Angiotensinogen gene variation and renoprotective efficacy of renin-angiotensin system blockade in IgA nephropathy.
BACKGROUND
Blockade of the renin-angiotensin system (RAS) is well documented to be renoprotective; however, not all patients with glomerulonephritis respond well to this therapy. The interindividual variation in response to the RAS blockade may be in part genetically determined, whereas the results have been controversial.


METHODS
We investigated whether the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker on renal prognosis is modified by the angiotensinogen gene (AGT) polymorphism in immunoglobulin A nephropathy (IgAN). In total, 259 patients with histologically proven IgAN were analyzed for clinical manifestations, renal survival, and their associations with AGT A(-20)C and M235T.


RESULTS
The renal prognosis of 110 patients, who received ACE inhibitors/angiotensin receptor blocker during their clinical course, was significantly better than those without ACE inhibitors/angiotensin receptor blockers despite higher blood pressures and heavier proteinuria. The Cox proportional hazards regression model showed an increased hazard ratio (HR) for urinary protein (more than 1.0 g/day) of 3.346 (P = 0.0001), hypertension of 1.949 (P = 0.01), deteriorated renal function of 3.040 (P < 0.0001), no ACE inhibitor/angiotensin receptor blocker administration of 2.725 (P = 0.0004), and the T235 and C(-20) haplotype of 1.608 (P = 0.0322). Only in patients carrying at least one M235 and A(-20) haplotype did the administration of ACE inhibitors/angiotensin receptor blockers have no significant effect on the prognosis of renal function (Kaplan-Meier, log rank test, chi2 = 0.700; P = 0.4028), whereas it was significant in patients who had other haplotypes of AGT (chi2 = 11.805; P = 0.0006).


CONCLUSIONS
This study provides evidence that the M235T and A(-20)C genotype of AGT can influence the therapeutic efficacy of a RAS blockade on the renal survival in IgAN.
Narita
Ichiei
I
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. naritai@med.niigata-u.ac.jp
Goto
Shin
S
Saito
Noriko
N
Song
Jin
J
Omori
Kentaro
K
Kondo
Daisuke
D
Sakatsume
Minoru
M
Gejyo
Fumitake
F
D000225:Adenine; D000328:Adult; D000483:Alleles; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000235:genetics*; D019610:Cytoprotection; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D006147:Guanine; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007674:Kidney Diseases / Q000209:etiology; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012307:Risk Factors; D013912:Threonine / Q000235:genetics
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D013912:Threonine; D006147:Guanine; D008715:Methionine; D000225:Adenine