title: Non-invasive diagnosis of acute rejection in renal transplant patients using mass spectrometry of urine samples - a multicentre phase 3 diagnostic accuracy study.
abstract: BACKGROUND
  Reliable and timely detection of acute rejection in renal transplant patients is important to preserve the allograft function and to prevent premature allograft failure. The current gold standard for the rejection diagnosis is an allograft biopsy which is usually performed upon an unexplained decline in allograft function. Because of the invasiveness of the biopsy, non-invasive tests have been suggested to diagnose acute rejection including mass spectrometry analysis of urine samples.
  
  
  METHODS
  The aim of this study is to examine the diagnostic accuracy of mass spectrometry analysis in urine for the diagnosis of acute rejections using the biopsy as gold-standard. The study is an ongoing prospective, single-arm, multicentre, phase 3 diagnostic accuracy study. It started in October 2011 and will be concluded in December 2015. Patient within the first year after transplantation who are scheduled for a biopsy to clarify unexplained impairment of the allograft are consecutively recruited into the study. The overall sample size (n = 600) was calculated to demonstrate a sensitivity of 83 % and a specificity of 70 % for a one-sided type one error of 2.5 % and a power of 80 % per hypothesis. Biopsy evaluation and mass spectrometry analysis of urine samples (obtained immediately before biopsy) are performed independently by different readers without knowledge from the respective other assessment. The follow-up observation period is 6 months. For the primary analysis, the lower limits of the two-sided 95 % Wald confidence intervals for sensitivity and specificity will be compared with the pre-specified thresholds (83 % for sensitivity and 70 % for specificity). In secondary analyses the predictive values, the diagnostic measures in subgroups, and the clinical course will be assessed.
  
  
  CONCLUSIONS
  Previous phase 2 diagnostic accuracy studies (in small selected study populations) provided sufficient evidence to suggest mass spectrometry on urine samples as a promising approach to detect acute rejections. This study determines the diagnostic performance of the test in the routine setting of post-transplant patient care, compared to the biopsy-based rejection diagnosis. The next step would be a randomized trial to compare the two diagnostic strategies (including the urine test or not) in relation to patient relevant endpoints.
  
  
  BACKGROUND
  NCT01315067 ; March 14, 2011.
authors.affiliation: Institute for Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073, Göttingen, Germany. Antonia.Zapf@med.uni-goettingen.de.
authors.forename: Antonia
authors.initials: A
authors.lastname: Zapf
authors.affiliation: Department of Nephrology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. Gwinner.Wilfried@mh-hannover.de.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Gwinner
authors.affiliation: Institute for Biostatistics, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. Karch.Annika@mh-hannover.de.
authors.forename: Annika
authors.initials: A
authors.lastname: Karch
authors.affiliation: Mosaiques Diagnostics and Therapeutics, Rotenburger Str. 20, 30659, Hannover, Germany. metzger@mosaiques-diagnostics.com.
authors.forename: Jochen
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Department of Nephrology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. Haller.Hermann@mh-hannover.de.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Institute for Biostatistics, Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. Koch.Armin@mh-hannover.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Koch
mesh_terms: D000208:Acute Disease; D001706:Biopsy; D006084:Graft Rejection / Q000175:diagnosis* / Q000652:urine*; D006801:Humans; D016030:Kidney Transplantation; D013058:Mass Spectrometry; D011446:Prospective Studies