Table 3.
Tryptophan and its metabolite association with post-Tx outcomes in human studies.
| Reference | Study Design | Population | Measurement | Follow-Up | Outcome Association | |||
|---|---|---|---|---|---|---|---|---|
| Graft Function | AR | Infection | Recipient Mortality | |||||
| Holmes et al. [143], 1992 | Retrospective | 32 kidney Tx recipients | Post-Tx serum Trp and Kyn | 3 weeks post-Tx | DGF: Trp↓, Kyn↑; SCr: Trp↓, Kyn↔ |
Trp↔, but ↓if failed AR treatment or concomitant infection; Kyn↑ | CMV, EBV, pneumonia, UTI: Trp↓, Kyn↑ | n.d. |
| Brandacher et al. [141], 2007 | Prospective | 43 kidney Tx recipients | Serum and urine Trp and Kyn 1, 8, 15 and 21 days post-Tx and at the time of AR | 3 weeks post-Tx | n.d. | Serum Trp↓, Kyn↑, Kyn/Trp↓ Urine Kyn/Trp↓ |
H. simplex (n = 4), UTI (n = 1), sepsis (n = 1): serum Trp↔, Kyn↔, Kyn/Trp↔ | n.d. |
| Lahdou et al. [140], 2010 | Retrospective | 210 first kidney Tx recipients | Pre-Tx plasma Trp, Kyn, post-Tx plasma Trp, Kyn, Kyn/Trp *available for 10 AR+ patients (median 7 days post-Tx) and 24 AR- patients (median 11 days post-Tx) | 6 months post-Tx | n.d. | Pre-Tx Trp↑ (sens. 61%, spec. 71%), Kyn↑ (sens. 64%, spec. 71%); Post-Tx Trp↔, Kyn↑ (sens. 80%, spec. 79%), Kyn/Trp↑ (sens. 70%, spec. 79%) | n.d. | n.d. |
| Kaden et al. [144], 2015 | Retrospective | 355 kidney Tx recipients | Post-Tx serum Kyn | 3 weeks post-Tx | DGF and PNF: slowed decrease or increase of serum Kyn | Kyn ↑ (level of increase strongly depends on AR severity in non-dialyzed patients) | CMV: Kyn↑ Pneumonia: Kyn↑ Sepsis: Kyn↑ |
n.d. |
| Vavrincova- Yaghi et al. [145], 2015 |
Prospective | 48 kidney Tx recipients | Serum and urine Trp, Kyn, Kyn/Trp at 2 weeks, 6 months and 2 years post-Tx | 24 months | SCr at 2 years: serum Kyn/Trp at 6 months↑; Kyn at 6 months↑ (AUC 0.76); CrCl at 2 years: urine Trp at 2 weeks↓ (AUC 0.44). Albuminuria at 2 years: Urine Trp↓; Kyn↑ at 2 weeks, Kyn/Trp↑ at 6 months |
n.d. | n.d. | n.d. |
| Kim et al. [146], 2019 | Cross-sectional | 385 kidney Tx recipients | Urine metabolomic analysis (LC-MS) | n.d. | n.d. | TCMR: Trp↓; Panel of 5 top metabolites, including Trp showed AUC 0.926, acc. 87.0% (training set) and 62.5% (validation set) | n.d. | n.d. |
| Blydt-Hansen et al. [147], 2014 | Cross-sectional | 277 biopsy-paired urine samples from 57 pediatric kidney Tx recipients | Urine metabolomic analysis (LC-MS) | n.d. | n.d. | TCMR: Kyn↑; TMCR discriminant score of 10 top metabolites, including Kyn showed AUC 0.892 | n.d. | n.d. |
| Dharnidharka et al. [148], 2013 | Prospective | 29 pediatric kidney Tx recipients | Serum and urine Trp, Kyn, Kyn/Trp | 12 months after Tx | n.d. | AR within the next 30 days from the test: serum Kyn/Trp↑; urine Kyn/Trp↔; serum and urine Trp and Kyn↔ | MIE (CMV, EBV, BKV, Tx pyelonephritis, fever with bacteriemia): serum and urine Kyn/Trp↔; serum and urine Trp and Kyn↔ | n.d. |
| Zhao et al. [149], 2014 | Cross-sectional | 27 primary kidney Tx recipients | Serum metabolomics analysis (LC-MS) pre-Tx and 7 days post-Tx | n.d. | n.d. | In non-rejecting patients: Trp↓; Kyn↑; Kyn/Trp↑ | n.d. | n.d. |
| Sadeghi et al. [150], 2012 | Cross-sectional | 86 kidney Tx recipients | Plasma Trp, Kyn, Quin, Kyn/Trp, Quin/Trp | n.d. | n.d. | n.d. | CMV: Trp↔; Kyn↑ (AUC 0.82), Kyn/Trp↑ (AUC 0.83) Quin↑ (AUC 0.85), Quin/Trp (sens. 83%, spec. 74%) (correlate with the severity); BKV: Trp, Kyn, Quin, Kyn/Trp, Quin/Trp↔ | n.d. |
| Zhang et al. [152], 2018 | Retrospective | 42 kidney Tx recipients | Plasma metabolomics (25 amino acids) analysis (UHPLC–MS/MS) | n.d. | AKI (↑ of SCr of > 0.3 mg/dL or ↑ ≥50% over baseline): Trp↓ (AUC 0.78); Trp+SDMA↓ (AUC 0.901) |
n.d. | n.d. | n.d. |
| Bassi et al. [11], 2017 | Cross-sectional | 40 kidney Tx recipients at least 6 months after Tx | Ex vivo (serum and urine) and in vivo metabolomics (LC-MS/MS, FIA-MS/MS (n = 40), 2D COSY with 3D-image transformation (n = 15) | n.d. | GFR 21–39 mL/min: serum Trp↓ | n.d. | n.d. | n.d. |
| de Vries et al. [153], 2017 | Prospective | 561 stable kidney Tx recipients with functioning graft for at least 1 year | Serum and urine Trp, Kyn, 3-HK, Kyn/Trp, 3-HK/Kyn | Median 7.0 [6.2–7.5] years | Graft failure, SCr, proteinuria: serum Trp↓, Kyn, 3-HK, Kyn/Trp, 3-HK/Trp↑; no significant changes in urine; GFR: serum Trp↑, Kyn, 3-HK, Kyn/Trp, 3-HK/Trp↓ |
n.d. | n.d. | Serum Trp↔; Kyn; 3-HK; Kyn/Trp; 3-HK/Kyn↑; no significant changes in urine |
| Meloni et al. [154], 2009 | Cross-sectional | 90 lung Tx recipients | Plasma Trp, Kyn, Kyn/Trp | n.d. | n.d. | BOS: Trp↔, Kyn↑, Kyn/Trp↑ | n.d. | n.d. |
| Oweira et al. [155], 2018 | Retrospective | 89 liver Tx recipients | Pre-Tx and early post-Tx serum Trp, Kyn, Quin, KYNA |
1 year | EAD: pre-Tx Kyn↑ (AUC 0.64); post-Tx day 3 Kyn↑ (AUC 0.69); day 5 Kyn↑ (AUC 0.74); day 10 Kyn↑ (AUC 0.77) | n.d. | n.d. | 1-year mortality: pre-Tx Kyn↑ (AUC 0.77), KYNA↑ (AUC 0.74), Quin↑ (AUC 0.72), Trp↑ (AUC 0.72); Post-Tx day 1 KYNA↑ (AUC 0.73); day 5 KYNA↑ (AUC 0.71); Kyn↑ (AUC 0.73). Pre-Tx Kyn↑ associated with 1-year mortality in univariate analysis |
| Perera et al. [156], 2014 | Prospective | 40 liver Tx recipients | Metabolomic analysis (CEAD) of liver micro-dialysis samples: pre-Tx (bench micro-dialysis) and every 6 h for 48 h post-Tx | 7 days post Tx | PNF/IPF: pre-Tx (bench) Kyn↑; Kyn↑ in DCD vs. DBD grafts at the end of cold ischemia |
n.d. | n.d. | n.d. |
Abbreviations: ↑: positive association, ↓: negative association, ↔: no association, n.d.: no data, sens.: sensitivity, spec.: specificity, acc.: accuracy, AUC: area under the curve, Tx: transplantation, Trp: tryptophan, Kyn: kynurenine, Quin: quinolinic acid, KYNA: kynurenic acid, SDMA: symmetric dimethylarginine, LC-MS: liquid chromatography-tandem mass spectrometry, UHPLC–MS/MS: ultra-high performance liquid chromatography-tandem mass spectrometry, FIA-MS/MS: flow injection analysis-tandem mass spectrometry, 2D COSY: two-dimensional correlated spectroscopy, CEAD: coulometric electrochemical array detection, DGF: delayed graft function, PNF: primary nonfunction, EAD: early allograft dysfunction, IPF: initial poor function, SCr: serum creatinine, GFR: glomerular filtration rate, CrCl: creatinine clearance, AR: acute rejection, TCMR: T-cell-mediated rejection, BOS: bronchiolitis obliterans syndrome, MIE: major infection event, UTI: urinary tract infection, CMV: cytomegalovirus, EBV: Ebstein Barr virus, DCD: donation after circulatory death, DBD: donation after brain-stem death and BKV: BK virus.