In Reply

Drug Therapy in Patients With Chronic Renal Failure by Dr. med. Bertram Hartmann, PD Dr. med. David Czock, Prof. Dr. med. Frieder Keller in volume 37/2010

We agree with Nocke that a clearance method is desirable to measure the individual glomerular filtration rate (GFR). The MDRD2 formula, however, constitutes an enormous advance in the routine estimation of the GFR and therefore in simply establishing clinical stages of renal function.

As Özcan says, in patients with a GFR <30 mL/min who are not receiving dialysis it needs to be critically considered for the individual whether hemodialysis has to be performed after administration of gadolinium. Gadolinium can be dialyzed, but the clinical benefit of dialysis is unproved. In patients who did not have dialysis before, the risks and benefits of catheterization for dialysis need to be considered.

The practice of evaluating calcium and phosphate individually should not be relinquished. It does make sense, however, to start with the tested and more cost-effective medications before using new preparations that are heavily advertised.

We don’t think that terms such as “compensated renal failure” or referring to creatinine values is helpful in adapting dosages. Instead of the creatinine concentrations reported by Günther Egidi, of >1.5 mg/dl, we would advise not to use metformin from a defined GFR level. A “safety range” in case of renal deterioration is advisable, since lactic acidosis in patients taking metformin is associated with high lethality. A study with diabetes patients with renal failure (including patients with a GFR <30 ml/min) found that sitagliptin is sufficiently safe (1).

Enoxaparin does not have a single distribution volume—such as Paar, Kienmitz, and Rosin write, on the basis of the licensing data, but corresponding to a two-compartment pharmacokinetic it has a peripheral compartment (2). The central distribution volume is estimated to be 6.78 liters and the peripheral distribution volume at 6.19 liters. Accordingly, the terminal distribution volume can be calculated to be some 23 liters. The non-renal clearance is 0.229 L/h and the renal clearance 0.744 L/h in normal renal function.

From these values, the calculated half-life for the rapid elimination phase is 3 hours (T_1/2α) and for the slow elimination phase it is 16 hours (T_1/2β). If repeated doses are given, the accumulation factor is much higher in the second compartment (R_β) than in the first compartment (R_α)—an effect that increases in patients with renal failure.

Consistent with this, enoxaparin has the highest accumulation factor compared with dalteparin, nadroparin, and tinzaparin (3). It is the subject of controversy how the dosage for enoxaparin should be adjusted. Calculations have shown that if the dose is administered every 24 hours only, therapeutic gaps may occur (2). In view of recent data we do not think it is contradictory to recommend against using a medication, even though it may be formally licensed. In the prospective registry study by Collet (2005) that Reinhard Klingel cites, it seemed that for a GFR <60 mL/min mortality was lower in patients receiving unfractionated heparin than in those receiving enoxaparin if glycoprotein IIb/IIIa inhibitors were given simultaneously. Two studies have shown that in patients with renal failure, significantly more hemorrhages developed under enoxaparin than for unfractionated heparin or fondaparinux.

DOI: 10.3238/arztebl.2011.0114b

Dr. med. Bertram Hartmann

Dr. med. David Czock

Prof. Dr. med. Frieder Keller

Sektion Nephrologie, Klinik für Innere Medizin I

Zentrum für Innere Medizin

Universitätsklinikum Ulm

Albert-Einstein-Allee 23

89081 Ulm, Germany

Conflict of interest statement
Dr Hartmann has received research funding from Wyeth and Novartis and travel expenses for participating in conferences.
Professor Keller has received financial funding from Novartis, Roche, Ratiopharm, TEVA, and Abbott.
Dr Czock declares that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.

References

1. Chan JC, Scott R, Arjona Ferreira JC, et al.: Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008; 10: 545–5.

2. Green B, Greenwood M, Saltissi D, et al.: Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Pharmacol 2005; 59(3): 281–90.

3. Schmid P, Fischer AG, Wuillemin WA: Low-molecular-weight heparin in patients with renal insufficiency. Swiss Med Wkly 2009; 139: 438–52.

4. Hartmann B, Czock D, Keller F: Drug therapy in patients with chronic renal failure. Dtsch Arztebl Int 2010; 107(37): 647–56.