Additional diagnostic evaluation of the patient with PLA2R-negative membranous nephropathy

MN: membranous nephropathy; PLA2R: phospholipase A2 receptor; NELL1: neural epidermal growth factor-like 1; THSD7A: thrombospondin type-1 domain-containing 7A; EXT 1/2: exostosin 1 and 2; IgG: immunoglobulin G; PCDH7: protocadherin 7; NTNG1: netrin G1; Sema3B: semaphorin 3B; NCAM1: neural cell adhesion molecule 1; TGFBR3: type III transforming growth factor beta receptor; SLE: systemic lupus erythematosus; CNTN1: contactin 1; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy; IFA: immunofluorescence assay; ELISA: enzyme-linked immunosorbent assay.

* Patients with PLA2R-negative MN have negative serologic testing for serum anti-PLA2R antibodies (both by IFA and ELISA) and negative immunofluorescence staining for PLA2R on kidney biopsy. Such patients may have either primary or secondary MN, and further diagnostic testing may be required. Evaluation should be tailored according to which assays are most available.

¶ Antibodies against NELL1, THSD7A, NCAM1, Sema3B, PCDH7, EXT1/2, HTRA1, TGFBR3, and NTNG1 are commercially available; testing for some of these antigens is presently available in a few specialized pathology laboratories.

Δ Positive staining for NELL1 or THSD7A may represent primary MN, but due to an increased association with malignancy, more frequent age- and risk-appropriate screening for cancer may be indicated if MN is determined to be associated with these antigens.

◊ Mass spectroscopic analysis of the tissue deposits represents an emerging alternative to immunostaining and may soon be available as a clinical test at specialized centers to determine the subtype of MN in cases that are anti-PLA2R negative and for which immunostaining for the individual antigens is not readily available.