Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency

Marked increases in metabolites of the L-tryptophan-kynurenine pathway, L-k ynurenine and quinolinic acid (Quin), were observed in serum and cerebrospi nal fluid (CSF) of both the rat and human with renal insufficiency. The mec hanisms responsible for their accumulation after renal insufficiency were i nvestigated. In patients with chronic renal insufficiency, elevated levels of serum L-kynurenine and Quin were reduced by hemodialysis. In renal-insuf ficient rats, Quin and L-kynurenine levels in serum, brain, and CSF were al so increased parallel to the severity of renal insufficiency. Urinary excre tion of Quin (3.5-fold) and L-kynurenine (2.8-fold) was also increased. Liv er L-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of t he kynurenine pathway, was increased in proportion to blood urea nitrogen a nd creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphor ibosyltransferase were unchanged, but the activities of kynureninase, 3-hyd roxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarbo xylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in c ontrol rats, demonstrating that changes in body ACMSDase activities in resp onse to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increas ed serum L-kynurenine concentrations are mainly due to the increased TDO an d decreased kynureninase activities in the liver and increased serum Quin c oncentrations are due to the decreased ACMSDase activities in the body afte r renal insufficiency. The accumulation of CSF L-kynurenine is caused by th e entry of increased serum L-kynurenine, and the accumulation of CSF Quin i s secondary to Quin from plasma and/or Quin precursor into the brain.