atypical haemolytic uraemic syndrome ( ahus ) is a rare , life - threatening , chronic , genetic disease due to uncontrolled alternative pathway complement activation . in most cases , ahus is associated with mutations or polymorphisms in the genes cfh ( encoding complement factor h ) , accounting for 1129% , cd46 ( mcp , membrane cofactor protein ) 317% and cfi ( encoding complement factor i ) 217% . mutations in more than one complement gene have been identified in some patients , and nucleotide polymorphisms in cfh and mcp genes can modulate the risk of ahus in mutation carriers . the investigations performed showed gallbladder infection and microangiopathic haemolytic anaemia , thrombocytopaenia and acute kidney injury . she had a past medical history of kidney stones and one uneventful pregnancy , and no previous history of diarrhoea . initial investigation revealed the following : haemoglobin 8.3 g / l , platelet count 140  10/l and serum creatinine 3.8 mg / dl . the gallbladder infection was treated with broad - spectrum antibiotics with resolution of symptoms . despite this , after 2 days she became thrombocytopaenic ( 73  10/l ) , and serum creatinine rose to 4.8 mg / dl accompanied by haematuria and proteinuria . her course was complicated with fluid overload and oliguria , leading to the need to perform a brief period of haemodialysis . following nine sessions of pe over a period of 2 weeks , her parameters improved ( haemoglobin 12.4 g / dl , platelet count 220  10/l , lactate dehydrogenase ( ldh ) 1054 after 4 years , her renal function and platelet number are normal , but the patient has persistent microangiopathic haemolytic anaemia ( table  1 ) . despite analytical parameters of haemolysis ( ldh 1554 u / l , indirect bilirubin 1.54 mg / dl and absent haptoglobin ) , the patient has no signs or symptoms of organ injury / thrombosis , no hypertension , no proteinuria and the haemoglobin levels remain stable with no need for blood transfusion . during these 4 years , the patient had possible triggering events ( infection and cholecystectomy ) , with no relapse of ahus . in keeping with this , we performed a genetic analysis to investigate whether the patient carried some genetic abnormalities associated with ahus . mutation screening of cfh , mcp and cfi by sanger sequencing revealed two heterozygous mutations : a cfh ( c.3493 c > t , p.his1165tyr ) and an mcp ( c.1058 c > t , pala353val ) . the first amino acid substitution is not described , and the second is known as a disease mutation [ 4 , 5 ] . table  1.variations on biochemical parameters during the 4-year follow - uphospital dischargetime from hospital discharge1 month6 months12 months18 months3 years4 yearsserum creatinine ( mg / dl)2.81.10.70.50.60.50.7haemoglobin levels ( g / dl)12.012.411.711.210.611.310.4platelet count ( cells  10/l)190262253254269195193ldh ( u / l)90310547749428509721554serum haptoglobin ( g / l)<10<10<10<10<10upcr ( mg / mg)0.650.140.070.060.010.080.05complement c3 ( mg / dl)96.877.2complement c4 ( mg / dl)21.815.7homocysteine levels ( mol / l)10.0upcr : protein  creatinine ratio on random urine sample . variations on biochemical parameters during the 4-year follow - up upcr : protein  creatinine ratio on random urine sample . ahus is a challenging disease to manage with a relatively poor prognosis , as up to 65% of patients treated with pe will sustain permanent renal damage , have progression to end - stage renal disease ( esrd ) or die within 1 year . in the past years , it became evident that ahus is associated with mutations in proteins needed for regulation of the alternative complement pathway . because of the multiple genetic susceptibility factors involving plasma- and membrane - associated regulators , the rarity of combined - mutated patients and the need for a triggering event , it is difficult to predict the clinical course of ahus . the combined cfh / mcp mutations reported in our patient ( cfh p.his1165tyr/mcp pala353val ) have not been previously described . as previously reported , it seems that mcp or cfh mutations confer a predisposition to develop ahus rather than directly cause the disease , and a second hit is necessary for the full - blown manifestation of the disease , as in all mcp - mutated and 70% of cfh - mutated patients the onset of ahus was associated with an infectious event . our patient showed an impaired capacity to protect vascular endothelial cells from complement attack after the activation caused by the gallbladder infection that led to ahus presentation . after that , the clinical course was clearly distinct from patients with other cfh mutation and was similar to patients with mcp mutations described previously . it has been reported that the most severe prognosis is in the cfh mutation patients , with 70% reaching esrd , and that patients with mcp mutations have a relapsing course , but none have reached esrd in the first year . in cases of combined mutations carriers , the concomitant presence of cfh and mcp risk haplotypes significantly increased disease penetration and modified the prognosis . among patients with cfh mutations , the presence of mutations in other genes did not modify prognosis ; however , 50% of patients with combined mcp mutation developed esrd within 3 years from onset compared with 19% of patients with an isolated mcp mutation . these two mutations ( cfh p.his1165tyr/mcp pala353val ) have a benign phenotype prediction ( polyphen-2 ) , and mcp pala353val has polymorphic prevalence ( 1000 genomes project ) . despite that , their cumulative effect confers a background genetic that seems to be a risk for ahus ; however , their benign character explains the mild clinical course . indeed , the response to pe would not be expected to be effective for patients with mutations in mcp , a transmembrane protein that is not removed by this treatment , but patients with combined mutations achieved remission with pe similar to patients with single non - mcp mutations . the excellent response of our patient could be related to the replacement of cfh proteins with pe . in our patient , it seems that the mutated expressed proteins can not fully protect vascular endothelial cells from activated complement translated by the persistently haemolytic microangiopathic anaemia ; however , the regulation of the complement attack is enough to protect her from a relapse . in summary , we describe the first reported case of ahus with the combination of a previously described mcp mutation with a new cfh mutation associated with a rare clinical outcome ( persistent haemolysis without renal failure or any other clinical manifestations of endothelial damage or platelet activation ) . we may therefore speculate that combination of these frequent mutations will worsen the phenotype and could be a common but under - diagnosed phenomenon . the findings in this patient underscore the influence of different genetic abnormalities on disease presentation , response to therapy and outcome in ahus patients . the authors declare that the results presented in this article have not been published previously in whole or part . thrombotic microangiopathy : expanding genetic , clinical and therapeutic spectra and the need for worldwide implementation of recent advances .
atypical haemolytic uraemic syndrome ( ahus ) is a rare , life - threatening , chronic , genetic disease due to uncontrolled alternative pathway complement activation . in this report 
 , we discuss the case of a heterozygous carrier of a mutation on both factor h and membrane cofactor protein , who persistently presents haemolytic anaemia without need for blood transfusions , normal platelet count , normal renal function and no signs or symptoms of organ injury due to thrombotic microangiopathy 4 years after the diagnosis of ahus .