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Arab Journal of Gastroenterology 13 (2012) 161–165

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Arab Journal of Gastroenterology

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Review

Relationship between non-alcoholic fatty liver disease and kidney function: A communication between two organs that needs further exploration

Asma A. Hamad a, Atif A. Khalil b, Vincent Connolly a, Mohamed H. Ahmed a,⇑ a Division of Acute Medicine, The James Cook University Hospital, Middlesbourgh, UK b Department of Nephrology, Royal Liverpool University Hospital, Liverpool, UK

a r t i c l e i n f o

Article history: Received 28 March 2012 Accepted 21 June 2012

Keywords: Fatty liver Kidney disease Insulin resistance

1687-1979/$ - see front matter � 2012 Arab Journal o http://dx.doi.org/10.1016/j.ajg.2012.06.010

⇑ Corresponding author. Tel.: +44 1642853938; fax E-mail address: [email protected] (M.H. Ahmed)

a b s t r a c t

Non-alcoholic fatty liver disease (NAFLD) is now regarded as hepatic component of the metabolic syn- drome. In addition, NAFLD has emerged as a growing public health problem worldwide and an important challenge for health authorities. NAFLD is associated with insulin resistance and hyperlipidaemia and this appears as the potential pathogenic role of NAFLD in the development and progression of chronic kidney disease (CKD). Interestingly, NAFLD and CKD may share common pathogenic mechanisms like obesity, abdominal obesity, insulin resistance, hyperlipidaemia, hypertension and inflammation. Importantly, the association between NAFLD and CKD is also being shown to be independent of obesity, hypertension, and other potentially confounding features of the metabolic syndrome, and it occurs both in patients without diabetes and in those with diabetes. How the liver communicates with kidney in individuals with NAFLD is not well known and indeed an urgent research is needed to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. One potential pathway for future exploration may be inflammatory mediators in NAFLD that may lead to deterioration in renal function. In addition, large clin- ical studies are needed to study the impact of NAFLD on the progression of CKD and in particular during dialysis and transplant and importantly how treatment of NAFLD and weight loss will have reversible potential benefit in improving renal function.

� 2012 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction

The prevalence of chronic kidney disease worldwide is esti- mated to increase significantly by year 2015. Over 1.1 million pa- tients are estimated to have End Stage Renal Disease (ESRD) worldwide, with an addition of 7% annually [1]. Therefore, the search for causes of CKD has attracted more research. The possible link between non-alcoholic fatty liver disease (NAFLD) and kidney disease is subject for considerable research interest.

NAFLD is emerging as an important public health problem across the globe with an estimated prevalence of 20–30% in Wes- tern communities and 90% in morbidly obese [2,3]. Nonalcoholic steatohepatitis (NASH), the more severe form of NAFLD is much less common at 2–3% prevalence [4]. NAFLD refers to a wide spec- trum of liver damage, ranging from simple steatosis to steatohep- atitis, advanced fibrosis, and cirrhosis. NAFLD is strongly associated with insulin resistance and is defined by accumulation of liver fat >5% per liver weight, in the presence of <10 g of daily alcohol con- sumption [5]. The characteristic histology of NAFLD resembles that of alcohol-induced liver injury, but occurs in people who consume

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minimal amounts of alcohol. NAFLD is regarded as the most com- mon cause of increased liver enzymes and is associated with met- abolic syndrome, obesity, type 2 diabetes and hyperlipidaemia [6]. The increase in prevalence of obesity is also associated with an in- crease in prevalence of NAFLD and type 2 diabetes. The most com- mon causes of fatty liver disease are attributable to alcohol excess; however, as obesity and type 2 diabetes are increasing in preva- lence it is likely that there will be a marked increase in numbers of individuals with NAFLD [6]. The importance of early diagnosis of NAFLD is the risk that it may progress silently to cirrhosis, portal hypertension, and liver-related death in early adulthood, in the ab- sence of successful orthotopic/living donor liver transplant. In addition, NAFLD is also associated with an increased risk of all- cause mortality and predicts future CVD events [7]. Hence, there is an urgent need for sensitive and specific biochemical markers for NAFLD as serial measurements of alanine aminotransferase (ALT) can be misleading and cannot accurately predict the severity or outcome [8]. Interestingly, different studies have shown that NAFLD is associated with an increase in incidence of CVD [9,10] and considerable numbers of studies show an increase in the inci- dence of CVD with CKD [11].

The subsequent discussion will focus on the association of NAFLD with CKD, insulin resistance and hyperlipidaemia and how ultimately this may lead to deterioration in renal function.

sevier B.V. All rights reserved.

162 A.A. Hamad et al. / Arab Journal of Gastroenterology 13 (2012) 161–165

NAFLD and kidney diseases

Several studies showed that NAFLD is associated with signifi- cant decrease in glomerular filtration rate (GFR), albuminuria and an increase in incidence of CKD. Yasui et al. showed that in a cross sectional study of 174 patients with liver biopsy-proven NAFLD, chronic kidney disease was present in 24 (14%) of 174 NAFLD pa- tients. The prevalence of CKD was significantly higher in NASH pa- tients than non-NASH patients. The presence of CKD was associated with a higher body mass index and the presence of hypertension and NASH. Their conclusion is that a higher preva- lence of CKD is present in NASH patients [12]. Furthermore, Cata- lano et al. showed that in 323 patients with NAFLD that the increase in liver brightness, abdominal obesity, triglyceride and body mass index are associated with marked decrease in GFR [13]. Arase et al. conducted a retrospective study in 5561 patients with NAFLD to assess the cumulative development incidence and predictive factors for new onset of CKD in Japanese patients with NAFLD. The mean observation period was 5.5 years and among these 5561 patients, only 263 patients developed CKD. The cumu- lative development rate of CKD was 3.1% at the 5th year and 12.2% at the 10th year. Multivariate Cox proportional hazards analysis showed that CKD development in patients with NAFLD occurred when patient had low level of GFR of 60–75 ml/min/1.73 m(2) [hazard ratio: 2.75; 95% confidence interval (CI) = 1.93–3.94; p < 0.001], age of P50 years (hazard ratio: 2.67; 95% CI = 2.06– 3.46; p < 0.001), diabetes (hazard ratio: 1.92; 95% CI = 1.45–2.54; p < 0.001), hypertension (hazard ratio: 1.69; 95% CI = 1.25–2.29; p < 0.001), and elevated serum gamma-glutamyltransferase of P109 IU/L (hazard ratio: 1.35; 95% CI = 1.02–1.78; p = 0.038). Their conclusion is that the annual incidence of CKD in Japanese patients with NAFLD is about 1.2% and aging, type 2 diabetes, hypertension, and elevated gamma-glutamyltransferase, increase the risk of the development of CKD [14]. Interestingly, a marked association be- tween NAFLD and deterioration in renal function was noted in indi- viduals with diabetes. Targher et al. showed that the age- and sex- adjusted prevalence of diabetic retinopathy (53.2 vs 19.8%) and CKD (37.8 vs 9.9%) was markedly higher in patients with ultra- sound-diagnosed NAFLD than in those without (p < 0.0001). In multivariate logistic regression analysis, NAFLD was associated with prevalent retinopathy (adjusted OR 3.31, 95% CI 1.4–7.6, p = 0.005) or CKD (adjusted OR 3.90, 95% CI 1.5–10.1, p = 0.005). Importantly, these associations were independent of age, sex, dia- betes duration, HbA1c, medication use and presence of the meta- bolic syndrome. These findings suggest that NAFLD is associated with a higher prevalence of CKD in an individual with diabetes [15]. Furthermore, in morbid obese patients with NASH it is asso- ciated with mild decreases in GFR, suggesting a common inflam- matory link between the liver and renal lesion [16]. In contrast, children with NAFLD are noted not to have that marked deteriora- tion in renal function as in adult population. Manco et al. reported insignificant changes in renal function in children with biopsy-pro- ven NAFLD. Accordingly, it is likely that the longer the duration of NAFLD the more pronounced adverse effect inflicted in renal func- tion [17]. Targher showed that in 80 patients with biopsy-proven NASH they have moderately decreased eGFR and a higher fre- quency of abnormal albuminuria and CKD. The severity of NASH histology is associated with decreased kidney function, indepen- dent of traditional risk factors, insulin resistance, and components of the metabolic syndrome [18]suggesting that there is a commu- nication between the liver and kidney in individuals with NAFLD. Importantly, it is estimated that insulin resistance is present in 90% of individuals with NAFLD [19]. Therefore the subsequent dis- cussion will focus on association between CKD and insulin resis- tance, hyperlipideamia, inflammation and metabolic syndrome.

Insulin resistance and kidney disease

Insulin resistance has been shown to be extensively linked to an increased incidence of CKD. The Cardiovascular Health Study in- cluded 4680 adults without baseline diabetes. Mean age was 72.5 years (range, 65–98 years). Mean eGFR was 72.2 (SD 17.1) ml/min per 1.73 m2. After adjustment, each 10 ml/min per 1.73 m2 eGFR decline was associated with a 2.2% increment in fast- ing insulin concentration (95% confidence interval [CI], 1.4%, 2.9%; p < 0.001) and a 1.1% reduction in insulin sensitivity index (95% CI, 0.03%, 2.2%; p = 0.04). During a 12 years’ follow-up, 437 participants (9.3%) developed diabetes. Data from this study showed that lower eGFR was associated with insulin resistance [20]. Furthermore, in a prospective cohort study in total of 1456 Asians individuals (65 years or older) who were followed for an average of 3.15 years; the adjusted odds ratio for prevalent CKD in association with meta- bolic syndrome was 1.778 (95% confidence interval, 1.188–2.465), the hazard ratio for rapid decline in renal function was 1.042 (0.802–1.355), and the hazard ratio for incident CKD was 1.931 (1.175–3.174). With each one-unit increment of insulin resistance, the odds ratio of prevalent CKD and proteinuria were raised 1.312-fold (1.114–1.545) and 1.278-fold (1.098–1.488), respec- tively. Increment of insulin resistance per unit was associated with 1.16-fold (1.06–1.26) elevation in the hazard ratios of the decline in renal function. Therefore it is possible to conclude that insulin resis- tance is associated with decline in renal function [21]. Interestingly, administration of vitamin D is shown to decrease insulin resistance in CKD patients. For instance, administration of activated vitamin D to non-diabetic CKD patients, is associated with significant improvement in insulin resistance especially in obese patients. The authors concluded that both vitamin D and BMI were indepen- dent predictors of fasting insulin [22]. While systemic inflammation is associated with an increase in insulin resistance in CKD patients [23]. In the Health, Aging and Body Composition study (of the 2418 individuals without reported diabetes at baseline), a study in older individuals aged 70–79 years, 15.6% had CKD. Individuals with insulin resistance had a lower eGFR (80.7 ± 20.9 versus 75.6 ± 19.6, p < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 ml/min/1.73 m(2) 0.92, 95% confidence interval 0.87–0.98) and CKD (1.41, 1.04–1.92) remained independently associated with insulin resistance. In individuals with and without CKD, the signifi- cant predictors of insulin resistance were male sex, black race, high- er visceral fat, abdominal subcutaneous fat and triglycerides (similar risk factors for NAFLD). In individuals without CKD, insulin resistance was associated with lower high-density lipoprotein. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with insulin resistance. In the fully ad- justed model, there was a trend for an interaction with adiponectin for eGFR (p = 0.08) and significant for CKD (p = 0.04), where adipo- nectin was associated with insulin resistance in those without CKD but not in those with CKD [24]. Therefore, the current evidence suggests that adiponectin is mediating insulin resistance in individ- uals without CKD but more evidence is needed to establish the role of adiponectin in insulin resistance in individuals with CKD. The ex- act causes of insulin resistance are not known but it was thought that vitamin D deficiency, obesity, metabolic acidosis, inflamma- tion, and accumulation of ‘‘uremic toxins’’ are believed to contribute to the development of insulin resistance and the acquired defects in the insulin-receptor signalling pathway in CKD population [25]. Importantly, insulin resistance is a significant risk factor for the deterioration of renal function in hypertensive non-diabetic pa- tients with CKD [26]. Insulin resistance is reported to occur in 95% of individuals with NAFLD and further research is needed to estab- lish the role of insulin resistance in increasing the incidence of CKD in individuals with NAFLD [27].

A.A. Hamad et al. / Arab Journal of Gastroenterology 13 (2012) 161–165 163

Metabolic syndrome and kidney disease

A joint interim statement from the International Diabetes Fed- eration Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; the American Heart Association; the World Heart Federation; the International Atherosclerosis Soci- ety; and the International Association for the Study of Obesity has revised the criteria used to define the metabolic syndrome. In this new definition, waist circumference is now one of the five criteria that physicians can use when diagnosing the metabolic syndrome (defined according to population and country-specific cut off points). The presence of any three features of increased glucose, decreased HDL-c, increased triglyceride, increased blood pressure and increased waist circumference is needed to identify the pres- ence of the syndrome [28]. It is not yet clear whether the deterio- ration in renal function associated with metabolic syndrome is due to the metabolic syndrome or the presence of clusters of metabolic syndrome (as each of these risk factors can lead to renal dysfunc- tion). For instance, we have shown the evidence that insulin resis- tance is associated with deterioration in renal function. In addition, obesity may increase the risk of renal dysfunction development probably through mechanisms associated with renal hyperfiltra- tion, hyperperfusion and focal glomerulosclerosis (Obesity-related glomerulopathy) [29]. Bai et al. have shown that metabolic syn- drome and abdominal obesity and fasting glucose are associated with endothelial dysfunction in 161 patients with CKD [30]. Raz- eghi et al. have shown that insulin resistance, hypertriglycerida- emia and hypertension are more prevalent in CKD prediabetic than non-diabetic CKD patients [31]. In a cross sectional study of 574 non-diabetic individuals, the CKD prevalence was higher and mean eGFR was lower in individuals who met the metabolic syn- drome criteria compared with those who did not, there was no sig- nificant relationship between insulin resistance and eGFR and among all the components of the metabolic syndrome, only

NAFLD

Fig. 1. Schematic figure illustrating the possible association of NAFLD with CKD and m confounding factors of metabolic syndrome features.

hypertension was significantly associated with CKD prevalence [odds ratio (95% confidence interval), 3.5 (1.2–10.1), p = 0.02] [32].

The association between CKD and metabolic syndrome has shown different association in different populations. For instance, a study from West African region showed higher prevalence of CKD among individuals with metabolic syndrome [33]. While in African-American population high blood pressure, impaired glu- cose tolerance and greater body mass index are associated with CKD in individuals with metabolic syndrome [34]. The prevalence of metabolic syndrome and CKD in Korean population was 19.0% and 7.2% respectively and those with metabolic syndrome had a higher prevalence of CKD (11.0% vs 6.3%, p < 0.001) than those without metabolic syndrome. Interestingly, in this Korean study the increase in the number of metabolic components was associ- ated with higher prevalence of CKD and marked decrease in eGFR [35]. While in Taiwanese population, high triglyceride, blood pres- sure and central obesity are associated with CKD in individuals with metabolic syndrome [36]. In a study from Thailand, abdominal obesity, high triglycerides, high blood pressure and impaired fast- ing glucose were significantly associated with an increased preva- lence of CKD among individuals with metabolic syndrome [37].

In a cross sectional study in the Veneto region in Italy which en- rolled 3,757 subjects participating in the INCIPE survey (Initiative on Nephropathy, of relevance to Public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points). Metabolic syndrome is associated with CKD (OR 2.17; p < 0.001) and albuminuria (OR 2.28; p < 0.001) and CVD (OR 1.58; p = 0.002). There is a direct correlation between the number of metabolic syndrome traits and nephropathy and CVD. CVD and nephropathies are associated even after adjustment for metabolic syndrome (OR 2.30; p < 0.001). The conclusion of authors is that in a homogeneous Caucasian European population, metabolic syndrome is associated with CKD and albuminuria, and CVD [38]. In a meta-analysis by Thomas et al. which included

echanisms involved. NAFLD per se can be associated with CKD in the absence of

164 A.A. Hamad et al. / Arab Journal of Gastroenterology 13 (2012) 161–165

eleven studies (n = 30,146), the metabolic syndrome was signifi- cantly associated with the development of eGFR <60 ml/min per 1.73 m(2) (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of metabolic syndrome increased (trend p value = 0.02). In patients with Metabolic syndrome, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m2 for individual components of met- abolic syndrome were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fast- ing glucose 1.14 (1.03, 1.26). In addition three studies reported an increased risk for development of microalbuminuria or overt pro- teinuria with metabolic syndrome [39].

Hyperlipidaemia and kidney disease

Hyperlipidaemia is one of the features of NAFLD and also con- tribute to the development of insulin resistance [40]. Importantly, hyperlipidaemia is also one of the challenging features to treat in individuals with CKD [41]. Prominent features of dyslipidaemia in mild and moderate CKD patients are elevated triglycerides (TG) and lipoprotein (a) Lp (a), lowered high-density lipoprotein cholesterol (HDL-c), with normal (or low) total cholesterol (TC), and normal (or low) low-density lipoprotein cholesterol (LDL-c) [42].

High triglyceride level is noted as an early feature in CKD and this may occur even when serum creatinine is within the normal range. Postprandial hyperlipideamia can be induced in these patients after fatty meal [43]. Interestingly, it has been shown in experimental studies there is an increase in chyliomicron remanant and triglycer- ide rich lipoprotein (VLDL) with marked decrease in their catabo- lism in CKD. The possible mechanism for hyperlipideamia in CKD was attributed to the decrease in the catabolism of lipids due to the toxic effect of uraemia, in addition to development of insulin resistance in CKD [44]. Furthermore, secondary hyperparathyroid- ism may in part contribute to hyper tri-glyceridaemia [45]. Despite the fact that the LDL-c may be low or normal, this was shown to be a small dense atherogenic particle that contributes to atherosclerosis [46]. Experimental and epidemiological studies showed that CKD was associated with low HDL-c. This is of significance as HDL-c par- ticles have antiatherogenic effect (reverse transport of cholesterol, antioxidative, anti-inflammatory and antithrombotic).

Conclusion

NAFLD is associated with insulin resistance and hyperlipida- emia. The epidemic of obesity and type 2 diabetes will likely lead to epidemic across the globe with NAFLD. Accumulative body of evidence has shown an increase in the incidence of CKD in individ- uals with NAFLD. It is possible to suggest that with an increase in the epidemic of NAFLD this may represent a potential for an in- crease in the incidence of CKD. The exact mechanism of NAFLD in- duced CKD is not known. Potential mechanisms are insulin resistance, hyperlipidaemia, obesity, abdominal obesity, hyperten- sion and inflammation (Fig. 1). Inflammation associated with NAFLD may represent an early stage for the communication be- tween the liver and the kidney. Further research is urgently needed to establish (i) the prognostic significance of NAFLD for the inci- dence of CKD, (ii) and to further elucidate the complex and inter- twined mechanisms that link NAFLD and CKD (iii) and prospective studies to assess the potential adverse impact of NAFLD on kidney disease progression.

Conflicts of interest

The authors declared that there was no conflict of interest.

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