Letter

ABO-Incompatible Kidney Transplantation Is a Novel Risk Factor for BK Nephropathy Andrew Bentall,1,2 Desley Neil,2 Adnan Sharif,1 and Simon Ball1

A

link between ABO-incompatible kidney transplantation and the risk of BK virus allograft nephropathy (BKVAN) has been identified in a report from Johns Hopkins Hospital.1 The 11 (17.7%) of 62 cases of BKVAN were identified by protocol (n = 5) or indication (n = 6) biopsies. The incidence of BKVAN in HLA–incompatible allograft recipients (transplantation after the removal of donor-specific HLA antibodies) and compatible allograft recipients was 5.9% and 3.0%, respectively. In a multivariable analysis, ABO-incompatible kidney transplantation was identified as an independent risk factor for the development of BKVAN. To date, no other report has corroborated this apparent overrepresentation of BKVAN in ABO-incompatible kidney transplant recipients. Between 2007 and 2013 with a median follow-up of 46.7 months (22.9–57.9), 59 ABO-incompatible kidney transplantations have been performed using antigenspecific immunoadsorption and rituximab induction (more recently basiliximab alone) at our center. Maintenance immunosuppression consists of tacrolimus, mycophenolate mofetil, and corticosteroids. In this cohort, 6 cases of BKVAN have been diagnosed on indication biopsy in the context of allograft dysfunction (10.2%, diagnosed 3–11 months after transplantation; Table 1). This incidence is similar to the indication biopsy cohort at Johns Hopkins Hospital and significantly greater than the frequency of detection in contemporaneous blood group–compatible transplants at our center (10.2% vs 3.2%, respectively, P = 0.014). In those with BKVAN, there is an overrepresentation of donor blood group B (5/6 vs 16/53, P = 0.018) and lower

Received 6 August 2014. Accepted for publication 2 September 2014. 1

Renal Institute of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom.

2

Department of Histopathology, Queen Elizabeth Hospital, Birmingham, United Kingdom.

anti–donor blood group antibodies (median, 0 vs 32; P = 0.027). The latter may however be a consequence of the former because we find higher anti-A than anti-B titers in recipient populations. This association with donor blood group has not been described before, and no significant difference was observed in the BKVAN ABO-incompatible kidney transplant cohort at Johns Hopkins Hospital (Edward Kraus, personal communication). It may be an anomaly consequent on small numbers and multiple comparisons (or at least one other comparison with donor blood group A). There are however reports that different blood group antigens may influence binding of pathogen receptors to sialic acid indirectly, albeit this has not been studied in the context of BK virus interactions with α2,3-linked sialic acid on renal tubular cells.2 Such a mechanism might be expected to also influence BKVAN in ABO-compatible kidneys; therefore, an additional role for the presence of blood group antigen-specific antibody would have to be invoked in any explanatory hypothesis. Rejection occurred in only 1 patient with BKVAN with steroid responsive Banff 1A classification. We monitor BK polymerase chain reaction only for the indication of allograft dysfunction in our transplant center. TABLE 1.

Demographics details of ABOi kidney allograft recipient stratified by BKVAN diagnosis Variable

ABOi BKVAN+ (n = 6)

ABOi BKVAN− (n = 53)

83.3% (5) 45.2 (6.8) 16.7% (1) 16.7% (1) 16.7% (1) 83.3% (5) 16.7% (1) 0.0% (0) 33.3% (2) 50% (3) 16.7% (1) 16.7% (1) 50% (3) 33.3% (2) 0 (0-33.5)

41.5% (22) 47.8 (13.1) 32.1% (17) 54.7% (29) 58.5% (31) 88.7% (47) 3.8% (2) 7.5% (4) 67.9% (36) 11.3% (6) 20.8% (11) 64.2% (34) 28.3% (15) 7.5% (4) 32 (3-64)

0.05 0.35 0.13 0.09 0.08 0.33

1 (1-2.75)

3 (2-4.5)

0.06

Male sex Age, mean (SD) Rejection episode Before dialysis Rituximab therapy Ethnicity

ISSN: 0041-1337/15/9902–e9

White Black South Asian Recipient ABO O A B Donor ABO A B AB Starting titer anti-donor IgG before desensitization, median (Q1-Q3) Median immunoabsorption treatments before transplantation (Q1-Q3)

DOI: 10.1097/TP.0000000000000483

ABOi indicates ABO incompatible; IgG, Immunoglobulin G.

Andrew Bentall is funded by a National Institute for Health Research (Clinical Lecturership award). This article/paper/report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The other authors declare no conflicts of interest. A.B., A.S., and S.B. participated in the research design. A.B., A.S., and S.B. participated in the writing of the article. A.B., D.N., A.S., and S.B. participated in the performance of the research. A.B., A.S., and S.B. participated in the data analysis. Correspondence: Andrew Bentall, MBChB MRCP(UK), Renal Institute of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom, Department of Nephrology, University Hospitals Birmingham, Edgbaston, Birmingham, B15 2WB, United Kingdom. ([email protected]) Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Transplantation



February 2015

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Volume 99



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Number 2

Letter to the Editor

© 2015 Wolters Kluwer

The level of overall immunosuppression in our ABOincompatible kidney transplant recipients is higher than in our compatible cohort; however, Sharif et al demonstrated that HLA-incompatible allograft recipients did not have a higher incidence despite increased conditioning. Studies have associated different immunosuppressive agents with the development of BK nephropathy.3,4 This Letter to the Editor corroborates the previous observation in a North American cohort of increased BKVAN associated with ABO-incompatible kidney transplantation. We suggest that an increased index of investigation for BKVAN may be reasonably considered in ABO-incompatible kidney transplantation. These observations need further assessment in larger studies; however, simple explanations such as increased antibody removal therapy or treatment of acute re-

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jection in those with BKVAN do not account for their findings. If the finding of a differential effect of donor blood group B is corroborated, this would suggest a possible focus for future pathophysiologic studies. REFERENCES 1. Sharif A, Alachkar N, Bagnasco S, et al. Incidence and outcomes of BK virus allograft nephropathy among ABO- and HLA-incompatible kidney transplant recipients. Clin J Am Soc Nephrol 2012;7:1320. 2. Cohen M, Hurtado-Ziola N, Varki A. ABO blood group glycans modulate sialic acid recognition on erythrocytes. Blood 2009;114:3668. 3. Manitpisitkul W, Drachenberg C, Ramos E, et al. Maintenance immunosuppressive agents as risk factors for BK virus nephropathy: a case–control study. Transplantation 2009;88:83. 4. Borni-Duval C, Caillard S, Olagne J, et al. Risk factors for BK virus infection in the era of therapeutic drug monitoring. Transplantation 2013;95:1498.

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