Renal health in patients with non-alcoholic fatty liver disease and metabolic syndrome

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a very common disorder characterized by fatty deposition in the hepatocytes; its development is associated with unhealthy lifestyle habits, visceral obesity, insulin resistance (IR) and metabolic syndrome (MetS), and is a risk factor for cardiovascular disease and type 2 diabetes (T2DM). Epidemiological evidence suggests that NAFLD is a risk factor for the development of chronic kidney disease (CKD), which is in turn is also associated with cardiometabolic risks. CKD may worsen as NAFLD progresses to later stages. Importantly, especially in metabolically compromised obese patients, CKD is often preceded by a phase of glomerular hyperfiltration, a risk factor for accelerated renal function loss. Amelioration of hyperfiltration through drug therapy or weight loss, has been observed to offer renoprotective effects in patients with T2DM by significantly slowing down long-term glomerular filtration rate (GFR) decline. Studies on the association between NAFLD and renal disease mainly focus on Stage-3 GFR, while no information is available on their relationship during the hyperfiltering stage. Moreover no evidence exists on whether reducing liver fat accumulation ameliorates hyperfiltration. It has been observed that about half of patients with NAFLD show signs of mildly-increased liver iron (HepFe) accumulation unrelated to hereditary hemochromatosis, and hyperferritinemia, in the context of the MetS. Iron may potentiate the progression of NAFLD to more advanced stages by increasing oxidative stress and altering insulin and lipid metabolism. Increased UACR is often associated with hyperferritinemia, and both, independently, are associated with MetS and IR. Several studies investigating the association between NAFLD and urinary albumin-to-creatinine ratio (UACR) concluded that NAFLD increases risk of albuminuria, possibly mediated by IR. Hyperferritinemia, IR and NAFLD are interrelated and significantly contribute to the risk of albuminuria. HepFe is also related to hyperferritinemia, IR and NAFLD, however there is no evidence on whether it is also associated with albuminuria. There is a paucity of data on the possible role of diet in the development of CKD, specifically increased albuminuria. Studies mainly focus on protein intakes and when distinguish between animal and vegetables sources, proteins from meat are observed to have possible implications, however results remain inconsistent. Generally, plant-based diets with low intakes of proteins and fats from animal sources show an inverse relationship with increased albuminuria, however more evidence is needed. For all of the above, the general objective of the present doctoral thesis is to explore a possible relationship between NAFLD and renal health. The study population includes adult patients, aged 40-60y, with MetS and ultrasound-proven NAFLD, enrolled in a 6-month intervention study on modification of lifestyle habits. Results show that patients with MRI-proven NAFLD are more likely to present increased estimated GFR (eGFR) than patients without, and that hyperfiltration is associated with liver fat. Following an intervention employing an energy restricted healthy diet and physical activity, patients who were hyperfiltrating at baseline experienced a significant reduction in eGFR. UACR was also reduced. Amelioration of hyperfiltration was associated with a reduction in liver fat content and IR, and an increase in energy expenditure. HepFe, IR, and serum ferritin are associated with mean UACR in patients with NAFLD and Mets. Consistently, patients with mildly-increased HepFe present higher levels of UACR, IR, serum ferritin, and hepatic fat content than those with no evidence of HepFe overload. Finally, in patients with MetS and NAFLD, increased intakes of fat from animal foods and IR are independent predictors of increased albuminuria. Taken together these results highlight a possible role of NAFLD on renal health in the context of MetS. Further evidence is needed to confirm early associations between NAFLD and CKD and whether interventions on lifestyle habit modification can change long-term renal outcomes.