Aristolochic Acid Nephropathy

Aristolochic acid nephropathy is a rapidly or slowly progressive tubulointerstitial kidney disease caused by plants of the genus Aristolochia. It carries a high risk of urothelial carcinoma of the upper urinary tract and bladder. It was first described in Belgian women taking a slimming preparation containing Aristolochia fangchi (Chinese herb nephropathy) in the early 1990s.

Sources include:

• Traditional Chinese, Ayurvedic, Unani and African herbal remedies (Aristolochia, Asarum, Bragantia and related species, such as guang fang ji, mu tong, fang ji and xi xin).
• Contaminated grain (Balkan endemic nephropathy).
• Misidentified substitutes in herbal products.

It is probably under recognised in Asia, Africa and the Balkans, and estimates suggest millions of people have been exposed.

Kidney failure develops in about 40 to 60% of people with heavy exposure within 5 years. Cumulative aristolochic acid doses above 200 g of plant material are associated with a high risk. Upper tract urothelial carcinoma develops in about 40 to 50% of those reaching kidney failure.

Pathophysiology. Aristolochic acid is taken up in proximal tubular cells, where it is metabolised to aristolactam-DNA adducts. These cause tubular necrosis, interstitial fibrosis and a characteristic signature of TP53 A to T transversion mutations in urothelial tumours. The injury affects the outer cortex more than the inner cortex.

• Subacute or progressive chronic kidney disease: creatinine rising over weeks to months after starting the herbal product; rapid progression to kidney failure in the acute form.
• Anaemia that is often disproportionate to the level of kidney function, mild proteinuria (under 1 g daily), tubular dysfunction (glycosuria, aminoaciduria, hypophosphataemia, acidosis), and hypertension in some.
• Small, shrunken, echogenic kidneys at presentation (a feature of advanced disease), with a bland or mildly abnormal sediment.
• Urothelial carcinoma: painless haematuria, flank pain, a ureteric or pelvic mass.
• Previous or current use of herbal preparations for weight loss, arthritis, eczema, urinary or other complaints.

Red flags

• Macroscopic haematuria or flank pain in anyone with known exposure.
• Rapid loss of kidney function after a herbal product.
• Kidney failure of unknown cause in a person from an endemic area or with herbal remedy use.
• Weight loss, haematuria and unexplained anaemia.
• Persisting exposure (ongoing herbal use).

• A careful history of all herbal, traditional and over-the-counter products over the previous 5 to 10 years; ask about the product names, ingredients and duration; collect samples.
• Creatinine, eGFR, urea, electrolytes, bicarbonate, glucose, phosphate, full blood count, urine microscopy, urine protein:creatinine ratio, urine beta-2 microglobulin.
• Kidney ultrasound: small kidneys with increased echogenicity and cortical thinning.
• Kidney biopsy: extensive hypocellular interstitial fibrosis predominating in the outer cortex with a gradient to the inner cortex, tubular atrophy, relative glomerular sparing, and few inflammatory cells; absence of immune deposits.
• Aristolactam-DNA adducts in kidney tissue or urothelial tissue (research and reference laboratories) confirm exposure; analysis of the product for aristolochic acid; mass spectrometry of the plant material.
• Cancer screening: urine cytology, cystoscopy, CT urography or MR urography every 6 to 12 months in exposed individuals; assessment of any haematuria.
• Kidney function tests for family members who share the exposure.

Differential diagnosis

• Other chronic tubulointerstitial diseases (analgesic nephropathy, lead, cadmium, lithium, reflux), hypertensive and diabetic nephrosclerosis, Balkan endemic nephropathy (same toxin in endemic areas), idiopathic interstitial nephritis, chronic kidney disease of uncertain cause, obstructive uropathy.

First line: stop all aristolochic acid exposure

• Stop all herbal products of uncertain content. Counsel the patient and household, report the product to public health authorities and keep samples, and test others exposed.
• Avoid Aristolochia and related plants in all forms permanently, and warn the patient not to restart.

Slowing progression

• Subacute disease with active inflammation: prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) for the first 1 to 3 months, with a slow taper over 6 to 12 months. Give with proton pump inhibitor, co-trimoxazole 480 mg daily and glucose monitoring.
• Small studies suggest a slower rate of decline with steroids. Benefit is uncertain, so stop at 3 months if there is no response.
• Renoprotection: blood pressure below 130/80 mmHg. Use ramipril 2.5 mg daily increased to 10 mg daily (creatinine and potassium at 1 to 2 weeks; accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L).
• Also use dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20). Restrict sodium to under 2 g daily and avoid nephrotoxins.
• Anaemia: iron when ferritin is under 200 microg/L or transferrin saturation is under 20%. Give epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is under 100 g/L; target 100 to 120 g/L.
• Metabolic acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Mineral and bone disorder at the usual thresholds.

Cancer surveillance and prevention (lifelong)

• Yearly urine cytology, cystoscopy and imaging of the upper tract (ultrasound or CT urography) in all patients with significant exposure. Repeat 6 to 12 monthly when haematuria occurs.
• Consider prophylactic bilateral nephroureterectomy at kidney failure or at the time of transplantation in patients with heavy exposure (high cumulative dose, adduct positive), as the risk of upper tract carcinoma is up to 40 to 50%.
• For any tumour, perform unilateral nephroureterectomy with surveillance of the remaining system.
• Treat urothelial cancer with a urologic oncologist: nephroureterectomy, cisplatin based chemotherapy when eGFR is at least 60, carboplatin based regimens when eGFR is 30 to 59.

Kidney replacement therapy

• Dialysis at eGFR 5 to 10 with symptoms or complications; peritoneal dialysis or haemodialysis as usual.
• Kidney transplantation is the preferred treatment, after excluding urothelial cancer (cystoscopy, imaging) and considering prophylactic nephroureterectomy. Continue cancer surveillance on immunosuppression.

Monitoring. Creatinine, eGFR, urine protein:creatinine ratio and haemoglobin every 3 months. Cystoscopy and urine cytology yearly (6 to 12 monthly if haematuria or high exposure). Imaging of the upper tract yearly.

Referral and escalation. Nephrology for any suspected case; urology for haematuria; oncology for tumours; public health for the product and community.

Special groups

• Women: more commonly affected in the slimming clinic cohorts; counsel on herbal use.
• Pregnancy: stop herbal products. Manage kidney disease as usual (stop ACE inhibitors, avoid steroids unless necessary).
• Children: exposure through herbal teas and remedies; stop exposure and refer to paediatric nephrology.
• Regions with traditional medicine use (Asia, Africa, the Balkans): high clinical suspicion for unexplained chronic kidney disease and upper tract urothelial carcinoma.