Anti–Thrombospondin Type-1 Domain-Containing 7A (THSD7A) Antibodies

Membranous nephropathy (MN) is the most common cause of adult nephrotic syndrome worldwide. Although it occurs predominantly in Caucasian men over 40 years of age, it can affect both sexes and all ethnic groups. The clinical course is variable: while in most cases it regresses spontaneously or remains stable, in about one third of cases it progresses to chronic kidney failure and the risk of end-stage renal disease. In approximately 20% of patients, MN is secondary. For therapeutic purposes, secondary MN must be distinguished from primary (idiopathic) MN (pMN).

The autoimmune mechanisms underlying pMN involve the formation of autoantibodies against the antigens PLA2R and THSD7A. These podocyte surface transmembrane proteins are expressed in human glomeruli. The binding of autoantibodies damages podocytes, allowing proteins to pass into the primary urine. As proteinuria rises, the long-term risk of kidney failure increases, with high morbidity and mortality rates, especially due to thromboembolic and cardiovascular complications.

The diagnosis of pMN is traditionally based on a kidney biopsy with histology and/or electron microscopy. The serological detection of pMN-specific antibodies is faster and less burdensome for the patient.

PLA2R is the main target antigen in pMN. Anti-PLA2R antibodies are highly specific and are detected in up to ~75% of affected patients.

Autoantibodies against THSD7A are detected mainly in pMN patients who are seronegative for anti-PLA2R, representing a second key diagnostic marker in more complex cases, with a prevalence ranging between ~2.5% and 14% in pMN patients. Only rarely do anti-PLA2R and anti-THSD7A occur simultaneously.