|LETTER TO EDITOR
|Year : 2020 | Volume
| Issue : 2 | Page : 182-184
Significance of anti-phospholipase A2 receptor antibodies in membranous nephropathy after renal transplantation
Praveen Kumar Etta, Thatipamula Madhavi
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana, India
|Date of Submission||06-Oct-2019|
|Date of Acceptance||15-Mar-2020|
|Date of Web Publication||06-Jul-2020|
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Etta PK, Madhavi T. Significance of anti-phospholipase A2 receptor antibodies in membranous nephropathy after renal transplantation. Indian J Transplant 2020;14:182-4
|How to cite this URL:|
Etta PK, Madhavi T. Significance of anti-phospholipase A2 receptor antibodies in membranous nephropathy after renal transplantation. Indian J Transplant [serial online] 2020 [cited 2020 Aug 6];14:182-4. Available from: http://www.ijtonline.in/text.asp?2020/14/2/182/289044
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with idiopathic or primary MN (pMN) variety contributes to 80% of all cases. pMN occurs due to the result of the development of antipodocyte autoantibodies, the most common being IgG antibodies against M-type phospholipase A2 receptor (PLA2R) expressed on glomerular podocytes (affecting up to 70% of pMN cases). In rest of the cases, other antigens such as thrombospondin Type 1 domain-containing 7A, aldose reductase, α-enolase, superoxide dismutase 2, cationic bovine serum albumin, or novel antigens such as exostosin 1 and 2 may be implicated. The risk of end-stage renal disease (ESRD) ranges between 10% and 35% over 10 years depending on the management of pMN. MN can occur after renal transplantation (RT) either as a recurrent MN (rMN) or de novo MN (dnMN) form. Protocol biopsy remains the gold standard for earlier, subclinical, histological diagnosis of recurrence of glomerulonephritis (GN) after RT in a patient with chronic GN in native kidneys. With the availability of sensitive assays for anti-PLA2R antibody (aPLA2R) measurements, post-RT monitoring of its level, especially in high-risk cases, may predict recurrence and early diagnosis of rMN and may obviate the need for invasive repeated protocol biopsies. The role of other antibodies in predicting rMN is still not known. In contrast, dnMN represents a separate entity with unclear pathogenesis and has a different clinical course. We, herein, report a case of rMN associated with high-level serum aPLA2R level at 10 months of RT and briefly reviewed the clinical utility of monitoring aPLA2R titers in patients with MN following RT.
A 38-year-old man presented at 10 months of RT, with complaints of edema feet and reduced urine output for 15-day duration. His native kidney disease was pMN, diagnosed 5 years before RT. He was treated conservatively due to significant chronicity on native kidney biopsy and reached ESRD stage gradually. Pretransplant serum aPLA2R level was not done. He received a live-related (one haplomatch) RT, with no induction. He was on triple-immunosuppressive therapy with prednisolone, mycophenolate mofetil, and tacrolimus and having normal graft function. At presentation to us, he had pallor, pedal edema, pulse rate of 90/min, and blood pressure of 140/90 mm Hg. Rest of the examination was unremarkable. The laboratory findings revealed hemoglobin of 10.2 g/dL, total leukocyte count of 10.0 × 103/μL, platelet count of 158 × 103/μL, blood urea of 30 mg/dl, serum creatinine of 1.4 mg/dl, total protein of 6.0 g/dl, and albumin of 3.2 g/dl. His urine examination showed 3 + albumin, 8–10 RBC/hpf, and 6–8 pus cells/hpf. Spot urine protein–creatinine ratio was 4.5; 24 h urine protein excretion was 3.8 g/day. Serology for human immunodeficiency virus, hepatitis B and C was negative. Serum complement C3 and C4 levels were normal. Whole blood tacrolimus trough level was optimal. Renal biopsy: Light microscopy showed classical glomerular basement membrane thickening with silver-positive spikes; immunofluorescence showed granular capillary loop staining for IgG and C3, suggestive of rMN. Electron microscopy was not performed. The serum aPLA2R level tested after biopsy result showed high titer result (76 RU/ml by ELISA); glomerular PLA2R antigen deposition was also positive on immunohistochemistry (IHC). He was treated with two doses of rituximab 500 mg each at 1-week interval, and he went into partial remission at 6 months of follow-up. His repeat aPLA2R level showed a significant reduction in titer (2 RU/ml). The circulating B cell depletion (by CD 19 count) was not evaluated in this case. He is currently on triple-drug immunosuppression and angiotensin receptor blockers and is asymptomatic.
The natural history of pMN is characterized by initial appearance of the immunological activity (with serum aPLA2R), followed by clinical renal disease; during recovery, immunological remission precedes clinical remission. The serial survey of the aPLA2R titers is important to assess the rate of disease progression and the response to treatment. Therapeutic interventions can be tailored depending on the serological activity rather than empirically based on the clinical variables such as proteinuria or reduced glomerular filtration rate (GFR). The persistent immunological activity identified by high titer aPLA2R antibody level at the time of and following RT may predict the risk of rMN after RT. The rate of recurrence may range between 30% and 45%, with higher rates reported by centers performing protocol biopsies. Histological recurrence can result in up to 60%–80% of patients, especially in those with high aPLA2R titers at the time of and after RT; rMN can occur as early as few weeks to months after RT. The monitoring of aPLA2R levels is, especially, useful in patients with high-risk characteristics for rMN such as patients with live-related donor RT, high pretransplant antibody titers, rapid progression to ESRD, and prior allograft failure due to rMN.
Stahl et al. first reported a case of rMN with high titers of aPLA2R at the time of transplant and at recurrence. Since then, several studies have published the relevance of monitoring aPLA2R activity to assess the risk of recurrence of pMN [Table 1].,,,, In one case series of 26 transplanted patients with underlying pMN, 18 had rMN; 10 out of 17 with rMN were aPLA2R positive at the time of RT. The positive predictive value (PPV) of pretransplant aPLA2R antibodies for rMN was 83%, and the negative predictive value (NPV) was 42%. In another case series, the authors have performed a receiver operating characteristic analysis and found that an aPLA2R cutoff of 45 RU/mL pretransplantation was predictive of rMN with a sensitivity of 85.3%, a specificity of 85.1%, a NPV of 92% and an area under the curve of 90.8%. In a recent case series, the authors found that an aPLA2R titer by ELISA > 30 RU/mL provided sensitivity of 83%, specificity of 100%, PPV of 100%, and NPV of 91% for recurrence. The variability in significance of aPLA2R in predicting rMN in different case series could be due to the use of different assays and lack of quantification of aPLA2R titer in some studies, and variability of the therapeutic protocols applied for pMN before RT and immunosuppressive protocols after RT. Similar to pMN of the native kidney, IgG4 is the dominant or codominant IgG subclass in rMN.
|Table 1: Case series of recurrent membranous nephropathy and anti-phospholipase A2 receptor antibody status|
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In contrast, most cases of dnMN occur several years following RT and are secondary to underlying disease or exposures. It most commonly appears to be associated with antibody-mediated rejection (ABMR). Hence, most of the dnMN cases are not PLA2R-mediated and the dominant IgG subtype within immune deposits being IgG1 in contrast to IgG4 of pMN and rMN. The renal biopsy in dnMN often shows signs of both the findings of MN and ABMR, and most of them have circulating donor-specific antibodies. The dnMN could result due to antibody reactivity to human leukocyte antigen (HLA) class II antigens expressed on podocytes or other podocyte-planted antigens, which require further investigation. dnMN can develop in RT recipients with viral hepatitis, Alport syndrome, ureteral obstruction, renal infarction, or in conjunction with recurrent IgA nephritis. The testing for aPLA2R activity, glomerular Ig subtype, and PLA2R staining may help to differentiate dnMN from rMN after RT.
In conclusion, the available literature suggests that measuring aPLA2R titers at the time of RT and serial monitoring of the antibody levels after RT might help to identify RT recipients at risk and early diagnosis of rMN. This may obviate the need for serial protocol biopsies in this group of patients and also help to identify patients who need further intervention with either increasing maintenance immunosuppression or other drugs like rituximab.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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