Citations

Resumo A glomerulopatia C3 (C3G) é uma entidade clinicopatológica caracterizada por inflamação glomerular com dominância de C3 à imunofluorescência. A microscopia eletrônica é utilizada para determinar a localização e o tipo de depósitos, o que permite subdividir a C3G em glomerulonefrite C3 (GNC3) e doença de depósitos densos (DDD) com base em achados ultraestruturais. Ambas as entidades são progressivas, com cerca de 60% dos pacientes evoluindo para doença renal terminal (DRT) em 10 anos. A recorrência após o transplante renal ocorre em até 60% dos casos de C3G. Novos conhecimentos sobre a fisiopatologia—diferentes padrões de lesão, escores histopatológicos, coloração para apolipoproteína E, desregulação da via alternativa do complemento, que inclui autoanticorpos e mutações em fatores reguladores do complemento, bem como análises proteômicas—permitiram uma melhor compreensão dos diferentes perfis fisiopatológicos e apresentações clínicas, possibilitando um tratamento individualizado. O papel da nefroproteção está bem estabelecido na C3G, assim como em outras doenças glomerulares. O tratamento não específico com corticosteroides e imunossupressores está associado a uma taxa de resposta variável. No entanto, mais recentemente, os resultados de ensaios clínicos com inibidores proximais da via alternativa do complemento demonstraram melhora significativa na proteinúria e atenuação da redução da taxa de filtração glomerular estimada (TFGe). Com base nos resultados desses ensaios com medicamentos que atuam especificamente nas vias do complemento a montante, incluindo a via alternativa, novas opções de tratamento tornaram-se disponíveis para pacientes com C3G.

Abstract C3 glomerulopathy (C3G) is a clinicopathologic entity characterized by glomerular inflammation with dominant staining for C3 on immunofluorescence microscopy. Electron microscopy is used to determine the location and type of deposits, which further divides C3G into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) based on ultrastructural findings. Both entities are progressive, with about 60% of patients progressing to end-stage kidney disease (ESKD) within 10 years. Recurrence after kidney transplantation occurs in up to 60% of C3G cases. New knowledge about the pathophysiology—different patterns of injury, histopathological scoring, apolipoprotein E staining, dysregulation of the alternative complement pathway (including both autoantibodies to and mutations in complement regulatory factors), as well as proteomic analyses—has allowed a better understanding of different pathophysiological profiles and clinical presentations, enabling individualized treatment. The role of nephroprotection is well established in C3G, as it is for other glomerular diseases. Non-specific treatment with corticosteroids and immunosuppression is associated with a variable response rate. However, more recently, results from clinical trials with proximal complement inhibitors have shown significant improvement in proteinuria and attenuation of the decline in estimated glomerular filtration rate (eGFR). Based on the results of these trials involving drugs that specifically target the upstream complement pathways, including the alternative pathway, new treatment options have recently become available for patients with C3G.

ABSTRACT C3 glomerulonephritis (C3GN) is a rare kidney disease driven by dysregulation of the alternative complement pathway. We report two challenging cases of patients with C3GN in whom various immunosuppressant therapies have failed to achieve complete remission, prompting treatment with eculizumab, an anti-C5 humanized monoclonal antibody that inhibits the terminal complement pathway. Although transient improvement in kidney function was observed, both patients eventually experienced worsening renal parameters, with increasing proteinuria and hematuria, culminating in progression to end-stage kidney disease. Repeated kidney biopsies following eculizumab therapy demonstrated persistent, granular mesangial and capillary wall C3 (3+) staining on immunofluorescence studies, indicating ongoing complement activation upstream of the C5 blockade and the perpetuation of C3 deposits in the glomeruli. These cases underscore the limited efficacy of terminal complement inhibition in halting disease progression in C3GN.

Complement activation occurs in most glomerular diseases. Complement activation on the kidney biopsy is evidenced by deposition of C3c and C1q on the kidney biopsy. The kidney biopsy provides only limited information as other complement proteins and complement-regulating proteins are not typically studied. Furthermore, kidney biopsy does not distinguish between activated versus inactive complement proteins. Laser microdissection and mass spectrometry (LMD/MS) is a relatively new methodology that can provide an in-depth evaluation of the proteomic profile of complement proteins, complement regulating proteins, complement pathways, and can also determine whether active complement fragments are present in the kidney biopsy sample. A semiquantitative burden of complement can be determined. Furthermore, proteins of a disease can be analyzed using principal component analysis, volcano plots, and heatmaps. In this review, the complement proteomic profile of diseases representing the spectrum of glomerular diseases are shown. The proteomic complement profile of membranous nephropathy associated with various antigens, Ig-associated GN, such as proliferative GN with monoclonal Ig deposits and fibrillary GN, C3 glomerulopathy, and IgA nephropathy, are shown. The findings show important differences in the complement profile including pathways of complement in each disease, and even within the disease, such as altered complement burden and profile between different antigens associated with membranous nephropathy. In conclusion, LMD/MS is a valuable tool for determining the complement proteins, complement-regulating proteins, complement pathways, and determining the burden of complement in each individual case of glomerular disease. In the era of new anticomplement drugs, it will become essential to accurately determine the complement profile in each kidney biopsy for a personalized approach to treating the glomerular disease. LMD/MS is a methodology that can help provide such answers.