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Volume: 15 Issue: 1 February 2017

FULL TEXT

LETTER TO EDITOR
Choice of Induction in the Era of Single-Antigen Bead Testing: An Idiosyncratic Case Report

Use of induction therapy after kidney transplant is based on immunologic risk status, but accurate assessment of risk in the era of advanced immunologic testing can be complex. Here, we describe the case of a young kidney recipient who had a Castleman disease, often regarded as a benign lymphoma. Our patient, a white male patient with Castleman disease, underwent a first kidney transplant with rabbit antithymocyte globulin induction but returned to dialysis after primary nonfunction occurred. A second donor became available who shared 3 class I HLA antigens with the first donor, but only low-level isolated donor-specific antibodies toward HLA-Cw were detected (mean fluorescence intensity < 1000). After consideration by clinicians, the patient received a second transplant and was again given rabbit antithymocyte globulin induction (total dose 6 mg/kg). Graft biopsy at month 3 showed no evidence of microvascular inflammation, and the patient was C4d negative. At last follow-up (18 mo), serum creatinine level was 11 mg/dL and Castleman disease remained quiescent. In this challenging case, after weighing various factors concerning immunologic risk status and risk for posttransplant lymphoproliferative disease in the presence of Castleman disease, induction with rabbit antithymocyte globulin appeared to be the appropriate option. Patients with end-stage renal disease and quiescent Castleman disease should receive induction therapy, with close monitoring.


Key words : Antithymocyte globulin, Castleman disease, Donor-specific antibodies, Risk, Thymoglobulin

Introduction

The current KDIGO 2009 guidelines suggest in­duction with lymphocyte-depleting agent for kidney transplant recipients at high immunologic risk and interleukin 2 receptor antagonist (IL-2RA) induction in standard-risk patients.1 However, since the development of these recommendations, risk stratification has been profoundly changed by the introduction of Luminex (Luminex Corporation, Austin, TX, USA) technology, which allows single-antigen testing for donor-specific antibodies (DSA). Other immunologic and nonimmunologic factors, however, must also be taken into account, such that decision making can include all possible aspects.

Furthermore, no trial has compared outcomes with rabbit antithymocyte globulin (rATG) versus IL-2RA induction in the era of Luminex technology. In a randomized, controlled trial, Brennan and associates reported a significantly lower rate of biopsy-proven acute rejection with rATG versus the IL-2RA basi­liximab in a population who, in retrospect, would probably be characterized as “moderate” risk.2 Biopsy-proven acute rejection was less frequent in the rATG group, at the cost of more bacterial infections and noncytomegalovirus viral infections. Consistent find­ings have been reported in a second randomized trial that included patients at much higher im­munologic risk.3 However, these trials took place before single-antigen characterization of antibodies was available and before antibody-mediated rejection was accurately diagnosed, making the results difficult to interpret.

We present here an idiosyncratic case in which the prognosis was ominous and in which multiple factors influenced the choice of induction therapy.

Case Report

A white male patient with Castleman disease and amyloidosis progressed to end-stage renal disease by 2008. He received a blood transfusion during the same year. In 2013, at age 37 years, he received a first kidney transplant. Low-level anti-DQ DSAs were present (mean fluorescence intensity < 1000), and the complement-dependent cytotoxicity cross-match was negative. The patient was given rATG (Thymoglobulin, Genzyme, Cambridge, MA, USA) at a total dose of 6 mg/kg. The graft had primary nonfunction, and he returned to dialysis.

In 2014, a second donor graft became available from a 30-year-old male patient who died from a cerebral aneurysm with no previous medical conditions (serum creatinine level of 0.70 mg/dL). The donor shared three class I HLA antigens with the first donor (A2, B7, Cw07), but only low-level isolated DSAs toward HLA-Cw were detected (mean fluo­rescence intensity < 1000), with again the complement-dependent cytotoxicity cross-match being negative.

After consideration, the patient underwent a transplant and was given rATG induction (total dose of 6 mg/kg). Graft biopsy at month 3 showed no evidence of microvascular inflammation, and the patient was C4d negative. He developed Streptococcus pneumoniae pneumonia at month 4, but the posttransplant course was otherwise uneventful. There was no flare-up of his initial disease, and human herpesvirus 8 remained undetectable. At last follow-up (1 year), serum creatinine was 11 mg/dL and transplant with rATG induction achieved a good outcome.

Discussion

Here, our case showed that, because the second donor shared HLA antigens with the failed first transplant and anti-HLA-Cw DSAs were present, combined with a retransplant (and hence potential exposure to many non-HLA alloantibodies), the patient appeared to be in the “high-risk” category. However, several points need to be addressed to assess the true immunologic risk. First, it was possible that DSA directed against A2 and B7 escaped detection, although unlikely because no case of DSA adsorbed by the graft and yet undetected by Luminex technology has so far been reported.4 Second, data on the clinical relevance of anti-HLA-Cw antibodies are sparse. A retrospective case-control study of 22 patients with an isolated anti-HLA-Cw DSA at time of transplant reported an increased rate of antibody-mediated rejection,5 although confirmation in a prospective study is awaited. Third, the role of non-HLA alloantigens is still being explored in solid-organ transplant. Finally, assessment based on the presence of a DSA is short-sighted; the affinity of an antibody for an epitope coating a bead may be an artifact caused by denaturation of the antigen on the bead or by immunoglobulin subclasses of unknown significance or may be underestimated as a result of the prozone effect (the use of acid, dithiothreitol, and EDTA have all been proposed to circumvent these problems but are not used clinically).

Despite these caveats, in our routine practice, we consider any preformed DSA to be potentially detrimental since antibody-mediated microcirculation injury is a major cause of late kidney graft loss. Brokhof and colleagues have reported in a retrospective analysis of 114 moderately sensitized patients that the incidences of de novo DSA and antibody-mediated rejection were both significantly lower with rATG than with IL-2RA induction.6 On that basis, rATG was still an appropriate option in this case. The situation was highly complex, however, because the cause of end-stage renal disease was Castleman disease, a condition classified as a “benign lymphoma” of viral origin. Although rATG per se does not cause posttransplant lympho­proliferative disease, its potent immuno­suppressive properties mean it could increase risk, and prospective studies of rATG versus IL-2RA induction have shown more frequent bacterial and viral infections. The literature is not helpful, since only 1 case of a patient knowingly transplanted with Castleman disease has been published, in a Japanese patient who received no induction and developed acute rejection on day 4 after transplant.7

We believe patients with end-stage renal disease and quiescent Castleman disease should receive induction therapy and of course be closely monitored. The case described here illustrates that rATG induction is appropriate in this situation, at least based on 1-year follow-up, if immunologic risk is a concern.


References:

  1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Transplant. 2009;9(Suppl 3):S1-155.
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  2. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D; Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355(19):1967-1977.
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  7. Murakami K, Kobayashi T, Okubo K, Kamba T, Yoshimura K, Ogawa O. Successful renal transplantation for end-stage renal insufficiency developed in a patient with Castleman's disease. Transpl Int. 2013;26(7):e61-62.
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Volume : 15
Issue : 1
Pages : 114 - 116
DOI : 10.6002/ect.2016.0152


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From the Université Pierre et Marie Curie, Paris 6, Sorbonne Universités and Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris, France
Acknowledgements: The author has received speaker's honoraria from Sanofi and research funding from Fresenius. Grateful thanks are given to Dr. Alexandre Lejoncour for careful patient treatment.
Corresponding author: Alexandre Hertig, UNTR, Hôpital Tenon, 4, rue de la chine, 75970 Paris CEDEX 20, France
Phone: +33 1 5601 6695
E-mail: alexandre.hertig@aphp.fr