Effectiveness of mycophenolate mofetil in C3 glomerulonephritis
2015; Elsevier BV; Volume: 88; Issue: 5 Linguagem: Inglês
10.1038/ki.2015.227
ISSN1523-1755
AutoresCristina Rabasco, Teresa Cavero, Elena Román, Jorge Rojas-Rivera, Teresa Olea, Mario Espinosa, Virginia Cabello, Gema Fernández‐Juárez, Fayna González, Ana Ávila, José María Baltar, Montserrat Díaz, Raquel Alegre, Sandra Elías, Monserrat Antón, M.Á. Frutos, A Pobes, Miguel Blasco, F. García Martín, Carmen Bernis, Manuel Macías, Sérgio Barroso, Alberto de Lorenzo, Gema Ariceta, Manuel López‐Mendoza, Begoña Rivas, Katia López-Revuelta, Josep M. Campistol, Santiago Mendizábal, Santiago Rodrı́guez de Córdoba, Manuel Praga,
Tópico(s)Platelet Disorders and Treatments
ResumoC3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing endstage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis. C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing endstage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis. C3 glomerulonephritis (C3GN) is a recently defined pathological entity characterized by the finding of glomerular lesions with bright C3 staining on immunofluorescence (IF) microscopy.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 2.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 3.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4.Servais A. Frémeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Gen. 2007; 44: 193-199Crossref PubMed Scopus (239) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 7.Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 Glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Original reports included only cases with strong C3 deposits and a complete absence of immunoglobulins or other complement components on IF staining, but more recent studies have proposed the inclusion of cases with mild deposits of immunoglobulins, provided the existence of dominant deposits of C3 of at least two orders of magnitude more intense than any other immune reactant.5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 7.Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 Glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar C3GN should be differentiated from dense deposit disease (DDD), another glomerulonephritis also characterized by the presence of bright, predominant staining of C3 on IF but showing in addition a peculiar type of dark, ribbon-like osmiophilic deposits within the glomerular basement membrane.5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 8.Appel G.B. Cook H.T. Hageman G. et al.Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.J Am Soc. Nephrol. 2005; 16: 1392-1403Crossref PubMed Scopus (313) Google Scholar, 9.Barbour T.D. Pickering M.C. Cook H.T. Dense deposit disease and C3 glomerulopathy.Semin Nephrol. 2013; 33: 493-507Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Deposits in C3GN are less electron-dense and less well defined than in DDD.5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar Both C3GN and DDD are considered to be different expressions of C3 glomerulopathy, which is defined as a glomerular pathology with C3 accumulation and absent or scanty immunoglobulin deposition.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar Membranoproliferative glomerulonephritis is the most common pathological lesion in C3GN1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 2.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 3.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4.Servais A. Frémeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Gen. 2007; 44: 193-199Crossref PubMed Scopus (239) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 7.Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 Glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar but other patterns of glomerular damage have been reported, including mesangioproliferative GN, diffuse endocapillary proliferative GN, focal segmental glomerulosclerosis, and crescentic GN.5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 10.Sethi S. Fervenza F.C. Zhang Y. et al.Atypical postinfectious glomerulonephritis in associated with abnormalities in the alternative. pathway of complement.Kidney Int. 2012; 83: 293-299Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 11.Fervenza F.C. Smith R.J. Sethi S. Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis.Am J Kidney Dis. 2012; 60: 126-132Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12.Sethi S. Fervenza F.C. Zhang Y. Smith R.J. Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in 30. the genes encoding complement factor H and C3.Am J Kidney Dis. 2012; 60: 316-321Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 13.Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google Scholar The pathogenesis of C3 GN relies on an abnormal activation of the alternative complement pathway. In some patients, this complement hyperactivation is caused by genetic abnormalities in the genes coding for complement activating proteins (C3, complement factor B) or regulatory proteins (complement factor H and factor I, CD46).1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 2.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 3.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4.Servais A. Frémeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Gen. 2007; 44: 193-199Crossref PubMed Scopus (239) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 7.Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 Glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar The important role of abnormalities in complement Factor H-related proteins has been demonstrated by several studies.13.Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google Scholar, 14.Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 15.Tortajada A. Yebenes H. Abarrategui-Garrido C. et al.C3 glomerulopathy associated CFHR1 mutation alters FHR oligomerization and complement regulation.J Clin Invest. 2013; 123: 2434-2446Crossref PubMed Scopus (149) Google Scholar, 16.Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. Nephrol Dial Transplant 2014 pii: gfu317. [Epub ahead of print].Google Scholar In other cases, complement dysregulation is caused by autoantibodies directed against complement regulatory proteins, such as complement factors B and I, or C3 nephritic factor (C3NeF). C3NeF, the first reported autoantibody involved in complement dysregulation, stabilizes the alternative pathway C3 convertase (C3bBb) preventing the inhibitory effect of Factor H5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 17.Paixão-Cavalcante D. López-Trascasa M. Skattum L. et al.Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation.Kidney Int. 2012; 82: 1084-1092Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 18.Servais A. Noel L.H. Roumenin L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 19.Barbour T.D. Pickering M.C. Cook H.T. Recent insights into C3 glomerulopathy.Nephrol Dial Transplant. 2013; 28: 1685-1693Crossref PubMed Scopus (67) Google Scholar and has been found in almost half of C3GN patients.18.Servais A. Noel L.H. Roumenin L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar Notably, the spectrum of genetic mutations and acquired autoantibodies reported in C3GN is very similar to that described in atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy due to abnormal hyperactivity of the alternative pathway of complement.20.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar The pathogenesis of atypical hemolytic uremic syndrome consists of an excessive complement activation in the endothelial cell surfaces, inducing the typical lesions of thrombotic microangiopathy, whereas complement activation in C3GN is thought to occur in the fluid phase, leading to the deposition of complement fragments in the glomerular basement membranes.3.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar Clinical manifestations of C3GN are remarkably variable, oscillating between minor persistent urinary abnormalities and nephrotic or nephritic syndromes with varying degrees of renal impairment.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 2.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 3.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4.Servais A. Frémeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Gen. 2007; 44: 193-199Crossref PubMed Scopus (239) Google Scholar, 5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 21.Medjeral-Thomas N.R. O’Shaughnessy M.M. O’Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53Crossref PubMed Scopus (143) Google Scholar This clinical heterogeneity, together with the scarcity of published studies, hinders a reliable evaluation of attempted treatments for the disease. Eculizumab, a monoclonal antibody directed against complement component C5 and whose efficacy in atypical hemolytic uremic syndrome patients has been demonstrated by prospective studies,22.Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (999) Google Scholar has been tried in a number of C3GN patients with discordant results.23.Bomback A.S. Smith R.J. Barile G.R. et al.Eculizumab for dense deposit disease and C3 glomerulonephritis.Clin J Am Soc Nephrol. 2012; 7: 748-756Crossref PubMed Scopus (253) Google Scholar, 24.Gurkan S. Fyfe B. Weiss L. et al.Eculizumab and recurrent C3 glomerulonephritis.Pediatr Nephrol. 2013; 28: 1975-1981Crossref PubMed Scopus (65) Google Scholar, 25.Le Quintrec M. Lionet A. Kandel C. et al.Eculizumab for treatment of rapidly progressive C3 glomerulopathy.Am J Kidney Dis. 2015; 65: 484-489Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 26.Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (390) Google Scholar, 27.Nester C.M. Smith R.J. Treatment options for C3 glomerulopathy.CurrOpin Nephrol Hypertens. 2013; 22: 231-237Crossref PubMed Scopus (46) Google Scholar Conventional immunosuppression (corticosteroids, cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), and rituximab) is generally deemed ineffective in C3GN, but this assertion is based on a limited number of case reports and short series of patients.5.Pickering M.C. D’Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 6.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (116) Google Scholar, 18.Servais A. Noel L.H. Roumenin L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar, 19.Barbour T.D. Pickering M.C. Cook H.T. Recent insights into C3 glomerulopathy.Nephrol Dial Transplant. 2013; 28: 1685-1693Crossref PubMed Scopus (67) Google Scholar, 21.Medjeral-Thomas N.R. O’Shaughnessy M.M. O’Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53Crossref PubMed Scopus (143) Google Scholar, 26.Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (390) Google Scholar, 27.Nester C.M. Smith R.J. Treatment options for C3 glomerulopathy.CurrOpin Nephrol Hypertens. 2013; 22: 231-237Crossref PubMed Scopus (46) Google Scholar To provide more valuable information on the role of immunosuppressive treatments (1ST) in C3GN, we designed a collaborative study of the Spanish Group for the Study of Glomerular Diseases (GLOSEN) to recruit patients with biopsy-proven C3GN. The main objectives of the study were to evaluate the response to 1ST and to analyze the long-term influence of treatment on renal survival. Sixty patients, who had been regularly visited after diagnosis, were finally collected among 21 participating departments. Patients were divided into two groups, one including those cases who had received any type of 1ST during their follow-up (1ST, n=40) and those who had not received 1ST (non-IST, n=20). 1ST patients were subclassified into two groups, those who had been treated with MMF-based IST (MMF-IST, n=22) and those who had received IST other than MMF (other-IST, n=18). The main baseline clinical and analytical characteristics of the patients are shown in Table 1. There were no significant differences regarding age, gender, proportion of diabetic or hypertensive patients, and renal function between non-IST and IST patients. IST patients showed significantly higher proteinuria and lower serum albumin at baseline than nonIST patients, and the proportion of patients showing C3 hypocomplementemia was significantly higher in the former. A family history of kidney disease was identified in four patients (6%) (two patients in the 1ST group and two in the non-IST group), but renal biopsies were not performed in affected relatives. Monoclonal gammopathy was detected in three patients (5%) (one patient in the IST group and two in the non-IST group). Among IST patients, there were no significant differences in baseline characteristics between MMF-IST and other-IST subgroups of patients.Table 1Characteristics of patients at baseline and clinical presentationAll patients (n=60)Non-IST (n=20)IST (n=40)P-valueaDifferences between non-IST and 1ST groups.MMF-IST (n=22)Other-IST (n =18)P-valuebDifferences between MMF-IST and other-IST groups.Age (years)cMedian (25th-75th percentile).27 (13–57)29 (18–49)24 (12–62)0.59435 (13–66)18 (10–41)0.109Gender, no. (%), male34 (57)14 (70)20 (50)0.17414 (64)6 (33)0.111Hypertension, no. (%)27 (45)11 (55)16 (40)0.2889 (41)7 (39)1.0Clinical presentation, no. (%)<0.0010.126Nephrotic syndrome31 (52)4 (20)27 (67)17(77)10 (55)Nephritic syndrome19 (32)7 (35)12 (30)4 (18)8 (44)Asymptomatic urinary abnormalities10 (17)9 (45)1 (2)1 (4)0 (0.0)SCr (mg/dl)cMedian (25th-75th percentile).1.4 (0.7–2.8)1.3 (0.8–2.0)1.4 (0.7–2.9)0.7721.3 (0.6–2.9)1.6 (0.8–2.9)0.838eGFR (ml/min per 1.73 m2)cMedian (25th-75th percentile).66 (25–104)65 (34–96)66 (24–113)0.96367 (23–119)66 (26–112)0.870Proteinuria (g/24 h)cMedian (25th-75th percentile).3.8 (1.4–7.0)1.4 (0.9–3.1)5.2 (3.4–7.4)0.0016.5 (3.9–8.6)4.3 (1.5–5.6)0.099Serum albumin (g/dl)cMedian (25th-75th percentile).3 (2.6–3.5)3.6 (2.9–4.3)2.8 (2.4–3.1)<0.0012.8 (2.1–3.1)2.9 (2.5–3.1)0.340Hypocomplementemia C3, no. (%)38 (63)8 (40)29 (72)0.02415 (68)14 (78)0.723Follow-up (months)cMedian (25th-75th percentile).47 (16–93)38 (11–136)50 (20–77)0.60544 (22–66)54 (13–78)0.744Abbreviations: eGFR, estimated glomerular filtration rate; 1ST, immunosuppressive treatments; MMF, mycophenolate mofetil; SCr, serum creatinine.a Differences between non-IST and 1ST groups.b Differences between MMF-IST and other-IST groups.c Median (25th-75th percentile). Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; 1ST, immunosuppressive treatments; MMF, mycophenolate mofetil; SCr, serum creatinine. As shown in Table 1, nephrotic syndrome was the most common type of presentation (52%), followed by nephritic syndrome (32%) and asymptomatic urinary abnormalities (17%). As compared with non-IST patients, IST patients showed a significantly higher proportion of nephrotic syndrome and a lower proportion of asymptomatic urinary abnormalities. No significant differences in the type of clinical presentation between MMF-IST and other-IST were observed, although there was a tendency toward a higher proportion of nephrotic syndrome and lower proportion of nephritic syndrome among MMF-IST patients. The median follow-up was 47 (16–93) months. There were no differences in the length of follow-up between non-IST and IST patients, or between MMF-IST and other-IST (Table 1). The histopathological findings are summarized in Table 2. Membranoproliferative glomerulonephritis was the predominant pattern of glomerular injury (n=45, 75%). In the remaining patients, various patterns of glomerular lesions were observed, including mesangial GN (n=9), endothelial proliferative GN (n=4), focal and segmental glomerulosclerosis (n=1), and crescentic GN (n=1). By definition, IF studies were performed in all renal biopsies, showing strong, isolated C3 deposits (n=35) or dominant C3 deposits accompanied by weak deposits of immunoglobulins (n=25). No patient showed the typical dark, osmiophilic, ribbon-like, deposits characteristics of DDD on electron microscopy.Table 2Histopathological findingsAll patients (n=60)Non-IST (n=20)IST (n=40)P -valueaDifferences between non-IST and IST groups.MMF-IST (n=22)Other-IST (n =18)P-valuebDifferences between MMF-IST and other-IST groups.Pattern of glomerular injury, no. (%)1.0001.000 MPGN45 (75)15 (75)30 (75)16(73)14 (78) Others15 (25)5 (25)10 (25)6 (27)4 (22)Glomerulosclerosis, no. (°%)0.8060.209 None25 (42)7 (35)18 (45)9 (41)9 (50) 503 (5)1 (5)2 (5)0 (0)2 (11)Interstitial fibrosis, no. (°%)0.0530.845 None23 (38)6 (30)17 (42)9 (41)8 (44) Mild16(27)8 (40)8 (20)4 (18)4 (22) Moderate19 (32)4 (20)15 (38)9 (41)6 (33) Severe2 (3)2 (10)00 (0)0 (0)Abbreviations: IST, immunosuppressive treatments; MMF, mycophenolate mofetil; MPGN, membranoproliferative glomerulonephritis.a Differences between non-IST and IST groups.b Differences between MMF-IST and other-IST groups. Open table in a new tab Abbreviations: IST, immunosuppressive treatments; MMF, mycophenolate mofetil; MPGN, membranoproliferative glomerulonephritis. As shown in Table 2, there were no significant differences in the type of glomerular lesions or in the degree of global glomerulosclerosis or tubulointerstitial fibrosis between the groups. As shown in Table 3, 10 patients (17%) developed end-stage renal disease (ESRD). The number of non-IST patients reaching ESRD (n=7, 35%) was significantly higher than that of IST patients (n=3, 7%; P=0.012). Among IST patients, no patient in the MMF-IST group developed ESRD, as compared with 3 (17%) in the other-IST patients (P=0.083). Fourteen patients (23%) doubled baseline serum creatinine. There was a tendency toward a higher number of patients doubling serum creatinine in non-IST patients (n=7, 35%) than in IST patients (n=7, 17%), but this difference did not reach statistical significance. No patient in the MMF-IST group showed doubling of serum creatinine, as compared with seven patients (39%) in the other-IST group (P=0.002).Table 3OutcomesAll patients (n=60)Non-IST (n=20)IST (n=40)P-valueaDifferences between non-IST and 1ST groups.MMF-IST (n=22)Other-IST (n =18)P-valuebDifferences between MMF-IST and other-IST groups.Primary outcome ESRD, no. (%)10 (17)7 (35)3 (7)0.0120 (0)3 (16)0.083Secondary outcomes Clinical remission, no. (%)33 (55)5 (25)28 (70)0.00219 (86)9 (50)0.018CR13 (39)2 (40)11 (39)6 (32)5 (56)PR20 (61)3 (60)17 (61)13 (68)4 (44) Doubling SCr, no. (%)14 (23)7 (35)7(17)0.1950 (0)7 (39)0.002Abbreviations: CR, complete remission; ESRD, end-stage renal disease; 1ST, immunosuppressive treatments; MMF, mycophenolate mofetil; PR, partial remission; SCr, serum creatinine.a Differences between non-IST and 1ST groups.b Differences between MMF-IST and other-IST groups. Open table in a new tab Abbreviations: CR, complete remission; ESRD, end-stage renal disease; 1ST, immunosuppressive treatments; MMF, mycophenolate mofetil; PR, partial remission; SCr, serum creatinine. The probability of renal survival, defined by a status free of ESRD, was significantly better in MMF-IST patients (100%), as compared with other-IST (87, 87, and 80% at 1, 3, and 5 years, respectively) and non-IST patients (88, 80, and 72% at 1, 3, and 5 years, respectively) (Figure 1). Clinical remission was observed in 33 patients (55%). Of them, 13 showed complete remission (CR) (39%) and 20 partial remission (PR) (61%). As shown in Table 3, the number of remissions, either CR or PR, was significantly higher in IST as compared with non-IST (70 vs. 25%; P=0.002
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