A contrast scan, a creatinine and three innocent-looking medicines
Mrs Rita Kovacs is 78 years old, weighs 52 kg and has type 2 diabetes, hypertension and knee osteoarthritis. Her medicines are metformin 1000 mg twice daily, perindopril 10 mg daily, frusemide 40 mg each morning and ibuprofen 400 mg three times daily, which she started three weeks ago. Today she feels light-headed, has vomited twice and is passing little urine. Pathology taken this morning shows a serum creatinine of 140 micromol/L (her baseline is 95), an eGFR reported as 33 mL/min/1.73 m2 and a potassium of 5.3 mmol/L. She is booked for a CT scan with intravenous contrast this afternoon. The radiology nurse rings the pharmacy to ask whether Mrs Kovacs should take her metformin before the scan.
1. Estimate her creatinine clearance using Cockcroft-Gault, and explain why it differs from the reported eGFR and which figure should guide drug dosing here.
Read the worked answer
Cockcroft-Gault (female)
CrCl (mL/min) = [(140 - age) x weight (kg)] / (0.814 x SCr in micromol/L), then x 0.85 for a female.
- (140 - 78) x 52 = 3224
- 0.814 x 140 = 113.96
- 3224 / 113.96 = 28.3 mL/min
- 28.3 x 0.85 = approximately 24 mL/min
Why this is not the same as the eGFR of 33
- eGFR is normalised to a body surface area of 1.73 m2. She is small (52 kg, BSA roughly 1.5 m2). De-indexing gives 33 x (1.5 / 1.73), which is about 29 mL/min - the same order of magnitude, but not the same number.
- eGFR equations assume a stable outpatient in steady state. She is vomiting, possibly dehydrated and in evolving acute kidney injury, so any equation derived from a single creatinine will overestimate her true clearance.
- Cockcroft-Gault estimates absolute clearance and is the equation behind most product information dose adjustments.
Which to use: use the absolute CrCl of about 24 mL/min for drug dosing. Reassuringly, both estimates sit below 30 mL/min, so the decision threshold is crossed either way - and I would not round 28 up to 30 to keep a drug on the chart.
2. What do you tell the radiology nurse about the metformin, and what is your plan for it beyond this afternoon?
Read the worked answer
Answer to the nurse: do not give metformin today. But the reason is wider than the contrast.
Clinical reasoning
- Australian product information contraindicates metformin when eGFR is below 30 mL/min/1.73 m2; she is at roughly 24-29 mL/min. Between 30 and 45 mL/min, initiation is not recommended and an existing dose needs review and usually reduction.
- Metformin itself does not damage the kidney. The danger is accumulation when clearance falls: it inhibits hepatic gluconeogenesis and lactate clearance, so lactate rises. Her age, dehydration from vomiting, possible acute kidney injury and potassium of 5.3 all amplify that risk of lactic acidosis.
- The osmolality/contrast insult is the trigger for further renal decline; the standard advice for eGFR below 60 is to withhold metformin at the time of the procedure and restart only after renal function has been rechecked and is stable, traditionally 48 hours later.
Plan
- Withhold metformin now and record why on the chart.
- Ensure she is well hydrated before and after contrast; review the other nephrotoxins (see next task).
- Repeat creatinine, eGFR and potassium in 48-72 hours.
- Restart only if renal function recovers: at eGFR 45 or above restart at the previous dose; 30-45 discuss a reduced dose with the GP; below 30 do not restart and consider an alternative agent.
- Reinforce sick-day advice: hold metformin during vomiting, diarrhoea or poor oral intake, and tell any prescriber that she is on it.
3. Which of her remaining medicines most plausibly explains the creatinine rise, by what mechanism, and what would you recommend today?
Read the worked answer
The ibuprofen, acting with the perindopril and frusemide - the 'triple whammy'.
Mechanism
- Glomerular filtration depends on prostaglandin-mediated vasodilation of the afferent arteriole and angiotensin II-mediated constriction of the efferent arteriole.
- The NSAID blocks COX-1/COX-2, removing afferent vasodilation. The ACE inhibitor removes efferent constriction. The loop diuretic reduces intravascular volume and renal perfusion pressure.
- With all three together the glomerulus cannot autoregulate, so GFR falls (creatinine 95 to 140). Risk is highest in the first month of combined use and in older, volume-depleted patients - she started ibuprofen three weeks ago.
- The NSAID also blunts the effect of both the ACE inhibitor and the diuretic, contributes to potassium retention (K 5.3 with an ACE inhibitor) and can raise blood pressure.
Recommendations today
- Stop ibuprofen and document the reason; advise her not to buy OTC ibuprofen, naproxen or combination cold and flu products containing them.
- Consider holding perindopril and frusemide while she is vomiting and hypovolaemic, and discuss with the GP - sick-day rules exist precisely for this scenario.
- Rehydrate and repeat creatinine, eGFR and potassium in 48-72 hours.
- Offer paracetamol (up to 3 g/day in a frail older adult) and a topical NSAID gel, which has roughly 5-10 per cent of the systemic exposure of oral dosing.
- Refer back to the GP and flag the interaction in the pharmacy record so it is not repeated.