C3 Glomerulopathy and Related Disorders in ChildrenEtiology-Phenotype Correlation and Outcomes

Edwin K.S. Wong ,1,2,3 Kevin J. Marchbank ,1,2 Hannah Lomax-Browne,4 Isabel Y. Pappworth,2 Harriet Denton,2

Katie Cooke,2 Sophie Ward,2 Amy-Claire McLoughlin,2 Grant Richardson,2 Valerie Wilson,1 Claire L. Harris ,1,2

B. Paul Morgan,5 Svetlana Hakobyan,5 Paul McAlinden,6 Daniel P. Gale ,7 Heather Maxwell,8 Martin Christian,9

Roger Malcomson,10 Timothy H.J. Goodship,1 Stephen D. Marks ,11,12 Matthew C. Pickering ,4

David Kavanagh ,1,2,3 H. Terence Cook,4 and Sally A. Johnson,1,2,13 on behalf of the MPGN/DDD/C3Glomerulopathy Rare Disease Group and National Study of MPGN/DDD/C3 Glomerulopathy Investigators*

AbstractBackground and objectivesMembranoproliferative GN and C3 glomerulopathy are rare and overlappingdisorders associated with dysregulation of the alternative complement pathway. Specific etiologic data forpediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based onretrospective studies without etiologic data.

Design, setting, participants, & measurementsA total of 80 prevalent pediatric patients withmembranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-upwithin the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determinedusing a Cox proportional hazards model. Kidney and transplant graft survival was determined using theKaplan–Meier method.

Results Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complexmembranoproliferative GN, and ten with immune-complex GN. Patients were aged 2–15 (median, 9; interquartilerange, 7–11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired(anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% ofpatients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18(interquartile range, 2.13–8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplantsperformed in eight patients, two of which failed due to recurrent disease. Presence of.50% crescents on theinitial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazardratio, 6.2; 95% confidence interval, 1.05 to 36.6; P,0.05). Three distinct C3 glomerulopathy prognostic groupswere identified according to presenting eGFR and.50% crescents on the initial biopsy specimen.

Conclusions Crescentic disease was a key risk factor associated with kidney failure in a national cohort ofpediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. PresentingeGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquiredabnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

CJASN 16: 1639–1651, 2021. doi: https://doi.org/10.2215/CJN.00320121

IntroductionMembranoproliferative GN (MPGN) is a pattern ofglomerular injury characterized by increased mesan-gial matrix and cellularity and thickening of capillarywalls (1). MPGN classifies into immune-complexMPGN and C3 glomerulopathy on the basis of relativecomplement and Ig staining on biopsy specimens.C3 glomerulopathy subclassifies into dense depositdisease (DDD), with characteristic dense osmophilicintramembranous deposits, and C3 glomerulonephri-tis (C3GN), where other patterns of electron-densedeposition are seen (2).

Immune-complex MPGN and C3 glomerulopathyare rare, with estimated incidence of 1–4 cases per

million population (3,4). Acquired and genetic abnor-malities associated with fluid-phase dysregulation ofthe alternative pathway of complement have beenidentified in immune-complex MPGN and C3 glomer-ulopathy (5–16).Immune-complex MPGN and C3 glomerulopathy

carry a poor kidney prognosis, with a median time tokidney failure of around 10 years from diagnosis(10,17–21). After kidney transplantation, disease recur-rence occurs in the majority of grafts and is the pre-dominant cause of graft failure in 50%–90% of trans-plant recipients (10,19,22–27).A diagnosis of MPGN/C3 glomerulopathy in child-

hood has lifelong consequences for children and their

Due to the number ofcontributing authors,the affiliations arelisted at the end of thisarticle.

Correspondence:Dr. Sally A. Johnson,National RenalComplementTherapeutics Centre,Building 26, RoyalVictoria Infirmary,Queen Victoria Road,Newcastle upon Tyne,NE1 4LP, UnitedKingdom. Email: sally.johnson15@nhs.net

www.cjasn.org Vol 16 November, 2021 Copyright © 2021 by the American Society of Nephrology 1639

Article

families. Pertinent questions focus on etiology, treatment,and prognosis. Until recently, most information to addressthese questions is extrapolated from cohort analyses, com-prising mixed groups of adults and children (10,11) orsmall pediatric cohorts (28,29).Our aim was to build a cohort of children with MPGN/

C3 glomerulopathy to describe the spectrum of histologicdisease, investigate the frequency of acquired and geneticalternative pathway defects, and define clear prognosticgroups to facilitate counseling and stratify emerging thera-peutic options in children. We extended the cohort toinclude patients with immune-complex GN withoutMPGN pattern, who did not fulfill diagnostic criteria forIgA nephropathy or systemic lupus erythematosus, whomwe hypothesized may also have underlying alternativepathway dysregulation.Here, we report our findings from the National Study of

MPGN, DDD, and C3 Glomerulopathy, which recruitedchildren from all pediatric nephrology centers in Great Brit-ain, using the infrastructure of the National Registry ofRare Kidney Diseases (RaDaR; https://rarerenal.org/radar-registry/).

Materials and MethodsStudy DesignPatients were recruited into a multicenter observational

cohort study from all pediatric kidney units in Great Brit-ain. Prevalent patients with a diagnosis of MPGN, DDD,C3GN, or immune-complex GN were identified by localclinicians and were eligible to be invited for recruitmentinto the study. Patients were recruited between 2011 and2015.

Histopathologic DataExpert central pathology review included the original

light microscopy, the original biopsy specimen report, and,where available, immunostaining and electron microscopy.Kidney biopsy specimens were classified according to theC3 glomerulopathy consensus report into four differentsubgroups: (1) C3GN and (2) DDD (together comprisingC3 glomerulopathy), and (3) immune-complex MPGN and(4) immune-complex GN (together comprising immune-complex disease [IC-disease]) (Figure 1A).

Clinical and Laboratory InformationClinical data were entered into clinical record forms

into the RaDaR database and included height, serum cre-atinine, urinary protein-creatinine ratio (P:Cr) or albumin-creatinine ratio (A:Cr), C3, and C3 and C4 nephritic factor,all collected at baseline (the time of initial diagnosticbiopsy). eGFR was calculated using the modified Schwartzformula (30).UK kidney units routinely report clinical data to the

Renal Registry via RaDaR—these data were extracted toprovide prospective longitudinal data and determineoutcomes.

Treatment InformationDetails of any use of angiotensin-converting enzyme

inhibitor/angiotensin receptor blocker (ACE/ARB) or

immunosuppression during the clinical course wereextracted from RaDaR. Treatments were used at the clini-cians’ discretion. In general, patients received (1) ACE/ARB use but no immunosuppression use at any time; (2)corticosteroids and no other immunosuppression; or (3)corticosteroids and mycophenolate mofetil (MMF). Weidentified a further group of patients receiving other non-specific immunosuppression that we subdivided into thoseusing azathioprine or calcineurin inhibitor and those (theintense group) who received any of cyclophosphamide, rit-uximab, eculizumab, or plasma exchange at any time.

Complement Testing, Autoantibodies, and GeneticsComplement and Autoantibody Testing. At recruit-

ment, blood samples were collected for further complementstudies. Serum C3 and C4 were measured by immunoturbi-dimetric assays (Roche Cobas Analyzer).

Screening for C3 nephritic factor was performed byimmunofixation (1).

Screening for autoantibodies to factor H (FH) usingELISA was performed as described previously, andincluded epitope binding studies of short consensusrepeats 1–7 (amino [N] terminus), 8–15, 16–18, and 19–20(carboxy terminus) (2). The ELISA was adapted to screenfor autoantibodies to C3b and factor B (FB) using purifiedproteins (Comptech) and FH-related (FHR) proteins usingrecombinant FHR proteins generated in mammalian celllines. Specificity of antibodies to FHR proteins was deter-mined by Western blotting. Screening for autoantibodies toCD35, CD46, and CD55 was performed as described previ-ously (3).

Control samples, as indicated, were randomly selectedfrom a batch of 200 healthy blood donors (National HealthService [NHS] Blood and Transplant), which were normallydistributed and ranging in age from 17 to 72 years of age(median age was 44, 56% were female, 95% were White).The 97.5 percentile was used to assign positive results.

Complement FHR protein 5 (CFHR5) was detected byWestern blotting using patient sera under nonreducingconditions. Plasma soluble C5b-9 levels were measured asdescribed (4).

Genetic Screening. Genetic screening of all exons andflanking regions of C3 (5), CFB (6), CFH (7), CFI (8), CD46(9), and DGKE (10) was performed and rare genetic var-iants and common polymorphisms were identified aftertargeted next-generation sequencing and confirmatorySanger sequencing. Rare genetic variants were defined asminor allele frequency ,0.01 in the exome variant serverdatabase (evs.gs.washington.edu). Screening for genomicdisorders affecting CFH, CFHR1, CFHR2, CFHR3, andCFHR5 was undertaken using multiplex ligation-dependent probe amplification (11).

Definitions and OutcomesDuration of follow-up was from baseline until latest

available eGFR or kidney failure (eGFR ,15 ml/min per1.73 m2, onset of maintenance dialysis, or preemptive trans-plantation). Patients with an eGFR of .90 ml/min per 1.73m2 at latest follow-up or those with an eGFR of ,90 ml/min per 1.73 m2 at latest follow-up, but their eGFR waswithin 15 ml/min per 1.73 m2 of baseline eGFR kidney

1640 CJASN

function, were classified as having either (1) completeremission if latest urinary P:Cr was ,500 mg/g or equiva-lent, or (2) partial remission if latest urinary P:Cr wasbetween 500 and 3000 mg/g or equivalent. Crescentic GNwas defined as having crescents within .50% of viableglomeruli.

Statistical AnalysisStatistical analysis was performed using SPSS software

(IBM). Baseline clinical and histologic characteristicswere expressed as median (interquartile range; IQR) forcontinuous variables and percentage for categoric varia-bles. These were compared using Kruskal–Wallis (for

continuous variables) and Fishers exact (for categoricvariables) tests. A Bonferroni correction was used formultiple comparisons. To determine risk factors for kid-ney survival, Cox proportional hazards models wereused. We assessed baseline clinical, histologic, and com-plement risk factors, including complement levels atbaseline and follow-up, presence of complement anti-bodies, and rare genetic variants. Significant risk factorsfor kidney survival identified by unadjusted analysiswere subjected to multivariable analysis. Kidney andtransplant graft survival was determined using theKaplan–Meier method, and group comparisons wereperformed using the log-rank test.

All Patients80

C3 dominance on immunostaining?

C3G39

C3GN25

DDD14

IC-MPGN31

IC-GN10

Immune-complexdisease

41

Yes

Linear intramembranous dense deposits on electron microscopy? MPGN pattern of glomerular injury?

No

Yes YesNo No

A

C3GNDDDIC-GNIC-MPGN

2.00

15B

10

Pathology

5

0

3.00

4.00

5.00

6.00

7.00

8.00

9.00

Age at Presentation (years)

Num

ber

of P

atie

nts

10.0

0

11.0

0

12.0

0

13.0

0

14.0

0

15.0

0

Figure 1. | Summary of pathology and age of patients included in the cohort. (A) Classification of pathology after central review. Patientswith C3 glomerulopathy (C3G) were subclassified into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Patients withnon–C3 glomerulopathy had immune-complex forms of GN and were subclassified into immune-complex membranoproliferative glomer-ulonephritis (IC-MPGN) and immune-complex glomerulonephritis (IC-GN). (B) Age distribution of patients. Age of presentation rangedfrom 2 years to 15 years, categorized by pathology classification.

CJASN 16: 1639–1651, November, 2021 Childhood C3G: Etiology and Outcome, Wong et al. 1641

The MPGN/DDD/C3 Glomerulopathy Rare DiseaseGroup (RDG) of the Renal Association acted as a steeringcommittee for the study.

Ethics StatementEthical approval for this study was granted by North

Somerset and South Bristol Research Ethics Committee (ref-erence 09/H0106/72, 11-12-09). Patients were includedafter informed consent/assent in accordance with the Dec-laration of Helsinki.

ResultsStudy CohortA total of 80 patients were recruited into the study,

median 1.95 (IQR, 0.25–4.13) years from baseline and fol-lowed up for a median of 5.18 (IQR, 2.13–8.08) years. Fol-lowing central histopathologic review, 39 patients wereclassified as having C3 glomerulopathy, including 14patients with DDD and 25 with C3GN. The other 41patients with IC-disease were classified as immune-complex MPGN (31 patients) and immune-complex GN(ten patients) (Figure 1A). Of the 80 patients in this study,51 were included in the recent National Institute for HealthResearch (NIHR) BioResource Rare Diseases study, whichreported the results of whole-genome sequencing and agenome-wide association study in 165 adult and pediatricpatients with primary MPGN and C3 glomerulopathy (31).

Clinical CharacteristicsPatients were aged 2–15 (median, 9; IQR, 7–11) years at

diagnosis (Figure 1B), and 45 patients (56%) were female.Patients typically presented with nephrotic-range protein-uria (68%), hypoalbuminemia (76%), and hematuria (91%).Low eGFR (,90 ml/min per 1.73 m2) was a feature at pre-sentation in 44% of patients. Patients with C3 glomerulop-athy were the only patients to present with severe kidneydysfunction (eGFR ,30 ml/min per 1.73 m2; Table 1).

Pathologic FeaturesThe most common pattern of glomerular injury was

MPGN (55 patients; 69%), observed in 41 patients (100%)with immune-complex MPGN, five patients (36%) withDDD, and 19 patients (76%) with C3GN (Table 1). Otherpathologic features are summarized in Table 1; notably,crescentic GN was observed in four patients (5%), all DDD.Most patients displayed no evidence of chronic damage.

Complement AbnormalitiesMedian C3 levels for the whole cohort were 0.31 (IQR,

0.14–0.50) g/L and ranged from a median of 0.15 g/L inpatients with DDD to 0.50 g/L in patients with immune-complex GN. Median C4 levels for the whole cohort were0.14 (IQR, 0.07–0.26) g/L, and levels were significantlylower in patients with immune-complex MPGN (median,0.12 g/L) and immune-complex GN (median, 0.13 g/L)compared with patients with DDD (0.26 g/L) (P50.02;Table 2).

AutoantibodiesAutoantibodies were identified in 37 patients (46%)

(Table 2); C3 nephritic factor in 22 patients (39%), autoanti-bodies to FH (anti-FH) in 13 patients (17%), autoantibodiesto FB (anti-FB) in seven patients (9%), and autoantibodiesto C3b (anti-C3b) in five patients (7%) (Figure 2). Eightpatients had more than one autoantibody detected (Table3). There were no differences in serum C3 or C4 concentra-tion at baseline, regardless of whether an autoantibody wasdetected (Table 3).

C3 nephritic factor was most likely to be detected inpatients with DDD (62%; P50.04; Table 2). Anti-FH boundpredominantly to the N terminus of FH in ten of 13patients and was not associated with the CFHR3/1 deletionin homozygosity (Supplemental Table 1). The age of onsetof disease in this group of patients was a median of 8 (IQR,6–9) years.

C3 levels during follow-up were lower (median, 0.55g/L; IQR, 0.35–0.74 g/L; P50.01) in patients who haddetectable C3 nephritic factor compared with those that didnot (median, 0.93 g/L; IQR, 0.69–1.08 g/L). C4 levels dur-ing follow-up were lower (median, 0.14 g/L; IQR, 0.09–0.18g/L; P50.03) in patients who had a detectable anti-FH anti-bodies compared with those that did not (median, 0.19g/L; IQR, 0.15–0.24 g/L; Figure 3).

Autoantibodies to other complement regulatory proteins(FI, CD46, CD35, CD55, and CD59) (Supplemental Figure1) and FHR proteins (Supplemental Figure 2) were notidentified. Soluble C5b-9 levels at recruitment were ele-vated (median, 223.3 ng/ml; IQR, 110.0–429.2 ng/ml; nor-mal range ,200 ng/ml; Supplemental Table 2), althoughno trends associated with presence of complement autoan-tibodies or rare genetic variants.

Genetic AnalysisRare genetic variants in the complement genes examined

were identified in six patients (9%; Table 2). Of these, twopatients had two rare genetic variants (SupplementalTable 3). Most variants have previously been categorizedas “likely benign” or of “uncertain significance” (32,33).Three patients with rare genetic variants (50%) also had acomplement autoantibody (Supplemental Table 3).

The C3 pR102G; c304C.G single nucleotide polymor-phism was associated with a higher risk of DDD (oddsratio, 3.14; 95% confidence interval [95% CI], 1.45 to 6.8;P50.004; Supplemental Table 4). None of the other singlenucleotide polymorphisms were associated with a higherrisk of disease (Supplemental Table 4). No patients had theCFHR3/1 deletion in homozygosity (Supplemental Table1). There was no evidence of other copy number variationin this cohort (data not shown) and no genomic or proteo-mic evidence (Supplemental Figure 3) of CFHR5 nephropa-thy. One previously reported patient with immune-complex GN had a likely pathogenic variant in DGKEfound in homozygosity (c.323G.A; p.C108Y; Table 2) (34).

TreatmentsTreatments used in the cohort are summarized in Table 4

and Supplemental Table 5. Overall, 16 patients (20%)received treatment with ACE/ARB only. The remainder allreceived immunosuppression with at least one agent, most

1642 CJASN

commonly prednisolone (22 patients) or prednisolone incombination with MMF (17 patients). Fourteen patientsreceived a more intense regimen that included at least oneof the following: rituximab, cyclophosphamide, plasmaexchange, or eculizumab.Patients receiving ACE/ARB only were less likely to

have an eGFR of ,90 ml/min per 1.73 m2 (P50.002) oralbumin ,3.5 g/dl (P50.006) at baseline. Patients receivinga more intense regime of immunosuppression were morelikely to have C3 glomerulopathy (P50.001), an eGFR of,90 ml/min per 1.73 m2 (P,0.001), or crescentic GN(P50.001).

OutcomesDisease Remission. Complete or partial remission was

observed in 28 patients (71%) with C3 glomerulopathy and36 patients (88%) with IC-disease. Among patients with C3glomerulopathy, complete or partial remission was lesslikely among patients presenting with low albumin(P50.01) or abnormal eGFR (P50.01) and those receivingintense immunosuppression (P50.008) (SupplementalTable 6). No clinical features were associated with a lowerlikelihood of remission in patients with IC-disease(Supplemental Table 7). The presence of C3 nephritic factoror anti-FH antibodies were not associated with remission

Table 1. Clinical and pathologic characteristics at presentation in pediatric C3 glomerulopathy, immune-complex membranoproli-ferative glomerulonephritis, and immune-complex glomerulonephritis

CharacteristicsNumber ofPatients withAvailable Data

C3 Glomerulopathy Immune-Complex Disease

C3Glomerulonephritis

DenseDepositDisease

Immune-ComplexMembranoproliferativeGlomerulonephritis

Immune-ComplexGlomerulonephritis

Number of patients 80 25 14 31 10Age, yr, median (IQR) 80 9 (7–12) 9.5 (6–11) 9 (6–11) 8 (3–8)Male patients, n (%) 80 8 (32) 9 (64) 14 (45) 4 (40)Patients with nephrotic-range

proteinuria (P:Cr .3000 mg/g,A:Cr .2500 mg/g, or 41 ondipstick), n (%)

73 13 (62) 7 (54) 22 (73) 8 (89)

Patients with serum albumin#3.5 g/dl, n (%)

75 16 (73) 10 (71) 26 (84) 5 (63)

Patients with hematuria, n (%) 60 16 (89) 12 (100) 19 (86) 8 (100)Patients with eGFR ,90 ml/min per

1.73 m2, n (%)75 10 (44) 12 (86) 7 (23) 4 (50)

Patients with eGFR ,30 ml/min per1.73 m2 (including patientsrequiring temporary KRT), n (%)

75 4 (17)a 4 (29)a 0 (0) 0 (0)

Patients with specified pattern ofglomerular injury, n (% ofhistologic subgroup)

80

Mesangial proliferative GN 4 (16) 5 (36) 0 (0) 7 (70)Diffuse endocapillary

proliferative GN2 (8) 0 (0) 0 (0) 2 (20)

Crescentic GN 0 (0) 4 (29) 0 (0) 0 (0)Membranoproliferative GN 19 (76) 5 (36) 31 (100) 0 (0)Other 0 (0) 0 (0) 0 (0) 1 (10)b

Patients with specified amount ofglomerulosclerosis, n (% ofhistologic subgroup)

74

None 18 (79) 12 (92) 23 (82) 9 (90)1%–25% 3 (13) 1 (8) 5 (18) 1 (10)26%–50% 2 (9) 0 (0) 0 (0) 0 (0)

Patients with specified amount ofcrescents, n (% of histologicsubgroup)

74

None 18 (78) 3 (23) 26 (93) 7 (70)1%–50% 5 (22) 6 (46) 2 (7) 3 (30).50% 0 (0) 4 (31) 0 (0) 0 (0)

Patients with specified amount ofinterstitial fibrosis/tubularatrophy, n (% of histologicsubgroup)

69

None 15 (71) 10 (77) 18 (69) 8 (89)1%–25% 5 (24) 3 (23) 6 (23) 1 (11)26%–50% 1 (5) 0 (0) 2 (8) 0 (0)

eGFR (expressed in ml/min per 1.73 m2) was calculated by modified Schwartz formula. IQR, interquartile range; P:Cr, urinaryprotein-creatinine ratio; A:Cr, urinary albumin-creatinine ratio.aIncludes one patient with C3 glomerulonephritis and three patients with dense deposit disease requiring KRT.bOne patient had focal and segmental necrotizing GN.

CJASN 16: 1639–1651, November, 2021 Childhood C3G: Etiology and Outcome, Wong et al. 1643

in patients with either C3 glomerulopathy (SupplementalTable 6) or those with IC-disease (Supplemental Table 7).

Kidney Survival. During the follow-up period, 11(14%) patients had progressed to kidney failure. In a multi-variable analysis that included C3 glomerulopathy, cres-centic GN, glomerulosclerosis, eGFR ,90 ml/min per 1.73m2 at presentation, and intense immunosuppression, onlycrescentic GN remained significantly associated with kid-ney failure (hazard ratio, 6.2; 95% CI, 1.05 to 36.8; P,0.05).The finding of rare complement gene variants, autoanti-bodies to complement components, or complement levelsat baseline or at follow-up did not associate with progres-sion to kidney failure.Kidney survival according to histologic subgroup is

shown in Supplemental Figure 4A. We stratified patientswith C3 glomerulopathy into three groups with signifi-cantly different short- and medium-term outcomes(Supplemental Figure 4B). Of the patients with C3 glomer-ulopathy, all 14 patients with an eGFR of .90 ml/min per1.73 m2 at baseline did not progress to kidney failure dur-ing the course of this study. All eight patients with C3 glo-merulopathy that progressed to kidney failure had aneGFR of ,90 ml/min per 1.73 m2 at baseline. Among these,a pattern of crescentic GN identified patients with theshortest kidney survival (mean, 1.7 years; 95% CI, 0.0 to3.8 years) compared with those that did not have crescenticGN (mean, 8.3 years; 95% CI, 6.0 to 10.6; P50.009). Threepatients with IC-disease reached kidney failure, includingtwo patients with immune-complex MPGN that did notprogress to kidney failure until after 10 years.

Kidney Transplant. Of 11 patients that progressed tokidney failure, eight underwent kidney transplantation.

Out of nine transplant grafts, there were four casesof recurrent disease (all C3 glomerulopathy), of whichtwo were lost due to recurrent disease (SupplementalFigure 5).

DiscussionWe report comprehensive etiologic and outcome

data from a national pediatric cohort of MPGN/C3glomerulopathy.

Cohorts comprising immune-complex MPGN, DDD, andC3GN are well described (Supplemental Table 8), and thedistribution of these diseases within our cohort is compara-ble, suggesting individual phenotypes are not seen morecommonly in children. The predominant age of diseasepresentation in children (between 7 and 11 years) is inkeeping with previous studies (28).

We identified acquired alternative pathway abnormali-ties in approximately half of patients, including in patientswith immune-complex GN, suggesting a role of comple-ment dysregulation in immune-complex GN. Therefore,further studies are required.

C3 nephritic factor was the most commonly detectedautoantibody in our cohort, although detected in a lowerproportion than in previously reported mixed age-groupcohorts (10,11). Our lower rate of C3 nephritic factor maybe due to our wide ascertainment of cases or could reflect alower prevalence of C3 nephritic factor in children.

Anti-FH in our cohort was identified in a comparableproportion of patients to previous reports (15,16,35), andwe confirm specificity of anti-FH in MPGN/C3 glomerul-opathy to the N-terminal regulatory domain of FH, and the

Table 2. Prevalence of complement abnormalities in C3 glomerulopathy, immune-complex membranoproliferative glomerulonephri-tis, and immune-complex glomerulonephritis

Complement AbnormalityNumber ofPatients withAvailable Data

C3 Glomerulopathy Immune-Complex Disease

C3Glomerulonephritis

Dense DepositDisease

Immune-ComplexMembranoproliferativeGlomerulonephritis

Immune-ComplexGlomerulonephritis

Serum C3 at presentation(g/L), median (IQR); n

57 0.39 (0.16–0.44); 18 0.15 (0.09–0.45); 11 0.23 (0.15–0.65); 21 0.50 (0.29–0.80); 7

Serum C4 at presentation(g/L), median (IQR); n

57 0.19 (0.08–0.26); 16 0.26 (0.15–0.31); 11 0.12 (0.06–0.14); 21 0.13 (0.07–0.18); 7

Patients with C3 nephriticfactor, n (%)a

80 6 (26) 8 (62) 7 (23) 1 (10)

Patients with anti-FH Ab, n (%) 78 3 (13) 3 (21) 4 (13) 3 (30)Patients with anti-FB Ab, n (%) 77 2 (8) 1 (7) 4 (14) 0 (0)Patients with anti-C3b Ab,

n (%)77 0 (0) 2 (15) 3 (11) 0 (0)

Patients with any complementautoantibody, n (%)

80 10 (40) 9 (64) 14 (45) 4 (40)

sC5b-9 (ng/L), median (IQR); n 72 217 (95–410); 21 232 (154–437); 12 235 (98–432); 30 225 (98–584); 9Patients with rare genetic variant

in complement gene, n (%)b70 1 (5) 1 (8) 4 (15) 0 (0)

Patients with rare geneticvariant in DGKE, n (%)

70 0 (0) 0 (0) 0 (0) 1 (13)

n refers to the number of patients with data available; percentages are expressed as number of patients tested. IQR, interquartilerange; FH, factor H; Ab, autoantibody; FB, factor B; sC5b-9 soluble C5b-9; DGKE, diacyl glycerol kinase «.aC3 nephritic factor detected at any point during presentation or follow-up.bComplement genes tested were C3, CFB, CFH, CFI, and CD46.

1644 CJASN

lack of association with CFHR3/CFHR1 homozygous dele-tion in our cohort, in keeping with previous studies (15,16).We identified patients with anti-FB and anti-C3b, both pre-viously reported in cohorts of immune-complex MPGN

and C3 glomerulopathy (36). The proportion with anti-FBis in keeping with the recent study showing anti-FB in 14%of patients with C3 glomerulopathy in contrast to 91% ofpatients with postinfectious GN (37).

4000

3000

2000

1250

1000

750

500

250

0

1.5 1.50

1.25

1.00

0.75

0.50

0.25

0.00

–0.25

–0.50

1.0

0.5

0.0OD

450

OD

450

RU

–0.5

–1.0

Patients Controls Patients Controls Patients Controls

Factor H Factor BC3b

A

B C

Figure 2. | Screening for antibodies against complement proteins. (A) Screening serum from 78 patients with C3GN, DDD, IC-MPGN, andIC-GN for autoantibodies against complement factor H (FH). Line indicates 97.5th percentile of samples from blood donor controls, theminimum threshold for identifying an autoantibody. Screening serum from 77 patients with C3GN, DDD, IC-MPGN, and IC-GN forautoantibodies against (B) C3b and (C) complement factor B (FB). Line indicates 97.5th percentile, the minimum threshold for identifying anautoantibody. Autoantibodies were identified against C3b (five patients) and FB (seven patients). OD 450, OD measured at 450 nm; RU,response units titrated to standard published in Goodship et al. (15).

Table 3. Complement profile of patients with anticomplement autoantibodies

Parameter

Complement AutoantibodyNo Detectable

Antibody P ValueaC3 NephriticFactor

AnticomplementFactor H

Autoantibodies

AnticomplementFactor B

Autoantibodies

Anti-C3bAutoantibodies

AnyAntibody

Patients testingpositive,n (% of cohort)

22 (29) 13 (17) 7 (9) 5 (7) 37 (46)b 43 (54)

Serum C3 atpresentation(g/L), median(IQR)

0.17 (0.09–0.50) 0.23 (0.14–0.52) 0.41 (0.09–1.15) 0.17 (0.15–0.17) 0.23 (0.13–0.69) 0.31 (0.14–0.49) 0.83

Serum C4 atpresentation(g/L), median(IQR)

0.21 (0.11–0.26) 0.12 (0.09–0.26) 0.11 (0.0.08–0.26) 0.14 (0.14–0.15) 0.15 (0.06–0.26) 0.14 (0.10–0.26) 0.77

Plasma C5b9 atrecruitment tostudy (mg/ml),median (IQR)

193 (95–360) 210 (121–998) 111 (49–339) 329 (131–416) 190 (103–342) 248 (146–466) 0.29

IQR, interquartile range.aP values are comparing patients from “Any Antibody” column and those in “No Detectable Antibody” column.bEight patients had more than one anticomplement autoantibody. All of these had a C3 nephritic factor plus additionalautoantibodies as follows: one with anti–factor B, three with anti–factor H, one with anti-C3b, one with anti–factor H andanti–factor B, and two with anti–factor H and anti-C3b autoantibodies.

CJASN 16: 1639–1651, November, 2021 Childhood C3G: Etiology and Outcome, Wong et al. 1645

The rate of rare genetic variation in our cohort was lowin comparison to larger cohorts (10,11), and this could bedue our wide ascertainment of cases or a lower rate inchildren compared with adults. However, the predomi-nance of acquired abnormalities compared with geneticones is comparable to previous cohorts (10,11). A possibleexplanation for an autoimmune basis of MPGN/C3 glo-merulopathy has been postulated in a recent study (to

which 51 of our 80 patients contributed data), whichshowed an association of HLA type with MPGN/C3 glo-merulopathy (31).

C3 levels were comparable, regardless of whether weidentified an alternative pathway abnormality. It is possiblethat patients with no alternative pathway abnormalitydetected in our cohort have an acquired alternative path-way abnormality that we have yet to identify (e.g., C5

C3GN DDD IC-GN IC-MPGN

2.00DiagnosisFollow-Up

1.50

1.00

.50

.00

2.00

1.50

1.00

.50

.00Detected

C3 Nephritic Factor C3 Nephritic Factor

Autoantibodies to FH Autoantibodies to FH

C3

leve

ls (

g/L

)C

3 le

vels

(g

/L)

C3

leve

ls (

g/L

)

Not Detected Detected Not Detected

Detected Not DetectedDetected Not Detected

2.00

1.50

1.00

.50

.00

C4

leve

ls (

g/L

)

.60

.40

.20

.00

C4

leve

ls (

g/L

)

.60

.40

.20

.00

DiagnosisFollow-Up

DiagnosisFollow-Up

DiagnosisFollow-Up

DiagnosisFollow-Up

C4

leve

ls (

g/L

)

C3GN DDD IC-GN IC-MPGN

.60

.40

.20

.00

DiagnosisFollow-Up *

*

A B

C D

E F

P=0.01

P=0.03

Figure 3. | Comparison of complement C3 and C4 levels in the cohort. Box and whisker plot showing C3 and C4 levels at diagnosis andat follow-up depending on (A and B) the four pathologic subgroups and whether patients had (C and D) detectable C3 nephritic factor or(E and F) anti–factor H (anti-FH) autoantibody.

1646 CJASN

nephritic factor), and further work is being undertaken toassess this.We also found that C4 levels were lower at presentation

compared with at follow-up in patients with IC-disease. Inprevious mixed age-group cohorts, low presenting C4 wasreported in up to 15% of patients (Supplemental Table 8),and in 25% of the previous largest pediatric cohort (28).The finding of lower C4 may indicate a transient responseto a triggering infection in pediatric MPGN/C3 glomerul-opathy. In keeping with this is the observation that C4 lev-els were higher at recruitment to the study. C4 levels werelower at follow-up in those with anti-FH antibodies, imply-ing ongoing classic pathway activation, possibly triggeredby deposited antibody/complement immune complexes(38).In contrast, antibodies to other complement proteins

were not detected (FI, CD35, CD46, CD55, and FHR pro-teins), and we found only one patient with a variant inDGKE (previously described in MPGN [39]), suggestingthese proteins do not play a major role in the etiology ofMPGN/C3 glomerulopathy.This study did not set out to determine treatment effi-

cacy. Our data are limited to which treatments were usedand are unable to take into account their timing in relation

to disease onset and relationship to complement bio-markers that were performed upon recruitment to ourstudy. However, our data help provide an overview oftreatments used in children with MPGN/C3 glomerulop-athy. We report favorable outcomes in a majority ofpatients receiving either ACE/ARB only or moderateimmunosuppression, including either prednisolone only orprednisolone and MMF. The favorable outcomes of thosereceiving moderate immunosuppression are comparablewith those in previous observational studies of childrenreceiving prednisolone only (40), or in mixed adult andpediatric cohorts receiving a combination of MMF andprednisolone (41–44). Otherwise, controlled trials inimmune-complex MPGN and C3 glomerulopathy are lack-ing, with only a randomized controlled trial in childrenwith MPGN (before the classification of immune-complexMGPN and C3 glomerulopathy) reporting a benefit in kid-ney survival of long-term treatment with high-dose cortico-steroids over placebo (45); however, such doses are associ-ated with adverse effects. In contrast, a final group (14 of80 patients; 18%) in our cohort received intense immuno-suppression. These patients predominantly had C3 glomer-ulopathy and were characterized by low eGFR or .50%crescents at presentation; suggesting that, at least in some

Table 4. Treatments received in pediatric C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, andimmune-complex glomerulonephritis

Parameter Number ofPatients

Treatment

Angiotensin-Converting

Enzyme Inhibitor/Angiotensin

Receptor Blocker

PrednisolonePrednisolone/Mycophenolate

MofetilPrednisolone/1 Intense

All patients, n (%) 80 16 (20) 22 (28) 17 (21) 11 (14) 14 (18)Pathologic subgroup; n

(% of subgroup) receivingeach treatmentC3GN 25 7 (28) 4 (16) 3 (12) 4 (16) 7 (28)Dense deposit disease 14 2 (14) 2 (14) 3 (21) 1 (7) 6 (43)Immune-complex MPGN 31 4 (13) 12 (39) 8 (26) 6 (19) 1 (3)Immune-complex GN 10 3 (30) 4 (40) 3 (30) 0 (0) 0 (0)

Patients with nephrotic-rangeproteinuria, n (%)a

50 8 (16) 16 (32) 13 (26) 6 (12) 7 (14)

Patients with non–nephrotic-rangeproteinuria, n (%)

23 7 (30) 5 (22) 3 (13) 4 (17) 4 (17)

Patients with eGFR ,90 ml/minper 1.73 m2, n (%)

33 1 (3) 9 (27) 7 (21) 4 (12) 12 (36)

Patients with eGFR .90 ml/minper 1.73 m2, n (%)

42 13 (31) 12 (29) 9 (21) 6 (14) 2 (5)

Patients with serum albumin,3.5 g/dl, n (%)

57 7 (12) 15 (26) 13 (23) 9 (16) 13 (23)

Patients with serum albumin.3.5 g/dl, n (%)

18 8 (44) 5 (28) 3 (17) 1 (6) 1 (6)

Patients with histology showing.50% crescents, n (%)

4 0 (0) 0 (0) 0 (0) 0 (0) 4 (100)

Patients with histology showing,50% crescents, n (%)

76 16 (21) 22 (29) 17 (22) 11 (15) 10 (13)

eGFR (expressed in ml/min per 1.73 m2) was calculated by modified Schwartz formula. n refers to the number of patients;percentages are expressed as number of patients tested. MPGN, membranoproliferative GN; prednisolone/1, patients receivingprednisolone in combination with azathioprine or tacrolimus; intense, patients who received any of rituximab, cyclophosphamide,plasma exchange, or eculizumab; C3GN, C3 glomerulopathy; P:Cr, urinary protein-creatinine ratio; A:Cr, urinary albumin-creatinine ratio.aNephrotic-range proteinuria defined as P:Cr of .3000 mg/g, A:Cr of .2500 mg/g, or 41 on dipstick.

CJASN 16: 1639–1651, November, 2021 Childhood C3G: Etiology and Outcome, Wong et al. 1647

patients, these clinical characteristics prompted clinicians tooffer more intense immunosuppression. Despite such treat-ment, these patients had the poorest outcomes, highlight-ing that currently available treatments are likely to beineffective in some patients with MPGN and C3 glomerul-opathy and the unmet need for novel therapies.We found that patients with C3 glomerulopathy and

normal kidney function at presentation had a low risk ofprogression to kidney failure during follow-up. Thesepatients and those with immune-complex MPGN appearto have a more favorable outcome than previous largecohorts (10,11), and are comparable with a recently pub-lished pediatric cohort of a similar size (40). This couldreflect the wide ascertainment of our cohort, and ongoingfollow-up is required to determine their longer-term riskof kidney failure. Nonetheless, these data help the clini-cian to offer more bespoke counseling on prognosis, pos-sibly distinguishing patients with potentially more favor-able longer-term outcomes from those with the worstshort-term outcomes.The question as to whether some children in our cohort

actually had postinfectious GN, contributing to a morefavorable outcome, is important. However, the vast major-ity of participants had evidence of ongoing kidney diseaseat recruitment, many months after onset, and thoserecruited ,6 months after diagnosis did not have betteroutcome than those recruited .6 months after diagnosis,which points away from inadvertent inclusion of patientswith postinfectious GN. Transplant recurrence rate wascomparable with previously described cohorts (25,27).Our study has a number of strengths. The multicenter

recruitment encouraged wide ascertainment, regardless ofdisease severity, and minimized the bias of reporting frompatients referred to a single specialist center. We were ableto conduct central pathology review, which ensured con-sistent classification across the multiple centers, and wefollowed patients longitudinally through the RaDaR data-base. However, the study also has specific limitations notalready discussed. We cannot rule out the possibility thatsome patients eligible for recruitment in our study werenot included. Complement biomarkers from disease onsetwere limited to serum C3 and C4 and C3 nephritic factorand are reliant upon local assays. Data for soluble C5b-9and other complement antibodies could only be measuredfrom samples taken at recruitment to study, a distinct timepoint from baseline. Finally, our cohort had relatively fewpatients progressing to kidney failure, which could explainwhy we did not find significant associations between thecomplement profile of our patients and outcomes.In summary, we propose that, in children diagnosed

with MPGN/C3 glomerulopathy and immune-complexGN, a cause of alternative pathway dysregulation shouldbe considered and that priority should be given to screen-ing for acquired abnormalities. We would start with C3nephritic factor and anti-FH autoantibodies, althoughscreening for anti-FB, C3b, or rare complement genetic var-iants could be considered if initial screening does not iden-tify an abnormality.Currently available treatment strategies, including

immunosuppression with a combination of MMF and corti-costeroids, may have a role in management in addition tosupportive treatments with ACE/ARB. However, children

with abnormal kidney function at presentation, especiallythose with crescentic disease, should be considered a prior-ity for studies of novel treatments, including those target-ing the alternative pathway.

DisclosuresH.T. Cook reports receiving honoraria from Alexion Pharma-

ceuticals and having consultancy agreements with Alexion Phar-maceuticals, Apellis Pharmaceuticals, and Novartis. D.P. Galereports attending advisory boards for Alexion Pharmaceuticals;receiving honoraria from Alexion Pharmaceuticals, Novartis, andOtsuka; having other interests in and relationships with AlportUK,as trustee, and Renal Association Rare Diseases Committee, aschair; and receiving research funding from Travere. T.H.J. Good-ship reports receiving honoraria from and/or attending advisoryboards for Alexion Pharmaceuticals. C.L. Harris reports receivingconsultancy income from, or attending scientific advisory boardsfor, Biocryst Pharmaceuticals, Freeline Therapeutics, GlaxoSmith-Kline, Q32 Bio, and Roche (all income is donated to the university);having consultancy agreements with BioMarin Pharmaceutical,Freeline Therapeutics, Gyroscope Therapeutics, Q32 Bio Inc., andSvar Life Sciences; having patents and inventions with Cardiff Uni-versity; having a secondment to Gyroscope Therapeutics; servingas a scientific advisor for, or member of, Gyroscope Therapeuticsand Q32 Bio Inc; having other interests in/relationships withRaDaR via focus groups related to kidney disease; and receivingresearch income from Ra Pharmaceuticals. S.A. Johnson reportsserving as a scientific advisor or member of the scientific advisoryboard for aHUS Global Registry sponsored by Alexion Pharma-ceuticals (payment is made directly from Alexion to employer andis used to support research at host institution); receiving honorariafrom and attending advisory boards for Alexion Pharmaceuticals;serving as a member of the grant committee for Kidney ResearchUK and as a trustee of the Northern Counties Kidney ResearchFund charity; and attending advisory boards for Novartis Pharma-ceuticals. D. Kavanagh reports receiving honoraria from AlexionPharmaceuticals, Apellis, Gyroscope Therapeutics, Idorsia, andNovartis; receiving research funding from Alexion Pharmaceuti-cals and Gyroscope Therapeutics; having consultancy agreementswith Alexion Pharmaceuticals, Gyroscope Therapeutics, andNovartis; attending advisory boards for Alexion Pharmaceuticalsand for Novartis Pharmaceuticals; having ownership interest in,having patents and inventions with, and serving as a scientificadvisor for/member of Gyroscope Therapeutics; receivingresearch income from Ra Pharmaceuticals; and serving as directorof the UK National Renal Complement Therapeutics Centre.D. Kavanagh’s spouse works for GlaxoSmithKline. R. Malcomsonreports having ownership interest (as an owner and director) inSatsuma Medical Limited, a private medicolegal pathology serv-ices limited company; undertaking fee-remunerated medicolegalwork in relation to child death investigations; and receiving royal-ties related to editorship of medical textbooks. K.J. Marchbankreports having other interests in/relationships with aHUS UK, andRaDaR (United Kingdom) aHUS and MPGN; having consultancyagreements with Bath ASU, Catalyst Biosciences, Freeline Thera-peutics, Gemini Therapeutics Ltd., and MPM Capital; receivingresearch funding from Catalyst Biosciences and Gemini Therapeu-tics; receiving honoraria from Freeline, MPM Capital, and SanquinResearch (Sanquin Blood Supply Foundation); and receivingresearch income from Ra Pharmaceuticals. S.D. Marks reports thatthe Great Ormond Street Hospital for Children NHS Foundation

1648 CJASN

Trust receives funding for immunosuppressive drug studies byAstellas and Novartis and reports serving as an associate editor forpediatric transplantation for British Journal for Renal Medicine, Pedi-atric Nephrology, Pediatric Transplantation, and Transplantation. B.P.Morgan reports receiving honoraria from AstraZeneca; receivingresearch funding from Janssen; and having consultancy agree-ments with, and serving as a scientific advisor for or member ofUCB/Ra Pharma. I.Y. Pappworth reports having consultancyagreements with K & I Consulting. M.C. Pickering reports receiv-ing consultancy fees from Alexion Pharmaceuticals and ApellisPharmaceuticals; having consultancy agreements with AlexionPharmaceuticals, Apellis Pharmaceuticals, and Gyroscope Pharma-ceuticals; and receiving fees for serving on the Gyroscope Pharma-ceuticals Scientific Advisory Board. G. Richardson reports havingconsultancy agreements with AMLo Biosciences. E.K.S. Wongreports receiving honoraria from, serving as a scientific advisor ormember of, and attending advisory boards for, Alexion Pharma-ceuticals, BioCryst Pharmaceuticals, and Novartis Pharmaceuticals.All remaining authors have nothing to disclose.

FundingThe study was funded by Kids Kidney Research and Northern

Counties Kidney Research Fund. E.K.S. Wong was funded by theMedical Research Council grant MR/K023519/1. D. Kavanaghwas funded by the Wellcome Trust and the Medical ResearchCouncil. D.P. Gale is supported by St. Peter’s Trust for Kidney,Bladder and Prostate Research. M.C. Pickering is a Wellcome TrustSenior Fellow in Clinical Science, grant 212252/Z/18/Z.

AcknowledgmentsWe acknowledge support for this project from the following: the

NIHR Biomedical Research Centres based at the BiomedicalResearch Building, Campus for Ageing and Vitality (Newcastleupon Tyne), Imperial College Healthcare NHS Trust and ImperialCollege London, Great Ormond Street Hospital for Children NHSFoundation Trust and University College London, and the NIHRClinical Research Network.

The views expressed are those of the authors and not necessarilythose of the NHS, the NIHR, or the Department of Health.

S.A. Johnson, H.T. Cook, and T.H.J. Goodship designed thestudy; S.A. Johnson was chief investigator; E.K.S. Wong carried outexperiments, analyzed the data, made the figures, and drafted andrevised the manuscript; H.T. Cook and R. Malcomson carried outcentral pathology review with support from H. Lomax-Browne; K.J.Marchbank, C.L. Harris, I.Y. Pappworth, H. Denton, K. Cooke, G.Richardson, B.P. Morgan, S. Hakobyan, and V. Wilson carried outexperiments; M.C. Pickering and D. Kavanagh supervised experi-ments; P. McAlinden was study coordinator; M. Christian and H.Maxwell recruited the most patients to the cohort; S.D. Marksrecruited patients and was chair of the RDG; S.A. Johnson, H.T.Cook, E.K.S. Wong, H. Lomax-Browne, K.J. Marchbank, C.L. Harris,M.C. Pickering, D. Kavanagh, D.P. Gale, and H. Maxwell are mem-bers of the RDG; S.A. Johnson, H.T. Cook, K.J. Marchbank, C.L. Har-ris, B.P. Morgan, M.C. Pickering, D. Kavanagh, D.P. Gale, M. Chris-tian, and S.D. Marks revised the manuscript; and all authorsapproved the final manuscript.

Supplemental MaterialThis article contains the following supplemental material online

at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.00320121/-/DCSupplemental.

Supplemental Appendix. References.Supplemental Table 1. Frequency of CFHR3/1 deletion in pedi-

atric C3 glomerulopathy, immune-complex MPGN, and immune-complex GN.

Supplemental Table 2. Soluble plasma C5b9 levels according tocomplement abnormality.

Supplemental Table 3. Summary of patients with rare comple-ment genetic variants.

Supplemental Table 4. Analysis of 10 single nucleotide polymor-phisms in pediatric C3 glomerulopathy, immune-complex MPGN,and immune-complex GN.

Supplemental Table 5. Immunosuppression regimen in pediatricC3 glomerulopathy, immune-complex MPGN, and immune-complex GN.

Supplemental Table 6. Factors associated with remission inpediatric C3 glomerulopathy.

Supplemental Table 7. Factors associated with remission inpediatric immune-complex disease.

Supplemental Table 8. Summary of previously describedcohorts of patients with MPGN/C3 glomerulopathy.

Supplemental Figure 1. Screening serum from patients with C3glomerulonephritis, dense deposit disease, immune-complexMPGN, and immune-complex GN following central pathologyreview for auto-antibodies against complement factor I (FI), CD46,CD35, CD55, or CD59.

Supplemental Figure 2. Screening serum from patients with C3glomerulonephritis, dense deposit disease, immune-complexMPGN, and immune-complex GN for auto-antibodies againstcomplement factor H–related proteins 1-5 (FHR1-5).

Supplemental Figure 3. Western blot to detect complement fac-tor H–related protein 5.

Supplemental Figure 4. Kaplan–Meier analysis of kidney sur-vival (a) whole cohort by pathology and (b) C3 glomerulopathy bystratified subgroups.

Supplemental Figure 5. Kaplan–Meier analysis of transplantgraft survival in patients with C3 glomerulopathy.

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Received: January 9, 2021 Accepted: September 17, 2021

*The MPGN/DDD/C3 Glomerulopathy Rare Disease Groupincludes Su Brimble, H. Terence Cook, Daniel P. Gale, Julie Gibbs,Rodney Gilbert, Lorraine Harper, Claire L. Harris, Kim Jessup,Sally A. Johnson, Helen Jones, David Kavanagh, Adam Levine,Hannah Lomax-Browne, Andrew Longfellow, Roger Malcomson,Kevin J. Marchbank, Stephen D. Marks, Heather Maxwell, PaulMcAlinden, David Milford, Matthew C. Pickering, Sandra Rich-ardson, Stephen Richardson, Neil Sebire, Mark Taylor, Julie Wes-sels, Sarah Whittall, and Edwin K.S. Wong (Rare Renal DiseaseRegistry [RaDaR], UK Renal Registry, Bristol, United Kingdom).The National Study of MPGN/DDD/C3 Glomerulopathy Investi-gators include Martin Christian, Eric Finlay, Rodney Gilbert, Shi-varam Hegde, Sally A. Johnson, Caroline Jones, Stephen D. Marks,Heather Maxwell, David Milford, Moin Saleem, Manish Sinha,and Nick Webb.

Published online ahead of print. Publication date available atwww.cjasn.org.

AFFILIATIONS

1National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom2Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UnitedKingdom3Department of Renal Medicine, Freeman Hospital, Newcastle upon Tyne, United Kingdom4Department of Immunology and Inflammation, Imperial College, London, United Kingdom5Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom6Research and Development Department, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne,United Kingdom7Department of Renal Medicine, University College London, London, United Kingdom8The Royal Hospital for Children, Glasgow, United Kingdom9Nottingham Children’s Hospital, Queens Medical Centre, Nottingham, United Kingdom10Histopathology Department, Leicester Royal Infirmary, Leicester, United Kingdom11Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom12National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond StreetInstitute of Child Health, London, United Kingdom13Department of Paediatric Nephrology, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom

CJASN 16: 1639–1651, November, 2021 Childhood C3G: Etiology and Outcome, Wong et al. 1651