Pediatr Nephrol (2015) 30:1033–1037 DOI 10.1007/s00467-015-3061-2
BRIEF REPORT
A case of C3 glomerulonephritis successfully treated with eculizumab Alexis Payette & Natalie Patey & Marie-Agnès Dragon-Durey & Véronique Frémeaux-Bacchi & Françoise Le Deist & Anne-Laure Lapeyraque
Received: 29 August 2014 / Revised: 26 January 2015 / Accepted: 27 January 2015 / Published online: 22 March 2015 # IPNA 2015
Abstract Background C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab. Case diagnosis/treatment A 5-year-old boy who presented with proteinuria, hematuria, high ASO titers, and low C3 levels was initially diagnosed with post-streptococcal GN. His first kidney biopsy confirmed this diagnosis, but complement investigations identified three alternative pathway dysregulation factors: C3 nephritic factor, complement factor I heterozygous mutation (I398L), and anti-factor H autoantibodies (4,500 AU/ml). A second biopsy performed 11 months after initial presentation (nephrotic range proteinuria) showed a C3GN suggestive of isolated C3 deposits. A. Payette : A.99 μg/ml; Cambridge Biomedical Inc. Boston, MA, USA) after
1036
two 900 mg doses. Prednisone was stopped 30 months after eculizumab initiation. Six years after initial presentation and 3 years after eculizumab initiation, the patient has continued to be treated with a maintenance dose of 1,200 mg every 2 weeks without the use of other immunosuppressive agents. His eculizumab trough level has been within the therapeutic range (171.4 μg/l) without adverse events. Proteinuria is decreased (1.7 g/day), and his creatinine level has remained in the normal range for his age (37 μmol/l). His blood pressure has been normal under ACE inhibitor therapy. His anti-CFH levels have slightly decreased (from 2,000 UA to 1,000 UA) despite the cessation of mycophenolate and remain stable since prednisone interruption. His C3 levels remained low and C3NeF remained present. A recent, fourth kidney biopsy (KB4) showed decreased polymorphonuclear leukocyte infiltration, mesangial proliferation, and less double contours, similar to his first kidney biopsy. No chronic tubulointerstitial lesions were observed at this time of follow-up. C3 deposits were comparable to previous biopsies. Ig deposits were not present. The C5b-9 deposits were significantly decreased and had focally disappeared (Fig. 2).
Discussion C3GN is a rare form of proliferative glomerulopathy, usually diagnosed in children or young adults [1]. The usual clinical findings include proteinuria, hematuria, and rapidly progressive renal insufficiency. The prognosis is generally poor with progression to end-stage renal disease within a decade in 36– 50 % of cases [1]. There is limited evidence and no randomized trials to inform therapeutic decisions with regards to nonspecific immunomodulatory therapies in C3GN. DDD is a related but separate entity from C3GN. Both diseases are grouped under the category of “C3 glomerulopathies”. Animal models have highlighted defects in the regulation of the complement alternative pathway as the central mechanism of C3GN pathogenesis [7, 8]. Complement studies allow the identification of regulation abnormalities in most patients diagnosed with C3GN [9]. Excessive C3 activation contributes to C5 convertase and membrane attack complex formation, both of which are implicated in glomerular inflammation [10]. Eculizumab is a fully humanized monoclonal antibody that prevents cleavage of complement component C5. It is a potential therapeutic option that precisely targets the physiopathology of C3GN. Its efficacy has been reported in several cases of C3GN, notably in patients with elevated sC5b-9 levels [3, 4, 6, 11, 12]. We present a case of initial PSGN with persistent hematuria and proteinuria suggesting the diagnosis of atypical post-infectious glomerulonephritis (atypical PSGN)
Pediatr Nephrol (2015) 30:1033–1037
as described by Sethi et al. [13]. The defect of the regulation of the complement AP was confirmed in this patient with the identification of three separate overactivation factors: C3NeF, anti-CFH autoantibodies, and heterozygous mutations I398L in the CFI gene. In this case, the pathologic pattern evolved into a C3GN pattern overtime. C3GN presentation as atypical PSGN is not unusual, especially in children. It was reported in 57 % of children with DDD in the Nasr cohort [14] and in three cases out of 18 in the Nicolas pediatric C3G cohort [15]. These data highlight that investigations of the complement AP have to be done in atypical PSGN patients to detect congenital or acquired regulation dysfunction. To our knowledge, this is the only case of C3GN with three combined abnormalities in the regulation of the complement alternative pathway reported in the literature. C3NeF is a C3 convertase-stabilizing IgG autoantibody. It is found in approximately 40 % of patients with C3GN, implying a pathogenic role [4], although it is also present in healthy individuals [2, 9]. It leads to C3 consumption and hypocomplementemia in patients with C3GN. Anti-CFH is an autoantibody directed again CFH, a complement regulating protein important for both fluid phase and cellular membrane protection against complement activation [2]. CFI is a serine protease that inactivates C3b, preventing its activation in C3 convertase [1]. CFI heterozygous mutation (I398L) has been reported in aHUS [16] and type 1 MPGN [9] patients and has been associated with quantitative FI deficiency. The relative contribution of each factor in the overactivation of the complement AP in this patient is not clear. Treatment with the anti-B-lymphocyte agent (rituximab) was used in an attempt to decrease production of C3NeF and antiCFH autoantibodies. Anti-CFH titers decreased without any improvement in the level of proteinuria. C3NeF remained positive during the follow-up period. The combination of mycophenolate and corticosteroids was also administered, as a potential benefit was suggested in prior short-term studies [17, 18]. These nonspecific agents were unsuccessful in decreasing our patient’s proteinuria. Eculizumab was initiated due to the presence of a nephrotic-range proteinuria, persistence of glomerular lesion activity, and the bad prognosis of the disease. The evolution of proteinuria correlated with eculizumab use, showing a significant decrease and subsequent increase upon withdrawal, and another decrease after it was resumed (Fig. 1). In addition to proteinuria, the changes noted histopathologically support a favorable response to eculizumab (Fig. 2). Importantly, no adverse effect of eculizumab was noted in our case. It is likely that the relatively short disease duration and initially elevated sC5b-9 level were important predictors of response to eculizumab in our patient. In our opinion, the
Pediatr Nephrol (2015) 30:1033–1037
decision to use eculizumab should include these considerations. The optimal duration of eculizumab treatment is still unknown.
Conclusions Our observation suggests that investigations of the complement AP in order to detect congenital or acquired regulation dysfunction are very important in managing atypical PSGN patients. Complement targeted therapy with eculizumab may be a valuable treatment option to reduce proteinuria and glomerular lesions in C3G steroid-resistant patients.
1037
8.
9.
10. 11.
12.
References 13. 1. Pickering MC, D’Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079–1089 2. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, Cramer C, Nester CM, Smith RJ (2011) Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 6:1009–1017 3. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D’Agati VD, Canetta PA, Radhakrishnan J, Appel GB (2012) Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 7:748– 756 4. Daina E, Noris M, Remuzzi G (2012) Eculizumab in a patient with dense-deposit disease. New Engl J Med 366:1161–1163 5. Vivarelli M, Pasini A, Emma F (2012) Eculizumab for the treatment of dense-deposit disease. New Eng J Med 366:1163–1165 6. Rousset-Rouviere C, Cailliez M, Garaix F, Bruno D, Laurent D, Tsimaratos M (2014) Rituximab fails where eculizumab restores renal function in C3nef-related DDD. Pediatr Nephrol 29:1107–1111 7. Hegasy GA, Manuelian T, Hogasen K, Jansen JH, Zipfel PF (2002) The molecular basis for hereditary porcine membranoproliferative
14.
15.
16.
17.
18.
glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am J Pathol 161:2027–2034 Hogasen K, Jansen JH, Mollnes TE, Hovdenes J, Harboe M (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J Clin Invest 95:1054–1061 Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, DragonDurey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464 Sethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis–a new look at an old entity. New Engl J Med 366:1119–1131 Gurkan S, Fyfe B, Weiss L, Xiao X, Zhang Y, Smith RJ (2013) Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol 28:1975–1981 Herlitz LC, Bomback AS, Markowitz GS, Stokes MB, Smith RN, Colvin RB, Appel GB, D’Agati VD (2012) Pathology after eculizumab in dense deposit disease and C3 GN. J Am Soc Nephrol 23:1229–1237 Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJ (2013) Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 83:293–299 Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D'Agati VD (2009) Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 4:22–32 Nicolas C, Vuiblet V, Baudouin V, Macher MA, Vrillon I, BiebuyckGouge N, Dehennault M, Gie S, Morin D, Nivet H, Nobili F, Ulinski T, Ranchin B, Marinozzi MC, Ngo S, Fremeaux-Bacchi V, Pietrement C (2014) C3 nephritic factor associated with C3 glomerulopathy in children. Pediatr Nephrol 29:85–94 Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautes-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V (2010) Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77:339–349 Yuan M, Zou J, Zhang X, Liu H, Teng J, Zhong Y, Ding X (2010) Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis. Clin Nephrol 73:354–359 Jones G, Juszczak M, Kingdon E, Harber M, Sweny P, Burns A (2004) Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids. Nephrol Dial Transplant 19:3160–3164
BRIEF REPORT
A case of C3 glomerulonephritis successfully treated with eculizumab Alexis Payette & Natalie Patey & Marie-Agnès Dragon-Durey & Véronique Frémeaux-Bacchi & Françoise Le Deist & Anne-Laure Lapeyraque
Received: 29 August 2014 / Revised: 26 January 2015 / Accepted: 27 January 2015 / Published online: 22 March 2015 # IPNA 2015
Abstract Background C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab. Case diagnosis/treatment A 5-year-old boy who presented with proteinuria, hematuria, high ASO titers, and low C3 levels was initially diagnosed with post-streptococcal GN. His first kidney biopsy confirmed this diagnosis, but complement investigations identified three alternative pathway dysregulation factors: C3 nephritic factor, complement factor I heterozygous mutation (I398L), and anti-factor H autoantibodies (4,500 AU/ml). A second biopsy performed 11 months after initial presentation (nephrotic range proteinuria) showed a C3GN suggestive of isolated C3 deposits. A. Payette : A.99 μg/ml; Cambridge Biomedical Inc. Boston, MA, USA) after
1036
two 900 mg doses. Prednisone was stopped 30 months after eculizumab initiation. Six years after initial presentation and 3 years after eculizumab initiation, the patient has continued to be treated with a maintenance dose of 1,200 mg every 2 weeks without the use of other immunosuppressive agents. His eculizumab trough level has been within the therapeutic range (171.4 μg/l) without adverse events. Proteinuria is decreased (1.7 g/day), and his creatinine level has remained in the normal range for his age (37 μmol/l). His blood pressure has been normal under ACE inhibitor therapy. His anti-CFH levels have slightly decreased (from 2,000 UA to 1,000 UA) despite the cessation of mycophenolate and remain stable since prednisone interruption. His C3 levels remained low and C3NeF remained present. A recent, fourth kidney biopsy (KB4) showed decreased polymorphonuclear leukocyte infiltration, mesangial proliferation, and less double contours, similar to his first kidney biopsy. No chronic tubulointerstitial lesions were observed at this time of follow-up. C3 deposits were comparable to previous biopsies. Ig deposits were not present. The C5b-9 deposits were significantly decreased and had focally disappeared (Fig. 2).
Discussion C3GN is a rare form of proliferative glomerulopathy, usually diagnosed in children or young adults [1]. The usual clinical findings include proteinuria, hematuria, and rapidly progressive renal insufficiency. The prognosis is generally poor with progression to end-stage renal disease within a decade in 36– 50 % of cases [1]. There is limited evidence and no randomized trials to inform therapeutic decisions with regards to nonspecific immunomodulatory therapies in C3GN. DDD is a related but separate entity from C3GN. Both diseases are grouped under the category of “C3 glomerulopathies”. Animal models have highlighted defects in the regulation of the complement alternative pathway as the central mechanism of C3GN pathogenesis [7, 8]. Complement studies allow the identification of regulation abnormalities in most patients diagnosed with C3GN [9]. Excessive C3 activation contributes to C5 convertase and membrane attack complex formation, both of which are implicated in glomerular inflammation [10]. Eculizumab is a fully humanized monoclonal antibody that prevents cleavage of complement component C5. It is a potential therapeutic option that precisely targets the physiopathology of C3GN. Its efficacy has been reported in several cases of C3GN, notably in patients with elevated sC5b-9 levels [3, 4, 6, 11, 12]. We present a case of initial PSGN with persistent hematuria and proteinuria suggesting the diagnosis of atypical post-infectious glomerulonephritis (atypical PSGN)
Pediatr Nephrol (2015) 30:1033–1037
as described by Sethi et al. [13]. The defect of the regulation of the complement AP was confirmed in this patient with the identification of three separate overactivation factors: C3NeF, anti-CFH autoantibodies, and heterozygous mutations I398L in the CFI gene. In this case, the pathologic pattern evolved into a C3GN pattern overtime. C3GN presentation as atypical PSGN is not unusual, especially in children. It was reported in 57 % of children with DDD in the Nasr cohort [14] and in three cases out of 18 in the Nicolas pediatric C3G cohort [15]. These data highlight that investigations of the complement AP have to be done in atypical PSGN patients to detect congenital or acquired regulation dysfunction. To our knowledge, this is the only case of C3GN with three combined abnormalities in the regulation of the complement alternative pathway reported in the literature. C3NeF is a C3 convertase-stabilizing IgG autoantibody. It is found in approximately 40 % of patients with C3GN, implying a pathogenic role [4], although it is also present in healthy individuals [2, 9]. It leads to C3 consumption and hypocomplementemia in patients with C3GN. Anti-CFH is an autoantibody directed again CFH, a complement regulating protein important for both fluid phase and cellular membrane protection against complement activation [2]. CFI is a serine protease that inactivates C3b, preventing its activation in C3 convertase [1]. CFI heterozygous mutation (I398L) has been reported in aHUS [16] and type 1 MPGN [9] patients and has been associated with quantitative FI deficiency. The relative contribution of each factor in the overactivation of the complement AP in this patient is not clear. Treatment with the anti-B-lymphocyte agent (rituximab) was used in an attempt to decrease production of C3NeF and antiCFH autoantibodies. Anti-CFH titers decreased without any improvement in the level of proteinuria. C3NeF remained positive during the follow-up period. The combination of mycophenolate and corticosteroids was also administered, as a potential benefit was suggested in prior short-term studies [17, 18]. These nonspecific agents were unsuccessful in decreasing our patient’s proteinuria. Eculizumab was initiated due to the presence of a nephrotic-range proteinuria, persistence of glomerular lesion activity, and the bad prognosis of the disease. The evolution of proteinuria correlated with eculizumab use, showing a significant decrease and subsequent increase upon withdrawal, and another decrease after it was resumed (Fig. 1). In addition to proteinuria, the changes noted histopathologically support a favorable response to eculizumab (Fig. 2). Importantly, no adverse effect of eculizumab was noted in our case. It is likely that the relatively short disease duration and initially elevated sC5b-9 level were important predictors of response to eculizumab in our patient. In our opinion, the
Pediatr Nephrol (2015) 30:1033–1037
decision to use eculizumab should include these considerations. The optimal duration of eculizumab treatment is still unknown.
Conclusions Our observation suggests that investigations of the complement AP in order to detect congenital or acquired regulation dysfunction are very important in managing atypical PSGN patients. Complement targeted therapy with eculizumab may be a valuable treatment option to reduce proteinuria and glomerular lesions in C3G steroid-resistant patients.
1037
8.
9.
10. 11.
12.
References 13. 1. Pickering MC, D’Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Fremeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodriguez de Cordoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079–1089 2. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, Cramer C, Nester CM, Smith RJ (2011) Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 6:1009–1017 3. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D’Agati VD, Canetta PA, Radhakrishnan J, Appel GB (2012) Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 7:748– 756 4. Daina E, Noris M, Remuzzi G (2012) Eculizumab in a patient with dense-deposit disease. New Engl J Med 366:1161–1163 5. Vivarelli M, Pasini A, Emma F (2012) Eculizumab for the treatment of dense-deposit disease. New Eng J Med 366:1163–1165 6. Rousset-Rouviere C, Cailliez M, Garaix F, Bruno D, Laurent D, Tsimaratos M (2014) Rituximab fails where eculizumab restores renal function in C3nef-related DDD. Pediatr Nephrol 29:1107–1111 7. Hegasy GA, Manuelian T, Hogasen K, Jansen JH, Zipfel PF (2002) The molecular basis for hereditary porcine membranoproliferative
14.
15.
16.
17.
18.
glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am J Pathol 161:2027–2034 Hogasen K, Jansen JH, Mollnes TE, Hovdenes J, Harboe M (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J Clin Invest 95:1054–1061 Servais A, Noel LH, Roumenina LT, Le Quintrec M, Ngo S, DragonDurey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grunfeld JP, Niaudet P, Lesavre P, Fremeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464 Sethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis–a new look at an old entity. New Engl J Med 366:1119–1131 Gurkan S, Fyfe B, Weiss L, Xiao X, Zhang Y, Smith RJ (2013) Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol 28:1975–1981 Herlitz LC, Bomback AS, Markowitz GS, Stokes MB, Smith RN, Colvin RB, Appel GB, D’Agati VD (2012) Pathology after eculizumab in dense deposit disease and C3 GN. J Am Soc Nephrol 23:1229–1237 Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJ (2013) Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 83:293–299 Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D'Agati VD (2009) Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 4:22–32 Nicolas C, Vuiblet V, Baudouin V, Macher MA, Vrillon I, BiebuyckGouge N, Dehennault M, Gie S, Morin D, Nivet H, Nobili F, Ulinski T, Ranchin B, Marinozzi MC, Ngo S, Fremeaux-Bacchi V, Pietrement C (2014) C3 nephritic factor associated with C3 glomerulopathy in children. Pediatr Nephrol 29:85–94 Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautes-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V (2010) Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77:339–349 Yuan M, Zou J, Zhang X, Liu H, Teng J, Zhong Y, Ding X (2010) Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis. Clin Nephrol 73:354–359 Jones G, Juszczak M, Kingdon E, Harber M, Sweny P, Burns A (2004) Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids. Nephrol Dial Transplant 19:3160–3164
