Anti-CD38 Monoclonal Antibodies Interfere With Isoagglutinin Detection

ABO-incompatible (ABOi) kidney transplantation is considered a safe procedure, respecting preformed donor-specific isoagglutinin elimination before the surgery.¹ Hemagglutination remains the most frequently used method to detect isoagglutinin. However, the presence of immunoglobulins causing pan-agglutination can cause false-positive results.² We assessed isoagglutinin titers in a candidate for ABOi-living donor kidney transplantation (A to O) who was treated by a humanized anti-CD38 IgG monoclonal antibody (daratumumab) a week before for multiple myeloma. Although IgM isoagglutinin titer was low before and after desensitization, IgG isoagglutinin titer, detected with the microcolumn agglutination method (Biorad Liss/Coombs IgG/C3d), was and remained very high (>2048) before and after desensitization using high-volume specific immunoadsorption (Table 1). The binding of daratumumab on CD38 that is highly expressed on the surface of red blood cells and myeloma cells induces their agglutination, leading to a false-positive isoagglutination test until 2 to 6 months postadministration.³ Dithiothreitol disrupts the bridging of the disulfide bonds between amino acid residues necessary for structural conformation of some proteins, such as the CD38 antigen (which presents 5 bridges). Hence, dithiothreitol prevents anti-CD38 binding on red blood cells treated and overcomes the interference of the daratumumab and agglutination tests. We reexamined our patient’s sera after treatment with dithiothreitol and found low IgG isoagglutinins (titer <1) before and after desensitization (Table 1). The detection of a high anti-A IgG titer in blood group A patient who had received daratumumab confirmed its interference with isoagglutinin tests (Table 1). Because more patients treated with daratumumab for multiple myeloma⁴ can be referred for ABOi-living donor kidney transplantation, transplant physician should be aware of this interference that can lead to the refusal of the project. Other monoclonal antibodies given to treat kidney diseases could also interfere with isoagglutinin. This has to be examined carefully.

TABLE 1. - Isoagglutinin detection with microcolumn agglutination method in 2 patients who were treated with monoclonal IgG anti-CD38 (daratumumab)

	1:1	1:2	1:4	1:8	1:16	1:32	1:64	1:128	1:256	1:1024	1:2048
Initial titers of ABOi-KT candidate
Anti-A IgG	++	++	++	++	++	++	++	++	++	++	++
Anti-A IgM	–	–	–	–	–	–	–	–	–	–	–
Anti-B IgG	+++	++	+++	++	++	++	++	++	++	++	++
Anti-B IgM	–	–	–	–	–	–	–	–	–	–	–
Isoagglutinin titers after specific IA
Anti-A IgG	++	++	++	++	++	++	++	++	++	++	++
Anti-A IgM	–	–	–	–	–	–	–	–	–	–	–
Anti-B IgG	+++	+++	++	++	++	++	++	++	++	++	++
Anti-B IgM	–	–	–	–	–	–	–	–	–	–	–
IgG isoagglutinin titers after DTT treatment, before specific IA
Anti-A IgG	++	+	–	–	–	–	–	–	–	–	–
Anti-B IgG	+++	+++	++	+	+	–	–	–	–	–	–
IgG isoagglutinin titers after DTT treatment, after specific IA
Anti-A IgG	+	–	–	–	–	–	–	–	–	–	–
Anti-B IgG	+++	++	++	+	+	–	–	–	–	–	–
Isoagglutinin titers in a second patient with type A blood group, and treated with IgG monoclonal anti-CD38 antibody
Anti-A IgG	++	++	++	++	++	++	++	++	++	++	++
Anti-A IgM	–	–	–	–	–	–	–	–	–	–	–
Anti-B IgG	++	++	++	++	++	++	++	++	++	++	++
Anti-B IgM	+	–	–	–	–	–	–	–	–	–	–

ABOi-KT, ABO-incompatible kidney transplantation; DTT, dithiothreitol; IA, immunofiltration; Ig, immunoglobulin.