Role of Endotoxemia in Causing Renal Dysfunction in Cirrhosis

Abstract

Renal failure is a challenging problem in patients with cirrhosis since mortality increases with worsening renal function, hence the inclusion of serum creatinine in calculating the Model for End-Stage Liver Disease score for liver transplant evaluation. Among the various causes, infection is the leading etiology of mortality associated with cirrhosis. Bacterial infection frequently precipitates renal failure in patients with cirrhosis with the reported prevalence around 34%. Patients with cirrhosis are at increased risk of infections due to impaired immunity and increased gut permeability leading to bacterial translocation in the setting of portal hypertension. One of the most feared complications of severely decompensated liver and renal failure is hepatorenal syndrome, of which liver transplant may be the only available treatment. Furthermore, in those with spontaneous bacterial peritonitis and urinary tract infection, progressive renal failure occurs despite resolution of infection. Thus, the effects of endotoxemia on renal function in cirrhosis have become a major focus of research. The mechanisms of the damaging effects of endotoxin on renal function are complex but, in essence, involve dysregulated inflammation, circulatory dysfunction, poor clearance of endotoxin burden, as well as vasomotor nephropathy. In this article, we will review the mechanisms of endotoxemia-induced renal dysfunction in the setting of cirrhosis through the effects on renal blood flow, renal vascular endothelium, glomerular filtration rate, and tubular function.

Impact of small intestinal bacterial overgrowth on systemic inflammation, circulatory and renal function, and liver fibrosis in patients with cirrhosis and ascites

“…In support of these observations, we have previously reported an improvement of renal function, along with amelioration of systemic hemodynamics, in patients with cirrhosis and ascites after prevention of endotoxemia with rifaximin treatment [ 23 ]. Experimental evidence has also confirmed that LPS may directly impair renal function in cirrhosis [ 24 ] via distortion of glomerular integrity [ 25 ] and renal vasoconstriction [ 26 , 27 ], independently of systemic hemodynamic changes [ 27 ]. On the other hand, it could be hypothesized that differences in renal function might be a potential factor contributing to SIBO in this subgroup [ 28 ].…”

Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats

“…In the Child–Pugh class of decompensated cirrhosis, urinary lipocalin-2/IL-18 levels increased and GFR decreased significantly [ 30 , 31 , 32 ]. The most common cause for acute on chronic renal dysfunction in cirrhosis is acute tubular necrosis (ATN), which occurs as a complication of sepsis [ 4 , 5 , 9 , 15 , 32 ]. Urine levels of IL-18 and lipocalin-2 from patients with cirrhosis discriminate between those with ATN and other types of kidney impairments [ 32 ].…”

“…NFκB plays a major role in the inflammatory response, and over-activation of NFκB induces the overexpression of TNFα, thus accelerating renal injury [ 4 , 7 , 8 , 13 , 34 ]. In streptozotocin-induced diabetic nephropathy rats, chronic pioglitazone treatment reduced renal NFκB, IL-1β and IL-18 levels, depressed the glomerular mesangial expansion, and decreased serum BUN/creatinine [ 35 ].…”

“…In cirrhosis, endotoxemia-activated tumor necrosis factor α (TNFα)/NFκB signals are involved in the development of systemic, pulmonary, splanchnic and renal dysfunction [ 1 , 2 , 3 ]. In cirrhotic kidneys, acute accumulation of lipopolysaccharide (LPS, endotoxin) results in TNFα/NFκB-mediated hypoperfusion and inflammation-driven acute on chronic renal dysfunction by increasing renal adhesion molecule, increasing renal M1 macrophage infiltration, decreasing renal blood flow (RABF), increasing renal vascular resistance (RVR), and increasing renal tissue/renal vascular inflammation [ 4 , 5 , 6 , 7 , 8 ].…”

Liver cirrhosis and complications from the perspective of dysbiosis

“…HRS is a severe complication of advanced liver cirrhosis with a prevalence between 11% and 20% ( 140 ). The mechanism of HRS is not clear, but it is mainly related to the following two aspects: on the one hand, the production of ascites increases, and the circulating blood volume decreases after decompensation of liver cirrhosis, resulting in prerenal renal failure ( 141 ); on the other hand, the bacterial dysbiosis and the translocation of bacteria and related products after decompensation of liver cirrhosis lead to the endotoxemia, which is closely related to HRS ( 142 , 143 ). Animal model studies have shown that the increased expression of TLR4 in the kidney tissue of cirrhotic rats increases the susceptibility to LPS, then activates the NF-κB pathway, increases the expression of proinflammatory cytokine tumor necrosis factor-α (TNF-α), and renal tubular injury ( 144 ).…”