Nephrology: 3. Safe drug prescribing for patients with renal insufficiency ========================================================================== * Joanne Kappel * Piera Calissi **Case** Ms. 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? 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 insufficiency All 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 View this table: [Table1](http://www.cmaj.ca/content/166/4/473/T1) Table 1. 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. View this table: [Table2](http://www.cmaj.ca/content/166/4/473/T2) Table 2. ## Management Once 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. View this table: [Table3](http://www.cmaj.ca/content/166/4/473/T3) Table 3. 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 View this table: [Table4](http://www.cmaj.ca/content/166/4/473/T4) Table 5. View this table: [Table5](http://www.cmaj.ca/content/166/4/473/T5) Table 4. 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 View this table: [Table6](http://www.cmaj.ca/content/166/4/473/T6) Table 6. ## Case revisited Using 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.* ## Comment 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. Additional resources * National Kidney Foundation Web site. Available: [www.kidney.org](http://www.kidney.org) (accessed 2002 Jan 16). Articles to date in this series * Morton AR, Iliescu EA, Wilson JWL. Nephrology: 1. Investigation and treatment of recurrent kidney stones. *CMAJ* 2002;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. 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 ## Footnotes * This article has been peer reviewed. *Contributors:* Both authors participated equally in the initial writing of the paper. Dr. Kappel was responsible for all revisions. Both authors have given their final approval for publication. *Competing interests:* None declared. * **Series editor: **Dr. A. Ross Morton ## References 1. 1. *Canadian Organ Replacement Register Annual Report 2000.* Ottawa: Canadian Institute for Health Information; 2000. 2. 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. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0272-6386(98)70074-5&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=9856515&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000077383900011&link_type=ISI) 3. 3. Lam FYW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. *Clin Pharmacokinet* 1997:32(1):30-57. 4. 4. Talbert RL. Drug dosing in renal insufficiency. *J Clin Pharmacol* 1994:34:99-110. 5. 5. Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. *Gerontology* 1999:45:243-53. 6. 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. 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. 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 9. 9. Groop LC, Luzi L, De Fronzo RA, Melander A. Hyperglycemia and absorption of sulphonylurea drugs. Lancet 1989;2(8655):120-30. 10. 10. Brater DC, Day B, Burdette A, Anderson S. Bumetanide and furosemide in heart failure. Kidney Int 1984;26(2):183-9. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1038/ki.1984.153&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=6503136&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=A1984TT61400011&link_type=ISI) 11. 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. 12. Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 1984;34:395-7. [Abstract/FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjg6IjM0LzMvMzk1IjtzOjQ6ImF0b20iO3M6MjA6Ii9jbWFqLzE2Ni80LzQ3My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 13. 13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1159/000180580&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=1244564&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=A1976AV14200003&link_type=ISI) 14. 14. *Compendium of pharmaceuticals and specialties.* 36th ed. Toronto: Canadian Pharmacists Association; 2001. 15. 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. 16. Bakris GL, Talbert R. Drug dosing in patients with renal insufficiency. Postgrad Med 1993;94(8):153-64. 17. 17. DerMarderosian A, editor. *The review of natural products*. Philadelphia: Philadelphia College of Pharmacy and Science; 1999. 18. 18. Ernst E. Harmless herbs? A review of the recent literature. Am J Med 1998;104:170-8. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0002-9343(97)00397-5&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=9528737&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000072337700011&link_type=ISI) 19. 19. Yang C, Lin C, Chang S, Hsu H. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000; 35(2):313-8. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0272-6386(00)70343-X&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10676733&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000085093300021&link_type=ISI) 20. 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. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0272-6386(00)70342-8&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10676732&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000085093300020&link_type=ISI) 21. 21. Vanherweghem JL. Nephropathy and herbal medicine [editorial]. Am J Kidney Dis 2000;35(2):330-2. [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0272-6386(00)70347-7&link_type=DOI) [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=10676737&link_type=MED&atom=%2Fcmaj%2F166%2F4%2F473.atom) [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000085093300025&link_type=ISI)