Decreased kidney function, whether the result of chronic kidney disease or acute injuries to the kidney, can substantially alter the removal of drugs from the body, leading to toxicity or even, in some cases, less effectiveness.
Approximately 13.4% of the world’s population has chronic kidney disease (with ~3 million people in the UK affected), and the incidence rises in older adults, where 24-36% of patients ≥ 65 years of age are impacted. Decreased kidney function is often overlooked clinically, particularly in younger patients, but new, acute-onset kidney impairment can occur at any time due to medication, illness, or trauma.
This type of injury occurs in 23% of hospitalised patients, and ≥ 50% of patients admitted to the intensive care unit. Regular monitoring of kidney function should be considered for many higher risk patient populations and is essential in patients with chronic kidney disease, patients with certain acute illnesses, and those requiring particular high-risk medications in order to allow for proper dose adjustments and monitoring, making this a critical aspect of precision medicine.
Creatinine based monitoring
Kidney function is typically assessed by measuring or estimating the glomerular filtration rate (GFR), which describes how well the kidneys filter the blood. GFR varies according to age, sex, and body size. GFR is most commonly determined by calculating an estimated GFR (eGFR) using serum Cystatin C or creatinine. In adults, there are various methods for estimating renal function, the most common of which are the Cockcroft-Gault equation, Modification of Diet in Renal Disease (MDRD) Study equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
In general, the CKD-EPI equation is preferred for estimating GFR. For drug dosing purposes, the correct equation is more controversial, with some clinicians utilising the CKD-EPI equation (preferably with the BSA normalisation removed when making estimations in patients with body size very different from average), and others utilising the Cockcroft-Gault equation, particularly in older patients, where the MDRD and CKD-EPI equations tend to produce significantly higher estimates of kidney function compared to the Cockcroft-Gault and can lead to higher drug dose being prescribed.
Just like in adults, there are many ways to measure and estimate renal function in paediatric patients. The preferred method uses serum creatinine (SCr), which is a readily available laboratory measurement, and the Bedside Schwartz equation to calculate and estimated GFR [eGFR (mL/min/1.73m2)=0.413 x (height (cm)/SCr)]. This equation has been modified over the years, with the final modification suitable for creatinine measurements calibrated to an international standard. The results will yield an eGFR suitable for estimating renal function for both children and adolescents.
Manufacturer labelling does not always include dose adjustment recommendations. The information that is provided can be as detailed as a specific dosing adjustment based on eGFR or as generic as 'use caution'. Before 1998, there was no official structured regulatory guidance for drug companies regarding when, how and for which drugs studies should be conducted. In fact, most information came from post-marketing studies which often utilised small numbers of patients and sometimes led to conflicting dosing recommendations. Furthermore, even with US and EU regulatory guidance in place, a single dose pharmacokinetic study conducted in patients with stable chronic kidney disease has limited applicability to patients with acute chronic kidney injury, the critically ill, or those receiving renal replacement therapies; thus significant gaps in knowledge continue to exist for most drugs utilised in patients with kidney disease.
As difficult as it is to find manufacturer recommendations for adult patients, it is even less common to find dosing recommendations for paediatric patients with kidney impairment. In paediatric patients, studies are less readily available because at best, paediatric trials are difficult to perform, and since these patients are generally healthier, the results affect a smaller segment of the population, especially those with kidney impairment.
Many independent researchers perform drug dosing trials trying to understand how the kidney handles these medications. While such studies are most commonly performed in adults, the knowledge gained can help clinicians by giving them principles discovered in the adult research that can then be applied to paediatric patient.
Drugs requiring adjustment
Any drug that is eliminated by the kidneys may require dosage adjustment in patients with impaired kidney function. Without adjustment, drug accumulation can occur, often leading to a greater risk for toxicity, with common culprits requiring adjustment including antibiotics, antihypertensives, diuretics, cholesterol-lowering medications and anti-seizure drugs. Well-known examples are medications like gentamicin, which require specific monitoring and dosage adjustment to help prevent worsening toxic effects on the kidney. Others, such as the anticoagulant apixaban, have dosing adjustment based on a combination of renal function, age and weight. In the case of apixaban, giving too little could result in a catastrophic stroke, while giving too much could lead to serious bleeding.
Despite the known risks, medications often go unadjusted for kidney function. In one meta analysis, 19-67% of medications prescribed in the hospital and 34% of medications prescribed in the community setting were not appropriately adjusted according to dosing guidelines. In patients with end stage kidney disease (ESKD) guideline compliance is even worse, with 84.3% of medications prescribed in surgical clinics and 46.2% of those prescribed in medical clinics dosed incorrectly.
Unfortunately, when dose adjustments are not made correctly there is a strong potential for patient harm. In one retrospective study looking at discharge medications in academic medical centres in the Netherlands, 46% of medications were not appropriately adjusted, and of these medications 71.4% of the cases had the potential to cause moderate to severe harm, which was described as moderate to severe patient discomfort or clinical deterioration.
While the term 'precision medicine' has often been used to describe advances in genomic testing (with drug therapy tailored to an individual’s genomic makeup), it also encompasses any interventions made to individualise therapy to a patient’s needs. In that sense, pharmacists have been practising precision medicine for decades, and tailoring a medication dose to a patient’s kidney function is an important way to optimise therapy while minimising toxicity in each patient.
In one study, a clinical pharmacist providing real-time feedback to interns at an academic medical hospital increased the proportion of appropriately adjusted medications from 33% to 81%. Unfortunately, even though the need for adjusting medications for kidney function is not a new idea, the complexity of each patient and the lack of published data in various populations (such as the critically ill, paediatrics and those with other types of organ failure), means that this practice continues to be difficult. Despite these challenges, monitoring and measurement of eGFR and proper adjusting of drug doses enhances safety and improves patient care, with pharmacists playing a critical role in monitoring and recommending dosage adjustment in patient care to improve outcomes.
Darcie Streetman is neonatal/paediatrics senior clinical content specialist for clinical effectiveness at Wolters Kluwer, Health and Rachel Eyler, is nephrology senior content specialist, also of Wolters Kluwer