Non-invasive diagnosis of acute rejection in renal transplant patients using mass spectrometry of urine samples - a multicentre phase 3 diagnostic accuracy study

BMC Nephrology

Armin Koch²  Hermann Haller¹  Jochen Metzger³  Annika Karch²  Wilfried Gwinner¹  Antonia Zapf⁴ 

[1] Department of Nephrology, Medical School Hannover, Carl-Neuberg-Str. 1, Hannover, 30625, Germany;Institute for Biostatistics, Medical School Hannover, Carl-Neuberg-Str. 1, Hannover, 30625, Germany;Mosaiques Diagnostics and Therapeutics, Rotenburger Str. 20, Hannover, 30659, Germany;Institute for Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, Göttingen, 37073, Germany

关键词: Specificity;    Sensitivity;    Diagnostic study;    Diagnosis;    Urinary peptides;    Mass spectrometry;    Urine analysis;    Allograft biopsy;    Acute rejection;    Kidney transplantation;   

Others  :  1225236
DOI  :  10.1186/s12882-015-0146-x

 received in 2015-06-30, accepted in 2015-08-29,  发布年份 2015

【 摘 要 】

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.

Design and 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.

Discussion

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.

Trial registration

NCT01315067; March 14, 2011

【 授权许可】

   
2015 Zapf et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]DeVos JM, Gaber AO, Teeter LD, Graviss EA, Patel SJ, Land GA, Moore LW, Knight RJ. Intermediate-term graft loss after renal transplantations is associated with both donor-specific antibody and acute rejection. Transplantation. 2014; 97:534-540.
• [2]Paraskevas S, Kandaswamy R, Humar A, Gillingham KJ, Gruessner RW, Payne WD, Najarian JS, Sutherland DE, Matas AJ. Risk factors for rising creatinine in renal allografts with 1 and 3 yr survival. Clin Transplant. 2006; 20:667-672.
• [3]El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM, Cosio FG. Identifying specific causes of kidney allograft loss. Am J Transplant. 2009; 9:527-535.
• [4]Gwinner W. Renal transplant rejection markers. World J Urol. 2007; 25:445-455.
• [5]EMA. Guideline on clinical evaluation of diagnostic agents. Doc. Ref. CPMP/EWP/1119/98/Rev.1 2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003580.pdf (date of last access 27/04/15)
• [6]Köbberling J, Trampisch HJ, Windeler J. Memorandum for the evaluation of diagnostic measures. J Clin Chem Clin Biochem. 1990; 28:873-879.
• [7]Clarke W, Silverman BC, Zhang Z, Chan DW, Klein AS, Molmenti EP. Characterization of renal allograft rejection by urinary proteomic analysis. Ann Surg. 2003; 237:660-664.
• [8]Schaub S, Rush D, Wilkins J, Gibson IW, WEiler T, Sangster K, Nicolle L, Karpinski M, Jeffery J, Nickerson P. Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol. 2004; 15:219-227.
• [9]O'Riordan E, Orlova TN, Mei JJ, Butt K, Chander PM, Rahman S, Mya M, Hu R, Momin J, Eng EW, Hampel DJ, Hartman B, Kretzler M, Delaney V, Goligorsky MS. Bioinformatic analysis of the urine proteome of acute allograft rejection. J Am Soc Nephrol. 2004; 15:3240-3248.
• [10]Wittke S, Haubitz M, Walden M, Rohde F, Schwarz A, Mengel M, Mischak H, Haller H, Gwinner W. Detection of acute tubulointerstitial rejection by proteomic analysis of urinary samples in renal transplant recipients. Am J Transplant. 2005; 5:2479-2488.
• [11]Sigdel TK, Kaushal A, Gritsenko M, Norbeck AD, Qian WJ, Xiao W, Camp DG, Smith RD, Sarwal MM. Shotgun proteomics identifies proteins specific for acute renal transplant rejection. Proteomics Clin Appl. 2010; 4:32-47.
• [12]Ling XB, Sigdel TK, Lau K, Ying L, Lau I, Schilling J, Sarwal MM. Integrative urinary peptidomics in renal transplantation identifies biomarkers for acute rejection. J Am Soc Nephrol. 2010; 21:646-653.
• [13]Metzger J, Chatzikyrkou C, Broecker V, Schiffer E, Jaensch L, Iphoefer A, Mengel M, Mullen W, Mischak H, Haller H, Gwinner W. Diagnosis of subclinical and clinical acute T-cell-mediated rejection in renal transplant patients by urinary proteome analysis. Proteomics Clin Appl. 2011; 5:322-333.
• [14]Al-Awwa IA, Hariharan S, First MR. Importance of allograft biopsy in renal transplant recipients: correlation between clinical and histological diagnosis. Am J Kidney Dis. 1998; 31:15-18.