This chapter answers parts from Section B(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the mechanisms of drug clearance and metabolism". Because the kidneys are responsible for the clearance of most drugs and their metabolites, renal clearance has the examiners' attention. This seems to have appeared three times in the history of the exam, with SAQs expecting a detailed level of understanding from the candidates.

The examined topics have included the characteristics of a drug that influence its excretion by the kidneys, factors affecting renal excretion in a broader sense, and "renal adjustment" of drug doses to account for impaired clearance mechanisms. The presence of these topics in the exam has influenced the structure and content of this revision chapter.

The official college textbook of pharmacokinetics (Birkett et al, 2009) has an entire chapter (Ch.7, p.64) dedicated to Clearance of Drugs by the Kidney. This has been the main source of information for this summary. For those unwilling to spend money on this official text, published articles which cover all the important points include Miners et al (2017) and Regårdh (1985) - the latter is the more attractive, because it has aged well and because a free full text version is available.

In summary:

  • 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 reabsored 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).
  • Dose adjustment for renal impairement requires the assessment of the degree of 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 impairement 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

Role of the kidney in drug elimination

In summary:

  • The kidneys excrete a large proportion of clinically relevant drug substances and their metabolites
  • This excretion is a combination of passive glomerular filtration and active tubular secretion
  • Some of the excreted drugs may also undergo reabsorption, which decreases their overall clearance
  • Small molecules may traffic in and out of the tubules directly though the cell membranes
  • A minority of substances are also metabolised by the kidney primarily.

Though already clear and unambiguous, this summary can also be expressed by means of a pointless uninformative diagram:

diagram of renal clearance mechanisms

Functionally, renal clearance of drugs in indistinguishable from renal clearance of anything else undesirable, including excess water. In an even broader sense, everything which can legitimately call itself a living thing has some mechanism for removal of  soluble wastes, ranging from bacterial efflux pumps and the contractile vacuoles of protists to organs possessed by the vertebrates which are more recognisably kidney-like. Mahasen (2016) discusses these in greater depth, throwing around terms like archinephros and mesonephros. The excretory organs of primitive lampreys are probably of little interest to the CICM primary exam candidate, and it would be pointless to expand any further on this topic except to point out that these systems have been in place for much longer than pharmacology, and that we have reinvented them as mechanisms of drug clearance only since we had started funneling drugs into each other.

Glomerular filtration of drugs

This is a fairly straightforward mechanism, whereby the glomerulus dumbly filters blood and the protein-poor ultrafiltrate which is formed by this process is essentially water which contains the same proportion of t. he dissolved drug as the circulating blood. The major determinant of how much drug ends up in the filtrate is the availability of dissolved drug, which is influenced by such things as volume of distribution, protein binding, lipid solubility, polarity of the drug, proportion carried inside red cells, and so forth. On top of that, the volume of filtrate determines the net total of the drug which is made available to the tubules, and this is influenced by all sorts of things like renal blood flow and the health of the glomerulus.  To put it more formally:

equation describing glomerular filtration of drugs

Thus, the clearance of a drug which does not undergo any active excretion or resorption by the tubule is described by this equation alone. If the drug is not protein bound, its fu is 1.0, which means its clearance is directly proportional to glomerular filtration rate. Creatinine and inulin fit this description, which is why renal clearance of creatinine is a commonly used measure of GFR (we all excrete creatinine in our urine, but few of us walk around with a convenient supply of circulating inulin).

Features of drugs which influence their glomerular filtration:

The degree to which a drug will be filtered depends on some physico-chemical features of the drug:

  • Protein binding: as mentioned above, only the free fraction of the drug is filtered, which means that highly protein bound drugs are poorly filtered in the glomerulus
  • Charge:  theoretically the negatively charged glomerular basement membrane should repel negatively charged drugs, but practically this does not seem to play much of a role (
  • Size: molecules less than 30 Angstroms are freely filtered at the glomerulus. According to classical works by Bott and Richards (1941) the molecular weight limit is somewhere around 14 kDa.

Apart from drug properties, glomerular filtration in general is also influenced by such things as renal disease, renal blood flow, age, etc. 

Active renal secretion of drugs

In summary, 

  • There are several active transporter systems, most of which are active in the proximal tubule:
    • Weak acid transporters
    • Weak base transporters
    • Nucleoside transporters
    • P-glycoprotein transporters
  • The specific clinical relevance of this:
    • These transport mechanisms are saturable.
    • When there are multiple suitable substrates for the transporters, they will compete with each other.
    • The rate of clearance by secretion depends on renal blood flow 
    • Molecules which are too large to be filtered in the glomerulus may still be cleared renally by these mechanisms
    • Protein-bound drugs are not cleared this way; only the unbound fraction is available for active secretion.

Notable substrates for active transport include:

  • For weak acid transporters:
    • β-lactam antibiotics
    • Frusemide
    • Hydrochlorothiazide
    • Probenecid
  • For weak base transporters:
    • Procainamide
    • Ranitidine
    • Trimethoprim
    • Ethambutol
  • For nucleoside transporters:
    • Zidovudine
    • Ribavirin
    • Gemcitabine
  • For p-glycoprotein transporters:
    • Digoxin
    • Verapamil
    • Cyclosporin

Nigam et al (2015) offers a thorough overview of active transport systems in the proximal tubule. To go through everything in that article would add to the waste of exam candidate time which is already a serious problem on this website. Interesting matters to note are the mechanisms of transport and their dependence on ATP. Most of these active transport pumps are symporters which use the concentration gradient of sodium and intracellular negative action potential to drive the transport of substrate out of blood and into the tubule. One step of the process in the absorption of the drug out of the peritubular capillaries (for example, using the H+ concentration gradient) and the other step is excretion of the drug via the tubular luminal surface (often exchanging it with something else). All these gradients require ATP to maintain.

Generally speaking, if the renal clearance of a drug is greater than GFR (i.e. it is cleared faster than a marker solute like creatinine) the drug is most likely being cleared by active secretion.

Passive tubular reabsorption of drugs

Some drugs are not reabsorbed by active transport, but they make their way back into the circulation anyway. Birkett (2009) offers an illustrative calculation to explain this phenomenon. In essence, the process of reclaiming water results in the urine becoming massivelly concentrated (from 120ml/min of glomerular filtrate down to 1-2ml/min of urine). If a drug becomes so significantly concentrated in the tubule, it sets up a gradient which favours the diffusion of drug back into the tubular cells, and back out into the blood. With the other variables which determine diffusion (surface area, membrane thickness etc) remaining static, the most important determinant of this passive reabsorption becomes the concentration gradient, which mainly depends on the degree to which the water is reclaimed. Highly concentrated urine will be full of highly concentrated drugs. Additionally, this applies only to the non-ionised drugs (i.e. those which can cross the lipid bilayers easily).

Factors which influence this process are therefore:

  • Drug concentration
  • Urine flow rate
  • Urine pH
  • Drug ionisation (i.e. ionised vs. non-ionised fractions)

The pH of the urine is what determines ionisation. This underpins the concept of urinary alkalinisation to assist in the clearance of drugs which have been taken in an overdose. For weakly acidic drugs, an alkaline urine will promote ionisation and decrease the amount of non-ionised drug available for reabsorption. The drug becomes trapped in the urine and its clearance is increased.

Active tubular reabsorption of drugs

Classically, the kidneys will make some attempt to reclaim those substances from the tubular fluid which the organism perceives as valuable. These substances include organic acids, water-soluble vitamins, ions and various metabolic substrates like glucose and lactate. Therefore, in order to be reabsorbed, a drug molecule has have some chemical resemblance to these substances. If sufficiently similar, it can then hijack the reabsorption mechanisms and return into the circulation. The main area where this happens is the proximal tubule. Most amino acid and metabolite reclamation occurs here, and together with reclaimed solutes some water is also removed from the tubular lumen.

There are few drugs which can fake their way into a proximal tubular transporter; usually by virtue of either looking a lot like an endogenous chemical or (occasionally) by being a naturally available and valuable metabolic substrate. Among the former is α-methyldopa; among the latter are dextrose and ascorbic acid (Bendayan et al, 1996). Because this phenomenon affects so few of the clinically relevant drugs, the discussion of it can be safely left out of a college exam answer.

Metabolism of drugs by the kidneys

The kidney is often unfairly viewed as a mindless filtration device, but in fact it plays a role in the metabolism of many drugs. Brater (2002) has an excellent section which discusses renal drug metabolism. The proximal tubule contains many enzymes (eg. peptidases) which are capable of digestion, i.e. breaking down filtered peptides and proteins into amino acids.

A good example of a substrate for this sort of renal metabolism is imipenem. It is metabolised so well by tubular peptidase that its efficacy in treating urinary tract infectious would be minimal if it were not co-administered with cilastatin, which inhibits the offending enzyme. There are other examples. For instance, renal metabolism accounts for approximately 30% of overall insulin elimination. Superoxide dismutase is a protein small enought to get through the glomerular pores, but little is recovered in the urine because of metabolism in the proximal tubule.   Some things happen in both the kidneys and the liver, but the kidneys do it better, eg. in the case of glycination of benzoic acid. (Lohr et al, 1998)

Dose adjustment in renal impairement

Question 3 from the second paper of 2011 and the identical Question 8 from the first paper of 2010 both asked for an approach to dose adjustment in renal impairement, as a 40% side-quest. This was done rather poorly, which is very surprising. Apparently in 2010 the pass rate was 0%. It is as if nobody could extrapolate their routine practice into a coherent response. Of course, of the trainees who failed that question, all were likely competent in the bedside management of renally excreted drug doses. Judging from the college answer, they were looking for something like this summary:

  • Dose adjustment in renal impairment requires the assessment of the degree of impairment, the alteration of the regular dose and dosing frequency, and the monitoring of plasma drug levels for drugs with a narrow therapeutic index.
  • Adjustment usually required if the drug is more than 50% renally cleared and the renal function is decreased to less than 50% of normal.
  • Assessment of the degree of dysfunction is performed by measuring the creatinine clearance, which is a marker of glomerular filtration rate.
    • Renal clearance of drugs is proportional to creatinine clearance, no matter the mechanism of drug elimination
  • Dose adjustment takes into account creatinine clearance and the fraction of the drug eliminated unchanged.
    • Dose is reduced in proportion to the decrease in creatinine clearance
    • Dose adjustment  = non-renal clearance + (fraction of renal clearance × fraction of residual renal function)
    • The loading dose does not need to be adjusted.
    • Maintenance dosing can be adjusted either by reducing the regular dose, or increasing the dosing interval, or both
  • Monitoring of drug levels becomes essential for drugs with a narrow therapeutic index because predictive equations are incompletely reliable and renal function in the critically ill can fluctuate significantly.

References

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.