Correspondence

1458 www.thelancet.com Vol 381 April 27, 2013

direct negative consequences for allograft survival.1 Importantly, there is growing awareness about the importance of antibody-mediated rejection in other solid organ transplants (including heart, lung, small bowel, and composite tissue), pointing our thinking towards the limitations of current diagnostic criteria.2

For kidney allografts, the international Banff classifi cation will probably be complemented by new clinically relevant entities including antibody-mediated vas-cular rejection,3 and C4d-negative antibody-mediated rejection.2 The deposition of complement fraction C4d in the graft capillaries (and in the artery), initially thought to be a major criterion in the diagnosis of antibody-mediated rejection, suff ers from low sensitivity, refraining many patients from accurate diagnosis and treatment.3

There is an unmet need for the transplant community to provide a more accurate and valid diagnostic system for allograft rejection. This is particularly important because rejections seen nowadays are more complex in terms of kinetics and clinical expression, blatant rejections being replaced by subtler or indolent forms not accompanied by a signifi cant degradation of the allograft function, representing a milder, but nonetheless progressing form of the disease.4

Population-based studies using contemporary methods for allograft phenotyping and antibody screening are needed to better defi ne disease stage, activity, and response to treatment. Gene profi ling in the allograft could be a promising strategy to enhance the accuracy of rejection classifi ers by acting as companion to conventional microscopy, providing mechanistic insights, and revealing changes invisible to histology and immunohistochemistry.5

We declare that we have no confl icts of interest.

also had arterial C4d staining, but did not report its specifi city. Previously, allo-antibodies were reported in only 50% of patients with arterial C4d staining.4 Therefore, caution is warranted for diagnostic use of arterial C4d before more evidence becomes available.

Additionally, antibodies could cause isolated vasculitis without parenchymal infl ammation.5

Therefore, we call for an urgent update of the diagnostic criteria for kidney transplant tissues to identify antibody-mediated vascular rejection, and guide treatment decisions.We declare that we have no confl icts of interest.

Serena Bagnasco, Edward Kraus, *Banu Sisbsis@ualberta.ca

Departments of Pathology (SB) and Medicine (EK), School of Medicine, University of Johns Hopkins, Baltimore, MD 21205-2196, USA; and Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada (BS)

1 Lefaucheur C, Loupy A, Vernerey D, et al. Antibody-mediated vascular rejection of kidney allografts: a population-based study. Lancet 2013; 381: 313–19.

2 Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classifi cation of renal allograft rejection. Am J Transplant 2003; 3: 708–14.

3 Sis B, Jhangri G, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant 2009; 9: 2312–23.

4 Batal I, Girnita A, Zeevi A, et al. Clinical signifi cance of the distribution of C4d deposits in diff erent anatomic compartments of the allograft kidney. Mod Pathol 2008; 21: 1490–98.

5 Sis B, Lategan B, Bagnasco S, et al. Signifi cance of isolated vasculitis (v1) in kidney transplants: a multicenter observational study. Am J Transplant 2011; 11: 58.

Diagnostic criteria for kidney transplant rejection: a call to action

The study by Carmen Lefaucheur and colleagues (Jan 26, p 313)1 shows the consequences of misdiagnosis of antibody-mediated vascular rejection. 45% of patients with antibody-mediated vascular rejection were misdiagnosed as T-cell-mediated vascular rejection, did not recover after anti-T-cell treatment, and most of these patients lost their transplanted kidneys.

We think these diagnostic errors can be explained by: inadequate criteria in the international Banff classifi cation; and lack of reliable biomarkers for antibody-mediated rejection.

The Banff classifi cation allows a diagnosis of antibody-mediated vascular rejection only if there is severe arteritis concomitant with donor-specifi c antibodies, and positive C4d staining in capillaries.2

The Banff criteria classify cases with less severe arteritis with an a-priori diagnosis of T-cell-mediated rejection.

Moreover, C4d capillary staining, used as a biomarker for antibody-mediated rejection, has a poor sensitivity.3

In Lefaucheur and colleagues’ study,1 82% of antibody-mediated vascular rejections had mild-or-moderate arteritis and 44% were C4d-negative. Interestingly, the authors noted that 75% of antibody-mediated vascular rejection biopsy samples with capillary C4d-positivity

Authors’replySerena Bagnasco and colleagues are raising an important point to the transplant community in calling for urgent action to update diagnostic criteria for kidney transplant rejection.

The last decade has been a turning point in the fi eld of allograft rejection with the demonstration that antibody-mediated rejection was largely underdiagnosed with

4 ten Cate FJ, Soliman OI, Michels M, et al. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail 2010; 3: 362–69.

5 Cuoco FA, Spencer WH III, Fernandes VL, et al. Implantable cardioverter-defi brillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol 2008; 52: 1718–23.

6 Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation 2006; 114: 1633–44.

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