Analgesic Nephropathy Due to NSAIDs

Analgesic nephropathy due to NSAIDs is chronic tubulointerstitial kidney disease with renal papillary necrosis and cortical scarring caused by prolonged, high cumulative intake of analgesics.

• Formerly caused by phenacetin-containing combinations; NSAIDs alone (with or without paracetamol or aspirin) now cause most cases.
• Mechanism: prostaglandin inhibition causes medullary ischaemia, with concentration of toxic metabolites in the renal medulla.
• Other NSAID kidney injuries: haemodynamic acute kidney injury, acute interstitial nephritis, nephrotic syndrome (minimal change, membranous), hyperkalaemia, sodium and water retention.
• Risk factors: chronic pain (arthritis, headache), self medication, combination analgesics, dehydration, concurrent diuretics and ACE inhibitors or angiotensin receptor blockers ("triple" exposure), older age, diabetes, pre-existing kidney disease.

Insidious chronic kidney disease: fatigue, anaemia (disproportionate to the degree of renal impairment), hypertension, polyuria and nocturia (concentrating defect), sterile pyuria, sodium wasting and acidosis.

• Papillary necrosis: renal colic and haematuria from sloughed papillae, sterile pyuria, urinary tract infection, acute obstruction.
• Peptic ulcer disease, gastrointestinal bleeding, and cardiovascular disease often coexist.
• Differential diagnosis: reflux nephropathy, chronic pyelonephritis, obstructive uropathy, sickle cell nephropathy, diabetic papillary necrosis, tuberculosis, vasculitis, hypertensive nephrosclerosis, sarcoidosis, lithium nephropathy.
• Complications: chronic kidney disease and end stage kidney disease, urothelial carcinoma (renal pelvis, ureter, bladder; risk is raised), recurrent infection, obstruction by papillae, hypertension, anaemia, mineral bone disease, hyperkalaemia and cardiovascular disease.

Detailed analgesic history (type, dose, duration, over-the-counter and herbal products).

• Creatinine, eGFR, electrolytes, bicarbonate, haemoglobin; urinalysis (sterile pyuria, mild proteinuria below 1.5 g daily, tubular proteinuria, haematuria), urine culture.
• Renal ultrasound shows small kidneys with irregular outline (bumpy contour) and papillary calcification; non-contrast CT shows reduced size, bumpy contour and papillary calcification ("ring" or "ball" sign); intravenous urography or CT urography shows papillary necrosis (calyceal clubbing, ring shadow).
• Urine cytology and cystoscopy for haematuria, given urothelial tumour risk.
• Renal biopsy if acute interstitial nephritis, nephrotic syndrome or unexplained disease.

Supportive: stop all NSAIDs and combination analgesics; stay hydrated (2 to 3 L daily); address underlying pain with physiotherapy, heat, topical agents and weight reduction; avoid raised-risk combinations (NSAID with diuretic and ACE inhibitor or angiotensin receptor blocker); avoid contrast and other nephrotoxins.

Pharmacological

• Alternative analgesia: paracetamol up to 3 g daily (2 g in malnutrition or liver disease), topical diclofenac gel 1 percent four times daily, tramadol 50 mg twice daily (renally adjusted), duloxetine 30 to 60 mg daily or amitriptyline 10 to 25 mg at night for chronic pain, gabapentin renally adjusted.
• Acute interstitial nephritis: stop the drug; prednisolone 1 mg/kg daily (maximum 60 mg) for 2 to 4 weeks then taper if no recovery in 1 week.
• Nephrotic syndrome from NSAIDs: stop the drug; corticosteroids if persistent.
• Chronic kidney disease care: blood pressure below 130/80 mmHg with ACE inhibitor or angiotensin receptor blocker (when NSAIDs are stopped), treat anaemia, acidosis (sodium bicarbonate 500 mg to 1 g twice to three times daily), hyperkalaemia, and mineral bone disease.
• Urinary tract infection: culture directed antibiotics.

Procedures: ureteric stent or percutaneous nephrostomy for papillae obstruction; ureteroscopy; nephroureterectomy for urothelial carcinoma; dialysis or transplantation when required.

Special groups: elderly (avoid NSAIDs), patients with heart failure or cirrhosis (very high risk), pregnancy (avoid NSAIDs after 20 weeks).

Red flags: haematuria in an analgesic user (exclude urothelial cancer), anuria from papillary obstruction, AKI after NSAID with diuretic and ACE inhibitor, rapidly rising creatinine.

Follow-up: creatinine every 3 months initially; annual urine cytology and ultrasound for 5 years in heavy users; counsel permanently against NSAIDs.