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. 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. However, there remained no clear cut-off value of fasting plasma PCS for unfavorable clinical outcomes.

Thus, we plan to establish an oral tyrosine challenge test (OTCT) integrated with dietary patterns, gut microbiome, and serum biochemistry to assess PCS synthesis capacity from host-diet-microbiota interactions.

Study Overview

• Status: Unknown
• Conditions: Healthy; Chronic Kidney Diseases
• Intervention / Treatment: Dietary supplement: Tyrosine, brand name: myprotein

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ting-Yun Lin, MD.; Phone Number: 2350 +886-2-66289779; Email: water_h2o_6@hotmail.com

Study Locations

• Taiwan
  • New Taipei City, Taiwan, 231
    • Recruiting
    • Taipei Tzu Chi Hospital
    • Contact: Ting-Yun Lin, MD; Phone Number: 2350 8862-6628-9779; Email: water_h2o_6@hotmail.com
    • Contact: Szu-chun Hung, MD; Phone Number: 2350 8862-6628-9779; Email: szuchun.hung@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• chronic kidney disease stages 3-5D patients OR
• healthy volunteers

Exclusion Criteria:

• subjects who has ever exposure to antibiotics or probiotics within the 3 months before entering the study
• patients with active gastrointestinal diseases or recent gastrointestinal discomfort (such as abdominal pain or diarrhea)
• patients with liver cirrhosis
• pregnant or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tyrosine loading	Dietary supplement: Tyrosine, brand name: myprotein; tyrosine at a dose of 100 mg/kg is then administered orally to the participants once

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
level of serum p-cresyl sulfate	serum p-cresyl sulfate level after oral tyrosine loading up to 48 hours	the area under curve of serum p-cresyl sulfate

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
level of serum phenyl sulfate	serum phenyl sulfate level after oral tyrosine loading up to 48 hours	the area under curve of serum phenyl sulfate

Collaborators and Investigators

• Sponsor: Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
• Investigators: Principal Investigator: Ting-Yun Lin, MD., Taichung Tzu Chi Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2019
• Primary Completion (Anticipated): February 28, 2020
• Study Completion (Anticipated): February 28, 2020

Study Registration Dates

• First Submitted: December 8, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 18, 2019

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 14, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: 08-X-108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: We have decided yet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No