BTS 2013 Report – Post-transplant antibody monitoring – for and against

by Maria Dalby reporting on the presentation by William McKane, Sheffield Teaching Hospitals NHS Foundation Trust & Declan de Freitas, Beaumont Hospital, Dublin, Ireland.   Pre-transplant and de novo development of donor-specific HLA antibodies are known to predict poor long-term outcomes in renal transplantation, and the value of HLA surveillance for confirming dysfunction is undisputed.

However, routine monitoring or screening for HLA antibodies is a more contentious issue. In this debate session, Drs William McKane from Sheffield and Declan de Freitas from Dublin argued against and for post-transplant HLA screening on the basis of, on the one hand, the technical and methodological limitations and cost of currently available protocols, and on the other hand the prognostic and risk stratification utility.

 

William McKane’s first major argument against routine HLA screening  revolves around the fact that the Luminex microbeads used display significant batch variation and are sufficiently non-physiological in their HLA protein conformation to render results too variable and unreliable to be of use for clinical application (1). A limitation which is further confounded by the fact that natural HLA antibodies have been detected in healthy individuals (2,3). Substances that are commonly used therapeutically in kidney transplantation, such as intravenous immunoglobulin, thymoglobulin and bortezomib, may interfere with the analysis, and there is no universal definition of the cut-off point for a negative test (1). William McKane stressed that the results generated from HLA testing are complex and must be interpreted in context, which requires a close collaboration between the clinician and the Histocompatibility & Immunogenics (H&I) team.

 

It is important to bear in mind that HLA screening, as it is used in a transplantation context, is not actually screening as per the definition of the word. In addition to an agreed cut-off point for a negative or positive test, a screening test also needs to be accompanied by a treatment for the condition that is being screened, and the natural history of the condition must be adequately understood – neither of these apply to post-transplant development of HLA antibodies. Randomised controlled clinical trials have indeed shown that DSA predict antibody-mediated rejection and graft loss (4-6); however, the applicability of this for clinical practice and the decision whether or not to transplant an individual patient is limited.

 

Another important argument against routine HLA screening is the expense – at an estimated cost of around 300 Euro per DSA test, it is estimated that detecting one case of de novo DSAs will incur a cost of around 130,000 Euro (7). A more reliable and better-value marker of declining graft function, in William McKane’s experience, is to screen for proteinuria, as this may be visible up to 6 months before any HLA antibodies may be detected (5).

 

Declan de Freitas pointed out that a common limitation of biopsy data for linking the development of DSA to rejection is that the biopsy is taken for a cause, that is, the patient is showing other signs of rejection and the biopsy is taken for  the purpose of confirmation rather than screening. Declan de Freitas stressed that there is a need for a prospective randomised trial documenting the role of DSA screening in a large population; in the meantime, a sensible approach is to use screening as a risk stratification tool, and test patients who are deemed to be at risk more frequently to pick up early signs of rejection, and treat based on biopsy results in patients who are found to be HLA positive. Tackling non-adherence is essential, as up to 50% of all kidney transplant failures are known to be caused by non-adherence. There is a clear need for further information on the diagnosis and screening for DSA in the field of kidney transplantation.

 

1.  Tait BD, Susal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and Non-HLA antibodies in transplantation. Transplantation. 2013;95(1):19-47. Epub 2012/12/15.

2.  El-Awar N, Terasaki PI, Nguyen A, Sasaki N, Morales-Buenrostro LE, Saji H, et al. Epitopes of human leukocyte antigen class I antibodies found in sera of normal healthy males and cord blood. Human immunology. 2009;70(10):844-53. Epub 2009/07/08.

3.  Morales-Buenrostro LE, Terasaki PI, Marino-Vazquez LA, Lee JH, El-Awar N, Alberu J. “Natural” human leukocyte antigen antibodies found in nonalloimmunized healthy males. Transplantation. 2008;86(8):1111-5. Epub 2008/10/24.

4.  Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505-13. Epub 2009/05/23.

5.  Fotheringham J, Angel CA, McKane W. Transplant glomerulopathy: morphology, associations and mechanism. Nephron Clinical practice. 2009;113(1):c1-7; discussion c. Epub 2009/07/11.

6.  Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. Journal of the American Society of Nephrology : JASN. 2005;16(9):2804-12. Epub 2005/07/15.

7.  Tait BD, Hudson F, Cantwell L, Brewin G, Holdsworth R, Bennett G, et al. Review article: Luminex technology for HLA antibody detection in organ transplantation. Nephrology (Carlton). 2009;14(2):247-54. Epub 2009/02/12.