title: Impact of the variability of cyclosporin A trough levels on long-term renal allograft function.
abstract: BACKGROUND
  Among renal allograft recipients, there is a considerable variability in cyclosporin A (CsA) trough levels. Some of the CsA metabolites are pharmacologically active. The variability of polyclonal CsA trough levels may contribute to the fact that long-term renal allograft survival is still not satisfactory. In a retrospective, single-centre study, we investigated the influence of the variability of polyclonal CsA trough levels on long-term renal allograft function.
  
  
  METHODS
  Patients (n=381) received double immunosuppression consisting of CsA and methylprednisolone (MP). For each patient the CsA coefficient of variation (CCV) and the mean CsA trough level during the observation period (5 years) were calculated. Based on receiver operating characteristic (ROC) analysis, patients were divided into two groups: group I, CCV <28.05%, n=231; group II, CCV >28.05%, n=150. Additionally, patients were divided into three groups according to their mean CsA trough level: group A, <270 ng/ml, n=50; group B, 270-370 ng/ml, n=282; group C: >370 ng/ml, n=49.
  
  
  RESULTS
  Compared to group I, patients in group II experienced a higher incidence of acute rejection episodes (40.7% vs 29.4%, P=0.02), reduced 5-year graft survival (81.1% vs 93.3%, P=0.002), and higher serum creatinine levels (1.7+/-1.2 mg/dl vs 1.4+/-0.5 mg/dl, P=0.03). In patients with low mean CsA trough levels, the incidence of acute rejection episodes was elevated (group A vs B, 50.0% vs 30.9%, P=0.008) and 5-year graft survival was reduced (group A vs B, 79.8% vs 89.5%, P=0.005). Multiple logistic regression analysis confirmed that the risk of graft failure within 5 years after transplantation was markedly elevated in group II (RR: 6.2, P=0.013) and in group A (RR: 8.9, P=0.008). Whereas the effect of CCV on 5-year graft survival was still evident in patients with normal or high mean CsA trough levels (>270 ng/ml, 81.9% vs 94.8%, P=0.0005), graft survival was independent from CCV in patients with low mean CsA trough levels (<270 ng/ml, 77.0% vs 81.7%, P=NS).
  
  
  CONCLUSIONS
  Both, the intra-individual variability and the mean of polyclonal CsA trough levels influence long-term renal allograft survival. Targeting at sufficiently high mean CsA levels with a low intra-individual variability may help to further improve long-term renal allograft survival.
authors.affiliation: Department of Internal Medicine-Nephrology, University Hospital Charité, Campus Charité Mitte, Humboldt-University, Berlin, Germany. johanne.waiser@charite.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Waiser
authors.forename: Torsten
authors.initials: T
authors.lastname: Slowinski
authors.forename: Andrea
authors.initials: A
authors.lastname: Brinker-Paschke
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Matthias
authors.initials: M
authors.lastname: Schreiber
authors.forename: Torsten
authors.initials: T
authors.lastname: Böhler
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Hauser
authors.forename: Hans-Hellmut
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D000704:Analysis of Variance; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival / Q000187:drug effects*; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000401:mortality / Q000502:physiology*; D008775:Methylprednisolone / Q000627:therapeutic use; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D008775:Methylprednisolone