Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway

Abstract

Kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway (AP) are traditionally classified on the basis of clinical presentation (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appearance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). Each is characterized by an inappropriate activation of the AP, eventuating in renal damage. The clinical diversity of these disorders highlights important differences in the triggers, the sites and intensity of involvement, and the outcome of the AP dysregulation. Nevertheless, we contend that these diseases should be grouped as disorders of the AP and classified on an etiologic basis. In this review, we define different pathophysiologic categories of AP dysfunction. The precise identification of the underlying abnormality is the key to predict the response to immune suppression, plasma infusion, and complement-inhibitory drugs and the outcome after transplantation. In a patient with presumed dysregulation of the AP, the collaboration of the clinician, the renal pathologist, and the biochemical and genetic laboratory is very much encouraged, because this enables the elucidation of both the underlying pathogenesis and the optimal therapeutic approach.

Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options

“…Dysfunction of these regulatory proteins leads conversion of the low-grade AP activation to uncontrolled levels leading to disease states such as C3 GN and aHUS. 23 …”

Does complement Factor H-Related protein 5 Nephropathy (Troodos Nephropathy) protect from rickettsial infections?

“…infections), causing damage to susceptible organs like the kidney [22]. Mutations in the CFH gene have been associated with kidney disease such as, atypical Haemolytic Uraemic Syndrome (aHUS) and C3 glomerulopathies [23][24][25]. More recently, the emerging role of Complement Factor-H Related proteins (CFHRs) in complement-mediated diseases has attracted increased interest with the identification of hybrid CFH/CFHR1 and CFH/CFHR3 genes causing aHUS [26][27][28].…”

Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN

“…Elimination of the auto-antibodies and/or mutant protein: The use of plasma exchange has a strong rationale [89] , but to date, its efficacy has only been con firmed by single case reports. Three patients with DDD had a beneficial effect from plasma exchange, but they were also treated with immunosuppression [9092] .…”

“…Very recently, the beneficial effect of mycophenolate mofetil (MMF) in C3G has been reported in a randomized Spanish study [98] . However, due to the lack of controlled trials, treatment with immunosuppressants should be restricted to patients with proteinuria, progressive loss of glomerular filtration rate (GFR) and those with signs of severe inflammation on renal biopsy [89] . An immunosuppressantbased strategy should also be attempted in patients with C3G associated with monoclonal gammopathy, even if the result of such a treatment differed according to different authors [50,51] .…”

“…Eculizumab is a reco mbinant, fully humanized monoclonal antibody that binds to the C5 complement protein and blocks C5 cleavage [89] . In recent years, eculizumab was highly effective in several kidney diseases, including aHUS and antibody mediated rejection (ABMR) after renal transplantation [99] .…”