Renal


Nephrology: 3. Safe drug prescribing for patients with renal insufficiency (Click)

Nephrology: 3. Safe drug prescribing for patients with renal insufficiency (Click)

Drug Dosing Adjustments in Patients with Chronic Kidney Disease (Click)

Drug-Induced Acute Renal Failure (Click) Guidelines for Drug Dosing Regimens in Chronic Kidney Disease (Click)

National Kidney Foundation (Click)

The more pharmacists learn about drugs that are used frequently among patients, the better prepared they will be to help their patients make informed decisions. Prevention is the treatment of choice for Acute Renal failure (ARF), as well as Drug Induced Renal Failure (DIRF). Identifying patients at high risk is the first step. Patients should be counseled on concomitant medications that might cause ARF and the risk of dehydration. Drug Therapy in Kidney Disease (Click)

A complete list of drugs that can result from toxicity can be seen below and therefore the following drugs would need renal adjustments (<< click here)

 

A -  CefaCefd - CipCla - EryEth - LepLev - OP - StaStr - ZAbacavir
Acamprosate 
Acyclovir
Adefovir
Allopurinol 
Amantidine
Amikacin
Amoxicillin
Amoxicillin/Clav
Ampicillin
Ampicillin Sulb.
Amprenavir
Azithromycin
Aztreonam 
Bactrim
Bivalirudin
Capecitabine 
Caspofungin
Cefaclor
Cefadroxil
CefazolinCefdinir
Cefepime
Cefixime
Cefpodoxime
Cefprozil
Ceftibuten
Cefoperazone
Cefotaxime
Cefotetan
Cefoxitin
Ceftazidime
Ceftizoxime
Ceftriaxone
Cefuroxime
Cephalexin
Cetirizine
Chloramphenicol
Cidofovir 
Cimetidine 
Ciprofloxacin  Clarithromycin
Clindamycin
Cloxacillin
Dapsone
Daptomycin
Delavirdine
Desloratidine
Dicloxacillin
Didanosine
Disopyramide
Dofetilide
Doxycycline
Efavirenz
Emtricitabine
Enoxaparin
Entecavir
Epzicom
Ertapenem 
Eptifibatide 
Erythromycin  Ethambutol
Exenatide
Famciclovir
Famotidine   
Fexofenadine 
Fluconazole
Flucytosine 
Fosfomycin
Gabapentin
Ganciclovir 
Gatifloxacin 
Gentamicin
Imipenem/cilastinInamrinone
Indinavir
Isoniazid 
Itraconazole
Ketorolac 
Lamivudine
Lamivudine/AZT
LepirudinLevetiracetam
Levofloxacin 
Linezolid   
Loracarbef
Loratidine
Memantine
Meperidine
Meropenem
Metformin
Metoclopramide 
Metronidazole
Milrinone
Minocycline 
Moxifloxacin
Nafcillin
Nelfinavir
Nevirapine
Nitrofurantoin
Nitroprusside   
Norfloxacin
OfloxacinPancuronium 
Penicillin G 
Pentamidine
Phenazopyridine
Piperacillin
Piperacillin /Tazo.
Pregabalin 
Primidone
Propoxyphene
Pyrazinamide
Ranitidine
Ribavirin
Rifampin
Rimantadine 
Ritonavir
Rosuvastatin 
Saquinavir
Sildenafil
Sotalol
Spironolactone 
StavudineStreptomycin
Sulfinpyrazone
Synercid
Tadalafil 
Telithromycin
Tenofovir
Terbinafine
Tetracycline 
Ticarcillin Clav.acid
Tirofiban 
Tobramycin
Tramadol 
Trimethoprim
TMP /SMX 
Truvada
Valacyclovir
Valganciclovir 
Vancomycin    
Voriconazole
Zalcitabine
Zidovudine
Zoledronic acidTABLE 1: Effect of renal insufficiency on drug pharmacokinetics

Absorption and bioavailability 9,10: Bioavailability is defined as the percentage of an administered drug dose that reaches the central circulation.

It is limited by firstpass hepatic metabolism and: Gastrointestinal transit time: Diabetic or uremic gastroparesis, or both, can alter rates of absorption of drugs such as short-acting sulfonylureas.

Gastric pH: Medications that alter gastric acidity, such as histamine2 blockers, can reduce the
absorption of drugs such as iron and ketoconazole.

Gastrointestinal tract edema: Edema caused by congestive heart failure, liver cirrhosis or nephrotic syndrome can slow drug absorption (i.e., absorption of furosemide).

Vomiting and diarrhea: Common in renal failure, these reduce the amount of drug absorbed.

Antacids or cholestyramine: Commonly taken by patients with renal failure, these can decrease the absorption of warfarin and digoxin.

Drug distribution6,11,12

Volume of distribution (Vd) is defined as the amount of drug in the body divided by the plasma concentration. Vd can be altered by:

Lipid v. water solubility: Edema or ascites may increase Vd for protein-bound or water-soluble drugs such
as vancomycin (possibly requiring a larger loading dose to achieve therapeutic drug concentrations).

Plasma protein drug binding: Uremic states can alter plasma protein binding, affecting acidic drugs like
phenytoin, valproic acid and ASA. Hypoalbuminemia and altered plasma protein binding can result in an increase in free or unbound concentrations of drugs such as phenytoin. Because assays for phenytoin measure total plasma concentrations and not the free fraction, patients with renal impairment who are taking this drug may have adequate seizure control at subtherapeutic concentrations, or conversely may show signs of toxicity at phenytoin concentrations within the usual therapeutic range.

Tissue protein drug binding: Tissue protein binding is reduced in uremic states, which can decrease the Vd for drugs like digoxin.

Metabolism 6,11: Metabolism can be affected by:
Hepatic biotransformations: These can be increased, decreased or unchanged by renal insufficiency, and
doses of metabolized drugs such as propranolol and dihydrocodeine should be adjusted accordingly.

Excretion6,11: Excretion is the most important pharmacokinetic factor altered in renal insufficiency by: Glomerular filtration, tubular secretion,reabsorption: Net renal excretion of a drug is a composite of these 3 factors. Generally it is assumed that all 3 decline in a parallel manner. Creatinine clearance is, therefore, the guiding factor for drug dosage.

 

TABLE 2: Cockcroft–Gault formula for creatinine clearance (CrCl)13

For Men: CrCl (mL/min) = (140 – age [yr]) x weight (kg)
SCr (μmol/L) x 0.81

For Women: CrCl (mL/min) = 0.85 x CrCl (men)

This formula is for adults with stable renal function and takes into account increased creatinine production with increasing weight and decreased creatinine production with increasing age. It will overestimate the true glomerular filtration rate (GFR), but it is important to appreciate that in most clinical settings exact knowledge of the true GFR is not required. Creatinine clearance formulas for pediatric care and for individuals with unstable renal function can be found in Lam and colleagues.3 There are many variations of the Cockcroft–Gault
formula. The one presented here is simply the one we use.

Ranges of normal and decreased creatinine clearance (SI units):
Normal renal function
Men                                                        95–145 mL/min (1.58–2.42 mL/s)
Women                                                 75–115 mL/min (1.25–1.92 mL/s)
Mild renal insufficiency*                   50–70 mL/min (0.83–1.17 mL/s)
Moderate renal insufficiency*         25–50 mL/min (0.42–0.83 mL/s)
Severe renal insufficiency*             < 25 mL/min (< 0.42 mL/s)
Note: SCr = serum creatinine.

*Please note that there is considerable controversy regarding what constitutes mild, moderate and severe renal insufficiency. It is also important to note that creatinine clearance declines by 1 mL/min per year (0.02 mL/s per year) after the age of 40 years. Therefore, these guidelines are for women and men aged < 65 years.

 

TABLE 3: Stepwise guide to adjusting drug dosages for patients with renal insufficiency

Safe drug prescribing for patients with renal insufficiency can be complex, but with the application of a stepwise approach the difficulties can be minimized. When in doubt, appropriate information for dosing guidelines should be sought in recently published monographs or texts.

Step 1 Take history including  notes of physical examination from MD

Record current medications, including over-the-counter drugs, recreational drugs, alcohol use. Drug allergies and sensitivities should be noted. Physical examination should include the following: height, weight, extracellular volume status (jugular venous pulse, blood pressure and heart rate with orthostatic changes, edema, ascites, lung crackles) and look for signs of chronic liver disease.

Step 2 Determine the degree of renal insufficiency

Measure serum creatinine. Order 24-hour urine collection or calculate creatinine clearance.

Step 3 Review the medication list

Ensure that all drugs are still required and that new medications have specific indications. Evaluate for potential drug interactions.

Step 4 Choose less nephrotoxic drugs

If the use of nephrotoxic drugs cannot be avoided without patient morbidity or mortality,then therapeutic drug monitoring or monitoring of renal function is mandatory.

Step 5 Select loading doses These are usually the same for patients with both normal and abnormal renal function.

Step 6 Select a maintenance regimen

Either reduce the dose of the drug and maintain the usual dosing interval or maintain the drug dose and extend the interval. Recommendations for adjusting regimens can be obtained in the Compendium of Pharmaceuticals and Specialties (CPS)14 product monographs. Remember to titrate the dose of the drug to patient effect, if applicable. For example, antihypertensives are dosed based upon blood pressure control, whereas antimicrobials are not adjusted according to response.

Step 7 Monitor drug levels  Monitor drug levels if monitoring is available to guide further therapy.

Step 8 Reassess the patient to evaluate drug effectiveness and the need for ongoing therapy. If
nephrotoxic drugs are used, remember to check the patient's serum creatinine and creatinine clearance again

 

TABLE 4: Dose modification for patients with renal insufficiency

Key points
• Identify those patients at risk for renal insufficiency
• Measure serum creatinine and either calculate or measure creatinine clearance
• Consider whether the patient’s medications should be altered because of the patient’s renal insufficiency
• Adjust drug doses if required
• Use the least nephrotoxic drug possible
• Monitor drug levels and renal function
• Keep up-to-date medication lists and be aware of complementary medicines


Drugs requiring dose modification                                                                                            Drugs not requiring dose modification.

All antibiotics                                                                                                                        EXCEPT Cloxacillin, clindamycin, metronidazole, macrolides

Antihypertensives Atenolol, nadolol, angiotensin-converting-enzyme inhibitors               Antihypertensives Calcium channel blockers, minoxidil, angiotensin 
                                                                                                                                                  receptor blockers, clonidine, α-blockers such as prazosin

Other cardiac medications Digoxin, sotalol                                                                       Other cardiac medications Amiodarone, nitrates

Diuretics AVOID potassium-sparing diuretics in patients with creatinine                               Narcotics Fentanyl, hydromorphone, morphine (may require 
clearance < 30 mL/min (< 0.5 mL/s)                                                                                         dose  if modificationgiven in a palliative care setting)                                                                    

Lipid-lowering agents HMG–CoA reductase inhibitors, benafibrate, clofibrate,                 Psychotropics Tricyclic antidepressants, nefazodone, other 
fenofibrate                                                                                                                                selective serotonin reuptake inhibitors

Narcotics Codeine, meperidine                                                                                               Hypoglycemia medications Repaglinide, rosiglitazone

Psychotropics Lithium, chloral hydrate, gabapentin, trazodone, paroxetine, primidone,    Miscellaneous Proton pump inhibitors 
topiramate, vigabatrin

Hypoglycemia medications Acarbose, chlorpropamide, glyburide, gliclazide, 
metformin,insulin

Miscellaneous Allopurinol, colchicine, histamine2 receptor antagonists,diclofenac, 
ketorolac, terbutaline

 

Table 5: Special considerations for drug use by patients with renal insufficiency

Meperidine: Metabolite normeperidine is neurotoxic and may cause seizures

NSAIDS: Decrease diuretic response and increase propensity to hyperkalemia if taken with potassium-sparing diuretics and angiotensin-converting-enzyme inhibitors

Chlorpropamide: Has increased half-life when taken by patients with renal insufficiency and prolongs hypoglycemia

Metformin: Should not be used if creatinine clearance < 50 mL/min (< 0.83 mL/s) because it can cause life-threatening lactic acidosis

Insulin: There is decreased renal clearance of exogenously administered insulin and, therefore, potential for increased hypoglycemic reactions as creatinine clearance declines.

Aminoglycosides and Vancomycin: Dosage adjustment is required, because these drugs will rapidly accumulate in renal insufficiency and are potentially nephrotoxic. Therapeutic drug monitoring is recommended.

Cimetidine, Triamterene, Trimethoprim: Inhibit tubular secretion of creatinine and therefore cause a rise in serum creatinine, which is reversible when these drugs are discontinued17

 

TABLE 6: Herbal products that may cause renal problems

Aristolochic acid Contained in Virginian and Texas snakeroot or in Chinese herbs like Stephania
tetranda and Magnolia officinalis. It causes rapidly progressive fibrosing interstitial nephritis and renal failure. It is also linked to urothelial malignancy.

Barberry Possibly causes interstitial nephritis

Buchu Causes renal irritation

Chinese herbal drugs Contain a variety of herbs, and often aristolochic acid

Juniper Causes renal fibrosis

Licorice Is associated with sodium and water retention, hypokalemia and hypertension Noni juice Also known as the Och plant (India), Nono (Tahiti), Nonu (Samoa), Nhau (Southeast Asia) and Chinese fruit (Australia), it is associated with hyperkalemia.

Drug-Induced Acute Renal FailureHannah R. Howell, PharmD 
Assistant Professor of Pharmacy Practice, LECOM School of Pharmacy, 
Eerie, Pennsylvania 

M. L. Brundige, BS, PharmD 
Clinical Pharmacy Specialist, 
Hamot Medical Center, 
Eerie, Pennsylvania 

Lindsay Langworthy, PharmD candidate 
LECOM School of Pharmacy, 
Eerie, Pennsylvania 

3/21/2007

US Pharm. 2007;32(3):45-50. 

Acute renal failure (ARF) is defined as a rapid loss of renal function due to damage to the kidneys. This results in electrolyte and acid-base abnormalities and retention of nitrogenous waste products, such as urea and creatinine. 

Patients with ARF are often asymptomatic and are diagnosed by observed elevations in blood urea nitrogen (BUN) and serum creatinine (SCr) levels. Common symptoms of ARF include anorexia, fatigue, mental status changes, nausea, vomiting, and pruritus. Seizures can occur if BUN levels are extremely high, and shortness of breath can result if volume overload is present.1However, alterations in urine volume may be the only symptom that patients notice. 

Populations most at risk include the elderly and those with underlying renal insufficiency. Conditions that compromise renal blood flow or alter effective circulatory volume--such as bilateral renal artery stenosis, cirrhosis, nephrotic syndrome, or congestive heart failure--are considered risk factors for ARF. 

Incidence and Reporting of ARF 
The incidence of ARF, although relatively common, is difficult to define, and the incidence of drug-induced renal failure (DIRF) is even more difficult to ascertain. Current information suggests that ARF accounts for 1% of hospital admissions, implicating occurrence in the outpatient setting, and occurs in 2% to 5% of in-hospital patients. For hospitalized patients in the intensive care unit (ICU), the occurrence rate is 1% to 25%, with a 15% occurrence for patients undergoing cardiopulmonary bypass.1-4Worldwide, the reported incidence of ARF in critical illness is 1% to 25%, with 3.4% to 4.9% of patients requiring renal replacement therapy (RRT).3 DIRF occurs in 18% to 27% of hospitalized patients with ARF, and 20% of hospital admissions for ARF are reportedly caused by drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs).5 

There are several explanations for the lack of an accurate incidence of ARF in the population. First, there is no universally accepted clinical definition for ARF. Historically, most definitions have relied on an increase in the concentration of SCr (e.g., >0.5 mg/dL or 25%). A recent review of the epidemiology of ARF revealed that approximately 35 definitions exist in the medical literature.3 With such a variety of definitions, the range may widen for those definitions using modest increases in SCr or narrow for those studies that use tighter criteria to define ARF, such as the need for RRT. 

The Acute Dialysis Quality Initiative (ADQI), a group composed of nephrologists and intensivists with expertise in renal disease, recently proposed the RIFLE criteria for acute renal dysfunction. The RIFLE criteria evaluate severity and outcome of ARF. The severity classes (Risk, Injury, and F ailure) are based on the degree of change in urine output or SCr, and the outcome classes (Loss and End-Stage Kidney Disease) are based on the duration of kidney function loss.6 

Several recent studies have begun using the RIFLE criteria. One major limitation they have encountered is that urine output cannot be accurately assessed without a urinary catheter, and use of diuretics, which increase urine output, decreases the validity of this measurement. Despite these limitations, the RIFLE criteria will provide a more accurate determination of the incidence not only of ARF but of DIRF as well.6 

Determining the incidence of DIRF is even more difficult, particularly in the community, because mild changes in renal function often go unrecognized and unreported. Furthermore, in-hospital occurrence rates are low, due to both underrecognition and underreporting. Not all hospitals actively report adverse drug reactions, and most data, if collected, remain unpublished. 

Morbidity and Mortality 
The mean age at onset of ARF is approximately 67 years.7 In a recent prospective study identifying 1,738 patients with an increase in plasma urea or renal dysfunction that required dialysis, the median age was 67 years, and the mean length of stay in the ICU was 10 days.8 

The mortality rate for patients with ARF is 23% to 80%, and this rate increases to 57% to 80% in patients requiring RRT. Hospital mortality for critically ill patients with ARF requiring RRT is approximately 60% to 70%.3 As with incidence data for ARF, mortality data for ARF are inaccurate due to the lack of a universally accepted definition for the condition and the disparate patient populations that have been studied. 

Most patients recover from ARF by 90 days, with 60% to 70% of patients recovering without the need for RRT. Patients with normal renal function prior to the first episode of ARF have a lower likelihood of needing long-term RRT.9 

Types of ARF 
There are three types of ARF--prerenal, intrinsic, and postrenal ARF--which are classified based on underlying causes. Although there are multiple pathophysiologic causes for each type of ARF, drugs are common precipitating factors for each category. 

Prerenal ARF accounts for 40% to 70% of cases and results from decreased perfusion to the kidney. It may be caused by decreased intravascular volume due to blood loss, dehydration, or disease states such as congestive heart failure, hypotension, and liver failure, which result in decreased effective blood volume. Pre- and postglomerular arteriolar resistance is responsible for maintaining renal perfusion and glomerular filtration rate. Preglomerular (afferent) vasodilation and post-glomerular (efferent) vasoconstriction are controlled by prostaglandins and angiotensin II, respectively. Interruption of these pathways by drugs such as NSAIDs and angiotensin-converting enzyme (ACE) inhibitors results in renal hypoperfusion. Patients with underlying disease, such as the elderly and those with hypotension and dehydration, are at particular risk for DIRF.1,4,5Considering the availability of NSAIDs and the growing size of the aging population, the risk of developing NSAID-induced renal failure is quite high. 

Intrinsic ARF accounts for 10% to 50% of ARFcases and results from damage to the kidney tissue. Various inflammatory diseases, such as systemic lupus erythematosus, can result in glomerulonephritis. Interstitial nephritis results from inflammation of the renal interstitium and tubules and can be caused by infections, immune-mediated diseases such as sarcoidosis and lymphomas, and drugs. Drugs most often implicated in the development of interstitial nephritis include certain antibiotics, antivirals, and immunosuppressants.4,10 

Renal tubular injury usually results from ischemia or drugs. The tubules have an inherently high-energy demand due to active transport mechanisms and metabolic processes. This makes the tubules particularly sensitive to decreases in oxygen. Drugs such as amphotericin B upset the balance between oxygen demand and supply, which results in tubular damage.5,10 Other drugs, such as aminoglycosides, radiocontrast media, and heavy metals, become concentrated in the kidney and cause a direct toxic effect, usually in a dose-dependent manner. 4,5,10 

Postrenal ARF accounts for only 10% of ARF cases and results from obstruction within the urinary tract that prevents the outflow and elimination of urine.4 The obstruction must involve both kidneys in order for ARF to develop.1 Patients at risk for postrenal ARF include those with malignancy, prostate disease, and bladder-outlet obstruction. Drugs such as acyclovir and methotrexate can cause crystal deposition in the tubules, which can occur when a patient is dehydrated. Drugs with low solubility may form crystals, causing obstruction of urine output and subsequent renal failure. 

NSAIDs

Each year, up to 5% of people who take NSAIDs will develop renal toxicity, resulting in hospital admissions and an increase in health care spending.1 

All NSAIDs inhibit cyclooxygenase, the enzyme that is required to convert arachidonic acid into prostaglandins. Prostaglandins are not only involved in the inflammatory process but are present in the kidneys. They balance the effects of vasoconstrictors (norepinephrine, angiotensin II, vasopressin) by causing vasodilation of the afferent arteriole and, ultimately, allow adequate renal blood supply and glomerular filtration pressure. 

Unopposed vasoconstriction of the afferent arteriole in a patient taking NSAIDs causes decreased blood flow to the kidneys, which results in decreased glomerular filtration rate and renal ischemia. 

NSAIDs should be avoided or used with caution in patients at high risk of renal failure. COX-2 inhibitors are included in this warning due to similar effects on renal function. Patients should continue taking aspirin for cardioprotection, because low doses do not significantly affect prostaglandin levels in the kidneys.11 

Patients taking high doses of NSAIDs, individuals with underlying renal insufficiency, and the elderly are at a greater risk of toxicity. Factors that cause decreased volume and/or blood flow to the kidneys, such as congestive heart failure, cirrhosis, dehydration, and overdiuresis, predispose patients to ARF.12 When dispensing medications that can precipitate ARF, counsel patients on the risk of using over-the-counter NSAIDs without consulting their pharmacist or physician. 

ACE Inhibitors and Angiotensin II Receptor Blockers

ACE inhibitors and angiotensin II receptor blockers are another frequent cause of ARF, especially in patients with severe renal artery stenosis or chronic kidney disease and in those hospitalized for congestive heart failure. Current guidelines recommend ACE inhibitors for patients with chronic kidney disease and systolic heart failure because of their proven benefits on morbidity and mortality;13 however, low doses should be used initially, and renal function should be monitored frequently. 

Glomerular pressure is normally high enough to maintain adequate filtration without relying on postglomerular resistance. In the setting of reduced blood flow, however, glomerular filtration is dependent on resistance in the efferent arteriole created by angiotensin II–mediated vasoconstriction. ACE inhibitors reduce the outflow resistance from the glomerulus, resulting in decreased pressure and glomerular filtration. 

An increase in SCr of up to 30% is expected in the first two to five days of therapy with an ACE inhibitor. This effect will stabilize after a few weeks of therapy and remain until discontinuation of the drug.5 Treatment with an ACE inhibitor should be stopped if SCr increases by more than 30% and reduced if reinitiated. A mild decrease in renal function due to ACE inhibitors is acceptable due to the benefits that result from long-term therapy. 

Treatment should be started at low dosages, especially in patients with underlying risk factors, and the dose should be titrated gradually. It is important to avoid dehydration and excessive use of diuretics and NSAIDs. 

Aminoglycoside Antibiotics 
Aminoglycosides are used to treat infections with gram-negative bacteria. They cause nephrotoxicity in up to 10% to 20% of patients when used for a full course of therapy.14 

The primary mechanism of aminoglycoside-induced ARF is injury to the proximal tubule leading to cellular necrosis. This occurs via binding of cationic charges on amino groups to tubular epithelial cells. Tubular cell death occurs from generation of oxygen-free radicals and subsequent alterations in cellular function. 

Risk factors for aminoglycoside-induced ARF include aminoglycoside dosing (i.e., large cumulative dose, prolonged therapy, trough concentrations >2 mg/dL), synergistic exposure to other nephrotoxins (especially concomitant vancomycin), and underlying condition of the patient. 

Typically, pharmacists monitor aminoglycoside levels during inpatient treatment. Inherent pharmacodynamic and pharmacokinetic properties of aminoglycosides have led to more frequent use of once-daily dosing as opposed to traditional multiple daily-dosing regimens. Aminoglycosides display concentration-dependent killing and significant "postantibiotic" effect; therefore, giving a higher dose less frequently is at least as effective and may decrease renal toxicity by allowing excretion of aminoglycosides from the tubular cells prior to the next dose.12 

SCr concentrations should be monitored in patients receiving aminoglycosides. Renal toxicity is usually seen in the first five to seven days of therapy but may occur earlier in certain high-risk patients. If aminoglycosides are the treatment of choice, ensuring adequate hydration and avoiding exposure to other nephrotoxic agents is imperative and may prevent aminoglycoside-induced ARF.

Radiocontrast Dye 
ARF is frequently caused by administration of radiographic contrast dye (RCD), which is used for diagnostic and treatment procedures. The incidence approaches nearly 50% in patients with combined diabetes and pre-existing renal insufficiency.5Other risk factors for RCD-induced ARF include volume depletion, high doses of RCD, and using other drugs that cause nephrotoxicity.  

Most patients experience a transient rise in SCr within two to five days after receiving RCD, followed by recovery to baseline over the next few days.15 High-risk patients may experience more severe toxicity and require dialysis. Hospital course is significantly affected due to comorbid conditions that worsen with the onset of ARF.16 

Nephrotoxicity appears to result from a combination of direct tubular necrosis and renal ischemia. Significant injury to the tubular cells and production of toxic-free radicals occur after RCD and may be accompanied by renal vasoconstriction and ischemia. 

Adequate hydration and discontinuation of nephrotoxic drugs is an essential part of the prevention of RCD-induced ARF. Many small trials have shown conflicting results regarding the use of various fluids, bicarbonate, diuretics, and acetylcysteine for prevention of RCD-induced ARF, and there are no clear recommendations based on proven benefit. 

Isotonic normal saline (1 mL/kg) may provide the most benefit and should be given at least six to 12 hours prior to RCD and continued six to 12 hours after the procedure.16 In addition, administration of sodium bicarbonate one hour prior to the procedure, with continued treatment for at least six hours after RCD, may also provide additional benefit.17 Though data are inconclusive at this time, acetylcysteine (600 to 1,200 mg by mouth) given in two doses the day of and after the procedure is reasonable based on low toxicity and cost. Diuretics should be given only if the patient is fluid overloaded.15 

Another ongoing debate involves the choice of an RCD agent. The newer RCD agents have a lower osmolality and have been associated with less renal toxicity in patients with diabetes and renal insufficiency. These agents are significantly more expensive than traditional RCD agents and do not completely eliminate nephrotoxicity. Most experts recommend low osmolality agents only for high-risk patients.18 Although this is a cost-effective strategy for high-risk patients, it is not recommended for the entire population of patients receiving RCD for a diagnostic procedure. 

Other Drugs 
Statin drugs, which are used for hypercholesterolemia, are typically thought of in association with elevated liver enzymes; however, statin drugs are associated with rhabdomyolysis, which is known to cause ARF. Rhabdomyolysis leads to muscle breakdown products in the circulation. ARF results from direct toxicity of myoglobin and intravascular volume depletion, partly from muscle edema.12 Patients should be warned to go to the emergency department immediately if they begin to experience a sudden increase in muscle pain and weakness, especially if it is associated with an increase in temperature. 

Despite approval of several new antifungals, amphotericin B continues to be the drug of choice for life-threatening systemic fungal infections. Dose-dependent acute tubular necrosis occurs often and requires discontinuation of the drug.5 Many liposomal amphotericin B formulations that are associated with less nephrotoxicity have been developed. These formulations are limited by their cost but are currently recommended for patients with preexisting kidney disease and those at a high risk of ARF. 

A complete list of drugs and the types of ARF that can result from toxicity can be found in Table 1.

 

 

 

 

Summary

DIRF is a serious, and often preventable, disease associated with significant morbidity and high health care costs. Drugs are often the culprit, and they range from commonly used over-the-counter analgesics to immunosuppressants and chemotherapeutic agents. As more and more drugs are introduced into the market without a clearly defined adverse drug reaction profile, recognition and reporting of potential adverse drug reactions, including nephrotoxicity, are becoming more important than ever. The FDA released a comprehensive statement early this year committing to a new initiative focusing on drug safety,19 including improving methods of surveillance to identify unforeseen drug toxicity.  

The more pharmacists learn about drugs that are used frequently among patients, the better prepared they will be to help their patients make informed decisions. Prevention is the treatment of choice for ARF, as well as DIRF. Identifying patients at high risk is the first step. Patients should be counseled on concomitant medications that might cause ARF and the risk of dehydration. 

References

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2. Gill N, Nally JV Jr, Fatica RA. Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.Chest. 2005;128:2847-2863.

3. Uchino S. The epidemiology of acute renal failure in the world. Curr Opin Crit Care. 2006;12:538-543.

4. Hilton R. Acute renal failure. BMJ. 2006;333:786-790.

5. Nolin TD, Himmelfarb J, Matzke GR. Drug-induced kidney disease. In: Pharmacotherapy. 6th ed. New York, NY: McGraw-Hill; 2005;871-87.

6. Hoste E, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care. 2006;12:531-537.

7. Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care. 2006;12:557-560.

8. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818.

9. Bagshaw SM. The long-term outcome after acute renal failure. Curr Opin Crit Care. 2006;12:561-566.

10. Schetz M, Dasta J, Goldstein S, Golper T. Drug-induced acute kidney injury. Curr Opin Crit Care. 2005;11:555-565.

11. Mene P, Pugliese F, Patrano C. The effects of nonsteroidal anti-inflammatory drugs on human hypertensive vascular disease. Semin Nephrol. 1995;15:244-252.

12. Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med. 2002;69:289-290,293-294,296-297.

13. Chobanian AV, Bakris GL, Black HR. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42:1206-1252.

14. Swan SK. Aminoglycoside nephrotoxicity. Semin Nephrol. 1997;17:27-33.

15. Fry AC, Farrington K. Management of acute renal failure. Postgrad Med J. 2006;82:106-116.

16. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006;354:379-386.

17. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291:2328-2334.

18. Lin J, Bonventre JV. Prevention of radiocontrast nephropathy. Curr Opin Nephrol Hypertens. 2005;14:105-110. 

19. The future of drug safety--promoting and protecting the health of the public: FDA's response to the Institute of Medicine's 2006 report. Released January 30, 2007. Available at: www.fda.gov/oc/reports/iom013007.html. 

Drug Dosing Adjustments in Patients with Chronic Kidney Disease

MYRNA Y. MUNAR, PharmD, BCPS, and HARLEEN SINGH, PharmD
Oregon State University College of Pharmacy, Portland, Oregon

Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance [metabolism]). Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes. Dosages of drugs cleared renally should be adjusted according to creatinine clearance or glomerular filtration rate and should be calculated using online or electronic calculators. Recommended methods for maintenance dosing adjustments are dose reductions, lengthening the dosing interval, or both. Physicians should be familiar with commonly used medications that require dosage adjustments. Resources are available to assist in dosing decisions for patients with chronic kidney disease. (Am Fam Physician 2007;75:1487-96. Copyright © 2007 American Academy of Family Physicians.)

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) definition of chronic kidney disease is the presence of kidney damage or a reduction in the glomerular filtration rate (GFR) for three months or longer. The K/DOQI chronic kidney disease staging system (Table 1) is based on GFR.1

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation

Evidence rating

References

In patients with chronic kidney disease, over-the-counter and herbal medicine use should be assessed to ensure that medications are indicated; medications with toxic metabolites should be avoided, the least nephrotoxic agents should be used, and alternative medications should be used if potential drug interactions exist.

C

17, 21, 25, 30, 36, 43

Physicians should be aware of drugs with active metabolites that can exaggerate pharmacologic effects in patients with renal impairment.

C

25

Dosages of drugs cleared renally should be adjusted based on the patient's renal function (calculated as creatinine clearance or glomerular filtration rate); initial dosages should be determined using published guidelines and adjusted based on patient response; serum drug concentrations should be used to monitor effectiveness and toxicity when appropriate.

C

1, 4

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1430 orhttp://www.aafp.org/afpsort.xml.

Inappropriate dosing in patients with chronic kidney disease can cause toxicity or ineffective therapy. In particular, older patients are at a higher risk of developing advanced disease and related adverse events caused by age-related decline in renal function and the use of multiple medications to treat comorbid conditions. Chronic kidney disease can affect glomerular blood flow and filtration, tubular secretion and reabsorption, and renal bioactivation and metabolism. Drug absorption, bioavailability, protein binding, distribution volume, and nonrenal clearance (metabolism) also can be altered in these patients. Physicians should pay careful attention when considering drug therapies with active or toxic metabolites that can accumulate and contribute to exaggerated pharmacologic effects or adverse drug reactions in patients with chronic kidney disease. Table 2includes resources for more information about dosing adjustments in patients with chronic kidney disease.

Table 1. National Kidney Foundation K/DOQI Staging System for Chronic Kidney Disease

Stage

Description

GFR (mL per minute per 1.73 m2)

1

Kidney damage with normal or increased GFR

>= 90

2

Kidney damage with a mild decrease in GFR

60 to 89

3

Moderate decrease in GFR

30 to 59

4

Severe decrease in GFR

15 to 29

5

Kidney failure

< 15 (or dialysis)

note: Chronic kidney disease is defined as the presence of kidney damage or a reduction in GFR for a period of three months or longer.

K/DOQI = Kidney Disease Outcomes Quality Initiative; GFR = glomerular filtration rate.

Adapted with permission from National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 suppl 1):S46.

Estimating GFR and Creatinine Clearance

Dosages of drugs cleared renally are based on renal function (calculated as GFR or creatinine clearance; Table 3). These calculations are valid only when renal function is stable and the serum creatinine level is constant.

The K/DOQI clinical practice guideline advocates using the traditional Cockcroft-Gault equation or the Modification of Diet in Renal Disease (MDRD) study equation (full or abbreviated) for routine estimation of GFR.1 However, in patients with a GFR lower than 60 mL per minute per 1.73 m2, the MDRD equation has been shown to be superior to the Cockcroft-Gault equation.2

Because the production and excretion of creatinine declines with age, normal serum creatinine values may not represent normal renal function in older patients. The MDRD equation has been shown to be the best method for detecting a GFR lower than 90 mL per minute per 1.73 m2 in older patients.3

Table 2. Resources for More Information About Dosing Adjustments in Patients with Chronic Kidney Disease

Drug Prescribing in Renal Failure: Dosing Guidelines for Adults
Publisher: American College of Physicians
PDA download: http://acp.pdaorder.com/pdaorder/-/605920537541/item?oec-catalog-item-id=1028

FDA Center for Food Safety and Applied Nutrition
Web site: http://www.cfsan.fda.gov/

FDA MedWatch
Web site: http://www.fda.gov/medwatch/index.html

Medline Plus (herbal medicine)
Web site: http://www.nlm.nih.gov/medlineplus/herbalmedicine.html

National Center for Complementary and Alternative Medicine
Web site: http://www.nccam.nih.gov/

National Kidney Disease Education Program
Web site: http://www.nkdep.nih.gov

National Kidney Foundation
Web site: http://www.kidney.org/

PDA = personal digital assistant; FDA = U.S. Food and Drug Administration.

Dosing Adjustments

Loading doses usually do not need to be adjusted in patients with chronic kidney disease. Published guidelines suggest methods for maintenance dosing adjustments: dose reduction, lengthening the dosing interval, or both.4 Dose reduction involves reducing each dose while maintaining the normal dosing interval. This approach maintains more constant drug concentrations, but it is associated with a higher risk of toxicities if the dosing interval is inadequate to allow for drug elimination. Normal doses are maintained with the extended interval method, but the dosing interval is lengthened to allow time for drug elimination before redosing. Lengthening the dosing interval has been associated with a lower risk of toxicities but a higher risk of subtherapeutic drug concentrations, especially toward the end of the dosing interval.

Dosing recommendations for individual drugs can be found in Drug Prescribing in Renal Failure: Dosing Guidelines for Adults.4The guidelines are divided into three broad GFR categories (less than 10 mL per minute per 1.73 m2, 10 to 50 mL per minute per 1.73 m2, and more than 50 mL per minute per 1.73 m2), encompassing an up to 10-fold range in renal function. The guidelines do not correspond with the K/DOQI staging system; therefore, although they can be used for initial dosages, regimens must be individualized further based on patient response and serum drug concentrations.

Table 3. Equations for Predicting Creatinine Clearance or GFR in Adults with Kidney Disease

Equation

Variables

Sources

Cockcroft-Gault

Age, weight, sex, serum creatinine

Nephron Information Center
Web site: http://www.nephron.com/cgi-bin/CGSI.cgi

Modification of Diet in Renal Disease

Age, sex, race, serum urea nitrogen, serum albumin, serum creatinine

National Kidney Disease Education Program
Web site:http://www.nkdep.nih.gov/professionals/gfr_calculators/index.htm

Nephron Information Center
Web site: http://www.nephron.com/cgi-bin/MDRDSI.cgi

GFR = glomerular filtration rate; PDA = personal digital assistant.

antihypertensives

Drug dosing requirements for antihypertensives in patients with chronic kidney disease are listed in Table 4.4,5 Thiazide diuretics are first-line agents for treating uncomplicated hypertension,6 but they are not recommended if the serum creatinine level is higher than 2.5 mg per dL (220 µmol per L) or if the creatinine clearance is lower than 30 mL per minute.7,8 Loop diuretics are most commonly used to treat uncomplicated hypertension in patients with chronic kidney disease.6 Although the addition of aldosterone blockers (e.g., spironolactone [Aldactone], eplerenone [Inspra]) has been shown to reduce mortality in patients with severe heart failure,9,10 potassium-sparing diuretics and aldosterone blockers should be avoided in patients with severe chronic kidney disease because of the rise in serum potassium that typically accompanies renal dysfunction.11-13

Table 4. Antihypertensive Agents: Dosing Requirements in Patients with Chronic Kidney Disease

Drug

Usual dosage*

Dosage adjustment (percentage of usual dosage) based on GFR (mL per minute per 1.73 m2)

> 50

10 to 50

< 10

ACE inhibitors†

Benazepril (Lotensin)

10 mg daily

100%

50 to 75%

25 to 50%

Captopril (Capoten)

25 mg every 8 hours

100%

75%

50%

Enalapril (Vasotec)

5 to 10 mg every 12 hours

100%

75 to 100%

50%

Fosinopril (Monopril)‡

10 mg daily

100%

100%

75 to 100%

Lisinopril (Zestril)

5 to 10 mg daily

100%

50 to 75%

25 to 50%

Quinapril (Accupril)

10 to 20 mg daily

100%

75 to 100%

75%

Ramipril (Altace)5

5 to 10 mg daily

100%

50 to 75%

25 to 50%

Beta blockers

Acebutolol (Sectral)

400 to 600 mg once or twice daily

100%

50%

30 to 50%

Atenolol (Tenormin)

5 to 100 mg daily

100%

50%

25%

Bisoprolol (Zebeta)§

10 mg daily

100%

75%

50%

Nadolol (Corgard)5

40 to 80 mg daily

100%

50%

25%

Diuretics

Amiloride (Midamor)

5 mg daily

100%

50%

Avoid

Bumetanide (Bumex)5

No adjustment needed

-

-

-

Furosemide (Lasix)5

No adjustment needed

-

-

-

Metolazone (Zaroxolyn)

No adjustment needed

-

-

-

Spironolactone (Aldactone)5

50 to 100 mg daily

Every 6 to 12 hours

Every 12 to 24 hours

Avoid

Thiazides||

25 to 50 mg daily

100%

100%

Avoid

Torsemide (Demadex)5

No adjustment needed

-

-

-

Triamterene (Dyrenium)

50 to 100 twice daily

100%

100%

Avoid

GFR = glomerular filtration rate; ACE = angiotensin-converting enzyme.

*-Table provides general dosing information; dosages may be different for specific indications.

†-May need to use lower initial doses in patients receiving diuretics.

‡-Less likely than other ACE inhibitors to accumulate in patients with renal failure. A fixed-dose combination with hydrochlorothiazide should not be used in patients with a creatinine clearance less than 30 mL per minute (0.5 mL per second).

§-Maximal dosage in patients with renal impairment is 10 mg daily.

||-Thiazides should not be used in patients with a creatinine clearance less than 30 mL per minute; however, thiazides are effective in these patients when used with loop diuretics.

Information from references 4 and 5.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are first-line hypertensive agents for patients with type 1 or 2 diabetes mellitus and proteinuria or early chronic kidney disease.6 These agents reduce blood pressure and proteinuria, slow the progression of kidney disease, and provide long-term cardiovascular protection.

ACE inhibitors and ARBs inhibit the renin-angiotensin-aldosterone system in patients with chronic kidney disease and in patients with normal baseline serum creatinine levels, causing efferent arteriolar dilation. This can cause an acute decline in GFR of more than 15 percent from baseline with proportional elevations in serum creatinine within the first week of initiating therapy.14-16 This most commonly occurs in patients with congestive heart failure, in patients using concomitant diuretics or nonsteroidal anti-inflammatory drugs (NSAIDs), and in patients receiving high doses of ACE inhibitors or ARBs. In most patients, ACE inhibitors and ARBs can be continued safely if the rise in serum creatinine is less than 30 percent. Typically, the level will return to baseline in four to six weeks.

A common practice is to discontinue ACE-inhibitor and ARB therapy when the serum creatinine level rises more than 30 percent or if the serum potassium level is 5.6 mEq per L (5.6 mmol per L) or higher.14-16 Because of long-term renoprotective and cardioprotective effects, no patient should be denied an ACE-inhibitor or ARB trial without careful evaluation. Dosages should be titrated carefully and followed by weekly monitoring of renal function and potassium levels until values return to baseline.

Hydrophilic beta blockers (e.g., atenolol [Tenormin], bisoprolol [Zebeta], nadolol [Corgard], acebutolol [Sectral]) are eliminated renally and dosing adjustments are needed in patients with chronic kidney failure.7 However, metoprolol tartrate (Lopressor), metoprolol succinate (Toprol XL), propranolol (Inderal), and labetalol (Normodyne) are metabolized by the liver and adjustments are not required. Other antihypertensive agents that do not require dosing adjustments include calcium channel blockers, clonidine (Catapres), and alpha blockers.17

hypoglycemic agents

Drug dosing requirements for hypoglycemic agents in patients with chronic kidney disease are listed in Table 5.4,18,19 Because metformin (Glucophage) is 90 to 100 percent renally excreted,18 its use is not recommended when the serum creatinine level is higher than 1.5 mg per dL (130 µmol per L) in men or higher than 1.4 mg per dL (120 µmol per L) in women, in patients older than 80 years, or in patients with chronic heart failure.19 The primary concern about the use of metformin in patients with renal insufficiency is that other hypoxemic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) increase the risk of lactic acidosis. Physicians may be apprehensive to maximize the use of metformin in appropriate patients because of these contraindications.

Table 5. Hypoglycemic Agents: Dosing Requirements in Patients with Chronic Kidney Disease

Drug

Usual dosage*

Special considerations

Acarbose (Precose)

Maximum: 50 to 100 mg three times daily

Lack of data in patients with a serum creatinine level higher than 2 mg per dL (180 µmol per L); therefore, acarbose should be avoided in these patients18

Chlorpropamide (Diabinese)

100 to 500 mg daily

Avoid in patients with a glomerular filtration rate less than 50 mL per minute because of the increased risk of hypoglycemia19

Glipizide (Glucotrol)

5 mg daily

Dosage adjustment not necessary in patients with renal impairment

Glyburide (Micronase)

2.5 to 5 mg daily

50 percent of the active metabolite is excreted via the kidney, creating a potential for severe hypoglycemia; not recommended when creatinine clearance is less than 50 mL per minute (0.83 mL per second)18

Metformin (Glucophage)

500 mg twice daily

Avoid if serum creatinine level is higher than 1.5 mg per dL (130 µmol per L) in men or higher than 1.4 mg per dL (120 µmol per L) in women, and in patients older than 80 years or with chronic heart failure; fixed-dose combination with metformin should be used carefully in renal impairment; metformin should be temporarily discontinued for 24 to 48 hours before use of iodinated contrast agents, not restarted for 48 hours afterward, and then restarted only when renal function has normalized19

Metformin (extended release)

500 mg daily

*-Table provides general dosing information; dosages may be different for specific indications.

Information from references 4, 18, and 19.

A Cochrane review showed that lactic acidosis did not occur in the more than 20,000 patients with type 2 diabetes studied (patients with standard contraindications to metformin were not included).20 Rather than avoid the drug completely in patients with chronic kidney disease, it would be reasonable to start with a low dose in these patients and titrate, with close monitoring, based on patient response and tolerability. A more common practice is to temporarily discontinue metformin therapy in patients at a higher risk of lactic acidosis, such as patients who become septic.

Sulfonylureas (e.g., chlorpropamide [Diabinese], glyburide [Micronase]) should be avoided in patients with stages 3 to 5 chronic kidney disease.18 The half-life of chlorpropamide is significantly increased in these patients, which can cause severe hypoglycemia.18 Glyburide has an active metabolite that is eliminated renally, and accumulation of this metabolite can cause prolonged hypoglycemia in patients with chronic kidney disease.18 Glipizide, however, does not have an active metabolite and is safe in these patients.18

antimicrobials

Many antimicrobial agents (Table 64,21) are eliminated renally and require dosing adjustments in patients with chronic kidney disease; however, several commonly used agents do not require adjustments.21

Table 6. Antimicrobial Agents: Dosing Requirements in Patients with Chronic Kidney Disease

Drug

Usual dosage

Dosage adjustment (percentage of usual dosage ) based on GFR (mL per minute per 1.73 m2)

> 50

10 to 50

< 10

Antifungals

Fluconazole (Diflucan)

200 to 400 mg every 24 hours

100%

50%

50%

Itraconazole (Sporanox)

100 to 200 mg every 12 hours

100%

100%

50% (IV form is contraindicated)

Ketoconazole (Nizoral)

No adjustment needed

-

-

-

Miconazole (Monistat)

No adjustment needed

-

-

-

Antivirals

Acyclovir IV (Zovirax)*

5 to 10 mg per kg every 8 hours

100%

100% every 12 to 24 hours

50% every 12 to 24 hours

Acyclovir (oral)

200 to 800 mg every 4 to 12 hours

100%

100%

200 mg every 12 hours

Valacyclovir (Valtrex)

500 mg every 12 hours to 1,000 mg every 8 hours, depending on indication

100%

100% every 12 to 24 hours

500 mg every 24 hours

Carbapenems

Ertapenem (Invanz)

1 g every 24 hours

100%

100%

50%

Imipenem

0.25 to 1 g every 6 hours

100%

50%

25%

Meropenem (Merrem)

1 to 2 g every 8 hours

100%

50% every 12 hours

50% every 24 hours

(GFR < 20)

Cephalosporins

Cefaclor (Ceclor)

250 to 500 mg every 8 hours

100%

50 to 100%

50%

Cefadroxil (Duricef)

0.5 to 1 g every 12 hours

100%

Every 12 to 24 hours

Every 36 hours

Cefamandole (Mandol)

0.5 to 1 g every 4 to 8 hours

Every 6 hours

Every 6 to 8 hours

Every 8 to 12 hours

Cefazolin (Ancef)

0.25 to 2 g every 6 hours

Every 8 hours

Every 12 hours

50% every 24 to 48 hours

Cefepime (Maxipime)

0.25 to 2 g every 8 to 12 hours

100%

50 to 100% every 24 hours

25 to 50% every 24 hours

Cefixime (Suprax)

200 mg every 12 hours

100%

75%

50%

Cefoperazone (Cefobid)

No adjustment needed

-

-

-

Cefotaxime (Claforan)

1 to 2 g every 6 to 12 hours

Every 6 hours

Every 6 to 12 hours

Every 24 hours or 50%

Cefotetan (Cefotan)

1 to 2 g every 12 hours

100%

Every 24 hours

Every 48 hours

Cefoxitin (Mefoxin)

1 to 2 g every 6 to 8 hours

Every 6 to 8 hours

Every 8 to 12 hours

Every 24 to 48 hours

Cefpodoxime (Vantin)

100 to 400 mg every 12 hours

Every 12 hours

Every 24 hours

Every 24 hours

Cefprozil (Cefzil)

250 to 500 mg every 12 hours

100%

50% every 12 hours

50% every 12 hours

Ceftazidime (Fortaz)

1 to 2 g every 8 hours

Every 8 to 12 hours

Every 12 to 24 hours

Every 24 to 48 hours

Ceftibuten (Cedax)

400 mg every 24 hours

100%

25 to 50%

25 to 50%

Ceftizoxime (Cefizox)

1 to 2 g every 8 to 12 hours

Every 8 to
12 hours

Every 12 to 24 hours

Every 24 hours

Ceftriaxone (Rocephin)

No adjustment needed

-

-

-

Cefuroxime axetil (Ceftin)

No adjustment needed

-

-

-

Cefuroxime sodium (Zinacef)

0.75 to 1.5 g every 8 hours

Every 8 hours

Every 8 to 12 hours

Every 12 hours

Cephalexin (Keflex)

250 to 500 mg every 6 to
8 hours

Every 8 hours

Every 8 to 12 hours

Every 12 to 24 hours

Cephradine (Velosef)

0.25 to 1 g every 6 to 12 hours

100%

50%

25%

Macrolides

Azithromycin (Zithromax)

No adjustment needed

-

-

-

Clarithromycin (Biaxin)

250 to 500 mg every 12 hours (Biaxin); 1 g daily (Biaxin XL)

100%

50 to 100%

50%

Dirithromycin

No adjustment needed

-

-

-

Erythromycin

No adjustment needed

-

-

-

Penicillins

Amoxicillin

250 to 500 mg every 8 hours

Every 8 hours

Every 8 to 12 hours

Every 24 hours

Ampicillin

0.25 to 2 g every 6 hours

Every 6 hours

Every 6 to 12 hours

Every 12 to 24 hours

Ampicillin/sulbactam (Unasyn)

1 to 2 g ampicillin and 0.5 to 1 g sulbactam every 6 to 8 hours

100% (GFR >= 30)

Every 12 hours (GFR 15 to 29)

Every 24 hours (GFR 5 to 14)

Carbenicillin (Geocillin), 382-mg tablet

1 or 2 tablets every 6 hours

Every 6 to 12 hours

Every 12 to 24 hours

Every 24 to 48 hours

Carbenicillin IV (not available in the United States)

200 to 500 mg per kg per day, continuous infusion or in divided doses

Every 8 to
12 hours

Every 12 to 24 hours

Every 24 to 48 hours

Dicloxacillin (Dynapen)

No adjustment needed

-

-

-

Nafcillin

No adjustment needed

-

-

-

Penicillin G

0.5 to 4 million U every 4 to 6 hours

100%

75%

20 to 50%

Penicillin VK

No adjustment needed

-

-

-

Piperacillin

3 to 4 g every 6 hours

Every 6 hours

Every 6 to 12 hours

Every 12 hours

Piperacillin/tazobactam (Zosyn)

3.375 to 4.5 g every
6 to 8 hours

100%

2.25 g every 6 hours; every 8 hours (GFR < 20)

2.25 g every 8 hours

Ticarcillin

3 g every 4 hours

1 to 2 g every 4 hours

1 to 2 g every 8 hours

1 to 2 g every 12 hours

Ticarcillin/clavulanate (Timentin)

3.1 g every 4 hours

100%

Every 8 to 12 hours

2 g every 12 hours

Quinolones

Ciprofloxacin (Cipro)

400 mg IV or 500 to 750 mg orally every 12 hours

100%

50 to 75%

50%

Gatifloxacin (Tequin)

400 mg every 24 hours

100%

400 mg initially, then 200 mg daily

400 mg initially, then 200 mg daily

Gemifloxacin (Factive)

320 mg every 24 hours

100%

50 to 100%

50%

Levofloxacin (Levaquin)

250 to 750 mg every 24 hours

100%

500 to 750 mg initial dose, then 250 to 750 mg every 24 to 48 hours

500 mg initial dose, then 250 to 500 mg every 48 hours

Moxifloxacin (Avelox)

No adjustment needed

-

-

-

Norfloxacin (Noroxin)

400 mg every 12 hours

Every 12 hours

Every 12 to 24 hours

Avoid

Ofloxacin (Floxin)

200 to 400 mg every 12 hours

100%

200 to 400 mg every 24 hours

200 mg every
24 hours

Trovafloxacin (not available in the United States)

No adjustment needed

-

-

-

Sulfas

Sulfamethoxazole (Gantanol)

1 g every 8 to 12 hours

Every 12 hours

Every 18 hours

Every 24 hours

Sulfisoxazole (Gantrisin)

1 to 2 g every 6 hours

Every 6 hours

Every 8 to 12 hours

Every 12 to 24 hours

Trimethoprim (Proloprim)

100 mg every 12 hours

Every 12 hours

Every 12 hours (GFR > 30); every 18 hours (GFR 10 to 30)

Every 24 hours

Tetracyclines

Doxycycline (Vibramycin)

No adjustment needed

-

-

-

Tetracycline

250 to 500 mg two to four times daily

Every 8 to 12 hours

Every 12 to 24 hours

Every 24 hours

Other

Chloramphenicol (Chloromycetin)

No adjustment needed

-

-

-

Clindamycin (Cleocin)

No adjustment needed

-

-

-

Dalfopristin/quinupristin (Synercid)

No adjustment needed

-

-

-

Linezolid (Zyvox)

No adjustment needed

-

-

-

Nitrofurantoin (Furadantin)

500 to 1,000 mg every 6 hours

100%

Avoid

Avoid

Telithromycin (Ketek)

No adjustment needed

-

-

-

GFR = glomerular filtration rate; IV = intravenous.

*-To avoid nephrotoxicity it is recommended that the patient have a daily urine output of 1 mL for every 1.3 mg of acyclovir administered.

Adapted with permission from Livornese LL Jr, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure. Infect Dis Clin North Am 2004;18:556-67, with additional information from reference 4.

Excessive serum levels of injectable penicillin G or carbenicillin (not available in the United States) may be associated with neuromuscular toxicity, myoclonus, seizures, or coma.22 Imipenem/cilastatin (Primaxin) can accumulate in patients with chronic kidney disease, causing seizures if doses are not reduced.23 Patients with advanced disease should receive a different carbapenem, such as meropenem (Merrem).24 Tetracyclines, with the exception of doxycycline (Vibramycin), have an antianabolic effect that may significantly worsen the uremic state in patients with severe disease. Nitrofurantoin (Furadantin) has a toxic metabolite that can accumulate in patients with chronic kidney disease, causing peripheral neuritis.25

Aminoglycosides should be avoided in patients with chronic kidney disease when possible. If used, initial doses should be based on an accurate GFR estimate. Renal function and drug concentrations should be monitored and dosages adjusted accordingly.

analgesics

Patients with stage 5 kidney disease are more likely to experience adverse effects from opioid use. Metabolites of meperidine (Demerol), dextropropoxyphene (propoxyphene [Darvon]), morphine (Duramorph), tramadol (Ultram), and codeine can accumulate in patients with chronic kidney disease, causing central nervous system and respiratory adverse effects.26-28These agents are not recommended in patients with stage 4 or 5 disease. A 50 to 75 percent dose reduction for morphine and codeine is recommended in patients with a creatinine clearance less than 50 mL per minute (0.83 mL per second).28 Extended-release tramadol should be avoided in patients with chronic kidney disease. The dosing interval of tramadol (regular release) may need to be increased to every 12 hours in patients with a creatinine clearance less than 30 mL per minute (0.5 mL per second).29 Acetaminophen can be used safely in patients with renal impairment.

nsaids

Adverse renal effects of NSAIDs include acute renal failure; nephrotic syndrome with interstitial nephritis; and chronic renal failure with or without glomerulopathy, interstitial nephritis, and papillary necrosis.30 The risk of acute renal failure is three times higher in NSAID users than in non-NSAID users.31 Other adverse effects of NSAIDs include decreased potassium excretion, which can cause hyperkalemia, and decreased sodium excretion, which can cause peripheral edema, elevated blood pressure, and decompensation of heart failure. NSAIDs can blunt antihypertensive treatment, especially if beta blockers, ACE inhibitors, or ARBs are used.32,33 Although selective cyclooxygenase-2 (COX-2) inhibitors may cause slightly fewer adverse gastrointestinal effects, adverse renal effects are similar to traditional NSAIDs.34,35

Table 7. Statins: Dosing Requirements in Patients with Chronic Kidney Disease

Drug

Usual dosage*38

Dosage adjustments based on degree of renal function

Atorvastatin (Lipitor)

10 mg daily

Maximal dosage: 80 mg daily

No adjustment needed

Fluvastatin (Lescol)

20 to 80 mg daily

80 mg daily (sustained release)

50% dose reduction in patients with a GFR less than 30 mL per minute per 1.73 m2

Lovastatin (Mevacor)

20 to 40 mg daily

Maximal dosage: 80 mg daily (immediate release) or 60 mg daily (extended release)

Use with caution in patients with a GFR less than 30 mL per minute per 1.73 m2

Pravastatin (Pravachol)

10 to 20 mg daily

Maximal dosage: 40 mg daily

Starting dosage should not exceed 10 mg daily in patients with a GFR less than 30 mL per minute per 1.73 m2

Rosuvastatin (Crestor)

5 to 40 mg daily

Recommended starting dosage is 5 mg daily in patients with a GFR less than 30 mL per minute per 1.73 m2 not to exceed 10 mg daily

Simvastatin (Zocor)

10 to 20 mg daily

Maximal dosage: 80 mg daily

Recommended starting dosage is 5 mg daily in persons with a GFR less than 10 mL per minute per 1.73 m2

GFR = glomerular filtration rate.

*-Table provides general dosing information; dosages may be different for specific indications.

Information from references 37 and 38.

Short-term use of NSAIDs is generally safe in patients who are well hydrated; who have good renal function; and who do not have heart failure, diabetes, or hypertension.36 Long-term use and high daily dosages of COX-2 inhibitors and other NSAIDs should be avoided if possible. Patients at high risk of NSAID-induced kidney disease should receive serum creatinine measurements every two to four weeks for several weeks after initiation of therapy because renal insufficiency may occur early in the course of therapy.

other medications

Drug dosing requirements for statins and for other commonly prescribed medications that require dosing adjustments in patients with chronic kidney disease are listed in Table 7 37,38 and Table 8,4,39 respectively.

Table 8. Other Common Agents: Dosing Requirements in Patients with Chronic Kidney Disease

Drug

Usual dosage*

Dosage adjustments based on (percentage of usual dosage ) GFR (mL per minute per 1.73 m2)

> 50

10 to 50

< 10

Allopurinol (Zyloprim)†

300 mg daily

75%

50%

25%

Esomeprazole (Nexium)

No adjustment needed

-

-

-

Famotidine (Pepcid)

20 to 40 mg at bedtime

50%

25%

10%

Gabapentin (Neurontin)39

300 to 600 mg three times daily

900 to 3,600 mg
three times daily (GFR >= 60)

400 to 1,400 mg twice daily (GFR > 30 to 59)

200 to 700 mg daily (GFR > 15 to 29)

100 to 300 mg daily (GFR <= 15)

Lansoprazole (Prevacid)

No adjustment needed

-

-

-

Metoclopramide (Reglan)

10 to 15 mg three times daily

100%

75%

50%

Omeprazole (Prilosec)

No adjustment needed

-

-

-

Ranitidine (Zantac)

150 to 300 mg at bedtime

75%

50%

25%

GFR = glomerular filtration rate.

*-Table provides general dosing information; dosages may be different for specific indications.

†-Elimination half-life of active metabolite oxypurinol increases from 24 hours to 125 hours in patients with renal failure. Accumulation of oxypurinol can lead to a toxic immune mediated reaction.

Information from references 4 and 39.

Although herbal therapies are commonly used,40 some may pose a risk in patients with chronic kidney disease. St. John's wort and ginkgo accelerate the metabolism of many medications, causing diminished pharmacologic effects. Ginkgo also can increase the risk of bleeding in patients taking aspirin, ibuprofen, or warfarin (Coumadin). Some herbal products (e.g., alfalfa, dandelion, noni juice) contain undisclosed amounts of potassium, which can cause hyperkalemia. Some may contain heavy metals that are toxic to the kidneys, or ephedra-like vasoconstrictive compounds that can cause hypertension.41-43 Chinese herbal medicines containing aristolochic acid (commonly used in weight-loss regimens) are nephrotoxic and can cause stage 5 kidney disease.3

This is one in a series of "Clinical Pharmacology" articles coordinated by Allen F. Shaughnessy, PharmD, Tufts University Family Medicine Residency Program, Malden, Mass.

The Authors

MYRNA Y. MUNAR, PharmD, BCPS, is an associate professor in the Department of Pharmacy Practice at Oregon State University College of Pharmacy, Portland, and is an adjunct assistant professor in the Department of Physiology and Pharmacology at the Oregon Health and Science University School of Medicine, Portland. Dr. Munar received her doctorate of pharmacy degree at the University of Southern California School of Pharmacy, Los Angeles.

HARLEEN SINGH, PharmD, is a clinical assistant professor in the Department of Pharmacy Practice at Oregon State University College of Pharmacy. Dr. Singh received her doctorate of pharmacy degree and completed an adult medicine residency at the Ohio State University College of Pharmacy, Columbus.

Address correspondence to Myrna Y. Munar, PharmD, BCPS, 3303 SW Bond Ave., Mail Code CH12C, Portland, OR 97239 (e-mail: munarm@ohsu.edu). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39 (2 suppl 1):S1-266.

2. Poggio ED, Wang X, Greene T, Van Lente F, Hall PM. Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 2005;16:459-66.

3. Burkhardt H, Hahn T, Gretz N, Gladisch R. Bedside estimation of the glomerular filtration rate in hospitalized elderly patients. Nephron Clin Pract 2005;101:c1-8.

4. Aronoff GR. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 4th ed. Philadelphia, Pa.: American College of Physicians, 1999.

5. Saseen JJ, Carter BL. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy. 6th ed. New York, N.Y.: McGraw-Hill, 2005:185-215.

6. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [Published correction appears in JAMA 2003;290:197]. JAMA 2003;289:2560-72.

7. Carter BL. Dosing of antihypertensive medications in patients with renal insufficiency. J Clin Pharmacol 1995;35:81-6.

8. Brater DC. Diuretic therapy. N Engl J Med 1998;339: 387-95.

9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al., for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.

10. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al., for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction [Published correction appears in N Engl J Med 2003;348:2271]. N Engl J Med 2003;348:1309-21.

11. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51

 

Nephrology: 3. Safe drug prescribing for patients with renal insufficiencyCanadian Medical Association Journal - Volume 166, Issue 4 (February 2002)  -  Copyright © 2002 Canadian Medical Association




PRACTICENephrology: 3. Safe drug prescribing for patients with renal insufficiency
 

Joanne Kappel 01Piera Calissi 02A. Ross Morton Dr. Series editor 03 

01 Dr. Kappel is with the Division of Nephrology, Department of Medicine. Saskatoon, Sask.
02 Dr. Calissi is with Pharmaceutical Services, St. Paul's Hospital, Saskatoon, Sask.
03 Division of Nephrology, Department of Medicine, Queen's University, Kingston, Ont.


 

CaseMs. J is a 33-year-old woman with type 1 diabetes mellitus who weighs 65 kg. She presents with an infected ulcer on her right foot. She is febrile, has obvious lymphangitic spread to her knee, palpable groin nodes and an elevated leukocyte count with a neutrophilic shift. Her complications of diabetes include proliferative retinopathy, peripheral neuropathy and nephropathy. The patient's serum creatinine before this recent illness was 150 μmol/L. You have chosen to prescribe a fluoroquinolone and metronidazole intravenously. Are antibiotic dose adjustments required for this patient? How would you rapidly calculate creatinine clearance? 

Correspondence to: Dr. Joanne Kappel, Division of Nephrology, Department of Medicine, St. Paul's Hospital, Saskatoon SK S7M 0Z9; fax 306 242-1866; jekappel@sk.sympatico.ca
© 2002 Canadian Medical Association or its licensors



The number of people with end-stage renal disease (ESRD) in Canada is increasing. In 1999, 142 individuals per million population were receiving renal replacement therapy, which is an increase from 83 per million population in 1990.[1] The leading cause of ESRD is diabetes (30%) followed by renal vascular disease, including hypertension (20%). Over the past decade, the number of older Canadians (aged ≥ 65 years) with ESRD has more than doubled.[1] Unfortunately, the number of people who have some degree of renal insufficiency, but have yet to need renal replacement therapy, is not fully known. Those groups at risk for developing renal impairment include individuals with diabetes, elderly people, those with hypertension, certain ethnic groups (i.e., Aboriginal people) and individuals with atherosclerotic disease elsewhere, autoimmune and genetic diseases, or a family history of renal disease. The third National Health and Nutrition Examination Survey (NHANES III) estimated that 14.7 million people in the United States had renal insufficiency. [2] Based on these data, one could estimate that there are about 1.5 million Canadians with renal insufficiency.

On average, patients with renal insufficiency are taking at least 7 different medications to manage not only their underlying disease (such as diabetes) but also the symptoms related to their renal impairment (i.e., problems with mineral metabolism, anemia).[3] [4] The frequency of adverse drug reactions increases with the number of medications used, the degree of renal dysfunction, the age of the patient and the number of comorbid conditions.[5] [6] As the kidney is a major organ of drug elimination, some knowledge of basic pharmacologic principles and a systematic approach to patients with renal insufficiency are necessary to ensure safe and effective patient care.



Diagnosis of renal insufficiencyAll patients who are at risk for renal insufficiency should have their renal function assessed as part of their periodic health examination. At the very least, serum creatinine should be tested, recognizing that measuring serum creatinine alone will fail to diagnose abnormal function in 35% of people aged 40-49 years and 92% of people more than 70 years old.[7] A more accurate reflection of renal function is creatinine clearance. Guidelines for the investigation of newly diagnosed renal insufficiency exist elsewhere.[8] For patients with established renal insufficiency, a thorough history-taking, physical examination and certain basic laboratory tests are essential to identify individuals who may require adjustments to their medication.

The patient's history should include a record of current medications, including over-the-counter drugs, recreational drugs, alcohol use, and drug sensitivities or allergies, and comorbid conditions such as diabetes, liver disease or congestive heart failure. The physical examination should include measurement of height, weight and extracellular volume status (blood pressure and heart rate with orthostatic changes, jugular venous pulse, edema, ascites, lung crackles) and a search for signs of chronic liver disease.

The history and physical examination will frequently point to factors that can affect drug pharmacokinetics, including alterations in drug absorption and bioavailability, distribution, metabolism and excretion ( Table 1 ). [9] [10] [11] [12]

TABLE 1 -- Effect of renal insufficiency on drug pharmacokineticsAbsorption and bioavailability [9] [10]Bioavailability is defined as the percentage of an administered drug dose that reaches the central circulation. It is limited by first-pass hepatic metabolism and:Gastrointestinal transit time:Diabetic or uremic gastroparesis, or both, can alter rates of absorption of drugs such as short-acting sulfonylureas.Gastric pH:Medications that alter gastric acidity, such as histamine2 blockers, can reduce the absorption of drugs such as iron and ketoconazole.Gastrointestinal tract edema:Edema caused by congestive heart failure, liver cirrhosis or nephrotic syndrome can slow drug absorption (i.e., absorption of furosemide).Vomiting and diarrhea:Common in renal failure, these reduce the amount of drug absorbed.Antacids or cholestyramine:Commonly taken by patients with renal failure, these can decrease the absorption of warfarin and digoxin.Drug distribution [6] [11] [12]Volume of distribution (Vd) is defined as the amount of drug in the body divided by the plasma concentration. Vd can be altered by:Lipid v. water solubility:Edema or ascites may increase Vd for protein-bound or water-soluble drugs such as vancomycin (possibly requiring a larger loading dose to achieve therapeutic drug concentrations).Plasma protein drug binding:Uremic states can alter plasma protein binding, affecting acidic drugs like phenytoin, valproic acid and ASA. Hypoalbuminemia and altered plasma protein binding can result in an increase in free or unbound concentrations of drugs such as phenytoin. Because assays for phenytoin measure total plasma concentrations and not the free fraction, patients with renal impairment who are taking this drug may have adequate seizure control at subtherapeutic concentrations, or conversely may show signs of toxicity at phenytoin concentrations within the usual therapeutic range.Tissue protein drug binding:Tissue protein binding is reduced in uremic states, which can decrease the Vd for drugs like digoxin.Metabolism [6] [11]Metabolism can be affected by:Hepatic biotransformations:These can be increased, decreased or unchanged by renal insufficiency, and doses of metabolized drugs such as propranolol and dihydrocodeine should be adjusted accordingly.Excretion [6] [11]Excretion is the most important pharmacokinetic factor altered in renal insufficiency by:Glomerular filtration, tubular secretion, reabsorption:Net renal excretion of a drug is a composite of these 3 factors. Generally it is assumed that all 3 decline in a parallel manner. Creatinine clearance is, therefore, the guiding factor for drug dosage.Determination of a patient's 24-hour creatinine clearance by urine collection, or by estimation using the Cockcroft-Gault formula ( Table 2 ),[13] will confirm the degree of suspected renal insufficiency and frequently assist with safer drug prescribing.

TABLE 2 -- Cockcroft-Gault formula for creatinine clearance (CrCl) [ 13]Women:   CrCl (mL/min)=0.85 × CrCl (men)This formula is for adults with stable renal function and takes into account increased creatinine production with increasing weight and decreased creatinine production with increasing age. It will overestimate the true glomerular filtration rate (GFR), but it is important to appreciate that in most clinical settings exact knowledge of the true GFR is not required. Creatinine clearance formulas for pediatric care and for individuals with unstable renal function can be found in Lam and colleagues.[3] There are many variations of the Cockcroft-Gault formula. The one presented here is simply the one we use.Ranges of normal and decreased creatinine clearance (SI units):Normal renal function

   Men95-145 mL/min(1.58-2.42 mL/s)   Women75-115 mL/min(1.25-1.92 mL/s)Mild renal insufficiency *50-70 mL/min(0.83-1.17 mL/s)Moderate renal insufficiency *25-50 mL/min(0.42-0.83 mL/s)Severe renal insufficiency *< 25 mL/min(< 0.42 mL/s)Note: SCr = serum creatinine.*Please note that there is considerable controversy regarding what constitutes mild, moderate and severe renal insufficiency. It is also important to note that creatinine clearance declines by 1 mL/min per year (0.02 mL/s per year) after the age of 40 years. Therefore, these guidelines are for women and men aged < 65 years.





 



ManagementOnce a physician has identified a patient with renal insufficiency and has recognized which of a drug's pharmacokinetic factors may be affected, a stepwise approach is important when prescribing drug therapy. This will help ensure the effectiveness of medication, avoid or minimize further kidney damage, and prevent drug nephrotoxicity ( Table 3 ).[14] It is important to note that these steps provide a framework for dosage adjustments and must be modified on an individual basis.

TABLE 3 -- Stepwise guide to adjusting drug dosages for patients with renal insufficiencyStep 1Take history and perform physical examinationRecord current medications, including over-the-counter drugs, recreational drugs, alcohol use. Drug allergies and sensitivities should be noted. Physical examination should include the following: height, weight, extracellular volume status (jugular venous pulse, blood pressure and heart rate with orthostatic changes, edema, ascites, lung crackles) and look for signs of chronic liver disease.Step 2Determine the degree of renal insufficiencyMeasure serum creatinine. Order 24-hour urine collection or calculate creatinine clearance.Step 3Review the medication listEnsure that all drugs are still required and that new medications have specific indications. Evaluate for potential drug interactions.Step 4Choose less nephrotoxic drugsIf the use of nephrotoxic drugs cannot be avoided without patient morbidity or mortality, then therapeutic drug monitoring or monitoring of renal function is mandatory.Step 5Select loading dosesThese are usually the same for patients with both normal and abnormal renal function.Step 6Select a maintenance regimenEither reduce the dose of the drug and maintain the usual dosing interval or maintain the drug dose and extend the interval. Recommendations for adjusting regimens can be obtained in the Compendium of Pharmaceuticals and Specialties (CPS)[14] product monographs. Remember to titrate the dose of the drug to patient effect, if applicable. For example, antihypertensives are dosed based upon blood pressure control, whereas antimicrobials are not adjusted according to response.Step 7Monitor drug levelsMonitor drug levels if monitoring is available to guide further therapy.Step 8ReassessReassess the patient to evaluate drug effectiveness and the need for ongoing therapy. If nephrotoxic drugs are used, remember to check the patient's serum creatinine and creatinine clearance again.The number of adverse drug reactions experienced by patients with renal insufficiency can be decreased if drugs are used for specific indications, potentially nephrotoxic drugs are avoided, medication lists are continuously updated and there is an awareness of potential drug interactions. Response to drug therapy may be variable, and adverse drug reactions may occur quickly. Some of the more common drugs that require or do not require dose modification in patients with renal insufficiency are listed in Table 4 .[15] [16] Information about commonly used drugs that require special consideration in this group of patients is provided in Table 5 .[3] [6] [15] [16]

TABLE 4 -- Dose modification for patients with renal insufficiencyDrugs requiring dose modificationDrugs not requiring dose modificationAll antibioticsEXCEPTCloxacillin, clindamycin, metronidazole, macrolidesAntihypertensivesAntihypertensivesAtenolol, nadolol, angiotensin-converting-enzyme inhibitorsCalcium channel blockers, minoxidil, angiotensin receptor blockers, clonidine, α-blockers such as prazosinOther cardiac medicationsOther cardiac medicationsDigoxin, sotalolAmiodarone, nitratesDiureticsNarcoticsAVOID potassium-sparing diuretics in patients with creatinine clearance < 30 mL/min (< 0.5 mL/s)Fentanyl, hydromorphone, morphine (may require dose modification if given in a palliative care setting)Lipid-lowering agentsPsychotropicsHMG-CoA reductase inhibitors, benafibrate, clofibrate, fenofibrateTricyclic antidepressants, nefazodone, other selective serotonin reuptake inhibitorsNarcoticsHypoglycemia medicationsCodeine, meperidineRepaglinide, rosiglitazonePsychotropicsMiscellaneousLithium, chloral hydrate, gabapentin, trazodone, paroxetine, primidone, topiramate, vigabatrinProton pump inhibitorsHypoglycemia medications
Acarbose, chlorpropamide, glyburide, gliclazide, metformin, insulin
Miscellaneous
Allopurinol, colchicine, histamine2 receptor antagonists, diclofenac, ketorolac, terbutaline
TABLE 5 -- Special considerations for drug use by patients with renal insufficiencyMeperidineMetabolite normeperidine is neurotoxic and may cause seizuresNSAIDSDecrease diuretic response and increase propensity to hyperkalemia if taken with potassium-sparing diuretics and angiotensin-converting-enzyme inhibitorsChlorpropamideHas increased half-life when taken by patients with renal insufficiency and prolongs hypoglycemiaMetforminShould not be used if creatinine clearance < 50 mL/min (< 0.83 mL/s) because it can cause life-threatening lactic acidosisInsulinThere is decreased renal clearance of exogenously administered insulin and, therefore, potential for increased hypoglycemic reactions as creatinine clearance declines.Aminoglycosides
VancomycinDosage adjustment is required, because these drugs will rapidly accumulate in renal insufficiency and are potentially nephrotoxic. Therapeutic drug monitoring is recommended.Cimetidine
Triamterene
TrimethoprimInhibit tubular secretion of creatinine and therefore cause a rise in serum creatinine, which is reversible when these drugs are discontinued[17]Complementary products, which are variably called herbal medicines, naturopathic remedies and phytomedicines, are becoming very popular. The practitioner should have some basic knowledge of the potential interactions with prescribed medications or simple adverse consequences in the patient with renal insufficiency. Some examples of herbal products that should be avoided by patients with renal insufficiency are listed in Table 6 . Comprehensive accounts of herbal medicines may be found elsewhere.[17] [18] [19] [20] [21]

TABLE 6 -- Herbal products that may cause renal problemsAristolochic acidContained in Virginian and Texas snakeroot or in Chinese herbs like Stephania tetranda andMagnolia officinalis. It causes rapidly progressive fibrosing interstitial nephritis and renal failure. It is also linked to urothelial malignancy.BarberryPossibly causes interstitial nephritisBuchuCauses renal irritationChinese herbal drugsContain a variety of herbs, and often aristolochic acidJuniperCauses renal fibrosisLicoriceIs associated with sodium and water retention, hypokalemia and hypertensionNoni juiceAlso known as the Och plant (India), Nono (Tahiti), Nonu (Samoa), Nhau (Southeast Asia) and Chinese fruit (Australia), it is associated with hyperkalemia.

Case revisitedUsing the Cockcroft-Gault formula for creatinine clearance, you calculate Ms. J's creatinine clearance to be 48 mL/minute (0.8 mL/second), which is reduced. You decide that the dose of metronidazole does not require any alteration, because it is hepatically metabolized. The recommended dose is 500 mg orally or intravenously every 8 hours. However, the dose of the fluoroquinolone taken intravenously needs to be reduced and after consulting the Compendium of Pharmaceuticals and Specialties[14] product monograph, you give ciprofloxacin 400 mg intravenously every 24 hours. An order is written for a repeat test of Ms. J's serum creatinine in 48 hours. Her medication list is reviewed, and no drug interactions are identified.



CommentSafe drug prescribing for patients with renal insufficiency can be complex, but with the application of a stepwise approach the difficulties can be minimized. When in doubt, appropriate information for dosing guidelines should be sought in recently published monographs or texts.



Key points

 • Identify those patients at risk for renal insufficiency • Measure serum creatinine and either calculate or measure creatinine clearance • Consider whether the patient's medications should be altered because of the patient's renal insufficiency • Adjust drug doses if required • Use the least nephrotoxic drug possible • Monitor drug levels and renal function• Keep up-to-date medication lists and be aware of complementary medicines



Articles to date in this series

Morton AR, Iliescu EA, Wilson JWL. Nephrology: 1. Investigation and treatment of recurrent kidney stones. CMAJ2002;166(2):213-8.

House AA, Cattran DC. Nephrology: 2. Evaluation of asymptomatic hematuria and proteinuria in adult primary care.CMAJ 2002;166(3):348-53.



References
1. Canadian Organ Replacement Register Annual Report 2000. Ottawa: Canadian Institute for Health Information; 2000.   

2. Jones CA, McQuillan GM, Kusek JW, Eberhardt MS, Herman WH, Coresh J, et al. Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998;32(6):992-9.   Abstract 

3. Lam FYW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clin Pharmacokinet 1997:32(1):30-57.  Abstract 

4. Talbert RL. Drug dosing in renal insufficiency. J Clin Pharmacol 1994:34:99-110.   Abstract 

5. Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999:45:243-53.   Abstract 

6. Matzke GR, Frye RF. Drug administration in patients with renal insufficiency: minimizing renal and extrarenal toxicity. Drug Saf 1997:16(3)205-31.   

7. Duncan L, Heathcote J, Dujurdjev O, Levin A. Screening for renal disease with serum creatinine: Who are we missing? [abstract]. J Am Soc Nephrol 1998;9:153A.   

8. Mendelssohn DC, Barrett BJ, Brownscombe LM, Ethier J, Greenberg DE, Kanani SD, et al. Elevated levels of serum creatinine: recommendations for management and referral. CMAJ 1999:161(4):413-7. Available: www.cma.ca/cmaj/vol-161/issue-4/0413.htm   Abstract 

9. Groop LC, Luzi L, De Fronzo RA, Melander A. Hyperglycemia and absorption of sulphonylurea drugs. Lancet 1989;2(8655):120-30.   Abstract 

10. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int 1984;26(2):183-9.   Abstract 

11. Frye RF, Matzke GR. Drug therapy individualization for patients with renal insufficiency. In: Dipiro JT, Talbert RL, Yee GC, editors.Pharmacotherapy: a pathophysiological approach. 4th ed. Stamford (CT): Appleton and Lange; 1999. p. 872-89.   

12. Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 1984;34:395-7.   Abstract 

13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.   Abstract 

14. Compendium of pharmaceuticals and specialties. 36th ed. Toronto: Canadian Pharmacists Association; 2001.   

15. Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, et al. Drug prescribing in renal failure. 4th ed. Philadelphia: American College of Physicians; 1999.   

16. Bakris GL, Talbert R. Drug dosing in patients with renal insufficiency. Postgrad Med 1993;94(8):153-64.   Abstract 

17. DerMarderosian A, editor. The review of natural products. Philadelphia: Philadelphia College of Pharmacy and Science; 1999.   

18. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998;104:170-8.   Abstract 

19. Yang C, Lin C, Chang S, Hsu H. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis2000;35(2):313-8.   Full Text 

20. Mueller BA, Scott MK, Sowinski KM, Prag KA. Noni juice (Morinda citrifolia): hidden potential for hyperkalemia. Am J Kidney Dis 2000;35(2):310-2.  Full Text 

21. Vanherweghem JL. Nephropathy and herbal medicine [editorial]. Am J Kidney Dis 2000;35(2):330-2.   Full Text