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

Giovanni Musso, Roberto Gambino, James H Tabibian, Mattias Ekstedt, Stergios Kechagias, Masahide Hamaguchi, Rolf Hultcrantz, Hannes Hagström, Seung Kew Yoon, Phunchai Charatcharoenwitthaya, Jacob George, Francisco Barrera, Svanhildur Hafliðadóttir, Einar Stefan Björnsson, Matthew J Armstrong, Laurence J Hopkins, Xin Gao, Sven Francque, An Verrijken, Yusuf Yilmaz, Keith D Lindor, Michael Charlton, Robin Haring, Markus M Lerch, Rainer Rettig, Henry Völzke, Seungho Ryu, Guolin Li, Linda L Wong, Mariana Machado, Helena Cortez-Pinto, Kohichiroh Yasui, Maurizio Cassader, Giovanni Musso, Roberto Gambino, James H Tabibian, Mattias Ekstedt, Stergios Kechagias, Masahide Hamaguchi, Rolf Hultcrantz, Hannes Hagström, Seung Kew Yoon, Phunchai Charatcharoenwitthaya, Jacob George, Francisco Barrera, Svanhildur Hafliðadóttir, Einar Stefan Björnsson, Matthew J Armstrong, Laurence J Hopkins, Xin Gao, Sven Francque, An Verrijken, Yusuf Yilmaz, Keith D Lindor, Michael Charlton, Robin Haring, Markus M Lerch, Rainer Rettig, Henry Völzke, Seungho Ryu, Guolin Li, Linda L Wong, Mariana Machado, Helena Cortez-Pinto, Kohichiroh Yasui, Maurizio Cassader

Abstract

Background: 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.

Methods and findings: 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.

Conclusion: 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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Flow of study selection.
Figure 1. Flow of study selection.
STROBE score of included studies is provided as median (range).
Figure 2. Forest plot of comparison.
Figure 2. Forest plot of comparison.
NAFLD versus non-NAFLD, outcome: prevalent chronic kidney disease in cross-sectional studies. Studies assessing NAFLD by imaging, histology or liver enzyme elevation were considered separately.
Figure 3. Forest plot of comparison.
Figure 3. Forest plot of comparison.
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.
Figure 4. Forest plot of comparison.
Figure 4. Forest plot of comparison.
(A) NASH versus simple steatosis in biopsy-proven non-cirrhotic NAFLD; outcome: prevalent chronic kidney disease in cross-sectional studies. (B) Advanced (stage F3) fibrosis versus no-advanced (stage F0–F2) fibrosis in biopsy-proven non-cirrhotic NAFLD, outcome: prevalent CKD in cross-sectional studies.
Figure 5. Forest plot of comparison.
Figure 5. Forest plot of comparison.
(A) NASH versus simple steatosis in biopsy-proven noncirrhotic NAFLD; outcome: incident CKD in prospective studies. (B) Advanced (stage F3) fibrosis versus no-advanced (stage F0–F2) fibrosis in biopsy-proven non-cirrhotic NAFLD, outcome: incident CKD in prospective studies.
Figure 6. Forest plot of comparison.
Figure 6. Forest plot of comparison.
(A) NASH versus simple steatosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident CKD stage 3b in prospective studies. (B) NASH versus simple steatosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident CKD stage 4 in prospective studies.
Figure 7. Forest plot of comparison.
Figure 7. Forest plot of comparison.
(A) NASH versus simple steatosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident CKD stage 5 (renal failure) in prospective studies. (B) Advanced (stage F3) fibrosis versus no advanced (stage F0–F2) fibrosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident CKD stage 3b in prospective studies.
Figure 8. Forest plot of comparison.
Figure 8. Forest plot of comparison.
(A) advanced (stage F3) fibrosis versus no advanced (stage F0–F2) fibrosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident CKD stage 4 in prospective studies. (B) Advanced (stage F3) fibrosis versus no advanced (stage F0–F2) fibrosis in biopsy-proven non-cirrhotic NAFLD; outcome: incident (CKD) stage 5 (renal failure) in prospective studies.

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