title: Low-dose sirolimus in combination with mycophenolate mofetil improves kidney graft function late after renal transplantation and suggests pharmacokinetic interaction of both immunosuppressive drugs.
abstract: OBJECTIVE
  Chronic allograft nephropathy and/or calcineurin inhibitor toxicity are common problems after organ transplantation. The aim of this study was to examine the safety and efficacy of switching from a calcineurin inhibitor-based to a calcineurin inhibitor-free immunosuppressive regimen consisting of sirolimus and mycophenolate mofetil (MMF) late after renal transplantation.
  
  
  METHODS
  Kidney biopsies were performed in renal-transplanted patients with increasing serum creatinine levels at least 6 months after transplantation (mean time +/- SD after renal transplantation: 76.4 +/- 50.4 months). Patients with no signs of acute rejection were switched to MMF (500-2,000 mg/day) in combination with a low dose of sirolimus (1 mg/day). Renal function, serum chemistry, blood trough levels of sirolimus and MMF, and blood pressure were monitored.
  
  
  RESULTS
  13 patients were investigated. During our observation period (mean observation time +/- SD: 11.2 +/- 5.9 months), an improvement in renal function was observed in 10/13 patients. In 3/13 patients, renal function deteriorated further and hemodialysis was initiated in 2 patients within the next 6 months. However, a serum creatinine concentration above 3.5 mg/dl was measured in 2 of those 3 patients prior to the switch of the immunosuppressive protocol. Administration of a low dosis of sirolimus (1 mg/day) led to relevant sirolimus (4.16 +/- 1.85 ng/ml) and MMF blood trough levels (month 1: 6.8 +/- 3.46; month 3: 4.67 +/- 1.78 mg/l). The following adverse events were observed: borderline acute rejection (1/11 patients), anemia responding to higher dosage of erythropoietin (3/11), hyperlipidemia (1/11), and urinary tract infections (4/11).
  
  
  CONCLUSIONS
  Low-dose sirolimus therapy in combination with concentration-adjusted MMF therapy leads to improvement of organ function late after renal transplantation. The follow-up of those patients should include assessments of blood cell counts, serum lipids and urinalysis to recognize the possible side effects.
authors.affiliation: Department of Nephrology, University of Kiel, Germany. Renders@nephro.uni-kiel.de
authors.forename: Lutz
authors.initials: L
authors.lastname: Renders
authors.forename: Reiko
authors.initials: R
authors.lastname: Steinbach
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.forename: Harald O
authors.initials: HO
authors.lastname: Schöcklmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001706:Biopsy; D065095:Calcineurin Inhibitors; D003404:Creatinine / Q000097:blood; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000008:administration & dosage; D005260:Female; D006454:Hemoglobins; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000473:pathology / Q000502:physiology; D016030:Kidney Transplantation; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D010976:Platelet Count; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000959:Antihypertensive Agents; D065095:Calcineurin Inhibitors; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D004921:Erythropoietin; D003404:Creatinine; D009173:Mycophenolic Acid; D020123:Sirolimus