Describe the role of the kidney in drug excretion and the factors affecting this (60% marks). Briefly outline how you would alter the dosing of a drug with high renal excretion in a patient with renal impairment (40% marks).
It was expected candidates would expand on the role of the kidney in the excretion of drugs and
metabolites. A statement that referred to the classical features of drugs that undergo renal
excretion (eg polarity, lipid solubility, size and protein binding, drug metabolites) and a definition
of renal clearance was expected and would have provided an excellent introduction to any
answer. It was then expected that candidates would mention, in some detail, the processes of
filtration and secretion (both active and passive and both proximal and distal along the renal
tubules). The question also asked for factors that affect renal drug excretion, for example, a
reduction in GFR or alteration in protein binding. An approach to alterations of dosing would
require some consideration of assessing degree of dysfunction (GFR estimation / calculation)
then an understanding that it would not impact on loading doses but would influence subsequent
dosing of renal cleared drugs. Plasma monitoring provides useful information for some drugs,
particularly those with a narrow therapeutic index.
This question closely resembles Question 8 from the first paper of 2010. The pass rate in 2010 was 0%. This year, it improved to 52%. The rather detailed and extensive college comment to a considerable extent illuminates the thinking of the examiners. On the basis of this, the following suggested answer is offered:
a) Role of the kidney in drug clearance
- The kidneys play the dominant role in clearing water-soluble sunstances, including drugs and their metabolites.
- The magnitude of renal drug clearance is the sum of glomerular filtration and active excretion, minus renal drug reabsorption
- Glomerular filtration (GFR) is influenced by the following factors, in the following ways:
- Molecule size (anything larger than 30 Angstrom is not filtered)
- Molecule charge (negatively charged molecules are repelled)
- Protein binding (only the free fraction is filtered)
- Renal blood flow
- Age and renal disease
- Drug secretion occurs in the proximal tubule and is mediated by active transporters and exchange pumps. It is influenced by the following factors
- Protein binding (only the free fraction is available for uptake from the blood)
- Renal blood flow
- Competition between substrates eligible for the same transporter
- Concentration of the drug (these transporters are saturable)
- Drug reabsorption can be active or passive, and occurs in the distal tubule and collecting duct. Most drugs are reabsorped passively by diffusion.
- Passive diffusion occurs along a the concentration gradient which develops because of the removal of water from the tubular lumen, and is therefore strongly influenced by the urine flow rate.
- It is affected by the fraction of non-ionised drug (only non-ionised drug can be reabsorbed passively), which is in turn influenced by the pH of the urine. Ionised drugs are "trapped" in the urine and are excreted.
- Only drugs which chemically resemble naturally available substrates are reabsorbed by active transport (eg. glucose, vitamins, amino acids).
b) Dose adjustment for renal impairment
- Adjustment of drug dosing requires the assessment of the degree of renal impairment, the alteration of the regular dose and dosing frequency, and the monitoring of plasma drug levels for drugs with a narrow therapeutic index.
- Renal impairement is quantified by measurement or estimation of the creatinine clearance
- Dose is adjusted according to the degree of impairment and the proportion of the drug excreted unchanged in the kidney
- Loading dose does not need to be adjusted; maintenance dose is adjusted by decreasing the regular dose, increasing the dosing interval, or both
- Plasma drug levels are measured for drugs which have a narrow therapeutic index to prevent toxicity, because predictive equations can be unreliable and renal function can fluctuate rapidly in critical illness.
Miners, J. O., et al. "The Role of the Kidney in Drug Elimination: Transport, Metabolism and the Impact of Kidney Disease on Drug Clearance." Clinical Pharmacology & Therapeutics (2017).
Mahasen, Laila M. Aboul. "Evolution of the Kidney." Anatomy Physiol Biochem Int J 1(1) : APBIJ.MS.ID.555554 (2016)
Brater, D. Craig. "Measurement of renal function during drug development." British journal of clinical pharmacology 54.1 (2002): 87-95.
Levy, Gerhard. "Effect of plasma protein binding on renal clearance of drugs." Journal of pharmaceutical sciences 69.4 (1980): 482-483.
Regårdh, Carl G. "Factors contributing to variability in drug pharmacokinetics. IV. Renal excretion." Journal of Clinical Pharmacy and Therapeutics 10.4 (1985): 337-349.
Miner, Jeffrey H. "The glomerular basement membrane." Experimental cell research 318.9 (2012): 973-978.
Elwi, Adam N., et al. "Renal nucleoside transporters: physiological and clinical implications This paper is one of a selection of papers published in this Special Issue, entitled CSBMCB—Membrane Proteins in Health and Disease." Biochemistry and cell biology 84.6 (2006): 844-858.
Nigam, Sanjay K., et al. "Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters." Clinical journal of the American Society of Nephrology 10.11 (2015): 2039-2049.
Bendayan, Reina. "Renal drug transport: a review." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 16.6 (1996): 971-985.
Birnbaum, Jerome, et al. "Carbapenems, a new class of beta-lactam antibiotics: Discovery and development of imipenem/cilastatin." The American journal of medicine 78.6 (1985): 3-21.
Lohr, James W., Gail R. Willsky, and Margaret A. Acara. "Renal drug metabolism." Pharmacological Reviews 50.1 (1998): 107-142.
Bott, Phyllis A., and A. N. Richards. "The passage of protein molecules through the glomerular membranes." Journal of Biological Chemistry 141.1 (1941): 291-310.