C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy

C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease. C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease. The term “C3 glomerulopathy” (C3G) denotes a glomerulonephritis with isolated or dominant C3 staining that implies an etiology rooted in dysregulation of the alternative complement pathway.1Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (267) Google Scholar This umbrella term encompasses both dense deposit disease (DDD, formerly known as membranoproliferative glomerulonephritis [MPGN] type 2) and C3 glomerulonephritis (C3GN, formerly known as MPGN type 1 or type 3 with isolated C3 staining). A genetic or acquired defect arising from rare genetic variants or autoantibodies that modulate activation of the C3 convertase of the alternative complement pathway can lead to a transformation from low-grade physiologic activity to unrestrained hyperactivity. This loss of alternative pathway control can result in a glomerulonephritis that on immunofluorescence stains only or dominantly for C3, consistent with mediation by deposition of complement proteins rather than immune complexes. The natural history of C3G, a rare disease with a reported incidence between 1 and 3 per million, is slowly being defined, and the heterogeneity among those diagnosed with C3G is striking. The clinical presentation can vary from asymptomatic hematuria and proteinuria with preserved renal function to the full nephrotic syndrome or a rapidly progressive glomerulonephritis.2Servais A. Noël L.H. Roumenina 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 (374) Google Scholar, 3Medjeral-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 (146) Google Scholar The most common histologic finding on light microcopy is membranoproliferative glomerulonephritis, although similar C3-dominant staining and deposits (presumably of complement components) in the mesangial, subepithelial, subendothelial, and intramembranous regions of the glomerulus have also been demonstrated in patients with mesangial proliferative or diffuse endocapillary proliferative patterns.4Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (117) Google Scholar, 5D'Agati V.D. Bomback A.S. C3 glomerulopathy: what's in a name?.Kidney Int. 2012; 82: 379-381Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 6Hou 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 (125) Google Scholar Progression to end-stage renal disease (ESRD) has been reported in up to 50% of patients within the first 5 years of diagnosis, with DDD patients reportedly progressing at twice the rate of C3GN patients.2Servais A. Noël L.H. Roumenina 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 (374) Google Scholar, 3Medjeral-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 (146) Google Scholar, 7Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (154) Google Scholar To date, the largest cohorts of C3G have emerged from centers in Japan,8Okuda Y. Ishikura K. Hamada R. et al.Membranoproliferative glomerulonephritis and C3 glomerulonephritis: frequency, clinical features, and outcome in children.Nephrology (Carlton). 2015; 20: 286-292Crossref PubMed Scopus (15) Google Scholar the United Kingdom,3Medjeral-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 (146) Google Scholar Spain,9Rabasco C. Cavero T. Román E. et al.Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.Kidney Int. 2015; 88: 1153-1160Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Turkey,10Caliskan Y. Torun E.S. Tiryaki T.O. et al.Immunosuppressive treatment in C3 glomerulopathy: is it really effective?.Am J Nephrol. 2017; 46: 96-107Crossref PubMed Scopus (26) Google Scholar Italy,11Iatropoulos P. Noris M. Mele C. et al.Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.Mol Immunol. 2016; 71: 131-142Crossref PubMed Scopus (93) Google Scholar and France.2Servais A. Noël L.H. Roumenina 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 (374) Google Scholar These reports have helped shape our current understanding of the natural history of C3G, but their generalizability to an ethnically diverse patient population in the United States remains unclear. In addition, these prior cohorts have often focused on either pediatric or adult populations, without taking into account the long disease course of many patients. Here, we present data on 111 pediatric and adult patients with C3G evaluated at the Center for Glomerular Diseases at Columbia University. This represents not only the largest C3G patient cohort in the United States but also the largest single-center experience reported worldwide. The cohort consisted of 111 patients, 87 with C3GN and 24 with DDD (Table 1). Patients with C3GN (mean age 28.3 years) were significantly younger than patients with DDD (mean age 40.0 years), with 36.8% of the C3GN subcohort considered pediatric (under 18 years) at the time of diagnosis versus 12.5% of the DDD subcohort. While whites comprised the majority (65%) of patients, Hispanic, Asian, and African-American patients accounted for 19%, 10%, and 5% of the cohort, respectively. The most common clinical presentation was hematuria and proteinuria with preserved kidney function, although about one-quarter of the patients presented with significant chronic kidney disease (CKD) at the time of diagnosis, as seen in the median and interquartile range of creatinine values at the time of diagnosis across the cohort (1.3 mg/dl, 0.8–2.0 mg/dl). Creatinine values appeared similar between patients with C3GN and DDD, but due to the significant age difference in the subcohorts, the mean estimated glomerular filtration rate (eGFR), by both MDRD and CKD-EPI estimating equations, was higher in C3GN patients than DDD patients. The average proteinuria was 3.9 g/d for the entire cohort, but patients with C3GN were more likely than patients with DDD to present with full nephrotic syndrome.Table 1Baseline clinical data of C3 glomerulopathy cohortCharacteristicC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Age at diagnosis (yr)28.340.00.03Age groups (%)0.05 <18 years36.812.5 18–50 years47.158.3 >50 years16.129.2Male/female (%)63.2/36.866.7/33.30.8Race/ethnicity (%)0.9 White63.270.8 Hispanic19.516.7 Asian12.68.3 African-American4.64.2Presentation (%)0.05 Hematuria and proteinuria, preserved eGFR40.741.7 Nephrotic syndrome32.616.7 AKI/RPGN8.10 CKD with hematuria and proteinuria18.641.7Antecedent infection (%)18.416.70.8Creatinine at diagnosis (mg/dl)2.02.10.9eGFR at diagnosis (ml/min per 1.73 m2) MDRD (4-variable) formula72.655.30.1 CKD-EPI formula75.758.80.1Proteinuria at diagnosis (mg/g or mg/d)377744100.5Low C3 at diagnosis (%)64.963.60.9Low C4 at diagnosis (%)13.913.61.0Complement factor gene variant (C3, CFH, CFI, CFB, CFHR5, MCP) identified (%)bTesting for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.21.4 (9 of 42)33.3 (3 of 9)0.5Complement auto-antibody (C3Nef, factor H Ab, factor B Ab) identified (%)bTesting for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.38.1 (16 of 42)22.2 (2 of 9)0.4Paraprotein detected in serum and/or urine (%)cTesting for paraproteins in serum and/or urine was performed on a subset of patients in the cohort (N = 38).25.0 (6 of 24)57.1 (8 of 14)0.05AKI, acute kidney injury; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; RPGN, rapidly progressive glomerulonephritis.Categorical variables are presented as percentage of total group; continuous variables are presented as mean value.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.b Testing for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.c Testing for paraproteins in serum and/or urine was performed on a subset of patients in the cohort (N = 38). Open table in a new tab AKI, acute kidney injury; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; RPGN, rapidly progressive glomerulonephritis. Categorical variables are presented as percentage of total group; continuous variables are presented as mean value. The prevalence of low complement levels was equal in C3GN and DDD patients, and we did not detect a difference in the rates of complement-associated gene variants or autoantibodies in the subgroup of patients (n = 51) for whom such testing was available (Supplementary Table S1). Pediatric patients demonstrated a significantly higher prevalence of low C3 levels (83.3%) compared with adult patients (56.5%, P = 0.01 for comparison) and demonstrated about twice the rate of detectable genetic variants and/or autoantibodies (24% vs. 13%), although this did not meet statistical significance (P = 0.2 for comparison). Rates of antecedent infections, defined as self-reported infectious illness (viral or bacterial) in the 3 months prior to C3G diagnosis, did not differ between adult (17%) and pediatric (21%) patients. We did, however, find more than twice the prevalence of monoclonal paraproteins (57% vs. 25%) in DDD patients compared with C3GN patients in those tested for dysproteinemias. The median (interquartile range) age in these 14 patients with detectable paraproteins was 53 (43–64) years, and 4 such patients had autoantibodies directed at the alternative complement pathway (2 with C3 nephritic factor and 2 with anti-Factor H). Biopsy materials (glass slides, immunofluorescence images, and electron microscopy scans) were available in 66 of the 111 cases for central re-review at Columbia University Medical Center; in the remaining 45 cases, histopathology data were extracted from the original biopsy reports (Table 2). The most common pattern on light microscopy was MPGN. In both the entire cohort and the subcohort with original biopsy materials re-reviewed, patients with DDD were more likely to have a diffuse sclerosing pattern on light microscopy. There was a trend toward greater likelihood of C3-alone staining (vs. C3-dominant staining) on immunofluorescence in DDD patients versus C3GN patients in both the entire cohort and the subcohort, although this did not reach statistical significance.Table 2Histopathology of entire C3 glomerulopathy cohort (N = 111) and subcohort with biopsy re-read at Columbia University Medical Center (N = 66)(A) Entire cohortC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Light microscopy pattern (%)0.2 MPGN68.845.8 Mesangial proliferative GN17.529.2 Diffuse endocapillary proliferative GN8.812.5 Diffuse sclerosing GN5.012.5Tubular atrophy/interstitial fibrosis (estimated %)28.423.40.4Cellular or fibrocellular crescents, any identified (%)10.316.70.4Immunofluorescence (%)0.3 C3 alone46.861.9 C3 dominant (with trace or 1+ Ig)53.238.1(B) CUMC subcohortC3GN (n = 46)DDD (n = 20)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Light microscopy pattern (%)0.1 MPGN60.935.0 Mesangial proliferative GN17.435.0 Diffuse endocapillary proliferative GN13.015.0 Diffuse sclerosing GN8.715.0Globally sclerotic glomeruli (calculated %)20.332.50.08Segmentally sclerotic glomeruli (calculated %)13.927.10.04Exudative features (%)23.915.00.4Cellular or fibrocellular crescents, any identified (%)17.410.00.4Tubular atrophy/interstitial fibrosis (estimated %)23.531.80.2Immunofluorescence (%)0.2 C3 alone39.155.0 C3 dominant (with trace or 1+ Ig)60.945.0C3GN, C3 glomerulonephritis; CUMC, Columbia University Medical Center; DDD, dense deposit disease; GN, glomerulonephritis; MPGN, membranoproliferative glomerulonephritis.Data presented are percentage of total groups, unless otherwise noted as mean estimated or calculated percentages of sampled glomeruli or tubulointerstitial area.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables. Open table in a new tab C3GN, C3 glomerulonephritis; CUMC, Columbia University Medical Center; DDD, dense deposit disease; GN, glomerulonephritis; MPGN, membranoproliferative glomerulonephritis. Data presented are percentage of total groups, unless otherwise noted as mean estimated or calculated percentages of sampled glomeruli or tubulointerstitial area. We subsequently used original biopsy material to develop a C3G histologic index for the degree of disease activity and chronicity (Table 3). A semiquantitative scale of 0 to 3 was used for 7 markers of activity, allowing for an activity score of 0 to 21. For a chronicity score, ranging from 0 to 10, we used a semiquantitative scale of 0 to 3 for glomerulosclerosis, tubular atrophy, and interstitial fibrosis, and a scale of 0 to 1 for severity of arteriosclerosis. There were no statistically significant differences detected in any of the parameters of activity between C3GN and DDD patients (Table 4), although there was a trend for higher total activity among patients with C3GN (average activity score 9.1 out of 21) versus patients with DDD (7.6). Patients with DDD demonstrated greater chronicity scores in all parameters evaluated compared with patients with C3GN, with total chronicity score averaging 6.0 (out of 10) compared with 4.1 (P = 0.02).Table 3C3 glomerulopathy histopathology indexComponentDefinitionScore(A) Activity score, 0–21Mesangial hypercellularity% glomeruli with >3 mesangial cells per mesangial area0 = none1 = 1%–25%2 = 26%–50%3 = >50%Endocapillary proliferation% glomeruli with an increased number of cells within glomerular capillary lumina, causing luminal narrowing0 = none1 = 1%–25%2 = 26%–50%3 = >50%Membranoproliferative morphology% glomeruli with GBM duplication with or without endocapillary proliferation0 = none1 = 1%–25%2 = 26%–50%3 = >50%Leukocyte infiltration% glomeruli with glomerular capillary infiltration by ≥3 neutrophils and/or macrophages0 = none1 = 1%–25%2 = 26%–50%3 = >50%Crescent formation% glomeruli with cellular and/or fibrocellular crescents0 = none1 = 1%–10%2 = 11%–25%3 = >25%Fibrinoid necrosis% glomeruli with presence of ≥2 of fibrin, karyorrhexis, and GBM rupture0 = none1 = 1%–10%2 = 11%–25%3 = >25%Interstitial inflammation% cortical tubulointerstitial area with inflammation in non-fibrotic cortex0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%(B) Chronicity score, 0–10Glomerulosclerosis% glomeruli with global and segmental sclerosis0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Tubular atrophy% cortical tubulointerstitial area involved with tubular atrophy0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Interstitial fibrosis% cortical tubulointerstitial area involved with interstitial fibrosis0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Arterio- and arteriolosclerosisIntimal thickening ≥ thickness of media0 = absent1 = presentGBM, glomerular basement membrane. Open table in a new tab Table 4C3 glomerulopathy (C3G) histopathology index values in the C3G cohortComponentC3GN (n = 46)DDD (n = 20)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test.(A) Activity scorebFor mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, and leukocyte infiltration, we used a scale of 0 = none, 1 = 1-25%, 2 = 26-50%, and 3 = >50% involvement of sampled glomeruli. For crescent formation and fibrinoid necrosis, we used a scale of 0 = none, 1 = 1-10%, 2 = 11-25%, and 3 = >25% involvement of sampled glomeruli. For interstitial inflammation, we used a scale of 0 = <10%, 1 = 10-25%, 2 = 26-50%, and 3 = >50% based on percentage of involved cortical tubulointerstitial area.Mesangial hypercellularity (0–3)2.72.30.06Endocapillary proliferation (0–3)1.71.30.2Membranoproliferative morphology (0–3)1.91.50.2Leukocyte infiltration (0–3)1.61.30.3Crescent formation (0–3)0.30.60.3Fibrinoid necrosis (0–3)0.20.10.7Interstitial inflammation (0–3)0.80.60.2Total Activity Score (0-21)9.17.60.1(B) Chronicity scorecGlomerulosclerosis, tubular atrophy, and interstitial fibrosis were assigned a score of 0 to 3 based on the percentage involvement (0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%). For vascular disease, we assigned 0 if intimal thickening was < thickness of media and 1 if intimal thickening was ≥ thickness of media.Global and segmental glomerulosclerosis (0–3)1.42.20.02Tubular atrophy (0–3)1.31.70.09Interstitial fibrosis (0–3)1.31.70.09Arterio- and arteriolosclerosis (0–1)0.20.50.03Total chronicity score (0–10)4.16.00.02C3GN, C3 glomerulonephritis; DDD, dense deposit disease.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test.b For mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, and leukocyte infiltration, we used a scale of 0 = none, 1 = 1-25%, 2 = 26-50%, and 3 = >50% involvement of sampled glomeruli. For crescent formation and fibrinoid necrosis, we used a scale of 0 = none, 1 = 1-10%, 2 = 11-25%, and 3 = >25% involvement of sampled glomeruli. For interstitial inflammation, we used a scale of 0 = <10%, 1 = 10-25%, 2 = 26-50%, and 3 = >50% based on percentage of involved cortical tubulointerstitial area.c Glomerulosclerosis, tubular atrophy, and interstitial fibrosis were assigned a score of 0 to 3 based on the percentage involvement (0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%). For vascular disease, we assigned 0 if intimal thickening was < thickness of media and 1 if intimal thickening was ≥ thickness of media. Open table in a new tab GBM, glomerular basement membrane. C3GN, C3 glomerulonephritis; DDD, dense deposit disease. The mean duration of follow-up was 69 months for C3GN patients and 83 months for DDD patients (P = 0.4). More than 75% of patients were treated with blockers of the renin-angiotensin-aldosterone system (RAAS). Eighty of the 111 patients were treated with at least 1 course of immunosuppression (Table 5), and there was no difference in this regard between C3GN and DDD patients (74% vs. 67% treated with immunosuppression). However, patients with C3GN vs. DDD were more likely to be treated with mycophenolate mofetil (44% vs. 17%, P = 0.02) and demonstrated a nonsignificant trend toward greater utilization of corticosteroids (70% vs. 50%, P = 0.09). Seven of the patients in the cohort received eculizumab at some point in their disease course, of which 4 progressed to ESRD and 2 progressed to CKD stage 5. Complete or partial remission occurred more often in C3GN patients (38%) vs. DDD patients (25%), although this was not statistically significant (P = 0.2, Figure 1). Likewise, a higher rate of complete remission was seen in C3GN (15%) versus DDD (8%), but this was not statistically significant (P = 0.4). Nineteen of the 42 C3G patients treated with mycophenolate mofetil (MMF) achieved complete or partial remission, of which 18 received concomitant treatment with corticosteroids. Among those patients treated with MMF, we did not detect any clear predictors of response to treatment. C3 levels were similar among responders and nonresponders, with approximately half demonstrating depressed C3 levels at initiation of treatment. Fifteen of the 42 MMF-treated patients demonstrated elevated levels of serum membrane attack complex (C5b-9): 10 nonresponders versus 5 responders. Testing for C3 nephritic factor was positive in 4 of 14 nonresponders and 4 of 9 responders. Only 3 patients in this MMF subcohort had detectable genetic variants.Table 5Treatment and outcome data of C3 glomerulopathy cohortParameterC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using Fisher exact test for treatment history and univariate Cox proportional hazards model for outcomes of interest.(A) TreatmentRAAS blockade: ACE-I, ARB, MRB75.679.20.8Steroids70.150.00.09Mycophenolate mofetil43.716.70.02Calcineurin inhibitor8.10.00.3Eculizumab4.612.50.2Rituximab8.10.00.3Cyclophosphamide4.68.30.6Other immunosuppression3.512.50.1Any immunosuppression73.666.70.5(B) OutcomesDuration of follow-up (months)69.183.20.4Remission (complete + partial)37.925.00.2Remission (complete)14.98.30.4Doubling of creatinine (eGFR > 15 ml/min per 1.73 m2)9.28.30.7Progression to CKD 5 (eGFR < 15 ml/min per 1.73 m2)9.20.0–Pre-emptive transplantation9.28.31.0ESRD11.520.80.3Death0.04.2–Combined outcome (doubling of creatinine, progression to CKD stage 5, ESRD, transplantation, death)39.141.70.7ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MRB, mineralocorticoid receptor blocker; RAAS, renin-angiotensin system.Data presented are percentage of total groups with the exception of duration of follow-up, given as mean months.a Testing for differences was performed using Fisher exact test for treatment history and univariate Cox proportional hazards model for outcomes of interest. Open table in a new tab ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MRB, mineralocorticoid receptor blocker; RAAS, renin-angiotensin system. Data presented are percentage of total groups with the exception of duration of follow-up, given as mean months. Progression to late-stage CKD and ESRD requiring dialysis and transplantation was common in the cohort (Table 5), with no detectable differences between those with C3GN (39.1%) and DDD (41.7%) for our primary outcome of doubling of creatinine, progression to CKD stage 5, ESRD, transplantation, or death (Figure 2). In univariate analyses, we did detect a trend toward faster progression to this combined outcome in older patients compared with younger patients (Figure 3), but this distinction was mitigated in a multivariate model that adjusted for sex, race and/or ethnicity, presenting renal function and proteinuria, complement levels, presence of complement-associated gene variants and/or autoantibodies, and utilization of immunosuppression (Table 6). In this clinical variables–only model, the sole predictor of progression to late-stage CKD, ESRD, or death was kidney function at the time of presentation. In the second multivariate model based on histopathology variables only, the strongest predictor for our combined outcome was degree of tubular atrophy and/or interstitial fibrosis (each 10% increase in fibrosis imparting approximately twice the risk for progression). In this model, we additionally found that the presence of C3-only staining on immunofluorescence, as opposed to C3-dominant staining with trace to 1+ Ig, was associated with higher risk of progression (hazard ratio 5.09, 95% confidence interval 1.49–17.35, P = 0.009). There was also a trend, not reaching statistical significance, for higher risk associated with the presence of cellular or fibrocellular crescents.Figure 3In univariate analysis, progression to end-stage renal disease, advanced chronic kidney disease (doubling creatinine or chronic kidney disease stage 5), or death was faster among adult patients diagnosed with C3 glomerulopathy than among pediatric patients. Survival analysis excludes 3 patients for whom time to outcome was unable to be verified (N = 108).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 6Predictors of progression to primary outcome in C3 glomerulopathy using 3 multivariate modelsPredictorHazard ratio (95% CI)P value(A) Clinical variables modelFemale1.44 (0.53–3.92)0.5Age Less than 18 years1.00 (reference)N/A 18-50 years0.91 (0.28–3.03)0.9 Over 50 years1.19 (0.30–4.81)0.8Race/ethnicity White1.00 (reference)N/A Hispanic1.29 (0.48–3.47)0.6 Asian4.01 (0.81–19.77)0.09 African-American3.24 (0.33–32.00)0.3eGFR via CKD-EPI equation (per 10 ml/min per 1.73 m2)0.69 (0.57–0.83)<0.001Proteinuria at diagnosis (per 1 g/d)1.03 (0.93–