Atypical hemolytic uremic syndrome : update on the complement system and what is new

Atypical hemolytic uremic syndrome (aHUS) is a rare disease of microangiopathic hemolytic anemia, thrombocytopenia, and predominant renal impairment. It is characterized by the absence of Shiga toxin-producing bacteria as a triggering factor. During the last decade, aHUS has been demonstrated to be a disorder of the complement alternative pathway dysregulation, as there is a growing list of mutations and polymorphisms in the genes encoding the complement regulatory proteins that alone or in combination may lead to aHUS. Approximately 60% of aHUS patients have so-called 'loss-of-function' mutations in the genes encoding the complement regulatory proteins, which normally protect host cells from complement activation: complement factor H (CFH), factor I (CFI) and membrane cofactor protein (MCP or CD46), or have 'gain-of-function' mutations in the genes encoding the complement factor B or C3. In addition, approximately 10% of aHUS patients have a functional CFH deficiency due to anti-CFH antibodies. Recent advances in understanding the pathogenesis of aHUS have led to a revised classification of the syndrome. Normal plasma levels of CFH and CFI do not preclude the presence of a mutation in these genes. Further, genotype-phenotype correlations of aHUS have clinical significance in predicting renal recovery and transplant outcome. Therefore, it is important to make a comprehensive analysis and perform genetic screening of the complement system in patients with aHUS to allow a more precise approach, especially before transplantation. This may also provide opportunities for more specific treatments in the near future, as complement inhibition could represent a therapeutic target in these patients who have a considerably poor prognosis in terms of both mortality and progression to end-stage renal disease and a great risk of disease recurrence after transplantation

Haemolytic uraemic syndrome caused by factor H mutation: is single kidney transplantation under intensive plasmatherapy an option?

Complement factor H (CFH) mutation is one of the causes of atypical haemolytic uraemic syndrome (aHUS). Patients with CFH mutation-associated aHUS progress often to end-stage renal disease despite plasma exchange therapy. When such patients are transplanted, aHUS recurs almost invariably and causes graft failure making the rationale of single kidney allograft transplantation questionable. Since CFH is synthesized mostly by the liver, combined liver-kidney transplantation has been recommended. However, fatal outcomes have been reported using this strategy. We report a case of successful single kidney allograft transplantation in a patient with a CFH gene mutation (R1210C), who had end-stage renal failure after three flares of aHUS treated with plasma exchange. He received peri- and postoperative infusions of fresh frozen plasma, which to date has prevented recurrence of the disease. He has preserved renal function 1-year post-transplan

Complement depletion during haemofiltration with polyacrilonitrile membranes

Background Polyacrylonitrile (PAN, AN69®) dialysis membranes have been shown to improve the outcome of critically ill patients. Factor D is an essential enzyme of the alternative pathway of complement and is increased during renal failure. On the other hand the contact of blood with biomaterials activates the complement cascade through the alternative pathway. PAN filters adsorb factor D which looses its enzymatic activity whilst bound to the membrane [1] the complement alternative pathway function of serum exposed to PAN filters is greatly diminished and restored after addition of purified factor D [1]. The aim of our study was to measure the time course of factor D adsorption and its blood concentration during CVVH in critically ill patients with acute renal failure. Methods We studied seven critically ill patients with ARF before, during and after continuous veno-venous haemofiltration (CVVH) with AN69. Results There was a rapid decrease of factor D levels to 62(±6%) of the pre-CVVH value during the first 2 h, which continued to 51(±7.3%) after 12 h; at 24 h there was a slight rise to 62±12%. Sequential use of Polyacrylonitrile (AN69®) filters lowered factor D levels below the normal plasma concentration in three patients, thus producing a state of factor D depletion. Conclusions The significant reduction of factor D levels during CVVH with PAN filters suggests that frequent changes of PAN filters may reduce alternative pathway function by lowering factor D levels. CVVH (as opposed to intermittent dialysis) with PAN membranes may further improve the outcome of critically ill patient