Yeow-Kok Lau

ACE Gene Polymorphism and Disease Progression of IgA Nephropathy in Asians in Singapore

The deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been considered as a risk factor for IgA nephropathy and for its progression to end-stage renal failure. However, results from various studies are conflicting. We had genotyped the ACE gene in 100 patients with IgA nephropathy, 32 of whom were in end-stage renal failure and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second 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 end-stage renal failure (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 3 series are in Hardy-Weinberg equilibrium. These results suggest that ACE gene polymorphism is not a risk factor for IgA nephropathy and is not a predictor for its progression. Definitive proof of association between ACE gene polymorphism and progression in IgA nephropathy will require a prospective study, controlled for important risk factors, with adequate patient numbers and facility for confirming DD genotypes.

Global evolutionary trend of the prevalence of primary glomerulonephritis over the past three decades.

Objective: The prevalence of primary glomerulonephritis in Singapore is compared with that of 28 other countries to review changing trends in the evolution of primary glomerulonephritis in Asia and other countries. Method: 2,586 renal biopsies in Singapore over the past 3 decades were reviewed and compared with data from 28 other countries. Results: In the 1st decade most Asian countries have mesangial proliferative glomerulonephritis as the most common form of primary glomerulonephritis, and in the 3rd decade there has been a dramatic increase in focal and segmental glomerulosclerosis reflecting aging and obesity in keeping with more developed countries. IgA nephritis remains the commonest glomerulonephritis in many countries. Membranous glomerulonephritis continues to be more prevalent in Western countries while mesangial proliferative glomerulonephritis remains prevalent in many Asian countries. Conclusion: Apart from geographical and genetic influences, socioeconomic factors may play a role in the evolution of the biopsy pattern in some countries. Worldwide, the prevalence of focal segmental glomerulosclerosis continues to increase. In third world countries some of the commoner forms of glomerulonephritis are related to infections, in contrast to developed countries where the antigenic exposure may be related to diet, allergens and other industrial agents.

Renin-Angiotensin System Gene Polymorphisms: Its Impact on IgAN and Its Progression to End-Stage Renal Failure among Chinese in Singapore

Background: Gene polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (ATR) had been associated with IgA nephropathy (IgAN) and its progression. Several studies on Caucasian and Japanese had reported contradicting results. We determined these polymorphisms in 118 Chinese patients with IgAN and 94 healthy Chinese to assess their clinical impact. Methods: Genotyping was performed with DNA from peripheral leukocytes, PCR amplification of the polymorphic sequence, restriction enzymes digestion, separation and identification of DNA fragments. Clinical data at renal biopsy and final status on renal function were determined from patients’ records. Results: Among controls, genotype distributions were in Hardy-Weinberg equilibrium. Comparing all IgAN patients with controls, AGT and ATR genotype distributions were similar whereas there was significant increase in the ACE DD genotype (p < 0.05). Comparing patients with end-stage renal failure (IgAN-ESRF) and without (IgAN-nonESRF), there was no difference in any of the three gene polymorphisms. But in contrast, there were significant differences in higher male prevalence (p < 0.05), increased serum creatinine at presentation (p < 0.05), more sclerosis (p < 0.01) and higher tubulointerstitial lesion score (p < 0.001) in the IgAN-ESRF group. Conclusion: Among the ACE, AGT and ATR gene polymorphisms, only the DD genotype may predispose the individual to IgAN in our Chinese population. In contrast to clinical and histological risk factors, these genetic variations showed no impact on disease progression to ESRF. It is unlikely that genotyping more patients will prove these genes useful. Nevertheless, preclinically determined genetic markers are very useful as risk factors for disease occurrence and as prognostic indices for disease progression. Therefore, continuing efforts should be made to look at other genes to find those with significance.

Polymorphism of renin-angiotensin system genes in IgA nephropathy.

Background and Aims:  Individuals are prone to disease because of certain disease‐susceptible genes. The angiotensin I‐converting enzyme (ACE) gene insertion/deletion (I/D), the angiotensinogen (AGT) gene, M235T, and the angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with IgA nephropathy (IgAN) and its progression. Several studies on Caucasians and Japanese patients have reported contradictory results. We determined these polymorphisms in 118 Chinese patients with IgAN and 94 healthy Chinese subjects to assess their clinical impact.

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

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.

Clinical Trials and Management of Chronic Kidney Disease

This article offers a Long-term perspective of clinical trials and management of chronic Kidney disease.