Kidd

While the Kidd blood group system (ISBT 009) not as immunogenic as RhD or Kell’s K antigen upon initial exposure, Kidd antigens (Jk^a and Jk^b) are critical players in transfusion medicine. These antigens are actually part of the urea transporter protein (UT-B) found on red blood cells, encoded by the SLC14A1 gene. The real clinical impact comes from the Kidd antibodies, which are infamous for causing delayed hemolytic transfusion reactions (DHTRs) due to their tendency to decline below detectable levels and then reappear strongly upon re-exposure, often efficiently activating complement

Genetics: The SLC14A1 Gene

• The Kidd antigens are encoded by the SLC14A1 gene (Solute Carrier family 14, member 1), located on chromosome 18
• This gene codes for a protein responsible for urea transport in red blood cells and the kidney

Biochemistry: The Kidd Glycoprotein (Urea Transporter B, UT-B)

Unlike systems defined by enzymes adding sugars (ABO, Lewis) or large structural proteins (Rh, Kell), the Kidd antigens reside on a specific functional protein:

• Structure: The SLC14A1 gene codes for the Kidd glycoprotein, also known as Urea Transporter B (UT-B). This is a multi-pass transmembrane protein, meaning it weaves back and forth through the red blood cell membrane multiple times (likely 10 loops)
• Function: Its primary job is to facilitate the rapid transport of urea across the red blood cell membrane. This is important for maintaining osmotic stability when RBCs pass through the high urea concentrations in the kidney medulla. It also plays a role in the kidney’s ability to concentrate urine
• Antigen Location: The Jk^a and Jk^b antigenic determinants are part of the protein structure itself, exposed on the external loops of the protein

The Major Kidd Antigens: Jk^a and Jk^b

These are the two principal, antithetical antigens of the system:

• Biochemical Difference: The difference between Jk^a and Jk^b arises from a single nucleotide polymorphism (SNP) in the SLC14A1 gene. This SNP results in a single amino acid substitution at position 280 of the Kidd protein:
  • Jk^a (JK1): Has Aspartic Acid (Asp) at position 280
  • Jk^b (JK2): Has Asparagine (Asn) at position 280
• Inheritance: An individual inherits one SLC14A1 allele from each parent, leading to three possible genotypes:
  • JK*A/JK*A (Homozygous Jk^a) → Phenotype: Jk(a+b-)
  • JK*B/JK*B (Homozygous Jk^b) → Phenotype: Jk(a-b+)
  • JK*A/JK*B (Heterozygous) → Phenotype: Jk(a+b+)
• Prevalence: Both Jk^a and Jk^b are common antigens, but their frequencies vary among ethnic populations:
  • Caucasians: ~77% Jk(a+), ~73% Jk(b+)
  • Black individuals: ~91% Jk(a+), ~49% Jk(b+)
  • Asians: ~73% Jk(a+), ~76% Jk(b+)

The Jk3 Antigen

• Description: Jk3 is a high-prevalence antigen present whenever either Jk^a or Jk^b antigens (or both) are expressed. Think of it as being associated with the common structure of the Kidd protein when it carries either the Asp280 or Asn280 residue
• Absence: Jk3 is absent only on the red cells of rare Jk(a-b-) individuals

The Null Phenotype: Jk(a-b-)

• Description: A rare phenotype where individuals lack expression of Jk^a, Jk^b, and Jk3 antigens on their red blood cells
• Genetics: Often caused by inheriting two non-functional SLC14A1 alleles. A common mechanism, especially in individuals of Polynesian, Filipino, or Finnish descent, is homozygosity for a specific splice site mutation in the SLC14A1 gene that prevents proper protein formation. Other mutations can also cause the null phenotype
• Biochemistry/Physiology: Since the Kidd protein (UT-B) is absent or non-functional, these individuals’ red cells cannot transport urea rapidly. While generally healthy, they exhibit a defect in maximal urinary concentrating ability
• Antibodies: Jk(a-b-) individuals, if immunized, can produce anti-Jk3. This antibody reacts with all cells positive for Jk^a or Jk^b (essentially all cells except other Jk(a-b-) cells). Finding compatible blood is extremely difficult

Effect of Reagents on Kidd Antigens

• Proteolytic Enzymes (Ficin, Papain, Bromelin): Reactivity of Kidd antibodies is often ENHANCED by treating test cells with enzymes. This is a key characteristic used in antibody identification! Enzymes likely remove some surrounding structures, making the Kidd antigens more accessible to antibodies
• Sulfhydryl Reagents (DTT, 2-ME): Kidd antigens are generally RESISTANT to treatment with DTT or 2-ME

Kidd Antibodies (Anti-Jk^a, Anti-Jk^b, Anti-Jk3)

These are the reason the Kidd system demands respect in the blood bank!

• Type: Usually IgG (often IgG1 and/or IgG3), reacting best at the AHG (Coombs) phase
• Stimulation: Typically immune stimulated (require exposure through transfusion or pregnancy)
• Complement Activation: Kidd antibodies are notorious for their ability to bind complement effectively. This contributes significantly to their ability to cause hemolysis, both in vitro (visible hemolysis in the test tube) and in vivo
• Dosage: Often show dosage, meaning they react more strongly with cells from individuals who are homozygous for the antigen (e.g., anti-Jk^a reacts stronger with Jk(a+b-) cells than Jk(a+b+) cells)
• Evanescence (The Treacherous Part!): Kidd antibody titers can decline rapidly in vivo after initial stimulation, sometimes becoming undetectable in routine antibody screening tests between exposures. However, upon re-exposure (e.g., transfusion with antigen-positive blood), a rapid and strong anamnestic response can occur, leading to
• Clinical Significance: HIGHLY Clinically Significant!
  • Delayed Hemolytic Transfusion Reactions (DHTRs): Kidd antibodies are a leading cause of DHTRs. The reaction typically occurs 3-14 days post-transfusion as the antibody level rapidly rises and destroys the transfused antigen-positive cells. Symptoms can range from mild (unexplained drop in hemoglobin, fever, jaundice) to severe (shock, renal failure)
  • Acute Hemolytic Transfusion Reactions: While less common than DHTRs, potent Kidd antibodies can cause immediate HTRs
  • Hemolytic Disease of the Fetus and Newborn (HDFN): Can cause HDFN, usually mild to moderate, but severe cases have been reported

Key Terms

• SLC14A1: Gene encoding the Kidd glycoprotein/urea transporter
• Kidd Glycoprotein (UT-B): Urea Transporter B; the protein carrying Kidd antigens
• Jk^a/Jk^b: Antithetical antigens differing by Asp/Asn at position 280
• Jk3: High-prevalence antigen associated with Jk^a/Jk^b expression
• Jk(a-b-): Rare null phenotype lacking Kidd antigens, associated with impaired urine concentration
• Dosage: Antibody reacts more strongly with homozygous cells
• Evanescent: Antibody titer tends to disappear or weaken over time in vivo
• Complement Activation: Ability of the antibody to initiate the complement cascade, often leading to hemolysis
• Delayed Hemolytic Transfusion Reaction (DHTR): Hemolysis occurring days to weeks after transfusion, commonly caused by Kidd antibodies due to an anamnestic response