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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1415-1419
The significance of anti-phospholipase receptor antibodies in a patient with membranous nephropathy

1 Department of Nephrology, Americare Kidney Institute, Akron, USA
2 Department of Internal Medicine, Akron General Medical Center, Akron, USA
3 Department of Chemistry, Case Western Reserve University, Cleveland, Ohio, USA
4 Department of Chemistry, Eastern Michigan University Ypsilanti, Michigan, USA
5 Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA
6 Department of Nephrology, Akron Nephrology Associates/Cleveland Clinic Akron General; Department of Nephrology, Akron Children’s Hospital, Akron, Ohio, USA

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Date of Web Publication29-Jan-2021


Membranous nephropathy (MN) is the major cause of nephrotic syndrome in adults and may be secondary to systemic lupus erythematosus or malignancy in 25% of patients. Without any etiology, it is called primary MN, which is usually associated with phospholipase A2 (PLA2) receptor antibodies. Secondary MN can appear months before a secondary cause is identified. Here, we report a case of MN, that was found to be secondary to pancreatic adenocarcinoma and positive for PLA2 receptor antibodies.

How to cite this article:
Dasari JR, Reddy P, Radhakrishnan Y, Nair N, Chakraborty R, Nemer L, Raina R. The significance of anti-phospholipase receptor antibodies in a patient with membranous nephropathy. Saudi J Kidney Dis Transpl 2020;31:1415-9

How to cite this URL:
Dasari JR, Reddy P, Radhakrishnan Y, Nair N, Chakraborty R, Nemer L, Raina R. The significance of anti-phospholipase receptor antibodies in a patient with membranous nephropathy. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2022 Dec 7];31:1415-9. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1415/308360

   Introduction Top

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. In about 25% of patients, MN is associated with a secondary cause, such as infections (hepatitis B), systemic autoimmune disease (lupus), and drugs or toxins.[1] The other 80% of nephrotic syndromes have no obvious secondary cause and are classified as primary MN. Primary MN is believed to occur when antiphospholipid (aPL) antibodies bind to antigens on glomerular podocytes and lead to destructive immune complexes in the glome-rular capillary walls.[2] Diagnosis is made through clinical classification criteria and a few laboratory markers, specifically positive aPL.[3] However, there are cases where non-clinical criteria manifestations occur with the antiphospholipid syndrome in the setting of a positive aPL, but the secondary cause does not clearly present itself for many months.[3] Herein, we report a patient diagnosed with MN, later found to be secondary, that was also associated with phospholipase A2 (PLA2) receptor antibodies.

   Case Report Top

Informed consent was obtained from the patient for the publication of this case report.

A 70-year old male was initially referred to us for evaluation of worsening lower extremity edema. He had a known history of chronic kidney disease stage II that was thought to be secondary to diabetes. He had recently been admitted to the hospital where he was found to have proteinuria in excess of 7 g over 24 h. Differential diagnoses included primary nephrotic syndrome, which included minimal change disease and MN. Consequently, a computed tomography (CT)-guided renal biopsy was ordered. The renal biopsy showed evidence of focal tubular atrophy along with granular deposition that was tested positive for immunoglobulin G and C3. Light microscopy of the glomeruli showed lesions with thickening of the glomerular basement membrane and a “spike” appearance, resulting from the projections of basement membrane matrix out toward the urinary space on a silver stain. Examination via electron microscopy revealed glomerular capillaries with subepithelial electron-dense deposits along with foot process effacement [Figure 1], [Figure 2], [Figure 3]. Findings were, hence, suggestive of membranous glome-rulonephritis superimposed on modest arterio-nephrosclerosis.
Figure 1: Trichrome loops with thickened loops and no proliferation. Silver stain shows epimembranous spikes

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Figure 2: Subepithelial electron-dense deposits partially surrounded by glomerular basement membrane with epithelial cell foot process effacement consistent with membranous glomerulonephritis.

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Figure 3: Fine granular deposits of IgG and C3 are present in glomerular capillary loops.

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To evaluate for malignancy-related MN, cancer screening was ordered. CT scan of the chest did not show any evidence of malignancy. Due to elevated serum creatinine, a CT scan of the abdomen was ordered but not completed. Anti-PLA2 receptor antibodies by indirect immunofluorescence assay (IFA) and ELISA were also sent. The IFA titer was noted to be 1:500 and was 186.00 RU/mL by ELISA. Furthermore, an IFA of anti-thrombospondin type-1 domain-containing 7A (THSD7a) antibodies was performed and came back negative. Immunohistochemistry studies of lymphoid follicles, which include CD10+, BCL6+, and BCL2–, were further performed and all came back negative. Glomerular expression of THSD7A antigen was also examined by immunohistochemistry and wasfound to be negative. In addition, the plasma cell infiltrates were IgG negative; thus, an IgG4 immuno-histochemical staining was not further performed since the overall morphology and immunohistochemistry were not consistent with an IgG4-related disease. With these results, primary MN was suspected and the patient was started on the Ponticelli regimen of methylprednisolone and chlorambucil (Chl). About four months later after treatment, multiple investigations were performed and showed normalization of proteinuria. However, a CT scan of the abdomen revealed the presence of pancreatic adenocarcinoma. The presence of pancreatic malignancy could be coincidental with the finding of primary MN or could represent secondary MN with a positive anti-PLA2 receptor antibody.

   Discussion Top

MN is one of the leading causes of nephrotic syndrome in the adult population. It is characterized by the formation of subepithelial immune complexes that damage the glomerulus.[4] MN can be categorized as either primary or secondary in nature. Primary (idiopathic) MN is usually a diagnosis made out of exclusion of differential diagnosis and further confirmed via ELISA, immunofluorescence testing, and renal biopsies.[5] Around 80% of MNs are classified as primary MN. The most common mechanism that occurs in primary MN is an IgG antibody attacking an anti-PLA2 receptor.[5] In approximately 20% of cases, MN may be secondary to various disorders including systemic diseases (systemic lupus erythematosus and sarcoidosis), infections (hepatitis B), drugs (nonsteroidal anti-inflammatory drugs), and malignancy.[6]

Antigenic targets implicated in primary membranous nephropathy include M-type PLA2 receptor (75%) and thrombospondin type-1 domain-containing 7A antigen (5%). Levels of the above antibodies have been found to correlate with both severity and prognosis of the disease.[7],[8],[9] Autoantibodies against PLA2 receptor are both sensitive and specific (about 70%) for primary MN. Recent studies have shown a correlation with the time of remission, the time between relapses, and the level of proteinuria with the level of antibody.[10],[11] However, these antibodies have been detected in some cases of secondary MN as well.[12] Interestingly enough, Qin et al showed that in 20 patients with lupus membranous nephropathy, only one sample contained anti-PLA2R antibodies, but the proportion of anti-PLA2R antibodies found in MN secondary to solid tumors was much higher.[11] In most cases, proteinuria was first discovered with secondary MN and the tumor was often asymptomatic and only found due to the workup of MN.[11] Whether this is a coincidental finding or related to the pathogenesis of secondary MN remains unclear.[6] Others have shown that resection of tumors did not change the persistence of relapse of clinical MN symptoms.[11]. Therefore, as in our case, the presence of PLA2 receptor autoantibodies may suggest the presence of primary MN in conjunction with malignancy or maybe a different autoimmune process altogether. Primary MN has a higher association in populations greater than the age of 57, and tumors also have a high incidence in this age range.[1] A combined approach of testing for both PLA2 receptor antigen and antibodies may have been useful as it was found to increase the sensitivity of detection from 77.8% to 89.6%.[9]

Although ELISA and immunofixation detection of autoantibodies seem to be the best way to confirm primary MN, as noted in our case, the presence of autoantibodies still poses a clinical dilemma. As demonstrated by previous studies, the presence of autoantibodies cannot effectively rule out the presence of a secondary etiology, and depending on the cause of secondary MN, incidences of positive aPL can be as high as 30%.[11] More recent studies are looking at identifying different autoantibodies, such as anti-aldose reductase and antimanganese superoxide dismutase, that may be more specific in detecting primary MN.[13]

   Conclusion Top

We strongly believe that more clinical studies will be needed in the upcoming future to clearly establish a distinction between primary and secondary MN in order to develop better clinical interventions.

Conflict of interest: None declared.

   References Top

Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol 2017;12:983-97.  Back to cited text no. 1
Beck LH, Salant DJ. Membranous nephro-pathy: From models to man. J Clin Invest 2014;124:2307-14.  Back to cited text no. 2
Emmi G, Silvestri E, Squatrito D, et al. An approach to differential diagnosis of antiphos-pholipid antibody syndrome and related conditions. ScientificWorldJournal 2014;2014: 341342.  Back to cited text no. 3
Beck LH, Bonegio RG, Lambeau G, et al. M-type phospholipase A(2) receptor as target antigen in idiopathic membranous nephro-pathy. N Engl J Med 2009;361:11-21  Back to cited text no. 4
Kronbichler A, Oh J, Meijers B, Mayer G, Shin JI. Recent progress in deciphering the etiopathogenesis of primary membranous nephropathy. Biomed Res Int 2017;2017: 1936372.  Back to cited text no. 5
De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol 2017;28:421-30.  Back to cited text no. 6
Beck LH Jr., Fervenza FC, Beck DM, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011; 22:1543-50.  Back to cited text no. 7
Radice A, Trezzi B, Maggiore U, et al. Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN). Autoimmun Rev 2016;15:146-54.  Back to cited text no. 8
Pourcine F, Dahan K, Mihout F, Cachanado M, Brocheriou I, Debiec H, et al. Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy: A single-centre study over 14 years. PLoS One 2017;12: e0173201.  Back to cited text no. 9
Hofstra JM, Beck LH Jr., Beck DM, Wetzels JF, Salant DJ. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2011;6:1286-91.  Back to cited text no. 10
Qin W, Beck LH Jr. Zeng C, et al. Anti-phospholipase A2 receptor antibody in mem-branous nephropathy. J Am Soc Nephrol 2011;22:1137-43.  Back to cited text no. 11
Obrisca B, Ismail G, Jurubita R, et al. Antiphospholipase A2 receptor autoantibodies: A Step forward in the management of primary membranous nephropathy. Biomed Res Int 2015;2015:249740.  Back to cited text no. 12
Prunotto M, Carnevali ML, Candiano G, et al. Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol 2010;21:507-19.  Back to cited text no. 13

Correspondence Address:
Nikhil Nair
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.308360

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