Palma, Lilian Monteiro P

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.

Laser capture microdissection and mass spectrometry (LCM/MS) is a technique that involves dissection of glomeruli from paraffin-embedded biopsy tissue, followed by digestion of the dissected glomerular proteins by trypsin, and subsequently mass spectrometry to identify and semiquantitate the glomerular proteins. LCM/MS has played a crucial role in the identification of novel types of amyloidosis, biomarker discovery in fibrillary GN, and more recently discovery of novel target antigens in membranous nephropathy (MN). In addition, LCM/MS has also confirmed the role for complement proteins in glomerular diseases, including C3 glomerulopathy. LCM/MS is now widely used as a clinical test and considered the gold standard for diagnosis and typing amyloidosis. For the remaining glomerular diseases, LCM/MS has remained a research tool. In this review, we discuss the usefulness of LCM/MS in other glomerular diseases, particularly MN, deposition diseases, and diseases of complement pathways, and advocate more routine use of LCM/MS at the present time in at least certain diseases, such as MN, for target antigen detection. We also discuss the limitations of LCM/MS, particularly the difficulties faced from moving from a research-based technique to a clinical test. Nonetheless, the role of LCM/MS in glomerular diseases is expanding. Currently, LCM/MS may be used to identify the etiology in certain glomerular diseases, but in the future, LCM/MS can play a valuable role in determining pathways of complement activation, inflammation, and fibrosis.