Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype.
BACKGROUND
Chronic allograft dysfunction (CGD) is a common outcome in kidney transplants, but its pathogenesis is unclear. We investigated the CGD phenotype and single-nucleotide polymorphisms (SNPs) associated with CGD.


METHODS
This prospective study enrolled 2336 transplants from seven transplant centers in North America. CGD was defined as a >25% rise in serum creatinine relative to a three-month post-transplant baseline, requiring a kidney biopsy. We genotyped 2724 SNPs in the initial 979 transplants, which form the test cohort.


RESULTS
CGD occurred 11.2 times per 100 person-years at a median of 509 ± 387 days from the three-month baseline. CGD was independently associated with death-censored, allograft failure, in an adjusted analysis [HR=20.6 (11.8-35.8, p < 0.001)]. Among 366 transplant recipients with CGD, 91% had inflammation on biopsy scores. 94 (26%) had inflammatory changes consistent with a diagnosis of concomitant acute rejection. SNPs in FM06 and FM03, potential drug metabolism genes, were associated with CGD, after accounting for multiple testing.


CONCLUSIONS
CGD phenotype with concomitant inflammation is associated with increased risk of allograft failure. SNPs associated with CGD in novel drug metabolism and transport genes, will be validated in subsequent transplants.
Nephrology Division, Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN 55415-1829, USA. isran001@umn.edu
Ajay K
AK
Israni
Robert
R
Leduc
Pamala A
PA
Jacobson
Winston
W
Wildebush
Weihua
W
Guan
David
D
Schladt
Arthur J
AJ
Matas
William S
WS
Oetting
D000328:Adult; D064591:Allografts; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D006085:Graft Survival; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D007674:Kidney Diseases / Q000150:complications* / Q000235:genetics / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010105:Oxygenases / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055031:Primary Graft Dysfunction / Q000209:etiology* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate
D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)