Dr. Thomas Nolin
Advancing nephropharmacology and precision pharmacotherapy in people with kidney disease through mechanistic pharmacokinetic research, innovative analytical methods, and clinical-translational science.
Projects
Effect of kidney disease and hemodialysis on nonrenal drug clearance
Our team mechanistically examines the effect of kidney disease and/or hemodialysis on pharmacokinetics (PK). Through human studies and physiologically-based PK modeling, we have demonstrated that nonrenal drug clearance mediated by metabolizing enzymes and transporters decreases in chronic kidney disease and acutely improves after hemodialysis.
Implications of using various kidney function estimates on drug selection and dosing
Understanding the implications of using various kidney function estimates on medication selection and dosing is paramount to optimizing pharmacotherapy in people with impaired kidney function.
We have extensively evaluated the impact of using new GFR estimating (eGFR) equations in lieu of creatinine clearance, with and without a race factor included, and have shown that it results in important discrepancies in corresponding drug eligibility and dosing. We are actively working towards harmonization in use of contemporary eGFR equations for medication related decisions across healthcare settings.
Impact of kidney replacement therapies on exposure and response of drugs/poisons
We assess the impact of kidney replacement therapy (KRT) on the systemic exposure and response to drugs and poisons. Our team has provided critical expertise to the development of consensus recommendations surrounding (i) pharmacokinetics and drug dosing in critically ill patients with acute kidney injury receiving KRT, and (ii) use of KRT in the setting of drug intoxications and poisoning. The latter was carried out through the multidisciplinary international Extracorporeal TReatments In Poisoning (EXTRIP) Workgroup.
Role of uremic toxins in kidney disease pathophysiology and outcomes
Ongoing research involves the assessment of uremic toxins in kidney disease pathophysiology and outcomes. Using in vitro and pre-clinical animal models, we have demonstrated acute modifications in the functional expression of nonrenal clearance pathways in the setting of experimental kidney disease and individual uremic toxins, and shown that removal of uremic toxins from plasma with hemodialysis attenuates the acute changes.
Clinically, our work demonstrates that systemic concentrations of the uremic toxin trimethylamine-N-oxide (TMAO) increase in early CKD, become substantially elevated as kidney disease progresses, and correlate with coronary atherosclerosis burden, therefore supporting a role of TMAO in promoting the inflammatory phenotype and accelerated atherosclerosis formation that accompanies CKD progression.
Development of novel quantitative analytical methods
Our team is continually developing novel quantitative analytical methods, which are critical to the success of clinical pharmacology and pharmacokinetics focused research efforts. Our team has extensive training and experience in quantitative drug analysis using high performance liquid chromatography with ultraviolet, fluorescence, and mass spectrometric detection. We have overseen the development, validation, publication and implementation of dozens of analytical methods, including novel ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) methods for measuring multiple analytes simultaneously with exquisite sensitivity.
