Let's make a somewhat daring comparison! Pharmacology and, more specifically, dose adjustment is a bit like the penal code: Everyone knows that it exists and has an idea of what it is, at least to some extent, but everyone also knows that it can be very complicated.
The relevance of drug dose adjustment, particularly in the case of renal disease, is undeniable. If not performed correctly, prescription errors are considerably augmented, with multiple and potentially very serious consequences, which are well documented in the scientific literature.
This is a complex topic. The role of the kidney in the elimination of hydrophilic drugs is well known to healthcare professionals. However, the situation is not that simple, as so often in medicine, and the whole issue of drug dose adjustment in the case of kidney disease cannot be summarized by this statement alone. The kidney and the diseases affecting it can likewise impact intestinal reabsorption, protein binding, and even hepatic drug metabolism! The question of dose adjustment in the context of renal disease should therefore be addressed for all drugs, not just those "eliminated by the kidneys".
The complexity of the subject - and this is probably where our "legal" comparison turns out to be most relevant - can simply be explained by the huge number of available drugs. And this number is continuously increasing, which is indeed good news. In spite of all their efforts, healthcare professionals cannot possibly remember all the details for all drugs, especially those they use less commonly.
This is where a tool like RENADAPTOR, which is continuously updated, takes on its full meaning. It is a simple and precise prescription support tool. The user only needs to type in the drug name and, with a single click, he or she knows what dose to prescribe in case of renal disease, depending on the glomerular filtration rate, specific pathologies, or the need for hemodialysis support or other techniques in the event of end-stage renal disease. In most cases, users receive the answer to their question in only one or two minutes, or perhaps a handful of seconds. The tool is designed to be very simple and pragmatic. To this day, nearly 3,000 drug information sheets have been entered into the program.
A quick look is all it takes to realize just how useful RENADAPTOR is in everyday clinical practice, helping to reduce the risk of prescription errors in patients with renal failure, with all the ethical and economic consequences that this entails.
Pierre Delanaye, PhD
Nephrology - University of Liège
Belgium
Chronic kidney disease (CKD) has a high prevalence, affects between 3% and 17% of the general population, and tends to increase with age. Currently, 0.1% of the population is in end-stage renal failure and requires dialysis replacement therapy [1,2,3,4,5,6]. Renal failure and extrarenal purification techniques change the pharmacokinetics of the majority of drugs [7,8,9]. The dosage of nearly 50% of pharmacological treatments must be adjusted by considering renal failure severity and the replacement therapy used. These adjustments concern a very large number of patients; therefore any prescribing physician will sooner or later have to deal with this issue.
After identifying a patient with renal failure, the main challenge for the clinician is to determine which drug should be adapted and to what extent. In most drug directories, the available information regarding this topic is evasive or absent, and divergent information can be found, even in specialized directories [10]. As a result, most practitioners neglect this aspect, especially when they have not been educated about kidney issues.
In a clinical study carried out in a 720-bed general hospital in Boston, Chertow et al. [11] showed that 43% of the prescriptions given to 7,904 patients with renal failure were non-compliant. Failure to adapt to CKD increases adverse events, sometimes with serious toxic consequences, including torsades de pointes-type malignant arrhythmias, bone marrow aplasia, acute renal failure, fulminant hepatitis, epilepsy, coma, etc.
Hug et al. [12] performed a retrospective study in six US public hospitals and found that out of 17,614 patients with CKD, more than 50% experienced a probable adverse reaction and 10% displayed a proven adverse reaction to one or more drugs. In more than 90% of these cases, ineffective dose adjustment to renal failure was involved. Of all the adverse events identified, 50% were considered as serious, with 4.5% being life-threatening. The failure to adjust drug doses to renal failure is therefore far from being an isolated problem. It is responsible for dangerous and costly iatrogenic diseases, which represent a real public health problem [13].
Conversely, excessive or "blind" dose reduction can result in particularly harmful therapeutic inefficiency, especially in intensive care units, but also in onco-hematology and infectiology. The fear of therapeutic error can also lead clinicians to stop proposing certain treatments, particularly in the field of cardiovascular prevention [14]. It is therefore essential to prescribe the right dose to obtain the optimal therapeutic quality. To achieve this goal in daily clinical practice, the correct information must easily and quickly be available, with automatic reminders whenever possible.
Even though all pharmacokinetic parameters may be altered, CKD primarily results in altered urinary excretion of unchanged active ingredient or its metabolites. This leads to an accumulation phenomenon with half-life (t1/2) prolongation, the extent of which varies according to renal failure stage and lowered glomerular filtration rate (GFR) [7,8,9].
Therefore, drug adjustment primarily consists of reducing maintenance doses or extending the interval between doses, depending on the stage of renal failure (1 to 5). There is a specific maintenance dose for each GFR level. However, the route of administration (intravenous, oral, intramuscular, etc.) and loading dose, which depend on bioavailability and distribution volume, respectively, are usually unchanged [8,9].
Extrarenal drug replacement therapy introduction in turn modifies the pharmacokinetics of many active ingredients, increasing their elimination [8,9], which requires a new dosage adjustment. In rare cases, doses must paradoxically be adjusted upwards, particularly when treating a patient with "uremic resistance" related to number or sensitivity reduction of peripheral drug receptors. Diuretics, and especially loop diuretics, are a typical example [15,16]. Finally, the nephrotoxicity of certain molecules must particularly be considered in uremic patients [17,18]. This aspect weighs heavily in the benefit/risk balance inherent in any treatment, frequently leading to contraindication in the case of CKD.
All these clinical, pharmacological, and toxicological considerations are integrated in RenAdaptor©. This computerized drug repertory compiles the international recommendations regarding the dosage adaptation to the different renal failure stages and extrarenal purification techniques. A team of nephrologists, clinical pharmacists, and computer scientists have been working for more than 20 years on the development of this software, motivated by the difficulties encountered by clinicians in finding this type of information in their daily practice.
All the data provided by the software are primarily taken from the labels issued by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA), but also from the most recent international medical and pharmaceutical literature. The molecules are classified into four levels according to a clinically relevant pharmacotherapeutic classification and to the international "Anatomical Therapeutic Chemical" (ATC) classification system. More than 1,900 drugs, with their international nonproprietary name (INN) and brand name available for 30 countries, and around 20,000 specific references are mentioned in the database. The database is continually updated, and all drugs approved by the EMA and the FDA since 2009 are available. Molecules which are not yet available will gradually be included in order to cover the entire world's pharmacopoeia in the next years.
Renadaptor© is practical, up-to-date, and its integration into hospital prescription software (Computerized Physician Order Entry [CPOE] systems) is fairly easy as it is written in php-mysql language. Thanks to automatic reminders, the integration of Renadaptor into CPOE systems has already shown a quality improvement of the proposed treatments [10,19]. The general recommendations regarding prescriptions for renal failure patients are the subject of an international consensus published in the KDIGO (Kidney Disease Improving Global Outcomes) [20].
Finally, it should be remembered that, despite adequate dosage adjustment, patients with renal failure are at greater risk of developing adverse or toxic effects, due to their specific fragility and individual pharmacokinetic changes [18,21,22,23]. The clinician must therefore remain vigilant when treating this type of patient, and each of his/her prescriptions, for which he/she is responsible, must be carefully considered.
The right prescription for renal failure and dialysis : RenAdaptor©
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