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NAFLD as a driver of chronic kidney disease

  • Christopher D. Byrne
    Correspondence
    Corresponding authors. Addresses: Nutrition and Metabolism, Faculty of Medicine. University of Southampton, Southampton SO16 6YD, UK
    Affiliations
    Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK

    Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, UK
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  • Giovanni Targher
    Correspondence
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
    Affiliations
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Published:February 11, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.013

      Summary

      Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are worldwide public health problems, affecting up to 25–30% (NAFLD), and up to 10–15% (CKD) of the general population. Recently, it has also been established that there is a strong association between NAFLD and CKD, regardless of the presence of potential confounding diseases such as obesity, hypertension and type 2 diabetes. Since NAFLD and CKD are both common diseases that often occur alongside other metabolic conditions, such as type 2 diabetes or metabolic syndrome, elucidating the relative impact of NAFLD on the risk of incident CKD presents a substantial challenge for investigators working in this research field. A growing body of epidemiological evidence suggests that NAFLD is an independent risk factor for CKD and recent evidence also suggests that associated factors such as metabolic syndrome, dysbiosis, unhealthy diets, platelet activation and processes associated with ageing could also contribute mechanisms linking NAFLD and CKD. This narrative review provides an overview of the literature on: a) the evidence for an association and causal link between NAFLD and CKD and b) the underlying mechanisms by which NAFLD (and factors strongly linked with NAFLD) may increase the risk of developing CKD.

      Keywords

      Linked Article

      • Incidence of chronic kidney disease in patients with non-alcoholic fatty liver disease
        Journal of HepatologyVol. 73Issue 1
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          We read with great interest the article by Byrne et al. who summarized recent advances in the association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), and reported that the prevalence rate of CKD in patients with NAFLD ranged from 20% to 55%.1 Given a high cardiovascular disease-specific mortality among NAFLD populations (4.79 per 1,000 person-years, 95% CI 3.43–6.70), NAFLD-related cardiovascular events have filtered into people's minds.2 By contrast, although CKD is another closely related extrahepatic disease, the burden of CKD, especially the incidence of CKD, has not been systematically described and quantitatively assessed in patients with NAFLD, with and without diabetes mellitus.
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      Introduction

      Readers of the Journal will be very familiar with non-alcoholic fatty liver disease (NAFLD) and how to define it, but will perhaps be less familiar with chronic kidney disease (CKD) and its definition.
      Both diseases are progressive chronic conditions that represent a spectrum of diseases extending from relatively mild disease, with only modest changes in function, to severe debilitating disease with end-stage organ damage, necessitating either chronic dialysis or organ transplantation in order to sustain life. NAFLD encompasses a histopathological spectrum of metabolic liver conditions encapsulating simple steatosis alone (non-alcoholic fatty liver, i.e. NAFL); steatosis, inflammation and ballooning of hepatocytes, with or without liver fibrosis (non-alcoholic steatohepatitis, i.e. NASH), and cirrhosis.
      • Bellentani S.
      The epidemiology of non-alcoholic fatty liver disease.
      ,
      • Younossi Z.M.
      • Marchesini G.
      • Pinto-Cortez H.
      • Petta S.
      Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: implications for liver transplantation.
      When advanced fibrosis or cirrhosis occur, the risk of hepatocellular carcinoma also increases markedly.
      CKD is a complex, progressive chronic condition that is defined by either abnormalities of kidney structure or function present for ≥3 months, with serious implications for health.
      • Group KDIGOKCW
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      ,
      • Akbari A.
      • Clase C.M.
      • Acott P.
      • Battistella M.
      • Bello A.
      • Feltmate P.
      • et al.
      Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management.
      Either markers of kidney damage or decreased glomerular filtration rate may be present.
      The National Kidney Foundation has identified 5 stages of CKD from 1 to 5 (as shown in Fig. 1).
      • Levey A.S.
      • Coresh J.
      • Balk E.
      • Kausz A.T.
      • Levin A.
      • Steffes M.W.
      • et al.
      National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
      In the presence of a urinary albumin-to-creatinine ratio (ACR) that is normal or very mildly increased (i.e. urinary ACR <30 mg/g) and an estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73 m2, the risk of progression to end-stage renal disease is very low and such patients usually do not undergo regular surveillance. Clinicians should therefore identify CKD stage 3 or above, because these stages of CKD are associated with a high or very high risk of disease progression. To define CKD stage ≥3, markers of kidney damage can include the presence of one of: abnormal albuminuria (ACR ≥30 mg/g) or overt proteinuria, urine sediment abnormalities and other abnormalities due to tubular disorders, abnormalities detected by kidney histology, structural abnormalities detected by imaging, or a history of renal transplantation. For decreased eGFR, CKD is defined by an eGFR value <60 ml/min/1.73 m2.
      • Group KDIGOKCW
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      ,
      • Akbari A.
      • Clase C.M.
      • Acott P.
      • Battistella M.
      • Bello A.
      • Feltmate P.
      • et al.
      Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management.
      Figure thumbnail gr1
      Fig. 1Risk factors in patients with NAFLD and CKD.
      The stages of CKD are also reported in the figure. CKD is defined as either kidney damage or eGFR <60 ml/min/1.73 m2 for at least 3 months or more. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or in imaging methods. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NAFLD, non-alcoholic fatty liver disease.
      NAFLD and CKD are associated with poor outcomes and high costs; they have become major public health problems owing to their increasing prevalence and incidence. Indeed, NAFLD affects up to ~25–30%
      • Bellentani S.
      The epidemiology of non-alcoholic fatty liver disease.
      ,
      • Coresh J.
      • Selvin E.
      • Stevens L.A.
      • Manzi J.
      • Kusek J.W.
      • Eggers P.
      • et al.
      Prevalence of chronic kidney disease in the United States.
      and CKD affects up to ~10–15% of the general adult population in many parts of the world.
      • Couser W.G.
      • Remuzzi G.
      • Mendis S.
      • Tonelli M.
      The contribution of chronic kidney disease to the global burden of major noncommunicable diseases.
      ,
      • Eckardt K.U.
      • Coresh J.
      • Devuyst O.
      • Johnson R.J.
      • Kottgen A.
      • Levey A.S.
      • et al.
      Evolving importance of kidney disease: from subspecialty to global health burden.
      It is well established that CKD is also a major risk factor for cardiovascular disease (CVD) and all stages of CKD are associated with an increased risk of cardiovascular morbidity, premature mortality and decreased quality of life.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O'Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease - a systematic review and meta-analysis.
      Recently, it has also been shown that NAFLD is an independent risk factor for CVD, regardless of the coexistence of cardiometabolic risk factors, such as obesity, hypertension, type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS).
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      ,
      • Wild S.H.
      • Walker J.J.
      • Morling J.R.
      • McAllister D.A.
      • Colhoun H.M.
      • Farran B.
      • et al.
      Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission.
      Therefore, since NAFLD and CKD often occur with features of the MetS that adversely affect the kidney, elucidating the relative impact of NAFLD on the risk of incident CKD presents a substantial challenge to investigators working in this field of research.
      Both NAFLD and CKD are major public health problems whose prevalence and incidence is growing.
      The main aims of this narrative review are to discuss: a) the evidence for an association and causal link between NAFLD and CKD and b) the putative mechanisms by which NAFLD (and factors strongly linked with NAFLD) may increase the risk of developing CKD.

      Evidence of an association between NAFLD and CKD

      Since patients with NAFLD exhibit multiple traditional and non-traditional risk factors for CKD (as summarised in Fig. 1),
      EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
      • Lonardo A.
      • Bellentani S.
      • Argo C.K.
      • Ballestri S.
      • Byrne C.D.
      • Caldwell S.H.
      • et al.
      Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • Hardy T.
      • Henry L.
      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      • Kendrick J.
      • Chonchol M.B.
      Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease.
      • Kronenberg F.
      Emerging risk factors and markers of chronic kidney disease progression.
      • Targher G.
      • Chonchol M.
      • Miele L.
      • Zoppini G.
      • Pichiri I.
      • Muggeo M.
      Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.
      • Targher G.
      • Byrne C.D.
      Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications.
      it is not surprising that these patients also have a higher prevalence and incidence of CKD compared with those who do not have steatosis.

      Cross-sectional studies

      Several hospital-based and community-based studies have documented that NAFLD, as assessed by imaging techniques or liver biopsy, is significantly associated with an increased prevalence of CKD (defined as eGFR <60 ml/min/1.73 m2, abnormal albuminuria or overt proteinuria).
      • 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.
      • 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.
      • Hwang S.T.
      • Cho Y.K.
      • Yun J.W.
      • Park J.H.
      • Kim H.J.
      • Park D.I.
      • et al.
      Impact of non-alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes.
      • Sirota J.C.
      • McFann K.
      • Targher G.
      • Chonchol M.
      • Jalal D.I.
      Association between nonalcoholic liver disease and chronic kidney disease: an ultrasound analysis from NHANES 1988-1994.
      • Ahn A.L.
      • Choi J.K.
      • Kim M.N.
      • Kim S.A.
      • Oh E.J.
      • Kweon H.J.
      • et al.
      Non-alcoholic fatty liver disease and chronic kidney disease in Koreans aged 50 years or older.
      • Park C.W.
      • Tsai N.T.
      • Wong L.L.
      Implications of worse renal dysfunction and medical comorbidities in patients with NASH undergoing liver transplant evaluation: impact on MELD and more.
      • Pan L.L.
      • Zhang H.J.
      • Huang Z.F.
      • Sun Q.
      • Chen Z.
      • Li Z.B.
      • et al.
      Intrahepatic triglyceride content is independently associated with chronic kidney disease in obese adults: a cross-sectional study.
      • Pacifico L.
      • Bonci E.
      • Andreoli G.M.
      • Di Martino M.
      • Gallozzi A.
      • De Luca E.
      • et al.
      The impact of nonalcoholic fatty liver disease on renal function in children with overweight/obesity.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • Lippi G.
      • Zoppini G.
      • Chonchol M.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      • Yilmaz Y.
      • Alahdab Y.O.
      • Yonal O.
      • Kurt R.
      • Kedrah A.E.
      • Celikel C.A.
      • et al.
      Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis.
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • Mitsuyoshi H.
      • Minami M.
      • Itoh Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      • Machado M.V.
      • Goncalves S.
      • Carepa F.
      • Coutinho J.
      • Costa A.
      • Cortez-Pinto H.
      Impaired renal function in morbid obese patients with nonalcoholic fatty liver disease.
      As reviewed extensively elsewhere,
      • Targher G.
      • Chonchol M.B.
      • Byrne C.D.
      CKD and nonalcoholic fatty liver disease.
      in these studies the prevalence of CKD ranged from approximately 20% to 55% among patients with NAFLD compared to 5% to 30% among their counterparts without NAFLD. Notably, in most of these studies the significant association between NAFLD and increased prevalence of CKD persisted, both in patients with T2DM and in those without diabetes, even after adjustment for common risk factors for CKD. Some smaller case-control studies using liver biopsy to diagnose NAFLD have also shown a significant, graded association between the histologic severity of NAFLD (mainly the hepatic fibrosis stage) and the presence of either decreased eGFR or abnormal albuminuria.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • Lippi G.
      • Zoppini G.
      • Chonchol M.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      • Yilmaz Y.
      • Alahdab Y.O.
      • Yonal O.
      • Kurt R.
      • Kedrah A.E.
      • Celikel C.A.
      • et al.
      Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis.
      • Yasui K.
      • Sumida Y.
      • Mori Y.
      • Mitsuyoshi H.
      • Minami M.
      • Itoh Y.
      • et al.
      Nonalcoholic steatohepatitis and increased risk of chronic kidney disease.
      • Machado M.V.
      • Goncalves S.
      • Carepa F.
      • Coutinho J.
      • Costa A.
      • Cortez-Pinto H.
      Impaired renal function in morbid obese patients with nonalcoholic fatty liver disease.
      For example, in a previous case-control study,
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • Lippi G.
      • Zoppini G.
      • Chonchol M.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      we found that patients with biopsy-confirmed NASH had a higher prevalence of both CKD and abnormal albuminuria than age-, sex- and body mass index (BMI)-matched controls, and that the histologic stage of liver fibrosis was associated with decreasing eGFR values, independently of age, sex, adiposity measures, hypertension, plasma triglyceride concentrations and homeostatic model assessment (HOMA)-estimated insulin resistance (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Renal function parameters in patients with NASH and controls.
      (A) The prevalence of both CKD (defined as eGFR <60 ml/min/1.73 m2 and/or abnormal albuminuria) and abnormal albuminuria (i.e. urinary albumin-to-creatinine ratio ≥30 mg/g) in 80 patients with biopsy-proven NASH and 80 non-steatotic control individuals who were matched for age, sex and body mass index. (B) The adjusted means (±SD) of eGFR values in patients with NASH according to the histologic stage of hepatic fibrosis. Data have been adjusted for age, sex, measures of adiposity (body mass index and waist circumference), hypertension, plasma triglyceride levels, and HOMA-estimated insulin resistance. Data are from.
      • Targher G.
      • Bertolini L.
      • Rodella S.
      • Lippi G.
      • Zoppini G.
      • Chonchol M.
      Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.
      Reproduced with permission. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HOMA, homeostatic model assessment; NASH, non-alcoholic steatohepatitis.

      Cohort studies

      Although the current evidence, from cross-sectional studies, for the existence of an association between NAFLD and increased prevalence of CKD is robust and consistent across different ethnicities and patient populations, whether NAFLD is also a “driving force” for the development and progression of CKD remains uncertain.
      • Marcuccilli M.
      • Chonchol M.
      NAFLD and chronic kidney disease.
      ,
      • Adams L.A.
      • Anstee Q.M.
      • Tilg H.
      • Targher G.
      Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases.
      However, to date, an ever-increasing number of retrospective and prospective cohort studies, with a reasonably long duration of follow-up, have consistently documented that NAFLD (diagnosed either by abnormal levels of serum liver enzymes or by imaging techniques) is significantly associated with an increased incidence of CKD
      • Ryu S.
      • Chang Y.
      • Kim D.I.
      • Kim W.S.
      • Suh B.S.
      gamma-Glutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men.
      • Chang Y.
      • Ryu S.
      • Sung E.
      • Woo H.Y.
      • Oh E.
      • Cha K.
      • et al.
      Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men.
      • 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.
      • 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.
      • 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.
      • Huh J.H.
      • Kim J.Y.
      • Choi E.
      • Kim J.S.
      • Chang Y.
      • Sung K.C.
      The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study.
      • Shen Z.W.
      • Xing J.
      • Wang Q.L.
      • Faheem A.
      • Ji X.
      • Li J.
      • et al.
      Association between serum gamma-glutamyltransferase and chronic kidney disease in urban Han Chinese: a prospective cohort study.
      • Kunutsor S.K.
      • Laukkanen J.A.
      Gamma-glutamyltransferase and risk of chronic kidney disease: a prospective cohort study.
      • Sinn D.H.
      • Kang D.
      • Jang H.R.
      • Gu S.
      • Cho S.J.
      • Paik S.W.
      • et al.
      Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: a cohort study.
      • Jang H.R.
      • Kang D.
      • Sinn D.H.
      • Gu S.
      • Cho S.J.
      • Lee J.E.
      • et al.
      Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: a cohort study.
      • Wilechansky R.M.
      • Pedley A.
      • Massaro J.M.
      • Hoffmann U.
      • Benjamin E.J.
      • Long M.T.
      Relations of liver fat with prevalent and incident chronic kidney disease in the Framingham heart study: a secondary analysis.
      • Onnerhag K.
      • Hartman H.
      • Nilsson P.M.
      • Lindgren S.
      Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD).
      • Park H.
      • Dawwas G.K.
      • Liu X.
      • Nguyen M.H.
      Nonalcoholic fatty liver disease increases risk of incident advanced chronic kidney disease: a propensity-matched cohort study.
      (Table 1). Notably, in most of these studies the significant association between NAFLD and increased incidence of CKD persisted even after adjustment for age, sex, obesity, hypertension, T2DM and other potential confounding factors. For example, in the Valpolicella Heart Diabetes Study, including 1,760 outpatients with T2DM who had preserved kidney function at baseline, the presence of NAFLD on ultrasonography was associated with a nearly 50% increase in the risk of incident CKD (adjusted hazard ratio 1.49; 95% CI 1.1–2.2) over a follow-up period of 6.5 years, independent of age, sex, adiposity measures, blood pressure, smoking, duration of diabetes, haemoglobin A1c, plasma lipids, baseline eGFR, microalbuminuria, and the use of hypoglycaemic, lipid-lowering, antihypertensive or antiplatelet drugs.
      • 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.
      Similar results have been also found in adults with type 1 diabetes and in other large community-based cohort studies of different ethnicities (Table 1).
      Table 1Principal observational cohort studies examining the association between NAFLD and risk of development or progression of CKD stage ≥3 (ordered by publication year).
      Authors, Country, Year (Ref.)Study design and populationDiagnosis of NAFLDDiagnosis of CKD and number of incident CKD casesCovariate adjustmentsMain results
      Ryu S et al., South Korea, 2007
      • Ryu S.
      • Chang Y.
      • Kim D.I.
      • Kim W.S.
      • Suh B.S.
      gamma-Glutamyltransferase as a predictor of chronic kidney disease in nonhypertensive and nondiabetic Korean men.
      Community-based cohort study: 10,337 non-diabetic and non-hypertensive male workers with normal kidney function and no overt proteinuria at baseline. Follow-up: 3 yearsSerum liver enzymes (serum GGT concentrations)eGFR <60 ml/min/1.73 m2 and/or overt proteinuria (urinary dipstick ≥1); 366 patients developed incident CKD during follow-upAge, BMI, alcohol intake, smoking, baseline eGFR, triglycerides, HDL-cholesterol, C-reactive protein, HOMA-IR, and incident cases of hypertension and diabetesNAFLD (i.e. top quartile of serum GGT concentrations) was independently associated with increased risk of incident CKD (aHR 1.87; 95% CI 1.31-2.67)
      Chang Y et al., South Korea, 2008
      • Chang Y.
      • Ryu S.
      • Sung E.
      • Woo H.Y.
      • Oh E.
      • Cha K.
      • et al.
      Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men.
      Community-based cohort study: 8,329 nondiabetic and non-hypertensive men with normal kidney function and no overt proteinuria at baseline. Follow-up: 3.2 yearsUltrasonography; the prevalence of NAFLD was 30.2%eGFR <60 ml/min/1.73 m2 and/or overt proteinuria (by urinary dipstick); 324 patients developed incident CKD during follow-upAge, BMI, alcohol intake, hypertension, smoking, fasting glucose, baseline eGFR, triglycerides, HDL-cholesterol, LDL-cholesterol, HOMA-IR, C-reactive protein, incident cases of hypertension and diabetesNAFLD was independently associated with increased risk of incident CKD (aHR 1.60; 95% CI 1.3-2.0)
      Targher G et al., Italy, 2008
      • 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.
      Prospective cohort study (Valpolicella Heart Diabetes Study): 1,760 type 2 diabetic outpatients with preserved kidney function and no overt proteinuria, free of CVD and known chronic liver diseases at baseline. Follow-up: 6.5 yearsUltrasonography; prevalence of NAFLD was 73.2%eGFR <60 ml/min/1.73 m2 and/or overt proteinuria; 547 patients developed incident CKD during follow-up (428 developed decreased eGFR alone, 112 developed proteinuria, irrespective of eGFR, and 7 developed kidney failure; no patients developed nephrotic syndrome)Age, sex, BMI, waist circumference, blood pressure, smoking, diabetes duration, haemoglobin A1c, plasma lipids, baseline eGFR, use of antihypertensive, lipid-lowering, antiplatelet or hypoglycaemic agentsNAFLD was independently associated with increased risk of incident CKD (aHR 1.49; 95% CI 1.1-2.2)
      Arase Y et al., Japan, 2011
      • 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.
      Retrospective cohort study: 5,561 middle-aged individuals with NAFLD and normal kidney function without overt proteinuria at baseline. Follow-up: 5.5 yearsUltrasonography and serum liver enzymes (serum GGT concentrations). Prevalence of NAFLD was 100%eGFR <60 ml/min/1.73 m2 and/or overt proteinuria (urinary dipstick); 263 patients developed incident CKD during follow-upAge, sex, hypertension, diabetes, total cholesterol, triglycerides, HDL-cholesterol, liver enzymes, haemoglobin, white blood cell count, platelet count, baseline eGFRAmong patients with NAFLD, elevated serum GGT concentrations were independently associated with an increased risk of incident CKD (aHR 1.35; 95% CI 1.02-1.8)
      Targher G et al., Italy, 2014
      • 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.
      Prospective cohort study: 261 type 1 diabetic adult outpatients with normal kidney function, free of CVD and known chronic liver diseases at baseline. Follow-up: 5.2 yearsUltrasonography; prevalence of NAFLD was 50.2%eGFR <60 ml/min/ 1.73 m2 and/or overt proteinuria; 61 patients developed incident CKD during follow-up (28 developed decreased eGFR with abnormal albuminuria, 21 developed reduced eGFR alone, and 12 developed macroalbuminuria alone; no patients developed kidney failure; no patients developed nephrotic syndrome)Age, sex, diabetes duration, haemoglobin A1c, hypertension, baseline eGFR, presence of microalbuminuriaNAFLD was independently associated with an increased risk of incident CKD (aHR 1.85; 95% CI 1.03-3.3). Measurement of NAFLD provided incremental risk reclassification beyond that of conventional CKD risk factors
      Huh JH et al., South Korea, 2017
      • Huh J.H.
      • Kim J.Y.
      • Choi E.
      • Kim J.S.
      • Chang Y.
      • Sung K.C.
      The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study.
      Prospective cohort study: 4,761 adults with normal kidney function and no overt proteinuria and free of CVD and known chronic liver diseases at baseline. Mean follow-up: 10 yearsFatty liver index (FLI); prevalence of NAFLD (defined as FLI ≥60) was 12.6%eGFR <60 ml/min/1.73 m2; 724 individuals developed incident CKD during follow-upAge, sex, smoking, diabetes status, physical exercise, alcohol intake, protein intake, systolic blood pressure, total cholesterol, C-reactive protein, baseline eGFRNAFLD (FLI ≥60) was independently associated with increased risk of incident CKD (aHR 1.46; 95% CI 1.19-1.79). FLI provided incremental risk reclassification beyond that of traditional renal risk factors
      Shen ZW et al., China, 2017
      • Shen Z.W.
      • Xing J.
      • Wang Q.L.
      • Faheem A.
      • Ji X.
      • Li J.
      • et al.
      Association between serum gamma-glutamyltransferase and chronic kidney disease in urban Han Chinese: a prospective cohort study.
      Prospective cohort study: 21,818 adults with normal kidney function and no overt proteinuria at baseline, who received routine health examination. Follow-up: 5 yearsSerum liver enzymes (serum GGT concentrations)eGFR <60 ml/min/1.73 m2 and/or overt proteinuria (urinary dipstick); 1,456 individuals developed incident CKD during follow-upAge, sex, BMI, alcohol intake, serum creatinine, albumin, alanine aminotransferase, haemoglobin, white blood count, triglycerides, total cholesterol, hypertension, smoking, history of CVD, history of diabetesNAFLD (i.e. top quartile of serum GGT levels) was independently associated with an increased risk of incident CKD (aHR 1.33, 95% CI 1.07-1.64)
      Kunutsor SK et al., Finland, 2017
      • Kunutsor S.K.
      • Laukkanen J.A.
      Gamma-glutamyltransferase and risk of chronic kidney disease: a prospective cohort study.
      Prospective cohort study (Kuopio Ischemic Heart Disease Study): 2,338 middle-aged men with normal kidney function at baseline. Median follow-up: 25.6 yearsSerum liver enzymes (serum GGT concentrations)eGFR <60 ml/min/1.73 m2; 221 individuals developed incident CKD during follow-upAge, BMI, systolic blood pressure, history of hypertension, smoking, history of coronary heart disease, diabetes, total cholesterol, HDL-cholesterol, alcohol intake, baseline eGFRNAFLD (i.e. top quartile of serum GGT concentrations) was not independently associated with increased risk of incident CKD (aHR 0.97, 95% CI 0.64-1.47)
      Sinn DH et al., South Korea, 2017
      • Sinn D.H.
      • Kang D.
      • Jang H.R.
      • Gu S.
      • Cho S.J.
      • Paik S.W.
      • et al.
      Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: a cohort study.
      Retrospective cohort study: 41,430 adults with normal kidney function and no overt proteinuria at baseline, free from known chronic liver diseases. Follow-up: 4.2 yearsUltrasonography; advanced NAFLD fibrosis assessed by the NFS (≥-1.455), FIB4 score (≥1.45) or APRI index (≥0.5); prevalence of NAFLD was 34.3%eGFR <60 ml/min/1.73 m2; 691 participants developed incident CKD during follow-upAge, sex, BMI, smoking, alcohol intake, systolic blood pressure, haemoglobin A1c, LDL-cholesterol, use of hypoglycaemic and lipid-lowering medications, baseline eGFR, time-varying development of diabetes and hypertension over the follow-upNAFLD was independently associated with increased risk of incident CKD (aHR 1.21, 95% CI 1.03-1.44). The association between NAFLD and CKD was consistent in all subgroups analysed. In addition, advanced NAFLD fibrosis (as detected by a NFS ≥-1.455) was associated with even a higher risk of incident CKD (aHR 1.59, 95% CI 1.31-1.93). When NAFLD participants were classified according to APRI index and FIB4 score, those with higher APRI index or FIB4 score also had an increasing risk of incident CKD
      Jang HR et al., South Korea, 2018
      • Jang H.R.
      • Kang D.
      • Sinn D.H.
      • Gu S.
      • Cho S.J.
      • Lee J.E.
      • et al.
      Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: a cohort study.
      Retrospective cohort study: 1,525 adults with CKD (baseline mean eGFR 59 ml/min/1.73 m2, 26% with overt proteinuria) free from known liver diseases, who underwent repeated health check-up examinations. Mean follow-up: 6.5 yearsUltrasonography; advanced NAFLD fibrosis assessed by the NFS (≥-1.455); prevalence of NAFLD was 40.9%Annual percent decline in eGFRAge, sex, year of visit, smoking, alcohol intake, BMI, hypertension, diabetes, dyslipidaemia, systolic blood pressure, haemoglobin A1c, LDL-cholesterol, triglyceridesNAFLD was independently associated with CKD progression. In multivariable-adjusted models, the average difference in annual percent change in eGFR decline comparing patients with NAFLD to those without NAFLD was −1.06% (−1.73%, −0.38%; p=0.002). The decline in eGFR associated with NAFLD was greater in patients with higher NFS, in those with proteinuria or with low eGFR (<45 ml/min/1.73 m2) at baseline
      Wilechansky RM et al., United States, 2019
      • Wilechansky R.M.
      • Pedley A.
      • Massaro J.M.
      • Hoffmann U.
      • Benjamin E.J.
      • Long M.T.
      Relations of liver fat with prevalent and incident chronic kidney disease in the Framingham heart study: a secondary analysis.
      Prospective cohort study (Framingham Heart Study): 688 adults with normal kidney function and abnormal albuminuria at baseline, free from known liver diseases. Median follow-up: 12.5 yearsMultidetector computed tomographyeGFR <60 ml/min/1.73 m2; microalbuminuria; number of incident CKD cases was not reportedAge, sex, BMI, smoking, drinks per week, systolic/diastolic blood pressure, use of antihypertensive medications, HDL, total cholesterol, regular aspirin use, diabetes and follow-up intervalLiver fat (measured by the average liver attenuation on CT) was significantly associated with incident microalbuminuria and CKD in age- and sex-adjusted models. These relationships were not significant in multivariable-adjusted models. However, there was a discrepancy between the timing of baseline kidney function measurements (1998-2001) and CT assessment of liver fat (2002-2005) of a median of 4.1 years
      Önnerhag K et al., Sweden, 2019
      • Onnerhag K.
      • Hartman H.
      • Nilsson P.M.
      • Lindgren S.
      Non-invasive fibrosis scoring systems can predict future metabolic complications and overall mortality in non-alcoholic fatty liver disease (NAFLD).
      Retrospective cohort study (identified from a computerised register in Malmö): 144 adult patients with biopsy-proven NAFLD. Mean follow-up: 18.8 yearsNon-invasive fibrosis scoring systems (i.e. FIB-4-index, NFS, APRI and BARD score)eGFR <60 ml/min/1.73 m2; 47 participants developed incident CKD during follow-upAge, sex, overweight/obesity, prior CVD, hypertension, liver fibrosis stageBoth the intermediate and high-risk category of NFS and FIB-4 scores were independently associated with increased risk of incident CKD
      Park H et al., United States, 2019
      • Park H.
      • Dawwas G.K.
      • Liu X.
      • Nguyen M.H.
      Nonalcoholic fatty liver disease increases risk of incident advanced chronic kidney disease: a propensity-matched cohort study.
      Retrospective propensity-matched cohort analysis of the Truven Health MarketScan Database (2006-2015): 262,619 newly diagnosed patients with NAFLD and 769,878 propensity (1:3)-matched non-NAFLD patients. Follow-up: 9 yearsInternational Classification of Diseases (ICD-9) codesCKD stages 3-5 identified by the ICD-9-CM codes; There were 5,766 new CKD cases in the NAFLD cohort and 8,655 new CKD cases in non-NAFLD cohortAge, sex, diabetes, hypertension, obesity, hyperlipidaemia, coronary artery disease, peripheral vascular disease, cerebrovascular disease, heart failure and chronic obstructive pulmonary disease, use of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers, mean number of outpatient visits and mean number of inpatient visits, cirrhosis, decompensated cirrhosis and hepatocellular carcinomaNAFLD was independently associated with increased risk of incident CKD (aHR 1.41, 95% CI 1.36-1.46). In the sensitivity analysis adjusting for time-varying covariates after NAFLD diagnosis, NAFLD persisted as a significant CKD risk factor (aHR 1.58, 95% CI 1.52-1.66)
      eGFR was estimated by using either the 4-variable Modification of Diet in Renal Disease (MDRD) study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) study equation (that was used by the last 9 studies reported in this table).
      aHR, adjusted hazard ratio; AST, aspartate aminotransferase; APRI, AST to platelet ratio index; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; FIB4, fibrosis-4 score; GGT, gamma-glutamyltransferase; HOMA-IR, homeostasis model assessment-insulin resistance; NFS, NAFLD fibrosis score.

      Systematic reviews and meta-analyses

      In a meta-analysis of 33 observational (20 cross-sectional and 13 longitudinal) studies published in 2014, Musso et al. examined the association between NAFLD and risk of prevalent and incident CKD (defined as eGFR <60 ml/min/1.73 m2, abnormal albuminuria or both).
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • 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.
      Meta-analysis of the data from 20 cross-sectional studies (involving nearly 30,000 individuals) showed that NAFLD was associated with a 2-fold increased prevalence of CKD (random-effects odds ratio 2.12, 95% CI 1.69–2.66). More interestingly, meta-analysis of data from the 13 longitudinal studies (involving a total of nearly 28,500 individuals) showed that NAFLD was associated with a nearly 80% increased risk of incident CKD (random-effects hazard ratio [HR] 1.79; 95% CI 1.65–1.95). Similarly, in a subgroup analysis of individual patient data from 5 small studies (involving a total of ~430 adults with biopsy-confirmed NAFLD with only 86 incident CKD cases), the authors also suggested that the presence of advanced hepatic fibrosis was associated with a higher prevalence (random-effects odds ratio 5.20; 95% CI 3.14–8.61) and incidence (random-effects HR 3.29; 95% CI 2.30–4.71) of CKD than either non-advanced fibrosis or simple steatosis, respectively.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • 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.
      In all of the aforementioned analyses, the presence and severity of NAFLD were associated with a higher prevalence and incidence of CKD even after adjustment for pre-existing T2DM and other common risk factors for CKD, such as age, ethnicity, BMI and smoking history.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • 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.
      Recently, we have also performed a comprehensive systematic review and meta-analysis that involved a total of 9 observational cohort studies (published up to August 2017) with aggregate data on ~96,500 middle-aged individuals (34.1% with NAFLD) of predominantly Asian descent and ~5,000 new cases of incident CKD (stage ≥3, defined as occurrence of eGFR <60 ml/min/1.73 m2, with or without accompanying proteinuria) over a median follow-up period of 5.2 years.
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • 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.
      No studies with biopsy-proven NAFLD were available for the analysis. As shown in Fig. 3, this updated meta-analysis confirmed that NAFLD (detected by serum liver enzymes, fatty liver index or ultrasonography) was associated with a nearly 40% increase in the long-term risk of incident CKD (random-effects HR 1.37; 95% CI 1.20–1.53; I2 = 33.5%), a risk that appeared to increase in parallel with the severity of NAFLD, as assessed by the NAFLD fibrosis score or other non-invasive markers of advanced fibrosis (n = 2 studies; random-effects HR 1.50; 95% CI 1.25–1.74; I2 = 0%), and remained significant in those studies where analysis was adjusted for common risk factors and potential confounders (i.e. age, sex, BMI, hypertension, smoking, diabetes, baseline eGFR and use of certain medications). In addition, as also shown in Fig. 3, when the analysis was stratified by the type of study population, the association between NAFLD and risk of incident CKD was essentially consistent for both patients with diabetes, and those without diabetes at baseline.
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • 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.
      In the few studies involving patients with T2DM, the association between NAFLD and risk of CKD remained significant even after adjusting for duration of diabetes, glycaemic control, hypertension and other established risk factors for CKD.
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • 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.
      In addition, when the analysis was stratified either by study country (Asian vs. European countries), the association between NAFLD and the risk of incident CKD appeared to be stronger in studies performed in Asian populations (n = 5 studies; random-effects HR 1.40; 95% CI 1.22–1.58; I2 = 36.5%) than in European populations (n = 3 studies; random-effects HR 1.29; 95% CI 0.82–1.76; I2 = 33.5%).
      Figure thumbnail gr3
      Fig. 3Risk of CKD in patients with NAFLD.
      Forest plot and pooled estimates of the effect of the presence of NAFLD on the risk of incident CKD (stage ≥3) in observational cohort studies, stratified either by (A) different non-invasive methodologies for the diagnosis of NAFLD, or by (B) study population (diabetes vs. no-diabetes). (C) The forest plot and pooled estimates of the effect of the severity of NAFLD (defined by either high-intermediate NAFLD fibrosis score [i.e. ≥-1.455] or increased serum gamma-glutamyltransferase levels [i.e. ≥109 U/L] in patients with ultrasound-detected NAFLD) on the risk of incident CKD (stage ≥3). Data are from.
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • 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.
      Reproduced with permission. CKD, chronic kidney disease; NAFLD, non-alcoholic fatty liver disease.
      Taken together, the findings of these 2 meta-analyses
      • Musso G.
      • Gambino R.
      • Tabibian J.H.
      • 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.
      ,
      • Mantovani A.
      • Zaza G.
      • Byrne C.D.
      • 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.
      clearly support the assertion that NAFLD identifies a group of individuals who are at increased risk of CKD, and who need more careful surveillance and treatment to reduce their risk of developing CKD. The results of these 2 meta-analyses also suggest that it is advanced NAFLD that carries a greater risk of incident CKD. This finding is in line with the results of a comprehensive meta-analysis supporting a strong link between the severity of NAFLD and increased risk of fatal and non-fatal cardiovascular outcomes.
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      However, this question remains largely unsolved, and further prospective studies in larger cohorts of both Asian and non-Asian patients with biopsy-confirmed NAFLD are needed, in order to definitively prove whether the severity of NAFLD adversely affects the risk of developing CKD. That said, we believe that the evidence from these 2 meta-analyses and other more recent follow-up studies published in 2018 and 2019 (as listed in Table 1) calls for a more active and systematic search for CKD in patients with NAFLD with a view to implementing earlier and more aggressive treatment whenever indicated, and also suggests that there is a need to include renal outcomes (such as temporal changes in eGFR and albuminuria or CKD development) in future randomised controlled trials focussed on testing the efficacy and safety of novel treatments for NAFLD or NASH.
      In line with these observations, Vilar-Gomez et al. found that the histologic resolution of NASH and improvement in liver fibrosis stage were independently associated with an increase in eGFR values in a post hoc analysis of a published clinical trial that included 261 patients with biopsy-confirmed NASH, who were treated with lifestyle modifications during a period of 52 weeks.
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Friedman S.L.
      • Gra-Oramas B.
      • Gonzalez-Fabian L.
      • Villa-Jimenez O.
      • et al.
      Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis.
      Recently, Önnerhag et al. examined the risk of overall mortality in patients with biopsy-proven NAFLD with the aim of investigating whether any increase in all-cause mortality was due to the presence of CKD.
      • Onnerhag K.
      • Dreja K.
      • Nilsson P.M.
      • Lindgren S.
      Increased mortality in non-alcoholic fatty liver disease with chronic kidney disease is explained by metabolic comorbidities.
      The authors measured eGFR values both at baseline and at the end of follow-up in a cohort of 120 middle-aged Swedish patients with biopsy-proven NAFLD, who were followed for a mean period of 19.5 years. The authors found that although patients with NAFLD and CKD had a significantly higher crude overall mortality rate than patients with NAFLD without CKD, the increased mortality risk was more strongly explained by an increased prevalence of metabolic comorbidities (including T2DM) rather than CKD.
      A number of observational studies have provided robust evidence of the association between NAFLD and CKD and the relevance of their coexistence on clinical outcomes.

      Study limitations

      It should be noted that the observational design of the available studies (Table 1) does not allow us to establish a causal association between NAFLD and risk of CKD stage ≥3, and that it is currently uncertain whether NASH or NAFLD with advanced fibrosis carry a higher risk of incident CKD than simple steatosis. Most of the available studies used ultrasonography, which is the recommended first-line imaging method for detecting NAFLD in clinical practice. No studies used liver biopsy, which is considered the ‘gold standard’ for diagnosing and staging NAFLD. Moreover, as shown in Table 1, the published cohort studies employed varying degrees of baseline adjustments for risk factors of CKD. In particular, almost all studies adjusted their results for BMI, but only a few of these studies additionally adjusted their results for body fat distribution, which plays a key role in the pathogenesis of NAFLD and CKD. An accurate assessment of abdominal visceral fat accumulation would be particularly important to better understand whether the association between CKD and NAFLD is affected by this metabolic risk factor. Other limitations include the use of the Modification of Diet in Renal Disease or the CKD-Epidemiology Collaboration study equations to calculate eGFR, neither of which are reliable in the presence of severe obesity or cirrhosis.
      • Levey A.S.
      • Inker L.A.
      Assessment of glomerular filtration rate in health and disease: a state of the art review.
      Furthermore, most of the available cohort studies have been conducted in Asian countries, where large populations undergo regular health check-up programmes, including liver ultrasonography. Since Asian and non-Asian populations have different genetic/cultural backgrounds, dietary factors and adipose tissue distributions, we believe that additional studies should be conducted in non-Asian populations. Another potential limitation is that no large prospective studies are available that have examined the rates of CKD progression to kidney failure (stage 5 CKD) in cohorts of patients with NAFLD, nor in cohorts of patients with advanced CKD. Finally, none of these studies have used renal biopsy to examine the specific renal pathology associated with NAFLD. So, it is currently uncertain if NAFLD is associated with a specific type of kidney disease, although we suggest that it is reasonable to assume that NAFLD may promote kidney injury, mostly through accelerated atherothrombosis.
      Nevertheless, it is important to consider that in a recent analysis of the Third National Health and Nutrition Survey database that included a total of ~11,700 Americans, Paik et al. showed that amongst patients with ultrasound-detected NAFLD, the presence of moderate to advanced stages of CKD was independently associated with increased all-cause mortality over a mean follow-up period of 19 years.
      • Paik J.
      • Golabi P.
      • Younoszai Z.
      • Mishra A.
      • Trimble G.
      • Younossi Z.M.
      Chronic kidney disease is independently associated with increased mortality in patients with nonalcoholic fatty liver disease.
      These findings point out that identification of CKD in patients with NAFLD has important prognostic implications. As also suggested by the authors, these data should inform clinicians and policy makers to identify those at the highest risk of adverse outcomes so that appropriate management strategies can be implemented.

      Putative mechanisms linking NAFLD with CKD

      T2DM and metabolic syndrome

      Although not conclusive, as discussed above, the current epidemiological evidence suggests that NAFLD is an independent risk factor for CKD and that the presence of NAFLD and associated features of the MetS
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force On Epidemiology And Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      may be causally involved, at least in part, in the development and progression of CKD.
      More than one-third of patients with NAFLD have impaired renal function and impaired renal function in patients with NAFLD is also associated with the severity of liver disease and presence of T2DM.
      • Nampoothiri R.V.
      • 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.
      ,
      • Chen P.C.
      • Kao W.Y.
      • Cheng Y.L.
      • Wang Y.J.
      • Hou M.C.
      • Wu J.C.
      • et al.
      The correlation between fatty liver disease and chronic kidney disease.
      When common diseases co-exist and share common risk factors, it can be difficult to disentangle causal relationships and understand the role of potential confounders. T2DM or MetS could be examples of confounding conditions linking NAFLD and CKD. In centrally obese individuals with T2DM, insulin resistance frequently occurs alongside other cardiometabolic risk factors that increase the risk of both NAFLD and CKD. The clustering of cardiometabolic risk factors that occur with visceral obesity and insulin resistance are encapsulated within the features of MetS, such as atherogenic dyslipidaemia, increased blood pressure and dysglycaemia.
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force On Epidemiology And Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      As mentioned in the Introduction, CKD stage ≥3 is defined by either abnormal albuminuria or decreased eGFR values. Whereas abnormal albuminuria (or overt proteinuria) is strongly associated with microvascular damage in renal glomeruli in diabetes and is a classical microvascular complication of diabetes, decreased eGFR values are more strongly associated with macrovascular damage. Macrovascular disease is strongly associated with CVD risk factors that occur alongside MetS, such as hypertension and atherogenic dyslipidaemia, as well as other risk factors not related to MetS, such as increased low-density lipoprotein-cholesterol concentrations. Thus, the clustering of cardiometabolic risk factors, occurring in patients with NAFLD and commonly referred to as the MetS, has the potential to cause both microvascular and macrovascular damage, giving rise to CKD.
      CKD also commonly occurs alongside the MetS.
      • Prasad G.V.
      Metabolic syndrome and chronic kidney disease: current status and future directions.
      ,
      • Thomas G.
      • Sehgal A.R.
      • Kashyap S.R.
      • Srinivas T.R.
      • Kirwan J.P.
      • Navaneethan S.D.
      Metabolic syndrome and kidney disease: a systematic review and meta-analysis.
      Consequently, it can be very difficult to disentangle the differential effects of insulin resistance, visceral obesity and the linked macrovascular and microvascular risk factors on the kidneys, from the consequences of liver disease per se. That said, this may be a moot point, given the close inter-relationships of insulin resistance, visceral adiposity and other MetS features with liver disease in NAFLD. Given that all these MetS risk factors are closely inter-related in NAFLD, even in the presence of known genetic modifiers of NAFLD severity, such as the common genetic variants in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2),
      • Anstee Q.M.
      • Seth D.
      • Day C.P.
      Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease.
      ,
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      it may be an arcane point to try and dissect out the relative contributions of individual NAFLD-associated hepatic or cardiometabolic risk factors on kidney function. In fact, since these risk factors cluster tightly together and NAFLD may also promote the development of these cardiometabolic risk factors,
      • Lonardo A.
      • Nascimbeni F.
      • Mantovani A.
      • Targher G.
      Hypertension, diabetes, atherosclerosis and NASH: cause or consequence?.
      we reason that it is perhaps more appropriate to refer to NAFLD as a metabolic liver disease with cardiovascular and metabolic risk factors; many of which have the potential to cause kidney dysfunction.
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      Whether liver fibrosis in NAFLD is associated with an even greater risk of extrahepatic complications than simple steatosis or NASH is uncertain. Since NASH can only be satisfactorily diagnosed by examination of liver histology, and there are far too few cohort studies that have utilised vibration-controlled transient elastography, or validated non-invasive liver fibrosis biomarkers to diagnose liver fibrosis,
      • Byrne C.D.
      • Patel J.
      • Scorletti E.
      • Targher G.
      Tests for diagnosing and monitoring non-alcoholic fatty liver disease in adults.
      ,
      • Jennison E.
      • Patel J.
      • Scorletti E.
      • Byrne C.D.
      Diagnosis and management of non-alcoholic fatty liver disease.
      the answer to this question remains unresolved. We have previously attempted to address the question of whether liver fibrosis with NAFLD further increases the risk of either incident CVD or incident T2DM. Although these data suggest that liver fibrosis is associated with a further increase in the risk of incident CVD events
      • Targher G.
      • Byrne C.D.
      • Lonardo A.
      • Zoppini G.
      • Barbui C.
      Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.
      compared to steatosis alone; liver fibrosis did not seem to further increase the risk of incident T2DM compared to the risk increase associated with liver steatosis alone.
      • Mantovani A.
      • Byrne C.D.
      • Bonora E.
      • Targher G.
      Nonalcoholic fatty liver disease and risk of incident type 2 diabetes mellitus: a meta-analysis.
      As mentioned, visceral obesity is a classical feature of the MetS. Many potential mechanisms by which accumulation of visceral fat causes chronic inflammation are well described
      • Engin A.
      The pathogenesis of obesity-associated adipose tissue inflammation.
      • Stolarczyk E.
      Adipose tissue inflammation in obesity: a metabolic or immune response?.
      • Reilly S.M.
      • Saltiel A.R.
      Adapting to obesity with adipose tissue inflammation.
      • Alexopoulos N.
      • Katritsis D.
      • Raggi P.
      Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis.
      and a detailed discussion of these is beyond the scope of this review. However, briefly, alongside increases in visceral obesity and ectopic fat accumulation, there is an increase in plasma concentrations of non-esterified fatty acids (NEFAs) and a failure to adequately suppress NEFA concentrations during hyperinsulinaemia.
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      • Holt H.B.
      • Wild S.H.
      • Wood P.J.
      • Zhang J.
      • Darekar A.A.
      • Dewbury K.
      • et al.
      Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects.
      • Byrne C.D.
      Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management.
      • Byrne C.D.
      • Targher G.
      Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease.
      With the increase in NEFA supply to the liver, a link has been proposed between NEFA overflow from the expanded and dysfunctional visceral adipose tissue and activation of hepatic macrophages that is independent of BMI.
      • Rosso C.
      • Kazankov K.
      • Younes R.
      • Esmaili S.
      • Marietti M.
      • Sacco M.
      • et al.
      Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease.
      Activation of hepatic macrophages and hepatic inflammation is associated with an increase in proinflammatory cytokines
      • Shoelson S.E.
      • Herrero L.
      • Naaz A.
      Obesity, inflammation, and insulin resistance.
      and hepatic/systemic insulin resistance,
      • Pawlak M.
      • Lefebvre P.
      • Staels B.
      Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
      ,
      • Cai D.
      • Yuan M.
      • Frantz D.F.
      • Melendez P.A.
      • Hansen L.
      • Lee J.
      • et al.
      Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
      increased activity of the renin-angiotensin-aldosterone system
      • Targher G.
      • Byrne C.D.
      Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease.
      and oxidative stress mediated by proinflammatory and profibrotic mediators.
      • Siragy H.M.
      • Carey R.M.
      Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease.
      The liver-kidney crosstalk in NAFLD also includes the role of the energy sensor 5'-AMP-activated protein kinase (AMPK) and its regulation of fetuin-A and adiponectin. In the liver and kidney, AMPK is pivotal to directing hepatocytes and renal podocytes to compensatory and potentially deleterious pathways, leading to inflammatory and profibrotic cascades culminating in end-organ damage.
      • Ix J.H.
      • Sharma K.
      Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK.
      Collectively, NAFLD and CKD share common proinflammatory and profibrotic mechanisms of disease progression.
      • Musso G.
      • De Michieli F.
      • Bongiovanni D.
      • Parente R.
      • Framarin L.
      • Leone N.
      • et al.
      New pharmacologic agents that target inflammation and fibrosis in nonalcoholic steatohepatitis-related kidney disease.
      ,
      • Musso G.
      • Cassader M.
      • Cohney S.
      • De Michieli F.
      • Pinach S.
      • Saba F.
      • et al.
      Fatty liver and chronic kidney disease: novel mechanistic insights and therapeutic opportunities.
      Experimental evidence also supports a role of the inflammasome and innate immune system in CKD.
      • Marcuccilli M.
      • Chonchol M.
      NAFLD and chronic kidney disease.
      ,
      • Li L.
      • Tang W.
      • Yi F.
      Role of inflammasome in chronic kidney disease.
      Therefore, all of these factors and pathways could indicate a causal link between NAFLD and CKD, whereby NAFLD increases the risk of incident CKD.
      Not only are many traditional risk factors shared between NAFLD, CKD and T2DM/MetS, but it has now become clear that newer and emerging risk factors are also frequently present with each of these conditions. These newer risk factors include perturbation of the intestinal microbiota (dysbiosis) with associated inflammation, intestinal dysfunction and platelet activation, The role of these newer risk factors in NAFLD and CKD will be discussed in the following sections.
      Newer risk factors that may link NAFLD and CKD are emerging, including dysbiosis, intestinal dysfunction and platelet activation.

      Dysbiosis and perturbed intestinal function affecting NAFLD and CKD

      Emerging experimental evidence suggests a role of the intestinal microbiota in the pathogenesis of both CKD
      • Marcuccilli M.
      • Chonchol M.
      NAFLD and chronic kidney disease.
      ,
      • Briskey D.
      • Tucker P.
      • Johnson D.W.
      • Coombes J.S.
      The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development.
      and NAFLD.
      • Wieland A.
      • Frank D.N.
      • Harnke B.
      • Bambha K.
      Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease.
      • Mouzaki M.
      • Comelli E.M.
      • Arendt B.M.
      • Bonengel J.
      • Fung S.K.
      • Fischer S.E.
      • et al.
      Intestinal microbiota in patients with nonalcoholic fatty liver disease.
      • Zhu L.
      • Baker S.S.
      • Gill C.
      • Liu W.
      • Alkhouri R.
      • Baker R.D.
      • et al.
      Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.
      • Jiang W.
      • Wu N.
      • Wang X.
      • Chi Y.
      • Zhang Y.
      • Qiu X.
      • et al.
      Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.
      Fig. 4 shows mechanisms and factors potentially linking intestinal dysbiosis, visceral adipose tissue dysfunction, NAFLD and CKD. With perturbation of the gut microbiota (dysbiosis), there is an increase in gram negative organisms, lipopolysaccharide, gut permeability, secondary bile acids (BAs) and renal toxins that may increase the risk of development and progression of both NAFLD
      • Scorletti E.
      • Byrne C.D.
      Extrahepatic diseases and NAFLD: the triangular relationship between NAFLD, type 2-diabetes and dysbiosis.
      ,
      • Kim H.N.
      • Joo E.J.
      • Cheong H.S.
      • Kim Y.
      • Kim H.L.
      • Shin H.
      • et al.
      Gut microbiota and risk of persistent nonalcoholic fatty liver diseases.
      and CKD.
      • Marcuccilli M.
      • Chonchol M.
      NAFLD and chronic kidney disease.
      ,
      • Wieland A.
      • Frank D.N.
      • Harnke B.
      • Bambha K.
      Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease.
      Intestinal microbiota-generated production of uraemic toxins (e.g., trimethylamine, cresol and indole)
      • Briskey D.
      • Tucker P.
      • Johnson D.W.
      • Coombes J.S.
      The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development.
      ,
      • Sabatino A.
      • Regolisti G.
      • Cosola C.
      • Gesualdo L.
      • Fiaccadori E.
      Intestinal microbiota in type 2 diabetes and chronic kidney disease.
      • Mahmoodpoor F.
      • Rahbar Saadat Y.
      • Barzegari A.
      • Ardalan M.
      • Zununi Vahed S.
      The impact of gut microbiota on kidney function and pathogenesis.
      • Evenepoel P.
      • Poesen R.
      • Meijers B.
      The gut-kidney axis.
      • Chung S.
      • Barnes J.L.
      • Astroth K.S.
      Gastrointestinal microbiota in patients with chronic kidney disease: a systematic review.
      has the potential to further damage renal, hepatic and cardiovascular function through inflammatory, oxidative and fibrotic pathways. The metabolism of the amino acids tyrosine and phenylalanine by a variety of obligate or facultative anaerobes, including the genera Bacteroides, Lactobacillus, Enterobacter, Bifidobacterium, and especially Clostridium difficile, results in the increased production of para-cresyl and the conjugate para-cresyl sulfate.
      • Cummings J.H.
      Fermentation in the human large intestine: evidence and implications for health.
      ,
      • Passmore I.J.
      • Letertre M.P.M.
      • Preston M.D.
      • Bianconi I.
      • Harrison M.A.
      • Nasher F.
      • et al.
      Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria.
      Escherichia coli has been shown to metabolise tryptophan, resulting in the production of indole that is metabolised in the liver to the uraemic toxin indoxyl sulfate.
      • Cummings J.H.
      Fermentation in the human large intestine: evidence and implications for health.
      ,
      • Passmore I.J.
      • Letertre M.P.M.
      • Preston M.D.
      • Bianconi I.
      • Harrison M.A.
      • Nasher F.
      • et al.
      Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria.
      A variety of other potentially nephrotoxic metabolites are also produced, such as ammonia, thiols and phenols.
      • Briskey D.
      • Tucker P.
      • Johnson D.W.
      • Coombes J.S.
      The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development.
      Figure thumbnail gr4
      Fig. 4Potential mechanisms and factors linking intestinal dysbiosis, visceral adipose tissue dysfunction, NAFLD and CKD.
      A calorie dense, fibre-poor diet is associated with changes in the intestinal microbiota (dysbiosis). With dysbiosis, production of incretins, fermentation of carbohydrate and metabolism of amino acids is affected, leading to changes in concentrations of SCFAs, LPS and the production of potentially hepatotoxic molecules such as ethanol and nephrotoxic molecules (i.e. hippuric acid, phenylacetic acid, TMA, cresol and indole). Some of these molecules (e.g. TMA) are oxidised, or conjugated (e.g., cresol and indole) within the liver, to potentially nephrotoxic compounds. Development and progression of liver disease occurs with visceral adipose tissue dysfunction. Hepatic de novo lipogenesis is stimulated by high levels of LCFAs and low levels of adiponectin from expanded and dysfunctional visceral adipose tissue, producing an excess of intrahepatic molecules, such as DAGs and ceramides that promote hepatic insulin resistance, necroinflammation (by Kupffer cell activation that enhances the production of multiple proinflammatory cytokines and hepatokines) with subsequent activation of hepatic stellate cells and increased production of collagen matrix and progression of liver disease. The inflammatory activation of hepatic stellate and Kupffer cells also results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer and natural killer T cells that are implicated in hepatic fibrogenesis. CKD, chronic kidney disease; CVD, cardiovascular disease; DAGs, diacylglycerols; eGFR, estimated glomerular filtration rate; LCFAs, long-chain fatty acids; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; SCFAs, short-chain fatty acids; PAI-1, plasminogen activator inhibitor 1; TMA, trimethylamine; TMAO, trimethylamine oxide; VLDL, very low-density lipoprotein.
      A complex interaction also exists between the gut microbiota and BA metabolism in NAFLD,
      • Kim H.N.
      • Joo E.J.
      • Cheong H.S.
      • Kim Y.
      • Kim H.L.
      • Shin H.
      • et al.
      Gut microbiota and risk of persistent nonalcoholic fatty liver diseases.
      wherein a diverse range of BAs can be detected in the plasma and have the potential to influence development and progression of the disease. Secondary BAs are generated from the 1–5% of primary BAs that are not re-absorbed in the jejunum. These BAs enter the ileum and colon and are modified by the gut microbiota hydrolases and dehydroxylases to create secondary BAs, such as deoxycholic acid and lithocholic acid. Further bacterial enzymes that include epimerases, oxidases and esterases, are capable of further modifying BAs before they are excreted in the stool. There is now evidence that the dynamic interaction existing between the microbiota and the BA pool can be modified by certain microbiota species to change the BA profile.
      • Martin G.
      • Kolida S.
      • Marchesi J.R.
      • Want E.
      • Sidaway J.E.
      • Swann J.R.
      In vitro modeling of bile acid processing by the human fecal microbiota.
      Specifically, NASH is associated with changes in the intestinal microbiota composition and metabolome, an intestinal and systemic inflammatory response, and BA profiles,
      • Brandl K.
      • Schnabl B.
      Intestinal microbiota and nonalcoholic steatohepatitis.
      and it has also been suggested that the composition of the gut microbiome associated with dysregulation of BA biosynthetic pathways may contribute to the persistence of NAFLD.
      • Kim H.N.
      • Joo E.J.
      • Cheong H.S.
      • Kim Y.
      • Kim H.L.
      • Shin H.
      • et al.
      Gut microbiota and risk of persistent nonalcoholic fatty liver diseases.
      Modification of the BA profile may be important in the treatment of NAFLD
      • Halilbasic E.
      • Fuchs C.
      • Traussnigg S.
      • Trauner M.
      Farnesoid X receptor agonists and other bile acid signaling strategies for treatment of liver disease.
      but mechanistic studies are required to elucidate causal links between intestinal dysbiosis, NAFLD and CKD.

      Dietary changes mediating a link between NAFLD, dysbiosis and CKD

      Increased consumption of sugar-sweetened beverages is linked with the development of NAFLD, hypertension, MetS and T2DM in both laboratory animals and humans
      • Hannou S.A.
      • Haslam D.E.
      • McKeown N.M.
      • Herman M.A.
      Fructose metabolism and metabolic disease.
      ,
      • Johnson R.J.
      • Perez-Pozo S.E.
      • Sautin Y.Y.
      • Manitius J.
      • Sanchez-Lozada L.G.
      • Feig D.I.
      • et al.
      Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?.
      although the association may be confounded by excess calorie intake or by unhealthy lifestyles. Today the most commonly consumed sugar is high fructose corn syrup. However, a causal role of excessive fructose consumption in the development of these metabolic diseases is still debated and the molecular mechanisms by which fructose elicits effects on dysregulated liver metabolism remain incompletely understood.
      • Hannou S.A.
      • Haslam D.E.
      • McKeown N.M.
      • Herman M.A.
      Fructose metabolism and metabolic disease.
      ,
      • Johnson R.J.
      • Perez-Pozo S.E.
      • Sautin Y.Y.
      • Manitius J.
      • Sanchez-Lozada L.G.
      • Feig D.I.
      • et al.
      Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?.
      Increased dietary fructose intake is associated with NASH and increased dietary fructose intake is also associated with increased serum uric acid concentrations in children and adolescents.
      • Mosca A.
      • Nobili V.
      • De Vito R.
      • Crudele A.
      • Scorletti E.
      • Villani A.
      • et al.
      Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents.
      Emerging experimental data suggest that increased dietary fructose might induce NAFLD, at least in part, due to the generation of uric acid during fructose metabolism that results in mitochondrial oxidative stress and impairment in ATP production.
      • Lanaspa M.A.
      • Cicerchi C.
      • Garcia G.
      • Li N.
      • Roncal-Jimenez C.A.
      • Rivard C.J.
      • et al.
      Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.
      • Lanaspa M.A.
      • Sanchez-Lozada L.G.
      • Choi Y.J.
      • Cicerchi C.
      • Kanbay M.
      • Roncal-Jimenez C.A.
      • et al.
      Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.
      • Sanchez-Lozada L.G.
      • Andres-Hernando A.
      • Garcia-Arroyo F.E.
      • Cicerchi C.
      • Li N.
      • Kuwabara M.
      • et al.
      Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats.
      Although it has been thought that most fructose in the body is derived from dietary fructose intake (principally sugar/corn syrup sweetened drinks), it has recently been shown that endogenous fructose can also be generated in the liver with activation of the polyol pathway. In this pathway, glucose is converted to sorbitol by aldose reductase and sorbitol is converted to fructose by sorbitol dehydrogenase.
      • Lanaspa M.A.
      • Ishimoto T.
      • Li N.
      • Cicerchi C.
      • Orlicky D.J.
      • Ruzycki P.
      • et al.
      Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.
      Aldose reductase is a NADPH-dependent aldo-keto reductase, best known as the rate-limiting enzyme of the polyol pathway. Recently, the effect of uric acid on aldose reductase expression and oxidative stress has been investigated.
      • Sanchez-Lozada L.G.
      • Andres-Hernando A.
      • Garcia-Arroyo F.E.
      • Cicerchi C.
      • Li N.
      • Kuwabara M.
      • et al.
      Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats.
      In this experimental study, it was shown that uric acid dose-dependently stimulated aldose reductase expression, and this phenomenon was associated with increased endogenous fructose production and hepatic triglyceride accumulation. This stimulatory mechanism was mediated by uric acid–induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5).
      • Sanchez-Lozada L.G.
      • Andres-Hernando A.
      • Garcia-Arroyo F.E.
      • Cicerchi C.
      • Li N.
      • Kuwabara M.
      • et al.
      Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats.
      The transcript and protein levels of aldose reductase are low in healthy livers, but increased in diseased human livers.
      • Brown K.E.
      • Broadhurst K.A.
      • Mathahs M.M.
      • Kladney R.D.
      • Fimmel C.J.
      • Srivastava S.K.
      • et al.
      Immunodetection of aldose reductase in normal and diseased human liver.
      Aldose reductase is expressed in both sinusoidal lining cells and Kupffer cells and also in the fibrous septa of cirrhotic livers.
      • Brown K.E.
      • Broadhurst K.A.
      • Mathahs M.M.
      • Kladney R.D.
      • Fimmel C.J.
      • Srivastava S.K.
      • et al.
      Immunodetection of aldose reductase in normal and diseased human liver.
      Overall, these data suggest that a positive feedback loop may exist in NASH, whereby increased dietary fructose consumption may increase hepatic de novo lipogenesis and uric acid production, generating oxidative stress. The increase in uric acid concentrations leads to a further increase in endogenous fructose production by stimulating aldose reductase in the polyol pathway,
      • Sanchez-Lozada L.G.
      • Andres-Hernando A.
      • Garcia-Arroyo F.E.
      • Cicerchi C.
      • Li N.
      • Kuwabara M.
      • et al.
      Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats.
      with the potential for not only uric acid-mediated kidney damage, but also fructose-mediated liver disease.

      Platelet activation as a mediator of the link between NAFLD and CKD

      The hepatic microenvironment plays a crucial role in liver disease development, as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix and a variety of immune cells or platelets may interact in complex and intertwined signalling pathways.
      • Pavlovic N.
      • Rani B.
      • Gerwins P.
      • Heindryckx F.
      Platelets as key factors in hepatocellular carcinoma.
      As mentioned, dyslipidaemia is a key feature of MetS, NAFLD and CKD and the specific dyslipidaemia involves an increase in hepatic-derived triglyceride-rich lipoproteins. Oxidative stress is a key feature of NAFLD
      • Engin A.
      Non-alcoholic fatty liver disease.
      • Ashraf N.U.
      • Sheikh T.A.
      Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease.
      • Sumida Y.
      • Niki E.
      • Naito Y.
      • Yoshikawa T.
      Involvement of free radicals and oxidative stress in NAFLD/NASH.
      and CKD;
      • Vaziri N.D.
      Oxidative stress in uremia: nature, mechanisms, and potential consequences.
      • Himmelfarb J.
      • Stenvinkel P.
      • Ikizler T.A.
      • Hakim R.M.
      The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.
      • Duni A.
      • Liakopoulos V.
      • Roumeliotis S.
      • Peschos D.
      • Dounousi E.
      Oxidative stress in the pathogenesis and evolution of chronic kidney disease: untangling ariadne's thread.
      both oxidative stress and an increase in triglyceride-rich lipoproteins (such as very low-density lipoprotein and remnant lipoproteins) are key regulators of platelet activation.
      • Krotz F.
      • Sohn H.Y.
      • Pohl U.
      Reactive oxygen species: players in the platelet game.
      • Fuentes E.
      • Gibbins J.M.
      • Holbrook L.M.
      • Palomo I.
      NADPH oxidase 2 (NOX2): a key target of oxidative stress-mediated platelet activation and thrombosis.
      • Englyst N.A.
      • Taube J.M.
      • Aitman T.J.
      • Baglin T.P.
      • Byrne C.D.
      A novel role for CD36 in VLDL-enhanced platelet activation.
      • Olufadi R.
      • Byrne C.D.
      Effects of VLDL and remnant particles on platelets.
      With oxidative stress and kidney dysfunction, there is a reduction in anti-oxidant protective factors produced by the kidneys, such as the Klotho protein,
      • Olejnik A.
      • Franczak A.
      • Krzywonos-Zawadzka A.
      • Kaluzna-Oleksy M.
      • Bil-Lula I.
      The biological role of Klotho protein in the development of cardiovascular diseases.
      and generation of metabolites such as plasma F2-isoprostanes, 8-oxo-7,8-dihydro-2'-deoxyguanosine, malonyldialdehyde, advanced oxidation protein products, carbamylated proteins, asymmetric dimethylarginine and oxidised lipoprotein particles.
      • Tucker P.S.
      • Dalbo V.J.
      • Han T.
      • Kingsley M.I.
      Clinical and research markers of oxidative stress in chronic kidney disease.
      • Dounousi E.
      • Papavasiliou E.
      • Makedou A.
      • Ioannou K.
      • Katopodis K.P.
      • Tselepis A.
      • et al.
      Oxidative stress is progressively enhanced with advancing stages of CKD.
      • Duni A.
      • Liakopoulos V.
      • Rapsomanikis K.P.
      • Dounousi E.
      Chronic kidney disease and disproportionally increased cardiovascular damage: does oxidative stress explain the burden?.
      • Small D.M.
      • Coombes J.S.
      • Bennett N.
      • Johnson D.W.
      • Gobe G.C.
      Oxidative stress, anti-oxidant therapies and chronic kidney disease.
      When platelets are activated, alpha granules and dense granules are released containing multiple proinflammatory cytokines, chemokines and growth factors. These include chemokine (CXC motif) ligand 4 (CXCL4), endothelial growth factor (EGF), interleukin-6 (IL-6), platelet-derived growth factor (PDGF), serotonin, insulin-like growth factor 1 (IGF-1), transforming growth factor (TGF)-beta, tumour necrosis factor (TNF)-alpha, vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF). The release of TGF-beta, PDGF, serotonin and CXCL4 can cause progression of liver disease by activating stellate cells with a consequent increase in extracellular matrix production. With CKD, there is also increased platelet activation, and an attenuated response to dual antiplatelet therapy, compared to patients without CKD.
      • Gremmel T.
      • Muller M.
      • Steiner S.
      • Seidinger D.
      • Koppensteiner R.
      • Kopp C.W.
      • et al.
      Chronic kidney disease is associated with increased platelet activation and poor response to antiplatelet therapy.
      Dysbiosis may also act to promote increased platelet activation since indoxyl sulfate activates platelets.
      • Yang K.
      • Du C.
      • Wang X.
      • Li F.
      • Xu Y.
      • Wang S.
      • et al.
      Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice.
      Decreased urinary Klotho protein levels have been identified as one of the earliest biomarkers of CKD progression,
      • John G.B.
      • Cheng C.Y.
      • Kuro-o M.
      Role of Klotho in aging, phosphate metabolism, and CKD.
      and the Klotho protein is also able to modulate the effect of indoxyl sulfate on platelet hyperactivity and thrombus formation, protecting against indoxyl sulfate-induced atherosclerosis in mice with CKD.
      • Yang K.
      • Du C.
      • Wang X.
      • Li F.
      • Xu Y.
      • Wang S.
      • et al.
      Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice.
      Thus, increased oxidative stress, intestinal dysbiosis, an increase in hepatic-derived triglyceride-rich lipoproteins and platelet activation are all closely inter-related with the potential for a “vicious” spiral of worsening liver and kidney disease in NAFLD and CKD. Recently, Malehmir et al. showed that platelet number, platelet activation and platelet aggregation are increased in NASH but not in simple steatosis or insulin resistance. Antiplatelet therapy (aspirin/clopidogrel, ticagrelor) but not non-steroidal anti-inflammatory drug treatment with sulindac also prevented NASH and subsequent development of hepatocellular carcinoma in a murine hIL4r-alpha-/GP1b-alpha transgenic mouse model of NASH.
      • Malehmir M.
      • Pfister D.
      • Gallage S.
      • Szydlowska M.
      • Inverso D.
      • Kotsiliti E.
      • et al.
      Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer.
      In addition, intra-vital microscopy also showed that antiplatelet therapy reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Taken together, these experimental results suggest that blocking platelet activation might ameliorate NASH and subsequently decrease the risk of developing hepatocellular carcinoma.
      • Byrne C.D.
      • Targher G.
      What’s new in NAFLD pathogenesis, biomarkers and treatment?.

      Premature ageing and age-related changes

      Older age is a risk factor for NAFLD,
      • Bellentani S.
      The epidemiology of non-alcoholic fatty liver disease.
      CKD
      • Bruck K.
      • Stel V.S.
      • Gambaro G.
      • Hallan S.
      • Volzke H.
      • Arnlov J.
      • et al.
      CKD prevalence varies across the European general population.
      and T2DM.
      • Palmer A.K.
      • Gustafson B.
      • Kirkland J.L.
      • Smith U.
      Cellular senescence: at the nexus between ageing and diabetes.
      Decreased urinary Klotho protein occurs with ageing, and with decreased Klotho protein excretion, there is an associated vascular phenotype of medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension and impaired angiogenesis.
      • Mencke R.
      • Hillebrands J.L.
      The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology.
      Decreased urinary Klotho protein has been also identified as one of the earliest biomarkers of CKD progression and the Klotho gene was identified first as a putative ageing-suppressor gene that extended life span when overexpressed, and accelerated ageing-like phenotypes when disrupted in mice.
      • John G.B.
      • Cheng C.Y.
      • Kuro-o M.
      Role of Klotho in aging, phosphate metabolism, and CKD.
      As mentioned, the Klotho protein modulates the effect of indoxyl sulfate on platelet hyperactivity,
      • Yang K.
      • Du C.
      • Wang X.
      • Li F.
      • Xu Y.
      • Wang S.
      • et al.
      Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice.
      and thus there is the potential for low levels of Klotho protein to mediate the increase in platelet reactivity that occurs with ageing.
      • Le Blanc J.
      • Lordkipanidze M.
      Platelet function in aging.
      Older patients with NAFLD are at a higher risk of CKD as a function of their increased age, but with advancing age, obesity and increased serum uric acid concentrations there is also increased risk of developing CKD.
      • 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.
      Age-related changes in the liver may also occur with alterations in hepatic sinusoidal endothelial cells,
      • Hunt N.J.
      • Kang S.W.S.
      • Lockwood G.P.
      • Le Couteur D.G.
      • Cogger V.C.
      Hallmarks of aging in the liver.
      increases in the hepatokine fetuin-A and decreases in adiponectin, potentially linking MetS, NAFLD and CKD.
      • Ix J.H.
      • Sharma K.
      Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK.
      In summary, these new mechanistic data suggest plausible mechanisms and new pathways linked to MetS, intestinal dysbiosis, excessive fructose consumption, platelet activation and ageing that might, at least in part, mediate links between NAFLD and the risk of CKD. However, more research is needed to better understand if experimental models of NAFLD/NASH, initiated by primary changes in lipid storage in the liver, ultimately lead to CKD.

      Effect of PNPLA3 polymorphism on renal function

      Several susceptibility gene variants predisposing to NAFLD have been consistently identified in different populations.
      • Anstee Q.M.
      • Seth D.
      • Day C.P.
      Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease.
      ,
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      Among the genetic factors that may influence the onset and progression of NAFLD, the minor allele G of rs738409, i.e. a non-synonymous single nucleotide polymorphism in the PNPLA3 gene encoding an Ile148Met change, has been recognised as a major common genetic variant associated with a greater predisposition to NASH and progressive liver fibrosis in both paediatric and adult populations.
      • Anstee Q.M.
      • Seth D.
      • Day C.P.
      Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease.
      ,
      • Eslam M.
      • Valenti L.
      • Romeo S.
      Genetics and epigenetics of NAFLD and NASH: clinical impact.
      The PNPLA3 rs738409 polymorphism which is associated with a predisposition to NASH has recently been shown to associate with worse kidney function.
      Emerging evidence is now suggesting that the G allele of rs738409 is significantly associated with decreased eGFR values, irrespective of established renal risk factors and presence of NAFLD, across different ethnicities and patient populations. Indeed, as summarised in Table 2, there are now half a dozen studies that have examined whether, and to what extent, the PNPLA3 rs738409 polymorphism is associated with decreasing kidney function in both adults and children or adolescents.
      • Oniki K.
      • Saruwatari J.
      • Izuka T.
      • Kajiwara A.
      • Morita K.
      • Sakata M.
      • et al.
      Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects.
      • Musso G.
      • Cassader M.
      • Gambino R.
      PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in nonalcoholic fatty liver disease.
      • Mantovani A.
      • Zusi C.
      • Sani E.
      • Colecchia A.
      • Lippi G.
      • Zaza G.L.
      • et al.
      Association between PNPLA3rs738409 polymorphism decreased kidney function in postmenopausal type 2 diabetic women with or without non-alcoholic fatty liver disease.
      • Sun D.Q.
      • Zheng K.I.
      • Xu G.
      • Ma H.L.
      • Zhang H.Y.
      • Pan X.Y.
      • et al.
      PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.
      • Targher G.
      • Mantovani A.
      • Alisi A.
      • Mosca A.
      • Panera N.
      • Byrne C.D.
      • et al.
      Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD.
      • Marzuillo P.
      • Di Sessa A.
      • Guarino S.
      • Capalbo D.
      • Umano G.R.
      • Pedulla M.
      • et al.
      Nonalcoholic fatty liver disease and eGFR levels could be linked by the PNPLA3 I148M polymorphism in children with obesity.
      • Di Costanzo A.
      • Pacifico L.
      • D'Erasmo L.
      • Polito L.
      • Martino M.D.
      • Perla F.M.
      • et al.
      Nonalcoholic Fatty Liver Disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children.
      For instance, our group recently showed for the first time that the presence of the risk allele (G) of rs738409 was strongly associated with both decreasing eGFR and increasing 24-hour urinary protein excretion in a sample of 142 overweight Italian children/adolescents with biopsy-proven NAFLD.
      • Targher G.
      • Mantovani A.
      • Alisi A.
      • Mosca A.
      • Panera N.
      • Byrne C.D.
      • et al.
      Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD.
      Notably, these associations were independent of sex, age, measures of adiposity, blood pressure, HOMA-estimated insulin resistance and also the histologic severity of NAFLD (i.e. NASH and liver fibrosis stage).
      • Targher G.
      • Mantovani A.
      • Alisi A.
      • Mosca A.
      • Panera N.
      • Byrne C.D.
      • et al.
      Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD.
      Similarly, Sun et al. reported that the PNPLA3 GG genotype was significantly associated with a higher risk of prevalent CKD, abnormal albuminuria or increased levels of urinary neutrophil gelatinase-associated lipocalin (i.e. a reliable marker of renal tubular injury) in 217 Chinese adults with biopsy-confirmed NAFLD.
      • Sun D.Q.
      • Zheng K.I.
      • Xu G.
      • Ma H.L.
      • Zhang H.Y.
      • Pan X.Y.
      • et al.
      PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.
      Also in this study, PNPLA3 GG genotype remained significantly associated with renal glomerular and tubular injury after adjusting for age, sex, BMI, waist circumference, hypertension, diabetes, HOMA-estimated insulin resistance, hyperuricemia, and histologic severity of NAFLD.
      • Sun D.Q.
      • Zheng K.I.
      • Xu G.
      • Ma H.L.
      • Zhang H.Y.
      • Pan X.Y.
      • et al.
      PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.
      In another study involving 740 elderly Japanese individuals, Oniki et al. found that the PNPLA3 GG genotype was associated with lower levels of eGFR, independently of common renal risk factors and presence of ultrasound-detected NAFLD, especially in those with normal body weight.
      • Oniki K.
      • Saruwatari J.
      • Izuka T.
      • Kajiwara A.
      • Morita K.
      • Sakata M.
      • et al.
      Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects.
      Notably, in a subgroup of these individuals, the authors also showed that the PNPLA3 GG genotype was associated with a significant decline in eGFR over a mean follow-up of 5.5 years.
      • Oniki K.
      • Saruwatari J.
      • Izuka T.
      • Kajiwara A.
      • Morita K.
      • Sakata M.
      • et al.
      Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects.
      Table 2Association between PNPLA3 rs738409 polymorphism and kidney dysfunction both in adults and in children or adolescents (ordered by publication year).
      Authors, Country, Year (Ref.)Study design and populationKidney outcome measuresCovariate adjustmentsMain results
      Adults
      Oniki K et al., Japan, 2015
      • Oniki K.
      • Saruwatari J.
      • Izuka T.
      • Kajiwara A.
      • Morita K.
      • Sakata M.
      • et al.
      Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects.
      Cross-sectional of 591 elderly individuals without known liver diseases (472 without NAFLD and 119 with NAFLD on ultrasonography) recruited during a health screening program and selected from an initial cohort of 740 individuals. Among these individuals, a retrospective longitudinal analysis with a median follow-up of 5.0 (range: 1.0–6.0 years) was also performed in 341 subjects (51 with NAFLD and 290 without NAFLD)eGFRCKD-EPI (considered as continuous measure)Age, sex, BMI, diabetes, hypertension, dyslipidaemia and presence of NAFLD on ultrasonographyPNPLA3 GG genotype was independently associated with lower eGFR values compared with carriers of the CC genotype, only in the subgroup of individuals with normal body weight (but not in those with overweight or obesity) in cross-sectional analyses. This association was also replicated in the longitudinal analyses
      Musso G et al., Italy, 2015
      • Musso G.
      • Cassader M.
      • Gambino R.
      PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in nonalcoholic fatty liver disease.
      Cross-sectional study of 202 nonobese, nondiabetic adults (61 non-cirrhotic biopsy-proven NAFLD and 81 controls)CKD (i.e. eGFRCKD-EPI <60 ml/min/1.73 m2 and/or microalbuminuria); microalbuminuria (30 - 300 mg/g)Not specifiedPNPLA3 GG or CG genotype (combined) was significantly associated with a higher risk of prevalent CKD, lower eGFR or microalbuminuria both in NAFLD patients and in controls
      Mantovani A et al., Italy, 2019
      • Mantovani A.
      • Zusi C.
      • Sani E.
      • Colecchia A.
      • Lippi G.
      • Zaza G.L.
      • et al.
      Association between PNPLA3rs738409 polymorphism decreased kidney function in postmenopausal type 2 diabetic women with or without non-alcoholic fatty liver disease.
      Cross-sectional study of 101 Caucasian post-menopausal women with non-insulin treated type 2 diabetes mellitus without known liver diseasesCKD (i.e. eGFRCKD-EPI <60 ml/min/1.73 m2 and/or abnormal albuminuria); abnormal albuminuria ≥30 mg/gAge, duration of diabetes, haemoglobin A1c, HOMA-IR, systolic blood pressure, hypertension treatment and presence of NAFLD on ultrasonographyPNPLA3 GG genotype was independently associated with lower eGFR values and higher prevalence of CKD compared with the CC or GC genotype
      Sun DQ et al., China, 2019
      • Sun D.Q.
      • Zheng K.I.
      • Xu G.
      • Ma H.L.
      • Zhang H.Y.
      • Pan X.Y.
      • et al.
      PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.
      Cross-sectional study of 217 adults with non-cirrhotic biopsy-proven NAFLDCKD (i.e. eGFRCKD-EPI <60 ml/min/1.73 m2 and/or abnormal albuminuria); abnormal albuminuria ≥30 mg/g, urinary NGAL levels ≥31.2 ng/mlAge, sex, BMI, waist circumference, hypertension, diabetes, HOMA-IR, hyperuricemia, presence of NASH (i.e. defined as a NAS ≥5) and histologic stage of fibrosisPNPLA3 GG genotype was independently associated with a higher risk of prevalent CKD, abnormal albuminuria or increased NGAL levels, especially in patients with persistently normal serum alanine aminotransferase levels
      Overweight/obese children or adolescents
      Targher G et al., Italy, 2019
      • Targher G.
      • Mantovani A.
      • Alisi A.
      • Mosca A.
      • Panera N.
      • Byrne C.D.
      • et al.
      Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD.
      Cross-sectional study of 142 Caucasian children/adolescents with biopsy-proven NAFLDeGFR (using the Bedside Schwartz equation); 24-hour proteinuria (both considered as continuous measures)Age, sex, systolic blood pressure, waist circumference, presence of NASH (i.e. defined as a NAS ≥5) and histologic stage of liver fibrosisPNPLA3 GG genotype was independently associated with lower eGFR values and increasing 24-hour proteinuria
      Marzuillo P et al., Italy, 2019
      • Marzuillo P.
      • Di Sessa A.
      • Guarino S.
      • Capalbo D.
      • Umano G.R.
      • Pedulla M.
      • et al.
      Nonalcoholic fatty liver disease and eGFR levels could be linked by the PNPLA3 I148M polymorphism in children with obesity.
      Cross-sectional study of 591 Caucasian children/adolescents with obesityeGFR (using the Schwartz equation) considered as continuous measureSex, duration of obesity, HOMA-IR score, BMI, LDL-cholesterol, triglyceridesPNPLA3 GG genotype was independently associated with lower eGFR values compared with the CC or GC genotype, only in the subgroup of children with NAFLD (defined by ultrasonography and/or serum ALT >40 IU/L)
      Di Costanzo et al., Italy, 2019
      • Di Costanzo A.
      • Pacifico L.
      • D'Erasmo L.
      • Polito L.
      • Martino M.D.
      • Perla F.M.
      • et al.
      Nonalcoholic Fatty Liver Disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children.
      Cross-sectional study of 230 overweight/obese children (105 with NAFLD defined as liver fat fraction ≥5% by magnetic resonance imaging)eGFR (using the Schwartz equation); abnormal albuminuria ≥30 mg/gAge, sex, pubertal status, diastolic blood pressure, waist circumference and presence of NAFLD on magnetic resonance imagingPNPLA3 G risk allele was not independently associated with eGFR <90 ml/min/1.73 m2 and/or abnormal albuminuria
      NB: In all aforementioned studies, the PNPLA3 genotyping was determined on blood samples. BMI, body mass index; CKD, chronic kidney disease; eGFRCKD-EPI, estimated glomerular filtration rate (estimated by the CKD-EPI equation); HOMA-IR, homeostasis model assessment-insulin resistance; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NGAL, neutrophil gelatinase-associated lipocalin; PNPLA3, patatin-like phospholipase domain-containing protein-3.
      To date, the putative mechanisms underlying the association between the G allele of rs738409 and decreasing kidney function are not entirely understood. The published studies
      • Oniki K.
      • Saruwatari J.
      • Izuka T.
      • Kajiwara A.
      • Morita K.
      • Sakata M.
      • et al.
      Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects.
      • Musso G.
      • Cassader M.
      • Gambino R.
      PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in nonalcoholic fatty liver disease.
      • Mantovani A.
      • Zusi C.
      • Sani E.
      • Colecchia A.
      • Lippi G.
      • Zaza G.L.
      • et al.
      Association between PNPLA3rs738409 polymorphism decreased kidney function in postmenopausal type 2 diabetic women with or without non-alcoholic fatty liver disease.
      • Sun D.Q.
      • Zheng K.I.
      • Xu G.
      • Ma H.L.
      • Zhang H.Y.
      • Pan X.Y.
      • et al.
      PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.
      • Targher G.
      • Mantovani A.
      • Alisi A.
      • Mosca A.
      • Panera N.
      • Byrne C.D.
      • et al.
      Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD.
      • Marzuillo P.
      • Di Sessa A.
      • Guarino S.
      • Capalbo D.
      • Umano G.R.
      • Pedulla M.
      • et al.
      Nonalcoholic fatty liver disease and eGFR levels could be linked by the PNPLA3 I148M polymorphism in children with obesity.
      • Di Costanzo A.
      • Pacifico L.
      • D'Erasmo L.
      • Polito L.
      • Martino M.D.
      • Perla F.M.
      • et al.
      Nonalcoholic Fatty Liver Disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children.
      show that the association between the PNPLA3 GG genotype and kidney dysfunction was largely independent of the shared renal/metabolic risk factors. It is reasonable to hypothesise that the G allele of rs738409, which is highly expressed in liver sinusoidal pericytes,
      • Pirazzi C.
      • Valenti L.
      • Motta B.M.
      • Pingitore P.
      • Hedfalk K.
      • Mancina R.M.
      • et al.
      PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells.
      might also exert direct adverse effects on the kidneys. These nephrotoxic effects may occur via activation of renal pericytes, as renal pericytes are stromal cells that play a key role in angiogenesis and in regulating renal medullary and cortical blood flow, promoting renal fibrogenesis and glomerulosclerosis.
      • Shaw I.
      • Rider S.
      • Mullins J.
      • Hughes J.
      • Peault B.
      Pericytes in the renal vasculature: roles in health and disease.
      ,
      • Kramann R.
      • Humphreys B.D.
      Kidney pericytes: roles in regeneration and fibrosis.
      However, further research is needed to better understand the role of the PNPLA3 rs738409 polymorphism on the development of glomerular and interstitial fibrosis.
      If confirmed in future larger studies, we believe that the results of these studies may have important clinical implications, because they support the notion that PNPLA3 genotyping might be useful not only to identify individuals with greater susceptibility to NAFLD development and progression, but also for those patients with NAFLD who may be at higher risk of CKD, thus promoting the implementation of specific prevention programmes and treatment strategies for CKD among carriers of the PNPLA3 rs738409 GG genotype.

      Conclusions

      This review article outlines the existence of a strong association between the presence and severity of NAFLD and the increased prevalence and incidence of CKD, independent of obesity, hypertension, T2DM and other common cardio-renal risk factors. The data also suggest that PNPLA3 genotyping might be useful not only to identify those with greater susceptibility to NAFLD development and progression, but also to identify a subgroup of patients with NAFLD who are at higher risk of developing CKD. Despite the convincing evidence linking NAFLD with a higher risk of CKD, it remains to be definitively established whether a causal association also exists. Moreover, it should also be noted that none of the available studies have used renal biopsy to examine the specific renal morphology/pathology associated with NAFLD, and therefore it is uncertain if NAFLD is associated with a specific type of kidney disease, although it is reasonable to assume that NAFLD may promote kidney damage, mostly through accelerated atherothrombosis. We suggest that future prospective and interventional studies of well-characterised cohorts of patients with biopsy-proven NAFLD are required to try and better elucidate whether it is the presence and severity of NAFLD, or whether it is the presence of co-existing risk factors that increases risk of incident CKD. In the meantime, however, given the close link between NAFLD and CKD, more careful surveillance of these patients is warranted.

      Abbreviations

      ACR, albumin-to-creatinine ratio; aHR, adjusted hazard ratio; AMPK, AMP-activated protein kinase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; BAs, bile acids; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; CXCL4, chemokine (CXC motif) ligand 4; DAGs, diacylglycerols; EGF, endothelial growth factor; eGFR, estimated glomerular filtration rate; FGF, fibroblast growth factor; FLI, fatty liver index; GGT, gamma-glutamyltransferase; HGF, hepatocyte growth factor; HOMA, homeostatic model assessment; HR, hazard ratio; IGF-1, insulin-like growth factor 1; IL-6, interleukin 6; LCFAs, long-chain fatty acids; LPS, lipopolysaccharide; MDRD, Modification of Diet in Renal Disease; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NEFA, non-esterified fatty acids; NFS, NAFLD fibrosis score; NGAL, neutrophil gelatinase-associated lipocalin; PAI-1, plasminogen activator inhibitor 1; PDGF, platelet-derived growth factor; PNPLA3, patatin-like phospholipase domain-containing 3; SCFAs, short-chain fatty acids; TGF, transforming growth factor; TM6SF2, transmembrane 6 superfamily member 2; TMA, trimethylamine; TMAO, trimethylamine oxide; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor; VLDL, very low-density lipoprotein.

      Financial support

      C.D.B. is supported in part by the Southampton NIHR Biomedical Research Centre (IS-BRC-20004), UK. G.T. is supported in part by grants from the University School of Medicine of Verona , Verona, Italy.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors' contributions

      The authors contributed equally to this manuscript.

      Supplementary data

      Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2020.01.013.

      Supplementary data

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