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The areas of current research focus are broadly categorised into the following :
- Glomerular disease
- Renal Failure
- Dialysis
- Transplantation
- Hypertension, and
- Diabetic Nephropathy
1) IgA Nephropathy
Principal Investigators: Prof Woo Keng Thye, Dr Lau Yeow Kok
IgA nephritis (IgAN) is the commonest form of primary glomerulonephritis (45%) in Singapore, contributing significantly to end-stage renal failures who need costly dialysis treatment for life. Despite more than 3 decades of studies, the aetiology and pathogenesis is still poorly understood. Study of IgAN remains a priority in renal medicine.
We had recently completed the study, Renin-angiotensin system gene polymorphisms: Its impact on IgAN and its progression to end-stage renal failure (ESRF) among Chinese in Singapore (Nephron Physiol 2004; 97:1-8). We found that among the angiotensin I-converting eznyme (ACE) insertion/deletion, angiotensinogen M235T and the angiotensin II receptor A1166C gene polymorphisms, only the DD genotype may predispose the individual to IgAN. In contrast to clinical and histological risk factors, these genetic variations showed no impact on disease progression to ESRF.
Single variant polymorphism (SVP) studies had shown much contradictory findings in IgAN. There had been suggestion that haplotypes (block of more than 1 SVP on the same chromosome) may be more helpful. In order to detect all available variants for haplotype construction, we had sequenced the ACE gene (24,000 base-pair) in 24 Chinese subjects, 20 with IgAN and 4 healthy controls. Fifty-five variants were found. Seventeen were unique to patients but none were identified as significant risk factor for developing the disease, as the frequencies were very low. Eleven variants were in absolute linkage with the Alu I/D variant and may therefore replace it as genetic marker. As these are single nucleotide variants, they can be more rapidly and cost effectively genotyped using real-time PCR technique which is not applicable to Alu I/D genotyping. Two 5-loci haplotypes (haplotypes 3 and 5) were found to predict progression or non-progression to ESRF. Further study in IgAN may lie in haplotying variants across many genes, genome-wide using the Affymetrix GeneChip Human Mapping 10K Array.
With the commercial availability of DNA microarrays, tens of thousands of gene expressions genome-wide can be examined and all at the same time. The stage is set for an explosion of knowledge in understanding the interlinking of diverse biological processes, pathways and their relations to the pathogenetic mechanisms of IgAN and other diseases. The Human Genome U133 Plus 2.0 Arrays (Affymetrix, USA) were used to quantitate the differential expression of 38,500 well-characterized human genes. In this preliminary study we examined 7 IgAN patients and 7 normal subjects. Ad hoc analysis of the results had pointed to the possible involvement of urotensin II, disturbance in lipid metabolism and vitamin A deficiency in the aetiology and pathogenesis of this renal lesion. These are new areas for further investigation into the aetiology and pathogenesis in IgAN and are new targets for developing more effective treatments.
We continue to explore the usefulness of SDS-PAGE analysis of proteinuria in patients with acute renal failure and to search for a mouse model of IgAN by feeding with ‘heaty’ diets.
2) Glomerular Disease
Principal Investigators: Dr Seow Ying-ying, Dr KS Wong, Dr M Foo, Dr Roger Tan, Dr Suhail
Prospective, randomised double-blind controlled trial comparing 2 induction and maintenance immunosupressive therapy regimes for SLE nephritis patients.
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To assess efficacy of MMF compared to IV cyclophsphamide in inducing response in patients with SLE nephritis.
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Also to compare long-term (3 year follow-up) efficacy of MMF compared to azathioprine in maintaining remission in SLE nephritis.
Part of phase III multi-centre clinical trial starting Oct 2005.
3) Critical Care Nephrology Research
Principal Investigator: Dr Tan Han Khim
Recent work has involved earlier initiation of renal replacement therapy (RRT) and at higher intensities to achieve more optimal clinical outcome. Wherever possible, continuous renal replacement therapy (CRRT) is the modality of choice especially among critically ill ICU patients. Slow low efficiency dialysis (SLED), and other forms of blood purification such as membrane plasma filtration have also been used and much clinical experience has accrued. Last but not least, the department has also been at the forefront of using the Molecular Adsorbent Recirculating System (MARS) to perform albumin liver dialysis in critically ill patients with severe liver dysfunction with or without multi-organ failure (MOF). Such artificial organ support has enabled homeostasis to be achieved when used in seriously ill patients in this institution.
4) Chronic Haemodialysis
Principal Investigator: Dr Lina Choong
Haemodialysis is currently the mainstay of renal replacement therapy in Singapore with over 80% of dialysis patients receiving this treatment for end stage renal failure. Ongoing clinical research is focused on the investigation of factors such as dialysate flow rate or blood flow rate that may improve dialyzer performance. Other areas of clinical research include complications of dialysis and studies on morbidity of renal failure.
5) Peritoneal Dialysis
Principal Investigator: Dr Marjorie Foo
The Peritoneal Dialysis Centre is currently focused on reduction of Staphyloccocal and gram negative infection with the use of prophylactic topical antibiotics. Current research is focused on the use of Icodextrin in the preservation of ultrafiltration, membrane function and improvement of metabolic control as well as the application of newer biocompatible solution in the preservation of residual renal function. We are also embarking on "telecare" monitoring: monitoring of patients’ vitals via internet and telephone messaging system aiming to reduce hospitalization and ad hoc outpatient visits and ultimately improving patient care and long term outcome.
6) Renal Transplantation
Principal Investigator: Dr A Vathsala
Transplantation is the best form of renal replacement therapy for patients with end stage renal failure. In ongoing research on mechanism of immunosuppression, immunosuppressive drugs have been shown to inhibit apoptosis of activated T lymphocytes, a finding with implications on clinical immunosuppression. Research focus in the department has also been on clinical trials with newer immunosuppressive agents, strategies in optimizing current immunosuppressants and retrospective reviews on outcomes and complications post renal transplantation. Presentation of the results of interim analysis of a clinical trial with a new immunosuppressant, Mycophenolate Mofetil, was awarded the Young Investigators Award at the 13th Singapore Pharmacy Congress, November 1999.
7) Renal Retardation Programme
Director: Dr Wong Kok Seng
Dr Chan Choong Meng
The incidence of ESRF is rising and this Renal Retardation Programme was set up in SGH and NUH. This programme is funded by MOH in an attempt to retard the progression of renal failure in patients with or without renal impairment (both diabetic and non diabetic renal disease) but have significant proteinuria (> 1 g/day).
This involved an intensive multidisciplinary approach in the control of proteinuria and blood pressure with medical therapy (combination of ACE inhibitor and Angiotensin II receptor Blocker), diabetic control with the diabetologist in situation of difficult and uncontrolled diabetes, dietary advice on protein intake and hyperlipidaemia control.
Targets:
- To achieve BP control< 130/80
- HBAic < 7%
proteinuria < 1g/day or < 50% of baseline
The ultimate goal is to achieve a reduction in the incidence of ESRF in these high risk patients
8) Renin Angiotensin System Polymorphisms and the response to dual blockade in diabetic proteinuria
Principal Investigator: Dr Chan Choong Meng
Co Investigator: Dr Seow Ying-ying
This study will examine the role of combined ACEI and ARB treatment and the RAS Polymorhisms on proteinuria and renal progression. in Diabetic Kidney Disease
We will study the genomic profile of patients with proteinuria and renal impairment who are resistant to the anti-proteinuric effects of dual blockade of the renin-angiotensin system (RAS) with respect to the following target genes:
- The Agt M235T and the T174M polymorphisms of the Angiotensinogen gene (AGT)
- The D/I polymorphism of the Angiotensin-Converting Enzyme gene (ACE)
- The A1166® C polymorphism of the Angiotensin II type I Receptor gene (ATR)
9) Immunolocalisation of P2 receptors in human biopsied kidneys (historical)
Principal Investigator: Dr Chan Choong Meng
This research involved the study of the distribution of purinergic receptors (P2, ATP receptors) in the kidney. We were able to localize the distribution of P2 receptors in archived human kidney specimens fixed in paraffin blocks. We examined the distribution of P2X7 and P2Y2 receptors as they are associated with apoptosis and cell proliferation respectively. We found that these receptors are up regulated in patients with Diabetes Mellitus, IgA nephritis, Chronic Transplant glomerulopathy and Crescentic Glomerulonephritis (Rapidly Progressive Glomerulonephritis). These receptors appeared to co localize and it is possible that in a pathological situation the balance in apoptosis and cell proliferation will result in cell loss or hypercellularity leading to scarring.
P2Y2 receptors were over expressed in the intimal thickening which suggested a potential role vascular remodelling. P2Y2 receptor activation can induce arterial smooth muscle cell migration via the action of osteopontin. Osteopontin is now recognized as a mediator of tubulointerstitial injury in animal renal injury models such as cyclosporine nephrotoxicity, Heyman nephritis and Thy-1 mesangial Proliferative nephropathy and their expression found up regulated in the renal tubules.
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