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Pharmacological adjustment for renal failure and renal replacement therapies

The prevalence of chronic renal failure is important and involves 0.3 % to 13% of the general population with 0.05% of patients depending on renal replacement therapy [1,2].

Renal impairment or dialysis modifies the pharmacokinetics of more then 50% of drugs, imposing dosage adjustments in renal failure [3]. Thus, given the high frequency of renal failure, clinicians are sooner or later confronted with this problem.

After identifying patients with renal failure, doctors will have to determine which drug has to be adjusted and in which extent. That’s the challenge for today.

In fact, these informations are lacking, incomplete or even divergent in most of drugs indexes or monographs, particularly for older drugs [4]. Consequently, a great majority of practitioners neglect this aspect especially if they are not acquainted with nephrological issues.

In a clinical trial conducted in a Boston general hospital with 720 beds, Chertow and Col. [5] reveal that 43% of the prescriptions collected for 7904 patients with renal failure, were not consistent. This non adjustment of drug dosage in renal failure can increase side effects, even induce intoxication and major toxic adverse events such as malignant arythmia, medullary aplasia, acute renal failure, toxic hepatitis, coma …. In a more recent trial Hug and Col. [6] showed that more than 50% of the 17614 patients with chronic renal failure had a probable, and 10% a proven, side effect due to the medication. In more then 90% the side effects were due to disadjustment of drug dosages. 50% of these side effects were considered serious while 4.5% were life threatening. In view of these publications, it seems that the disadjustment of drug dosage in renal failure represents a very costly iatrogenic public health problem.

Conversely, an excessive reduction of drug dosage could lead to therapeutic ineffectiveness which is particularly dangerous in intensive care units and in onco-hematology or infectious diseases. The fear of a therapeutic error also discourages some clinicians to prescribe some treatments particularly in cardiovascular prevention [7].

So it is essential to prescribe the correct dose in order to obtain an optimal therapeutic quality.

In order to obtain such a quality in current practice, high quality information has to be easily and quickly accessible.

Even if all pharmacokinetic parameters can be altered by chronic renal failure, it is mainly the urinary excretion of the intact drug or its metabolites which is decreased. In consequence, the total drug half-life increases, proportionally to the severity of renal impairment [3]. Thus, adjustments of drug dosages consist mostly in a reduction of the maintenance dose and/or in an increase of the interval between each dose (the adaptations required for each drug, are consistent with the 5 known stages in renal failure). Administration modes (IV, IM, Oral …) and loading doses, respectively dependent on bio availabilities and distribution volumes, are mostly unchanged.

Renal replacement therapy again modifies most of drug pharmacokinetics, by improving their elimination, imposing a new dosage adjustment [3].

In a few cases dosages have to be increased due to « uremic resistance » relevant to a reduction of the number and the sensibility of the drug receptors (Loop diuretics, Insulin …) [8,9].

Finally, the nephrotoxicity and other toxic effects of some molecules has to be considered more particularly in uremic patients [10]. Thus, the risk/benefit ratio of some drugs can change, leading to specific contra-indications.

General recommendations concerning prescription of drugs for renal failure patients, are now the subject of an international consensus published in the KDIGO (Kidney Disease: Improving Global Outcomes) [14].

All these clinical, pharmacological and toxicological considerations are included in Renadaptor©, a software drugs index, offering dosing guidelines for patients with renal failure and/or treated by dialysis. Information about detoxification possibilities by extracorporeal techniques in case of drugs intoxication, and recommendations in liver failure are also available.

Development of this software started 20 years ago by a team of nephrologists, driven by the difficulty to find the accurate information in their daily practice. All the data results from an exhaustive medical and pharmacological literature analysis. More than 1400 drugs, available in INN and brand names of more than 30 countries, classified into four levels of pharmacotherapeutic groups, with more then 4000 references, are today available in the database. Main references are available under the tab « references ». More specific references for particular drugs are available on the information page of the corresponding record

The database is updated continuously through several medico-pharmaceutical magazine or website subscriptions, as well as tracking drug approvals on the European Medical Agency (EMA) and the American Food and Drugs Association (FDA) websites. All drugs approved by the EMA and the FDA since 2009 are available. Older molecules, not yet available, will be included gradually in order to cover the whole world pharmacopoeia in the next years.

Thus, Renadaptor© is a practical, up to date and extensive compilation of existing pharmacological data made by physicians for a daily clinical use. Written in php-mysql language, it can be easily integrated into in a computerized physician order entry (CPOE) system for an additional improvement of the quality of ordered treatments [5,6,11].

Let us finally remind that in spite of adequate dose adjustments, renal failure patients are at high risk for side effects or toxic effects due to individual changes of the pharmacokinetics of the drug and their co-morbidities [12,13]. Thus, clinicians have to remain vigilant towards these patients. Furthermore each prescription which is the prescriber’s responsibility , has to be well reflected on.

Bibliography :

[1] Hill NR, Fatoba ST, Oke JL, Hirst JA, O Callaghan CA, Lasserson DS, Hobbs FD. Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One. 2016 Jul 6;11(7):e0158765.

[2] Frimat L, Loos-Ayav C, Briançon S, Kessler M. Epidémiologie des maladies rénales chroniques. EMC néphrologie . Paris : Elsevier Masson ; 2005. 18-025-A/B-10.

[3] Clase CM, Grag AX, Kiberd BA. Prevalence of low glomerular filtration rate in nondiabetic Americans : Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 2002 ; 13(5) : 1338-49.

[4] Aronoff GR, Bennett WM, Berns JS, Brier ME, Kasbekar N, Mueller BA, Pasko DA, Smoyer WE. Drug prescribing in renal failure. Dosing guidelines for adults and children. Fifth edition. Philadelphia : ACP Vers Press ; 2007.  

[5] Vidal L, Shavit M, Fraser A, Paul M, Leibovici L. Systematic comparison of four sources of drug information regarding adjustment of dose for renal function. BMJ 2005 ; 331(7511) : 263.

[6] Chertow GM, Lee J, Kuperman GJ, Burdick E, Horsky J, Seger DL, Lee R, Mekala A, Song J, Komaroff AL, Bates DW.Guided medication dosing for inpatients with renal insufficiency. JAMA 2001 ; 286(22) : 2839-44.

[7] Hug BL, Witowski DJ, Sox CM, Keohane CA, Seger DL, Yoon C, Matheny ME, Bates DW. Occurrence of adverse, often preventable, events in community hospitals involving nephrotoxic drugs or those excreted by the kidney. Kidney Int. 2009 ; 76(11) : 1192-8

[8] Makary MA, Daniel M. Medical error-the third leading cause of death in the US. BMJ. 2016 May 3;353:i2139.

[9] Cardinal H, Madore F. La pharmacopée de prévention cardiovasculaire est-elle sous utilisée chez le patient souffrant d’insuffisance rénale chronique après un infarctus du myocarde ? Nephrol & Therap 2010 ; 6(3) : 162-70.

[10] Swan SK. Diuretic strategies in patients with renal failure. Drugs 1994 ; 48(3) : 380-5

[11] Presne C, Monge M, Mansour J, Oprisiu R, Choukroun G, Achard JM, Fournier A. Diuretic-based therapy. Nephrol & Therap 2007 ; 3(6) : 392-426.

[12] Karie S, Launay-Vacher V, Deray G, Isnard-Bagnis C. Toxicité rénale des medicaments. Nephrol & Therap 2010; 6(1): 58-74.

[13] Field TS, Rochon P, Lee M, Gavendo L, Baril JL, Gurwitz JH. Computerized clinical decision support during medication ordering for long-term care residents with renal insufficiency. J Amm Led Inform Assoc 2009 ; 16(4) : 480-5.

[14] Drug dosing consideration in patients with acute and chronic kidney disease - a clinical update from Kidney Disease : Improving Global Outcomes (KDIGO). Matzke GR, Aronoff GR, Atkinson AJ Jr, Bennett WM, Decker BS, Eckardt KU, Golper T, Grabe DW, Kasiske B, Keller F, Kielstein JT, Mehta R, Mueller BA, Pasko DA, Schaefer F, Sica DA, Inker LA, Umans JG, Murray P. Kidney Int. 2011 Dec;80(11):1122-37.

 [15] Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol 2009 ; 65(8) : 757-73

[16] Ponticelli C, Graziani G. Management of drug toxicity in patients with renal insufficiency. Nat Rev Nephrol 2010 ; 6(6) : 317-8