DRUGS AND THE KIDNEY

Drugs and renalinsufficiencyCaroline Ashley

AbstractRenal insufficiency induces profound pharmacokinetic and pharmacody-

namic changes. The widespread reporting of estimated glomerular filtra-

tion rate (eGFR) has alerted clinicians to the incidence of renal

insufficiency and the need for drug dose amendment. For drugs with

a high therapeutic index, the eGFR can be used as a guide to dose adjust-

ment. However, for drugs with a low therapeutic index, pending further

experimental data relating drug excretion to the modification of diet in

renal disease (MDRD) determination of eGFR, the Cockcroft and Gault

equation using the patient’s ideal body weight is the most reliable way

to determine dose adjustment.

Keywords determination of renal function; drug dosing; loading dose;

maintenance dose; pharmacodynamics; pharmacokinetics; renal

insufficiency

The widespread reporting of estimated glomerular filtration rates

(eGFR) has brought greater awareness of the prevalence of renal

insufficiency and thereby encouraged medical practitioners to

take account of reduced renal function when prescribing. It is

well recognized that serum creatinine per se is not an accurate

marker of renal function. However, by employing one of several

equations, the principal two being Cockcroft and Gault, and the

modification of diet in renal disease (MDRD),1 the creatinine

clearance (CrCl) or estimated glomerular filtration rate (eGFR)

may be calculated. It is still a matter of debate as to which

equation is more accurate, and which should be used with

respect to drug dosing. However, the general consensus is that

for drugs with a high therapeutic index (the ratio between the

highest tolerated dosage and the lowest effective dosage), MDRD

eGFR is sufficient. However, for those drugs with a low thera-

peutic index, where the dosing regimen needs to be adjusted

more precisely in patients with renal dysfunction, the Cockcroft

and Gault equation using the patient’s ideal body weight is more

accurate.2

Pharmacokinetic changes to consider in renal disease

For drugs that are excreted by the kidneys, reduced clearance

in renal insufficiency will lead to a prolonged half-life and

accumulation of the drug if the dose and/or dosing frequency

are not amended. Reduced GFR will also have pharmacokinetic

effects if a drug has active metabolites that are excreted in the

urine.

Caroline Ashley MSc BPharm MRPharmS is Lead Pharmacist for Renal

Services at the Royal Free Hampstead NHS Trust, London, UK.

Competing interests: none declared.

MEDICINE 39:6

� If a patient requires renal replacement therapy (RRT), the

type of RRT used will determine the rate of elimination of

a drug.

� Renal disease may alter plasma protein binding (e.g.

phenytoin), thereby increasing the fraction of the drug unbound

and hence active.

� Drugs that act on the luminal side of the renal tubule (e.g. loop

and thiazide diuretics, and antibiotics for urinary tract infections)

reach their site of action by glomerular filtration, and higher

doses may be required as GFR falls. In severe renal insufficiency

(eGFR <25 ml/minute), thiazide diuretics are ineffective.

Pharmacodynamic changes in renal disease

� The sensitivity of the brain to the effects of some psychoactive

drugs is increased.

� Tissue sensitivity to the effects of some endogenous

hormones (e.g. insulin, vitamin D analogues and growth

hormone) is reduced.

� Sensitivity to the effects of acetylcholinesterase inhibitors is

increased.

Drug dosing regimens in renal insufficiency

When initiating therapy, the usual approach is to start at the

lower end of the recommended dosage range, monitor the

response and, if the desired therapeutic effect is not achieved,

increase the dosage gradually. If a drug is eliminated by metab-

olism in the liver, in general, standard therapeutic doses may be

used. However, it is important to beware of pharmacologically

active metabolites that are cleared by the kidney, as these may

accumulate and cause toxic effects. A typical example is

morphine, which is metabolized by the liver to its 3- and 6-

glucuronides. These metabolites are opioids in their own right,

with greater potency than the parent drug, and are excreted via

the kidneys.3 Thus, morphine should be used with great caution

in those individuals with severe renal impairment, who are at

greatly increased risk of central nervous system (CNS) and

respiratory depression.

The half-life (t½) of a drug determines the rate at which it will

accumulate in the body during repeated dosing. With any given

drug, it takes approximately four to five half-lives to reach steady

state, when the rate of drug elimination equates to the rate of

drug intake. In patients with decreased renal function, any drug

that is excreted via the kidneys will have an extended half-life,

and take longer to reach steady state. For example, digoxin has

a half-life of approximately 40 hours in someone with normal

renal function, so it will take about 1 week to reach steady state.

In someone with an eGFR of less then 15 ml/minute, the half-life

of digoxin is increased to approximately 100 hours, and it will

take nearly 1 month to reach steady state.

Loading dose

If there is likely to be a delay in reaching steady state, a loading

dose may be required. In most cases, the loading dose is unaf-

fected by renal insufficiency. For example, with teicoplanin, the

loading dose will still be 400 mg every 12 hours for three doses

even if the patient has an eGFR <15 ml/minute. The plasma

concentration of a drug that is excreted by the kidney will take

353 � 2011 Published by Elsevier Ltd.

Teicoplanin 400 mg every 72 hours

Teicoplanin 400 mg every 24 hours

Time (days)

0 2 31

Log

pla

sma

co

nce

ntr

ati

on

Dose constant, dosing interval increased

Figure 1

Teicoplanin 400 mg every 72 hours

Teicoplanin 400 mg every 24 hours

Time (days)

0 2 31

Log

pla

sma

co

nce

ntr

ati

on

Dose reduced, dosing interval unchanged

Figure 2

DRUGS AND THE KIDNEY

longer to decay after a loading dose if GFR is reduced, but would

also take longer than usual to reach steady state with repeated

maintenance doses, so a therapeutic concentration is still ach-

ieved rapidly and maintained. In a few instances, if the volume of

distribution of a drug is decreased, the loading dose may also

need to be reduced. For example, in someone with severe renal

insufficiency, digoxin tends to be displaced from its binding sites

on cardiac muscle, which effectively reduces its volume of

distribution. Hence, the total loading dose is often reduced from

1000e1500 mg down to 750e1000 mg.

Maintenance dose

In order to prevent drug accumulation, or to avoid under-treating

a patient, the general rule for maintenance dosing is to dose once

every half-life. If a drug is excreted via the kidneys, the half-life is

increased in renal insufficiency, so the dosing regimen will need

to be amended to prevent toxicity. There are three main

approaches to dosage alteration:

� increase the dosing interval, while leaving the dose

unchanged

� decrease the dose while leaving the dosing interval

unchanged

� decrease the dose and increase the dosing interval.

Which ploy is used often depends on the desired therapeutic

effect. For instance, with antibiotics, a reasonably high peak

concentration is still required in order to combat the infection, so

the first approach is employed. An example of this is teicoplanin,

where the maintenance dose is reduced from 400 mg daily to 400

mg every 3 days in severe renal insufficiency (Figure 1).4 Low-

molecular-weight heparins are excreted via the kidneys, and

accumulate in severe renal impairment, potentially leading to

haemorrhage. Therefore, treatment doses (e.g. for acute coronary

syndrome) need to be reduced; for example, enoxaparin 1 mg/kg

once daily rather than twice daily, with close monitoring of anti-

factor Xa concentration.5

In contrast, with digoxin, a high peak concentration is not

required, so the second approach will suffice, and a typical dose

of 62.5 mg instead of 250 mg daily will achieve an adequate

plasma concentration4 (Figure 2). With some drugs, it is neces-

sary both to reduce the dose and increase the dosing interval in

MEDICINE 39:6 354

order to avoid toxicity. A prime example is gentamicin, where

a typical dose in someone with an eGFR of less than 15 ml/

minute is 2 mg/kg three times a week, dependent on close

monitoring of plasma concentration.4

Effects of drugs on renal function

Medications cause renal failure by a variety of mechanisms. Non-

steroidal anti-inflammatory drugs (NSAIDs) are renowned for

inducing haemodynamic renal failure by reducing renal prosta-

glandins, and hence renal blood flow and GFR.More recently it has

been shown that the cyclooxygenase-2 (COX2) selective inhibitors

also have this potential.6 Direct renal tubular toxicity has also been

described with the antiviral agents, cidofovir, adefovir, and teno-

fovir, as well as the bisphosphonate pamidronate.7 Additionally,

crystal deposition in the kidney may promote obstructive

nephropathy, for example, during treatment with acyclovir or the

protease inhibitor, indinavir. Finally, an unusual form of renal

failure characterized by swollen, vacuolated proximal tubular cells

can develop from hyperosmolar substances, such as intravenous

immunoglobulin,mannitol and the plasma expander, hydroxyethyl

starch. Risk factors for the development of nephrotoxicity from

high-risk therapies (e.g. aminoglycosides, NSAIDs, angiotensin-

converting enzyme (ACE) inhibitors and radiographic contrast

media) are predictable and include pre-existing renal insufficiency,

concomitant administration of other nephrotoxins, volume deple-

tion, and concomitant hepatic disease or congestive heart failure.8

Metformin is known to cause lactic acidosis, especially in

those with severe renal insufficiency. Traditionally, the limit for

using this drug is a GFR of 30 ml/minute, although some recent

data have suggested this adverse effect may be less common than

previously thought.9 A

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DRUGS AND THE KIDNEY

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FURTHER READING

Aronson JK. Prescribing in renal insufficiency: principles and practice.

In: Jamison RL,Wilkinson R, eds. Nephrology. London: Chapman&Hall,

1997 [Chapter 69].

Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with

renal insufficiency. CMAJ 2002; 166: 473e7.

National Kidney Foundation. K/DOQI clinical practice guidelines for

chronic kidney disease: evaluation, classification, and stratification.

Am J Kidney Dis 2002; 39(2 suppl 1): S1e266.

� 2011 Published by Elsevier Ltd.