Kynurenine Levels Predict Severity, Treatment Response, Survival

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by Steve Bryson, PhD |

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Elevated metabolites of the kynurenine pathway in the bloodstream of people with pulmonary arterial hypertension (PAH) when they’re diagnosed predicted disease severity, their response to therapy, and survival, a study discovered.

Activation of the kynurenine pathway, related to vitamin B3 production, was found to be linked to inflammation via the immune signaling molecule interleukin-6 and its receptor.

Whether targeting this pathway leads to a new treatment strategy for PAH remains to be established, the researchers noted.

The study, “Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα,” was published in the journal Scientific Reports.

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Studies have highlighted the importance of inflammation and defects in energy-producing mitochondria in PAH’s development and progression. PAH is marked by the blood vessels in the lungs, or pulmonary arteries, narrowing, causing high blood pressure.

Nicotinamide adenine dinucleotide (NAD), a molecule produced from vitamin B3, is known to be an important modulator of inflammation and mitochondrial function.

NAD can come from one’s diet or be generated in the body by the kynurenine pathway (KP). This pathway starts with the conversion of the amino acid tryptophan, a protein building block, to kynurenine (Kyn), followed by several metabolic steps to make NAD. Metabolites are intermediate or end products made or used in the process of cellular metabolism.

A correlation between elevated metabolites of the kynurenine pathway in PAH patients and increased resistance to blood flow in their pulmonary arteries has been reported. Similarly, elevated kynurenine levels were observed in PAH and correlated with immune impairment and clinical outcomes.

“Together, these studies highlight the importance of the KP in PAH,” researchers at the Erasmus University Medical Center, the Netherlands, wrote.

The PAH patients in these studies were receiving PAH therapies, however. As such, the kynurenine pathway-metabolite profile in treatment-naïve PAH patients as well as the impact of PAH therapy on the pathway are currently unknown.

The team first examined the kynurenine pathway profile in 43 treatment-naïve — or those who had not had any approved treatment — PAH patients at diagnosis compared to 111 healthy people who served as controls. Although the amino acid tryptophan was significantly lower in the blood of the patients than in controls, kynurenine, along with four pathway metabolites, was significantly higher.

The altered kynurenine pathway profile significantly distinguished PAH patients from controls at diagnosis, even after correcting for age, sex, and body mass index, a measure of body fat, statistical analysis showed.

Next, the team measured the kynurenine pathway profile in two rat models of PAH: monocrotaline (MCT)-induced PH and Sugen-hypoxia-induced PH (SuHx).

The MCT-PH rats had a similar profile as the PAH patients. In comparison, the kynurenine pathway profile in SuHx-PH rats differed from that in patients. As the MCT-PH rats showed the most severe inflammation, “these results suggest a link between inflammation and KP-metabolism in PAH,” the research team wrote.

Because of the connection with inflammation, three types of cells from the lungs of PAH patients were exposed to different immune signaling proteins.

The complex of interleukin-6 (IL-6) with its receptor (IL-6R-alpha) induced a PAH-like kynurenine profile in all the cell types, showing that “inflammation — particularly activation of IL-6/IL-6R-[alpha] signaling — contributed to the KP activation in PAH patients,” the researchers said.

The impact of subsequent PAH therapy showed tryptophan was still significantly lower than in controls after six months, but now kynurenine and three metabolites were elevated. Similar results were seen after one year, though only two metabolites were elevated, suggesting the profile was partly normalized in PAH patients after therapy, the researchers noted.

During a median follow-up of 42 months (3.5 years), 12 PAH patients died. At diagnosis, kynurenine levels were significantly higher in non-survivors versus survivors. In measurements after diagnosis, kynurenine and the four metabolites were all significantly higher in non-survivors than survivors.

In survivors, these metabolites were significantly lower after one year but not six months of PAH therapy, “indicating that only long-term PAH therapy decreased KP-metabolite levels,” the scientists noted.

The levels of all metabolites, except for tryptophan, correlated with each other in PAH patients at diagnosis and after six months and one year of treatment.

Compared to controls, elevated levels of kynurenine and certain metabolites were related to higher pulmonary vascular resistance, worse heart function, more severe disease, reduced exercise capacity, impaired kidney function, and C-reactive protein levels, a marker for inflammation.

Lastly, in an analysis of survivors, PAH patients were divided into two groups based on the median levels of kynurenine pathway metabolites at diagnosis. High levels of kynurenine and two metabolites predicted worse survival, while high kynurenine predicted worse long-term survival. Similar findings were observed in metabolite measurements after diagnosis.

“These results indicate that elevations in [kynurenine pathway]-metabolites are potential predictors of survival for PAH patients, with Kyn being the strongest prognostic biomarker,” the scientists wrote.

“Activation of kynurenine pathway with increased levels of circulating KP-metabolites predict disease severity, response to PAH therapy, and survival in PAH patients,” the authors concluded. “Whether KP activation … may provide a novel treatment strategy for PAH remains to be established.”