Assessment and clinical implications of functional vitamin B6 deficiency
Minovic, Isidor
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General Discussion,
and Future Perspectives
Prelude
With improved diet quality, hygiene, and health care, general life expectancy has risen from 61.7 years in 1980 to 71.8 years in 2015, albeit the commonly known sex-specific difference has not markedly been affected (1). However, the gain in life expectancy is accompanied by an increased burden of non-communicable diseases that not only negatively affects quality of life, but also contributes to the upward trends of national health care expenses (2). Of approximately 57 million deaths globally in 2015, 40 million (71%) were attributable to non-communicable diseases (NCDs), which particularly comprised cardiovascular diseases (18 million, 45% of NCD total) and cancer (9 million, 22% of NCD total) (3). In search of modifiable factors to lower burden of existing NCDs and to prevent or delay manifestation of future NCDs, vitamins have gained considerable attention. Over the past decades, public interest in vitamins has increased globally and has led to an increased prevalence of (multi)vitamin supplement use (4, 5). In the US general population, for example, it was estimated that approximately one-third of adults were using multivitamin and-mineral supplements in 2012 (5). These supplements are part of a multibillion dollar dietary supplement industry that involved a whopping 40 billion dollar sale in 2016, in the US market alone (6).
Studies that have investigated the effects of vitamin supplementation on incidence and burden of various NCDs, have yielded variable results, with some of the studies observing a beneficial effect, and others reporting null or even harmful effects of vitamin supplementation (7-11). The latter two types of outcome have generated some skepticism regarding their use (12), which may have been one of the underlying causes for the observed slight decrease in the use of multivitamin and -mineral supplements in the US general population in the period of 1999-2012 (5).
Furthermore, the discordant findings of such studies make it difficult to draw meaningful conclusions based on single studies and may therefore necessitate combined analysis and interpretation of the data, as is done in meta-analyses.
While the rationale for vitamin supplementation may in some cases be valid, it is important to realize that many vitamins have an optimal range in which intracellular vitamin availability is sufficient for optimal enzymatic efficiency but does not exceed toxicity limits. In the future, it could be possible that biomarkers of vitamin status and particularly of vitamin functionality during use of vitamin supplements, will ‘guide’ dosing
regimens based on personalized needs. Such biomarker-guided personalized vitamin supplementation will not necessarily pertain to research settings, but will also likely find merit in other settings, such as professional sports and routine medical patient care. This approach would be desirable for every supplemented vitamin that is able to cause toxicity. However, it has not been well-documented which vitamins could be potentially toxic, since chronic vitamin toxicity often culminates in vague and ambiguous symptoms and therefore goes by unrecognized and unreported (13). Importantly, however, for many vitamins, measurement of the vitamin itself (i.e. direct biomarker, usually measured in the circulation) may not always reliably estimate true vitamin status, which is most precisely defined as the bioavailability of a vitamin at it active sites. These active sites are typically present intracellularly, and therefore efforts should be directed towards developing and validating functional biomarkers for every vitamin that can cause clinically relevant deficiency or toxicity.
One of the rationales for using vitamin supplements, is to alleviate symptoms of less clearly defined pre-existing conditions, such as FM and CFS. Accordingly, it has been shown that use of nutritional supplements is higher in these patients (35-68%) compared to the general population (27-56%) (14-18), and in some cases may lead to dangerously high vitamin intakes. However, the available evidence for a role of vitamins in the pathophysiology of FM and CFS is inconclusive. Moreover, it is not known whether vitamin supplementation has any effect on the spectrum of symptoms associated with FM and CFS.
A role for vitamins and minerals in fibromyalgia and chronic fatigue syndrome?
In chapter 1, we performed a systematic review with quality assessment to provide the first systematic overview of the existing literature on vitamins and minerals in the NCDs FMS and CFS. Moreover, by performing a meta-analysis of the included observational and intervention studies, we aimed to assess whether the available evidence supports a role for vitamins and minerals in the pathophysiology of FMS and CFS that could justify the frequent use of micronutrient supplements in this population.
Our findings from chapter 1 confirmed that the existing data, in particular data from randomized controlled trials, regarding many vitamins and minerals are scarce and conflicting. While no included study assessed vitamin B6 status, sufficient numbers of studies concerning vitamins C, D, and
E, calcium, and magnesium were included for meta-analysis. Only the data for vitamin E reached statistical significance, implying that vitamin E could be of importance in these disorders. Importantly, however, the outcome for vitamin E was significantly influenced by publication bias and thus might not have been truly significant. In general, the number of RCTs was alarmingly low and, despite adhering to our inclusion criteria, the included studies were of poor quality. The need for high-quality studies to provide more conclusive and mechanistic data on the potential role of vitamins and minerals in FMS and CFS, therefore remains.
In addition to alleviating of symptoms of pre-existing diseases, vitamin supplements are also consumed with the desire to prevent, or at least delay, the onset of age-related diseases, such as cardiovascular disease. Cardiovascular disease has been associated with many different vitamin deficiencies (19-21), including vitamin B6 (22). However, data regarding this association are conflicting in the general population, and are absent in other more specific populations, such as renal transplant recipients.
Cardiovascular Aspects of Vitamin B6: Implications for the General Population?
Early studies that demonstrated the detrimental effects of severe vitamin B6 deficiency on the cardiovascular system in monkeys (23, 24), have motivated a plethora of researchers to scrutinize the cardiovascular implications of vitamin B6 deficiency in humans. Constrained by ethical, financial, and technical issues, researchers were largely limited to observational studies, in which they had repeatedly observed strong inverse associations between plasma PLP and risk of adverse cardiovascular outcome (25-31) . However, progressive insights into this topic have led to the belief that the association between a low plasma PLP concentration and a high risk of cardiovascular disease may be secondary to inflammation (32, 33). Unfortunately, data regarding a potential effect of inflammation were conflicting and were difficult to extrapolate to the general population. Therefore, in chapter 2, we comprehensively assessed the potential effect of inflammation on the association of plasma PLP with cardiovascular disease in a large general population-based prospective cohort.
We found that the association between plasma PLP and cardiovascular disease, defined as the composite of non-fatal and fatal cardiovascular events, was not independent of inflammation in the overall cohort. However, while plasma PLP concentration was similar between men and women, we observed
that the prospective association between plasma PLP and cardiovascular disease was significantly modified by gender. Our data inferred that plasma PLP is inversely associated with risk of cardiovascular disease in women, but not in men, independent of potential confounders such as inflammation. Albeit it is well known that there are great differences between sexes in terms of susceptibility to disease and treatment (34), little is known about potential sex-specific effects of vitamin B6. To the best of our knowledge, the current evidence for sex-specificity of vitamin B6 is provided by two studies. A rat study performed back in 1965, showed that vitamin B6 deficient female rats on a high-cholesterol diet were more prone to developing severe aortic lesions, compared to vitamin B6 deficient male rats (35). More recently, a metabolomics study by Krumsiek et al aiming at characterizing metabolic differences between sexes, showed and replicated a significant sex-specific difference in vitamin B6 metabolism (36). They revealed that vitamin B6 metabolism was significantly higher in males compared to females (P-value= 7x10-13), but the researchers did not discuss potential implications of this difference. However, a more active vitamin B6 metabolism in males could potentially explain the findings from the 1965 rat study and thus possibly indicate that vitamin B6 deficiency could disproportionally increase susceptibility to cardiovascular disease in women, compared to men. This hypothesis fits with our data from chapter 2, where the association between plasma PLP and cardiovascular disease was stronger in women, compared to men. Importantly, Krumsiek et al justly noted that the statistical significance does not equal biological relevance and that more studies are necessary to investigate in more detail the potential clinical implications of sex-specific differences in vitamin B6 metabolism in humans, as we found in chapter 2. For this, conclusive data should preferably be obtained from carefully performed, biomarker-guided, intervention studies.
Prevalence, Functional Effects, and Clinical Implications of Vitamin B6 Deficiency in Renal Transplant Recipients
Chronic kidney disease (CKD) poses a major global disease burden, as it affects up to 16% of the general population (37). CKD patients suffer from a progressive loss of kidney function, which culminates in end-stage renal disease (ESRD). For the majority of ESRD patients, the renal replacement therapy of choice is renal transplantation, resulting in marked improvements in quality of life and life expectancy compared to dialysis (38, 39). While improved pharmacotherapy and surgical techniques have markedly improved
short-term survival, considerable improvements on the long-term remain to be achieved (40). With 10-year mortality rates ranging from 24% for living-donor recipients to 36% for deceased-donor recipients, RTR remain at increased risk of mortality compared to the general adult population (10-year mortality rates <1%) (41). In RTR, cardiovascular disease is the major cause of death, accounting for approximately 28% of deaths (41, 42). Altogether, these data reflect the need for non-conventional strategies to ameliorate cardiovascular outcome and improve long-term survival of recipients. In light of this, we assessed plasma PLP in a large cohort of stable RTR with long-term follow-up in chapter 3. We demonstrated that vitamin B6 deficiency is prevalent in RTR, despite adequate intake of vitamin B6 in this population. It thus seems that renal insufficiency, or a related factor, adversely influences the handling of vitamin B6 in humans. Future studies should attempt to identify the mechanisms behind these observations. In addition, we showed that vitamin B6 deficient RTR were at increased risk of cardiovascular mortality, compared to vitamin B6 sufficient recipients. In
chapter 4, we investigated whether vitamin B6 functionality was affected in
vitamin B6 deficient RTR, by measuring the functional vitamin B6 marker plasma 3-HK/XA ratio. Indeed, we found that vitamin B6 deficient RTR had a significantly lower functional vitamin B6 status compared to vitamin B6 sufficient RTR. Importantly, a low functional vitamin B6 status was independently associated with increased risk of mortality.
Chapters 3 and 4 collectively show that vitamin B6 deficiency has
functional and long-term clinical implications after renal transplantation. However, while 3-HK/XA ratio has several important advantages over plasma PLP, e.g. a weaker association with inflammation, it is not without drawbacks. Both 3-HK and XA are hydrophilic compounds that are eliminated from the circulation by the kidneys. An impaired kidney function could therefore influence circulating concentrations of these compounds and thus result in a biased 3-HK/XA ratio. Our data from chapter 4 support the possibility of bias by renal function, as they revealed a positive association between the ratio and eGFR. Notably, the association between eGFR and XA was much stronger compared to that with 3-HK, indicating that bias from renal function may be due to an easier elimination of XA, compared to 3-HK. It would be important to distinguish whether the observed prospective associations are causal or whether vitamin B6 deficiency is merely a risk factor of an unfavorable risk profile. If vitamin B6 deficiency is causally related with outcome, it could serve as a modifiable factor to improve cardiovascular
outcome and survival in RTR. Promisingly, pyridoxine-supplementation in patients with suspected coronary artery disease, not only increased plasma PLP concentration, but also resulted in an improvement of functional vitamin B6 status, especially in patients with low plasma PLP concentrations at baseline (43).
The Kynurenine Pathway after Kidney Transplantation
Vitamin B6 deficiency and chronic low-grade inflammation are prevalent in RTR and have both been associated with adverse long-term outcome (44). Since these conditions are able to influence activities of kynurenine pathway enzymes (45, 46), it is likely that the flow of metabolites through this pathway is disturbed in many RTR. It has long been known that the kynurenine pathway constitutes several highly bioactive compounds, e.g. 3-HK (47), and it is this conceivable that a disturbed kynurenine pathway may have clinical implications on the long-term. Strikingly, however, these implications had not been fully evaluated in RTR (48-51).Therefore, in chapter 5, we studied the potential clinical implications of kynurenine pathway activation in RTR. To this end, we assessed the potential relationships of Trp, Kyn, 3-HK, IDO-activity, and KMO-activity, with long-term graft failure and all-cause mortality in a large prospective cohort of stable RTR. Our main findings were that the assessed kynurenine pathway parameters were consistently associated with the different inflammation parameters and that higher plasma concentrations of Kyn, 3-HK, and higher activities of IDO and KMO were independently associated with increased long-term risk of graft failure. Moreover, we found higher plasma 3-HK concentration to be associated with increased risk of long-term all-cause mortality in RTR. Although 3-HK had not previously been studied in the context of renal transplantation, our data are in line with neurological studies which revealed that 3-HK was able to induce cell death by causing formation of reactive oxygen species and by impairing cellular energy metabolism (52, 53). The cytotoxic effects 3-HK might be of particular importance in RTR with low functional vitamin B6 status, as inflammation and vitamin B6 deficiency may synergistically increase plasma 3-HK concentration by increasing the flow of Trp to 3-HK and by impairing metabolism of 3-HK to either XA or HAA, respectively. However, the impact of vitamin B6 deficiency on the kynurenine pathway in RTR is yet to be assessed.
While clearly indicating the clinical relevance of the kynurenine pathway, our data pose several limitations that are worth considering. For example, it is
difficult to ascertain to what extent the Trp/Kyn and 3-HK/Kyn ratios reflect the appropriate enzyme activities and thus it remains uncertain whether the increased risk of graft failure is related to the enzyme functions or whether it could be ascribed to the biological functions of Trp, Kyn, or both. Similarly, the putative adverse effects of 3-HK on graft function and survival may not necessarily be due to the cytotoxic effects of 3-HK, but instead may be a reflection of functional vitamin B6 deficiency. Previous studies have indeed shown that plasma 3-HK increases in vitamin B6 deficient individuals. However, due to the strong associations of 3-HK with inflammation markers and kidney function, as observed by others (43, 54) and our group in chapter
5, plasma 3-HK concentration is nowadays considered a less reliable marker
of functional vitamin B6 status compared to, for example, the 3-HK/XA ratio in plasma (55).
General Conclusions
Based on findings of this thesis, we conclude that the available data for a role for vitamins and minerals in the pathophysiology of FMS and CFS are derived from poor-quality studies and are conflicting. These data do not support such a role for vitamins or minerals and, therefore, do not justify the use of micronutrient supplements to alleviate FMS and CFS symptoms. Furthermore, a low (functional) vitamin B6 status is independently linked to adverse long-term outcome in women and RTR. In RTR, Trp metabolism along the kynurenine pathway seems disturbed, which might give rise to an disadvantageous profile of bioactive kynurenines and thus, especially though increased levels of 3-HK, might adversely affect long-term graft function and survival.
Future Perspectives
Vitamin research is moving forward and continues to provide new useful insights into the relevance of vitamins for a healthy and longer life. While this thesis has contributed to our knowledge on vitamins, in particular vitamin B6 and related pathways, many aspects are yet to be elucidated.
For example, we have shown that vitamin B6 deficiency in RTR is not due to inadequate vitamin B6 intake or the presence of chronic low-grade inflammation, but we do not know which factors are responsible for this observation. There are several hypotheses that may explain our findings. First, vitamin B6 deficiency in RTR may be caused by impaired absorption
of vitamin B6 in the small intestine. This hypothesis might be relevant, since RTR frequently suffer from gastrointestinal complications as a side effect of commonly used immunosuppressive and antibiotic drugs and as a consequence of infection with pathogenic microorganisms (56). Second, it is possible that vitamin B6 deficiency in RTR is due to increased catabolism of PLP to PA, as observed during systemic inflammation (57). These hypotheses could be investigated in an intervention study involving vitamin B6 deficient recipient. The study design would preferable involve administration of labeled vitamin B6 and repeated collection of blood, urine, and faeces, to comprehensively assess the metabolic fate of ingested vitamin B6 in RTR. Vitamin B6 catabolism could in that case be estimated via the PAr index, which is calculated from the concentrations of pyridoxic acid (PA), PLP, and pyridoxal (PL) in plasma (57).
In addition, plasma levels of kynurenines depend highly on kidney function (58, 59). Since kidney function is thus likely to confound interpretation of substrate product ratios of enzymes in the kynurenine pathway as indicators of functional vitamin B6 status, it would be important to validate these ratios in a population with impaired kidney function, e.g. RTR.
Furthermore, the potential long-term implications of many kynurenines remain uninvestigated in the context of renal transplantation. Examples of potentially relevant bioactive kynurenines, include the neuroprotective kynurenic acid, the neurotoxic N-methyl-D-aspartate receptor agonist quinolinic acid, and the relatively unknown picolinic acid (60, 61). Also, it is conceivable that activation of the kynurenine pathway, which is likely the case in RTR, might deprive circulating Trp levels and thereby affect levels of other bioactive Trp metabolites, such as melatonin and serotonin (62-65). Therefore, it would also be important to assess a potential link between inflammation, Trp metabolism, mood, and sleep in RTR.
To further increase our knowledge on the (patho)physiological relevance of vitamins, future studies will rely on innovations in the area of clinical chemistry. Through development of more sensitive and comprehensive laboratory assays, as seen with modern liquid chromatography mass spectrometry assays, these innovations will enable assessment of the effects of vitamin insufficiencies and deficiencies on the flow of a related biochemical pathway, thereby likely providing a better understanding of the functionality of a vitamin, compared to measurement of one pathway constituent or of the vitamin itself. The resulting development of functional biomarkers, like the 3-HK/XA ratio for vitamin B6, would not only provide information on the
need for supplementation, but would also enable biomarker-guided titration of vitamin supplementation. Such functional biomarkers would be a useful addition to vitamin supplementation studies, and could also be of added value in preventing toxicity in individual cases, such as that of Sven Kramer. However, it is important to note that functional biomarkers may also be affected by various factors, such as kidney function in the case of the 3-HK/ XA ratio, and that they should be interpreted with caution in individuals with abnormalities in these factors. Identification of possible interferences should therefore be a vital part of validation during development of biomarkers of functional vitamin status. In conclusion, the vast and continuously growing body of evidence in support of potential health benefits of an adequate vitamin B6 status, should prompt researchers to further identify biochemical pathways, types of pathophysiology, and populations that might be affected by an inadequate vitamin B6 status. Moreover, this evidence should motivate the scientific community to address the need for long-term intervention studies with biomarker-guided personalized vitamin B6 supplementation that will accommodate assessment of the potential implications of correcting vitamin B6 deficiency in susceptible populations, such as women and RTR, without abandoning safety.
References
1. Global Health Observatory (GHO) data; 2015 [updated 2018; ]. Available from: http://www.who.int/gho/mortality_burden_disease/life_tables/situation_ trends/en/.
2. GBD 2013 DALYs and HALE Collaborators, Murray CJ, Barber RM, Foreman KJ, Abbasoglu Ozgoren A, Abd-Allah F, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015 Nov 28;386(10009):2145-91.
3. GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1659-724. 4. Blumberg JB, Bailey RL, Sesso HD, Ulrich CM. The Evolving Role of
Multivitamin/Multimineral Supplement Use among Adults in the Age of Personalized Nutrition. Nutrients. 2018 Feb 22;10(2):10.3390/nu10020248. 5. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. Trends in Dietary
Supplement Use Among US Adults From 1999-2012. JAMA. 2016 Oct 11;316(14):1464-74.
6. The $37 billion supplement industry is barely regulated — and it’s allowing dangerous products to slip through the cracks. [updated 2017/11/08; ]. Available from: https://www.businessinsider.nl/supplements-vitamins-bad-or-good-health-2017-8/?international=true&r=US.
7. Rautiainen S, Rist PM, Glynn RJ, Buring JE, Gaziano JM, Sesso HD. Multivitamin Use and the Risk of Cardiovascular Disease in Men. J Nutr. 2016 Jun;146(6):1235-40.
8. Neuhouser ML, Wassertheil-Smoller S, Thomson C, Aragaki A, Anderson GL, Manson JE, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women’s Health Initiative cohorts. Arch Intern Med. 2009 Feb 9;169(3):294-304.
9. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009 Jan 7;301(1):39-51.
10. Sesso HD, Christen WG, Bubes V, Smith JP, MacFadyen J, Schvartz M, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012 Nov 7;308(17):1751-60.
11. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996 Nov 6;88(21):1550-9.
12. Guallar E, Stranges S, Mulrow C, Appel LJ, Miller ER,3rd. Enough is enough: Stop wasting money on vitamin and mineral supplements. Ann Intern Med. 2013 Dec 17;159(12):850-1.
13. Sizer F, Whitney E. Nutrition: Concepts and Controversies, MyPlate Update. 12th ed. Cengage Learning; 2011.
14. Grant JE, Veldee MS, Buchwald D. Analysis of dietary intake and selected nutrient concentrations in patients with chronic fatigue syndrome. J Am Diet Assoc. 1996 Apr;96(4):383-6.
15. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord. 2007 Mar 9;8:27,2474-8-27.
16. Wahner-Roedler DL, Elkin PL, Vincent A, Thompson JM, Oh TH, Loehrer LL, et al. Use of complementary and alternative medical therapies by patients referred to a fibromyalgia treatment program at a tertiary care center. Mayo Clin Proc. 2005 Jan;80(1):55-60.
17. van’t Leven M, Zielhuis GA, van der Meer JW, Verbeek AL, Bleijenberg G. Fatigue and chronic fatigue syndrome-like complaints in the general population. Eur J Public Health. 2010 Jun;20(3):251-7.
18. Van Rossum C, Fransen H, Verkaik-Kloosterman J, Buurma-Rethans E, Ocké M. Dutch national food consumption survey 2007–2010: Diet of children and adults aged 7 to 69 years. . RIVM; 2011. Report No.: 350050006.
19. Judd SE, Tangpricha V. Vitamin D deficiency and risk for cardiovascular disease. Am J Med Sci. 2009 Jul;338(1):40-4.
20. Gaziano JM. Antioxidant vitamins and cardiovascular disease. Proc Assoc Am Physicians. 1999 Jan-Feb;111(1):2-9.
21. Saremi A, Arora R. Vitamin E and cardiovascular disease. Am J Ther. 2010 May-Jun;17(3):e56-65.
22. Friso S, Lotto V, Corrocher R, Choi SW. Vitamin B6 and cardiovascular disease. Subcell Biochem. 2012;56:265-90.
23. Greenberg LD, Rinehart JF. Studies on pyridoxine deficiency in rhesus monkeys. Fed Proc. 1946;5(1 Pt 2):222.
24. Rinehart JF, Greenberg LD. Vitamin B6 deficiency in the rhesus monkey; with particular reference to the occurrence of atherosclerosis, dental caries, and hepatic cirrhosis. Am J Clin Nutr. 1956 Jul-Aug;4(4):318,25; discussion, 325-8. 25. Serfontein WJ, Ubbink JB, De Villiers LS, Rapley CH, Becker PJ. Plasma
pyridoxal-5-phosphate level as risk index for coronary artery disease. Atherosclerosis. 1985 Jun;55(3):357-61.
26. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998 Jul 21;98(3):204-10.
27. Kelly PJ, Kistler JP, Shih VE, Mandell R, Atassi N, Barron M, et al. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke. 2004 Jan;35(1):12-5.
28. Friso S, Girelli D, Martinelli N, Olivieri O, Lotto V, Bozzini C, et al. Low plasma vitamin B6 concentrations and modulation of coronary artery disease risk. Am J Clin Nutr. 2004 Jun;79(6):992-8.
29. Lin PT, Cheng CH, Liaw YP, Lee BJ, Lee TW, Huang YC. Low pyridoxal 5’-phosphate is associated with increased risk of coronary artery disease. Nutrition. 2006 Nov-Dec;22(11-12):1146-51.
30. Cheng CH, Lin PT, Liaw YP, Ho CC, Tsai TP, Chou MC, et al. Plasma pyridoxal 5’-phosphate and high-sensitivity C-reactive protein are independently associated with an increased risk of coronary artery disease. Nutrition. 2008 Mar;24(3):239-44.
31. Page JH, Ma J, Chiuve SE, Stampfer MJ, Selhub J, Manson JE, et al. Plasma vitamin B(6) and risk of myocardial infarction in women. Circulation. 2009 Aug 25;120(8):649-55.
32. Dierkes J, Hoffmann K, Klipstein-Grobusch K, Weikert C, Boeing H, Zyriax BC, et al. Low plasma pyridoxal-5’phosphate and cardiovascular disease risk in women: results from the Coronary Risk Factors for Atherosclerosis in Women Study. Am J Clin Nutr. 2005 Mar;81(3):725,7; author reply 727-8.
33. Dierkes J, Weikert C, Klipstein-Grobusch K, Westphal S, Luley C, Mohlig M, et al. Plasma pyridoxal-5-phosphate and future risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition Potsdam cohort. Am J Clin Nutr. 2007 Jul;86(1):214-20.
34. Regitz-Zagrosek V. Sex and gender differences in health. Science & Society Series on Sex and Science. EMBO Rep. 2012 Jun 29;13(7):596-603.
35. Shue GM, Hove EL. Interrelation of Vitamin B6 and Sex on Response of Rats to Hypercholesterolemic Diets. J Nutr. 1965 Mar;85:247-54.
36. Krumsiek J, Mittelstrass K, Do KT, Stuckler F, Ried J, Adamski J, et al. Gender-specific pathway differences in the human serum metabolome. Metabolomics. 2015;11(6):1815-33.
37. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013 Jul 20;382(9888):260-72.
38. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999 Dec 2;341(23):1725-30.
39. Schippers HM, Kalff MW. Cost comparison haemodialysis and renal transplantation. Tissue Antigens. 1976 Feb;7(2):86-90.
40. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004 Mar;4(3):378-83.
41. United States Renal Data System. Epidemiology of kidney disease in the United States. . Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2017.
42. Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006 Sep 15;82(5):603-11.
43. Ulvik A, Theofylaktopoulou D, Midttun O, Nygard O, Eussen SJ, Ueland PM. Substrate product ratios of enzymes in the kynurenine pathway measured in plasma as indicators of functional vitamin B6 status. Am J Clin Nutr. 2013 Oct;98(4):934-40.
44. Abedini S, Holme I, Marz W, Weihrauch G, Fellstrom B, Jardine A, et al. Inflammation in renal transplantation. Clin J Am Soc Nephrol. 2009 Jul;4(7):1246-54.
45. Ciorba MA. Kynurenine pathway metabolites: relevant to vitamin B6 deficiency and beyond. Am J Clin Nutr. 2013 Oct;98(4):863-4.
46. Wang Q, Liu D, Song P, Zou MH. Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Front Biosci (Landmark Ed). 2015 Jun 1;20:1116-43.
47. Eastman CL, Guilarte TR. Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res. 1989 Aug 28;495(2):225-31.
48. Brandacher G, Cakar F, Winkler C, Schneeberger S, Obrist P, Bosmuller C, et al. Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation. Kidney Int. 2007 Jan;71(1):60-7.
49. Lahdou I, Sadeghi M, Daniel V, Schenk M, Renner F, Weimer R, et al. Increased pretransplantation plasma kynurenine levels do not protect from but predict acute kidney allograft rejection. Hum Immunol. 2010 Nov;71(11):1067-72. 50. Zhao X, Chen J, Ye L, Xu G. Serum metabolomics study of the acute graft
rejection in human renal transplantation based on liquid chromatography-mass spectrometry. J Proteome Res. 2014 May 2;13(5):2659-67.
51. Vavrincova-Yaghi D, Seelen MA, Kema IP, Deelman LE, van der Heuvel MC, Breukelman H, et al. Early Posttransplant Tryptophan Metabolism Predicts Long-term Outcome of Human Kidney Transplantation. Transplantation. 2015 Aug;99(8):e97-104.
52. Fujigaki H, Yamamoto Y, Saito K. L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences. Neuropharmacology. 2017 Jan;112(Pt B):264-74.
53. Reyes-Ocampo J, Ramirez-Ortega D, Cervantes GI, Pineda B, Balderas PM, Gonzalez-Esquivel D, et al. Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production. Neurotoxicology. 2015 Sep;50:81-91.
54. Midttun O, Ulvik A, Ringdal Pedersen E, Ebbing M, Bleie O, Schartum-Hansen H, et al. Low plasma vitamin B6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. J Nutr. 2011 Apr 1;141(4):611-7.
55. Ueland PM, Ulvik A, Rios-Avila L, Midttun O, Gregory JF. Direct and Functional Biomarkers of Vitamin B6 Status. Annu Rev Nutr. 2015;35:33-70.
56. Ponticelli C, Passerini P. Gastrointestinal complications in renal transplant recipients. Transpl Int. 2005 Jun;18(6):643-50.
57. Ulvik A, Midttun O, Pedersen ER, Eussen SJ, Nygard O, Ueland PM. Evidence for increased catabolism of vitamin B6 during systemic inflammation. Am J Clin Nutr. 2014 Jul;100(1):250-5.
58. Schefold JC, Zeden JP, Fotopoulou C, von Haehling S, Pschowski R, Hasper D, et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant. 2009 Jun;24(6):1901-8.
59. Saito K, Fujigaki S, Heyes MP, Shibata K, Takemura M, Fujii H, et al. Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency. Am J Physiol Renal Physiol. 2000 Sep;279(3):F565-72.
60. Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA. Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med. 2006 Aug 31;8(20):1-27.
61. Lovelace MD, Varney B, Sundaram G, Lennon MJ, Lim CK, Jacobs K, et al. Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology. 2017 Jan;112(Pt B):373-88.
62. Christmas DM, Potokar J, Davies SJ. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat. 2011;7:431-9.
63. Miura H, Ozaki N, Sawada M, Isobe K, Ohta T, Nagatsu T. A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress. 2008 May;11(3):198-209.
64. Oxenkrug GF. Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later. Isr J Psychiatry Relat Sci. 2010;47(1):56-63. 65. Mutsaers HA, Masereeuw R, Olinga P. Altered tryptophan metabolism and
