Think ‘kidney function’ when prescribing

Kidney function progressively declines with age.¹ The decline in kidney function associated with ageing increases susceptibility to acute kidney injury and toxic accumulation of renally cleared medicines.² A person aged 80 years has about half the kidney function that they had when aged 20 years.³

In Australia, older people are often prescribed renally cleared medicines outside the recommended guidelines.^4-7

Which medicines need to be front of mind?

Medicines that need to be front of mind include those used to treat common diseases such as diabetes, cardiovascular disease, osteoporosis, infections and pain in older people,³ and include:

• gabapentin, pregabalin, metformin,⁸ digoxin,⁹ direct acting oral anticoagulants¹⁰ and some antidepressants, including serotonin and noradrenaline reuptake inhibitors.¹¹ These medicines can accumulate as a result of slower elimination in reduced kidney function and cause adverse effects.⁸
• non-steroidal anti-inflammatory drugs (NSAIDs),^8, 11 angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).⁸ These medicines can impair or worsen kidney function or cause acute kidney injury.⁸
• thiazides, nitrofurantoin,⁸ loop diuretics such as furosemide¹¹ and sodium-glucose co-transporter 2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin and ertugliflozin.¹² Reduced kidney function can lessen the effectiveness of these medicines.⁸
• some antibiotics and antivirals, including trimethoprim and ciprofloxacin.¹¹ Trimethoprim and ciprofloxacin can cause hyperkalaemia and acute kidney injury in older people.^11, 13
• some medicines purchased over-the-counter, including NSAIDs and proton pump inhibitors (PPIs).^11, 15 Although rare, there is an increased risk of interstitial nephritis and acute kidney injury associated with long-term use of PPIs, particularly when used at high doses.¹⁵

Other examples of medicines that need to be front of mind can be found in a previous MATES topic Know your patient’s renal function – an important prescribing consideration available at: www.veteransmates.net.au/topic-30-therapeutic-brief

What is the patient’s kidney function?

Check kidney function if not done in the last three months before prescribing any medicine that requires dose adjustment in patients who:

• are aged over 65 years¹¹
• have recently had an acute illness, for example a urinary tract infection, myocardial infarction or pneumonia^12, 16
• have recently been discharged from hospital¹²
• are experiencing symptoms suggestive of an adverse effect from a medicine. For example, drowsiness with morphine use, or dehydration and hypotension with concurrent use of a SGLT2 inhibitor and a loop diuretic or during hot weather¹²
• have chronic kidney disease or other renal disease or abnormality¹⁷
• are at a high risk of developing chronic kidney disease, including those who:¹⁸

• smoke
• have a body mass index greater than 30 kg/m²
• have a family history of kidney failure
• have diabetes or hypertension
• have established cardiovascular disease, coronary heart disease or peripheral vascular disease
• have a history of acute kidney injury.¹⁸

Re-assess kidney function every six months after prescribing any medicine that requires dose adjustment, before re-prescribing, or more often if there is clinical suspicion that kidney function could decline.¹¹

Kidney function may be substantially impaired in older people despite them having a normal serum creatinine concentration.¹² The most accurate indicator of kidney function is the direct measurement of glomerular filtration rate (GFR),¹⁹ but because of the complexities associated with measuring this, estimates of GFR (eGFR) are used.^3, 20 The eGFR is routinely provided with laboratory reports that include serum creatinine.¹⁶

An alternative estimate, the Cockcroft-Gault estimate can be ordered from pathology laboratories, or can be calculated using most GP practice software packages.¹⁶

What actions to take and when?

If impaired kidney function is detected, consider reducing the dose in proportion to the loss of function, extending the dosing interval or stopping the medicine, where appropriate (see Table 1).²³

Adjust the dose and monitor drug concentrations when prescribing medicines with a narrow therapeutic index, such as digoxin and lithium.^9, 11 Reduce the dose, and monitor antifactor Xa levels when prescribing enoxaparin in patients with reduced kidney function to avoid accumulation of the drug and an increased risk of bleeding.^11, 24

After starting a medicine, monitor your patient for any adverse effects and re-adjust the dose if necessary.¹¹ Patients who have been taking a medicine long term that requires dose adjustment may need their dose re-adjusted as they age.³

Table 1 Medicines most commonly dispensed to DVA patients that require attention in reduced kidney function
Medicines	Estimated kidney function (CrCl): suggested dose	Considerations
Angiotensin-converting enzyme (ACE) inhibitors	Perindopril (arginine or erbumine) For treating hypertension, the initial dose of perindopril arginine is 2.5 mg or of perindopril erbumine is 2 mg, when CrCl is: 15–60 mL/min: give once daily Less than 15 mL/min: give on alternate days11 For other ACE inhibitors, use low initial doses and titrate up slowly according to the patient’s response.11	ACE inhibitors have class effects.11 There is an increased risk of hyperkalaemia in reduced kidney function.11 Check kidney function and electrolytes before starting an ACE inhibitor and review after one to two weeks. A mild non-progressive reduction in kidney function is acceptable.11 Kidney function may worsen or acute kidney failure may develop, especially when used in combination with NSAIDs (including selective COX-2 inhibitors), other ACE inhibitors or ARBs.11, 27
Angiotensin II receptor blockers (ARBs)	Irbesartan Start dose at 75 mg once daily in patients aged over 75 years.11 For dose recommendations of other ARBs, refer to the Australian Medicines Handbook.	Considerations as per ACE inhibitors. ARBs have class effects.11 ARBs and ACE inhibitors increase the risk of kidney failure in bilateral renal artery stenosis.11
Atenolol	For initial dose: 35–60 mL/min: 25–50 mg once daily and adjust dose according to response11 15–35 mL/min: 25 mg once daily or 50 mg on alternate days and adjust dose according to response11 Less than 15 mL/min: 25 mg once daily or 25–50 mg on alternate days11
Opioids	Codeine Avoid use11 Oxycodone 10–30 mL/min: for initial dose, give three quarters of the estimated dose12 Less than 10 mL/min: give half of the estimated dose12 Morphine Less than 50 mL/min: reduce dose and monitor patient closely or use an alternative opioid11 Less than 10 mL/min: avoid chronic use11	Symptoms of overdose include drowsiness and sedation.12 Acute severe overdose is manifest by respiratory depression, excessive sedation, cold and clammy skin, constricted pupils and delirium.11, 28
Metformin	In patients with stable kidney function: 60–90 mL/min: maximum 2 grams daily11 30–60 mL/min: maximum 1 gram daily11 15–30 mL/min: maximum 500 mg daily and monitor kidney function closely11 Less than 15 mL/min: metformin is not recommended11	Reduced kidney function in older people and high doses above 2 g per day increases the risk of lactic acidosis.12, 27 Review the dose and monitor kidney function in older patients where kidney function can worsen, including when initiating antihypertensives, diuretics or NSAIDs.27 Fixed dose combinations of metformin can make dose titration difficult.11 Stop metformin if your patient becomes acutely unwell and is at risk of further deterioration of kidney function.11
Neurological medicines for pain or epilepsy	Pregabalin 30–60 mL/min: initially give 75 mg daily, with a maximum daily dose of 300 mg in one or two doses11, 29 15–30 mL/min: initially give 25–50 mg daily, with a maximum daily dose of 150 mg in one or two doses11, 29 Less than 15 mL/min: initially give 25 mg daily, with a maximum daily dose of 75 mg as a single dose11, 29 Gabapentin 50–79 mL/min: 0.6–1.8 g daily in three doses11 30–49 mL/min: 300–900 mg daily in two or three doses11 15–29 mL/min: 300 mg once every two days to 600 mg daily in two to three doses11 Less than 15 mL/min: 300 mg once every two days to 300 mg daily at night11	Most commonly reported side effects that are dose dependent include dizziness and drowsiness.11
Direct acting oral anticoagulants (DOACs)	Apixaban 25–60 mL/min: no dose adjustment needed, but monitor patient for signs of bleeding27 Less than 25 mL/min: contraindicated11	Increased risk of bleeding in severe kidney impairment.27
	Rivaroxaban 30–49 mL/min: for atrial fibrillation (AF) 15 mg once daily,11 for venous thromboembolism (VTE) 15 mg twice daily for three weeks, then 15–20 mg once daily27 15–30 mL/min: contraindicated for AF and treatment of VTE11 Less than 15 mL/min: contraindicated11	Other medicines may increase rivaroxaban concentration, including other anticoagulants, and some antifungals and antivirals.11, 27
	Dabigatran In patients aged 75 years or over: reduce dose to 110 mg twice daily11 Less than 30 mL/min: contraindicated11	Monitor for signs of bleeding and check kidney function before prescribing, every three months during treatment and if there is clinical suspicion that kidney function could decline.11
Non-steroidal anti-inflammatory drugs (NSAIDs)	Meloxicam Less than 25 mL/min: avoid use11 Celecoxib Less than 30 mL/min: contraindicated11 Diclofenac Less than 25 mL/min: avoid use11	Increased risk of adverse effects, in particular heart failure, gastrointestinal ulceration and kidney impairment in older patients.11 Dehydration, for example from vomiting or diarrhoea, increases the risk of adverse effects.11
Allopurinol	Use a low starting dose, then increase slowly to achieve a serum urate less than 0.36 mmol/L (less than 0.3 mmol/L if tophi are present)11 For the initial dose: eGFR more than 60 mL/min/1.73 m2: give 100 mg once daily11 eGFR 30–60 mL/min/1.73 m2: give 50 mg once daily11 eGFR 15–30 mL/min/1.73 m2: give 50 mg on alternate days11 eGFR less than 15 mL/min/1.73 m2: give 50 mg twice a week11	Check serum urate levels before dose adjustment while titrating the dose.30 Monitor kidney function during early stages of treatment, and reduce the dose or stop the medicine if increased abnormalities in kidney function appear.30, 31 Patients may require a dose in excess of 300 mg per day to achieve the targeted serum urate.30
Spironolactone	In heart failure: 30–50 mL/min: reduce initial dose to 12.5 mg once daily or 25 mg on alternate days and increase to 25 mg once daily after eight weeks if heart failure progresses and the potassium level is lower than 5 mmol/L11 Less than 30 mL/min: avoid use11	There is an increased risk of hyperkalaemia in patients using spironolactone in combination with ACE inhibitors, NSAIDs, ARBs, low molecular weight heparins, potassium supplements, a diet rich in potassium or other potassium sparing agents.11, 32 Monitor potassium and serum creatinine levels one week after initiation, then monthly for the first three months, then quarterly for a year and then every four to six months or when clinically indicated.11, 32
Medicines for osteoporosis	Alendronate Less than 35 mL/min: not recommended11 Zoledronic acid Less than 35 mL/min: not recommended11 Risedronate Less than 30 mL/min: not recommended11 Denosumab Greater than 30 mL/min: no dose adjustment required33 Less than 30 mL/min: not recommended34	Zoledronic acid and denosumab can cause hypocalcaemia, particularly in patients with impaired kidney function, and vitamin D or calcium deficiency.11, 34 Check kidney function, and calcium and vitamin D levels before giving the first and subsequent doses.34
Colchicine	Acute gout flare up: Less than 30 mL/min: 1 mg orally as soon as possible, then 500 mcg one hour later. Do not repeat course within two weeks11 Gout flare up prophylaxis: Less than 30 mL/min: initially 250 mcg orally once daily11	Reduced elimination of colchicine occurs in impaired kidney function, increasing the risk of adverse effects.11 Treatment of acute gout flare up with colchicine is not recommended in patients with any degree of impaired kidney function who are receiving colchicine for prophylaxis, due to an increased risk of toxicity.11, 34

Note: CrCl: mL/min=Creatinine Clearance: millilitres per minute

References

1. Stevens L, Coresh J, Greene T, Levey A. Assessing kidney function - measured and estimated glomerular filtration rate. N Eng J Med. 2006; 354: 2473-83.
2. Rule A, Glassock R. The aging kidney. Updated 2018. UpToDate, available at: www.uptodate.com [Accessed April 2019].
3. Faull R, Lee L. Prescribing in renal disease. Aust Prescr. 2007; 30: 17-20.
4. Khanal A, Peterson G, Castelino R, Jose M. Potentially inappropriate prescribing of renally cleared drugs in elderly patients in community and aged care settings. Drugs Aging. 2015; 32: 391-400.
5. Doody H, Peterson G, Watson D, Castelino R. Retrospective evaluation of potentially inappropriate prescribing in hospitalized patients with renal impairment. Curr Med Res Opin. 2015; 31(3): 525-35.
6. Nair N et al. Adverse drug reaction-related hospitalizations in elderly Australians: a prospective cross-sectional study in two Tasmanian hospitals. Drug Saf. 2017; 40: 597-606.
7. Gheewala P, Peterson G, Curtain C, Nishtala P, Hannan P, Castelino R. Impact of the pharmacist medication review services on drug-related problems and potentially inappropriate prescribing of renally cleared medications in residents of aged care facilities. Drugs Aging. 2014; 31(11): 825-835.
8. Wood S, Petty D, Glidewell L, Raynor D. Application of prescribing recommendations in older people with reduced kidney function: a cross sectional study in general practice. Br J Gen Pract. 2018; 68(670): e378-87.
9. Lea-Henry T, Carland J, Stocker S, Sevastos J, Roberts D. Clinical pharmacokinetics in kidney disease: fundamental principles. Clin J Am Soc Nephrol. 2018; 13: 1085-1095.
10. Jain N, Reilly R. Clinical pharmacology of oral anticoagulants in patients with kidney disease. Clin J Am Soc Nephrol. 2019; 14: 278-287.
11. Australian Medicines Handbook. Adelaide. Australian Medicines Handbook Pty Ltd. 2019.
12. Australian Medicines Handbook Aged Care Companion. Adelaide. Australian Medicines Handbook. 2018.
13. Crellin E et al. Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ. 2018; 360: 1-9.
14. Antoniou T et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015; 3: E166-71.
15. Therapeutic Goods Administration. Medicines Safety Update. Aust Prescr. 2012; 35(3): 98-101.
16. bpac better medicine. Clinical Audit. Testing renal function in elderly people. Available at: www.bpac.org.nz/audits [Accessed June 2019].
17. Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice. 9^th edn. East Melbourne, Vic. RACGP. 2016.
18. Webster A, Nagler E, Morton R, Masson P. Chronic kidney disease. Lancet. 2017; 389: 1238-52.
19. Kidney Health Australia. Chronic Kidney Disease (CKD) Management in General Practice. 3^rd edn. 2015. Available at: www.kcat.org.au [Accessed June 2019].
20. Australian and New Zealand Society for Geriatric Medicine. Choosing Wisely Australia. 5 Things clinicians and consumers should question. 2016. Available at: www.choosingwisely.org.au [Accessed June 2019].
21. Australian Government Department of Health. For Health Professionals: Medication management reviews. Available at: www.health.gov.au/internet/main/publishing.nsf/Content/medication_management_reviews.htm [Accessed May 2019].
22. Western Australia Health. Medication Safety Group. Dose calculations for drugs cleared by glomerular filtration quick reference guideline. Available at: ww2.health.wa.gov.au/~/media/Files/Corporate/general%20documents/WATAG/Renal-cleared-drug-dosing-calculations.pdf [Accessed May 2019].
23. Shaikh S, Regal R. Dosing of enoxaparin in renal impairment. P&T. 2017; 42(4): 245-249.
24. Johnson D et al. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations. Med J Aust. 2012; 197: 224-5.
25. Australian Product Information. Empagliflozin. Revised 2019. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2014-PI-01783-1&d=201906241016933 [Accessed May 2019].
26. Ashley C, Dunleavy A. The Renal Drug Handbook. 5^th edn. Boca Raton, UK. CRC Press. 2019.
27. Australian Product Information. Morphine. Revised 2019. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01928-1 [Accessed June 2019].
28. Australian Product Information. Pregabalin. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2018-PI-01983-1 [Accessed June 2019].
29. bpac better medicine. Managing gout in primary care. Part 2 - controlling gout with long-term urate-lowering treatment. 2018. Available at: https://bpac.org.nz/2018/gout-part2.aspx [Accessed June 2019].
30. Australian Product Information. Allopurinol. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-01426-1 [Accessed June 2019].
31. Australian Product Information. Spironolactone. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04112-3 [Accessed June 2019].
32. Australian Product Information. Denosumab. Available at: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07242-3&d=201906241016933 [Accessed June 2019].
33. Therapeutic Guidelines. Melbourne. Therapeutic Guidelines Limited. March 2019. Available at: http://online.tg.org.au/ip/desktop/index.htm [Accessed June 2019].
34. Takeda Pharmaceuticals America. Prescribing Information for Colcrys (colchicine) tablets. Revised 2015. Available at: https://general.takedapharm.com/COLCRYSPI [Accessed July 2019].

Return to top