New Progress Disclosure Of C3G And IgA Nephropathy - Quick Overview Of New Research At ERA 2023 European Congress!

In recent years, complement-associated nephropathy caused by abnormal activation of the complement system has become a hot topic in the field of nephrology, especially C3 glomerulopathy (C3G) and IgA nephropathy. The two types of diseases have their challenges in diagnosis and treatment, and clinical staff are also perseveringly exploring the way of diagnosis and treatment.

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As a prestigious international conference in the field of nephrology, the 60th Congress of the European Renal Association (ERA 2023) will be held in Milan from June 15th to 18th, 2023. This year's conference still invites international experts in nephrology to focus on the frontier progress of nephrology.

The differential diagnosis of C3G is difficult and there are few treatment options. How to break the situation?

C3G is a group of rare glomerular diseases redefined in 2012, characterized by renal tissue mainly composed of glomeruli with only C3 deposits or with weakly positive deposits of immunoglobulin and/or C1q, including C3 glomeruli under electron microscopy There are two subtypes of nephritis (C3GN) and dense deposit disease (DDD).

At the ERA 2023, Fadi Fakhouri from the University Hospital Center of Valdova, Switzerland, reported the diagnosis and treatment process of a difficult case, explaining in simple terms the challenges faced by C3G diagnosis and treatment practice today.

The diagnosis of C3G requires the pathological diagnosis of renal biopsy. The diagnostic criteria are that the intensity of C3 immunofluorescence is ≥2+ higher than the intensity of other immunoglobulins. The final diagnosis needs to be combined with immunopathology, light microscopy, electron microscopy, and clinical manifestations. Not all glomerulonephritis with C3 deposition is mainly C3G, and it may also be other diseases such as C3 post-infectious glomerulonephritis (C3-PIGN). However, due to similar immunopathological characteristics and the lack of biomarkers with strong differential values, it is currently difficult to differentiate clinically.

It is known that C3G differs from the following three types of glomerulonephritis with C3 deposition mainly: ① PIGN is often caused by group A hemolytic streptococcal bacterial infection (in the throat or skin), and the C3 level within 3 months Low, prone to glomerular co-deposition of C3 and IgG; ②Immune complex-mediated membranous proliferative glomerulonephritis (IC-MPGN) usually manifests as low complement C4 levels, C3 and IgG/ IgM/C2q/C4; ③ Paraprotein-associated glomerulonephritis most commonly occurs in >50 years old, with monoclonal gammopathy and abnormal complement biomarkers.

The case reported by Fadi Fakhouri also experienced a series of differential diagnosis difficulties. A 28-year-old woman was referred for edema and hematuria and had developed severe tonsillitis 10 days before admission, which had been treated with a macrolide. On admission, the patient still had lower extremity edema, but hematuria disappeared. Initial laboratory tests showed that the patient's serum creatinine was 167 μmol/L, albumin 28 g/L, C-reactive protein (CRP) 20 mg/L, and plasma C3 level 0.27 g/L. The albumin-to-creatinine ratio was 245 mg/mmol/L. In addition, the patient also underwent renal biopsy at the same time to further differentiate C3G or other glomerulonephritis with C3 deposition.

Based on the results of two renal punctures, Fadi Fakhouri suspected that the patient might be C3G or IC-MPGN. Even though the case underwent two renal punctures and under the detailed pathological classification, the final diagnosis could not be made. The distinguishing points between C3G and IC-MPGN are that IC-MPGN patients are more prone to nephrotic syndrome, and both have similar clinical outcomes, frequency of low serum C3 levels, frequency of gene mutations encoding alternative pathway proteins, and frequency of low serum C4 levels. Similar to [1], due to the lack of specific biomarkers, there are still great challenges in the differential diagnosis of C3G.

The patient received only diuretics during treatment. After 4 months of follow-up, the patient's serum creatinine was 153 μmol/L, proteinuria increased to 4.3 g/L, and C3 level returned to normal. Professor Fadi Fakhouri also mentioned that there is currently no evidence that the existing treatment options are different in the treatment of C3G and IC-MPGN. For the treatment of C3G, the KDIGO guidelines point out that the current moderate to severe C3G with proteinuria greater than 1g There is still a lack of optimized treatment options for patients, and supportive care is the mainstay. For moderate to severe patients, steroids combined with mycophenolate mofetil (MMF) are recommended as initial treatment[3]. This recommendation is based on only one retrospective study, and overall Currently, effective clinical treatment options are limited.

Excessive activation of the alternative complement pathway is the core pathogenesis of C3G. So far, breakthroughs have been made in targeted therapy for this cause. For example, the global phase III clinical trial of the complement factor B inhibitor Iptacopan, which was added in China at the same time, is in progress (NCT04817618 ). The follow-up results of the previous clinical phase II extension study of Iptacopan showed that patients with primary C3G achieved the preset composite renal endpoint after 12 months of treatment with factor B inhibitors, and the urinary protein-to-creatinine ratio (UPCR) decreased by 57% compared with the baseline (P <0.0001); in addition, biomarker analysis suggested that factor B inhibitors had a clear inhibitory effect on the alternative complement pathway in patients with primary and recurrent C3G after transplantation, and could stabilize eGFR. It was well tolerated, and most adverse events were mild. Iptacopan is expected to become the first targeted drug approved for the treatment of C3G in China [4-5].

As a rare kidney disease, C3G lacks effective methods in both diagnosis and treatment and still needs more attention from all walks of life. To this end, Marianne Silkjaer Nielsen and others launched the CompCure project to help solve the problems of diagnosis and treatment of rare diseases such as C3G. At the ERA 2023 conference, Marianne Silkjaer Nielsen said that the main purpose of the CompCure project is to improve the compliment by improving awareness, improving evidence, and close cooperation among patients, doctors, industry, and other relevant stakeholders. To help patients obtain more effective treatment options, and strive to improve the quality of life of patients with rare kidney diseases.

Currently, the CompCure project is conducting a comprehensive European registration study for C3G and IC-MPGN, hoping to improve the research and treatment of C3G and IC-MPGN with all relevant parties. At the same time, she also called on people from all walks of life to give more attention and support to rare diseases.

Challenges and opportunities in IgA nephropathy: Where are new treatment approaches?

Smeeta Sinha from Salford Royal Hospital, UK, talked about the challenges faced in the clinical practice of IgA nephropathy today. She said that the KDIGO guidelines state that IgA nephropathy can only be diagnosed by renal biopsy and recommend the use of international predictive tools to predict the progression of biopsy [3]. Scoring of renal biopsy samples based on the Oxford classification system (MEST-C score) can help predict the rate of decline in renal function [6]. In addition, the KDIGO guidelines also emphasize that there are no clinically valid prognostic serum or urine biomarkers other than proteinuria and estimated glomerular filtration rate (eGFR) [3].

For the treatment of high-risk patients with IgA nephropathy (KDIGO guidelines defined as patients with proteinuria > 0.75-1g/d after 3 months of optimal supportive therapy), the guidelines point out that glucocorticoids are currently the only option other than maximum supportive therapy. options, while the safety and efficacy of immunosuppressants are uncertain [3].

Other treatment options have specific applicable populations. For example, MMF is only recommended as a glucocorticoid reserve agent for Chinese patients who need glucocorticoids, and tonsillectomy is only used as a routine program in Japanese patients[3].

Overall, therefore, current treatment options for patients at high risk of progression to renal failure remain limited.

Not only that but patients with IgA nephropathy face the dilemma that even with treatment, the lifetime risk of developing end-stage renal disease remains high. In a case reported by Smeeta Sinha, the patient received RASi, BBC, β-blocker, hormone, MMF, SGLTi treatment, and diet management for 6 years, but eGFR continued to decline.

The data of a UK national registry study also suggested the current clinical dilemma, pointing out that almost all patients with IgA nephropathy are at risk of developing ESKD (unless the decline rate of eGFR is <1mL/min/year), even if they were once classified as " Low-risk” patients and current treatments cannot even reduce eGFR to the level of “low-risk” [7].

To explore more treatments for IgA nephropathy, clinicians have also begun to focus on its pathophysiological mechanism. Sydney Tang, a scholar from the same team, introduced that during the development of IgA nephropathy, the excessive activation of the bypass pathway and the deposition of IgA immune complexes can trigger the formation of glomerular and tubulointerstitial scars, and promote renal inflammation and glomerulus. Ball damage, which in turn leads to proteinuria, hematuria, and even chronic kidney disease.

Previous studies have confirmed that the levels of biomarkers of alternative pathway activity (including urinary F factor, lysin, serum Ba factor, etc.) in patients with IgA nephropathy are higher than those in healthy controls [8-10], especially C3 deposition, whose intensity The higher the value, the more serious the pathological lesions and the higher the MEST-C score [11-13].

A retrospective study included 4786 biopsy-confirmed primary IgA nephropathy patients in the First Affiliated Hospital of Zhengzhou University. role in. The results of this study showed that C3 deposition is an independent risk factor for the severity and progression of IgA nephropathy, and the prognosis of IgA nephropathy patients with C3 deposition was significantly worse than that of IgA nephropathy patients without C3 deposition[11].

However, the results of a survey on "complement pathway involved in IgA nephropathy" conducted at the conference showed that only 13% of voters would evaluate complement biomarkers in patients with IgA nephropathy. It can be seen that although the activation of complement by the alternative pathway plays an important role in IgA nephropathy, clinical recognition is not high, and attention should be paid to it.

At present, significant progress has been made in the clinical practice of complement inhibitors targeting the alternative pathway, such as factor B inhibitor Iptacopan, Roche IONIS-FB-L Rx, etc., which are worthy of clinical expectation and application. Among them, the clinical phase II study of Iptacopan showed that in the 6th month, the patient's UPCR decreased by 41%, the changes in serum Wieslab activity, Bb, factor B, and lysin levels, and the small increase in complement C3 levels indicated that factor B inhibitors could Selectively inhibit the alternative complement pathway [14].

summary:

Complement-associated nephropathy C3G and IgA nephropathy are now receiving increasing clinical attention. However, the treatment methods for the two types of diseases are very scarce, and there are many unmet clinical needs. It is expected that more targeted therapies will come out in the future, which can effectively improve the prognosis of patients and bring them a brighter future.