Drug Induced Renal Hypoperfusion

Drug induced renal hypoperfusion is a reduction in glomerular filtration caused by drugs that lower glomerular perfusion pressure or alter renal autoregulation, without direct tubular toxicity. The injury is haemodynamic and reversible, usually within 3 to 5 days of withdrawal, but prolonged exposure can lead to ischaemic tubular necrosis.

Glomerular filtration pressure depends on dilation of the afferent arteriole by prostaglandins and constriction of the efferent arteriole by angiotensin II. Drugs disrupt this balance:

• NSAIDs and COX-2 inhibitors block prostaglandin synthesis and constrict the afferent arteriole
• ACE inhibitors and angiotensin receptor blockers dilate the efferent arteriole, reducing filtration pressure
• Calcineurin inhibitors (ciclosporin, tacrolimus) constrict the afferent arteriole
• SGLT2 inhibitors reduce intravascular volume and restore tubuloglomerular feedback, causing an early dip in eGFR
• Diuretics cause volume depletion
• Antihypertensives, nitrates and sedatives that lower systemic pressure
• Contrast agents and amphotericin B cause vasoconstriction
• Vasopressors, terlipressin and alpha agonists at high dose

The classic combination ("triple whammy") is an ACE inhibitor or angiotensin receptor blocker, a diuretic and an NSAID taken together, especially during intercurrent illness. Patients dependent on angiotensin II or prostaglandins are at greatest risk: bilateral renal artery stenosis, cirrhosis, heart failure, volume depletion, chronic kidney disease, older age and sepsis.

• Often asymptomatic, with a rise in creatinine of 30% or more within 1 to 2 weeks of starting or increasing the drug
• Oliguria, postural hypotension, thirst, weight loss if volume depletion coexists
• Hyperkalaemia (ACE inhibitors, angiotensin receptor blockers) and metabolic acidosis
• Fluid retention, hypertension and hyponatraemia (NSAIDs)
• Flash pulmonary oedema and sudden creatinine rise on starting ACE inhibitor (bilateral renal artery stenosis or stenosis in a single kidney)
• Recent illness with vomiting, diarrhoea or reduced intake

Red flags: creatinine rise above 30% from baseline within 2 weeks of starting an ACE inhibitor or angiotensin receptor blocker, potassium above 6.0 mmol/L, oliguria, systolic pressure below 90 mmHg, signs of renal artery stenosis (renal bruit, asymmetric kidneys with a difference above 1.5 cm, flash pulmonary oedema).

• Temporal relationship between the drug, intercurrent illness and the rise in creatinine; full medication review including over-the-counter and herbal NSAIDs
• Creatinine, urea, potassium, bicarbonate; BUN:creatinine ratio above 20:1 (urea in mmol/L to creatinine in micromol/L ratio above 0.08)
• Urinalysis: bland sediment, minimal protein
• Urine sodium below 20 mmol/L and fractional excretion of sodium below 1% (may be misleading with diuretics; use fractional excretion of urea below 35%)
• Renal ultrasound with Doppler for renal artery stenosis if creatinine rises more than 30% after ACE inhibitor; CT or magnetic resonance angiography for confirmation
• Response to drug withdrawal and volume restoration within 3 to 5 days

Differentials: acute tubular injury, interstitial nephritis (rash, eosinophilia, pyuria), obstruction, cardiorenal syndrome, progression of chronic kidney disease.

First line

• Stop the offending drug (NSAID, diuretic, ACE inhibitor, angiotensin receptor blocker, SGLT2 inhibitor, calcineurin inhibitor dose reduction directed by drug levels).
• Restore volume with balanced crystalloid 250 to 500 mL aliquots, assessing after each.
• Treat hyperkalaemia: calcium gluconate 10% 10 mL for ECG changes, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised, sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours.
• Monitor creatinine and electrolytes every 24 hours until baseline is regained.

Restarting renin angiotensin blockers

• Restart once the patient is eating and drinking and creatinine is back to baseline, at half the previous dose, then retitrate over 2 to 4 weeks.
• At initiation, tolerate a creatinine rise up to 30% and a potassium up to 5.5 mmol/L. Stop if creatinine rises more than 30% or potassium rises above 6.0 mmol/L despite binder therapy.
• Check creatinine and potassium at 1 to 2 weeks after every dose change.
• Bilateral renal artery stenosis: do not restart; revascularise if flash pulmonary oedema or refractory hypertension.

Prevention

• Sick day rules for patients on ACE inhibitors, angiotensin receptor blockers, diuretics, metformin, NSAIDs and SGLT2 inhibitors: pause during vomiting, diarrhoea, fever or poor intake and restart 24 to 48 hours after eating and drinking normally.
• Avoid NSAIDs in chronic kidney disease, heart failure, cirrhosis and older age; use paracetamol 1 g up to four times daily (maximum 4 g daily; 3 g in older or low weight patients).
• Avoid combined ACE inhibitor, diuretic and NSAID therapy.
• Dose reduce calcineurin inhibitors based on trough levels (tacrolimus 5 to 10 ng/mL early after transplant).

Escalation. Refer to nephrology if creatinine does not return to within 20% of baseline after 5 days of withdrawal, or if renal artery stenosis is suspected.

Special groups. Cirrhosis: NSAIDs and ACE inhibitors are contraindicated; stop diuretics and give albumin 1 g/kg (maximum 100 g) for 2 days at the first sign of renal impairment. Older adults: lower starting doses and more frequent laboratory review.