This pathway provides a novel insight into regulation of HIF-1 in ischemic kidney, characterized by co-existent hypoxia and inflammation. TOMINAGA NAOTO1, KIDA KEISUKE2, MATSUMOTO NAOKI3, AKASHI YOSHIHIRO J2, MIYAKE FUMIHIKO2, KIMURA KENJIRO1, SHIBAGAKI YUGO1 1Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine; 2Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine; 3Department of Pharmacology, St. Marianna University School of Medicine Introduction: Administration
of high-dose loop diuretics, such as furosemide,
to overcome diuretic resistance is sometimes inevitable during the treatment for severe congestive heart failure (CHF). Administration of diuretics at high dose, however, might cause a variety learn more Depsipeptide in vitro of complications including worsening renal function or metabolic/electrolyte disturbances, and a large-scale clinical study showed that this is also related to worsening prognosis. Co-administration of a novel vasopressin V2 receptor antagonist, tolvaptan, can lessen such adverse events by sparing the dose of loop diuretics; however, its safety in patients with significantly reduced renal function is not yet known. Methods: We co-administered tolvaptan 15 mg Non-specific serine/threonine protein kinase once daily orally for 7 days to 22 patients with CHF complicated by advanced chronic kidney disease (CKD) after administration of high dose of furosemide which was inadequate to control fluid overload. We classified these patients into three groups according to their estimated glomerular filtration rate (eGFR): CKD stages G3b, G4, and G5. Results: In the G3b group, serum sodium concentrations were significantly higher (P = 0.020) on day 8 (one day after the last dose) and, in the G5 group, serum potassium significantly increased (P = 0.037) compared to baseline values,
although these values stayed within reference range and did not seem clinically significant. Though serum urea nitrogen and serum creatinine concentrations rose significantly in the G4 group (P = 0.017 and P = 0.012, respectively), no patient in any group showed deterioration of renal function on day 2 and day 3. Significant change in serum uric acid was not observed in any group, and no significant change was observed in blood pressure or heart rate. Conclusion: We conclude that add-on tolvaptan to high-dose furosemide in patients with furosemide-resistant CHF complicated with advanced CKD was safe and was not associated with significant adverse events.
Background: Maternal smoking has been closely associated with underdevelopment of fetal/neonatal organs, as well as increased risk of numerous diseases such as hypertension, type 2 diabetes and chronic kidney disease in adulthood. Evidence Tofacitinib solubility dmso suggests that oxidative stress and mitochondrial dysfunction might be the two underlying mechanisms. L-carnitine is a natural substance that was shown to benefit both antioxidant defense and mitochondrial
performance in different disorders, thus might be able to reverse the negative impacts of mCSE on the offspring’s kidney. Methods: Female Balb/c mice were exposed to cigarette smoke generated from 2 cigarettes twice daily for 6 weeks before mating, throughout gestation and lactation. A sub-group of SCE mice were administrated with L-carnitine from conception to weaning. Offspring’s kidneys were harvested at birth, weaning and adulthood. Oxidative stress was evaluated by determining the levels of ROS, MnSOD, GPx-1
and mitochondrial SOD activity. Mitochondrial function was examined by the levels of TOM20 and OXPHOS complexes I–V. Body and kidney weight, glucose tolerance, TG and NEFA were also measured. Results: L-carnitine reversed low birth weight, glucose Sorafenib purchase intolerance, and high level of TG in the mCSE mice offspring and this was associated with normalizations of renal MnSOD, GPx-1, TOM20, and most of the OXPHOS complexes at birth and adulthood, but not at weaning. Conclusions: L-carnitine significantly reduces renal oxidative stress and mitochondrial dysfunction in the offspring, induced by maternal smoking. This suggests a potential role for L-carnitine in preventing Chronic kidney disease. 167 MATERNAL OBESITY IS ASSOCIATED WITH RENAL OXIDATIVE STRESS AND INFLAMMATION WHICH IS AMELIORATED BY THE GLP-1 RECEPTOR AGONIST EXENDIN-4 SJ GLASTRAS1, H CHEN2, C POLLOCK1, S SAAD1 1Renal Research Group, Kolling Institute, Royal North Shore Hospital, Sydney, NSW; 2School of Biomedical Sciences, University of Technology, Thiamine-diphosphate kinase Sydney, NSW, Australia Aim: We hypothesized that GLP-1 agonists may reduce markers of oxidative stress and inflammation in the kidneys of offspring of obese mothers. Background: GLP-1 receptor
agonists improve glycaemic control in diabetes and promote weight loss. They may also have beneficial effects on the kidney. Obesity increases risk of associated metabolic diseases and indeed maternal obesity may also increase susceptibility to diabetes, hypertension and chronic kidney disease in the offspring. Methods: Female rats were fed either normal or high-fat diet (HFD) for 6 weeks prior to pregnancy, during pregnancy and weaning and their offspring were weaned to normal or HFD. They were randomised to exendin-4 (Exd4) or placebo at Day 21 and their kidneys harvested at Week 9. Results: Offspring of obese mothers fed HFD had increased weight and glucose intolerance. Exd4 reduced weight and improved glucose tolerance in HFD animals.
The sample remains frozen during PLX4032 in vivo imaging on the cold stage, which is cooled by liquid nitrogen. Even though the frozen state stabilizes the soft material and liquids of the biofilm (which would otherwise be impossible to examine at high magnification, because
of sample movement or beam damage), the cryo-SEM images (Fig. 3) appear to be of a lower resolution compared to conventional SEM. This is partly attributable to a lower conductivity of the frozen surface compared to the dehydrated gold-sputtered surface we employ in conventional SEM. Another downside of cryo-SEM is that the frozen surface melts and cracks at high magnifications because of the heat generated by the focused electron beam. However, we were able to produce images of the biofilm that clearly show that the bacteria are enveloped in a gel-like matrix. We were not able to
obtain high-magnification images showing details of the matrix. Cryo-SEM also allows for freeze-fracture, which exposes the internal structure of the biofilm and may thus reveal how the bacteria are interconnected. The ESEM was developed in the late C59 wnt mouse 1980s (Danilatos, 1988). The ESEM retains many of the advantages of a conventional SEM, without the high vacuum requirement by varying the sample environment through a range of pressures, temperatures, and gas compositions. Wet and nonconductive samples may be examined in their natural state without modification or preparation. The ESEM offers high-resolution secondary electron imaging in a gaseous environment. The obvious advantage of ESEM is the total lack of preparation. The sample is placed directly on a stub and placed in the SEM chamber. However, with ESEM, we had problems obtaining high-resolution images of the biofilm because of the lack of conductivity in the wet sample. We experienced that close to magnifications of 10 000× and more, where the beam current is locally very out high, the focused electron beam seemed to destroy the 3D biofilm structure. We also observed that during prepumping, the sample also slightly dehydrates, but not to near the same extent as the dehydration used in conventional
SEM (Fig. 4). A superior, yet more sophisticated alternative to the conventional SEM and CLSM is the FIB–SEM. Similar to confocal scanning microscopy, it is possible with FIB–SEM to create 3D reconstructions. With a process termed ‘slice and view’, the FIB can sequentially mill away down to 10-nm-thick sections from the surface of a resin embedded specimen and subsequently record a SEM image (Fig. 5a) of the exposed block surface using a back scattered electron detector (BSED). Following acquisition of the successive image slices, the image data are processed to perform a 3D volume reconstruction (Fig. 5b and c). We were able to produce stunning 3D reconstructions of the spatial interaction of bacteria down through the 3-day-old biofilm (Supporting information, Movie S1).
In mouse fibroblasts STAT1 appears to down-regulate the expression of genes
not essential for cellular survival in a phosphorylation-independent manner. GAS or GAS-like sequences remain important targets for STAT1 binding to achieve this regulatory function. This work was supported by American Heart Association Scientist development grant 0535032N awarded to M.M. We would like to express our gratitude to Dr M. Kaplan (Indiana University School of Medicine) for helpful input and to Dr D. Levy (NYU School of Medicine) for providing cell lines and plasmids as well as helpful suggestions. The authors Selleck GDC-973 confirm that the manuscript, the title of which is given above, is original and has not been submitted elsewhere.
Each NVP-LDE225 price author acknowledges that he/she has contributed in a substantial way to the work described in the manuscript and its preparation. “
“Sendai virus (SeV), a pneumotropic virus of rodents, has an accessory protein, V, and the V protein has been shown to interact with MDA5, inhibiting IRF3 activation and interferon-β production. In the present study, interaction of the V protein with various IRF3-activating proteins including MDA5 was investigated in a co-immunoprecipitation assay. We also investigated interaction of mutant V proteins from SeVs of low pathogenicity with MDA5. The V protein interacted with at least retinoic acid inducible gene I, inhibitor of κB kinase epsilon and IRF3 other than MDA5. However, only MDA5 interacted with the V protein dependently on the C-terminal V unique (Vu) region, inhibiting IRF3 reporter activation. The Vu region has been shown to be important
for viral pathogenicity. We thus focused on interaction of the V protein with MDA5. Point mutations in the Vu region destabilized the V protein or abolished the interaction with MDA5 when the V protein was stable. The V-R320G protein was highly stable and interacted with MDA5, but did not inhibit activation of IRF3 induced by MDA5. Viral pathogenicity of SeV is related to the inhibitory effect of the V protein on MDA5, but is not always related Astemizole to the binding of V protein with MDA5. SeV, which belongs to the genus Respirovirus in the family Paramyxoviridae, is a respiratory tract pathogen of rodents. It is an enveloped virus with a single-stranded, negative-sense RNA genome of approximately 15.4 kilobases. The SeV genome comprises six genes encoding structural proteins, including N (nucleocapsid), P (phospho-), M (matrix), F (fusion), HN (hemagglutinin-neuraminidase), and L (large) proteins (1). The P gene, unlike the other genes, encodes not a single protein but multiple proteins. The colinear transcript encodes the P protein as well as C’, C, Y1 and Y2 proteins; the latter four proteins are translated in a shifted frame by alternative translational starts and a common stop codon.
This finding raises the possibility that IVIG blocks MMP activities at the interface
between the blood stream and CNS. With in situ zymography, we also observed that gelatinase activities were expressed mainly in astrocytes in the inflamed spinal cord of control rats and that this expression was attenuated by the treatment. These findings provide useful information to set optimal conditions for IVIG treatment of MS and to obtain more beneficial effects. “
“We report four cases of biopsy-proven B-cell-rich primary angiitis of the central nervous system (PACNS). The mean age of the patients was 29 years (range, 23–37 years). The patients suffered from unilateral weakness (n = 2), seizure (n = 1), and hypersomnia, anorexia and confusion (n = 1). The vital signs and the results of laboratory Sirolimus concentration tests were within normal limits in all the four cases except erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ESR was elevated in one patient and CRP was elevated in two patients. The magnetic resonance imaging (MRI) scans revealed Bioactive Compound Library single (n = 2) or multiple (n = 2) irregularly enhancing lesions. Radiological studies initially indicated tumors such
as glioma (n = 2) or lymphoma (n = 1), except in one case, in which the radiological analysis indicated vasculitis or demyelinating disease. All the cases involved both medium-sized (50–250 µm in diameter) and small-sized vessels (20–49 µm in diameter). The vascular, perivascular mafosfamide and parenchymal lymphocytes were polymorphous; however, CD20-positive B-cells were predominated in blood vessels while the CD8-positive T-cells infiltrated predominantly in brain parenchyma. Therefore, our patients revealed B-cell dominant lymphocytic vasculitis. Two patients who underwent active treatment (corticosteroid alone or with cyclophosphamide) showed remarkable clinical and radiological improvement but two patients still have initial neurological symptoms, namely, confusion and newly developed seizures, respectively,
during the 19–101-month follow-up periods; this effect can be attributed to irreversible brain damage. Therefore, although early brain biopsy may be associated with histopathologic diagnostic pitfalls, it is a mandatory procedure for obtaining a confirmative diagnosis as well initiating early therapy, thereby reducing brain damage. “
“Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes.
By contrast, when IFNAR−/− bone marrow cells were cultured with influenza viruses, the proportion of CD11c+/MHCII+ BMDCs generated was similar to that observed in untreated cultures, suggesting that the IFNAR was required to mediate these effects. To further investigate the role of type 1 IFN, BALB/c bone marrow was cultured in the presence of GM-CSF, with or without Jap or recombinant IFN-α. The data (Fig. 5b) demonstrated that cultures treated with IFN-α showed a reduction
in BMDC production similar to that observed in cultures stimulated with Jap virus. We next examined the effects of neutralizing IFN. Cultures were treated with IFN-α in the presence or absence of neutralizing antibody to IFN-α. mTOR inhibitor The results (Fig. 5c) showed that in the presence of neutralizing antibody the effects of IFN-α were negated and CD11c+/MHCII+ BMDC production was restored to levels corresponding to those observed in unstimulated cultures. To investigate whether the effects of influenza virus were mediated by IFN-α, cultures were treated with the Jap virus in the presence or absence of neutralizing anti-IFN-α (Fig. 5d). The addition of antibody clearly reversed the effects induced by the virus. Taken together, this evidence clearly demonstrates a role for type 1 IFN, signalling through the IFNAR, in mediating
click here responses to influenza viruses that lead to the observed changes in BMDC generation. As described above, ligands for TLRs 3, 4 and 9 were shown to initiate changes in haematopoiesis, inducing a marked reduction in BMDC production. In many cells the cytokine
TNF-α is produced in response to MyD88-dependent TLR signalling and this cytokine has also been shown to inhibit haematopoiesis19. To examine a possible role Rho for TNF in mediating the observed effects, recombinant TNF-α was added to bone marrow cultures containing GM-CSF. The results (Fig. 6a) show that the addition of TNF-α led to a reduction in the production of CD11c+/MHCII+ BMDC similar to that observed in cultures stimulated with influenza viruses or TLR ligands. The addition of a neutralizing antibody, anti-TNF-α (Fig. 6b), restored the production of CD11c+/MHCII+ BMDCs, confirming that TNF-α was responsible and that the antibody could abolish its effects. To assess whether TNF-α was mediating the effects of LPS and CpG ODN, bone marrow cells were cultured with GM-CSF and these stimuli in the presence or absence of the neutralizing antibody, anti-TNF-α. The resulting data (Fig. 6c) showed that anti-TNF-α had no effect on the modulation of BMDC production by LPS or CpG ODN. Data compiled from cell numbers (Fig. 6d) revealed that although there was little change in the proportion of cells displaying a CD11c+/MHCII+ phenotype, anti-TNF-α did appear to suppress the increase in cell number usually observed to occur in response to LPS and CpG ODN.
Activation of Jak3/1-PI3K-Akt elevated Bcl-2
abundance, selleck while Jak3/1-PI3K-Akt-dependent ERK1/2 activation resulted in Bim phosphorylation and its subsequent dissociation from Bcl-2 without affecting the level of Bim. This pathway differs from the IL-15-triggered survival pathways reported previously. In human ACD and RCDII iIEL lines, the IL-15-triggered survival involves Jak3, STAT5, and Bcl-xL, but not ERK, PI3K, or Mcl-1 . In primary human NK cells, IL-15 maintains or slightly upregulates Bcl-2 level while reduces Bid abundance, but does not affect the level of Bcl-xL, Mcl-1, and other BH3-only molecules [34, 35]. In IL-15-expanded murine NK cells, IL-15 promotes cell survival by limiting Bim abundance and by maintaining Mcl-1 level without involving Bcl-2/Bcl-xL/Bcl-w . The reduction of Bim was independently contributed by the degradation of phosphorylated Bim after ERK1/2-induced phosphorylation
and by reduction of Bim transcription through phosphorylation of Foxo3a by PI3K-Akt . These previous studies selleck kinase inhibitor and our work together indicate that IL-15 triggers differential survival signals depending on cell type, condition, and species. The regulation of Bim by cytokines occurs at the level of mRNA abundance, protein abundance, and protein localization [36-40]. Phosphorylation of Bim at Ser65 by ERK1/2 results in the ubiquitylation and proteasome degradation of Bim. This regulation was observed in several types of cells under different conditions [25, 30, 31]. Using both IL-15 treatment and withdrawal conditions, we found that IL-15 induced ERK1/2 activation and subsequent BimEL phosphorylation at Ser65 in CD8αα+ iIELs but did not affect Bim abundance (Fig. 3).
Recent studies indicate that Carnitine dehydrogenase phosphorylation of Bim at sites other than Ser65 also affects Bim stability. Hubner et al.  indicated that simultaneous mutation at Ser55, Ser65, and Ser73 stabilizes Bim by preventing proteasomal degradation without marked change in interaction with Bcl-2 in MEFs. Dehan et al.  reported that PMA induces phosphorylation of Bim at Ser93/94/98, which provides the binding site for E3 ligase (βTrCP) and results in Bim degradation in HEK293 cells. It is thus possible that the overall phosphorylation status of Bim in IL-15-treated CD8αα+ iIELs was not sufficient to result in proteasome degradation of Bim. On the other hand, we found that treating CD8αα+ iIELs with IL-15 reduced the association between Bim and Bcl-2 in an ERK1/2-dependent manner (Fig. 4D). This finding is in line with an earlier study on serum starved CC139 cells in the presence of thrombin or FBS, in which ERK1/2 mediated Bim phosphorylation at Ser65 and led to rapid dissociation of the BimEL-Mcl-1 complex independent of BimEL degradation .
This was made known at various
nationwide meetings. In 2009, service providers for the hemodialysis population were 68.4% at voluntary welfare (charity) organisations, 2.5% public hospitals and 29.1% private facilities. We describe our experience with use of the hotline over years 2011–2012 with a retrospective survey. Methods: Renal coordinators (RCs) receive email or phone calls from DCs nationwide. Cases are triaged by protocol and are referred to a nephrology trainee for discussion with a specialist nephrologist, vascular surgeon or directed to DEM. The coordinator may be asked to assist with further actions. Results: The number of cases handled was 433. Non-SGH cases (n = 6) were removed from analysis. The remaining 427 cases were see more from 305 patients aged 62 +/− 10 years of age, Male: Female 2.02:1. Etiology of renal failure included diabetic nephropathy 54.6% (n = 233), chronic glomerulonephritis 25.8% (n = 110), hypertension 13.3% (n = 57), others 6.3% (n = 27). Co-morbidities in these patients included diabetes mellitus 62.8% (n = 268), ischemic heart disease 34.4% (n = 147). Over the two years, 52.4% were unique cases, 27.2% (58 patients) cases referred twice, 20.4% (23 patients) three or more times. Referral sources were National Kidney Foundation 90.6% (n = 387), Kidney Dialysis Foundation 6.3% this website (n = 27)
and private DCs 3.1% (n = 13). Access types handled included Arteriovenous fistula 75.2% (n = 321), Arteriovenous graft 22.9% (n = 98) and tunnelled catheters 1.9% (n = 8). Causes of referral included poor access flow 65.6% (n = 280), recirculation 8.0% (n = 34), swollen upper limbs 3.5% (n = 15), high venous pressure
2.1% (n = 9), high access flow 2.4% (n = 10), infected access 2.1% (n = 9), thrombosed access 3.0% (n = 13), other reasons 13.3% (n = 57). The actions taken included early vascular surgery reviews 33.7% (n = 144), elective angioplasty appointments 25.3% (n = 108), continuation with previously arranged vascular appointments 6.6% (n = 28) referral to DEM for admission 7.7% (n = 33), other actions 26.7% (n = 114). Conclusion: The vascular hotline creates a channel for dialysis Mirabegron centres to arrange for early assessments of vascular accesses. However, trained personnel are essential for effective use. UBUKATA MASAMITSU1, AMEMIYA NOBUYUKI2, TAKEI TAKASHI3 1Department of Nephrology, Saiseikai Kurihashi Hospital; 2Department of Nephrology, Saiseikai Kurihashi Hospital; 3Department of Nephrology, Saiseikai Kurihashi Hospital Introduction: Patients with end-stage renal disease under maintenance hemodialysis are prone to malnutrition because of a poor diet and/or uremic complications. There are some reports that dialysis patients are at a high risk for thiamine deficiency, which may be caused by dietary deficiency and/or loss during dialysis, and the complications associated with it, including encephalopathy and beriberi.
 The macrophages appear large, polygonal with foamy eosinophillic cytoplasm check details – the so-called von Hansemann cell. Attempts to correct the abnormal ratio of cGMP to cyclic adenosine monophosphate (cAMP) with the cholinergic agonist bethanechol chloride and ascorbic acid have had mixed results. Due to the protean nature of presentation and histopathological findings, it is likely the disease is under-recognized. A positive result from renal biopsy may yield the correct diagnosis in only 30% of cases. The disorder
most commonly associates with recurrent E. coli infection (80% of cases), with the exception of those cases related to human immunodeficiency virus (HIV), wherein infection with Rhodococcus equi is the rule. In some cases, inciting organisms have been cultured from biopsy tissue, just as we were able to demonstrate K. pneumoniae in the bladder biopsies in our patient, despite sterile urine. This suggests that the local environment may be permissive for bacterial survival and provide a viable reservoir for the ongoing aberrant inflammatory process. Malakoplakia can present with Decitabine infection at multiple sites but expresses particular affinity for the genitourinary tract, especially
in females, with 58% cases involving this organ system. The kidney is the predominant site of involvement in 15% of cases, but has only been reported in renal allografts on fewer than 20 occasions. In the kidney, the enlarging parenchymal nodules can sometimes be mistaken for malignancy, with the diagnosis only made following transplant nephrectomy. The gastrointestinal tract is the second most common site with a spectrum of presentations possible, from an incidental Palbociclib mw finding to haemorrhage or obstruction. Historically, malakoplakia was associated with poor outcomes, with a 6-month mortality rate above 50%. The development of quinolone antibiotics in the 1990s, agents with high bioavailability within macrophages, has improved the outlook. Sulphonamides are similarly active against malakoplakia. However, despite the success of these agents, malakoplakia has resulted in permanent
loss of renal function through graft failure, transplant nephrectomy and salt losing nephropathy over time.[2, 5] Patients with bilateral disease tend to fare especially poorly. These cases pose a difficult question as to whether treating nephrologists should pursue repeat transplantation, given the risk of recurrence on long-term immunosuppression is unknown. However, successful outcomes with preserved renal function have been documented. In our case, and in a few recent case reports, a strategy of minimization of immunosuppressive medications and prolonged antibiotic therapy has resulted in patient and allograft survival. In particular, the use of purine synthesis inhibitors such as azathioprine or mycophenolate mofetil might relate to poor outcomes through suppression of monocyte function.
Neopterin was not associated
with smoking in the multivariate model (Table 4). This community-based study among 7052 individuals investigated potential determinants of plasma neopterin, KTR and a large panel of kynurenines. Higher concentrations of neopterin, KTR and most kynurenines were observed in elderly compared to middle-aged subjects, and concentrations of Trp and most kynurenines were higher in men than in women. Furthermore, renal function was associated inversely with plasma levels of neopterin, KTR and most kynurenines. Lastly, higher concentrations of KTR, Trp and most kynurenines were found in overweight/obese compared to normal-weight participants, whereas Trp and most kynurenines were lower in heavy than in never smokers. The higher plasma levels of neopterin and KTR observed in the older group are in agreement find more with previous studies [9-12, 33]. In the present study, elevated KTR in the elderly was driven mainly by markedly increased Kyn concentrations, indicating a more pronounced IDO activation in this age group. Elevated neopterin and KTR indicate increased IFN-γ activity in the older group, accompanying age-related inflammation . Older Lapatinib ic50 age was also associated with higher concentrations of all kynurenines, except XA. Others have reported no association of age with serum
Kyn  or KA . This discrepancy may be explained by a smaller sample size (n < 50) in previous studies. We
observed lower neopterin in men than in women in the middle-aged group, but not in the elderly. This observation is in accordance with published results . There was no difference in KTR between genders in the present study in subjects aged 45–72 years, which is in agreement with a previous study on subjects older than 50 years of age , but in contrast to an observation of higher KTR in men in a younger population (21–64 years) . This indicates no differences in activities of IDO or TDO between genders among middle-aged and elderly people, but possibly in younger subjects, including premenopausal women. The higher concentrations of Trp Docetaxel price and most kynurenines in men may be related to higher protein intake and/or turnover; the latter may be explained by higher muscle mass in men. The downstream effects on most kynurenines may simply reflect that Trp availability increases the flux through the kynurenine pathway, as more than 90% of Trp is metabolized through this pathway . The higher concentrations of neopterin, KTR and kynurenines in individuals with moderately reduced renal function – indicated by lower eGFR (eGFR < 98 ml/min/1·73 m2 in the middle-aged and eGFR < 78·7 ml/min/1·73 m2 in the elderly) – are in line with studies in patients with severe renal disease reporting increased plasma concentrations of neopterin , Kyn [16, 17] and KA .