.42,67

Recently, the ability of some nontraditional indicators to predict the incidence of CKD has also been investigated. Urinary neutrophil gelatinase-associated lipocalin, which is an early marker of renal tubular injury, was found to be a significant predictor for CKD in NAFLD patients who were diagnosed by biopsy or transient elastography, in a cross-sectional study. The cut-off value was reported to be 36.75 ng/mL, with the specificity of 85% and sensitivity of 75%; a higher incidence of CKD in advanced fibrosis has also been found (15.4 vs. 3.4%, p=0.056).68,69 Fatty acid-binding protein plays an important role in liver lipometabolism and is associated with inflammation and fibrosis in NAFLD patients.70 Retinol-binding protein 4 was also found to be significantly increased in patients with severe NAFLD.71 Vascular cell adhesion molecule-1 is produced by liver cells through the stimulation of C-reactive protein, tumor necrosis factor-α, and other cytokines under the chronic inflammatory state, and is involved in the initiation of atherosclerosis; thus, it can be regarded as having a role in NAFLD pathogenesis.72,73 All three indicators are considered proven as predictors of CKD progression in NAFLD patients with hypertension.43

In addition to the aforementioned risk factors that affect both NAFLD and CKD, there are some independent risk factors for each. In addition to the components of the metabolic syndrome, some genetic factors are believed to be related to the occurrence of NAFLD. The PNPLA3-I148M variant was found to be associated with the maximized risk of NAFLD when accompanied with adiposity.74,75 HSD17B13 silencing was observed to reduce liver damage in patients with fatty liver.76 In addition, a high-fat, high-sodium, low-nutrition diet, and low physical activity lifestyle are considered as risk factors for NAFLD.77–79 Moreover, along with DM and hypertension, CKD could be caused by the use of nephrotoxic drugs as well as glomerular, infectious, and other diseases.80,81 Sex and age also affect the incidence of CKD. CKD was most common in females and people of age >65 years,82 indicating that elderly women should focus on the early detection of renal function abnormality.

In general, indicators of NAFLD severity, components of the metabolic syndrome, and some indicators related to renal function predict the risk of CKD in patients with NAFLD. Moreover, the risk factors individually related to the occurrence of NAFLD and CKD should not be ignored. A comprehensive evaluation of these factors has a certain guiding significance for clinical practice.

Putative biological mechanisms

With the ongoing studies on NAFLD and CKD, several metabolic comorbidities associated with NAFLD have been found to be potential risk factors for CKD. Because of the significant social, economic, and psychological burdens of the two diseases, the pathogenesis that links them needs to be identified. On the one hand, it can provide a new direction for treatment, on the other hand, the prevention of CKD occurrence in NAFLD patients would be possible. However, this pathogenesis is not clear at present. All the potential mechanisms are presented in Figure 1.

Putative biological mechanisms linking NAFLD and CKD.
Fig. 1  Putative biological mechanisms linking NAFLD and CKD.

In NAFLD patients, cytokine imbalance caused by increased release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), transforming growth factor-β (TGF-β) and other cytokines lead to inflammation, then cause renal injury. Impaired oxidative stress activates the C-Jun-N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) pathways, promoting systemic inflammatory response, further exaggerating oxidative stress. Renin-angiotensin-aldosterone system (RAAS) components produced by fat cells can promote the production of proinflammatory factors. Increased production of fetuin-A leads to downregulation of adiponectin levels, while the latter can reduce the activation of 5′-AMP-activated protein kinase, thereby exacerbating renal damage and insulin resistance. Insulin resistance can not only damage the kidneys directly but also indirectly by promoting the formation of atherogenic dyslipidemia. Under the state of intestinal microbiota dysbiosis, increased release of endotoxin destroys the intestinal barrier, then exaggerates inflammation. The increased production of uremia toxins excreted through urine is toxic to the kidneys. The increased production of secondary bile acids also produces proinflammatory effects. Meanwhile, the decreased production of short-chain fatty acids reduces the production of glucagon-like peptide-1 (GLP-1) and incretins peptide YY (PYY), which then aggravates insulin resistance. ↑ indicates an increase, ↓ indicates a decrease, and → signifies the consequences that result. CKD, chronic kidney disease; NAFLD, non-alcoholic fatty liver disease.

Inflammatory cytokines

The imbalance of cytokines may contribute to the development of CKD, the increased systematic release of various proinflammatory, procoagulant, profibrogenic, and pro-oxidant factors, such as tumor necrosis factor-α, transforming growth factor-β, C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, and connective tissue growth factor (produced by hepatic stellate cells and Kupffer cells from the steatosis liver), may play significant roles in CKD occurrence.83–85

Oxidative stress

Impaired oxidative stress is also a potential pathogenic mechanism. Energy metabolism is reported to be accelerated and oxidative stress is observed to be increased by fat deposition in liver cells. Subsequently, C-Jun-N-terminal kinase and nuclear factor-κB pathways are activated, leading to an increase in the transcription of proinflammatory genes. This then promotes the systemic inflammatory response, exaggerates oxidative stress, enhances immunologic inflammatory responses of the kidney, and eventually leads to renal injury.86–89

Activation of the RAAS

Activation of the RAAS is also reported to be involved in the deterioration of renal function in NAFLD patients. Fat cells produce all RAAS ingredients and contribute as much as 30% of circulating angiotensin II, which promotes the production of proinflammatory factors and lipogenesis.90 On the one hand, it can induce NAFLD progression, on the other hand can cause contraction of glomerular efferent arteriole through ectopic lipid deposition, thereby leading to inflammation and oxidative stress, followed by eventual development of glomerular sclerosis.91

Insulin resistance

The fact that NAFLD patients have increased visceral fat deposition and insulin resistance activated by C-Jun-N-terminal kinase-1 from adipose tissue has been confirmed in animal experiments.92 Fetuin-A, produced by expanded and inflamed adipose tissue, has been found to play an important role in promoting insulin resistance.93 However, renal hemodynamics are reported to deteriorate under the combined action, induced by insulin resistance, activation of the sympathetic nervous system, downregulation of the natriuretic peptide system, and generation of sodium retention, ultimately promoting renal disease progression.84,94 Adiponectin is a protein that has anti-inflammatory and antiatherogenic capacities and is secreted by adipose tissue.95 In patients with NAFLD, high fetuin-A levels are often reported to cause downregulation of adiponectin levels. Hypoadiponectinemia is observed to mediate damage to hepatocytes and renal podocytes by reducing the activation of 5′AMP-activated protein kinase, thereby promoting renal inflammation and fibrosis and exacerbating insulin resistance.83,96.

Atherogenic dyslipidemia

The formation of atherogenic dyslipidemia can be promoted by insulin resistance, which is characterized by high levels of triglycerides and small, dense low-density lipoprotein cholesterol, and low levels of high-density lipoprotein cholesterol. This is then associated with renovascular damage, renal endothelial dysfunction, and glomerular injury.95,97,98

Intestinal microbiota dysbiosis

Intestinal microbiota dysbiosis is common in patients with NAFLD. Increased release of endotoxin from Gram-negative bacteria destroys the intestinal barrier, thus increasing intestinal permeability. The introduction of endotoxin into the blood increases circulating lipopolysaccharide levels, thus leading to the systemic inflammatory state and thereby increasing CKD risk.99 Indole produced by Escherichia coli, and p-cresol and trimethylamine produced by many obligate or facultative anaerobes, such as genera Bacteroides, Enterobacter, and Clostridium diffificile,100,101 are further metabolized by the liver to produce trimethylamine-N-oxide, p-cresol sulfate and indole sulfate, which are excreted through urine but toxic to the kidneys.102 The phenomenon whereby trimethylamine-N-oxide induces atherosclerosis103 and leads to renal fibrosis has been demonstrated.104 Increased production of secondary bile acid dysregulates the farnesoid X nuclear receptor system, which can improve liver histology in NASH by being activated105 and induces DNA damage in hepatic stellate cells through enterohepatic circulation, thereby increasing the secretion of various tumor-promoting and inflammatory factors. Thus, a systemic inflammatory state is formed and risk of CKD increases.106 Decrease in short-chain fatty acids produced by Lactobacilli and Bifidobacteria in NAFLD patients can reduce the production of glucagon-like peptide-1 and incretins peptide YY, which are produced after the activation of the short-chain fatty acids receptor, and is believed to increase insulin secretion and improve satiety. Thereby, the reduction of these two substances can aggravate insulin resistance, leading to kidney damage.107,108

The pathogenesis linking NAFLD and CKD has not been confirmed yet, but inflammation, oxidative stress, activation of the RAAS, insulin resistance, intestinal microbiota dysbiosis, as well as a series of downstream effects caused by them seem to all play a role in the pathogenesis of both diseases. However, further studies are warranted to explain the contribution of each of the factors to the incidence of CKD.

Perspectives

Although there is increasing evidence demonstrating an association between NAFLD and CKD, further improvement of experimental design is required to fulfil the limitations of the existing studies. First, most studies are cross-sectional studies that could not establish an exact causality between the two diseases. On the other hand, the efficiency of the retrospective study design is insufficient; therefore, multicenter prospective studies are required. Second, conducting liver biopsy routinely is not realistic and fat deposition in NAFLD patients is also considered to be patchy, which further increases the chance of misdiagnosis. Thus, most studies have diagnosed NAFLD through ultrasound; however, a biopsy is expected to be included in future experiments as a diagnostic gold standard. Third, due to different adjustments for confounding factors, the strength of the correlation between the two diseases obtained from different studies has a discrepancy; the usage of drugs, such as antihypertensive drugs and cholesterol-lowering agents, and drugs effecting renal functions, were often not included in the studies. Therefore, it is necessary to further complete the clinical data of the patients. Fourth, CKD has many pathologies and their prognoses vary massively. No study has investigated the relationship between NAFLD and the different pathological types of CKD, which needs to be further explored. Fifth, the pathogenesis linking NAFLD and CKD is still not specific, and the contribution of various potential mechanisms causing renal insufficiency in NAFLD patients is also unclear. To conduct accurate treatment and target the etiology, further experiments need to be conducted.

Conclusions

Recent studies have suggested that NAFLD is associated with an increased risk of CKD, but more proof is needed for confirmation. Inflammatory cytokines, oxidative stress, activation of RAAS, insulin resistance, atherogenic dyslipidemia, and intestinal microbiota dysbiosis were reported as potential pathogenesis. Early detection of CKD in NAFLD patients by monitoring the renal function closely to reduce the incidences of liver and kidney transplants is expected to attract the attention of clinicians. On the other hand, CKD patients are also suggested to closely examine their hepatic fatty deposition levels. Numerous studies are hence needed to suggest a proper treatment in the future.

Abbreviations

BUN: 

blood urea nitrogen

CI: 

confidence interval

CKD: 

chronic kidney disease

Cr: 

creatinine

DM: 

diabetes mellitus

FLI: 

fatty liver index

eGFR: 

estimated glomerular filtration rate

aHR: 

adjusted hazard ratio

HR: 

hazard ratio

MAFLD: 

metabolic dysfunction-associated fatty liver disease

NAFLD: 

non-alcoholic fatty liver disease

NASH: 

non-alcoholic steatohepatitis

OR: 

odds ratio

RAAS: 

renin–angiotensin–aldosterone system

Declarations

Acknowledgement

The authors are sincerely grateful to all the paper supervisors.

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Drafting of the manuscript (ZT), critical revision of the manuscript for important intellectual content (YL, BC, TZ, and YG), and final approval of the version to be published (YG).

References

  1. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006;43(2 Suppl 1):S99-s112 View Article PubMed/NCBI
  2. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51(5):1820-1832 View Article PubMed/NCBI
  3. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55(6):2005-2023 View Article PubMed/NCBI
  4. Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2011;33(5):525-540 View Article PubMed/NCBI
  5. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article PubMed/NCBI
  6. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10(11):686-690 View Article PubMed/NCBI
  7. Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 2016;64(5):1577-1586 View Article PubMed/NCBI
  8. Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014;63(5):713-735 View Article PubMed/NCBI
  9. Marcuccilli M, Chonchol M. NAFLD and chronic kidney disease. Int J Mol Sci 2016;17(4):562 View Article PubMed/NCBI
  10. Glassock RJ, Warnock DG, Delanaye P. The global burden of chronic kidney disease: estimates, variability and pitfalls. Nat Rev Nephrol 2017;13(2):104-114 View Article PubMed/NCBI
  11. Targher G, Chonchol MB, Byrne CD. CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 2014;64(4):638-652 View Article PubMed/NCBI
  12. Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014;59(3):1174-1197 View Article PubMed/NCBI
  13. Mikolasevic I, Racki S, Bubic I, Jelic I, Stimac D, Orlic L. Chronic kidney disease and nonalcoholic Fatty liver disease proven by transient elastography. Kidney Blood Press Res 2013;37(4-5):305-310 View Article PubMed/NCBI
  14. Xu HW, Hsu YC, Chang CH, Wei KL, Lin CL. High FIB-4 index as an independent risk factor of prevalent chronic kidney disease in patients with nonalcoholic fatty liver disease. Hepatol Int 2016;10(2):340-346 View Article PubMed/NCBI
  15. Targher G, Mantovani A, Pichiri I, Mingolla L, Cavalieri V, Mantovani W, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care 2014;37(6):1729-1736 View Article PubMed/NCBI
  16. Sirota JC, McFann K, Targher G, Chonchol M, Jalal DI. Association between nonalcoholic liver disease and chronic kidney disease: an ultrasound analysis from NHANES 1988-1994. Am J Nephrol 2012;36(5):466-471 View Article PubMed/NCBI
  17. Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link?. J Hepatol 2011;54(5):1020-1029 View Article PubMed/NCBI
  18. Targher G, Bertolini L, Rodella S, Zoppini G, Lippi G, Day C, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51(3):444-450 View Article PubMed/NCBI
  19. Targher G, Bertolini L, Chonchol M, Rodella S, Zoppini G, Lippi G, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 2010;53(7):1341-1348 View Article PubMed/NCBI
  20. Targher G, Pichiri I, Zoppini G, Trombetta M, Bonora E. Increased prevalence of chronic kidney disease in patients with Type 1 diabetes and non-alcoholic fatty liver. Diabet Med 2012;29(2):220-226 View Article PubMed/NCBI
  21. Targher G, Bertolini L, Rodella S, Lippi G, Zoppini G, Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin J Am Soc Nephrol 2010;5(12):2166-2171 View Article PubMed/NCBI
  22. Ahn AL, Choi JK, Kim MN, Kim SA, Oh EJ, Kweon HJ, et al. Non-alcoholic fatty liver disease and chronic kidney disease in Koreans aged 50 years or older. Korean J Fam Med 2013;34(3):199-205 View Article PubMed/NCBI
  23. Zeng J, Sun C, Sun WL, Chen GY, Pan Q, Yan SY, et al. Association between non-invasively diagnosed hepatic steatosis and chronic kidney disease in Chinese adults on their health check-up. J Dig Dis 2017;18(4):229-236 View Article PubMed/NCBI
  24. Choudhary NS, Saraf N, Kumar N, Rai R, Saigal S, Gautam D, et al. Nonalcoholic fatty liver is not associated with incident chronic kidney disease: a large histology-based comparison with healthy individuals. Eur J Gastroenterol Hepatol 2016;28(4):441-443 View Article PubMed/NCBI
  25. Targher G, Chonchol M, Bertolini L, Rodella S, Zenari L, Lippi G, et al. Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. J Am Soc Nephrol 2008;19(8):1564-1570 View Article PubMed/NCBI
  26. Zou ZY, Fan JG. Incidence of chronic kidney disease in patients with non-alcoholic fatty liver disease. J Hepatol 2020;73(1):214-216 View Article PubMed/NCBI
  27. Wilechansky RM, Pedley A, Massaro JM, Hoffmann U, Benjamin EJ, Long MT. Relations of liver fat with prevalent and incident chronic kidney disease in the Framingham Heart Study: a secondary analysis. Liver Int 2019;39(8):1535-1544 View Article PubMed/NCBI
  28. Zhang M, Lin S, Wang MF, Huang JF, Liu SY, Wu SM, et al. Association between NAFLD and risk of prevalent chronic kidney disease: why there is a difference between east and west?. BMC Gastroenterol 2020;20(1):139 View Article PubMed/NCBI
  29. Sinn DH, Kang D, Jang HR, Gu S, Cho SJ, Paik SW, et al. Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: a cohort study. J Hepatol 2017;67(6):1274-1280 View Article PubMed/NCBI
  30. Park H, Dawwas GK, Liu X, Nguyen MH. Nonalcoholic fatty liver disease increases risk of incident advanced chronic kidney disease: a propensity-matched cohort study. J Intern Med 2019;286(6):711-722 View Article PubMed/NCBI
  31. Mantovani A, Zaza G, Byrne CD, Lonardo A, Zoppini G, Bonora E, et al. Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis. Metabolism 2018;79:64-76 View Article PubMed/NCBI
  32. Chen PC, Kao WY, Cheng YL, Wang YJ, Hou MC, Wu JC, et al. The correlation between fatty liver disease and chronic kidney disease. J Formos Med Assoc 2020;119(1 Pt 1):42-50 View Article PubMed/NCBI
  33. Jang HR, Kang D, Sinn DH, Gu S, Cho SJ, Lee JE, et al. Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: a cohort study. Sci Rep 2018;8(1):4718 View Article PubMed/NCBI
  34. Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014;11(7):e1001680 View Article PubMed/NCBI
  35. Kasim H, Zatalia SR, Rasyid H, Bakri S, Parewangi ML, Akil F, et al. Correlation between non-alcoholic fatty liver and chronic kidney disease. Open Urol Nephrol J 2020;13(1):1-4 View Article PubMed/NCBI
  36. Arase Y, Suzuki F, Kobayashi M, Suzuki Y, Kawamura Y, Matsumoto N, et al. The development of chronic kidney disease in Japanese patients with non-alcoholic fatty liver disease. Intern Med 2011;50(10):1081-1087 View Article PubMed/NCBI
  37. Luo K, Bian J, Wang Q, Wang J, Chen F, Li H, et al. Association of obesity with chronic kidney disease in elderly patients with nonalcoholic fatty liver disease. Turk J Gastroenterol 2019;30(7):611-615 View Article PubMed/NCBI
  38. Wijarnpreecha K, Thongprayoon C, Scribani M, Ungprasert P, Cheungpasitporn W. Noninvasive fibrosis markers and chronic kidney disease among adults with nonalcoholic fatty liver in USA. Eur J Gastroenterol Hepatol 2018;30(4):404-410 View Article PubMed/NCBI
  39. Sesti G, Fiorentino TV, Arturi F, Perticone M, Sciacqua A, Perticone F. Association between noninvasive fibrosis markers and chronic kidney disease among adults with nonalcoholic fatty liver disease. PLoS One 2014;9(2):e88569 View Article PubMed/NCBI
  40. Yasui K, Sumida Y, Mori Y, Mitsuyoshi H, Minami M, Itoh Y, et al. Nonalcoholic steatohepatitis and increased risk of chronic kidney disease. Metabolism 2011;60(5):735-739 View Article PubMed/NCBI
  41. Huh JH, Kim JY, Choi E, Kim JS, Chang Y, Sung KC. The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study. PLoS One 2017;12(7):e0180951 View Article PubMed/NCBI
  42. Chang Y, Ryu S, Sung E, Woo HY, Oh E, Cha K, et al. Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men. Metabolism 2008;57(4):569-576 View Article PubMed/NCBI
  43. Tsai YL, Liu CW, Huang SF, Yang YY, Lin MW, Huang CC, et al. Urinary fatty acid and retinol binding protein-4 predict CKD progression in severe NAFLD patients with hypertension: 4-year study with clinical and experimental approaches. Medicine (Baltimore) 2020;99(2):e18626 View Article PubMed/NCBI
  44. Sun DQ, Jin Y, Wang TY, Zheng KI, Rios RS, Zhang HY, et al. MAFLD and risk of CKD. Metabolism 2021;115:154433 View Article PubMed/NCBI
  45. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008;28(4):339-350 View Article PubMed/NCBI
  46. Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 2017;14(1):32-42 View Article PubMed/NCBI
  47. Mantovani A, Petracca G, Beatrice G, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut 2021;70(5):962-969 View Article PubMed/NCBI
  48. Chen TK, Knicely DH, Grams ME. Chronic kidney disease diagnosis and management: a review. JAMA 2019;322(13):1294-1304 View Article PubMed/NCBI
  49. Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. Multiple risk factor intervention trial. JAMA 1997;278(23):2069-2074 View Article PubMed/NCBI
  50. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24(7):908-922 View Article PubMed/NCBI
  51. Lorbeer R, Bayerl C, Auweter S, Rospleszcz S, Lieb W, Meisinger C, et al. Association between MRI-derived hepatic fat fraction and blood pressure in participants without history of cardiovascular disease. J Hypertens 2017;35(4):737-744 View Article PubMed/NCBI
  52. Ma J, Hwang SJ, Pedley A, Massaro JM, Hoffmann U, Chung RT, et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol 2017;66(2):390-397 View Article PubMed/NCBI
  53. Wu SJ, Zou H, Zhu GQ, Wang LR, Zhang Q, Shi KQ, et al. Increased levels of systolic blood pressure within the normal range are associated with significantly elevated risks of nonalcoholic fatty liver disease. Medicine (Baltimore) 2015;94(19):e842 View Article PubMed/NCBI
  54. Sun D, Wang J, Shao W, Wang J, Yao L, Li Z, et al. Pathogenesis and damage targets of hypertensive kidney injury. J Transl Int Med 2020;8(4):205-209 View Article PubMed/NCBI
  55. Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M. Hypertension and kidneys: unraveling complex molecular mechanisms underlying hypertensive renal damage. J Hum Hypertens 2014;28(2):74-79 View Article PubMed/NCBI
  56. Rossi GM, Regolisti G, Peyronel F, Fiaccadori E. Recent insights into sodium and potassium handling by the aldosterone-sensitive distal nephron: a review of the relevant physiology. J Nephrol 2020;33(3):431-445 View Article PubMed/NCBI
  57. Ku E, Lee BJ, Wei J, Weir MR. Hypertension in CKD: core curriculum 2019. Am J Kidney Dis 2019;74(1):120-131 View Article PubMed/NCBI
  58. Ramadhan Z, Rasyid H, Bakri S, Kasim H, Parewangi AL, Akil F, et al. MON-267 relationship between liver fibrosis and chronic kidney disease in non-alcoholic fatty liver disease subjects. Kidney Int Rep 2019;4(7):S408 View Article PubMed/NCBI
  59. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021;18(9):599-612 View Article PubMed/NCBI
  60. Nampoothiri RV, Duseja A, Rathi M, Agrawal S, Sachdeva N, Mehta M, et al. Renal dysfunction in patients with nonalcoholic fatty liver disease is related to the presence of diabetes mellitus and severity of liver disease. J Clin Exp Hepatol 2019;9(1):22-28 View Article PubMed/NCBI
  61. Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol 2020;73(2):263-276 View Article PubMed/NCBI
  62. Chon YE, Hwang SG, Kim MN, Park H, Lee JH, Ha Y, et al. Weight loss significantly reduces the risk of chronic kidney disease development in patients with non-alcoholic fatty liver disease. The International Liver Congress; 2019 Apr 10-Apr 14; Vienna, Austria. Elsevier; 2019. p. e292-e293. View Article PubMed/NCBI
  63. Chin JL, Pavlides M, Moolla A, Ryan JD. Non-invasive markers of liver fibrosis: adjuncts or alternatives to liver biopsy?. Front Pharmacol 2016;7:159 View Article PubMed/NCBI
  64. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149(2):389-397.e310 View Article PubMed/NCBI
  65. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44(4):865-873 View Article PubMed/NCBI
  66. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6:33 View Article PubMed/NCBI
  67. Luyckx FH, Desaive C, Thiry A, Dewé W, Scheen AJ, Gielen JE, et al. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998;22(3):222-226 View Article PubMed/NCBI
  68. Huttakan N, Chonlada P, Nattachai S, Sombat T. Urinary neutrophil gelatinase associated lipocalin (NGAL); a new biomarker for predicting chronic kidney disease (CKD) in patients with nonalcoholic fatty liver disease (NAFLD). 29th Annual Conference of Asian Pacific Association for the Study of the Liver; 2020 Mar 04-Mar 08; Bali, Indonesia. Elsevier; 2020. p. s334. View Article PubMed/NCBI
  69. Żyłka A, Dumnicka P, Kuśnierz-Cabala B, Gala-Błądzińska A, Ceranowicz P, Kucharz J, et al. Markers of glomerular and tubular damage in the early stage of kidney disease in type 2 diabetic patients. Mediators Inflamm 2018;2018:7659243 View Article PubMed/NCBI
  70. Milner KL, van der Poorten D, Xu A, Bugianesi E, Kench JG, Lam KS, et al. Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease. Hepatology 2009;49(6):1926-1934 View Article PubMed/NCBI
  71. Terra X, Auguet T, Broch M, Sabench F, Hernández M, Pastor RM, et al. Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women. Obesity (Silver Spring, Md) 2013;21(1):170-177 View Article PubMed/NCBI
  72. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340(2):115-126 View Article PubMed/NCBI
  73. Cottone S, Mulè G, Nardi E, Vadalà A, Lorito MC, Guarneri M, et al. C-reactive protein and intercellular adhesion molecule-1 are stronger predictors of oxidant stress than blood pressure in established hypertension. J Hypertens 2007;25(2):423-428 View Article PubMed/NCBI
  74. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40(12):1461-1465 View Article PubMed/NCBI
  75. Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017;49(6):842-847 View Article PubMed/NCBI
  76. Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018;378(12):1096-1106 View Article PubMed/NCBI
  77. Kim CH, Kallman JB, Bai C, Pawloski L, Gewa C, Arsalla A, et al. Nutritional assessments of patients with non-alcoholic fatty liver disease. Obes Surg 2010;20(2):154-160 View Article PubMed/NCBI
  78. McCarthy EM, Rinella ME. The role of diet and nutrient composition in nonalcoholic Fatty liver disease. J Acad Nutr Diet 2012;112(3):401-409 View Article PubMed/NCBI
  79. Keating SE, George J, Johnson NA. The benefits of exercise for patients with non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2015;9(10):1247-1250 View Article PubMed/NCBI
  80. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382(9888):260-272 View Article PubMed/NCBI
  81. Stanifer JW, Kilonzo K, Wang D, Su G, Mao W, Zhang L, et al. Traditional medicines and kidney disease in low- and middle-income countries: opportunities and challenges. Semin Nephrol 2017;37(3):245-259 View Article PubMed/NCBI
  82. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One 2016;11(7):e0158765 View Article PubMed/NCBI
  83. Orlić L, Mikolasevic I, Bagic Z, Racki S, Stimac D, Milic S. Chronic kidney disease and nonalcoholic Fatty liver disease-is there a link?. Gastroenterol Res Pract 2014;2014:847539 View Article PubMed/NCBI
  84. Kronenberg F. Emerging risk factors and markers of chronic kidney disease progression. Nat Rev Nephrol 2009;5(12):677-689 View Article PubMed/NCBI
  85. Nagy J, Kovács T. A brief review on the rising incidence of chronic kidney diseases and non-alcoholic fatty liver disease. Physiol Int 2019;106(4):305-310 View Article PubMed/NCBI
  86. Willy JA, Young SK, Stevens JL, Masuoka HC, Wek RC. CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of nonalcoholic steatohepatitis. Mol Biol Cell 2015;26(12):2190-2204 View Article PubMed/NCBI
  87. Ix JH, Sharma K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol 2010;21(3):406-412 View Article PubMed/NCBI
  88. Massy ZA, Stenvinkel P, Drueke TB. The role of oxidative stress in chronic kidney disease. Semin Dial 2009;22(4):405-408 View Article PubMed/NCBI
  89. Anders HJ, Jayne DR, Rovin BH. Hurdles to the introduction of new therapies for immune-mediated kidney diseases. Nat Rev Nephrol 2016;12(4):205-216 View Article PubMed/NCBI
  90. Musso G, Cassader M, Cohney S, Pinach S, Saba F, Gambino R. Emerging liver-kidney interactions in nonalcoholic fatty liver disease. Trends Mol Med 2015;21(10):645-662 View Article PubMed/NCBI
  91. de Vries AP, Ruggenenti P, Ruan XZ, Praga M, Cruzado JM, Bajema IM, et al. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol 2014;2(5):417-426 View Article PubMed/NCBI
  92. Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science (New York, NY) 2008;322(5907):1539-1543 View Article PubMed/NCBI
  93. Auberger P, Falquerho L, Contreres JO, Pages G, Le Cam G, Rossi B, et al. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 1989;58(4):631-640 View Article PubMed/NCBI
  94. Spoto B, Pisano A, Zoccali C. Insulin resistance in chronic kidney disease: a systematic review. Am J Physiol Renal Physiol 2016;311(6):F1087-f1108 View Article PubMed/NCBI
  95. Targher G, Byrne CD. Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease. Nat Rev Nephrol 2017;13(5):297-310 View Article PubMed/NCBI
  96. Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Fetuin-A and kidney function in persons with coronary artery disease—data from the Heart and Soul Study. Nephrol Dial Transplant 2006;21(8):2144-2151 View Article PubMed/NCBI
  97. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015;62(1 Suppl):S47-64 View Article PubMed/NCBI
  98. Gyebi L, Soltani Z, Reisin E. Lipid nephrotoxicity: new concept for an old disease. Curr Hypertens Rep 2012;14(2):177-181 View Article PubMed/NCBI
  99. Scorletti E, Byrne CD. Extrahepatic diseases and NAFLD: the triangular relationship between NAFLD, type 2-diabetes and dysbiosis. Dig Dis 2016;34(Suppl 1):11-18 View Article PubMed/NCBI
  100. Cummings JH. Fermentation in the human large intestine: evidence and implications for health. Lancet (London, England) 1983;1(8335):1206-1209 View Article PubMed/NCBI
  101. Passmore IJ, Letertre MPM, Preston MD, Bianconi I, Harrison MA, Nasher F, et al. Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria. PLoS Pathog 2018;14(9):e1007191 View Article PubMed/NCBI
  102. Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res 2017;179:24-37 View Article PubMed/NCBI
  103. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472(7341):57-63 View Article PubMed/NCBI
  104. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 2015;116(3):448-455 View Article PubMed/NCBI
  105. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet (London, England) 2015;385(9972):956-965 View Article PubMed/NCBI
  106. Hara E. Relationship between obesity, gut microbiome and hepatocellular carcinoma development. Dig Dis 2015;33(3):346-350 View Article PubMed/NCBI
  107. Bashiardes S, Shapiro H, Rozin S, Shibolet O, Elinav E. Non-alcoholic fatty liver and the gut microbiota. Mol Metab 2016;5(9):782-794 View Article PubMed/NCBI
  108. Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 2015;39(3):424-429 View Article PubMed/NCBI