Klotho Levels and Their Relationship with Inflammation and Survival among Alcoholic Patients

Abstract

α-Klotho (Klotho) is an antiaging hormone with anti-inflammatory and antioxidative properties. Some studies suggest that Klotho increases in response to enhanced oxidative damage and inflammation. Alcoholism is a proinflammatory condition. The aim of this study was to analyze the relationship between Klotho and the serum levels of the inflammatory markers in alcoholic liver disease and to assess its prognostic value. We included 184 alcoholics and 35 age- and sex-matched controls. We determined the serum levels of Klotho, the tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and malondialdehyde (MDA), and routine laboratory variables. Patients were followed-up with during 16 ± 18 months; 67 patients died. Klotho levels were higher among cirrhotics (with KW = 37.00 and p < 0.001) and were related to the Child–Pugh score (with KW = 15.96 and p < 0.001) and to the TNF-α (ρ = 0.28; p < 0.001) and MDA (ρ = 0.21; p = 0.006). The child’s groups were associated with mortality, both in the univariate (with the log-rank = 13.56, p = 0.001, Breslow = 12.33, and p = 0.002) and multivariate (with β = 0.43, p = 0.02, and OR = 1.53 (1.07–2.15)) analyses, also introducing Klotho and the TNF-α as dichotomic variables. However, the independent prognostic value of the Child’s groups was displaced by Klotho when only cirrhotics were considered; Klotho, over the median (574.4 pg/mL), was associated with higher mortality (with p = 0.04 and OR = 2.68 (1.06–6.84)). We conclude that Klotho is increased in liver cirrhosis. It is directly related to TNF-α, MDA, and to mortality in cirrhotics.

Association between soluble α-klotho and mortality risk in middle-aged and older adults

“…In alcoholic cirrhotic patients, studies showed higher-than-normal levels of soluble α-klotho in association with liver function derangement, possibly reflecting an attempt to regulate increased inflammation ( 40 ). In addition, in alcoholic individuals, those with higher klotho levels were found to have a greater mortality risk compared to those with lower levels, and this correlation was even more pronounced in cirrhotic patients ( 39 ). Whether our observation that HCV infection was associated with higher soluble α-klotho levels involved similar mechanisms remains to be elucidated.…”

“…Our study showed that HCV infection was significantly associated with higher soluble α-klotho levels, whereas other comorbidities including diabetes, hypertension, CVD, and previous stroke were not. Previous studies had suggested that an increased level of klotho could represent a compensatory response to physiologic stress and inflammation ( 38 , 39 ). In alcoholic cirrhotic patients, studies showed higher-than-normal levels of soluble α-klotho in association with liver function derangement, possibly reflecting an attempt to regulate increased inflammation ( 40 ).…”

Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation

“…However, it is plausible that the positive correlation found between SCI and s-Kl at month 3 post-KT may be an early compensatory response to graft inflammation and that s-Kl would act as an anti-inflammatory molecule. The fact that s-Kl is found to be remarkably high in major inflammatory diseases such as rheumatoid arthritis [ 20 ], alcoholism-associated inflammation [ 21 ] and sepsis [ 22 ] supports this argument. Thus, individual cytokines in the inflammatory environment (e.g., proinflammatory cytokines such as TNF-α) might exert a dual effect on soluble klotho, decreasing the transcription of the transmembrane molecule but increasing the shedding of soluble klotho by augmenting ADAM expression, a secretase that promotes the shedding of the soluble protein klotho [ 23 , 24 ].…”

Advances in genetic variation in metabolism-related fatty liver disease

“…It is located in 13q12. The total length of the 50 kb gene contains 4 introns and 5 exons, and has various biological effects such as antioxidant, anti-inflammatory and anti-apoptosis ( Martin-Gonzalez et al, 2022 ). The human KL gene encodes alpha-Klotho protein, a multifunctional protein that regulates phosphate, calcium, and vitamin D metabolism, it is mainly expressed as a single transmembrane glycoprotein in kidney, parathyroid, brain and adipose tissue, and as a co-receptor of fibroblast growth factor 23(FGF23) ( Kuro, 2019 ).…”