Clinical Presentation, Treatment Patterns, Burden of Disease, and the Association of Proteinuria with Clinical Outcomes in C3 Glomerulopathy and Primary Immune Complex Membranoproliferative Glomerulonephritis: A Systematic Review

Fernando Caravaca-Fontán; Fadi Fakhouri; Matthew C Pickering; Vikte Lionikaite; Alison Baird; Regina Horneff; Luis López-Lázaro; Lucia Quintana-Gallardo; Carly Rich

doi:10.1159/000548245

. 2025 Sep 19;150(1):25–40. doi: 10.1159/000548245

Clinical Presentation, Treatment Patterns, Burden of Disease, and the Association of Proteinuria with Clinical Outcomes in C3 Glomerulopathy and Primary Immune Complex Membranoproliferative Glomerulonephritis: A Systematic Review

Fernando Caravaca-Fontán ^a, Fadi Fakhouri ^b, Matthew C Pickering ^c, Vikte Lionikaite ^d, Alison Baird ^d, Regina Horneff ^e, Luis López-Lázaro ^e, Lucia Quintana-Gallardo ^e, Carly Rich ^e,^✉

PMCID: PMC12795539 PMID: 40971335

Abstract

Introduction

Knowledge gaps and controversies remain regarding the natural history and variability of C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN). The objectives were to provide an overview of these diseases for the following outcomes of interest: clinical presentation, treatment patterns, and disease burden, including the association between proteinuria and kidney outcomes.

Methods

This systematic literature review (SLR) included studies of adults and children with C3G or primary IC-MPGN investigating outcomes of interest. Embase and MEDLINE were searched from January 2012 to February 22, 2024, combining terms for C3G or IC-MPGN and outcomes of interest. Supplementary congress searches and reference list checking of relevant articles were conducted. Study details, outcomes of interest, and key findings were extracted, and data were narratively summarized.

Results

In total, 148 articles were included. No clear trend for differences between C3G and primary IC-MPGN were observed for clinical presentation. Treatments included immunosuppressive therapies and off-label anti-complement agents. Kidney failure occurred in up to 50% and 37% of patients with C3G and primary IC-MPGN, respectively, and kidney transplantation was required in up to 32% and 24% of patients, respectively. Mortality was reported in up to 21% of patients. No clear trend of complete remission across treatments was observed. In longitudinal studies, proteinuria was associated with increasing risk of kidney failure. No articles reported on patient quality of life or caregiver burden. Several articles reported an economic burden according to length of hospital stay. Possible limitations include that terms used for electronic searches limited which articles were identified, many studies were retrospective and small (<10 participants), and risk of bias was not performed.

Conclusions

This SLR provides insights into C3G and primary IC-MPGN, emphasizing the need for new targeted and effective treatments. Proteinuria was identified to be an acceptable marker in assessing the efficacy of treatments on long-term kidney outcomes.

Keywords: C3 glomerulopathy, Immune complex membranoproliferative glomerulonephritis, Disease burden, Proteinuria, Surrogate marker

Introduction

C3 glomerulopathy (C3G) and primary or idiopathic immune complex membranoproliferative glomerulonephritis (IC-MPGN, also known as immunoglobulin-associated MPGN) are rare, complement-mediated kidney diseases that can affect both children and adults [1–4]. C3G results from overactivation of the alternative complement pathway and comprise two major subgroups: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) [5]. In primary IC-MPGN, C3 deposition is accompanied by immunoglobulins in the absence of any known secondary causes [6]. Presenting features of primary IC-MPGN are similar to those of C3G, which make differential diagnosis challenging [6].

The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend an individualized treatment approach [7] because optimal treatment strategies have not yet been established. Immunosuppressive therapy (IST) with mycophenolate mofetil (MMF) plus glucocorticoids is recommended for patients with progressive kidney function decline or persistent proteinuria, although its effectiveness, analyzed in retrospective studies, is variable and often associated high relapse rate after MMF discontinuation [8]. For patients who fail to respond to this treatment, particularly for those with rapidly progressive disease, guidelines suggest off-label use of eculizumab, despite the limited evidence to support its efficacy in patients with C3G or primary IC-MPGN, and/or enrollment in clinical trials [7]. Assessing long-term outcomes in clinical trials may not be feasible and therefore identifying markers of kidney function like proteinuria that can indicate clinically significant effects in a shorter period of time is of interest.

Despite the significant improvement in the understanding of C3G and primary IC-MPGN in recent years, significant knowledge gaps and controversies remain regarding the natural history and variability of this spectrum of diseases. Therefore, the aims of this systematic literature review (SLR) were to evaluate the available literature on adults and children with C3G and primary IC-MPGN and to provide an overview of the clinical presentation, treatment patterns, and disease burden including the association between proteinuria and kidney outcomes.

Methods

The SLR was compliant with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9].

Search Strategy and Sources

A search strategy was created combining terms for C3G or IC-MPGN and outcomes of interest, which were clinical similarities, standards of care, disease burden, and proteinuria (online suppl. Tables 1–4; for all online suppl. material, see https://doi.org/10.1159/000548245). Embase and MEDLINE were searched from January 2012 to February 22, 2024. Searches were limited to 2012 to capture the most recent evidence and coincided with recognition of C3G as a distinct condition.

Supplementary congress searches were performed to identify relevant congress abstracts presented at meetings of the European Renal Association (ERA) and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) from 2021 to 2023 and the American Society of Nephrology (Kidney Week), UK Kidney Week, and World Congress of Nephrology for 2023. Other supplementary searches included gray literature searches of reports published outside of traditional commercial publishing [10] and bibliographic reference list screening of reviewed articles and relevant systematic reviews.

Selection Criteria

Results from the database searches were combined and duplicates were removed. Titles and abstracts were screened for eligibility by a single reviewer against predefined eligibility criteria (Table 1). Full texts of references meeting the inclusion criteria were obtained and reviewed by one or more reviewers to confirm eligibility (Table 1). Uncertainties regarding eligibility were resolved by an independent reviewer. References identified from the supplementary searches were added to the database findings to create a final list of references for data extraction.

Table 1.

Eligibility criteria for SLR

Description	Inclusion criteria	Exclusion criteria
Population	Patients with primary C3G (including subtypes DDD and C3GN) or IC-MPGN	Patients with secondary C3G (including subtypes DDD and C3GN) or IC-MPGN^a Any other population No age restrictions
Intervention	Any
Comparators	Any
Outcomes	Clinical similarities and dissimilarities between C3G and IC-MPGN Current standard of care and treatments Association between proteinuria and kidney function including eGFR, mutations in proteins, polymorphisms in genes, antibodies, and levels of C3, C4, C5b-9, CH50, AH50, and C5b-9 Human and economic burden	Any other outcomes not listed under inclusions
Study design	All other study designs	Case reports^b Case series^b Narrative reviews/editorials^b Animal/in vitro/genetic design study^b
Article type	Full-text publications Congress abstracts from 2018 onward^b	Congress abstracts from before 2018^b
Language	English language only
Country restrictions	Any
Date restrictions	2012 onward	Pre-2012

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C3G, C3 glomerulopathy; C3GN, C3 glomerulonephritis; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; IC-MPGN, immune complex membranoproliferative glomerulonephritis; SLR, systematic literature review.

^aSecondary C3G or IC-MPGN includes disease triggered by infection, medication, or malignancy and C3G or IC-MPGN present with monoclonal gammopathy, other autoimmune disease, or chronic thrombotic angiopathy.

^bAdditional criteria were introduced at full-text review of the SLR searches performed in 2023. The SLR update in 2024 implemented these conditions.

Data Extraction and Quality Assessment

Data were extracted for a predetermined range of variables, including study details, outcome measures of interest, and key findings, with all data being checked by a second independent reviewer. An appraisal to assess the methodological quality and rigor of the trials or studies included in this SLR was not performed.

Analytical Approach

No quantitative analyses were possible owing to heterogeneity in study designs and methodologies; therefore, data were narratively summarized.

Results

General Findings

Database searches identified 5,083 articles and, after removing duplicates, 4,036 underwent title and abstract screening with 395 proceeding to full-text review. In total, 144 articles were identified via database searches and four articles were identified by supplementary searches (Fig. 1; online suppl. Item 1 for references).

Fig. 1. — PRISMA flow diagram. Searches were performed on January 23, 2023, and updated on February 22, 2024. Record numbers are combined for both searches. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Articles included in this SLR comprised 75 full-text publications and 73 congress abstracts. Geographically, articles presented studies conducted across a wide range of countries: the largest number of studies were multinational (n = 22), followed by the USA (n = 19) and India (n = 16). The most commonly identified study type was observational (including retrospective [n = 91], prospective [n = 24], and cross-sectional [n = 7]), followed by interventional (including phase 2 open-label trial [n = 10], pooled data from multiple trials [n = 3], randomized controlled trial [n = 2], phase 1 open-label trial [n = 1], long-term extension [n = 1], and comparative study [n = 1]), review and/or meta-analysis (n = 5), focus group (n = 1), survey (n = 1), or validation study (n = 1). Of the 122 articles that included sufficient detail to determine the age of patients, 58 articles reported results for adults, 18 for children, and 46 for adults and children.

Clinical Similarities between C3G and Primary IC-MPGN

Thirty-four articles assessed the clinical presentation of C3G or primary IC-MPGN [11–44]. The study designs of the articles reporting clinical presentation of patients with C3G or primary IC-MPGN were mainly observational (retrospective [n = 24], prospective [n = 5], and cross-sectional [n = 1]) or interventional (phase 2 open-label trial [n = 4]). No clear trend for differences between C3G and primary IC-MPGN was observed.

Nephrotic Syndrome

Across seven articles, nephrotic syndrome was observed in 11.9–83.3% of patients with C3G or primary IC-MPGN at diagnosis (Fig. 2) [3, 17, 32, 45–48]. Statistical analyses comparing the proportion of patients with nephrotic syndrome among those with C3GN versus primary IC-MPGN were performed in two retrospective observational studies. In one study conducted in Japan, a significantly lower proportion of patients with C3GN presented with nephrotic syndrome compared with primary IC-MPGN (2/14 [14.3%] vs. 38/67 [56.7%]; p = 0.016) [17]. Patients with C3GN were also younger than those with primary IC-MPGN (median 19 vs. 62 years; p < 0.001) [17]. In the second study, there was almost a two-fold difference in the proportion of children with C3G or primary IC-MPGN presenting with nephrotic syndrome, which was nonsignificant (5/43 [11.9%] vs. 9/42 [22.0%], p = 0.25) [3].

Kidney Function

Mean baseline serum creatinine (SCr) ranged from 0.46 to 6.7 mg/dL in 16 articles including patients with C3G or primary IC-MPGN [11–26], with the lowest levels corresponding to pediatric patients [23, 24]. Five articles compared SCr between patients with C3G and primary IC-MPGN [3, 17, 20, 22, 49]. Two studies found lower median SCr levels in C3GN versus primary IC-MPGN (0.65 vs. 1.16 mg/dL, p = 0.003 and 0.8 vs. 1.5 mg/dL, p = 0.02) [17, 20]. Conversely, two articles reported higher mean SCr in C3G/C3GN versus primary IC-MPGN (1.91 vs. 1.06 mg/dL [calculated from μmol/L], p = 0.253 and 1.58 vs. 0.97 mg/dL, significance not reported) [3, 49]. The fifth article reported similar mean SCr values in patients with C3G and primary IC-MPGN (1.88 vs. 1.75 mg/dL [calculated from μmol/L], p > 0.05) [22].

Median baseline estimated glomerular filtration rate (eGFR) ranged from 39.3 to 111 mL/min/1.73 m² in C3G [11, 19, 20, 27–44] and from 53.4 to 89.69 mL/min/1.73 m² in primary IC-MPGN [18, 20, 27, 32, 33, 37, 38, 40, 42]. Four articles conducted statistical comparisons on eGFR at baseline/diagnosis between C3G or primary IC-MPGN: no statistically significant differences were reported in three articles (median 85.58 vs. 88.99 mL/min/1.73 m², respectively, p = 0.947 [27]; mean 49 vs. 56 mL/min/1.73 m², respectively, p > 0.05 [22]; mean 50.1 vs. 53.7 mL/min/1.73 m², respectively, p > 0.05 [50]); and one article reported a statistically significantly higher mean eGFR in patients with C3GN than in those with primary IC-MPGN (99.3 vs. 53.0 mL/min/1.73 m², p < 0.001) [17].

Treatment Patterns

Treatment patterns for patients with C3G or primary IC-MPGN were described in 79 articles [3, 11–15, 17–39, 42–45, 47, 48, 50–93]. The study designs of the articles detailing treatments were predominantly observational (retrospective [n = 50], prospective [n = 13], and cross-sectional [n = 5]), interventional (open-label phase 2 or extension trial [n = 7] and randomized controlled trial [n = 1]), or review and/or meta-analysis (n = 3). Patients received anti-proteinuric treatment to control hypertension and reduce proteinuria. Furthermore, most patients received ISTs, including corticosteroids, MMF, and/or cyclophosphamide. Off-label use of eculizumab was identified in some patients with C3G or primary IC-MPGN. Other investigational anti-complement agents used in patients with C3G or primary IC-MPGN included avacopan (C5aR antagonist), danicopan (factor D inhibitor), iptacopan (factor B inhibitor), and pegcetacoplan (C3 inhibitor). Overall, there were no notable differences in treatment patterns between diseases (C3G vs. primary IC-MPGN) or disease subtypes (DDD vs. C3GN) [3, 17, 20, 22, 32, 33].

Disease Burden

Disease burden was reported across 128 articles [11–45, 47, 49–51, 54–56, 59–63, 65–73, 75, 76, 78, 79, 81–83, 85–89, 91–134], with the majority presenting data from observational studies (retrospective [n = 83], prospective [n = 21], and cross-sectional [n = 4]), followed by interventional studies (phase 2 open-label trial [n = 10], randomized controlled trial [n = 1], phase 1 trial [n = 1], pooled data of two trials [n = 2], and long-term extension [n = 1]), reviews and/or meta-analyses (n = 3), a survey (n = 1), and a focus group (n = 1) [3, 11–157].

Clinical Burden

Clinical burden of C3G or primary IC-MPGN was reported in 122 articles and included kidney failure, kidney transplantation, mortality, and remission. In articles including more than 10 patients, the time from diagnosis or study initiation to kidney failure ranged from 3 to 148.6 months, with kidney failure occurrence up to 50% in C3G, 20% in C3GN, 50% in DDD, and 37% in primary IC-MPGN [11, 15, 17–20, 29, 31, 33, 35, 39, 50, 67, 72, 76, 89, 92–98]. Age, blood pressure, eGFR, baseline proteinuria, and treatment class used were significant risk factors for kidney failure in some studies [17, 31, 94, 95, 99].

In articles including more than 10 patients with C3G or primary IC-MPGN, the prevalence of kidney transplantation was similar between C3G (8–32%) [19, 22, 42, 72, 98, 100] and primary IC-MPGN (24%) [22, 42]. The median time from kidney transplantation to disease recurrence was 1.3–13.5 years [45, 78]. In patients with C3G or primary IC-MPGN (deemed MPGN in publications), the prevalence of graft loss ranged from 23 to 59% within 1.5–15 years [45, 101, 102], and in a subgroup of patients with recurrent disease, prevalence of graft loss was 80% within 21 months [91]. Specifically in patients with C3G, graft loss ranged from 50 to 62% [56, 65] within 2.2–5.6 years [42, 56]. Mortality due to any cause was reported in up to 21% of patients in articles including more than 10 patients (Fig. 3) [17, 32, 37, 44, 50, 54, 68, 89, 93, 94, 98, 101, 103, 104], with no difference in mortality based on treatment received [17, 32, 61, 63, 76, 89, 93, 94, 98, 101, 103–106].

Fig. 3. — Studies reporting mortality risk in patients with C3G or primary IC-MPGN. Note that there may be a potential overlap of cohorts across the articles. C3G, C3 glomerulopathy; C3GN, C3 glomerulonephritis; DDD, dense deposit disease; IC-MPGN, immune complex membranoproliferative glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; NR, not reported. ^aDeemed as MPGN in publication. ^bPatients with C3GN. ^cPatients with C3G. ^dReported as medians, means, or ranges.

Treatment Response

Thirty-five articles reported data related to treatment response as measured by complete remission over a follow-up period of 6 months to >5 years [11, 15–17, 19, 21, 27–29, 32, 35, 37, 40, 47, 49, 51, 60, 66, 68, 71, 72, 75, 76, 86–88, 92, 97, 98, 107–112]. Across these studies, there were no clear trends of higher or lower rates of complete remission across treatments in C3G or primary IC-MPGN [11, 15–17, 19, 21, 27–29, 32, 35, 37, 40, 47, 49, 51, 60, 66, 68, 71, 72, 75, 76, 86–88, 92, 97, 98, 107–112]. The definition of complete remission most frequently used was proteinuria <0.5 g/day and eGFR ≥60 mL/min/1.73 m².

For treatment with MMF and/or corticosteroids, there was inconclusive evidence of their benefit regarding remission rates. Three articles, reporting on retrospective observational studies, compared the rates of complete remission between treatment groups in patients with C3G [19, 29, 86]. Two articles found no statistically significant differences between MMF and/or corticosteroids and other treatment groups, while the third did not perform statistical tests but found very similar results between groups [19, 29, 86]. In the first article, the rates of complete remission were 40.7% (11/27) in the MMF group at a median follow-up of 44 months, 30.4% (7/23) in the non-MMF group at a median follow-up of 36 months, and 18.8% (3/16) in the non-IST group at a median follow-up of 30.5 months (p = 0.381) [29]. In the second article, the rates of complete remission, defined as 500 mg/day urine protein during the mean 21-month follow-up with normal SCr, were 42.9% (3/7) in the MMF group and 28.6% (4/14) in the non-MMF group (p = 0.4) [19]. The third article reported complete remission rates of 38.2% (13/34) in the MMF plus steroids group and 32.0% (8/25) in the steroids without MMF group after a mean follow-up of 32 months (p not reported) [86]. In contrast, two other articles found that the MMF plus corticosteroids group had the highest remission rates (complete and partial) versus other treatment groups [11, 87]. In the first article, which reported on a retrospective observational study, rates were 78.6% (33/42) in the MMF plus corticosteroids group after a median follow-up of 49 months versus 24.1% (7/29) in the “other IST” group after a median follow-up of 43 months, 33.3% (3/9) in the eculizumab group after a median follow-up of 46 months, and 17.6% (3/17) in the “no IST” group after a median follow-up of 44 months (p not reported; partial remission defined as >50% reduction of proteinuria and stabilization [±25%] or improvement in eGFR) [11]. In this study, responders to MMF plus corticosteroids received significantly lower initial doses of MMF compared with nonresponders (p = 0.01), while the corticosteroid initial dose was similar between the two groups (p = 0.97). In the second article, which reported on a prospective observational study, remission rates were 86.7% (39/45) in the MMF plus steroid group versus 56.7% (17/30) in the steroid without MMF group after a median follow-up of 33 months (p not reported) [87].

Treatment-related adverse events with MMF and/or corticosteroids were noted in two retrospective observational studies [11, 29]. In one study, of 27 patients receiving MMF-based treatment, gastrointestinal effects were reported in six patients, pneumonia and anemia in two patients each, and leukopenia and thrombocytopenia in one patient each [29]. In another study, which included 42 patients receiving MMF plus corticosteroids, five patients experienced infections, one experienced diabetes mellitus, and four experienced cytopenia, cardiovascular events, and other adverse events (including gastrointestinal intolerance, cataracts, and avascular necrosis of the hip) [11].

Three articles reported on remission rates with eculizumab but included very few participants [11, 49, 110]. Remission rates with eculizumab were variable in two observational studies: complete and partial remission with eculizumab was 33.3% (3/9) at a median follow-up of 46 months in a retrospective observational study [11]; in the second study, a prospective observational study, 66.7% of patients (6/9) achieved remission (complete or partial; not defined) after 6–12 months of treatment (exact duration not clear) [110]. Similarly, in a phase 2 open-label interventional trial, after 48 weeks of eculizumab, partial remission, defined as proteinuria <3.5 g/day with >50% reduction from baseline, was 30% (3/10) [49]. Adverse events were reported with eculizumab and included infection complications in 56% of patients (5/9) and cardiovascular events in 6% of patients (1/9) [11]. Acute reactions (including chest pain and headache) were reported during 8 of 69 (11.6%) eculizumab infusions, which were resolved without sequelae [49].

Proteinuria Association with Clinical Outcomes

An association between proteinuria and kidney function was reported in 14 articles [11–13, 29, 30, 33, 38, 39, 42, 44, 47, 73, 99, 113], 13 of which were observational (nine retrospective and four prospective) with one being a systematic review. Eight of these publications reported on four longitudinal studies, which found that proteinuria at baseline or diagnosis was associated with an increased risk of kidney failure in C3G or primary IC-MPGN [12, 13, 29, 30, 33, 38, 42, 47].

The GLOSEN retrospective observational study [12, 13, 30, 47] collected data from 20 patients with DDD and 95 patients with C3GN (median age 30 [interquartile range, IQR 19–50] years) from Spain [47]. Median (IQR) baseline proteinuria was 3 (1.6–5.7) g/day and was significantly associated with kidney failure (≥1 to <3 g/day: hazard ratio [HR] 2.12, 95% confidence interval [CI]: 1.17–5.84; ≥3 to <5 g/day: HR 2.11, 95% CI: 1.22–5.78; ≥5 g/day: HR 4.59, 95% CI: 2.43–7.67; all p = 0.002) [12]. From a multivariable model, 24-h proteinuria was identified as a predictor of kidney failure (HR per 1 g/day increment: 1.11, 95% CI: 1.04–1.19; p = 0.004) [13]. Of patients with longitudinal data, the median (IQR) change in proteinuria of patients reaching kidney failure was 2.5 (0.5–4.5) g/day/year. Patients who showed a progressive reduction in proteinuria over time did not reach kidney failure [47]. From baseline to a median follow-up of 42 months, doubling of proteinuria increased the risk of kidney failure (HR 2.5, 95% CI: 1.4–4.9; p < 0.001) and a reduction of ≥50% in proteinuria was significantly associated with a lower risk of kidney failure (HR 0.79, 95% CI: 0.56–0.97; p < 0.001) [30].

Similarly, another retrospective observational study conducted in Australia, the UK, and the USA of 106 patients with C3GN, 17 with DDD, and 33 with IC-MPGN (mean [IQR] age of 25 [16–45], 34 [13–61], and 22 [9–59] years, respectively; baseline proteinuria of 3 [1.2–5.7], 3.04 [0.69–8.9], and 3.91 [1.86–5.81] g/day, respectively) reported that a doubling of proteinuria over 75 months significantly increased the risk of kidney failure (odds ratio 1.98, 95% CI: 1.21–3.85; p = 0.002) [33]. There were no significant differences in outcome-free survival, defined as time to kidney failure (eGFR <15 mL/min/1.73 m², dialysis, or transplantation), doubling of SCr from baseline (adults), or 30% reduction of eGFR (for pediatric patients) between those who did and did not achieve a 50% decrease in proteinuria at 12 months following baseline biopsy [33].

In a retrospective observational study conducted in Turkey of 66 patients with C3G (mean age range 32–40 years), no remission of proteinuria was significantly associated with kidney failure (HR 2.42, 95% CI: 2.45–51.34; p = 0.002) [29]. Median baseline proteinuria ranged from 2.5 to 5.1 g/day [29].

Finally, in 135 prospectively recruited patients with C3G and 152 with primary IC-MPGN from the UK National Registry of Rare Kidney Diseases (RaDaR) with a median (IQR) age at diagnosis of 14 (9–34) and 23 (9–55) years, respectively, proteinuria level soon after diagnosis was associated with risk of long-term kidney failure [38, 42]. At diagnosis, median (IQR) urine protein-to-creatinine ratio was 3.62 (1.11–6.16) and 4.10 (1.50–7.21) g/g for patients with C3G and primary IC-MPGN, respectively [42]. Proteinuria reduction of <0.88 g/g creatinine per day at 12 months was associated with a reduced risk of kidney failure at 20 years in the total cohort (HR adjusted for eGFR 0.13, 95% CI: 0.03–0.56; p = 0.007) [42]. Several other parameters have been associated with kidney outcomes, including blood pressure [75], serum C3 levels [93], changes in kidney biopsy (including changes to histology, activity, and chronicity) [47], eGFR [29, 30, 33, 75, 79], and SCr [11, 19, 51, 72, 88, 91, 92].

Patient and Caregiver Burden

No articles identified by the SLR reported data related to patient quality of life (QoL) or caregiver burden.

Economic Burden

Six articles were identified that reported economic burden [67, 98, 113–116]. A 2018 congress abstract reported on a review that aimed to identify all types of burden associated with C3GN and DDD. The authors found there was no published evidence of evaluations related to economic burden [113]. Two articles reported a substantial economic burden experienced by patients as a result of lengthy hospital stays. A review of hospital records in India from 2013 to 2020 demonstrated that the mean length of hospital stay in 43 children with C3G was 16.2 days (standard deviation 16.3) [98]. In the second article, a large database analysis from the USA using data from 1997, 2000, 2003, and 2006 reported that the mean length of hospital stay among 1,279 children with MPGN was shorter; however, the study noted that it increased over time (5 days in 1997 to 8.4 days in 2006) and also noted the comparison with non-MPGN-related admissions, which had a shorter mean length of stay of 4.2 days [67].

In three articles, challenges regarding care were reported for patients with C3G [114–116]. In Germany, 48% of patients with MPGN (types I–III) were reported to be treated in nephrological departments, 39% at university institutions, 26% in general internal, 22% in pediatrics, and 4% in urology (denominator not presented) [116]. A survey of 400 nephrologists from the USA reported that 35% of patients with C3G seen in the past year were referred to specialized care, suggesting challenges in disease management [114]. In a focus group of 8 patients with C3G, patients reported facing difficulties in identifying healthcare providers who were knowledgeable about C3G and with experience treating patients with C3G, which led several to travel far for their care [115].

Discussion

In this comprehensive SLR performed in early 2024, no clear trend for differences between patients with C3G and primary IC-MPGN was identified for clinical presentation. Disease management was similar between the two diseases; however, despite treatment, a significant clinical burden remained. Proteinuria at baseline was significantly associated with long-term kidney outcomes or mortality.

Currently, there are no approved therapies for C3G or primary IC-MPGN. The current SLR identified 79 articles, most of which were observational, that reported similar treatment patterns between C3G and primary IC-MPGN. Trends on the effectiveness of MMF plus corticosteroids were variable. For eculizumab, a small number of studies with few patients with C3G or primary IC-MPGN reported variable rates of remission (30–66.7%). This limited benefit with eculizumab is expected because it targets C5, whereas the hallmark of C3G and IC-MPGN is C3 dysregulation [7, 158]. These findings highlight the need for new targeted and effective therapies for patients with C3G and primary IC-MPGN.

A high clinical burden with C3G or primary IC-MPGN was reported across several studies in this SLR. The proportions of patients with C3G or primary IC-MPGN experiencing kidney failure in the period from diagnosis or study initiation (3–148.6 months of follow-up) ranged from 34 to 50%. These observations are supported by a recent retrospective analysis of 1,089 patients with C3G or primary IC-MPGN from the UK RaDaR registry, which reported a 10-year renal survival of 0.67 (95% CI: 0.63–0.70), suggesting that 33% of patients with C3G or primary IC-MPGN reached kidney failure within 10 years of diagnosis [159]. Kidney transplant rates in the studies identified in this SLR were up to 30% in patients with C3G or primary IC-MPGN, with graft loss reaching up to 80%. These observations are consistent with another review, which reported disease recurrence in up to 86% of kidney transplant recipients with C3G [160]. In a large study using the US Renal Data System, transplant recipients with MPGN had a 76% higher mortality and a 52% higher all-cause allograft failure rate when compared with otherwise similar patients with immunoglobulin (Ig)A nephropathy [161]. These data and findings indicate that patients with C3G and primary IC-MPGN have worse outcomes compared with other patients who received kidney transplantation.

The high clinical burden observed in patients with C3G or primary IC-MPGN would be expected to reduce patient QoL, as has been shown in patients with chronic kidney disease [162] or on dialysis [163]. However, no evidence of the effects of these diseases on QoL was identified in this SLR. Furthermore, although no study addressed the impact of C3G or primary IC-MPGN on caregivers, moderate-to-severe caregiver burden may be expected, based on findings from patients with kidney failure [164]. A small number of studies noted the economic burden in patients with C3G or primary IC-MPGN, with the outcomes assessed being limited to length of hospital stay. No studies were identified in the SLR that presented data on costs. Further investigation of the burden and challenges experienced by patients with C3G and primary IC-MPGN and its impact on their QoL, as well as the economic costs associated with these diseases, is warranted.

Studies identified in this SLR highlighted proteinuria as an acceptable marker for long-term outcomes, such as kidney failure or mortality: proteinuria was associated with an increased risk of kidney failure, and decreased proteinuria was associated with a decreased risk of kidney failure. The use of proteinuria as a surrogate for long-term kidney outcomes have been supported in CKD [165], IgA nephropathy [166, 167], and in C3G [168]. In 2024, the Kidney Health Initiative convened a panel of experts in C3G to review available evidence for the association between clinical benefit and three endpoints: proteinuria, eGFR, and histopathology [168]. The panel concluded that in the absence of alignment in all three endpoints, a treatment may be considered if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR [168]. Several ongoing trials of complement inhibitors including iptacopan and pegcetacoplan in patients with C3G and/or IC-MPGN are using change from baseline in proteinuria to assess long-term clinical outcomes [21, 26, 83, 169].

There are several limitations to the findings of the present SLR. Studies were included when the terms for C3G or IC-MPGN and the outcomes of interest were used; therefore, studies using terminology not included in the search strings may not have been identified. Many articles included in the SLR had fewer than 10 participants, limiting the generalizability of the results. However, it should be noted that, because C3G and IC-MPGN are rare diseases, the pool of patients to recruit from is small. Additionally, most of the evidence identified in the current SLR comes from retrospective studies, which makes it subject to selection and information bias. Future studies with a prospective design are warranted to generate higher quality evidence, which may establish causality. Owing to the variability in the study designs identified in this SLR, a risk of bias assessment was not performed, which may limit the reliability and validity of the findings. Although studies included in this review distinguished between C3G and primary IC-MPGN, which allowed for the observation of similarities or differences in these patients, not all articles distinguished between the C3G subgroups, DDD and C3GN. Therefore, reported outcomes of patients with C3G may have been influenced by the mixing of these distinct entities. Lastly, clearly defined causes of primary IC-MPGN, which may influence clinical presentation, treatment patterns, and disease burden, were not reported in the articles, which limits the understanding of the disease.

Conclusion

This SLR has shown that there is variability in the clinical presentation of C3G and primary IC-MPGN, with no clear trends for differences between the diseases. Despite treatment with current standard of care therapies that target symptoms of C3G or primary IC-MPGN, patients continue to experience a significant clinical burden associated with these diseases, indicating a need for alternative targeted and effective treatments. Evidence from a number of studies indicate that proteinuria is an acceptable marker in assessing the efficacy of treatments on long-term kidney outcomes. Future studies need to assess the patient and caregiver and economic burden of disease.

Acknowledgments

Medical writing support was provided by Alan Storey, PhD, and Anne-Marie Couto, DPhil, of Oxford PharmaGenesis, Oxford, UK, and was funded by Swedish Orphan Biovitrum AB (Sobi).

Statement of Ethics

Ethical approval was not required for this systematic review.

Conflict of Interest Statement

F.C.F. has received consultation honoraria from Apellis, AstraZeneca, Novartis, and Sobi. F.F. has received consultation honoraria from Alexion, Apellis, AstraZeneca, Novartis, Roche, and Sobi. M.C.P. has received consulting fees from Achillion, Alexion, Annexon, Apellis, BioCryst, ChemoCentryx, Complement Therapeutics, Gemini, Gyroscope, MIRNA Therapeutics, Omeros, and Q32Bio Pharma, and is supported by a Wellcome Trust Senior Fellow in Clinical Science grant 212252/Z/18/Z. V.L. is an employee of Oxford PharmaGenesis, Oxford, UK. A.B. was an employee of Oxford PharmaGenesis, Oxford, UK, at the time of the study. R.H., L.L.L., L.Q.G., and C.R. are employees of Swedish Orphan Biovitrum AB (Sobi).

Funding Sources

This study was funded by Swedish Orphan Biovitrum AB (Sobi).

Author Contributions

All authors provided substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work. All authors drafted or revised the work critically for important intellectual content and provided final approval of the version to be published.

Funding Statement

This study was funded by Swedish Orphan Biovitrum AB (Sobi).

Data Availability Statement

This systematic literature review did not generate any new data. All data analyzed in this study are derived from previously published sources, which are cited within the manuscript.

Supplementary Material.

Supplementary_material-Suppl.1-s1.docx^{(68.5KB, docx)}

Supplementary Material.

Supplementary_material-Suppl.2-s2.docx^{(31.5KB, docx)}

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Associated Data

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Supplementary Materials

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Data Availability Statement

This systematic literature review did not generate any new data. All data analyzed in this study are derived from previously published sources, which are cited within the manuscript.

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PERMALINK

Clinical Presentation, Treatment Patterns, Burden of Disease, and the Association of Proteinuria with Clinical Outcomes in C3 Glomerulopathy and Primary Immune Complex Membranoproliferative Glomerulonephritis: A Systematic Review

Fernando Caravaca-Fontán

Fadi Fakhouri

Matthew C Pickering

Vikte Lionikaite

Alison Baird

Regina Horneff

Luis López-Lázaro

Lucia Quintana-Gallardo

Carly Rich

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Methods

Search Strategy and Sources

Selection Criteria

Table 1.

Data Extraction and Quality Assessment

Analytical Approach

Results

General Findings

Fig. 1.

Clinical Similarities between C3G and Primary IC-MPGN

Nephrotic Syndrome

Fig. 2.

Kidney Function

Treatment Patterns

Disease Burden

Clinical Burden

Fig. 3.

Treatment Response

Proteinuria Association with Clinical Outcomes

Patient and Caregiver Burden

Economic Burden

Discussion

Conclusion

Acknowledgments

Statement of Ethics

Conflict of Interest Statement

Funding Sources

Author Contributions

Funding Statement

Data Availability Statement

Supplementary Material.

Supplementary Material.

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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