Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Musso, Giovanni; Cassader, Maurizio; Cohney, Solomon; Pinach, Silvia; Saba, Francesca; Gambino, Roberto

doi:10.1016/j.molmed.2015.08.005

Cited by 107 publications

(98 citation statements)

References 137 publications

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“…The liver contains up to 80% of all macrophages of the body, and the steatotic liver may represent a more relevant source of proinflammatory cytokines than adipose tissue (30 Atherogenic dyslipidemia is the most common lipid abnormality in CKD and an independent predictor of the incidence and progression of CKD and of CVD in patients with CKD (108,109). Atherogenic dyslipidemia promotes CKD through receptor-mediated uptake of qualitatively abnormal lipoproteins by glomerular and tubulointerstitial cells (110).…”

Section: Nafld As a Determinant Of Ckd: Targeting The Liver To Improvmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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Section: Nafld As a Determinant Of Ckd: Targeting The Liver To Improvmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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“…In addition to insulin resistance, several other interlinking inflammatory and oxidative stress mechanisms have been postulated to link NAFLD, CKD and CVD [5,6]. Studies on the association of NAFLD with diabetic kidney disease (DKD) have shown variable results.…”

Section: Introductionmentioning

confidence: 99%

Increased Risk for Cardiovascular Events in Patients with Diabetic Kidney Disease and Non-Alcoholic Fatty Liver Disease

Chinnadurai

Chrysochou

Kalra³

2018

Nephron

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Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is recognised to be a strong risk factor for causing cardiovascular disease (CVD) and chronic kidney disease (CKD), independent of the presence of diabetes mellitus. The association of NAFLD with outcomes in patients with diabetic kidney disease (DKD) has been variably reported. This study aimed to investigate the association of NAFLD with cardiovascular, renal outcomes and mortality in patients with advanced DKD (CKD 3–5, not on dialysis). Methods: This observational study was carried out on 192 patients with DKD within a cohort of 2,974 non-dialysis CKD patients, who had an ultrasound (US) of their liver done between January 2000 and end of December 2014. From these 192 patients, 149 patients (NAFLD 48 and normal US 101) were included for comparative analysis, as they had complete datasets. Patient demographics, comorbidities and blood results were collected at study baseline. Follow-up data on non-fatal cardiovascular events (NFCVE), mortality and serial estimated glomerular filtration rate (eGFR) was gathered until study end point. Cox-regression analysis was used to study the association of NAFLD with NFCVE and mortality, and linear regression analysis was used for the estimation of renal progression. Results: Median follow-up time was 69 months, similar in both groups (p = 0.09). Median eGFR was 31.6 mL/min/1.73 m², with a median urine protein creatinine ratio of 46 g/mol. A total of 20 (41.7%) NFCVE were recorded in the NAFLD group compared to 14 (13.9%) in the normal US group. Multivariable Cox-regression analysis showed NAFLD as an independent risk factor (hazard ratio 2.95; 95% CI 1.31–6.60; p = 0.01) for NFCVE even after including all cardiovascular risks parameters that were significant in the univariable model. There was no significant difference in survival between the 2 groups over the follow-up period (log-rank test, p = 0.76). The overall rate of decline in eGFR was 3.46 mL/min/1.73 m²/year and this was not observed to be different between the groups (p = 0.65). Conclusion: In our cohort of patients with advanced DKD, NAFLD showed a strong independent association with cardiovascular outcomes. Further prospective studies are warranted to strengthen these associations and plan a strategy for screening NAFLD in this high-risk group.

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“…The steatotic hepatocytes may be a more important source of proinflammatory cytokines resulting from altered lipid and immune homeostasis [37-39]. Furthermore, a heterogeneous class of hepatokines such as plasminogen activator inhibitor-1 and tumor necrosis factor-α can modulate reversed renal lipid accumulation, glomerular sclerosis, and tubulointerstitial inflammation [40-42]. …”

Section: Discussionmentioning

confidence: 99%

Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

Zhang

Zhao

et al. 2017

Ann Nutr Metab

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Background: We aimed to explore the association between urinary alpha₁-microglobulin (A1M) levels and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. Study: We performed a cross-sectional study among 2,215 Chinese who attended their annual health examination at First Affiliated Hospital, College of Medicine, Zhejiang University. Urinary A1M-creatinine ratio and other clinical and laboratory parameters were measured. Results: A total of 20.9% of subjects fulfilled the diagnostic criteria of NAFLD. NAFLD subjects had significantly higher urinary A1M-creatinine ratios. These levels were positively associated with NAFLD prevalence. The association between A1M-creatinine ratio and NAFLD was independent of hyperglycemia status. Stepwise regression showed that urinary A1M-creatinine ratio was significantly associated with the risk for NAFLD. Urinary A1M-creatinine ratio was an independent factor predicting advanced fibrosis (FIB-4 ≥1.3) in NAFLD patients. Conclusions: Our results showed a significant association between urinary A1M-creatinine ratio and NAFLD.

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Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Cited by 107 publications

References 137 publications

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Increased Risk for Cardiovascular Events in Patients with Diabetic Kidney Disease and Non-Alcoholic Fatty Liver Disease

Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

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