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PubMed2006

3rd College of Physicians' lecture--translational research: From bench to bedside and from bedside to bench; incorporating a clinical research journey in IgA nephritis (1976 to 2006).

Translational research (TR) can be defined as research where a discovery made in the laboratory (bench) can be applied in the diagnosis, treatment or prevention of a disease. Examples of medical discoveries contributing to translational medicine (TM) include the isolation of insulin by Banting (Nobel Laureate, 1923), the discovery of penicillin by Alexander Fleming (Nobel Laureate, 1945) and recently the discovery of the role of bacterium Helicobacter pylori in the causation of gastritis and peptic ulcer by Marshall and Warren (Nobel Laureates, 2005). Clinical research (CR) would be a more appropriate term for the bulk of research work undertaken by doctors. CR embraces both clinical based and laboratory-based research. The terminology "bedside to bench" applies more to CR as opposed to "bench to bedside" in the case of TR. But regardless of who does it, as long as the discovery can be translated to the bedside and results in improvement in patient care it can be considered a contribution to TM. Our work spans a 30-year period, involving laboratory-based research, clinical trials and genomics of IgA nephritis (Nx). This is a series of work to elucidate the pathogensis and therapy of IgANx. Plasma beta-thromboglobulin (BTG) an in-vivo index of platelet aggregation and anti-thrombin III increase due to a constant thrombogenecity resulting from platelet degranulation formed the basis for anti-platelet and low-dose warfarin therapy. A study of the natural history of IgANx revealed 2 courses, a slowly progressive course with end-stage renal failure (ESRF) at 7.7 years and a more rapid course at 3.3 years. Triple therapy (cyclophosphamide, persantin and low-dose warfarin) delayed progression to ESRF by about 8 years and for some patients up to 20 years. Documentation of abnormal suppressor T cell function provided the basis for immune therapy. Four patterns of proteinuria were present in IgANx and it is the quality and not so much the quantity of proteinuria which determined the prognosis. Low molecular weight proteinuria was a bad prognostic marker. A controlled therapeutic trial using ACEI/ATRA showed that therapy decreases proteinuria, improves renal function and converts non-selective to selective proteinuria. Subsequent work confirmed that it was the ATRA, not the ACEI which contributed to improved renal function. Individual anti proteinuria response to ATRA varies depending on ACE gene polymorphism. We found that the II genotype of the ACE gene was renoprotective and patients with this genotype had significantly reduced incidence of ESRF compared to those with the DD genotype. Patients responsive to ATRA therapy can retard progression to ESRF by up to 32 years. Mild renal failure can be reversed with possible regression of glomerulosclerosis because of glomerular remodelling by ATRA.

Disease Progression↗
PubMed1996

The 1995 Ciba-Geigy Award Lecture. Intrinsic regulation of hepatic blood flow.

Intrinsic regulation of hepatic blood flow is mediated only through the hepatic artery because the liver is not able to directly regulate portal vein blood flow. Hepatic metabolic activity does not affect hepatic artery flow. Although the hepatic artery is affected by sympathetic nerves and blood-borne agents, the intrinsic regulation of the hepatic artery can be demonstrated if these factors are controlled. The primary intrinsic regulator of the hepatic artery is the hepatic arterial buffer response, which is the inverse response of the hepatic artery to changes in portal vein flow. The hepatic arterial buffer response is sufficiently powerful that doubling portal vein flow leads to maximal constriction in the hepatic artery, while low portal vein flow can result in maximal dilation. The mechanism of the hepatic arterial buffer response is based on adenosine washout, whereby adenosine is produced at a constant rate, independent of oxygen supply or demand, and secreted into a small fluid compartment that surrounds the hepatic arterial resistance vessels. If portal vein flow decreases, less adenosine is washed away into the portal blood and the accumulated adenosine leads to hepatic arterial dilation. Similarly, hepatic arterial autoregulation operates by the same mechanism, whereby a decrease in arterial pressure leads to a decrease in hepatic arterial flow, thus resulting in less adenosine washout into the hepatic artery blood. The accumulated adenosine leads to hepatic artery dilation. These intrinsic regulatory mechanisms tend to maintain total hepatic blood flow at a constant level, thus stabilizing hepatic clearance of hormones, venous return, and cardiac output.

Buffers↗