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Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling.

Background: Interactions between the digestive system and the brain functions have become in recent years an important field of psychiatric research. These multidirectional interactions take place in the so called microbiota-gut-brain axis and emerging scientific data indicate to the significant role of microbiota in the modulation of the central nervous system (CNS) including affective and cognitive functions., Objective: An assessment of psychobiotic and immunomodulatory effects of probiotic bacteria Lactobacillus Plantarum 299v (LP299v) by measuring affective, cognitive functions and biochemical parameters in patients with MDD undergoing treatment with selective serotonin reuptake inhibitors (SSRI)., Design: Seventy nine patients with MDD were randomized and allocated to a double-blind, placebo-controlled trial. Participants received either a SSRI with the probiotic LP299v (n = 40) for a period of 8 weeks or a SSRI with the placebo of the probiotic (n = 39) for the same period. The severity of psychiatric symptoms was assessed using Hamilton Depression Rating Scale (HAM-D 17), Symptom Checklist (SCL-90) and Perceived Stress Scale (PSS-10). Cognitive functions were assessed using the Attention and Perceptivity Test (APT), Stroop Test parts A and B, Ruff Figural Fluency Test (RFFT), Trail Making Test (TMT) Parts A and B and the California Verbal Learning Test (CVLT). Biochemical parameters such as tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HKYN), anthranilic acid (AA), 3-hydroxy anthranilic acid (3HAA), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL-1b) and cortisol plasma concentrations were measured., Results: Sixty participants finished the study and were analyzed: 30 participants in the LP299v group and 30 participants in the placebo group. There was an improvement in APT and in CVLT total recall of trials 1-5 in the LP299v group compared with the placebo between baseline and after 8 weeks of intervention. There was a significant decrease in KYN concentration in the LP299v group compared to the placebo group. We also observed significant increase in 3HKYN:KYN ratio in the LP299v group compared with the placebo group. Additionally, Repeated Measures ANOVA revealed a significant effect of interaction of Treatment x time for AA concentration. However, results of post hoc analysis did not reach statistical significance in neither probiotic nor placebo group. There were no significant changes of TNF-α, IL-6 and IL-1b and cortisol concentrations in neither probiotic nor placebo groups., Conclusions: Augmentation of SSRI treatment with probiotic bacteria Lactobacillus Plantarum 299v improved cognitive performance and decreased KYN concentration in MDD patients. Decreased KYN concentration could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group. To our knowledge results of this study are the first evidence of improvement of cognitive functions in MDD patients due to probiotic bacteria and this is the first evidence of decreased KYN concentration in MDD patients due to probiotic bacteria., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the mechanisms underlying this phenomenon are unclear, our experiment showed a link between renovascular hypertension and activation of kynurenine pathway. Impact statement As hypertension is a major health problem, our research has focused on the connection between the kynurenine pathway and hypertension. We assessed the levels of the main metabolites of dietary tryptophan and analyzed its levels in terms of high blood pressure. The results of our work indicated that in the renovascular rat's model of hypertension, an alteration of the kynurenine pathway occurred. According to our knowledge, this is the first study that has investigated in a comprehensive manner the alteration of the kynurenine pathway under the condition of elevated blood pressure. On the one hand, the work supports a better understanding of pathophysiological basics of the occurrence of hypertension, and on the other hand it provides potential opportunities to treat this disease.

Introduction: The haemostatic and biochemical abnormalities participate in the progression of cardiovascular disease (CVD) in peritoneally dialysed (PD) patients. Recently, the role of kynurenine (KYN) pathway of tryptophan (TRP) degradation in the development of CVD has been postulated., Materials and Methods: The present study was undertaken to investigate haemostatic parameters, biochemical profiles and kynurenines in PD patients both with and without CVD compared to age- and sex-matched healthy controls., Results: The multiple biochemical abnormalities were present in PD patients, particularly in those with CVD. Tissue factor (TF), its inhibitor (TFPI), prothrombin fragment 1+2 (F(1+2)), urokinase-type plasminogen activator (uPA), its soluble receptor (suPAR), plasmin/antiplasmin (PAP) complexes, KYN, kynurenic (KYNA) and quinolinic (QA) acids levels were significantly higher, whereas TRP was significantly lower in the PD patients than in the controls. Tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were higher in the patients with CVD than in the patients without CVD and controls. PD patients with CVD had higher F(1+2), and they had lower suPAR and KYNA levels compared with PD patients without CVD. KYNA was positively associated with TFPI, whereas its was inversely associated with F(1+2) both in the whole PD group and in CVD patients. Logistic regression analysis showed that low KYNA, high glucose, low HDL-cholesterol levels and the duration of dialysis treatment were independently associated with the presence of CVD in PD patients., Conclusions: The present study suggests a relationship between kynurenine pathway of tryptophan degradation, haemostatic and biochemical disturbances and CVD prevalence in peritoneally dialyzed patients., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Disturbances of the fibrinolytic system and kynurenine (KYN) pathway of tryptophan (TRP) metabolism have been postulated as important factors in the pathogenesis of cardiovascular disease (CVD). However, no data are yet available on the associations between these 2 systems in relation to CVD prevalence in patients with chronic renal failure (CRF)., Methods: We evaluated TRP and its metabolites, KYN, 3-hydroxykynurenine, and quinolinic acid (QA), and their relations with the parameters of the fibrinolytic system, such as tissue-type plasminogen activators and urokinase-type (uPA) plasminogen activators, plasmin-antiplasmin (PAP) complexes, plasminogen activator inhibitor-1, and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels as the marker of oxidative stress in a population of 50 patients with CRF and 20 healthy controls. In addition, the relations of these parameters to CVD prevalence in patients with CRF were also determined., Results: Compared with controls, the CRF group had significantly increased KYNs, PAP, uPA, soluble urokinase PA receptor (suPAR), plasminogen activator inhibitor-1 (all P < 0.0001), and tissue-type plasminogen activators (P < 0.01) concentrations. TRP levels were significantly lower (P < 0.0001), whereas Cu/Zn SOD levels did not differ significantly between patients with CRF and controls. An accelerated PAP formation was positively correlated with age, inflammatory state, creatinine, uPA/suPAR system, 3-hydroxykynurenine, QA, Cu/Zn SOD, and CVD prevalence, whereas it was inversely associated with TRP levels and estimated glomerular filtration rate. Multivariable analysis confirmed that QA, TRP, suPAR, and Cu/Zn SOD levels were the independent variables significantly associated with the hyperfibrinolytic state in patients with CRF., Conclusions: This cross-sectional study has demonstrated that hyperfibrinolysis was associated with uPA/suPAR system, KYNs, oxidative status, and CVD prevalence in patients with CRF.

Purpose: The kynurenine pathway (KP) is a major route of tryptophan metabolism. Several metabolites of this pathway are proposed to be involved in the pathogenesis of Alzheimer's disease. The aim of this study was to evaluate peripheral KP in patients with Alzheimer type dementia and a detailed analysis of correlation between kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), anthranilic acid (AA), quinolinic acid (QUIN) and degree of neuropsychological changes in AD., Material/methods: The plasma concentration of tryptophan and its products degradation by kynurenine pathway were analyzed in 34 patients suffering from Alzheimer type dementia and 18 controls in similar age using high-performance liquid chromatography technique., Results: In demented patients we found lower tryptophan and KYNA concentrations. There was a non-significant increase of KYN, 3-HK and AA levels, and a Marked increase of QUIN in Alzheimer's disease group. We observed positive correlations between cognitive function tests and plasma KYNA levels, and inversely correlations between these tests and QUIN levels in Alzheimer type dementia., Conclusions: Increased TRP degradation and simultaneous altered kynurenines levels were found in plasma of AD patients. It proves activation of peripheral kynurenine pathway in this type of dementia. The alterations of two main KYN metabolites: KYNA and QUIN seem to be associated with the impairment of the cognitive function in AD patients. This appears to offer Novel therapeutic opportunities, with the development of new compounds as a promising perspective for brain neuroprotection.

Purpose: The endothelium dysfunction is an important component of atherosclertic cardiovascular disease. It has been also suggested that kynurenine pathway activation may be involved in the pathogenesis of this disease., Material/methods: This is a cross-sectional study in chronic kidney disease (CKD) patients (n=106; 60 Males). The plasma markers of endothelial dysfunction and kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), kynurenic acid (KYNA), anthranilic acid (AA) and quinolinic acid (QA) were measured in relation to an early indicator of the systemic atherosclerosis - intima-media thickness (IMT)., Results: Kynurenines, von Willebrand factor (vWF), thrombomodulin (TM), soluble adhesion molecules (sICAM-1, sVCAM-1) and IMT in each uraemic group were significantly higher than in healthy people. In contrast, no significant differences in sE-selectin and sP-selectin concentrations were observed between CKD patients and controls. Kynurenines were positively associated with vWF, TM, sICAM-1 and sVCAM-1, whereas sP-selectin was inversely associated with the most of kynurenines. IMT was positively correlated both with kynurenines: KYN, 3-HKYN, QA as well as with endothelial markers: TM, vWF, sICAM-1 and sVCAM-1 (all p<0.01). Finally, multiple regression analysis identified age, vWF, sVCAM-1 and QA levels as the independent variables significantly associated with increased IMT in this population (adjusted r² = 0.51)., Conclusions: This study suggests a relationship between kynurenine pathway activation, endothelial dysfunction and the progression of atherosclerosis in CKD patients. It opens a new idea that the inhibition of kynurenine pathway may provide an effective strategy to slow down endothelial dysfunction and thereby the prevalence of atherosclerosis in this population.

The abnormalities of tissue factor (TF) and its inhibitor (TFPI) system could potentially contribute to high incidence of thrombotic complications and atherosclerosis in patients with chronic kidney disease (CKD). Recently, the role of the kynurenine (KYN) pathway of tryptophan (TRP) degradation has been postulated in the progression of cardiovascular complications. We compared the plasma TF, TFPI and the metabolites of TRP degradation: KYN and 3-hydroxykynurenine (3-HKYN) levels in 55 CKD patients on conservative treatment and 19 healthy controls; and we tried to establish whether or not there is an association between TF/TFPI system and above-mentioned metabolites in these patients. Compared with the controls, the patients with CKD showed a significant increase in plasma concentrations of TF (P < 0.01), KYN, 3-HKYN (both P < 0.0001), KYN-to-TRP (kyn/trp) ratio (P < 0.001) and 3-HKYN-to-KYN (3-hkyn/kyn) ratio (P < 0.05). In contrast, TRP concentrations were significantly decreased in the CKD group compared with controls (P < 0.001). The difference in TFPI levels between CKD patients and controls was not statistically significant. TF/TFPI system was inversely correlated with TRP, whereas it was positively related to the 3-HKYN, kyn/trp and 3-hkyn/kyn ratios. Moreover, both the TF/TFPI system and KYNs were associated with the markers of kidney function. These data suggested for the first time a significant relationship between TF/TFPI system and KYN pathway in CKD patients on conservative treatment.

Background: Cellular adhesion molecules and oxidative stress play a role in the pathogenesis of atherosclerosis in patients with chronic kidney disease (CKD). Recently, it has been postulated that the kynurenine (KYN) pathway could be involved in the pathogenesis of atherosclerosis., Methods: We evaluated the KYN, kynurenic acid (KYNA), anthranilic acid (AA), and their relations with cellular adhesion molecules: soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), sE-selectin, sP-selectin, and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels as the markers of oxidative stress in the population of 132 patients with CKD and 28 healthy controls., Results: Compared with the controls, 2 groups of dialyzed patients had significantly increased KYN (both P < 0.01), KYNA, AA, sICAM-1, sVCAM-1, and Cu/Zn SOD levels (all P < 0.001, respectively). KYN, AA, sICAM-1, and sVCAM-1 concentrations were significantly higher in undialyzed patients with CKD compared with healthy subjects (P < 0.001, P < 0.01, and both P < 0.05, respectively). sICAM-1 and sVCAM-1 were positively associated with KYN (P < 0.0001 and P < 0.01), KYNA (P < 0.05 and P < 0.0001), AA (P < 0.01 and P < 0.0001), and with Cu/Zn SOD (both P < 0.0001, respectively) in the whole CKD group. The positive relationship existed between sICAM-1, sVCAM-1 and age, high-sensitivity C-reactive protein, creatinine, and the duration of dialysis therapy. Multivariable analysis showed that KYN was a strong independent correlate of sICAM-1, whereas Cu/Zn SOD and platelets independently and significantly predicted sVCAM-1 in patients with CKD., Conclusions: This study demonstrated that KYN is independently and significantly associated with elevated sICAM-1, whereas oxidative status and platelets independently and significantly predicted increased sVCAM-1 levels in patients with CKD.

Introduction: Increased oxidative stress (SOX) is one of the most potent inductors of endothelial dysfunction in end-stage renal disease (ESRD) patients. Kynurenines are the metabolites of tryptophan (TRP) degradation in mammals. However, the role of kynurenines in the function of the endothelium is still not recognized., Materials and Methods: We determined the plasma concentrations of TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), quinolinic acid (QA); markers of SOX: Cu/Zn superoxide dismutase (Cu/Zn SOD), malondialdehyde (MDA); and endothelial dysfunction markers: thrombomodulin (TM) and von Willebrand factor (vWF) levels in 148 ESRD patients and healthy controls., Results: TM, vWF, KYN, 3-HKYN and QA levels were significantly elevated in ESRD patients compared to controls. TRP concentrations in uremics were significantly lower than in healthy people. Both dialyzed groups showed a significant increase Cu/Zn SOD and MDA levels compared to controls. TM and vWF were positively associated with kynurenine pathway metabolites: KYN, 3-HKYN, QA (all p<0.001), and with SOX markers: Cu/Zn SOD (both p<0.0001) and MDA levels (p<0.05, and p<0.0001; respectively) in the whole ESRD group. The positive relationship were between Cu/Zn SOD and KYN (p<0.010), 3-HKYN and QA levels (both p<0.0001), whereas MDA was correlated with 3-HKYN and QA concentrations (both p<0.05). Multiple stepwise regression analysis showed that KYN metabolites and oxidative status were the independent variables significantly associated with increased both TM and vWF levels in uremic patients., Conclusions: Our study demonstrated that kynurenine metabolites and increased oxidative status are independently and significantly associated with endothelial dysfunction in ESRD patients.

Patients with end-stage renal disease (ESRD) exhibit features of a hypercoagulable state, which may contribute to atherosclerosis. Kynurenines are the metabolites of tryptophan degradation in mammals. We examined the relationship between coagulation activation and kynurenines in 92 patients with ESRD on maintenance haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) and 20 healthy controls. We measured the plasma levels of: tissue factor (TF), its pathway inhibitor (TFPI), the marker of coagulation activation - prothrombin fragments 1+2 (F(1+2)), kynurenine (KYN) and its metabolites: kynurenic (KYNA), anthranilic (AA) and quinolinic (QA) acids. The ratio of KYNA to KYN (kyna/kyn), AA to KYN (aa/kyn) and QA to KYN (qa/kyn), reflecting intensified activity of enzymes which converted KYN to its metabolites, were also determined. Measured coagulation parameters and kynurenines were significantly elevated in ESRD patients compared to controls. TF, TFPI and F(1+2) were significantly associated with AA, aa/kyn, QA and qa/kyn ratio. Multiple regression analysis showed that fibrinogen (p<0.01) and above mentioned KYN metabolites (all p<0.05) were the independent variables significantly associated with increased F(1+2) levels, reflecting hypercoagulability in ESRD patients. In conclusion, this study represents the first to investigate both the coagulation system and KYN pathway in ESRD patients. The coagulation was enhanced in dialysed uraemic patients compared with the healthy controls demonstrated by increased TF, TFPI and F(1+2) levels. These changes were correlated with activation of the KYN pathway. Finally, fibrinogen and KYN metabolites are independently and significantly associated with the hypercoagulable state in uraemic patients on CAPD and HD treatment.

Increased oxidative stress (SOX), inflammation and accelerated atherosclerosis have been reported in end-stage renal disease (ESRD), but their associations with kynurenine pathway activation remain unknown. We determined the plasma concentrations of kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA); three distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD), total peroxide and malondialdehyde (MDA), high sensitivity C-reactive protein (hs CRP) as a indicator of inflammation, and intima-media thickness (IMT)--an early reflection of the systemic atherosclerosis in the population of 124 patients with ESRD. In uraemia, the concentrations of KYN, KYNA and QA were increased by 37-105%, by 84-428%, and by 394-1018% of the control values; respectively. These changes were accompanied by significant increase in kyna/kyn and qa/kyn ratios, reflecting increased activity of kynurenine pathway enzymes. KYN, QA and qa/kyn ratio were positively associated with inflammation, SOX markers, and IMT values in uraemics. Moreover, multiple stepwise regression analysis identified age, presence of diabetes mellitus, QA and qa/kyn ratio as the independent variables significantly associated with increased IMT in this population. In conclusion, the results of the present study suggest a relationship between kynurenine pathway activation and increased oxidative stress, inflammation and the progression of atherosclerosis in end-stage renal disease patients.

Increased oxidative stress (SOX), inflammation and prevalence of cardiovascular disease (CVD) have been reported in end-stage renal disease (ESRD), but their associations with kynurenine (KYN) pathway activation remain unknown. We determined the plasma concentrations of tryptophan (TRP), KYN, 3-hydroxykynurenine (3-HKYN); two distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD) and total peroxide; and high sensitivity C-reactive protein (hs CRP) as a indicator of inflammation in 146 ESRD patients and healthy controls. Analysis of TRP degradation through the KYN pathway demonstrated that in uremia the concentrations of this aminoacid were decreased by 40-60% in comparison with controls. In contrast, the plasma levels of KYN and 3-HKYN in ESRD patients were increased by 32-96% and 184-306%, respectively. These changes were accompanied by significant increase in the kyn/trp ratios by 140-240%, and 3-hkyn/kyn ratios by 40-154% in uremics compared to controls. ESRD patients showed a significant increase in Cu/Zn SOD, total peroxide and hs CRP levels between controls and all patients group. KYN and 3-HKYN were positively associated with inflammation and SOX markers in uremics. Logistic regression analysis showed that age, gender, presence of DM (all p<0.001), elevated hs CRP (p<0.01) and 3-HKYN levels (p<0.05) were independently associated with the presence of CVD in this population. These results suggest a relationship between KYN pathway activation and increased SOX, inflammation and CVD prevalence in ESRD patients.

Aim: Disturbances in amino acids metabolism are common in chronic renal failure and subside partially after renal tranplantation. Tryptophan (TRP) is one of the most important exogenous amino acids. Its main derivative is L-kynurenine (KYN). Disorders in the TRP metabolism via kynurenine pathway may lead to neurologic disturbances, hypertension and anaemia. The aim of this study was to assess peripheral kynurenine pathway in 28 renal allograft recipients (RAR) (12 women and 16 men) in comparison to 10 hemodialysed patients with chronic renal failure (CRF) and 10 healthy subjects., Methods: TRP, KYN, 3-hydroxykynurenine (3-HKYN), kyn-urenic acid (KYNA) and quinolinic acid (QA) were determined in plasma using high performance liquid chromatography technique., Results: The plasma concentration of tryptophan in RAR was not significantly different from the control group, but it was almost twice higher than in CRF. There was an increase in most of kynurenine metabolites in RAR as compared to healthy subjects, although not as high as in CRF. We found a significant negative correlation between TRP and serum concentration of urea and creatinine as well as a positive correlation with GFR., Conclusions: Kidney transplantation tends to normalize TRP level and markedly lowers blood concentration of kynurenine and its main derivatives. A significant negative correlation was found between TRP level and the concentration of urea and creatinine. Lowering of the KYN metabolites level may play a role in lessening uremic neurological symptomes as well as hypertension and anemia in kidney graft recipients.

In patients that developed a chronic renal failure the augmentation in tryptophan degradation is reflected in the increase in plasma metabolites of kynurenine pathway. Hemodialysis is one of therapeutic approaches that significantly reduce all plasma kynurenine metabolites in uremic patients. In spite of haemodialysis, plasma concentration of kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid and quinolinic acid were still elevated in uremic patients in comparison with healthy volunteers. These data shows significant disturbances in kynurenine metabolism in uremic patients. Accumulation of these substances in uremic blood is capable to account for certain uremic symptoms.