Haemolytic
Uremic Syndrome in Children (1955-2015): A 60 Years Journey
Ashraf Bakr, Riham
Eid
Ashraf Bakr, Riham Eid, Paediatric Nephrology and Dialysis
Unit, Mansoura University Children’s Hospital, Egypt
Correspondence to: Riham
Eid, Paediatric Nephrology and Dialysis
Unit, Mansoura University Children’s Hospital, Egypt
Email:
rihameid@mans.edu.eg
Telephone: +201004816421 Fax: +20502230376
Received: May 14, 2015
Revised: August 2, 2015
Accepted: August 7, 2015
Published online: October 26, 2015
ABSTRACT
Haemolytic uremic syndrome (HUS) is the most common cause
of acute kidney injury in children. HUS was first described in 1955.Since then
major advances had been achieved in understanding pathogenesis and improving
patient management and outcomes. Despite these achievements, atypical HUS
diagnosis and management in developing countries is still mostly impossible
because of the very high cost and non-availability of different tests required
for diagnosis, lack of consensus on maintenance plasmapheresis therapy or
long-term Eculizumab treatment for a-HUS and the high risk of recurrence after
renal transplantation are all challenges.
© 2015 ACT. All rights reserved.
Key words: Haemolytic uremic
syndrome; Children; Plasma exchange; Eculizumab
Bakr A, Eid R. Haemolytic Uremic Syndrome in Children
(1955-2015): A 60 Years Journey. Journal of
Nephrology Research 2015; 1(2): 69-79 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1202
INTRODUCTION
Haemolytic uremic syndrome (HUS) is the most common cause of acute
kidney injury (AKI) in children[1-4]. HUS is defined by the triad of
non-immune haemolytic anaemia (hemoglobin < 10 g/dL) with schistocytes,
thrombocytopenia (platelets < 150×103/mm3) and renal impairment (serum creatinine
> upper limit of normal for age)[5].
Before 1955,
cases with acute renal failure following gastroenteritis were explained as
either: prerenal failure (severe dehydration), acute tubular necrosis (ATN),
sepsis, renal vein thrombosis or disseminated intravascular coagulopathy. Such
cases were treated by antibiotics and haemodynamic support only.
Haemolytic
uremic syndrome was first described in 1955[6]. Since then major
advances have been achieved in understanding aetiology, pathogenesis, diagnosis
and optimum management of such cases. Major mile stones in these 60 years are:
linking diarrhoea associated HUS (D+HUS) to Shiga like toxins producing
organisms, differentiating HUS into D+HUS and diarrohea –ve (D-HUS) (this
classification was modified later), genetic diagnosis of atypical HUS (a-HUS),
plasmapheresis, Eculizumab (considered as the most exciting development in HUS
history) use in a-HUS management and finally renal transplantation of HUS
patients with end stage renal disease(ESRD).
Despite these
advances a lot is still required; a-HUS diagnosis and management in developing
countries is still mostly impossible, very high cost of Eculizumab is limiting
its widespread use and still no consensus on maintenance plasmapheresis therapy
or long-term Eculizumab treatment.
History
of haemolytic uremic syndrome
Diarrhoea
associated (D+HUS)/Typical HUS
In 1955, Gasser et al first described five children with haemolytic
anaemia, thrombocytopenia, and renal failure. This combination of clinical
presentations was referred to as HUS[6].This was followed by reports
of similar cases including individual cases, large series and epidemics from
different parts of the world[7-13].
Outbreaks of
HUS forced researchers to think into a possible infectious cause. In 1966 the
first identified outbreak of HUS was reported in Wales. A number of possible
environmental factors were examined including food, water, and other toxins but
no definite cause was detected, however a response to an infection was
suspected to be underlying mechanism[12].
In 1985
Karmali et al[14] showed that patients with HUS preceded by
diarrhoea contained E. coli strains in their stools which produced a toxin that
caused irreversible damage to cultured vero cells (kidney cells from the
African green monkey). Another working group demonstrated that the
verocytotoxin produced by strains of Enterhemorrahagic E. coli (EHEC)
associated with HUS is related to Stx of Shigella dysenteriae type 1[15].
Following these descriptions, it is now known that E-coli-producing Stx and
other factors, are the main causes of paediatric D+HUS[16].
Hereditary/familial/Diarrhoea
–ve/atypical HUS
Hagge et al[17] (1967) reported HUS
in 2 siblings, one of them had repeated attacks, developed ESRD and died at age
8 years while the other recovered completely after one attack.This was followed
by many reports of HUS in families and cases from non-endemic areas[18-21]
which forced researchers to think that there is different group of HUS patients
(other than D+HUS) with possible genetic background.
Complement
factor H (CFH) mutations were the first identified genetic association with
a-HUS in 1973[22], while an acquired dysfunction of CFH due to
anti-CFH antibodies was described in 2005 for the first time[23].
Membrane co-factor protein (MPC) mutation in a-HUS was first reported in 2003[24].
More than 40 different mutations in MCP have been identified so far in patients
with a-HUS[25-27]. Up to 12% of a-HUS patients have different
combinations of 2 or more mutations of CFH, CFI, MCP, C3, (Complement factor B)
CFB or (Thrombomodulin)THBD[28-31].Despite all these discoveries
still 30% of a-HUS cases are unexplained[5] suggesting that
pathogenic pathways and genetic susceptibility loci are still unexplored.
Clinical presentation of the different subgroups of HUS and thrombotic
thrombocytopenic purpure (TTP) and investigations to confirm diagnosis are
summarized in (Table 1)[5].
Classification
Haemolytic uremic syndrome has been divided into D+HUS and D-HUS, with
D+HUS resulting from verocytotoxin-producing E. coli and Shigella dysenteriae
type 1, while a-HUS resulting from all other causes. Because diarrhoea is not a
reliable characteristic feature, currently HUS is divided into ‘typical’ for
that due to infective causes and a-HUS for all other causes (Table 2). Typical HUS is
more common, with verocytotoxin-producing organisms being the commonest
aetiology, however the incidence of Pneumococcal infection as a cause of HUS is
higher in some countries[32].
Pathogenesis
of HUS
Diarrheal
prodrome is not always bloody
Haemolytic uremic syndrome typically follows an enteric infection with
a Shiga toxin-producing E. coli, usually serotype O157:H7 (Figure 1).
The infection is almost always non-bloody diarrhoea at first. In 80% of
patients, the diarrhoea becomes bloody between one and five days after the
onset of diarrhoea[33]. However, some patients may be infected with E.
coli O157:H7 and develop HUS, and without having diarrhoea at all[34,35].
So the presence of non-bloody diarrhoea is not against diagnosis of D+HUS.
The mechanisms
by which hemorrhagic colitis and HUS occurs are not fully clear. The bacteria
adhere to the mucosa of the colon causing bloody diarrhea then shiga like
toxins reach the blood stream and attach to the endothelium of the small
arterioles of the kidneys and other organs. The endothelial cells express a
toxin-specific receptor that enables the contact between toxin and cells
leading to endothelial damage which causes platelet aggregation , activation
and fibrin deposition[36].
Role of
Podocyte dysfunction in HUS
Abnormal complement signalling as the only cause of a-HUS has been
recently challenged as mutations in diacylglycerol kinase ε (DGKE) (which
encodes a protein, diacylglycerol kinase ε) have been reported in children with
a-HUS which is not a component of the complement system. Patients with DGKE
mutations developed proteinuria which highlighted podocyte dysfunction as a
complication of this form of a-HUS[37]. Complement activation in
a-HUS patients with genetic or autoimmune complement abnormalities, might also
result in podocyte dysfunction and vice versa podocyte dysfunction that leads to
nephrotic-range proteinuria might also predispose patients to the development
of thrombotic microangiopathy (TMA)[38].
In 2013,
Lemaire and colleagues identified compound heterozygous and homozygous
mutations in DGKE as the cause of a recessive form of a-HUS. Affected patients
had a specific clinical phenotype with disease onset in the first year of life,
several relapses before age of 5 years and all progressed to CKD before
adulthood, long after the last relapse of a-HUS had occurred. Three of 12 patients
developed nephrotic syndrome (NS) due to glomerular filtration barrier
dysfunction. Compound heterozygous or homozygous mutations of DGKE were found
in 27% of those patients with no anti-CFH autoantibodies or mutations in known
complement a-HUS-associated genes detected[37]. A Spanish cohort of
83 a-HUS children with onset before age of 2 years in 2014 described homozygous
or compound heterozygous DGKE mutations in four patients (5%); three of these
patients had recurrence of disease, however, also carried heterozygous
mutations in THBD or C3[39].
A two-way
relationship between podocyte dysfunction and a-HUS pathogenesis is suggested.
On one side, nephrotic-range proteinuria may occur in childhood forms of a-HUS
associated with complement dysregulation and also in patients with DGKE
genetic. Activation of Diacylglycerol - Protein kinase C (DAG–PKC) signalling
is a common pathogenetic mechanism in a-HUS with both complement dysregulation
and DGKE deficiency, leading to podocyte dysfunction. Conversely, podocyte
dysfunction leading to nephrotic range proteinuria predisposes HUS cases to TMA
by inducing prothrombotic abnormalities and endothelial dysfunction[40].
Complement
regulator factor H autoantibodies
Complement regulator factor H (CFH) autoantibodies (CFH-AAs) formation
is a common cause of a-HUS; these patients have autoantibodies against CFH
domains 19-20 (CFH19-20) which are nearly identical to CFH related protein-1
domains 4-5 (CFHR1 4-5). It is not known why nearly all the patients with autoimmune
a-HUS lack CFHR1. CFH-AAs bind to a common site on the loop R1182-L1189 of CFH
next to the buried two residues different in CFH19-20 and CFHR14-5. The crystal
structure of CFHR1 4-5 also showed that the conformation of the autoantigenic
loop is different on CFH and CFHR1. These data provided the basis for the
suggested novel model to explain how CFHR1 deficiency is linked to CFH-AA
formation[41], the autoantigenic epitope of CFH and its homologous
site in CFHR1 are structurally different which provides an explanation for
formation of autoantibodies caused by deficiency of CFHR1 in autoimmune a-HUS[41].
Clinical
presentation of HUS
Extra renal
manifestations of D+HUS and Diabetes risk
Whereas the kidney and gastrointestinal tract(GIT) are the most commonly
affected organs in HUS, central nervous system (CNS), pancreatic, myocardial
and skeletal, involvement is also reported[42-44]. GIT involvement
with severe colitis may lead to transmural necrosis with perforation and/or
colonic stricture later on[43,44]. CNS involvement in D+HUS is
common and manifest as irritability and seizures, and in more severe cases,
paresis, coma, and cerebral oedema. Skeletal muscle involvement manifested as
rhabdomyolysis occurs in rare cases, and myocardial involvement is very rare as
well[45,46].
Pancreatic
involvement is uncommon in HUS. Autopsy studies reported thrombosis of vessels
supplying the islets of Langerhans with preservation of the exocrine pancreas[47,48].
Little is known about the incidence and management of diabetes mellitus (DM)
during D+HUS. A systematic review and metanalysis was conducted in 2005 to
detect incidence of DM in D+HUS, severity of HUS attacks associated with DM and
long term prognosis of such patients. The incidence of DM (hyperglycaemia
requiring insulin) during acute D+HUS in children below16 years of age was
0-15%, with pooled incidence estimated at 3.2% (95% CI 1.3-5.1). The
development of DM was associated with severe disease, marked by CNS symptoms,
the need for acute dialysis, and mortality. Children who developed DM during
D+HUS and survived, one-third had permanent DM requiring insulin 6 months to 15
years after the acute phase, whereas two-thirds were reported to recover[49].
No evidence supports that individuals infected with E. coli O157:H7 who
develop gastroenteritis without HUS are at increased risk of DM[50].
So frequent
monitoring of blood glucose during acute D+HUS is a must, especially for
patients on peritoneal dialysis (PD). Early aggressive treatment of hyperglycaemia
will prevent ketoacidosis and improve acute outcomes, as in other critically
ill patients[51,52]. Continued loss of islet cells after recovery of
acute attack of HUS may be due to ongoing inflammation and fibrosis, or
decreased islet reserve which manifests clinically in those predisposed to type
2 DM. So, even cases that were not identified to have hyperglycaemia during the
acute phase of D+ HUS may be at long-term risk of DM. Thus, consideration
should be given to long-term screening of D+ HUS survivors for DM; the optimal
timing of screening is unclear[50].
Laboratory
tests for HUS
Diagnosis of HUS depends on careful history taking (Family history,
history of diarrhoea and other infections), exclusion of D+HUS [screening for
Shiga-toxin producing E-coli (STEC)] first followed by ADAMTS13 level
assessment to exclude TTP and anti CFH antibodies followed by full complement
pathway assessment including genetic studies (Figure 2).
Lactate
Dehydrogenase levels in HUS
Lactate dehydrogenase (LDH) level is elevated in HUS and TTP cases. It
is not diagnostic but used mainly in follow up. Total serum LDH rises mainly
due to the release of red blood cell LDH due to intravascular haemolysis[53]
as in other haemolytic anaemias[54,55]. This widely accepted belief
has not been supported by LDH isoenzyme analysis[56]. A large
proportion of the increase in total serum LDH in patients with TTP is the
result of systemic microvascular compromise, rather than erythrocyte lysis.
Widespread tissue ischemia caused by occlusion of microvasculature by platelet
thrombi has been well described in autopsy studies of patients with fulminant
forms of HUS and TTP[55].
Imaging
of HUS with central nervous system involvement
The central nervous system (CNS) is involved in 20–50% of HUS cases[43,47,57].
A toxin-mediated vasculopathy involving the small intracerebral vessels similar
to the kidneys is the probable mechanism[58,59]. Severe fluid and
electrolyte disturbances and hypertension may be responsible for encephalopathy
in HUS patients[43,47]. In many cases, Computed tomography (CT) has
been the initial diagnostic imaging study of choice because of its greater
availability, However magnetic resonant imaging (MRI) is nowadays the modality
of choice for the evaluation of most non-traumatic CNS disease in children[60].
Basal ganglia lesions
was reported as the most frequent with HUS[61-66]. Other findings,
including territorial infarction or diffuse white-matter changes similar to
posterior leukoencephalopathy, have been described, reflect complications
rather than specific changes of the disease[64,67,68]. Involvement
of the basal ganglia is not specific for HUS and is seen in different
conditions as severe hypoxia, intoxication and infectious diseases. This
supports the theory of a direct or receptor-mediated verotoxin-induced injury
as a mechanism of CNS involvement in HUS patients[69].
Management
of HUS
Antimotility
and Antibiotics in D+HUS
Antidiarrheal agents should be avoided in haemorrhagic colitis due
EHEC, as it is thought that it lead to retention of Stx within the colon, which
could enhance absorption of the toxin and confers greater risk for developing
HUS[70-72]. There is a long history of the discussion of antibiotic
treatment for EHEC-induced diarrhoea. In vitro studies demonstrated that
EHEC produces more toxins when stimulated by nonlethal concentrations of
antibiotics, this issue has been under controversial discussion[16].
During the large EHEC outbreak in Japan in 1996, it was suggested that
treatment with Fosfomycin on day 2 after disease onset reduced the risk of developing
HUS but this suggestion has several drawbacks. Fosfomycin is rarely used for
this indication at all outside of Japan. Furthermore, recent epidemiological
studies conducted by the Centre for Disease Control proved that antibiotic
therapy for EHEC enteritis resulted in a significantly higher risk of
developing HUS[73]. This adverse outcome may reflect the effect of
specific antimicrobial agents on phage induction and subsequent Stx gene
expression and transcription or increased Stx release after induced bacteria
lysis[70,74-76].
Some studies
demonstrated a harmful effect of antibiotic therapy in haemorrhagic colitis[75-77].
Other studies have not demonstrated such an association. So currently, there is
no consensus on the use of antibiotic therapy in children with haemorrhagic
colitis or HUS; however, antibiotics are not usually prescribed in children
with HUS until there are specific indications for antibiotic therapy. In
conclusion, during the diarrheal phase, antibiotic treatment should be avoided,
as beneficial effects regarding initiation of HUS cannot be deduced from recent
studies[70,77,78].
Role of
steroids in HUS
In a-HUS as a result of CFH, CFI, C3, THBD, CFB, MCP mutations steroids
are of no value, hence not indicated. Nevertheless a small subset of a-HUS
patients (6-10%) develops CFH autoantibodies. They bind to C-terminus of CFH
and decrease CFH binding to C3b with lack of complement control on cells.
Plasma
exchange (PE) removes anti-CFH antibodies, but this effect is transient. Immunosuppressive
therapy (steroids, azathioprine, MMF) and Rituximab (anti-CD20 antibody)
combined with PE allowed long term dialysis free remission in 60-70% of
patients[23,79,80]. In countries where rapid assessment of CFH
antibodies is not readily available or delayed, it is controversial wether to
start empirical steroid therapy in all a-HUS cases.
Renal
replacement therapy in D+HUS
To date, there is no effective preventive or specific treatment for
D+HUS. Symptomatic and supportive measures are the main options[16,81].
About two thirds of D+HUS children need dialysis therapy. General management of
AKI as fluid and electrolyte balance, antihypertensives if required, and
initiation of renal replacement therapy when indicated[16].
In most
centers, PD is the preferential choice. However, there is no priority to one or
the other. Haemodialysis may be started if a-HUS is suggestive. This is true in
older children and those without clear diarrhoea. In younger children, most
centres prefer PD. It has been argued that PD may have a higher risk of
peritonitis in patients with bloody diarrhoea. However this has not yet been
reported[72].
Platelet
transfusions in HUS
Despite thrombocytopenia (30×103- 60×103/mm3) or
even less, purpuric eruptions are uncommon with no or minimal bleeding reported
in children with HUS[5]. It has been theoretically postulated that
transfusions of platelets should be avoided unless there is severe bleeding or
an invasive procedure is to be done. A study compared 22 (30%) cases who
received platelet transfusion with 51 (70%) who did not and observed no
bleeding complications related to these procedures in either group despite the
associated thrombocytopenia[82].
The rationale
for avoiding platelet transfusion is the possibility that infused platelets may
worsen the microvascular thrombosis and aggravating course of the disease[16,82-84].
However, information on the effects of platelet infusions in D + HUS patients
is scarce. In 2009 a report of 22 children with D + HUS showed that seven of
them (31.8%) required platelet transfusions without reported additional
morbidity or mortality[85]. Due to limitations of studies, platelet
transfusion should be avoided or minimized as possible in patients with HUS and
decision to give a platelet transfusion must include the consideration that the
perceived benefits outweigh the potential complications.
Intravenous
Volume Expansion during E-coli O157:H7 infections
HUS can be categorized as either oligoanuric (which probably signifies
ATN) or non-oligoanuric. Children with oligoanuric renal failure during HUS
generally require dialysis, have more complicated courses, and at increased
risk for chronic sequelae than children who experience non-oligoanuric HUS[86].
Volume
expansion during acute E-coli O157:H7 infection may oppose the small
vessel thrombi formation by improving renal perfusion, preventing glomerular
tubular imbalance from hypoperfusion and ischemia, and maintaining tubular
flow. Volume expansion may also mitigate the nephrotoxicities of filtered urate[87,88]
and haemoglobin and of Shiga toxin’s effects on renal tubular epithelial cells[89]
and monocytes[90] that are independent of thrombotic changes.
However, renal injury can still follow E coli O157:H7 infections in
well-hydrated children. The only way to prevent HUS is prevention of E-coli
O157:H7 infections[86].
Guidelines
of The European Paediatric Study Group for HUS
The European Paediatric Study Group for HUS in 2006 published “Classification
of HUS, TTP and related disorders” (Table 3)[91]. While the
Guidelines for the investigation and initial therapy of D-HUS were published in
2009. The guideline describes a clinical pathway for cases of HUS and is
intended to offer an approach based on opinion, as evidence is lacking. It is
designed to streamline the recognition of those cases of HUS that have
aetiologies other than EHEC (Table 4, Figures 3, 4)[92]. Since then
these guidelines are a standard and being followed worldwide and led to marked
improvement in understanding and management of this disease. However after
introduction of Eculizumab, clinicians worldwide believe that it should be the
standard of care for all a-HUS cases[92-94].
Interventions
to promote endothelial cell health
Endothelial cell dysfunction, due to complement activation, is an
intermediate stage in the pathogenesis of HUS[95] so targeting
endothelial cell dysfunction is gaining importance in the management of TMA[96]
with promising results in experimental settings. Inhibitors of
angiotensin-converting enzyme (ACE), HMG- CoA reductase (statins), and xanthine
oxidase as well as antioxidants (such as ascorbic acid) may have beneficial
effects a-HUS. ACE inhibitors reduce angiotensin II-mediated oxidative stress
within the vessel wall[97]. By reducing oxidative inactivation of
nitric oxide, ACE inhibitors improve endothelium-dependent vasodilation[97,98].
Therefore, ACE
inhibitors may be useful in a-HUS treatment by decreasing oxidant stress and
increasing bioavailability of nitric oxide[97]. Statins improve
endothelial cell dysfunction by nitric oxide and decreased thrombogenicity.
Statins also have immunomodulatory and anti-inflammatory properties[99,100].
Allopurinol, is an inhibitor of xanthine oxidase, improve endothelial cell
dysfunction[101-103].Ascorbic acid restores endothelium-dependent
vasodilation by oxidative stress[104] and increases the
bioavailability of nitric oxide by scavenging reactive oxygen species[95].
Haemolytic
uremic syndrome after introduction of Eculizumab
For years, the only available treatment for a-HUS was plasma exchange,
outcomes were poor and up to 60% of patients with CFH mutations (the most
severe form) developed ESRD shortly after onset[105]. First report
of successful treatment HUS patients with Eculizumab was in 2009[106].
The drug was approved by the Food and Drug Administration (FDA) for use in a-
HUS treatment in September 2011 (FDA. News release September 23, 2011).
Eculizumab
(Soliris) is a humanised monoclonal IgG2/4κ antibody produced from murine
myeloma cells. It is a complement inhibitor, binding to complement protein C5
with high affinity, thus inhibiting cleavage to C5a, a proinflammatory and
prothrombotic and C5b, so prevent the generation of the terminal complement
complex C5b-9[94]. It is now used for paroxysmal nocturnal
haemoglobinuria (PNH) and was tested for rheumatoid arthritis without success[107].
A favourable outcome after use of eculizumab in three patients with
severe D+HUS and CNS involvement was reported[108]. A retrospective
review of the excessive uncontrolled use of eculizumab, during outbreak of
D+HUS in Germany, did not demonstrate a benefit for patients who received
eculizumab, compared to patients who did not receive eculizumab[109].
So no sufficient evidence is available currently to support the use of
eculizumab for D+HUS patients[33,110]. With time, the use of
Eculizumab in a-HUS has increased. Renal function recovery has been described
even after 6 months of dialysis[111], neurological and ocular
involvement (bilateral serous retinal detachment) were reported also to reverse
with eculizumab[112,113].
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[114,115]. This indicates
subclinical activity, and that an increased platelet count is not always a
reliable recovery marker, so other biomarkers of disease activity are required[116].
Preventive measures (vaccination and if needed prophylactic antibiotics) should
be initiated against Neisseria meningitides prior to starting treatment with
eculizumab[117]. Studies of long-term safety and efficacy of
eculizumab are still few[118,119].
Trials of
discontinuation of life long maintenance Eculizumab
Discontinuing eculizumab therapy has been described in few reports[120-125].
The main rationale for discontinuing eculizumab therapy was to protect patients
from the risk of the potentially side effects as meningococcal infection[126,127]
and immune-mediated drug reactions, including the theoretical risk of
developing neutralizing anti-drug antibodies that ultimately would deprive the
patient of a life-saving therapeutic resource. Additionally, eculizumab is
among the most expensive life-long medical treatments[125].
Outcome
of transplanted HUS children
Patient with D+HUS rarely develop ESRD so renal transplantation is
rarely required. However, reviews support that, a recurrence of HUS is the
absolute exception in D+ HUS patients so transplantation can be performed
without increased risk for failure[128,129]. Before transplantation
all a-HUS cases should have a complete genetic analysis to detect known
complement mutations and anti-CFH antibodies and possibly the recurrence risk
(Table 4). TMA presents in the transplanted kidney in around 50% of patients
who undergo transplantation, and graft failure occurs in 80% – 100% of those
with TMA[25].
With a lack of
guidelines, patients in whom a kidney transplant is considered should be
evaluated on an individual basis, based on the risk of graft failure and
availability of eculizumab[117,130]. Different protocols to prevent
recurrence of TMA including prophylactic plasmapheresis (Figure 5)[5,131],
Eculizumab[132-134] or both are followed with variable results.
Combined liver
and kidney transplantation in HUS
The most common mutation of complement regulatory proteins associated
with a HUS is in the gene encoding CFH. Combined liver-kidney transplantation
may correct this complement abnormality and prevent recurrence when the defect
involves genes encoding circulating proteins that are synthesized in the liver,
such as factor H or I. Good outcomes are reported when surgery is combined with
intensive plasma therapy[135].
Long
term follow up of D+HUS
Diarrhea associated HUS generally has a good prognosis as more than 95%
of children recover from the acute phase[136], however long-term
renal sequelae have been reported in up to 25% of cases[137]. Long
term follow up of all D+HUS patients is mandatory. Studies have suggested that
patients with less severe forms of HUS including those with a preserved urine
output, may also develop renal sequel at follow up[138,139].
Studies did
not differentiate patients who apparently completely recovered after the acute
illness from those who demonstrated persistent renal abnormalities regarding
development of long term renal sequel[78]. A study suggested that a
quarter of those who recovered with an absence of proteinuria(<250 mg/day)
went to develop renal sequel during long term follow up[140].
Prognostic
factors associated with poor outcomes in D+HUS cases include: severity of acute
illness (greater infection or host response) including elevated white blood
cell count higher than 20×103 with neutrophilia[141],
a high serum creatinine[142], CNS involvement[34,138,140,143]
and hypertension[138,144]. Compared with patients with oliguria of 8
days or less, those with oliguria greater than 8 days or anuria1-8 days and
those with anuria of greater than 8 days had a step-wise worsening of prognosis[9,144-146].
Dialysis therapy required for more than 4 weeks was associated with worse
prognosis and no patient achieved full renal recovery[138,141,147,148].
Progression of
renal disease in HUS
Children with most severe forms of HUS do not recover from AKI and
become dialysis dependence. A second group recovers renal function partially,
with persistent proteinuria and hypertension and progress to ESRD within 2-5
years. The third group may recover normal serum creatinine and creatinine
clearance but with persistent proteinuria. They are at risk of progressing to
CKD and ESRD after 5 -20 years following the acute attack[150].
Hyperfunction
(hyperfiltration injury) of the remaining nephrons after acute attack of HUS is
a probable mechanism of deterioration of kidney function after recovery of
acute illness leading to progressive scarring and loss of renal function[150-152].
Histologic changes in biopsied HUS patients during follow up (Biopsies done
because of late or persistent proteinuria, hypertension, and prolonged renal
failure) show focal and segmental glomerulosclerosis sclerosis(FSGS) and
mesangial expansion in the glomeruli[152]. This may highlight HUS as
one of the possible causes of secondary FSGS. Close follow up and prompt
control of hypertension to average or low-normal values, and treatment of
proteinuria persisting for 6 months after the acute period with ACE inhibitors
is recommended[150].
Atypical
HUS in developing countries
An adequate diagnostic work-up as an essential requirement for proper
therapy, is currently impossible and unaffordable for most a-HUS patients in
developing countries. International cooperation facilitating a proper diagnostic
work-up in a stringent and cost-efficient manner are indispensable for
diagnosis and therapy of many individuals suffering from these serious and
life-threatening diseases. Nevertheless, while the costs for complement
targeting drugs remain high, treatment
of a-HUS patients especially in developing countries will remain a challenge[153].
CONFLICT OF INTERESTS
The authors declare no conflict
of interest.
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Peer reviewer: Zuo, Li MD PhD, Department of
Nephrology, Peking University People’s Hospital, 11 Xizhimennan Street, Haidian
District, Beijing, 100044, China.
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