Ed: Prescribing medications for patients with kidney failure can tread the fine line between achieving therapeutic drug levels and toxicity.
The clearance of several medications depends upon reasonable kidney function, particularly important for those drugs with a narrow therapeutic index. Dose reduction may be required, not because these drugs are directly harmful to the kidneys but because they have the potential to cause toxicity through reduced drug elimination and accumulation of metabolites (examples in table 1). Apart from avoiding side effects through dose reduction, other methods include lengthening the dosing interval or using a safer alternative.
Making sense of the eGFR
Most commonly, the estimated glomerular filtration rate (eGFR) is used as a guide to give drugs at an appropriate dose. Its calculation depends upon creatinine (an endogenous substance) as a marker of kidney function. While a number of formulae exist to calculate the eGFR, they have disadvantages and cannot be relied upon if kidney function changes rapidly such as in acute kidney injury.
We have the Cockcroft Gault equation (developed in the 1970s) which, however has not been validated with standardised creative assays, the move to automation and the MDRD formula (after 2006), which lacks accuracy in populations with normal or near-normal kidney function, categorizing more people as having chronic kidney disease (CKD). Then the eGFR was calculated using the CKD EPI equation (2009), which became the equation of choice in most laboratories because it led to reduced prevalence of CKD with a more accurate risk prediction for adverse outcomes.
The use of creatinine to estimate the GFR has its limitations: variations in creatinine production (e.g. diet, muscle mass), creatinine secretion (effect of drugs); issues with laboratory measurements (assays used); and the non-linear relationship between creatinine and kidney function (e.g. a doubling of creatinine does not necessarily mean a halving of kidney function).
Furthermore, if the CKD-EPI or MDRD equations are used for drug dosing in very large or small patients the estimated GFR (normalized to body surface area) should be multiplied by the estimated body surface area before being divided by 1.73 to obtain an estimated GFR in units of mL/min.
Key Messages
- Drug doses usually need reduction or cessation with significant kidney impairment as clearances are reduced, resulting in an increased risk of toxic side effects.
- eGFR measured by the CKD EPI equation is now routinely used to estimate kidney function.
- eGFR relies on creatinine which is inaccurate when kidney function is not stable.
Table 1. Toxicity from accumulated metabolites if doses are unadjusted in significant kidney impairment
| eGFR* | Adverse effects | |
| Metformin1 | <30 | Lactic acidosis |
| Sulphonylureas2 | <15 | May predispose to hypoglycemia, especially in longer acting agents |
| Allopurinol2 | <30 | May result in higher frequency of developing hypersensitivity reactions |
| Apixaban2
Enoxaparin2 |
<15
<30 |
Increased bleeding risk
Increased bleeding risk |
| Pregabalin2 | <30 | Drowsiness, narcosis |
*ml/min/1.73m2
1Avoid in significant kidney impairment
2Dose reduction suggested; monitor for toxicity
References available on request.
Questions? Contact the editor.
Author competing interests: nil relevant disclosures.
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