Original Investigation Clinical Profiles and Patterns of Kidney Disease Progression in C3 Glomerulopathy Fernando Caravaca-Fontán ,1,2 Teresa Cavero ,3 Montserrat Dı´az-Encarnación,4 Virginia Cabello,5 Gema Ariceta,6 Luis F. Quintana ,7 Helena Marco,8,9 Xoana Barros,10 Natalia Ramos ,11 Nuria Rodrı´guez-Mendiola,12 Sonia Cruz,13 Gema Fernández-Juárez,14,15 Adela Rodrı´guez,16 Ana Pérez de José,17 Cristina Rabasco,18 Raquel Rodado,19 Loreto Fernández,20 Vanessa Pérez-Gómez,21 Ana Ávila,22 Luis Bravo,23 Natalia Espinosa,24 Natalia Allende,25 Maria Dolores Sanchez de la Nieta,26 Eva Rodrı´guez,27 Bego~ na Rivas ,28 Marta Melgosa ,29 Ana Huerta,30 Rosa Miquel, Carmen Mon, Gloria Fraga, Alberto de Lorenzo,34 Juliana Draibe,35 Fayna González,36 31 32 33 Amir Shabaka ,37 Maria Esperanza López-Rubio,38 Marı´a Ángeles Fenollosa,39 Luis Martı´n-Penagos,40 Iara Da Silva,4,41 Juana Alonso Titos,42 Santiago Rodrı´guez de Córdoba ,43 Elena Goicoechea de Jorge ,1,44 and Manuel Praga,1,2,3 on behalf of the Spanish Group for the Study of Glomerular Diseases (GLOSEN) Key Points c Kidney survival in C3 glomerulopathy is significantly higher in patients with a disease chronicity score ,4 and proteinuria ,3.5 g/d, regardless of baseline eGFR. c A faster eGFR decline in C3 glomerulopathy is associated with higher probability of kidney failure. c Patients with glomerulopathy with a progressive reduction in proteinuria over time did not reach kidney failure. Abstract Background C3 glomerulopathy is a rare kidney disease, which makes it difficult to collect large cohorts of patients to better understand its variability. The aims of this study were to describe the clinical profiles and patterns of progression of kidney disease. Methods This was a retrospective, observational cohort study. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. Study population was divided into clinical profiles by combining the following predictors: eGFR under/above 30 ml/min per 1.73 m2, proteinuria under/above 3.5 g/d, and histologic chronicity score under/above 4. The change in eGFR and proteinuria over time was evaluated in a subgroup with consecutive measurements of eGFR and proteinuria. Results One hundred and fifteen patients with a median age of 30 years (interquartile range 19–50) were included. Patients were divided into eight clinical profiles. Kidney survival was significantly higher in patients with a chronicity score ,4 and proteinuria ,3.5 g/d, both in those presenting with an eGFR under/above 30 ml/min per 1.73 m2. The median eGFR slope of patients who reached kidney failure was 26.5 ml/min per 1.73 m2 per year (interquartile range 21.6 to 217). Patients who showed a reduction in proteinuria over time did not reach kidney failure. On the basis of the rate of eGFR decline, patients were classified as faster eGFR decline ($5 ml/min per 1.73 m2 per year), slower (,5 ml/min per 1.73 m2 per year), and those without decline. A faster eGFR decline was associated with higher probability of kidney failure. Conclusions Kidney survival is significantly higher in patients with a chronicity score ,4 and proteinuria ,3.5 g/d regardless of baseline eGFR, and a faster rate of decline in eGFR is associated with higher probability of kidney failure. KIDNEY360 4: 659–672, 2023. doi: https://doi.org/10.34067/KID.0000000000000115 Introduction Cumulative experience from cohort studies has C3 glomerulopathy (C3G) is a highly complex kidney shown that age, eGFR, and proteinuria are among disease caused by alternative complement pathway the most important clinical predictors of kidney dysregulation.1–3 The estimated incidence of C3G is failure.5–10 Furthermore, the changes in proteinuria 1–3 cases per million population per year,4,5 which over time have also been associated with outcomes in makes it difficult to collect large cohorts of patients. C3G.11 On the other hand, histologic features of Due to the number of contributing authors, the affiliations are listed at the end of this article. Correspondence: Dr. Manuel Praga, Department of Nephrology, Hospital Universitario 12 de Octubre, Avenida de Córdoba sn, Madrid, Spain. Email: mpragat@senefro.org Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. www.kidney360.org Vol 4 May, 2023 659 660 KIDNEY360 disease activity and, particularly disease chronicity, have according to the previously published C3G histologic been associated with outcomes in C3G, demonstrating index.4,12 that a timely diagnosis is essential to mitigate the extent This study was approved by the Institutional Review of kidney damage.4,10,12 Despite this, the individual var- Board of Hospital Universitario 12 de Octubre (CEI16/ iability in clinical course and patterns of disease progres- 266) and was conducted in accordance with the Declara- sion according to baseline characteristics have rarely been tion of Helsinki. Written informed consent was obtained studied in C3G. from participants or their parents to participate in the After years of research, several new anticomplement study. agents are currently under investigation.3 Preliminary re- sults with the use of avacopan, a selective C5a receptor Definitions and Outcome inhibitor, revealed that the drug attenuated the histologic Baseline was defined as the time at which the diagnosis of disease chronicity compared with placebo, although this C3G was made and follow-up period as the interval be- study failed to achieve the primary end point which was the tween kidney biopsy and last outpatient visit or kidney reduction in disease activity.13 In addition, preliminary failure. results with pegcetacoplan, a C3 inhibitor administered Nephrotic syndrome was defined as a proteinuria of through subcutaneous infusion, showed a reduction in pro- .3.5 g/d along with serum albumin ,3 g/dl. Nephritic teinuria and stabilization of kidney function.14 Finally, pre- syndrome was the combination of hematuria, non- liminary results with iptacopan, an oral selective inhibitor of nephrotic proteinuria, hypertension, and kidney function factor B, showed a proteinuria reduction by 45% in native impairment. Asymptomatic urinary abnormalities were kidneys, together with a significant reduction in C3 deposits defined by the presence of non-nephrotic proteinuria in kidney transplant recipients, and sustained normalization and/or persistent microscopic hematuria .5 erythrocytes of plasma C3 and creatinine clearance levels, associated per high power field. with an improvement in eGFR slope.15 The main outcome was kidney failure, defined as an Pending the definitive results from ongoing trials with eGFR ,15 ml/min per 1.73 m2, the need for dialysis or these agents, there is a need from a clinical perspective to kidney transplantation. Secondary outcomes included better describe the patterns of disease progression according complete remission, as an eGFR .60 ml/min per 1.73 m2 to baseline characteristics.16 This real-world evidence could and proteinuria ,0.5 g/24 hours, and partial remission, help to identify subgroups of patients who could benefit as a proteinuria reduction .50% plus stabilization/im- most from these newer anticomplement therapies when provement in kidney function. Relapse was defined as they become available. the return of pretreatment proteinuria and/or declining Hence, the aims of this study were to describe the kidney function after any remission. different clinical profiles and patterns of progression of Since we previously found that baseline eGFR, protein- kidney disease in a multicentric cohort of 115 Spanish uria, and histologic total chronicity score were the main patients with C3G. predictors of kidney failure,19 the study population was divided into different clinical profiles by combining these predictors: eGFR under/above 30, proteinuria under/ Methods above 3.5 g/d, and total chronicity score under/above 4. Study Patients Patients diagnosed with C3G between 1995 and 2020 in 35 nephrology departments belonging to the Spanish Group Statistical Analyses for the Study of Glomerular Diseases were enrolled. Both This was a retrospective, longitudinal, multicenter, ob- pediatric and adult populations were included. Patients servational cohort study. Descriptive statistics are presented with missing data on baseline kidney function, proteinuria, as mean6SD or median and interquartile ranges (IQR) for or outcomes were excluded. continuous variables and frequencies or percentages for A diagnosis of C3G required C3 staining on immunoflu- categorical variables. Comparisons of continuous variables orescence at least two orders of magnitude greater than any between two groups were assessed by using the unpaired t immunoglobulin staining.17 Patients were considered to test or the Mann–Whitney U test, where appropriate. Chi- have dense deposit disease when highly electron-dense squared test or Fisher exact test was used for categorical intramembranous deposits were observed on electron mi- variables. croscopy and C3 glomerulonephritis when deposits did not The incidence rate was calculated as average annual in- fulfill this criterion. cidence over the study period. The numerator included all Baseline and follow-up data were compiled from the patients diagnosed with C3G during each distinct year of the medical records as described elsewhere.12,18 Data on eGFR, study period. The denominator was calculated based on an serum albumin, C3 levels, and proteinuria were collected at estimate considering the number of hospitals participating in baseline and after 1, 3, 6, 12, 24, 60 months, and/or last the study and the population covered by these hospitals, follow-up. Complement genetics were performed as shown assuming that all patients during the specified year were in Supplemental Methods. Plasma C3 levels were catego- followed up for the entire year without loss to follow-up. rized as under/above 77 mg/dl, on the basis of 85% lower For the evaluation of the change in eGFR and proteinuria limit of the laboratory normal range. over time, a subgroup of 85 patients who had at least four Kidney biopsy specimens were examined in the pathol- consecutive measurements of eGFR and proteinuria was ogy departments of the participating hospitals. The de- used. Estimation of eGFR slope and change in proteinuria gree of disease activity and chronicity was analyzed over time were analyzed with linear mixed-effects models. KIDNEY360 4: 659–672, May, 2023 Clinical Profiles of C3 Glomerulopathy, Caravaca-Fontán et al. 661 Negative or positive values of these parameters indicated an $3.5 g/d (Table 1). As expected, significant differences increase/decrease over time. were observed in the clinical presentation across groups, Subject-specific longitudinal trajectory plots and locally the frequency of hypoalbuminemia and proteinuria. In ad- weighted smoothing plots were used to represent the dition, differences were also observed in the total disease change of eGFR and proteinuria over follow-up. activity being lower in patients with a chronicity score ,4 Distributions of time to kidney failure were depicted by and proteinuria ,3.5 g/d. Figure 3A shows the survival survival curves using the Kaplan–Meier method, and the curves of patients with baseline eGFR $30, according survival curves by clinical profiles were compared using the to clinical profiles. Kidney survival was significantly log-rank test. higher in patients with a chronicity score ,4 and proteinuria A P value ,0.05 was considered to be significant. Anal- ,3.5 g/d. yses were performed using IBM SPSS Statistics 24.0 and R Of the 41 (36%) patients with baseline eGFR ,30: software v.3.6.3. 8 (20%) had a chronicity score ,4 and proteinuria ,3.5 g/d, 5 (12%) had a chronicity score ,4 and pro- teinuria $3.5 g/d, 18 (44%) had a chronicity score $4 Results and proteinuria ,3.5 g/d, and 10 (24%) had a chronicity Estimated Incidence and Cohort Description score $4 and proteinuria $3.5 g/d (Table 2). Most of The total study group consisted of 115 patients after these patients were adults, and the presence of alterna- excluding patients not fulfilling diagnostic criteria for tive complement pathway pathogenic variants was C3G (n521), those without alternative complement path- significantly lower in patients with a chronicity score way genetic studies (n520), and those with underlying ,4 and proteinuria ,3.5 g/d. This latter group was monoclonal gammopathy (n523). further characterized by a trend toward a lower fre- Assuming an estimated referral population of 7 million quency in the prescription of renin-angiotensin system over the 25-year study period in the participating hospitals, blockade and a higher frequency in the prescription of this equated to an annual incidence of biopsy-proven C3G of corticosteroids plus mycophenolate mofetil (MMF) as the almost 1 case/million per year. immunosuppressive regimen. The probability of com- The median age was 30 years (IQR 19–50), and 51 subjects plete remission was significantly higher in patients with (44%) were female (Supplemental Table 1). Twenty-eight lower chronicity and proteinuria. Figure 3B shows the (24%) were pediatric patients. Forty-one (36%) patients survival curves of patients with baseline eGFR ,30, had a baseline eGFR,30, and 47 (41%) patients had baseline according to clinical profiles. Similarly, kidney survival proteinuria $3.5 g/d. Nephrotic syndrome was the most was significantly higher in patients with a chronicity common clinical presentation. Regarding the histologic score ,4 and proteinuria ,3.5 g/d. characteristics, 46 (40%) patients had a total activity score Initial doses of each immunosuppressive regimen, dura- $9, and 44 (38%) patients had a total chronicity score $4. tion, and adverse events, according to baseline eGFR, are Supplemental Table 2 presents the pathogenic variants in presented in Supplemental Table 3. No significant differ- complement genes and acquired abnormalities in the study ences were observed in the median initial doses received population. across groups. Over a median follow-up of 49 months (IQR 24–112), Regarding the treatment-related adverse events, infectious 23 (20%) patients achieved complete remission, 31 (27%) complications were the most common (17%)—particularly patients achieved partial remission, and 46 (40%) urinary tract infections (10%) followed by cardiovascular patients reached kidney failure. Figure 1 shows the events (13%), cytopenia (10%), new-onset diabetes mellitus individual clinical course of patients who reached kid- (4%), and avascular necrosis of the hip (4%). ney failure at the last follow-up. Most of these patients had significant kidney function impairment at baseline, Change in eGFR and Proteinuria Over Time together with heavy proteinuria, reaching kidney failure For the evaluation of the slope of eGFR and change in before 40 months. Two (4%) patients reached kidney proteinuria over follow-up time, a subgroup of 85 patients failure after developing a clinical relapse. Figure 2 with similar characteristics to those of the overall cohort was shows the individual clinical course of patients who used (Supplemental Table 1). achieved complete remission at the last follow-up. Nineteen (22%) patients achieved complete remis- The degree of proteinuria decreased during follow-up, sion, 29 (34%) patients achieved partial remission, and 25 and of note, six of the 23 (26%) patients had a clinical (29%) patients reached kidney failure. The median eGFR relapse during the tapering phase of immunosuppres- slope of this latter group was -6.5 ml/min per 1.73 m2 per sive treatment. year (IQR 21.6 to 217). Supplemental Figure 1 shows the individual-specific longitudinal trajectories of eGFR for each Characteristics According to Baseline Clinical Profiles treatment category, according to the development of kidney On the basis of eGFR, proteinuria, and the total disease failure. A progressive increase in eGFR was observed in the chronicity in kidney biopsy, the study population was di- group of patients not reaching kidney failure. This rise in vided into eight clinical profiles. eGFR was steeper in patients treated with corticosteroids Of the 74 (64%) patients with baseline eGFR $30: 3 (48%) plus MMF, whereas in the rest of therapeutic groups, the had a chronicity score ,4 and proteinuria ,3.5g/day, 22 eGFR exhibited a trend toward a nonlinear quadratic (30%) had a chronicity score ,4 and proteinuria $3.5 g/d, 8 pattern. (11%) had a chronicity score $4 and proteinuria ,3.5 g/d, On the other hand, the median change in proteinuria and 8 (11%) had a chronicity score $4 and proteinuria of patients reaching kidney failure was 2.5 g/d per year 662 KIDNEY360 Figure 1. Detailed description of patients who reached kidney failure at the last follow-up in the overall cohort (n546, out of total 115 patients). Each Pt is identified by a correlative number (e.g., Pt.1, Pt.2...). Age at diagnosis is shown (yo: years old). eGFR at baseline is expressed as ml/min per 1.73 m2. Prot at baseline is expressed as grams/day (g/d). Each bar represents the clinical course of each patient, and the colors represent the type of clinical presentation/outcome over time. Each arrow represents the type of immunosuppressive therapy prescribed and the time at which the treatment was first prescribed. Prot, Proteinuria; Pt, patient. (IQR 0.5–4.5). Supplemental Figure 2 shows the development of kidney failure. Patients who showed a individual-specific longitudinal trajectories of protein- progressive reduction in proteinuria over time did not uria for each treatment category, according to the reach kidney failure. KIDNEY360 4: 659–672, May, 2023 Clinical Profiles of C3 Glomerulopathy, Caravaca-Fontán et al. 663 Figure 2. Detailed description of patients who achieved complete remission at the last follow-up in the overall cohort (n546, out of total 115 patients). Each Pt is identified by a correlative number (e.g., Pt.1, Pt.2...). Age at diagnosis is shown (yo: years old). eGFR at baseline is expressed as ml/min per 1.73 m2. Prot at baseline is expressed as grams/day (g/d). Each bar represents the clinical course of each patient, and the colors represent the type of clinical presentation/outcome over time. Each arrow represents the type of immunosuppressive therapy prescribed and the time at which the treatment was first prescribed. Prot, Proteinuria; Pt, patient. A trend toward a decrease in C3 levels was also observed in Discussion patients who reached kidney failure (Supplemental Figure 3). In this study, we described the spectrum of clinical In addition, when kidney survival was analyzed according profiles and patterns of progression of kidney disease to the categories of serum C3 levels at the end of follow- in a large cohort of patients with C3G. Our study confirms up, a nonsignificant trend was observed toward a better an estimated incidence rate of C3G of almost one case per survival in patients with C3 levels $77 mg/dl (Supplemental million population per year. Second, we showed the indi- Figure 4). vidual clinical evolution of patients who achieved com- plete remission and the temporal relationship with each treatment initiation. Third, we analyzed the different clin- Patterns of eGFR Decline ical profiles of patients at the time of clinical diagnosis by On the basis of the slope of eGFR over time, patients combining the main predictors of outcomes (eGFR, pro- were classified as those with a faster eGFR decline teinuria, and disease chronicity in kidney biopsy). Kidney ($5 ml/min per 1.73 m2 per year), those with a slower survival was significantly higher in patients with a chro- eGFR decline (,5 ml/min per 1.73 m2 per year), and nicity score ,4 and proteinuria ,3.5 g/d, regardless of those without decline (i.e. positive slope in eGFR over eGFR at presentation. Finally, we assessed the different follow-up) (Table 3). patterns of eGFR change over time, and as expected, a Patients with a faster eGFR decline were predominantly faster rate of decline in eGFR was associated with higher women with dense deposit disease, presenting more fre- probability of reaching kidney failure. quently with nephrotic syndrome, and were less frequently Eight clinical profiles of patients were identified. treated with corticosteroids plus MMF. These patients Among the group of patients with a baseline eGFR exhibited a progressive increase in proteinuria as eGFR $30, those with lower disease chronicity in kidney biopsy declined over time (Figure 4, A and B). A faster rate of were more likely to respond to immunosuppressive reg- decline in eGFR was associated with higher probability of imens and to achieve remission (partial/complete). Most kidney failure (Table 3). Figure 4C shows the survival of these patients were treated with corticosteroids plus curves according to the rate of decline of eGFR. Kidney MMF. Although the mechanism of action of this thera- survival was significantly lower in patients with a faster peutic regimen is not well understood, some studies have decline of eGFR. found beneficial effects with this regimen,18,20 while 664 KIDNEY360 Table 1. Clinical characteristics of patients with baseline eGFR ‡30 ml/min per 1.73 m2, according to clinical profiles at baseline Chronicity Chronicity Chronicity Chronicity Score ,4 and score ,4 and score $4 score $4 and Characteristic P Proteinuria proteinuria and proteinuria proteinuria ,3.5 g/d (n536) $3.5 g/d (n522) ,3.5 g/d (n58) $3.5 g/d (n58) Baseline Age, yr 0.31 ,18 16 (44) 5 (23) 2 (25) 2 (25) $18 20 (56) 17 (77) 6 (75) 6 (75) Sex, N (%) 0.86 Female 17 (47) 12 (55) 4 (50) 5 (63) Male 19 (53) 10 (45) 4 (50) 3 (38) Hypertension, N (%) 0.49 Yes 16 (44) 14 (64) 4 (50) 5 (63) No 20 (56) 8 (36) 4 (50) 3 (38) Clinical presentation, N (%) ,0.001 Nephrotic syndrome 0 (0) 17 (77) 0 (0) 6 (74) Nephritic syndrome 9 (25) 3 (13) 0 (0) 1 (13) Isolated non-nephrotic proteinuria 16 (44) 1 (5) 4 (50) 1 (13) Asymptomatic urinary abnormalities 11 (31) 1 (5) 4 (50) 0 (0) Serum albumin (g/dl), N (%) ,0.001 ,3.5 15 (42) 21 (95) 3 (38) 7 (88) $3.5 21 (58) 1 (5) 5 (62) 1 (12) Serum C3 (mg/dl), N (%) 0.91 ,77 24 (67) 16 (73) 5 (63) 6 (75) $77 12 (33) 6 (27) 3 (37) 2 (25) Proteinuria (g/24 h), N (%) ,0.001 ,3.5 36 (100) 0 (0) 8 (100) 0 (0) $3.5 0 (0) 22 (100) 0 (0) 8 (100) Microscopic hematuria, N (%) 0.74 Yes 28 (78) 18 (82) 6 (75) 5 (63) No 8 (22) 4 (18) 2 (25) 3 (38) Alternative complement pathway studies Complement pathogenic variants, N (%) 8 (22) 2 (9) 3 (38) 3 (38) 0.22 Variants of unknown significance, N (%) 14 (39) 10 (45) 0 (0) 2 (25) 0.11 Antibodies against complement 10 (28) 8 (36) 2 (25) 2 (25) 0.87 components, N (%) Kidney biopsy Histologic subtype, N (%) 0.18 C3GN 29 (81) 19 (86) 6 (75) 4 (50) DDD 7 (19) 3 (14) 2 (25) 4 (50) C3G histologic index—total activity score 0.01 ,9 29 (81) 12 (55) 2 (25) 4 (50) $9 7 (19) 10 (45) 6 (75) 4 (50) C3G histologic index—total ,0.001 chronicity score ,4 36 (100) 22 (100) 0 (0) 0 (0) $4 0 (0) 0 (0) 8 (100) 8 (100) Treatment RAS blockade 33 (92) 20 (91) 6 (75) 6 (75) 0.37 ACEI 21 (58) 12 (54) 4 (50) 4 (50) ARB 5 (14) 4 (18) 1 (12) 2 (25) Both 7 (19) 4 (18) 1 (12) 0 (0) Nonimmunosuppressive therapy 3 (8) 1 (4) 1 (12) 0 (0) 0.73 Corticosteroids only 6 (17) 2 (9) 2 (25) 1 (12) 0.72 Corticosteroids plus MMF 15 (42) 13 (59) 4 (50) 4 (50) 0.64 Rituximab 3 (8) 2 (9) 0 (0) 0 (0) 0.68 Anti-C5 2 (6) 2 (9) 1 (12) 0 (0) 0.74 Other immunosuppressive therapy 7 (19) 2 (9) 0 (0) 3 (37) 0.15 Outcomes at the last follow-up Follow-up, mo 57 (37–129) 46 (30–68) 36 (15–101) 80 (23–162) 0.32 Complete remission 10 (28) 6 (27) 1 (12) 0 (0) 0.14 Partial remission 14 (39) 6 (27) 3 (38) 2 (25) 0.76 Kidney failure 5 (14) 6 (27) 4 (50) 4 (50) 0.04 C3GN, C3 glomerulonephritis; DDD, dense deposit disease; C3G, C3 glomerulopathy; RAS, renin-angiotensin system; ACEI, angiotensin- converting enzyme inhibitor; ARB, angiotensin receptor blocker; MMF, mycophenolate mofetil. KIDNEY360 4: 659–672, May, 2023 Clinical Profiles of C3 Glomerulopathy, Caravaca-Fontán et al. 665 Figure 3. Kidney survival according to clinical profiles. (A) Kaplan–Meier curves for kidney survival in patients with baseline eGFR $30 ml/min per 1.73 m2, according to clinical profiles. (B) Kaplan–Meier curves for kidney survival in patients with baseline eGFR ,30 ml/min per 1.73 m2, according to clinical profiles. others have not.7,9 Kidney failure was less likely in pa- $30 was higher in those with concomitant higher disease tients with lower disease chronicity in kidney biopsy and chronicity in kidney biopsy, which points toward a po- lower proteinuria. These findings are in line with tential point of no return in the disease.12 others9,10,21 and suggest that the importance of protein- The group of patients with a baseline eGFR ,30 was uria in C3G not only as a marker of disease severity but predominantly comprised by adults. Interestingly, within also as a predictor of kidney damage.11,22,23 On the other this group of patients with lower disease chronicity and hand, the percentage of patients who reached kidney proteinuria, five (63%) patients achieved complete remis- failure in the group of patients with a baseline eGFR sion at the last follow-up, pointing toward a reversible 666 KIDNEY360 Table 2. Clinical characteristics of patients with baseline eGFR <30 ml/min per 1.73 m2, according to clinical profiles at baseline Chronicity Chronicity Chronicity Chronicity score ,4 and score ,4 and score $4 and score $4 and Characteristic P proteinuria proteinuria proteinuria proteinuria ,3.5 g/d (n58) $3.5 g/d (n55) ,3.5 g/d (n518) $3.5 g/d (n510) Baseline Age, yr 0.004 ,18 3 (38) 0 (0) 0 (0) 0 (0) $18 5 (62) 5 (100) 18 (100) 10 (100) Sex, N (%) 0.95 Female 2 (25) 2 (40) 6 (33) 3 (30) Male 6 (75) 3 (60) 12 (67) 7 (70) Hypertension, N (%) 0.10 Yes 5 (63) 5 (100) 17 (94) 9 (90) No 3 (37) 0 (0) 1 (6) 1 (10) Clinical presentation, N (%) 0.02 Nephrotic syndrome 0 (0) 1 (20) 0 (0) 6 (60) Nephritic syndrome 5 (63) 4 (80) 8 (45) 4 (40) Isolated non-nephrotic proteinuria 2 (25) 0 (0) 6 (33) 0 (0) Asymptomatic urinary abnormalities 1 (12) 0 (0) 4 (22) 0 (0) Serum albumin (g/dl), N (%) 0.06 ,3.5 7 (88) 5 (100) 10 (56) 9 (90) $3.5 1 (12) 0 (0) 8 (44) 1 (10) Serum C3 (mg/dl), N (%) 0.13 ,77 6 (75) 4 (80) 8 (44) 3 (30) $77 2 (25) 1 (20) 10 (56) 7 (70) Proteinuria (g/24 h), N (%) ,0.001 ,3.5 8 (100) 0 (0) 18 (100) 0 (0) $3.5 0 (0) 5 (100) 0 (0) 10 (100) Microscopic hematuria, N (%) 0.52 Yes 7 (88) 5 (100) 13 (72) 8 (80) No 1 (12) 0 (0) 5 (28) 2 (20) Alternative complement pathway studies Complement pathogenic variants, N (%) 0 (0) 3 (60) 3 (17) 1 (10) 0.04 Variants of unknown significance, N (%) 2 (25) 2 (40) 8 (44) 3 (30) 0.76 Antibodies against complement 2 (25) 2 (40) 6 (33) 1 (10) 0.51 components, N (%) Kidney biopsy Histologic subtype, N (%) 0.68 C3GN 8 (100) 4 (80) 16 (89) 9 (90) DDD 0 (0) 1 (20) 2 (11) 1 (10) C3G histologic index—total activity 0.83 score ,9 4 (50) 2 (40) 11 (61) 5 (50) $9 4 (50) 3 (60) 7 (39) 5 (50) C3G histologic index—total chronicity ,0.001 score ,4 8 (100) 5 (100) 0 (0) 0 (0) $4 0 (0) 0 (0) 18 (100) 10 (100) Treatment RAS blockade 4 (50) 5 (100) 16 (89) 8 (80) 0.08 ACEI 3 (38) 4 (80) 15 (83) 4 (40) ARB 1 (12) 1 (20) 1 (6) 2 (20) Both 0 (0) 0 (0) 0 (0) 2 (20) Nonimmunosuppressive therapy 0 (0) 0 (0) 9 (50) 4 (40) 0.03 Corticosteroids only 0 (0) 1 (20) 3 (17) 0 (0) 0.32 Corticosteroids plus MMF 5 (63) 1 (20) 2 (11) 2 (20) 0.04 Rituximab 1 (12) 0 (0) 0 (0) 1 (10) 0.43 Anti-C5 0 (0) 1 (20) 1 (11) 2 (20) 0.57 Other immunosuppressive therapy 2 (25) 2 (40) 2 (11) 1 (10) 0.39 Outcomes at the last follow-up Follow-up, mo 36 (18–47) 6 (3–27) 12 (6–27) 20 (5–43) 0.12 Complete remission 5 (63) 0 (0) 1 (6) 0 (0) ,0.001 Partial remission 2 (25) 1 (20) 2 (11) 1 (10) 0.76 Kidney failure 1 (12) 3 (60) 14 (78) 9 (90) 0.003 C3GN, C3 glomerulonephritis; DDD, dense deposit disease; C3G, C3 glomerulopathy; RAS, renin-angiotensin system; ACEI, angiotensin- converting enzyme inhibitor; ARB, angiotensin receptor blocker; MMF, mycophenolate mofetil. KIDNEY360 4: 659–672, May, 2023 Clinical Profiles of C3 Glomerulopathy, Caravaca-Fontán et al. 667 Table 3. Clinical characteristics of patients according to the rate of decline of eGFR, in a subgroup of 85 patients with consecutive measurements of eGFR and proteinuria over time Faster Decline Slower Decline (eGFR Slope (eGFR Slope No Progression Characteristic $5 ml/min per ,5 ml/min per P (n536) 1.73 m2 per year) 1.73 m2 per year) (n526) (n523) Baseline Age, yr 0.81 ,18 9 (35) 6 (26) 11 (31) $18 17 (65) 17 (74) 25 (69) Sex, N (%) 0.005 Female 18 (69) 11 (48) 10 (28) Male 8 (31) 12 (52) 26 (72) Hypertension, N (%) 0.79 Yes 15 (58) 12 (52) 22 (61) No 11 (42) 11 (48) 14 (39) Clinical presentation, N (%) 0.24 Nephrotic syndrome 14 (54) 10 (44) 10 (28) Nephritic syndrome 5 (19) 5 (22) 15 (42) Isolated non-nephrotic proteinuria 4 (15) 2 (9) 5 (14) Asymptomatic urinary abnormalities 3 (12) 6 (26) 6 (17) eGFR at diagnosis, ml/min per 1.73 m2 0.25 ,30 6 (23) 5 (22) 14 (39) $30 20 (77) 18 (78) 22 (61) Serum albumin, g/dl 0.54 ,3.5 18 (69) 13 (57) 25 (69) $3.5 8 (31) 10 (43) 11 (31) Serum C3, mg/dl 0.47 ,77 19 (73) 13 (57) 24 (67) $77 7 (27) 10 (43) 12 (33) Proteinuria, g/24 h 0.87 ,3.5 14 (54) 14 (61) 21 (58) $3.5 12 (46) 9 (39) 15 (42) Microscopic hematuria, N (%) 0.12 Yes 17 (65) 19 (63) 31 (86) No 9 (35) 4 (17) 5 (14) Alternative complement pathway studies Complement pathogenic variants, N (%) 3 (12) 9 (39) 4 (11) 0.01 Variants of unknown significance, N (%) 13 (50) 6 (26) 17 (47) 0.17 Antibodies against complement 11 (42) 4 (17) 9 (25) 0.13 components, N (%) Kidney biopsy Histologic subtype 0.27 C3GN 19 (73) 19 (83) 32 (89) DDD 7 (27) 4 (17) 4 (11) C3G histologic index—total activity score 0.43 ,9 16 (62) 13 (57) 26 (72) $9 10 (38) 10 (43) 10 (28) C3G histologic index—total chronicity 0.29 score ,4 16 (62) 13 (57) 27 (75) $4 10 (38) 10 (43) 9 (25) Treatment RAS blockade 22 (85) 21 (91) 31 (86) 0.76 Nonimmunosuppressive therapy 4 (15) 5 (22) 3 (8) 0.34 Corticosteroids only 5 (19) 1 (4) 6 (17) 0.27 Corticosteroids plus MMF 8 (31) 9 (39) 23 (64) 0.02 Rituximab 3 (12) 2 (9) 1 (3) 0.38 Anti-C5 3 (12) 2 (9) 2 (6) 0.69 Other immunosuppressive therapy 3 (12) 4 (17) 1 (3) 0.15 Outcomes Follow-up, mo 35 (15–64) 73 (37–186) 38 (17–51) 0.01 Kidney failure 16 (62) 9 (39) 0 (0) ,0.001 C3GN, C3 glomerulonephritis; DDD, dense deposit disease; C3G, C3 glomerulopathy; RAS, renin-angiotensin system; MMF, mycophenolate mofetil. 668 KIDNEY360 Figure 4. Patterns of eGFR and proteinura change over time. (A) Subject-specific longitudinal trajectories of eGFR over follow-up (time points are 0, 1, 2, 3, 6, 12, and 24 months) in a subgroup of 85 patients with consecutive measurements of eGFR and proteinuria over time. The gray lines show individual subject trajectories, and the color lines show LOESS with the corresponding 95% confidence interval. The first graph (in green) represents patients with no decline of eGFR over time; the second graph (in yellow) represents patients KIDNEY360 4: 659–672, May, 2023 Clinical Profiles of C3 Glomerulopathy, Caravaca-Fontán et al. 669 Figure 4. (Continued). with a slower eGFR decline (,5 ml/min per 1.73 m2 per year); and the third graph represents patients with a faster eGFR decline ($5 ml/min per 1.73 m2 per year); (B) Subject-specific longitudinal trajectories of 24-hour proteinuria over follow-up (time points are 0, 1, 2, 3, 6, 12, and 24 months) in a subgroup of 85 patients with consecutive measurements of eGFR and proteinuria over time. The gray lines show individual subject trajectories, and the color lines show LOESS with the corresponding 95% confidence interval. The first graph (in green) represents patients with no decline of eGFR over time; the second graph (in yellow) represents patients with a slower eGFR decline (,5 ml/min per 1.73 m2 per year); the third graph represents patients with a faster eGFR decline ($5 ml/min per 1.73 m2 per year). (C) Kaplan–Meier curves for kidney survival according to the rate of decline of eGFR (patients with faster eGFR decline, slower eGFR decline, and no eGFR decline). LOESS, locally weighted smoothing plots. kidney damage at the time of clinical diagnosis. Similarly, who experienced a decrease in proteinuria or a change in these patients were mostly treated with corticosteroids the rate of decline of eGFR would be those associated plus MMF. As expected, the probability of kidney failure with a better renal prognosis in the medium and long was higher in those with higher disease chronicity and term, although further studies are warranted to better proteinuria. We speculate that this could be due to a more address this issue. aggressive clinical phenotype or a late diagnosis of the This study is subject to limitations. First, owing to the disease. observational and retrospective nature of the study, no Another interesting observation in our study was that a causal relationships can be established. Second, given the subset of patients had a clinical relapse of the disease after retrospective nature of this study and the large period having achieved some degree of remission with immuno- covered, some cases of C3G might not have been correctly suppressive therapy. Although the overall clinical course is identified during follow-up in the participating centers, slowly progressive in most of the patients, disease exacer- which could have affected the estimated incidence rate. bations may also occur in the context of superimposed Third, although in this study, we were able to identify alternative complement activation by intercurrent factors, patients with C3G with poor short-term and medium- such as infections.16 Thus, patients with C3G require a close term kidney prognosis, longer follow-up may be necessary follow-up after diagnosis, although the most appropriate to fully capture the natural history of the disease in some strategy or biomarker to monitor relapses of the disease patients. Despite these limitations, this study further con- remains to be defined. tributes to the understanding of the disease by providing Finally, we analyzed the clinical patterns of eGFR additional information for predicting outcomes in clinical change over time and confirmed the inverse relationship settings. between eGFR change and proteinuria among different In conclusion, kidney survival was significantly higher subgroups of patients with C3G on the basis of the rate of in patients with a disease chronicity score ,4 and pro- decline.11 Three different groups were distinguished: teinuria ,3.5 g/d, regardless of baseline eGFR; a faster faster, lower, and no decline of eGFR over time. A large eGFR decline was associated with higher probability of proportion of patients with a faster decline corresponded kidney failure; and patients with a progressive reduction to dense deposit disease cases—although the differences in proteinuria over time did not reach kidney failure. did not reach statistical significance—and had been treated Nevertheless, several questions remain open for further with an immunosuppressive regimen different than corti- research, and therefore, prospective studies are warranted costeroids plus MMF. Patients without progression of to better elucidate them. kidney disease were mostly men, with nephritic syndrome as the most frequent presentation and low degree of chro- Disclosures nicity in kidney biopsy. G. Ariceta reports the following: Consultancy: Advicenne, According to our results, the decline in eGFR over time is Alexion Pharmaceuticals; Alnylam; AstraZeneca Recordati Rare not uniformly linear in patients with C3G, and the rate of Diseases; Chiesi; Dicerna, Kyowa Kirin; Honoraria: Speaker decline can vary widely between individuals. Therefore, honoraria from; Advicenne; AstraZeneca Alexion; Chiesi; Kyowa these different patterns of progression should be considered Kirin; Recordati; and Advisory or Leadership Role: AstraZeneca for both clinical studies and trial recruitment. Moreover, Alexion; Ana Avila reports the following: Consultancy: Alexion, from a clinical standpoint, they could also help to titrate the GSK, Vifor; Honoraria: Alexion; GSK, Vifor; Advisory or Lead- intensity of treatments or to schedule the initiation of di- ership Role: Alxn, GSK; and Speakers Bureau: Alexion, otsuka, alysis or kidney transplantation, particularly at later stages gsk. F. Caravaca-Fontán reports the following: personal fees from of the disease.24 Apellis and Novartis; M. Díaz-Encarnación reports the following: Taken together, our study suggests that the clinical personal fees from Novartis. G. Fernández-Juárez reports the profile of patients who could benefit most from anti- following: Research Funding: Instituto Salud Calos III; Hono- complement therapies would be those with lower degree raria: GSK OTSUKA; and Speakers Bureau: GSK OTSUKA. E. of disease chronicity in kidney biopsy. In a subset of Goicoechea de Jorge reports the following: Honoraria: Alexion patients with a low eGFR at clinical presentation, the Pharmaceuticals; Astellas; Sobi. A. Huerta reports the following: kidney function may recover—at least partially—and Honoraria: Alexion Pharmaceuticals for giving lectures and thus, in our opinion this sole criterion should not be used participating in advisory boards. L. Martín-Penagos reports the to decide whether to treat a patient with C3G with future following: Honoraria: ASTRA-ZENECA, GSK, OTSUKA. C. Mon anticomplement drugs. One might speculate that once reports the following: Other Interests or Relationships: Spanish these new anticomplement agents were prescribed, those Nephrology Society. Vanessa Pérez Gómez reports the following: 670 KIDNEY360 Employer: Honoraria: Teacher of the CatedraMundipharma- Miquel, Carmen Mon, Ana Pérez de José, Vanessa Pérez-Gómez, UAM of Diabetic Kidney Disease and the CatedraAstrazeneca- Manuel Praga, Luis F. Quintana, Cristina Rabasco, Natalia UAM of Chronic Kidney Disease and Electrolytes; and Speakers Ramos, Bego~ na Rivas, Raquel Rodado, Adela Rodríguez, Eva Bureau: speaker fees from Alexion, AstraZeneca, Kyowa Kirin, Rodríguez, Santiago Rodríguez de Córdoba, Nuria Rodríguez- Otsuka, and Sanofi-Genzyme. M. Praga reports the following: Mendiola, Amir Shabaka. Consultancy: Alexion, Apellis, Astra Zeneca, GSK, Novartis, Each author contributed important intellectual content during Otsuka, Silence, Travere, Vifor; and Honoraria: Alexion, GSK, manuscript drafting or revision and agrees to be personally ac- Novartis, Otsuka, Travere, Vifor. L.F. Quintana reports the fol- countable for the individual’s own contributions and to ensure that lowing: Employer: Hospital Clínic of Barcelona; Consultancy: questions pertaining to the accuracy or integrity of any portion of GSK; Otsuka; Honoraria: Alexion; GSK; Otsuka; and Advisory or the work. Leadership Role: Alexion; GSK; Novartis; Otsuka. C. Rabasco reports the following: Speakers Bureau: Boeringher, GSK. N. Data Sharing Statement Ramos reports the following: Consultancy: Alexion; Advisory or The data underlying this article will be shared on reasonable Leadership Role: Alexion; and Other Interests or Relationships: request to the corresponding author. Sociedad Espa~ nola Nefrologia; Societat Catalana de Nefrologia. S. Rodriguez de Cordoba reports the following: Ownership In- Supplemental Material terest: Secugen S.L.; Research Funding: Alexion Pharmaceuticals; This article contains the following supplemental material online and Honoraria: Alexion Pharmaceuticals. All remaining authors at http://links.lww.com/KN9/A337. have nothing to disclose. Supplemental Methods. Supplemental Table 1. Clinical characteristics of patients Funding according to study population subgroups. Analyses in this publication were conducted through a research Supplemental Table 2. Pathogenic variants in complement genes collaboration with Novartis Pharma AG, who provided funding and acquired abnormalities in the study population. and also provided input to the analysis protocol. Work in this Supplemental Table 3. Initial dose of treatment regimens, dura- study was supported by the Instituto de Salud Carlos III/Fondo tion, and adverse events, according to age groups. Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/ Supplemental Figure 1. Subject-specific longitudinal trajectories 01685 and PI19/1624, and Red de Investigación Renal (RedInRen) of eGFR over follow-up, according to immunosuppressive (RD12/0021/0029) (to MP), the Autonomous Region of Madrid treatments. (S2017/BMD-3673) (to MP). SRdeC is supported by Ministerio de Supplemental Figure 2. Subject-specific longitudinal trajectories Economia y Competitividad grant PID2019-104912RB-I00 y Au- of 24 hours proteinuria over follow-up, according to immuno- tonomous Region of Madrid grant S2017/BMD-3673. suppressive treatments. Supplemental Figure 3. Subject-specific longitudinal trajectories of C3 in adult and pediatric patients, according to the development Author Contributions Conceptualization: Fernando Caravaca-Fontán, Gema Fernández- of kidney failure. Juárez, Elena Goicoechea de Jorge, Manuel Praga. Supplemental Figure 4. Kaplan–Meier curves for kidney survival according to serum C3 levels at the last follow-up. Data curation: Fernando Caravaca-Fontán, Elena Goicoechea de Jorge, Manuel Praga. Formal analysis: Fernando Caravaca-Fontán, Elena Goicoechea de References Jorge, Manuel Praga. 1. Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy— Funding acquisition: Fernando Caravaca-Fontán, Elena Goi- understanding a rare complement-driven renal disease. Nat coechea de Jorge, Manuel Praga. Rev Nephrol. 2019;15(3):129–143. doi:10.1038/s41581-018- 0107-2 Investigation: Fernando Caravaca-Fontán, Manuel Praga. 2. Caravaca-Fontán F, Lucientes L, Cavero T. 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Kidney Int Rep. 2022; Received: December 2, 2022 Accepted: February 7, 2023 7(6):1165–1178. doi:10.1016/j.ekir.2022.02.021 Published Online Ahead of Print: March 30, 2023 AFFILIATIONS 1 Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain 2 Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain 3 Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain 4 Department of Nephrology, Fundación Puigvert, Barcelona, Spain 5 Department of Nephrology, Hospital Universitario Virgen del Rocı́o, Sevilla, Spain 6 Department of Pediatric Nephrology, Hospital Universitario Vall d’Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain 7 Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona; Department of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain 8 Department of Nephrology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain 9 Current address: Department of Nephrology, Fundación Puigvert, Barcelona, Spain 10 Department of Nephrology, Hospital Universitario Doctor Josep Trueta, Gerona, Spain 11 Department of Nephrology, Hospital Universitario Vall d’Hebron, Barcelona, Spain 12 Department of Nephrology, Hospital Universitario Ramón y Cajal, Madrid, Spain 13 Department of Nephrology, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain 14 Department of Nephrology, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain 15 Current address: Department of Nephrology, Hospital Universitario La Paz, Madrid, Spain 16 Department of Pediatric Nephrology, Hospital Universitario Virgen del Rocı́o, Sevilla, Spain 17 Department of Nephrology, Hospital Universitario Gregorio Mara~ nón, Madrid, Spain 18 Department of Nephrology, Hospital Universitario Reina Sofı́a, Córdoba, Spain 19 Department of Nephrology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain 20 Department of Nephrology, Complejo Hospitalario de Navarra, Navarra, Spain 21 Department of Nephrology, Hospital Universitario Fundación Jiménez Dı́az, Madrid, Spain 22 Department of Nephrology, Hospital Universitario Doctor Peset, Valencia, Spain 23 Department of Nephrology, Hospital Universitario A Coru~ na, La Coru~ na, Spain 24 Pediatric Nephrology Unit, Hospital Universitario Son Espases, Balearic Islands Health Research Institute (IdISBa). Palma de Mallorca, Spain 25 Department of Nephrology, Hospital Universitario Son Espases, Palma de Mallorca, Spain 26 Department of Nephrology, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain 27 Department of Nephrology, Hospital del Mar, Barcelona, Spain 28 Department of Nephrology, Hospital Universitario La Paz, Madrid, Spain 29 Department of Pediatric Nephrology, Hospital Universitario La Paz, Madrid, Spain 30 Department of Nephrology, Hospital Universitario Puerta de Hierro, Madrid, Spain 31 Department of Nephrology, Hospital Universitario Canarias, Tenerife, Spain 32 Department of Nephrology, Hospital Universitario Severo Ochoa, Leganés, Madrid, Spain 33 Department of Pediatric Nephrology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 34 Department of Nephrology, Hospital Universitario de Getafe, Madrid, Spain 35 Department of Nephrology, Hospital Universitario de Bellvitge, Barcelona, Spain 672 KIDNEY360 36 Department of Nephrology, Hospital Doctor Negrı́n, Gran Canaria, Spain 37 Department of Nephrology, Hospital Universitario Clı́nico San Carlos, Madrid, Spain 38 Department of Nephrology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 39 Department of Nephrology, Hospital General Universitario de Castellón, Castellón, Spain 40 Department of Nephrology, Hospital Universitario Marqués de Valdecilla, Santander, Spain 41 Current address: Department of Nephrology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain 42 Department of Nephrology, Hospital Regional Universitario Carlos Haya, Málaga, Spain 43 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientı́ficas, Madrid and Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid, Spain 44 Department of Immunology, Universidad Complutense de Madrid, Madrid, Spain