Membranoproliferative glomerulonephritis (MPGN) has traditionally been classified into three subtypes: type I and type III, characterized by immunoglobulins and complement deposits, and type II (dense deposit disease [DDD]), defined as the presence of dense deposits in the basement membrane on electron microscopy study. A new classification has been proposed to consider the wide variety of pathologic patterns of MPGN on light microscopy.
The classification distinguishes (1) C3 glomerulopathies (C3Gs), a group of nephropathies with exclusive or predominant glomerular C3 deposits, with (DDD) or without (C3 glomerulonephritis) dense deposits on electron microscopy study, and (2) immunoglobulin-associated MPGN. According to Moglie Le Quintrec, MD, PhD, and colleagues, the classification has “reemphasized the suspected role of complement dysregulation in the pathophysiology of these nephropathies.”
The new classification has coincided with the availability of the first complement inhibitor, eculizumab, an anti-C5 monoclonal antibody. Data from case reports and a small prospective study on the efficacy of eculizumab have shown varying results. Dr. Quintrec et al. working as the Francophone Working Group on C3G recently conducted an analysis of data from all cases of children, adolescents, and adults with C3G who were treated with eculizumab in France and in a referral pediatric center in Quebec, Canada. Results of the analysis were reported in the American Journal of Kidney Diseases [2018;72(1):84-92].
The outcomes of interest were global or partial clinical renal response to treatment with eculizumab. Measurements of note were the evolution of serum creatinine and proteinuria values.
The analysis included 13 adults and 13 children/adolescents with C3G who were treated with eculizumab between 2010 and 2016. Mean age at initiation of eculizumab treatment was 18 years (range, 9-65 years). All of the patients received angiotensin-converting enzyme inhibitors and/or angiotensin II receptor antagonists; there were no changes to doses following start of eculizumab treatment. Median time from diagnosis to initiation of eculizumab treatment was 16 months (range, 0.5-150 months).
At baseline (initiation of eculizumab treatment), median serum creatinine concentration was 0.6 mg/dL in children/adolescents and 2.3 mg/dL in adults, corresponding to median estimated glomerular filtration rates (eGFRs) of 110 and 28 mL/min/1.73 m2, respectively. Nineteen patients (73%) had nephrotic syndrome, 11 (42%) had chronic kidney disease (CKD), seven (27%; patients 2, 14-16, 17, 19, and 20) had a rapidly progressive form of C3G, and three (12%; patients 2, 17, and 19) required dialysis. None of the 26 patients had monoclonal gammopathy.
At initiation of eculizumab treatment, children/adolescents had milder disease compared with adults: eGFR 110 vs 36 mL/min/1.73 m2; P=.001).
Twenty patients had received steroids with or without plasma exchanges or an immunosuppressive treatment (mycophenolate mofetil [MMF], n=8; rituximab, n=4; cyclophosphamide, n=2; or tacrolimus, n=1) prior to eculizumab treatment. Median time between those treatments and eculizumab was 18 months (range, 1-58 months).
Treatment with eculizumab was initiated for persistent nephrotic syndrome in 15 patients; for rapidly progressing disease in seven patients, including three (patients 2, 15, and 16) in whom C3G had rapidly progressed despite the use of steroids and MMF, and the use of rituximab in patient 6. Four children (patients 1, 8, 11, and 19) were treated for persistent non-nephrotic proteinuria.
Following treatment with eculizumab for a median duration of 14 months, six patients (23%) had a global clinical response, six (23%) had a partial clinical response, and 14 (54%) had no response. At the end of treatment or at last follow-up for those maintained on eculizumab, of the 15 patients with increased concentrations of serum creatinine at initiation of treatment, seven (47%) had improved kidney function, two (13%) had deterioration in kidney function, and six (40%) had no change in kidney function. Of the 11 patients whose serum creatinine concentration at treatment initiation was normal, concentration of serum creatinine increased in two (18%) and was unchanged in nine (82%).
Following discontinuation of eculizumab, there was a sharp increase in serum creatinine in one patient who did not respond to treatment with eculizumab; that patient reached end-stage renal disease 2 months following discontinuation of treatment despite progressive spacing of infusions prior to treatment cessation. Because the patient had severe CKD, no rescue treatment was instituted. Regardless of response to eculizumab, there was no deterioration of kidney function after treatment in all other patients.
Compared with patients with partial clinical or no response, those with global clinical response had lower eGFRs (9 mL/min/1.73 m2 vs 104 mL/min/1.73 m2), a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. There were no differences between responders and nonresponders in age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants.
The authors cited some limitations to the study, including the retrospective design based on a registry and a questionnaire, the relatively small number of mixed pediatric and adult patients, and the lack of electron microscopy data for all patients, creating the inability to assess whether the presence of DDD affects the response to eculizumab.
In summary, the researchers said, “Taken together, our results indicate that eculizumab is a potentially efficacious treatment in patients with crescentic rapidly progressive C3G, mainly through an anti-inflammatory effect but with no or limited impact on the deposition of C3G degradation products in glomeruli. Optimal duration of eculizumab in responders remains to be determined, but limited duration of treatment may be sufficient. The benefit of eculizumab in the majority of patients with non-rapidly progressing forms of MPGN seems to be limited, and in these patients, C5 blockade does not seem to significantly alter the course of the disease. The long-awaited new complement modulators targeting C3 convertase may transform more radically than eculizumab the treatment paradigm of C3G.”
- Researchers presented a case series of patients with C3 glomerulopathy treated with the first complement inhibitor eculizumab, an anti-C5 monoclonal antibody.
- Of the 23 patients (13 children/adolescents and 13 adults) treated with eculizumab, six had a global clinical response, six had a partial clinical response, and 14 had no response.
- Patients with a global clinical response had lower estimated glomerular filtration rate, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy than those with partial or no response.