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Table of Contents
CASE REPORT
Year : 2022  |  Volume : 16  |  Issue : 1  |  Page : 130-134

Posttransplant membranous nephropathy - A case report


1 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
5 Department of Renal Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission28-Oct-2021
Date of Acceptance02-Feb-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Dr. Raja Ramachandran
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_109_21

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  Abstract 


Primary membranous nephropathy (PMN) is a common cause of adult-onset nephrotic syndrome. Anti-M-type phospholipase A2 receptor (PLA2R) antibodies are pathogenic and correlate with clinical outcomes. The role of anti-PLA2R in recurrent PMN is unclear. In the present manuscript, we report five cases of PMN who underwent kidney transplantation (KT) with varying titers of anti-PLA2R pre-kidney transplantation (KT). Two patients with anti-PLA2R in the second and third tertiles had a recurrence of PMN, whereas patients with a negative or anti-PLA2R in the first tertile had no recurrence. The report signals a heightened risk of PMN recurrence in patients with elevated anti-PLA2R antibody titer at KT.

Keywords: Membranous nephropathy, PLA2R positive, transplantation


How to cite this article:
Sullaiman S, Chauhan P, Kumar A, Nada R, Minz R, Kumar V, Sharma A, Singh S, Kumar V, Rathi M, Kohli HS, Ramachandran R. Posttransplant membranous nephropathy - A case report. Indian J Transplant 2022;16:130-4

How to cite this URL:
Sullaiman S, Chauhan P, Kumar A, Nada R, Minz R, Kumar V, Sharma A, Singh S, Kumar V, Rathi M, Kohli HS, Ramachandran R. Posttransplant membranous nephropathy - A case report. Indian J Transplant [serial online] 2022 [cited 2022 May 29];16:130-4. Available from: https://www.ijtonline.in/text.asp?2022/16/1/130/342421




  Introduction Top


The anti-M-type phospholipase A2 receptor (PLA2R) antibody is critical to the management of primary membranous nephropathy (PMN)[1],[2] and is also valuable in predicting posttransplant recurrence.[3] Emerging data suggests the presence of anti-PLA2R antibody, and the titers preceding transplant are paramount and decide the posttransplant course.[4],[5],[6] In the current manuscript, we report the outcome of five patients with anti-PLA2R-related PMN undergoing kidney transplantation (KT) with varying anti-PLA2R titer.


  Case Report Top


Case 1

A 30-year-old male, 8 months posttransplant, was referred for the evaluation of anasarca and frothiness of urine. His past investigations revealed nephrotic range proteinuria at month-2 posttransplant (6.80 g/day at 2 months and 7.40 g/day at 8 months) and serum creatinine of 3.60 mg/dl. The patient's native kidney disease was a biopsy-proven PLA2R-related PMN (at our center), diagnosed when the patient presented with nephrotic syndrome (proteinuria of 4.00 g/day, serum albumin of 3.06 g/dl, and anti-PLA2R level of 143.96 RU/ml) and kidney dysfunction (serum creatinine 5.50 mg/dl). The patient progressed to end-stage kidney disease (ESKD) at 12 months, despite rituximab therapy (anti-PLA2R 6-months postrituximab of 41.60 RU/ml). The patient underwent a kidney transplant with his mother as the donor (68 years) at an outside center and had an anti-PLA2R titer of 404.00 RU/ml before (1-month) transplant. The patient received no induction therapy, and the maintenance immunosuppression was tacrolimus, mycophenolate mofetil (MMF), and steroids. An allograft biopsy performed for posttransplant nephrotic syndrome revealed PLA2R-related PMN with chronicity. The anti-PLA2R titer was 264.00 RU/ml. Citing financial issues, the patient refused any additional immunosuppression and progressed to ESKD. The patient developed pneumonia and succumbed to the illness at 12 months of transplant.

Case 2

A 46-year-old man developed swelling in both lower limbs. Evaluation at a local health facility revealed nephrotic syndrome (proteinuria of 13.1 g/day, serum albumin of 2.6 g/dl) and impaired kidney function (serum creatinine of 2.8 mg/dl). He was treated empirically with oral steroids without a kidney biopsy but progressed to ESKD. On self-referral, the patient attended our outpatient care for a kidney transplant. The donor was his mother. He received triple-drug immunosuppression (tacrolimus, MMF, and steroids). Posttransplant, the patient had a slow graft function. Allograft biopsy on day-7 showed acute tubular necrosis. However, the glomeruli were normal on light microscopy (LM) and immunofluorescence. At 1-month posttransplant, the patient had proteinuria. Eight weeks after the transplant, proteinuria was 1.7 g/day, serum creatinine of 1.6 mg/day, and serum albumin of 4.4 g/dl. A repeat biopsy showed normal glomeruli (LM) [Figure 1]a (with IgG and C3 granular positivity along with the capillary loops) and a diffuse glomerular capillary staining for PLA2R [Figure 1]b, suggesting a diagnosis of PLA2R-related membranous nephropathy. Serum anti-PLA2R was negative by ELISA. Anti-PLA2R in the pretransplant stored serum sample at the immunopathology laboratory revealed a titer of 208 RU/mL. Despite starting the patient on olmesartan, the proteinuria increased to 3.6 g/day at 6 months. Because of persistent proteinuria and graft dysfunction, a third allograft biopsy was performed, which showed findings indistinguishable from the second biopsy, albeit with a thickened glomerular basement membrane [Figure 1]c and more intense PLA2R staining [Figure 1]d. There was no evidence of rejection. Repeat anti-PLA2R was still negative by ELISA. The proteinuria declined to 1.40 g/day at the end of 8 months and serum creatinine remained at 1.60 mg/dl, indicating partial remission. At the last follow-up (30-month posttransplant), the proteinuria serum creatinine was 0.64 g/day and 1.80 mg/dl, respectively.
Figure 1: (a) Normal glomerulus with mild stiffening of glomerular basement membrane. (b) Phospholipase A2 receptor showing granular (2+) staining along glomerular basement membrane. (c) Thickened glomerular basement membrane. (d) Phospholipase A2 receptor showing granular (3+) staining along glomerular basement membranes, (Massons Trichrome-a, Periodic acid–Schiff-c, immunohistochemistry phospholipase A2 receptor -b and d, ×200 original magnification)

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Case 3

A 28-year-old male presented with nephrotic syndrome (proteinuria of 6.20 g/day, serum albumin of 2.30 g/dl, and serum creatinine of 4.20 mg/dl) and the biopsy revealed PLA2R-related PMN with chronicity. The patient received cyclical cyclophosphamide and steroids. However, despite a reduction in proteinuria (2.20 g/day) at 12 months, the patient progressed to ESKD at 24 months of follow-up. He underwent a live-related kidney transplant (pretransplant anti-PLA2R was 120.00 RU/ml) with an unrelated/related donor. He received antithymocyte globulin induction and triple immunosuppressive therapy. Posttransplant proteinuria was 116 mg/day and 212 mg/day at 2 months and 6 months, respectively. Anti-PLA2R antibody repeated twice posttransplant was <0.60 RU/ml. Currently, the patient is doing fine with serum creatinine and proteinuria of 1 mg/dL and 0.24 g/day at 18-month posttransplant, respectively.

Case 4

A 20-year-old male was diagnosed with PLA2R-positive PMN and had advanced renal dysfunction at the time of presentation. He refused treatment and progressed to ESKD. Live donor KT (LDKT) was done with sibling donor. Pretransplant anti-PLA2R titers were negative by Indirect immuno fluorescence(IIF) 1-month prior to transplant. He has been free of clinical/histological recurrence with follow-up of 12 months.

Case 5

A 45-year-old male was diagnosed with anti-PLA2R-positive PMN in 2014 and received multiple courses of immunosuppressive therapy. The patient was diagnosed with ESKD. He underwent LDKT with brother as a donor. Pre-transplant anti-PLA2R antibody was negative. He has a stable posttransplant course with no recurrence of proteinuria at 6 months of follow-up.


  Discussion Top


The current report highlights recurrent PMN in patients with a varying titer of anti-PLA2R pretransplant. Thus, the patients with a plethoric anti-PLA2R before transplant are at heightened risk of recurrence in the immediate posttransplant period.

In the post-PLA2R era, there are discrete signals suggestive of the pre-KT antibody (titers) in predicting the recurrence of the disease.[1],[4],[6] The summary of studies on recurrent PMN is shown in [Table 1]. Stahl et al.[7] in 2010, reported recurrent PMN on the 3rd postoperative day in a patient with massive proteinuria, where the authors demonstrated the presence of circulating anti-PLA2R antibody both pre-and immediate posttransplant. A declining titer with a paralleling reduction in proteinuria is suggestive of the antibody being pathogenic. Blosser et al.[8] and Ishiwatari et al.[9] reported recurrent PMN in the early postoperative period in patients with high antibody titer preceding transplant. In native kidneys, the baseline anti-PLA2R antibody titers correlate with disease activity and predict the probability of achieving spontaneous remission, response to immunosuppressive therapy, and long-term prognosis.[10] A decline in antibody titers predicts immunologic remission and subsequently, clinical remission.[1]
Table 1: Summary of all the studies

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A few studies have evaluated the role of monitoring the anti-PLA2R antibody titers pretransplant and its role in predicting recurrence; the results are divergent.[4],[6],[11],[12] The first such study was by Seitz Polski et al.[11] who studied ten patients of recurrent PMN, monitoring their pre-and post-transplant titers and seeking their correlation with recurrence. The study failed to demonstrate the role of pretransplant titers in predicting recurrence but found that the antibodies detected during posttransplant follow-up (>6 months) significantly correlated with recurrence. The authors suggested monitoring antibody titers and proteinuria regularly in the posttransplant period. Debiec et al.[12] evaluated ten patients of recurrent PMN and nine patients of posttransplant de novo membranous nephropathy (MN). Fifty percent of the patients with recurrent PMN tested positive for anti-PLA2R antibodies. However, none of the nine patients with de novo MN had any autoantibodies to PLA2R. There existed a marked heterogeneity in the titers of anti-PLA2R, eventually leading to the conclusion that there was no correlation between pretransplant antibody titers and recurrent PMN. Many subsequent studies confirmed the correlation of pretransplant anti-PLA2R antibody titers with recurrence posttransplant[4],[5],[6],[13] with good negative and positive predictive values. Kattah et al.[14] studied 26 patients of MN, of which 18 patients had a recurrence (median time to recur-4 months). Patients with pretransplant anti-PLA2R antibodies were at an increased risk of recurrence as compared to seronegative patients. However, the negative predictive value of the autoantibodies was meager (42%), which remains unexplained. A retrospective study of 21 patients by Quintana et al.[6] confirmed the association of elevated pretransplant anti-PLA2R antibody titer (over 45RU/ml) to histological recurrence. In the study by Grupper et al.,[5] 30 of 63 patients (48%) had a histologic recurrence. The authors described an association of elevated risk of recurrent PMN in patients with higher pretransplant proteinuria and anti-PLA2R antibodies. Gupta et al.[4] in 2016 reported recurrent PMN in 37% of patients of antibody-positive patients. An anti-PLA2R titer of >29 RU/mL predicted recurrent PMN with a sensitivity of 85% and a specificity of 92%.[4] Furthermore, an undetectable anti-PLA2R antibody before transplantation predicts a significantly reduced risk of recurrence. An exceptional negative predictive value was consistent across most studies.[4],[6],[11]

Since immunological remission antedates histological remission in PMN and good correlation between anti-PLA2R antibody titers and disease activity, it may be possible to individualize immunosuppressive therapy based on the anti-PLA2R titers as well as predict the risk of recurrence posttransplant.[15] In our prior study,[1] we divided 114 cases of PLA2R-related PMN into three tertiles based on anti-PLA2R titers, with higher treatment resistance among the third tertile. Thus, patients with antibodies in the third tertile are likely to have persistent antibodies resistant to immunosuppressive therapies. Therefore, a word of caution needs an emphasis while proceeding to transplant in such a scenario. However, there is no consensus on how to proceed in ESKD patients with a high titer of antibodies. Therefore, whether to consider pretransplant immunosuppressive therapy or conservative management remains unanswered.

The five cases mentioned in the current report demonstrate various scenarios, ranging from high (pre-transplant) antibody titers resulting in early recurrence and graft loss to a situation with a negative or low pretransplant titer, with no evidence of recurrence on a reasonable follow-up. These cases illustrate the importance of pretransplant anti-PLA2R antibody titers and the risk of recurrence. The case 1 had many risk factors for recurrence, such as a malignant pretransplant course, a high pretransplant anti-PLA2R antibody titer, late presentation, and a low kidney reserve of the donor, which ultimately culminated in graft loss at 1 year. The case 2 had a moderately high anti-PLA2R pretransplant, resulting in immediate recurrence in the allograft. His circulating antibody titers were consistently negative despite nephrotic range proteinuria, which could result from the adsorption of the antibodies by the allograft kidney, manifesting as PLA2R stain positive PMN in the biopsy.[16] A negative or a low pretransplant titer portends a better prognosis and low risk of recurrence, as demonstrated in case 3, 4, and 5. Apart from the pretransplant antibody titers, there may be other additional factors (unknown) that predict recurrence. A recent report from Europe illustrates an association of various interactions between single-nucleotide polymorphism in the human leukocyte antigen-D and PLA2R1 loci of the donor with recurrent PMN.[17] Tacrolimus is an established therapeutic option for managing PMN. Cytochrome P450 polymorphism is a critical determinant of tacrolimus trough levels. All the patients in the current report had tacrolimus trough levels between 10 and 12 ng/ml during the 1st-month posttransplant, 8–10 ng/ml in-between months 1 and 3, and between 5 and 8 ng/ml after that.

The absence of antibodies at transplantation may suggest a lack of immunological activity and thus indicate a lesser chance of recurrence. However, further large-scale randomized controlled trials are needed to formulate recommendations regarding the timing of transplant and ascertain what level of antibodies will ensure safety in proceeding with the transplant. The report had few limitations, mainly a small sample size and a lack of protocolized approach in managing posttransplant PMN. The report had few limitations, mainly a small sample size, lack of protocolized approach in managing posttransplant PMN, and lack of details pertaining to CYP450 polymorphism. To conclude, there are signals suggesting a high anti-PLA2R antibody titer at the time of transplantation to an increased risk of PMN recurrence.

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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ramachandran R, Kumar V, Kumar A, Yadav AK, Nada R, Kumar H, et al. PLA2R antibodies, glomerular PLA2R deposits and variations in PLA2R1 and HLA-DQA1 genes in primary membranous nephropathy in South Asians. Nephrol Dial Transplant 2016;31:1486-93.  Back to cited text no. 1
    
2.
Hoxha E, Thiele I, Zahner G, Panzer U, Harendza S, Stahl RA. Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. J Am Soc Nephrol 2014;25:1357-66.  Back to cited text no. 2
    
3.
Leon J, Pérez-Sáez MJ, Batal I, Beck LH Jr., Rennke HG, Canaud G, et al. Membranous nephropathy posttransplantation: An update of the pathophysiology and management. Transplantation 2019;103:1990-2002.  Back to cited text no. 3
    
4.
Gupta G, Fattah H, Ayalon R, Kidd J, Gehr T, Quintana LF, et al. Pre-transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation. Clin Transplant 2016;30:461-9.  Back to cited text no. 4
    
5.
Grupper A, Cornell LD, Fervenza FC, Beck LH Jr., Lorenz E, Cosio FG. Recurrent membranous nephropathy after kidney transplantation: Treatment and long-term implications. Transplantation 2016;100:2710-6.  Back to cited text no. 5
    
6.
Quintana LF, Blasco M, Seras M, Pérez NS, López-Hoyos M, Villarroel P, et al. Antiphospholipase A2 receptor antibody levels predict the risk of posttransplantation recurrence of membranous nephropathy. Transplantation 2015;99:1709-14.  Back to cited text no. 6
    
7.
Stahl R, Hoxha E, Fechner K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation. N Engl J Med 2010;363:496-8.  Back to cited text no. 7
    
8.
Blosser CD, Ayalon R, Nair R, Thomas C, Beck LH Jr. Very early recurrence of anti-Phospholipase A2 receptor-positive membranous nephropathy after transplantation. Am J Transplant 2012;12:1637-42.  Back to cited text no. 8
    
9.
Ishiwatari A, Wakai S, Shirakawa H, Honda K. Recurrent membranous nephropathy after kidney transplantation associated with phospholipase A2 receptor and successfully treated with rituximab: A case report. Transplant Proc 2018;50:2565-8.  Back to cited text no. 9
    
10.
Beck LH Jr., Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, 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. 10
    
11.
Seitz-Polski B, Payré C, Ambrosetti D, Albano L, Cassuto-Viguier E, Berguignat M, et al. Prediction of membranous nephropathy recurrence after transplantation by monitoring of anti-PLA2R1 (M-type phospholipase A2 receptor) autoantibodies: A case series of 15 patients. Nephrol Dial Transplant 2014;29:2334-42.  Back to cited text no. 11
    
12.
Debiec H, Martin L, Jouanneau C, Dautin G, Mesnard L, Rondeau E, et al. Autoantibodies specific for the phospholipase A2 receptor in recurrent and De novo membranous nephropathy. Am J Transplant 2011;11:2144-52.  Back to cited text no. 12
    
13.
Anjum N, Nabi Z. The beneficial role of anti-phospholipase A2 receptor auto-antibodies and rituximab in the management of recurrent primary membranous nephropathy after kidney transplantation. J Ayub Med Coll Abbottabad 2021;33:315-8.  Back to cited text no. 13
    
14.
Kattah A, Ayalon R, Beck LH Jr., Sethi S, Sandor DG, Cosio FG, et al. Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy. Am J Transplant 2015;15:1349-59.  Back to cited text no. 14
    
15.
Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol 2015;26:2545-58.  Back to cited text no. 15
    
16.
Ramachandran R, Kumar V, Nada R, Jha V. Serial monitoring of anti-PLA2R in initial PLA2R-negative patients with primary membranous nephropathy. Kidney Int 2015;88:1198-9.  Back to cited text no. 16
    
17.
Berchtold L, Letouze E, Alexander MP, Canaud G, Logt AV, Hamilton P, et al. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients. Kidney Int 2021;99:671-85.  Back to cited text no. 17
    


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