NSAIDS and Membranous Nephropathy: A True Link or Coincidence?

Nawaz et al AJKD

Fig 2 from Nawaz et al.

Twenty-five percent of cases of membranous nephropathy (MN) may be a manifestation of another systemic disorder, such as autoimmune conditions, infection, malignancy, toxin exposure, or drugs (classically gold). In a recent report in AJKD, Nawaz et al present a case of recurrent nephrotic syndrome with biopsy-proven membranous nephropathy closely associated with use of the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen and piroxicam. NSAIDS classically have been associated with minimal change disease and acute interstitial nephritis. MN due to NSAID use is a rare but under-diagnosed entity. Onset of nephrotic syndrome while taking NSAIDS and rapid resolution of MN when NSAIDS are discontinued can suggest a cause and association of the two entities. In this case, characterization of the immunoglobulin G (IgG) subclass profile of the deposits showed abundant IgG1, weak IgG4, and interestingly positive staining for phospholipase A2 receptor.

Podocyte transmembrane glycoprotein M-type phospholipase A2 receptor (PLA2R) auto-antibodies were first identified by Beck et al in 2009 in patients with primary MN. These antibodies belong to the IgG4 subclass, suggesting a Th-2 response.  Recently, Hoxha et al showed enhanced staining of PLA2R in glomeruli of patients with primary MN compared with tumor-associated MN.  While the current report suggests a temporal relationship of NSAIDS and MN, it is possible that the association may be coincidental. While the IgG1  and 2 staining might suggest a secondary cause, the patient had a positive staining for PLA2R suggesting a primary MN. This brings to notion the concept of a “second hit”. This patient likely had an initial insult of PLA2R autoantibodies, priming them for idiopathic MN. The NSAID served as second hit and precipitated the injury. PLA2R autoantibody-associated MN typically is an IgG4 mediated response, and this case had mostly IgG1 and 2 staining on IF with weak IgG3 and IgG4. Cases like this bring insight about how each individual might react differently when a second nephrotoxin is introduced.

It has not yet been established whether PLA2R-associated MN in the setting of a known secondary cause represents coincidental disease or an altered inflammatory environment in the setting of the secondary cause playing a permissive role in development of PLA2R autoantibodies. It brings to light the most important question: Will PLA2R antibody serum levels or staining on kidney biopsy be clinically useful in differentiating primary vs. secondary MN? Are there certain secondary diseases that also produce this antibody? What do our readers think?

Kenar D. Jhaveri, MD
eAJKD Blog Editor

To view the article abstract or full-text (subscription required), please visit AJKD.org.

2 Comments on NSAIDS and Membranous Nephropathy: A True Link or Coincidence?

  1. weam elnazer // July 22, 2013 at 12:18 pm // Reply

    I think we can use PLA2R autoantibdies as aguide in diagnosis of the cause of MN (primary or secondary).but not absolute diagnosis.

  2. lasfer ala eddine // July 22, 2013 at 11:01 pm // Reply

    I think we can use PLA2R autoantibdies as a guide in diagnosis of the cause of MN (primary or secondary).but not absolute diagnosis.

    Yes absolutely, even in the first time discovered this was positive just in 70% of cases, so what about the remaining ?

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