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Nephrology 20, Suppl. 2 (2015) 101–104

Brief Communication

Phospholipase A2 receptor positive membranous nephropathy long after living donor kidney transplantation between identical twins HISAKO SAITO,1 YOSHIFUMI HAMASAKI,1 AKIHIRO TOJO,1 YUKAKO SHINTANI,2 AKIRA SHIMIZU3 and MASAOMI NANGAKU1 1 Division of Nephrology and Endocrinology and 2Department of Pathology, Graduate School of Medicine, The University of Tokyo, and 3Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan

KEY WORDS: HCV infection, kidney transplantation, membranous nephropathy, phospholipase A2 receptor, steroid therapy. Correspondence: Yoshifumi Hamasaki, 22nd Century Medical and Research Center, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected] Accepted for publication 14 March 2015. doi:10.1111/nep.12458 Conflict of Interest: The authors have no conflict of interest to declare.

ABSTRACT: Although membranous nephropathy (MN) is a commonly observed cause of post-transplant glomerulonephritis, distinguishing de novo from recurrent MN in kidney allograft is often difficult. Phospholipase A2 receptor (PLA2R) staining is useful for diagnosing recurrent MN in allografts similarly to idiopathic MN in native kidney. No specific treatment strategy has been established for MN, especially when accompanied with HCV infection in kidney transplant recipients. This report describes a 66-year-old man who was diagnosed as having PLA2R positive membranous nephropathy accompanied with already-known IgA nephropathy and HCV infection 26 years after kidney transplantation conducted between identical twins. PLA2R was detected along capillary loops, implying that this patient is affected by the same pathogenic mechanism as idiopathic MN, not secondary MN associated with other disorders such as HCV infection. The patient successfully achieved clinical remission after steroid therapy.

Membranous nephropathy (MN), a main cause of posttransplant glomerulonephritis developed with nephrotic syndrome,1 can engender poor graft survival.2 Phospholipase A2 receptor (PLA2R) staining in kidney biopsy specimens is useful to distinguish between recurrent and de novo MN.3 De novo MN develops in about 2% of adult kidney transplanted allografts.4 The pathogenesis of de novo MN remains unclear. Frequently observed histological changes of antibody-mediated rejection (AMR) in the allograft of kidney transplant recipients with de novo MN suggest that AMR has a role in the pathogenesis of de novo MN.5 An association between the development of de novo MN and hepatitis C virus (HCV) infection or IgA nephropathy in kidney allografts has also been reported.6 Incidence of recurrent MN is reported as 10–30%. No risk factors for recurrent MN have been identified. Few reports describe recurrent MN in patients with HCV infection. Several reports in the relevant literature have described that MN was developed with IgA nephropathy or occurred in HCV positive patients6,7 but none has described a case of combined MN and IgA nephropathy in a HCV positive patient. No established treatment strategy exists for MN in kidney transplant recipients. This report describes a case of © 2015 Asian Pacific Society of Nephrology

PLA2R positive MN developing in a patient with both HCV infection and IgA nephropathy 26 years after kidney transplantation between identical twins.

CASE REPORT A 40-year-old man developed end-stage renal disease caused by glomerulonephritis without histopathology. He started hemodialysis from 1987. Four months later, kidney transplantation from his identical twin brother was performed. Cyclosporine, azathioprine, and prednisolone were used for induction and were discontinued from April 1988. Ten years later, he presented with proteinuria of 2+. Therefore, his first allograft biopsy was performed. Based on findings of the proliferation of mesangial cells and matrix on light microscopy and deposits of IgA on immunofluorescence staining in glomeruli, the biopsy results indicated IgA nephropathy. Segmental sclerosis was found in 1 of 24 glomeruli, but no crescent formation was found. At that time, no histological finding suggested MN. Oral dipyridamole was started. From that time, serum creatinine levels remained stable: approximately 1.1 mg/dL. Proteinuria was negative over the 101

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basement membrane were found (Fig. 1B). Neither endocapillary proliferation nor a double contour of glomerular basement membrane was found. IgA deposition in the mesaigial lesions and granular deposits of IgG in the capillary loops were found from immunofluoresence staining. (Figs. 2A and 2B). C3 and C1q were negative in glomeruli. As a pattern of IgG subclass deposition, IgG1 staining was codominant with IgG4 (Figs. 2C and 2D).8 Small subepithelial and paramesangial electron dense deposits were detected using electron microscopy (Figs. 2E and 2F). PLA2R was detected along capillary loops (Fig. 3).3 The biopsy results indicated already-known IgA nephropathy and MN. Pathology findings did not indicate clearly whether MN was de novo or recurrent. Although 100 mg/day of losartan was started, levels of proteinuria increased to 20 g/ gCr, serum albumin levels decreased to 1.7 g/dL, and serum creatinine levels increased to 2.0 mg/dL. Oral administration of prednisolone was initiated with a dose of 0.9 mg/kg/day (50 mg/day). It was maintained for a month, then tapered over several months. Subsequently, proteinuria decreased dramatically to around 500 mg/gCr; levels of serum albumin were increased to 3.7 g/dL. The serum creatinine concentration decreased to 1.2 mg/dL. Remission of proteinuria continued even after the prednisolone dosage was decreased gradually to 10 mg/day.

DISCUSSION Fig. 1 Findings from light microscopy. No thickening of the glomerular basement membrane was found, but proliferation of mesangial cells and matrix on light microscopy were found (PAS staining, ×400) (Fig. 1A). No spike or thickening of the glomerular basement membrane were found (PAM staining, ×400) (Fig. 1B).

following years. In 2001, the patient was found to be infected with HCV, but the degree of disease progress and duration were unknown. Sixteen years after his first allograft biopsy, he presented with proteinuria (6.4 g/gCr) and hypoalbuminemia (3.3 g/ dL). His serum creatinine levels had increased to around 1.4 mg/dL. The cause of serum creatinine elevation was inferred to be the reduction of effective circulating plasma volume triggered by nephrotic syndrome. He was admitted to our hospital in July 2013. Complement and immunoglobulin levels were within normal ranges; anti-nuclear antibody was negative. Cryoglobulin was positive. Blood HCV-RNA titer was 6.1 logIU/mL. Because his kidney transplantation had been conducted between identical twins, the presence of a donor-specific antibody was not considered. His second allograft biopsy was performed. Of the total 14 glomeruli, 6 showed proliferation of mesangial cells and matrix and 4 showed global sclerosis on light microscopy (Fig. 1A). No glomeruli with thickening or spikes of the glomerular 102

In this case, nephrotic syndrome manifested in a patient with both already-known IgA nephropathy in allograft and HCV infection 26 years after living donor kidney transplantation conducted between identical twins. Renal allograft biopsy revealed granular deposits of IgG in the capillary loops. Immunofluorescence staining showed that IgG1 staining was codominant with that of IgG4. PLA2R was positive along the glomerular basement membrane. These histological findings suggest the presence of MN. After starting oral prednisolone therapy, remission of nephrotic syndrome was achieved. The level of serum creatinine decreased. Although MN was diagnosed by second allograft biopsy of this patient, it was not easy to clarify whether it was de novo or recurrent MN. Reportedly, de novo MN is associated with several clinical conditions such as HCV infection, recurrent IgA nephropathy6 and AMR.5 Actually, the incidence of de novo MN among HCV positive kidney transplant recipients is 3.7%, which is higher than in HCV negative patients or general adult kidney recipients, each showing incidence of 2.0%.9 A few cases of simultaneous occurrence of IgA nephropathy and de novo MN in transplanted kidney have been reported.10 In this case, HCV infection and IgA nephropathy in renal allograft had already been recognized from a dozen years before the diagnosis of MN without findings of AMR. In general, recurrent MN occurs earlier than de novo MN after kidney transplantation. The mean duration from transplantation to the onset of recurrent MN was reported as © 2015 Asian Pacific Society of Nephrology

Membranous nephropathy in allograft

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Fig. 2 Findings from immunofluorescence staining and electron microscopy. IgA in the mesangial lesions (Fig. 2A) and granular deposits of IgG in the capillary loops (Fig. 2B) on immunofluorescence staining. Pattern of IgG subclass deposit: IgG1 staining (Fig. 2C) was codominant with IgG4 (Fig. 2D). Small subepithelial (Fig. 2E) and paramesangial (Fig. 2F) electron dense deposits were found from electron microscopy.

approximately 15 months.4 No pathological finding of MN was made in the patient’s first allograft biopsy performed about 10 years after kidney transplantation. The long duration he spent free from MN after kidney transplantation suggests de novo MN. PLA2R is a recently identified major target antigen of idiopathic MN in native kidney.11 Its staining might be more sensitive than serological testing of anti-PLA2R antibody for the diagnosis of idiopathic MN.12 Larsen et al. reported that recurrent MN is correlated closely with PLA2R positivity, with sensitivity of 83% and specificity of 92% for recurrent MN.3 It cannot be concluded whether our case is recurrent or de novo MN because native kidney biopsy was not performed. Based on the fact that PLA2R was positive in capillary loops, the most reasonable understanding of pathogenesis in this patient might be that the same pathogenic mechanism as that for idiopathic MN occurred, not as secondary MN associated with systemic disorders such as HCV infection. © 2015 Asian Pacific Society of Nephrology

Fig. 3 Immunofluorescence staining for phospholipase A2 receptor. PLA2R is detected on the glomerular capillary loops.

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No validated specific treatment strategy exists for MN in kidney transplanted patients. A retrospective study showed that steroid therapy did not decrease the level of proteinuria in MN.1 Okyay et al. reported an MN patient who had remission of proteinuria and preserved graft function after increased prednisolone dosage.13,14 In our case, although the level of proteinuria was not decreased initially by losartan, treatment by prednisolone improved proteinuria, hypoalbuminemia, and kidney function. During treatment with prednisolone, the blood HCV-RNA concentration did not increase. Herein, we presented an extremely rare case of PLA2R positive MN development in a kidney transplant recipient with both IgA nephropathy and HCV infection long after kidney transplantation was conducted between identical twins. Clinical situations suggested de novo MN, except for detection of PLA2R along capillary loops. The possibility exists that MN having the same pathogenic mechanism as idiopathic MN occurred in a kidney transplant patient. After the initiation of prednisolone, the patient maintained clinical remission with preserved graft functions without increase of the blood HCV-RNA level.

ACKNOWLEDGEMENTS None.

REFERENCES 1. Schwarz A, Krause PH, Offermann G, Keller F. Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation. Transplant. 1994; 58: 650–4. 2. Hariharan S, Adams MB, Brennan DC et al. Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplant. 1999; 68: 635–41. 3. Larsen CP, Walker PD. Phospholipase A2 receptor (PLA2R) staining is useful in the determination of de novo versus recurrent membranous glomerulopathy. Transplant. 2013; 95: 1259–62.

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4. Aline-Fardin A, Rifle G, Martin L et al. Recurrent and de novo membranous glomerulopathy after kidney transplantation. Transplant. Proc. 2009; 41: 669–71. 5. Honda K, Horita S, Toki D et al. De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney. Clin. Transplant. 2011; 25: 191–200. 6. Ponticelli C, Glassock RJ. De novo membranous nephropathy (MN) in kidney allografts. A peculiar form of alloimmune disease? Transpl. Int.: Official J. Eur. Soc. Organ. Transplant. 2012; 25: 1205–10. 7. Koselj-Kajtna M, Rott T, Koselj M, Ferluga D et al. Recurrent immunoglobulin A nephropathy complicated with de novo membranous glomerulonephritis in renal allografts. Transplant. Proc. 2002; 34: 3117–8. 8. Kearney N, Podolak J, Matsumura L, Houghton D, Troxell M. Patterns of IgG subclass deposits in membranous glomerulonephritis in renal allografts. Transplant. Proc. 2011; 43: 3743–6. 9. Morales JM, Pascual-Capdevila J, Campistol JM et al. Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients. Transplant. 1997; 63: 1634–9. 10. Kfoury HK, Alghonaim M, AlSuwaida AK, Zaidi SN, Arafah M. Nasopharyngeal T-cell monomorphic posttransplant lymphoproliferative disorders and combined IgA nephropathy and membranous glomerulonephritis in a patient with renal transplantation: a case report with literature review. Transplant. Proc. 2010; 42: 4653–7. 11. Beck LH, Jr., Bonegio RG, Lambeau G et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 2009; 361: 11–21. 12. Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol., Dial., Transplant.: Off. Publ. Eur. Dial. Transplant. Association – Eur. Ren. Association. 2013; 28: 1839–44. 13. Poduval RD, Josephson MA, Javaid B. Treatment of de novo and recurrent membranous nephropathy in renal transplant patients. Semin. Nephrol. 2003; 23: 392–9. 14. Okyay GU, Inal S, Onec K, Gonul, II, Guz G. Remission of de novo membranous nephropathy in a kidney allograft recipient: a case report. Ren. Fail. 2012; 34: 1341–3.

© 2015 Asian Pacific Society of Nephrology

Phospholipase A2 receptor positive membranous nephropathy long after living donor kidney transplantation between identical twins.

Although membranous nephropathy (MN) is a commonly observed cause of post-transplant glomerulonephritis, distinguishing de novo from recurrent MN in k...
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