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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 13  |  Issue : 2  |  Page : 122-126

Utility of plasma exchange in early recurrent C3 glomerulopathy


1 Department of Histopathology, Post-Graduate Institute of Medical Institute and Research (PGIMER), Chandigarh, India
2 Department of Nephrology, Post-Graduate Institute of Medical Institute and Research (PGIMER), Chandigarh, India
3 Department of Transplant Surgery, Post-Graduate Institute of Medical Institute and Research (PGIMER), Chandigarh, India

Date of Submission23-Nov-2018
Date of Acceptance01-Feb-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Raja Ramachandran
Department of Nephrology, PGIMER, Chandigarh - 160 012
India
Ritambhra Nada
Professor, Department of Histopathology, PGIMER, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_78_18

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  Abstract 


Introduction: Treatment options for recurrent C3 glomerulopathy (C3G) are not explored in large trials. Only Eculizumab has been successfully used to improve the renal function in patients with recurrent C3G. In the current report, we are sharing our experience with plasma exchange (PLEX) in the management of early recurrent C3G post-renal transplantation. Materials and Methods: A total of four patients underwent PLEX. Time to recur was less than two weeks in all the patients. Serology levels, autoantibody testing and limited genetic workup was done in all the four patients. The clinical details of patients were recorded. Results: All the patients underwent 5 PLEX (40 ml/kg/session) with fresh frozen plasma as the replacement. The median time for post-transplant recurrence was 3-days. Immediate reduction in serum creatinine was seen in three (75%) patients. After a median last follow-up of 8.5 (range: 4-18) months, two (50%) patients achieved remission and the other two (50%) had resistant disease resulting in graft loss. Three patients tested positive for autoantibodies (two cases had positive C3-nephritic factor and one had anti-complement factor-H autoantibodies. Complement factor H gene analysis revealed rs1061170; p.His402Tyr (missense variant), rs1061147; p.Ala307= (synonymous variant) and rs2274700; p.Ala473= (synonymous variant) in three cases. All the three patients who had immediate response to PLEX had positive autoantibodies against complement pathway regulators. Conclusion: In the present report, we performed extensive workup for complement pathway abnormality and found that patients with recurrent C3G following transplantation having autoantibodies benefited with PLEX.

Keywords: Anti-factor-H autoantibodies, C3 glomerulopathy, C3 nephritic factor, dense deposit disease, plasma exchange


How to cite this article:
Kumar A, Bharati J, Nada R, Singh S, Sharma A, Gupta KL, Ramachandran R. Utility of plasma exchange in early recurrent C3 glomerulopathy. Indian J Transplant 2019;13:122-6

How to cite this URL:
Kumar A, Bharati J, Nada R, Singh S, Sharma A, Gupta KL, Ramachandran R. Utility of plasma exchange in early recurrent C3 glomerulopathy. Indian J Transplant [serial online] 2019 [cited 2019 Sep 15];13:122-6. Available from: http://www.ijtonline.in/text.asp?2019/13/2/122/261852

Authors Ashwani Kumar, Joyita Bharati, Ritambhra Nada and Raja Ramachandran has equally contributed





  Background Top


C3 glomerulopathy (C3G) is a glomerular histological entity with varied clinical manifestations. It was classified as a type of membranoproliferative glomerulonephritis and further subdivided into two entities, which included dense deposit disease (DDD) and proliferative glomerulonephritis with C3 deposits (C3GN), both characterized by predominant C3 deposition (C3 more than 2 magnitudes greater than other immune reactants) along the glomerular capillary wall/mesangium.[1],[2] Dysregulation of alternative complement pathway (ACP) is caused by genetic mutations or acquired antibodies to complement regulating proteins that result in C3G.[3]

Although pathogenically similar, the clinical manifestations and outcome of DDD and C3GN differ in various studies. Sethi et al.[4] found proteinuria and hematuria to be universal in 12 patients of C3GN, with 83.33% maintaining normal renal function at a mean follow-up of 26.4 months. On the contrary, about 60% of patients with DDD presented with renal insufficiency and around 75% patients had persistent renal dysfunction and/or end-stage renal disease (ESRD) on follow-up (mean: 63 months) in a study from North America.[5] Overall, a significant proportion of patients with C3G develop ESRD, and the risk factors for rapid progression ESRD are young age at presentation, severe renal dysfunction, and proteinuria.[6]

Recurrences of both DDD and C3GN after transplant are common, with graft loss in more than 50% of patients.[7],[8] The management of posttransplant recurrent C3G is not structured as various therapies have been inconsistently effective. Eculizumab has been described to be heterogeneously effective in cases with recurrent C3G.[9],[10] An extreme cost and uncertain duration of therapy prohibit its use in most of the patients. Rituximab, although effective in native C3G, was found ineffective in recurrent DDD.[11] Plasmapheresis, given along with immunosuppressants, is widely available and has been useful in patients with antibody-positive C3G.[12]


  Methods Top


This was a prospective observational study carried out at the Departments of Histopathology, Nephrology, and Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, from July 2014 to July 2017. ACP-related workup was approved by ethical committee vide letter number 13/2088. Clinical and histopathological data were recorded in a prespecified format. All the patients had biopsy-proven C3G pre- and posttransplant, respectively. C3G was defined based on immunofluorescence study showing predominant C3 staining with absent or <2 magnitude staining of other immunoglobulins/complements as compared to C3. The histopathological patterns on light microscopy and electron microscopy, both pre- and posttransplant, were available in all the cases. Patients with osmiophilic ribbon-like deposits in the lamina densa of the glomerular basement membrane on electron microscopy were classified as DDD, and those without these typical deposits and having subendothelial/mesangial deposits were classified as C3GN. Additional serology and genetic analyses were done as described earlier.[13] Alternate pathway functional assay (APFA) was performed using the Wieslab ELISA kit (Malmö, Sweden) as per manufacturer instructions. Complement factor-H (CFH) and factor-B (CFB) levels were estimated using Assay Max, human CFH, and CFB ELISA Kits (Assaypro, St. Charles, MO). C3Nef, CFH and CFB autoantibodies (ab-CFH; ab-CFB) were also analyzed by ELISA.[13] Genetic testing of all exons of CFH and CFHR5 genes was done. Patients with recurrent C3G who underwent plasma exchange (PLEX) were included for the study. All patients underwent five sessions of alternate-day PLEX (40 ml/kg/session with membrane filter) using fresh-frozen plasma and albumin as the replacement fluid. An algorithm of workup for C3G patients is described in [Flowchart 1].




  Results Top


A total of four patients with early recurrent C3G underwent PLEX. Two patients received induction therapy with rabbit antithymocyte globulin, and all were on maintenance immunosuppression comprising tacrolimus, mycophenolate mofetil, and steroids. The median age of the patients at diagnosis was 23.5 years (range: 19–27 years) (mean ± SD: 23.25 ± 4.34 years). During the pretransplant period, all the patients received immunosuppression with oral prednisolone. The median time from onset of C3G to dialysis was 3 months (range: 1–12 months) (mean ± SD: 4.75 ± 4.92 months). The median serum creatinine and proteinuria at the time of recurrence was 5.75 mg/dl and 2.49 g/day, respectively. Of four patients, three had DDD and one had C3GN. Kidney biopsy showed mesangial proliferative, membranoproliferative, and crescentic glomerulonephritis patterns [Table 1] at the first presentation (native kidneys). All patients showed mild mesangial expansion or normal morphology and at the time of recurrence in posttransplant biopsies [Figure 1]. Three patients were positive for autoantibodies against complement pathway regulators. Patients 1 and 3 had C3 nephritic factor (C3Nef) and patient 4 had ab-CFH [Table 2]. Missense variant of CFH gene (rs1061170 and p. His402Tyr) was present in three cases and synonymous variants, rs1061147 and rs2274700, were seen in two cases [Table 2]. Details of genetic and serological complement pathway abnormality of individual cases are shown in [Table 2]. All, except one, transplants were from living donors. The median time for recurrence posttransplant was 3 days. Immediate reduction in serum creatinine was seen in three (75%) patients. Details of trends in serum creatinine for all the four patients are plotted in [Figure 2]. After a median last follow-up of 8.5 months (range: 4–18 months) (mean ± SD: 9.75 ± 6.55 months), two (50%) patients achieved remission and the other two (50%) had resistant disease resulting in graft loss. One out of two patients who had resistant disease at last follow-up was positive for ab-CFH antibodies and initially responded to PLEX, which was later discontinued due to financial constraints. All the three patients who had immediate response to PLEX had positive autoantibodies against complement pathway regulators. We could not be able to do all serological testing posttransplant due to limited funds. Only C3/C4 levels were tested after transplant. Posttransplant, C3 was low in all and C4 was low in one patient only.
Table 1: Demographic and clinical profile of patients before transplant

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Figure 1: A C3GN case showing (a) membranoproliferative pattern, (b) immunofluorescence showing only C3 (3+) staining, (c) allograft biopsy (6 postoperative days) with normal glomerulus and focal basement membrane thickening, (d) immunofluorescence for C3 (2+), (e) electron microscopy showing subendothelial localization of immune complex type of deposits (C3GN), and (f) electron microscopy of a posttransplant case showing immune complex type of deposit only in the mesangium (PAS-a, c; human anti-C3-FITC tagged antibody-b, d; ×40 original magnification, Uranyl Acetate-5271-e, 2541-f original magnification)

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Table 2: Biopsy finding, clinical, serological, and genetic profile of patients after transplant

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Figure 2: Trend in serum creatinine/proteinuria on follow-up in individual patients (value in X-axis: Duration in months and Y-axis: Serum creatinine/24 h urine protein)

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  Discussion Top


The literature on genetics and treatment of posttransplant recurrent C3G is scanty. We report four cases of recurrent C3G following transplantation who were extensively worked up for ACP abnormalities and treated with PLEX. Three-fourth of the patients showed a favorable response to PLEX therapy.

Recurrence of C3G is usually seen within the first 2 years following transplant with a recurrence rate of ~ 70% in C3GN[7] and 80–90% in DDD.[9],[10],[11],[12],[13],[14] Our patient presented with early recurrence at a median of 3 days after transplant. The clinical presentation of C3G includes nephrotic syndrome, proteinuria, hematuria, and/or renal dysfunction. All patients presented with renal insufficiency and proteinuria. Risk factors for recurrence of C3G include complement pathway abnormalities and monoclonal gammopathy-mediated C3G.[7]

Alternative pathway dysregulation was first demonstrated in patients with C3G based on laser microdissection followed by mass spectrometry showing the presence of alternative pathway components in the glomerular deposits.[15],[16] APFA was low in 100% of our patients as compared to 88.89% of patients tested in a previous report by Sethi et al.[4] In earlier reports, autoantibodies (C3Nef and ab-CFH) were seen in 50% and 11.12% of patients with C3GN[4] and 78% and 3.22% of patients with DDD, respectively.[17] Of three, two (66%) of our patients with DDD were positive for C3Nef and one patient with C3GN was positive for ab-CFH. These findings suggest the need to screen posttransplant C3G patients for autoantibodies workup. Genetic variants of CFH found in our series (rs1061170, rs1061147, and rs2274700) were found to be associated with DDD[18],[19] and C3GN[4] in studies by other groups. Presence of these variants in our series supports the combined role of autoimmune and genetic dysregulation in C3G in posttransplant setting.

The treatment of recurrent C3G is not codified as of now owing to the rarity of the disease and lack of complete workup for complement pathway abnormality. Small trials have described success with eculizumab.[10],[11] There are few isolated case reports on the use of plasmapheresis in recurrent C3G. Plasmapheresis was described to be useful along with immunosuppressants in a patient with native kidney DDD with crescentic pattern and progressive renal failure.[20] Later, plasmapheresis was shown to be effective in C3Nef-positive patients with recurrent C3G following renal transplantation,[20] C3G associated with monoclonal gammopathy,[2] and in other complement-mediated disease atypical hemolytic uremic syndrome (aHUS). Although the functional characteristics of anti-factor-H antibody in aHUS differ from that in C3G,[21] the concept of removal of antibody by plasmapheresis should theoretically hold the same effect. Sinha et al.[22] reported the successful use of PLEX along with immunosuppression in pediatric aHUS patients positive for ab-CFH. Similarly, Pipeleers et al. reported the successful use of PLEX to prevent recurrence of C3GN in a patient with loss of previous graft due to disease recurrence.[23] The patient was started on prophylactic maintenance PLEX along with triple immunosuppression after the second renal transplantation, on which she had good graft function at the end of 1 year.

In the current series, patients having autoantibodies against C3 convertase and CFH benefited with PLEX, although not every patient who was treated successfully with plasmapheresis previously had documented antibodies to the complement regulating proteins.[20],[23] We assume that other autoantibodies described in C3G (i.e., antibodies to CFI and recently described C4Nef autoantibodies) have not been tested in these patients and should also be investigated.


  Conclusion Top


The data on PLEX in recurrent posttransplant C3G are very scanty and, in most instances, are limited by inadequate workup for complement abnormalities. Although limited by small numbers, the current report is evidence generating with regard to utility of PLEX in recurrent posttransplant C3G.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3 glomerulopathy: A new classification. Nat Rev Nephrol 2010;6:494-9.  Back to cited text no. 3
    
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Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, et al. C3 glomerulonephritis: Clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012;82:465-73.  Back to cited text no. 4
    
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Lu DF, Moon M, Lanning LD, McCarthy AM, Smith RJ. Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol 2012;27:773-81.  Back to cited text no. 8
    
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Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 2012;7:748-56.  Back to cited text no. 9
    
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Welte T, Arnold F, Kappes J, Seidl M, Häffner K, Bergmann C, et al. Treating C3 glomerulopathy with eculizumab. BMC Nephrol 2018;19:7.  Back to cited text no. 10
    
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12.
Braun MC, Stablein DM, Hamiwka LA, Bell L, Bartosh SM, Strife CF, et al. Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: The North American pediatric renal transplant cooperative study experience. J Am Soc Nephrol 2005;16:2225-33.  Back to cited text no. 12
    
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Nada R, Kumar A, Agrawal P, Ramachandran R, Sethi S. Renal and pulmonary dense deposit disease presenting as pulmonary-renal syndrome. Kidney Int Rep 2018;3:755-61.  Back to cited text no. 13
    
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Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 2011;6:1009-17.  Back to cited text no. 14
    
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Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR 3rd, Zipfel PF, et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int 2009;75:952-60.  Back to cited text no. 15
    
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Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, et al. Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol 2012;7:265-74.  Back to cited text no. 16
    
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Sozeri B, Mir S, Berdeli A, Dincel N, Sarsik B. Gene polymorphism of complement factor H in a Turkish patient with membranoproliferative glomerulonephritis type II. Iran J Kidney Dis 2012;6:149-53.  Back to cited text no. 17
    
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Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 2006;43:582-9.  Back to cited text no. 18
    
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Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, et al. Acute renal failure in dense deposit disease: Complete recovery after combination therapy with immunosuppressant and plasma exchange. Clin Nephrol 2011;75 Suppl 1:4-10.  Back to cited text no. 19
    
20.
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21.
Blanc C, Togarsimalemath SK, Chauvet S, Le Quintrec M, Moulin B, Buchler M, et al. Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: One target, two diseases. J Immunol Baltim Md 2015;194:5129-38.  Back to cited text no. 21
    
22.
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23.
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