Prognostication for C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis

The field of complement kidney diseases is one of the fields of clinical nephrology in which major strides have been made in recent decades. C3 glomerulopathy, a paradigmatic example of this type of diseases, is caused by an alternative complement pathway dysregulation in plasma and the glomerular microenvironment (1,2). The pathogenesis is frequently driven by autoantibodies against complement components, such as C3 nephritic factors (present in 40%–80% of the cases) or rare variants in complement genes (mainly loss of function in complement factor H and I genes, gain of function in C3, or mutations in factor H–related proteins) found in almost one fourth of the patients. Moreover, a clear association has been made between C3 glomerulopathy and monoclonal gammopathies, particularly in patients older than 50 years. In a few cases, however, the underlying pathogenic factor (genetic or acquired) is not precisely identified in clinical practice. The diagnosis of C3 glomerulopathy relies on the presence of intense exclusive or predominant (of at least two orders of magnitude greater than other immune reactants) C3 deposits in the glomeruli, thus requiring the performance of a kidney biopsy. A membranoproliferative GN (MPGN) is the most commonly found lesion, although other histologic patterns may be observed (2). MPGN represents a pattern of glomerular injury, which may be shared by many diverse etiologies. On the basis of the immunofluorescence staining, MPGN is currently classified into the immunofluorescence-negative subgroup, the complement-dominant subgroup, and the Ig subgroup (with or without complement). The latter lesion should lead clinicians to evaluate for an underlying cause, such as systemic autoimmune diseases, infections, or malignancy, and when none of these conditions are found, the disease is classified under the umbrella term of "idiopathic" Ig-mediated MPGN. From a clinical perspective, the identification of pure idiopathic Ig-mediated MPGN cases is often challenging because certain antibodies may not be routinely available for diagnosis. The indolent course of some uncommon forms of infections or malignancy may also hinder the establishment of proper diagnosis. Cumulative experience has shown that in a subset of patients with Ig-mediated MPGN, an underlying dysregulation of the alternative complement pathway can also be identified, suggesting that both C3 glomerulopathy and Ig-mediated MPGN may represent two entities within the same disease spectrum, although the boundaries between the two are still unclear (2). Despite the high heterogeneity of these diseases, significant progress has been made in the last few years in both the diagnosis and prediction of disease prognosis, mainly through multicenter and collaborative studies (summarized in Table 1). Several clinical parameters have been identified as predictors of kidney survival in previous C3 glomerulopathy cohorts, such as the age at diagnosis, the eGFR or serum creatinine, and the degree of proteinuria at clinical presentation (34–5). Regarding histologic predictors of outcomes, greater variability has been observed among the different studies, including both parameters of disease activity and especially disease chronicity. Table 1. - Summary of the main C3 glomerulopathy/Ig-mediated membranoproliferative GN cohort studies with the clinical and histologic parameters associated with outcomes in unadjusted or multivariable analyses Reference Patients Outcomes Clinical Covariates Histologic Parameters Servais et al. (9) (2012) C3 GN (n=56), DDD (n=29), Ig-MPGN (n=49) Kidney failure eGFR; age; angiotensin-converting enzyme inhibitors or angiotensin receptor blockers — Medjeral-Thomas et al. (10) (2014) C3 GN (n=59), DDD (n=21) Kidney failure Age; SCr Crescentic GN; DDD Caliskan et al. (11) (2017) C3 GN (n=59), DDD (n=7) Kidney failure or eGFR decline ≥50% from the baseline Age; eGFR; proteinuria; no remission of proteinuria Percentage of crescents; percentage of sclerotic glomeruli; severity of interstitial fibrosis Bomback et al. (4) (2018) C3 GN (n=87), DDD (n=24) Doubling of SCr or kidney failure eGFR Interstitial fibrosis/tubular atrophy; total activity score; total chronicity score Ravindran et al. (5) (2018) C3 GN (n=102), DDD (n=12) Doubling of SCr or kidney failure SCr; proteinuria Global glomerulosclerosis; interstitial fibrosis/tubular atrophy Caravaca-Fontán et al. (3) (2020) C3 GN (n=81), DDD (n=16) Disease remission; kidney failure Sex; age; proteinuria; MMF treatment; eGFR —; interstitial fibrosis/tubular atrophy Khandelwal et al. (12) (2020)a C3 GN (n=26), DDD (n=48), Ig-MPGN (n=18) Disease remission; kidney failure Serum albumin; low C3; age; eGFR; rapid progression — ; DDD; interstitial fibrosis/tubular atrophy Wong et al. (13) (2021)a C3 GN (n=25), DDD (n=14), Ig-MPGN (n=31), IC GN (n=10) Kidney failure — Presence of >50% crescents Lomax-Browne et al. (6) (2022) C3 GN (n=106), DDD (n=17), Ig-MPGN (n=33) Doubling of SCr or kidney failure eGFR; proteinuria Interstitial fibrosis/tubular atrophy; cellular/fibrocellular crescents DDD, dense deposit disease; Ig-MPGN, Ig-mediated membranoproliferative GN; —, no data; SCr, serum creatinine; MMF, mycophenolate mofetil; IC, immune complex.aPediatric patients. In this issue of CJASN, Lomax-Browne et al. (6) evaluated a large international, retrospective cohort of 156 patients with C3 glomerulopathy (n=123) and idiopathic Ig-mediated MPGN (n=33). A major objective of the authors was to identify histologic features associated with clinical outcomes after a comprehensive centralized kidney biopsy review. Mesangial expansion, mesangial hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity with or without capillary lumen occlusion were the most common histologic features. In addition, through multivariable regression analyses, the authors found that the main parameters associated with eGFR at the time of kidney biopsy were mesangial hypercellularity, interstitial fibrosis/tubular atrophy, interstitial inflammation, and cellular/fibrocellular crescents. Informed by the Columbia University C3 glomerulopathy histologic index (4), the authors found a positive correlation between the activity score with proteinuria (but not with eGFR), whereas the chronicity score negatively correlated with eGFR (but not with proteinuria). Finally, the authors examined the relationship between outcome-free (the time to first occurrence of a doubling of serum creatinine or kidney failure) survival and each score; cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy were associated with outcome-free survival. By multivariable Cox regression analysis, the two most important predictors of poor outcome were interstitial fibrosis/tubular atrophy and cellular/fibrocellular crescents. Another interesting observation in this study was that a subset of 39 patients had a second kidney biopsy, which allowed the authors to compare the histologic changes over time. In patients with an initial diagnosis of Ig-mediated MPGN, the diagnosis changed to C3 GN on second biopsy in three of 11 individuals. Conversely, there were no cases where the diagnosis changed from C3 GN to Ig-mediated MPGN. These findings are consistent with the hypothesis that during the course of C3 glomerulopathy, there would be episodes of immune complex deposition, possibly triggered by infections. Lomax-Browne et al. (6) also managed to compare the histology scores between the baseline and second biopsy and subgrouped the patients into those who had been treated with immunosuppression (n=26) and those who had not (n=13). No difference was found in the progression of the lesions between these groups. Although the role of immunosuppression in C3 glomerulopathy and the potential benefit of certain regimens are not completely understood, it is also possible that some of these patients were subject to bias by indication. One might speculate that only those patients without clinical response or those with worse clinical course underwent a second kidney biopsy. Despite the recent accumulation of data on C3 glomerulopathy, clinicians still face several uncertainties in the management of patients with this disease. The recently released Kidney Disease Improving Global Outcomes Guideline for the Management of Glomerular Diseases recommends the usual supportive measures together with immunosuppression in the setting of moderate to severe disease (initially with mycophenolate mofetil plus glucocorticoids, and if this fails, with eculizumab). Nonetheless, the future therapeutic landscape in C3 glomerulopathy/Ig-mediated MPGN seems more encouraging thanks to the new anticomplement molecules that counteract alternative complement pathway dysregulation directly targeting C3 (e.g., pegcetacoplan), C3 convertase (e.g., iptacopan or danicopan), or other complement factors, such as C5a (e.g., avacopan). Some of these molecules have shown encouraging preliminary results in C3 glomerulopathy and likely will move the management of this disease toward a more precision medicine–based approach. In this regard, there is a need in clinical settings not only to prognosticate but also to assist in decision making on the choice of the most appropriate therapeutic agents, which will likely require additional biomarkers. Another aspect that requires careful investigation in C3 glomerulopathy is the change in proteinuria/albuminuria over time and the potential effect on kidney prognosis. The confirmation that an early reduction in albuminuria can be accepted as a surrogate end point for disease progression would have a decisive effect on the design of clinical trials, as has happened in IgA nephropathy. Our group recently analyzed the relationship between the longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy (7). We found that proteinuria strongly associated with this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold higher risk. Furthermore, we found that ≥50% proteinuria reduction within the first 6 and 12 months of follow-up was significantly associated with a lower risk of kidney failure. Although the former results were confirmed in the study by Lomax-Browne et al. (6), the latter were not. Thus, further research is warranted in this issue. The development of prediction tools to provide both patients and treating physicians with very relevant information is crucial for clinical and research purposes. Our group has recently proposed a simple and easy to use nomogram to predict the risk of kidney failure in C3 glomerulopathy (8) on the basis of the eGFR, proteinuria, and total chronicity score at baseline, although these results have not yet been validated in independent cohorts. The study by Lomax-Browne et al. (6) is undoubtedly one of the most important cohorts published to date and sheds light on the main histologic determinants of outcomes in C3 glomerulopathy/Ig-mediated MPGN. Their main strengths are the large number of patients included from different countries, the inclusion of well-characterized idiopathic Ig-MPGN, and most importantly, the centralized review of all kidney biopsies. However, the definitive achievement of validated predictive scores in diseases as rare as C3 glomerulopathy and Ig-mediated MPGN will require sustained international collaboration to share and analyze data from different cohorts of patients. Disclosures F. Caravaca-Fontán reports consultancy agreements with Apellis and Novartis, research funding from Novartis Pharmaceuticals, and speakers bureau for Novartis Pharmaceuticals. M. Praga reports consultancy agreements with Alexion, Apellis, AstraZeneca, GlaxoSmithKline, Novartis, Otsuka, Silence, Travere, and Vifor and honoraria from Alexion, GlaxoSmithKline, Novartis, Otsuka, Travere, and Vifor. Funding None.