Our results show that Advagraf bioequivalence cannot be ensured in this population. Significant changes in tacrolimus levels and dose were observed on long-term follow-up.

SummaryTo develop limited sampling strategies (LSSs) to predict total tacrolimus exposure (AUC 0-24 ) after the administration of Advagraf â and Prograf â (Astellas Pharma S.A, Madrid, Spain) to pediatric patients with stable liver or kidney transplants. Forty-one pharmacokinetic profiles were obtained after Prograf â and Advagraf â administration. LSSs predicting AUC 0-24 were developed by linear regression using three extraction time points. Selection of the most accurate LSS was made based on the r 2 , mean error, and mean absolute error. All selected LSSs had higher correlation with AUC 0-24 than the correlation found between C 0 and AUC 0-24 . Best LSS for Prograf â in liver transplants was C 0_1.5_4 (r 2 = 0.939) and for kidney transplants C 0_1_3 (r 2 = 0.925). For Advagraf â , the best LSS in liver transplants was C 0_1_2.5 (r 2 = 0.938) and for kidney transplants was C 0_0.5_4 (r 2 = 0.931). Excluding transplant type variable, the best LSS for Prograf â is C 0-1-3 (r 2 = 0.920) and the best LSS for Advagraf â was C 0_0.5_4 (r 2 = 0.926). Considering transplant type irrespective of the formulation used, the best LSS for liver transplants was C 0_2_3 (r 2 = 0.913) and for kidney transplants was C 0_0.5_4 (r 2 = 0.898). Best LSS, considering all data together, was C 0_1_4 (r 2 = 0.898). We developed several LSSs to predict AUC 0-24 for tacrolimus in children and adolescents with kidney or liver transplants after Prograf â and/or Advagraf â treatment.

Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.