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Clinical Chemistry 47: 1679-1687, 2001;
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(Clinical Chemistry. 2001;47:1679-1687.)
© 2001 American Association for Clinical Chemistry, Inc.

Articles

Whole-Blood Calcineurin Activity Is Not Predicted by Cyclosporine Blood Concentration in Renal Transplant Recipients

Raffaele Caruso1, Norberto Perico1, Dario Cattaneo1, Giampiero Piccinini1, Samantha Bonazzola1, Giuseppe Remuzzi1 and Flavio Gaspari1a

1 Department of Immunology and Clinics of Organ Transplantation, Ospedali Riuniti di Bergamo, Mario Negri Institute for Pharmacological Research, 24125 Bergamo, Italy

aAddress correspondence to this author at: ‘Mario Negri’ Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Fax 39-035-319331; e-mail gaspari{at}marionegri.it.

Background: In transplant patients, current cyclosporine (CsA) dose monitoring with classic pharmacokinetics has demonstrated limitations. Evaluation of the activity of calcineurin (CN), the serine-threonine phosphatase enzyme target of CsA, has been proposed as a reliable way to optimize CsA dosing.

Methods: CN activity was measured in whole blood in an attempt to overcome the high variability of results obtained previously with peripheral blood mononuclear cells (PBMCs). We also explored, in vitro, a possible relationship between the CsA concentration and CN inhibition in whole blood. Finally, we assessed whether the CsA blood trough concentration correlates with whole-blood CN activity in kidney transplant recipients (n = 15) on maintenance immunosuppression with CsA.

Results: In 14 healthy individuals, less scattered CN activity values were documented in whole blood than in the PBMC fraction. Whole-blood CN activity was higher than the sum of the enzyme activity in each cell blood fraction. After ex vivo incubation of whole blood from healthy subjects (n = 5) with increasing concentrations of CsA (50–1000 µg/L for 1 h), a concentration-dependent inhibition of CN activity was found comparable to that in the PBMC fraction. Moreover, in 15 kidney transplant recipients, no relationship was found between CsA pharmacokinetic parameters and CN activity at time 0. However, a highly significant correlation was found between CN area under the CN activity-time curve, which represents the extent of the CN daily inhibition, and CN activity at time 0 (r = 0.79; P <0.01) and at 12 h postdosing (r = 0.96; P <0.01).

Conclusions: Measuring CN activity in whole-blood samples is a reproducible method. In kidney transplant recipients, CsA trough concentrations do not predict baseline CN activity. Moreover, a single CN activity monitoring at baseline or at time 12 h post-CsA dosing may be a useful surrogate for the inhibition of this enzyme by CsA during 12 h.




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