Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies.
BACKGROUND
At present it is unclear which dose and consecutive blood levels of cyclosporine A (CsA) are optimal with respect to immunosuppressive efficacy and drug specific side effects at the level of individual patients. Several pharmacodynamic measures of CsA effects have been proposed, but have not become clinical routine yet. Besides the lack of practicability, the biological relevance of these assays has not been determined so far.


METHODS
Residual expression of nuclear factor of activated T-cells (NFAT)-regulated genes two hours after drug intake was used as molecular pharmacodynamic marker to assess CsA effects on lymphocytes and correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation.


RESULTS
Recurrent infectious complications were observed in 44% and malignancies in 20% of the 133 patients studied. Patients with a strong suppression of NFAT-regulated genes by CsA--as judged by a residual level of transcription of less than 15% after drug intake--develop more frequent infections (53% vs. 29%; P = 0.005) and malignancies (22% vs. 4%; P = 0.002). The lack of correlation between the incidence of these complications and CsA blood concentration might point to the interindividual differences in the sensitivity towards calcineurin inhibition.


CONCLUSIONS
The data presented here reveal a clear relation between the frequency of infectious and malignant complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients. Therefore, pharmacodynamic monitoring of CsA efficacy in transplanted patients might be a useful tool to adjust immunosuppressive therapy in individual patients.
Sommerer
Claudia
C
Department of Nephrology, University of Heidelberg, Heidelberg, Germany. claudia.sommerer@med.uni-heidelberg.de
Konstandin
Mathias
M
Dengler
Thomas
T
Schmidt
Jan
J
Meuer
Stefan
S
Zeier
Martin
M
Giese
Thomas
T
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring; D005260:Female; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007239:Infections / Q000453:epidemiology*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology*; D011183:Postoperative Complications / Q000453:epidemiology*; D012008:Recurrence
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine