Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS - A study of 274 men

The impact of renin-angiotensin system (RAS) gene polymorphism on the progn osis of IgA nephropathy (IgAN) is still debated. A longitudinal study of re nal prognosis in patients with IgAN was conducted to search retrospectively for a genotype-phenotype association between RAS polymorphisms and end-sta ge renal failure (ESRF). A classification based on serum creatinine (S-cr) and 24-h proteinuria (24-P) measured at the time of renal biopsy was used t o estimate the risk of ESRF in IgAN: stage 1 (S-cr less than or equal to 15 0 mu mol/L and 24-P < 1 g), stage 2 (S-cr > 150 mu mol/L and 24-P < 1 g or S-cr <less than or equal to> 150 mu mol/L and 24-P greater than or equal to 1 g), stage 3 (S-cr > 150 mu mol/L and 24-P greater than or equal to 1 g). Deletion/insertion polymorphism (D/I) of the angiotensin I converting enzy me gene, M235T polymorphism (T/M) of the angiotensinogen gene and A1166C po lymorphism (C/A) of the angiotensin II type 1 receptor gene were determined in 274 Caucasian men with biopsy-proven IgAN (n = 86, 112, and 76 in stage s 1, 2, and 3, respectively). Mean global follow-up was 6 +/- 5 yr after re nal biopsy. For stages 1, 2, and 3, ESRF developed in 7 (8.1%), 39 (34.8%), and 39 (64.4%) cases (P < 0.0001), 11.7 +/- 4, 5.3 +/- 4, and 2 +/- 2 yr, respectively, after renal biopsy (P < 0.001). The distributions of the thre e genotypes into the three stages were similar. Different distributions wer e observed when patients were grouped by stage and genotype: ID + DD: 72% i n stage 1 versus 84.6% in stages 2 + 3 (P = 0.02; kappa = 0.14); MT + TT: 6 6.2% in stages 1 + 2 versus 78.9% in stage 3 (P = 0.04; kappa = 0.09); and AA + AC: 89.9% in stages 1 + 2 versus 97.4% in stage 3 (P = 0.04; kappa = - 0.1). However, with the use of the Cox proportional hazard model, none of t he three genotypes was found to have predictive value fur renal survival. C ompared with S-cr and 24-P, genotypes DD, TT, and AA are unlikely to serve as clinically useful predictors of ESRF in IgAN.