History

In 1951, a patient called Mrs. Kidd was found to have produced antibodies targeted against a then unknown red cell antigen during her pregnancy. The marker was present on the RBCs of her fetus, and the maternal antibodies targeted against it caused fatal hemolytic disease in her newborn child.

The protein was given the name Jk^a and was the first antigen to be discovered in the Kidd blood group system. Since this time, two other antigens, Jk^b and Jk3, have been found.

In 1959, the first example of the null phenotype, i.e., Jk(a-b-), was found in a woman who had become jaundiced after a blood transfusion. Her serum was found to contain an antibody that recognized both Jk^a and Jk^b. This antibody was subsequently named anti-Jk3.

Nomenclature

• Number of Kidd antigens: 3
• ISBT symbol: JK
• ISBT number: 009
• Gene symbol: SLC14A1
• Gene name: Solute carrier family 14, member 1

Phenotypes

There are three common Kidd phenotypes: JK(a+b-), JK(a-b+), and JK(a+b+).

The Jk-null phenotype, JK(a-b-), is rare in most populations. Individuals with this blood type are often detected after they have been immunized to Kidd antigens during a previous blood transfusion or pregnancy. After immunization, JK(a-b-) individuals form anti-Jk3, which can cause HDN in subsequent pregnancies and hemolyse donor blood that contains Jk^a and/or Jk^b antigens during a subsequent blood transfusion.

Expression of Kidd antigens

The expression of the Kidd antigens is limited to RBCs and the kidney (in the vasa recta).

Function of Kidd protein

The Kidd protein is a major urea transporter in RBCs. It rapidly transports urea into and out of RBCs and in the process helps to maintain osmotic stability. The urea transport across Kidd null RBC membranes is ~1000 times slower than across normal RBC membranes (2, 3).

The transport of urea by the Kidd glycoprotein in the kidney enables the kidney medulla to maintain a high concentration of urea, which in turn enables the kidney to produce concentrated urine.

However, the absence of the Kidd glycoprotein is not associated with disease. The RBCs in Kidd null individuals have a normal shape and lifespan (3). Individuals with the Jk(a-b-) phenotype are unable to maximally concentrate urine, but it does not cause any other health problems (4).

Transfusion reactions

Anti-Jk^a can cause severe and fatal hemolytic transfusion reactions (6) but is more commonly associated with less severe DHTRs. It has been estimated that over one-third of DHTRs are caused by anti-Jk^a (7, 8). Case studies have also pointed to anti-Jk^b as being responsible for severe DHTR (9, 10). Anti-Jk3 has also been responsible for causing severe hemolytic transfusion reactions, both immediate and delayed (5).

Hemolytic disease of the newborn

During pregnancy, fetal Kidd antigens are capable of causing alloimmunization of the mother (11). But in contrast to the hemolytic activity of Kidd antibodies in incompatible blood transfusions, anti-Jk^a and anti-Jk^b are only rarely responsible for severe HDN (12). Likewise, anti-Jk3 is a rare cause of HDN, but the first documented case in Mrs. Kidd's newborn was fatal.

Gene

The SLC14A1 gene (Solute carrier family 14, member 1) is a member of the urea-transporter gene family and is located on chromosome 18 (18q12-q21). The gene is organized in 11 exons distributed across than 30kb of DNA. The first three exons and part of the fourth are not translated; exons 4-11 encode the mature Kidd protein.

The Jk^a and Jk^b antigens are the products of two alleles that are inherited in a co-dominant fashion. The Jk^a/Jk^b polymorphism results from a 838G→A transition, resulting in an D280N substitution (13). Based on this, several investigators have suggested different methods for JK genotyping (13–15).

The Jk(a-b-) phenotype is generally inherited as a recessive trait—a number of different mutations have been found to be responsible 16). In the Polynesian population where the null phenotype is less rare, a splice site mutation causes loss of exon 6 from mRNA transcripts and it is unlikely that the truncated Kidd protein produced is transported to the RBC membrane (17). A similar situation holds true in the Finnish population in which another genetic explanation causes the same phenotype (17, 18).

Protein

The Kidd protein urea transporter is an integral protein of the RBC membrane. It is a transmembrane protein containing 389 amino acid residues. The protein is predicted to span the membrane 10 times with both the N terminus and C terminus being intracellular. This membrane topology is shared by the anion exchanger that bears the Diego blood group antigens.

The Kidd protein consists of two hydrophobic domains that each span the membrane five times, and they are linked by a large glycosylated extracellular loop. The Asn211 on this third loop carries 1% of ABO antigens found on the RBC. The Jk^a/Jk^b polymorphism is found on the neighboring fourth extracellular loop (19).