Renal Failure Drug Dose Adjustments


Definition/Introduction

Chronic kidney disease (CKD) is a form of kidney disease in which there is a gradual loss of kidney function occurring over a period of months to years.[1] Although many sites of drug metabolism and excretion exist, the chief organ of metabolism is the liver, whereas the organ primarily tasked with excretion is the kidney.

By definition, the presence of both factors (glomerular filtration rate [GFR] less than 60mL/min and albumin greater than 30mg per gram of creatinine) accompanied by abnormalities of kidney structure or function for longer than three months signifies chronic kidney disease. End-stage renal disease, furthermore, is defined as a GFR less than 15mL/min.

Renal impairment modifies the effects of many medications, occasionally diminishing them but more usually enhancing or even multiplying them, thus leading to accumulation and potential toxicity. Many of these alterations can be and should be predicted and subsequently alleviated by adjusting drug doses.

Chronic kidney disease interacts with drugs in three specific pathways. The first is that patients with renal impairment are more susceptible to an administered medication effect (patient vulnerability). The second is that a medication effect may be amplified or diminished in patients with renal impairment (pharmacodynamic modification). The third, and most important, is that certain medications have greater steady-state concentrations when administered at normal doses to patients with renal insufficiency (pharmacokinetic modifications). 

Summarizing the above: The medication dose should be decreased equivalently to the calculated reduction of drug clearance.

Issues of Concern

Chronic kidney disease (CKD) subdivides into five stages (table1). It is essential to know whether a patient has renal insufficiency (CKD stages 2 through 5) and, if so, at what stage, because the kidneys excrete almost half of all drugs or their metabolites, and 30% of all adverse effects of medication are attributed either a renal cause or a renal effect.[2] Chronic kidney disease affects a significant number of the general population, especially hospitalized patients. As estimated in the NHANES study, the prevalence of renal insufficiency with a glomerular filtration rate (GFR) under 60 mL/min is 11% to 13%.In the meantime, 20% of all hospitalized patients have impaired renal function.[3]

In patients with renal impairment, the dosing of renally secreted drugs has to be adjusted based on the patient's actual glomerular filtration rate (GFR). In the past, this was by using the Cockcroft-Gault equation or measuring creatinine clearance.[4] Lately, the MDRD (Modification of Diet in Renal Disease) formula is available to physicians, providing an assessment of GFR readily accessible on routine pathology reports.[5] 

The existence of these four different methods of evaluating renal function usually confuses healthcare workers as to which is the best approach. Recently a newer formula, CKD-EPI (named after the Chronic Kidney Disease Epidemiology Collaborative), is being used.[3] However, there is no consensus as to which method better estimates accurate GFR values.[6]

The GFR estimation according to every formula is:

1) The Cockroft Gault formula(1973)

GFR={((140–age) x weight)/(72xCreatinine)}x 0.85 (if female)

2) MDRD equation 

186 x (Creatinine/88.4) x (Age) x (0.742 if female) x (1.210 if black)

3) CKD-EPI equation

GFR = 141 × min(S/κ, 1) × max(S/κ, 1) × 0.993 × 1.018 [if female] × 1.159 [if black]

Abbreviations/UnitsS is serum creatinine in mg/dL,κ = 0.7 for females and 0.9 for males,α = -0.329 for females and -0.411 for males,min = the minimum of S/κ or 1, andmax = the maximum of S/κ or 1

CKD Stage / GFR (mL/min) / Renal insufficiency

  • 1 / 120 to 90 / none
  • 2 / 89 to 60 / mild
  • 3a / 59 to 45 / intermediate
  • 3b / 44 to 30 / moderate
  • 4 / 29 to 15 / severe
  • 5 / 14 to 0 / preterminal, requires dialysis

Table 1. Chronic kidney disease stages and severity of renal insufficiency

Clinical Significance

In renal insufficiency:

  • Specific drugs are notably useful
  • Any medication can be administered to any patient since the clinician can adjust the dose, considering the appropriate pharmacokinetics and pharmacodynamics.

On the other hand, some medications apply their effects independently. Without deteriorating renal function, so it is often appropriate for physicians to find and administer those drugs when necessary.[7]

Factors and conditions that may worsen the renal injury and thus should be either avoided or resolved are:

  • Nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast)
  • Uncontrolled diabetes
  • Systemic hypertension
  • Proteinuria
  • Dehydration
  • Smoking
  • Hyperlipidemia
  • Hyperphosphatemia

Nursing, Allied Health, and Interprofessional Team Interventions

Based on several studies, 34 to 53% of the drugs that required adjustment were not taken into consideration by the physicians’ instructions.[8][9] Various explanations exist regarding this inadequacy of medication dose regulation. The most frequent reason is that physicians often underestimate the impact of mild and intermediate renal insufficiency or that they have inadequate knowledge of the medications that require dose adjustment in renal insufficiency. Even though the serum creatinine level is a widely used value in everyday practice,  this biomarker is usually improper to evaluate actual renal function, thus leading to underestimating renal impairment, specifically among the elderly. 

Another possible explanation is that physicians, due to insufficient time, do not calculate the creatinine clearance by using one of the three existing formulas, which leads to underrating the need to adjust medication dosage[10] [Level 3] There are particular guidelines from the FDA and EMA about the pharmacokinetics, concerning patients with an impaired renal function, that should be followed when developing new drugs.[11][12] [Level 1] Taking into consideration the potential adverse effects, drug interactions, and treatment failure or discontinuation due to nephrotoxicity is something every physician should always do, before any drug administration.

Good communication between physicians, pharmacists, and nurses is important for the safe and appropriate drug administration in patients with renal impairment.


Article Details

Article Author

Chris Kyriakopoulos

Article Editor:

Vikas Gupta

Updated:

7/26/2020 10:33:17 AM

References

[1]

Stevens LA,Nolin TD,Richardson MM,Feldman HI,Lewis JB,Rodby R,Townsend R,Okparavero A,Zhang YL,Schmid CH,Levey AS, Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2009 Jul;     [PubMed PMID: 19446939]

[2]

Lattanzio F,Corsonello A,Montesanto A,Abbatecola AM,Lofaro D,Passarino G,Fusco S,Corica F,Pedone C,Maggio M,Volpato S,Incalzi RA, Disentangling the Impact of Chronic Kidney Disease, Anemia, and Mobility Limitation on Mortality in Older Patients Discharged From Hospital. The journals of gerontology. Series A, Biological sciences and medical sciences. 2015 Sep;     [PubMed PMID: 25991829]

[3]

Levey AS,Stevens LA,Schmid CH,Zhang YL,Castro AF 3rd,Feldman HI,Kusek JW,Eggers P,Van Lente F,Greene T,Coresh J, A new equation to estimate glomerular filtration rate. Annals of internal medicine. 2009 May 5;     [PubMed PMID: 19414839]

[4]

Cockcroft DW,Gault MH, Prediction of creatinine clearance from serum creatinine. Nephron. 1976;     [PubMed PMID: 1244564]

[5]

Gelsomino S,Bonacchi M,Lucà F,Barili F,Del Pace S,Parise O,Johnson DM,Gulizia MM, Comparison between three different equations for the estimation of glomerular filtration rate in predicting mortality after coronary artery bypass. BMC nephrology. 2019 Oct 16;     [PubMed PMID: 31619211]

[6]

Guo M,Niu JY,Ye XW,Han XJ,Zha Y,Hong Y,Fang H,Gu Y, Evaluation of various equations for estimating renal function in elderly Chinese patients with type 2 diabetes mellitus. Clinical interventions in aging. 2017;     [PubMed PMID: 29070944]

[7]

Czock D,Markert C,Hartman B,Keller F, Pharmacokinetics and pharmacodynamics of antimicrobial drugs. Expert opinion on drug metabolism     [PubMed PMID: 19416084]

[8]

Alahdal AM,Elberry AA, Evaluation of applying drug dose adjustment by physicians in patients with renal impairment. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2012 Jul;     [PubMed PMID: 23960796]

[9]

Salomon L,Deray G,Jaudon MC,Chebassier C,Bossi P,Launay-Vacher V,Diquet B,Ceza JM,Levu S,Brücker G,Ravaud P, Medication misuse in hospitalized patients with renal impairment. International journal for quality in health care : journal of the International Society for Quality in Health Care. 2003 Aug;     [PubMed PMID: 12930048]

[10]

Mariani LH,Bomback AS,Canetta PA,Flessner MF,Helmuth M,Hladunewich MA,Hogan JJ,Kiryluk K,Nachman PH,Nast CC,Rheault MN,Rizk DV,Trachtman H,Wenderfer SE,Bowers C,Hill-Callahan P,Marasa M,Poulton CJ,Revell A,Vento S,Barisoni L,Cattran D,D'Agati V,Jennette JC,Klein JB,Laurin LP,Twombley K,Falk RJ,Gharavi AG,Gillespie BW,Gipson DS,Greenbaum LA,Holzman LB,Kretzler M,Robinson B,Smoyer WE,Guay-Woodford LM, CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019 Feb;     [PubMed PMID: 30420158]

[11]

Paglialunga S,Offman E,Ichhpurani N,Marbury TC,Morimoto BH, Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines. Expert review of clinical pharmacology. 2017 Mar;     [PubMed PMID: 27998190]

[12]

Zhang L,Xu N,Xiao S,Arya V,Zhao P,Lesko LJ,Huang SM, Regulatory perspectives on designing pharmacokinetic studies and optimizing labeling recommendations for patients with chronic kidney disease. Journal of clinical pharmacology. 2012 Jan;     [PubMed PMID: 22232757]