Peri-transplant renal dysfunction in patients with non-alcoholic steatohepatitis undergoing liver transplantation

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently the most common etiology of chronic liver disease (CLD) caused by an accumulation of fat in the liver and globally is the leading indication of liver transplantation. Emerging data has recognized an increased association of NAFLD with risk of other metabolic liver diseases like type 2 diabetes mellitus, chronic kidney disease (CKD) and cardiovascular diseases. Pathophysiologically, NAFLD patients have a state of low-grade systemic inflammation, insulin resistance and atherogenic dyslipidemia which causes renal dysfunction. Patients with NAFLD cirrhosis awaiting liver transplant (LT) face unique challenges and have a significantly higher requirement of simultaneous-liver-kidney transplant as compared to other etiologies. Further, NAFLD not only recurs but also occurs as a de novo manifestation post-LT. There is also a significantly higher risk of waiting list stagnation and dropouts due to burdensome cardiometabolic disorders in NAFLD patients. The current review aims to understand the prevalence and pathogenetic basis of renal dysfunction in NAFLD. Additionally, the review describes the choice of immunosuppression protocols and use of intraoperative renal replacement therapy in context of intra and post-operative renal dysfunction in NAFLD patients. Prospective controlled trials focusing on NAFLD and development of CKD are needed to assess the existence of a causal and/or a bidirectional relationship between NAFLD and CKD.

Keywords: Non-alcoholic fatty liver disease (NAFLD); cardio-metabolic disorders; chronic kidney disease (CKD); diabetes; dyslipidemia; gut dysbiosis; hypertension; obesity.

Figure 1

Organ crosstalk in the pathophysiology of NAFLD and CKD. Multiple environmental and genetic factors adipose tissue inflammation can predispose to NAFLD. NEFAs from the intra-abdominal visceral adipose tissue cause activation of inflammation by increasing the levels of NF-κB and inflammatory pathways, dysregulation of adipokine production and impairment of insulin signaling. With increasing severity or progression of disease there is an increase in the pathways that influence the development of CKD. Increased production of uraemic toxins is seen by concomitant gut dysbiosis with an increase in the intestinal permeability. Intestinal microbiota further leads to renal, liver and cardiovascular damage via endothelial dysfunction in patients with NAFLD and CKD. Intestinal dysbiosis frequently occurs in obesity, potentially influences NAFLD, CKD, and T2DM through complex mechanisms (8). DAMPS-Damage associated molecular patterns, PAMPS-pathogen associated molecular patterns; ROS, reactive oxygen species; CKD, chronic kidney disease; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2 diabetes mellitus.

Figure 2

Approach to renal dysfunction in a cirrhotic awaiting liver transplantation with non-alcoholic fatty liver disease. Patients with non-alcoholic liver disease should be stratified based on risk factors i.e., advanced age, obesity, diabetes mellitus, dyslipidemia and hypertension and also those with prior AKI for possible CKD. In patients with risk factors and diagnosis of chronic kidney disease (CKD), the decision to proceed for simultaneous liver-kidney transplant should be done while in the remaining liver transplant alone with close follow up of kidney functions both intra and postoperatively should be done.

Figure 3

Management of non-alcoholic fatty liver disease with or without associated renal dysfunction.