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Indian Pediatr 2020;57: 744-747 |
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Guidelines on Hemolytic
Uremic Syndrome by Indian Society of Pediatric
Nephrology: Key Messages
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Priyanka Khandelwal and Arvind Bagga
From the Division of Pediatric Nephrology, Department of
Pediatrics, All India Institute of Medical Sciences, New
Delhi, India.
Correspondence to: Dr Arvind Bagga, Division of Pediatric
Nephrology, Department of Pediatrics, All India Institute of
Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Email:
[email protected]
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Hemolytic uremic syndrome
is an important cause of acute kidney injury that requires
dialysis in children. The diagnosis and management is
difficult due to limited diagnostic facilities and
non-availability of specific complement inhibitors. We
describe salient features of the recent Indian Society of
Pediatric Nephrology consensus guidelines on hemolytic
uremic syndrome.
Keywords: Factor H antibodies,
Plasma exchange, Thrombotic microangiopathy.
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H emolytic uremic syndrome (HUS) is an important
cause of acute kidney injury (AKI) requiring renal replacement therapy.
Rapid diagnosis and management is necessary to limit irreversible renal
damage. Although Shiga toxin-associated HUS constitutes the chief form
of the disease worldwide, burden of this illness in India is not clear.
School-going children show high prevalence of anti-factor H (FH)
antibody-associated HUS. While International guidelines emphasize
comprehensive diagnostic evaluation and complement blockade with
eculizumab, access to these facilities is limited in India. Given the
difference in epidemiology and challenges in management, guidelines for
treatment of HUS were recently published by the Indian Society of
Pediatric Nephrology (ISPN) [1]. This article highlights key messages
from these guidelines.
DIAGNOSIS
Importance of Demonstrating Schistocytes and Thrombocytopenia
The diagnosis of HUS requires all of the following:
(i) microangiopathic hemolysis characterized by anemia
(hemoglobin <10 g/dL), fragmented red cells on peripheral smear (schistocytes
³2%) and
either high lactate dehydrogenase >450 IU/l or undetectable haptoglobin;
(ii) thrombocytopenia (platelets <150,000/µL), and (iii)
AKI (rise in creatinine by 50% over baseline). Guidelines for
identifying schistocytes on peripheral smear are available [2]. Rarely,
HUS may have an indolent presentation with AKI and systemic hypertension
without thrombocytopenia or microangio-pathic hemolysis. Renal biopsy is
usually not required.
Rule-out Infections
Disseminated intravascular coagulation (DIC) and
thrombotic thrombocytopenic purpura (TTP) should be ruled out in
patients with suspected HUS. Infections that mimic/trigger HUS, e.g.,
malaria, leptospirosis, dengue, rickettsia and H1N1 infection should be
excluded, if clinically suspected.
DIC is characterized by prolonged prothrombin time or
activated partial thromboplastin time, low fibrinogen, elevated D-dimer
and soluble fibrin monomers. TTP is rare in childhood; persistent
thrombocytopenia (<30,000/µL) and mild/no AKI is suggestive. Blood
samples should be stored and later processed for ADAMTS13 activity, if
etiology of microangiopathic anemia is unclear.
Evaluation
ISPN guidelines endorse the etiology-based
classification of HUS (Fig.1) [3]. Epidemiology of HUS in
India differs from that in developed countries. Worldwide, the chief
cause of HUS is gastrointestinal infection with Shiga toxin producing
E. coli (STEC-HUS), which is seen in 80% patients. In India,
infection with S. dysenteriae has declined significantly and
prevalence of patients with STEC-HUS is also low. STEC-HUS is suspected
if occurring within 2 weeks of bloody diarrhea – infection is diagnosed
by stool culture and demonstration of virulence genes, fecal Shiga toxin
or IgM antibodies to serogroup specific lipopoly-saccharide.
ADAMTS13, A disintegrin and metalloproteinase
with a thrombospondin type 1 motif, member 13; CD46, membrane
co-factor protein; DIC, disseminated intravascular coagulation;
LDH, lactate dehydrogenase; *See Box I for evaluating patients
with HUS, including storing and processing of samples; **Also
consider atypical HUS if positive non-synchronous family history
or recurrent disease.
Reprinted by permission from Springer Nature:
Pediatric Nephrology (Bagga A, Khandelwal P, Mishra K,
Thergaonkar R, Vasudevan A, Sharma J, et al. Hemolytic uremic
syndrome in a developing country: Consensus guidelines. Pediatr
Nephrol. 2019;34:1465-82.).
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Fig. 1 Approach to patients with
hemolytic uremic syndrome (HUS).
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Cobalamin deficiency accounts for ~6-8% patients with
HUS. Feeding difficulties, seizures, abnormal muscle tone, developmental
delay and megaloblastic anemia are common; one-third lack extra-renal
features. High blood levels of total homocysteine (>100 µM/L) followed
by genetic screening is confirmatory [4]. Samples may be stored and
processed later (Box I). Specific therapy includes
parenteral hydroxycobalamin, oral betaine and folate [4]. Secondary
causes of HUS include systemic lupus, malignant hypertension and
antiphospholipid antibody syndrome.
BOX I
Evaluation of Patients With Hemolytic Uremic Syndrome |
Diagnosis
Complete blood counts; peripheral smear for
schistocytes; reticulocyte counta
Lactate dehydrogenase, haptoglobina, direct
Coombs testb
Blood: creatinine, electrolytes, transaminases,
bilirubin, complement C3a
Urinalysis
Rapid test for malaria, dengue; IgM antibodies
for dengue, leptospirosis (if suspected)
Coagulation profilea(suspected systemic sepsis)
Ultrasound abdomen
If clinical features present: Echocardiogram,
neuroimaging, amylase, troponin T
Determining cause of HUS
Essential
• Investigate for infection associated or
secondary HUS, if clinically suspected
• Anti-factor H antibodiesa,d; antinuclear
antibodies
• CD46 expression on neutrophils (flow cytometry)a,d
• Store blood for ADAMTS13 activitya,c,e; total
homocysteinea,c
Selected patients
• Suspected Shiga toxin associated HUS: Stool
culture; PCR for stx1, stx2 genesf
• Suspected pneumococcal HUS: Culture, PCR,
ELISA; peanut lectin agglutination assay
• Gene sequencing: CFH, CFI, CFB,
C3, CD46, DGKE, THBD, MMACHC
• Multiplex ligation-dependent probe
amplification: Copy number variations CFHR1-5
ADAMTS13 disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13; CD46 membrane cofactor
protein; CFHR complement factor H related; ELISA enzyme linked
immunosorbent assay; PCR polymerase chain reaction; stx Shiga toxin;
aBlood samples should be drawn before plasma exchanges or infusion;
bPositive with pneumococcal infection, lupus; must be tested prior
to administering blood products; cPlasma to be separated from fresh
citrated blood (ADAMTS13) and EDTA blood (homocysteine) within 1-hr
of collection and frozen at -20 to -70oC; dDivision of Nephrology,
Department of Pediatrics, All India Institute of Medical Sciences,
New Delhi; eDepartment of Hematology, Christian Medical College,
Vellore; fPostgraduate Institute of Medical Education and Research,
Chandigarh.
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In a significant proportion of patients, HUS is
associated with uncontrolled activation of the alternate complement
pathway, termed atypical HUS (aHUS). A diagnosis of aHUS is made when
infection, cobalamin-associated and secondary forms of HUS are excluded
(Fig. 1). These patients need detailed evaluation to
determine the underlying cause. However, access to microbiological and
complement assays is limited in India. Given the implications of
accurate diagnosis, physicians taking care of these patients must be
aware regarding appropriate screening. Units lacking facilities for
assays must store samples for later analyses.
Screen for anti-FH Antibodies
Unlike European cohorts, anti-FH antibody-associated
illness accounts for ~50% pediatric atypical HUS (aHUS) in India,
chiefly affecting children aged between 5 and 15 years. Given
therapeutic implications of this diagnosis, experts recommend prompt
screening for anti-FH antibodies prior to instituting plasma exchange
(PEX) therapy. ELISA test is available at multiple centers, with
turn-around of 7-14 days [5]. Commercial ELISA kits may show false
positive results and underestimate antibody titers, limiting their role
on follow-up; a positive threshold for these kits is also not defined
[6].
Pathogenic variants in genes encoding proteins of
complement and coagulation pathways: CFH, CFI, CFB,
C3, CD46, THBD and DGKE are associated with
aHUS in 30-40% cases. Patients without anti-FH antibodies require
sequencing of these and other genes by next-generation sequencing (NGS)
and CFHR1-5 copy number variations by multiplex
ligation-dependent probe amplification (MLPA). These studies are useful
for guiding management, prognosis, risk of relapses and allograft
recurrence, and allow genetic counseling. NGS allows rapid, simultaneous
sequencing of multiple genes; declining costs have made studies more
accessible. Patients with anti-FH antibody-associated HUS do not require
genetic screening, except if: (i) onset before 4 years of
age, (ii) relapsing course, (iii) family history of
HUS, (iv) illness that is refractory to PEX, and (v)
prior to kidney transplantation.
MANAGEMENT
Atypical HUS: Across the developed world,
complement blockade with eculizumab, the C5 monoclonal antibody, is the
standard of care for patients with aHUS. However, eculizumab is
expensive and not available in India and developing countries. In
absence of anti-complement therapies, intensive PEX is less than ideal,
but the only alternative. For our country, timely institution of PEX
(60-75 mL/kg; fresh frozen plasma as exchange fluid) is most appropriate
for patients with suspected aHUS.
PEX by filtration or centrifugation method, must be
done at centers with expertise [7]. PEX is administered daily until
hematological remission (platelets >100,000/ mL,
schistocytes <2%, LDH less than upper limit of normal for 2 consecutive
days) and tapered over 4-6 weeks. Maintenance therapy with plasma
infusions is advised every 10-14 days for patients with mutations in
complement genes, especially CFH and CFI. There is limited
benefit of PEX in patients with: (i) microbiologically confirmed
STEC-HUS, without cardiac or neurological involvement, (ii)
infection-associated HUS or, (iii) pathogenic variants in
CD46 and DGKE.
Anti-FH antibody associated aHUS:
Since aim of therapy for patients with anti-FH associated HUS is
reduction of titers, PEX are most appropriate to achieve this goal.
Plasma infusions do not remove antibodies and are not a substitute for
PEX. Findings from a nationwide database on 436 patients with
anti-FH disease show that high antibody titers
³8000 AU/mL at onset,
delayed PEX and short duration PEX (<14 days) predict adverse outcomes
[8]. Combination of PEX and immuno-suppression was most useful [1,8].
Immunosuppression must not be used without confirming
presence of anti-FH antibodies. Therapy is
initiated with prednisolone 1 mg/kg/day for 4 weeks, then alternate-day
followed by tapering over 10-12 months. Therapy includes
cyclophosphamide (500 mg/m 2
intravenously once in 4-weeks) for 5 doses. About 15-30% patients
relapse; high anti-FH titers (>1300 AU/mL) during remission predict
early relapses [8,9]. Antibody titers should be sequentially measured,
especially in the first 12-24 months of follow up. Maintenance
therapy with mycophenolate mofetil or azathioprine for 18-24 months, and
tapering prednisolone further reduces the risk of relapses.
CONCLUSIONs
Given limited diagnostic capabilities and lack of
access to eculizumab, international guidelines on aHUS are not likely to
be implemented in developing countries in the near future. The present
guidelines provide a systematic and algorithmic approach to management
of patients with HUS, tailored to the distinct epidemiology and
available repertoire of investigations and therapy. The guidelines
underscore the importance of appropriate supportive care, and need for
regular and prolonged follow-up. Capacity building for diagnosis and
therapy of HUS and other complement related disorders is also required.
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