Marked increases in metabolites of the
L-tryptophan-
kynurenine pathway, L-
kynurenine and
quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with
renal insufficiency. The mechanisms responsible for their accumulation after
renal insufficiency were investigated. In patients with
chronic renal insufficiency, elevated levels of serum L-
kynurenine and Quin were reduced by
hemodialysis. In renal-insufficient rats, Quin and L-
kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of
renal insufficiency. Urinary excretion of Quin (3.5-fold) and L-
kynurenine (2.8-fold) was also increased. Liver
L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting
enzyme of the
kynurenine pathway, was increased in proportion to blood
urea nitrogen and
creatinine levels.
Kynurenine 3-hydroxylase and
quinolinic acid phosphoribosyltransferase were unchanged, but the activities of
kynureninase, 3-hydroxyanthranilate
dioxygenase, and
aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of
pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to
renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum L-
kynurenine concentrations are mainly due to the increased TDO and decreased
kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after
renal insufficiency. The accumulation of CSF L-
kynurenine is caused by the entry of increased serum L-
kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain.