Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.Italian Ministry of University/FIRB/MERIT RBNE08NKH7_00

Adjusted effect estimates for non-alcoholic fatty liver disease, non-alcoholic steato-hepatitis, advanced (stage F3) fibrosis and prevalent/incident chronic kidney disease, based on individual participant data meta-analysis from 20 studies (29,282 participants).

<p>Data from all studies providing IPD were pooled together into a single dataset and effect estimates were calculated using multivariate logistic regression (cross-sectional studies) or Cox proportional hazard models (longitudinal studies). In these models, studies were incorporated as cluster and treated as random-effect, while covariates were treated as fixed-effect. The individual patient covariates entered in the models were: age, BMI, metabolic syndrome, hypertension, smoking status, diabetes, ethnicity (Asian versus non-Asian population), presence of cirrhosis, waist circumference, HOMA-IR index, duration of follow-up (for longitudinal studies). Finally, a fully adjusted model was run, with all covariates entered.</p><p>HTN, hypertension; Met Sy, metabolic syndrome; waist, waist circumference.</p>a<p>For continuous variables, median (range) of values is reported.</p>b<p>All cirrhotic individuals derive from the study by Park et al. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001680#pmed.1001680-Park1" target="_blank">[30]</a>.</p

Forest plot of comparison.

<p>NAFLD versus non-NAFLD, outcome: incident chronic kidney disease in prospective studies. NAFLD was defined by imaging, histology, or liver enzyme elevation. Studies assessing NAFLD by imaging, histology, or liver enzyme elevation were considered separately.</p

Longitudinal studies connecting NAFLD to chronic kidney disease included in the meta-analysis.

<p>Studies with different definitions of NAFLD (histology, imaging, liver enzyme elevation) were analyzed separately and are grouped together.</p>a<p>Asian ethnicity was defined by birth within boundaries delineated West by the Red Sea, the Suez Canal, the Dardanelles strait, the Bosphorus the Caucasus and the Urals and East by the Bering Sea, the Japan and Indonesian archipelagos.</p>b<p>Modified 25-item <b>STROBE score</b>, with the item(s) not satisfied by the study indicated in parentheses: (a) title and abstract informative and balanced; (b) background/rationale stated in the introduction; (c) objective(s) specified in the introduction; (d) study design correctly and presented early in the paper; (e) setting, locations, and relevant dates described; (f) eligibility criteria, methods of selection, and follow-up described; (g) diagnostic criteria, outcomes, exposures, predictors, potential confounders, and effect modifiers for all variables clearly defined. Specifically, regarding the definition of NAFLD: for radiological assessment: radiological exam performed by radiologists blinded to clinical data and following pre-specified, standardized criteria to detect steatosis; for histological assessment of NAFLD: adequate biopsy specimen (fragment length ≥1.5 cm with >6 portal tracts) and liver biopsy processed and scored by blinded pathologist according to standard criteria; (h) sources of data and details of methods of measurement given for each variable of interest; (i) any efforts to address potential sources of bias described; (j) how the study size was arrived at clearly explained; (k) how quantitative variables were handled in the analyses clearly explained; (l) all statistical methods, how missing data and loss to follow-up were addressed, any sensitivity analyses clearly described; (m) numbers of individuals at each stage of study reported; (n) characteristics of study participants, number of participants with missing data, average, and total follow-up time clearly described; (o) outcome events or summary measures over time reported; (p) unadjusted and confounder-adjusted estimates and their precision (e.g., 95% CI) reported; (q) analyses of subgroups and interactions, and sensitivity analyses reported; (r) key results with reference to study objectives summarised; (s) limitations of the study discussed; (t) cautious overall interpretation of results given; (u) generalizability (external validity) of the study results discussed; (v) source of funding and role of the funders described.</p><p>ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; DM, diabetes mellitus; GGT, gamma-glutamyltransferase; HDL-C, high density lipoprotein cholesterol; HTN, hypertension; LDL-C, low density lipoprotein cholesterol; MELD, model for end-stage liver disease; Met Sy, metabolic syndrome; NA, not available; OSAS, obstructive sleep apnoea; Tg, triglycerides.</p

Flow of study selection.

<p>STROBE score of included studies is provided as median (range).</p

Cross-sectional studies connecting NAFLD to chronic kidney disease included in the meta-analysis.

<p>Studies with different definitions of NAFLD (histology, imaging, liver enzyme elevation) were analyzed separately and are grouped together.</p>a<p>Asian ethnicity was defined by birth within boundaries delineated West by the Red Sea, the Suez Canal, the Dardanelles strait, the Bosphorus the Caucasus and the Urals and East by the Bering Sea, the Japan and Indonesian archipelagos.</p>b<p>Modified 25-item <b>STROBE score</b>, with the item(s) not satisfied by the study indicated in parentheses: (a) title and abstract informative and balanced; (b) background/rationale stated in the introduction; (c) objective(s) specified in the introduction; (d) study design correctly and presented early in the paper; (e) setting, locations, and relevant dates described; (f) eligibility criteria, methods of selection, and follow-up described; (g) diagnostic criteria, outcomes, exposures, predictors, potential confounders, and effect modifiers for all variables clearly defined. Specifically, regarding the definition of NAFLD: for radiological assessment: radiological exam performed by radiologists blinded to clinical data and following pre-specified, standardized criteria to detect steatosis; for histological assessment of NAFLD: adequate biopsy specimen (fragment length ≥1.5 cm with >6 portal tracts) and liver biopsy processed and scored by blinded pathologist according to standard criteria; (h) sources of data and details of methods of measurement given for each variable of interest; (i) any efforts to address potential sources of bias described; (j) how the study size was arrived at clearly explained; (k) how quantitative variables were handled in the analyses clearly explained; (l) all statistical methods, how missing data and loss to follow-up were addressed, any sensitivity analyses clearly described; (m) numbers of individuals at each stage of study reported; (n) characteristics of study participants, number of participants with missing data, average, and total follow-up time clearly described; (o) outcome events or summary measures over time reported; (p) unadjusted and confounder-adjusted estimates and their precision (e.g., 95% CI) reported; (q) analyses of subgroups and interactions, and sensitivity analyses reported; (r) key results with reference to study objectives summarised; (s) limitations of the study discussed; (t) cautious overall interpretation of results given; (u) generalizability (external validity) of the study results discussed; (v) source of funding and role of the funders described.</p><p>ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; DM, diabetes mellitus; GGT, gamma-glutamyltransferase; HDL-C, high density lipoprotein cholesterol; HTN, hypertension; LDL-C, low density lipoprotein cholesterol; MELD, model for end-stage liver disease; Met Sy, metabolic syndrome; NA, not available; OSAS, obstructive sleep apnoea; Tg, triglycerides.</p

Results of subgroup analysis for the outcome: chronic kidney disease.

<p>Subgroup analysis was planned a priori to assess the impact of the following items on the association between NAFLD and CKD: (1) Fulfilment of STROBE items: we planned to repeat the analysis after excluding studies not fulfilling each STROBE item (different STROBE items are described in footnote to <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001680#pmed-1001680-t001" target="_blank">Table 1</a>). (2) Diabetes: studies including exclusively non-diabetic individuals versus studies including diabetic individuals. (3) Studies simultaneously adjusting versus studies not adjusting for all the following risk factors for CKD: age and BMI and metabolic syndrome (overall or each of its components) and hypertension and smoking. (4) Study design (population-based versus community-based). (5) Ethnicity (Caucasian versus Asian). (6) Studies including only non-cirrhotic patients versus studies including cirrhotic patients. (7) Studies using the CKD-EPI versus studies using the MDRD equation to estimate GFR. (8) Outcomes related to CKD: studies assessing both eGFR and proteinuria versus studies assessing either eGFR or proteinuria. (9) Type of data available: studies with IPD versus studies with AD.</p