No abstract

Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.

No abstract

‘C3 glomerulopathy’ is a recent disease classification comprising several rare types of glomerulonephritis (GN), including dense deposit disease (DDD), C3 glomerulonephritis (C3GN) and CFHR5 nephropathy. These disorders share the key histological feature of isolated complement C3 deposits in the glomerulus. A common aetiology involving dysregulation of the alternative pathway (AP) of complement has been elucidated in the past decade, with genetic defects and/or autoantibodies able to be identified in a proportion of patients. We review the clinical and histological features of C3 glomerulopathy, relating these to underlying molecular mechanisms. The role of uncontrolled C3 activation in pathogenesis is emphasized, with important lessons from animal models. Methods, advantages and limitations of gene testing in the assessment of individuals or families with C3 glomerulopathy are discussed. While no therapy has yet been shown consistently effective, clinical evaluation of agents targeting specific components of the complement system is ongoing. However, limits to current knowledge regarding the natural history and the appropriate timing and duration of proposed therapies need to be addressed.