Presence of KIR2DL2/S2, KIR2DL5, and KIR3DL1 Molecules in Liver Transplant Recipients with Alcoholic Cirrhosis Could Be Implicated in Death by Graft Failure

Abstract

Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient's vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival.

Keywords: KIR genes; alcoholic cirrhosis; causes of death; liver transplant; sepsis.

Figure 1

Analysis of the frequency of KIR genes in causes of death in patients with and without ascites. (A) Deceased patients due to multiorgan failure. (B) Deceased patients due to sepsis. (C) Deceased patients due to GF.

Figure 2

Analysis of the frequency of KIR genes in the main causes of death in patients with and without encephalopathy. (A) Deceased patients due to multiorgan failure. (B) Deceased patients due to sepsis. (C) Deceased patients due to GF. * p = 0.018; OR = 2.124; 95% CI: 1.264–2.146, p value obtained by comparing encephalopathy-/KIR2D2DL5+ with encephalopathy+/KIR2D2DL5+ AC patients. (D) Comparison of the different causes of death in AC patients KIR3DL1+ with and without encephalopathy.

Figure 3

Kaplan–Meier patient survival curves according to the main cause of death and KIR genes. (A–E) Kaplan–Meier patient survival curves according to the frequency of iKIRs (KIR2DL1+, KIR2DL2+, KIR2DL3+, KIR2DL5+, and KIR3DL1+). iKIR, inhibitory KIR; aKIR, activatory KIR. Other causes of deaths include; Lung edema, pharynx neoplasia, pancreatitis, pneumonia, chronic rejection, primary dysfunction, and HCV relapse.

Figure 4

Kaplan–Meier patient survival curves based on the main cause of death and KIR genes. (A) Kaplan–Meier patient survival curves according to the presence of KIR2DL3+. (B–F) Kaplan–Meier patient survival curves according to the presence of KIR2DS2+, KIR2DS3+, KIR2DS4+ and KIR2DS5+, KIR3DS1+.