Keng-Thye Woo

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.

The contribution of chronic kidney disease to the global burden of major noncommunicable diseases

To the Editor: We have read the report of the ISN Global Outreach Programme,1 which confirms that, for the less developed countries compared with the more developed ones, chronic glomerulonephritis (GN) and not diabetic nephropathy (DiabNx) is still the leading cause of end-stage renal failure (ESRF).

Cell-mediated immunity in patients on hemodialysis: relationship with hepatitis B carrier status.

We compared cell-mediated immune responses in two groups of patients on hemodialysis. One group of patients were chronic carriers of hepatitis B virus (HBV), and the patients of the other group were HBV antigen negative. Our results show that despite the presence of normal numbers of T cells and an increased CD4/CD8 ratio in both groups of patients compared to healthy controls (p less than 0.0001), only the group of patients who were chronic HBV carriers showed depressed lymphoproliferative responses to phytohemagglutinin (p less than 0.001) and concanavalin A (p less than 0.0001). In contrast, a control group of healthy adult HBV carriers showed normal T cell subsets and lymphoproliferative responses to mitogens, indicating that HBV infection per se did not result in depressed lymphoproliferative responses. These results further substantiate the notion that depressed cell-mediated immunity in chronic renal failure is an important factor in predisposing patients to HBV infection with subsequent development of the chronic carrier state.

On uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka

To the Editor: We read with great interest the above article,1 in which the authors had accrued data from a population survey of chronic kidney disease (CKD) in a rural population in Sri Lanka. Our experience in Singapore in the 1970s2 was very similar to the Sri Lankan study in which Lim et al.2 conducted a community survey of the population. The prevalence of proteinuric CKD was also low, i.e., 0.63%.

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.

A retrospective Aliskiren and Losartan study in non-diabetic chronic kidney disease.

AIM To assess the efficacy of combined Aliskiren and Losartan vs high dose Losartan and Aliskiren alone in chronic kidney disease (CKD). METHODS This is a retrospective study of 143 patients with non-diabetic CKD comparing combined Aliskiren (150 mg/d) with Losartan (100 mg/d) therapy vs High dose Angiotensin receptor blockers (ARB) (Losartan 200 mg/d) and the third group Aliskiren (150 mg/d) alone. This study involved only patient medical records. Entry criteria included those patients who had been treated with the above drugs for at least 36 mo within the 5 years period; other criteria included proteinuria of 1 g or more and or CKD Stage 3 at the start of the 36 mo period. The study utilised primary renal end points of estimated Glomerular Filtration Rate (eGFR) < 15 mL/min or end stage renal failure. RESULTS Patients treated with high dose ARB compared to the other two treatment groups had significantly less proteinuria at the end of 36 mo (P < 0.007). All 3 groups had significant reduction of proteinuria (P < 0.043, P < 0.001). Total urinary protein was significantly different between the 3 groups over the 3-year study period (P = 0.008), but not eGFR. The changes in eGFR from baseline to each year were not significantly different between the 3 therapeutic groups (P < 0.119). There were no significant differences in the systolic and diastolic blood pressure between the 3 drug groups throughout the 3 years. The incidence of hyperkalemia (> 5.5 mmol/L) was 14.2% (7/49) in the Combined Aliskiren and ARB group, 8.7% (4/46) in the Aliskiren alone group and 6.3% (3/48) in the High dose ARB group (P < 0.001). CONCLUSION This study in non-diabetic CKD patients showed that Combination therapy with Aliskiren and ARB was effective but was not safe as it was associated with a high prevalence of hyperkalaemia.

Telmisartan is more effective than losartan in reducing proteinuria.

ence in the systolic blood pressure between the two groups before and after the study (P1⁄4 0.447). Neither was there a difference in the diastolic blood pressure (P1⁄4 0.159). The decrease in the estimated glomerular filtration rate (eGFR) was 3.5 ml/min/year for the losartan 100 mg group compared to 0.7 ml/min/year for the losartan 200 mg group (Po0.0005) and there were significantly less patients with chronic kidney disease (CKD) 4 and 5 in the losartan 200 mg group compared to the 100 mg group (Po0.005) at the end of 6 years. From our experience, dose for dose, losartan is probably equipotent to telmisartan, that is if prescribed in the dose of losartan 150 mg versus telmisartan 80 mg. Telmisartan, because of its longer half-life in terms of blood pressure control has the advantage of offering better renoprotection in hypertensive CKD patients (whether diabetic or IgA nephropathy). But for patients who do not have hypertension associated with CKD, losartan may be more appropriate as it is a relatively weaker hypotensive drug and one can prescribe larger doses without the side effects of giddiness and hypotension. In the long term, what is of paramount importance is preservation of renal function and prevention of renal failure. In this respect, data for telmisartan 80 mg and our own studies on losartan 200 mg have shown that after 5 years therapy there is a gain in eGFR for both of these drugs which has yet to be demonstrated by other angiotension receptor blocker (ARBs) or angiotension converting enzyme inhibitor (ACEI).

The incidence of IgA nephropathy is associated with socioeconomic deprivation

To the Editor: We read with great interest the article by McQuarrie et al.1 on the increased incidence of biopsy-proven immunoglobulin A (IgA) nephropathy associated with multiple socioeconomic deprivation in Scotland. In the paper, patients from deprived areas were significantly more likely to undergo native renal biopsy, suggesting a higher prevalence of renal disease, and these patients had significantly more IgA nephropathy. The authors had demonstrated for the first time a definitive link between socioeconomic deprivation and biopsy-proven renal disease. As the authors stated, this is a report on association and not causation. Globally, studies have shown an association between chronic kidney disease and socioeconomic deprivation.2 Based on the hygiene hypothesis,3 it would appear that IgA nephropathy, being a mesangial proliferative glomerulonephritis (GN), would appear to be more prevalent among the socioeconomically deprived and this would be one explanation for the increased incidence of IgA nephropathy in Scotland.