Definition/Introduction

The effects of many drugs get altered in renal impairment particularly when a drug has renal clearance. Drug doses should be altered in renal disease in accordance with the predicted reduction in the clearance of the drug. Some patient factors also influence the decision to adjust drug doses, such as the degree of renal disease and patient size. There are some drug factors to be considered to adjust doses including the drug excretion and the therapeutic index. Estimation of renal function is helpful in the dosing of renally excreted drugs.

Renal disease can alter the drug concentration in the body and the effects of many drugs, sometimes reducing their effects but more commonly escalating their effects and thus causing potential toxicity. Most of these changes are predictable and may be prevented by altering drug doses in accordance with the established guidelines.

Mainly, there are three ways in which renal disease affects a drug:

1. Patient susceptibility - patients with renal impairment may be more vulnerable to a certain drug effect
2. Pharmacodynamic change - a drug effect may be increased or decreased in patients with renal disease
3. Pharmacokinetic changes - some drugs, when given at usual doses, have higher steady-state concentrations in patients with renal impairment

Increased drug clearance leads to lower drug concentrations and decreased drug clearance leads to higher drug concentrations; hence greater drug effects. To avoid harm, the dose of renally cleared drugs should be decreased in patients with renal disease.

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 60 mL/min and albumin greater than 30 mg 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 15 mL/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.

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. 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 to 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%. While 20% of all hospitalized patients have impaired renal function.[3]

In patients with renal impairment, the dosing of renally cleared drugs has to be adjusted based on the patient's actual glomerular filtration rate (GFR). In the past, this was done 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), has been greatly adapted for this purpose.[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

The units of drug dosing are amount per unit time, for instance, 500 mg twice daily. Dose adjustment is usually crude for most drugs in many circumstances, such as doubling or halving doses. In most cases, having the means to establish when drug dose should be doubled or halved is crucial, whereas a 20% alteration in dose is usually impractical and unnecessary. However, there are many drugs for which minor changes in dose or concentration may cause a significant effect, commonly called a narrow therapeutic index. The therapeutic index is calculated by using the following formula:

• The therapeutic index = Minimum toxic dose / Minimum effective dose

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 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 safe and appropriate drug administration in patients with renal impairment.