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. 2022 Mar;37(3):601-612.
doi: 10.1007/s00467-021-05221-6. Epub 2021 Sep 2.

Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort

Marloes A H M Michels  1 , Kioa L Wijnsma  2 , Roel A J Kurvers  3 , Dineke Westra  2 , Michiel F Schreuder  2 , Joanna A E van Wijk  4 , Antonia H M Bouts  4 , Valentina Gracchi  5 , Flore A P T Engels  3 , Mandy G Keijzer-Veen  6 , Eiske M Dorresteijn  7 , Elena B Volokhina  2   8 , Lambertus P W J van den Heuvel  2   8   9 , Nicole C A J van de Kar  2
Affiliations

Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort

Marloes A H M Michels et al. Pediatr Nephrol. 2022 Mar.

Abstract

Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G.

Methods: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood.

Results: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m2 at last follow-up.

Conclusions: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; C3 nephritic factor; Children; Complement system; Dense deposit disease.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Serial C3 nephritic factor measurements over time in relation to serum C3 levels. In eight patients, C3 nephritic factors (C3NeFs) were detected on multiple occasions during follow-up (indicated by red downward pointing arrowheads) and were correlated to C3 levels in time. Closed dots represent dense deposit disease (DDD, n = 4) patients and open dots represent C3 glomerulonephritis (C3GN, n = 4) patients. The gray dotted lines indicate the lower cutoff value for normal C3 levels. Length of x-axes represents the clinical follow-up time. Plus signs indicate that patients received plasma exchange; multiplication signs indicate that patients received plasma infusion. In two patients (patients 7 and 23), C3 levels normalized during follow-up while patients were treated with prednisolone and mycophenolate mofetil
Fig. 2
Fig. 2
C3 levels at presentation versus last known value at follow-up and in relation to presence of C3 nephritic factors. A Closed dots represent dense deposit disease (DDD) patients and open dots represent C3 glomerulonephritis (C3GN) patients. The gray dotted line indicates the lower cutoff value for normal C3 levels. B–C The distribution of C3 levels measured at presentation (B) and the last reported C3 level during follow-up (C) according to whether patients were found positive for C3 nephritic factors (C3NeFs) or not. The box plots show the median with the quartiles and the 5th and 95th percentiles (whiskers). P-values were calculated with the Mann–Whitney U test
See this image and copyright information in PMC

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