IgA nephropathy: effects of clinical indices, ACEI/ATRA therapy and ACE gene polymorphism on disease progression

Abstract

SUMMARY: In 1985 the authors studied 151 patients with biopsy‐proven IgA nephropathy (IgAN). After a mean follow‐up period of 5 years, 84% had stable renal function, 5% had renal impairment and 11% progressed to end‐stage renal failure (ESRF). The unfavourable prognostic indices were proteinuria > 1 g/day, hypertension, crescents on renal biopsy, glomerulosclerosis and medial hyperplasia of blood vessels. The cumulative renal survival was 89% at 5 years. Fifteen years later, in 2000, with data from the Singapore Renal Registry it was ascertained that 53 patients (35%) had developed ESRF. Using multivariate analysis by the regression model of Cox it was found that serum creatinine, protein selectivity, segmental glomerulosclerosis, crescents and medial hyperplasia were significant predictors of progression. It is also shown that the presence of low‐molecular‐weight (LMW) proteinuria is another index of poor prognosis. Cumulative renal survival of the 151 patients was 65% at 20 years. In a recent study, the response of patients with IgAN to angiotensin‐converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) therapy was examined. There were 21 patients in the treatment group and 20 as controls. After 13 ± 5 months of treatment, 10 responders had improved selectivity index (SI; from 0.26 ± 0.07 to 0.18 ± 0.07, P < 0.001), indicating a shift towards selective proteinuria. This was associated with improvement in serum creatinine from a mean of 1.7 ± 0.6 to 1.5 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 ± 1.1 g/day to 0.7 ± 0.5 g/day (P < 0.001). Eight out of 21 patients in the treatment group who had documented renal impairment had improvement in their renal function, three of whom had normalized renal function. The angiotensin‐converting enzyme insertion/deletion (ACE I/D) polymorphism gene was also genotyped in 100 patients with IgAN (32 of whom were in ESRF) and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second polymerase chain reaction (PCR), performed with the insert‐specific forward primer. Similar genotype frequencies were obtained for the 90 normal control subjects (II: 47%, ID: 44%, DD: 9%); for the 68 patients not in ESRF (II: 47%, ID: 46%, DD: 7%) and for the 32 patients with ESRF (II: 53%, ID: 38%, DD: 9%). The genotype frequencies in all three series are in Hardy–Weinberg equilibrium. These results suggest that ACE I/D polymorphism is not a risk factor for IgAN and is not a predictor for its progression. In conclusion the predictors in the progression of IgAN include abnormal renal function at presentation, segmental glomerulosclerosis, crescents, medial hyperplasia of blood vessels, non‐selective proteinuria, LMW proteinuria and failure to respond to antiproteinuria therapy with ACEI/ATRA. However, the D‐allele of ACE gene polymorphism is not a risk factor.