Discussion:
Our study is one of the few trying to elaborate various complement
abnormalities, presentation and outcome in pediatric aHUS, albeit in the
absence of targeted therapy. While a myriad of mutations have been
documented, yet the whole picture is still not as vivid as we want it to
be. Besides, the phenotype association in different mutations is
something that we need to understand further.
In our cohort, the median age of presentation was 49 months which was
different from other studies where it is around 24 months [7-10].The
reason for this difference could be that previous studies included more
of infection associated HUS, especially STEC HUS, while our study
population had included only aHUS. However, the possibility remains that
in India, HUS is more common in older age group. A retrospective study
by Aditi et al. in children with anti-FH antibody HUS observed that mean
age was 8.4 ± 4.1 years [11].
It was a male predominant study similar to that done by Srivastava et
al. [7]. However, a lower sex ratio was noted in western countries
with a ratio of 0.9 [12]. This difference could be due to the male
predominant society, though the possibility that boys have a more
propensity for these abnormalities remains.
Oliguria was the most common presentation (71.4%) followed by
progressive pallor (48.6%) as HUS itself is a triad of hemolytic
anemia, thrombocytopenia and AKI. One-third children had loose stools (1
with bloody diarrhea) as prodromal feature suggesting, loose stools as a
prodromal feature can also be noted in aHUS as shown in previous studies
[11,13]. Seizure was the commonest extra-renal presentation similar
to that observed by Hughes et al. [8]. Neurological involvement
might be due to disease as such or can be secondary due to sequel of
disease like azotemia, electrolyte imbalances and posterior reversible
encephalopathy due to hypertension.
Prevalence of acute hypertension in our cohort was similar to that
observed by Hughes et al. They documented that 61% had hypertension.
However, other studies showed an incidence of 15–30% [7, 14]. This
may be due to the fact that STEC HUS is known to have less severe
manifestations. Hypertension in HUS is mainly due to pre-glomerular
vessel involvement which causes a break in renin angiotensin axis and
result in hyperreninemic state aggravating hypertension [15].
Severe anemia was noted initially in half, however, because of on-going
hemolysis, 88% subsequently had severe anemia. Similar haemoglobin
levels were noted in other studies where children were assessed
retrospectively after being diagnosed as HUS [8,9]. Anemia in HUS is
mainly due to intravascular hemolysis caused by stress of constricted
small vessels and microthrombi formed due to endothelial damage. In our
study, there was no correlation between levels of haemoglobin and
outcome, though it was not powered for the same. Thus, further larger
studies are required. Two-third children had moderate to many
schistocytes in peripheral smear suggesting severe hemolysis. Studies
have been published for standardization of schistocyte counting and
reporting, that may help in decreasing the observer bias [16].
Severe thrombocytopenia was noted in one-third of children at admission
but there was a two-fold decrease during the course. Similar results
were noted in other studies [7-9]. This is due to excessive
consumption of platelets in endothelial damage induced fibrin and
platelet thrombi formation.
In our study, 80% children presented with AKI stage 3. Staging of AKI
helps in prognostication and assessment of outcome. Although 93%
children had AKI stage 3 during hospital course, 14 children showed
recovery.
Proteinuria was found consistently in studies where urine analysis was
performed [16]. It can result due to podocyte dysfunction caused by
activated alternate complement pathway. Interestingly, nephrotic range
proteinuria was noted in a higher proportion (34.3%) in our cohort
compared to other studies [7]. Hematuria was noted in 60% children
which was consistent with other studies [9]. It is due to complement
mediated damage to endothelium of glomerular arterioles. Hematuria and
proteinuria suggests glomerular involvement. Doorn et al, reported a
child who was initially treated as MPGN and was later diagnosed to have
HUS because of recurrent relapses [17].
We observed that C3 was low in 57.1% and C4 in 25.7 % of our study
cases. Kaplan et al., and Stuthlinger et al., [18, 19] have
described hypo-complementemia in HUS. They explained that low C3 is due
to intravascular activation of classical complement pathway. This might
also explain low C4 levels, as it is part of classical pathway. Similar
data of low C4 levels were noted in a study by Song et al., where he
assessed C4 levels in anti-FH antibody associated HUS children [20].
Both C3 and C4 can be low in SLE which is a disease affecting classical
pathway. All our 6 children who had low C3 and C4 were screened with ANA
which was negative. Therefore, it maybe plausible that the classical
pathway is activated in aHUS.
Further, three-fourth of the study population had abnormalities in at
least one component of complement system. Anti-FH antibody HUS was found
in 15 children (44%). This is different to a European study where only
22% children had anti-FH associated HUS [21]. However, it is
similar from studies from India where it forms the predominant group
[10].In our study, low CD46 expression which constituted 26.7% of
study population was more compared to that by Khandelwal et al where
12.7% had CD46 defect [22]. However, this has to be confirmed with
genetic mutation studies. Interestingly, three children in this
sub-group also had elevated anti-FH levels which had been previously
described in literature [22].
Treatment of HUS is based on etiology. In our study, children with
suspicion of aHUS based on clinical presentation and investigations,
especially antibody associated HUS, underwent plasma therapy if
amenable. In India, as per literature, anti- FH antibody HUS is more
common than other forms of atypical as well as STEC associated HUS
[10]. Hence empirical treatment with PEX and immunotherapy was
offered.
Almost all children who underwent PEX were initiated with
immunosuppressive therapy which included methylprednisolone followed by
oral steroids and cyclophosphamide. It has been found that PEX followed
by immunosuppression had a better renal outcome than immunosuppression
alone in case of rapidly progressive glomerulonephritis [23]. Sana
et al., observed that in anti-FH HUS too, early immunosuppression using
cyclophosphamide pulse therapy along with PEX caused sustained
remission, decreasing need of maintenance therapy [24].
Previous literature described a lower mortality rate of 25% after
increased utility of plasma therapy in HUS [25, 26] and a French
cohort reported only in 8.6% [27]. However, overall outcome of our
cohort was worse. This could be due to many factors, but etiology, poor
socio-economic status, affordability for PEX and non-availability of
eculizumab could be important reasons. However, further larger studies
are needed to assess prognostic factors.
Age of onset of illness is an important predictor for outcome of
disease. Previous studies suggest that poor outcome is noted in children
of younger age when compared to toddlers and school going age group
[11]. Similarly, our study also showed a significant poorer outcome
in younger children, especially in infants (p value <0.01).
This age dependent outcome might be due to multiple factors like greater
prevalence of familial HUS, difficult in amenability to treatment
modalities like hemodialysis, PEX. Hence children with HUS presenting at
less than 2 years needs to be worked up and diagnosed early. Further,
there is a need for improving targeted therapy.
Conclusion: We observed that aHUS was more common in boys, with
hypertension as a common presentation. While various complement
abnormalities were detected, anti-FH antibody and low MCP expression
seems to be common. Remission was seen only in half of the patients. We
recommend a comprehensive complement analysis in pediatric aHUS as it
has therapeutic implications.