ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients.
BACKGROUND
Chronic renal failure (CRF) is a major cause of morbidity and mortality after orthotopic liver transplantation (OLTX) and is predominantly caused by calcineurin inhibitors (CI)-induced nephrotoxicity. The activation of the renin angiotensin system (RAS) has been implicated in the pathogenesis of chronic nephrotoxicity from CI.


METHODS
We retrospectively investigated the genes coding for components of the RAS (ACE gene, Angiotensin II receptor 1 gene, Angiotensinogen gene) in 233 liver transplant recipients receiving Cyclosporine (CsA) or Tacrolimus (Tac) as maintenance immunosuppressant. All patients with serum creatinine (sCr) <1.0 mg/dL (n=143) before orthotopic liver transplantation (OLTX) were included in the final analysis. Patients were than categorized into two groups based upon their most recent postliver transplant sCr level: Group 1 (n=83) with sCr <1.5 mg/dL (mean 1.1+/-0.2) and group 2 (n=60) with sCr > or =1.5 mg/dL (mean 2.5+/-1.3)


RESULTS
ACE D/D genotype was found in 57% of patients with sCr > or =1.5 mg/dL compared to 20% of patients with sCr <1.5 mg/dL (P<0.0001)


CONCLUSIONS
Our analysis strongly suggests that liver transplant patients with ACE gene D/D genotype are at a significant higher risk of developing CI-induced chronic nephrotoxicity.
Department of Medicine, Division of Nephrology, Northwestern University, Chicago, IL 60611, USA. L-gallon@northwestern.edu
Lorenzo
L
Gallon
Enver
E
Akalin
Patrick
P
Lynch
Laura
L
Rothberg
Michele
M
Parker
Thomas
T
Schiano
Michael
M
Abecassis
Barbara
B
Murphy
D000808:Angiotensinogen / Q000235:genetics; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000235:genetics; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D016572:Cyclosporine; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; D016559:Tacrolimus