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Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation

The Pharmacogenomics Journal volume 8, pages 248–255 (2008)Cite this article

Abstract

Renal disease is a major complication in patients following myeloablative allogeneic hematopoietic cell transplantation (HCT). Post-HCT patients receive immunosuppressive regimens containing calcineurin inhibitor (CNIs), cyclosporine or tacrolimus, for graft-versus-host disease prophylaxis. In this retrospective trial, we investigated pharmacogenomic associations in the multidrug resistance (ABCB1) and cytochrome P450 3A5 (CYP3A5) genes and acute kidney injury (AKI) and chronic kidney disease (CKD) in a cohort of 121 patients. ABCB1 and CYP3A5 are responsible for the renal disposition of CNIs, which are known to be nephrotoxic. AKI was defined as doubling of baseline serum creatinine during the first 100 days post-HCT, and CKD as at least one glomerular filtration rate <60 ml/min/m2 between 6 and 18 months post-HCT. Patients were genotyped for CYP3A5*1>*3 and ABCB1 single nucleotide polymorphisms (SNPs) (1199G>A, 1236C>T, 2677G>T/A and 3435C>T). Odds ratios were calculated using logistic regression. Haplotype estimation and univariate association analyses were performed because of strong ABCB1 linkage disequilibrium (LD). AKI occurred in 48 of 121 patients (39.7%) and CKD in 16 of 66 patients (24.2%). No pharmacogenomic associations were found between ABCB1 and CYP3A5 SNPs and the incidences of AKI or CKD. The degree of LD(r2) between ABCB1 SNPs was estimated as follows: 2677G>T/3435C>T (0.44), 1236C>T/3435C>T (0.42) and 1236C>T/2677G>T (0.72). ABCB1 1199G>A showed no LD to other SNPs (<0.05). No associations were found between the most common ABCB1 haplotypes and AKI or CKD. Since no significant pharmacogenomic associations were observed, tailoring CNIs dosing based on these genotypes is unlikely to lower significantly the risk of renal injury following myeloablative HCT.

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Abbreviations

ABCB1 or MDR1:

multidrug resistance gene

AKI:

acute kidney injury

CKD:

chronic kidney disease

CNIs:

calcineurin inhibitors

CYP3A5:

cytochrome P450 3A5

GVHD:

graft-versus-host disease

HCT:

hematopoietic cell transplantation

LD:

linkage disequilibrium

OR:

odds ratio

P-gp:

P-glycoprotein

SNP:

single nucleotide polymorphism

SOS:

sinusoidal obstruction syndrome

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Acknowledgements

We thank Dr Rodney JY Ho, Dr Edward J Kelly and Tot Bui from the DNA Sequencing and Gene Analysis Center in the Department of Pharmaceutics at the University of Washington. This study was supported by NIH CA18029. SRH is the principal investigator for NIDDK K23-DK063038. ELW is the recipient of the Elmer M and Joy B Plein Fellowship for Excellence in Pharmacy Education, School of Pharmacy, University of Washington.

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Authors and Affiliations

  1. Department of Pharmacy, University of Washington, Seattle, WA, USA

    E L Woodahl & J S McCune

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    E L Woodahl, S R Hingorani, J Wang, K A Guthrie, G B McDonald, A Batchelder, H G Schoch & J S McCune

  3. Department of Pediatrics, University of Washington, Seattle, WA, USA

    S R Hingorani

  4. Department of Pharmaceutics, University of Washington, Seattle, WA, USA

    J Wang & M Li

  5. Department of Medicine, University of Washington, Seattle, WA, USA

    G B McDonald

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  1. E L Woodahl
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Correspondence to J S McCune.

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Woodahl, E., Hingorani, S., Wang, J. et al. Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation. Pharmacogenomics J 8, 248–255 (2008). https://doi.org/10.1038/sj.tpj.6500472

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