title: Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity:  results from a kidney transplant consortium.
abstract: BACKGROUND
  Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity.
  
  
  METHODS
  We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant.
  
  
  RESULTS
  Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity.
  
  
  CONCLUSIONS
  We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA. jacob117@umn.edu
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: David
authors.initials: D
authors.lastname: Schladt
authors.forename: Ajay
authors.initials: A
authors.lastname: Israni
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
authors.forename: Yi Cheng
authors.initials: YC
authors.lastname: Lin
authors.forename: Robert
authors.initials: R
authors.lastname: Leduc
authors.forename: Weihau
authors.initials: W
authors.lastname: Guan
authors.forename: Vishal
authors.initials: V
authors.lastname: Lamba
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011183:Postoperative Complications; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus