Factor H and Other Studies
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This was a Workshop Given in Germany on HUS
Innate Immunity Abstract S.21 s20.htms20.htms22.htms22.htm
1Bernhard-Nocht-Institute of Tropical Medicine, Hamburg, Departments of 2Nephrology and 3Pediatrics, University of Freiburg, Freiburg, and 4Department of Infection Biology, Hans-Knöll-Institute of Natural Products Research, Jena, Germany
The role of plasma factor H in atypical hemolytic uremic syndrome (HUS)
T. Manuelian1, H.P.H Neumann2, F. Zimmerhakl3, and P.F. Zipfel
emolytic Uremic Syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, caused by platelet thrombi in the microcirculation. Recent studies confirmed the hereditary trait of HUS by reporting low C3 levels and factor H abnormalities found in patients and relatives of several families (Warwicker 1998, Noris 1998). Complement Factor H is a 150 kDa multidomain protein in human plasma where it controls the activity of C3 convertases of the alternative pathway of complement. Factor H is composed of 20 short consensus repeat (SCR) modules, each containing about 60 amino acids. The amino acid sequence within each single SCR is highly conserved in various positions, including four cysteine residues which are required for disulfide-bond formation occuring in a 1–3 and 2–4 manner. In HUS patients three mutations in the factor H gene have been described so far, as a premature stop codon within the N-terminal SCR-1 and two mutations have been localised within the most C-terminal domain, i.e. SCR 20 (Warwicker 1998, Buddels 2000). In order to characterise the role of factor H in patients with HUS and to search for additional new mutations in the factor H gene we investigated factor H deficiency and gene mutations in a group of 36 patients with atypical form of HUS. By western blot analyses we could identify an unusual pattern in Factor H mobility in two serum samples, which were additionally accompanied with low Factor H levels. In order to gain further insight into the functional characteristics of the reported factor H mutations in HUS we used an In Vitro Mutagenesis assay to recombinantly express the single point mutations within SCR 20. Experimental data regarding C3b binding, Heparin binding and protein secretion of Factor H mutants will be presented. This analysis will show the functional consequences of Factor H
1st Orphan Europe Academy Workshop
A CASE STUDY OF FAMIAL HUS YEAR 2001
Familial hemolytic uremic syndrome associated with complement factor H deficiency.
Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L.
Department of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Atypical hemolytic uremic syndrome (HUS) associated with factor H deficiency (FHD) carries a poor prognosis. A 3-year-old girl with FHD-HUS reached end-stage renal disease at age 6 months after experiencing numerous relapses; she underwent a cadaveric renal transplant at age 46 months. One month after transplantation, she experienced an extensive non-hemorrhagic cerebral infarction. Later, hematologic and renal manifestations of HUS developed, followed by another massive cerebral infarction and death in spite of multiple plasma transfusions. A 14-month-old boy with FHD-HUS experienced numerous HUS episodes starting at the age of 2 weeks. Daily plasma transfusions during relapses brought about only a temporary state of remission. However, prophylactic twice-weekly plasma therapy has been successful in preventing relapses and preserving renal function. With this regimen, serum factor H was increased from 6 mg/dL to subnormal values of 12 to 25 mg/dL (normal >60 mg/dL). We conclude that FHD-HUS recurs because FHD is not corrected by renal transplantation. A hypertransfusion protocol may prevent FHD-HUS.
Familial hemolytic uremic syndrome associated with complement factor H deficiency.
Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L.
Department of Pediatrics, Soroka University Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Atypical hemolytic uremic syndrome (HUS) associated with factor H deficiency (FHD) carries a poor prognosis. A 3-year-old girl with FHD-HUS reached end-stage renal disease at age 6 months after experiencing numerous relapses; she underwent a cadaveric renal transplant at age 46 months. One month after transplantation, she experienced an extensive non-hemorrhagic cerebral infarction. Later, hematologic and renal manifestations of HUS developed, followed by another massive cerebral infarction and death in spite of multiple plasma transfusions. A 14-month-old boy with FHD-HUS experienced numerous HUS episodes starting at the age of 2 weeks. Daily plasma transfusions during relapses brought about only a temporary state of remission. However, prophylactic twice-weekly plasma therapy has been successful in preventing relapses and preserving renal function. With this regimen, serum factor H was increased from 6 mg/dL to subnormal values of 12 to 25 mg/dL (normal >60 mg/dL). We conclude that FHD-HUS recurs because FHD is not corrected by renal transplantation. A hypertransfusion protocol may prevent FHD-HUS.
HUS Studies and Statistics
Pediatric Database (PEDBASE)
Discipline: GU
Last Updated: 10/22/94
HEMOLYTIC UREMIC SYNDROME
DEFINITION:
A systemic disease characterized by the triad of microangiopathic pathic hemolytic anemia, thrombocytopenia, and acute renal failure.
EPIDEMIOLOGY:
incidence: 1-3/100,000
age of onset:
most common under the age of 4 years
most common cause of acute renal failure in children
risk factors:
M = F
highest incidence in summer and fall
TYPES:
1. Typical Form (Idiopathic)
prodrome - diarrhea associated
usually affects children 3 months -> 6 years (80% <3 years)
1. Pathogenesis
E. coli serotype 0157:H7 can produce specific enterocytotoxins:
1. Verotoxin-1 (VT-1)
100% DNA homology to shiga-like toxin-1 (SLT-1)
2. Verotoxin-2 (VT-2)
50-60% DNA homology to SLT-2
these protein synthesis-inhibiting toxins adhere to the intestinal epithelium and are then elaborated into circulating cytotoxins
endothelial cells are targetted by these cytotoxins producing endothelial cell injury which:
releases vWF multimers from damaged endothelial cells which aggregate platelets (intrarenal) -> thrombocytopenia
decreases prostacyclin synthesis which interferes with endothelial repair mechanisms
microangiopathic anemia results from mechanical damage to RBC's as they pass through altered vasculature
risk factors for E. coli acquisition: undercooked ground beef, contact with a person with diarrhea within 2 weeks prior to disease onset
1 in 10 children who have E. coli 0157:H7 will go on to develop HUS
2. Atypical or Sporadic Form
prodrome - none
Classification:
1. Inherited autosomal recessive or dominant forms
2. Complement abnormality associated
3. Associated with SLE, Scleroderma, radiation of kidneys, Essential or Malignant Hypertension
4. Pregnancy or oral contraceptive related
Pre-eclampsia
Post Partum Renal Failure
5. Chemotherapy associated
mitomycin
CLINICAL FEATURES:
1. Prodrome
1. Gastroenteritis
usually precedes illness by 5-10 days
diarrhea +/- bloody stool -> severe colitis
fever, nausea and vomiting
rectal prolapse
2. Renal Manifestations
1. Hematuria
microscopic or gross
2. Proteinuria
can progress to the nephrotic level
3. Complications
Nephritic Syndrome (edema, hypertension, azotemia, oliguria)
Nephrotic Syndrome (edema, hypoalbuminemia, hyperlipidemia)
Renal Failure
ranges from mild renal insufficiency to acute renal failure (ARF)
3. Hematologic Manifestations
1. Anemia
sudden onset of pallor, irritability, lethargy, weakness
hepatomegaly/hepatosplenomegaly
2. Thrombocytopenia (90%)
petechiae
4. Complications
1. Neurological (CNS)
irritability, seizures, coma
2. Gastrointestinal
colitis with melena and perforation
3. Others
acidosis, congestive heart failure, diabetes mellitus, fluid overload, hyperkalemia, rhabdomyolysis
INVESTIGATIONS:
1. Urinalysis
hematuria, hemoglobinuria, proteinuria (minimal -> nephrotic)
microscope - glomerular pattern - damaged RBC's and RBC casts
2. Serum
1. Microangiopathic Hemolytic Anemia
usually 50-90 g/L
evidence of RBC hemolysis
smear: burr cells, helmet cells, fragmented RBC's
elevated plasma hemoglobin level
decreased plasma haptoglobin level
moderately elevated reticulocyte count
negative Coombs test
2. Thrombocytopenia
ranges from 20-100
3. Others
leukocytosis (may rise to 30) with left shift
normal PT, PTT, and fibrinogen
acute renal failure (elevated BUN, creatinine, uric acid, potassium, phosphate)
decreased calcium, bicarbonate, albumin
3. Stool
culture for E. coli serotype 0157:H7
MANAGEMENT:
1. Supportive
90% survive the acute phase with no renal impairment if aggressive management of acute renal failure (ARF) is instituted
2. Medical
medical management of complications:
1. Acute Renal Failure
diuretics, moniter fluids and electrolytes
2. Nephritic Syndrome
fluid restriction, control hypertension, manage hyperkalemia, manage pulmonary edema
3. Nephrotic Syndrome
fluid restriction, salt-free diet, diuretics, albumin transfusion, prednisone, alkylating agents
see file on "Idiopathic Nephrotic Syndrome"
4. Chronic Renal Failure
dialysis, kidney transplant
3. Prognosis
mortality: 7-10%
morbidity: 20% renal dysfunction from ARF
1. Good
young
typical form
summer months
2. Poor
WBC >20
shock
significant renal involvement
neurological signs and symptoms
atypical form
INTERNET LINKS:
Lois Joy Galler Foundation.
Discipline: GU
Last Updated: 10/22/94
HEMOLYTIC UREMIC SYNDROME
DEFINITION:
A systemic disease characterized by the triad of microangiopathic pathic hemolytic anemia, thrombocytopenia, and acute renal failure.
EPIDEMIOLOGY:
incidence: 1-3/100,000
age of onset:
most common under the age of 4 years
most common cause of acute renal failure in children
risk factors:
M = F
highest incidence in summer and fall
TYPES:
1. Typical Form (Idiopathic)
prodrome - diarrhea associated
usually affects children 3 months -> 6 years (80% <3 years)
1. Pathogenesis
E. coli serotype 0157:H7 can produce specific enterocytotoxins:
1. Verotoxin-1 (VT-1)
100% DNA homology to shiga-like toxin-1 (SLT-1)
2. Verotoxin-2 (VT-2)
50-60% DNA homology to SLT-2
these protein synthesis-inhibiting toxins adhere to the intestinal epithelium and are then elaborated into circulating cytotoxins
endothelial cells are targetted by these cytotoxins producing endothelial cell injury which:
releases vWF multimers from damaged endothelial cells which aggregate platelets (intrarenal) -> thrombocytopenia
decreases prostacyclin synthesis which interferes with endothelial repair mechanisms
microangiopathic anemia results from mechanical damage to RBC's as they pass through altered vasculature
risk factors for E. coli acquisition: undercooked ground beef, contact with a person with diarrhea within 2 weeks prior to disease onset
1 in 10 children who have E. coli 0157:H7 will go on to develop HUS
2. Atypical or Sporadic Form
prodrome - none
Classification:
1. Inherited autosomal recessive or dominant forms
2. Complement abnormality associated
3. Associated with SLE, Scleroderma, radiation of kidneys, Essential or Malignant Hypertension
4. Pregnancy or oral contraceptive related
Pre-eclampsia
Post Partum Renal Failure
5. Chemotherapy associated
mitomycin
CLINICAL FEATURES:
1. Prodrome
1. Gastroenteritis
usually precedes illness by 5-10 days
diarrhea +/- bloody stool -> severe colitis
fever, nausea and vomiting
rectal prolapse
2. Renal Manifestations
1. Hematuria
microscopic or gross
2. Proteinuria
can progress to the nephrotic level
3. Complications
Nephritic Syndrome (edema, hypertension, azotemia, oliguria)
Nephrotic Syndrome (edema, hypoalbuminemia, hyperlipidemia)
Renal Failure
ranges from mild renal insufficiency to acute renal failure (ARF)
3. Hematologic Manifestations
1. Anemia
sudden onset of pallor, irritability, lethargy, weakness
hepatomegaly/hepatosplenomegaly
2. Thrombocytopenia (90%)
petechiae
4. Complications
1. Neurological (CNS)
irritability, seizures, coma
2. Gastrointestinal
colitis with melena and perforation
3. Others
acidosis, congestive heart failure, diabetes mellitus, fluid overload, hyperkalemia, rhabdomyolysis
INVESTIGATIONS:
1. Urinalysis
hematuria, hemoglobinuria, proteinuria (minimal -> nephrotic)
microscope - glomerular pattern - damaged RBC's and RBC casts
2. Serum
1. Microangiopathic Hemolytic Anemia
usually 50-90 g/L
evidence of RBC hemolysis
smear: burr cells, helmet cells, fragmented RBC's
elevated plasma hemoglobin level
decreased plasma haptoglobin level
moderately elevated reticulocyte count
negative Coombs test
2. Thrombocytopenia
ranges from 20-100
3. Others
leukocytosis (may rise to 30) with left shift
normal PT, PTT, and fibrinogen
acute renal failure (elevated BUN, creatinine, uric acid, potassium, phosphate)
decreased calcium, bicarbonate, albumin
3. Stool
culture for E. coli serotype 0157:H7
MANAGEMENT:
1. Supportive
90% survive the acute phase with no renal impairment if aggressive management of acute renal failure (ARF) is instituted
2. Medical
medical management of complications:
1. Acute Renal Failure
diuretics, moniter fluids and electrolytes
2. Nephritic Syndrome
fluid restriction, control hypertension, manage hyperkalemia, manage pulmonary edema
3. Nephrotic Syndrome
fluid restriction, salt-free diet, diuretics, albumin transfusion, prednisone, alkylating agents
see file on "Idiopathic Nephrotic Syndrome"
4. Chronic Renal Failure
dialysis, kidney transplant
3. Prognosis
mortality: 7-10%
morbidity: 20% renal dysfunction from ARF
1. Good
young
typical form
summer months
2. Poor
WBC >20
shock
significant renal involvement
neurological signs and symptoms
atypical form
INTERNET LINKS:
Lois Joy Galler Foundation.
Atypical Case
.