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  • (neuraminidase, T antigen exposure)
  • 2/4 children never recovered GFR after HUS 2/4 evolved from recovery with proteinuria
  • ADAMSTS13: due to intrinsic deficiency or development of autoantibodies against ADAMSTS13; low ADAMSTS13 leads to failure to cleave large vWF multimers, which leads to unmitigated platelet-multimer binding to the endothelium and a microvascular occlusion. Quinine– due to development of drug-induced antibodies against platelets and other hematological cell lines as well as against endothelium; Patients with cobalamin-C deficiency usually present in the early days and months of life with failure to thrive, poor feeding, and vomiting. Rapid deterioration occurs due to metabolic acidosis, gastrointestinal bleeding, hemolytic anemia, thrombocytopenia, severe respiratory and hepatic failure, and renal insufficiency. It is likely that some die undiagnosed. Besides the early fulminant course, a more protracted disease can manifest later in childhood and adolescence. Renal biopsy showed a chronic TMA. Serum homocysteine can be 10 times normal values and urinary methylmalonic acid markedly increased but correct with daily hydroxycobalamin administration
  • 1981: Thompson and Winterborn in Birmingham UK 1998: Warwicker et al in Newcastle, UK
  • Exceptions. There are some occasions when clinicians may elect not to use this empirical guideline. (a) where the effect of an alternative treatment can be anticipated. For example,HUS in a sibling of a patient with congenital ADAMTS13 deficiency is likely to have the same diagnosis and might be expected to respond to plasma infusion 10 ml/kg per day. (b) where the clinical presentation strongly suggests early onset cobalamin-C disorder (feeding difficulty, failure to thrive, hypotonia, lethargy, leukopenia and megaloblastic anemia). (c) where there are technical difficulties in achieving vascular access in small children. (d) where the clinician considers that the risks of plasmapheresis outweigh the benefits in a child with apparently mild renal involvement and conserved urine output, in which case the decision might be deferred. However, clinicians should be aware that thrombotic microangiopathy is a destructive process, and that, in the few reported patients with factor H mutations in whom plasma therapy appeared successful, treatment had been started before there was renal impairment
  • (A and B) Periductal fibrosis involving medium-sized bile ducts (hematoxylin and eosin stain, 50x). (C and D) Mild fibrosis of terminal hepatic venules (trichrome stain, 100x). The abnormal histologic findings in the native liver were unexpected and prompted us to closely re-examine the native liver of our patient 1 ( 16 ). Indeed, patient 1 had been evaluated well before LKT because of intermittent transaminase elevations and was found to have mild hepatomegaly with diffusely increased liver echogenicity by sonography. In neither patient were there biochemical signs of native liver disease at the time of transplant. Nonetheless, like the patient presented here, the native liver histology of patient 1 revealed periductal fibrosis of scattered medium and large bile ducts and focal mild fibrosis of the central hepatic venules ( Figure 1 , B and D) in addition to previously reported focal fatty change, glycogenic foci, and a single granuloma ( 16 ). The extent of periductal fibrosis was more extensive in the patient presented here than in patient 1. Periductal fibrosis falls into the generic classification of sclerosing cholangitis. This finding is typical of primary sclerosing cholangitis, but is also a consequence of such "secondary" causes as biliary surgery, cholelithiasis, biliary neoplasia, toxins, and ischemia. Although episodic hemolysis presents a possible link to biliary tract disease, a more likely cause of periductal fibrosis in our patients is microangiopathic disease within the hepatic circulation. The site of endothelial injury and vascular compromise would appear to be the peribiliary vascular plexus. This plexus is derived from branches of the hepatic arteries and feeds the epithelium and wall of medium and large bile ducts. Microthrombi in the plexus would result in ischemia and reactive fibrosis in these larger caliber bile ducts. Fibrosis of the terminal hepatic venules is nonspecific and although direct endothelial injury to the venous microcirculation from aHUS is one potential cause, this injury could also be explained by other insults including episodes of shock both patients experienced during the course of their illness. Liver involvement in HUS is not uncommon, and although catastrophic disease has been reported ( 39 ), usually the effect is subclinical and limited to alterations of liver enzymes or occasionally manifesting with significant signs of cholestasis ( 40 – 42 ). Our experience allowed direct examination of the native liver and we believe this is the first report to describe periductal fibrosis of the medium-sized and large intrahepatic bile ducts in HUS. Although morphologically noteworthy, this periductal fibrosis was not clinically significant at the time of transplant. Moreover, with only two patients, it is not possible to say that our conclusions are definitive. Nonetheless, this is a relevant finding because it suggests that chronic or recurrent HUS has adverse and likely cumulative effects on the liver. It leaves open the distinct possibility that similar subclinical disease may be widespread in such patients, particularly in those organs occasionally found to manifest severe disease such as the brain, pancreas, and intestines.

2009 Dr. Saland Presentation Powerpoint 2009 Dr. Saland Presentation Powerpoint Presentation Transcript

  • ESRD Management of Atypical Hemolytic-Uremic Syndrome (HUS) Jeff rey M. Saland , M.D. Department of Pediatrics Mount Sinai School of Medicine
  • Conflicts / Disclosures Will discuss off label uses No financial interests in any agents discussed No financial interest in any healthcare-related entity
  • Overview
    • A significant percentage of cases of atypical HUS are due to disorders of complement regulation.
  • Overview
    • A significant percentage of cases of atypical HUS are due to disorders of complement regulation.
    • Empiric plasma therapy can delay or prevent ESRD in many of those cases
  • Overview
    • A significant percentage of cases of atypical HUS are due to disorders of complement regulation.
    • Empiric plasma therapy can delay or prevent ESRD in many of those cases
    • Risk of post-transplant recurrence depends on the specific disorder of complement regulation.
  • Overview
    • A significant percentage of cases of atypical HUS are due to disorders of complement regulation.
    • Empiric plasma therapy can delay or prevent ESRD in many of those cases
    • Risk of post-transplant recurrence depends on the specific disorder of complement regulation.
    • Emerging therapy may expand ESRD options
  • Typical HUS
    • Triad of :
      • Microangiopathic hemolytic anemia
      • Thrombocytopenia
      • Acute renal failure
    • Generally diarrhea-associated
      • Shiga toxin produced by E coli serotype O157:H7
      • Shigella, Salmonella, others also
      • Food borne disease: uncooked / unpasteurized
      • products contaminated by animal wastes
    • Or other infections (respiratory):
      • Invasive S. Pneumoniae or viral infections
  • Typical HUS A severe condition: acutely 2.5% mortality, often significant morbidity Spizzirri et al. Pediatric Nephrology 1996 Long term results (10-20 years after HUS*) 63% Complete recovery 12% Recovery with proteinuria 6% Recovery with proteinuria and HTN 16% Recovery with low GFR ± proteinuria or HTN 3% ESRD * Diarrheal or URI- related only, pediatric
  • Atypical HUS Taylor et al Ped Neph 2004 Clinically very severe 15% died 25% ESRD 60% major sequelae 15% renal insufficiency 1/3 recover without significant renal disease most (75%) of these had a single episode few (25%) of these had recurrent aHUS (a pediatric series)
  • A Classification of TMA (Thrombotic Microangiopathy) Besbas et al. Kidney International 2006 Typical / diarrheal (HUS or TTP) Complement defects Atypical HUS von Willebrand proteinase (ADAMSTS13) defeciency Generally TTP Cobalamin-C deficiency TMA + multiorgan failure Quinine-related Abrupt TMA, exposure related Post transplantation (calcineurin inhibitior related) De-novo renal TMA May be renal “isolated” Others: HIV, radiation, chemotherapy HELLP, antiphospholipid Ab syndrome, unclassified
  • Complement and Atypical HUS Since the early 1970’s alternative pathway complement activation (low C3), has been recognized in some cases of atypical HUS Clin. Exp. Immunol. (1981), Kidney International (1998) 1981: 1 st case of HUS with factor H deficiency described 1998: Linkage analysis in 3 families with HUS provided clear association with CFH
  • Complement and Atypical HUS About 50%-60% of aHUS cases are associated with a mutation in a complement-related gene Jozsi et al. Blood 2008, Frémeaux-Bacchi V et al. Blood 2008, Goicoechea de Jorge 2007, Caprioli, et al Blood 2006, Kavanagh Curr Opin Nephrol Hypertens, 2007 Protein Gene Source Location % of aHUS Factor H CFH Liver circulates ~ 15-30% Factor I CFI Liver circulates ~ 5-10% Membrane Cofactor Protein MCP Widespread Membrane bound ~ 10-15% Factor B CFB Liver, ? circulates <5% C3 C3 Liver, ? circulates ~ 5-10% Anti-FH-Ab CFHR1/CFHR3 Lymphocyte circulates ~ 10% Unknown ~ 40-50%
  • Sellier-Leclerc, A.-L. et al. J Am Soc Nephrol 2007;18:2392-2400 C3 Levels By Mutation
  • Recommended Initial Evaluation of HUS Because infections trigger both typical and atypical HUS, initial evaluation should encompass both Testing should include C3 level as well as classic evaluation (stool culture, LDH, smear, etc.) ADAMSTS13 / auto-Ab analysis if TTP not ruled out Save some plasma for later analysis
  • Plasma Therapy Fluid phase complement proteins reside in plasma and are therefore subject to plasma therapy Caprioli, et al. Blood. 2006
  • Plasma Therapy
    • Fluid phase complement proteins reside in plasma and are therefore subject to plasma therapy
    • Plasma Infusion:
      • Repletes but does not remove mutant protein
    • Plasma Exchange:
      • Removes mutant protein and repletes
    Caprioli, et al. Blood. 2006
  • Plasma Therapy
    • Fluid phase complement proteins reside in plasma and are therefore subject to plasma therapy
    • Plasma Infusion:
      • Repletes but does not remove mutant protein
    • Plasma Exchange:
      • Removes mutant protein and repletes
    • There are MANY anecdotes of prolonged preservation of kidney function in patients with CFH mutation, though most eventually suffer ESRD.
    • Benefit is not clear for MCP mutations– most (single) episodes seem to recover with or without exchange
    Caprioli, et al. Blood. 2006
  • Detecting Complement-related HUS (Trying to Prevent ESRD) Saland, et al. JASN 2009, Ariceta et al. Ped Neph 2008 Criteria for empiric plasma therapy treatment of aHUS Presence of any of the following or Absence of the Following Patient age < 6 months Slow or insidius onset of HUS Multiple HUS Episodes or relapses Asynchronous family history of HUS Previous unexplained anemia HUS after any type of organ transplantation Prodromal diarhhea Invasive S. pneumoniae infection
  • Empiric Plasma Exchange Ariceta et al. Ped Neph 2009 Diagnosis of HUS Atypical presentation Plasma Exchange within 24 hrs 1.5 Volumes (60-75 ml/kg) per session FFP or Octaplas® Repeat Plasma Exhange Daily x 5 Then 5 sessions/week for 2 weeks Then 3 sessions/week for 2 weeks Assess Outcome at Day 33 Clinical Exceptions Withdrawal Alternate Diagnosis Plasma Exchange Complication Early remission
  • Summary #1 Key atypical features require empiric plasma exchange.
  • Summary #1 Key atypical features require empiric plasma exchange. C3 levels should be part of every HUS evaluation Save blood from before plasma exchange
  • Summary #1 Key atypical features require empiric plasma exchange. C3 levels should be part of every HUS evaluation Save blood from before plasma exchange Patients with aHUS should undergo genotyping for the most up-to-date list of complement-related disorders:
  • Summary #1 Key atypical features require empiric plasma exchange. C3 levels should be part of every HUS evaluation Save blood from before plasma exchange Patients with aHUS should undergo genotyping for the most up-to-date list of complement-related disorders: CFH , CFI , MCP , C3 , CFB , anti-FH-Ab – CFHR1/CFHR3 (more likely to be added)
  • Summary #1 Key atypical features require empiric plasma exchange. C3 levels should be part of every HUS evaluation Save blood from before plasma exchange Patients with aHUS should undergo genotyping for the most up-to-date list of complement-related disorders: CFH , CFI , MCP , C3 , CFB , anti-FH-Ab – CFHR1/CFHR3 (more likely to be added) Contacting one of the major registries is prudent
  • ESRD Management of aHUS
  • ESRD Management
    • Do not diagnose ESRD too soon.
    • Renal recovery may occur if TMA is halted.
    • In dialysis dependent patients, native nephrectomy should be considered for:
      • Ongoing HUS (clinical or biochemical)
      • Severe hypertension
  • ESRD Management: Dialysis
    • aHUS is generally quiescent during ESRD
    • Rare findings reported during dialysis:
      • Angioedema, complement activation (hemodialysis)
      • Hemolysis / thrombocytopenia
      • Subclinical hepatic (or other organ) involvement
    Jalanko, et al. AJT 2007, Saland, et al. CJASN 2009
  • Saland et al. CJASN 2009 Subclinical Hepatic Involvement
  • ESRD Management: Dialysis Due to a high rate of transplant failures, aHUS patients have been faced with extremely long dialysis duration and its accompanying risks.
  • Transplant Considerations Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; Bartleby.com, 2000. www.bartleby.com/107/ .
  • Complement and Atypical HUS Risk of recurrence after “unmodified” kidney transplant Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009 Protein Gene Source Location Recurrence Rate Factor H CFH Liver circulates > 80% Factor I CFI Liver circulates > ~ 80% MCP MCP Widespread Membrane bound ~ 20% Factor B CFB Liver, ? circulates ? C3 C3 Liver, ? circulates ? Anti-FH-Ab CFHR1/CFHR3 Lymphocyte circulates ? No known mutation 30%
  • Post-Transplant HUS Recurrence Most are within 1 month Plasma responsiveness of the underlying defect is often retained. If untreated, most result in graft loss Chronic plasmapheresis may be required Seitz, B et al. Transplantation Proceedings 2007,
  • Options for Transplantation Kidney transplantation*
  • Options for Transplantation Kidney transplantation* Combined liver-kidney transplantation*
  • Complement and Atypical HUS Risk of recurrence after “unmodified” kidney transplant Loirat, C et al. Pediatric Transplantation 2008, Saland et al. JASN 2009 Protein Gene Source Location Recurrence Rate Factor H CFH Liver circulates > 80% Factor I CFI Liver circulates > ~ 80% MCP MCP Widespread Membrane bound ~ 20% Factor B CFB Liver, ? circulates ? C3 C3 Liver, ? circulates ? Anti-FH-Ab CFHR1/CFHR3 Lymphocyte circulates ? No known mutation 30%
  • Auxiliary liver, several month function followed by acute decompensation, death Hepatic graft failure * with neurological deficits, 2 nd liver transplant at 1 month Primary hepatic non-function * , death * Complement mediated injury to liver vasculature Cheong HI. (Abstract) ASN/ISN World Congress 2001, Remuzzi G, et al. Lancet 2002, Remuzzi G, et al. AJT 2005, Cheong HI et al. Pediatr Nephrol 2004 Combined Liver Kidney Transplant For aHUS Secondary to CFH Mutation First 3 Experiences not Encouraging
  • Surgery is a trigger for complement activation Preparative plasma exchange before transplant followed by serial plasma exchange is recommended
    • Hemodialysis (if needed) session no heparin
    • Plasma exchange with FFP (minimum 1.5 volumes)
    • < 6 hours of surgery
    • 10- 20 ml/kg FFP intraoperatively
    • Additional FFP if clinically indicated
    • Post-operative LMW heparin prophylaxis
    • Low dose aspirin prophylaxis
    Liver-Kidney Transplant Protocol Modified by Plasma Exchange Plasma exchange removes mutant FH, replaces normal LMW heparin used empirically Hold anticoagulation for bleeding or coagulopathy Saland, J et al. JASN 2009
    • NYC #1: whole liver
    • Helsinki #1: whole liver
    • Helsinki #2: whole liver
    • NYC #2: split liver
    • Helsinki #3: adult, whole liver
    • UK #1: whole liver*
    • Boston #1: whole liver
    • NYC #3: split liver, death (hepatic artery thrombosis)
    • NYC #4: split liver, death (SVC syndrome complication))
    • * Native kidney function preserved, liver tx only
    Saland et al, AJT 2006, Jalanko et al. AJT 2008, Saland et al. CJASN 2009 and verbal communications: Jalanko 2007, Milford 2008, Milner 2008 Combined Liver Kidney Transplant For aHUS Secondary to CFH Mutation A Modified* Approach is Potentially Successful, Though Risky.
  • Options for Transplantation Kidney transplantation* Combined liver-kidney transplantation* Kidney transplantation* followed by chronic plasma exchange prophylaxis Not yet … followed by chronic anti-complement therapy followed by specific factor replacement (eg. FH)
  • Transplant Decisions MCP Mutation Transplantation Reasonable Current consensus for now is to provide pre-operative plasma exchange and at least one month of tapering plasma exchange protocol LMW heparin anticoagulation Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
  • Transplant Decisions MCP Combined with other Mutations No consensus, isolated kidney may be reasonable If transplanted, provide pre-operative plasma exchange and at least one month of tapering plasma exchange protocol LMW heparin anticoagulation Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
  • Transplant Decisions CFH or CFI Mutation*
    • Wait for new Rx
    • FH concentrate
    • Complement inhibitors
    Renal Tx * Plasma exchange before and chronically after LMW heparin anticoagulation * Especially if kidney transplant in family members with same mutation was successful Combined Liver-Kidney Tx Pre-operative Plasma exchange LMW heparin anticoagulation Loirat, C et al. Pediatric Transplantation 2008, Saland,et al. JASN 2009
  • Transplant: Anti-FH-Autoantibodies One Successful Case Reported
    • Pretransplant preparation using:
      • plasma exchanges over several weeks
      • (the response was not complete)
      • 4 weekly doses of rituximab added
      • Anti-FH-Ab levels were monitored
    • Fairly routine transplant protocol:
    • Basiliximab, prednisone, cyclosporine
    • Resulted in sustained antibody supression
    • for over 4 months
    Kwon et al, NDT 2008 Anti-FH Autoantibodies
  • Transplant Decisions CFB, C3 Mutations Case by Case : Unclear impact of: Non-hepatic protein sources Complement activating potential of residual protein Therapeutic potential of future anti-complement Rx Saland et al. JASN 2009
  • Transplant Decisions No Known Mutation Transplantation Reasonable Current consensus for now is to provide pre-operative plasma exchange and at least one month of tapering plasma exchange protocol LMW heparin anticoagulation Loirat, C et al. Pediatric Transplantation 2008 Saland, J et al. JASN 2009
  • Atypical HUS has a high risk of ESRD Transplantation options depend on the specific cause Transplant surgery triggers complement activation For high-recurrence risk conditions: Current options are risky and limited Emerging treatments are promising Final Summary
  • Foundation for Children with Atypical HUS Censensus Group, Liver-Kidney Transplantation for HUS Bergamo: Drs. Giussepe Remuzzi & Piero Ruggenenti Newcastle: Dr. Timothy Goodship U. Iowa: Dr. Richard Smith Acknowledgments