Identification of P-cresyl Sulfate Producer Phenotype by Oral Tyrosine Challenge Test: Interactions Among Diet, Gut Microbiota, and Host Genome

Patients with chronic kidney disease (CKD) display a substantial increase in cardiovascular disease (CVD). Moreover, the prognosis of CVD in CKD is extremely poor. Understanding the pathophysiology of CVD in CKD might help to develop treatment strategies to reduce its morbidity and mortality. Traditional CV risk factors for the general population, such as diabetes mellitus, high blood pressure, and dyslipidemia, are more common in patients with CKD, but cannot entirely explain the increased CV risk. Compelling evidence suggests that the uremic milieu itself plays a critical role in the development and progression of CVD in CKD. The gut microbiota is markedly altered in CKD. Fermentation of protein and amino acids by certain gut microbiota results in the generation of different uremic toxins. p-cresyl sulfate (PCS) is among the most representative gut-derived uremic toxins implicated in the pathogenesis of CVD in CKD (JAHA 6:e005022, 2017). However, there remained no clear cut-off value of fasting plasma PCS for unfavorable clinical outcomes (Clin J Am Soc Nephrol 4:1551-8, 2009). The benefit of adding an orally administered adsorbent (AST-120) to standard therapy in unselected patients with moderate to severe CKD is also not supported by data from a recent randomized controlled trial (J Am Soc Nephrol 26:1732-46, 2015).

It has been shown that uremic toxicity is related to the peak rather than the time-averaged urea concentration (Perit Dial Int 9:257-60, 1989). PCS is mainly produced from the metabolism of dietary tyrosine by gut bacteria. PCS concentration may fluctuate widely from time to time in response to meals. A postprandial plasma PCS might theoretically reflect the pathophysiological level of PCS. Thus, we plan to establish an oral tyrosine challenge test (OTCT) to simulate the postprandial plasma PCS among patients with CKD to identify "PCS producers" who are likely to be at high risk for CVD and are more likely to respond to adsorbent therapy. The OTCT survey is integrated with dietary patterns, gut microbiome, and serum biochemistry to assess PCS synthesis capacity from host-diet-microbiota interactions.