title: Microangiopathy in kidney and simultaneous pancreas/kidney recipients treated with tacrolimus: evidence of endothelin and cytokine involvement.
abstract: BACKGROUND
  In the past 3 years, three transplant recipients [one kidney, two simultaneous pancreas/kidney (SPK)] developed a thrombotic thrombocytopenic purpura-like clinical syndrome. This was characterized by an abrupt fall in the hematocrit and platelet count with evidence of hemolysis (fragmented red blood cells and schistocytes) and transplant kidney dysfunction during the first 2 weeks after transplantation. This was also associated with pancreatic dysfunction in the two SPK recipients. In all three patients, elevated tacrolimus levels (>24 ng/ml) occurred.
  
  
  METHODS
  Serum cytokine and endothelin levels were determined retrospectively from stored (-70 degrees C) sera.
  
  
  RESULTS
  In each case tacrolimus was discontinued, and treatment with plasmapheresis, fresh frozen plasma, steroids, and OKT3 was begun. The clinical courses varied from mild (one patient), to moderate (one patient), to severe (one patient), complicated with seizures and coma. Each patient responded clinically and ultimately was converted to cyclosporine A, and/or mycophenolate mofetil. These clinical events were associated with a rise in serum levels of endothelin and several cytokines. Levels of endothelin were elevated at 209+/-137 pg/ml, particularly in the severe episode where peak levels reached 480 pg/ml (normal 0-20 pg/ml). Peak levels of IL-8 (104+/-36 pg/ml), interleukin- (IL) 10 (238+/-105 pg/ml), and/or IL-12 (306+/-119 pg(ml) mean+/-SE, occurred during or before the clinical event. Serum levels of tumor necrosis factor-a and interferon-gamma were elevated in 2 patients while levels of IL-2, IL-4, and IL-6 were not elevated during the acute phase.
  
  
  CONCLUSIONS
  These data are consistent with a mechanism of microangiopathy involving endothelial cell injury (associated with tacrolimus treatment), and accompanied by cytokines (IL-10, IL-12, tumor necrosis factor-a, interferon-gamma) that affect expression of adhesion molecules, chemokines (IL-8) that direct the influx of white blood cells and endothelins that may exacerbate underlying hypertension and increase shear force-related red blood cell destruction.
authors.affiliation: University of Miami Medical Center, Department of Surgery, Florida 33136, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Burke
authors.forename: G
authors.initials: G
authors.lastname: Ciancio
authors.forename: R
authors.initials: R
authors.lastname: Cirocco
authors.forename: M
authors.initials: M
authors.lastname: Markou
authors.forename: L
authors.initials: L
authors.lastname: Olson
authors.forename: N
authors.initials: N
authors.lastname: Contreras
authors.forename: D
authors.initials: D
authors.lastname: Roth
authors.forename: V
authors.initials: V
authors.lastname: Esquenazi
authors.forename: A
authors.initials: A
authors.lastname: Tzakis
authors.forename: J
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D016207:Cytokines / Q000097:blood / Q000502:physiology*; D016232:Endothelins / Q000097:blood / Q000502:physiology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008875:Middle Aged; D016035:Pancreas Transplantation / Q000009:adverse effects*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology*; D012189:Retrospective Studies; D016559:Tacrolimus / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D016232:Endothelins; D007166:Immunosuppressive Agents; D016559:Tacrolimus