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. 2022 Jul;17(7):994-1007.
doi: 10.2215/CJN.16801221.

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

Hannah J Lomax-Browne  1 , Nicholas R Medjeral-Thomas  1 , Sean J Barbour  2 , Jack Gisby  1 , Heedeok Han  3 , Andrew S Bomback  3 , Fernando C Fervenza  4 , Thomas H Cairns  5 , Richard Szydlo  6 , Sven-Jean Tan  7 , Stephen D Marks  8   9 , Aoife M Waters  8 , Gerald B Appel  3 , Vivette D D'Agati  10 , Sanjeev Sethi  11 , Cynthia C Nast  12 , Ingeborg Bajema  13 , Charles E Alpers  14 , Agnes B Fogo  15 , Christoph Licht  16 , Fadi Fakhouri  17 , Daniel C Cattran  18 , James E Peters  1 , H Terence Cook  1 , Matthew C Pickering  1
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Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

Hannah J Lomax-Browne et al. Clin J Am Soc Nephrol. 2022 Jul.

Abstract

Background and objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years.

Design, setting, participants, & measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome.

Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores.

Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

Keywords: complement; glomerulonephritis; kidney biopsy; membranoproliferative glomerulonephritis (MPGN).

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Figures

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Graphical abstract
Figure 1.
Figure 1.
Study overview and outcome-free survival. (A) Study recruitment and inclusion. From 193 recruited participants, 156 were eligible for inclusion. Participants were excluded either due to insufficient biopsy material (n=34) or incorrect diagnosis (n=3). (B) Progression to a combined outcome event was assessed in relation to diagnosis. The C3 glomerulopathy (C3G) cohort (n=118) consisted of C3 GN (n=101) and dense deposit disease (DDD; n=17), and there were 32 patients with idiopathic Ig-associated membranoproliferative GN (Ig-MPGN).
Figure 2.
Figure 2.
Box plots depicting the pathology scores of (A) active and (B) chronic lesions. The cohort was divided into those with C3 GN (n=106), DDD (n=17), and Ig-MPGN (n=33). The median glomerular basement membrane (GBM) double-contours score was significantly greater in the Ig-MPGN group versus either the C3 GN (P=0.001) or DDD (P<0.001) group. Horizontal bars within boxes denote medians. The vertical size of boxes denotes the interquartile range (quartile 1, lower hinge and quartile 3, upper hinge). Whiskers denote minimum and maximum data points not exceeding 1.5 times the interquartile range from quartiles 1 and 3, respectively. Data points exceeding this range (outliers) are denoted by circles. P values were derived from the Kruskal–Wallis test with the Dunn multiple comparisons test. EH, endocapillary hypercellularity; IFTA, interstitial fibrosis/tubular atrophy.
Figure 3.
Figure 3.
Outcome-free survival in the whole and C3G cohorts by histologic scores. The significant histology covariates of risk to progression to the combined event in (A) the C3G cohort (n=118) and (B) the whole cohort (n=150) were segmental sclerosis, cellular/fibrocellular crescents, and IFTA. Outcome-free survival for the other histologic scores are shown in Supplemental Figure 12. P values were derived from the log-rank test.
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References

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