Scott C. Thomson Research

Control of Renal Function

My time is divided between laboratory research and the daily practice of medicine. My research interest lies in the control of renal function, in particular the basic physiology of crosstalk between the glomerulus and proximal tubule. My approach to solving problems in research or in clinical medicine is an outgrowth of prior education in physics and electrical engineering where I learned a concise logic for causal analysis in systems of interacting parts and conditional probabilities.

Applying engineering principles to micropuncture experiments

In 1986, I began to learn micropuncture. Thereafter, I discovered ways that I could apply rudimentary engineering principles to my own micropuncture data to achieve new understanding. For the past 30 years, this has remained my modus operandi — to perform my own micropuncture experiments and analyze the results using motifs from control theory. This has led to several important findings from our laboratory.

Examples of findings include:

• The original direct proof that the functional component of cyclosporine nephrotoxicity results from pre-glomerular vasoconstriction (J Clin Invest 1989).

• The adaptation of tubuloglomerular feedback to protect its own efficiency (Am J Physiol 1993).

• A counterintuitive realization that feedback control of proximal tubular Angiotensin II actually makes salt homeostasis less efficient (J Clin Invest 2006).

• A mechanism whereby a shift in relative activities of adenosine and nitric oxide signaling in the juxtaglomerular apparatus of chronically diseased kidneys facilitates whole-body NaCl balance but causes nephron function to become unstable on a high NaCl diet (Am J Physiol 2019).

• Error signals in the macula densa salt delivery imply that the proximal tubule is the dominant controller of glomerular filtration in early diabetes (reviewed Am J Physiol 2004, updated Ann Rev Physiol 2012).

• Proof that hypersensitivity of the diabetic proximal tubular to dietary NaCl predicts the paradoxical effect of dietary NaCl on renal hemodynamics in diabetes (J Am Soc Neph 2002), which potentially explains why effect of dietary NaCl on renal outcomes in the Finnish Diabetic Nephropathy study were contrary to prior expectation (Nature Rev Endocrin 2011).

• A model for glomerular-tubular interaction for predicting glomerular hemodynamic effects of SGLT2 inhibitors (Am J Physiol 2012). These effects are being credited for improved hard renal outcomes recently reported for SGLT2 inhibitors from major clinical trials including EMPAREG-Outcomes and CREDENCE.

Goal for the future

My goal for the future is to concentrate on the commonest problems in nephrology where there are knowledge gaps most amenable to causal analysis and where the underlying physiology provides a basis for more focused clinical investigation and rational prescribing.