Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET)-Rationale and database description

Qi-Fang Huang, Sander Trenson, Zhen-Yu Zhang, Wen-Yi Yang, Lucas Van Aelst, Esther Nkuipou-Kenfack, Fang-Fei Wei, Blerim Mujaj, Lutgarde Thijs, Agnieszka Ciarka, Jerome Zoidakis, Walter Droogné, Antonia Vlahou, Stefan Janssens, Johan Vanhaecke, Johan Van Cleemput, Jan A Staessen, Qi-Fang Huang, Sander Trenson, Zhen-Yu Zhang, Wen-Yi Yang, Lucas Van Aelst, Esther Nkuipou-Kenfack, Fang-Fei Wei, Blerim Mujaj, Lutgarde Thijs, Agnieszka Ciarka, Jerome Zoidakis, Walter Droogné, Antonia Vlahou, Stefan Janssens, Johan Vanhaecke, Johan Van Cleemput, Jan A Staessen

Abstract

Objectives: Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients.

Methods: HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement.

Results: Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ≥ 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy.

Conclusions: uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients.

Conflict of interest statement

Competing Interests: Esther Nkuipou-Kenfack is an employee of Mosaiques-Diagnostics AG (Hannover, Germany) and advised on the interpretation of the urinary proteomic data and participated in the critical review of the final draft of the manuscript. Her commercial affiliation did not play any role in study design, data collection and analysis, or decision to publish the manuscript and did not influence the statement on data sharing. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Number of heart transplantations performed…
Fig 1. Number of heart transplantations performed at the University Hospitals Leuven from 1989 until 2015.
Fig 2. Distributions of the multidimensional urinary…
Fig 2. Distributions of the multidimensional urinary proteomic classifiers HF1, HF2, HfrEF103 and HFP, consisting of 85, 671, 103 and 96 urinary peptide fragments and designed for diagnosis and prognostication in the framework of subclinical diastolic left ventricular dysfunction (HF1) or symptomatic heart failure (HF2, HFrEF103 and HFP).
The P value is for departure of the actually observed distribution (kernel distribution; dotted line) from normality (full line).
Fig 3. Distributions of the multidimensional urinary…
Fig 3. Distributions of the multidimensional urinary proteomic classifiers CAD238, ACSP75 and CKD273, consisting of 238, 75 and 273 urinary peptide fragments and designed for diagnosis and prognostication in the framework coronary heart disease (CAD238 and ACSP75) or chronic kidney disease (CKD273).
The P value is for departure of the actually observed distribution (kernel distribution; dotted line) from normality (full line).

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