Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients.
BACKGROUND
The mechanism of avascular osteonecrosis (AVN) is controversial. Besides an increased bone marrow pressure with reduced blood supply, an enhanced coagulation has been considered. We hypothesize that a genetic variant of the plasminogen activator inhibitor-1 (PAI-1) determines the risk of AVN in glucocorticoid-treated patients.


METHODS
Genotyping for the 4G/5G PAI-1 polymorphism was performed in 228 glucocorticoid-treated renal transplant patients. AVN of the hip was present in 26 patients. Magnetic resonance imaging (MRI) of the hips was obtained in 81 of the remaining renal transplant patients without clinical symptoms of AVN.


RESULTS
The presence of the homozygous 4G/4G PAI-1 genotype was higher in patients with AVN (60.3%) as compared with patients without either clinical (20.6%, P<0.007) or radiological signs of AVN (17.3%, P<0.002). The prevalence of AVN by genotype was 1.8% with the 5G/5G, 7.7% with the 5G/4G, and 30.3% with the 4G/4G alleles (P<0.001 vs. 5G/4G and 5G/5G). The prevalence of AVN increased with increasing body mass index (BMI) (P=0.04). The prevalence of AVN by genotype in subjects with persistent hyperparathyroidism was 4.2% with the 5G/5G, 15.2% with the 5G/4G, and 55.5% with the 4G/4G alleles (P<0.003 vs. 5G/4G and P<0.001 vs. 5G/5G).


CONCLUSIONS
Hypofibrinolysis conferred by the 4G/4G PAI-1 gene variant is a major predisposing factor for AVN in renal transplant patients. The risk is particularly high in obese subjects or patients with persistent hyperparathyroidism. A prospective intervention study of early anticoagulation after renal transplantation is needed to assess whether glucocorticoid-associated AVN can be prevented.
Ferrari
Paolo
P
Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland.
Schroeder
Verena
V
Anderson
Suzanne
S
Kocovic
Leonardo
L
Vogt
Bruno
B
Schiesser
Daniela
D
Marti
Hans-Peter
HP
Ganz
Reinhold
R
Frey
Felix J
FJ
Kohler
Hans P
HP
D000328:Adult; D005260:Female; D005271:Femur Head Necrosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D006621:Hip Joint / Q000473:pathology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics / Q000601:surgery; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D015995:Prevalence; D012307:Risk Factors; D017678:Sex Distribution; D014184:Transplantation, Homologous
D005938:Glucocorticoids; D017395:Plasminogen Activator Inhibitor 1