Prescribing in Renal Impairment

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Introduction

Chronic kidney disease (CKD) can be defined as a reduction in kidney function, or structural damage, present for more than 3 months.1

In contrast, an acute kidney injury (AKI) involves a reduction in kidney function over hours to days and, unlike CKD, is usually reversible with prompt treatment. AKI occurs in around 20% of emergency hospital admissions and it’s estimated that there are 3 million people living with CKD in the UK.2

It is, therefore, important to be aware of how to prescribe safely in patients who have reduced renal function.


Assessing renal function

Creatinine Clearance (CrCl) or Estimated Glomerular Filtration Rate (eGFR) are generally used to provide an estimate of renal function.3

True GFR can be determined through intravenous administration of radioisotopes and taking further blood samples at timed intervals. This is time-consuming and is only really performed for specific indications such as chemotherapy.

Both CrCl and eGFR require measurements of serum creatinine (a product of muscle breakdown) and serum creatinine can have vastly different significance in different patients. For example, higher serum creatinine may mean normal kidney function in a bodybuilder but it may indicate renal impairment in an amputee or a frail elderly patient.

eGFR (ml/min/1.73m2)

This is estimated using one of two different equations and is based on population studies. It is usually reported using a standardised body surface area (BSA) of 1.73m2. Therefore, it is likely to overestimate renal function in smaller patients and underestimate it in larger patients. We can correct for this in patients at extremes of body weight by using the following equation:4

  • GFR = eGFR x (BSA/1.73)

CrCl (ml/min)

This estimate of kidney function uses a patient’s age, weight and serum creatinine and is, therefore, best used in those patients at extremes of body weight or in drugs with a narrow therapeutic index. Unlike eGFR, the equation used to calculate CrCl uses a patient’s weight so it is not reported with a standardised BSA.

In the absence of advice from the manufacturer of the drug (based on their pharmacokinetic studies required for marketing authorisation) over whether to use CrCl or eGFR, it is prudent to calculate creatinine clearance. In borderline cases, the lower value, either eGFR or CrCl, should be used in drug dosing.

When calculating CrCl for patients who weigh less than their Ideal Body Weight (IBW), use their actual body weight.3 Controversy exists over when to use IBW or actual body weight in obese patients and it may vary depending on the drug in question. For patients with a BMI>40, use their IBW to calculate CrCl. This is based on the fact that with a BMI of >40 the largest contributor to mass is almost certainly fat and not muscle.

Serum creatinine will depend on many factors such as muscle mass and diet. The value itself is only a snapshot and the trend is more important. Measurements of renal function such as creatinine clearance are far less useful during periods of rapidly fluctuating renal function. For a clear diagnosis of an AKI to be made, previous measurements of creatinine are helpful.

Note that creatinine values provide no useful information in patients receiving renal replacement therapy since they will simply increase between dialysis sessions.


Drug administration in renal impairment

Many drugs are excreted from the body by the kidneys. In renal impairment, the main issue is drug accumulation and a significantly longer half-life; single doses or loading doses are therefore often the same as in those with normal renal function.

There are three main approaches to altering drug administration in patients with renal impairment:3

  1. Increase the interval between doses (e.g. administer once daily instead of twice daily)
  2. Decrease the dose
  3. A combination of dose reduction and extended interval

The half-life quoted for drugs by manufacturers will, in reality, be different for everybody. This is particularly true in renal patients where the pharmacokinetic effects are less well studied and understood.

In addition, some drugs may be less effective in renal impairment. This could be due to reduced activation of drugs by the kidneys, as occurs when vitamin D3 (colecalciferol) is not converted to the active form. It may also occur with drugs such as nitrofurantoin which fail to achieve an adequate urine concentration to be effective in treating urinary tract infections in patients with renal impairment.

Renal patients may also be more sensitive to certain medications as well as experiencing more side effects.4

Dose adjustment example 1

A patient with CKD is admitted with a lower respiratory tract infection. As per local hospital policy, they are started on intravenous co-amoxiclav 1.2g three times daily. After checking their blood results you see their eGFR has been reported as 18ml/min/1.73m. As per the advice in the renal drug database, this should be reduced to intravenous co-amoxiclav 1.2g given twice daily.2,4

Dose adjustment example 2

An 85-year-old man with atrial fibrillation usually takes rivaroxaban 20mg once daily. He weighs 65kg and his most recent blood test shows a creatinine level of 176μmol/L. Using your hospital’s online creatinine clearance calculator you calculate a CrCl of 25ml/min. Advice from the manufacturer states that patients with a CrCl of between 15 to 49 ml/min should receive rivaroxaban 15mg once daily. This patient should therefore have his dose reduced.5


Acute kidney injury

A full discussion of Acute Kidney Injury (AKI) is outside the scope of this article but it is important to note that certain medications should be withheld during an episode of AKI.

One way to remember which medicines should be held is by Considering the Action of Nasty Drugs:

C – Contrast media

A – ACE-inhibitors and Angiotensin Receptor Blockers (ARBs)

N – Non-steroidal anti-inflammatory drugs (NSAIDs)

D – Diuretics

The drugs above are not inherently nephrotoxic to tubular cells but they become so when the kidneys have reduced filtration as they will, through various mechanisms, inhibit the recovery of the kidneys, reduce filtration and exacerbate the AKI.

Contrast media is not absolutely contraindicated but carries more risk of nephropathy in patients with pre-existing renal impairment.6

The above list is not exhaustive and many other medicines may need to be adjusted or withheld in AKI, such as opioids, metformin or some antibiotics. There are few drugs (amphotericin, gentamicin) that are truly nephrotoxic to tubular cells and reactions to drugs such as proton pump inhibitors causing interstitial nephritis are rare.7


Key points

  • For most patients and most medicines, eGFR is the most practical and readily available measure of renal function.
  • CrCl is best used in drugs with a narrow therapeutic index or in patients at extremes of body weight.
  • Pharmacokinetics will vary in each patient – drugs do not have half-lives, patients have half-lives.
  • Standard single doses or loading doses are often the same in renal impairment but remember that reduced filtration means accumulation.
  • All prescribed medicines must be reviewed in AKI or progression of CKD.
  • Serum creatinine measurements provide a snapshot, the trend is more important.

Reviewer

Dr Stewart H Lambie

Consultant Nephrologist

Raigmore Hospital


Editor

Dr Chris Jefferies


References

  1. Clinical Knowledge Summaries [CKS]. Chronic Kidney Disease. NICE Clinical Knowledge Summaries [Updated May 2021]. Available from: [LINK
  2. Kidney Care UK. 2021. Facts and Stats. Available from: [LINK]
  3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Available from: [LINK]
  4.  Ashley, C. and Currie, A., 2021. The Renal Drug Database. [online] Renaldrugdatabase.com. Available from: [LINK]
  5. Bayer (August 2021) Xarelto 20mg film-coated tablets SmPC. Available from: [LINK]
  6. Specialist Pharmacy Services. Sps.nhs.uk. 2018. What factors need to be considered when dosing patients with renal impairment?. [online] Available from: [LINK]
  7. UK Renal Registry. 2016. Guidelines for Medicines Optimisation in Patients with Acute Kidney Injury. [online] Available from: [LINK]

 

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