The Role of the Kidd-Antibodies in Posttransfusion Reactions A

1 Clinic for Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia 2 Institute of Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia 3 Center for Anesthesiology and Reanimatology, Clinical Center of Serbia, Belgrade, Serbia 4 Blood Transfusion Institute of Serbia, Belgrade, Serbia 5 Faculty of Physical Chemistry, University of Belgrade, Belgrade, Serbia 6 Clinical Centre of Serbia, Belgrade, Serbia 7 Hospital for Cerebrovascular Diseases “St Sava”, Belgrade, Serbia


TOPIC
Th e Kidd blood group (Jk) was discovered in 1951 and according to International Society for blood transfusion (ISBT) the Kidd (Jk) blood group is registered under the number 009. It was named aft er a patient, a pregnant woman Mrs. Kidd [1]. Antigens of the Kidd system are detected only on RBCs and kidney [2,3]. Th ey are carried by an integral membrane glycoprotein, which transports urea through the RBC's membrane [4]. Jka antigen is known as urea transporter UT-B (synonyms: UT3, UT11) [5]. Kidd antigen and UT-B are coded by gene chromosome 18q11-q12 [6]. Th e null phenotype Jk(a-b-) is usually results from homozygosity for a silent gene at the Jk locus and it is rare in most populations. Incompatibile transfusion in Jk blood group can provoke sensitization and appearance of anti-Jka or Jkb antibodies [7][8][9]. Jk antibodies are common cause of delayed hemolytic transfusion reactions (DHTRs) [8]. Alloimmunization is more common in females (2.38%) than males (1.68%). One in 1200 transfused patients experience a delayed haemolytic transfusion reaction [10,11].
It is quite intriguing for clinical practice that in approximately 50% of patients with detected Jka antibodies neither clinical nor laboratory signs of transfusion hemolytic reaction were not found [10,11]. Clinical and laboratory signs of a haemolysis reaction will not be demonstrated in 2 cases: 1) if the present Ig antibodies belong to the IgG2 or IgG4 class, which do not bind complement, and 2) in cases of detecting positivity to Jka, in fact, it is a reaction caused by preservatives present in using reagents. Th e aim is to underline Jka antibodies laboratory characteristics, their role in delayed posttransfusion reactions and possible complications of blood transfusions.

THE TOPIC POSITION IN SCIENTIFIC/PROFESSIONAL PUBLIC
Anti-Jka and anti-Jkb are uncommon. Th ey are usually warm-reacting IgG1 and IgG3 but may also include IgG2, IgG4 or IgM. Approximately 50% of anti-Jka and anti-Jkb antibodies are capable of binding complement [12]. Kidd antibodies have a tendency to fall rapidly to low or undetectable levels in the plasma, therefore they are oft en diffi cult to detect in pretransfu-sion testing. Th e Kidd antibodies react better on antiglobulin testing with polyspecifi c anti-IgG + anti-C3d as well as with monospecifi c anti-C3d since they are usually detected indirectly through the complement as they bind to RBCs. Th ese antibodies usually give stronger hemagglutination with enzyme treated test red cells [13]. Anti-Jka antibodies show antigen dosage eff ect, so the most anti-Jka react more intensely with Jk(a+b-) red cells than Jk(a+b+) red cells. Kidd system antibodies are noted, in developing an anamnestic response to the antigen [8,14].
Anti-Jka antibodies may cause acute and delayed hemolytic transfusion reactions (DHTR). Although Kidd antibodies can lead to acute reactions, kidney damage and hemoglobinuria are very rare [15]. More important is Kidd-antibody ability for delayed hemolytic reactions. Kidd-antibodies, usually, destroy transfused red cells aft er a variable period of between 7 and 21 days [8,16].
DHTRs commonly result in posttransfusion jaundice and may signifi cantly reduce the patient's hemoglobin level [8]. Patients may be free of any hemolytic reactions when bilirubin and lactate dehydrogenase are in the normal range, so then we are talking about laboratory DHTR. DHTR is the result of Jka antibodies tendency to fall rapidly to undetectable levels even aft er incompatible transfusion. It is known from literature that one-third of DHTR is caused by anti-Jka antibodies [8,10,17,18]. For this reason, it is essential to perform crossmatch before each transfusion, because this is the only way to discover anamnestic (memory) RBC antibodies [8,14]. Anti-Jka has been reported as reason for kidney transplant rejection [19]. In patient noncompliant with immunosuppressive regimes, acute graft rejection occurred simultaneously with the occurrence of a Kidd antibodies [20,21]. Overcoming this problem is very important for patients who are transfusion-dependent or candidates for monoclonal antibody therapy, or candidates for kidney transplantation [22,23].
Preservatives Na-azide and esters of parabens, and antibiotics are added to commercially available LISS(C-LISS)® to prevent microbial growth [24][25][26]. Th e additives used for the storage, preservation, and coloring of blood bank reagents can be a source of false www.hophonline.org positive agglutination reactions [27]. Agglutination of red blood cells used for blood typing, antibody detection and identifi cation may be related to the presence of these materials in blood bank reagents. Th ese substances include acrifl avin and other dyes; antibiotics, such as penicillin and neomycin; EDTA; caprylate; and occasionally saline [27,28]. Th ere were examples of anti-Jka that react only when preservatives such as p-hydroxybenzoic acid (parabens) or related compounds are present in the reaction mixture [29-31]. Antibodies against preservatives like Na-azide were also reported [30,32]. When results are inexplicitly positive by using commercially reagents, the solution could be to repeat immunohematological tests using saline instead of LISS, and additionally wash commercially RBCs [24,33].
Antibiotics used for classic patient therapy and antibiotics added to blood groups reagents for immunohematological transfusion testing could be false positive to RBC antibodies [34] Th e most frequent antibiotics used as a preservative in diluents for commercial RBCs reagents, such as chloramphenicol, neomycin sulfate, co-trimoxazole, and gentamycin could cause false positive RBC antibodies (Ab) [26,35]. In these cases of false positive RBC Ab there were no clinical or laboratory evidence of hemolysis [5,18,26,34,36].
Antigen-free RBC ie universal RBC would be the best choice for transfusion, and using specifi c monoclonal antibodies would be the therapeutic choice in patients who are sensitive to erythrocyte antigens [37,38]. It is recommended, prior to initiate monoclonal antibody therapy, along with baseline ABO, RhD, DAT and IAT, to perform extended RBC phenotype: Rh, MNSs, Kell, Kidd and Duff y blood group systems. Extended RBC phenotyping is important in the provision of phenotype-matched RBC for future transfusions and thus reduces the possibility of RBC antibodies formation [22,23]. Phenotyping may be inaccurate if a patient has received a blood transfusion in the previous 3 months [39,40]. In this case, the genotype is unaff ected, and blood group genotyping is the method of choice [22,41,42].
Obviously, these can be confusing or may be a source of problems in the interpretation of results in various ways. Due to the low incidence of existing undiscovered Kidd antibodies, the authors suggest a multicentric academic observation studies, that would save 796 Volume 6 • Number 2 • August 2019 • HOPH the data in database which give the chance to upgrade the guidelines. Data exchange among world-renowned experts would make this problem more understandable and easier to fi x [43][44][45].

FURTHER ACTION NEEDED FOR BETTER TOPIC COVERING IN FUTURE
Except in life threatening condition, reduction of allogenic blood transfusion is recommended. Increase the number of autologous transfusions in all cases when the patient's clinical condition allows.
Antigen-free RBC ie universal RBC would be the best choice for transfusion. Using specifi c monoclonal antibodies against RBC antibodies would be the therapeutic choice in patients who are sensitized to erythrocyte antigens.
Transfusiologist has to perform crossmatch in order to make transfusion decision, because this is the only way to discover unexpected RBC antibodies.
It is essential to perform extended erythrocyte phenotyping prior to initiation of monoclonal antibodies therapy or renal transplantation. As a minimum blood typing for Rh, K, Jka,Jkb, Fya, Fyb and Ss antigens should be done for every patient who is planned to be treated with monoclonal antibodies.
In patients treated with monoclonal antibodies who were already transfused in the last 3 months period, the method of choice would be genetic blood group testing.