Hemolytic uremic syndrome: Investigations and management SAWAI Toshihiro M.D., Ph.D. Department of Pediatrics, Shiga University of Medical Science Otsu, JAPAN
AGENDA TMA; Thrombotic micro angiopathy STEC-HUS; Shigatoxigenic Escherichia coli induced HUS AHUS; Atypical HUS PHUS; Pneumococcal HUS
WHAT IS TMA? http://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/thrombotic-microangiopathy-tma
HOW IS TMA DEFINED? TMA is defined by: Thrombocytopenia PLT count < 150,000/µL or >25% decrease from baseline AND Microangiopathic hemolysis Schistocytes, Elevated LDH, low haptoglobin, low hemoglobin Plus 1 or more of the following Neurological symptoms Renal impairment Gastrointestinal symptoms Cardiovascular symptoms Pulmonary Symptoms Visual symptoms
TMA CAN RESULT FROM DIFFERENT UNDERLYING ETIOLOGIES Without a complement amplifying condition Underlying Etiology Chronic uncontrolled complement activation STEC- HUS ahus TMA Unmasked by a complement amplifying condition TMA associated with a complement amplifying condition TTP Underlying Etiology Shiga toxin-induced endothelial damage Complement amplifying conditions include: Infection Pregnancy-associated Autoimmune disorders (eg, SLE) Drug therapy Malignant hypertension Organ or stem cell transplantation Glomerulopathy Malignancy Underlying Etiology Severe ADAMTS13 deficiency
SYSTEMIC TMA AFFECTS MULTIPLE VITAL ORGANS AND TISSUES Central nervous system: Up to 48% of patients experience neurological symptoms 1 Confusion 2,3 Stroke 3 Seizures 1,3,4 Other cerebral abnormalities 2,5 CV: Up to 43% of patients experience CV symptoms 1 MI 6,7 Hypertension 8 Arterial stenosis 6,9 Peripheral gangrene 10 GI: Up to 37% of patients experience GI symptoms 11 Diarrhea ± blood 3,12 Nausea/vomiting 4,7 Abdominal pain 4 Gastroenteritis/pancreatitis 4,13 Visual: Case reports of patients with visual impairments 14 Pain and blurred vision 14 Retinal vessel occlusion 15 Ocular hemorrhage 14,15 Pulmonary: Up to 46% of patients experience pulmonary symptoms 16 Dyspnea 7 Pulmonary hemorrhage 17 Pulmonary edema 7 Renal: More than 50% of patients progress to ESRD 18 Elevated serum creatinine level 17,19 Decreased egfr 20 Elevated blood pressure 7 Abnormal urinalysis results 17 Imagery supplied by ScienceSource
STEC-HUS Shigatoxigenic Escherichia coli induced HUS
SHIGA TOXIN-PRODUCING ESCHERICHIA COLI- HEMOLYTIC UREMIC SYNDROME Schweiz Med Wochenschr. 85,905,1955
MANAGEMENT OF BLOODY DIARRHEA AND ISOLATION OF STEC
INVESTIGATIONS TO CONSIDER IN CHILDREN WITH SUSPECTED OF STEC-HUS Tests Full blood count Blood film Urea and creatinine Biochemistry Faecal culture Faecal PCR for STEC genes Coagulation Serology Urinalysis Direct antigen test Group and save Results seen in HUS Leucocytosis Anaemia, thrombocytopaenia Red cell fragments Raised Raised LDH and bilirubin, low haptoglobins Presence of organisms Normal Antibodies to STEC Haematuria, proteinuria, red cell casts Negative
AVOIDING AND ANTIDIARRHEAL DRUGS
VOLUME AND CHARACTERISTICS OF FLUIDS ADMINISTRATED DURING 4 DAYS OF ILLNESS Julie A. Ake et al. Pediatrics 2005;115:e673-e680
LACK OF SPECIFIC THERAPIES FOR STEC-HUS
ATYPICAL HUS
UNFETTERED COMPLEMENT ACTIVATION ULTIMATELY RESULTS IN THROMBUS FORMATION, PLATELET CONSUMPTION, AND MECHANICAL HEMOLYSIS Vicky Brocklebank et al. CJASN doi:10.2215/cjn.00620117
SIMPLE IS BEST 30 3
DISTINCT PATHOPHYSIOLOGIES DIFFERENTIATE AHUS AND TTP TTP 2-3 ahus 4 TTP 2-3 Insufficient ADAMTS13 activity activity ( 5%) ( 5%) Insufficient leaves ADAMTS leaves vwf vwf 13 intact activity intact ( 5%) leaves vwf intact ADAMTS13 ADAMTS13 vwf vwf ADAMTS13 deficiency deficiency ADAMTS13 deficiency Genetic Genetic defects defects lead lead to chronic to chronic unco u complement sy Chronic uncontrolled activation of the complement system Gain of Function Loss of Function Autoantibodies Classical Classical Classical Alternative C3 Gain Gain of function of function C3b Loss Loss of function of function Autoantibodies Autoantibodies C3 convertase C5 convertase Lectin Alternat C3 C3b C3 conve C3 co C5 conve C5 co C5a C5 C5a C5b-9 C5a C5 Progressively Progressively smaller, smaller, smaller, inactive Fully inactive Fully unfolded Fully unfolded vwf vfw aggregates vfw aggregates inactive multimers multimers multimers with with platelets with platelets J. Clin Adv Hematol Oncol. 2012;10(10)(suppl 17):1-12. Int J Hematol. 2010;91(1):1-19. Blood. 2008;112(1):11-18. Nat Rev Nephrol. 2012;8(11):622-633. Am J Med. 2013;126(3):200-209. Endothelial damage Platelet activation Inflammation Endothelial Endoth D Platelet Platelet Acti Inflamma Infla
REGULATION OF COMPLEMENT Factor H Factor I MCP
SO-CALLED DYSREGULATION OF COMPLEMENT
UNFETTERED COMPLEMENT ACTIVATION ULTIMATELY RESULTS IN THROMBUS FORMATION, PLATELET CONSUMPTION, AND MECHANICAL HEMOLYSIS Vicky Brocklebank et al. CJASN doi:10.2215/cjn.00620117
Clin J Am Soc Nephrol. 2010;5:1844-1859. Blood. 2006;108(4):1267-1272. AHUS IS A CHRONIC AND PROGRESSIVE DISEASE WITH LIFE-THREATNING CONSEQUENCES Patients with ahus progressing to ESRD, permanent renal damage, or death 80 Patients, % 60 40 79% 20 33-40% 0 First clinical manifestation (death or ESRD) despite the use of PE/PI 3 years after diagnosis
TREATMENTS FOR AHUS Diagnosis of HUS Atypical presentation PE within 24hr of diagnosis 1.5 PV (60-75mL/kg) Repeat PE daily x5 5 sessions/w for 2w 3sessions/w for 2w Assess outcome at day33
ECULIZUMAB BLOCKS TERMINAL COMPLEMENT Eculizumab binds with high affinity to C5 Terminal complement - C5a and C5b-9 formation blocked Proximal functions of complement remain intact - Weak anaphylatoxin - Microbial opsonization
PNEUMOCOCCAL-HUS
PNEUMOCOCCAL HUS Plasma therapy Unwashed RBC and PLTs
TAKE-HOME MESSAGES Improved supportive care has led to a reduction in mortality, but there is still a real need for targeted therapies that affect the disease course.
MCQ 1 Which of the following best describes STEC-HUS? a. As a treatment for STEC-HUS, corticosteroid is extremely effective. b. Enterohemorrhagic E.coli O157:H7 is the only pathogen of STEC- HUS. c. STEC-HUS is a syndrome with a good prognosis for renal function. d. There is no specific treatment drug for STEC-HUS.
MCQ 2 Which of the following best describes atypical HUS? a. Atypical HUS is a syndrome caused by dysfunction of ADAMTS13. b. Atypical HUS is a syndrome caused by abnormal activation of the complement system. c. As a treatment for atypical HUS, plasma exchange is extremely effective. d. Atypical HUS is a syndrome with a good prognosis for renal function.
MCQ 3 A 1-year-old boy is brought to a physician because of a high fever, dyspnea, wet cough, and decreased SpO2%. Laboratory data shows increased WBC, elevated CRP, hemolytic anemia, thrombocytepenia, and acute kidney injury. The pediatrician notices that his condition is compatible with P-HUS. Which of the following would be the best treatment to improve his P-HUS? a. Red cell transfusion b. Platelet transfusion c. Plasma infusion d. Antibiotics