by sally campoy, ms, aprn,bc, cnn, and rowland elwell ... · 9/30/2007 · leads the chronic kidney...

60 AJN t September 2005 t Vol. 105, No. 9 http://www.nursingcenter.com

Pharmacology

Sally Campoy is a clinical preceptor at the University of Colorado Health Sciences Center School of Nursing and a nurse practitioner inthe Renal Section, Veterans Affairs Medical Center, Denver, CO, where she serves on the Pharmacy and Therapeutics Committee. Sheleads the Chronic Kidney Disease Special Interest Group for the American Nephrology Nurses’ Association. Rowland Elwell is an assis-tant professor of pharmacy practice at the Albany College of Pharmacy, Albany, NY. Contact author, Sally Campoy: [email protected].

This article is the fourth in a series on chronic kidney disease supported in part by a grant from the National KidneyFoundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI), which is underwritten by educational grants from Amgen,Bayer Diagnostics, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, and Ortho Biotech Products, LP. Sally Burrows-Hudson, MS, RN, CNN ([email protected]), is the series coordinator. Since taking on that role, she has become director ofMedical Affairs at Bone Care International in Middleton, WI.

Author disclosures: Sally Campoy has received honoraria and travel expenses for lectures from Amgen (the manufacturer ofEpogen, a drug mentioned in this article), Ortho Biotech (the manufacturere of Procrit, a drug mentioned in this article), andGenzyme (the manufacturer of Renagel, a drug mentioned in this article). She has also received honoraria and travel expensesfrom Amgen for participation in advisory board meetings. Rowland Elwell has received honoraria and travel expenses fromAmgen and Genzyme for lectures.

& CKDHow chronic kidney disease and its complications alter drug response.

By Sally Campoy, MS, APRN,BC, CNN,and Rowland Elwell, PharmD

OVERVIEW: People with chronic kidney disease often live with many illnesses andcomplex treatment regimens. As the disease progresses, the number of drugs prescribedmay increase substantially; by the time a patient is in stage 5, he may be taking 11 ormore drugs daily. The effects of the disease on pharmacokinetics (drug absorption,metabolism, distribution, and elimination) and pharmacodynamics (a drug’s mecha-nism of action and effects at the target site) further increase the potential for adversedrug reactions and drug toxicity. Nurses’ roles in evaluating patients’ responses todrugs and teaching about the risks involved are discussed.

ohn Luzon, a 56-year-old Filipino American with type 2 diabetes, reports having had frequentepisodes of hypoglycemia—tremor, lightheadedness, weakness, irritability—in the pastmonth. He says that he has made no changes to his diet, level of activity, or treatment regi-men, which includes glyburide (Diaβeta and others) 10 mg twice daily. Mr. Luzon weighs 94kg (207 lbs.) and has a serum creatinine level of 3 mg/dL; with an estimated glomerular fil-tration rate (GFR) of 36 mL/min/1.73 m2, he has stage 3 chronic kidney disease. After review-ing his list of medications, the prescribing physician determines that the hypoglycemia is theresult of renal impairment affecting the metabolism of glyburide.

J

[email protected] AJN t September 2005 t Vol. 105, No. 9 61

CE4Continuing Education

HOURS

Phenytoin (Dilantin) is a highly protein-boundmedication that usually has a low volume of dis-tribution. In chronic kidney disease, organicacids usually excreted in the urine, such as uricacid, lactic acid, and hippuric acid, accumulatein the plasma and compete with phenytoin forbinding sites on albumin molecules. This occur-rence, along with the decreased concentration ofalbumin in plasma that occurs in chronic kidneydisease, leads to a significantly greater amountof phenytoin available for distribution to the tis-sues, creating a greater risk of drug toxicity andadverse reactions.

More than 20 millionpeople in the United States

(11% of the total adult popu-lation) have chronic kidney dis-

ease,1 traditionally described as aprogressive and irreversible loss of

kidney function resulting in theinability to concentrate urine, conserve

electrolytes, and excrete waste. In 2002the Kidney Disease Outcomes Quality

Initiative (K/DOQI) of the National KidneyFoundation (NKF) published the Clinical

Practice Guidelines for Chronic KidneyDisease (www.kidney.org/professionals/kdoqi/

guidelines_ckd). The guidelines provide a pre-cise definition of chronic kidney disease as the

presence of kidney damage, a GFR of less than 60mL/min/1.73 m2, or both. Either of these condi-

tions must be present for at least three months. Theguidelines also offer a method for classifyingpatients into one of five discrete stages of the dis-ease (see Table 1, page 63).2

Patients with chronic kidney disease often haveconcomitant conditions such as hypertension, dia-betes, hyperlipidemia, congestive heart failure, oranemia, among others, requiring numerous pre-scribed medications. By the time patients reachstage 5 chronic kidney disease, they will be takingan average of 11 medications and 14 doses daily.3, 4

But complications arising from diminishing kidneyfunction (such as cardiovascular disease, hyperten-sion, renal osteodystrophy, and nutritional distur-bances) affect drug response. Ill

ustra

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by Je

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ith

FIGURE 1. Altered Protein Bindingof Phenytoin in CKD

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This article outlines the ways in which decliningkidney function affects the efficacy of various drugsand discusses changes that can be made in the drugregimen and in nursing management strategies,according to the stage of chronic kidney disease.(We focus on patients in stages 1 through 4; stage 5presents more complex issues than can be coveredhere.)

CKD AND PHARMACOKINETICSPharmacokinetics is concerned with the ways inwhich a drug is absorbed, distributed, metabolized,and excreted.

Drug absorption refers to the percentage of anadministered dose that reaches the systemic circula-tion (usually characterized as bioavailability [F]).The absorption of IV drugs is complete (F = 100%);other routes (oral, subcutaneous, intramuscular)usually result in incomplete absorption (F less than100%), depending on the drug, the route, and thepatient. Chronic kidney disease involves such fac-tors as altered gastrointestinal transit time, alteredgastric pH, vomiting, diarrhea, and drug–druginteractions that affect absorption. Unfortunately,there is little evidence measuring the precise influ-ence of impaired kidney function on drug absorp-tion.

Distribution refers to the ability of a drug to pen-etrate (distribute itself in) body tissues (described bythe apparent volume of distribution [Vd]). Accordingto The Merck Manual of Diagnosis and Therapy,17th edition, the Vd “is the amount of fluid thatwould be required to contain the drug in the body atthe same concentration as in the blood or plasma. Itcan be used to estimate the dose required to producea given concentration and the concentration expect-ed for a given dose.” In patients with chronic kidneydisease, the Vd of many drugs can be significantlyincreased or decreased by alterations in body com-position or changes in protein binding.

Phenytoin (Dilantin) is an excellent example of adrug with an increased Vd resulting from changesin protein binding related to chronic kidney dis-ease. In patients with normal kidney function,phenytoin has a relatively low Vd (0.64 L/kg)because it’s highly (approximately 90%) bound toalbumin. But in chronic kidney disease organicacids, normally excreted in the urine, accumulateand compete with phenytoin for binding sites onalbumin molecules. Uremia also changes the shapeof albumin molecules (and that of other serum pro-teins), affecting phenytoin attachment. Moreover,patients with chronic kidney disease may havehypoalbuminemia. All of these changes result insignificantly limited binding of phenytoin to albu-min and greater distribution of the drug to othertissues; Frye and Matzke reported that in patients

with end-stage renal disease, Vd increased by up to119% (1.4 L/kg).5 This increases the risk of adversereactions and drug toxicity (see Figure 1, page 61).

Conversely, the Vd of digoxin (Lanoxin and oth-ers) is reduced in people with chronic kidney dis-ease as a result of decreased binding to body tissues,which causes more of the drug to remain in the cir-culation. Digoxin, which is excreted renally, has arelatively high Vd (7.3 L/kg) in healthy people, butit has been shown to decrease by nearly 50% (4 L/kg) in those with end-stage renal disease.5, 6

Therefore, the daily dosage of digoxin should belowered gradually as the disease progresses. Instage 5, every-other-day dosing is often required toavoid digoxin toxicity.

Metabolism. In addition to performing excreto-ry and endocrine functions, the kidneys also pro-duce numerous enzymes involved in drug metabo-lism, including the cytochrome P-450 (CYP)enzymes. Although the liver is the main producer ofthese enzymes, the kidneys may contribute up to18% of total CYP-activated drug metabolism.5, 7 Inaddition, the kidneys have been shown to beinvolved in the glucuronide, glutathione, and sul-fate conjugation reactions that occur during drugmetabolism.

Chronic kidney disease significantly altersinsulin metabolism. In people with diabetes with-out kidney impairment, the kidneys metabolizeabout 30% of an insulin dose. But in patients whohave both diabetes and kidney disease, insulinmetabolism decreases with diminishing kidneyfunction: in stages 3 or 4 chronic kidney disease, aninsulin dosage reduction of 25% may be indicated,and in those in stage 5 it may need to be reduced by50% or more.8 Of course, insulin dosage adjust-ments should be based on patient response andblood glucose monitoring.

Some hepatically metabolized drugs have activemetabolites that are excreted renally. In renalimpairment these metabolites can accumulate andlead to drug toxicity. For example, the pain relieveracetaminophen (Tylenol and others) yields themetabolite N-acetyl-p-benzoquinoneimine; accu-mulation results in hepatotoxicity.5 The antiar-rhythmic procainamide (Procan SR and others)yields N-acetylprocainamide; accumulation cancause cardiac toxicity.5

Excretion. Many drugs are excreted primarily bythe kidneys, and dosing should be considered careful-ly when prescribing to patients with chronic kidneydisease. As kidney function declines, the renal clear-ance of a drug decreases and the half-life of a renallyexcreted drug lengthens. Renally excreted drugs oftengiven to these patients for concomitant conditionsinclude acetazolamide (Diamox and others), amanta-dine (Symmetrel), the aminoglycoside antibiotics,


atenolol (Tenormin), captopril (Capoten), lithium(Lithane and others), and vancomycin (Vancocin,Vancoled). Drugs with a narrow therapeutic index,such as digoxin, warrant particular caution. It hasbeen well established that toxic drug accumulationcan result when drugs such as metformin(Glucophage), the fluoroquinolones, and allopurinol(Aloprim, Zyloprim) are used in patients with dimin-ished kidney function.

It’s important to remember that the combinedeffects of glomerular filtration, renal tubular secre-tion, and tubular reabsorption determine the kid-ney’s ability to excrete drugs. Since tubular func-tion is not clinically measured, clinicians rely onestimates of GFR or creatinine clearance to adjustdrug dosage in patients with chronic kidney dis-ease. Most dosing recommendations are based onarbitrary GFR values; for example, one text makesrecommendations according to whether thepatient’s GFR is greater than 50 mL/min/1.73 m2,between 10 and 50 mL/min/1.73 m2, or less than10 mL/min/1.73 m2.9 Dosage adjustments are gen-erally not recommended until GFR is 50mL/min/1.73 m2 or lower (stages 3 to 5 chronickidney disease). These GFR values were estab-lished before, and therefore do not coincide with,the current K/DOQI CKD staging guidelines.

CKD AND PHARMACODYNAMICSPharmacodynamics is the study of a drug’s mecha-nism of action and effects at the target site—that is,what happens at a molecular level that causes adrug to produce a result. It considers how drugresponse is altered not only by pharmacokineticsbut also by disease.

Few clinical studies have evaluated the pharma-codynamics of drugs in patients with chronic kid-ney disease. But clinicians have observed that

patients with chronic kidney disease may experi-ence adverse effects when given a drug dosage thatis safe and effective for patients with normal kidneyfunction. For example, the antihypertensivenifedipine has been reported to produce a “greaterblood pressure lowering effect” in patients withchronic kidney disease.10 And certain drug classes,such as the aminoglycosides (including amikacin[Amikin], gentamicin [Garamycin and others], andtobramycin [Nebcin]) and the antineoplastics(including carboplatin [Paraplatin] and cisplatin[Platinol]), are known to have nephrotoxic effects.Dosage must be carefully monitored in patientswith kidney disease who receive these drugs.

PHARMACOTHERAPY IN PATIENTS WITH CKD Assessing kidney function vigilantly, and adjustingmedication dosages accordingly, is crucial inpatients with chronic kidney disease. A simple firststep may be a dosage reduction based on an esti-mated GFR. Numerous references have generalrenal dosing guidelines (a useful text is Aronoff andcolleagues’ Drug Prescribing in Renal Failure:Dosing Guidelines for Adults, American College ofPhysicians, 1998), but specific recommendationsfor chronic kidney disease are not necessarily avail-able. It’s important to monitor serum concentra-tions, especially when potentially toxic, renallyeliminated drugs are prescribed. Other strategiesinclude the following.

Use estimated GFR to determine kidney func-tion. The NKF recommends the GFR as the mark-er of kidney function, rather than the serum creati-nine level alone.2 Creatinine, a byproduct of thebreakdown of muscle, is excreted at a fairly con-stant rate. For older adults and others who havelost muscle mass, serum creatinine levels alone canbe misleading. The NKF has recommended two

TABLE 1. The Stages of Chronic Kidney Disease

Stage 1 kidney damage with a normal or elevated glomerular filtration rate (GFR) (a GFR equal to or greater than 90 mL/min/1.73 m2)

Stage 2 kidney damage with a mildly decreased GFR (a GFR 60–89 mL/min/1.73 m2)

Stage 3 a moderately decreased GFR (a GFR 30–59 mL/min/1.73 m2)

Stage 4 a severely decreased GFR (a GFR 15–29 mL/min/1.73 m2)

Stage 5 kidney failure (a GFR less than 15 mL/min/1.73 m2; or dialysis)

National Kidney Foundation. Am J Kidney Dis 2002;39(2 Suppl 1):S216.

Note: In a May 31 press release, the National Kidney Foundation reported that these stages will be reflectedin expanded coding in the next edition of the International Classification of Diseases, Ninth Revision, ClinicalModification, coming in October.


tion, you determine that her creatinine clearance is34 mL/min, suggesting an estimated GFR of 34mL/min/1.73 m2. According to the K/DOQI guide-lines, she has stage 3 chronic kidney disease anddosage adjustments should be considered. Compareher case with that of a 22-year-old black man whoalso weighs 75 kg and has a serum creatinine levelof 1.5 mg/dL. Using the same equation, you findthat his creatinine clearance is 82 mL/min, suggest-ing a GFR of 82 mL/min/1.73 m2. This indicatesthat he has stage 2 chronic kidney disease; dosageadjustments would not be necessary.

When assessing kidney function to determinedrug dosage, the Cockcroft–Gault equation may bethe better option. Although the MDRD equationmay provide a more accurate estimate of the GFR,most clinical studies that have assessed the impactof kidney failure on pharmacokinetics were per-formed prior to the MDRD study and thereforeemployed the Cockcroft–Gault equation; we use itas the basis for estimating the GFR for the remain-der of this discussion.

Know the patient’s relative risk for adversedrug effects. A person in stage 1 or 2 chronic kidneydisease will not require dosage adjustments. But she isat risk for continuing kidney insult from disease pro-gression, adverse drug reactions, or both. And at anystage, concurrent conditions such as diabetes orhypertension and factors such as age over 65, havinga family history of kidney disease, or taking nephro-toxic drugs increase the risk of further kidney dam-age. It’s important to monitor the patient’s fluid vol-ume status (because of the risk of fluid retention orexcessive diuresis), maintain hydration, and watch foradverse effects of medication.

A patient in stage 3 or 4 chronic kidney diseaseis likely to need dosage adjustments. Close moni-toring is essential.

Create a list of drugs to which kidney dysfunc-tion causes altered response by using drug refer-ences and conferring with a pharmacist or renalspecialist. In general, dosage adjustments becomenecessary in stage 3 and later stages and can bemade by lengthening the time between doses, low-ering doses, or both—depending on a drug’s phar-macokinetics, its therapeutic index (ratio of toxicdose to therapeutic dose), and the desired concen-tration-versus-time profile (serum concentration ofa drug over time).

Digoxin, for example, requires a 25% to 75%dosage reduction when the GFR falls below 50 mL/min/1.73 m2.11 The dosages of antiepilepticssuch as gabapentin (Neurontin) and topiramate(Topamax), which are excreted renally, will need tobe tapered as the GFR falls. And allopurinol, an anti-hyperuricemic, can cause interstitial nephritis whengiven at full dosage (300 mg per day). In patients

formulas for quantifying renal function in adults;both have been shown to be valid and reliable. Thefirst, the Cockcroft–Gault equation, estimates creati-nine clearance and can be calculated in a clinical set-ting. Creatinine clearance values have been found toapproximate the GFR closely. The second is a predic-tion equation derived from the Modification of Dietin Renal Disease (MDRD) study, known as theMDRD formula. An estimate of the GFR is madeusing the patient’s serum creatinine level, age, sex,and race. Online calculators for both formulas areavailable for free from the NKF (www.kidney.org/kls/professionals/gfr_calculator.cfm). (For moreon their use, see “Chronic Kidney Disease: AnOverview,” February.)

The following examples illustrate how age andsex can affect the GFR. An 82-year-old black womanwho weighs 75 kg (165 lbs.) has a serum creatininelevel of 1.5 mg/dL. Using the Cockcroft–Gault equa-

Adjusting One Patient’s Regimen

Barry King, a 55-year-old black man, has hyper-tension, hyperlipidemia, and diabetes. Hisdrug regimen includes hydrochlorothiazide

(HCTZ) 25 mg/day by mouth, pravastatin (Pravachol)20 mg/day by mouth, and subcutaneous NPH insulin(Humulin N) 20 units every morning and 10 unitsevery evening. A week ago, his primary care physi-cian added an angiotensin-converting enzyme (ACE)inhibitor, lisinopril (Prinivil) 5 mg/day by mouth, inresponse to elevated blood pressure (178/94 mmHg).At that time, his serum creatinine level was 1.2 mg/dLand his weight was 82 kg (180 lbs.). Using theCockcroft–Gault formula, it’s determined that his GFRis 81 mL/min/1.73 m2, and he is diagnosed withstage 2 chronic kidney disease.

At his follow-up visit a week later, Mr. King complainsof dizziness. During the interview, he reveals that hisurine production decreased during the past week. Hisjob requires him to work long hours outdoors in hotweather, and he is dehydrated. His blood pressure is105/46 mmHg. A serum electrolyte panel reveals ablood urea nitrogen (BUN) level of 61 mg/dL and aserum creatinine level of 3.5 mg/dL. This increase of2.3 mg/dL in the course of one week indicates that he isin acute renal failure. His BUN–serum creatinine ratio is17.4:1 (normal is 10:1), which suggests that this ishemodynamically mediated or prerenal acute renal fail-ure. Further dehydration could result.

A decision is made to hold the ACE inhibitor whileMr. King’s dehydration is treated. Once his fluid volumestatus is corrected, the ACE inhibitor is reintroduced atthe lower dosage of 2.5 mg/day. After his serum creati-nine returns to the baseline level of 1.2 mg/dL, thedosage of the ACE inhibitor is increased to 5 mg/day.


whose GFR is less than 50 mL/min/1.73 m2, this riskcan be minimized by tapering to half dosage.12

Thiazide diuretics are recommended as first-linetreatment for hypertension and are effective instages 1 and 2.13, 14 But as the GFR falls, less of thedrug reaches the nephron, and the diuretic may loseeffectiveness. This is an excellent example of howchronic kidney disease affects pharmacodynamics.When the GFR falls below 30 mL/min/1.73 m2, orif “blood pressure control worsens or if volumeexpansion occurs” as the disease progresses to thelater stages,14 a thiazide diuretic should be replacedby a more potent loop diuretic, such as furosemide(Lasix).15 In the case of diuretic resistance, whichtypically occurs in the advanced stages of chronickidney disease or nephrotic syndrome, a combina-tion of diuretics that work on different parts of thetubule system may help.16

Angiotensin-converting enzyme (ACE) inhibit-ors, angiotensin receptor blockers (ARBs), or bothare recommended as first-line treatment for hyper-tension in people with diabetes or with nondiabet-ic proteinuria.13, 14 Angiotensin II causes systemicvasoconstriction, which increases blood pressureand kidney perfusion; it also causes vasoconstric-tion of the efferent arteriole, increasing intra-glomerular hydrostatic pressure. ACE inhibitors actto inhibit production of angiotensin II; ARBs inhib-it the angiotensin II receptors. Because of theirintraglomerular effects, the rate of proteinuriadeclines, which will slow the progression of chron-ic kidney disease to stage 5. Thus ACE inhibitorsand ARBs are renoprotective.

With both ACE inhibitors and ARBs, serum cre-atinine elevations can occur. A modest increase (nomore than 30%) is acceptable, as long as the crea-tinine level doesn’t continue to rise.17

Inhibition of the renin–angiotensin–aldosteronesystem in patients with diminished renal bloodflow is a common cause of hemodynamicallymediated acute renal failure. Impaired kidney per-fusion activates the renin–angiotensin–aldosteronesystem, resulting in the production of angiotensinII—an important compensatory response todecreased renal circulation, and its inhibition canresult in reductions in intraglomerular hydrostaticpressure and the GFR. Acute renal failure inducedby ACE inhibitors or ARBs usually reverses withintwo to three days of discontinuing the drug. Itoccurs more often in hypotensive patients, thosewith renal artery stenosis, or those with fluid vol-ume depletion or dehydration; in such cases, it’simportant to replace lost fluids. Drug therapy canoften be reinstituted once hemodynamic stability isrestored.18

Other potential adverse effects of ACE inhibitorsinclude hyperkalemia, for which patients with renal

impairment are at higher risk. Symptoms should bereviewed with the patient. Hyperkalemia can becontrolled with diet modifications, diuretics, and insome cases, sodium bicarbonate. If any of thesemeasures fails to reduce serum potassium levels tobelow 5.5 mEq/L, stopping the ACE inhibitor orARB is necessary.17

Atenolol, another antihypertensive, is excretedby the kidneys and tends to accumulate in peoplewith chronic kidney disease.19 One may taper thedose or switch to metoprolol (Lopressor and oth-ers), which is hepatically metabolized.

Make a list of each patient’s prescribed med-ications, and update and review it at each meeting.A patient with chronic kidney disease often seesmany providers, any of whom may adjust the drugregimen, increasing the potential for error. Forexample, a provider who is unaware of the patient’sdisease stage might order a higher-than-neededdosage of a drug.

Good communication among providers is criti-cal, and nurses can do several things to make it pos-sible. For example, a nurse might say: “Based onthis patient’s last serum creatinine reading, his esti-mated GFR is below 50 mL/min/1.73 m2. I noticedthat his current dosage of allopurinol is 300 mgdaily. Usually at this stage of kidney disease, thedosage is reduced by 50%.” The nurse can alsoencourage the patient to speak up about his kidneyfunction when providers are discussing medicationswith him.

In some cases the health care facility or thepatient’s pharmacist may be able to provide a computer-generated list; the nurse or the patientmay also provide it. Simple medication charts thatlist each medication, its purpose, and the dosagecan be formatted to include administration timesaccording to the patient’s usual daily routine.

There are no specific drugs for stages 1 and 2.But diabetes and hypertension are known to causealmost 75% of all cases of chronic kidney disease;most patients in any stage may take one or more

Acute renal failure induced by

angiotensin-converting enzyme

inhibitors or angiotensin receptor

blockers usually reverses within two to

three days of discontinuing the drug.


antidiabetic, antihypertensive, or lipid-loweringagents.20 As kidney disease progresses to stage 3 andbeyond, additional medications may be needed tomanage complications such as anemia, hyperphos-phatemia, renal osteodystrophy, hyperkalemia, ormetabolic acidosis. Treatment of anemia involvesepoetin alfa (Epogen, Procrit) or darbepoetin alfa(Aranesp) injections (given every one to two weeksand adjusted to maintain a hemoglobin levelbetween 11 and 12 mg/dL21, 22) and iron (an oraldosage of 200 mg of elemental iron daily; variousforms are available over the counter, including fer-rous fumarate [100 mg provides 33 mg elementaliron] and ferrous gluconate [100 mg provides 11.6mg elemental iron]). Oral iron has low bioavailabil-ity and adverse gastrointestinal effects. If thepatient is also taking epoetin alfa, a higher IV irondosage might be necessary.

Management of renal osteodystrophy consists ofphosphate binders and vitamin D therapy. Calcium-containing phosphate binders, such as calcium car-bonate and calcium acetate, are first-line treatmentfor hyperphosphatemia, a concomitant condition.Yet at high doses, calcium-containing phosphatebinders can increase the risk of hypercalcemia; insuch cases newer non–calcium-containing binderssuch as sevelamer (Renagel) are used.23 Calcium-containing phosphate binders can cause constipa-tion; a stool softener may offset this effect.Sevelamer has been shown to cause nausea and

loose stools. Vitamin D is added to the regimenwhen there is evidence of vitamin D 25-hydroxydeficiency; vitamin D analogs (calcitriol [Calcijex,Rocaltrol], doxercalciferol [Hectorol]) are addedwhen there is evidence of hyperparathyroidism.23

Vitamin D toxicity can result in albuminuria, cal-culi, impaired renal function, and reversibleazotemia; vitamin D is given at a lower dose inpatients with chronic kidney disease. Monitoring ofcalcium, phosphorous, and parathyroid hormonelevels is required.

During stage 4 chronic kidney disease, metabol-ic acidosis or hyperkalemia may develop. Judicioususe of sodium bicarbonate or sodium polystyrenesulfonate (Kayexalate) may be instituted.24 Carefulmonitoring of electrolytes and fluid volume statusmust be done to assess response to therapy.

Although the use of nephrotoxic agents in this pop-ulation is discouraged, it’s sometimes unavoidable. Forexample, some diagnostic procedures (such as IV pyel-ogram and some computed tomographic scans)require the use of contrast dye, which is nephrotoxicin everyone. In people with chronic kidney disease, itcan hasten the onset of stage 5 and the need for dialy-sis. Several measures have been aimed at reducing thenephrotoxic effects of contrast media—IV salinehydration, N-acetylcysteine, the iso-osmolar contrastagent iodixanol, and hemofiltration—with varyingresults (some were quite costly).25 And in a recentrandomized study, IV hydration using sodium bicar-bonate was more effective than sodium chloride forpreventing contrast nephropathy.26

Aminoglycoside antibiotics are also nephrotoxic.Reducing the frequency of doses, monitoring serumconcentrations closely, and maintaining adequatefluid volume can help. The concomitant use ofother nephrotoxic agents should be avoided and aswitch to a nonnephrotoxic antibiotic made assoon as possible. (See Table 2, at left.)

List all over-the-counter drugs and herbalremedies. Many people erroneously believe that if a drug is available over the counter, it’s safe. But ifa patient with kidney dysfunction does not followusage directions exactly, she may be at higher riskfor complications.

For example, nonsteroidal antiinflammatorydrugs (NSAIDs) are generally safe and effective. Butthey inhibit prostaglandins, which cause vasodila-tion at the afferent arterioles and maintain renal cir-culation; in cases of already-diminished renal bloodflow, the GFR can plummet. Also, NSAIDs cancause interstitial nephritis, reduced sodium excre-tion, and possibly, damage to the renal tubularepithelium.27, 28 These effects can develop slowly andwithout relation to duration of use or dosage,although interstitial nephritis can also occur as anacute, often allergic, response to NSAIDs.

TABLE 2. Potential NephrotoxicEffects of Certain Drugs Acute tubular necrosis

• Aminoglycosides (such as amikacin, gentamicin, tobramycin)

• Radiographic contrast media• Antineoplastics (such as carboplatin, cisplatin)• Amphotericin B

Hemodynamically mediated renal failure

• Angiotensin-converting enzyme inhibitors • Angiotensin II receptor blockers• Nonsteroidal antiinflammatory drugs (NSAIDs)

Glomerular diseases

• NSAIDs• Gold• Hydralazine

Tubulointerstitial diseases

• Methicillin• NSAIDs• Cyclosporine• Lithium


Decongestants such as ephedrine can elevateblood pressure—an especially dangerous effect inpeople with kidney impairment because it can has-ten progression to stage 5. Magnesium- or aluminum-containing antacids or laxatives shouldbe avoided, as well; these minerals can accumulateand cause metabolic complications, such as neuro-muscular depression, dementia, cardiac changes,and respiratory depression.29

Many people don’t consider herbal remedies tobe medications and don’t disclose their use in themedication history30; as a result, providers can’twarn them about potential adverse effects or moni-tor for drug–herb interactions. Nurses should askspecifically about the use of herbal remedies at everymeeting with a patient who has kidney impairment.Myhre’s review of herbal therapy, published in theOctober 2000 issue of Nephrology Nursing Journal,discusses the risks many common remedies pose forpeople with chronic kidney disease.31

For example, according to Myhre, Ginkgo bilobacan enhance the anticoagulant effects of warfarin(Coumadin), increasing the risk of gastrointestinalbleeding. In people with chronic kidney disease, cer-tain herbs that act as diuretics (such as juniper berry,lovage root, asparagus root, and parsley leaf or root)have been “associated with irritation of the renalepithelial tissues” and can further damage an alreadycompromised renal system.31 Buckthorn bark orberry, cascara sagrada bark, rhubarb root, and sennaleaf or pod can cause hematuria and albuminuria;these herbs and others, such as licorice root, can alsocause electrolyte disturbances (including hypo-kalemia) that may affect the kidneys’ ability to main-tain homeostasis, which may be worsened by con-comitant use of a prescribed diuretic.

Products that contain several herbs are of con-cern as well. One or more of the ingredients mayadversely affect the kidneys or interact with a drug.And because herbal remedies are dietary supple-ments, they are not regulated as drugs are; qualityand quantity vary, even among batches of the sameproduct from the same manufacturer.

Nurses can share with patients the data availableon products they’re taking. Excellent resourcesinclude the following:• the NKF’s Use of Herbal Supplements in Chronic

Kidney Disease (www.kidney.org/atoz/atozItem.cfm?id=123; free)

• PDR Health’s Natural Medicines Indexed byCommon Name (www.pdrhealth.com/drug_info/nmdrugprofiles/herbaldrugs/index.shtml; free)

• Natural Medicines Comprehensive Database(www.naturaldatabase.com; subscription is re-quired)Inform patients of their level of kidney func-

tion. For example, you might say, “Your estimated

GFR is 35 mL/min/1.73 m2. This means that youhave moderately reduced kidney function and arein stage 3 chronic kidney disease. We’ll have towatch how you respond to certain drugs.” Explainthat this may involve adjusting drug dosages andmonitoring for adverse effects or toxicity. It’s alsohelpful if you reiterate periodically which drugs andherbs are best avoided. For example, if a patientpresents with new pain, you can ask what analgesiche’s taking and remind him that NSAIDs are notrecommended.

Review all of the patient’s medications andherbal remedies. Ask the patient to bring in allprescribed and over-the-counter drugs and herbalproducts for a review of the purpose, the dosage,the administration schedule, and the possibleadverse effects of each. Patients should receive writ-ten and oral directions on the drug regimen at everyvisit and whenever a new drug is added. Advisepatients to check with a renal specialist beforebeginning any new drugs or remedies.

These patients will probably be taking manydrugs. For example, a patient with hypertensionwill usually need two or more drugs to control it.13

In people who also have chronic kidney disease, thenumber of antihypertensives required is oftengreater.14 A patient who also has diabetes may betaking two to three drugs to control blood glucoseand one to two drugs to manage hyperlipidemia.Ongoing medication review is one way to help thepatient manage a complex medication regimen andpreclude problems with adherence, drug–druginteractions, and drug toxicity.

Memory deficits are more common in stages 4and 5. Having the patient repeat dosing directionsaloud may help to reinforce these instructions.

Promote patient adherence to the regimen.Poor patient–provider communication, frequentdosing, poor understanding of treatment benefits, afear of possible adverse effects of treatment, a lackof motivation, lower socioeconomic status, a lack of

Nurses should ask specifically about

the use of herbal remedies at every

meeting with a patient who has

kidney impairment.


Complication Medication Treatment Considerations,Stages 1–2 CKD

Treatment Considerations,Stages 3–4 CKD

Diabetes Oral hypoglycemics

• No dose adjustments needed.• Biguanides (such as metformin) are

not used when serum creatinine isgreater than 1.5 mg/dL, because ofrisk of lactic acidosis.

• Half-life is prolonged for many oral agents.• Monitor blood glucose and adjust regimen

accordingly.

Insulin • No dose adjustments needed. • Half-life is prolonged; monitor blood glucose and adjust dose as necessary.

Hypertension,heart failure, or both

Diuretics • No dose adjustments needed. • Thiazide diuretics may lose effectiveness;loop diuretics are preferred.

• Avoid potassium-sparing diuretics. If thesemust be used, monitor potassium intakeand serum concentration.

ACE inhibitors,ARBs

• No dose adjustments needed.• Monitor for potential serum creatinine

and potassium elevation.

• Continue use through all CKD stages.

b-blockers • No dose adjustments needed. • Metoprolol and carvedilol do not require dose adjustments in later stages of CKD.

Calcium channel blockers

• No dose adjustments needed. • No dose adjustments needed.

a-blockers • No dose adjustments needed. • No dose adjustments needed.

Clonidine • No dose adjustments needed. • No dose adjustments needed. • Can cause increased thirst, contributing to

volume overload in the later stages of CKD.

Vasodilators • No dose adjustments needed. • May cause edema.

• No dose adjustments needed.

Digoxin • No dose adjustments needed. • Half-life is prolonged; may require lowerdose or extended dose interval.

Dyslipidemia HMG-CoA reductaseinhibitors

• No dose adjustments needed. • Risk of myopathy, especially with combination therapy.

• Dose adjustments may be needed.

Fibrates(Gemfibrozil is the onlyfibrate recommended in CKD stage 5 by the NKF guidelines on dyslipidemia.)

• No dose adjustments needed. • Risk of myopathy, especially with combination therapy.

Nicotinic acid • No dose adjustments needed. • May cause hyperuricemia; not recom-

mended for patients with gout.

• No dose adjustments needed.

Ezetimibe • No dose adjustments needed. • No dose adjustments needed.

TABLE 3. CKD and Drug ResponseTreatment considerations for common complications and their drug therapies.


family or social support, and younger age havebeen associated with poor adherence in patients ondialysis and patients who have received kidneytransplants; these factors probably affect adher-ence in patients in the earlier stages of chronic kid-ney disease.32, 33

Challenges to the patient include learning tolive with and manage the disease and its compli-cations. The nurse plays a central role in provid-ing education and support and making referralsas needed. And a patient who feels the nurse to behis ally is more apt to disclose difficulties withadherence.

Encourage patients to be involved in their careand to understand the purpose and benefits oftreatment. To do so, you should assess his ability tomanage a complex regimen, his reading level, sup-port system, and barriers to care (such as the inabil-ity to pay for treatment). Whenever possible, sim-plify the regimen. You may need to specify whichdays the patient should take each medication; aninstruction might be, “Take this pill every Monday,Wednesday, and Friday” instead of “Take this pillthree times a week.” Use colored dots to markthose days on a calendar, and time dosing accord-ing to the patient’s routine. If the patient needs

Complication Medication Treatment Considerations,Stages 1–2 CKD

Treatment Considerations,Stages 3–4 CKD

Anemia Iron • Oral dosing, if tolerated • May require IV dosing, if patient is con-currently using epoetin alfa.

Folate, vitamin B12

• Give as indicated for underlying deficiency.

• Give as indicated for underlying deficiency.

Epoetin alfa and darbepoetin alfa

• Usually not treated at these stages. • Given as weekly or biweekly injections.

Renal osteodystrophy

Phosphate binders • Usually not treated at these stages. • First-line treatment is usually calcium car-bonate or calcium acetate.

• Non–calcium-containing binders can beused when higher doses are required orin presence of vascular calcification.

Vitamin D • Usually not treated at these stages. • Given for vitamin D deficiency. • Monitor calcium and phosphorous levels.

Vitamin D analogs,such as calcitriol

• Usually not treated at these stages. • Given to treat hyperparathyroidism.• Monitor calcium, phosphorous, and

PTH levels.

Hyperkalemia Sodium polystyrenesulfonate

• Usually not treated at these stages. • Hyperkalemia is more common in stage4 CKD.

• Treatment will cause diarrhea; monitorfluid volume and sodium status.

Metabolic acidosis

Sodium bicarbonate • Usually not treated at these stages. • Metabolic acidosis is more common instage 4 CKD.

• Monitor fluid volume and blood pressurestatus.

Constipation Stool softeners • Use as needed. • Daily or twice daily dosing is often necessary.

Gastroesophagealreflux

H2 blockers or pro-ton pump inhibitors

• Use as needed. • Daily dosing may be necessary as CKD progresses to stages 4 and 5.

Key: ACE = angiotensin-converting enzyme; ARBs = angiotensin II receptor blockers; GI = gastrointestinal; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; PTH = parathyroid hormone; H2 = histamine 2


assistance in managing the regimen, say, “You’vesaid that it’s hard to remember to take so manypills. Do you have someone at home who can helpyou with this?”

Identifying barriers to adherence requires carefulquestioning without a judgmental or punitive tone.For example, you might say, “I notice that your vialof Zocor is half full. According to the prescription,it should be empty. Are you having difficulty withthe medicine?” A patient may stop taking a drugbecause of its adverse effects, cost, or inconven-ience. He may be overwhelmed, in denial, ordepressed about having chronic kidney disease.Some patients may need counseling to help themadjust to living with chronic illness.

One approach involves helping patients under-stand the connection between adherence to andoutcomes of treatment. For instance, you might say,“Your blood pressure is still higher than the goalwe set, 130/80 mmHg. How are you doing with theblood pressure medication?” Develop clear andcongruent goals with the patient when recommend-ing a new medication. For example, a patient whobegins taking a diuretic may need to identify aweight-loss goal, as well as actions to take if shemeets or doesn’t meet that goal. Congratulate thepatient when she succeeds; for example, “Wow,you did a great job getting your hemoglobin A1cbelow seven. Tell me how you did it.” Ac-knowledging the patient’s achievements will helpbuild her confidence so that she can manage a com-plex regimen.

With each new drug that is ordered, review thepossible adverse effects, identify those that are crit-ical, and discuss actions to take if they occur. Forexample, sexual dysfunction is a common effectseen with several antihypertensives. The nurse canask, “One of the side effects of this medicine isimpotence. Have you noticed any changes in yoursexual drive?” Reducing the dosage or changing toa different medication may reduce the severity ofthis effect.

WHAT HAPPENED TO MR. LUZON?Mr. Luzon was taking glyburide, which stimulatesinsulin release from the pancreas, 10 mg twice perday. Glyburide produces a pharmacologicallyactive metabolite that’s excreted renally. Thismetabolite accumulated as a result of Mr. Luzon’sdeclining kidney function, causing hypoglycemia.In addition, his impaired renal function diminishedinsulin metabolism and lowered blood glucose lev-els. To avoid this response, Mr. Luzon’s drug regi-men was modified. Metformin, a commonly pre-scribed oral antidiabetic, was not considered be-cause of the potential complication of lactic acidosis(metformin is excreted renally and contraindicatedwhen the serum creatinine level is greater than 1.5mg/dL in males or 1.4 mg/dL in females). Glipizide(Glucotrol), an antidiabetic that doesn’t depend onthe kidneys for clearance of the active drug ormetabolites, was prescribed. Mr. Luzon’s blood glu-cose level was monitored carefully; the number ofhypoglycemic episodes was substantially reduced. t

REFERENCES

1. Excerpts from the United States Renal Data Systems 2002annual report: atlas of end-stage renal disease in the UnitedStates. Am J Kidney Dis 2003;41(4 Suppl 2):v-ix, S7-254.

2. National Kidney Foundation. K/DOQI clinical practiceguidelines for chronic kidney disease: evaluation, classifica-tion, and stratification. Am J Kidney Dis 2002;39(2 Suppl1):S1-266.

3. Grabe DW, et al. Evaluation of drug-related problems in anoutpatient hemodialysis unit and the impact of a clinicalpharmacist. Clin Nephrol 1997;47(2):117-21.

4. Kaplan B, et al. Chronic hemodialysis patients. Part I: char-acterization and drug-related problems. Ann Pharmacother1994;28(3):316-9.

5. Frye RF, Matze GR. Drug therapy individualization forpatients with renal insufficiency. In: DiPiro JT, et al., editors.Pharmacotherapy: a pathophysiologic approach. 5th ed.New York: McGraw-Hill; 2002. p. 939-52.

6. Malini PL, et al. Digitalis receptors and digoxin sensitivityin renal failure. Clin Exp Pharmacol Physiol 1985;12(2):115-20.

7. Elston AC, et al. Effect of renal failure on drug metabolismby the liver. Br J Anaesth 1993;71(2):282-90.

8. Snyder RW, Berns JS. Use of insulin and oral hypoglycemicmedications in patients with diabetes mellitus and advancedkidney disease. Semin Dial 2004;17(5):365-70.

9. Aronoff G, et al., editors. Drug prescribing in renal failure:dosing guidelines for adults. 4th ed. Philadelphia: AmericanCollege of Physicians; 1999.

10. Kleinbloesem CH, et al. Nifedipine: influence of renal func-tion on pharmacokinetic/hemodynamic relationship. ClinPharmacol Ther 1985;37(5):563-74.

11. Gupta R, et al. The renal patient with coronary artery dis-ease: current concepts and dilemmas. J Am Coll Cardiol2004;44(7):1343-53.

‘Chronic Kidney Disease’ Online

Do you have questions or comments aboutthis article? You can share them with yourcolleagues and the authors by going to

www.NursingCenter.com/AJNchronickidney. Thislink will take you to the “Chronic Kidney Disease”series online and to a forum where you can discussyour ideas, questions, and concerns with others.

Complete the CE test for this article byusing the mail-in form available in thisissue, or visit NursingCenter.com’s “CE Connection” to take the test and find other CE activities and “My CE Planner.”


12. Paller MS. Drug-induced nephropathies. Med Clin NorthAm 1990;74(4):909-17.

13. Chobanian AV, et al. The Seventh Report of the JointNational Committee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure: the JNC 7 report.JAMA 2003;289(19):2560-72.

14. National Kidney Foundation. K/DOQI clinical practiceguidelines on hypertension and antihypertensive agents inchronic kidney disease. Am J Kidney Dis 2004;43(5 Suppl1):S1-290.

15. Suki WN. Use of diuretics in chronic renal failure. KidneyInt Suppl 1997;59:S33-5.

16. Wilcox CS. New insights into diuretic use in patients withchronic renal disease. J Am Soc Nephrol 2002;13(3):798-805.

17. Lesho E, et al. Common errors in internal medicine: treatinghypertension in patients with elevated serum creatinine.Federal Practitioner 2003;20(9):11-5, 31.

18. Schoolwerth AC, et al. Renal considerations in angiotensinconverting enzyme inhibitor therapy: a statement for health-care professionals from the Council on the Kidney inCardiovascular Disease and the Council for High BloodPressure Research of the American Heart Association.Circulation 2001;104(16):1985-91.

19. Wadworth AN, et al. Atenolol: a reappraisal of its pharma-cological properties and therapeutic use in cardiovasculardisorders. Drugs 1991;42(3):468-510.

20. Holcomb SS. Evaluating chronic kidney disease risk. NursePract 2005;30(4):12-25.

21. Barre P, et al. Efficacy of once-weekly epoetin alfa. ClinNephrol 2004;62(6):440-8.

22. Toto RD, et al. Darbepoetin alfa effectively treats anemia inpatients with chronic kidney disease with de novo every-other-week administration. Am J Nephrol 2004;24(4):453-60.

23. National Kidney Foundation. K/DOQI clinical practiceguidelines for bone metabolism and disease in chronic kid-ney disease. Am J Kidney Dis 2003;42(4 Suppl 3):S1-201.

24. Prough DS. Physiologic acid-base and electrolyte changes inacute and chronic renal failure patients. Anesthesiol ClinNorth America 2000;18(4):809-33.

25. Chertow GM. Prevention of radiocontrast nephropathy:back to basics. JAMA 2004;291(19):2376-7.

26. Merten GJ, et al. Prevention of contrast-induced nephropa-thy with sodium bicarbonate: a randomized controlled trial.JAMA 2004;291(19):2328-34.

27. Curhan GC, et al. Lifetime nonnarcotic analgesic use anddecline in renal function in women. Arch Intern Med2004;164(14):1519-24.

28. Kurella M, et al. Analgesia in patients with ESRD: a reviewof available evidence. Am J Kidney Dis 2003;42(2):217-28.

29. Dykeman-Sharpe J. Over-the-counter remedies in chronicrenal insufficiency: risks versus benefits. Cannt J 2003;13(2):17-28.

30. Eisenberg DM, et al. Trends in alternative medicine use inthe United States, 1990-1997: results of a follow-up nation-al survey. JAMA 1998;280(18):1569-75.

31. Myhre MJ. Herbal remedies, nephropathies and renal dis-ease. Nephrology Nursing Journal 2000;27(5):473-80.

32. Horne R, Weinman J. Patients’ beliefs about prescribedmedicines and their role in adherence to treatment in chron-ic physical illness. J Psychosom Res 1999;47(6):555-67.

33. Loghman-Adham M. Medication noncompliance in patientswith chronic disease: issues in dialysis and renal transplanta-tion. Am J Manag Care 2003;9(2):155-71.

GENERAL PURPOSE: To provide registered professionalnurses with current information on how declining kid-ney function affects the efficacy of various drugs andto suggest ways that the drug regimen and nursingstrategies can be altered to manage these effects.LEARNING OBJECTIVES: After reading this article andtaking the test on the next page, you will be able to:• discuss basic aspects of pharmacokinetics and

pharmacodynamics as they apply to the man-agement of patients with chronic kidney disease.

• outline the principles and tools used in manag-ing patients with chronic kidney disease pharma-cologically.

• describe the implications of specific drugs ortypes of drugs for patients with chronic kidneydisease.

To earn continuing education (CE) credit, follow these instructions:

1. After reading this article, darken the appropriate boxes(numbers 1–16) on the answer card between pages 48and 49 (or a photocopy). Each question has only onecorrect answer.2. Complete the registration information (Box A) and helpus evaluate this offering (Box C).*3. Send the card with your registration fee to: ContinuingEducation Department, Lippincott Williams & Wilkins, 333Seventh Avenue, 19th Floor, New York, NY 10001. 4. Your registration fee for this offering is $26. If you taketwo or more tests in any nursing journal published byLippincott Williams & Wilkins and send in your answers toall tests together, you may deduct $0.75 from the price ofeach test.

Within six weeks after Lippincott Williams & Wilkinsreceives your answer card, you’ll be notified of your testresults. A passing score for this test is 12 correct answers(75%). If you pass, Lippincott Williams & Wilkins will sendyou a CE certificate indicating the number of contact hoursyou’ve earned. If you fail, Lippincott Williams & Wilkinsgives you the option of taking the test again at no addi-tional cost. All answer cards for this test on “Pharmacologyand CKD” must be received by September 30, 2007.

This continuing education activity for 4 contact hoursis provided by Lippincott Williams & Wilkins, which isaccredited as a provider of continuing nursing educa-tion (CNE) by the American Nurses CredentialingCenter’s Commission on Accreditation and by theAmerican Association of Critical-Care Nurses (AACN00012278, category A). This activity is also providerapproved by the California Board of RegisteredNursing, provider number CEP11749 for 4 contacthours. Lippincott Williams & Wilkins is also anapproved provider of CNE in Alabama, Florida, andIowa, and holds the following provider numbers: AL#ABNP0114, FL #FBN2454, IA #75. All of its homestudy activities are classified for Texas nursing continu-ing education requirements as Type 1.*In accordance with Iowa Board of Nursing administrativerules governing grievances, a copy of your evaluation of thisCNE offering may be submitted to the Iowa Board of Nursing.

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by sally campoy, ms, aprn,bc, cnn, and rowland elwell ... · 9/30/2007 · leads the chronic kidney...

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