Increased pretransplantation plasma kynurenine levels do not protect from but predict acute kidney allograft rejection

Lahdou, Imad; Sadeghi, Mahmoud; Daniel, Volker; Schenk, Martin; Renner, Fritz; Weimer, Rolf; Löb, Stefan; Schmidt, Jan; Mehrabi, Arianeb; Schnitzler, Paul; Königsrainer, Alfred; Döhler, Bernd; Opelz, Gerhard; Terness, Peter

doi:10.1016/j.humimm.2010.08.013

Cited by 16 publications

(16 citation statements)

References 29 publications

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“…Our results of serum kyn/trp ratios in relation to acute rejection are in accord with those of Brandacher et al and Lahdou et al, who have previously demonstrated a rise in serum kyn/trp ratios in association with acute rejection events shortly thereafter, within 13 or 3 days, respectively (23, 25). The studies used differing units of expression for the kyn/trp ratio, but the results were very similar once units are converted to a common unit system, as we reported previously (10).…”

Section: Discussionsupporting

confidence: 93%

Verification of Association of Elevated Serum IDO Enzyme Activity With Acute Rejection and Low CD4-ATP Levels With Infection

et al. 2013

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Introduction Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3 dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. Methods We prospectively tested 217 blood and 167 urine serial samples, collected monthly for twelve months post-transplant from 29 consecutive children receiving a kidney transplant. The IDO activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR or MIE or stable group (no events) in the next 30 days. Results Using absolute cutoffs and allocating to samples to AR, MIE or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (p = 0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (p = 0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that over time, serum kyn/trp ratios were higher prior to acute rejection (p = 0.031) and blood CD4-ATP levels were lower prior to MIE (p = 0.008). Conclusions These results from our pilot discovery group suggest that a panel of biomarkers together can predict over- or under-immunosuppression. Further independent validation in a multi-center cohort is suggested.

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Section: Discussionsupporting

confidence: 93%

Verification of Association of Elevated Serum IDO Enzyme Activity With Acute Rejection and Low CD4-ATP Levels With Infection

et al. 2013

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“…and Lahdou et al. (21, 23), who have previously demonstrated a rise in serum kyn/trp ratios in association with acute rejection events shortly thereafter, within thirteen or three days, respectively. However, it is pertinent to note that the apparent differences in the values presented in earlier studies relate to different ways of expressing individual ratios.…”

Section: Discussionmentioning

confidence: 92%

“…For example, studies by Lahdou et al. (23) and Holmes et al. (24) utilized μmol units for both kyn and trp.…”

Section: Discussionmentioning

confidence: 99%

Immune biomarker panel monitoring utilizing IDO enzyme activity and CD4 ATP levels: Prediction of acute rejection vs. viral replication events

Dharnidharka

Gupta

Khasawneh

et al. 2011

Pediatric Transplantation

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Infections have become as important an event as acute rejection post-transplant for long-term allograft survival. Less invasive biomarkers tested so far predict risk for one event or the other, not both.We prospectively tested blood and urine monthly for twelve months post-transplant from children receiving a kidney transplant. The indoleamine 2,3 dioxygenase (IDO) enzyme pathway was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with acute rejection or major infection events or stable group (no events) in the next 30 days.The 25 subjects experienced 6 discrete episodes of acute rejection in 5 subjects and 16 discrete events of major infection in 14 subjects (7 BK viruria, 6 cytomegaloviremia, 1 Epstein-Barr and cytomegaloviremia, 2 transplant pyelonephritis). Mean serum kyn/trp ratios were significantly elevated in the group that experienced acute rejection (p = 0.02).Within-subject analyses revealed that over time, urine kyn/trp ratios showed an increase (p = 0.01) and blood CD4-ATP levels showed a decrease (p = 0.007) prior to a major infection event.These pilot results suggest that a panel of biomarkers together can predict over-or underimmunosuppression, but need independent validation.

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“…IDO activity correlates with clinical severity of chronic kidney disease and with serum levels of inflammatory biomarkers, such as C-reactive protein and soluble TNF receptor-1 [33]. Also, increased serum levels of KYN in patients with end-stage renal disease were predictive of biopsy-proven kidney rejection [34].…”

Section: Introductionmentioning

confidence: 99%

Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases

Filippini

Papa

Sambataro

et al. 2012

CMC

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The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissuedependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis.

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Increased pretransplantation plasma kynurenine levels do not protect from but predict acute kidney allograft rejection

Cited by 16 publications

References 29 publications

Verification of Association of Elevated Serum IDO Enzyme Activity With Acute Rejection and Low CD4-ATP Levels With Infection

Verification of Association of Elevated Serum IDO Enzyme Activity With Acute Rejection and Low CD4-ATP Levels With Infection

Immune biomarker panel monitoring utilizing IDO enzyme activity and CD4 ATP levels: Prediction of acute rejection vs. viral replication events

Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases

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