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MEDICINE

CONTINUING MEDICAL EDUCATION

Drug Therapy in Patients With


Chronic Renal Failure
by Bertram Hartmann, David Czock, and Frieder Keller

SUMMARY hronic kidney disease (CKD) is divided into five


Background: Roughly 20% of patients in hospital have im-
C stages; thus, the global term compensated renal
insufficiency should no longer be used (Table 1). It is
paired kidney function. This is frequently overlooked be-
important to know whether a patient is suffering from
cause of the creatinine-blind range in which early stages
renal insufficiency (CKD stages 2 through 5) and, if so,
of renal failure are often hidden. Chronic kidney disease is
at what stage, because roughly half of all drugs or their
divided into 5 stages (CKD 1 to 5).
metabolites are excreted by the kidneys, and 30% of all
Methods: Selective literature search. adverse effects of medication have either a renal cause
Results: Methotrexate, enoxaparin and metformin are or a renal effect (1).
examples of drugs that should no longer be prescribed if As estimated in the NHANES study, the prevalence
the glomerular filtration rate (GFR) is 60 mL/min or less. of renal insufficiency with a glomerular filtration rate
With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. (GFR) under 60 mL/min is 11% to 13% (e1). Some
atenolol) or anticonvulsive (e.g. gabapentin) drugs, the ad- 20% of all hospitalized patients have impaired renal
vice is to use alternative preparations such as gliquidone, function. The creatinine-blind range corresponds to a
metoprolol or carbamazepine which are independent of GFR value between 120 and 60 mL/min. In persons
kidney function. Drug dose adjustment should be con- over age 65, a GFR that is lower than it was, but still
sidered with antimicrobial (e.g. ampicillin, cefazolin), above 60 mL/min (CKD stage 1 or 2), may well reflect
antiviral (e.g. aciclovir, oseltamivir) and, most recently, also a decline in renal function as part of normal aging.
for half of all chemotherapeutic and cytotoxic drugs in pa- The Modification of Diet in Renal Disease (MDRD)
tients with impaired kidney function (with e.g. cisplatin, for formula is used, in a reversal of the usual logic, to infer
instance, but not with paclitaxel). an independent variable, the glomerular filtration rate
Conclusion: Decisions concerning drug dose adjustment (GFR), from a dependent variable, the serum creatinine
must be based on the pharmacokinetics but this is an ad- level (SCrea mg/dL). The classic MDRD2 formula has
equate prerequisite only in conjunction with the pharma- had to be modified for recently recalibrated measure-
codynamics. There are two different dose adjustment rules: ments of the creatinine level (e1). According to this for-
proportional dose reduction according to Luzius Dettli, and mula, the GFR (in mL/min per 1.73 m2 of body surface
the half dosage rule according to Calvin Kunin. The latter area [BSA]) depends mainly on the patients age, but
leads to higher trough concentrations but is probably more also on his or her skin color and sex: white and
efficient for anti-infective therapy. male are both assigned coefficients of 1.0, while
black is assigned a coefficient of 1.212 and female
Cite this as: Dtsch Arztebl Int 2010; 107(37): 64756 a coefficient of 0.742.
DOI: 10.3238/arztebl.2010.0647

Universitt Ulm, Medizinische Fakultt, Nephrologie: Dr. med. Hartmann, The MDRD-GFR can also be used to adjust drug
Prof. Dr. med. Keller
Universittsklinikum Heidelberg, Abteilung Klinische Pharmakologie und doses in the setting of renal insufficiency (2), but, when
Pharmakoepidemiologie: PD Dr. med. Czock this is done, the calculation must include an estimate of

Prevalence
The prevalence of renal insufficiency with a
glomerular filtration rate (GFR) below 60 mL/
min was estimated at 11% to 13% in the
NHANES study.

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MEDICINE

TABLE 1 CKD stage 4 and above, magnetic resonance imaging


with gadolinium is no longer a risk-free alternative to
The severity of renal insufficiency and stages of chronic iodinated media. In these stages of CKD, gadolinium
kidney disease (CKD) with additional findings such as
microalbuminuria*1 preparations (linear ones more often than cyclic ones)
can cause a serious condition known as nephrogenic
CKD Stage GFR (mL/min) Renal systemic fibrosis. Thus, if the GFR is under 30 mL/
insufficiency
min, gadolinium should be eliminated from the body
1 12090 none with hemodialysis immediately after the MRI study
2 9060 mild (6).
3 6030 intermediate ACE inhibitors, AT1 blockers, and the renin inhibitor
aliskiren have renally dependent pharmacokinetics, so
4 3015 severe
that it suffices to give these drugs in half the normal
5 150 preterminal, dose to patients with renal insufficiency. In this situ-
requires dialysis
ation, special attention must be paid to the risk of
*1 modified from (e15)
hyperkalemia. To avoid hyperkalemia, spironolactone
should be given only in a low dose (no higher than 25
mg/day), or not at all, to patients with renal insuffi-
ciency; if it is given, then only in combination with a
the patients BSA, for example, with the Mosteller for- thiazide diuretic, furosemide, or both.
mula (3) (www.halls.md/body-surface-area/bsa.htm). As there are some drugs that exert their effects inde-
pendently of renal function, it is often useful to search
for one of these drugs as a clinical alternative (Table 2).
Cefepime should not be given from CKD stage 4 on-
ward, i.e., when the GFR is below 30 mL/min, because
there have been eight reported cases of lethal central
Learning objectives nervous system intoxication occurring after five to
The purpose of this article is to demonstrate that, in seven days of parenteral treatment in dialysis-
renal insufficiency, dependent patients (7). Drugs that should not, in gen-
certain drugs are particularly useful, and eral, be given to patients in CKD stage 3 or higher
in principle, any drug can be given to any patient, (GFR under 60 mL/min) include methotrexate, enoxa-
as long as the dose is adjusted in accordance with parin, metformin, and lithium (Table 3).
the relevant pharmacokinetics and pharmacody- Methotrexate and enoxaparin accumulate in a deep
namics. compartment. After four to eight weeks of use, metho-
trexate can cause long-lasting bone marrow toxicity
Special aspects of pharmacotherapy (8). With enoxaparin (unlike tinzaparin), eight days of
in renal insufficiency treatmenteven if the dose is adjusted to the
If the GFR is below 60 mL/min, i.e., if the patient is in GFRcan lead to hemorrhagic complications, which
CKD stage 3 or higher, certain drugs should no longer become more likely each day that the drug is given (9).
be given, either because they tend to damage the kid- Lithium is excreted through the kidneys and can induce
neys or because they are insufficiently eliminated by toxic effects such as athetosis, renal diabetes insipidus,
poorly functioning kidneys and will therefore accumu- and renal failure (10); therefore, its use in CKD 3 or
late in the body and cause toxic side effects on other or- higher requires expert management (e2). The example
gans (4). Radiological contrast media containing iodine of lithium also reminds us, however, that the discon-
should be given to patients with renal insufficiency tinuation of a drug is always fraught with risk and must
only after prophylactic hydration. In order to prevent always be discussed with the prescribing physician (a
contrast-medium toxicity, the authors additionally give psychiatrist, in this particular case). Once all the risks
1600 mg of MESNA (methoxyethylsulfonate sodium) have been taken into consideration, it may turn out to
in 500 mL of normal saline 0.9% intravenously im- be best to continue giving a nephrotoxic medication
mediately before and during the contrast study (5). In despite a low GFR.

Radiological contrast media Gadolinium


Patients with renal insufficiency should undergo Linear gadolinium preparations can bring about
prophylactic hydration before they are given the clinical picture of nephrogenic systemic
radiological contrast media that contain iodine. fibrosis when given to patients in CKD stage 4
or higher.

648 Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37): 64756
MEDICINE

Metformin is considered to be an insulin sensitizer, TABLE 2


and there is a current trend toward increasing use of this
drug. Although lactic acidosis is a rare complication of Drugs that do and do not depend on renal function (e2)
metformin, and is even rarer when the dose is reduced Class Dependent on renal Independent of renal
(500 mg b.i.d.), it remains highly lethal when it occurs function function
(11). As the patients renal function may be unstable, Analgesics Morphine (M6-glucuro- Fentanyl,
patients whose GFR is under 60 mL/min should be nide), pethidine levomethadone
treated with less dangerous alternative drugs, such as (norpethidine)
the DPP-IV inhibitor sitagliptin (Table 2), whose dose Antiarrhythmic drugs Sotalol Amiodarone
should be halved if the GFR is under 30 mL/min. Half Antibiotics Ciprofloxacin, levofloxacin Moxifloxacin
of therapeutically administered insulin is metabolized in
Antidiabetic drugs Glibenclamide, glimepride Gliquidone, gliclacide
the renal parenchyma (e3); thus, in renal insufficiency, (hydroxy metabolite)
the insulin effect often lasts longer, so that the patient
Nateglinide Pioglitazone
needs less insulin overall. It is a common scenario for a
diabetic patient to be admitted to hospital with hypo- Sitagliptine
glycemia as the result of a worsening of renal function. Anticonvulsants Gabapentin, pregabalin, Carbamazepine,
For patients whose GFR is below 60 mL/min, the lamotrigine, levetiracetam phenytoin, valproate
proper use of analgesics remains an important issue. In Antihypertensive drugs Atenolol Bisoprolol, carvedilol,
the authors view, combined analgesic preparations are metoprolol, propranolol
contraindicated in patients with renal insufficiency, as Cholesterol-lowering drugs Bezafibrate, fenofibrate Simvastatin, niacin
they may cause dependency. The kidneys major en- Drugs for gout and other Methotrexate Colchicine,
emies are now the nonsteroidal anti-inflammatory rheumatological conditions hydroxychloroquine,
drugs (NSAIDs), such as diclofenac, iboprofen, and in- leflunomide
domethacin, and the selective COX-2 inhibitors, which Cardiovascular drugs Digoxin Digitoxin
should only be given with monitoring of the serum
Psychoactive drugs Lithium, mirtazapine Amitriptyline, citalopram
creatinine level. In patients with preexisting renal (metabolites?),
damage, the use of NSAIDs can lead to further, perma- haloperidol, risperidone
nent renal damage (12). The opioid drug pethidine Antiviral drugs Acyclovir Brivudine
should not be given to patients with renal insufficiency,
Cytostatic drugs (20) Actinomycin D, Anastrozole, docetaxel,
because its renal-dependent metabolite, normeperidine, bleomycin, capecitabine, doxorubicin-peg-liposomal,
can cause cerebral convulsions (Table 3). Morphine can carboplatin, cisplatin, erlotinib, fluorouracil,
be given with clinical follow-up at short intervals, but cyclophosphamide, gefitinib, leuprorelin,
doxorubicin, epirubicin, megestrol, paclitaxel,
the necessary dose of morphine is lower in the setting etoposide, gemcitabine tamoxifen, terozol,
of renal insufficiency, and the physician must be aware (dFdU), ifosfamide, vincristine, trastuzumab
that respiratory depression can arise in delayed fashion, irinotecan, melphalan,
methotrexate, oxaliplatin,
after a few days of treatment, because of a gradual ac- topotecan
cumulation of the active metabolite M6-glucuronide.
Fentanyl and levomethadone may be advantageous, as
these drugs have no active metabolites and are indepen-
dent of the GFR. Because renal insufficiency is associated with so-
dium retention (13), diuretic treatment is usually
The treatment of comorbidity in CKD necessary; for this purpose, the best strategy is usually
The treatment of comorbidity in patients with chronic sequential nephron blockade with furosemide and hy-
renal insufficiency becomes an important issue no later drochlorothiazide.
than when CKD stage 4 is reached, with a GDR below The TREAT, CREATE, and CHOIR studies have
30 mL/min. The evidence grade and recommendation shown that, in pre-dialysis patients, high-dose treat-
strength for the various treatment options can be de- ment with drugs that are intended to stimulate erythro-
rived from Cochrane Reviews and published meta- poiesis can lead to strokes or tumor progression without
analyses (Table 4). protecting the kidneys (e4e6). Therefore, the new

The kidneys main enemies are: Opioids


Nonsteroidal anti-inflammatory drugs (NSAIDs) The opioid drug pethidine should not be given to
such as diclofenac, ibuprofen, and indomethacin patients with renal insufficiency, because its
Selective COX-2 inhibitors renal-dependent metabolite, normeperidine, can
cause cerebral convulsions.

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MEDICINE

TABLE 3 recommendation is for a target hemoglobin value of 10


mg/dL (14). Before an erythropoietic hormone is given,
The most important drugs whose use in patients with renal iron should be given first. Iron is poorly taken up by
insufficiency is absolutely or relatively contraindicated or problematic
from a clinical nephrological standpoint*1 patients with renal insufficiency when given orally, be-
cause of the elevated hepcidin level (15); it is thus best
Class Drug Contraindicated or Reason to give iron IV.
to be avoided if
possible when: Large-scale observational studies have revealed that
the additional administration of active vitamin D (e.g.,
Analgesics Pethidine GFR <60 Convulsions
calcitriol) in the predialysis phase is associated with
Antibiotics Cefepime GFR <30 CNS toxicity lower mortality (16). It is important to monitor the cal-
Phase-prophylactic Lithium GFR <60 Nephro- and cium level and the calcium-phosphate product (Ca
psychotropic drugs neurotoxicity PO4). Paricalcitol and cinacalcet should remain in re-
Antidiabetic drugs Glibenclamide, GFR <60 Hypoglycemia serve for the treatment of severe, clinically manifest
gimepiride hyperparathyroidism. Oral neutralization of acidosis
Metformin GFR <60 Lactic acidosis with bicarbonate in the predialysis phase protects the
Diuretics Spironolactone, GFR <30 Hyperkalemia bones, lessens malnutrition, and slows the progressive
eplerenone loss of renal function (17). A stepwise algorithm for the
Immune Methotrexate GFR <60 Myelotoxicity use of phosphate binders has been published (e7): The
suppressants treatment begins with calcium acetate. If this is ineffec-
Radiological Gadolinium GFR <30 Nephrogenic tive or poorly tolerated, sevelamer (or the newly avail-
contrast media systemic fibrosis able sevelamer carbonate) should be given instead as a
LMW-heparin Enoxaparin GFR <60 Risk of hemorrhage powder. The authors use lanthanum and phosphate
binders containing aluminum only for short times, and
*1 after (4) only in otherwise intractable cases.

Pharmakokinetics
Calvin Kunin, in the 1950s, carried out the first sys-
tematic study of the prolongation of drug half-lives in
TABLE 4
the setting of progressively severe renal insufficiency
Evidence levels (from 1 = high to 5 = low) and recommendation strengths (e8). Drugs for which this is true are excreted more
(from A = strong to C = weak) for the treatment of comorbidity in chronic renal
insufficiency*1 slowly than normal and can, therefore, accumulate to
toxic levels if given repeatedly. The dosage of these
Condition Treatment Evidence level References drugs must be adjusted according to the patients de-
and recommendation
strength gree of renal insufficiency. Not only is every patient
different, every drug is different as well. Nonetheless,
Sodium retention Diuretics 3A (13, e17)
there are simple rules of pharmacokinetics and pharma-
Target Hb 10 rather than Epo 1A (14, e4e6, codynamics that apply to every drug and every patient.
1213 g/dL e18)
With the aid of these rules, the dosage of any drug can
Inadequate iron resorption Iron IV 1A (15, e19) be adjusted for any patient.
1a-hydroxylase deficiency Calcitriol 2C (16, e20) Friedrich Hartmut Dost described long ago the prac-
Hyperparathyroidism Paricalcitol 3C (e7, e20) tical advantages of using a drugs half-life (T) rather
than its clearance (e9). The dominant half-life is the
Hyperparathyroidism Cinacalcet 1B (e7, e21)
most important part of the concentration time curve
Neutralization of acidosis Bicarbonate 3B (17, e22) with respect to the drugs exerting its intended, primary
Ca PO4-product Sevelamer 2B (e7, e23) effect (Luzius Dettli). The renally eliminated fraction
Ca PO4-product Lanthanum 3C (e7, e23)
of a drug (fren) is the key to predicting its pharmacoki-
netics in patients with renal insufficiency. For healthy
*1 Some of the Cochrane Reviews and Cochrane Meta-Analyses cited (e18, e20, e22) do not consider the subjects, fren is calculated from the quantity of drug
more recent studies (e4e6, 16, 17) eliminated in the urine (Murine) and the dose after

Problematic drugs whose use in patients with renal Pharmacokinetics


insufficiency is nephrologically contraindicated: The renally eliminated fraction of a drug is a key
Pethidine, cefepime, lithium, gilbenclamide, gimepiride, metformin, to predicting its pharmacokinetics in patients with
spironolactone, eplerenone, methotrexate, gadolinium, enoxaparin. renal insufficiency.

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intravenous administration (D), or else from the half-


FIGURE 1
life of the drug in patients with normal (Tnorm) and
failing (Tfail) renal function.

Luzius Dettli (e10) had the innovative idea of corre-


lating the elimination rate constant, which is inversely
proportional to the half-life (ke = 0.693 / T1/2), linearly
with renal function (Figure 1). To estimate the expected
half-life of a drug based on the patients individual
GFR, we need to know the two extreme values of the
half-life (Tnorm und Tfail), which, in turn, tell us what
fraction of the drug is normally eliminated renally
(fren):
Drug elimination and renal function. According to Luzius Dettli,
the elimination rate constant (ke = 0.693 / T1/2) depends linearly on
the glomerular filtration rate (GFR) (e10). The non-renal elimination
rate constant (kenonren) is calculated as the difference of the normal
and renal elimination rate constants (kenonren = ke keren). The drug
dose (D) is adjusted to renal function proportionally to the elimi-
nation rate constant, and therefore inversely proportionally to the
The renally eliminated fraction can also be derived half-life (e10). D % norm, dose change expressed as a percentage of
from its counterpart, the non-renally eliminated frac- the normal dose
tion Q0 (fren = 1 Q0), and can be obtained online on the
dosing website (www.dosing.de). Like the serum cre-
atinine level, the half-life has a hyperbolic dependence FIGURE 2
on renal function (Figure 2). There is a range of non-
critical values for the half-life when the GFR is above
60 mL/min; this is analogous to the creatinine-blind
range (18).

Dose adjustment
Many drugs must have their doses adjusted to renal
function in patients with CKD stage 3 or higher, i.e.,
GFR lower than 60 mL/min. In the absence of dose ad-
justment, aciclovir and valaciclovir can be neurotoxic,
ganciclovir and valganciclovir myelotoxic, foscavir
nephrotoxic, and cidofovir both myelo- and nephro-
toxic. Dose adjustment has proved to be outstandingly
useful for these vitally indicated drugs. Further drugs
whose doses need to be adjusted are oseltamivir, which
is effective against the H1N1 virus, and intravenous za-
namivir.
Drugs for which dose adjustment is often forgotten Half-life and renal function. The half-life (T1/2) depends in hyper-
bolic fashion on the glomerular filtration rate (GFR). The dependence
include the newer antiepileptic drugs, such as gabapen-
is stronger with a higher renal elimination fraction (fren). There is,
tin (19), pregabalin, lamotrigine, and levetiracetam. For however, a range of non-critical values for the half-life when the
these drugs, half the normal dose or an even smaller GFR is above 60 mL/min; this is analogous to the creatinine-blind
amount will often suffice (Table 2). range (18)

Dose adjustment Cytostatic agents that depend on


For patients in CKD stage 3 or above whose GFR renal function
is below 60 mL/min, the dose of many drugs must When a drug of this type is given to a dialysis patient, its dose must
be adjusted in accordance with renal function. be reduced to 40% to 80% of the standard dose.

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FIGURE 3 the drug must have a rapid onset, then the treatment
should begin with a normal starting dose, so that an ef-
fective drug concentration can be established at once.
With antibiotics, in particular, one should never commit
the capital error of forgetting the starting dose. One al-
ways begins with the normal dose as the starting dose;
only the maintenance dose is adjusted to the patients
renal function, as reflected by the drugs half-life.
The second innovative idea of Luzius Dettli was to
realize (e10) that the necessary dose adjustment could
be calculated proportionally to the changed elimination
rate (and thus inversely proportionally to the half-life)
(Figure 1). Either the dose (D) of a drug must be re-
duced in inverse proportion to the half-life T1/2 (the
Dettli-1 rule), or else the interval (Tau) between doses
must be prolonged proportionally to the half-life T1/2
Dose adjustment in renal insufficiency (e16). The Kunin rule (the Dettli-2 rule). These two rules can also be applied
(e12) with halving of the starting dose leads to higher trough values in combination.
and more frequent peak values than the Dettli-2 rule with the same
dose given at longer intervals (e10). The Dettli-1 rule, with a reduced
dose and a constant interval, results in lower peaks and higher
troughs than normal (e10)

If, for example, the half-life of a drug is five times


longer because of renal insufficiency, its dose should be
More and more commonly, cancer patients with reduced to 20% of the normal dose (1/5 = 0.20). If the
renal insufficiency undergo treatment with cytostatic dose is thus reciprocally lowered and the interval be-
and other chemotherapeutic drugs. It is helpful to dis- tween doses is unchanged, then the area under the curve
tinguish cytostatic agents that depend on, or are inde- will be the same as in the normal case, but with higher
pendent of, renal function (20). Those that depend on trough values (Figure 3), which are what is customarily
renal function must be given to dialysis patients in 40% measured in drug monitoring. This can easily lead
to 80% of the standard dose (21). Those that are inde- physicians unfamiliar with the relevant pharmaco-
pendent of renal function do not require dose adjust- kinetics to draw false conclusions and then reduce the
ment for renal function, but rather for the patients gen- dose of the drug still further, e.g., in the case of van-
eral condition. Unlike the authors of an article on this comycin or gentamicin. In order to achieve effective
topic that was published in 2007 (20), the authors of the levels in patients with renal failure, the trough values of
current article consider gemcitabin to depend on renal vancomycin should lie between 10 and 15 mg/L, and
function because of its active metabolite dFdU those of gentamicin between 2 and 4 mg/L.
(Table 2). The dose of gemcitabin, platinum deriva- Dettlis proportionality rule often implies the admin-
tives, or of cyclophosphamide need not be lowered if istration of absurdly low doses, or much too wide inter-
the patient undergoes hemodialysis on three consecu- vals between doses, in patients with renal failure who
tive days, one to twelve hours after the administration are under treatment in intensive care units. In the case
of either of these dialyzable drugs. For carboplatin and of ampicillin, for example, one would have to reduce
cisplatin, dialysis must begin one to two hours after the the dose of ampicillin from 1000 mg every 8 hours to
infusion in order to be effective. Etoposide and epirubi- 100 mg every 8 hours, or perhaps 1000 mg every 80
cin are not dialyzable. hours. This illustrates the importance of a second dos-
Cumulation kinetics implies that there are separate ing rule, the halving rule of Calvin Kunin (e12), which
considerations for the starting dose and the mainten- generally yields higher doses than Dettlis rule and thus
ance dose, as Augsberger already pointed out with seems to provide severely ill patients with a higher
respect to the digitalis glycosides (e11). If the effect of chance of effective treatment (Figure 3). This rule

Starting dose and maintenance dose The halving rule of Kunin


of antibiotics If the half-life is shorter than the dosing interval,
It should not be forgotten that patients with renal dose adjustment is usually unnecessary.
insufficiency need a higher starting dose! Begin
with the normal dose. The maintenance dose is ad-
justed to renal function depending on its half-life.

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states that the starting dose should be the same as the FIGURE 4 Sigmoid effect-
normal dose (Dstart equals Dnorm), and thereafter half the concentration
starting dose should be given at intervals equal to one curve. The higher
the Hill coefficient
half-life (Tau equals T1/2). The main benefit of this
(H>1.5), the closer
scheme is to achieve effective peak levels. the threshold con-
centration (CE05)
and the ceiling con-
centration (CE95) lie
to the concentration
Kunins halving rule makes it immediately clear that with half-maximal
patients with life-threatening conditions generally do effect (CE50).
not need dose adjustment when the half-life of a drug is
shorter than the dosing interval.
The halving rule results in peak drug levels that are
the same as those in patients with normal renal func-
tion, but markedly higher trough levels; the area under
the curve is greater than with the Dettli rule (Figure 3).
This larger area under the curve can, however, be as-
sociated with more frequent adverse effects. The The examples of furosemide and torasemide show
authors prefer to use the Kunin rule in the intensive that pharmacodynamic parameters can also change in
care unit for pharmacodynamic reasons (4), and we renal insufficiency. The required concentration of these
have published corresponding dosing recommen- drugs to achieve a half-maximal effect becomes higher
dations in tabular form (www.uni-ulm.de/nephrologie). in renal insufficiency (CE50fail > CE50norm): both must
Underdosing of antibiotics, in comparison to overdosing, often be dosed 10 times higher in order to achieve an
can have much worse, indeed potentially fatal effects. adequate diuretic effect.
The importance of pharmacodynamics also becomes The sigmoid Emax model (Figure 4) involves the
clear in the use of loop diuretics such as furosemide and definition of a threshold concentration CE05 (18) at
torasemide. Starting in CKD stage 5, i.e., when the which only 5% of the maximal effect is achieved (E05
GFR is 15 mL/min or less, these drugs must be given in equals 0.05 Emax).
higher rather than lower doses to be effective.

Pharmacodynamics
Dose adjustment is a question not just of pharmaco- Similarly, the so-called ceiling concentration CE95 is
kinetics, but also of pharmacodynamics, i.e., of the ef- that at which 95% of the maximal effect is achieved
fect that one intends to achieve. Pharmacodynamics in- (E95 equals 0.95Emax).
volves a formulation of the relationship between the
concentration of a drug and its effect, most commonly
described in terms of the so-called sigmoid Emax model.
In this mode, the effect is a non-linear function of the For a Hill coefficient of 1.0, the threshold concen-
concentration of the drug at its site of action (C) and of tration is only 1/19 of that which produces a half-maxi-
the concentration that produces a half-maximal effect mal effect, while the ceiling concentration is 19 times
(CE50). The parameter Emax is associated with the maxi- as high as that which produces a half-maximal effect
mal effect, and the Hill coefficient H describes the de- (Figure 4). On the other hand, when the Hill coefficient
gree of sigmoidicity (S-shapedness) of the relation- equals 4.25 (for example), the threshold concentration
ship. When the Hill coefficient H equals 1, the Emax is half that which produces a half-maximal effect, and
model yields the Michaelis-Menten equation. the ceiling concentration is only twice the concen-
tration that produces a half-maximal effect (Figure 4).
The therapeutically effective range of a drug thus
depends on its Hill coefficient: the higher the Hill

Pharmacodynamics Antibiotic effect


The therapeutically effective target range of a Antibiotics whose effect depends on their concen-
drug depends on the Hill coefficient. tration have a low Hill coefficient (H<1.5), while
antibiotics whose effect is time-dependent have a
high Hill coefficient (H>1.5).

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FIGURE 5 physician often does not know the value of CE95 or


CE50 with any precision. Beta-lactams, such as cefazo-
lin, and antiviral drugs, such as valganciclovir, are
examples of antibiotics whose effect is time-dependent
and for which the concentration should not become any
lower than the threshold concentration CE05. These two
classes of antibiotics, distinguished by the concen-
tration- or time-dependency of their effects, differ in
the height of their Hill coefficients (Figure 4): anti-
biotics of the former type have a low Hill coefficient
(H<1.5), while those of the latter type have a high Hill
coefficient (H>1.5) (22).
The starting dose is important for both types of anti-
biotic, those whose effect is concentration-dependent
and those whose effect is time-dependent. After the
starting dose is given, the important consideration for
antibiotics of the former type is the drug concentration
at the beginning of each dosing interval, while that for
the latter type is the drug concentration at the end of
each dosing interval. Thus, for drugs of the former type,
such as ciprofloxacin or levofloxacin, there is less rea-
son to reduce the dose (23); it would seem to be better
to prolong the interval between doses for patients with
renal insufficiency, while keeping the individual dose
the same as usual (Figure 5). Further examples of drugs
of this pharmacodynamic type are cytostatic agents
such as cyclophosphamide, melphalan, and daunoblas-
tin (18). For cytostatic agents with a narrow therapeutic
window, careful consideration of pharmacodynamics is
Dose adjustment for ciprofloxacin, a drug whose effect is concentration-depend- needed, because adverse effects may be correlated with
ent, according to a mechanistic model (23). If renal failure causes a doubling of the the area under the curve and might arise even after the
half-life from four to eight hours, the dose should not be halved (upper graph); rather, the administration of a single dose.
interval between doses should be doubled (lower graph). If half the normal dose is given, it
On the other hand, for antibiotics whose effect de-
will take 168 hours for E. coli to be eliminated (above), but if the interval is doubled, the
pathogen will be eliminated in 96 hours, as it is when renal function is normal (below); pends on time, such as ceftazidime (a beta-lactam) and
log CFU = logarithm of colony-forming units the virustatic agents, it is less important to achieve peak
levels that are well above CE50, but it is absolutely
necessary to ensure that the trough level at the end of
each dosing interval does not drop below CE05, as this
coefficient, the narrower the desired range is, and the might lead to loss of the antimicrobial effect. It follows
more closely it centers on CE50. that a continuous infusion might be a better adminis-
Antibiotics provide a good illustration of the ex- tration strategy for beta-lactams, as has been shown in
planatory power of pharmacodynamics. Antibiotics can the case of oxacillin (24). The same consideration often
be classified into those whose effect depends on con- applies in antiviral HIV therapy: the trough levels must
centration, and those whose effect depends on time not drop below the therapeutically effective concen-
(22). Aminoglycosides such as gentamicin and fluoro- tration, as this will allow the pathogen to replicate,
quinolones such as levofloxacin are examples of anti- leading to the danger that resistance will develop (25).
biotics whose effect is concentration-dependent and for For antibiotics whose effect depends on time, such as
which the ceiling concentration CE95 should be reached cefotaxime or aciclovir, it makes more sense to lower
to make the treatment effectiveeven if the treating the dose rather than prolong the interval between doses,
as is done in the case of ciprofloxacin or daptomycin.

Conclusion
Principle In the field of gerontopharmacology, one often hears
Paul Ehrlichs principle, Go fast, start high, the principle Start low, go slow, which was formu-
lated by Jerry Gurwitz and applies mainly to drugs that
applies in renal pharmacology as well, es-
exert an effect in the central nervous system (e13). On
pecially for antibiotics, but also for oncological the other hand, there is a much older principle that has
cytostatic drugs. been, to some extent, forgotten over the years: Go fast,
start highin the original German, Sofort und hoch
dosieren, as stated by Paul Ehrlich in 1913 with regard

654 Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37): 64756
MEDICINE

to anti-infective therapy (e14). This remains an impor- 19. Onuigbo MA, Nye D, Iloanya PC: Drug-induced encephalopathy secondary
tant principle in nephropharmacology today, particu- to non renal dosing of common medications in two dialysis patients. Adv
Perit Dial 2009; 25: 8991.
larly for antibiotics and antiviral drugs, but also for on- 20. Li YF, Fu S, Hu W et al.: Systemic anticancer therapy in gynecological cancer
cological cytostatic drugs. Go fast, start high applies patients with renal dysfunction. Int J Gynecol Cancer 2007; 17: 73963.
not only in the intensive care unit, but also in general 21. Boesler B, Czock D, Keller F et al.: Clinical course of haemodialysis patients
with malignancies and dose-adjusted chemotherapy. Nephrol Dial Trans-
medical practice. Above all, one must not make the plant 2005; 20: 118791.
mistake of dosing anti-infective or cytostatic drugs too 22. Czock D, Keller F: Mechanism-based pharmacokinetic-pharmacodynamic
low at the start, or of forgetting the starting dose en- modeling of antimicrobial drug effects. J Pharmacokinet Pharmacodyn
2007; 34: 72751.
tirely. This mistake should be avoided in all patients, 23. Czock D, Rasche FM: Dose adjustment of ciprofloxacin in renal failure: re-
including those with renal insufficiency. duce the dose or prolong the administration interval? Eur J Med Res 2005;
10: 1458.
Conflict of interest statement 24. Hughes DW, Frei CR, Maxwell PR et al.: Continuous versus intermittent infu-
Dr. Hartmann and Professor Keller state that they have received payment of sion of oxacillin for treatment of infective endocarditis caused by methicillin-
travel expenses and research support from Wyeth and Novartis. PD Dr. Czock susceptible Staphylococcus aureus. Antimicrob Agents Chemother 2009;
states that he has no conflict of interest as defined by the guidelines of the In- 53: 20149.
ternational Committee of Medical Journal Editors. 25. Czock D, Markert C, Hartman B, Keller F: Pharmacokinetics and pharma-
codynamics of antimicrobial drugs. Expert Opin Drug Metab Toxicol 2009; 5:
Manuscript submitted on 6 April 2010, revised version accepted on 5 July
47587.
2010.
Corresponding author
Prof. Dr. med. Frieder Keller
Translated from the original German by Ethan Taub, M.D. Section Nephrologie
Klinik fr Innere Medizin I
Zentrum fr Innere Medizin
REFERENCES Universittsklinikum Ulm
1. Corsonello A, Pedone C, Corica F, et al.: Concealed renal insufficiency Albert-Einstein-Allee 23
and adverse drug reactions in elderly hospitalized patients. Arch Intern 89081 Ulm, Germany
Med 2005; 165: 7905.
2. Stevens LA, Nolin TD, Richardson MM, et al.: Chronic Kidney Disease
Epidemiology Collaboration. Comparison of drug dosing recommen-
dations based on measured GFR and kidney function estimating
equations. Am J Kidney Dis 2009; 54: 3342.
@ For eReferences please refer to:
www.aerzteblatt-international.de/ref3710
3. Czock D, Bertsche T, Haefeli WE: Drug dose adjustments in patients Case illustration available at:
with renal impairment. Am J Kidney Dis 2009; 54: 9834. www.aerzteblatt-international.de/10m0647
4. Keller F: Nephrotoxische Strungen und nierenabhngige Arzneimittel.
In: Risler T, Khn K (eds.): Facharzt Nephrologie. Mnchen: Urban &
Fischer 2008: 891960.
5. Ludwig U, Riedel MK, Backes M, Imhof A, Muche R, Keller F:
MESNA (Sodium 2-Mercaptoethanesulfonate) for prevention of
contrast medium-induced nephrotoxicity. Clin Nephrol 2010 (in
press).
6. Kielstein JT, Schiffer M: Nephrogenic systemic fibrosis: a rare disease
with grave consequences. Internist 2010; 51: 3944.
7. Sonck J, Laureys G, Verbeelen D: The neurotoxicity and safety of treat-
ment with cefepime in patients with renal failure. Nephrol Dial Trans- FURTHER INFORMATION ON CME
plant 2008; 23: 96670.
8. Karie S, Gandjbakhch F, Janus N, et al.: Kidney disease in RA patients: This article has been certified by the North Rhine Academy for Postgraduate and
prevalence and implication on RA-related drugs management: the MA-
TRIX study. Rheumatology 2008; 47: 3504. Continuing Medical Education.
9. Mah I, Aghassarian M, Drouet L, et al.: Tinzaparin and enoxaparin Deutsches rzteblatt provides certified continuing medical education (CME) in
given at prophylactic dose for eight days in medical elderly patients with
impaired renal function: a comparative pharmacokinetic study. Thromb accordance with the requirements of the Medical Associations of the German
Haemost 2007; 97: 5816. federal states (Lnder). CME points of the Medical Associations can be acquired
10. Bendz H, Schn S, Attman PO, Aurell M: Renal failure occurs in chronic only through the Internet, not by mail or fax, by the use of the German version of
lithium treatment but is uncommon. Kidney Int 2010; 77: 21924. the CME questionnaire within 6 weeks of publication of the article. See the
11. Almirall J, Bricull M, Gonzalez-Clemente JM: Metformin-associated following website: cme.aerzteblatt.de
lactic acidosis in type 2 diabetes mellitus: incidence and presentation in
common clinical practice. Nephrol Dial Transplant 2008; 23: 24368. Participants in the CME program can manage their CME points with their 15-digit
12. Schwarz A, Krause PH, Kunzendorf U, Keller F, Distler A: The outcome of uniform CME number (einheitliche Fortbildungsnummer, EFN). The EFN must
acute interstitial nephritis: risk factors for the transition from acute to
chronic interstitial nephritis. Clin Nephrol 2000; 54: 17990. be entered in the appropriate field in the cme.aerzteblatt.de website under
13. Salem MM: Pathophysiology of hypertension in renal failure. Semin meine Daten (my data), or upon registration. The EFN appears on each
Nephrol. 2002; 22: 1726. participants CME certificate.
14. Singh AK: Does TREAT give the boot to ESAs in the treatment of CKD
anemia? J Am Soc Nephrol 2010; 21: 26. The solutions to the following questions will be published in issue 45/2010.
15. Cui Y, Wu Q, Zhou Y: Iron-refractory iron deficiency anemia: new mol- The CME unit The Post-Mortem External Examination (issue 33/2010) can be
ecular mechanisms. Kidney Int 2009; 76: 113741.
16. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B: Associ-
accessed until 2 October 2010.
ation of oral calcitriol with improved survival in nondialyzed CKD. J Am For issue 41/2010 we plan to offer the topic Dyslexia: Diagnosis, Treatment, and
Soc Nephrol 2008; 19: 16139.
Prevention.
17. De Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM: Bicarbonate
supplementation slows progression of CKD and improves nutritional Solutions to the CME questionnaire in issue 2829/2010:
status. J Am Soc Nephrol 2009; 20: 207584.
Vogel M et al.: The Treatment of Patients With HIV.
18. Aymanns C, Keller F, Maus S, Hartmann B, Czock D: Review on phar-
macokinetics and pharmacodynamics and the aging kidney. Clin J Am 1b, 2b, 3d, 4e, 5c, 6b, 7c, 8a, 9d, 10a
Soc Nephrol. 2010; 5: 314327.

Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37): 64756 655
MEDICINE

Please answer the following questions to participate in our certified Continuing Medical Education
program. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1 Question 6
Chronic renal insufficiency is divided into how many CKD Which of the following variables is linearly related to the GFR?
stages? a) Serum creatinine concentration
a) One b) Elimination rate constant
b) Two c) Half-life
c) Three d) Non-renally eliminated fraction Q0
d) Four e) Threshold concentration CE05
e) Five

Question 7
Question 2 Which of the following anti-infective drugs exerts its effect in time-
According to epidemiological studies, what is the prevalence of dependent fashion?
renal insufficiency with a GFR below 60 mL/min?
a) Gentamicin
a) 510%
b) Cefazolin
b) 1015%
c) Fluoroquinolone
c) 1520%
d) Levofloxacin
d) 2025%
e) Ciprofloxacin
e) 2530%

Question 3 Question 8
With what glomerular filtration rate does it usually become Which of the following drugs must be given at a higher dose than
necessary to adjust drug doses to renal function? normal in the setting of renal insufficiency?
a) GFR <15 mL/min a) Atenolol
b) GFR <30 mL/min b) Enoxaparin
c) GFR <60 mL/min c) Etoposide
d) GFR <90 mL/min d) Furosemide
e) GFR <120 mL/min e) Gabapentin

Question 4
Question 9
Which of the following drugs can cause long-lasting bone mar-
The threshold concentration produces what percentage of the
row toxicity four to six weeks after it is given to a patient with
maximal effect?
renal insufficiency?
a) 5%
a) Methotrexate
b) 20%
b) Hydroxychloroquine
c) 35%
c) Colchicine
d) Leflunomide d) 50%
e) Levomethadone e) 75%

Question 5 Question 10
Which of the following drugs is unsuitable for the treatment of How must the dosage of ciprofloxacin be adjusted in a patient with
comorbidity in patients with renal insufficiency? renal insufficiency if the half-life of the drug is doubled?
a) Captopril a) The dose should be halved.
b) Bicarbonate b) The interval between doses should be doubled.
c) Calcitriol c) The drug concentration should be monitored.
d) Diclofenac d) The dose of the drug should be gradually increased.
e) Phosphate binders e) The duration of therapy should be doubled.

656 Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37): 64756
MEDICINE

CONTINUING MEDICAL EDUCATION

Drug Therapy in Patients With


Chronic Renal Failure
Bertram Hartmann, David Czock, Frieder Keller

eReferences e13. Gurwitz JH: Start low and go slow: dosing of antipsychotic medi-
e1. Levey AS, Stevens LA, Schmid CH, et al.: CKD-EPI (Chronic Kid- cations in elderly patients with dementia. Arch Intern Med 1995;
ney Disease Epidemiology Collaboration): A new equation to esti- 155: 20178.
mate glomerular filtration rate. Ann Intern Med 2009; 150: e14. Ehrlich P: Address in pathology on chemotherapeutics: Scientific
60412. principles, methods, and results. Lancet 1913; 4694: 44551.
e2. Schou M, Kampf D: Lithium and the kidneys. In: Bauer M, Grof P, e15. Uhlig K, Macleod A, Craig J, et al.: Grading evidence and recom-
Mueller-Oerlinghausen B (eds.): Lithium in Neuropsychiatry. The mendations for clinical practice guidelines in nephrology. A posi-
comprehensive guide. London Infarma Healthcare 2006: 2518 tion statement from Kidney Disease: Improving Global Outcomes
(KDIGO). Kidney Int 2006; 70: 205865.
e3. Rabkin R, Ryan MP, Duckworth WC: The renal metabolism of insu-
lin. Diabetologia 1984; 27: 3517. e16. Chennavasin P, Brater DC: Nomograms for drug use in renal
disease. Clin Pharmacokinet. 1981; 6: 193214.
e4. Dreke TB, Locatelli F, Clyne N, et al.: CREATE Investigators: Nor-
malization of hemoglobin level in patients with chronic kidney e17. Segura J, Ruilope LM: Should diuretics always be included as in-
itial antihypertensive management in early-stage CKD? Curr Opin
disease and anemia. N Engl J Med 2006; 355: 207184.
Nephrol Hypertens 2009; 18: 3926.
e5. Singh AK, Szczech L, Tang KL, et al.: CHOIR Investigators: Correc-
e18. Strippoli GF, Navaneethan SD, Craig JC: Haemoglobin and hae-
tion of anemia with epoetin alfa in chronic kidney disease. N Engl matocrit targets for the anaemia of chronic kidney disease.
J Med 2006; 355: 208598. Cochrane Database Syst Rev. 2006; 4: CD003967.
e6. Pfeffer MA, Burdmann EA, Chen CY, et al.: TREAT Investigators: A e19. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O,
trial of darbepoetin alfa in type 2 diabetes and chronic kidney Gafter U: Intravenous versus oral iron supplementation for the
disease. N Engl J Med 2009; 361: 201932. treatment of anemia in CKD: systematic review and meta-
e7. Tonelli M, Pannu N, Manns B: Oral phosphate binders in patients analysis. Am J Kidney Dis 2008; 52: 897906.
with kidney failure. N Engl J Med 2010; 362: 131224. e20. Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli
e8. Kunin CM, Rees SB, Merrill JP, Finland M: Persistence of anti- GF: Vitamin D compounds for people with chronic kidney disease
biotics in blood of patients with acute renal failure. I. Tetracycline not requiring dialysis. Cochrane Database Syst Rev. 2009; 4:
and chlortetracycline. J Clin Invest 1959; 38: 148797. CD008175.
e9. Dost FH: Die Clearance. Klin Wochenschr 1949, 27: 25764. e21. Strippoli GF, Tong A, Palmer SC, Elder G, Craig JC: Calcimimetics
for secondary hyperparathyroidism in chronic kidney disease
e10. Dettli L: Drug dosage in renal disease. Clin Pharmacokinet. 1976; patients. Cochrane Database Syst Rev. 2006; 4: CD006254.
1: 12634.
e22. Roderick P, Willis NS, Blakeley S, Jones C, Tomson C: Correction
e11. Augsberger A: Quantitatives zur Therapie mit Herzglykosiden. of chronic metabolic acidosis for chronic kidney disease patients.
II. Mitteilung. Kumulation und Abklingen der Wirkung. Klin Wo- Cochrane Database Syst Rev. 2007; 1: CD001890.
chenschr 1954; 32: 94551.
e23. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF:
e12. Kunin CM: A guide to use of antibiotics in patients with renal Benefits and harms of phosphate binders in CKD: a systematic
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serum levels. Ann Intern Med 1967; 67: 1518. 61937.

I Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37) | Hartmann et al.: eReferences
MEDICINE

CONTINUING MEDICAL EDUCATION

Drug Therapy in Patients With


Chronic Renal Failure
Bertram Hartmann, David Czock, Frieder Keller

Case Illustration She weighs 59 kg and is 170 cm tall. The systolic blood
A 33-year-old woman is admitted to hospital in prep- pressure is 130 mmHg and the pulse 72/min. The heart,
aration for peritoneal dialysis and implantation of a lungs, abdomen, and limbs are all unremarkable on
Tenckhoff catheter. She suffers from chronic transplant examination. Her current medications are prednisolone,
failure 12 years after renal transplantation. She devel- mycophenolate, and sirolimus.
oped end-stage renal failure at age 19 because of focal The surgeons and anesthetists are ready to implant a
segmental glomerulosclerosis. Tenckhoff catheter, but the patients labial herpes must
10 months ago, she underwent a biopsy of the trans- be treated first with an antiviral drug. She refuses IV
planted kidney, which revealed interstitial fibrosis with drug therapy and is therefore given valacyclovir by
tubular atrophy and calcineurin-inhibitor damage. The mouth. The normal dosage is two 500-mg tablets taken
serum creatinine was 1220 micromoles/L, correspond- three times daily.
ing to a GFR of 5.7 mL/min. There were no other im-
portant laboratory abnormalities. She categorically re- What dose would you have given?
fused hemodialysis, the creation of a dialysis fistula, or The authors gave valganciclovir in a reduced dose, a
the implantation of a Shaldon catheter. single 500-mg tablet taken twice daily. This adjusted
Her general condition is surprisingly good; indeed, dose was still twice as high as the dose recommended
she is asymptomatic except for labial herpes (Figure). in our tables, namely, 500 mg once daily (4). Today, we
would give brivudine instead, in a single daily dose of
125 mg, as this drug is converted outside the kidneys to
its inactive metabolite bromovinyluracil.
Labial herpes resolved completely within 48 hours,
whereupon the patient was transferred to the surgery
ward and operated on under a brief general anesthetic
the next day. Two days after surgery, we were called to
see the patient because she could not speak and could
only sit up with difficulty. We suspected a neurotoxic
Foto: picture-alliance

adverse effect of valaciclovir and reassured the patient


that her condition would improve within 24 hours.
Valaciclovir was stopped and her neurotoxic manifes-
Figure: Herpes labialis tations promptly resolved.

Deutsches rzteblatt International | Dtsch Arztebl Int 2010; 107(37) | Hartmann et al.: Case Illustration I

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