Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C3 glomerulopathy is a recent disease classification comprising several rare types of glomerulonephritis, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The most common histological feature in these diseases is the presence of glomerular deposition of C3 within the mesangium and along the glomerular basement membrane (GBM) in the subendothelial area or within the GBM. The key role of complement alternative pathway (AP) in these disorders has been recently shown with the identification of acquired or genetic abnormalities. Low serum C3 level but normal C4 is a common finding. The acquired AP dysregulation in DDD and C3GN may be first induced by C3 nephritic factor (C3NeF). C3NeF activity is found in approximately 80% of patients with DDD and in 45% of patients with C3GN. The correlation with the complement is further supported by the detection of homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3. The genetic background of the patients may also influence the disease manifestation since common genetic variants including single nucleotide polymorphisms in the CFH, C3 and CFHR5 genes are associated with DDD and one at-risk MCP haplotype have been found to be significantly increased in C3GN. C3 glomerulopathies can present over a broad age range. DDD is more often diagnosed in children and age at diagnosis is significantly higher for patients with C3GN. Presenting features comprise any of proteinuria, hematuria, hypertension and renal failure. These glomerulonephritides are associated with chronic deterioration of renal function, leading to ESRD within 10 years of the diagnosis in 36-50% of patients. Outcomes of renal transplantation are characterized by histological recurrence which may contribute to increased rates of allograft failure. Administration of recombinant FH if it becomes available or replacement of FH via plasma exchange may be efficacious in the cases of FH deficiency. However, therapeutic inhibition of complement C3 and C5 is the main perspective.
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PMID:C3 glomerulopathy. 2368 80

Despite the success of desensitization protocols, antibody-mediated rejection (AMR) remains a significant contributor to renal allograft failure in patients with donor-specific antibodies. Plasmapheresis and high-dose intravenous immunoglobulin have proved to be effective treatments to prevent and treat AMR, but irreversible injury in the form of transplant glomerulopathy can commonly manifest months to years later. There is an unmet need to improve the outcomes for patients at risk for AMR. Updated Banff criteria now take into account the increasing understanding of the complex and heterogeneous nature of AMR phenotypes, including the timing of rejection, subclinical and chronic AMR, C4d-negative AMR, and antibody-mediated vascular rejection. Treatment for AMR is not standardized, and there is little in the way of evidence-based treatment guidelines. Refining more precisely the mechanisms of injury responsible for different AMR phenotypes and establishing relevant surrogate endpoints to facilitate more informative studies will likely allow for more accurate determination of prognosis and efficacious intervention using new therapeutic approaches. In addition to plasma exchange and intravenous immunoglobulin, a number of other add-on therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-interleukin-6 receptor blockers, and immunoglobulin G-degrading enzyme of Streptococcus pyogenes (called IdeS).
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PMID:Antibody-mediated rejection: New approaches in prevention and management. 2987 37