Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray


Kidney Int. 2011;80(11):1122-1137. 

In This Article

Drug Dosing Considerations for Patients Receiving CRRT

Continuous renal replacement therapy (CRRT) is commonly used to manage hemodynamically unstable AKI patients. Several modes of therapy (convective, diffusive, or both), a variety of filter materials, and different effluent flow rates are used,[111,119] all of which can influence drug removal.

PK and PD Data

Despite the large variability in CRRT techniques, a review of published clearance studies found that <90% of studies specified the prescribed CRRT dose and only 58% of continuous venovenous hemofiltration studies specified whether pre- or post-dilution mode was used.[120] Two basic PK values necessary for interpretation of study results, V D and CL, were specified in only 79% and 81% of studies, respectively. None of the reviewed studies contained the 'ideal data set' formulated by the authors.

Hybrid RRTs that utilize higher dialysate flow rates than those used in CRRT, and shorter treatment periods (6–12 h in duration), are frequently prescribed as well. Hybrid therapies include slow low-efficiency dialysis (SLED), extended daily dialysis, continuous SLED, slow low-efficiency daily dialysis (SLEDD), and slow low-efficiency daily hemodiafiltration (SLEDD-f). Finding relevant literature for application to a given clinical situation is thus challenging and PK interpretation difficult.[121–125] The intermittent nature of most hybrid RRTs can further complicate drug dosing, as higher doses may be needed during the therapy, whereas lower doses may be adequate during therapy downtime. To date, hybrid RRT PK data have been published for only 12 drugs.[126–139]

Assessment of the Impact of CRRT and Hybrid RRT

CRRT parameters substantially influence drug clearance. The mode of therapy (diffusion, convection, or both) can be influential, as both therapy modes can remove small solutes, but convective therapies are superior at removing larger solutes.[140,141] Drug clearance is affected by where replacement fluids are given, because this influences the drug concentration within the filter. Mathematical calculations can account for this,[142–144] but published studies do not always specify this information.[120] Filter composition can also influence drug removal.[145,146] Some degree of drug adsorption occurs with many CRRT membranes (particularly sulfonated polyacrylonitrile and polymethylmethacrylate), although it is difficult to quantify adsorption in both in vitro and in vivo studies.[95,147,148] Dialysis dose is one of the most influential factors, with increased dialysate/ultrafiltration/effluent flow rates resulting in greater drug removal.[146,147]

Drug Dosing Approaches

The clinical desire to deliver higher RRT doses as well as the improvement of RRT machines and filters has rendered old dosing guidelines for drugs, especially antibiotics, ineffectual and potentially dangerous.[55,64] PK studies conducted in critically ill patients receiving CRRT or hybrid RRT are rare and dosing guidelines for these therapies are not often presented in a drug's product labeling. There are several published dosing recommendation guidances that are widely used.[62,64,108,149,150] These recommendations have not been prospectively tested to see if their application increases the attainment of therapeutic target serum concentrations or, more importantly, patient outcomes. The limitations of those calculations are illustrated by the fact that two different recommended doses for some antibiotics differ by up to an order of magnitude (Table 7).


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