Pharmacodynamic Monitoring of Calcineurin Inhibitor in Pediatric Kidney Transplantation

Han Ahn Yo; Il Min Sang; Jongwon Ha; Il-Soo Ha; Il Cheong Hae; Gyung Kang Hee

doi:10.4285/jkstn.2015.29.1.16

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Yo, Sang, Ha, Ha, Hae, and Hee: Pharmacodynamic Monitoring of Calcineurin Inhibitor in Pediatric Kidney Transplantation

Original Article

J Korean Soc Transplant 2015;29(1):16-22.

Published online: 10 March 2015

DOI: https://doi.org/10.4285/jkstn.2015.29.1.16

Pharmacodynamic Monitoring of Calcineurin Inhibitor in Pediatric Kidney Transplantation

Han Ahn Yo, M.D¹, Il Min Sang, M.D.², Jongwon Ha, M.D.², Il-Soo Ha, M.D.¹, Il Cheong Hae, M.D.¹, Gyung Kang Hee, M.D.¹

¹Department of Pediatrics, Seoul National University Children’ s Hospital, Seoul, Korea

²Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Hee Gyung Kang, Department of Pediatrics, Seoul National University Children’ s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: 82-2-2072-0658, Fax: 82-2-2072-0274, E-mail: kanghg@snu.ac.kr

Received 25 February 2015 Revised 26 February 2015 Accepted 26 February 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Introduction of calcineurin inhibitor (CNI) has markedly improved the outcome of kidney transplantation. While therapeutic drug monitoring is used to adjust the dosage of CNI, some patients, particularly children, still suffer from rejection, infection, and CNI toxicity. This study was conducted in order to assess the adequacy of immunosuppression using pharmacodynamic monitoring.

Methods

Pharmacodynamic monitoring was performed for 64 pediatric kidney allograft recipients. Expression of nuclear factor of activated T lymphocytes (NFAT)-regulated genes in patients' mononuclear cells was measured by quantitative polymerase chain reaction of interleukin-2, interferon-gamma (IFN-), and granulocyte-macrophage colony stimulating-factor before (trough) and 1.5 hour (peak) after ingestion of tacrolimus and the residual gene expression (RGE) was calculated. Global immune response was assessed by Cylex-ImmuKnow assay. Trough and peak levels of tacrolimus were measured and clinical findings of rejection episodes and infectious complications were reviewed retrospectively.

Results

Global immune response measured byImmuKnow did not show correlation with trough and peak levels of tacrolimus. Adenosine triphosphate level of ImmuKnow was higher in patients with Epstein-Barr virus (EBV) infection than in those without infectious complications (515.4±149.0 ng/mL vs. 342.7±155.3 ng/mL, P=0.006). Mean RGE of the three NFAT-regulated genes showed negative correlation with tacrolimus peak levels. RGE of IFN- was lower in patients with other infections except EBV than in those without infectious complications (34.0%±7.5% vs. 56.0%±30.2%, P＜0.001).

Conclusions

RGE of NFAT-regulated genes and ImmuKnow did not show significant correlation with clinical manifestation of under- or over-suppression of immune function in pediatric kidney allograft recipients. Further studies are required for development of optimal pharmacodynamic monitoring for pediatric kidney transplantation recipients.

Keywords: Kidney transplantation, Calcineurin inhibitor, Pharmacodynamic monitoring

References

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Table 1.

Characteristics of patients (n=62)

Characteristic	Value
Gender (male:female)	35:27
Age (yr)	12.9 (4.1∼19.2)
Time after kidney transplantation (yr)	2.9 (0.2∼10.9)
Cause of ESRD
NPHP/MCKD	15 (24.2)
Focal segmental glomerular sclerosis	11 (17.7)
Reflux nephropathy	11 (17.7)
Renal hypoplasia/dysplasia	7 (11.3)
Unknown	5 (8.1)
Others	13 (21.0)
No. of drug monitoring	128
Age at drug monitoring (yr)	12.9 (4.1∼19.2)
Immunosuppressant regimen
CNI+MMF	78 (60.9)
CNI+MMF+steroid	31 (24.2)
CNI+steroid	11 (8.6)
CNI only	6 (4.7)
CNI+azathioprine	2 (1.6)
Infectious complications at drug monitoring
EBV infection	8 (6.1)
CMV infection	2 (1.5)
Viral gastroenteritis	3 (2.3)
Upper respiratory infection	3 (2.3)
Rejections at drug monitoring
Acute T cell-mediated type	4 (3.1)
Acute antibody-mediated type or mixed	4 (3.1)
Data are presented as median (range) or number (%).

Abbreviations: ESRD, end stage renal disease; NPHP, nephrono-phthisis; MCKD, medullary cystic kidney disease; CNI, calcineurin inhibitor; MMF, mycophenolate mofetil; EBV, Epstein-Barr virus; CMV, cytomegalovirus.

Table 2.

Correlation between pharmacokinetic and pharmacodynamic monitoring of calcineurin inhibitor

	Tacrolimus through level		Tacrolimus 1.5 hr level
	r²	P-value	r²	P-value
ImmuKnow	0.001	0.757	0.021	0.167
IL-2 RGE	0.001	0.764	0.021	0.174
IFN- RGE	0.003	0.620	0.041	0.055
GM-CSF RGE	0.046	0.037	0.066	0.015
Mean RGE	0.011	0.312	0.060	0.019

Abbreviations: IL-2, interleukin-2; RGE, residual gene expression; IFN-, interferon-gamma; GM-CSF, granulocyte-macrophage colony stimulating-factor.

Table 3.

Results of pharmacokinetic and pharmacodynamic monitoring according to the clinical status

Variable	Stable (n=104)	Infection (n=16)	Rejection (n=8)
Age (yr)	12.4±2.9	10.8±4.0	14.5±2.3 ^a
Duration after TPL (yr)	3.6±2.4	3.0±2.3	3.8±2.3
Gender (male:female)	56:48	11:5	6:2
ImmuKnow (ng/mL)	344.5±152.9	412.1±168.0	320.2±211.0
IL-2 RGE (%)	50.9±62.1	23.8±28.0	46.4±22.5
IFN- RGE (%)	56.5±29.4	50.9±29.7	52.9±45.1
GM-CSF RGE (%)	54.7±64.4	41.5±37.8	32.2±27.1
Mean RGE (%)	54.0±42.2	38.7±27.0	43.8±28.7
Tac trough level (ng/mL)	4.27±1.60	4.29±1.62	4.34±1.60
Tac 1.5 hr level (ng/mL)	12.35±4.3	14.08±6.69	10.99±6.66
Tac dose (mg/BSA)	3.12±1.42	2.84±1.50	2.90±0.94
Tac 1.5 hr level/dose	4.62±2.52	5.86±3.18	3.93±2.11
Data are presented as mean±SD.

Abbreviations: TPL, transplantation; IL-2, interleukin-2; RGE, residual gene expression; IFN-, interferon-gamma; GM-CSF, granu-locyte-macrophage colony stimulating-factor; Tac, Tacrolimus; BSA, body surface area.

^a P＜0.05 compared with stable group.

Table 4.

Results of pharmacokinetic and pharmacodynamic monitoring according to the causes of infection

Variable	Other infection (n=7)	No infection (n=113)	EBV infection (n=8)
Age (yr)	13.3±3.9	12.6±2.9	8.2±2.6 ^b
Duration after TPL (yr)	2.3±1.7	3.7±2.5	2.7±1.2
Gender (male:female)	5:2	63:50	5:3
ImmuKnow (ng/mL)	283.0±101.7	342.7±155.3	515.4±149.0 ^a
IL-2 RGE (%)	13.1±18.0	50.2±59.7	34.4±36.7
IFN- RGE (%)	34.0±7.5 ^b	56.0±30.2	69.3±36.7
GM-CSF RGE (%)	33.7±33.0	52.5±62.5	57.3±41.1
Mean RGE (%)	26.9±16.6	52.9±41.2	53.7±32.0
Tac trough level (ng/mL)	4.73±2.35	4.27±1.59	3.94±0.76
Tac 1.5 hr level (ng/mL)	15.23±7.05	12.20±4.51	13.93±6.75
Tac dose (mg/BSA)	3.41±1.73	3.09±1.40	2.55±1.20
Tac 1.5 hr level/dose	4.92±1.87	4.58±2.48	6.67±4.13 ^a
Data are presented as mean±SD.

Abbreviations: EBV, Epstein-Barr virus; TPL, transplantation; IL-2, interleukin-2; RGE, residual gene expression; IFN-, interferon-gamma; GM-CSF, granulocyte-macrophage colony stimulating-factor; Tac, tacrolimus; BSA, body surface area.

^a P＜0.05 compared with no infection group;

^b P＜0.001 compared with no infection group.

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