Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, acute kidney injury, and thrombocytopenia. It is classified as Shiga toxin-associated HUS or atypical HUS. Shiga toxin-associated HUS is typically caused by infection with Shiga toxin-producing E. coli or Shigella dysenteriae type 1. Atypical HUS is caused by abnormalities or mutations involving complement regulatory factors. Diagnosis involves confirming hemolytic anemia, thrombocytopenia, and kidney injury along with identifying the underlying etiology. Renal biopsy may demonstrate thrombotic microangiopathy but is not required for diagnosis. Treatment differs depending
2. • First described by Gasser et al in 1955.
• Hemolytic uremic syndrome (HUS) is a leading cause of acute kidney
injury in children. It is a triad of
Micro-angiopathic hemolytic
anemia (MAHA)
Acute kidney injury (acute renal
failure)
Thrombocytopenia
3. EPIDEMIOLOLOGY
• Epidemiology of HUS in India differs from that in developed countries.
• Worldwide, the chief cause of HUS is Shiga toxin producing E. coli
(STECHUS), which is seen in 80% patients.
• In India, infection with S. dysenteriae is the commonest cause, recent
times prevalence declined significantly.
4. CLASSIFICATION
Classification of hemolytic uremic syndrome (HUS)
Shiga toxin-associated HUS Shiga toxin-producing Escherichia coli, Shigella dysenteriae type 1,
- Citrobacter, Campylobacter
Pneumococcal HUS Invasive infection with neuraminidase-producing Streptococcus pneumoniae
Infection-associated HUS −Triggered by influenza A, human immunodeficiency virus,
−cytomegalovirus, Epstein-Barr virus, parvovirus B19, Coxsackie virus,
−echovirus, varicella virus, hepatitis A, B, and C, Salmonella typhi,
−Bartonella, leptospira, malaria, dengue, and rickettsia
5. Type
Secondary HUS Systemic lupus erythematosus; antiphospholipid antibody syndrome
Hematopoietic stem cell or solid organ transplant
Malignancy
Malignant hypertension
Drugs: quinine, mitomycin, ticlopidine, clopidogrel, calcineurin
inhibitors, sirolimus, oral contraceptives, bevacizumab
Defective cobalamin
metabolism
Homozygous or compound heterozygous mutation in MMACHC
Atypical HUS • Factor H deficiency (mutations, autoantibodies)
• Factor I deficiency (mutations)
• Factor B (gain-of-function mutations)
• Membrane cofactor (MCP) deficiency (mutations)
• C3 deficiency (mutations, autoantibodies)
• Thrombomodulin deficiency (mutations)
• Anti–complement factor H antibody
• Unknown
6. Two main categories of HUS
Stx-HUS: (tHUS)
D+ HUS
D- HUS
Non-StxHUS: (aHUS)
Sporadic
Familial
• Shiga-like toxin associated HUS (Stx-HUS)
• Non-shiga-like toxin associated HUS (non-Stx-HUS)
7. Typical/Diarrhea associated/Shiga Toxin
associated HUS
• Enterohaemorrhagic E. coli (EHEC) infection (serotype O157:H7 )
• Shigella dysenteriae type 1 infection
• Rarely, HUS can occur with E. coli urinary tract infection.
8. • Shigatoxins (also called verotoxins [VT] or shiga-like toxins [ST]) are composed of two subunits:
• a larger A subunit - that inhibits protein synthesis by blocking elongation factor-1 dependent binding
of aminoacyl-tRNA to ribosomes
• Five B subunits- mediate binding of the toxin with a membrane glycolipid, globotriaosylceramide or
Gb3
• Gb3 is the cell surface receptor for shigatoxin found in kidney, brain liver, pancreas and heart.
• S. dysenteriae 1 is the most potent toxin producer, S. dysenteriae invades the bowel wall, thus
allowing larger quantities of the toxin to enter the circulation
• Shigatoxin 1 (ST-1) produced by E. coli is identical to the shigella shigatoxin, differing by only one
amino acid in the A subunit
9. Risk factors for occurrence of HUS are:
young age (< 5 years)
> 3 days of diarrhea,
blood in stools
high leukocyte count (> 15,000/μl)
10. Source of infection
• feco-oral transmission.
• Milk and animal products (incompletely cooked)
• Veges, salads, drinking water contaminated by bacteria shed in
animal wastes.
11. Pathogenesis
• Shiga-like toxin affects endothelial cells with Gb3 and initiates intravascular thrombo-
genesis.
• After entering the circulation via the gastrointestinal mucosa, the toxin preferentially
localizes to the kidneys, inhibiting protein synthesis and eventually leading to cell necrosis or
apoptosis.
• Endothelial cell damage subsequently potentiates renal microvascular thrombosis by
promoting activation of the blood coagulation cascade.
• Platelet aggregation results in a consumptive thrombocytopenia.
• Microangiopathic hemolytic anemia results from mechanical damage to red blood cells
circulating through partially occluded microcirculation.
12. Histopathological hallmark of HUS
• Thrombotic microangiopathy (TMA) Characterized by:
− Capillary endothelial damage.
− Microvascular formation of platelet/fibrin plugs.
− This induces tissue ischemia
− Damage to erythrocytes
− Consumptive thrombocytopenia.
13. Pneumococcal HUS
• 5% of all HUS
• 38-43% non-diarrheal HUS are associated with invasive Streptococcus pneumoniae infection
• patients, usually younger than 2 years, with sepsis, pneumonia or meningitis
- positive direct Coombs’ test without features of DIC.
• Renal endothelial cells, erythrocytes and platelets have a structure on their surface called Thomsen-
Friedenreich antigen (TAg). This is normally obscured by neuraminic acid.
• Pneumococci containing the enzyme-neuraminidase, which cleave this neuraminic acid from the cell surface
thus exposing the TAg .
• This leads to antigen-antibody binding, activation of an immune cascade, with resultant, glomerular
endothelial cell damage, hemolytic anemia, platelet aggregation and consumption, and a fall in GFR.
• This TAg is also present on hepatocytes, and hepatic dysfunction may coexist.
14. HUS DUE TO COMPLEMENT ABNORMALITIES
• The majority of non-infection related HUS in children is due to complement dysregulation.
• Complement gene mutations are found in 30-50% patients with aHUS.
Includes abnormalities of
Factor H (FH) gene, (14-33%)
membrane co-factor protein (MCP) gene (10-15%)
Factor I (FI) gene 2-13%.
• These genes code for proteins that inhibit activity of complement C3b.
• Deficiency causes- unregulated amplification of the alternative pathway and deposition of
activated complement on the surface of invading bacteria or damaged self-tissue, such as
apoptosed or inflamed renal endothilial cells.
15. ADAMTS13 deficiency and HUS/ TTP
• ADAMTS-13 is an enzyme produced by stellate cells in the liver.
• It acts as a von Willebrand factor (VWF) cleaving protease, and degrades
large multimeric forms of VWF by cleaving peptide bonds.
• In the deficiency of this enzyme, ultralarge multimeric form of VWF
(ULVWF) released by stimulated endothelial cells circulate in plasma.
• Circulating platelets spontaneously and preferentially bind to ULVWF strings
(rather than to smaller VWF). Continuing platelet aggregation, ensuing TMA
and embolisation of ULVWF-platelet strings causes tissue ischemia.
16. ADAMTS-13 deficiency
Familial:
• usually in children.
• rare.
Acquired:
• more common in adults and older children.
• Associated with presence of anti-ADAMTS13 antibodies.
• Manifestation classically of frank TTP (pentad of fever, neurological manifestations,
TMA, severe thrombocytopenia, and relatively less severe renal dysfunction)
17. Cobalamin deficiency-associated HUS
• Cobalamin deficiency accounts for a small (~ 6–8%) proportion of patients with HUS
• Homozygous or compound heterozygous mutation in MMACHC
• It can present at all ages, ranging from neonates to adults, and does not respond to PEX
• Features include - failure to thrive, feeding difficulties, seizures, abnormal muscle tone, visual
impairment, and developmental delay.
• Megaloblastic anemia is present in 10– 25%.
• two-third patients have extrarenal feature
neurological (44%) or cardiopulmonary (39%) disease and pulmonary hypertension (17%) are
frequent.
18. CLINICAL FEATURES
shiga Toxin associated HUS
It occurs commonly in children between 1-5 years of age
The commonest clinical presentations
• HUS occurs 5-7 days after the onset of gastroenteritis with fever, vomiting,
abdominal pain, diarrhea or dysentery.
• Following the prodromal illness, the sudden onset of- pallor, weakness, and
lethargy
• Significant dehydration or volume overload
19. • Renal - Oliguria present in early stages /masked by ongoing diarrhea
- Hematuria and hypertension are common
- Renal insufficiency can be mild to severe oliguric or anuric renal failure.
- life-threatening hyperkalemia(renal failure+severe hemolysis)
- Severe acute kidney injury requiring dialysis develops in about 50% of
patients with STEC-HUS.
- The duration of the dialysis requirement is usually about 2 wk.
20. • Cardiac - heart failure(Volume overload, hypertension, and severe
anemia )
- Direct cardiac involvement is rare
- pericarditis, myocardial dysfunction, or arrhythmias can
occur without predisposing features of hypertension, volume overload,
or electrolyte abnormalities.
21. • CNS- mild manifestations - irritability, lethargy, or nonspecific encephalopathic features.
• Severe CNS involvement- ≤ 20% of cases.
- Seizures and significant encephalopathy resulting from focal ischemia secondary to microvascular CNS
thrombosis
• Hypertension encephalopathy and seizures.
• Intestinal complications are variable
- include severe inflammatory colitis, ischemic enteritis, bowel perforation, intussusception, and pancreatitis.
• hematological - petechiae, significant or severe bleeding is rare despite very low platelet counts
22. CLINICAL FEATURES..
• pneumococci-associated HUS- pt will be ill with pneumonia,
empyema, and bacteremia when they develop HUS
• genetic forms of HUS – insidious, triggered by a variety of illnesses,
including mild, nonspecific gastroenteritis or respiratory tract
infections.
23. CLINICAL FEATURES..
• Cobalamin deficiency-associated HUS
c/f
• Feeding difficulties, seizures ,abnormal muscle tone, developmental
delay and megaloblastic anemia are common;
• Rarely- HUS have an indolent presentation- with AKI and systemic
hypertension without thrombocytopenia or microangiopathic
hemolysis.
24. DIAGNOSIS OF HUS
(i) microangiopathic hemolysis characterized by
- anemia -(hemoglobin <10 g/dL)
- fragmented red cells on peripheral smear (schistocytes ≥2%),
- High lactate dehydrogenase >450 IU/l (increased breakdown and turnover of RBC’S)
or - undetectable haptoglobin(binding with released hemoglobin. )
(ii) thrombocytopenia (platelets <150,000/μL)
(iii) AKI- (rise in creatinine by 50% over baseline).
.
25.
26. • The degree of leukocytosis -poor outcome
• Reticulocyte levels are high.
• The degree of renal involvement - increase in blood urea, creatinine,
potassium and phosphate.
• liver transaminases, pancreatic enzymes and glucose levels may be
affected.
• Urinalysis reveals- hemoglobinuria, hematuria and proteinuria.
27. SUSPECTED SHIGA TOXIN ASSOCIATED HUS: DIAGNOSIS
confirmed by positive stool culture and either of the following
(i) Detection of virulence genes on fecal extracts or cultures
(stx1, stx2, and eae gene by PCR)
(ii) Free fecal Shiga toxin (detected on tissue culture or immunoassay)
(iii) The presence of serum IgM antibodies against specific E. coli
lipopolysaccharide -evidence for recent STEC infection
(by ELISA, passive hemagglutination assay)
28. DIAGNOSIS OF PNEUMOCOCCAL HUS
• positive direct Coombs’ test without features of DIC
• confirmed by either:
(i) S. pneumoniae isolation - bacterial culture
- detection of pneumococcal antigen by PCR or ELISA in appropriate
body fluids (sputum/CSF/blood/pus) or
- positive peanut lectin (Arachis hypogaea) agglutination assay
29. COBALAMIN DEFICIENCY-ASSOCIATED HUS
• screening for cobalamin C (cblC) deficiency by estimating total
homocysteine levels
• Probable cblC deficiency-related HUS- elevated plasma total
homocysteine level (> 50–100 μM/l by chromatography, immunoassay)
with normal levels of vitamin B12 and folate.
• Confirmed cblC deficiency-related HUS- Homozygous or compound
heterozygous mutation in the MMACHC gene in a patient with probable
cblC deficiency.
30. Rule-out
• Disseminated intravascular coagulation (DIC) - prolonged prothrombin time or
activated partial thromboplastin time, low fibrinogen, elevated D-dimer and soluble
fibrin monomers.
• Thrombotic thrombocytopenic purpura (TTP) -rare in childhood
-persistent thrombocytopenia (<30,000/μL) and mild/no AKI is suggestive
• Infections that mimic/trigger HUS, e.g., malaria, leptospirosis, dengue, rickettsia
and H1N1 infection should be excluded, if clinically suspected.
• Blood samples should be stored and later processed for ADAMTS13 activity, if
etiology of microangiopathic anemia is unclear.
31. EVALUATION OF ATYPICAL HUS
Complement C3 - A low C3 level is not specific for aHUS, nor does it
correlate with severity of disease
test for anti-factor H (FH) antibodies – ELIZA
flow cytometry for expression of membrane cofactor protein (MCP, CD46) on
neutrophils
Gene sequencing:of CFH, CFI, CFB, C3, CD46, THBD, and DGKE.
• Blood specimens for C3 and anti-FH antibodies should be drawn prior to
instituting therapy.
32. Genetic screening is advised
(i) early age of onset
(ii) relapsing course,
(iii) family history of HUS,
(iv) illness that is refractory to therapy with PEX, and
(v) prior to renal transplantation.
33. RENAL BIOPSY
• Renal biopsy is not essential for diagnosis
• cannot be performed in the acute stage due to thrombocytopenia.
• Indicated - partial forms where the diagnosis is in doubt,
or in recurrent or severe disease,
to confirm the diagnosis before starting aggressive therapies.
The pathognomic finding of TMA is common to all types.
34. RENAL BIOPSY.
Thus - predominantly fibrin thrombi are found in glomerular capillaries.
aHUS- the thrombi are made up of a combination of fibrin, platelet and VWF clumps that involve
larger renal and interlobular arterioles, thus causing ischemia and inflammation of larger volumes of
renal parenchyma
- Glomerular capillary wall thickening, occlusion or narrowing of capillary lumens, inflammation and
necrosis of endothelial cells and their detachment from the basement membrane may be observed.
- Tubular epithelial injury, mesangial expansion and mesangiolysis may also occur
• Cortical necrosis is present in severe cases, and indicates a poor outcome
35. A) Occluded afferent arteriole with ischemic changes in the accompanying glomerulus
B) Glomerulus showing mesangiolysis and ectatic dilatation of glomerular capillaries (silver
methenamine
C) (C) Necrotizing vascular lesions of the afferent and efferent arterioles
D) (D) Fibrin rich thrombus occluding the lumen of a small artery with ischemic changes in adjacent
glomerulus
39. Supportive Therapy
• In all patients, supportive treatment is primary.
• Close clinical monitoring of :
-Fluid status
-Blood pressure
-Neurological
-Ventilatory parameters
• Blood levels of glucose, electrolytes, creatinine and hemogram need frequent
monitoring
40. MANAGEMENT..
• Dialysis - early institution- if the patient - significantly oliguric or anuric, with
hyperkalemia.
• The duration of the dialysis requirement is usually about 2 wk.
• Red cell transfusions required because hemolysis can be brisk and recurrent until the
active phase of the disease has resolved.
-In pneumococci associated HUS- administer washed red cells to be given
Platelets should not be administered ( Rapidly consumed by the active coagulation
,worsen the clinical course)
41. • Anticoagulation, antiplatelet, and fibrinolytic therapies are specifically
contraindicated- increase the risk of serious hemorrhage.
• Antibiotic therapy to clear enteric toxigenic organisms (STEC) can result in
increased toxin release, potentially exacerbating the disease, and therefore is
not recommended.
- Indicated in pneumococcal infection.
• Plasma infusion or plasmapheresis- patients suffering from severe
manifestations of HUS with serious CNS involvement.
• contraindicated in pneumococcal associated HUS -exacerbate the disease
42. MANAGEMENT- Atypical HUS:
ECULIZUMAB
• Across the developed world, eculizumab, is the standard of care for
patients with aHUS.
• FDA approved for the treatment of atypical HUS
• Eculizumab is an anti-C5 antibody that inhibits complement activation,
a pathway that contributes to active disease in atypical familial HUS.
43. • recommended to give the meningococcal vaccine prior to giving
eculizumab (if the patient has not been primarily immunized)- risk of
meningococcal disease in patients with defects in terminal
complement components
• eculizumab is expensive and not available in India and developing
countries.
44. PLASMA EXCHANGE
• In absence of anti-complement therapies, intensive PEX is less than ideal, but the only alternative.
• PEX - (60- 75 mL/kg; fresh frozen plasma as exchange fluid) - appropriate for patients with
suspected aHUS.
• PEX is administered daily until hematological remission and tapered over 4-6 weeks.
- (platelets >100,000/ μL, schistocytes <2%, LDH less than upper limit of normal for 2 consecutive
days)
• Maintenance therapy with plasma infusions is advised every 10-14 days for patients with
mutations in complement genes, especially CFH and CFI.
45. • Limited benefit of PEX in patients with:
(i) microbiologically confirmed STEC-HUS, without cardiac or
neurological involvement,
(ii) infection-associated HUS or pathogenic variants in CD46 and DGKE.
46. MANAGEMENT - ANTI-FH ANTIBODY ASSOCIATED AHUS:
• Aim of therapy - anti-FH associated HUS is reduction of titers, PEX are most appropriate to achieve this goal.
• Combination of PEX and immunosuppression was most useful.
• 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/m2 intravenously once in 4-weeks) for 5 doses
• About 15- 30% patients relapse; 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.
47.
48. Management - Miscellaneous
• In infants with HUS associated with cobalamin abnormalities:
Treatment with hydroxycobalamin, Oral betaine, Folic acid
• Normalizes the metabolic abnormalities - prevent further episodes.
• In patients with persistent ADAMTS13 antibodies and poor response
to plasma exchange:
• Immunosuppressive therapy with high dose -
steroids/cyclophosphamide/cyclosporin/rituximab
49. PROGNOSIS
• With early recognition and intensive supportive care, the mortality
rate for diarrhea-associated HUS is < 5% in most major medical
centers.
• Up to half of patients may require dialysis support during the acute
phase of the disease.
• Recovery of platelet counts usually occurs first, followed by renal
recovery about 5 days later, and finally by resolution of anemia.
• Surviving patients, 5% remain dependent on dialysis, and up to 30%
are left with some degree of chronic renal insufficiency.
50. • The prognosis for HUS not associated with diarrhea is more severe.
• Pneumococci-associated HUS causes increased patient morbidity
(>80% require dialysis), with the mortality rate reported as 20%.
• familial, genetic forms of HUS can be insidiously progressive or
relapsing diseases and have a poor prognosis
52. REFERENCES
• Guidelines on Hemolytic Uremic Syndrome by Indian Society of
Pediatric Nephrology
• Hemolytic uremic syndrome in a developing country: Consensus
guidelines Pediatric Nephrology Arvind Bagga/Revised: 6 January
2019
• Bagga text book of paediatric nephrology
• Nelson text book of paediatrics 21st edition