Optimising prescribing in renal impairment

Chronic kidney disease (CKD) is becoming a major public health problem worldwide. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) defines chronic kidney disease as the presence of kidney damage or a reduction in the glomerular filtration rate (GFR) to <60ml/min/1.73 m2 for three months or longer.(1)

According to a systematic review of published data on the prevalence of CKD in various populations, the median prevalence of CKD was 7.2% in persons aged 30 years or older and varied from 23.4% to 35.8% in persons aged 64 years or older.(2)

The ERPHOS study, conducted in Spanish hospitals, found a GFR <60ml/min in 28.4% of hospitalised patients and <44ml/min in 13.1 % of patients. Additionally, 42% of men and 59% of women older than 80 years had a GFR of <60ml/min.(3)

CKD is becoming a common disease throughout the world and this problem will increase in the future owing to the ageing population and the increasing prevalence of diabetes and hypertension.(4)

CKD affects renal drug elimination and other pharmacokinetic and pharmacodynamic processes. Dosages of a number of drugs should be adjusted in the presence of renal failure to avoid drug toxicity, ineffective therapy and increased costs.(5)

There are several published guidelines that suggest dosing adjustments for individual drugs based on renal function. The first step to optimise drug prescribing in renal impairment patients is identifying patients with renal failure. GFR is accepted as the best overall index of renal function and serum creatinine level has been used to estimate it in traditional practice. However, the use of an equation to routinely estimate GFR rather than using serum creatinine levels alone is recommended because the equations take into account several clinical and demographic parameters and are considered the best index of GFR in clinical practice.(1,5)

There are two commonly used equations to estimate GFR in clinical practice: the Modification of Diet in Renal Disease (MDRD) Study equation and the Cockcroft-Gault equation.(1,3)

The Cockcroft-Gault formula aims to predict creatinine clearance from knowledge of serum creatinine, age, weight, and gender.(1,4)

Creatinine clearance (ml/min) = eClCr = [(140 – age in years) x (weight in kg) x (0.85 if women)]/(72 x serum creatinine mg/dl)

The MDRD study equations consider serum creatinine, age, gender and race. There are several versions of the MDRD study formula.(1,4)

Although the Cockcroft-Gault equation is the equation most commonly used in pharmacokinetics studies developed to establish drug dosing, the National Kidney Disease Education Programme (NKDP) suggests that either equation can be used to estimate kidney function for drug dosing.(5)

The Cockcroft-Gault formula is also the equation most commonly used in consensus-based medication dosing guidelines for patients with renal impairment.

Both estimation equations that use serum creatinine are limited for some cases (patients with unusual diets, at extremes of muscle mass, with changes in creatinine secretion or populations with normal or near normal GFR) and do not accurately reflect renal function in non-steady state conditions.(4–7)

Variability among clinical laboratories in calibration of serum creatinine assays introduced error in GFR estimates. In 2005, the National Institute of Standards and Technologies released materials that are traceable to the certified reference materials for creatinine whose value was assigned using isotope dilution mass spectroscopy (IDMS), avoiding the variability in serum creatinine assays among laboratories as well as within laboratories over time. Currently, the majority of laboratories use creatinine methods calibrated to be IDMS traceable and report the IDMS-traceable MDRD4 revised equation.

Estimated glomerular filtration rate (ml/min/1.73m2 = eGFR = 175 x (standardised serum creatinine mg/dl)–1.154 x (age years)–0.203 x (0.742 if female) x (1.212 if African–American)

The equation does not require weight because the results are reported normalised to 1.73m2 body surface area, which is an accepted average adult surface area.(6,7)

 The use of IDMS methods leads to less variation in estimating kidney function and more consistent drug dosing. Although the variation in the creatinine assays before the availability of standardised creatinine assays does affect the relationships from pharmacokinetic/pharmacodynamic drug studies of the past, for the majority of patients and for most drugs tested, there is likely to be little difference in the drug dose.(6,7)

Taking all these data into account, the NKDP suggests the use of eGFR or eCrCl for drug dosing with recommendations in some cases (very large or very small patients, when prescribing drugs with narrow therapeutic indices or for patients in whom any estimates based on creatinine are likely to be inaccurate). In these cases, assessment of kidney function using alternative methods is recommended.(8)

Despite the existence of published guidelines for dosing adjustments based on renal function, inappropriate dosing of renally cleared or potentially nephrotoxic drugs is a common drug-related problem in inpatient care.(9)

Frequencies of inappropriate orders in patients with renal impairment reported in several hospital-based studies ranged from 15% to 67%.(10,11)

These differences can be explained by differences in guideline compliance among institutions, inconsistent definitions of CKD, the type of drugs evaluated, and differences between dosage guidelines used. In any case, they point to a need to evaluate the situation in each institution and the need for interventions that improve compliance with renal dosing guidelines.

Several studies have been developed to assess the efficacy of computerised provider order entry (CPOE) with clinical decision support system (CDSS) and/or review of orders by pharmacists for reducing prescription errors related to drug dosage in renal insufficiency.(10–16)

Manual or semi-automated programmes helped pharmacists to identify patients with reduced renal function, identify medication orders that may require dosage modifications based on renal function, and generate an alert with a recommendation of specific dosage adjustments (based on current dosage guidelines).(12–14)

Completely automated programmes implemented alerts for drug dosing adjustment into the daily routine use of a CPOE.(10,11,15)

The interventions differed from manual reviews to a completely automated alert system with varying results.(10–16) The frequency of accepted recommendations found in these hospital-based studies ranged from 41.8%(14) to 88%.(12) According to the results, these kinds of intervention improved renal dosing guideline compliance in inpatient care.

The review of these studies allows pharmacists to develop an alert system for checking doses of medications according to the patient’s renal function.

Before the implementation of this kind of programmeme, the designers should take into consideration:

These seven steps can help pharmacists to design an alert programmeme without considering the level of automation.

Once we have designed the programme, we have to decide how to assess its impact. Patient-outcome measures are preferable over surrogated outcomes (for example, frequency of inappropriate dosing of drugs). To our knowledge, only two studies assessed clinical outcomes. They demonstrated the programmeme’s efficacy with different clinical outcomes.(11,15) Chertow et al found significantly shorter length of stay (adjusted for age, sex, and diagnosis-related group weight) during the interventions period.(11) In the study by Rind and colleagues, the intervention resulted in a decrease of relative risk of serious renal impairment, although they excluded patients with pre-existing moderate or severe renal insufficiency.(15)

Another important issue is the efficiency of this kind of programme. As far as we know, only two studies have evaluated the cost of these programme, and found contradicting results.(11,12) Álvarez et al defined the economic impact of the programmeme as the difference between the real cost of drugs correctly adjusted based on renal function and the assumed cost without any intervention. They reported an average saving per medication intervention amounting to €62.57.(12)  Chertow et al measured hospital and pharmacy costs compared among patients with renal impairment during the interventions versus control periods. They did not find differences in estimated hospital and pharmacy costs.(11)

There is, to our knowledge, no study that addresses the ability of this kind of programmeme to change prescription patterns over time. Further research is needed to elucidate these points.

Automated, semi-automated and manual drug-dosage programmemes to optimise drug prescribing in renal failure patients reduced the number of inappropriate orders due to renal insufficiency. This kind of intervention may result in a substantial reduction of inappropriate drug orders and, consequently, may prevent adverse drug reactions. Pharmacists should lead the implementation of this kind of interventional programmeme adapted to each institution.