Renal Medication Dosing

Renal Medication Dosing

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Introduction

Dosing medications for patients with Chronic Kidney Disease (CKD) is a most difficult proposition for practitioners. The Kidney Disease: Improving Global Outcomes (KDIGO) experts predict that there will be a major increase in the number of patients with CKD.[1]  As a result, they convened for a global discussion revolving around what we know, what we do not know, and what research and regulatory goals will help clinicians treat millions of CKD patients safely and effectively.[2] This is an update for the non-nephrology practitioner on the practical dosing of medications for the CKD patient..

Assessing Kidney Function

Prior to treating CKD patients, one must define kidney function. The most commonly used is the Glomerular Filtration Rate (GFR) but this calculation can be done in many ways. While the most frequent research equation is the Cockcroft/Gault, this formula does not adjust for body surface area and is fraught with difficulties for medication dosing for the practitioner.[3][4] The Modification of Diet in Renal Disease formula (MDRD) was developed for patients with known kidney disease and is invalid with GFR> 60 ml/min.[5] The most common formula is the CKD-Epidemiology Collaboration (CKD-EPI), which is reported by LabCorp and Quest (the two largest labs in the US) in ml/min per 1.72m2 to account for body surface area and is considered to be the most accurate GFR for medication dosing.[6] While  medications with small therapeutic windows require the practitioner to know what formula was used to calculate kidney function, for the vast majority of medications any GFR formula is acceptable.

Historical Considerations

Before 1998, there was no requirement for testing medications in CKD patients or at differing levels of kidney function.  Then, in 1998, the FDA published guidance requiring renal dosing so many of the newer medications included CKD patients using a GFR calculation for the dosing adjustments.[7]  The European Medicines Agency (EMA) guidelines, published in 2004, took this 2nd step and required that all manufactures test and dose correct their medications for the Acute Kidney Injury (AKI) patient.[8] Many older, common medications used in CKD patients have dosing algorithms that are invalid.  A typical example is Metformin. (See Table 1)

While most of us worry about the CKD patient being overdosed, there is also the worry if the metabolite of the original medication is toxic to the CKD patient.[9] There is also the question of ‘true’ GFR in the rapidly deteriorating AKI patient and the third spacing of fluid in the CKD patient. This makes research and calculation of renal dosing for both CKD and AKI more of an art than a science.

Dosing Goals

Each class of medication has different goals: some require maintenance for a specific time frame, some have a narrow therapeutic window while others require a high peak. Some medications are very protein bound and as kidney disease progresses, malnutrition plays a role in the dosing of medications.[10] Many medications can be adjusted by decreasing the number of doses after an initial loading dose. This is commonly done for antibiotic dosing in CKD patients.[11-15] Measuring drug concentration levels may be useful for dosing in the hospital setting but it is not practical in the outpatient setting.

A loading dose is rarely recommended by the package insert but it is often the most effective way to give medications in a CKD patient…especially for those drugs with long half-lives.[2][16] A protein-bound drug requires serum albumin to be measured and adjustments made to correct for the lower albumin levels seen in the CKD patient. For the CKD patient with proteinuria, this requires a lowering of the usual medication dose.[10][12]

Non-steroidals (NSAIDS) are contraindicated in the CKD patient due to the activation of the renin-angiotensin-aldosterone (RAAS) system which reduces flow to the distal tubules.[17] Damage from NSAIDS use can be reversed but the safer method is to avoid NSAIDS and give low dose narcotics.

Dosing Class Suggestions

Using the general guidelines above and the dosing guidelines in the published literature, suggestions for classes of medications can be made. Since diabetes and hypertension are the most common causes of CKD[1], medications to manage those conditions are highlighted.

Diabetes Medications
All second generation Sulfonylureas are used in CKD although Glyburide cannot be used when the GFR< 50ml/min.[18] Glipizide requires no renal adjustment thus it is used frequently by nephrology.[18] As noted in Table 1, while the FDA insert packet of Metformin specifies discontinuation when the SCr is below 1.5, most practitioners will stop Metformin at a GFR of 50 ml/min to be safe.[19] The newer insulin medications, the dipeptidyl peptidase-4 (DPP-4) inhibitors such as Sitagliptin and Saxagliptin, are safe for CKD patients but care must be taken when using the combinations of a DPP-4 inhibitor and Metformin.[20] Often, the GFR is not followed closely and the patient stays on the combination drug past the safe GFR< 50 ml/min. Exenatide is not recommended with a GFR<30 [21] while Sitagliptin has dosing adjustments for a dropping GFR.[22] Insulin, and especially the long-acting insulins (Glargine and Detemir), is extremely easy to adjust in the CKD patient. Forty to fifty percent of insulin is excreted by the kidney so dose decreases must be made as the loss of the kidney function progresses.[23] The American College of Physicians has an algorithm for adjusting insulin doses[13] but the need for dose adjustments in the CKD patient is very patient specific and does not always lead itself to a strict algorithm.[24]

Hypertension
All CKD patients with proteinuria should be on angiotensin converting enzymes inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) unless contraindicated by a side effect.[25] Since all ACEIs have some renal excretion, a lower dose allows both reno-protection and blood pressure effects. Beta-blockers are renally excreted and adjustments can be made by monitoring the heart rate.[18] Diuretics, a cornerstone of CKD blood pressure management, have to be adjusted as the GFR falls below 30 ml/min by converting thiazides to loop diuretics.[26] Many nephrologists feel that a change to a loop diuretic may be more useful at a GFR of 50 ml/min since the thiazide diuretic has difficulty getting to the distal tubule (its point of action) as the kidney fails.[27] Aldosterone antagonists (spirolactone and eplerenone) have seen a resurgence in use after publication of an article outlining reno-protective benefits in the proteinuric CKD patient but potassiums must be closely monitored.[28] Calcium channel blockers are extremely effective in blood pressure control but remember that the dihydropiridine versions can worsen proteinuria in patients with nephropathy.[29] However, NKF has published a table of oral anti-hypertensive drugs that can positively influence cardiovascular or renal outcomes and two dihydropyridines (amlodipine and nisoldipine) were on the list.[30] A wonderful overview with dosing tables was published in 2011.[31]

Special Circumstances
Hemodialysis requires dosing adjustments for almost all medications used in kidney failure. Since 2000, dialyzers have made a generational leap forward with high-flux dialyzers used by most dialysis patients.[32][33] High-flux dialyzers are larger, more aggressive and will allow passage of most solutes. The large charts of ‘Dialyzable Drugs’ that so many of us remember, are no longer produced due to removal of all drugs, except for the most protein-bound, by the new dialyzers.  Studies of Peritoneal Dialysis (PD) patients have shown similar pharmacokinetics between PD and a GFR of 15.[34][35] Thus, the PD patient is to be dosed identically to the Stage 5 CKD patient. The pregnant patient will present with the same difficulty as the AKI patient: the increase in blood volume of the pregnant patient corresponds to the 3rd spacing seen in the AKI patient in the ICU. Often the pharmacist is your most important resource in these rapidly changing patients.

Conclusion

The renal community and KDIGO want to update practitioners about the dosing of medications for the CKD and AKI populations. Medication renal adjustments are rare in the FDA dosing inserts for medications released prior to 1998. For those after 1998, the renal adjustments can often be inadequate.

 

Kim Zuber, PAC, MS, DFAAPA
Metropolitan Nephrology
Published on February 12, 2013

Biosketch
Kim Zuber, PAC practices nephrology in Alexandria, VA and Prince George’s, MD. She graduated from the St. Louis University PA program a number of years ago. She is the award winning past chair of the National Kidney Foundation’s Council of Advanced Practitioners, and speaks and writes for the NKF nationally.

References

  1. U.S. Renal Data System, USRDS 2009 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009.
  2. Matzke G, et al. Drug Dosing Consideration in Patients with Acute and Chronic Kidney Disease-A Clinical Update from Kidney Disease: Improving Global Outcomes (KDIGO), KI. 2011;80:1122-1137.
  3. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
  4. Froissart, M, Rossert, J, Jacquot, C, Paillard, M, Houllier, P Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol. 2005;16(3):763-773.
  5. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–470.
  6. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-612.
  7. FDA. Guidance, Compliance & Regulatory Information (Biologics). Characterization of the relationship between pharmacokinetics and pharmacodynamics of a drug and renal function. 1998.
  8. Anonymous. Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. 2004.
  9. Buxton, ILO. Pharmacokinetics and pharmacodynamics: The dynamics of drug absorption, distribution, action, and elimination. In Brunton LL, Lazo JS, & Parker KL (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics (11th ed). McGraw-Hill: New York, NY, 2006:1-39.
  10. Meijers BK, Bammens B, Verbeke K, et al. A review of albumin binding in CKD. Am J Kidney Dis. 2008;51:839-850.
  11. Matzke GR, Dowling T. Dosing concepts in renal dysfunction. In: Murphy JE (ed). Clinical Pharmacokinetics Pocket Reference, 5th ed. American Society of Health-System Pharmacists: Bethesda, MD, 2011.
  12. Thummel K, Shen D, Isoherranen N, et al. Design and optimization of dosage regimens: pharmacokinetic data. In: Hardman J, Limbird L, Goodman G (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. McGraw-Hill: New York, NY, 2006.
  13. Aronoff G, Bennett W, Berns J, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. American Society of Physicians – American Society of Internal Medicine: Philadelphia, PA, 2007.
  14. McEvoy G, Litvak K, Welsh O. American Hospital Formulary Service, Drug Information. American Society of Hospital Pharmacists: Bethesda, MD, 2011.
  15. Olyaei AJ, Bennett WM. Drug dosing in the elderly patients with chronic kidney disease. Clin Geriatr Med. 2009;25:459–527.
  16. Craig WA. Pharmacokinetic/Pharmacodynamic Parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1–10; quiz 11–12.
  17. NKF Primer of Kidney Diseases, 5th ed. Greenberg A, Editor. Elsevier Health Sciences. Feb 2009:315.
  18. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. American Family Physician. 2007;75:1487-1496.
  19. Brazie M. Finding the Sweet Spot: Trouble-shooting diabetic dilemmas. Oral Presentation, NKF Spring Clinical Meetings, 11 May 2012, Washington, DC.
  20. Hocher B, Reichetzeder C, Alter ML. Renal and Cardiac Effects of DPP-4 Inhibitors – from Preclinical Development to Clinical Research. Kidney Blood Press Res. 2012;36(1):65-84
  21. Anonymous. Exenatide (marketed as Byetta) Information. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm113705.htm
  22. Anonymous. Merck Pharmaceuticals Package Insert (2006). Revised April 2012. http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf.
  23. Charpentier G, et al. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes and Metabolism. 2000;26(S4):73-85
  24. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Seminars in Dialysis. 2004;17(5):365-370.
  25. NKF/KDOQI Guideline 6: Management of hypertension in diabetes and chronic kidney disease. 2004;updated 2012.
  26. Wilcox CS. New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrology. 2002;13:798-805.
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  28. Jain G, Campbell RD, Warnock D. Mineralocorticoid receptor blockers and chronic kidney disease. Clinical Journal of the American Society of Nephrology. 2009;4:1685-1691.
  29. Remuzzi G, Scheppati A, Ruggenenti P. Clinical practice nephropathy in patients with type 2 diabetes. NEJM. 2002:346(15):1145-1151.
  30. NKF Primer of Kidney Diseases, 5th ed. Greenberg A, Editor. Elsevier Health Sciences. Feb 2009:553.
  31. Liles AM. Medication considerations for patients with chronic kidney disease who are not yet on dialysis. Nephrology Nursing Journal. 2011;38(3):263-270.
  32. NKF Primer of Kidney Diseases, 5th ed. Greenberg A, Editor. Elsevier Health Sciences. Feb 2009:446.
  33. Matzke GR. Status of hemodialysis drugs in 2002. J Pharm Pract. 2002;15:405-418.
  34. Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65:757–773.
  35. Paton TW, Cornish WR, Manuel MA, et al. Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations. Clin Pharmacokinet. 1985;10:404-425.

1 Comment

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  1. Odun Obisesan

    February 19, 2015 at 8:54 am

    Thank you

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