#NephMadness 2022: PLA2R Is Still King of the Kidney Biomarkers

Posted on March 14, 2022 by AJKDblog in NephMadness // 0 Comments

Submit your picks! | NephMadness 2022 | #NephMadness | #Nephropath

Jonathan Zuckerman @JZRenalPath

Jonathan Zuckerman is an Assistant Professor in the Department of Pathology and Laboratory Medicine at University of California Los Angeles where he also completed his medical and post-graduate medical education. At UCLA he is the renal pathology service chief, associated autopsy service chief, director of the surgical pathology fellowship programs, and incoming pathology residency program director.

***Competitors for the* *Nephropath Region***

PLA₂R vs Other Membranous Antigens

DNAJB9 vs IgG4

NephMadness 2022 showcases an entire region dedicated to nephropathology and features heavy hitters in our arsenal of kidney biomarkers used to both make diagnoses and guide treatment.

The first match-up in this region pits the M-type phospholipase A₂ receptor (PLA₂R) against the tidal wave of newer antigens described in membranous nephropathy (e.g., THSD7A, EXT1/EXT2, NCAM-1, NELL1, Sema3B). Altogether, the discovery of these antigens changes our perception of membranous nephropathy to be one of a pattern of injury caused by multiple etiologies defined by individual target antigens. Recognition of these antigens blurs the traditional dichotomy of primary and secondary membranous nephropathy.

The second match-up pits DNAJB9-associated fibrillary glomerulonephritis (FGN) against IgG4-related kidney disease. DNAJB9 has revolutionized our ability to make a specific diagnosis of FGN. No longer must we hem and haw about fibrill size measured on slightly blurry high magnification electron microscopy images or debate about weak congo red positivity. A simple immunostain — DNAJB9 — now provides the answer with 97.6% sensitivity and 99.2% specificity for FGN. IgG4 also boasts impressive diagnostic stats (100% sensitivity and 92% specificity) and much like DNAJB9 is a disease-defining stain.

Considering this loaded regional bracket of biomarkers, how do we crown a champion? A biomarker is a measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure. A good biomarker typically havs several important technical attributes:

The marker must be present in peripheral body tissue and/or fluid (e.g., blood, urine, saliva, breath, or cerebrospinal fluid)
It must be easy to detect or quantify in assays that are both affordable and robust
Its appearance must be associated as specifically as possible with damage of a particular tissue, preferably in a quantifiable manner

Amongst these biomarkers, PLA₂R checks all the boxes as an excellent biomarker. It is easily detectable in kidney tissue using either immunohistochemistry or immunofluorescence and is often performed at local renal pathology labs or as a sendout test at a larger reference lab. Anti-PLA₂R antibodies are also detectable in serum using an enzyme-linked immunosorbent assay (ELISA) and/or by indirect immunofluorescence, the former providing accurate quantification which correlates with disease activity and severity. Most importantly, it is recognized that in non-diabetic patients with preserved kidney function (eGFR > 60 mL/min/1.73 m²) and negative secondary workup for membranous nephropathy, anti-PLA₂R Ig ELISA values >14 RU/ml alone, or ELISA values 2-14 RU/ml with a positive IFA confirm the diagnosis of MN. Thus, anti-PLA₂R Ig can serve as a non-invasive biomarker to both detect and monitor disease without the need for a kidney biopsy! Incredibly, the KDIGO 2021 Guidelines now include PLA₂R antibody titers as part of the criteria to establish the different risk categories and guide therapy (levels > 50 RU/ml and > 150 RU/ml define high risk and very high risk MN, respectively). Lastly, anti-PLA₂R Ig level >45 RU/mL is also associated with increased risk of recurrence following kidney transplantation.

The newer membranous antigens also check some biomarker boxes; however, with some bigger caveats. These new membranous antigens have been amazing in helping better define disease associations with a membranous pattern of injury on biopsy (e.g., EXT → lupus/collagen vascular disease; CNTN1 → Inflammatory neuropathies). However, in most cases simply knowing that a membranous nephropathy is PLA₂R-negative would typically induce an identical clinical work up regardless of other antibody staining. Also, current testing for many of these antigens (e.g., NCAM-1, Sema3BP, CNTN1, PCDH7) in tissue specimens and/or serum autoantibodies is restricted to research labs. Most renal pathologists and nephrologists do not have access to these stains and ELISAs on a routine basis. Furthermore, the sensitivity and specificity of circulating anti-antigen Ig have yet to be established for these newer antigens and a kidney biopsy is still required for diagnosis. With some antigens such as EXT1/EXT2, circulating anti-antigen Ig have yet to be identified. While they show impressive potential for the future, these new membranous antigens have yet to break through into primetime.

In regards to sensitivity and specificity, DNAJB9 certainly presents stiff competition for PLA₂R. However, DNAJB9 FGN still requires a kidney biopsy for diagnosis. There is no blood- or serum-based test for DNAJB9 FGN. Moreover, the discovery of PLA₂R has enlightened us to the human pathophysiology of MN as the corollary to the Heymann nephritis mouse model which demonstrated that MN pattern of injury results from in situ immune complex formation along the subepithelial surface of the glomerular basement membranes. While now disease defining, the role of DNAJB9 in pathogenesis of FGN still remains much of a mystery.

IgG4 disease may have a leg up on DNAJB9 in that serum IgG4 levels can be measured. With elevated IgG4 levels, the disease may be suspected based on non-invasive imaging findings; however, a tissue biopsy is still required for definitive diagnosis. Also, IgG4 staining of plasma cells in a kidney biopsy does not necessarily make the diagnosis of IgG4-associated kidney disease. Increased IgG4 positive plasma cells can be seen in a variety of other diseases including ANCA vasclulitis, lupus nephritis, MN, diabetic nephropathy, and anti-LRP2 nephropathy.

Among this field of fabulous kidney biomarkers, PLA₂R still remains the favorite and is my choice to win the Nephropath region!

– Guest Post written by Jonathan Zuckerman @JZRenalPath

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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