ABSTRACT
Introduction: Complement plays an important role in the pathogenesis of glomerulonephritis (GN). Even though the underlying etiology of GN might be different, complement activation with subsequent glomerular deposition of complement proteins result in glomerular injury and progression of the lesions. Routine immunofluorescence microscopy (IF) includes staining for only complement factors C3c and C1q. Therefore, with regard to evaluation of the complement pathways, routine kidney biopsy provides only limited information. Methods: In this study, using laser microdissection of glomeruli followed by mass spectrometry, complement proteins and pathways involved in GN were analyzed. Results: We found that C3 followed by C9 are the most abundant complement proteins in GN, indicating activation of classical or lectin or alternative, and terminal pathways, either exclusively or in a combination of pathways. Furthermore, depending on the type of GN, C4A and/or C4B were also present. Therefore, membranous nephropathy (MN), fibrillary GN, and infection-related GN showed C4A dominant pathways, whereas lupus nephritis (LN), proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease (MIDD), and immunotactoid glomerulopathy showed C4B dominant pathways. Significant deposition of complement regulatory proteins, factor H-related protein-1 (FHR-1) and factor H-related protein-5 (FHR-5), were also detected in most GN. Conclusions: This study shows accumulation of specific complement proteins in GN. The complement pathways, complement proteins, and the amount of complement protein deposition are variable in different types of GN. Selective targeting of complement pathways may be a novel option in the treatment of GN.
ABSTRACT
The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.
