Evaluation of Soluble alpha-Klotho
in Neuropsychiatric Systemic Lupus Erythematosus

ABSTRACT

Background/Purpose:
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication
in SLE that presents a variety of symptoms. No reliable diagnostic markers for
NPSLE have been identified, because of the variability of NPSLE manifestations and
the absence of appropriate diagnostic criteria. Alpha-Klotho
is a single-pass transmembrane protein expressed in multiple tissues,
especially brain and kidneys. A reduction of Klotho
protein is known to be associated with endothelial dysfunction and neuronal
damage.

Methods:
We sought to determine whether soluble alpha-Klotho (s-Klotho) in cerebrospinal fluid (CSF) could be a candidate
marker for the diagnosis of NPSLE. We retrospectively analyzed the laboratory
data, symptoms and radiological image findings of patients with NPSLE (n=34)
admitted to our hospital during a 10-year period from 2006 through 2015. Patients
with SLE (n=17), viral meningitis (VM) (n=19), multiple sclerosis (MS) (n=15) or
neuromyelitis optica (NMO)
(n=16) were included as controls. The s-Klotho level in
the CSF of each subject was measured by enzyme-linked immunosorbent assay. We
conducted univariate and multivariable competing-risks regression analyses to
determine the predictive factors for diagnosing NPSLE. We also evaluated a
cutoff value of s-Klotho for the diagnosis of NPSLE by determining the receiver
operating characteristic (ROC) curve.

Results:
There was no significant difference in the clinical background between the NPSLE
and SLE patients. The median CSF s-Klotho level in the
NPSLE, SLE, VM, MS and NMO groups (in pg/mL) were 136.7,
380.2, 302.1, 186.4 and 203.1, respectively. We found that the CSF s-Klotho levels
of the NPSLE patients were significantly lower than those of the other groups. The
multivariable analyses revealed that lower CSF s-Klotho
level (odds ratio [OR], 0.98; 95% confidential interval [CI], 0.96–0.99), lower
anti-Smith antibodies (U/mL) (OR, 0.93; 95%CI, 0.82–0.99) and higher C3 (mg/dL) (OR, 1.08; 95%CI, 1.02–1.18) were significant factors
for predicting NPSLE. The sensitivity and specificity of the CSF s-Klotho level
for the diagnosis of NPSLE were 94.1% and 76.5%, respectively at the cut-off
value of 294.8 pg/mL.

Conclusion: Our
data suggested that lower CSF s-Klotho levels may be associated with the endothelial
dysfunction and neuronal damage in NPSLE patients. The determination of CSF s-Klotho
levels may contribute to the diagnosis of NPSLE and may help elucidate the
mechanisms underlying this disease.