title: Conversion from calcineurin inhibitor to either mycophenolate mofetil or sirolimus improves renal function in liver transplant recipients with chronic kidney disease: results of a prospective randomized trial.
abstract: BACKGROUND
  Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function.
  
  
  METHODS
  In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m(2)) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm > versus <30 mL/min/1.73 m(2). The 25 patients were enrolled for MMF (n = 13) or SRL (n = 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n = 12) and SRL (n = 10).
  
  
  RESULTS
  Mean GFRm for the whole cohort (n = 25) was 31+/-8 mL/min/1.73 m(2) at baseline. After 3 months the GFRm (n = 23) increased to 40+/-10 mL/min/1.73 m(2) (P = .0001) and at 1 year 42 +/- 11 mL/min/1.73 m(2) (n = 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n = 8) with baseline GFRm <30 mL showed a 63% (P = .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes.
  
  
  CONCLUSIONS
  CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.
authors.affiliation: Sahlgrenska Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. gustaf.herlenius@gmail.com
authors.forename: G
authors.initials: G
authors.lastname: Herlenius
authors.forename: M
authors.initials: M
authors.lastname: Felldin
authors.forename: G
authors.initials: G
authors.lastname: Nordén
authors.forename: M
authors.initials: M
authors.lastname: Olausson
authors.forename: L
authors.initials: L
authors.lastname: Bäckman
authors.forename: B
authors.initials: B
authors.lastname: Gustafsson
authors.forename: S
authors.initials: S
authors.lastname: Friman
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use; D065095:Calcineurin Inhibitors; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology*; D016031:Liver Transplantation; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000959:Antihypertensive Agents; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D020123:Sirolimus