atypical haemolytic uraemic syndrome ( ahus ) is an orphan disease , with an incidence of 25 cases per million [ 1 , 2 ] .
ahus is characterized by haemolytic microangiopathic anaemia , thrombocytopaenia and acute renal failure ( arf ) , with signs or symptoms of thrombotic microangiopathy ( tma ) in other organs .
it is due to uncontrolled activation of the alternative pathway of the complement system , caused by genetic mutation in complement genes ( > 60% of patients ) , anti - fh antibodies ( 56% of patients ) and other mutations not related to the complement system recently described , as dkge gene mutation or methylmalonic aciduria .
approximately one - third of patients remain without identified mutation [ 35 ] . clinical manifestation of ahus can be triggered by other complement - amplifying conditions ( infection , pregnancy , organ transplant , malignant hypertension and systemic lupus erythematosus ) that can increase the risk of misdiagnosis .
onset of symptoms can be sudden and present as the full triad described above . however , clinical disease manifestation can also progress more slowly with mild anaemia , progressive renal insufficiency and oscillating thrombocytopaenia .
the kidney is the most frequent organ involved , although manifestations can occur in the brain ( 1020% of cases ) , heart , lungs and gastrointestinal tract .
diagnosis of ahus relies on exclusion ; no evidence of shigatoxin - hus , no criteria for thrombotic thrombocytopaenic purpura ( normal adamts13 activity ) and no medical history indicating other causes of tma ( e.g. malignancy , drug use , etc . ) .
plasma exchange ( pe ) has been the standard first - line therapy , with variable efficacy .
published studies have shown that up to 40% of patients die or progress to end - stage renal disease ( esrd ) during the first episode .
eculizumab , a monoclonal antibody directed against c5 that blocks the cleavage of c5 into c5a and c5b , has demonstrated better efficacy and tolerability in the treatment of ahus .
we report a case of ahus with long evolution , subclinical haemolytic signs , progressive rf and neurological impairment resistant to pe , which showed a full reversal of neurological lesions after initiation of eculizumab therapy .
. family history : her sister had been diagnosed with membranoproliferative glomerulonephritis ( mpgn ) at age 14 . over the disease course , she had anaemia , increased lactate dehydrogenase ( ldh ) and decline in c3 .
epilepsy was diagnosed and well controlled , but she developed neurological impairment with progressive mental retardation . magnetic resonance imaging ( mri ) revealed ischaemic lesions in small vessels and progressive renal failure developed over 11 years .
she started peritoneal dialysis in 2010 and suffered further neurological impairment and died due to a respiratory infection in august , 2012 .
our 27-year - old patient was diagnosed with arf , anaemia and thrombocytopaenia aged 1 year .
she recovered spontaneously without sequalae , and no new episodes of anaemia , thrombocytopaenia , ldh and bilirubin increase nor renal impairment was observed during 14 years . at age 15 , she presented with hyperuricaemia , non - nephrotic proteinuria ( 2 g/24 h ) , arterial hypertension [ blood pressure ( bp ) 160/90 mmhg ] and anaemia [ haemoglobin ( hb ) 11.5 g / dl ] , without thrombocytopaenia or schistocytes in peripheral blood .
serum creatinine ( scr ) was 88.4 mol / l , and creatinine clearance ( clcr ) was 96 ml / min .
renal biopsy showed focal proliferative glomerulonephritis , affecting 28% of glomeruli , with mesangial matrix and cellularity proliferation , and focal hyaline material deposits , conditioning sclerosis in one of the glomeruli .
on immunofluorescence , there were intense igm and weak cq deposits ( figure  1a ) .
her scr was stable , and no evidence of tma was found ( normal platelet count , no schistocytes , normal bilirubin ) other than a slight and maintained increase in ldh possibly indicating ongoing haemolysis .
she also required angiotensin - converting enzyme inhibitors for proteinuria treatment . when she was 26 , arterial hypertension , proteinuria and anaemia worsened , and serum creatinine increased to 176.8 mol / l , with poor response to antiproteinuric therapy .
five months later , she had a hypertensive emergency ( bp 216/120 mmhg ) , with hypertonic hypertensive retinopathy on funduscopy , kidney failure ( scr 366.86 mol / l ) , haemolytic microangiopathic anaemia ( hb 6.7 g / dl , ldh 350 ui / l , haptoglobin < 5 mg / dl and schistocytes ) and severe thrombocytopaenia ( 22  109/l ) .
coombs test and autoimmunity were negative , complement component c3 was normal ( 85 mg / dl ) and adamts13 activity was 83% .
a misdiagnosis of tma secondary to hypertensive emergency in the context of uncontrolled glomerulopathy was made .
a kidney biopsy showed advanced tma , with acute and subacute lesions over chronic vascular involvement ( figure  1b and figure  2 ) .
the patient remained hypertensive on dialysis , requiring seven drugs to control bp ( table  1 ) .
three months later , she presented with mild neurological symptoms ( decreased intellectual performance , a self - limited episode of loss of consciousness ) and a new episode of tma with c3 consumption ( 68 mg / dl ) .
an mri was performed , showing several high - intensity subcortical white matter lesions in the frontal lobes , with the appearance of hypoxic - ischaemic or inflammatory lesions .
mild cerebral atrophy was also present ( figure  3a ) . despite a neurological evaluation , no other aetiology than tma
genetic investigation showed no mutation in fh , fi and mcp genes , but she is homozygotic for a risk haplotype ( h3 ) . based on the patient 's past history , the patient 's sister bad evolution and the presence of a new episode of tma while on dialysis , with better bp control
, we reconsider our previous diagnosis of tma secondary to malignant hypertension to ahus being the primary cause and probably also in the sister .
after seven sessions without response and persistent haemolytic signs ( marked thrombocytopaenia , anaemia , increased ldh and schistocytes in peripheral blood sample ) , eculizumab was initiated ( 900 mg / week , during 4 weeks followed by 1200 mg/14 days ) .
after the third dose , a repeat mri revealed improvement of the cerebral lesions ( figure  3b ) .
after 18 months of eculizumab therapy , the patient is still requiring dialysis , but signs of haemolysis and neurological symptoms are completely absent .
anaemia is controlled ( hb 12.5 g / dl ) with a lower esa requirement ( darbepoetin 30 g / weekly ) .
bp has improved after 2 months of eculizumab and normal bp is maintained with four antihypertensive drugs .
table  1.changes in biochemical parameters and treatmentperiod200111 ( clinical stability)dec 2011apr 2012 ( clinical worsening)may 2012 ( hospital admission)jun 2012 ( start dialysis)aug 2012 ( dialysis , stability)oct 2012 ( dialysis , neurological disorders)jun 2014 ( dialysis , stability)scr ( mol / l)88.4176.8366.86750proteinuria ( g/24 h)1.032.212.71n.d.n.d.n.d.n.d.bp ( mmhg)140/85160/90216/120190/100145/80170/110140/80hb ( g / dl)12  19  0.56.78  0.510.69.512.5platelets ( cells/10 l)256  40231  40224  3022  1521549  20157  20ldh
ui / l ( normal range : 125243)265  10300  20377500354363216haptoglobin ( mg / dl)<512579schistocytes ( per hpf)absentabsent2/hpf2/hpfabsentabsentabsenttreatment  darbepoetin80  20 g / month80 g/15d80 g/15d150 g / week10 g/15d150 g / week30 g / week  aceiramipril 10 mg / bidramipril 10 mg / bid 
arbsirbesartan 300 mg / dirbesartan 300 mg / d  other antihypertensiveamlodipine 5 mg / dhydrochlorotiazide ( hctz ) 25 mg / damlodipine 5 mg / dhctz 25 mg / ddoxazosin 4 mg / bidmethyldopa 500 mg / bidamlodipine 5 mg / dtorasemide 5 mg / ddoxazosin 4 mg / bidmethyldopa 500 mg / bidnebivolol 5 mg / dbarnidipine 10 mg / bidfurosemide 80 mg / dhctz 25 mg / ddoxazosin 4 mg / bidlabetalol 100 mg / bidhydralazine 50 mg / tidbarnidipine 10 mg / bidlabetalol 100 mg / bidhydralazine 50 mg / tidaliskiren 150 mg / dbarnidipine 10 mg / bidfurosemide 40 mg / ddoxazosin 4 mg / bidatenolol 25 mg / bidbarnidipine 10 mg / bidfurosemide 40 mg / ddoxazosin 4 mg / bidatenolol 25 mg / bid  pe5 sessions7 sessions  eculizumab900 mg / week1200 mg/14dn.d . ,
not documented ; d , day ; bid , twice a day ; tid , three times a day . 

focal proliferative glomerulonephritis , with mesangial matrix and cellular proliferation , and focal hyaline material deposits .
signs of acute thrombotic microangiopathy with endoluminal collapse , endothelial and myointimal proliferation . 
 fig . 
3.evolution of mri before ( a ) and after ( b ) . ( a ) mri before eculizumab therapy .
, not documented ; d , day ; bid , twice a day ; tid , three times a day .
focal proliferative glomerulonephritis , with mesangial matrix and cellular proliferation , and focal hyaline material deposits .
evolution of mri before ( a ) and after ( b ) . ( a ) mri before eculizumab therapy .
apart from the efficacy of eculizumab for controlling neurological manifestations of ahus , the present case highlights the difficulties in diagnosing ahus when signs of the disease are mild ( anaemia with subclinical haemolytic signs , gradual impairment of renal function and the absence of thrombocytopaenia ) and progress slowly .
usually , ahus has an abrupt onset , with a complete clinical picture that helps the differential diagnosis .
the lack of thrombocytopaenia , schistocytes and worsening anaemia until the last episode of kidney failure made diagnosis difficult .
slow disease development has been described in 20% of patients , with proteinuria , elevated bp and progressive renal failure . in relapsing / remitting disease
our patient was initially diagnosed with focal glomerulosclerosis with igm deposits and non - nephrotic proteinuria ( but she had a previous episode of arf , probably due to tma episode ) . her sister was diagnosed with mpgn .
mpgn and ahus may sometimes look similar on a biopsy and partially recovered tma could possibly mimic chronic glomerulonephritis .
the association between them has been made as both are diseases related to aberrant complement activation .
proteinuria could be explained by endothelial dysfunction caused by tma , but nephrotic syndrome itself can trigger ahus by inducing endothelial injury in patients with genetic mutations [ 13 , 14 ] .
moreover , alternative pathway dysregulation can manifest only as low - grade proteinuria and chronic kidney disease [ 13 , 15 ] .
vasculitis can trigger ahus by intensive complement activation or by endothelial damage in a patient with a genetic predisposition .
in our case , glomerulonephritis was not the initial event ; she had a prior episode of arf .
it is possible that partially recovered tma episodes mimic chronic glomerulonephritis on biopsy , as in the present case .
the non - classical presentation in both sisters made diagnosis of ahus as a primary disease complex .
the biopsy findings were in addition not entirely conclusive for a diagnosis of ahus , as the biopsy showed focal proliferative glomerulonephritis .
the importance of risk polymorphisms in the development of ahus is increasingly being recognized , and a lack of identified complement mutations is observed in 2530% of patients [ 3 , 17 ] .
the similar evolution in the two sisters , and the good response to eculizumab in our patient , suggests a complement system disturbance , despite the absence of identified mutations .
the evolution of the two patients supports the evidence that prognosis for ahus with no identified mutation is as poor as in patients with identified complement factor mutations , in the absence of adequate therapy .
the prognosis for patients with ahus before eculizumab was poor , with up to 40% of patients dying or progressing to esrd during the first episode .
renal function recovery has been described with eculizumab even after 6 months of dialysis . in our case ,
kidney function did not improve despite treatment , probably due to the long - term nature of the organ damage causing irreversible damage and the delay in starting eculizumab therapy . in our patient , neurological damage progressed despite cessation of clinical haemolysis and esrd .
therefore , the presence of extrarenal symptoms is critical when deciding to maintain anti - c5 therapy , regardless of renal replacement therapy requirement .
damage to extrarenal organs can progress in patients without renal function [ 21 , 22 ] .
this indicates subclinical activity , showing that an increase in platelet count is not always a reliable marker of recovery , highlighting the need for other biomarkers of disease activity . in the present case ,
rapid neurological recovery after eculizumab has been described previously , and it is maintained over time [ 20 , 22 , 24 , 25 ] . in conclusion , nephrologists should be aware of the possibility of ahus with a slow , low - grade chronic evolution that can be difficult to diagnose .
our case suggests that neurological involvement can be reversed with eculizumab that is becoming the standard of care in ahus therapy , even in patients with ahus on dialysis .
 atypical haemolytic uraemic syndrome ( ahus ) is a rare disease characterized by haemolytic microangiopathic anaemia , thrombocytopaenia and acute onset of renal failure , in the absence of escherichia coli infection . 
 renal damage usually progresses to end - stage renal disease ( esrd ) , sometimes being accompanied by signs of extrarenal thrombotic microangiopathy ( tma ) . 
 we report a case of full neurological and haematological recovery after eculizumab treatment in a patient with esrd secondary to chronic ahus refractory to plasmatherapy while she was under dialysis . 
 it highlights the use of eculizumab for controlling extrarenal manifestations of ahus in this population . 
Background
Case report
Discussion
Conflict of interest statement